@article {pmid42716046, year = {2026}, author = {Benzinger, TLS and Cogswell, PM and Arani, A and Chaney, AM and Hutson, K and Glasser, MF and Graff-Radford, J and McConathy, J and Raji, CA and Teunissen, C and Vemuri, P and Zaharchuk, G and Jack, CR}, title = {Neuroimaging in the era of biologically defined Alzheimer's disease and disease-modifying therapy.}, journal = {The Lancet. Neurology}, volume = {25}, number = {10}, pages = {939-951}, doi = {10.1016/S1474-4422(26)00285-1}, pmid = {42716046}, issn = {1474-4465}, mesh = {Humans ; *Alzheimer Disease/diagnostic imaging/therapy/drug therapy ; *Neuroimaging/methods ; *Brain/diagnostic imaging/pathology ; Positron-Emission Tomography/methods ; Magnetic Resonance Imaging/methods ; Biomarkers ; }, abstract = {Disease-modifying therapies and biomarker-based diagnostic frameworks will fundamentally altered the clinical diagnosis and management of Alzheimer's disease. Diagnosis is increasingly anchored in the biological evidence of pathology rather than clinical presentation alone, with implications for treatment eligibility, prognosis, and monitoring. In clinical practice, patients with memory complaints can present with complex mixed pathologies that develop across the lifespan. Brain imaging, particularly MRI and PET, plays a crucial role in visualising these cumulative abnormalities. With Alzheimer's disease-specific therapies now available in many regions of the world, amyloid PET plays a central role in establishing Alzheimer's disease diagnosis, determining eligibility for amyloid-targeting therapies, and quantifying treatment-related amyloid clearance. In settings where available, tau PET informs biological stage, prognosis, and clinical heterogeneity. MRI remains indispensable for differential diagnosis, the assessment of comorbid and vascular pathology, and monitoring for complications, particularly amyloid-related imaging abnormalities. Technological advances-including quantitative imaging, artificial intelligence, accelerated acquisition, and workflow optimisation-are improving reliability, efficiency, and access to these tools. Neuroimaging is now a cornerstone of Alzheimer's disease care and a crucial discriminator tool for characterising brain injury across the lifespan. With emerging fluid biomarkers, neuroimaging supports accurate diagnosis, prognosis, and treatment monitoring.}, } @article {pmid42716047, year = {2026}, author = {Graff-Radford, J and Karliner, L and Barnes, DE and Frisoni, GB and Sperling, R and Villain, N and Benzinger, TLS and Teunissen, C and Jack, CR}, title = {Clinical pathways for cognitively unimpaired individuals with Alzheimer's disease neuropathological change.}, journal = {The Lancet. Neurology}, volume = {25}, number = {10}, pages = {952-964}, doi = {10.1016/S1474-4422(26)00248-6}, pmid = {42716047}, issn = {1474-4465}, mesh = {Humans ; *Alzheimer Disease/pathology/therapy/diagnosis/drug therapy ; Biomarkers ; *Brain/pathology ; }, abstract = {The recent approval of disease-modifying therapies for symptomatic Alzheimer's disease is a major advance for a condition with few therapeutic options. Anti-amyloid monoclonal antibodies have shown clinically meaningful benefits in slowing cognitive decline. Clinical trials in symptomatic Alzheimer's disease suggest that anti-amyloid therapies might provide the greatest benefit in subgroups who have low baseline levels of Alzheimer's disease pathology; ongoing prevention trials are evaluating these therapies in cognitively unimpaired individuals who have biomarker evidence of Alzheimer's disease neuropathological change (ADNC). However, the possibility of biomarker testing and treatment in cognitively unimpaired people raises key questions about ethics and the consequences that follow from a positive test or an uncertain result (ie, the so-called downstream effects on patients and health systems). Furthermore, test accuracy might be questioned when ADNC has a low prevalence in the population being tested and in the case of intermediate-range biomarker concentrations that might not reliably indicate true ADNC or be false positives. If anti-amyloid therapies prove beneficial for cognitively unimpaired people with ADNC and become part of routine practice, several key knowledge gaps must be addressed to support safe, scalable, real-world implementation of Alzheimer's disease treatment.}, } @article {pmid42716318, year = {2026}, author = {Bu, X and Yuan, Y and Song, W and Wang, W}, title = {Music intervention as a therapeutic approach to cognitive impairments in APP/PS1 mice.}, journal = {Brain research bulletin}, volume = {245}, number = {}, pages = {112113}, doi = {10.1016/j.brainresbull.2026.112113}, pmid = {42716318}, issn = {1873-2747}, abstract = {Alzheimer's disease (AD) is typified by progressive deterioration in memory and executive capacities. Although music-based interventions represent a promising non-pharmacological strategy for AD, the underlying mechanisms remain insufficiently understood. APP/PS1 transgenic mice were subjected to 30 consecutive days of musical stimulation, with wild-type C57BL/6 J and untreated APP/PS1 mice serving as controls. Neurobehavioral assessments revealed that music intervention substantially improved memory performance in transgenic AD mice. Mechanistically, music attenuated oxidative stress in both serum and hippocampus of APP/PS1 mice, as evidenced by decreased nitric oxide (NO) and malondialdehyde (MDA) levels along with enhanced antioxidant activities of superoxide dismutase (SOD), glutathione peroxidase (GSH-Px), catalase (CAT), and total antioxidant capacity (T-AOC). Peripheral and hippocampal inflammatory responses were also effectively inhibited following musical treatment. Music restored synaptic plasticity-related protein expression, increased postsynaptic density thickness, narrowed synaptic cleft, and elevated dendritic spine density. Additionally, music exposure alleviated Aβ deposition and neuronal loss in APP/PS1 mice. These findings indicate that music-based auditory enrichment exerts neuroprotective effects against AD through synergistically modulating oxidative stress, neuroinflammation, synaptic plasticity, and neuronal survival, providing mechanistic insights into its intervention potential for AD.}, } @article {pmid42718894, year = {2026}, author = {Lin, W and Grewal, SS and Byrne, RW}, title = {Two serial MoCA assessments may support biomarker-sparing triage between Parkinson's disease/Lewy body dementia and frontotemporal dementia: a progressive inclusion analysis of 1,129 participants.}, journal = {Frontiers in aging neuroscience}, volume = {18}, number = {}, pages = {1848105}, pmid = {42718894}, issn = {1663-4365}, abstract = {Reliable differentiation of Parkinson's disease/Lewy body dementia (PD/LBD) from frontotemporal dementia (FTD) affects treatment strategy and clinical trial eligibility, yet confirmatory biomarker testing remains costly and unevenly available. Whether routine cognitive trajectories can support testing prioritization has not been systematically quantified. We performed a progressive inclusion analysis of 1,129 National Alzheimer's Coordinating Center participants with PD/LBD (n = 385) or FTD (n = 744) to determine the minimum number of serial Montreal Cognitive Assessment (MoCA) administrations required for diagnostic separation. Random forest classifiers used seven MoCA subdomain slopes from the first k chronological assessments (k = 2 through k = 8), with five-fold stratified cross-validation and 500-iteration bootstrap confidence intervals. In the primary full-cohort analysis, two assessments yielded AUC = 0.785 (95% CI 0.757-0.814; sensitivity = 0.922; specificity = 0.525). The interval-restricted 6-12 month subset yielded AUC = 0.837 (95% CI 0.787-0.885), near the lower edge of published biomarker-panel ranges in an indirect comparison, although its lower confidence bound remained below 0.85. Discrimination persisted after age matching (AUC = 0.794, 95% CI 0.761-0.826; residual age gap = -0.3 years) and age restriction to 55-75 years (AUC = 0.777, 95% CI 0.741-0.814). Age alone yielded lower discrimination (AUC = 0.721, 95% CI 0.691-0.751) than MoCA slopes, while slopes plus age yielded AUC = 0.867 (95% CI 0.845-0.888). Four-assessment performance was AUC = 0.831 (95% CI 0.791-0.873), consistent with an apparent sample-size-limited plateau as eligible N contracted from 391 at k = 4 to 98 at k = 6. These findings support serial MoCA trajectory analysis as an exploratory tool for prioritizing confirmatory diagnostic testing, with age sensitivity, subtype sensitivity, and operating-point performance quantified.}, } @article {pmid42719214, year = {2026}, author = {Mittal, D and Solanki, P and Jain, GK and Jhawat, V and Kesharwani, P and Dutt, R and Arora, S and Singh, RP}, title = {Herbal nanoparticles in the treatment of neurodegeneration: from molecular mechanisms to therapeutic translation.}, journal = {3 Biotech}, volume = {16}, number = {10}, pages = {420}, pmid = {42719214}, issn = {2190-572X}, abstract = {UNLABELLED: Neurodegenerative diseases (NDDs), including Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis, are characterized by progressive neuronal loss involving multiple pathological mechanisms, including protein aggregation, oxidative stress, neuroinflammation, and mitochondrial dysfunction. Although conventional therapies provide symptomatic relief, they fail to halt disease progression and are limited by poor blood-brain barrier (BBB) penetration, off-target effects, and systemic toxicity. Likewise, several herbal bioactives, such as curcumin, resveratrol, quercetin, and epigallocatechin gallate, exhibit promising neuroprotective properties but suffer from poor aqueous solubility, low oral bioavailability, rapid metabolism, and inadequate brain delivery. Nanotechnology-based delivery systems have emerged as a promising approach to overcome these pharmacokinetic limitations by enhancing stability, controlled release, BBB transport, and brain accumulation of herbal therapeutics. This review critically summarizes recent advances in herbal nanoformulations, emphasizing disease-specific molecular targets, BBB-targeting strategies, comparative nanocarrier systems, pharmacokinetic optimization, intracellular trafficking, and translational challenges. Unlike previous reviews, it integrates recent evidence on nanotoxicology, manufacturing scalability, quality control, regulatory considerations, and emerging technologies, including biomimetic nanoparticles and extracellular vesicles. Despite encouraging preclinical outcomes, clinical evidence remains limited, and no herbal nanoformulation has yet demonstrated definitive efficacy or received regulatory approval for neurodegenerative diseases. Future clinical translation will require standardized formulations, rigorous safety evaluation, and well-designed clinical trials. Unlike previous reviews that primarily summarize individual nanocarrier systems or herbal therapeutics, the present review provides a comprehensive and critical synthesis of the current evidence by integrating disease-specific molecular mechanisms, herbal bioactives, nanocarrier design strategies, blood-brain barrier transport mechanisms, intracellular trafficking, pharmacokinetic considerations, translational barriers, regulatory challenges, clinical evidence, and emerging technologies. Furthermore, the review identifies major knowledge gaps and future research priorities to facilitate the successful clinical translation of herbal nanoformulations for neurodegenerative disorders.

SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at https://doi.org/10.1007/s13205-026-05048-8.}, } @article {pmid42719255, year = {2026}, author = {El Fadili, M and Er-Rajy, M and Mujwar, S and Aloui, M and Samadi, A and Chtita, S and Elhallaoui, M}, title = {Multiscale mechanistic modeling for the rational design of novel dual-target candidates against acetylcholinesterase and NADPH oxidase: an advanced computational study.}, journal = {Frontiers in chemistry}, volume = {14}, number = {}, pages = {1917677}, pmid = {42719255}, issn = {2296-2646}, abstract = {INTRODUCTION: Alzheimer's disease is a complex neurodegenerative illness strongly associated with oxidative stress, which requires immediate intervention for therapeutic agents with potent antioxidant properties.

METHODS: In this work, novel derivatives based on benzofuran and pyrazole scaffolds were designed and assessed for their antioxidant potential and acetylcholinesterase inhibitory activity. The identification of key molecular characteristics that are important for the ability of a compound to scavenge DPPH radicals and AChE cholinesterase and has been accomplished through SAR, then both CoMFA and CoMSIA 3D-QSAR modelling have been used to design fifteen new compounds (D1-D15) which inhibit both DPPH and AChE to a significantly greater extent than the parent compound. Density functional theory calculations at the B3LYP/6-31G (d,p) level revealed that the three most promising candidates (M12, D8, and D9) have quite high electronic and molecular stability.

RESULTS AND DISCUSSION: The results of pharmacokinetic tests, molecular docking, and 100 ns molecular dynamics experiments confirm that these examined compounds interact favorably with both human acetylcholinesterase and NADPH oxidase enzymes with excellent thermodynamic stability. These results provide further evidence for the potential of the designed compounds to behave as multi-target ligands with AChE inhibition and antioxidant properties that would be effective in the treatment of the complex Alzheimer's disease.}, } @article {pmid42719334, year = {2026}, author = {Huang, Q and Xie, Y and Zhang, X and Zuo, Y and Wang, L and Xu, H and Yu, M and Liu, C}, title = {Traditional Chinese medicine ginseng regulates neurotrophic factors to improve neurodegenerative diseases: A potential strategy for Alzheimer's disease treatment.}, journal = {Journal of ginseng research}, volume = {50}, number = {5}, pages = {101078}, pmid = {42719334}, issn = {1226-8453}, abstract = {Alzheimer's disease (AD) is a neurodegenerative disorder characterized by memory impairment and progressive cognitive decline. Its core pathological mechanisms include β-amyloid deposition, abnormal tau phosphorylation, neuroinflammation, and decreased levels of neurotrophic factors. In recent years, the deficiency of neurotrophic factors has been recognized as a key driver of impaired neuronal survival and synaptic dysfunction. Consequently, restoring or enhancing neurotrophic factor signaling has emerged as a major therapeutic target for AD. As a traditional medicinal plant, ginseng exhibits multi-targeted, multi-level neuroprotective effects. Its active components-including ginsenosides, ginseng polysaccharides, and ginseng proteins-have been demonstrated to promote neuronal survival, inhibit apoptosis, and enhance synaptic plasticity by upregulating signaling pathways such as BDNF/TrkB and NGF/TrkA. Additionally, ginseng suppresses inflammatory responses and oxidative stress, thereby indirectly correcting neurotrophic factor imbalances and demonstrating significant neuroprotective potential. This review summarizes recent advances in ginseng's regulation of neurotrophic factor levels and signaling pathways, focusing on its molecular mechanisms for improving neuronal dysfunction and delaying AD progression. It also outlines future research strategies and prospects for clinical translation. In summary, ginseng's neuroprotective effects achieved through regulating the neurotrophic factor network offer a potential natural drug intervention strategy for AD treatment.}, } @article {pmid42720212, year = {2026}, author = {Song, B and Wang, W and Liu, S and Jin, X and Qi, Y and Li, M and Yue, D and Liu, Y and Li, X and Yin, L and Feng, L}, title = {Novel Therapeutic Insights Into Alzheimer's Disease: Glymphatic System and Meningeal Lymphatic Vessels.}, journal = {Aging cell}, volume = {25}, number = {9}, pages = {e70699}, doi = {10.1111/acel.70699}, pmid = {42720212}, issn = {1474-9726}, support = {ZR2023QH159//Natural Science Foundation of Shandong Province/ ; ZR2020MH357//Natural Science Foundation of Shandong Province/ ; 82274538//National Natural Science Foundation of China/ ; 2023NS469//Taian City Science and Technology Innovation Development Project/ ; Z20243705//Shandong Province Traditional Chinese Medicine Science and Technology Project/ ; YPM202532//Clinical Research Special Project of Shanghai Yangpu District Health System/ ; 202313011384//Shandong Province Medical Health Science and Technology Development Plan Project/ ; }, mesh = {Humans ; *Alzheimer Disease/therapy/pathology/metabolism ; *Glymphatic System/metabolism/pathology ; *Lymphatic Vessels/metabolism/pathology ; Animals ; *Meninges/pathology/metabolism ; }, abstract = {With the acceleration of global aging, the relationship between Alzheimer's disease (AD) and the glymphatic system (GS) has become a research hotspot in the field of neuroscience in recent years. Traditionally, the central nervous system was thought to lack a lymphatic system; however, research over the past decade has overturned this view. Studies have revealed the existence of GS and meningeal lymphatic vessels (mLVs) in the brain, which clear metabolic waste (such as amyloid-β and tau proteins) through the exchange of cerebrospinal fluid (CSF) and interstitial fluid (ISF). Dysfunction of the GS can lead to abnormal deposition of pathological proteins, which may trigger or exacerbate AD. Currently, the association between the GS and AD treatment mainly focuses on drug development (such as small molecules that promote glymphatic circulation), physical therapies (such as 40 Hz photoacoustic therapy), and surgical interventions (primarily deep cervical lymphatic-vein anastomosis and cranial bone maneuver), all of which are under exploration. With the precision of diagnostic technologies and the targeting of therapeutic methods, future intervention strategies surrounding GS may become a significant breakthrough in overcoming the treatment impasse of AD, bringing new hope to tens of millions of AD patients worldwide.}, } @article {pmid42720565, year = {2026}, author = {Pereira Da Silva, AM and Haddad Santos, D}, title = {GLP-1 receptor agonism in Alzheimer's disease after EVOKE: From single hypothesis to stratified program.}, journal = {Journal of Alzheimer's disease : JAD}, volume = {}, number = {}, pages = {13872877261485580}, doi = {10.1177/13872877261485580}, pmid = {42720565}, issn = {1875-8908}, abstract = {The phase 3 EVOKE and EVOKE + trials of oral semaglutide in early Alzheimer's disease missed their primary endpoint and every cognitive or functional secondary endpoint. A recent article by Hölscher revisits extension-phase data and reports partial separation at later timepoints, attributing the failure to limited brain penetration. We argue that attrited extension cohorts bear limited inferential weight and that the biomarker substudy, read in full, complicates a clean disease-modification reading. EVOKE does not refute the cardiometabolic hypothesis but reframes the open questions: which pathways, which patients, and which disease stages are most likely to benefit.}, } @article {pmid42720842, year = {2026}, author = {Demirdaş, A and Nazıroğlu, M}, title = {Brain-derived neurotrophic factor via TRPM2 inhibition reduces amyloid-beta-mediated increases of apoptosis and mitochondrial oxidative neurotoxicity in neuronal cells.}, journal = {Metabolic brain disease}, volume = {41}, number = {1}, pages = {}, pmid = {42720842}, issn = {1573-7365}, support = {TDK-2021-8386//Süleyman Demirel Üniversitesi/ ; }, mesh = {*Apoptosis/drug effects/physiology ; *TRPM Cation Channels/antagonists & inhibitors/metabolism ; Humans ; *Amyloid beta-Peptides/toxicity/pharmacology ; *Oxidative Stress/drug effects/physiology ; *Neurons/drug effects/metabolism ; *Brain-Derived Neurotrophic Factor/pharmacology ; Cell Line, Tumor ; *Mitochondria/drug effects/metabolism ; Reactive Oxygen Species/metabolism ; Calcium/metabolism ; Membrane Potential, Mitochondrial/drug effects ; }, abstract = {Brain-derived neurotrophic factor (BDNF) has particular importance in the modulation of Alzheimer's disease (AD)-related pathologies such as apoptosis and mitochondrial reactive oxygen species (mROS). The cation channel, transient receptor potential melastatin 2 (TRPM2), stimulation is important for the generation of AD-related pathologies. Antioxidant treatments through the inhibition of TRPM2 play an essential role in the inhibition of Ca[2+] entry, mROS, and apoptosis changes in the SH-SY5Y neuronal cells. However, the effects of antioxidant and antiapoptotic roles of BDNF have not yet been studied in SH-SY5Y treated with amyloid-beta (Aβ). The aim of the present study was to investigate the protective action of BDNF via TRPM2 inhibition on the apoptotic and oxidant values in Aβ-induced SH-SY5Y cells. Five groups of SH-SY5Y cells were established: control, BDNF, Aβ, Aβ + BDNF, and Aβ + TRPM2 channel blockers. The Aβ-induced increases in intracellular Ca[2+] and TRPM2 currents were decreased by BDNF and PARP-1 inhibition. The levels of mROS, intracellular ROS, dysfunction of mitochondrial membrane, SH-SY5Y death, apoptosis, and caspases (caspases-3, -8, and - 9) were increased in the cells treated with Aβ, although glutathione (GSH) and glutathione peroxidase (GSH-Px) were decreased by the treatment. However, the levels of these oxidative and apoptotic markers through the increases in GSH and GSH-Px were reduced in the cells by the incubations of BDNF and TRPM2 channel blockers. Finally, it was shown that BDNF protects neuronal cells against Aβ-induced excessive Ca[2+] entry, oxidative stress, and apoptotic parameters via inhibiting TRPM2. Treatment with BDNF appears to have the capacity to reduce apoptosis and oxidative stress caused by Aβ through inhibiting TRPM2.}, } @article {pmid41017722, year = {2026}, author = {Xu, X and Li, J and Wang, F and Xue, K and He, J and Meng, X and Shen, Y}, title = {Genetic and pathway complexity in Alzheimer's disease: Insights from multi-omic data about the immune response and mitochondrial function.}, journal = {Neural regeneration research}, volume = {21}, number = {9}, pages = {4406-4423}, pmid = {41017722}, issn = {1673-5374}, abstract = {Despite recent developments, the genetics and biology of Alzheimer’s disease remain insufficiently characterized. As an important first step toward developing effective treatment strategies to slow or prevent Alzheimer’s disease onset, the identification of relevant genetic markers is crucial. In the present study, we analyzed transcriptomic and multi-omic datasets across multiple cohorts (the Alzheimer’s Disease Neuroimaging Initiative, Religious Orders Study and Rush Memory and Aging Project, Mount Sinai Brain Bank, and Mayo Clinic Alzheimer’s Disease Genetics Studies) using gene set enrichment analysis, machine learning algorithms, and polygenic risk scoring to identify gene sets relevant to Alzheimer’s disease risk and pathological features. For prioritized gene sets, we performed epigenome-wide association studies to assess DNA methylation patterns, and used multi-omic mediation analysis to characterize the causal gene regulatory networks. Overall, we identified several key gene sets relevant to Alzheimer’s disease pathology—particularly, those related to immune system function and mitochondrial dysfunction. Upregulated pathways, including neutrophil degranulation and tumor necrosis factor-α signaling pathways, correlated strongly with aspects of neuroinflammation in Alzheimer’s disease. By contrast, downregulated oxidative phosphorylation pathways further suggested mitochondrial dysfunction. Gene sets that contained mitochondrially located genes (e.g., SGK1 and LRRK1) were identified as significantly contributing to neurodegeneration. Moreover, genes such as CXCL1, TGFB2, and DUSP1 were consistently implicated in all datasets, thus emphasizing their involvement in immune modulation and mitochondrial function. The multimodal investigation outlined in the current study represents useful steps toward comprehending the genetic architecture of Alzheimer’s disease, including an expanded understanding of the spatial interactions of genes associated with disease susceptibility. Mitochondrial dysfunction and immune modulation were pathological pathways that converged on Alzheimer’s disease and future treatment novel options. Using the frameworks provided in the current comprehensive study, we present opportunities to explore targeted treatment strategies that may alter immune systems and mitochondrial function to optimize treatment outcomes for individuals at increased risk of or living with Alzheimer’s disease.}, } @article {pmid42710551, year = {2026}, author = {Kosa, AC and Lopez-Gutierrez, L and Ando, K and Doeraene, E and Aydin, E and Lasri, H and Wathelet-Depauw, A and Pieters, K and Van Morckhoven, D and Dubois, C and Hupkens, E and Jespers, P and Dewachter, L and Stamatopoulos, B and Brion, JP and Leroy, K}, title = {Effect of tau silencing on tau pathology propagation, a treatment efficient at the earliest stages of the disease?.}, journal = {Neurobiology of disease}, volume = {229}, number = {}, pages = {107598}, doi = {10.1016/j.nbd.2026.107598}, pmid = {42710551}, issn = {1095-953X}, abstract = {Cognitive decline in Alzheimer's disease (AD) correlates more strongly with tau pathology than with amyloid plaques, switching the therapeutic focus towards targeting tau pathology. Tau silencing therapies present an increasing interest as potential therapeutical approaches to treat AD due to their efficiency in reducing pathological tau burden. However, the effects of tau silencing on tau pathology formation and spreading, as well as on cognitive deficits, have not been investigated in AD or AD preclinical models expressing WT tau. In this study, we investigated the effects of Tau siRNA on tau pathology propagation in a mouse model of AD expressing 6 human WT tau isoforms, in which tau pathology formation and spreading has been initiated by intracerebral injection of pathological tau from a human AD brain. Specifically, we examined whether tau silencing affects tau pathology progression when started either simultaneously with the induction of tau pathology or subsequent to the onset of tau lesions, thereby mimicking the clinical scenario in which AD patients are typically diagnosed. Three months after tau pathology was induced, spatial learning and tau pathology were assessed. Cognitive performance was rescued, and tau pathology development was reduced when tau silencing started simultaneously with the induction of tau lesions. Nevertheless, Tau siRNA was ineffective on both cognitive performance and tau pathology propagation when administered after some development of tau pathology. Our results indicate that tau silencing therapy should be administered in early stages of the disease to achieve therapeutic efficacy on the development of tau pathology in AD.}, } @article {pmid42710608, year = {2026}, author = {Liu, S and Ren, L and Liu, L and Chen, LL and Zhang, Y and Wang, P and Xie, GJ}, title = {Du-Shu-Wan alleviates Tau protein phosphorylation in Alzheimer's disease by regulating MAPK/JNK signaling pathway.}, journal = {Journal of ethnopharmacology}, volume = {}, number = {}, pages = {122380}, doi = {10.1016/j.jep.2026.122380}, pmid = {42710608}, issn = {1872-7573}, abstract = {Alzheimer's disease (AD) is one of the leading causes of cognitive impairment and dementia among the elderly and has become an urgent public health challenge due to population ageing. Du-Shu-Wan (DSW) is an ancient Chinese herbal medicine that aims to enhance memory and soothe the spirit, and has long been applied for forgetfulness and cognitive decline. At present, there is still no systematic research on the pharmacological basis of DSW and its specific molecular mechanisms for alleviating AD.

AIM OF THE STUDY: The researchers aimed to investigate the mechanisms by which DSW attenuates AD-related pathological changes in animal models and in vitro cultured cells.

MATERIALS AND METHODS: The chemical composition of DSW was characterized using UPLC-Q-TOF-MS. Subsequently, HE staining, Nissl staining, and silver staining were employed to evaluate the effects of DSW on neuronal damage in an AD rat model induced by intracerebral injection of Aβ1-42 into the lateral ventricle. Potential mechanisms of action were investigated through network pharmacology, molecular docking, and transcriptomics. Finally, the results of the in vivo experiments were validated in an HT22 cell model.

RESULTS: This study reports the identification of 101 compounds from DSW for the first time. After a four-week course of DSW treatment, AD model rats exhibited significantly improved cognitive function, along with decreased neuronal injury and reduced neurofibrillary tangle pathology. A comprehensive analysis suggests that DSW enhanced cognitive function, an effect associated with inhibition of the MAPK/JNK pathway and reduction in the level of phosphorylated Tau at Ser422 sites. Additionally, in vitro experiments further showed that the protective effect of DSW-containing serum against Aβ1-42-induced neurotoxicity was associated with reduced JNK activation, and this reversal was obviously compromised by a JNK activator.

CONCLUSIONS: According to this study, DSW may enhance cognitive function in AD rats, an effect that is associated with reduced JNK pathway activity and reduced tau protein hyperphosphorylation at Ser422.}, } @article {pmid42710609, year = {2026}, author = {Zheng, J and Tan, Q and Liu, G and Xie, R and Wang, Q and Liang, Y}, title = {Bushen-Yizhi formula promotes neurogenesis and ameliorates cognitive impairment by activating ST8Sia Ⅱ/Ⅳ-PSA-NCAM pathway in ibotenic acid induced mice.}, journal = {Journal of ethnopharmacology}, volume = {374}, number = {Pt 1}, pages = {122356}, doi = {10.1016/j.jep.2026.122356}, pmid = {42710609}, issn = {1872-7573}, abstract = {Bushen-Yizhi formula (BSYZ), a traditional Chinese herbal prescription, has been widely used to treat kidney deficiency syndrome and alleviate cognitive impairment associated with Alzheimer's disease (AD). Loss of polysialylation of the neural cell adhesion molecule (PSA-NCAM) is closely associated with cognitive dysfunction. However, whether BSYZ regulates PSA-NCAM polysialylation and the underlying mechanisms remain unclear.

AIM OF THE STUDY: This study aimed to investigate whether BSYZ promotes hippocampal neurogenesis and ameliorates cognitive impairment through activation of the ST8Sia II/IV-PSA-NCAM pathway.

METHODS: An AD-like mouse model was established by bilateral ibotenic acid (IBO) injections into the basal nuclei of C57BL/6 mice. Animals were randomly assigned to five groups: control, model, low- BSYZ (1.46 g/kg), high-dose BSYZ (5.84 g/kg), and donepezil (3 mg/kg). Cognitive function was evaluated using the open field test (OFT), novel object recognition test (NORT), and Morris water maze (MWM). Hippocampal PSA-NCAM expression was assessed by immunofluorescence staining and further investigated using proteomic analysis combined with network pharmacology. PSA-NCAM-associated polysialic acid levels were quantified by hydrochloric acid hydrolysis followed by 4,5-methylenedioxy-1,2-phenylenediamine dihydrochloride (DMB) derivatization coupled with mass spectrometry. The mRNA and protein expression levels of α-2,8-sialyltransferase II and IV (ST8Sia II/IV) were determined by quantitative reverse transcription polymerase chain reaction (qRT-PCR) and Western blotting. Hippocampal neurogenesis was evaluated by immunofluorescence double-labeling. The bioactive compounds targeting ST8Sia II/IV were identified using HPLC-Q-TOF MS/MS, followed by molecular docking and molecular dynamics simulations to predict their binding affinities.

RESULTS: The IBO-induced mouse model exhibited significant cognitive deficits, confirming successful model establishment. Behavioral assessments demonstrated that both low- and high-dose BSYZ significantly improved learning and memory performance. Proteomic analysis and immunofluorescence staining revealed that BSYZ markedly increased hippocampal PSA-NCAM expression (**P < 0.01, n = 5). Quantitative analysis further showed that PSA-NCAM-associated polysialic acid levels increased by 78% (*P < 0.05, n = 5) and 102% (**P < 0.01, n = 5) following low- and high-dose BSYZ treatment. BSYZ significantly increased the number of PSA-NCAM[+]/DCX[+] cells in the hippocampal dentate gyrus (*P < 0.05), accompanied by significant increases in Nestin[+]/BrdU[+] (*P < 0.05), DCX[+]/BrdU[+] (**P < 0.01), and NeuN[+]/BrdU[+] (**P < 0.01) double-positive cells, indicating enhanced neurogenesis and neuronal maturation. Furthermore, BSYZ significantly upregulated both the mRNA and protein expression of ST8Sia II (**P < 0.01) and ST8Sia IV (**P < 0.01) in the hippocampus. HPLC-Q-TOF MS/MS, molecular docking, and molecular dynamics simulations identified isoimperatorin as a major active constituent of BSYZ with strong binding affinity toward both ST8Sia II/IV, exhibiting docking energies of -8.7 and -7.6 kcal/mol, respectively (n = 3, RSD < 2%).

CONCLUSIONS: Our study demonstrates BSYZ promotes hippocampal neurogenesis to ameliorate cognitive impairment by activating ST8Sia II/IV-PSA-NCAM pathway. These findings provide mechanistic evidence supporting the therapeutic potential of BSYZ for AD treatment.}, } @article {pmid42711466, year = {2026}, author = {Mimica, N and Dumitrescu, L and Gregorič Kramberger, M and Hort, J and Kovács, T and Popadić, K and Popescu, BO and Rakuša, M and Rejdak, K and Turčáni, P}, title = {Expert opinion on Alzheimer's disease diagnostics and management in Central Eastern European countries representing 88 million population.}, journal = {Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology}, volume = {47}, number = {10}, pages = {}, pmid = {42711466}, issn = {1590-3478}, mesh = {Humans ; *Alzheimer Disease/diagnosis/therapy/epidemiology ; Europe, Eastern/epidemiology ; *Disease Management ; }, abstract = {The expert panel from Croatia, Czech Republic, Hungary, Poland, Romania, Slovakia and Slovenia discussed the current situation of various topics related to the diagnostics, general management and treatment of Alzheimer's disease (AD) in these Central Eastern European (CEE) countries, representing around 88 million population. The aim was to estimate AD prevalence, confirm the presence of AD patients/caregivers' associations and AD registries, and establish the availability and reimbursement of costs for AD diagnostic biomarkers and treatment. The panel acknowledged similarities and differences among CEE countries and issued recommendations for cross specialty collaboration between experts in neurology, psychiatry and general practitioners for the early AD diagnosis. They also agreed that CEE countries should provide comprehensive education and training and encourage collaboration between health experts. The panel suggested that CEE countries should involve various stakeholders, policymakers, implement routine screening, combine advanced diagnostic tools and use telemedicine and remote monitoring technologies, invest in research to develop AI-based analyses, new AD diagnostic and monitoring methods, digital tools and wearables. The focus is to address the stigma, reimburse costs of diagnostic tests and therapy, and reduce the modifiable risk factors for AD.}, } @article {pmid42711740, year = {2026}, author = {Papait, A and Natale, F and Silini, AR and Nifo Sarrapochiello, I and Orecchini, E and Sollazzo, R and Rinaudo, M and Farigu, S and Garofalo, N and Mantini, G and Giuffrè, GM and Romele, P and Ragozzino, E and Dellaria, A and Giacò, L and Marra, C and Ripoli, C and Grassi, C and Parolini, O and Fusco, S}, title = {Human amniotic mesenchymal stromal cell-derived extracellular vesicles reprogram microglia and prevent neurodegeneration in experimental models of Alzheimer's disease.}, journal = {Translational neurodegeneration}, volume = {15}, number = {1}, pages = {}, pmid = {42711740}, issn = {2047-9158}, mesh = {*Alzheimer Disease/pathology/metabolism ; *Extracellular Vesicles/transplantation/metabolism ; Animals ; Humans ; *Microglia/metabolism/pathology ; Female ; Mice ; *Mesenchymal Stem Cells/metabolism ; Disease Models, Animal ; Mice, Transgenic ; *Amnion/cytology ; Hippocampus/metabolism ; Administration, Intranasal ; }, abstract = {BACKGROUND: Alzheimer's disease (AD) is the most prevalent neurodegenerative disorder and disproportionately affects women, with neuroinflammation emerging as a key driver of disease onset and progression. Beyond amyloid-β (Aβ) and hyperphosphorylated tau protein accumulation, chronic activation of microglia and astrocytes amplifies synaptic dysfunction and neuronal loss. Mesenchymal stromal cell-derived extracellular vesicles (MSC-EVs) represent a promising translational strategy due to their capacity to modulate inflammation and promote neuroprotection. Here, we investigated whether intranasal administration of extracellular vesicles derived from human amniotic membrane MSCs (hAMSC-EVs) could counteract cognitive decline, neuroinflammation, and synaptic alterations in experimental and human cellular models of AD.

METHODS: hAMSC-EVs were isolated and characterized for size, markers, and biodistribution. Female 3 × Tg-AD mice received chronic intranasal hAMSC-EV administration from 3 to 9 months of age. Cognitive performance was assessed using novel object recognition, object place recognition, and Y-maze tests. Hippocampal Aβ levels, tau phosphorylation, glial density, microglial morphology, cytokine profiles, and synaptic protein expression were analyzed by immunoblotting, ELISA, immunofluorescence, and morphometric analyses. Bioinformatic analyses were performed to investigate the miRNA cargoes of hAMSC-EVs. Translational relevance of the hAMSC-EV effects was assessed in glutamatergic neurons differentiated from induced pluripotent stem cells derived from sporadic AD patients.

RESULTS: The hAMSC-EVs delivered intranasally reached the hippocampus and were internalized by neurons and microglia. hAMSC-EV treatment significantly improved cognitive performance of female 3 × Tg-AD mice and reduced hippocampal Aβ levels without affecting tau phosphorylation. The hAMSC-EVs attenuated neuroinflammation by reducing microglial and astrocytic density, inducing microglial structural remodeling, and downregulating TMEM119 and TREM2 expression. We also detected a shift toward an anti-inflammatory cytokine profile and increased expression of neuroplasticity-related proteins, including BDNF, GluA1, and ARC in the hippocampus of 3 × Tg-AD mice. Bioinformatic analyses identified EV miRNA cargoes enriched in immunomodulatory and neuroprotective pathways. In human AD neurons, hAMSC-EVs prevented neurite atrophy and rescued synaptic protein expression without affecting the cell viability.

CONCLUSIONS: hAMSC-EVs exert robust anti-inflammatory and neuroprotective effects in both murine and human AD models, improving cognition, modulating glial activation, and restoring synaptic integrity. These findings highlight the translational potential of intranasal hAMSC-EVs as an adjuvant therapeutic strategy targeting neuroinflammation and neurodegeneration in AD.}, } @article {pmid42711950, year = {2026}, author = {Hwang, J and Pietras, A and Naasan, G and Elahi, FM and Gandy, S}, title = {Rapid plaque clearance with anti-amyloid therapy for Alzheimer's disease: in consideration of donanemab treatment duration from real-world cases.}, journal = {Neurocase}, volume = {}, number = {}, pages = {1-4}, doi = {10.1080/13554794.2026.2730462}, pmid = {42711950}, issn = {1465-3656}, abstract = {To assess the possibility that individualized duration of donanemab treatment might enable early pausing of therapy, and to explore the possible utility of plasma P-tau[217] as a biomarker for treatment response monitoring in real-time, two unrelated patients with early-stage Alzheimer's disease were treated with donanemab at the Icahn School of Medicine at Mount Sinai. Clinical progress was monitored via medical chart review, including serial brain MRI, amyloid PET scans, and blood-based biomarker assays (Quanterix Simoa® and Fujirebio Lumipulse®). Both patients achieved complete amyloid clearance as judged by amyloid PET prior to their 6th and 9th infusions, which were significantly earlier than the 12-month mark typically recommended for follow-up amyloid assessment. In agreement with the amyloid PET, concurrently measured plasma P-tau[217] levels fell within a low range. Treatment was discontinued for both patients. These patients highlight the possibility of individualized treatment durations for anti-amyloid therapy with donanemab, guided by biomarker response. Early cessation following rapid plaque clearance could reduce healthcare costs and minimize exposure to the risk of amyloid-related imaging abnormalities and the generation of neutralizing antibodies. Plasma P-tau[217] warrants further investigation as a reliable, cost-effective surrogate for PET scans to monitor real-time treatment response and guide the timing of discontinuation.}, } @article {pmid42712219, year = {2026}, author = {Wang, H and Li, L and He, X and Shen, S and Chao, L and You, P and Ji, K and Liu, Y and Hong, Z}, title = {UHPLC-Q/TOF-MS Characterization of Danshen-Chuanxiong and Mechanistic Insights Into Its Protective Effects Against Aβ1-42-Induced Brain Endothelial Injury Through Metabolomics.}, journal = {Journal of separation science}, volume = {49}, number = {9}, pages = {e70527}, doi = {10.1002/jssc.70527}, pmid = {42712219}, issn = {1615-9314}, support = {82173777//National Natural Science Foundation of China/ ; 82504742//National Natural Science Foundation of China/ ; 82473885//National Natural Science Foundation of China/ ; }, mesh = {*Amyloid beta-Peptides/antagonists & inhibitors/metabolism ; Humans ; *Metabolomics ; Chromatography, High Pressure Liquid ; *Endothelial Cells/drug effects/metabolism ; *Drugs, Chinese Herbal/pharmacology/chemistry/metabolism/analysis ; *Peptide Fragments/antagonists & inhibitors ; Salvia miltiorrhiza/chemistry ; *Brain/drug effects/metabolism ; Cell Survival/drug effects ; Mass Spectrometry ; }, abstract = {Danshen-Chuanxiong is a traditional herb pair used for cardiovascular and cerebrovascular disorders, but its chemical basis and potential effects in Alzheimer's disease (AD)-related endothelial injury remain incompletely defined. Here, an integrated analytical workflow combining reversed-phase liquid chromatography (RPLC) and hydrophilic interaction liquid chromatography (HILIC) with quadrupole time-of-flight mass spectrometry (Q-TOF-MS), cellular assays, metabolomics, and network pharmacology was applied in an amyloid-β1-42 (Aβ1-42) oligomer-induced human brain microvascular endothelial cell (hBMEC) injury model. The complementary RPLC/HILIC and positive/negative electrospray-ionization strategy expanded coverage across a broad polarity range. UHPLC-Q/TOF-MS detected 90 compounds, mainly phenolic acids, phthalides, tanshinones, diterpenoids, and other aromatic or terpenoid constituents. The reductions in cell viability and zonula occludens-1 expression following Aβ1-42 exposure confirmed the successful establishment of the cellular injury model, whereas pretreatment with Danshen, Chuanxiong, or their combination increased cell viability and alleviated Aβ1-42-induced cellular injury. Untargeted metabolomics annotated 38 differential metabolites, of which 30 showed a recovery-associated shift toward the control state after Danshen-Chuanxiong treatment; the associated pathways included amino-acid, purine, glutathione, and glycerophospholipid metabolism. Integrative analysis prioritized seven candidate targets of Danshen-Chuanxiong, namely ACHE, VEGFA, NOS2, NOS3, AKR1B1, MDM2, and XDH. These findings provide a separation-MS-based chemical characterization and mechanistic framework for further validation of Danshen-Chuanxiong in AD-related endothelial injury models.}, } @article {pmid42714032, year = {2026}, author = {Li, Y and Ye, T and Lu, H and Wang, S and Yu, T and Li, H and Cheng, X}, title = {Effects of Qi-fu-yin on Improving Cognitive Impairment and Reducing Cellular Senescence in the Brains of 5xFAD Mice.}, journal = {Journal of visualized experiments : JoVE}, volume = {}, number = {235}, pages = {}, doi = {10.3791/72118}, pmid = {42714032}, issn = {1940-087X}, mesh = {Animals ; Mice ; *Brain/drug effects/metabolism/pathology ; *Alzheimer Disease/drug therapy/metabolism/pathology ; *Cellular Senescence/drug effects ; *Drugs, Chinese Herbal/pharmacology ; Mice, Transgenic ; Amyloid beta-Peptides/metabolism ; *Cognitive Dysfunction/drug therapy/metabolism/pathology ; Male ; }, abstract = {Although the mechanism of Qi-fu-yin (QFY), a traditional Chinese medicine prescription, remains incompletely understood, it has shown therapeutic potential in Alzheimer's disease (AD). This study aimed to investigate the association between QFY treatment and cognitive impairment in 5xFAD mice. We used grip strength, gait, colony nesting, shuttle box, Morris water maze test, and ELISA to evaluate the levels of Amyloid-β protein 1-42 (Aβ1-42), Aβ1-40, Growth-associated protein 43 (GAP-43), Synaptophysin (SYN), and Postsynaptic density protein 95 (PSD-95) in the brains of 5xFAD mice. Luminex cytokine analysis was used to quantify Senescence-associated secretory phenotype (SASP) levels in the cortex. The amount of Senescence-associated β-galactosidase (SA-β-Gal), Aβ deposition, and dendritic spines in the animals' brains was measured by SA-β-Gal staining, immunohistochemistry, and Golgi-Cox staining, respectively. QFY treatment dramatically reduced cortical Aβ plaque burden and decreased p21 expression in 5xFAD mice, according to immunofluorescence tests. In 5xFAD mice, QFY therapy markedly enhanced learning and memory performance, alleviated aging, and increased the amounts of GAP-43, PSD-95, and SYN proteins in the mice's cortex. Following QFY treatment, there was a significant decrease in Aβ plaque and SA-β-Gal activity in the brain, as well as Aβ1-42 and Aβ1-42/Aβ1-40 levels in the hippocampus. The levels of IL-1α, IL-1β, IL-6, IL-17A, and IFN-γ were considerably reduced in the cortex of the 5xFAD mice. PCA and Pearson correlation analyses demonstrated a strong negative association between SASP cytokines and synaptic protein levels. These findings suggest an association between QFY treatment and improvements in age‑related cognitive decline and cellular senescence phenotypes in 5xFAD mice, alongside mitigated synaptic structural damage. These findings support further investigation of QFY as a potential therapeutic candidate for Alzheimer's disease.}, } @article {pmid42714614, year = {2026}, author = {Schnieder, M}, title = {[Antibody therapy in Alzheimer's disease].}, journal = {Zeitschrift fur Gerontologie und Geriatrie}, volume = {}, number = {}, pages = {}, pmid = {42714614}, issn = {1435-1269}, abstract = {Alzheimer's disease, the leading cause of dementia, is defined by extracellular amyloid‑β (Aβ) plaques, intracellular tau aggregates and neurodegeneration. Lecanemab and donanemab, are the first disease-modifying antibodies available for early Alzheimer's disease. Both reduce Aβ plaques and slow cognitive decline. Lecanemab targets soluble protofibrils and donanemab targets fibrillar Aβ. The primary side effect is amyloid-related imaging abnormalities (ARIA), which can occur as edema (ARIA-E) or hemorrhages (ARIA-H). The risk is higher in APOE4 homozygotes, anticoagulation or cerebrovascular diseases. Therefore, during treatment a regular monitoring with magnetic resonance imaging (MRI) is mandatory.}, } @article {pmid42714783, year = {2026}, author = {Verma, E and Mishra, S and Chellammal, HSJ and Khandige, PS and Gasmi, A}, title = {Gut microbiota as a modulator of HDAC: insights into Alzheimer's disease treatment.}, journal = {Pharmacological reports : PR}, volume = {}, number = {}, pages = {}, pmid = {42714783}, issn = {2299-5684}, abstract = {The human gut microbiota (GMB) has a significant impact on physiological function, including gastrointestinal health, immune regulation, and redox homeostasis. It consists of diverse microorganisms that support digestion, nutrient absorption, and intestinal barrier function. Emerging evidence suggests that gut microbiota-derived metabolites may influence the gut-brain axis and regulate epigenetic mechanisms through modulation of histone deacetylases (HDAC). HDAC are key enzymes involved in gene expression, neuronal survival, neuroinflammation, and the pathogenesis of Alzheimer's disease (AD). Gut microbiota-derived metabolites have been reported to modulate HDAC activity and may contribute to neuroprotective and anti-inflammatory effects. Through these mechanisms, the GMB may influence cognitive function and the progression of AD. However, the precise molecular mechanisms involved in these interactions are not yet fully understood and continue to be extensively investigated. Therefore, this review focuses on the correlation between HDAC and the restoration of a healthy GMB as a therapeutic approach for the treatment and prevention of AD. It emphasizes the role of gut-derived metabolites, peptides, and dietary bioactive compounds in regulating HDAC-mediated epigenetic pathways. These interactions may influence gene expression, neurotransmitter biosynthesis, neuroinflammation, and neuroprotective signalling associated with cognitive function. Furthermore, the review delineates the bidirectional interplay among neurotransmitter signalling, GMB composition, and HDAC-mediated epigenetic regulation, along with their potential roles in the pathophysiology of neurodegenerative disorders.}, } @article {pmid42716045, year = {2026}, author = {Teunissen, CE and Vermunt, L and Barthélemy, NR and Benzinger, TLS and Graff-Radford, J and Verberk, IMW and Zetterberg, H and Schindler, SE and Jack, CR}, title = {Fluid biomarkers in the evolving care landscape of Alzheimer's disease and related disorders.}, journal = {The Lancet. Neurology}, volume = {25}, number = {10}, pages = {926-938}, doi = {10.1016/S1474-4422(26)00246-2}, pmid = {42716045}, issn = {1474-4465}, mesh = {Humans ; *Biomarkers/cerebrospinal fluid/blood ; *Alzheimer Disease/cerebrospinal fluid/diagnosis/blood ; tau Proteins/cerebrospinal fluid ; Animals ; }, abstract = {Fluid biomarkers for Alzheimer's disease have advanced rapidly during the past several years driven by breakthroughs including development of ultrasensitive and multiplexing technologies and high specificity antibodies. Blood-based biomarkers, such as neurofilament light for frontotemporal dementia and amyotrophic lateral sclerosis, and phosphorylated tau 217 for the diagnosis of Alzheimer's disease, are now being implemented in clinical practice, which is particularly timely because of the increasing clinical availability of amyloid-targeting treatments in Alzheimer's disease. Multiple fluid biomarkers are needed to capture the complexity of disease mechanisms for precise diagnosis and to measure the diverse pathologies that lead to dementia, such as vascular, α-synuclein, and TDP-43 pathologies. Moreover, fluid biomarkers can aid in capturing heterogeneity in treatment course between patients, probably due to copathologies or key intermediates, including microglia and astrocyte dysregulation. Increased focus on biomarker-pathology relationships in experimental models will likely accelerate biomarker development and further the understanding of their precise substrates. Future clinical implementation of biomarkers to capture the full complexity of pathologies will likely be facilitated by the expansion of diagnostic methods, development of point of care technologies, and remote sampling approaches.}, } @article {pmid42705844, year = {2026}, author = {Zhou, Q and Yang, MX and Zhang, QQ and Li, YQ and Wang, ZQ}, title = {Efficacy and Durability of Repetitive Transcranial Magnetic Stimulation on Cognitive Function in Patients With Mild-to-Moderate Alzheimer's Disease: A Systematic Review and Meta-Analysis.}, journal = {Psychogeriatrics : the official journal of the Japanese Psychogeriatric Society}, volume = {26}, number = {5}, pages = {e70199}, pmid = {42705844}, issn = {1479-8301}, support = {2022ZD0208506//STI 2030-Major Projects/ ; 82201628//National Natural Sciencen Foundation of China/ ; U24A20274//National Natural Sciencen Foundation of China/ ; S23042//SiChuan Province Medical Research Project Program/ ; 513//2024 Annual Specialized Research Project on Traditional Chinese Medicine of SiChuan Provincial Administration of Traditional Chinese Medicine/ ; }, mesh = {Humans ; *Alzheimer Disease/therapy/psychology ; *Transcranial Magnetic Stimulation/methods ; *Cognition/physiology ; Treatment Outcome ; Cognitive Enhancement ; Randomized Controlled Trials as Topic ; Aged ; }, abstract = {Repetitive transcranial magnetic stimulation (rTMS) is a non-invasive brain stimulation technique that has shown potential for improving cognitive function in Alzheimer's disease (AD), though findings remain inconsistent. This meta-analysis evaluated the efficacy and durability of rTMS in patients with mild to moderate AD and explored potential moderating factors. Randomised controlled trials (RCTs) comparing active rTMS with sham stimulation were identified through systematic searches of major databases. Effect sizes were calculated using Hedges' g, with random-effects models applied. Risk of bias was assessed using the Cochrane RoB 2 tool. Five RCTs (N = 143) were included in the primary analysis. rTMS showed a small-to-moderate improvement in MMSE scores (g = 0.41, 95% CI [0.06, 0.75], p = 0.021, I[2] = 6.5%). Excluding two studies with methodological concerns yielded a similar effect (g = 0.46), though with wider confidence intervals. Sensitivity analysis including studies with change scores confirmed the robustness of results (g = 0.48). Given the limited number of studies (k < 10), formal publication bias tests and trim-and-fill adjustment were not applied, in line with current methodological guidance. Notably, all five studies employed excitatory stimulation protocols (high-frequency rTMS or iTBS), with four of five targeting the left dorsolateral prefrontal cortex (DLPFC), suggesting that excitatory stimulation of key cognitive network hubs represents the most consistent evidence base to date. Meta-regression identified treatment duration as a significant moderator (β = -0.193, p = 0.034), suggesting shorter, more intensive protocols may be more effective. Follow-up analyses indicated a nonsignificant trend towards sustained benefits (g = 0.25), while time-trend analysis demonstrated a stable overall effect (g = 0.38). In conclusion, rTMS provides modest cognitive benefits in mild to moderate AD, with excitatory protocols targeting the left DLPFC showing the most consistent efficacy and treatment duration influencing outcomes. However, evidence remains limited, highlighting the need for larger, standardised, multi-centre trials with long-term follow-up.}, } @article {pmid42706500, year = {2026}, author = {Ding, J and Miao, J and Zhang, L and Liu, Q and Zhang, Y and Li, J and Li, Y}, title = {Cognitive safety of statin use in the elderly: Evidence from a nationally representative sample.}, journal = {Journal of internal medicine}, volume = {}, number = {}, pages = {}, doi = {10.1111/joim.70159}, pmid = {42706500}, issn = {1365-2796}, support = {SCYG2025-1//Sichuan Hospital Management and Development Research Center/ ; YF25-Y15//Sichuan Medical and Health Rule of Law Research Center-Chinese Society of Health Law Joint Project/ ; scsyxh202502//Hospital Pharmaceutical Research Funding Project of 'Yue·Stealth' of Sichuan Province Pharmaceutical Association/ ; 26MSZX599//Special Science and Technology Research Project of the Sichuan Province Administration of Traditional Chinese Medicine/ ; 26MSZX601//Special Science and Technology Research Project of the Sichuan Province Administration of Traditional Chinese Medicine/ ; CSXL-26209//Foundation of the Sichuan Research Center of Applied Psychology/ ; MZSJ202602//Mianyang Key Laboratory of Anesthesia and Neuroregulation/ ; 17PJ332//Sichuan Province Health Commission Project/ ; }, abstract = {OBJECTIVE: To systematically evaluate the association between current statin use and global cognitive impairment in US older adults and examine potential variations across treatment intensity, duration, and specific cognitive domains to guide clinical cardiometabolic management.

METHODS: This survey-weighted cross-sectional study included 3137 National Health and Nutrition Examination Survey 2011-2014 participants aged ≥60 years. Cognitive performance across Consortium to Establish a Registry for Alzheimer's Disease, animal fluency, and digit symbol substitution test (DSST) was composite-summarized to define impairment (Z-score ← 1.5 standard deviation). Survey-weighted multivariable models adjusted for sociodemographic, lifestyle, cardiometabolic, psychotropic medication, polypharmacy, and substance-use proxies, supplemented by inverse probability of treatment weighting (IPTW) and multiple imputation.

RESULTS: In the primary fully adjusted model, current statin use was not associated with global cognitive impairment (odds ratio [OR] = 0.90, 95% confidence interval: 0.48-1.67, p = 0.736). Results remained consistent across psychotropic-adjusted (OR = 0.91), IPTW (OR = 1.03), and multiply imputed models (OR = 0.86). Domain-specific analyses showed statin use was associated with lower odds of DSST impairment (OR = 0.51, p = 0.009), with no clear trend across statin intensity or duration categories.

CONCLUSION: Current statin use was not significantly associated with global cognitive impairment in older adults. Although cross-sectional observational neutrality precludes inferring long-term safety, indicated statin therapy should not be routinely withheld over cognitive concerns, with prescribing remaining firmly guided by established atherosclerotic cardiovascular disease risk guidelines.}, } @article {pmid42706972, year = {2026}, author = {Yu, X and Yi, Y and Liu, X and Zhao, C and Li, C and Shang, Y and He, K and Zhai, Y}, title = {Scutellaria Barbata Flavonoids Mitigate Alzheimer's Disease-related Aβ25-35 Toxicity in N2a Cells through CREB Phosphorylation.}, journal = {Current medicinal chemistry}, volume = {}, number = {}, pages = {}, doi = {10.2174/0109298673438931260822121059}, pmid = {42706972}, issn = {1875-533X}, abstract = {BACKGROUND: Mouse neuroblastoma cells (N2a) are spontaneously derived from mice and possess the characteristics of neural stem cells. The proliferation, differentiation, and protrusion growth of N2a cells in vitro are consistent with those in vivo. Flavonoids isolated from the aerial parts of Scutellaria barbata (SBFs) can improve learning and memory deficits and protect against neuronal injury in many in vivo AD-- like models. N2a cells exposed to Aβ25-35 for Alzheimer's disease-related toxicity were subsequently used to observe the ameliorative effects of SBFs, and the effective mechanism through which SBFs promote the phosphorylation of CREB was further studied by using BI-D1870, an indirect inhibitor, and Rolipram, an activator of CREB phosphorylation.

METHODS: Immunofluorescence (IF) was used to detect the protein expression of the neuron-specific proteins NeuN, NeuroD1, and DCX. N2a cells were exposed to 100 μM Aβ25-35 and treated with SBFs at doses of 17.5, 35 and 75 mg·L-1 or 363 μM Rolipram. Cell morphology was observed under an inverted microscope, the cell survival rate was detected by the Cell Counting Kit-8 (CCK-8) method, and the release of lactate dehydrogenase (LDH) into the cell culture medium was determined by the pyruvate reduction method. The mRNA expression levels of ERK, RSK, CREB, and EGR-1 in cells were detected by real-time quantitative polymerase chain reaction (qPCR). IF and/or western blotting (WB) were used to measure the protein expression levels of BDNF, NGF, TrkB, Ras, ERK/p-ERK, Rsk/p90RSK, CREB/p-CREB-Ser133, and EGR-1 in N2a cells.

RESULTS: NeuN, NeuroD1, and DCX expression in N2a cells was positive, as indicated by green fluorescence. Both Aβ25-35 and BI-D1870 resulted in abnormal morphological changes in N2a cells, reduced the cell survival rate (P<0.01), increased the release of LDH (P<0.01) into the culture medium, and decreased the mRNA expression levels of ERK, RSK, and CREB and the protein expression levels of p-ERK, TrkB, p90RSK, pCreb-SER133, BDNF, NGF and EGR-1 (P<0.01) in cells. However, SBFs, to varying degrees, reversed the aforementioned abnormal changes in N2a cells caused by Aβ25-35 or BI-D1870, and the effects of SBFs were consistent with those of Rolipram.

CONCLUSION: SBFs protected against N2a cell damage induced by toxic Aβ25-35, and the effective mechanism by which SBFs promote the phosphorylation of CREB at the Ser133 site was confirmed through the application of the indirect CREB phosphorylation inhibitor BI-D1870 and the activator Rolipram. These findings suggest that SBFs may be helpful in the treatment of AD by intervening in CREB phosphorylation.}, } @article {pmid42706977, year = {2026}, author = {Saxena, B and Sisodiya, N and Khabiya, R and Pandit, A and Rajput, MS and Gupta, R}, title = {AI-Driven Precision Medicine in Alzheimer's Disease: Drug Repurposing, Digital Therapeutics and Clinical Decision Support.}, journal = {Current pharmaceutical design}, volume = {}, number = {}, pages = {}, doi = {10.2174/0113816128478269260818075055}, pmid = {42706977}, issn = {1873-4286}, abstract = {Alzheimer's Disease (AD) is a neurodegenerative disease that causes significant clinical, social, and economic burden worldwide. Despite improvements in understanding its multifaceted pathogenesis, current treatments are mostly symptomatic and ineffective across varied patient populations. To overcome these constraints, AI-driven precision medicine allows tailored risk assessment, treatment selection, and disease monitoring. This review covers AI's role in AD precision medicine, focusing on drug repurposing, digital therapies and clinical decision support systems. Machine and deep learning models are used to predict medication response, integrate heterogeneous data sources such as genomics, transcriptomics, neuroimaging and electronic health records, and uncover pharmacogenomic treatment success factors. The paper covers AIenabled precision pharmacology, including tailored dosing algorithms, adaptive therapeutic monitoring, and adverse drug reaction prediction. Bioinformatics-based target identification, network pharmacology, graphbased AI models, virtual screening, and real-world and clinical data validation are emphasized in AI-driven medication repurposing. AI-powered digital treatments like personalized cognitive training platforms, wearable- derived digital biomarkers, virtual and mixed reality interventions, adherence monitoring, and digital twins for therapy optimization have been discussed. AI-based clinical decision support systems are also thoroughly assessed for clinical value, accuracy, and explainability in disease subtyping, trajectory prediction, and risk stratification in preclinical and prodromal AD. Despite these promises, data heterogeneity, algorithmic bias, legal barriers, and privacy concerns exist. Federated learning enables safe multi-center collaboration and hybrid AI-human approaches, and it represents the future. AI's ability to alter AD care opens the door to precision medicine paradigms that use repurposed medications, digital tools and intelligent decision-making to improve patient outcomes.}, } @article {pmid42707167, year = {2026}, author = {Zhao, K and Dai, S and Zhang, Y and Liu, G and Gu, P and Lin, C and Thompson, PM and Leow, A and Huang, H and He, L and Zhan, L and Tang, H}, title = {Interpretable multimodal learning for integrating neuroimaging and genetic data in Alzheimer's disease.}, journal = {Frontiers in radiology}, volume = {6}, number = {}, pages = {1912277}, pmid = {42707167}, issn = {2673-8740}, abstract = {INTRODUCTION: Early detection of Alzheimer's disease (AD) requires models that combine brain structure changes with genetic risk, but existing methods struggle to align these different data types.

METHODS: We present R-GenIMA, an interpretable multimodal large language model that pairs a region-of-interest vision transformer with genetic prompting to jointly analyze structural MRI and single nucleotide polymorphisms (SNPs). Each brain region becomes a visual token and SNP profiles are encoded as structured text, letting the model link regional atrophy to genetic factors through cross-modal attention. Tested on the ADNI cohort, R-GenIMA performs well in classifying four groups: normal cognition, subjective memory concerns, mild cognitive impairment, and AD.

RESULTS: Beyond accuracy, it produces biologically meaningful explanations, identifying stage-specific brain regions and genes. The model consistently highlighted known AD risk genes (APOE, BIN1, CLU, RBFOX1) and revealed stage-specific patterns: striatal involvement in subjective decline, frontotemporal changes in early impairment, and broad network disruption in AD.

DISCUSSION: These results show that interpretable multimodal AI can integrate imaging and genetics to reveal disease mechanisms, providing a foundation for clinical tools that enable earlier risk assessment and inform precision treatment in Alzheimer's disease.}, } @article {pmid42708270, year = {2026}, author = {Rajput, R and Sharma, A and Mittal, V and Sharma, D}, title = {Circadian Rhythm Disruption in Alzheimer's Disease: Molecular Mechanisms, Clinical Implications, and Therapeutic Approaches.}, journal = {Current neurovascular research}, volume = {}, number = {}, pages = {}, doi = {10.2174/0115672026473002260820065219}, pmid = {42708270}, issn = {1875-5739}, abstract = {INTRODUCTION: Alzheimer's Disease (AD) is a progressive neurological disorder characterized by unusual behavior, memory deterioration, and a decline in cognitive abilities. A growing body of research indicates that circadian rhythm disturbances play a crucial role in the pathophysiology of AD, impacting both molecular processes and clinical outcomes. This review critically evaluates the molecular interplay between circadian rhythm disruption and AD pathology, explores its impact on clinical manifestations and disease progression, and assesses emerging diagnostic and therapeutic strategies to restore circadian regulation and improve patient outcomes.

METHODS: A thorough analysis of recent research on molecular clock genes (CLOCK, BMAL1, PER, and CRY) and their roles in regulating hormone rhythms, metabolism, and sleep-wake cycles was conducted. Research on technology-based methods, therapeutic treatments, and circadian biomarkers was assessed to determine their applicability in AD.

RESULTS: Circadian gene dysregulation was found to exacerbate tau hyperphosphorylation, amyloid- β accumulation, oxidative stress, and neuroinflammation. Clinically, circadian disruption manifests itself as mood disorders, sleep-wake abnormalities, and accelerated cognitive deterioration.

DISCUSSION: Light therapy, melatonin supplements, chrono-pharmacology, and behavioural techniques are among the interventions that have shown promise in restoring rhythm stability. Wearables, smart lighting, neuromodulation, and multi-omics modelling are examples of technological advancements that increase the range of diagnostic and treatment possibilities.

CONCLUSION: Patient heterogeneity, translational gaps, and a lack of mechanistic knowledge continue to pose difficulties despite progress. To enhance AD outcomes, future research should focus on integrated, customized therapies that target the circadian rhythm.}, } @article {pmid42708376, year = {2026}, author = {Hosoki, S and Sachdev, PS and Ihara, M}, title = {Arterial spin labeling-derived cerebral blood flow as a translational biomarker and candidate surrogate endpoint for cognitive impairment.}, journal = {Current opinion in psychiatry}, volume = {}, number = {}, pages = {}, doi = {10.1097/YCO.0000000000001112}, pmid = {42708376}, issn = {1473-6578}, abstract = {PURPOSE OF REVIEW: Arterial spin labeling (ASL) MRI noninvasively quantifies cerebral blood flow (CBF), but its role as a mechanistic biomarker and surrogate endpoint in trials of cognitive impairment remains undefined. This review evaluates evidence linking regional CBF to cognition across Alzheimer's disease, mild cognitive impairment (MCI), and cerebral small vessel disease (SVD), with particular emphasis on CADASIL as a mechanistically informative model.

RECENT FINDINGS: Multipostlabeling-delay ASL, spatial coefficient of variation metrics, and harmonized processing pipelines have improved reproducibility. Cross-sectional and longitudinal studies consistently link reduced CBF to cognitive impairment, with baseline CBF predicting cognitive decline, MCI-to-Alzheimer's disease conversion, white matter hyperintensity progression, and vascular events. In CADASIL, CBF is independently associated with cognitive performance and predicts subcortical hyperintensity progression over 2 years. Interventional data from SPRINT MIND, PRESERVE, and pilot lecanemab studies indicate that ASL-CBF is responsive to therapy.

SUMMARY: Within the FDA-NIH BEST framework, ASL-CBF appears to meet several criteria consistent with a reasonably likely surrogate endpoint, capturing upstream, potentially reversible hemodynamic dysfunction beyond established structural markers. CADASIL provides an optimal context for qualifications. Larger clinical trials linking treatment-induced CBF changes to clinical benefit, further protocol harmonization, and regulatory engagement are needed to translate ASL-CBF into a validated trial endpoint.}, } @article {pmid42709250, year = {2026}, author = {Yang, W and Lu, Y}, title = {Cross-disease protein aggregate interactions in neurodegeneration: from molecular mechanisms to therapeutic strategies.}, journal = {Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology}, volume = {47}, number = {10}, pages = {}, pmid = {42709250}, issn = {1590-3478}, mesh = {Humans ; *Neurodegenerative Diseases/metabolism/therapy/pathology ; *tau Proteins/metabolism ; *Amyloid beta-Peptides/metabolism ; *alpha-Synuclein/metabolism ; Animals ; *DNA-Binding Proteins/metabolism ; *Alzheimer Disease/metabolism ; *Protein Aggregation, Pathological/metabolism/therapy ; }, abstract = {BACKGROUND: Neurodegenerative diseases have traditionally been classified by their predominant protein pathology. However, accumulating evidence reveals extensive molecular cross-talk between distinct pathological proteins, particularly in Alzheimer's disease (AD).

OBJECTIVE: This review examines cross-disease protein interactions and their implications for diagnosis and treatment.

METHODS: We systematically reviewed peer-reviewed literature published between 2020 and 2025, complemented by seminal earlier studies, examining molecular mechanisms of protein cross-seeding, clinical evidence of co-pathology, and emerging therapeutic strategies.

RESULTS: Cross-seeding between amyloid-β (Aβ), tau, α-synuclein, and TDP-43 has been demonstrated in vitro and in vivo. Harmonized autopsy studies reveal that 91% of individuals over 80 years harbor multiple neuropathologies. Co-pathology accelerates cognitive decline and complicates biomarker interpretation. Anti-amyloid immunotherapies lecanemab and donanemab demonstrate 27-35% slowing of cognitive decline, while anti-tau antibodies targeting N-terminal epitopes have uniformly failed, prompting investigation of combination approaches.

CONCLUSIONS: Recognition of cross-disease protein interactions necessitates a paradigm shift toward multi-target therapeutic strategies and precision medicine approaches accounting for individual co-pathology burden.}, } @article {pmid42709336, year = {2026}, author = {Colosimo, C}, title = {The Great Transatlantic Divide: The Case of Experimental Neuropharmacology.}, journal = {Clinical drug investigation}, volume = {}, number = {}, pages = {}, pmid = {42709336}, issn = {1179-1918}, abstract = {Despite substantial agreement between the Food and Drug Administration (FDA) and the European Medicines Agency (EMA) on new drug approval in the past decades, a few new drugs for the treatment of some of the most prevalent and severe neurological disorders, such as Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis, as well as much rarer neurogenetic disorders, were handled differently by the two regulatory agencies. The possible reasons for the differing behaviors of the FDA and EMA are several and wide-ranging, and they will be examined in this opinion-based analysis. How patients' perceptions of the complex approaches to drug approval and commercialization may create disappointment and confusion will also be reappraised.}, } @article {pmid42709795, year = {2026}, author = {Du, X and Liu, N and Zhang, T and Yang, C and Luo, H}, title = {Size-tailored nanoparticle-antibody conjugates overcome hepatic sequestration in Alzheimer's disease treatment.}, journal = {Proceedings of the National Academy of Sciences of the United States of America}, volume = {123}, number = {37}, pages = {e2603034123}, doi = {10.1073/pnas.2603034123}, pmid = {42709795}, issn = {1091-6490}, support = {0214187096//Huazhong University of Science and Technology (HUST)/ ; XJ2400008870//Hainan University (HU)/ ; }, mesh = {Animals ; *Alzheimer Disease/drug therapy/therapy/metabolism/immunology ; *Nanoparticles/chemistry ; Amyloid beta-Peptides/metabolism/immunology ; *Liver/metabolism/drug effects ; Silicon Dioxide/chemistry ; Mice ; *Antibodies, Monoclonal/chemistry ; Particle Size ; Mice, Transgenic ; Polyethylene Glycols/chemistry ; Brain/metabolism ; Humans ; *Immunoconjugates/chemistry ; }, abstract = {Antibody-based immunotherapy targeting amyloid-β (Aβ) is a promising approach for Alzheimer's disease (AD). However, its efficacy is limited by rapid hepatic sequestration, complement activation, and liver dysfunction. In this study, we synthesized low-immunogenic 450-nm functionalized mesoporous silica nanoparticles (PEG-MSN-1F12) by conjugating the anti-Aβ42 monoclonal antibody 1F12 to polyethylene glycol-modified mesoporous silica nanoparticles to address these challenges. In APP/PS1 mice, intravenous PEG-MSN-1F12 administration markedly enhanced peripheral Aβ clearance, promoted intestinal excretion, reshaped gut microbiota, and alleviated intestinal inflammation, thus reducing AD-associated hepatic burden. Peripheral Aβ removal further led to decreased brain Aβ deposition, attenuated microglial activation, and improved cognition. These findings highlight that the use of particle size-engineered antibody-nanoparticle conjugates is a safe and effective strategy to overcome hepatic sequestration, augment Aβ clearance, and improve AD outcomes.}, } @article {pmid42709901, year = {2026}, author = {}, title = {In brief: Subcutaneous lecanemab (Leqembi Iqlik) for initial treatment of Alzheimer's disease.}, journal = {The Medical letter on drugs and therapeutics}, volume = {68}, number = {1763}, pages = {151}, doi = {10.58347/tml.2026.1763c}, pmid = {42709901}, issn = {1523-2859}, } @article {pmid42697379, year = {2026}, author = {Mohammad, SI and Vasudevan, A and Oriquat, G and Gajjar, TB and Hanumanthayya, M and Shukla, SK and Tailor, NK and Baig, MR and Fadaam, O and Abdul, AS}, title = {Extracellular Vesicles in Neurodegenerative Diseases: A New Frontier in Diagnosis and Therapy.}, journal = {Behavioural brain research}, volume = {}, number = {}, pages = {116455}, doi = {10.1016/j.bbr.2026.116455}, pmid = {42697379}, issn = {1872-7549}, abstract = {Neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and Huntington's disease are among the progressive disorders of the nervous system that are characterized by the gradual destruction of neurons, the accumulation of misfolded proteins, and the limited effective therapeutic options. In recent years, numerous lines of evidence have emphasized the important role of extracellular vesicles (EVs) in the formation and progression of these diseases. These vesicles are membrane-bound nanoscale structures that are secreted by almost all cell types and play a role in cell-cell communication through the transfer of molecules such as proteins, lipids, and nucleic acids. In neurodegenerative disorders, EVs can facilitate the transport and dissemination of disease-related proteins, including amyloid-β, tau, α-synuclein, mutant huntingtin, SOD1, and TDP-43, thus contributing to the spread of pathological processes in different parts of the nervous system. On the other hand, the ability of these vesicles to cross the blood-brain barrier and reflect molecular changes occurring in the central nervous system makes them valuable candidates for the development of minimally invasive biomarkers. This review reviews the biogenesis, classification, isolation methods, and molecular content of EVs, and analyzes their role in the pathogenesis, diagnosis, and treatment of the most important neurodegenerative diseases. Also, the importance of EV-associated proteins, RNAs, and lipids as emerging diagnostic biomarkers, as well as the therapeutic potential of natural and engineered vesicles as drug delivery systems and regulators of neuroinflammation and neurodegenerative processes, is discussed.}, } @article {pmid42697496, year = {2026}, author = {Zhang, J and Chen, X and Hu, Z and Zhang, J and Wu, T and Zhou, J and Song, B and Xu, Y and Yang, H and Zhu, X}, title = {Breaking the autophagy-oxidative stress vicious cycle in Alzheimer's disease: Lactiflorin unlocks P62 dual phosphorylation via ULK1 targeting.}, journal = {Journal of ethnopharmacology}, volume = {374}, number = {Pt 1}, pages = {122367}, doi = {10.1016/j.jep.2026.122367}, pmid = {42697496}, issn = {1872-7573}, abstract = {The dried root of Paeonia lactiflora Pall. has a long history of medicinal use in traditional Chinese medicine. Classical materia medica and traditional practice describe Paeonia-related medicinal materials for headache, dizziness, restlessness, and other neurological or behavioral manifestations, particularly in disorders traditionally associated with blood or yin deficiency and liver-yang hyperactivity. Modern pharmacological studies have further demonstrated neuroprotective and antioxidant effects of Paeonia lactiflora and its bioactive monoterpene glycosides. Lactiflorin (LAC) is a naturally occurring monoterpene glycoside reported as a constituent of Paeonia lactiflora and exhibits antioxidant and cytoprotective properties; however, its therapeutic potential and underlying mechanisms in Alzheimer's disease (AD) remain unclear. This study therefore investigated the protective effects of LAC against AD and explored its underlying mechanisms.

AIM OF THE STUDY: This study investigated whether LAC could break the self-reinforcing vicious cycle between autophagic dysfunction and oxidative stress in AD by engaging ULK1 to promote P62 phosphorylation at two key residues.

MATERIALS AND METHODS: APP/PS1 transgenic mice and Aβ1-42-treated HT22 cells served as in vivo and in vitro AD models, respectively, with cognitive performance assessed through a battery of behavioral tests. Integrated bioinformatics and machine-learning analyses were applied to map AD-related molecular networks and prioritize candidate targets. Aβ deposition, autophagic flux, and oxidative stress were evaluated by immunofluorescence, Western blotting, biochemical assays, and the mCherry-EGFP-LC3 tandem fluorescent reporter system. The interaction between LAC and ULK1 was subsequently evaluated by molecular docking, molecular dynamics simulation, thermal shift assay, DARTS, and SPR.

RESULTS: LAC alleviated cognitive deficits in male APP/PS1 mice and reduced hippocampal Aβ deposition. Bioinformatics analysis subsequently suggested that LAC may regulate AD-related pathology mainly through autophagy- and oxidative stress-associated networks. Consistent with these predictions, LAC increased the LC3-II/LC3-I ratio and decreased P62 expression, while also alleviating redox imbalance and lipid peroxidation in brain tissue and HT22 cells, as evidenced by decreased malondialdehyde (MDA) levels and restored superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) activities. Mechanistically, LAC engaged ULK1 via a His24-dependent interaction, thereby enhancing P62 phosphorylation at Ser403/Ser351, activating the Keap1/Nrf2/HO-1 pathway, and restoring the Beclin-1/VPS34-associated autophagy-initiation machinery.

CONCLUSIONS: LAC alleviated Aβ deposition, oxidative injury, and cognitive dysfunction by engaging ULK1, suggesting its potential as a promising natural compound for AD treatment.}, } @article {pmid42697812, year = {2026}, author = {Clark, ED and Perin, J and Devanand, DP and Padala, PR and Shade, DM and Lyketsos, CG and Porsteinsson, AP and , }, title = {Effects of Escitalopram on Neuropsychiatric Symptoms in Alzheimer Disease: A Secondary Analysis From the S-CitAD Study.}, journal = {The American journal of geriatric psychiatry : official journal of the American Association for Geriatric Psychiatry}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.jagp.2026.08.011}, pmid = {42697812}, issn = {1545-7214}, abstract = {OBJECTIVE: Using Neuropsychiatric Inventory (NPI) data from the Escitalopram for agitation in Alzheimer disease (S-CitAD) study, the authors explored the potential impact of escitalopram on neuropsychiatric symptom domains and caregiver distress scores outside of agitation.

METHODS: Caregiver-rated scores were compared from baseline to week 12 in 173 participants receiving escitalopram (5-15 mg/day) or placebo examining the presence or absence of individual neuropsychiatric symptoms, emergence of new symptoms, and median NPI domain severity scores between groups at week 12. Caregiver distress scores were additionally examined by NPI domain at baseline and at week 12 for between group changes.

RESULTS: Statistical significance was seen in the depression/dysphoria domain median scores favoring the escitalopram group at week 12. Caregiver distress scores in the domains of apathy/indifference and irritability/lability favored escitalopram at week 12; however, the median NPI domain scores in these domains weren't statistically different from placebo. In evaluating the emergence of new symptoms over the 12-week period, no participants (0%) in the escitalopram group reported new hallucinations versus 5 participants (7%) in the placebo group.

CONCLUSION: Escitalopram may have an impact on the severity of symptoms of depression/dysphoria in AD. No new symptoms of hallucinations in the escitalopram group throughout the 12 week trial suggest a possible direction for future research into selective serotonin reuptake inhibitors (SSRIs) and the treatment and/or delaying of psychotic symptoms in AD. As this was an exploratory analysis involving multiple comparisons, findings may be spurious.}, } @article {pmid42699154, year = {2026}, author = {Rouault, M and Kindler, DR and Ni, R and Liberale, L and Seiler, R and Ielacqua, GD and Nitsch, R and Pryce, C and Camici, GG and Kulic, L and Klohs, J}, title = {Coagulation factor XII deficiency alleviates vascular dysfunction and cognitive impairment in a mouse model of cerebral β-amyloidosis and cerebral amyloid angiopathy.}, journal = {Aging brain}, volume = {10}, number = {}, pages = {100167}, pmid = {42699154}, issn = {2589-9589}, abstract = {Amyloid-β (Aβ) can activate the factor XII (FXII)-driven contact system, which exerts several downstream effects on Alzheimer's disease (AD) pathology associated with cognitive impairment. Here, using genetically modified FXII deficient mice crossed with arcAβ mice, we show that genetic deletion of FXII ameliorates β-amyloidosis-mediated susceptibility to arterial thrombus formation, blood-brain barrier leakage, and cerebral microbleed load. Furthermore, we show that genetic deletion of FXII improves cognitive deficits, without affecting Aβ deposition. Thus, the FXII-driven contact system constitutes an important pathway contributing to vascular dysfunction and cognitive impairment in AD, independent of Aβ neuropathology, with important implications for the diagnosis and treatment of the disease.}, } @article {pmid42699553, year = {2026}, author = {Laginha, I and Schmitz, M and da Silva Correia, Â and Saleem, T and da Silva Correia, S and Zafar, S and Younas, N and Canaslan, S and Göbel, S and Root, E and Breitbarth, M and Fischer, AL and Dittmar, K and Žakova, D and Hermann, P and Zerr, I}, title = {Prion protein (PrP) profiles in blood and CSF: insights into pre-symptomatic and symptomatic prion disease.}, journal = {Brain communications}, volume = {8}, number = {5}, pages = {fcag321}, pmid = {42699553}, issn = {2632-1297}, abstract = {The conversion of native prion protein (PrP) into its misfolded isoform, scrapie (PrP[Sc]) and its intracellular accumulation represent central events in the pathogenesis of prion diseases. Reduction of native PrP in the central nervous system (CNS) has emerged as a promising strategy for treatment and prevention of prion diseases in humans. To facilitate translation into clinical practice, it is essential to identify at-risk individuals through biomarker development and to elucidate PrP behaviour across prion disease subtypes and biological fluids. Measurements of PrP in accessible biofluids, such as plasma and cerebrospinal fluid (CSF), may provide a pharmacodynamic readout and enable monitoring for PrP-targeted therapies. This study systematically quantifies PrP in plasma and CSF of individuals with sporadic and genetic prion diseases, healthy controls (HC), patients with non-neurodegenerative neurological conditions (ND) and Alzheimer's disease (AD). We analysed 136 plasma and 84 CSF samples, including HC, AD, sporadic Creutzfeldt-Jakob disease (sCJD), as well as symptomatic patients and asymptomatic carriers of the mutations D178N, E200K and P102L. Quantification of PrP was performed using a BetaPrion Human ELISA. Statistical analyses assessed differences between diagnostic groups, associations with demographic factors and PRNP codon 129 polymorphism, and diagnostic accuracy via ROC curves. Plasma PrP was significantly reduced in patients with sCJD (P = 0.043), in symptomatic patients with the E200K (P = 0.0078) and in both symptomatic and asymptomatic D178N carriers (P = 0.0002) compared to HC. Furthermore, symptomatic and asymptomatic D178N carriers had significantly lower plasma PrP levels than patients with AD (P = 0.0025 and P = 0.0041, respectively). In CSF, PrP concentrations were notably lower in D178N symptomatic patients (P = 0.0026) versus non-neurodegenerative (ND) controls. Plasma PrP levels showed no association with age, sex or disease onset and were lower in genetic prion disease patients with the methionine/valine (MV) genotype at PRNP codon 129. The diagnostic accuracy for PrP quantification in plasma as a biomarker discriminated D178N asymptomatic carriers [area under the curve (AUC) = 0.96] and D178N symptomatic patients (AUC = 0.90) from HC with excellent accuracy. In CSF, PrP quantification discriminated D178N symptomatic patients from ND with good accuracy (AUC = 0.64). Taken together, this study defines a characteristic profile of persistently low plasma and CSF PrP in D178N symptomatic and asymptomatic mutation carriers. Low plasma levels in sCJD and E200K, in contrast to P102L, are puzzling. Mutation-specific patterns of PrP need to be considered for monitoring purposes in clinical trials.}, } @article {pmid42700283, year = {2026}, author = {Atiq, A and Choe, K and Kang, MH and Park, HY and Atiq, U and Ahmad, W and Ali, W and Park, TJ and Kim, MO}, title = {Neuroprotective Effect of Isorhapontigenin (ISO) Against LPS-Induced Neurodegenerative Condition via TLR4/RAGE-Mediated p-NF-kB Activation.}, journal = {Molecular neurobiology}, volume = {63}, number = {1}, pages = {}, pmid = {42700283}, issn = {1559-1182}, mesh = {Animals ; *Toll-Like Receptor 4/metabolism ; *Neuroprotective Agents/pharmacology/therapeutic use ; Lipopolysaccharides ; *NF-kappa B/metabolism ; *Stilbenes/pharmacology/therapeutic use ; Signal Transduction/drug effects ; *Receptor for Advanced Glycation End Products/metabolism ; Oxidative Stress/drug effects ; Male ; Mice ; *Neurodegenerative Diseases/metabolism/drug therapy/chemically induced/pathology ; Microglia/metabolism/drug effects ; Glycogen Synthase Kinase 3 beta/metabolism ; Mice, Inbred C57BL ; }, abstract = {Alzheimer's disease (AD) is a complex neurodegenerative disorder characterized by persistent neuroinflammation, oxidative imbalance, cognitive decline, Aβ buildup, tau phosphorylation, and synaptic dysfunction. Despite progress in understanding AD's development, effective treatments are still limited. Isorhapontigenin (ISO), a methoxylated stilbenoid similar to resveratrol, shows neuroprotective, anti-inflammatory, and antioxidative effects. In this study, we explored ISO's therapeutic potential in a mouse model of AD-like pathology induced by LPS, focusing on TLR4/RAGE-triggered NF-κB signaling pathway and related neuroinflammatory responses, oxidative stress, GSK3β signaling, tau pathology, Aβ accumulation, glial activation, and synaptic health. Western blot and immunofluorescence techniques were used to measure the levels of TLR4/RAGE signaling components, glial markers (GFAP and Iba-1), p-NF-κB signaling pathway activation, proinflammatory cytokines (TNF-α, COX-2, and IL-1β), oxidative stress indicators (Nrf2 and HO-1), neurodegeneration markers (p-GSK3β, p-tau, and Aβ), and synaptic proteins (PSD-95, SNAP-23, and SYP). Nissl staining helped assess neuronal density and structure. BV2 microglial cells were treated similarly in vitro, followed by viability tests and Apotox-Glo™ triplex assays, along with protein expression analysis. The levels of TLR4, RAGE, GFAP, and Iba-1 increased in the LPS-treated group, along with proinflammatory mediators, ROS, LPO, and neurodegenerative markers. Yet, ISO treatment significantly reduced their expression. Moreover, LPS lowered Nrf2 and HO-1 levels, reduced p-GSK3β, and decreased synaptic proteins, indicating oxidative damage and synaptic failure. ISO reversed these changes by restoring p-GSK3β, activating Nrf2/HO-1, and boosting synaptic protein levels, followed by behavioral improvement as evidenced by reduced escape latency and increased spontaneous alternations in the Morris water maze (MWM) and Y-maze tests. Additionally, ISO preserved neuronal and synaptic integrity and provided consistent neuroprotection in BV2 cells. Overall, these results demonstrate that ISO reduces LPS-induced AD-like pathology by activating TLR4/RAGE-driven p-NF-κB, decreasing neuroinflammation, enhancing Nrf2/HO-1 activity, inhibiting GSK3β, lowering Aβ and p-Tau accumulation, preserving synaptic health, and prominent improvement in spatial memory, emphasizing its potential as an AD treatment.}, } @article {pmid42700644, year = {2026}, author = {Cote, I and Valfort, AC and Sanders, RK and Burris, SL and Hayes, ME and Arya, R and Maram, L and Elgendy, B and Yue, F and Burris, TP}, title = {BE2012 a novel, REV-ERB antagonist that promotes regenerative myogenesis in vivo with substantially improved pharmacokinetics relative to SR8278.}, journal = {The Journal of pharmacology and experimental therapeutics}, volume = {393}, number = {9}, pages = {105011}, doi = {10.1016/j.jpet.2026.105011}, pmid = {42700644}, issn = {1521-0103}, abstract = {Pharmacological inhibition of REV-ERBs has emerged as a potential therapeutic strategy for several diseases with unmet medical needs. Indeed, chronic treatment with SR8278, a synthetic REV-ERB antagonist, has mitigated pathology in various preclinical models of human musculoskeletal and neurological diseases, including Duchenne muscular dystrophy, epilepsy, Alzheimer disease, Parkinson disease, and frontotemporal dementia. However, SR8278, the first and most widely used REV-ERB antagonist, has poor pharmacokinetic properties, which limits its utility. The REV-ERBs (α and β) are widely expressed nuclear receptors that function as ligand-dependent transcriptional repressors, and the therapeutic potential for inhibition of these receptors remains unclear because of the lack of adequate pharmacological tools. Here, we report BE2012, a significantly improved REV-ERB antagonist with >22-fold longer half-life than SR8278. In a cell-based reporter assay, BE2012 exhibited greater potency toward REV-ERBα (EC50 = 0.38 μM) and REV-ERBβ (EC50 = 0.57 μM) compared with SR8278. Notably, in primary myoblast differentiation assays, BE2012 outperformed SR8278 in increasing the proportion of MyoG[+] cells as well as differentiation and fusion indices. In a cardiotoxin-induced muscle injury model, both BE2012 and SR8278 led to increased myofiber cross-sectional area (22%-34% higher than controls). Lastly, transcriptomic profiling revealed remarkable overlap of differentially expressed genes between the 2 compounds, with oxidative phosphorylation and mitochondrial protein complex emerging as the most significantly enriched pathways for both ligands, which have been shown to accelerate regenerative myogenesis. These results establish BE2012 as a refined REV-ERB antagonist for in vivo applications and a valuable tool for deeper exploration of the therapeutic potential of inhibiting REV-ERB activity. SIGNIFICANCE STATEMENT: This study establishes BE2012 as a novel REV-ERBα/β antagonist with a 22-fold longer half-life and improved potency compared with SR8278, the only available REV-ERB antagonist whose poor bioavailability has limited its utility for in vivo use. In an acute muscle injury model in mice, BE2012 promoted regenerative myogenesis and induced a broad transcriptomic reprogramming that was highly concordant with that of SR8278, suggesting it could serve as a new gold-standard REV-ERB antagonist tool compound in the field.}, } @article {pmid42700810, year = {2026}, author = {Han, Z and Liu, W and Fu, W and Wang, K and Tan, Z and Zhang, D and Yang, F and Dong, W and Sang, Z}, title = {Imidazo[1,2-a]pyridine-based HDAC6 inhibitor a17 for the treatment of Alzheimer's disease.}, journal = {European journal of pharmacology}, volume = {1034}, number = {}, pages = {179320}, doi = {10.1016/j.ejphar.2026.179320}, pmid = {42700810}, issn = {1879-0712}, abstract = {Alzheimer's disease (AD) is a prevalent, chronic, and progressive neurodegenerative disorder that predominantly affects the elderly population, and no effective pharmacological treatments are currently available. Histone deacetylase 6 (HDAC6) is overexpressed in the hippocampus of AD patients, and its inhibition has been shown to clear amyloid-β (Aβ) deposits, promote tau protein degradation, ameliorate mitochondrial transport deficits, and restore α-tubulin acetylation. Thus, selective HDAC6 inhibition represents a promising therapeutic strategy for AD, yet the underlying mechanisms by which HDAC6 inhibitors ameliorate cognitive impairment in AD remain elusive. In our previous study, a series of novel imidazo [1,2-a]pyridine-based HDAC6 inhibitors were developed, among which compound a17 exhibited potent HDAC6 inhibitory activity with an IC50 value of 7.51 nM, warranting further investigation into its anti-AD effects. Herein, we demonstrated that a17 exerted robust neuroprotective effects against L-Glutamate (L-Glu-)/Aβ25-35-induced HT22 cell injury. Additionally, a17 displayed favorable blood-brain barrier (BBB) permeability in vitro and drug-likeness properties. In vivo studies revealed that a17 significantly attenuated AD-like phenotypes in an Aluminium chloride (AlCl3)-induced zebrafish AD model, a mechanism potentially associated with the differential regulation of ODC1, Serpine1, and PAG-1. Furthermore, a17 markedly improved scopolamine-induced memory deficits in mice. Collectively, these findings indicate that an HDAC6 inhibitor, a17, was found to attenuate AD-associated pathological and behavioral markers by regulating the expression of ODC1, Serpine1, or PAG-1. Accordingly, a17 merit consideration for a pharmacological treatment of choice for AD.}, } @article {pmid42701177, year = {2026}, author = {Riedlinger, D and Karamercan, MA and Dündar, ZD and Janssens, K and Adam, VN and Bjørnsen, LP and Fabbri, A and Laribi, S and Möckel, M and Polyzogopoulou, E and Somodi, S and Koc, M and Colak, T and Slagman, A and , }, title = {Non-traumatic chief complaints in older patients in European emergency departments and associated outcomes during the Covid-19 pandemic - a secondary analysis of the cross sectional EGERS study.}, journal = {BMC geriatrics}, volume = {26}, number = {1}, pages = {}, pmid = {42701177}, issn = {1471-2318}, mesh = {Humans ; Cross-Sectional Studies ; Female ; Europe/epidemiology ; *Emergency Service, Hospital/statistics & numerical data ; Male ; Aged, 80 and over ; *COVID-19/epidemiology ; Aged ; Prospective Studies ; Hospital Mortality ; Emergency Room Visits ; Hospitalization/statistics & numerical data ; Pandemics ; }, abstract = {BACKGROUND: The scope of medical conditions addressed in Emergency Departments (ED) increases with growing numbers of older patients among the ED patient population. More information on their chief complaints and related treatment outcomes is essential to ensure high-quality ED care. The objective of this study was to describe the pattern of chief complaints of older ED patients and evaluate the associations between these complaints and outcomes such as mortality and hospital admission.

METHODS: This secondary analysis is based on the observational 'Epidemiology of Geriatric patients in Europe' (EGERS) study. This prospective, routine data cross-sectional study was conducted in 36 EDs across 9 European countries. Data collection from routine clinical records of all patients aged 65 and older over a 7-day period from October 19 to November 30, 2020 during the Covid-19 pandemic. Patients with one documented non-traumatic chief complaint were analyzed. Descriptive statistics, logistic regression, and general linear mixed models were used to assess factors associated with hospital admission and in-hospital mortality. Odds ratios (OR) and 95% confidence intervals (CI) were reported.

RESULTS: The study population consisted of 2,794 patients with one specified chief complaint. The mean age was 77.4 (± 8.2) years. The most frequent chief complaints were shortness of breath, abdominal pain, chest pain, weakness and fatigue, and extremity pain and numbness, representing 59% of the cohort. Highest age (≥ 85), geriatric risks (i.e. presence of dementia/Alzheimer's disease (AD), home help service or previous falls), polypharmacy, and shortness of breath increased the odds of being admitted to hospital (OR 1.4 [1.2-1.9]; OR 1.6 [1.3-1.9]; OR 1.3 [1.1-1.6]; OR 3.0 [2.4-3.8]), while female sex was negatively associated with admission (OR 0.7 [0.6-0.8]). Shortness of breath was positively associated with in-hospital mortality (OR 2.2 [1.4-4.3]).

CONCLUSION: Older patients frequently require hospital admission. As chief complaints do not reflect underlying condition or severity, structured evaluation, staff training and geriatric specific care pathways may improve care and reduce adverse clinical outcomes.}, } @article {pmid42701205, year = {2026}, author = {Gabb, VG and Harding, S and Lemke, T and Alderman, S and Woodward, N and Clayton, J and McNair, A and Barrett-Muir, W and Richardson, A and Dooley, J and Rudd, S and Coulthard, E and Turner, N}, title = {Outcomes reported in interventional studies for mild cognitive impairment: a scoping umbrella review to inform core outcome set development.}, journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association}, volume = {22}, number = {9}, pages = {e71800}, pmid = {42701205}, issn = {1552-5279}, support = {NIHR204135//National Institute for Health Research (NIHR)/ ; }, mesh = {Humans ; *Cognitive Dysfunction/therapy ; *Outcome Assessment, Health Care ; Treatment Outcome ; }, abstract = {There is currently no consensus on the most important treatment outcomes in patients with mild cognitive impairment (MCI). As part of developing a core outcome set for MCI, we conducted a pragmatic scoping umbrella review to summarize outcomes reported in previous studies. Six electronic databases were searched from inception to August 2023. Systematic and scoping reviews in English with ≥70% of studies describing at least one quantitative outcome of interventions involving adults with MCI were eligible. Verbatim outcomes were extracted from eligible papers within selected reviews. From 170 papers covering 153 studies from 42 reviews, 143 unique outcomes were identified. Global cognition was the only outcome reported by more than 50% of studies. Two-thirds of outcomes were reported by no more than three studies. Heterogeneous outcome reporting limits evidence synthesis and treatment evaluation. A core outcome set for MCI is warranted to standardize outcome reporting and offer stronger evidence for decision-making.}, } @article {pmid42702949, year = {2026}, author = {Moro, V and Vianello, G and Gambina, G and Gobbetto, V and Gasparini, M and Beccherle, M}, title = {The clinical implications of anosognosia in Alzheimer's disease.}, journal = {Expert review of neurotherapeutics}, volume = {}, number = {}, pages = {1-13}, doi = {10.1080/14737175.2026.2726416}, pmid = {42702949}, issn = {1744-8360}, abstract = {INTRODUCTION: Assessing awareness of patients with Alzheimer's disease (AD) is essential for diagnosis and treatment. Anosognosia, defined as impaired awareness of cognitive and functional deficits, is associated with poorer prognosis, reduced decision-making capacity, increased risk of accidents, and earlier institutionalization.

AREAS COVERED: This narrative review examines 53 studies. After outlining the main theoretical models of awareness in dementia, the multidimensional nature of anosognosia and its impact on patients' autonomy and decision-making abilities are discussed. This review also describes the main instruments available for assessing awareness deficits and highlights their relevance in clinical practice. Particular attention is given to the implications of anosognosia for treatment adherence, patient care, and decision making.

EXPERT OPINION: Taking care of unaware AD patients represents a challenge, and anosognosia is often underestimated in clinical practice. Evidence suggests that awareness deficits may emerge even in the earliest stages of AD, affecting patients' autonomy and capacity to make informed decisions. A two-step assessment process is recommended, consisting of an initial screening followed by a comprehensive evaluation carried out by specialized neuropsychologists. Targeted caregiver training is also essential to address the challenges associated with impaired awareness.}, } @article {pmid42704398, year = {2026}, author = {Zhu, Z and Jiang, X and Huang, R and Guo, X and Wang, Y and Liu, T and Wang, J and Huang, J and Huang, W and Zhang, D and Li, Q and Chen, S and Yang, Z and Liu, Q and Wei, Z}, title = {Deferiprone Modulates Ferroptosis to Protect Macrophages and Liver during Neospora caninum Infection.}, journal = {Acta parasitologica}, volume = {71}, number = {5}, pages = {}, pmid = {42704398}, issn = {1896-1851}, support = {32002309//the National Natural Science Foundation of China/ ; 2022A1515010960//Guangdong Basic and Applied Basic Research Foundation/ ; NJTG20240253//Guangdong Provincial Department of Agriculture and Rural Affairs - Guangdong Agricultural Technical Service "Light Cavalry" Project 2024/ ; SWU-KQ24021//Central University Basic Scientific Research Program of Southwest University/ ; }, mesh = {Animals ; *Ferroptosis/drug effects ; *Neospora/drug effects/physiology ; *Deferiprone/pharmacology/administration & dosage ; *Coccidiosis/drug therapy/parasitology ; *Liver/parasitology/drug effects ; Mice ; *Macrophages/drug effects/parasitology ; Mice, Inbred C57BL ; Iron/metabolism ; Reactive Oxygen Species/metabolism ; Oxidative Stress/drug effects ; Female ; }, abstract = {BACKGROUND: Neospora caninum (N. caninum), an obligate intracellular apicomplexan parasite, infects nucleated cells across diverse mammalian hosts, resulting in severe clinical outcomes, including reproductive failure (abortion, stillbirth) and neurological impairment. Ferroptosis, an iron-dependent, non-apoptotic cell death pathway characterized by excessive lipid peroxidation, is closely associated with disrupted iron metabolism and oxidative stress. Deferiprone (DFP), a clinically approved iron chelator, is widely used in the treatment of iron overload disorders such as β-thalassemia, Alzheimer's disease, and superficial hemosiderosis. While ferroptosis has been implicated in various disease states, its role in N. caninum infection remains unknown.

METHODS: This study established in vitro and in vivo infection models to investigate the role of ferroptosis in N. caninum pathogenesis and the protective mechanism of DFP. In vitro, RAW 264.7 were infected with N. caninum and treated with DFP, followed by comprehensive assessment of reactive oxygen species (ROS), glutathione (GSH) levels, intracellular iron content, GPX4 expression, and parasite proliferation via qPCR. In vivo, C57BL/6 mice were intraperitoneally inoculated with 1 × 10[^7] tachyzoites and orally administered DFP for seven days. Body weight, food intake, hepatic pathology, oxidative stress markers (GSH and MDA), iron levels, and ferroptosis-related gene expression (GPX4, FTH1, and TRF) were monitored.

RESULTS: Our in vitro findings demonstrated that N. caninum infection significantly elevated ROS production and intracellular iron accumulation while depleting GSH and suppressing GPX4 transcription-hallmarks of ferroptosis. Remarkably, DFP treatment reversed these effects, restoring redox balance and protecting host tissue, not host control of infection. In vivo, DFP alleviated N. caninum-induced hepatic ferroptosis, as evidenced by normalized iron homeostasis, upregulated GPX4 and ferritin expression, and reduced histopathological damage. However, DFP exacerbated weight loss, suggesting a potential trade-off between ferroptosis inhibition and metabolic adaptation.

CONCLUSIONS: In summary, these results establish ferroptosis as a critical pathogenic mechanism in N. caninum infection and highlight DFP's dual role in mitigating oxidative injury while possibly impairing host metabolic responses. Our findings provide novel insights into iron-targeted therapeutic strategies for combating intracellular parasitic infections, paving the way for future investigations into optimizing host-directed antiparasitic interventions.}, } @article {pmid42705162, year = {2026}, author = {Guarneri, L and Beh, C and de Campo, L and Whitten, AE and Moir, M and Hung, A and Clulow, AJ and Conn, CE and van 't Hag, L}, title = {Nanoscale localisation of memantine governs structural modulation and loading in bicontinuous cubic phase systems.}, journal = {Journal of colloid and interface science}, volume = {726}, number = {}, pages = {141405}, doi = {10.1016/j.jcis.2026.141405}, pmid = {42705162}, issn = {1095-7103}, abstract = {Memantine is a primary pharmacological treatment for moderate-to-severe Alzheimer's disease but its efficacy and brain delivery remain limited. Lipid bicontinuous cubic phases and their nanoparticle dispersions (cubosomes) offer platforms for enhancing central nervous system drug delivery, yet the rigid adamantane scaffold of memantine can destabilise lipid organisation. This study resolves how an amphiphilic, adamantane-containing drug interacts with non-lamellar lipid bilayers using monoolein-based bulk cubic mesophases and cubosomes formulated with biomimetic lipid compositions and multiple stabilisers. SAXS revealed that lipid composition primarily governed mesophase structure, while memantine induced only modest structural changes in bulk cubic phases. Following memantine incorporation, cubosomes retained cubic symmetry and colloidal stability across stabilisers, although they were more susceptible than bulk phases to additive-induced disorder, with cryo-TEM showing transitions toward less ordered, lower curvature sponge-like structures. Bulk mesophases exhibited 3-5-fold higher apparent drug retention than nanoparticle dispersions. Under excess hydration, however, even bulk phases released memantine rapidly, losing ∼65% of the drug within 24 h. SANS and molecular dynamics simulations revealed a mobile state of memantine with predominantly interfacial localisation rather than stable burial within the hydrophobic tails, providing a mechanistic explanation for its mesophase-dependent structural effects and its limited retention. These findings show that the adamantane scaffold alone is insufficient to ensure efficient incorporation into cubic phases. Localisation, accommodation, and retention are governed by the balance between hydrophobic anchoring and the hydration demands of attached functionalities, establishing a mechanistic framework for predicting the behaviour of amphiphilic adamantane-containing therapeutics in non-lamellar lipid nanocarriers.}, } @article {pmid42697072, year = {2026}, author = {Wu, Q and Li, L and Lei, Y and Zhou, T and Tang, H and Zhang, B and Lu, Y and Salvatore, M and Zhang, D and Tong, J and Wang, T and Chen, S and Li, H and Xu, Z and Huang, Y and Hu, Y and Hong, N and Zhou, Y and Lin, F and O'Brien, KS and Chen, Y and Li, R and Xu, H and Wang, F and Bian, J and Wolk, DA and Chen, Y}, title = {Discovering repurposable drugs for Alzheimer's disease and related dementias: target trial emulation using decentralised real-world data.}, journal = {EBioMedicine}, volume = {132}, number = {}, pages = {106466}, doi = {10.1016/j.ebiom.2026.106466}, pmid = {42697072}, issn = {2352-3964}, abstract = {BACKGROUND: Alzheimer's disease and related dementias (ADRD) affect nearly 6.9 million Americans, with the number expected to triple by 2050, while disease-modifying therapies remain unavailable. Drug repurposing, which identifies new indications for already approved medications, offers a more efficient and cost-effective pathway to accelerate development of effective therapies for ADRD. The aim of this study is to identify potential drug repurposing signals by systematically screening routinely prescribed drugs for associations with progression from mild cognitive impairment (MCI) to ADRD.

METHODS: We conducted a multi-site target trial emulation using electronic health record (EHR) data from four decentralised databases: INSIGHT Clinical Research Network, OneFlorida + Clinical Research Consortium, the University of Pennsylvania Health System, and Yale New Haven Health System. We performed an independent validation using EHR data from the TriNetX Research Network and a genetic risk-stratified sensitivity analysis in the Penn Medicine BioBank (PMBB) database. Eligible participants were adults aged 50 years or older at the time of MCI diagnosis, with no prior diagnosis of ADRD and no prior use of the trial drugs. Initiation of each of 181 routinely prescribed drugs was compared with two active control groups defined by initiation of supplements or cardiovascular medications. Risk ratios (RRs) and 95% CIs were estimated using a federated target trial emulation framework (LATTE) with stabilised inverse probability of treatment weighting and Poisson regression.

FINDINGS: A total of 122,972 eligible patients were identified from the four decentralised databases, 335,506 patients identified from the TriNetX network for validation and 898 from PMBB database. Federated, multi-site target trial emulation identified 20 drug repurposing hypotheses with statistically significant protective effects, including anti-inflammatory and pain-modulating agents (celecoxib: RR 0.43; 95% CI: 0.23-0.81; dexamethasone RR 0.46; 95% CI: 0.29-0.73; gabapentin: RR 0.55; 95% CI: 0.36-0.83; ketorolac: RR 0.50; 95% CI: 0.31-0.80; methylprednisolone: RR 0.43; 95% CI: 0.24-0.76; prednisone: RR 0.48; 95% CI: 0.28-0.83; pregabalin: RR 0.53; 95% CI: 0.35-0.79), antimicrobial and microbiome-associated agents (cefazolin: RR 0.62; 95% CI: 0.45-0.84; clavulanate: RR 0.56; 95% CI: 0.44-0.71; fluconazole: RR 0.36; 95% CI: 0.23-0.58), neuromodulators and adrenergic agents (epinephrine: RR 0.42; 95% CI: 0.31-0.56; propranolol: RR 0.56; 95% CI: 0.37-0.85; salmeterol: RR 0.49; 95% CI: 0.32-0.74; tizanidine: RR 0.29; 95% CI: 0.14-0.57), vascular, metabolic, and hormonal modulators (empagliflozin: RR 0.29; 95% CI: 0.17-0.50; oestradiol: RR 0.47; 95% CI: 0.28-0.81; ezetimibe: RR 0.69; 95% CI: 0.52-0.91; sodium bicarbonate: RR 0.49; 95% CI: 0.29-0.84; spironolactone: RR 0.43; 95% CI: 0.31-0.60), and histamine-related and gastrointestinal agents (famotidine: RR 0.64; 95% CI: 0.55-0.74). Results were consistent in the independent validation using TriNetX network and sensitivity analysis in PMBB database.

INTERPRETATION: 20 widely used medications may be associated with reduced progression from MCI to ADRD and represent promising candidates for clinical evaluation as repurposed therapies for dementia.

FUNDING: National Institutes of Health.}, } @article {pmid42697176, year = {2026}, author = {Bellelli, G and Brignoli, O and Canevelli, M and Cherubini, A and Clegg, A and Dubois, B and Ferrara, MC and Fratiglioni, L and Frisoni, GB and Grande, G and Jessen, F and Kennelly, SP and Magni, A and Marelli, M and Marengoni, A and Velilla, NM and Shenkin, SD and Suárez-Calvet, M and Timmons, S and Padovani, A}, title = {Integrating frailty into decision-making for disease-modifying therapies in Alzheimer's disease: a proposed expert-opinion based approach.}, journal = {The journal of prevention of Alzheimer's disease}, volume = {13}, number = {9}, pages = {100666}, doi = {10.1016/j.tjpad.2026.100666}, pmid = {42697176}, issn = {2426-0266}, abstract = {The introduction of disease-modifying therapies for Alzheimer's disease (AD-DMTs) is reshaping clinical practice, raising critical questions about patient selection, diagnostic pathways, treatment appropriateness, and equity of access. Frailty, a multidimensional condition of reduced physiological reserve and increased vulnerability to stressors, is common in older adults with AD, yet has not been systematically assessed in AD-DMTs trials, limiting the generalizability of trial findings to real-world populations. In this review, we examine the role of frailty in the emerging era of AD-DMTs, summarizing evidence on its prevalence and prognostic relevance, approaches to its assessment, and its potential impact on treatment safety and effectiveness. We propose that regular frailty assessment should inform decision-making in both clinical trials and clinical practice, while frailty-informed management-including medication review and multidomain interventions-may support more appropriate, individualized care.}, } @article {pmid42697335, year = {2026}, author = {Li, X and Wan, R and Wu, Y and Zhao, Y and Chen, X and Li, Y and Yang, R and Zhang, D and Li, Q and Luo, C}, title = {Targeting the mitochondrial functional network: Decoding upstream pathological mechanisms and novel therapeutic paradigms for Alzheimer's disease.}, journal = {Ageing research reviews}, volume = {}, number = {}, pages = {103359}, doi = {10.1016/j.arr.2026.103359}, pmid = {42697335}, issn = {1872-9649}, abstract = {Alzheimer's disease (AD) is the most prevalent neurodegenerative disorder worldwide. Conventional downstream interventions targeting β-amyloid (Aβ) and tau proteins have repeatedly failed in clinical practice, and mitochondrial functional decline has been identified as the core upstream driver of AD pathogenesis. Focusing on the mitochondrial functional network as the core target, this paper systematically dissects the key molecular mechanisms of mitochondrial dysfunction during AD progression, including oxidative phosphorylation impairment, mitochondrial DNA (mtDNA) mutations and genetic defects, excessive reactive oxygen species (ROS) production, mitochondrial dynamics imbalance, mitophagy dysfunction, calcium homeostasis dysregulation, mitochondrial transport defects, and the bidirectional regulatory pathway of tau pathology, and elucidates the pathological network featured by cascade amplification and reciprocal regulation among these abnormal mechanisms. It also comprehensively summarizes mitochondria-targeted intervention strategies for AD, analyzes the research limitations in this field such as model heterogeneity, lack of specific biomarkers and inefficient drug delivery, and prospects future research directions by integrating cutting-edge technologies including cell reprogramming and artificial intelligence (AI). This study provides a novel interpretation of the aging-related pathogenic mechanisms of AD from a mitochondrial perspective, lays a theoretical foundation for the development of precise and efficient mitochondria-targeted therapeutic strategies for AD, and offers a new paradigm for breaking through the bottlenecks of clinical diagnosis and treatment of AD.}, } @article {pmid42697346, year = {2026}, author = {Cai, J and Luo, J and Cai, Y and Xu, Y and Ran, R and Xiao, M and Ye, Q and Zheng, W and Li, S}, title = {Artemether alleviates Aβ1-42-induced neuronal cell damage via PGC-1α-mediated mitochondrial homeostasis in Alzheimer's disease.}, journal = {Cellular signalling}, volume = {149}, number = {}, pages = {112879}, doi = {10.1016/j.cellsig.2026.112879}, pmid = {42697346}, issn = {1873-3913}, abstract = {BACKGROUND: Alzheimer's disease (AD) is the most common neurodegenerative disorder worldwide and the leading cause of dementia. Mitochondrial dysfunction is a key pathogenic event that drives neuronal damage and disease progression. Thus, protecting against mitochondrial damage in neuronal cells has become a critical therapeutic target for AD prevention and treatment. Our previous research has shown that artemether can protect PC12 cells from oxidative stress damage induced by Aβ and oxygen-glucose deprivation, but its underlying regulatory mechanisms remain elusive. Therefore, it is essential to elucidate the role and mechanism of artemether in Aβ-induced mitochondrial damage.

OBJECTIVE: Evaluate the protective effects of artemether on Aβ-induced mitochondrial dysfunction and the underlying molecular mechanism in AD.

METHODS: The HT-22 cell line and primary hippocampal neurons were employed in the present study owing to their greater physiological relevance to hippocampal neuronal injury. In order to evaluate the protective effects of artemether against mitochondrial damage in neuronal cells, we performed Cell Counting Kit-8 assays to assess cell viability and LDH release assays to measure cytotoxicity. Furthermore, we evaluated mitochondrial membrane potential, quantified ATP content, and detected ROS production in Aβ-induced neuronal cell damage. In addition, we used transmission electron microscopy to observe mitochondrial ultrastructural changes and performed immunofluorescence staining to analyze mitochondrial protein localization and morphology. In the AD mouse model, we conducted behavioral tests to assess cognitive function, while using H&E staining, immunohistochemistry, and TUNEL staining to evaluate artemether's effects on AD-related pathological hallmarks. Furthermore, Western blot analysis was performed to dissect the molecular mechanism underlying artemether's protective effect against Aβ-induced mitochondrial damage, focusing on the expression of key proteins in the PGC1/ERRα/TFAM signaling pathway.

RESULTS: Artemether protects against Aβ1-42 induced mitochondrial damage in HT-22 cells and alleviates Aβ1-42 injection induced memory deficits, mitochondrial dysfunction and neuroinflammation in the AD mice model. Mechanistically, artemether treatment upregulated the protein levels of PGC1, which contributes to mitochondrial homeostasis and further activation of the ERRα/TFAM signaling pathway. Moreover, Inhibition of PGC1α abrogates artemether's protective effects.

CONCLUSION: Our findings indicate that neuronal mitochondrial dysfunction serves as a central driver in AD pathogenesis, and activating the PGC1α/ERRα/TFAM axis through artemether offers an effective and feasible strategy for the prevention and treatment of AD.}, } @article {pmid42694564, year = {2026}, author = {Lu, P and Liu, M and Zhang, L and Fan, JJ and Sun, Y}, title = {Synergistic Regulation of Alzheimer's Disease and Intestinal Microbiota Metabolism Mediated by the Gut-Brain Axis: A Comprehensive Analysis from a Multidisciplinary Perspective.}, journal = {International journal of medical sciences}, volume = {23}, number = {9}, pages = {2939-2962}, pmid = {42694564}, issn = {1449-1907}, mesh = {Humans ; *Alzheimer Disease/microbiology/metabolism/immunology/therapy ; *Gastrointestinal Microbiome/immunology/physiology ; *Brain/metabolism/immunology ; Animals ; Multiomics ; *Brain-Gut Axis/immunology/physiology ; *Dysbiosis/microbiology/immunology ; }, abstract = {Alzheimer's disease (AD), as a neurodegenerative disease with the interaction of multiple factors, has a close association between its pathological process and the metabolic imbalance of the gut microbiota mediated by the gut-brain axis. This review systematically summarizes the molecular mechanisms by which the gut microbiota regulates the functions of the central nervous system bidirectionally through molecular pathways such as metabolites (e.g., short-chain fatty acids, tryptophan-kynurenine metabolites), immunomodulatory mediators (e.g., cytokines, chemokines), and bioactive substances (e.g., γ-aminobutyric acid, 5-hydroxytryptophan) via the gut-brain axis. It synthesizes current evidence suggesting the imbalance of microbiota homeostasis may be closely associated with the core pathologies of AD (including β-amyloid deposition and tau protein hyperphosphorylation) through mechanisms such as the activation of the C/EBPβ-AEP signaling pathway, induction of chronic neuroinflammation, oxidative stress cascade reactions, and metabolic network remodeling. These findings, primarily derived from preclinical models and correlational human studies, indicate potential mechanisms but require further causal validation and rigorous clinical translation, including the downregulation of butyrate synthesis pathways and their associated epigenetic and immunomodulatory consequences (as mechanistically dissected in Section 5.2). Multi-omics integration (metagenomics, metabolomics, spatial transcriptomics) has delineated characteristic microbial and metabolic alterations in AD, while computational approaches are beginning to elucidate the complex networks underlying these associations (see Sections 6 and 7 for details).Intervention strategies based on microbiota regulation (such as microbiota-targeted dietary interventions and postbiotics) are emerging as promising approaches, although their clinical applications remain in early stages. Preliminary evidence suggests that fecal microbiota transplantation may improve cognitive outcomes in AD patients with comorbid conditions; however, rigorous randomized controlled trials are essential to validate its efficacy and safety. Critically, translating these mechanistic insights into clinical practice requires overcoming three translational bottlenecks: inferring causality from correlational multi-omics data, resolving species/strain-level functional heterogeneity masked by genus-level taxonomy, and establishing standardized safety protocols for live biotherapeutic products. Addressing these challenges defines the near-term roadmap for precision medicine in AD. However, current research still faces challenges such as the heterogeneity of cross-omics data, the lack of technical standardization, and insufficient interdisciplinary cooperation mechanisms. In the future, it is necessary to promote the early molecular diagnosis and personalized targeted treatment of AD through longitudinal multi-omics dynamic monitoring, modeling of the microbiota-host interaction network, and optimization of the ethical-translational medicine framework.}, } @article {pmid42695408, year = {2026}, author = {Li, Y and Fan, H and Han, X and Ni, M and Hou, X and Xia, H and Shi, Y and Zhang, L and Sun, J}, title = {Effect of MALT1 inhibition by MI‑2 on the microglial phenotype switch, inflammatory cytokine secretion, neuronal loss and oxidative stress in Alzheimer's disease.}, journal = {International journal of molecular medicine}, volume = {58}, number = {5}, pages = {}, doi = {10.3892/ijmm.2026.5973}, pmid = {42695408}, issn = {1791-244X}, mesh = {*Microglia/metabolism/drug effects/pathology ; *Oxidative Stress/drug effects ; *Mucosa-Associated Lymphoid Tissue Lymphoma Translocation 1 Protein/antagonists & inhibitors/metabolism ; *Alzheimer Disease/metabolism/pathology/drug therapy ; Humans ; *Neurons/metabolism/pathology/drug effects ; Animals ; *Cytokines/metabolism ; Mice ; Phenotype ; Reactive Oxygen Species/metabolism ; NF-kappa B/metabolism ; Cell Line ; Amyloid beta-Peptides ; Cell Survival/drug effects ; }, abstract = {Mucosa‑associated lymphoid tissue lymphoma translocation protein 1 (MALT1) is a key paracaspase enzyme regulating immune responses, inflammation and oxidative stress. The present study aimed to investigate the effect of MALT1 inhibition on neuroinflammation, neuronal loss and oxidative stress in Alzheimer's disease (AD). A co‑culture system involving microglia and neuron cells under β‑amyloid (Aβ) intervention was used to establish AD cellular models using human microglia HMC3 cells and neuroblastoma SH‑SY5Y cells and mouse microglia BV‑2 and hippocampal neuron HT‑22 cells. The inhibition of MALT1 proteolytic activity was achieved by MALT1 inhibitor 2 (MI‑2) treatment, and the NF‑κB pathway was activated by phorbol 12‑myristate 13‑acetate (PMA) treatment in HMC3 and BV‑2 cells. Western blotting, ELISA, Cell Counting Kit‑8, EdU staining, reactive oxygen species (ROS) detection and reduced glutathione (GSH) assays were performed to evaluate molecular changes, inflammatory responses, neuronal viability and oxidative stress. MALT1 expression was upregulated following Aβ treatment in HMC3 and BV‑2 cells. MALT1 inhibition by MI‑2 suppressed the microglial M1 phenotype but enhanced the M2 phenotype, reduced the levels of the proinflammatory cytokines TNF‑α and IL‑1β and inactivated the NF‑κB pathway in HMC3 and BV‑2 cells. Moreover, microglial MALT1 inhibition elevated cell viability (verified by Cell Counting Kit‑8 and EdU assays), increased the level of reduced glutathione and decreased the levels of reactive oxygen species in SH‑SY5Y and HT‑22 cells. NF‑κB activation by PMA attenuated the effects of MALT1 inhibition on the microglial phenotype switch and proinflammatory cytokine secretion in HMC3 and BV‑2 cells, as well as cell viability and oxidative stress in SH‑SY5Y and HT‑22 cells. The present study reveals that MALT1 inhibition may suppress microglial M1 phenotype, neuroinflammation, neuronal loss and oxidative stress by inactivating the NF‑κB pathway in AD.}, } @article {pmid42693185, year = {2026}, author = {Dalakas, MC and Lünemann, JD}, title = {Role of complement and complement-targeted therapeutics in neurological diseases.}, journal = {Nature reviews. Neurology}, volume = {}, number = {}, pages = {}, pmid = {42693185}, issn = {1759-4766}, abstract = {Complement comprises a group of plasma and membrane proteins that provide an effective bridging function for innate and adaptive humoral immunity. Understanding complement pathophysiology is fundamental given that inappropriate complement function in host defence can lead to infectious diseases and inefficient disposal of altered, damaged or senescent cells can lead to or enhance autoimmune neurological processes. Although the rising number of approved drugs targeting complement pathways remains primarily focused on diseases with complement-fixing pathogenic antibodies (such as myasthenia gravis and neuromyelitis optica spectrum disorder), a robust pipeline of emerging treatments holds promise for expanding complement-targeted therapies to a broader spectrum of autoimmune neurological diseases, such as multiple sclerosis and even neurodegenerative diseases such as Alzheimer disease or amyotrophic lateral sclerosis. This Review presents insights into complement biology as it relates to the development or initiation of autoimmune and possibly degenerative diseases affecting the central and peripheral nervous systems or muscle. The effects, merits, risks and challenges of marketed drugs or biologic agents in ongoing phase I-III clinical trials engineered to inhibit proximal or distal components of the complement cascade are also discussed. Anti-complement therapeutics are destined to change the treatment of autoimmune neurologic conditions in which the therapeutic landscape is now becoming crowded with biologic agents targeting other key autoimmunity factors.}, } @article {pmid42693696, year = {2026}, author = {Catakli, D and Ozen-Basoglu, O and Tuncgovde, EB and Ozsarlak-Sozer, G}, title = {The Crosstalk Between Diabetes and Alzheimer's Disease: A Molecular Perspective.}, journal = {Basic & clinical pharmacology & toxicology}, volume = {139}, number = {4}, pages = {e70294}, pmid = {42693696}, issn = {1742-7843}, mesh = {Humans ; *Alzheimer Disease/drug therapy/metabolism/physiopathology/epidemiology ; *Diabetes Mellitus, Type 2/drug therapy/metabolism/epidemiology/physiopathology/complications ; Animals ; Insulin Resistance ; Signal Transduction/drug effects ; Brain/metabolism/drug effects ; Oxidative Stress ; Amyloid beta-Peptides/metabolism ; Hypoglycemic Agents/pharmacology/therapeutic use ; Insulin/metabolism ; }, abstract = {The global prevalence of type 2 diabetes mellitus (T2DM) and Alzheimer's disease (AD) is increasing significantly in an age-dependent manner. Growing evidence supports the conceptualization of AD as 'type 3 diabetes,' a term proposed to describe a metabolic disease primarily driven by impaired insulin signalling and insulin resistance within the brain. This review explores the shared molecular mechanisms underlying both T2DM and AD, including chronic neuroinflammation, oxidative stress, mitochondrial dysfunction and impaired glucose metabolism. Specifically, the crosstalk involves the phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt) pathway, where insulin resistance leads to increased glycogen synthase kinase 3β (GSK-3β) activity, promoting tau hyperphosphorylation and amyloid-β (Aβ) accumulation. Furthermore, the article examines the roles of the NOD-like receptor protein 3 (NLRP3) inflammasome, O-linked β-N-acetylglucosamine modification (O-GlcNAcylation), and the gut-brain axis as critical mediators linking metabolic dysfunction to neurodegeneration. Unlike previous reviews that predominantly address individual pathways in isolation, this review provides an integrated molecular framework that connects insulin resistance to neurodegeneration through converging signalling cascades and highlights emerging therapeutic targets including the NLRP3 inflammasome and O-GlcNAcylation as potential mechanistic bridges between T2DM and AD. Finally, the therapeutic potential of various antidiabetic agents such as glucagon-like peptide-1 (GLP-1) receptor agonists, sodium-glucose cotransporter-2 (SGLT-2) inhibitors and thiazolidinediones is discussed, as these drugs offer promising opportunities for the treatment and prevention of AD by targeting these common molecular pathways.}, } @article {pmid42693831, year = {2026}, author = {Lin, LY and Wu, JS and Jeng, WJ and Tsai, CH and Liu, SY and Huang, TW and Yuliani, FS and Lin, SH}, title = {Dementia Risk After Glaucoma Surgery and Medical Therapy: A Multicentre Real-World Cohort Study.}, journal = {International journal of geriatric psychiatry}, volume = {41}, number = {9}, pages = {e70252}, pmid = {42693831}, issn = {1099-1166}, mesh = {Humans ; Female ; Aged ; *Dementia/epidemiology/etiology ; *Glaucoma/surgery/drug therapy/therapy ; Male ; Middle Aged ; Risk Factors ; Aged, 80 and over ; Vision Disorders/epidemiology ; Alzheimer Disease/epidemiology ; Cohort Studies ; }, abstract = {BACKGROUND AND PURPOSE: Glaucoma, a neurodegenerative optic neuropathy and leading cause of irreversible vision loss, shares vascular and neurodegenerative mechanisms with dementia. The 2024 Lancet Commission newly identified visual impairment as a modifiable dementia risk factor. As glaucoma management ranges from long-term medical therapy to laser/surgical intervention, it remains uncertain whether treatment modality influences long-term systemic outcomes such as dementia. This study compares dementia risk in patients receiving glaucoma surgery versus medical therapy.

METHODS: Glaucoma patients aged ≥ 40 years and diagnosed and managed before July 2021 were identified in the TriNetX database and followed from the first definitive treatment-surgery or initiation of medical therapy-until dementia diagnosis, death, or July 2026. The primary outcome was all-cause dementia; secondary outcomes included Alzheimer's disease, vascular dementia, and visual loss. Subgroup analyses examined surgical timing, modality, age, sex, and comorbidities.

RESULTS: After 1:1 propensity score matching, 51,923 patients were included in each cohort (mean age 64 years; 55.3% female). Glaucoma surgery was associated with reduced risks of all-cause dementia (HR 0.81) and vascular dementia (HR 0.53), a non-significant reduction in Alzheimer's disease (HR 0.87), and a higher risk of visual loss (HR 1.52), consistent with more advanced disease among surgical candidates. Associations were stronger with late surgery, traditional incisional procedures, younger age, and absence of comorbidities.

CONCLUSIONS: Patients who underwent glaucoma surgery were associated with a lower subsequent risk of all-cause dementia and vascular dementia, with a non-significant trend for Alzheimer's disease, compared with those receiving medical therapy. These findings suggest that surgical management is associated with more favourable long-term cognitive outcomes beyond ocular benefits, which may provide additional context for treatment-escalation decisions in suitable patients.}, } @article {pmid42693863, year = {2026}, author = {Chauhan, SB and Bhardwaj, A and Jain, C and Singh, I}, title = {Nano-Magnetism for Precision Neuroscience: Biohybrid Magnetoelectric Nanocarriers as Next-Generation Neural Drug Delivery Platforms.}, journal = {CNS & neurological disorders drug targets}, volume = {}, number = {}, pages = {}, doi = {10.2174/0118715273397455251030094458}, pmid = {42693863}, issn = {1996-3181}, abstract = {Neuroscience is making tremendous progress toward precision medicine, with nanotechnology playing a critical role in overcoming hurdles to successful brain medication delivery. Nano magnetism, namely biohybrid magnetoelectric nanocarriers (MENs), has emerged as a potential method for targeted and non-invasive medication delivery in neurological illnesses. These nanocarriers possess magnetoelectric properties, enabling stimulus-responsive drug release that is externally controlled. This allows for precise targeting across the blood-brain barrier (BBB), with exceptional spatial and temporal resolution. MENs can deliver neurotherapeutics deep into brain regions by combining magnetic guidance with electrical stimulation, thereby improving treatment outcomes for conditions such as Alzheimer's, Parkinson's, epilepsy, and glioblastoma. Furthermore, their biohybrid nature, which is accomplished by functionalizing nanocarriers with biocompatible coatings, peptides, or membranes produced from neural cells, increases biostability, decreases immune response, and improves neuron targeting. This review investigates the underlying concepts of magnetoelectric nanocarriers, production processes, and interactions with brain tissue. It dives deeper into recent advances in precision neural drug delivery, including the effect of external magnetic and electric fields on regulated drug release, neurostimulation, and neuromodulation. While MENs have tremendous promise, long-term biocompatibility, precise control systems, and regulatory restrictions continue to impede clinical translation. Future research should concentrate on enhancing nanocarrier design, increasing targeting efficiency, and undertaking large-scale preclinical and clinical trials. Magnetoelectric nanocarriers have the potential to transform non-invasive neurotherapeutics by bridging the gap between nano magnetism and neuroscience, resulting in safer and more successful treatment paradigms for complex brain illnesses.}, } @article {pmid42694488, year = {2026}, author = {Wang, M and Qian, Y and Huang, E and Chu, C and Gao, T and Chen, S and Zhao, N and Luo, C and Liu, Y and Zheng, X and Hu, H and Han, B and Chen, M and Mao, W and Li, W}, title = {Identification of interleukin-11 as a comorbid risk factor for prostate cancer and Alzheimer's disease using integrated bioinformatics and machine learning.}, journal = {Frontiers in immunology}, volume = {17}, number = {}, pages = {1911726}, pmid = {42694488}, issn = {1664-3224}, mesh = {Male ; *Interleukin-11/genetics/metabolism ; Humans ; *Alzheimer Disease/epidemiology/genetics/immunology/metabolism ; *Prostatic Neoplasms/epidemiology/genetics/metabolism/immunology ; *Machine Learning ; Animals ; Mice ; Risk Factors ; Computational Biology/methods ; Comorbidity ; Gene Expression Profiling ; Cell Line, Tumor ; Transcriptome ; Gene Expression Regulation, Neoplastic ; Mice, Inbred C57BL ; }, abstract = {BACKGROUND: Prostate cancer (PCa) and Alzheimer's disease (AD) are age-related disorders with a complex epidemiological association and limited therapeutic options. Identifying shared molecular drivers may reveal new treatment targets.

OBJECTIVE: To identify common transcriptomic signatures between PCa and AD and validate the role of interleukin-11 (IL11) as a functional comorbidity factor.

METHODS: Multi-cohort transcriptomic datasets (GSE48350, GSE5281 and GSE28146 for AD; TCGA-PRAD, DKFZ2018 and MSKCC for PCa) were analyzed. Differential expression analysis and weighted gene co-expression network analysis (WGCNA) were performed, followed by a two-tier machine learning pipeline (Random Forest and LASSO Cox regression) to screen overlapping genes. Immune infiltration was evaluated by CIBERSORT and single-cell transcriptomics for PCa. The functional role of IL11 was assessed in RM-1 murine and DU145 human PCa cells using colony formation, wound healing, Transwell assays, and immunocompetent C57BL/6 orthotopic and subcutaneous xenograft models. The cognitive effects of IL11 were evaluated using Morris water maze (MWM) tests, and the neuropathological changes were assessed by detecting hippocampal amyloid-β (Aβ) deposition. Additionally, a cross-sectional analysis was performed in a population cohort (n=215) to investigate the associations between IL11 levels and AD pathological biomarkers.

RESULTS: A total of 455 shared candidate genes were identified, and a 10-gene signature (NDRG4, ISG15, IL11, ENO2, DYNC1I1, DNASE1, ATP6V1G2, ATCAY, ANLN, AGAP9) was established. The risk score effectively stratified PCa patients with poor progression-free interval (log-rank P < 0.001; AUC for 1-,3-,5-year = 0.78,0.73,0.70), validated in two external cohorts (DKFZ2018, MSKCC). IL11 was the top candidate and was significantly upregulated in both diseases. High IL11 expression correlated with an immunosuppressive microenvironment, characterized by increased M2 macrophages and regulatory T cells, and with higher tumor mutation burden. Single-cell analysis localized IL11 to a subset of cancer-associated fibroblasts. In vitro, IL11 treatment enhanced PCa cell proliferation, migration, and invasion. In vivo, intraperitoneal IL11 accelerated PCa tumor growth in mice. In the MWM test, IL11-treated mice exhibited significantly longer escape latencies and fewer platform crossings, which were accompanied by increased hippocampal Aβ deposition, suggesting that IL11 induced cognitive dysfunction. Cross-sectional cohort analyses further linked higher serum IL11 to reduced CSF Aβ42 and elevated p-tau181.

CONCLUSION: IL11 acts as a shared risk factor related to PCa progression and cognitive decline in AD, representing a convergent molecular pathway and a potential therapeutic target for both age-related diseases.}, } @article {pmid42683436, year = {2026}, author = {Guth, MAS}, title = {The highest clinical trial failure rate for any disease in modern medicine: How both amyloid- and non-amyloid-targeting therapies failed to alter disease course in Alzheimer's disease.}, journal = {Free neuropathology}, volume = {7}, number = {}, pages = {22}, pmid = {42683436}, issn = {2699-4445}, abstract = {Background: Alzheimer's disease drug development has produced a 99.6 percent failure rate for disease-modifying compounds (244 compounds tested 2002-2012, one regulatory approval; Cummings et al., 2014; Cummings, 2018)-the most sustained and costly therapeutic failure in the history of modern medicine. The field's standard explanation is that the biology is intractable. The present analysis offers a different and more instructive diagnosis: the failure was not primarily scientific. It was institutional. Objective: To characterize the structural and institutional forces that sustained investment in repeatedly ineffective mechanisms of action across 567 Phase 2 and Phase 3 Alzheimer's trials from 2010 to 2026, and to determine whether peer-reviewed alternative pathogenic frameworks were available at the time each major Go/No Go decision was made. Methods: Trials were identified from ClinicalTrials.gov using the following criteria: primary diagnosis of Alzheimer's disease or mild cognitive impairment attributed to Alzheimer's disease; Phase 2 or Phase 3; status of terminated or completed; primary completion date between January 1, 2010 and May 4, 2026. After exclusion of 70 trials not classifiable by mechanism of action, a final analytic dataset of 497 trials was classified by primary mechanism using the Common Alzheimer's Disease Research Ontology (CADRO). A temporal alignment analysis was conducted for the 12 largest trials by enrollment (N ≥ 1,300), mapping each trial's initiation date against the publication dates of peer-reviewed alternative mechanistic frameworks available at the time of trial launch. Results: Amyloid-targeting approaches accounted for approximately 31 percent of the 497 classified trials, nearly all of which failed to demonstrate clinical efficacy. Among the 12 largest trials, 11 targeted amyloid pathology and 10 were terminated for futility or lack of efficacy. All 12 trials were initiated after the publication in high-impact journals of peer-reviewed alternative frameworks, including the TREM2 neuroinflammation pathway, the antimicrobial protection hypothesis, the periodontitis-associated bacterial pathogenesis hypothesis, and the GLP-1 metabolic pathways. The post-2022 period revealed that genuinely novel non-amyloid mechanisms-TREM2 agonism, GLP-1 receptor stimulation, filamin A modulation, and progranulin/sortilin restoration-also failed to produce clinical benefit at scale despite confirmed target engagement. Three establishment forces are identified as operative causes: regulatory path dependency, institutional entrenchment within grant and editorial review panels, and shareholder-driven sunk-cost pressures. Conclusion: The 567-trial record constitutes a structural verdict on a model of drug development that was never designed to solve a problem of this complexity. The uniformity of negative results across all mechanism categories-amyloid, tau, neuroinflammation, metabolic, and synaptic-points toward deeper problems of disease definition, intervention timing, and endpoint validity that institutional and financial pressures have prevented the field from confronting. The Dominantly Inherited Alzheimer Network (DIAN) biomarker data demonstrates that pathology precedes symptoms by 15-25 years; the 2025 DIAN Trials Unit (DIAN-TU) extension provides the first evidence that treatment before symptom onset may delay dementia. Prevention trials in asymptomatic at-risk populations represent the only strategy the accumulated trial record has not yet refuted.}, } @article {pmid42684813, year = {2026}, author = {Unger, RH and Rohatgi, S and Ferraciolli, SF and Kako, B and Omid-Fard, N and Imbett, REM and Dowling, T and Zhu, S and Romero, JM and Ford, JN}, title = {Real-World Challenges in the MRI Detection and Classification of Amyloid-Related Imaging Abnormalities.}, journal = {AJR. American journal of roentgenology}, volume = {}, number = {}, pages = {}, doi = {10.2214/AJR.26.35478}, pmid = {42684813}, issn = {1546-3141}, abstract = {Anti-amyloid monoclonal antibody therapies (AATs) are increasingly used for the treatment of early symptomatic Alzheimer disease. Safe implementation of AATs relies on accurate assessment for exclusionary findings on baseline brain MRI and reliable longitudinal detection of amyloid-related imaging abnormalities (ARIA), including ARIA-H (hemosiderin or hemorrhage) and ARIA-E (edema or effusion). In routine clinical practice, MRI findings encountered during baseline screening and ARIA surveillance sometimes fall into borderline or ambiguous categories that do not clearly conform to trial-defined criteria. For example, subtle or artifactual FLAIR signal abnormality, equivocal microhemorrhage counts, and overlapping features of ARIA-E and ARIA-H can create uncertainty with direct implications for treatment management. Given limited practical guidance addressing these and other gray zones, this imaging-focused review synthesizes common interpretive challenges encountered in a high-volume AAT program and offers practical management-oriented recommendations. Key issues addressed include recognizing technical factors that affect interpretation of susceptibility-weighted and FLAIR images, managing variability in lesion detection across serial examinations, and accurately reporting the temporal evolution of ARIA-related findings. As AAT use expands, recognition of the presented pitfalls can improve diagnostic confidence and help avoid misclassification of findings that may influence therapeutic decisions.}, } @article {pmid42686946, year = {2026}, author = {Trushin, S and Nguyen, TKO and Ostroot, M and Nesbitt, JJ and Kovalenko, T and Galkin, A and Nambara, T and Lu, W and Kanekiyo, T and Johnson, G and Trushina, E}, title = {Discovery and preclinical validation of a translationally optimized mitochondrial complex I modulator for Alzheimer's disease.}, journal = {npj drug discovery}, volume = {3}, number = {1}, pages = {}, pmid = {42686946}, issn = {3005-1452}, support = {23AARF-1027342/ALZ/Alzheimer's Association/United States ; U19 AG069701/AG/NIA NIH HHS/United States ; R01AG 55549//NIH/ ; }, abstract = {Alzheimer's disease (AD) is characterized by progressive metabolic failure, impaired mitochondrial function, and diminished adaptive stress responses, highlighting the need for disease-modifying therapies that restore cellular resilience rather than target downstream pathology. Here, we report the discovery and preclinical validation of C273, a translationally optimized, brain-penetrant mitochondrial complex I (mtCI) modulator developed through medicinal chemistry optimization of our first-generation compounds. C273 retained nanomolar neuroprotective activity against Aβ-induced toxicity while exhibiting favorable drug-like properties, including high oral bioavailability, efficient brain penetration, microsomal stability, minimal CYP and off-target pharmacology liabilities, and selective mild modulation of mtCI. Mechanistic studies demonstrated that C273 activated AMP-activated protein kinase (AMPK) and coordinated antioxidant, autophagic, anti-inflammatory, and mitochondrial quality-control pathways in cultured cells and mouse brain. These responses were absent in AMPKα1/α2-deficient cells, establishing AMPK as an essential mediator, while rotenone pretreatment abolished C273-mediated neuroprotection, supporting engagement of the mtCI quinone-binding site. Repeated administration to wild-type mice for 30 days produced no detectable cardiac or hepatic toxicity. Importantly, C273 activated the same neuroprotective pathways and reduced Aβ and p-Tau levels in induced pluripotent stem cell-derived cerebral organoids from patients with sporadic AD. Together, these findings establish mild modulation of mtCI as a therapeutic strategy to restore metabolic resilience and identify C273 as a promising disease-modifying candidate for AD treatment.}, } @article {pmid42687900, year = {2026}, author = {McClarty, B and Monteiro, R and Dong, H}, title = {Histone Deacetylase Inhibitors Improve Memory Function and Decrease Neuropathology in APP/PS1 Mice.}, journal = {Research square}, volume = {}, number = {}, pages = {}, doi = {10.21203/rs.3.rs-10816126/v1}, pmid = {42687900}, issn = {2693-5015}, abstract = {Although histone deacetylase (HDAC) inhibitors have shown therapeutic potential in aging and Alzheimer's disease (AD), direct comparisons of nonselective and selective HDAC inhibitors across aging and AD models are lacking. We compared the effects of the broad-spectrum HDAC inhibitor valproic acid (VPA) and the selective class I HDAC inhibitors entinostat (MS-275) and tacedinaline (CI-994) in 3-, 12-, and 18-month-old wild-type and APP/PS1 mice. Mice received 30 days of treatment, followed by a series of behavioral tests assessing different memory domains. Brain tissue was then analyzed for molecular and pathological changes. Both MS-275 and CI-994 improved recognition memory and short-term working memory in 12- and 18-month-old APP/PS1 mice, whereas only CI-994 restored long-term spatial reference memory. CI-994 increased hippocampal synapse-related gene expression and H3K9 acetylation at their promoters, consistent with improved hippocampus-dependent memory. In contrast, MS-275 enhanced synapse-related gene expression and H3K9 acetylation, in the prefrontal cortex (PFC), corresponding to improvements in recognition and working memory. MS-275 also significantly reduced amyloid plaque burden in the hippocampus and PFC, whereas both MS-275 and CI-994 decreased microglial density in APP/PS1 mice. These findings demonstrate distinct spatial and functional effects of selective HDAC inhibition in AD. CI-994 primarily targets hippocampal synaptic plasticity to improve long-term spatial memory, whereas MS-275 preferentially modulates PFC synaptic function and reduces amyloid pathology, leading to improved recognition and working memory. Together, these results identify region-specific HDAC mechanisms that differentially regulate cognitive function and AD pathology, supporting selective HDAC inhibition as a promising therapeutic strategy for AD.}, } @article {pmid42687965, year = {2026}, author = {Zeidan, HM and Shah, GH and Zeidan, IH and Samawi, HM and Jones, JA}, title = {Association between Internet Use for Health Information and Self-reported Alzheimer's Disease Diagnosis among Older Adults in the United States: Racial and Gender Disparities.}, journal = {Research square}, volume = {}, number = {}, pages = {}, doi = {10.21203/rs.3.rs-10570409/v1}, pmid = {42687965}, issn = {2693-5015}, abstract = {UNLABELLED: Background Alzheimer's disease (AD) disproportionately affects racial and ethnic minority populations, reflecting broader inequities in access to diagnosis, treatment, and long-term care. As digital health technologies become increasingly widespread, understanding whether internet use for health information is associated with Alzheimer's disease diagnosis may inform strategies to address disparities in aging populations.

AIM: This study examined the association between internet use for health or medical information and AD diagnosis among older adults in the United States and assessed whether this association varied by race/ethnicity, gender, and socioeconomic status.

SUBJECT AND METHODS: Data were drawn from Round 13 (2024) of the National Health and Aging Trends Study, a nationally representative survey of adults aged 65 years and older. Internet use for health information was assessed via self-report, binary and multivariable logistic regression models estimated adjusted odds ratios for AD diagnosis, controlling for sociodemographic characteristics.

RESULTS: Internet use for health information was significantly associated with Alzheimer's disease diagnosis. Stratified analyses by race/ethnicity and gender showed consistent patterns, although no statistically significant interaction effects were observed.

CONCLUSION: These findings suggest that digital health engagement is associated with Alzheimer's disease diagnosis among older adults and underscore the importance of equitable and culturally responsive access to digital health resources to address persistent disparities in cognitive aging.}, } @article {pmid42687999, year = {2026}, author = {Hai, H and Li, M and Hu, X and Peng, J and He, Z}, title = {Targeting cellular senescence with Traditional Chinese Medicine: advances in neurodegenerative disorder treatment.}, journal = {Frontiers in neurology}, volume = {17}, number = {}, pages = {1875385}, pmid = {42687999}, issn = {1664-2295}, mesh = {Humans ; *Cellular Senescence/drug effects/physiology ; *Neurodegenerative Diseases/drug therapy/metabolism ; *Medicine, Chinese Traditional/methods ; Animals ; *Drugs, Chinese Herbal/therapeutic use/pharmacology ; Signal Transduction/drug effects ; }, abstract = {Neurodegenerative diseases (NDDs), including Alzheimer's disease (AD), Parkinson's disease (PD), and Huntington's disease (HD), represent formidable health challenges, particularly within aging populations. Cellular senescence, marked by irreversible cell cycle arrest and the secretion of pro-inflammatory cytokines, has emerged as a crucial factor in the pathogenesis of these disorders. The accumulation of senescent cells in the nervous system exacerbates neuroinflammation, impairs neuronal function, and accelerates tissue degeneration, all of which are key features of NDDs. In this context, bioactive components derived from Traditional Chinese Medicine (TCM) have attracted significant attention for their potential to modulate cellular senescence and alleviate neurodegeneration. This review examines the shared molecular signaling pathways linking cellular senescence to NDDs, explores the mechanisms by which TCM-derived compounds-such as ginsenosides, ginkgo biloba extract, and curcumin-intervene in senescence-related processes, and discusses the translational potential of these natural compounds for clinical application.}, } @article {pmid42688139, year = {2026}, author = {Zupan, M and Prelog, PR and Kramberger, MG and Frol, S}, title = {Anti-amyloid treatment in Alzheimer disease: updated implications for patients with cerebral amyloid angiopathy and other cerebrovascular conditions.}, journal = {Frontiers in neurology}, volume = {17}, number = {}, pages = {1889769}, pmid = {42688139}, issn = {1664-2295}, mesh = {Humans ; *Cerebral Amyloid Angiopathy/drug therapy/complications ; *Alzheimer Disease/drug therapy/complications ; *Cerebrovascular Disorders/drug therapy ; *Antibodies, Monoclonal/therapeutic use ; }, abstract = {Anti-amyloid treatment (AAT) with monoclonal antibodies represents a major therapeutic advance in early Alzheimer disease (AD), but its introduction has important and underappreciated implications for vascular neurology. Because many patients with AD also have cerebral amyloid angiopathy and other cerebrovascular pathology, AAT influences stroke diagnosis, acute reperfusion therapy, and long-term antithrombotic management. Clinical trials of lecanemab and donanemab enrolled highly selected patients with minimal baseline cerebrovascular pathology, limiting generalizability to real-world populations with prevalent vascular comorbidity. Amyloid-related imaging abnormalities, particularly vasogenic edema and microhemorrhages, constitute a central safety concern and may clinically mimic acute ischemic stroke, complicating emergency decision-making and increasing the risk of inappropriate intravenous thrombolysis (IVT). Emerging reports of intracerebral hemorrhage following IVT in treated patients underscore the need for revised acute stroke pathways and support consideration of mechanical thrombectomy when otherwise indicated, although AAT-specific safety data are lacking. Beyond the hyperacute phase of stroke, concomitant use of anticoagulants or dual antiplatelet therapy raises unresolved questions regarding hemorrhagic risk, particularly in patients with atrial fibrillation or those requiring complex antithrombotic regimens. Alternative strategies, including left atrial appendage closure, may be considered in selected patients, although evidence in AAT recipients remains limited. As AAT enters routine practice, multidisciplinary collaboration, dedicated imaging protocols, and prospective safety registries will be essential to integrate disease-modifying AD treatment with safe and effective cerebrovascular care.}, } @article {pmid42688663, year = {2026}, author = {Svintozelskiy, PV and Wahlert, AJ and Harrod, C and Kay, DG and Grady, KP and Grossberg, GT}, title = {Nicotinic Acetylcholine Receptor Modulation Distinguishes Clinical Benefits of Galantamine in Alzheimer's Disease.}, journal = {Sage open aging}, volume = {12}, number = {}, pages = {30495334261485634}, pmid = {42688663}, issn = {3049-5334}, abstract = {Alzheimer's disease (AD) is the leading cause of dementia and represents a public health challenge in aging populations. Acetylcholinesterase inhibitors (AChEIs) remain first-line symptomatic therapy for mild to moderate AD, with real-world effectiveness largely influenced by tolerability, adherence, and treatment persistence. Galantamine and its inactive prodrug benzgalantamine are differentiated within the class by a dual mechanism that combines reversible acetylcholinesterase inhibition with positive allosteric modulation of nicotinic acetylcholine receptors. This narrative review synthesizes preclinical and clinical evidence examining galantamine-based therapy, with a focus on aspects related to nicotinic acetylcholine receptors: behavioral symptoms and sleep-related effects. Across randomized, observational, and longitudinal studies, galantamine has been associated with improvement or stabilization in behavioral domains including aberrant motor behavior, agitation/aggression, anxiety, apathy, delusions, disinhibition, and hallucinations. However, like other members of the AChEI class, gastrointestinal tolerability issues may affect treatment persistence. Benzgalantamine was developed to address gastrointestinal tolerability, with the aim of improving adherence and long-term treatment continuity.}, } @article {pmid42689394, year = {2026}, author = {Liu, Y and Wu, J}, title = {Low-dose N-methyl-D-aspartate protects against amyloid-β-induced neurotoxicity by suppressing the MLK3-MKK7-JNK3 pathway and activating the PI3K-PDK1-Akt pathway.}, journal = {Neuroreport}, volume = {}, number = {}, pages = {}, doi = {10.1097/WNR.0000000000002310}, pmid = {42689394}, issn = {1473-558X}, abstract = {OBJECTIVE: Oligomeric amyloid-β (Aβ) peptide-induced neuronal apoptosis is a key process in Alzheimer's disease pathogenesis. Low-dose N-methyl-D-aspartate (NMDA) has been shown to promote cell survival both in vitro and in vivo, but its effect on Aβ neurotoxicity remains largely unknown. This study aimed to investigate whether low-dose NMDA protects against Aβ-induced neurotoxicity and to elucidate the underlying molecular mechanisms.

METHODS: Primary rat cortical neurons were exposed to 10 μM Aβ25-35 to establish a neurotoxicity model. Neuronal apoptosis was assessed by 4',6-diamidino-2-phenylindole staining. The effects of low-dose NMDA (10 μM) on the PI3K-Akt and MLK3-MKK7-JNK3 signaling pathways were examined by immunoprecipitation and Western blotting. The PI3K inhibitor LY294002 was used to verify the role of PI3K signaling in NMDA-mediated regulation of the JNK3 pathway.

RESULTS: Low-dose NMDA (10 μM) significantly reduced 10 μM Aβ25-35-induced neuronal apoptosis. Mechanistically, NMDA reversed the Aβ-induced decrease in p-PDK1 and p-Akt levels and concurrently suppressed the activation of the MLK3-MKK7-JNK3 cascade. Moreover, treatment with LY294002 attenuated the inhibitory effect of NMDA on the MLK3-MKK7-JNK3 pathway.

CONCLUSION: Low-dose NMDA exerts neuroprotective effects against Aβ-induced neurotoxicity. These effects are mediated by the dual modulation of the pro-survival PI3K-PDK1-Akt pathway and the pro-apoptotic MLK3-MKK7-JNK3 pathway.}, } @article {pmid42689975, year = {2026}, author = {Pupyshev, AB and Ovsyukova, MV and Akopyan, AA and Tenditnik, MV and Korolenko, TA and Dubrovina, NI and Tikhonova, MA}, title = {Role of AMPK Signaling in the Neuroprotective Effects of Trehalose in Mice With a Pharmacological Model of Alzheimer's Disease.}, journal = {Frontiers in bioscience (Landmark edition)}, volume = {31}, number = {8}, pages = {53657}, doi = {10.31083/FBL53657}, pmid = {42689975}, issn = {2768-6698}, support = {theme no. 126020316369-9 (2026-2028)//Ministry of Science and Higher Education of the Russian Federation for the Scientific Research Institute of Neurosciences and Medicine/ ; }, mesh = {Animals ; *Alzheimer Disease/drug therapy/chemically induced/metabolism/pathology ; *Neuroprotective Agents/pharmacology ; *Trehalose/pharmacology ; Mice ; *AMP-Activated Protein Kinases/metabolism ; Disease Models, Animal ; Signal Transduction/drug effects ; Male ; Mice, Inbred C57BL ; Autophagy/drug effects ; Amyloid beta-Peptides/metabolism ; Brain/drug effects/metabolism/pathology ; Hippocampus/drug effects/metabolism ; Cognition/drug effects ; Pyrazoles ; Pyrimidines ; }, abstract = {BACKGROUND: Trehalose (TRE) has demonstrated neuroprotective potential in models of Alzheimer's disease (AD)-like pathology and has been shown to activate AMP-activated protein kinase (AMPK) and induce autophagy in hepatocytes. The molecular mechanisms underlying the neuroprotective effects of TRE in the brain, including the involvement of AMPK signaling and autophagy, remain unclear.

METHODS: AD was modeled in C57BL/6 mice by intracerebroventricular administration of the amyloid-β (Aβ) fragment Aβ(25-35). The effects of TRE treatment (a 3% water solution in drinking water for 20 days) on AD-like pathology in the brain (frontal cortex, amygdala, and hippocampus) were assessed by immunohistochemical analysis, while cognitive function was evaluated using the passive avoidance test. AMPK activation was assessed by measuring AMPK (p-AMPK) levels in the brain and by evaluating the effects of its inhibitor dorsomorphin (DM; 10 mg/kg, i.p., 20 days, every other day for 20 days).

RESULTS: Aβ-treated mice exhibited markedly increased Aβ levels and neuroinflammatory responses in the brain, whereas levels of the autophagy marker LC3-II and p-AMPK were moderately reduced. TRE markedly reduced Aβ accumulation and neuroinflammation and restored cognitive performance to levels comparable to those of the Control group; it also increased LC3-II immunoreactivity and p-AMPK levels in the hippocampus and amygdala. DM did not abolish the neuroprotective effects of TRE but moderately inhibited AMPK in the hippocampus.

CONCLUSIONS: Marked changes in brain Aβ levels and cognitive performance were not associated with either p-AMPK or autophagy marker levels, suggesting that additional mechanisms contribute to the neuroprotective effects of TRE in AD. Markers of autophagy initiation and AMPK activity responded similarly to AD modeling and TRE treatment and were positively correlated in the hippocampus, suggesting a role for AMPK in the regulation of TRE-induced hippocampal autophagy.}, } @article {pmid42690003, year = {2026}, author = {Sonkodi, B}, title = {Alzheimer's Disease, Piezo2 Channelopathy, Piezo1 Channelopathy, and the Body-Wide Piezo2 System.}, journal = {Frontiers in bioscience (Landmark edition)}, volume = {31}, number = {8}, pages = {52555}, doi = {10.31083/FBL52555}, pmid = {42690003}, issn = {2768-6698}, support = {23-2026/ HUSS_PUBL_FUND//Hungarian University of Sports Science/ ; }, mesh = {*Alzheimer Disease/metabolism/genetics/physiopathology ; *Ion Channels/metabolism/genetics ; Humans ; Animals ; *Channelopathies/metabolism/genetics ; Mice ; Phosphatidylinositol 4,5-Diphosphate/metabolism ; }, abstract = {Alzheimer's disease initiates pathophysiology in the 10 to 20 years prior to detectable clinical symptoms. A recent genetic analysis implicated the critical role of Piezo2 in Alzheimer's disease pathophysiology. A recent genetic study, involving PIEZO1 manipulation, showed that phosphatidylinositol 4,5-bisphosphate (PIP2) rectified brain capillary endothelial Piezo1 channelopathy in a mouse model of Alzheimer's disease. However, the present opinion paper posits that the initiating microdamage is in the prefrontal cortex, further upstream of pathophysiology, namely an irreversible Piezo2 channelopathy of glutamatergic terminals that is proposed to finely regulate oxytocin release resulting from stressful ultradian events, leading to impaired ultradian rhythm. The involvement of Piezo2 in the defensive arousal response reveals an underlying body-wide Piezo2 system of which the proposed prefrontal Piezo2 channelopathy is possibly a critical locus. PIP2 is emerging as a potential treatment method for Piezo channelopathy in Alzheimer's disease. However, the challenge of its more precise administration to target affected regions of the brain still remains.}, } @article {pmid42691219, year = {2026}, author = {Iqbal, T and Tabassum, S and Imran, M and Tang, S and Xiao, P and Wei, T and Hailaiti, D and Fan, P and Lu, W and Li, H and Huang, J}, title = {The Glymphatic and Meningeal Lymphatic Systems: Gatekeepers of Brain Health in Aging and Neurodegeneration.}, journal = {Aging and disease}, volume = {}, number = {}, pages = {}, doi = {10.14336/AD.2026.0009}, pmid = {42691219}, issn = {2152-5250}, abstract = {The discovery of the glymphatic system and of meningeal lymphatic vessels has substantially revised our understanding of how the central nervous system clears waste and maintains neuroimmune homeostasis. Acting in series, these two pathways remove interstitial solutes, metabolic by-products, and neurotoxic proteins such as tau and amyloid-β from the brain parenchyma and deliver them to the peripheral lymphatic system. Converging experimental and clinical evidence indicates that both pathways decline with age, and that impaired clearance contributes to the onset and progression of Alzheimer's disease, Parkinson's disease, and stroke, although the direction of causality in these associations is not yet fully resolved. In this review, we summarize current knowledge of the anatomy and physiology of the glymphatic and meningeal lymphatic systems; examine the molecular and cellular mechanisms by which their function deteriorates with age; appraise the imaging modalities and fluid biomarkers used to assess them; and evaluate the therapeutic strategies being developed to restore them. A clearer understanding of this clearance pathways may open new avenues for the treatment of age-related neurodegenerative disease.}, } @article {pmid42691804, year = {2026}, author = {Sato, S and Sasabuchi, Y and Yamana, H and Kohro, T and Yasunaga, H}, title = {Treatment Duration of Cholinesterase Inhibitor Formulations in Alzheimer's Disease.}, journal = {Journal of the American Medical Directors Association}, volume = {27}, number = {11}, pages = {106481}, doi = {10.1016/j.jamda.2026.106481}, pmid = {42691804}, issn = {1538-9375}, abstract = {OBJECTIVES: To examine treatment duration of oral and transdermal cholinesterase inhibitor formulations in older adults with severe Alzheimer's disease (AD) in routine clinical practice.

DESIGN: Retrospective population-based cohort study.

SETTING AND PARTICIPANTS: Linked medical and long-term care insurance claims databases from Tochigi Prefecture, Japan, between April 2019 and October 2023. We included patients aged ≥65 years with AD who were certified at care needs level 4 or 5 (indicating complete dependence in activities of daily living) or were institutionalized under the Japanese Long-Term Care Insurance system.

METHODS: Patients were classified according to the initial cholinesterase inhibitor formulation: oral formulations (donepezil or galantamine) or transdermal patches (rivastigmine or donepezil). The primary outcome was duration of treatment with the initial formulation. Continuous treatment was defined using a 30-day grace period. Kaplan-Meier analysis and Cox proportional hazards models were used to compare treatment discontinuation between groups. Hospitalization and mortality were evaluated as exploratory outcomes.

RESULTS: Among 8117 eligible patients, 6467 initiated oral formulations and 1650 initiated transdermal patches. Mean treatment duration was longer in the oral group than in the patch group (1.5 vs 0.6 years; log-rank P < .001). In adjusted Cox regression analysis, the patch group showed a higher risk of discontinuation than the oral group (hazard ratio, 11.3; 95% CI, 10.2-12.4). Hospitalization and mortality rates were lower in the oral group than in the patch group (236 vs 272 and 210 vs 272 per 1000 person-years, respectively).

CONCLUSIONS AND IMPLICATIONS: In older adults with severe AD, oral cholinesterase inhibitor formulations were continued substantially longer than transdermal patches. Given the limited evidence supporting prolonged cholinesterase inhibitor use in severe AD, these findings raise concerns regarding long-term prescribing practices in advanced dementia care.}, } @article {pmid42693052, year = {2026}, author = {Yu, YZ and Zhu, YH and Yang, XK and Wang, SS and Sun, JQ and Qiu, Y and Zhao, W and Yao, LM and Li, WR}, title = {[Danggui Shaoyao San promotes ketone body production and utilization to improve brain energy metabolism and prevent Alzheimer's disease].}, journal = {Zhongguo Zhong yao za zhi = Zhongguo zhongyao zazhi = China journal of Chinese materia medica}, volume = {51}, number = {15}, pages = {4377-4386}, doi = {10.19540/j.cnki.cjcmm.20260505.801}, pmid = {42693052}, issn = {1001-5302}, mesh = {Animals ; Male ; *Ketone Bodies/metabolism/biosynthesis ; *Alzheimer Disease/metabolism/prevention & control/genetics/drug therapy ; *Drugs, Chinese Herbal/administration & dosage ; *Energy Metabolism/drug effects ; *Brain/metabolism/drug effects ; Mice ; Mice, Inbred C57BL ; Humans ; }, abstract = {This study focuses on the mechanism by which Danggui Shaoyao San(DSS) regulates hepatic fatty acid metabolism to promote ketone body production, transport, and utilization, thereby alleviating brain energy metabolism disorders in APP/PS1 mice and enhancing their cognitive abilities. Six SPF-grade 3-month-old male C57BL/6J mice served as the control group. Thirty 3-month-old male APP/PS1 mice were randomly allocated into a model group, a low-dose DSS(DSS-L, 3.2 g·kg~(-1)) group, a medium-dose DSS(DSS-M, 6.4 g·kg~(-1)) group, a high-dose DSS(DSS-H, 12.8 g·kg~(-1)) group, and a ketogenic diet(KD) group. The control and model groups received 8 weeks of normal saline gavage, while the DSS-L, DSS-M, and DSS-H groups received corresponding concentrations of DSS via gavage for 8 weeks. The KD group was fed the ketogenic diet for 8 weeks. After 8 weeks of treatment, the Morris water maze test, novel object recognition test, Y-maze test, and open field test were carried out to evaluate the cognitive function, memory processing, spatial memory, and spontaneous activity and exploratory behavior, respectively. A Roche meter was used to measure the fasting blood glucose level. The β-hydroxybutyrate(BHB) and lactate levels in the liver and brain tissue were quantified by the microplate assay. The adenosine triphosphate(ATP) and adenosine diphosphate(ADP) levels were detected by chemiluminescence. ELISA was employed to measure the serum level of insulin and brain tissue levels of mitochondrial complexes Ⅰ-Ⅳ, citrate synthase(CS), isocitrate dehydrogenase(ICD), and α-ketoglutarate dehydrogenase(α-KG). Immunofluorescence assay was employed to detect the expression of monocarboxylate transporter 2(MCT2) in the hippocampus. Western blot was used to determine the expression levels of 3-hydroxy-3-methylglutaryl-coenzyme A synthase 2(HMGCS2) in the liver, as well as 3-oxoglutarate-CoA transferase(OXCT1) and 3-hydroxybutyrate dehydrogenase(BDH1) in the brain. The results showed that compared with the control group, the model group exhibited reduced time and distance in the target quadrant in the Morris water maze, weakened novel object recognition, decreased Y-maze alternation percentage, and reduced distance and average speed in the open field(P<0.01, P<0.001). Furthermore, the model group exhibited raised levels of fasting blood glucose, insulin in the serum, and lactic acid in the brain, declined level of BHB in the liver(P<0.05, P<0.01), reduced levels of mitochondrial respiratory chain complexes Ⅰ-Ⅳ, CS, ICD, α-KG, ADP and ATP in the brain tissue(P<0.01, P<0.001), down-regulated expression of HMGCS2 in the liver, OXCT1 in the cortex and hippocampus, and BDH1 in the hippocampus(P<0.05, P<0.01). Compared with the model group, the DSS groups and the KD group showed increases in time in the target quadrant, levels of BHB in the liver and brain, mitochondrial complexes Ⅰ and Ⅳ, CS, α-KG, and ATP, and expression of BDH1 in the hippocampus and OXCT1 in the cortex, and reduced levels of fasting blood glucose, insulin in the serum, and lactate in the brain(P<0.05, P<0.01). All the DSS groups exhibited increased average speed in the open field test(P<0.05, P<0.01). The distance in the target quadrant, levels of mitochondrial complexes Ⅱ and Ⅲ, ICD, and ADP, and expression of BDH1 in the cortex increased in the DSS-M, DSS-H, and KD groups(P<0.05, P<0.01). The novel object recognition index and HMGCS2 expression in the liver raised in the DSS-L, DSS-H, and KD groups(P<0.05, P<0.01). The total distance traveled in the open field test increased in the DSS-L, DSS-M, and KD groups(P<0.05, P<0.01). The percentage of alternation in the Y-maze test and MCT2 expression level in the DG region increased in the KD group(P<0.05). In addition, the OXCT1 expression level in the hippocampus was up-regulated in the DSS-H and KD groups(P<0.05, P<0.01). DSS can promote the generation of ketone bodies in the liver and the transport and utilization of ketone bodies in the brain tissue, thereby alleviating the brain energy crisis and cognitive impairment of APP/PS1 mice.}, } @article {pmid42678603, year = {2026}, author = {Hey, JA and Abushakra, S and Power, A and Watson, D and Porsteinsson, A and Sabbagh, M and MacSweeney, E and Cohen, S and Boada, M and Doraiswamy, PM and Elahi, FM and Rissman, RA and Liang, E and Flint, S and Hristova, E and Kesslak, P and McLaine, R and Albayrak, A and Schaefer, JF and Yu, JY and Tolar, L and Tolar, M}, title = {Plasma Biomarker Effects of Oral Valiltramiprosate/ALZ-801 in Early Alzheimer's Disease from Phase 3 and Phase 2 Trials: Analysis of Core Biomarkers and Correlations with Clinical and Neuroimaging Outcomes.}, journal = {Drugs}, volume = {}, number = {}, pages = {}, pmid = {42678603}, issn = {1179-1950}, abstract = {BACKGROUND: Alzheimer's disease (AD) is a progressive neurodegenerative disorder with few treatment options, especially for APOE4/4 homozygotes who carry high genetic risk. Valiltramiprosate/ALZ-801 is an oral small-molecule inhibitor of amyloid-beta oligomer formation in late-stage development as a disease-modifying therapy for AD. A recent Phase 3 trial did not meet its primary clinical endpoint in the overall population, but demonstrated significant benefits in cognition, function, and brain volumetric MRI (vMRI) in the prespecified subgroup with mild cognitive impairment (MCI). Here, we report plasma p-tau217, p-tau217/Aβ42, and neurofilament light chain (NfL) results from the Phase 3 trial, along with 4-year fluid biomarker data from the Phase 2 study in APOE4 carriers with early AD.

METHODS: The 78-week, APOLLOE4 Phase 3 trial randomized APOE4/4 homozygotes to placebo (n = 162) or valiltramiprosate 265 mg BID (n = 163). The Phase 2 trial was an open-label biomarker study in APOE4 carriers with early AD who received valiltramiprosate 265 mg BID (N = 84) for 104 weeks, followed by a 2-year extension on the same regimen. Plasma p-tau217 and p-tau217/Aβ42 were measured every 6 months in both trials using FDA-approved Fujirebio Lumipulse G assay. Plasma NfL was measured in the Phase 3 trial using the Simoa assay. Associations between plasma biomarkers and clinical or vMRI outcomes were assessed using Spearman's correlation. Data are reported separately by study.

RESULTS: Baseline plasma p-tau217/Aβ42 confirmed amyloid positivity in 94% of 294 Phase 3 APOE4/4 subjects, including 91% of those with MCI, as well as in 97% of 80 Phase 2 subjects. In the overall Phase 3 population, valiltramiprosate significantly reduced plasma p-tau217 compared with placebo at weeks 26, 52, and 78 (all p < 0.025, observed values). A similar effect was seen in the Phase 3 MCI subgroup (p < 0.05 at weeks 52 and 78), whereas the Mild AD subgroup showed only a numerical trend. In observed case analyses of MCI subjects, plasma p-tau217 decreased by 36% from baseline with valiltramiprosate and increased by 17% with placebo. In the same subgroup, the p-tau217/Aβ42 ratio decreased by 40% with valiltramiprosate and increased by 7% with placebo. Among Phase 3 MCI subjects, week 78 reductions in p-tau217 correlated significantly with improvements in ADAS-Cog13 (r = 0.276, p = 0.039), CDR-SB (r = 0.377, p = 0.005), hippocampal volume (r = - 0.353, p = 0.013), cortical thickness (r = - 0.337, p = 0.018), and whole brain volume (r = - 0.312, p = 0.029). Plasma NfL was also significantly lower with valiltramiprosate than placebo at week 78 in MCI subjects (p = 0.032). NfL stability over 78 weeks correlated significantly with improvements in ADAS-Cog13 (r = 0.29, p = 0.03) and hippocampal volume (r = - 0.282, p = 0.047), and with reductions in p-tau217 (r = 0.42, p = 0.001). In Phase 2 APOE4 carriers, valiltramiprosate-induced reductions in plasma p-tau217 were sustained over 4 years and remained significantly lower in both MCI APOE4 carriers and heterozygotes than in the Phase 3 APOE4/4 MCI placebo group at weeks 26, 52, and 78 (all p < 0.001).

CONCLUSIONS: Valiltramiprosate 265 mg BID produced early and sustained reductions in plasma p-tau217 and p-tau217/Aβ42 in APOE4 homozygotes and carriers with MCI. In Phase 3 MCI subjects, drug effects on both p-tau217 and NfL correlated significantly with clinical and vMRI benefits, and the two biomarkers were also significantly correlated with each other. These findings suggest that valiltramiprosate engages its central target, thereby reducing Aβ aggregation, tau hyperphosphorylation, and downstream neurodegeneration. The consistent associations of plasma p-tau217 and NfL changes with positive clinical and vMRI outcomes in MCI indicate that the pharmacodynamic biomarker response reflects broader disease-modifying biological effects and are consistent with valiltramiprosate's mode of action. Together with the previously reported favorable safety and absence of increased ARIA-E risk, these biomarker findings and their clinical correlations support the promising benefit-risk profile of valiltramiprosate in APOE4/4 MCI patients.

CLINICAL TRIAL REGISTRY: NCT04770220 and NCT04693520.}, } @article {pmid42678693, year = {2026}, author = {Zhang, Q and Zhou, Q and Yang, M and Zou, S and Li, Y and Wang, Z}, title = {Non-pharmacological interventions for sleep improvement in Alzheimer's disease: A systematic review and meta-analysis.}, journal = {Journal of Alzheimer's disease : JAD}, volume = {}, number = {}, pages = {13872877261480066}, doi = {10.1177/13872877261480066}, pmid = {42678693}, issn = {1875-8908}, abstract = {BackgroundSleep disturbances are common in Alzheimer's disease (AD) and may worsen neuropsychiatric symptoms, caregiver burden, quality of life, and disease progression. Non-pharmacological strategies are increasingly used because long-term hypnotic or antipsychotic treatment may be limited by safety concerns, but their effects on subjective and objective sleep outcomes remain uncertain.ObjectiveTo evaluate the efficacy of non-pharmacological interventions for improving sleep in patients with AD.MethodsFollowing PRISMA guidelines, we searched PubMed, Embase, the Cochrane Library, Web of Science, and CINAHL through June 6, 2025, for randomized controlled trials of non-pharmacological interventions in AD. The primary outcome was the Pittsburgh Sleep Quality Index (PSQI); secondary outcomes were actigraphy-derived sleep efficiency, total sleep time, wake after sleep onset, number of awakenings, and time in bed. Standardized mean differences were pooled using fixed- or random-effects models. Subgroup, sensitivity, publication-bias, and meta-regression analyses were performed where appropriate.ResultsFourteen randomized controlled trials comprising 937 participants were included. Non-pharmacological interventions significantly reduced PSQI scores (SMD = -0.46, 95% CI -0.70 to -0.21). Neuromodulation-based interventions showed potentially favorable effects on PSQI, and caregiver-delivered programs such as NITE-AD modestly reduced nocturnal awakenings. No significant effects were observed for sleep efficiency, total sleep time, wake after sleep onset, or time in bed.ConclusionsNon-pharmacological interventions may modestly improve subjective sleep quality in AD, but objective sleep benefits remain limited. Larger, multicenter trials with standardized protocols, longer follow-up, harmonized subjective and objective outcomes, and AD-related biomarker assessment are needed.}, } @article {pmid42678698, year = {2026}, author = {Luster, CB and Nowinski, CJ and Abdolmohammadi, B and Feigel, ED and Mastrodicasa, MJ and Finegan, B and Goldstein, L and Katz, DI and Cantu, RC and Dwyer, B and Tripodis, Y and Stein, TD and Alosco, ML and McKee, AC and Mez, J and Daneshvar, DH}, title = {Neurodegenerative Disease Death Certification Among National Football League Players With Dementia.}, journal = {JAMA network open}, volume = {9}, number = {9}, pages = {e2631614}, pmid = {42678698}, issn = {2574-3805}, mesh = {Humans ; Male ; *Dementia/mortality ; *Death Certificates ; *Football/statistics & numerical data ; *Neurodegenerative Diseases/mortality ; Aged ; Retrospective Studies ; Middle Aged ; United States/epidemiology ; *Athletes/statistics & numerical data ; Cohort Studies ; }, abstract = {IMPORTANCE: Researchers frequently use death certificate data to evaluate occupational risks among National Football League (NFL) players, demonstrating elevated neurodegenerative mortality risk. Robust epidemiologic data suggest deaths attributable to neurodegenerative disease (NDD) are frequently underreported on death certificates, leading to substantial underascertainment of neurodegenerative mortality. Better characterization of the factors underlying neurodegenerative death certification is critical to addressing underreporting of NDDs, informing disease surveillance and resource allocation.

OBJECTIVE: To elucidate clinical, exposure, and neuropathologic factors associated with neurodegenerative death certification.

This cohort study included 202 brain donors with clinician-adjudicated dementia who underwent postmortem neuropathologic assessment and retrospective clinical assessment with informants from February 15, 2008, to December 30, 2021, to ascertain clinical and lifetime exposure history. Statistical analysis was performed from October 2025 to June 2026.

EXPOSURE: NFL career.

MAIN OUTCOMES AND MEASURES: Neuropathologic diagnosis based on established diagnostic criteria, as well as informant-reported clinical measures and exposure history. Multiple logistic regression analysis was conducted to examine the association between factors and NDD death certification, adjusted for age at death, race and ethnicity, and educational level.

RESULTS: Of 202 male brain donors (mean [SD] age at death, 73.1 [10.5] years) with clinician-adjudicated dementia, 62 (30.7%) had a neurodegenerative underlying cause of death listed on their death certificate. Behavior Rating Inventory of Executive Function-Adult Version (BRIEF-A) Global Executive Composite T-score (odds ratio [OR], 1.04; 95% CI, 1.01-1.06), BRIEF-A Metacognition Index T-score (OR, 1.03; 95% CI, 1.01-1.06), Cognitive Difficulties Scale score (OR, 1.02; 95% CI, 1.01-1.03), and Functional Activities Questionnaire score (OR, 1.13; 95% CI, 1.06-1.21), as well as a history of emergency department treatment for head injury (OR, 4.11; 95% CI, 1.72-9.82), were associated with increased odds of neurodegenerative death certification. High Alzheimer disease neuropathology (OR, 5.27; 95% CI, 1.93-14.40), frontotemporal lobar degeneration (OR, 4.48; 95% CI, 1.61-12.50), Braak stage IV to VI (OR, 2.99; 95% CI, 1.54-5.79), frequent diffuse plaques (OR, 4.21; 95% CI, 1.56-11.38), moderate to severe neuritic plaques (OR, 3.42; 95% CI, 1.55-7.54), and Thal phase 4 (OR, 4.50; 95% CI, 1.39-14.60) were associated with increased odds of neurodegenerative death certification.

CONCLUSIONS AND RELEVANCE: This cohort study found that only 30.7% of brain donors with clinician-adjudicated dementia had neurodegenerative death certification. These results add to growing evidence of frequent NDD underascertainment where more severe disease is associated with neurodegenerative death certification, offering insight into factors that must be considered when using death certificate data to assess NDD burden. Factors such as worsened executive functioning and cognitive symptoms, greater functional impairment, and more severe neuropathology may be associated with an increased likelihood of neurodegenerative death certification among NFL players.}, } @article {pmid42679930, year = {2026}, author = {Kılınç, S and Yılmaz, ŞG and Bozkurt, AS and Balcı, SO}, title = {Bovine lactoferrin can reduce Aβ /TAU accumulation in two major pathological Alzheimer's Disease rat models.}, journal = {Behavioural brain research}, volume = {}, number = {}, pages = {116453}, doi = {10.1016/j.bbr.2026.116453}, pmid = {42679930}, issn = {1872-7549}, abstract = {INTRODUCTION: Alzheimer's disease (AD) is a neurodegenerative disease characterized by progressive cognitive decline. Bovine lactoferrin (bLf) is an iron-binding protein with immunomodulatory effects both in the intestine and throughout the body. In this study, the potential therapeutic effects of bLf were evaluated using two different rat models that mimic key aspects of AD pathology.

METHOD: Forty-two female Wistar albino rats (10-12 weeks old, weighing 200-250g) were included in the study and randomly assigned to 7 groups of 6 rats each. The groups were: 1- Control, 2- Phosphate-buffered saline (PBS), 3- bLf, 4- Colchicine (COL) (for the TAU model), 5- Okadaic acid (OKA) (for the Aβ model), 6- COL + bLf, 7- OKA + bLf. Cognitive deficits were tested using the Morris Water Maze (MWM). Motor coordination and anxiety levels were assessed using the OFT. Following these assessments, cerebrospinal fluid (CSF), hippocampal tissue, serum, and whole blood samples were collected. Aβ, TAU, Ferritin, TAS, and TOS levels in these samples were measured using ELISA. For genetic modulation, the gene expression patterns of Fpn, Bax, Bcl-2, p38, FoxO, and GSK-3β were analyzed by quantitative Real-Time PCR (qRT-PCR).

RESULTS: bLf reduced oxidative stress. Decreases in Aβ and TAU levels were observed in the hippocampus and CSF. Ferritin levels were relatively lower in the hippocampus, CSF, and serum. Fpn and Bcl-2 were downregulated in the hippocampus of AD models but upregulated after bLf treatment. Expression levels of Bax, p38, FoxO, and GSK-3β were also downregulated following bLf administration.

CONCLUSION: These findings were consistent across both models. Overall, bLf holds promise as a therapeutic candidate capable of simultaneously targeting two key pathological features of AD.}, } @article {pmid42680070, year = {2026}, author = {Wang, J and Luo, L and Zhang, J and Yu, L and Cui, L}, title = {The gut microbiota and gut-brain axis in Alzheimer's disease: From pathogenesis to treatment.}, journal = {Ageing research reviews}, volume = {122}, number = {}, pages = {103345}, doi = {10.1016/j.arr.2026.103345}, pmid = {42680070}, issn = {1872-9649}, abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder whose pathological course involves amyloid-β (Aβ) deposition, tau abnormalities, neuroinflammation, and neurovascular dysfunction. Interest in the microbiota-gut-brain axis does not arise because gut dysbiosis has been established as an independent initiating cause of sporadic AD, but because this axis connects modifiable peripheral factors-including diet, medication, ageing, and intestinal physiology-with barrier homeostasis, immunometabolic state, neural afferent signaling, and the brain's response to pathology. Human studies have detected microbiota differences in biomarker-positive preclinical AD and suggest that barrier abnormalities may be associated with subsequent cognitive change; patient-derived microbiota transfer, APOE-dependent tau models, and immune-vagal circuit studies further support phenotype modifiability under defined experimental conditions. This review therefore integrates barrier, immune, metabolic, and neural pathways and emphasizes that diverse microbial alterations may converge on a limited set of measurable functional nodes that could be more informative than individual genera for mechanistic validation, risk stratification, and treatment monitoring. Although clinical intervention evidence remains at an early stage, the peripheral accessibility and modifiability of the microbiota provide a rationale for investigating it as an adjunctive target alongside standard AD therapy. Future work should concurrently evaluate the microbiome, metabolites, both barriers, and immune and neural readouts in longitudinal cohorts and stratified randomized trials to determine which patients, disease stages, and intervention modalities are most likely to benefit.}, } @article {pmid42680110, year = {2026}, author = {Nie, T and Li, J and Tan, S and Chen, S and Yang, D and Nepovimova, E and Wu, Q and Kuca, K}, title = {T-2 toxin disrupts Alzheimer's-relevant App/Tau homeostasis via circadian-p53-senescence crosstalk: Evidence from human neuroblastoma cells.}, journal = {Neurotoxicology}, volume = {117}, number = {}, pages = {103559}, doi = {10.1016/j.neuro.2026.103559}, pmid = {42680110}, issn = {1872-9711}, abstract = {Environmental mycotoxins are pervasive exposures, yet how they perturb Alzheimer's disease (AD)-relevant proteostasis remains unclear. We treated SH-SY5Y cells with low-dose T-2 toxin (6 nM) for 24 h, and profiled AD-relevant protein changes alongside transcriptomic, circadian, and senescence-related readouts. We report that T‑2 toxin remodels APP and Tau homeostasis, featuring an early decrease in full‑length APP and a delayed, sustained increase in Tau phosphorylation and total Tau, accompanied by dynamic cytokine release. RNA‑seq at 12 h revealed a p53‑centered stress response and enrichment of circadian‑related pathways. Cosinor analysis indicated that CLOCK rhythmicity is preserved but reparameterized following T-2 toxin exposure, with a marked phase shift and an elevated mesor. Pharmacological disruption of CLOCK attenuated p53 induction and Tau elevation, whereas inhibition of p53 partially restored APP and reduced Tau changes while reshaping CLOCK abundance and localization, consistent with CLOCK-p53 cross‑regulation. T‑2 toxin also induced a time‑dependent senescence‑like phenotype that was attenuated by CLOCK and/or p53 inhibition. Post‑treatment with senolytic drugs dasatinib and quercetin reduced SA‑β‑gal burden, dampened p53 signaling, and improved the APP/Tau profile. Together, these data link T‑2 toxin exposure to AD‑relevant proteostasis remodeling through a CLOCK-p53-senescence axis and suggest circadian and senescence‑targeting strategies as complementary intervention points.}, } @article {pmid42680930, year = {2026}, author = {Ballard, C and Doherty, P and Ismail, Z and Corbett, A and Cummings, JL}, title = {Symptomatic treatment for Alzheimer disease: current evidence and future directions.}, journal = {Nature reviews. Neurology}, volume = {}, number = {}, pages = {}, pmid = {42680930}, issn = {1759-4766}, abstract = {Symptomatic treatment remains central to the clinical management of Alzheimer disease (AD), even as disease-targeted therapies emerge. This Review synthesizes current evidence for pharmacological and non-pharmacological symptomatic therapies targeting cognition, function and neuropsychiatric symptoms in AD. Non-pharmacological interventions, including cognitive training, physical exercise, cognitive stimulation therapy and multimodal lifestyle programmes, show small-to-moderate benefits, particularly in mild cognitive impairment, although implementation challenges persist. Established pharmacological treatments, notably cholinesterase inhibitors and memantine, deliver modest but significant benefits, with biomarker-stratified analyses suggesting the greatest benefit in individuals with confirmed AD pathology. Advances in muscarinic agonists, multitarget agents, neurotrophic modulators and repurposed drugs highlight emerging opportunities for broader symptomatic benefit. Neuropsychiatric symptoms remain highly prevalent and burdensome; personalized psychosocial interventions demonstrate meaningful reductions in agitation and depression, whereas atypical antipsychotics offer only modest efficacy with substantial safety concerns. Newer agents, including brexpiprazole for agitation and pimavanserin for psychosis, show promise but require careful interpretation of effect size and safety. Future progress will depend on biomarker-informed patient selection, integration of circuit-level measures, rational combination strategies spanning pharmacological and non-pharmacological modalities, and adoption of patient-centred outcomes. Symptomatic therapies will remain essential for improving quality of life in people with AD, even as disease-targeted therapies reshape disease trajectories.}, } @article {pmid42682011, year = {2026}, author = {Yang, Q and Chen, Z and Zhu, J and Chai, T and Tang, F and Fan, M and Li, Y and Chen, S and Liu, Y and Zheng, M}, title = {Brain-Targeting siRNA Delivery to Tackle Alzheimer's Disease.}, journal = {Wiley interdisciplinary reviews. Nanomedicine and nanobiotechnology}, volume = {18}, number = {5}, pages = {e70076}, pmid = {42682011}, issn = {1939-0041}, support = {25IRTSTHN032//Program of Technology Innovation Team of the Colleges and Universities of Henan Province/ ; SBGJ202503048//the Henan Provincial Medical Science and Technology Research Program, Joint Provincial-Ministerial Project, the Henan Provincial Health Commission/ ; 2025M780051//the China Postdoctoral Science Foundation/ ; 32601935//National Natural Science Foundation of China/ ; }, mesh = {Humans ; *Alzheimer Disease/therapy ; *RNA, Small Interfering/therapeutic use/administration & dosage/metabolism ; *Brain/metabolism ; Animals ; }, abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder that places an increasing burden on patients, caregivers, and healthcare systems worldwide. Current disease-modifying therapies (DMTs) are limited by high costs, complex administration, and reliance on advanced biomarker infrastructure, highlighting the shortcomings of existing treatment paradigms. These limitations have sparked growing interest in gene- and nucleic acid-based interventions as upstream strategies to modify AD pathogenesis. Among these, small interfering RNA (siRNA) is especially compelling because it can be rationally programmed, directed at multiple molecular pathways, and paired with rapidly evolving delivery technologies. However, the clinical translation of siRNA therapies for AD is still constrained by challenges in brain-targeted delivery, safety, and sustained efficacy. In this review, we summarize current concepts in AD pathology, highlight recent clinical and translational advances, and critically assess emerging brain-targeted siRNA delivery platforms and their key bottlenecks. Within a precision-medicine framework, brain-targeted siRNA offers the possibility of aligning patient selection, molecular targets, and delivery strategies with biomarker-defined AD endotypes. We discuss both the therapeutic promise and the realistic limitations of siRNA-based approaches for AD, outline priorities for future development, and identify key gaps that must be addressed to enable meaningful clinical implementation.}, } @article {pmid42682321, year = {2026}, author = {Chen, L and Sun, H and Fang, MJ and Cheng, N and Xu, Y}, title = {Proteome-wide genetic study identified therapeutic targets for early-onset and late-onset Alzheimer's disease.}, journal = {International journal of surgery (London, England)}, volume = {112}, number = {6}, pages = {12666-12678}, pmid = {42682321}, issn = {1743-9159}, abstract = {BACKGROUNDS: Given the distinct pathogenic mechanisms of early-onset Alzheimer's disease (EOAD) and late-onset Alzheimer's disease (LOAD), identifying disease-specific therapeutic targets for each subtype is particularly critical.

METHODS: We performed proteome-wide Mendelian randomization (MR), colocalization analysis, summary-data-based MR, and Heterogeneity in Dependent Instruments (HEIDI) tests to identify the causal roles of candidate proteins in EOAD and LOAD. Further analyses included protein-protein interaction network analysis, GO/KEGG enrichment analyses, and single-cell RNA sequencing annotation. Druggability evaluation of the target proteins, Phenome-wide association study was conducted to systematically evaluate the potential adverse effects associated with druggable proteins. High-throughput molecular docking and molecular dynamics simulations were conducted to target the top therapeutic targets.

RESULTS: Genetically predicted levels of three proteins (APOE, NECTIN2, and PVR) were associated with EOAD risk, nine proteins (APOE, NECTIN2, PVR, EPHB4, SEMA3F, RNASET2, BTN1A1, PSAPL1, and GRN) were associated with LOAD risk, three proteins (APOE, NECTIN2, and PVR) were colocalized with EOAD, and six proteins (APOE, NECTIN2, PVR, SEMA3F, BTN1A1, and EPHB4) were colocalized with LOAD. Three of the proteins (APOE, NECTIN2, and PVR) serve as common targets for both EOAD and LOAD. EPHB4 and BTN1A1 were prioritized for LOAD with the most convincing evidence. The small molecule cucurbit[8]uril exhibits excellent binding affinity with both EPHB4 and BTN1A1 target proteins for the treatment of Alzheimer's disease.

CONCLUSIONS: This study pinpointed APOE, NECTIN2, and PVR as shared therapeutic targets for EOAD and LOAD, and EPHB4 and BTN1A1 singled out as a priority target for LOAD.}, } @article {pmid42682633, year = {2026}, author = {Yang, Z and Zeng, Y and Deng, J and Zhang, S and Xue, J and Li, Q and Feng, Y and Zeng, Y}, title = {Integrated metabolomics and mass spectrometry imaging reveal the Anti-Alzheimer's mechanisms of turmeric and curcumin.}, journal = {Frontiers in cell and developmental biology}, volume = {14}, number = {}, pages = {1895521}, pmid = {42682633}, issn = {2296-634X}, abstract = {INTRODUCTION: Turmeric and its major bioactive component, curcumin, have shown promising potential in the prevention and management of Alzheimer's disease (AD). However, the underlying molecular mechanisms and the contribution of turmeric residues remain incompletely understood. This study aimed to investigate the protective effects of curcumin and turmeric residue in an Aβ1-42-induced AD mouse model and to elucidate their metabolic regulatory mechanisms.

METHODS: The phytochemical profiles of turmeric and turmeric residue were characterized using UPLC-MS/MS combined with bioinformatics analysis. An Aβ1-42-induced AD mouse model was established, and mass spectrometry imaging (AFAI-MSI) was applied to determine the optimal modeling time point. The therapeutic effects of curcumin and turmeric residue were evaluated through behavioral assessments, including the Morris water maze test, as well as histopathological and molecular analyses involving H&E staining, Nissl staining, immunofluorescence, and immunohistochemistry. Furthermore, non-targeted metabolomics was performed to identify metabolic alterations associated with treatment.

RESULTS: UPLC -MS/MS analysis identified 132 and 104 compounds in turmeric and turmeric residue, respectively, with 10 compounds showing significant differences in abundance between the two materials. AFAI-MSI analysis indicated that three weeks after Aβ1-42 injection represented an optimal time point for AD model establishment. Behavioral experiments demonstrated that both curcumin and turmeric residue significantly improved spatial learning and memory impairment in AD mice. Histological and molecular analyses revealed reduced neuronal damage and modulation of Aβ1-42 and Iba-1 expression in brain tissues. Metabolomic profiling identified 25 differential plasma metabolites and 38 differential brain metabolites following treatment. Pathway enrichment analysis suggested that these metabolic alterations were mainly associated with ether lipid, sphingolipid, glycerophospholipid, glutamate, purine, and arachidonic acid metabolism.

DISCUSSION: These findings demonstrate that curcumin and turmeric residue exert neuroprotective effects against AD-related pathological alterations by regulating metabolic disturbances and restoring metabolite homeostasis. The integration of chemical profiling, AFAI-MSI, and metabolomics provides new insights into the therapeutic potential and metabolic mechanisms of turmeric-derived resources in Alzheimer's disease.}, } @article {pmid42682864, year = {2026}, author = {Li, L and Ding, G and Zhang, L and Luo, H and Boyd, E and Li, Q and Kaur, J and Bohara, M and Chopp, M and Zhang, ZG and Jiang, Q}, title = {Imaging the therapeutic effects of cerebral endothelial cell derived exosome treatment of a preclinical model of Alzheimer's disease.}, journal = {Frontiers in aging neuroscience}, volume = {18}, number = {}, pages = {1788077}, pmid = {42682864}, issn = {1663-4365}, abstract = {BACKGROUND: Alzheimer's disease (AD) is characterized by the excessive accumulation of select proteins in the brain, associated with altered vascular function, glymphatic transport, cerebrospinal fluid (CSF) dynamics, and cerebral microstructure. Exosomes derived from cerebral endothelial cells (CEC-Exo) have been demonstrated to reduce vascular dysfunction, which may beneficially impact perivascular glymphatic clearance, and potentially, protein aggregates and the corresponding microstructural disruption.

METHODS: We investigated the effect of CEC-Exo therapy on AD by assessing glymphatic transport, CSF motion, and microstructural integrity using magnetic resonance imaging (MRI), and measuring cognitive performance. TgF344-AD rats, at 12-months of age, were randomly treated with CEC-Exo (1×10[11] particles/intravenous injection) or saline twice-weekly for four consecutive weeks. MRI measurements, including dynamic 3D T1-weighted imaging with contrast agent and diffusion MRI (dMRI) with multiple b-values, were conducted for all rats at 13-months. Glymphatic function was evaluated with tracer-induced time signal curve (TSC), while microstructural state and CSF motion were assessed with parameters derived from dMRI acquired at high (dMRIhigh-b) and low (dMRIlow-b) b-values, respectively. Cognitive performance was assessed by the Morris water maze (MWM) test.

RESULTS: TSCs demonstrated significantly higher peak values in the olfactory bulb and whole brain in the CEC-Exo-treated group than in the saline-treated group. With the CEC-Exo treatment, a significantly increased MDlow-b, a measure of pseudorandom CSF motion derived from dMRIlow-b, was observed in the representative CSF-filled space. As revealed by dMRIhigh-b-derived parameters, CEC-Exo treatment resulted in significantly elevated axonal water fraction, fractional anisotropy, and Kurtosis in white matter, as well as significantly reduced mean diffusivity, axial diffusivity, and radial diffusivity in both white and gray matter in the AD brain. In the MWM test, CEC-Exo-treated rats spent a significantly greater percentage of time in the correct quadrant than did saline-treated rats.

CONCLUSION: CEC-Exo treatment preserved glymphatic transport, CSF motion, and microstructural integrity in the AD brain, accompanied by a reduced cognitive decline. With a global therapeutic impact, the CEC-Exo therapy provides a novel strategy on the treatment of AD. Our data support the value of dMRIlow-b as a clinically feasible imaging tool for assessing alterations in CSF dynamics that mediate perivascular glymphatic clearance.}, } @article {pmid42683384, year = {2026}, author = {Liu, J and Xu, C and Wang, Y and Zhang, J and Hui, R and Lv, W and Xu, A and Dang, Y and Su, S and Zhao, H and Gao, Y and Zhang, J}, title = {From amyloid PET to plasma biomarkers: A multimodal imaging framework for early diagnosis and staging of Alzheimer's disease.}, journal = {Alzheimer's & dementia (Amsterdam, Netherlands)}, volume = {18}, number = {3}, pages = {e70463}, pmid = {42683384}, issn = {2352-8729}, abstract = {INTRODUCTION: Alzheimer's disease (AD) is biologically defined by amyloid beta and tau pathology. Available biomarkers enable early diagnosis but differ in targets, accessibility, and utility. This review synthesizes evidence for plasma biomarkers, magnetic resonance imaging (MRI), and positron emission tomography (PET) to develop a pragmatic, stage-aware framework for early diagnosis and staging.

METHODS: We conducted a narrative review of recent literature and professional guidance (2024-2026) covering plasma biomarkers; structural/functional MRI; and amyloid, tau, and fluorodeoxyglucose (FDG) PET. Evidence was organized by biological target, diagnostic role, disease stage, and intended-use population.

RESULTS: For symptomatic individuals, high-performance plasma biomarkers (especially phosphorylated tau at threonine 217 [p-tau217]) support scalable triage and biological enrichment. MRI provides anatomical, differential-diagnostic, and treatment-safety information. Amyloid PET offers biological confirmation; tau PET adds regional staging and prognosis; FDG PET characterizes synaptic dysfunction and distinguishes dementia patterns. Emerging endogenously cleaved microtubule-binding region tau containing residue 243 (eMTBR-tau243) and brain-derived p-tau217 remain investigational. In cognitively unimpaired at-risk individuals, routine screening is not implied; use is for research or trial enrichment.

DISCUSSION: The preferred pathway is sequential: clinical evaluation and MRI establish context, validated plasma tests guide referral, and PET resolves uncertainty or refines staging when results may change management. This resource-aware integration improves diagnostic specificity and treatment decisions. Prospective implementation studies are needed to validate thresholds and equitable performance across diverse settings.}, } @article {pmid42676482, year = {2026}, author = {Ren, X and Jin, X and Li, L and Li, F}, title = {Direct toll-like receptor 4 inhibition in Alzheimer's disease models: a focused scoping review of inflammatory, amyloid-handling, and functional outcomes.}, journal = {Frontiers in aging neuroscience}, volume = {18}, number = {}, pages = {1889254}, pmid = {42676482}, issn = {1663-4365}, abstract = {OBJECTIVE: This focused scoping review evaluated whether direct toll-like receptor 4 (TLR4) inhibition, antagonism, or genetic suppression in Alzheimer's disease (AD)-related models was associated with concordant inflammatory, amyloid-β (Aβ)-handling, and functional outcomes.

METHODS: Original AD- or Aβ-related animal, cellular, and ex vivo studies were eligible when they directly inhibited, antagonized, or genetically suppressed TLR4 signaling using pharmacological approaches, including TAK-242/CLI-095/resatorvid, IAXO-101, RSLA, or related TLR4-targeting strategies, or genetic approaches such as TLR4 siRNA, knockdown, knockout, or loss-of-function mutation. Evidence was synthesized using a three-layer framework comprising inflammatory activation, Aβ handling, and neuronal, synaptic, or behavioral consequences.

RESULTS: Direct TLR4 suppression generally attenuated target-proximal inflammatory activation, including microglial activation, pro-inflammatory mediator expression, NF-κB signaling, NLRP3 inflammasome activation, and reactive microglial phenotypes. In contrast, amyloid-related and functional outcomes were heterogeneous. Some studies reported reduced Aβ pathology, enhanced phagocytosis, synaptic protection, or cognitive improvement, whereas others showed impaired amyloid clearance, increased Aβ deposition, or worsened memory-related outcomes. APOE genotype, sex, treatment window, model system, Aβ species, and intervention type appeared to modify the direction of downstream effects.

CONCLUSION: Toll-like receptor 4 suppression relatively consistently attenuated inflammatory readouts, whereas amyloid-related and functional outcomes remained heterogeneous, supporting an exploratory, hypothesis-generating model of context-dependent inflammatory-amyloid-functional dissociation rather than a uniform therapeutic benefit.}, } @article {pmid42676794, year = {2026}, author = {Cui, X and Wei, Z and Wang, Q and Du, S and Lin, Z and Chen, Z and Zhang, J and Li, C and Tang, L and Dai, X and He, W}, title = {Astragalus polysaccharide alleviates neuropathology and cognitive deficits by modulating gut microbiota and neuroinflammation in an Alzheimer's disease model.}, journal = {Frontiers in pharmacology}, volume = {17}, number = {}, pages = {1830927}, pmid = {42676794}, issn = {1663-9812}, abstract = {BACKGROUND: Emerging evidence indicates that the neuroprotective effects of Astragalus polysaccharides (APS), an extract compound and bioactive constituent derived from traditional Chinese herbs, may be relevant to an effective prescription for delaying progression of Alzheimer's disease (AD), yet the underlying mechanisms remain to be fully elucidated. This study aimed to investigate the therapeutic efficacy of APS in alleviating cognitive impairment and neuropathology in 5×FAD transgenic mice, with a specific focus on the regulatory role of the gut-brain axis.

METHODS: Male 5×FAD mice were orally administered APS (200 mg/kg/day) for 60 days. General observations were conducted to assess the in vivo tolerance of APS. Cognitive function was evaluated using the Morris water maze (MWM). Neuropathological assessments included immunofluorescence and Western blotting for amyloid-β (Aβ) deposition, synaptic proteins, and neuroinflammatory markers. Gut microbiota composition and metabolic profiles were analyzed via 16S rRNA gene sequencing and targeted metabolomics. Furthermore, fecal microbiota transplantation (FMT) was performed to verify the causal contribution of gut microbiota to the observed therapeutic effects.

RESULTS: APS administration was well-tolerated throughout the study period, with no overt toxic effects observed. Moreover, APS administration significantly ameliorated spatial learning and memory deficits in 5×FAD mice. Mechanistically, APS treatment reduced Aβ plaque burden, restored synaptic protein expression (PSD-95 and Syntaxin), and attenuated microglia-mediated neuroinflammation by suppressing pro-inflammatory cytokines (IL-6, TNF-α) and upregulating TREM2. Microbiome analysis revealed that APS reshaped gut microbial diversity and composition, enriching beneficial taxa such as Lactobacillus. Metabolomics indicated a partial restoration of amino acid metabolism. Notably, FMT from APS-treated donors successfully reproduced the cognitive improvements and anti-inflammatory effects in recipient mice.

CONCLUSION: These findings demonstrate that APS alleviates cognitive deficits and AD-like pathology, partially through remodeling gut microbiota and modulating the gut-brain axis. APS represents a promising natural compound-based therapeutic candidate for managing cognitive decline associated with Alzheimer's disease.}, } @article {pmid42677254, year = {2026}, author = {Dönmez, MO and Şener, A and Karaman Ersoy, Ş and Marzi, M and Şener, G}, title = {L-theanine attenuates AlCl3-induced cognitive dysfunction and neurotoxicity in rats: a behavioral and biochemical study.}, journal = {Turkish journal of medical sciences}, volume = {56}, number = {4}, pages = {1308-1319}, pmid = {42677254}, issn = {1303-6165}, mesh = {Animals ; *Glutamates/pharmacology ; Aluminum Chloride/toxicity ; Male ; Rats, Wistar ; Rats ; *Cognitive Dysfunction/chemically induced/drug therapy ; Lipid Peroxidation/drug effects ; Aluminum Compounds ; Disease Models, Animal ; *Alzheimer Disease/chemically induced/drug therapy ; Brain/drug effects/metabolism ; *Neurotoxicity Syndromes/drug therapy/etiology ; Glutathione/metabolism ; Oxidative Stress/drug effects ; Chlorides ; Acetylcholinesterase/metabolism ; Maze Learning/drug effects ; Neuroprotective Agents/pharmacology ; }, abstract = {BACKGROUND/AIM: The effects of L-theanine (LTN), a natural compound found in tea leaves, on biochemical parameters and cognitive functions were investigated in an aluminum chloride (AlCl3)-induced Alzheimer's disease-like experimental model.

MATERIALS AND METHODS: A total of 32 male Wistar rats were allocated into four groups: control, AlCl3-induced AD-like group, LTN-treated AD-like group, and donepezil-treated AD-like group. Donepezil was used as a reference drug. For the induction of AlCl3-induced neurotoxicity, AlCl3 was administered by gavage at a dose of 25 mg/kg/day during the 1st week and 150 mg/kg/day for the subsequent 3 weeks. LTN was administered orally at a dose of 100 mg/kg. Spatial memory was assessed using the Morris water maze and the novel object recognition test. Brain tissues were collected to analyze acetylcholinesterase, catalase, and myeloperoxidase activities, as well as amyloid beta (Aβ), lipid peroxidation, glutathione, and nitric oxide levels.

RESULTS: LTN reversed AlCl3-induced cognitive deficits. Moreover, the elevations in acetylcholinesterase and myeloperoxidase activities, as well as increased Aβ levels in the brain tissues of AlCl3-treated rats, were significantly reduced following LTN treatment. The increases in lipid peroxidation and nitric oxide observed in the AlCl3 group were suppressed by LTN treatment, while decreased antioxidant defenses, namely reduced glutathione levels and catalase activity, were restored.

CONCLUSION: The findings demonstrate that AlCl3 exposure impairs cholinergic function, induces oxidative damage, and leads to cognitive dysfunction, whereas LTN treatment effectively mitigates these effects, suggesting potential neuroprotective benefits against aluminum-induced neurotoxicity.}, } @article {pmid42669622, year = {2026}, author = {Sun, W and Yang, B and Zheng, H and Wang, Q and Shi, Y and Wang, G and Yin, W and Wang, H and Qi, X and Yao, Y and Wang, J and Cui, S and Cui, K and Mao, J and Xia, Y and Deng, J and Zhao, S and Wang, Z and Liu, F and Yi, M and Ding, J and Le, W and Li, X and Yuan, J and Wan, Y and Zheng, J}, title = {Extracellular matrix remodeling upregulates hippocampal neurogenic niche stiffness and impairs neurogenesis in Alzheimer's disease.}, journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association}, volume = {22}, number = {9}, pages = {e71784}, pmid = {42669622}, issn = {1552-5279}, support = {2025ZD0217600//Brain Science and Brain-like Intelligence Technology-National Science and Technology/ ; BMU2022YJ003//Peking University Talent Startup Fund supported by the Fundamental Research Funds for the Central Universities/ ; PKU2026PKULCXQ003//Clinical Medicine Plus X - Young Scholars Project of Peking University, the Fundamental Research Funds for the Central Universities/ ; 2024300CC0020//Scientific Project of Beijing Life Science Academy/ ; 2023000CB0010//Scientific Project of Beijing Life Science Academy/ ; 2023000CA0060//Scientific Project of Beijing Life Science Academy/ ; HBCAD2024-03//Opening Project of Hubei Key Laboratory of Cognitive and Affective Disorders/ ; LGL-2614-02//Lingang Laboratory/ ; 2024302RPIB03//Supporting Project for Principle Investigators of Beijing Life Science Academy/ ; 82671849//National Natural Science Foundation of China/ ; }, mesh = {Animals ; *Alzheimer Disease/metabolism/pathology/physiopathology ; *Extracellular Matrix/metabolism ; *Neurogenesis/physiology ; Mice ; Humans ; *Hippocampus/metabolism/pathology ; YAP-Signaling Proteins ; Male ; Mice, Transgenic ; Disease Models, Animal ; *Dentate Gyrus/metabolism ; Up-Regulation ; }, abstract = {INTRODUCTION: Preserving adult hippocampal neurogenesis alleviates cognitive deficits in Alzheimer's disease (AD), yet how biophysical alterations in such as stiffness in the neurogenic niche regulate neurogenesis remains unclear.

METHODS: Stiffness in the hippocampal dentate gyrus subgranular cell zone (SGZ) of 5×FAD mice was measured using atomic force microscopy. Extracellular matrix (ECM) components in mice and AD patients were profiled through proteomics. Hydrogels were supplemented in the SGZ to upregulate local stiffness in wildtype mice, while glycosaminoglycanases was injected to downregulated stiffness in 5×FAD mice. Gene expression in the neurogenic lineage was analyzed through single nucleus sequencing. Conditional knockdown or overexpression of mechanosensors and/or Yes-associated protein 1 (YAP1) were achieved using viral vectors.

RESULTS: We found SGZ stiffening occured early in 3-month 5×FAD mice, associating with ECM remodeling and neurogenesis impairment. Upregulation of tissue stiffness in the SGZ of wild-type mice via supplementing high-density hydrogel suppressed neurogenesis, whereas downregulaion of the niche stiffness in AD mice using hyaluronidase-1 (HAase1) and other glycosaminoglycanases preserved neurogenesis. Single-nucleus transcriptomics reveals that the HAase1 treatment reshaped transcriptome of the neural stem cells (NSCs) lineage. Specifically, we found that the integrin-YAP1 mechanotransduction axis played important roles in the stiffness-induced neurogenesis deficits. Conditional knockdown of both integrin β1 and YAP in the NSC lineage mitigated stiffness-induced deficits. Consistently, the association of ECM remodeling and neurogenesis impairments were also observed in post mortem AD patients.

DISCUSSION: ECM stiffness plays as a critical regulator of hippocampal neurogenesis, providing potential targets for pro-neurogenic therapeutics of AD.}, } @article {pmid42669911, year = {2026}, author = {Demirbas, ZS and Naharci, MI}, title = {Antiplatelet use in all-cause dementia and dementia subtypes among older adults: a population-based retrospective study.}, journal = {Croatian medical journal}, volume = {67}, number = {4}, pages = {297-305}, pmid = {42669911}, issn = {1332-8166}, mesh = {Humans ; Female ; Retrospective Studies ; Male ; Aged ; *Platelet Aggregation Inhibitors/therapeutic use ; *Dementia/drug therapy/classification ; Aged, 80 and over ; Aspirin/therapeutic use ; Risk Factors ; Clopidogrel/therapeutic use ; }, abstract = {AIM: To evaluate the appropriateness of antiplatelet use across dementia subtypes in older adults and to identify factors associated with inappropriate antiplatelet use.

METHODS: This population-based retrospective study enrolled adults aged ?65 years with dementia evaluated at a tertiary geriatric outpatient clinic at Gulhane Training and Research Hospital between 2016 and 2025. Antiplatelet (aspirin or clopidogrel) use was categorized as appropriate use, underuse, overuse, or appropriate non-use according to the 2021-2024 European Society of Cardiology guidelines. Multivariable logistic regression analyses were performed to identify the factors associated with inappropriate antiplatelet use.

RESULTS: Among 683 older adults with dementia, 40.7% received antiplatelet therapy. Antiplatelet underuse and overuse were observed in 16.8% and 16.1% of the participants, respectively. Underuse was most prevalent in vascular dementia (38.9%), whereas overuse was most prevalent in Alzheimer disease (20.2%) and frontotemporal dementia (19.0%). In multivariable analyses, antiplatelet overuse was independently associated with diabetes mellitus (odds ratio [OR] 4.31; 95% confidence interval [CI] 1.66-11.16) and inversely associated with current smoking (OR 0.06; 95% CI 0.06-0.67). Antiplatelet underuse was independently associated with female sex (OR 4.44; 95% CI 1.52-12.92).

CONCLUSIONS: Our findings highlight the gaps between guideline recommendations and real-world practice and support the need for individualized dementia-sensitive antiplatelet treatment strategies.}, } @article {pmid42670073, year = {2026}, author = {Ma, J and Wei, Z and Rong, C and He, W and Wang, X and Zhao, D}, title = {The Relationship Between Biomarkers in Blood and Urine and Alzheimer's Disease and Sleep Disorders (Long Sleep): A Mendelian Randomization Study.}, journal = {Current Alzheimer research}, volume = {}, number = {}, pages = {}, doi = {10.2174/0115672050466562260804080255}, pmid = {42670073}, issn = {1875-5828}, abstract = {INTRODUCTION: Alzheimer's Disease (AD) is a neurological condition that increases in severity from a gradual start. Previous studies have found an association between long sleep (LS) and AD. To slow its progression, it is important to recognize biomarkers associated with the early stages of both AD and LS.

METHODS: This study aimed to use two-sample Mendelian Randomization (MR) to identify blood and urine biomarkers associated with AD and LS. Thirty-five biomarkers from blood and urine were included as exposures in the MR analysis, while AD and LS were considered the outcomes. The AD dataset included 39,106 patients and 46,828 controls from Europe. Data on sleep duration were obtained from a GWAS in 34,184 cases and 305,742 controls of European ancestry. This study included 35 blood and urine biomarkers across 355,891 participants, including 318,953 white British, 23,582 non-white British, 6,019 African, and 7,338 South Asian participants from the UK Biobank.

RESULTS: Cystatin C, CRP, and Non-Albumin protein showed genetic association with AD and LS. The genetic association results after Bonferroni's correction are significant for Non-Albumin Protein in AD and LS.

DISCUSSION: This study provides further insight into the genetic associations and relationships among AD, LS, and other biomarkers; it also presents several potential candidates for AD and LS diagnosis and treatment. The opposing roles of C-reactive Protein, Cystatin C, and Non-Albumin protein in AD and LS warrant a greater exploration of their differential functions at various ages and in specific brain microenvironments in future studies.

CONCLUSION: This study provides a theoretical basis for the diagnosis and treatment of AD and LS. More experiments are needed in the future to verify this prediction.}, } @article {pmid42670527, year = {2026}, author = {Pan, L and Liu, B and Xu, J and Mu, X and Fan, L}, title = {Mesenchymal Stem Cells and Extracellular Vesicles for Neurodegenerative Diseases: Therapeutic Advances and Challenges.}, journal = {International journal of nanomedicine}, volume = {21}, number = {}, pages = {628071}, pmid = {42670527}, issn = {1178-2013}, mesh = {Humans ; *Neurodegenerative Diseases/therapy ; *Extracellular Vesicles/transplantation ; *Mesenchymal Stem Cells/cytology ; *Mesenchymal Stem Cell Transplantation/methods ; Animals ; }, abstract = {Mesenchymal stem cells (MSCs), as a type of adult stem cells, exhibit robust self-renewal, multi-lineage differentiation, paracrine and immunomodulatory capacities, demonstrating broad application prospects in the treatment of neurodegenerative diseases. This review systematically summarizes the mechanisms of action, therapeutic advances and comparative analyses of various MSCs and their derived extracellular vesicles (EVs) in Alzheimer's disease (AD), Parkinson's disease (PD) and amyotrophic lateral sclerosis (ALS), and discusses the optimization effects of gene modification and pretreatment on therapeutic efficacy. This article not only highlights the advantages of various MSCs and their corresponding EVs, but also provides unique insights into their differentiated therapeutic potential and mechanism of action, which have not been fully elucidated in previous studies. Meanwhile, although current research results are encouraging, this paper also critically points out that existing studies suffer from insufficient elucidation of mechanisms and lack of large-scale clinical trials. Finally, the article prospects future directions of MSC-based therapeutic strategies, including mechanism deepening, treatment optimization and standardization system construction, to promote their translation into clinical application. However, most of the current evidence is still preclinical, and the recognized clinical efficacy in humans is still limited. This is a narrative review. Literature was screened from Web of Science and PubMed by thematic relevance and research quality, without systematic review protocol or meta-analysis.}, } @article {pmid42671006, year = {2026}, author = {Ayuba, M and Che Mohd Nassir, CMN and Abdul Hamid, H and Hein, ZM and Alhaji Modu, B and Mohd Moklas, MA and Mehat, MZ}, title = {Ficus deltoidea preserves neuronal-glial ultrastructure and attenuates neuroinflammation in an Alzheimer's disease-like rat model.}, journal = {Nutritional neuroscience}, volume = {}, number = {}, pages = {1-18}, doi = {10.1080/1028415X.2026.2717205}, pmid = {42671006}, issn = {1476-8305}, abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by β-amyloid (Aβ) plaques, hyperphosphorylated tau tangles, cognitive decline, neuroinflammation, and neuronal-glial dysfunction, yet effective disease-modifying therapies remain unavailable. Increasing evidence suggests that preservation of neuronal and glial integrity is critical for mitigating disease progression. In the present study, we investigated the neuroprotective effects of Ficus deltoidea Jack (FD) in a D-galactose and aluminum chloride (D-gal/AlCl3)-induced rat model of AD-like neurodegeneration. Adult male Wistar rats were treated with FD (50, 100, and 200 mg/kg) for ten weeks and assessed for cognitive performance, cortical neuronal integrity, hippocampal ultrastructure, and neuroinflammatory signaling. FD treatment significantly improved spatial learning and memory in the Morris water maze without affecting locomotor activity. Histopathological analysis demonstrated dose-dependent preservation of pyramidal neurons in prefrontal cortex and hippocampal layers II (p < 0.0001), III (p < 0.0001), and V (p < 0.0001), with the highest dose of FD producing neuronal viability comparable to donepezil. Importantly, transmission electron microscopy demonstrated that FD markedly preserved the ultrastructural integrity of hippocampal microglia and astrocytes, maintaining mitochondrial morphology, rough endoplasmic reticulum organization, and myelin integrity. Consistent with these structural effects, FD significantly suppressed neuroinflammatory cytokine expression (IL-1β, IL-6, and TNF-α) in the prefrontal cortex. Collectively, this study provides the first integrated ultrastructural and molecular evidence that FD confers multi-level neuroprotection across the cortical-hippocampal axis by preserving neuronal-glial architecture and attenuating neuroinflammation. These findings highlight FD as a promising multi-target natural candidate for mitigating neurodegenerative processes associated with AD.}, } @article {pmid42671152, year = {2026}, author = {Otani, K}, title = {From public preferences to clinical tasks in anti-amyloid therapy for Alzheimer's disease.}, journal = {Psychiatry and clinical neurosciences}, volume = {}, number = {}, pages = {}, doi = {10.1111/pcn.70128}, pmid = {42671152}, issn = {1440-1819}, abstract = {Tajika and colleagues found that, among Japanese respondents willing to consider lecanemab, the median smallest worthwhile difference exceeded the absolute benefit used in their study scenario. This commentary argues that this expectation-efficacy gap should be translated into concrete clinical tasks across the anti-amyloid care pathway, including expectation assessment, biomarker and eligibility counseling, shared decision-making, treatment monitoring, support for non-initiation or discontinuation, and continuing psychosocial care.}, } @article {pmid42671334, year = {2026}, author = {Zhang, W and Wang, S and Gou, X}, title = {Research progress on terpenoids alleviating Alzheimer's disease through the Keap1/Nrf2/ARE pathway by exerting antioxidant effects and promoting mitophagy.}, journal = {Journal of Alzheimer's disease : JAD}, volume = {}, number = {}, pages = {13872877261480043}, doi = {10.1177/13872877261480043}, pmid = {42671334}, issn = {1875-8908}, abstract = {The exact initiating causes of Alzheimer's disease (AD) remain inconclusive. Meanwhile, the causal sequence and interactions within its pathological network are still poorly understood, which limits the efficacy of single treatment strategies and impedes drug development. Oxidative stress, identified as a central intersection point within this network, drives the deposition of amyloid-β protein, excessive tau phosphorylation, neuroinflammation, and mitochondrial damage, creating a self-perpetuating cycle. Consequently, oxidative stress has become a focal point for multi-target interventions. This review systematically investigates the evidence of terpenoids in cellular and animal models, elucidating their protective effects via a dual antioxidant mechanism. Firstly, terpenoids activate the Keap1/Nrf2/ARE pathway, leading to the upregulation of antioxidant genes and reduced free radical generation. Secondly, they enhance PINK1/Parkin-mediated mitophagy, facilitating the clearance of damaged organelles and preventing the release of reactive oxygen species. The review also delves into the positive feedback regulatory network involving molecules like Nrf2 and key proteins of mitophagy, such as p62/SQSTM1, offering a detailed mechanistic insight into the synergistic effects of terpenoids. This study underscores the significance of natural terpenoids, with their unique regulatory role in oxidative stress, as a promising candidate library for Alzheimer's drug development due to their diverse structures, clear mechanisms, and high safety profile. Additionally, it establishes a theoretical and experimental basis for the development of novel intervention strategies targeting multiple pathways with a single drug.}, } @article {pmid42671540, year = {2026}, author = {Vernooij, MW and Oliveira, TG and Wiest, R and Fox, NC and Frisoni, GB and Barkhof, F}, title = {SWI versus T2*GRE for ARIA-H monitoring: a pragmatic perspective on adoption in clinical practice.}, journal = {Neuroradiology}, volume = {}, number = {}, pages = {}, pmid = {42671540}, issn = {1432-1920}, abstract = {Although radiological severity thresholds for amyloid-related imaging abnormalities with hemosiderin deposition (ARIA-H) were developed using 2-dimensional acquisitions of T2*-weighted gradient-recalled echo (T2*GRE) MRI in pivotal anti-amyloid trials, adoption of well established 3D susceptibility-weighted imaging (SWI) in ARIA-H monitoring in clinical practice represents a reasonable long-term direction for clinical practice. SWI provides documented higher sensitivity and comparable or superior inter-rater reliability compared with conventional T2*GRE for detecting cerebral microbleeds and cortical superficial siderosis, the two key imaging manifestations of ARIA-H. Moreover, SWI is already incorporated into most contemporary dementia MRI protocols, offering important practical and logistical advantages. Available preliminary evidence suggests that the downstream clinical impact of detecting a few additional microbleeds or areas of siderosis may remain modest for most patients. Earlier and more reliable detection could potentially enhance safety by identifying individuals at higher risk of ARIA-H before treatment initiation. The critical requirements are transparency regarding sequence choice and consistency within individual patients over time.}, } @article {pmid42673747, year = {2026}, author = {Pyne, IT and Roy, AJ and Boraschi, S and Hajgude, SS and Hall, RA}, title = {Panoramic characterization of proposed ligands for GPR3: oleoylethanolamide as a pharmacological chaperone.}, journal = {Molecular pharmacology}, volume = {108}, number = {8}, pages = {100146}, doi = {10.1016/j.molpha.2026.100146}, pmid = {42673747}, issn = {1521-0111}, abstract = {G protein-coupled receptor 3 (GPR3) is a constitutively active G protein-coupled receptor known to regulate β-amyloid deposition in the brain and metabolism in brown adipose tissue. Although multiple compounds have been proposed to activate GPR3 signaling, it is still considered an orphan receptor. Recently, structural evidence revealed a hydrophobic tunnel in GPR3, suggesting that a lipid may be an endogenous agonist for GPR3. We sought to characterize the reported agonists for GPR3 to determine which might be authentic agonists and found that only the synthetic ligand, diphenyleneiodonium chloride, and the endogenous lipids, oleoylethanolamide (OEA) and oleamide, stimulated cAMP generation in a GPR3-dependent manner. Although treatment of cells with diphenyleneiodonium chloride stimulated rapid cAMP generation, we observed gradual increases in GPR3 activation over multiple hours after OEA treatment. Additionally, we found that chronic stimulation with OEA caused an increase in GPR3 cell surface expression. Coupled with the slow activation kinetics of OEA-stimulated GPR3 signaling, these findings suggest that OEA does not behave strictly as a classical agonist for GPR3. Indeed, we found that the OEA-mediated increase in GPR3 on the cell surface can be blocked by inhibiting receptor forward trafficking through the endoplasmic reticulum and Golgi, which positions OEA as a pharmacological chaperone that increases GPR3 signaling by promoting receptor trafficking to the cell surface. These findings suggest a novel mechanism for the regulation of the constitutively active receptor GPR3, whereby the amount of receptor at the plasma membrane, and therefore, the receptor's signaling activity, can be regulated by lipid binding in the endoplasmic reticulum/Golgi. SIGNIFICANCE STATEMENT: This study proposes a novel mechanism for the regulation of the activity of the G protein-coupled receptor, G protein-coupled receptor 3. This study found that the endogenous lipid oleoylethanolamide functions as a pharmacological chaperone by promoting the accumulation of G protein-coupled receptor 3 at the plasma membrane through increased forward trafficking, thereby inducing increased receptor signaling activity.}, } @article {pmid42675112, year = {2026}, author = {Maas, C and Fang, L and Mathey, E and Jacob, C and Stremel, T and Viering, T and Fliedner, R and Schnieder, M and von Arnim, CAF}, title = {A comprehensive German claims data analysis of care pathways, risk factors and comorbidities among acetylcholinesterase inhibitor initiators in Alzheimer's disease.}, journal = {Scientific reports}, volume = {16}, number = {1}, pages = {}, pmid = {42675112}, issn = {2045-2322}, mesh = {Humans ; *Alzheimer Disease/drug therapy/epidemiology/diagnosis ; Germany/epidemiology ; Female ; *Cholinesterase Inhibitors/therapeutic use ; Risk Factors ; Retrospective Studies ; Male ; Comorbidity ; Aged ; Aged, 80 and over ; }, abstract = {Early stages of Alzheimer's Disease (AD), commonly referred to as early AD (eAD), represent a critical phase for timely diagnosis and intervention. However, significant gaps remain in understanding real-world care of individuals initiating first-line treatment such as acetylcholinesterase inhibitors (AChE-I) in Germany. A retrospective study was conducted using the German InGef claims database with a pragmatic proxy approach, identifying de novo AChE-I initiators as individuals suspected of having eAD. Two cohorts were defined: a pre-cohort (2022) capturing eight-years prior to AChE-I initiation, and a post-cohort (2017), analyzing five-years following initiation. Patients were matched 1:1 to controls without AD based on demographic characteristics. Outcomes included comorbidities, risk factors, diagnostics, prescriptions, and survival. The study identified 1,994 (pre-cohort) and 2,051 (post-cohort) AChE-I initiators, and respective controls. Mobility disorders increased significantly (+ 55%) over the eight years preceding treatment. Eight years pre-initiation, 81.9% of initiators exhibited at least one modifiable risk factor compared to 76.2% in controls (p < 0.001). Advanced diagnostic procedures were underutilized (MRI: 39.0%, cerebrospinal fluid analysis: 9.2%, in year -1). Only 78.6% received an AD-specific diagnosis within the first year post-initiation. Extensive use of psycholeptics and psychoanaleptics was observed, with a notable decline in dementia-specific medications post-initiation. Post-initiation, initiators showed higher comorbidity burden (e.g., urinary incontinence: 40.2% vs. 10.7% by year 5) and higher observed, unadjusted mortality (53.3% vs. 21.7%, p < 0.001). This study highlights patterns suggestive of gaps in the management of AChE-I initiators in Germany, including underutilization of guideline-based diagnostics, high comorbidity burden, and higher observed mortality. Improved management strategies and the development of more precise diagnostic coding that reflects disease stages could help to address these issues.}, } @article {pmid42675683, year = {2026}, author = {Wu, HY and Wang, XS and Yang, M and Cai, J}, title = {The global research of artificial intelligence on Alzheimer disease: A 25-year bibliometric analysis.}, journal = {Medicine}, volume = {105}, number = {35}, pages = {e50370}, doi = {10.1097/MD.0000000000050370}, pmid = {42675683}, issn = {1536-5964}, mesh = {*Alzheimer Disease/diagnosis ; *Bibliometrics ; Humans ; *Artificial Intelligence/trends ; *Biomedical Research ; }, abstract = {BACKGROUND: With the increasing global prevalence of Alzheimer disease (AD), there has been heightened attention on the onset and progression of AD. Studies indicate that artificial intelligence (AI) has demonstrated potential in the early prediction and diagnosis of AD. However, current research still falls short in terms of data diversity and the application of personalized models.

OBJECTIVE: This manuscript utilizes bibliometric methods to explore the application trends and emerging frontiers of AI in AD research.

METHODS: In the Web of Science Core Collection, we gathered documents from 1999 to 2023 focusing on the application of AI in AD. CiteSpace and VOSviewer were utilized to conduct a thorough analysis of various aspects, including countries, institutions, authors, journals, and keywords.

RESULTS: A total of 5347 articles were selected for this study. The United States of America leads this field. The University of London, Harvard University, the University of North Carolina, and the University of California are the top 4 institutions by publication volume. Daoqiang Zhang is identified as the most influential scholar in this field. NeuroImage is regarded as the most influential journal in this field. The keyword co-occurrence analysis indicates that this study focuses on the application of machine learning and deep learning (DL) in predicting and diagnosing AD. Research trends show an increasing preference for using DL in combination with multimodal data for AD classification and early diagnosis.

CONCLUSIONS: AI is accelerating AD research through DL and multimodal imaging, driving progress in early diagnosis and biomarker discovery. However, challenges remain, including limited data diversity and a lack of model interpretability. Future efforts should focus on developing robust, generalizable, and clinically interpretable models by integrating diverse and longitudinal data to enable personalized diagnosis and treatment.}, } @article {pmid42676462, year = {2026}, author = {Noh, MY and Sung, W and Kim, H and Son, B and Kim, YE and Choi, YY and Holtzman, DM and Kim, SH}, title = {Lecanemab in symptomatic PSEN1 p.Met233Val early-onset Alzheimer's disease: Neuroimaging safety, regional amyloid-PET dynamics, and longitudinal plasma biomarkers.}, journal = {Alzheimer's & dementia (Amsterdam, Netherlands)}, volume = {18}, number = {3}, pages = {e70468}, pmid = {42676462}, issn = {2352-8729}, abstract = {INTRODUCTION: The presenilin 1 (PSEN1) p.Met233Val variant is a Dominantly Inherited Alzheimer Network-Trials Unit (DIAN-TU)-eligible autosomal-dominant Alzheimer's disease (ADAD) variant for which lecanemab response data are unavailable.

METHODS: A 34-year-old symptomatic PSEN1 p.Met233Val carrier (APOE ε3/ε3) was prospectively followed through 26 lecanemab infusions over 12 months, with serial magnetic resonance imaging (MRI), amyloid positron emission tomography (PET), and plasma biomarkers.

RESULTS: No amyloid-related imaging abnormalities occurred. Composite Centiloid increased modestly (+7.2), masking regional divergence: basal ganglia (-24.5) and medial temporal cortex (-22.1) declined, whereas posterior cortical regions accrued amyloid. Plasma amyloid beta (Aβ) 42/40 rose to 122% by T22, with concurrent decreases in phosphorylated tau at threonine 217 (p-tau217), p-tau181, neurofilament light chain (NfL), and glial fibrillary acidic protein (GFAP). Global Clinical Dementia Rating (CDR) score remained 0.5; caregiver reports noted improvements in spasticity, dystonia, and affective features.

DISCUSSION: Lecanemab demonstrated neuroimaging safety and evidence of biological target engagement in this symptomatic PSEN1 p.Met233Val ADAD carrier. These longitudinal neuroimaging and plasma biomarker findings may help inform interpretation of treatment responses in genetically defined ADAD.}, } @article {pmid42667649, year = {2026}, author = {O'Neil, LM and Qureshi, HA and Lindemann, L and Cvancara, DJ and Lehmann, AE and Jafari, A}, title = {Cognitive Dysfunction in Chronic Rhinosinusitis: A Scoping Review.}, journal = {International forum of allergy & rhinology}, volume = {}, number = {}, pages = {}, doi = {10.1002/alr.70262}, pmid = {42667649}, issn = {2042-6984}, abstract = {BACKGROUND: Cognitive dysfunction is increasingly recognized as an extra-nasal manifestation of chronic rhinosinusitis (CRS). This scoping review characterizes the primary evidence on cognition in adult CRS, covering measures, treatment response, and incident dementia.

METHODS: We searched EMBASE, PubMed/MEDLINE, Web of Science, the Cochrane Library, CINAHL, and Global Index Medicus through May 2026 using a MeSH and free-text strategy. Inclusion criteria include primary studies of adult CRS with a formal clinical diagnosis (AAO-HNS, EPOS or ICD-coded) reporting at least one validated cognitive measure or recognized cognitive impairment. Two reviewers screened independently. Animal studies, reviews, conference abstracts, and non-CRS populations were excluded. PRISMA-ScR reporting was performed; heterogeneity precluded meta-analysis.

RESULTS: Twenty-four primary studies met inclusion criteria. Adults with CRS perform worse than controls on subjective (Cognitive Failures Questionnaire [CFQ], Neuro-QoL) and objective (Montreal Cognitive Assessment [MoCA], Automated Neuropsychological Assessment Metrics [ANAM], eye movement assessment, P300) cognitive instruments. Deficits correlate with disease-specific QoL severity (SNOT-22, Rhinosinusitis Disability Index [RSDI]). Cognitive measures improve after medical therapy or endoscopic sinus surgery. Two resting-state fMRI analyses identified altered orbitofrontal-precuneus connectivity scaling with sinonasal inflammation. Dementia results are mixed: a UK Biobank analysis (7176 CRS cases among 364,945 participants) reported increased Alzheimer disease risk (HR 1.33), while two Korean cohorts and a 2025 meta-analysis found no association.

CONCLUSION: Adults with CRS show measurable cognitive dysfunction that may improve with treatment, with a plausible neuroinflammatory pathophysiology. Whether this translates to incident dementia is contested. Outcome heterogeneity limits synthesis; therefore, development of a CRS-specific cognitive measurement set is recommended.}, } @article {pmid42668333, year = {2026}, author = {Kalra, P and Chaturvedi, D and Kumar, A and Grewal, AK and Khan, H and Singh, V and Singh, TG and Singh, T and Ahmad, SF and Attia, SM}, title = {AMBMP Hydrochloride Reverses STZ-Induced Alzheimer-Type Dementia Associated with Wnt/β-catenin/TLR4 Signaling.}, journal = {Neuromolecular medicine}, volume = {28}, number = {1}, pages = {}, pmid = {42668333}, issn = {1559-1174}, support = {ORF-2026-748//King Saud University/ ; }, mesh = {Animals ; *Alzheimer Disease/drug therapy/chemically induced ; *Toll-Like Receptor 4/physiology/agonists ; Streptozocin/toxicity ; Male ; Mice ; *Wnt Signaling Pathway/drug effects ; *Neuroprotective Agents/therapeutic use/pharmacology ; Oxidative Stress/drug effects ; Donepezil/therapeutic use/pharmacology ; Disease Models, Animal ; Maze Learning/drug effects ; beta Catenin/physiology ; Acetylcholinesterase/metabolism ; Palmitic Acid/pharmacology ; }, abstract = {Alzheimer's disease (AD) is a debilitating neurodegenerative disorder with progressive cognitive decline and neuronal loss. This study investigated the neuroprotective effects of AMBMP Hydrochloride, a Wnt/β-catenin agonist, in a streptozotocin (STZ)-induced mice model of AD, elucidating the interplay between dysregulated Wnt/β-catenin signaling and Toll-Like Receptor 4 (TLR4)-mediated inflammation, with Palmitic acid used as a TLR4 pathway modulator. Mice received bilateral intracerebroventricular (i.c.v.) injections of STZ (3 mg/kg) on Day 1 and Day 3, followed by administration of Donepezil (3 mg/kg)/ AMBMP Hydrochloride (5 mg/kg and 10 mg/kg)/Palmitic acid (TLR4 agonist, 20 mg/kg) via the intraperitoneal (i.p.) route from Day 4 to Day 22. STZ-treated mice exhibited significant cognitive dysfunction, characterized by impaired performance in the Morris Water Maze (MWM) task along with increase in acetylcholinesterase (AChE) activity, oxidative stress (thiobarbituric acid reactive substances; TBARS), neuroinflammation [tumor necrosis factor alpha (TNF-α)/Interleukin-6 (IL-6)/Interleukin-1 beta (IL-1β) and nuclear factor kappa B (NF-κB)] and decreased reduced glutathione (GSH) levels. However, AMBMP Hydrochloride significantly improved behavioral and biochemical alterations possibly through modulation of Wnt/β-catenin signaling and attenuation of TLR4-mediated inflammation. Interestingly, Palmitic acid co-treatment was found to counteract these protective effects, further pointing to a role of TLR4 in the pharmacological effect of AMBMP Hydrochloride. In summary, we confirmed that AMBMP Hydrochloride exhibits potent neuroprotective effects associated with modulating Wnt/β-catenin/TLR4 signaling, offering a promising therapeutic approach against Alzheimer-Type Dementia. Future studies should delve deeper into the molecular mechanisms and translational promise of AMBMP hydrochloride, paving the way for its development as a potential candidate for AD management.}, } @article {pmid42668348, year = {2026}, author = {Han, Z and Chen, H and Yao, Y and Bo, X and Ni, X and Liu, H and Bai, M and Li, T and Bao, L and Zhang, D and Dong, W}, title = {Promoting Effect of (+)-Borneol on Alzheimer's Disease Treatment in APP Transgenic Zebrafish and Its Blood-Brain Barrier Permeation Mechanism.}, journal = {Molecular neurobiology}, volume = {63}, number = {1}, pages = {}, pmid = {42668348}, issn = {1559-1182}, mesh = {Animals ; *Blood-Brain Barrier/drug effects/metabolism/pathology ; Zebrafish/genetics ; Animals, Genetically Modified ; *Alzheimer Disease/drug therapy/genetics/pathology/metabolism ; *Camphanes/pharmacology/therapeutic use ; *Amyloid beta-Protein Precursor/genetics/metabolism ; Brain/pathology/metabolism/drug effects ; }, abstract = {(+)-Borneol (Bor) has been shown to enhance drug penetration across the blood-brain barrier (BBB); yet its mechanisms of action and adjuvant effects on Alzheimer's disease (AD) drugs remain insufficiently investigated. This study systematically explored the adjuvant effects of Bor and its underlying mechanisms by employing AB wild-type zebrafish and APP transgenic zebrafish models. Results demonstrated that Bor at concentrations of 0.05 mM or lower exhibited no toxicity toward AB wild-type zebrafish, whereas 0.01 and 0.05 mM Bor significantly increased the expression of green fluorescent protein (GFP) in the zebrafish brain. Genetic analyses revealed that Bor downregulated genes encoding tight junction proteins and P-glycoprotein (P-gp). Drug treatment experiments showed that Bor enhanced the efficacy of AD therapeutic agents, including Zhenbaopill (ZBP, a traditional medicinal preparation) and the synthetic drug 8e. Specifically, Bor ameliorated AD-related behavioral impairments, inhibited cerebral apoptosis, restored the expression of AD-associated genes, normalized the activities of acetylcholine (ACh)-related enzymes, and downregulated both the mRNA and protein levels of Claudin 5. In summary, Bor enhances BBB permeability by regulating the expression of genes encoding BBB-related proteins, thereby increasing the brain concentration and bioavailability of AD drugs with anticholinesterase activity. An appropriate dose of Bor may thus contribute to enhancing the therapeutic efficacy of AD drugs.}, } @article {pmid42668476, year = {2026}, author = {Wu, B and Wu, J and Zhu, L and Li, A and Fu, Y and Lei, Z and Wu, D and Peng, W and Xie, L}, title = {Intranasal L-DOPA/TPP-engineered extracellular vesicles deliver icariin to ameliorate mitochondrial dysfunction with associated sphingolipid remodeling in Alzheimer's disease models.}, journal = {Materials today. Bio}, volume = {40}, number = {}, pages = {103563}, pmid = {42668476}, issn = {2590-0064}, abstract = {Alzheimer's disease (AD) is associated with mitochondrial dysfunction, oxidative stress, and disrupted lipid homeostasis, but the therapeutic translation of mitochondrial-protective agents remains limited by inefficient brain delivery, insufficient neuronal selectivity, and poor subcellular precision. Here, we developed an intranasal extracellular vesicle formulation (L-DOPA/TPP-EV-ICA) by loading icariin (ICA) into mesenchymal stem cell-derived extracellular vesicles and post-inserting DSPE-PEG-Levodopa and TPP-PEG-PE to enhance nasal environment, neuronal association, and mitochondria-associated intracellular enrichment. The engineered vesicles retained EV-like morphology, showed measurable ICA encapsulation, and maintained colloidal stability under the tested storage and simulated nasal conditions. In a human nasal epithelial Transwell model, L-DOPA/TPP-EV-ICA showed greater neuronal uptake than unmodified EVs without detectable disruption of epithelial barrier integrity and exhibited preferential colocalization with mitochondria-associated structures after cellular internalization. In Aβ-injured neuronal cells, L-DOPA/TPP-EV-ICA treatment reduced mitochondrial oxidative stress and mPTP opening, improved membrane potential, and enhanced ATP production and redox-related parameters. Following intranasal administration, the engineered formulation generated stronger and more persistent brain-associated fluorescence and showed preferential association with NeuN-positive cells. In APP/PS1 mice, treatment improved cognitive performance, and attenuated histopathological and mitochondrial abnormalities. Integrated proteomic, metabolomic analyses, and protein-level analyses further identified treatment-associated alterations in sphingolipid-related pathways. These findings support L-DOPA/TPP-EV-ICA as a promising preclinical intranasal EV platform for improving mitochondrial function and modulating sphingolipid-associated alterations in AD-related models.}, } @article {pmid42668611, year = {2026}, author = {Gao, F and Luo, G and Liu, B and Qiu, X and Bai, J and Wang, R}, title = {Comparative effectiveness of multiple interventions for Alzheimer's disease on ABC syndromes and QoL: A Bayesian network meta-analysis.}, journal = {iScience}, volume = {29}, number = {9}, pages = {117250}, pmid = {42668611}, issn = {2589-0042}, abstract = {Evidence comparing directly pharmacological and non-pharmacological treatments for Alzheimer's disease (AD) is scarce. The ABC symptoms-activities of daily living (ADLs) (A), behavioral and psychological symptoms (BPSs) (B), cognitive function (C), and quality of life (QoL)-are critical for diagnosing and assessing treatment effects in AD. This study aims to evaluate five interventions for AD: pharmacological therapy (PT), photobiomodulation (PBM), cognitive therapy (CT), exercise therapy (ET), and repetitive transcranial magnetic stimulation (rTMS) using a Bayesian network meta-analysis approach. Among 6,450 records screened, 91 randomized controlled trials (RCTs) involving 12,242 participants met the inclusion criteria. PBM and rTMS showed significant benefits for cognitive function in AD patients. PT and CT showed notable effectiveness in enhancing activities of daily living. For QoL, CT and ET were identified as more favorable outcomes. Collectively, each intervention exerts unique merits targeting ABC symptoms and QoL, implying combined pharmacological and non-pharmacological regimens could optimize therapeutic gains for AD management.}, } @article {pmid42669137, year = {2026}, author = {Xu, B and Li, X and Dong, S and Zhang, Z and Jin, D and Li, G and Wang, J}, title = {Modulating the Gut-Microbiota-Brain Axis in Alzheimer's Disease: Therapeutic Potential of Nutritional and Metabolic Factors.}, journal = {CNS neuroscience & therapeutics}, volume = {32}, number = {9}, pages = {e71117}, pmid = {42669137}, issn = {1755-5949}, mesh = {Humans ; *Alzheimer Disease/metabolism/diet therapy/microbiology/therapy ; *Gastrointestinal Microbiome/physiology ; Animals ; *Brain/metabolism ; *Brain-Gut Axis/physiology ; Fecal Microbiota Transplantation/methods ; }, abstract = {BACKGROUND: Alzheimer's disease (AD) is a progressive neurodegenerative disorder and the leading cause of dementia among the elderly, characterized by a gradual decline in memory and cognitive function. The growing body of evidence highlighting the interaction between the gut microbiota and the central nervous system has positioned the gut microbiota as a key area of research in AD pathogenesis.

METHODS: This review critically evaluates the preclinical evidence and clinical trial outcomes, complemented by mechanistic studies and Mendelian randomization analyses, to assess the therapeutic potential of nutritional interventions targeting the gut-microbiota-brain axis in AD.

RESULTS: Dietary components and patterns regulate the composition and function of the gut microbiota, which in turn influence brain function through the gut-microbiota-brain axis via chemical/metabolic, immune-mediated, and neural pathways. Specific nutrients, microbial metabolites, and dietary patterns have been shown to exert either protective or detrimental effects on AD pathology and cognitive function. Emerging strategies, including precision nutrition, fecal microbiota transplantation, and next-generation microbiome-based therapies, offer new avenues for AD prevention and treatment.

CONCLUSIONS: Nutritional interventions targeting the gut-microbiota-brain axis represent a promising approach for the comprehensive prevention and management of AD. Further mechanistic and clinical studies are warranted to translate these findings into effective therapeutic strategies.}, } @article {pmid42669176, year = {2026}, author = {Forsyth, F and Diaz, A and Andersson, V and Haraldsen, IH and Gove, D}, title = {Ethical considerations of fluid biomarker use in alzheimer's disease - a rapid review.}, journal = {Aging & mental health}, volume = {}, number = {}, pages = {1-14}, doi = {10.1080/13607863.2026.2719938}, pmid = {42669176}, issn = {1364-6915}, abstract = {OBJECTIVE: Alzheimer's disease (AD) care has been reshaped by the integration of fluid biomarkers. This review addressed the question "What are the ethical considerations of fluid biomarker use in eligibility assessments for treatment in AD and mild cognitive impairment?"

METHODS: A rapid review following established guidelines was performed. Relevant data were identified and organised within the four pillars of biomedical ethics. Results were reported in line with the PRISMA checklist.

RESULTS: Searches identified 10,611 records; 34 were included following screening. Narrative synthesis suggests there are a greater number of ethical risks over benefits within the current clinical context. However, interpretation is subjective and empirical data is lacking.

CONCLUSIONS: Multiple ethical concerns surround the use of fluid biomarkers in AD treatment decisions, and there is limited empirical evidence to substantiate claims about benefits and harms. Uncertainty in biomarker performance, particularly in underrepresented groups, raises risks to non-maleficence, autonomy, and justice and complicates clinical decision making.}, } @article {pmid42665145, year = {2026}, author = {Yu, X and Gao, P and Yao, Q and Yuan, F and Jing, W}, title = {Polysaccharides targeting organelle network dysfunction in Alzheimer's disease: A review.}, journal = {International journal of biological macromolecules}, volume = {}, number = {}, pages = {154255}, doi = {10.1016/j.ijbiomac.2026.154255}, pmid = {42665145}, issn = {1879-0003}, abstract = {Alzheimer's disease (AD) is driven by an interrelated pathological network, which to some extent explains the limited efficacy of single-target therapies and constitutes a significant challenge in current clinical treatment. Emerging evidence indicates that dysfunction and crosstalk among mitochondria, the endoplasmic reticulum, and lysosome-autophagy form a core organelle network that amplifies oxidative stress and exacerbates proteostatic imbalance, neuroinflammation, and synaptic failure. In this review, we summarize natural and engineered polysaccharides as potential multitarget modulators that may influence individual organelle-associated pathways involved in AD-related dysfunction. We discuss how the structural parameters of polysaccharides (e.g., molecular weight, monosaccharide composition, glycosidic linkages, branching, and charge density) are associated with bioactivities through receptor-related signaling pathways, redox and inflammatory regulation, proteostasis/autophagy modulation, and, when applicable, potential gut-brain axis involvement. Furthermore, we highlight rational design strategies (e.g., sulfation and carboxymethylation) and formulation/delivery considerations that may increase efficacy and translational readiness. Finally, key challenges, including heterogeneity, mechanism attribution, brain delivery, and standardization, are outlined to guide the development of polysaccharide-based strategies potentially addressing organelle-associated dysfunction in AD.}, } @article {pmid42665355, year = {2026}, author = {Afonso, AS and Schroeder, KM and Mitchell, L and Carragher, N and Casey, C and Patel, N}, title = {Characterising patients with Alzheimer's disease in England: a cohort study using data from Clinical Practice Research Datalink linked to Hospital Episode Statistics.}, journal = {BMJ open}, volume = {16}, number = {8}, pages = {e115438}, doi = {10.1136/bmjopen-2025-115438}, pmid = {42665355}, issn = {2044-6055}, mesh = {Humans ; Female ; *Alzheimer Disease/epidemiology/drug therapy ; England/epidemiology ; Aged, 80 and over ; Male ; Comorbidity ; Aged ; Databases, Factual ; Cohort Studies ; Algorithms ; Middle Aged ; Polypharmacy ; Hospitalization/statistics & numerical data ; }, abstract = {OBJECTIVES: To characterise demographics, comorbidities, co-medications and healthcare resource utilisation (HCRU) in patients newly diagnosed with Alzheimer's disease (AD) in England using published and validated AD algorithms.

DESIGN: Observational cohort study.

SETTING: Real-world data in England from the Clinical Practice Research Datalink Aurum primary care database linked to the Hospital Episode Statistics secondary care database.

PARTICIPANTS: Two disease-based algorithms (Imfeld et al and Douros et al) and one medication-based algorithm (Schroeder et al) were selected from the literature to identify patients with AD. The index period for patient selection was from 1 January to 31 December 2019. Patients were grouped into three non-mutually exclusive cohorts reflecting these algorithms (cohorts A-C), then patients aged ≥60 years were further grouped into three subcohorts (subcohorts 1-3). Subcohort 1 included 9826 patients, subcohort 2 included 10 265 patients and subcohort 3 included 7355 patients.

PRIMARY OUTCOME MEASURES: Demographics, comorbidities, co-medications and HCRU present up to and including the date of cohort qualification were described.

RESULTS: Across subcohorts 1-3, mean age at index ranged from 81 to 83 years, and most patients were female (59%-63%) and White (93%). Common comorbidities were hypertension (67%-71%), asthma and chronic obstructive pulmonary disease (60%-63%) and arthritis and osteoarthritis (51%-53%). Common co-medications were analgesics (87%-89%), systemic corticosteroids (83%-84%) and anti-inflammatory and anti-rheumatic agents (81%-82%). Up to 34% of patients had a specialist referral or visit, with up to 18% involving a neurologist. In the 12 months prior to and including the index date, up to 46% of patients had an emergency department visit or inpatient visit for any cause.

CONCLUSIONS: In England, most newly diagnosed patients with AD were White females in their early 80s with common comorbidities including hypertension, asthma, chronic obstructive pulmonary disease, arthritis and osteoarthritis. This study addresses a critical evidence gap by quantifying the England-specific burden of comorbidity, polypharmacy, and HCRU among patients with AD using multiple validated and published AD algorithms. Findings were broadly consistent across the three subcohorts identified using disease-based and medication-based algorithms, strengthening internal validity of the study and demonstrating that the findings are robust to the method of AD case definition. This study provides a novel insight into the real-world AD population in England, and findings may help healthcare professionals to identify patients living with AD, understand patients' needs and tailor treatment strategies.}, } @article {pmid42665452, year = {2026}, author = {Huang, WL and Wang, LL and Shi, JR and Liu, Q}, title = {Acupuncture for Alzheimer's disease: A systematic review and meta-analysis integrating traditional insights and scientific evidence.}, journal = {Journal of integrative medicine}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.joim.2026.08.002}, pmid = {42665452}, issn = {2095-4964}, abstract = {BACKGROUND: Alzheimer's disease (AD), a leading cause of dementia in the elderly, is characterized by progressive cognitive impairment, and still lacks effective therapeutic interventions.

OBJECTIVE: This systematic review synthesizes the classical theoretical foundations, clinical evidence, and modern mechanistic insights for the use of acupuncture to treat AD.

SEARCH STRATEGY: A meta-analysis was conducted based on a comprehensive literature search of PubMed, Embase, the Cochrane Library, CNKI, VIP information, and Wanfang Data, covering the period from inception until September 2025.

INCLUSION CRITERIA: Eligible randomized controlled trials (RCTs) compared acupuncture (manual or electroacupuncture) with control interventions, including sham acupuncture, donepezil, placebo, or no treatment.

DATA EXTRACTION AND ANALYSIS: Data were extracted by two reviewers working independently and then analyzed using the meta and meta for packages in R (v4.3.2). Weighted mean differences (WMDs) and 95% confidence intervals (CIs) were calculated.

RESULTS: A total of 21 RCTs comprising 1354 participants met the inclusion criteria. Compared with no-treatment controls, acupuncture significantly improved cognitive performance, as measured by the Mini-Mental State Examination (MMSE) (WMD = 3.74, 95% CI: 1.34-6.14), and outperformed placebo controls (WMD = 2.13, 95% CI: 1.39-2.87). Acupuncture showed efficacy comparable to that of donepezil on MMSE and Activity of Daily Living (ADL), suggesting non-inferiority to standard pharmacotherapy. Frequently used acupoints included GV20, ST36, GB20, LR3, and ST40, often combining local (GV24, EX-HN1) and distal (SP10, KI3) points. Reported adverse events were mild and transient, with no significant difference from controls. Biomarker analyses indicated that acupuncture enhanced acetylcholine levels and reduced plasma Aβ1-40, Aβ1-42, and Tau levels, implying modulation of cholinergic transmission and AD-related pathology.

CONCLUSION: This review highlights acupuncture as a holistic, multi-targeted therapy with promising potential for managing AD. Future research should aim to standardize acupuncture protocols, integrate TCM syndrome differentiation, and adopt neurobiological and imaging techniques to explore mechanisms. Please cite this article as: Huang WL, Wang LL, Shi JR, Liu Q. Acupuncture for Alzheimer's disease: A systematic review and meta-analysis integrating traditional insights and scientific evidence. J Integr Med. 2026; Epub ahead of print.}, } @article {pmid42665539, year = {2026}, author = {Lu, H and Hu, C and Fu, Y}, title = {Fabrication of Mesoporous Manganese Nanoparticles Incorporated Aβ-Peptide Inhibits Aβ Aggregation and Alleviates Neuroinflammation Against Alzheimer's Disease.}, journal = {Journal of biomedical materials research. Part B, Applied biomaterials}, volume = {114}, number = {9}, pages = {e70131}, doi = {10.1002/jbm.b.70131}, pmid = {42665539}, issn = {1552-4981}, mesh = {Animals ; *Alzheimer Disease/drug therapy/metabolism/pathology ; *Amyloid beta-Peptides/chemistry/metabolism ; Mice ; *Manganese/chemistry/pharmacology ; Humans ; Porosity ; *Nanoparticles/chemistry ; Blood-Brain Barrier/metabolism ; *Neuroinflammatory Diseases/metabolism/drug therapy/pathology ; Protein Aggregation, Pathological ; tau Proteins/metabolism ; Protein Aggregates/drug effects ; }, abstract = {Extracellular amyloid plaques from Aβ accumulation and intracellular neurofibrillary tangles (NFTs) from hyperphosphorylated Tau (p-Tau), both leading to neuronal dysfunction, synapse loss, and cognitive decline. Nonetheless, achieving an effective therapeutic outcome is challenging due to the limited drug bioavailability through the blood-brain barrier (BBB) and the complex microenvironment within the brain. This study proposes MM-TA for the synergistic treatment of AD, utilizing mesoporous manganese (MM) as a nanocarrier to deliver a LK7 (Aβ-inhibiting peptide) and a DAA (amino acid-peptide) that inhibits Tau-related fibrils formation. A biomimetic nanocarrier (MM-LD@4CM termed as MLDC) encapsulated with 4T1 cell membranes (4CM) was developed, inspired by 4T1 cells' ability to facilitate BBB penetration. Following traversal of the BBB, MLDC concurrently prevented Tau phosphorylation and suppressed Aβ aggregation. Furthermore, by leveraging MM's catalase-mimetic properties, MLDC mitigated oxidative stress and altered the microenvironment associated with AD progression. In contrast to the singular therapeutic agent, MLDC ameliorated nerve damage and enhanced cognitive function in AD mice by reducing Aβ oligomers, phosphorylated Tau, and inflammation, thereby providing a synergistic therapeutic approach with significant potential for effective AD treatment.}, } @article {pmid42665946, year = {2026}, author = {Le, N and Anne, N and Shen, C and Pallapothu, R and Liu, Y and Park, C}, title = {Dementias in Older Women With Early-Stage HER2-Negative Breast Cancer Treated With Anthracycline Plus Taxane Versus Taxane-Based Chemotherapy Regimens.}, journal = {Pharmacoepidemiology and drug safety}, volume = {35}, number = {9}, pages = {e70457}, pmid = {42665946}, issn = {1099-1557}, mesh = {Humans ; Female ; *Taxoids/adverse effects/administration & dosage ; Aged ; *Anthracyclines/adverse effects/administration & dosage ; SEER Program/statistics & numerical data ; *Antineoplastic Combined Chemotherapy Protocols/adverse effects/administration & dosage ; *Breast Neoplasms/drug therapy/pathology ; Erb-b2 Receptor Tyrosine Kinases ; *Dementia/epidemiology/chemically induced ; United States/epidemiology ; Aged, 80 and over ; Bridged-Ring Compounds/adverse effects/administration & dosage ; Medicare/statistics & numerical data ; Incidence ; Neoplasm Staging ; Longitudinal Studies ; Alzheimer Disease/epidemiology/chemically induced ; }, abstract = {BACKGROUND: Anthracycline plus taxane (ATAX) regimens are associated with improved survival in HER2-negative breast cancer (HBC) compared to taxane-based (TAX) regimens. However, anthracyclines are known for their cardiotoxicity, which could increase the risk of neurocognitive deficits, raising concerns about neurocognitive safety, particularly in older adults. Limited evidence exists comparing neurocognitive outcomes between these two regimens.

OBJECTIVE: To compare the incidence of Alzheimer's disease and related dementias (ADRD) between ATAX and TAX regimens in neoadjuvant (Trial #1) and adjuvant (Trial #2) settings among older women with early-stage HBC.

METHODS: Using SEER-Medicare data (2010-2021), we identified women aged ≥ 66 years with newly diagnosed HBC and no prior neurocognitive conditions between 2011 and 2021. Patients were longitudinally tracked, and their eligibility for each regimen was evaluated. We applied the clone-censor-weight method and used weighted pooled logistic regression to estimate the 10-year risks of ADRD, Alzheimer's disease (AD), and vascular dementia (VD).

RESULTS: We identified 14 079 and 9321 eligible individuals in Trial #1 and Trial #2, respectively. For ADRD outcome, the 10-year risk difference (RD) was -6.91% (95% CI: -15.60% to 0.91%) for HR+/HER2- cohort and -2.14% (95% CI: -9.57% to 5.46%) for TNBC cohort in Trial #1. The 10-year RD was -1.42% (95% CI: -9.33% to 6.98%) for HR+/HER2- cohort and -2.91% (95% CI: -9.54% to 7.86%) for TNBC cohort in Trial #2.

CONCLUSION: Our findings suggest that ATAX regimens were not associated with increased risks of ADRD, AD, and VD compared to TAX regimens in older women with HBC. However, the risks of AD and VD should be interpreted with caution due to sparse events. These findings may support the continued use of ATAX regimens in this population, while also informing more personalized, risk-adapted treatment strategies.}, } @article {pmid42666495, year = {2026}, author = {Hölscher, C}, title = {GLP-1 and GIP class drugs have neuroprotective properties in Alzheimer's and Parkinson's disease.}, journal = {Frontiers in neuroscience}, volume = {20}, number = {}, pages = {1906426}, pmid = {42666495}, issn = {1662-4548}, abstract = {Alzheimer's and Parkinson's disease are two CNS diseases with a large unmet need for disease-modifying therapies. Recently, two phase 3 clinical trials testing the GLP-1 analogue Semaglutide (Wegovy, Ozempic) in patients with Alzheimer's disease did not show improvements. This failure should not have been a surprise, since it has been known for many years that Semaglutide does not cross the blood-brain barrier (BBB) and enters the brain only in very small amounts. It is designed to stay in the blood stream and has a very long half-life in the blood (168 h). The GLP-1 analogue Liraglutide (Victoza), in contrast, has a much shorter half-life (13 h), and a phase 2 clinical trial showed improvements in cognitive tests after 1 year of treatment. GLP-1 receptor agonists have been tested in clinical trials in Parkinson's patients, and a similar picture emerged. Drugs that can cross the BBB well (exenatide, lixisenatide) show good protection, while a drug that cannot cross the BBB showed no effects (NLY01). Clearly, when treating CNS diseases, it is of importance to get the drug into the brain to ensure target engagement. This review will look at the clinical trials that have been conducted in more detail, describe the mode of action as derived from preclinical trials, and discuss novel strategies for getting GLP-1 receptor agonists into the brain to successfully treat CNS diseases.}, } @article {pmid42667351, year = {2026}, author = {Yuan, Y and Liu, P and Yin, C and Zhu, J and Xu, J and Xiong, H and Xu, R}, title = {Mechanism and progress of deep brain stimulation in the treatment of neurological and psychiatric disorders.}, journal = {MedScience}, volume = {}, number = {}, pages = {}, pmid = {42667351}, issn = {3091-4981}, abstract = {Deep brain stimulation (DBS) is a reversible and adjustable neurostimulation technique, and has been established as a significant therapeutic modality in functional neurosurgery although its mechanisms are not yet fully understood. The primary indications for DBS include movement disorders such as Parkinson's disease (PD) and dystonia, essential tremor (ET), and Huntington's disease (HD). In recent years, its application has expanded to encompass the treatment of various other neurological and psychiatric conditions, including epilepsy, depression, obsessive-compulsive disorder (OCD), Alzheimer's disease (AD), and Tourette syndrome (TS), although the indications for DBS currently approved by the Food and Drug Administration (FDA) are PD, dystonia, ET, OCD, and epilepsy. In this review, we summarize the prevailing hypotheses regarding the mechanisms through which DBS ameliorates neurological and psychiatric disorders. We also describe the advancements in DBS for treating PD, dystonia, epilepsy, and other brain disorders. Furthermore, we outline the limitations associated with DBS treatment to date. Through this comprehensive analysis, we aim to enhance the understanding of DBS applications in neurological and psychiatric diseases and suggest potential avenues for technological advancement.}, } @article {pmid42662336, year = {2026}, author = {Reinapu, A and Kirss, S and Tõugu, V and Palumaa, P}, title = {Distinct Effects of Copper Ionophores on Intracellular Copper and Cell Viability in Wild-Type and CTR1-Deficient SH-SY5Y Cells.}, journal = {ACS omega}, volume = {11}, number = {33}, pages = {49807-49814}, pmid = {42662336}, issn = {2470-1343}, abstract = {Copper homeostasis is essential for neuronal function, and its dysregulation has been implicated in neurodegenerative disorders. In particular, reduced intracellular copper levels alongside with elevated extracellular copper concentrations have been associated with Alzheimer's disease (AD). Therefore, strategies aimed at restoring intracellular copper levels represent a potential therapeutic approach. In this study, we investigated the effects of selected copper-binding compounds(?)α-lipoic acid (LA), elesclomol (ES), disulfiram (DSF), thiourea (TU), and triapine (3-AP)(?)on copper uptake and cytotoxicity in SH-SY5Y wild-type (WT) and CTR1-deficient (CTR1[-/-]) cells. Intracellular copper levels were quantified using inductively coupled plasma mass spectrometry (ICP-MS), and cell viability was assessed by using propidium iodide assay under various treatment conditions. Among the tested compounds, LA, ES, and DSF significantly increased intracellular copper levels in both WT and CTR1[-/-] cells, whereas TU and 3-AP did not enhance copper accumulation beyond copper-only treatment. Notably, CTR1[-/-] cells exhibited reduced sensitivity to copper-associated toxicity compared to WT cells. Under copper-supplemented conditions, DSF and ES displayed concentration-dependent cytotoxicity, while LA and TU induced only mild effects. In contrast, 3-AP toxicity was abolished in the presence of copper. Furthermore, cotreatment with LA and copper increased cell proliferation and promoted differentiation-associated morphological changes in CTR1[-/-] cells. Overall, our results demonstrate that copper ionophores can enhance intracellular copper levels dependently and independently of CTR1, with distinct effects on cell viability. Among the tested compounds, LA and DSF showed a favorable profile by increasing copper levels while maintaining low cytotoxicity, highlighting their potential for modulating cellular copper homeostasis.}, } @article {pmid42662931, year = {2025}, author = {Davis, L and Obisesan, T}, title = {The Shifting Treatment Landscape for Alzheimer's Disease in Primary Care.}, journal = {Federal practitioner : for the health care professionals of the VA, DoD, and PHS}, volume = {42}, number = {Suppl5}, pages = {S37-S42}, pmid = {42662931}, issn = {1078-4497}, } @article {pmid42663490, year = {2026}, author = {Dejgaard, MS and Eide, PK and Tangen, GG and Skovlund, E and Selbæk, G and Wyller, TB}, title = {Cognitive profiles in idiopathic normal pressure hydrocephalus and Alzheimer's disease.}, journal = {Journal of Alzheimer's disease : JAD}, volume = {}, number = {}, pages = {13872877261478264}, doi = {10.1177/13872877261478264}, pmid = {42663490}, issn = {1875-8908}, abstract = {BackgroundIdiopathic normal pressure hydrocephalus (iNPH) and Alzheimer's disease (AD) are neurodegenerative disorders with partly overlapping clinical features. Since the treatment is different, we need better knowledge about how the cognitive profile differs between these conditions.ObjectiveWe aimed to compare the cognitive profile of iNPH patients with that of a large cohort of confirmed AD patients.MethodsPatients diagnosed with iNPH and accepted for shunt surgery were compared with patients with biomarker verified Alzheimer's disease in The Norwegian Register of Persons Assessed for Cognitive symptoms (NorCog). All patients underwent a standardized cognitive assessment with age and education adjusted z-scores. We used the Clinical Dementia Rating Scale (CDR) to adjust for disease severity. Since the cognitive score distributions were highly skewed, we used nonparametric analyses stratified by CDR stage combined with multinomial logistic regression.ResultsIn total, 276 iNPH patients were compared to 1113 AD patients. iNPH patients performed significantly poorer on phonemic fluency [median z-score difference (AD-iNPH) 0.30, 95% confidence interval (CI) 0.20 to 0.50], but significantly better on other cognitive tests, in particular immediate (median difference -0.35, 95% CI -0.49 to -0.20) and delayed recall (median difference -0.46, 95% CI -0.59 to -0.34). The differences persisted after adjustment for CDR and were most pronounced in early stages of the disease.ConclusionsiNPH seems to affect phonemic fluency more and memory less than AD. As the disease progresses, the cognitive profiles become more similar, and the conditions cannot be distinguished by cognitive tests.}, } @article {pmid42664573, year = {2026}, author = {Noguchi-Shinohara, M and Muramatsu, D and Shima, A and Sakashita, Y and Tada, Y and Yamaguchi, H and Komatsu, J and Ikeda, T and Ono, K}, title = {Real-world long-term continuation of lecanemab therapy and the clinical utility of phosphorylated tau 181.}, journal = {The journal of prevention of Alzheimer's disease}, volume = {13}, number = {9}, pages = {100664}, doi = {10.1016/j.tjpad.2026.100664}, pmid = {42664573}, issn = {2426-0266}, abstract = {This real-world study evaluated the long-term feasibility of lecanemab treatment in 117 patients with early Alzheimer's disease at Kanazawa University Hospital. To assess treatment persistence over a full 18-month course, we focused on the 64 patients who initiated treatment between January and December 2024. Of these 64 patients, 78.1% completed the full 18-month course, and all 48 eligible patients elected to continue beyond 18 months. The overall discontinuation rate was 21.9%, with amyloid-related imaging abnormalities (ARIA) (27.7%), decreased motivation (22.2%), and cognitive decline (11.1%) as the primary reasons. Among all 117 patients, ARIA occurred in 12.9% and was significantly associated with apolipoprotein Eε4 carrier status, elevated baseline cerebrospinal fluid (CSF)-phosphorylated tau (ptau) 181 (ptau181; ≥78.6 pg/ml), ≥2 microbleeds, and Fazekas score≥2 deep white matter hyperintensity. Elevated CSF-ptau181 also independently predicted cognitive decline during treatment and ARIA-related discontinuation. These findings suggest that integrating CSF-ptau181 measurement and baseline MRI into clinical decision-making may support individualized risk stratification and the safe, sustained use of lecanemab in real-world practice.}, } @article {pmid42654012, year = {2026}, author = {Karageçili, H and Yerlikaya, E and Ertürk, A and Aslan, K and Akıncıoglu, H and Gülçin, İ}, title = {Comprehensive Evaluation of Peonidin: Antioxidant and Multi-Enzyme Inhibitory Abilities with Molecular Docking Insights.}, journal = {Molecules (Basel, Switzerland)}, volume = {31}, number = {16}, pages = {}, pmid = {42654012}, issn = {1420-3049}, mesh = {*Molecular Docking Simulation ; *Antioxidants/chemistry/pharmacology ; *Anthocyanins/chemistry/pharmacology ; Free Radical Scavengers/chemistry/pharmacology ; Humans ; Biphenyl Compounds/chemistry ; Sulfonic Acids/chemistry ; }, abstract = {Anthocyanins are water-soluble plant pigments. They give many plants, fruits, vegetables, and cereal kernels their red, purple, and blue colors. This research aims to reveal the biological properties of peonidin as an anthocyanin. To comprehend the antioxidant capabilities of peonidin, 2,2'-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) radical (ABTS[•+]), N,N-dimethyl-p-phenylenediamine dihydrochloride radical (DMPD[•+]), and 1,1-diphenyl-2-picrylhydrazyl free radical (DPPH[•]) scavenging, Fe[3+]-2,4,6-tris(2-pyridyl)-s-triazine (TPTZ), and Cu[2+] reducing assays were recorded. The IC50 values for peonidin against ABTS[•+], DMPD[•+] and DPPH[•] scavenging capabilities were determined to compare with standard antioxidants. ABTS[•+] radical scavenging activity of peonidin had an IC50 value of 15.40 μg/mL, while the IC50 values for BHA, BHT, Trolox, and α-Tocopherol were 12.82, 11.78, 12.67, and 10.83 μg/mL, respectively. DPPH radical scavenging activity of peonidin had an IC50 value of 41.63 μg/mL, while the IC50 values for BHA, BHT, Trolox, and α-Tocopherol were 8.45, 23.10, 6.30, and 18.73 μg/mL, respectively. Enzyme inhibition was studied to investigate the effects of peonidin. The Ki values of peonidin were 114.33, 63.02, 2.99, 9.76, and 15.14 nM toward hCA I, hCA II, AChE, BChE, and α-glycosidase enzymes, respectively. Furthermore, peonidin's interactions with target enzymes BChE, hCA I, hCA II, AChE, and α-glycosidase were investigated by molecular docking. The results suggest that antioxidant-rich peonidin is a plant-based compound with potential use in the treatment of glaucoma, Alzheimer's disease, and diabetes.}, } @article {pmid42654104, year = {2026}, author = {Farias, G and Chahinian, H and Hauchard, N and Brunet, D and Fantini, J and Yahi, N and Fantini, D and Aulas, A}, title = {An Optimal Spray Device for the Nose-to-Brain Delivery of AmyP53, an Adaptive Therapeutic Peptide for Alzheimer's and Parkinson's Diseases.}, journal = {Pharmaceutics}, volume = {18}, number = {8}, pages = {}, pmid = {42654104}, issn = {1999-4923}, abstract = {Background: Nose-to-brain delivery offers a noninvasive route to bypass the blood-brain barrier for the treatment of neurodegenerative diseases. AmyP53 is a first-in-class adaptive 12-mer peptide that prevents the formation of neurotoxic amyloid oligomers by competitively targeting lipid raft gangliosides on brain cell membranes, thereby blocking the shared pathological mechanism underlying both Alzheimer's and Parkinson's diseases. Objective: Here, we report the identification of optimal spray devices for the nose-to-brain delivery of AmyP53, ahead of a planned Phase 1 clinical trial. Method/Results: Among six devices evaluated (four commercial systems and two novel devices specifically engineered for nose-to-brain delivery), two systems were identified as optimal for further clinical development (narrower plume angles and significantly higher deposition in the olfactory region): the Neurospray™ and Neurospray™ Preservative-Free (PF). AmyP53 was quantitatively and reproducibly delivered by both Neurospray™ systems, retaining full recognition of its therapeutic target (gangliosides), as assessed by a surface pressure-based ganglioside-binding assay. In a rabbit preclinical model, intranasal administration of AmyP53 with the Neurospray™ resulted in rapid and sustained brain delivery, detectable at 10 min and persisting at 24 h post-administration, without significant systemic exposure. Conclusions: These results validate the Neurospray™ drug delivery systems as optimal drug delivery systems for the clinical development of AmyP53.}, } @article {pmid42654386, year = {2026}, author = {Rus Prelog, P and Zupan, M and Šabović, M and Frol, S and Kramberger, MG}, title = {Beyond Amyloid: Systemic and Brain Frailty as Determinants of Response to Anti-Amyloid Therapy in Alzheimer's Disease-A Conceptual Review.}, journal = {Medicina (Kaunas, Lithuania)}, volume = {62}, number = {8}, pages = {}, pmid = {42654386}, issn = {1648-9144}, mesh = {Humans ; *Alzheimer Disease/drug therapy/physiopathology/complications ; *Frailty/physiopathology/complications ; *Brain/physiopathology ; Antibodies, Monoclonal/therapeutic use ; Biomarkers/analysis ; Aged ; Magnetic Resonance Imaging/methods ; *Amyloid ; }, abstract = {Anti-amyloid therapy (AAT) with monoclonal antibodies (mAbs) modestly slow cognitive and functional decline in early Alzheimer's disease (AD). However, both the magnitude of clinical benefit and the risk of treatment-related complications vary substantially even among patients with similar biomarker profiles. Frailty, both brain and systemic, is highly prevalent in older adults with AD and affects a large proportion of those considered for AAT. Despite this, it has been largely absent from current decision frameworks. Brain frailty, defined by structural and microvascular damage (e.g., small-vessel disease, microbleeds, and atrophy), limits the clinical benefit of amyloid clearance and increases susceptibility to amyloid-related imaging abnormalities. In contrast, systemic frailty, reflecting reduced physiological reserve, mainly affects treatment tolerance and recovery from adverse events. In this narrative, conceptual review, we synthesize evidence that both forms of frailty act as biologically grounded modifiers of AAT efficacy and safety and may limit the clinical benefit while increasing susceptibility to complications and decompensation. Importantly, the precise empirical thresholds at which frailty begins to exert harmful effects remain unknown. We further outline how MRI-based markers of brain frailty, combined with brief systemic frailty measures, could support risk stratification, patient selection, monitoring intensity, and shared decision-making, including deferring treatment when the benefit-risk balance is unfavorable, while avoiding exclusion of patients who may still benefit. Taken together, we propose that future studies should incorporate frailty measures and perform precise assessments of both brain and systemic frailty, as this may improve patient stratification and better characterize the effects of AAT.}, } @article {pmid42655989, year = {2026}, author = {Sayyed, N and Afzal, M and Rafeeq, M and Omer, AB and Al-Abbasi, FA and Rahman, S and Al-Zharani, M and Alzarea, SI and Kazmi, I}, title = {Erucic acid arbitrates neuroprotection in streptozotocin-induced memory deficit via improving oxidative stress/neuroinflammatory indicators/cholinergic activity in rodents.}, journal = {Nutritional neuroscience}, volume = {}, number = {}, pages = {1-23}, doi = {10.1080/1028415X.2026.2718394}, pmid = {42655989}, issn = {1476-8305}, abstract = {BACKGROUND: Erucic acid (EA), a monounsaturated omega-9 fatty acid derived from Raphanus sativus L. seeds, has antioxidant and anti-inflammatory properties. This study investigated its neuroprotective effects against streptozotocin (STZ)-induced diabetes-associated cognitive dysfunction in rats.

METHODS: Male Wistar rats were randomly assigned to five groups: normal control, STZ control (60 mg/kg), STZ + EA (10 mg/kg), STZ + EA (20 mg/kg), and EA (20 mg/kg) per se. EA was administered orally for 38 days. Blood glucose and body weight were measured before STZ administration and at the end of the study. Cognitive function was assessed using the Y-maze and Morris water maze (MWM). Cholinergic function, oxidative stress, neurotransmitters, inflammatory mediators, apoptosis, and cellular energy status were evaluated biochemically, and hippocampal histopathology was performed.

RESULTS: EA treatment significantly reduced hyperglycemia and attenuated diabetes-induced body weight loss. EA improved spontaneous alternation in the Y-maze and spatial learning and memory in the MWM, reducing escape latency and increasing target-quadrant time. EA decreased acetylcholinesterase activity while increasing choline acetyltransferase activity, restored antioxidant defenses, and reduced MDA, ROS, and NO levels. It also normalized neurotransmitter levels, suppressed TNF-α, IL-1β, IL-6, NF-κB, and caspase-3, increased IL-10, and improved the ATP/ADP ratio. Histopathology demonstrated preservation of hippocampal neuronal architecture.

CONCLUSIONS: EA ameliorated diabetes-associated cognitive dysfunction by improving learning and memory, preserving cholinergic neurotransmission, reducing oxidative stress and neuroinflammation, inhibiting neuronal apoptosis, and restoring cellular energy metabolism. These findings support the therapeutic potential of EA for managing cognitive impairment associated with diabetes.}, } @article {pmid42656799, year = {2026}, author = {Cecchetto, R and Diani, E and Lotti, V and Palmisano, A and Lagni, A and Mantoan, M and Turrina, S and Raniero, D and Paolone, G and Mazzariol, A and Gibellini, D}, title = {HIV-1 Tat and gp120 as key drivers of neurodegeneration in the central nervous system.}, journal = {Frontiers in microbiology}, volume = {17}, number = {}, pages = {1895162}, pmid = {42656799}, issn = {1664-302X}, abstract = {Combined antiretroviral therapy (cART) has deeply changed the approach to HIV disease treatment. cART tackles HIV replication and improves the life expectancy of HIV-infected people. Notwithstanding the effectiveness of cART in HIV infection control, several observations have determined that 15-50% of HIV-infected people display HIV-associated neurocognitive disorders (HAND) even under long-term viral suppression. Persistent production of the viral proteins Tat and gp120 by central nervous system reservoirs drives chronic neurotoxicity due to their remarkable extracellular stability and efficient uptake by neurons and glial cells. In this review, we will discuss current evidence on the molecular mechanisms by which extracellular Tat and gp120 orchestrate neurodegeneration. Four principal interconnected pathways emerge: (i) mitochondrial dysfunction; (ii) synaptodendritic injury; (iii) chronic neuroinflammation; and (iv) crosstalk with Alzheimer's disease (AD) pathways. Converging data achieved from in vitro models, Tat and gp120-transgenic mice, post-mortem tissue, and cerebrospinal fluid (CSF) biomarkers indicate that these viral proteins contribute to frontostriatal atrophy and hybrid HAND-AD phenotypes increasingly observed in aging HIV patients. Understanding these mechanisms highlights the need for adjunctive neuroprotective strategies targeting CXCR4/CCR5 signaling, mitochondrial quality control, inflammatory pathways, and Aβ/Tau homeostasis derangement and supports the integration of multimodal neuroimaging and CSF proteomics in future longitudinal studies aimed at improving diagnosis and therapeutic development.}, } @article {pmid42657250, year = {2026}, author = {Napoleon, T and Akinrinde, D and Femi-Lawal, VO and Adebajo, GO and Yokolo, H and Okei, FU and Alabi, G and Ifeoluwa, OI and Lawal, SO and Abati, SO and Duru, CN and Oluwatosin, O and Sanusi, IO and Solomon, AO and Clement, A and Bello, T and Egwu, EO and Chukwuemeka, EK}, title = {Repetitive Transcranial Magnetic Stimulation in Alzheimer's Disease Cognitive Impairment: A Narrative Review of Clinical Trials.}, journal = {Health science reports}, volume = {9}, number = {9}, pages = {e73104}, pmid = {42657250}, issn = {2398-8835}, abstract = {BACKGROUND AND AIMS: Alzheimer's disease (AD), primarily characterized by cognitive impairment, places an immense burden on patients and caregivers. Non-invasive neuromodulation with repetitive transcranial magnetic stimulation has been proposed to improve cognition in mild to moderate AD. This narrative review aimed to summarize clinical trial evidence on the effects, safety, and tolerability of rTMS for AD-related cognitive impairment and to identify research gaps.

METHODS: A narrative review of clinical trials was performed. PubMed/MEDLINE, Embase, Cochrane Google scholar, and Scopus were searched from inception to January 25, 2025, using terms for "repetitive transcranial magnetic stimulation", "Alzheimer's disease", "cognitive impairment", "clinical trials", and "randomized controlled trial". Clinical trials of active rTMS versus sham or treatment-as-usual in adults with mild to moderate AD that reported validated cognitive outcomes were included. Data on rTMS protocols, cognitive measures, adverse effects, and follow-up were extracted and synthesized narratively without statistical pooling.

RESULTS: 14 trials were included. Across most studies, rTMS delivered at 5-20 Hz for 4 to 12 weeks, at least 5 days per week, was associated with improved cognitive function. Improvements were reported on tools such as the MMSE, CDR-SB, SIB, and ADAS-Cog, with statistically significant differences versus sham in most trials [p < 0.05], and some evidence of sustained benefit at follow-up. rTMS was generally safe and tolerable. Reported adverse effects were mild to moderate and included transient headache, scalp or skin discomfort, pain, and fatigue. Preliminary evidence also suggested potential neuropsychiatric benefits. However, substantial heterogeneity in duration, frequency, treatment plan, targets, and outcome measures limited definitive conclusions.

CONCLUSION: rTMS appears safe in the short term and may be linked to short-term cognitive and neuropsychiatric gains in mild to moderate AD. However, marked protocol heterogeneity, small sample sizes, short follow-up, and risk of bias limit certainty and prevent identification of optimal parameters. rTMS is not ready for routine AD care. Larger, sham-controlled trials with standardized protocols and biomarker or long-term outcomes are needed.}, } @article {pmid42657669, year = {2026}, author = {Romano, CD and Bratlee-Whitaker, E and Hartry, A and Taylor, J and Callahan, LF and Monks, D and Kremer, I and Lappin, D and Frangiosa, T and Sangodkar, S and Lee, J and Shirneshan, E and Slowiejko, D and DiBenedetti, D and Herring, WL and Bussberg, C and Dardis, GJ and Goss, D and Edwards, T and McLeod, L and Poulos, C and Paulsen, R}, title = {Priorities of people living with Alzheimer's and care partners: What Matters Most?.}, journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association}, volume = {22}, number = {8}, pages = {e71554}, pmid = {42657669}, issn = {1552-5279}, support = {//UsAgainstAlzheimer's/ ; }, mesh = {Humans ; *Alzheimer Disease/psychology ; Female ; Male ; *Caregivers/psychology ; Cross-Sectional Studies ; Aged ; Aged, 80 and over ; Qualitative Research ; Activities of Daily Living ; Middle Aged ; Surveys and Questionnaires ; }, abstract = {INTRODUCTION: Understanding the experience of people living with Alzheimer's disease (PLWAD) and care partners is central to defining meaningful treatment outcomes. The What Matters Most (WMM) research program seeks to identify and measure treatment-related needs, preferences, and priorities across the disease continuum.

METHODS: This mixed-methods, observational, US-based study included qualitative interviews and a cross-sectional, web-based quantitative survey assessing priorities among WMM model concepts and domains.

RESULTS: Racially and ethnically diverse participants represented the full spectrum of disease severity. Qualitative interviews (N = 64) supported a WMM conceptual model of disease comprising 50 concepts across six domains: General Independence, Thought Processing, Communication, Daily Activities, Emotions, and Social Life/Activities. All WMM concepts were deemed important, but the quantitative survey priority ranking (N = 640) identified differences in prioritization among PLWAD and care partners.

DISCUSSION: These findings provide novel, critical insights into the lived experience of Alzheimer's disease (AD) and the identification of meaningful treatment outcomes.}, } @article {pmid42661318, year = {2026}, author = {Kiyota, M and Jin, Y and Nemoto, N and Kakikawa, M}, title = {Low-frequency magnetic fields can improve behavioral abnormalities and suppress Aβ accumulation detected by thioflavin T in Caenorhabditis elegans models of Alzheimer's disease.}, journal = {Electromagnetic biology and medicine}, volume = {}, number = {}, pages = {1-8}, doi = {10.1080/15368378.2026.2722639}, pmid = {42661318}, issn = {1536-8386}, abstract = {Amyloid β (Aβ) accumulation and Aβ-related senile plaques, the pathological hallmarks of Alzheimer's disease (AD), damage neurons and impair cognitive functions in patients. Previous studies have shown that low‑field magnetic stimulation attenuates Aβ and enhances cognitive performance. In this study, AD models of Caenorhabditis elegans expressing Aβ in the nerves were placed in a low-frequency magnetic field (LFMF) and then subjected to a chemotaxis assay to evaluate attractive behavior. In control C. elegans (CL2122), which do not express Aβ but carried only the vector, the chemotactic behavior was normal and unaffected by LFMF. In contrast, in the AD model expressing Aβ within the nervous system, abnormalities in chemotactic behavior were observed; however, these were improved in a manner dependent on LFMF strength. In addition, the AD model expressing Aβ in the muscle exhibited paralysis, which was significantly attenuated by LFMF. Thioflavin T staining revealed that, in the AD model expressing in muscles, Aβ accumulation declined in the LFMF-treated group compared to that of the non-LFMF group. These results suggest that LFMF can improve abnormal chemotactic behavior and attenuate Aβ-induced paralysis by suppressing the accumulation and aggregation of Aβ in a C. elegans model of AD.}, } @article {pmid42644373, year = {2026}, author = {Jiyah, A and Bulama, I and Onu, A and Gimba, AY and Abbas, AY and Saidu, Y and Bilbis, LS and Muhammad, SA}, title = {Turmeric nanovesicles loaded with vitamins C and E attenuate oxidative stress and improve cognitive outcomes in rats with memory deficits.}, journal = {Therapeutic delivery}, volume = {}, number = {}, pages = {1-14}, doi = {10.1080/20415990.2026.2715894}, pmid = {42644373}, issn = {2041-6008}, abstract = {AIM: Oxidative stress (OS) contributes to Alzheimer's disease (AD) pathology. Vitamins C and E target OS, but their efficacies are limited by poor intracellular delivery. Encapsulation in nanovesicles (NVs) may improve targeted delivery for AD treatment.

METHODS: Forty-five rats were randomly assigned to nine groups (n = 5 per group): normal control, scopolamine control, vitamin C, vitamin E, vitamin C + E, turmeric NVs (TNV), TNV-C, TNV-E, and donepezil. Treatment was administered intraperitoneally (IP) for one week before induction of the AD-like model using daily IP administration of scopolamine and continued for two weeks. During this time, behavioral activities were conducted, and brain tissues were collected for analysis.

RESULTS: Vitamins C and E showed encapsulation efficiencies of 12.36 ± 1.01% and 55.24 ± 5.82%, with loading capacities of 14.34 ± 1.37% and 40.70 ± 3.52, respectively. TNV-C and TNV-E increased brain levels of vitamins E and C, enhanced antioxidant defense and cognitive abilities, and reduced acetylcholinesterase activity in dementia rats. TNV-C and TNV-E also protected against neuroinflammation and neuritic plaque formation. Vitamin-loaded TNVs were more effective than free vitamins in improving antioxidant status and cognitive outcomes in AD rats.

CONCLUSION: This study highlights the potential of vitamin-loaded NVs as therapeutics for AD.}, } @article {pmid42644414, year = {2026}, author = {Hendrix, S and Mallinckrodt, C and Abschneider, RM and Atri, A and Bendtsen, MD and Colombo, TL and Feldman, HH and Johannsen, P and Cummings, J}, title = {Estimating treatment effects in clinical studies of Alzheimer's disease: What are estimands and why do we need them?.}, journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association}, volume = {22}, number = {8}, pages = {e71676}, pmid = {42644414}, issn = {1552-5279}, support = {//Novo Nordisk/ ; }, mesh = {*Alzheimer Disease/drug therapy ; Humans ; Semaglutide ; Antibodies, Monoclonal, Humanized/therapeutic use ; *Clinical Trials as Topic ; Treatment Outcome ; *Research Design ; }, abstract = {In clinical studies, it is scientifically important, and a regulatory expectation, that objectives be translated into key clinical questions by specifically defining treatment effects to be estimated. Estimands are part of a structured framework, as presented in International Council for Harmonisation (ICH) E9(R1), by which study objectives are linked to a suitable study design and tools for estimation. Estimands are constructed using five attributes: treatment, population, variable (or endpoint), population-level summary for the variable, and intercurrent events (ICEs). ICEs occur after treatment initiation and can affect the existence or interpretation of the measurements. In Alzheimer's disease (AD), potential ICEs include additional AD medication use, discontinuation of treatment, and death. We describe estimands in recent clinical studies of anti-amyloid therapies, including gantenerumab, lecanemab, and donanemab, in AD and use the evoke and evoke+ studies of semaglutide in early-stage symptomatic AD as examples of estimand application in AD trials.}, } @article {pmid42645044, year = {2026}, author = {Gao, F and Liu, L and Li, J and Chen, S and Yi, X}, title = {Overview in Electrochemical and Electrical Biosensors for Determining Blood Protein Biomarkers of Alzheimer's Disease.}, journal = {Biosensors}, volume = {16}, number = {8}, pages = {}, pmid = {42645044}, issn = {2079-6374}, mesh = {*Alzheimer Disease/blood/diagnosis ; Humans ; *Biosensing Techniques ; *Biomarkers/blood ; *Electrochemical Techniques ; *Blood Proteins/analysis ; Amyloid beta-Peptides/blood ; }, abstract = {Early diagnosis of Alzheimer's disease (AD) can facilitate the establishment and implementation of therapeutic interventions. The currently used diagnosis methods for AD mainly include cerebrospinal fluid analysis and positron emission tomography imaging. Due to their high invasiveness, high cost, and limited accessibility, these technologies are difficult to meet the needs of large-scale population screening, grading diagnosis, and treatment, thereby limiting the popularization of early diagnosis of AD. The detection of blood biomarkers has become an important breakthrough in early screening and diagnosis of different diseases due to its non-invasive, low-cost, and easy-to-operation advantages. Recently, blood proteins such as amyloid-beta (Aβ), total and phosphorylated Tau, light chain neurofilaments (NFL), and glial fibrillary acidic protein (GFAP) have been considered promising biomarkers for the diagnosis of AD. However, there is currently no effective, minimally invasive, and easily accessible detection method for clinical diagnosis and risk prediction of AD. Electrochemical and electrical biosensors are highly sensitive, simple, fast, and cost-effective analytical tools for disease monitoring, drug development, and target detection. In this work, we comprehensively and systematically overview the progress of various electrochemical and electrical techniques for determining AD-related blood protein biomarkers, mainly including electrochemistry, electrochemiluminescence, photoelectrochemistry, quartz crystal microbalance, field-effect transistor, and organic electrochemical transistor. This work can provide guidance for researchers to develop novel electrochemical and electrical biosensors for early and accurate diagnosis of AD.}, } @article {pmid42645215, year = {2026}, author = {Saitta, A and Basilotta, R and Lanza, M and Scuruchi, M and Casili, G and Giovani, P and Copani, A and Esposito, E and Oddo, S and Caccamo, A}, title = {Isoserine Improves Spatial Memory and Remodels Synaptic and Inflammatory Gene-Expression Programs in APP/PS1 Mice.}, journal = {Cells}, volume = {15}, number = {16}, pages = {}, pmid = {42645215}, issn = {2073-4409}, support = {2022B7AFK2//Ministero dell'università e della ricerca/ ; }, mesh = {Animals ; *Spatial Memory/drug effects ; *Synapses/drug effects/metabolism/genetics ; Mice ; *Amyloid beta-Protein Precursor/metabolism/genetics ; Mice, Transgenic ; Alzheimer Disease/genetics/drug therapy ; Male ; *Inflammation/genetics ; *Gene Expression Regulation/drug effects ; *Presenilin-1/metabolism/genetics ; Disease Models, Animal ; Receptors, N-Methyl-D-Aspartate/metabolism ; Maze Learning/drug effects ; }, abstract = {Synaptic dysfunction is a major contributor to cognitive decline in Alzheimer's disease (AD) and represents an attractive therapeutic target. Here, we investigated whether chronic isoserine treatment improves cognition and alters the expression of synaptic-related genes in APP/PS1 mice. Isoserine was well tolerated and did not adversely affect body weight. In the Morris water maze, isoserine improved probe-trial performance in APP/PS1 mice, significantly reducing latency to the first platform-location crossing, while time spent in the target quadrant showed a directionally consistent but non-significant increase. To identify molecular correlates, we profiled 84 synaptic-related genes using a targeted RT[2] Profiler PCR Array. Gene-level factorial analyses identified several nominal treatment-associated effects, but no individual isoserine effect in APP/PS1 mice remained significant after false-discovery-rate correction. In contrast, module-level analyses identified False-discovery rate (FDR)-significant changes in NF-κB/inflammatory, synaptic-maintenance, and glutamatergic-signaling gene-expression modules, with significant genotype × treatment interactions for the NF-κB/inflammatory and synaptic-maintenance modules. Exploratory heatmap and principal component analyses further illustrated disease-context-dependent expression patterns. Western blot analyses showed that isoserine reduced nuclear factor kappa B (NF-κB p65) and NMDA receptor subunit GluN2B (GluN2B) and increased postsynaptic density protein 95 (PSD-95) levels in APP/PS1 mice. These findings suggest that isoserine improves spatial memory retention and coordinately remodels synaptic and inflammatory molecular programs in APP/PS1 mice.}, } @article {pmid42645689, year = {2026}, author = {Wu, Z and Kong, N}, title = {Exosomes: Mechanisms, Diagnosis, and Therapeutic Progress in Vascular Cognitive Impairment.}, journal = {Molecular neurobiology}, volume = {63}, number = {1}, pages = {}, pmid = {42645689}, issn = {1559-1182}, mesh = {*Exosomes/metabolism ; Humans ; Animals ; *Dementia, Vascular/diagnosis/therapy/metabolism ; *Cognitive Dysfunction/diagnosis/therapy/metabolism ; }, abstract = {Vascular cognitive impairment and dementia (VCID) is a cognitive impairment syndrome triggered by cerebrovascular lesions and their associated risk factors, representing the second most prevalent cognitive disorder after Alzheimer's disease (AD). Currently, there are no disease-modifying therapies available for VCID. In recent years, significant progress has been made in the study of exosomes in the context of neurodegenerative diseases (NDs). Given the shared pathophysiological features and underlying heterogeneity between VCID and neurodegenerative disorders, it is hypothesized that exosomes may play a critical role in the pathogenesis, diagnosis, and treatment of VCID. This review systematically summarizes recent advances in the study of exosomes in VCID, elaborates on the potential mechanisms by which exosomes influence the onset and progression of VCID, and highlights their promising applications in the diagnosis and treatment of the condition. In conclusion, exosome-based research offers novel perspectives and strategies for the clinical diagnosis and intervention of VCID, potentially leading to more effective options for affected patients.}, } @article {pmid42646579, year = {2026}, author = {Calabrò, RS and Calderone, A and Ravi, D and Galipò, C and Crupi, MF and Quartarone, A}, title = {Hospital-to-Home Neurological Transition Care: A Scoping Review Across Selected Chronic Neurological Disorders.}, journal = {Medical sciences (Basel, Switzerland)}, volume = {14}, number = {4}, pages = {}, pmid = {42646579}, issn = {2076-3271}, mesh = {Humans ; *Nervous System Diseases/therapy ; *Transitional Care ; Multiple Sclerosis ; Hospitalization ; Chronic Disease ; Amyotrophic Lateral Sclerosis ; }, abstract = {BACKGROUND: Returning home after neurological hospitalization, rehabilitation, or specialist care transfers responsibility to patients, caregivers, and community services. We mapped mechanisms and gaps across dementia/Alzheimer's disease and related dementias (ADRD), Parkinson's disease (PD), multiple sclerosis (MS), and amyotrophic lateral sclerosis (ALS).

METHODS: Following JBI guidance and PRISMA-ScR, eligibility was derived using population-concept-context. We included empirical reports involving adults with a target condition, a post-discharge, return-home, rehabilitation, telehealth, caregiver, treatment, respiratory, or palliative continuity component, and post-transition patient, caregiver, service, safety, rehabilitation, equity, or implementation outcomes. Five databases were searched through to 11 May 2026. Two reviewers independently screened records; charting and classification were verified by R.S.C., A.C., and A.Q.

RESULTS: Of 24,417 records, 69 reports were included: Dementia/ADRD, 28; PD, 10; MS, 9; and ALS, 22. Eighteen were core transition reports (26.1%), 14 return-home/community re-entry reports (20.3%), 16 adjacent continuity reports (23.2%), and 21 companion/secondary reports (30.4%). Dementia/ADRD provided discharge-anchored evidence; PD and MS mapped functional carry-over; ALS mapped adjacent respiratory, telehealth, and palliative continuity.

CONCLUSIONS: The main contribution is an operational cross-disease framework separating direct discharge, return-home, adjacent-continuity, and companion evidence while linking mechanisms to disease-specific pathways. This framework maps disease-specific functions, not comparative effectiveness. The proposed frameworks are author-derived and hypothesis-generating. Future studies should use explicit anchors, standardized outcomes, longer follow-up, and equity-sensitive implementation measures addressing caregiver workload, digital access, feasibility, and sustainability. They inform testable, context-sensitive intervention designs for future neurological transition-care research and practice.}, } @article {pmid42648539, year = {2026}, author = {Shi, K and Luo, XY and Liu, TT and Liu, WZ and Dong, YF and Zheng, FB and Zhou, X and Xing, JS and Sun, ZH and Chen, QQ and Jiang, L and Tan, CC and Tan, L and Xu, W and , }, title = {Cerebral amyloid-β burden and white matter injury: associations, clues for underlying mechanisms, and implication on cognitive trajectory after lecanemab therapy.}, journal = {Journal of advanced research}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.jare.2026.08.057}, pmid = {42648539}, issn = {2090-1224}, abstract = {INTRODUCTION: White matter hyperintensities (WMH) are linked to cognitive decline and risk of Alzheimer's disease (AD).

OBJECTIVES: To test whether amyloid-β (Aβ) deposition contributes to white matter injury and whether WMH dynamics can modulate the clinical efficacy of the anti-Aβ therapy.

METHODS: Twenty patients with early AD who are receiving lecanemab and a matched cohort of 110 untreated AD patients were followed. Linear mixed-effects models were used to examine the interplay between WMH trajectories and lecanemab on cognitive decline. The roles of Aβ burden in predicting baseline severity and progression rates of WMH were evaluated in a larger cohort of 1,031 adults. Finally, cerebrospinal fluid (CSF) proteomic and bioinformatic analyses were performed to identify potential candidate mediators and pathways linking Aβ to WMH progression.

RESULTS: Following lecanemab treatment (median = 13 times), 80 % of patients showed WMH reductions, predominantly in periventricular and frontoparietal regions. Compared to the reference cohort, WMH progression is significantly slower among those with anti-Aβ therapy. WMH trajectory significantly modified the relationship between anti-Aβ therapy and cognitive decline, with greater cognitive improvement observed among those with smaller WMH reductions. The levels of Aβ burden were correlated with higher burden and accelerated rates of WMH. Eight proteins in CSF were identified as candidate mediators linking WMH to Aβ. They were enriched in vascular-endothelial, neuro-cytoskeletal, and neuroinflammation pathways.

CONCLUSION: The interplay of Aβ with white matter integrity contributes to cognitive decline in the context of Alzheimer's disease.}, } @article {pmid42650743, year = {2026}, author = {Zhou, Y and Diao, Y and Yan, Z and Shui, X and Huang, Z and Sun, Y and Wang, S and Xia, Y and Lee, TH and Wang, L}, title = {Development of a Novel AAV-Mediated microRNA Gene Therapy for Spatial Suppression of BACE1 to Improve Cognitive Function in Alzheimer's Disease Model Mice.}, journal = {Biomolecules}, volume = {16}, number = {8}, pages = {}, doi = {10.3390/biom16081075}, pmid = {42650743}, issn = {2218-273X}, support = {82401642, 82404101, 82271449 and 82571556//National Natural Science Foundation of China/ ; 2022J01666//Fujian Provincial Department of Science and Technology/ ; 2025Y9117, 2024Y9094 and 2023Y9008//Fujian Provincial Department of Science and Technology/ ; }, mesh = {Animals ; *MicroRNAs/genetics/metabolism ; *Alzheimer Disease/therapy/genetics/metabolism ; *Amyloid Precursor Protein Secretases/genetics/metabolism/antagonists & inhibitors ; *Aspartic Acid Endopeptidases/genetics/metabolism/antagonists & inhibitors ; *Dependovirus/genetics ; *Genetic Therapy/methods ; Mice ; Disease Models, Animal ; Humans ; *Cognition ; Gene Therapy Agents ; Hippocampus/metabolism ; Male ; }, abstract = {The beta-site amyloid precursor protein (APP)-cleaving enzyme 1 (BACE1) is a promising and rational target for Alzheimer's disease (AD), but current clinical trials have been disappointing. Consequently, utilizing the intrinsic regulatory mechanisms of BACE1 during AD pathogenesis might provide valuable insights into the treatment of this devastating disease. In this study, we proposed a combination of AAV delivery and microRNA therapeutics targeting AD at its root by sustained and spatial inhibition of BACE1 with a single therapeutic injection. We demonstrate that upregulation of BACE1 is correlated with downregulation of miR-143-3p in the hippocampus of individuals with AD, and miR-143-3p can directly target BACE1 to inhibit Aβ generation. In the brains of 5×FAD model mice, BACE1 levels are found to be elevated with age in the cornu ammonis 1 (CA1) subfield of the hippocampus. AAV-mediated miR-143-3p restoration in the hippocampal CA1 subfield of AD mice can improve cognitive performance, attenuate BACE1 expression, reduce Aβ levels, induce microglia polarization toward the anti-inflammatory phenotype, modulate neural-related genes including Gal3, and promote synaptic functions. Collectively, the AAV-mediated microRNA gene therapy approach developed for spatial suppression of BACE1 can effectively enhance cognitive performance in AD model mice, offering an attractive therapeutic option for AD treatment with long-lasting efficacy.}, } @article {pmid42651097, year = {2026}, author = {Heath, S and Ruzicka, M and McLoon, T and Gupta, D and Emeri, O and Nnabugwu, Z and Adeniji, A and Brackett, C and Slack, S and Agbowuro, A}, title = {The Role of the NMDA Receptor in the Treatment of Psychiatric and Neurological Diseases.}, journal = {Brain sciences}, volume = {16}, number = {8}, pages = {}, doi = {10.3390/brainsci16080786}, pmid = {42651097}, issn = {2076-3425}, abstract = {The N-methyl-D-aspartate receptor (NMDAR) is an ionotropic glutamate receptor widely expressed in the CNS and in peripheral tissues where it mediates crucial physiological functions and its dysregulation has been linked to a host of neurological and psychiatric disorders including Alzheimer's disease, schizophrenia, epilepsy, and chronic pain. This work highlights the therapeutic potential in targeting the NMDAR in these disease states by providing a holistic analysis of the existing literature focused on the molecular role of the receptor in applicable disease conditions. While several drugs targeting the NMDAR have been approved for clinical use, many more are in clinical and preclinical development. A significant part of this review assesses the chemical and pharmacological attributes of these molecules and provides a prognostic perspective for their use.}, } @article {pmid42651126, year = {2026}, author = {Wang, H and Wang, Y and Lv, Z and Deng, Y and Pan, C and Li, Y and Zhou, Z}, title = {State-Dependent Alterations of Hippocampal Theta-Gamma Coupling in 5xFAD Mice and Their Differential Modulation by Donepezil.}, journal = {Brain sciences}, volume = {16}, number = {8}, pages = {}, doi = {10.3390/brainsci16080816}, pmid = {42651126}, issn = {2076-3425}, support = {2025ZD1801202//National Science and Technology Major Project/ ; }, abstract = {BACKGROUND/OBJECTIVES: Alzheimer's disease (AD) is associated with progressive hippocampal circuit dysfunction, but electrophysiological measures of state-dependent abnormalities and treatment responsiveness remain incompletely characterized. We examined hippocampal theta-gamma coupling in 5xFAD mice across behavioral states and after donepezil.

METHODS: Local field potentials were recorded from CA1 in freely behaving wild-type (WT) and 5xFAD mice during home-cage activity, open-field exploration, and Y-maze testing. Power spectral density and theta-gamma phase-amplitude coupling (PAC) were quantified at the animal level at baseline and after seven days of donepezil.

RESULTS: Untreated 5xFAD mice showed reduced theta-low-gamma coupling during home-cage and open-field activity, but not Y-maze exploration, and elevated theta-high-gamma coupling in all three contexts. Donepezil increased theta-low-gamma coupling during open-field and Y-maze exploration and produced a partial numerical shift toward WT levels in the home cage. For theta-high-gamma coupling, the treated group did not differ significantly from either comparator. Untreated 5xFAD mice also showed reduced center exploration and distance traveled in the open field, while Y-maze spontaneous alternation was unchanged. Theta-high-gamma coupling correlated positively with open-field center time in WT mice only.

CONCLUSIONS: Hippocampal theta-gamma coupling shows frequency- and context-dependent abnormalities in 5xFAD mice. Theta-low-gamma coupling is sensitive to short-term cholinergic modulation during exploration, whereas donepezil's effect on theta-high-gamma coupling remains inconclusive. Animal-level PAC may provide a candidate functional readout, but longitudinal and cross-model validation is required before biomarker claims are justified.}, } @article {pmid42651656, year = {2026}, author = {Ding, X and Wang, P and Zhou, L and Li, X}, title = {Revealing the Mechanisms of Alzheimer's, Parkinson's and Huntington's Diseases Through Invertebrate Models.}, journal = {Biology}, volume = {15}, number = {16}, pages = {}, doi = {10.3390/biology15161351}, pmid = {42651656}, issn = {2079-7737}, support = {X2026161//College Students' Innovation and Entrepreneurship Training Program/ ; }, abstract = {The neural circuits of the human brain are highly complex (due to the number of neurons and the diversity of synaptic connections), hindering the analysis of the pathological mechanisms of neurodegenerative diseases. Invertebrates with simple yet well-differentiated nervous systems have a natural advantage over mammalian model organisms in the identification of pathogenic genes and functional studies of neurodegenerative diseases. They can provide unique and profound insights into the pathogenesis of complex human neurodegenerative diseases and the formulation of intervention strategies. This article reviews the conserved mechanisms of three neurodegenerative diseases across species, including protein homeostasis imbalance and aggregation toxicity, mitochondrial dysfunction and metabolic abnormalities, axonal transport defects, and loss of synaptic function. Based on research on three invertebrates in the field of neurodegeneration, namely Caenorhabditis elegans (C. elegans), Drosophila melanogaster (D. melanogaster), and Bombyx mori (B. mori), we cover three major types of neurodegenerative diseases: Alzheimer's disease (AD), Parkinson's disease (PD), and Huntington's disease (HD). The aim is to find important inspirations for the future prevention and treatment of neurodegenerative diseases from the aspects of the material basis and existing treatment strategies.}, } @article {pmid42652920, year = {2026}, author = {Jehu, DA and Hanson, M and Huang, Y and Soares, A and Hergott, C and Waller, JL and Young, L and Hall, W and Robinson-Johnson, D and Allen, C and Sams, R and Carrick, RM and Fulzele, S and Hamrick, M and Zhu, H and Dong, Y}, title = {Multifactorial Exercise and Inflammatory Responses in Dementia: Findings from a Randomized Controlled Trial Secondary Analysis.}, journal = {Life (Basel, Switzerland)}, volume = {16}, number = {8}, pages = {}, doi = {10.3390/life16081230}, pmid = {42652920}, issn = {2075-1729}, support = {IGPCT00028//Augusta University/ ; IGPP00033//Augusta University/ ; P01 AG036675 (Core C)//NIA/ ; }, abstract = {The objective of this randomized controlled trial was to evaluate the impact of a multifactorial exercise program on circulating inflammation in people living with dementia (PWD) in residential care. This parallel-group, 6-month assessor-blinded trial (NCT05488951) allocated (1:1) 42 PWD to a multifactorial exercise intervention or usual care alone in residential care settings between July 2022 and January 2023. The exercise group engaged in 30 min of physical therapist-led strength and balance training, followed by 30 min of walking 3 x/week over 6 months, and received usual care. The usual care group only received care from healthcare providers, ongoing medical treatment, and opportunities to participate in social activities. Fasted blood was drawn at baseline and 6 months. Intention-to-treat (ITT) and per-protocol (PP; ≥2 x/week exercise vs. usual care) analyses were conducted. The ITT analysis revealed no differences between groups over time (p > 0.05). In adjusted PP analyses, there was a group-by-time interaction trend resulting in decreases in IL-1β (-3.6; +5.0 pg/mL) and IL-8 (-13.4; +14.0 pg/mL) in the exercise group compared with usual care (IL-1β: p = 0.089; IL-8: p = 0.087). Findings suggest adherence-dependent reductions in pro-inflammatory cytokines, indicating potential benefits of exercise. However, this trial was not powered for this secondary analysis, necessitating the need for larger, adequately powered trials.}, } @article {pmid42653437, year = {2026}, author = {Khan, A and Khan, H and Park, IH and Aldahmash, BA and Khan, MS and Yang, G and Kang, KS}, title = {Alkaloids as Emerging Neuroprotective Agents for Neurodegenerative Disorders: Insights into Tryptanthrin and Its Derivatives.}, journal = {International journal of molecular sciences}, volume = {27}, number = {16}, pages = {}, doi = {10.3390/ijms27167436}, pmid = {42653437}, issn = {1422-0067}, mesh = {Humans ; *Neuroprotective Agents/therapeutic use/pharmacology/chemistry ; *Quinazolines/therapeutic use/chemistry/pharmacology ; *Neurodegenerative Diseases/drug therapy/metabolism ; Animals ; Oxidative Stress/drug effects ; *Alkaloids/therapeutic use/pharmacology/chemistry ; }, abstract = {Neurodegenerative conditions are incurable, progressive disorders characterized by the slow and irreversible loss of neurons. This neuronal loss can lead to several neuropsychiatric disorders and long-term complications. Despite significant advances in understanding the mechanisms of neurodegenerative disease, currently, there is no cure for neurodegenerative diseases, highlighting the urgent need for novel neuroprotective strategies. Alkaloids are an important class of bioactive substances that exhibit neuroprotection against several neurodegenerative diseases. Tryptanthrin, an indoloquinazoline alkaloid, shows strong anti-inflammatory, antioxidant, and neuroprotective properties. In this review, we described the pathophysiology of neurodegenerative diseases and summarized several alkaloids' neuroprotective properties. Furthermore, we showed protective benefits of tryptanthrin and its derivatives against neurodegenerative illnesses, focusing on their modulation of oxidative stress, neuroinflammation, neuronal death, and related signaling pathways in cellular and animal models of neurodegenerative diseases. However, various challenges, such as clinical evidence, pharmacokinetic studies, and long-term treatment effects, are not well documented. Future research on tryptanthrin and its derivatives should focus on the optimization of drug delivery methodologies and clinical studies to establish its potential as a therapeutic candidate for neurodegenerative diseases.}, } @article {pmid42653654, year = {2026}, author = {Choi, IA and Yun, JH and Lee, J and Choi, DH}, title = {Therapeutic Potential of 2-(2-Benzofuranyl)-2-Imidazoline in Preclinical CNS Models: A Systematic Review of Mechanisms, Disease Models, and Cellular Targets.}, journal = {Pharmaceuticals (Basel, Switzerland)}, volume = {19}, number = {8}, pages = {}, doi = {10.3390/ph19081155}, pmid = {42653654}, issn = {1424-8247}, support = {RS-2025-23963199//Ministry of Science and ICT/ ; }, abstract = {Background/Objectives: 2-(2-Benzofuranyl)-2-imidazoline (2-BFI) is a selective imidazoline I2-site ligand that has shown neuroprotective and neuromodulatory effects in preclinical central nervous system (CNS) studies. However, the primary preclinical literature remains fragmented across disease models, outcome types, mechanistic endpoints, and cellular targets, making it difficult to define where its therapeutic-development potential is strongest and how disease- or model-specific functional effects relate to molecular, cellular, tissue, and blood-brain barrier/neurovascular unit (BBB/NVU)-related findings. Methods: This systematic review integrated preclinical evidence from 36 original studies identified in the PubMed, Web of Science, Embase, and Scopus databases through searches last updated on May 19, 2026, to evaluate the strength of evidence for 2-BFI across CNS-related models and to connect functional, molecular, cellular, and neurovascular findings. The evidence categories included ischemic stroke/neurovascular outcomes (n = 13), traumatic CNS injury (n = 2), neuroinflammatory/neurodegeneration-related models (n = 9), behavioral pharmacology (n = 8), and cellular mechanisms (n = 4). Eligible studies were original CNS-related animal, cellular, or behavioral/pharmacological studies that directly evaluated 2-BFI and reported neuroprotective, neurological, cellular, molecular, vascular, inflammatory, neurotransmitter-related, or behavioral outcomes. Findings were synthesized qualitatively, and risk of bias in in vivo animal studies was assessed using SYRCLE's risk-of-bias tool. Results: The most extensive preclinical evidence was found in ischemic stroke and neurovascular injury models, in which 2-BFI attenuated infarct size, neurological deficits, and edema, and suppressed apoptosis-related injury and blood-brain barrier/neurovascular unit (BBB/NVU) disruption. Across models, these effects are best interpreted as modulation of interconnected secondary injury processes involving N-methyl-D-aspartate receptor (NMDAR)/Ca[2+]-dependent excitotoxicity, oxidative and mitochondrial stress, inflammatory amplification, regulated cell death, and neurovascular destabilization. Evidence from traumatic CNS injury, autoimmune neuroinflammation, Alzheimer's disease-related models, chronic epilepsy, and cellular stress models broadened the CNS relevance of 2-BFI but remained less replicated or more mechanistically indirect than the stroke/neurovascular evidence. Behavioral and pharmacological studies additionally indicated that 2-BFI modulates neurotransmitter-related systems associated with pain-, affective-, addiction-, opioid-, and compulsivity-related outcomes, although these findings should be distinguished from disease-modifying neuroprotective evidence. Conclusions: Meta-analysis was not conducted because of heterogeneity in models, dosing regimens, treatment timing, and outcomes. Overall, the current evidence does not yet support definitive dosing, treatment timing, or clinical development recommendations for 2-BFI. The strongest preclinical therapeutic rationale is currently found in ischemic stroke and neurovascular injury settings, whereas other CNS indications require further validation. Future studies should define dose-response relationships, therapeutic windows, pharmacokinetic and safety profiles, sex- and age-related effects, and efficacy in clinically relevant comorbid models before clinical translation is considered. The review was not prospectively registered. Funding was provided by a National Research Foundation of Korea grant funded by the Korean government.}, } @article {pmid42653713, year = {2026}, author = {Mendes, GO and Bento, LDP and Oliveira, TM and Barbosa, DB and Tsui, GS and Gomes, EN and Sales, RO and Rocha, MSC and Silva, MPD and Oliveira, TA and Maia, EHB and Falkoski, DL and Marra, IFS and Andrade, LSM and Mendes, LCVP and Fonseca, BS and Oliveira, LMG and Silva, VDAD and Carvalho, PB and Silva, AMD and Taranto, AG and Damázio, LCM and Valle, MS and Leite, FHA}, title = {Design, Synthesis, In Vitro and In Vivo Evaluation of Novel Anti-Alzheimer's (1E,4E)-1,5-Bis[(het)aryl]penta-1,4-dien-3-one Derivatives.}, journal = {Pharmaceuticals (Basel, Switzerland)}, volume = {19}, number = {8}, pages = {}, doi = {10.3390/ph19081216}, pmid = {42653713}, issn = {1424-8247}, support = {APQ-04559-22//Fundação de Amparo à Pesquisa do Estado de Minas Gerais/ ; APQ-07852-25//Fundação de Amparo à Pesquisa do Estado de Minas Gerais/ ; APQ-03224-24//Fundação de Amparo à Pesquisa do Estado de Minas Gerais/ ; 305452/2025-8//National Council for Scientific and Technological Development/ ; }, abstract = {Background/Objectives: Alzheimer's disease (AD) is a progressive, multifactorial neurodegenerative condition characterized by neurofibrillary tangles, neuronal loss, cognitive impairment, and accumulation of β-amyloid plaques. Considering the limitations of current treatments, which present adverse effects and only alleviate symptoms without modifying disease progression, there is an urgent need for new therapeutic approaches. This study aimed to investigate the neuroprotective potential of synthetic derivatives of (1E,4E)-1,5-bis[(het)aryl]penta-1,4-dien-3-ones, focusing on the inhibition of the cholinesterase enzymes acetylcholinesterase (AChE) and butyrylcholinesterase (BChE), targets directly related to the cholinergic deficit observed in AD. Methods: The compounds were initially synthesized by aldol condensation reactions, with subsequent physicochemical characterization. They were then subjected to in silico assays that demonstrated high binding affinity to the active sites of AChE and BChE. The derivatives were evaluated in vitro for their inhibitory activity on these enzymes and in vivo in an experimental model of AD induced by streptozotocin in Wistar rats. Results: The synthesized derivatives showed favorable predicted interactions with the active sites of AChE and BChE, supporting their potential as cholinesterase inhibitors. In vitro assays demonstrated inhibitory activity against both enzymes, with selected derivatives showing improved activity compared with the parent scaffold. In the in vivo model, treatment with the selected compounds was associated with neuroprotective effects, suggesting preservation of nervous tissue integrity under AD-like conditions. Conclusions: These findings indicate that derivatives may represent promising candidates for further investigation as multitarget agents for AD. The study reinforces the relevance of integrating organic synthesis, molecular modeling, enzymatic assays, and in vivo evaluation in the search for new therapeutic strategies for neurodegenerative diseases.}, } @article {pmid42639707, year = {2026}, author = {Najmi, AK and Yaduvanshi, D and Aggarwal, R and A, S and Aqil, M and Mujeeb, M and Akhtar, M}, title = {Targeting the NLRP3 inflammasome pathway associated with neuroinflammation mediated Alzheimer's disease: pre-clinical and clinical status of emerging therapeutics.}, journal = {Expert opinion on therapeutic targets}, volume = {}, number = {}, pages = {}, doi = {10.1080/14728222.2026.2723488}, pmid = {42639707}, issn = {1744-7631}, abstract = {INTRODUCTION: Alzheimer's disease (AD) is a rising global health problem, but current treatments only target symptoms rather than fixing their underlying root causes. A major pathological feature is neuroinflammation, which is specifically driven by the Nucleotide-binding domain, Leucine-rich-repeat and Pyrin domain-containing 3 (NLRP3) inflammasome cascade, which acts as a 'molecular switch' that causes immune cells in the brain to trigger robust secretion of pro-inflammatory cytokines (e.g. IL-1β, IL-18) and pyroptosis, causing systemic inflammation, thereby the neuroinflammation.

AREAS COVERED: This review breaks down the pathways triggered by immune cells activation (neurotoxic microglial phenotype) and majorly focusing over the NLRP3 inflammasome neuroinflammation pathway. It explores the promising therapeutic potential of specific bioactive phytochemicals, repurposed and novel synthetic drugs/agents, to shut-down this molecular switch i.e. NLRP3 inflammasome pathway.

EXPERT OPINION: To truly stop AD, we must shift our focus from treating merely the symptoms, by stopping the disease at its roots. While discovering the novel NLRP3 inflammasome inhibitors is exciting, but the biggest hurdle is getting them into the brain. Future of AD treatment relies on combining these targeted drugs with advanced nanotechnology, like nano-particles, to successfully cross the blood-brain barrier (BBB) and safely deliver the drugs exactly where they are needed.}, } @article {pmid42639919, year = {2026}, author = {Morató, X and Hinojosa-Calleja, A and Jofresa, S and Calm, B and Cano, A and Blazquez-Folch, J and Alarcón-Martín, E and Montrreal, L and Muñoz-Morales, Á and Olivé, C and Bayón, P and Sotolongo-Grau, O and Orellana, A and Sanz-Cartagena, P and Montalban, X and Marquié, M and Fernandez, MV and Ruiz, A and Boada, M and Valero, S}, title = {When treatment becomes risk: polypharmacy and inappropriate prescribing in cognitive impairment in 2379 consecutive patients from a memory clinic.}, journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association}, volume = {22}, number = {8}, pages = {e71708}, pmid = {42639919}, issn = {1552-5279}, support = {//Lilly through an Investigator-Initiated Trial/ ; 77225//Eli Lilly and Company/ ; }, mesh = {Humans ; *Polypharmacy ; Female ; *Inappropriate Prescribing/statistics & numerical data ; Aged ; *Cognitive Dysfunction/drug therapy/chemically induced ; Retrospective Studies ; Male ; Aged, 80 and over ; Spain ; Alzheimer Disease/drug therapy ; }, abstract = {BACKGROUND: Polypharmacy, potentially inappropriate medications (PIMs), and drugs associated with drug-induced cognitive impairment (DICI) are highly prevalent in older adults and may affect cognitive decline.

METHODS: This observational retrospective study included 2379 patients evaluated at Ace Alzheimer Center Barcelona. Medication data were extracted from electronic health records using a large language model (LLM). Polypharmacy (≥5), hyperpolypharmacy (≥10), PIMs, and DICI drugs were analyzed across cognitive stages, Alzheimer's disease biomarkers, ApoE subtype, and estimated glomerular filtration rate.

RESULTS: Among patients with cognitive impairment (Clinical Dementia Rating [CDR] ≥ 0.5), 67% presented polypharmacy and 21% hyperpolypharmacy. Higher odds of polypharmacy were observed across the CDR scale, while higher education showed a protective effect. Altered renal function was found in 20.8% of patients with polypharmacy. Indeed, significant differences were found between amyloid beta-positive and negative (Aβ[+]/Aβ[-]) subjects and between the whole population and subjects participating in clinical trials.

DISCUSSION: Polypharmacy is extremely common in patients attending memory clinics. LLMs could facilitate systematic structured medication reviews.}, } @article {pmid42640603, year = {2026}, author = {Pereira da Silva, AM and Santos do Nascimento, MDV and Menegucci, G and Caruso Novaes Tudella, G and Silva Cabeça, L and Ribeiro Gonçalves, O and Vieira Nogueira, B and Oliveira Franco, J and Haddad Santos, D and Silveira Duarte, F and Perry, G and de Souza Franco, E and Bernadete de Sousa Maia, M}, title = {Pioglitazone and Cognitive Outcomes in Mild Cognitive Impairment and Alzheimer Disease: A Systematic Review and Meta-Analysis of Randomized Trials.}, journal = {Alzheimer disease and associated disorders}, volume = {}, number = {}, pages = {}, doi = {10.1097/WAD.0000000000000744}, pmid = {42640603}, issn = {1546-4156}, abstract = {BACKGROUND: Cognitive impairment is increasingly recognized among older adults with metabolic disorders, including type 2 diabetes. Metabolic dysfunction and insulin resistance have been implicated in neurodegenerative processes. Pioglitazone, an insulin-sensitizing agent widely used in the treatment of type 2 diabetes, has been investigated for potential effects on cognitive outcomes. This systematic review and meta-analysis evaluated the efficacy and safety of pioglitazone on cognitive outcomes in individuals with mild cognitive impairment or Alzheimer disease.

METHODS: PubMed, Embase, and the Cochrane Central Register of Controlled Trials were searched through July 2025 for randomized controlled trials comparing pioglitazone with placebo in adults with mild Alzheimer disease or mild cognitive impairment. Cognitive outcomes included the Mini-Mental State Examination, the Wechsler Memory Scale-Revised, and the Alzheimer's Disease Assessment Scale-Cognitive subscale. Safety outcomes included adverse events, serious adverse events, treatment discontinuation, and peripheral edema. Random-effects meta-analyses were conducted using frequentist and Bayesian approaches.

RESULTS: Six randomized trials, including 3680 participants, were analyzed. Pioglitazone was not associated with differences in Mini-Mental State Examination or Wechsler Memory Scale-Revised scores compared with placebo. Alzheimer's Disease Assessment Scale-Cognitive subscale estimates modestly favored pioglitazone, although this finding was not consistent across other cognitive measures. Overall, adverse events and serious adverse events were similar between treatment groups. Treatment discontinuation occurred less frequently with pioglitazone. Peripheral edema was reported more frequently with pioglitazone, although estimates were based on a small number of events and wide CIs.

CONCLUSION: Pioglitazone was not associated with consistent differences in global cognitive outcomes in individuals with mild cognitive impairment or Alzheimer disease. Safety outcomes were broadly comparable to placebo, although peripheral edema occurred more frequently.}, } @article {pmid42640625, year = {2026}, author = {Kim, MH and Colantonio, LD and Glymour, MM and Hamad, R and Adler-Milstein, J and Kershaw, KN and Boscardin, J and Wang, Z and Oti, AS and Howard, VJ}, title = {Discordance Between Cognitive Impairment Status and Claims-Based ADRD Diagnosis: Temporal Patterns and Racial Differences in the REGARDS Cohort, 2006 to 2021.}, journal = {Alzheimer disease and associated disorders}, volume = {}, number = {}, pages = {}, pmid = {42640625}, issn = {1546-4156}, abstract = {INTRODUCTION: Understanding the concordance between incident cognitive impairment status and the diagnosis of Alzheimer disease and related dementias (ADRD) is clinically important, as a diagnosis serves as the gateway for treatment, care planning, and supportive services.

METHODS: Using the REGARDS cohort (2006 to 2021) linked to Medicare claims, we examined the discordance between incident cognitive impairment and claims-based ADRD diagnoses. Directly standardized diagnosis rates were estimated by year, overall, and race, and stratified by cognitive impairment status. Logistic regression models were used to examine sociodemographic correlates of diagnosis.

RESULTS: The sample included 45,191 observations (23% Black) of 8368 participants. Among those with incident cognitive impairment, 30.8% received a claim-based diagnosis, and while 8.9% of those without incident cognitive impairment received a claim-based diagnosis. ADRD diagnosis rates remained stable, whereas rates among observations with incident cognitive impairment rose through the early 2010s, then plateaued and declined. The black race and education below the college level were associated with lower odds of diagnosis in this group; female sex was associated with higher odds. Among observations without cognitive impairment, older age and female sex were associated with higher odds; Midwest or West/Northeast residence and less than high school education were associated with lower odds.

DISCUSSION: Differences observed in the study may potentially represent underlying disparities in access to care and dementia diagnosis in clinical practice.}, } @article {pmid42641545, year = {2026}, author = {Gao, W and Hu, K and Yang, G and Pan, J and Xu, X and You, P and Li, K and Zhao, Y and Wang, X and Xu, Y}, title = {Puerarin alleviates memory deficits through the modulation of D‑serine-mediated N-methyl-D-aspartate receptor activity in presenilin 1/2 conditional double knockout mice.}, journal = {Phytomedicine : international journal of phytotherapy and phytopharmacology}, volume = {161}, number = {}, pages = {158727}, doi = {10.1016/j.phymed.2026.158727}, pmid = {42641545}, issn = {1618-095X}, abstract = {BACKGROUND: Alzheimer's disease (AD) is a neurodegenerative disorder characterized by progressive cognitive decline, the formation of amyloid-β plaques and neurofibrillary tangles, and synaptic dysfunction. Puerarin (PUE), an isoflavone C-glycoside extracted from Pueraria lobata, has demonstrated potential in attenuating AD-related cognitive decline; however, the mechanisms governing the effects of PUE remain incompletely understood.

PURPOSE: To investigate the mechanisms underlying PUE's anti-AD effects.

METHODS: Presenilin 1/2 conditional double knockout mice served as the AD model. Following one month of PUE administration, memory function was evaluated through behavioral testing, and hippocampal synaptic plasticity was assessed using electrophysiological recordings. D‑serine levels were quantified via ELISA. Additionally, Western blotting and qRT-PCR were employed to analyze the expression of glutamate receptor subunits and key enzymes involved in D‑serine metabolism. The mechanistic role of D‑serine was further validated through intrahippocampal D‑serine injections in mice and the application of a serine racemase (SR) inhibitor in N2a cells.

RESULTS: PUE administration reversed memory impairment and enhanced both hippocampal long-term potentiation and synaptic transmission by increasing the open probability of N-methyl-D-aspartate receptor (NMDAR) channels. Furthermore, PUE elevated D‑serine levels and upregulated the expression of SR. Notably, these therapeutic effects were replicated by exogenous D‑serine and abolished by treatment with an SR inhibitor.

CONCLUSION: These findings indicate that PUE alleviates cognitive deficits by promoting SR-mediated D‑serine biosynthesis and subsequently restoring NMDAR activity. Accordingly, PUE represents a viable therapeutic candidate for the prevention and management of AD.}, } @article {pmid42641765, year = {2026}, author = {Solfrizzi, V and Lozupone, M and Panza, F}, title = {Anti-Amyloid Drugs: Integrated Clinical Pathways for Treating Older Patients with Frailty and Dementia.}, journal = {Ageing research reviews}, volume = {}, number = {}, pages = {103331}, doi = {10.1016/j.arr.2026.103331}, pmid = {42641765}, issn = {1872-9649}, abstract = {The introduction of anti-amyloid therapies for Alzheimer's disease challenged current care models, particularly for older adults with frailty. The potential low efficacy of anti-amyloid drugs in these patients may be attributed to chronic inflammation, impaired repair mechanisms, and multisystem dysregulation. Neuropathological studies suggested that the accumulation of common brain pathologies may contribute to progressive physical frailty in older age. At present, there is no certified diagnostic-therapeutic pathway governing the management of patients eligible for anti-amyloid treatment, regardless of the presence of frailty. In the present view point, we argued that frailty should not be treated as an exclusion criterion for anti-amyloid therapies, but as a stratification dimension requiring integrated, multidimensional clinical pathways. Without embedding frailty assessment into eligibility, monitoring, and outcome evaluation, the real-world implementation of disease-modifying therapies risks being ineffective, inequitable, and ethically problematic. Here, we proposed to integrate frailty assessment with biological and neuroimaging criteria to promote ethical, equitable, and clinically-feasible access to disease-modifying treatments in real-world settings.}, } @article {pmid42642009, year = {2026}, author = {Wright, KA and Horta, M and Hayes, A and Ebner, NC}, title = {Oxytocin as regulator of stress and inflammation in aging.}, journal = {Neuroscience and biobehavioral reviews}, volume = {}, number = {}, pages = {106924}, doi = {10.1016/j.neubiorev.2026.106924}, pmid = {42642009}, issn = {1873-7528}, abstract = {Chronic stress and inflammation are potent determinants of negative health trajectories across adulthood, contributing to the progression of neurodegenerative diseases. In aging, these processes become increasingly intertwined, forming a feedforward loop in which chronic stress activates pro-inflammatory cascades in the brain and body, while pro-inflammatory cytokines stimulate stress-response pathways. Together, these interactions accelerate neuronal vulnerability, cognitive decline, and even Alzheimer's disease and Related Dementia (ADRD) pathology. The neuropeptide oxytocin (OT), a modulator of neurophysiological and social-affiliative processes, may buffer against stress and inflammation. There is evidence suggesting that OT dampens hypothalamic-pituitary-adrenal (HPA) axis reactivity, reduces pro-inflammatory cytokines, and promotes adaptive behaviors that restore physiological balance and promote healthy coping. OT can be synthetically produced and delivered via intranasal administration (IN-OT), providing a potential means of enhancing OT signaling. Understanding OT's role in aging, however, remains limited but of high relevance, also given the convergence of stress and inflammatory cascades in ADRD. This narrative review integrates previously distinct lines of research to delineate proposed pathways through which OT regulates stress and inflammation in aging and ADRD. Using systematic search strategies, this review also provides a structured synthesis of recent studies to evaluate evidence for IN-OT as a therapeutic for mitigating stress and inflammation, with discussion of its potential application in aging and ADRD. Research gaps and future directions are offered regarding OT's mechanisms of action, moderators of IN-OT's treatment response, and enhanced attention to midlife in IN-OT research on stress and inflammation in older adults as well as individuals with ADRD.}, } @article {pmid42643714, year = {2026}, author = {Budson, AE and Ljubenkov, PA and Ritter, A and Leahy, C and Ramanan, VK and Brosch, J and Burke, A and Matthews, BR}, title = {Considerations for using amyloid-targeting therapies for the treatment of early symptomatic Alzheimer's disease.}, journal = {Frontiers in neurology}, volume = {17}, number = {}, pages = {1863897}, pmid = {42643714}, issn = {1664-2295}, mesh = {Humans ; *Alzheimer Disease/drug therapy/metabolism/diagnostic imaging ; *Amyloid/metabolism ; *Antibodies, Monoclonal, Humanized/therapeutic use ; *Amyloid beta-Peptides/metabolism ; }, abstract = {Amyloid-targeting therapies (ATTs), including donanemab and lecanemab, are FDA-approved disease-modifying therapies for Alzheimer's disease in the mild cognitive impairment or mild dementia stages. Early initiation is important for optimal outcomes. This article summarizes practical strategies for implementing ATTs in clinical practice, focusing on leadership alignment and infrastructure development, as well as patient identification, diagnosis, and monitoring protocols. Key recommendations include establishing appropriate patient tracking systems, infusion and imaging protocols, and interprofessional collaboration. Approaches for systematic patient routing (e.g., hub-and-spoke models, fast-track mechanisms) and biomarker-integrated assessments are critical to facilitating timely diagnosis and treatment. Education for patients, care partners, and clinicians is crucial for managing the risks associated with amyloid-related imaging abnormalities. Successful ATT implementation requires coordinated systems, timely diagnosis, and robust safety monitoring. These measures can enable frameworks for ATT administration to optimize outcomes for patients, care partners, and health systems.}, } @article {pmid42643819, year = {2026}, author = {Jiang, S and Sydney, EJ and Runyan, AM and Serpe, R and Srikanth, M and Figueroa, HY and Yang, M and Myeku, N}, title = {Correction: 5-HT4 receptor agonists treatment reduces tau pathology and behavioral deficit in the PS19 mouse model of tauopathy.}, journal = {Frontiers in cellular neuroscience}, volume = {20}, number = {}, pages = {1945844}, doi = {10.3389/fncel.2026.1945844}, pmid = {42643819}, issn = {1662-5102}, abstract = {[This corrects the article DOI: 10.3389/fncel.2024.1338502.].}, } @article {pmid42643967, year = {2026}, author = {Shaik, NS and Balya, H and Ramamurthy, S and Pandiyan, B and Elias, JM and Gunturu, S}, title = {Evaluating the safety of investigational anti-Alzheimer's drugs: a comprehensive meta-analysis in the past to current decade.}, journal = {Dementia & neuropsychologia}, volume = {20}, number = {}, pages = {e20250472}, pmid = {42643967}, issn = {1980-5764}, abstract = {UNLABELLED: Alzheimer's disease is a progressive illness that results in the degeneration of neurons with considerable burden. The pharmacological treatments for Alzheimer's disease include cholinesterase inhibitors, monoclonal antibodies, NMDA receptor antagonists despite having different adverse drug reactions (ADR) alongside the health benefits. Limited data exists for the complete safety evaluation across different classes of anti-Alzheimer's drugs.

OBJECTIVE: The meta-analysis evaluated the severity, frequency and variability of ADR as a result of Alzheimer's drugs to determine relative safety across various classes.

METHODS: This meta-analysis followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines with studies derived from the United States National Library of Medicine (PubMed), Embase, Scopus and ClinicalTrials.gov that focus on randomized controlled trials (RCTs) and observational studies which detailed ADRs of anti-Alzheimer's drugs. Jeffrey's Amazing Statistics Program (JASP) software was used to conduct heterogeneity assessment (I2), risk ratio (RR) and publication bias analysis in addition to meta-regression.

RESULTS: 31 studies were utilized. The studies with cholinesterase inhibitors exhibited more gastrointestinal ADRs and monoclonal antibodies exhibited amyloid-related imaging abnormalities (ARIA-H and E). The BACE1 inhibitors showed liver toxicity that led to increased patient drug discontinuation. A random-effects model was used for the analysis due to heterogeneity (I[2]>50%). The meta-regression analysis indicated drug class as a predictor for the type of ADR.

CONCLUSION: The research demonstrates considerable variations in the safety of Alzheimer's drugs that need tailored treatment supported by post-approval monitoring systems. The literature needs extended investigations of safety evaluation as well as practical treatment investigations in actual clinical settings. Unlike conventional reviews focusing solely on currently approved therapies, this study provides a cross-generational analysis of adverse drug reactions across both historical and investigational anti-Alzheimer's agents, offering insights into mechanism-related safety patterns that may inform the development and clinical use of emerging therapies.}, } @article {pmid42644303, year = {2026}, author = {Brookfield, N and Hauck, PM and Doty, EG and Zimmer, JA and Yang, F and Chen, YF and Ardayfio, P and Khanna, R and Ye, W and Tockhorn-Heidenreich, A and Patel, N}, title = {Donanemab for early symptomatic AD in the UK-indicated population: safety and efficacy in those who are non-carriers or heterozygous for APOE ε4.}, journal = {Neurodegenerative disease management}, volume = {}, number = {}, pages = {1-11}, doi = {10.1080/17582024.2026.2723524}, pmid = {42644303}, issn = {1758-2032}, abstract = {BACKGROUND: Licensing of donanemab in the United Kingdom (UK) for the treatment of early symptomatic Alzheimer's disease is limited to adults who are Apolipoprotein E (APOE) ε4 non-carriers or heterozygotes.

AIM: To assess safety and efficacy of donanemab in the UK-indicated population.

METHODS: Post-hoc analysis of APOE ε4 non-carriers or heterozygotes from a pooled TRAILBLAZER-ALZ and TRAILBLAZER-ALZ 2 population and the TRAILBLAZER-ALZ 2 population assessed safety and efficacy, respectively.

RESULTS: By 76 weeks, 13/825 (1.6%) and 170/816 (20.8%) participants in the placebo and donanemab arms experienced amyloid-related imaging abnormalities (ARIA)-edema/effusion, 96/825 (11.6%) and 218/816 (26.7%) participants experienced ARIA-microhemorrhages/superficial siderosis and 3/825 (0.4%) and 67/816 (8.2%) participants experienced infusion-related reactions, respectively. Donanemab significantly slowed disease progression versus placebo across multiple clinical scales, including a 40.3% (p < 0.0001) lower risk of progression to the next stage as measured by the Clinical Dementia Rating-Global score. Amyloid clearance occurred in 80.8% of donanemab-treated participants.

CONCLUSIONS: In the UK-indicated population, excluding APOE ε4 homozygotes reduced, but did not eliminate, ARIA risk with donanemab. Treatment slowed disease progression and reduced brain amyloid plaque by 76 weeks. Therefore, donanemab treatment requires structured risk-benefit discussion and appropriate monitoring.

CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, NCT03367403, https://clinicaltrials.gov/study/NCT03367403 (TRAILBLAZER-ALZ) and NCT04437511, https://clinicaltrials.gov/study/NCT04437511 (TRAILBLAZER-ALZ 2).}, } @article {pmid42634550, year = {2026}, author = {Du, Y and Li, J and Han, F and Li, J and Lin, H and Ge, F}, title = {Safety Comparison of Acetylcholinesterase Inhibitors Using FAERS Spontaneous-Reporting Data: Drug-Specific Reporting Signals and Time-to-Onset Dynamics.}, journal = {Current Alzheimer research}, volume = {}, number = {}, pages = {}, doi = {10.2174/0115672050497124260720115932}, pmid = {42634550}, issn = {1875-5828}, abstract = {INTRODUCTION/OBJECTIVE: Acetylcholinesterase Inhibitors (AChEIs) are widely used for symptomatic treatment of Alzheimer's disease, but their post-marketing reporting profiles may differ. This study compared FAERS disproportional reporting signals and Time-To-Onset (TTO) patterns for donepezil, galantamine, and rivastigmine.

METHODS: FAERS reports from Q1 2004 to Q2 2025 were analyzed. Reports listing donepezil, galantamine, or rivastigmine as the primary suspect drug were retained. Unique case-drug-Preferred Term (PT) triplets were constructed after case-level and drug-event-level de-duplication. Positive signals were defined conservatively by the intersection of ROR, PRR, BCPNN, and MGPS/EBGM criteria. TTO was evaluated using cumulative onset-distribution curves, Weibull models, and Accelerated Failure-Time (AFT) models.

RESULTS: The analysis included 9,474 donepezil reports, 3,042 galantamine reports, and 14,666 rivastigmine reports. The four-method intersection identified 286 positive PT reporting signals for donepezil, 143 for galantamine, and 259 for rivastigmine. Donepezil showed prominent cardiac reporting signals, including sinus bradycardia (ROR = 49.0) and electrocardiogram QT prolongation (ROR = 16.75). Rivastigmine showed application-site signals, including application-site erythema (ROR = 21.36) and application-site pruritus (ROR = 18.07). Galantamine showed signals including bradycardia (ROR = 15.37), fall (ROR = 3.44), and decreased appetite (ROR = 3.57). Median TTOs were 38, 44, and 64 days for donepezil, galantamine, and rivastigmine, respectively. Rivastigmine showed a later reported onset than donepezil in the AFT model (TR = 1.08; p = 0.008).

DISCUSSION: The findings suggest shared cholinergic reporting patterns and drug-specific signal profiles. Because FAERS lacks exposure denominators, these results indicate disproportional reporting rather than incidence, causality, or comparative clinical risk.

CONCLUSION: Donepezil, galantamine, and rivastigmine showed distinct FAERS reporting profiles and early post-initiation TTO patterns. These findings are hypothesis-generating and require confirmation in independent pharmacovigilance or clinical datasets.}, } @article {pmid42634764, year = {2025}, author = {Kordi, MR and Kooshan, AR and Jafari-Hokmabadi, SP and Gaeini, AA and Zobeydi, AM}, title = {Combating cognitive decline in a rat model of Alzheimer's disease: The role of high-intensity interval training and cannabidiol administration in modulating microRNA-124, BACE1, and nestin.}, journal = {Current journal of neurology}, volume = {24}, number = {3}, pages = {219-228}, pmid = {42634764}, issn = {2717-011X}, abstract = {Background: The global prevalence of Alzheimer's disease (AD) has emerged as a paramount concern due to the aging population. The current research examines the effects of six-week high-intensity interval training (HIIT), with and without cannabidiol (CBD) supplementation, on cognitive decline, micro ribonucleic acid (miRNA)-124 expression levels, and the protein expression of beta-site amyloid precursor protein cleaving enzyme 1 (BACE1) and nestin in the hippocampus of rats with amyloid beta (Aβ)-induced AD. Methods: 30 male Wistar rats were randomly divided into six groups: control (CNT), sham, Alzheimer (AD), Alzheimer + HIIT (H-AD), Alzheimer + CBD (C-AD), and Alzheimer + HIIT + CBD (CH-AD). Following the hippocampal injection of Aβ1-42, the HIIT protocol and CBD supplementation [20 mg/kg/day, per os (P.O.)] were initiated and conducted over six weeks. After the last intervention, the hippocampus tissues were collected to assess miRNA-124 expression levels and the protein expression of BACE1 and nestin. Results: HIIT alone and in combination with CBD treatment significantly improved cognitive impairment induced by AD. Moreover, both treatments significantly reduced BACE1 protein expression and increased nestin protein expression in AD rats. However, despite decreased miRNA-124 expression levels in the AD group in comparison with the CNT group, HIIT and CBD administration did not alter miRNA-124 expression levels in other groups. Conclusion: The findings can contribute to a higher understanding of the beneficial effects of HIIT combined with CBD administration in mitigating AD-induced cognitive impairment by reducing BACE1 protein expression and increasing nestin protein expression.}, } @article {pmid42634953, year = {2026}, author = {Du, L and Yan, S and Ren, X and Hassan, SSU and Sun, Y and Gan, Y and Xiao, X and Li, S and Jin, H}, title = {Breaking Alzheimer's Disease Barrier: The Role of Xanthoceras sorbifolia Bunge Oil in Gut-Brain Axis and TLR4/Myd88/MAPK Pathway Inhibition.}, journal = {Phytotherapy research : PTR}, volume = {}, number = {}, pages = {}, doi = {10.1002/ptr.70432}, pmid = {42634953}, issn = {1099-1573}, support = {81830117//National Natural Science Foundation of China/ ; 2020YFC2003100//National Key R&D Program of China/ ; U22A20365//Joint Funds of National Natural Science Foundation of China/ ; }, abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder associated with cognitive decline and neuroinflammation. Xanthoceras sorbifolia Bunge oil (XSBO), a woody plant oil rich in bioactive fatty acids, has shown potential health benefits. This study aimed to investigate the neuroprotective effects and underlying mechanisms of XSBO in AD. A scopolamine-induced AD rat model was established to evaluate the effects of XSBO on cognitive function, pathological changes, and neuroinflammation. Gut microbiota alterations were analyzed by 16S rDNA sequencing. Fecal microbiota transplantation (FMT) and short-chain fatty acid (SCFA) supplementation experiments were performed to explore the role of gut microbiota-derived metabolites. The TLR4/MyD88/MAPK signaling pathway was further examined. XSBO treatment improved cognitive deficits, reduced neuronal damage and neuroinflammation, and enhanced intestinal barrier integrity in AD rats. XSBO restored gut microbiota dysbiosis and increased SCFA-producing bacteria. FMT and SCFA supplementation confirmed that microbiota-derived metabolites contributed to XSBO-mediated cognitive improvement and neuroprotection. Mechanistically, XSBO inhibited lipopolysaccharide-induced neuroinflammation by suppressing TLR4/MyD88/MAPK signaling activation. XSBO alleviates AD-related cognitive impairment and neuroinflammation by modulating the gut microbiota-SCFA axis and inhibiting TLR4/MyD88/MAPK-mediated inflammatory responses. These findings suggest that XSBO may serve as a promising dietary intervention for neurodegenerative disease management.}, } @article {pmid42635855, year = {2026}, author = {Gönüllü, S and Dalkılınç, E and Çelik, O and Çelik, H and Küçükler, S and Topal, A and Akay, R and Yıldız, MO and Alım, B and Özdemir, S}, title = {Therapeutic Effects of miR-29b-Enriched Nanovesicles on Mitochondrial Injury and Neuroinflammatory Processes in Alzheimer's Disease.}, journal = {Neurotoxicity research}, volume = {44}, number = {5}, pages = {}, pmid = {42635855}, issn = {1476-3524}, mesh = {*MicroRNAs/administration & dosage ; Humans ; *Alzheimer Disease/metabolism/drug therapy ; *Mitochondria/drug effects/metabolism/pathology ; *Neuroinflammatory Diseases/metabolism/drug therapy ; Oxidative Stress/drug effects/physiology ; Cell Line, Tumor ; Amyloid beta-Peptides/toxicity ; *Extracellular Vesicles/metabolism ; }, abstract = {Alzheimer's disease (AD) is defined by the accumulation of extracellular amyloid-β plaques and intracellular neurofibrillary tangles, which drive neuronal and synaptic impairment. In AD, the accumulation of protein aggregates leads to neuroinflammation, increased oxidative stress, and mitochondrial damage, resulting in neuronal loss and cognitive impairment. Emerging evidence highlights that microRNAs (miRNAs) modulate AD-related pathological pathways and may offer opportunities for therapeutic intervention. In this study, we investigated the therapeutic potential of microRNA-29b (miR-29b) delivered via small extracellular vesicles (sEVs) in an in vitro neuroblastoma model of AD. Four experimental groups were established using SH-SY5Y neuroblastoma cells: (1) untreated control cells, (2) Aβ-treated cells to model AD-like pathology, (3) cells treated with unloaded sEVs, and (4) cells treated with miR-29b-loaded sEVs (sEV-miR-29b). To evaluate treatment effects, we assessed markers of oxidative stress (ROS, LDH, SOD, MDA, GPX1), neuroinflammation (BDNF, ICAM1, TNF-α, NfL, MIF, VEGFA, MCP-1), mitochondrial dysfunction (Cytc, TFAM, PINK1, DNM1L), synaptic integrity (CPLX2, ROR1), and AD pathology (Amyloid-β, Total Tau, pTau181, pTau217). Our findings demonstrate that treatment with sEV-miR-29b attenuated Aβ-induced oxidative stress, reduced pro-inflammatory signaling, and improved mitochondrial homeostasis compared with Aβ-only and sEV-only groups. Moreover, sEV-miR-29b treatment partially restored synaptic protein expression and decreased pathological tau phosphorylation. These results indicate that miR-29b plays a regulatory role in neuroinflammation, oxidative stress, and mitochondrial function, suggesting that sEV-mediated delivery of miR-29b represents a promising therapeutic strategy for modulating AD-related neurodegenerative mechanisms. This study highlights the potential of miR-29b-loaded sEVs as a therapeutic approach for AD.}, } @article {pmid42636218, year = {2026}, author = {Nasir, AB and Kilani, Y and Aldiabat, M and Abdelghany, O and Hafez, Y and Desai, N and Madi, MY and Wade, FG and Qureshi, K and Frey, LJ and Farmer, AD and Syn, WK}, title = {Antidiabetic medications and risk of cognitive disorders in type 2 diabetes: A retrospective cohort study.}, journal = {PloS one}, volume = {21}, number = {8}, pages = {e0356138}, pmid = {42636218}, issn = {1932-6203}, mesh = {Humans ; *Diabetes Mellitus, Type 2/drug therapy/complications ; Female ; Retrospective Studies ; *Hypoglycemic Agents/therapeutic use/adverse effects ; Metformin/therapeutic use/adverse effects ; Middle Aged ; Male ; Aged ; Insulin/therapeutic use/adverse effects ; Adult ; *Cognitive Dysfunction/epidemiology/chemically induced ; Alzheimer Disease/epidemiology ; Dipeptidyl-Peptidase IV Inhibitors/therapeutic use/adverse effects ; Incidence ; Sodium-Glucose Transporter 2 Inhibitors/therapeutic use/adverse effects ; *Cognition Disorders/epidemiology ; Glucagon-Like Peptide-1 Receptor Agonists ; Dementia, Vascular/epidemiology ; }, abstract = {OBJECTIVE: To evaluate the associations between commonly used antidiabetic regimens and incidence of mild cognitive disorder, Alzheimer disease, and vascular dementia in adults with type 2 diabetes.

This retrospective cohort study used the TriNetX US Collaborative Network of electronic health records from 2010 to 2024. Adults aged 40-69 years with type 2 diabetes and at least 1 year of follow-up were included. Propensity score matching was applied to balance covariates.

EXPOSURE: Patients were classified into 5 treatment groups: metformin only (reference), metformin plus DPP-4 inhibitors, metformin plus GLP-1 receptor agonists, metformin plus SGLT-2 inhibitors, and insulin monotherapy. Exposure was defined by first recorded prescription and continued use during follow-up.

MAIN OUTCOMES AND MEASURES: Primary outcomes were incident mild cognitive disorder, Alzheimer disease, and vascular dementia, identified using ICD-10 codes. Hazard ratios with 95% confidence intervals were estimated from Cox proportional hazards models, with landmark analyses for follow-up shorter and longer than 5 years.

RESULTS: Among 1,528,885 adults with type 2 diabetes (mean age, 58 years; 49.2% women), GLP-1 receptor agonists plus metformin were associated with lower incidence of vascular dementia (HR, 0.46; 95% CI, 0.37-0.57), mild cognitive disorder (HR, 0.79; 95% CI, 0.66-0.95), and Alzheimer disease (HR, 0.46; 95% CI, 0.31-0.70). SGLT-2 inhibitors plus metformin reduced vascular dementia risk (HR, 0.68; 95% CI, 0.54-0.87) but not other outcomes. Insulin monotherapy was associated with higher incidence of vascular dementia (HR, 3.27; 95% CI, 3.03-3.52), mild cognitive disorder (HR, 1.71; 95% CI, 1.56-1.87), and Alzheimer disease (HR, 1.56; 95% CI, 1.32-1.84).

CONCLUSIONS AND RELEVANCE: GLP-1 receptor agonists and SGLT-2 inhibitors combined with metformin were associated with reduced risk of cognitive decline. Insulin monotherapy was associated with higher incidence of all three outcomes; however, this association is likely influenced by confounding by indication, unmeasured markers of diabetes severity (including diabetes duration, cardiovascular and renal disease severity, and microvascular and macrovascular complications), and shorter follow-up among insulin users, and should not be interpreted as a direct drug effect. Because standard Cox models do not account for death as a competing event, reported hazard ratios reflect cause-specific hazards and may not directly correspond to cumulative incidence, particularly for the insulin group, in which mortality and censoring were substantially higher. Antidiabetic medication choice may influence long-term cognitive outcomes and should be considered in diabetes management.}, } @article {pmid42636356, year = {2026}, author = {Chen, H and Mcintyre, MK and Aktay, S and Yen, M and Gunawardane, S and Lakhani, DA and Malhotra, A and Colasurdo, M and Gandhi, D}, title = {Endovascular thrombectomy versus medical management in patients with dementia and acute ischaemic stroke.}, journal = {Age and ageing}, volume = {55}, number = {8}, pages = {}, doi = {10.1093/ageing/afag241}, pmid = {42636356}, issn = {1468-2834}, mesh = {Humans ; *Thrombectomy/methods/adverse effects ; Female ; *Ischemic Stroke/therapy/complications/mortality ; *Endovascular Procedures/methods/adverse effects ; Male ; Aged ; Retrospective Studies ; Aged, 80 and over ; *Dementia/complications ; Treatment Outcome ; Length of Stay/statistics & numerical data ; Hospital Mortality ; United States/epidemiology ; }, abstract = {OBJECTIVE: While pre-existing dementia is a known negative predictor for good endovascular thrombectomy (EVT) outcomes, comparative efficacy and safety data of EVT versus best medical management (BMM) for large vessel occlusion (LVO) patients with dementia are limited. This study compares hospitalisation outcomes of EVT versus BMM for LVO patients with underlying dementia.

METHODS: Using the US Nationwide Readmissions Database from 2016 to 2022, we retrospectively identified adult patients with dementia who presented with LVO stroke. The primary outcome was discharge to home. Secondary outcomes included in-hospital mortality, length-of-stay and complications. Patients who underwent EVT were compared to those who received BMM after propensity score matching. Interaction and subgroup analyses assessed treatment effect heterogeneity associated with age and dementia type.

RESULTS: Among 37 298 patients included, 6618 EVT and 13 092 BMM patients remained after propensity score matching. Home discharge rates were similar between groups (27.1% vs 26.4%, P = .51). EVT was associated with longer length-of-stay (median 7 vs 6 days, P < .001) and increased intracranial haemorrhage (23.9% vs 11.1%, P < .001), with no significant difference in mortality (15.0% vs 14.9%, P = .87). Patient age significantly moderated EVT effectiveness (interaction P < .001), and EVT among patients <75 years old was significantly associated with higher rates of home discharge (36.7% vs 26.8%, P < .001). Additionally, EVT appeared more effective for patients with vascular dementia (vs Alzheimer's disease, interaction, P = .014), among whom EVT was associated with significantly higher rates of home discharge (32.7% vs 25.2%, P = .007).

INTERPRETATION: Treatment response to EVT among LVO stroke patients with dementia was heterogeneous, and EVT was beneficial for patients <75 years old and those with vascular dementia.}, } @article {pmid42636468, year = {2026}, author = {Ranganathan, M and Jakob, S and Cerrato, F and Urban Spillane, L and Daryoush, TS and Shuster, S and Dokholyan, K and Herrera, S and Koo, BB and Markowitz, C and Deng, P and Rush, S and Calkins, ME and Troyan, S and Ruparel, K and Gur, RC and Reynolds, H and Wegel, C and Johnson, MB and Hom, L and Bryant, S and Mair, RW and Buckner, RL and , and Birnbaum, R and Birnbaum, R and Kohler, CG and Corcoran, CM and Gur, RE and Hyman, SE}, title = {Schizophrenia Spectrum Biomarkers Consortium: Establishment of a Biorepository for the Discovery of Quantitative Fluid Biomarkers.}, journal = {Schizophrenia bulletin}, volume = {52}, number = {5}, pages = {}, doi = {10.1093/schbul/sbag113}, pmid = {42636468}, issn = {1745-1701}, support = {//Stanley Center for Psychiatric Research/ ; }, mesh = {Humans ; *Schizophrenia/blood/cerebrospinal fluid/diagnosis/physiopathology ; Biomarkers/cerebrospinal fluid/blood ; Female ; Male ; Adult ; Pilot Projects ; *Biological Specimen Banks ; Middle Aged ; Longitudinal Studies ; *Psychotic Disorders/cerebrospinal fluid/blood/physiopathology ; Feasibility Studies ; }, abstract = {BACKGROUND AND HYPOTHESIS: Schizophrenia spectrum disorders (SSDs) produce severe symptoms, disability, and premature mortality, but only partially effective symptomatic treatments exist. Treatment development is impeded by lack of insight into disease mechanisms or objective biomarkers for clinical trials. Advances in genetics and neurobiology have converged on strong pathogenic hypotheses for SSDs centered on synapse dysfunction and excessive pruning, pathogenic processes that may produce measurable proteomic evidence in cerebrospinal fluid (CSF). Leveraging design precedents from successful fluid biomarkers discovery for Alzheimer's disease, we undertook a pilot study to test the feasibility of repeated CSF and blood samples collection from individuals with SSDs. Here we report on successful implementation of longitudinal bio-behavioral phenotyping in SSDs and establishment of a repository to permit broad sample and data sharing.

STUDY DESIGN: The Schizophrenia Spectrum Biomarkers Consortium (SSBC) study principles included longitudinal study design, paired CSF and plasma collection associated with robust phenotypic characterization, at 3 academic sites and the establishment of a biorepository. Participants underwent clinical and cognitive assessments, neuroimaging, blood draws, and CSF collection via lumbar puncture (LP) every 6 months.

STUDY RESULTS: SSBC successfully enrolled 48 SSD and 41 Healthy Controls with a 73% longitudinal retention. Clinical, cognitive, and neuroimaging results were consistent across sites and with existing studies. Study procedures were well tolerated, and almost all LPs (99%) resulted in either no or minor headache/backache that resolved without medical interventions.

CONCLUSIONS: The pilot SSBC study demonstrates that a multi-site, longitudinal study with repeat CSF collection is feasible, with excellent participant acceptability and retention.}, } @article {pmid42638207, year = {2026}, author = {Li, X and Zhou, Q and Ding, S and Pan, W and Liu, R and Yan, Y and Huang, C}, title = {Shape-Based Partially Linear Single-Index Cox Model for Alzheimer's Disease Conversion.}, journal = {Statistics in medicine}, volume = {45}, number = {20-22}, pages = {e70708}, doi = {10.1002/sim.70708}, pmid = {42638207}, issn = {1097-0258}, support = {12288201//National Natural Science Foundation of China/ ; 12322113//National Natural Science Foundation of China/ ; 11901599//National Natural Science Foundation of China/ ; 71991474//National Natural Science Foundation of China/ ; 72495122//National Natural Science Foundation of China/ ; XDA0500400//Chinese Academy of Sciences/ ; 2025A1515012189//GuangDong Basic and Applied Basic Research Foundation/ ; }, mesh = {Humans ; *Alzheimer Disease/pathology/diagnostic imaging ; Cognitive Dysfunction/pathology/diagnostic imaging ; *Disease Progression ; Proportional Hazards Models ; Computer Simulation ; Neuroimaging ; Aged ; Female ; Corpus Callosum/pathology/diagnostic imaging ; Magnetic Resonance Imaging ; }, abstract = {Alzheimer's disease (AD) is the major cause of dementia in the elderly, and characterizing the time to conversion to AD is crucial in preventative treatment. While existing statistical methods have proven effective in modeling AD conversion involving various clinical, genetic, and neuroimaging predictors, limited research has explored scenarios where these predictors are shapes derived from the shape space, a nonlinear Hilbert space. In addition, the linear relationship assumption in existing methods may be violated, leading to substantial efficiency losses in real-world applications. To address these challenges, we propose a shape-based partially linear single-index Cox (SPLS-Cox) model that accommodates both scalar and shape predictors. This new development is motivated by establishing the likelihood of conversion to AD in 372 patients with mild cognitive impairment (MCI) enrolled in the Alzheimer's Disease Neuroimaging Initiative, leveraging the early shape-based markers of conversion extracted from the brain white matter region, corpus callosum (CC). These 372 MCI patients were followed over 48 months, during which 161 progressed to AD. Our SPLS-Cox model establishes both the estimation procedure and the pointwise confidence band. Simulation studies are conducted to evaluate the finite-sample performance of our SPLS-Cox. The real application reveals that the CC contour shape is a significant predictor for AD conversion.}, } @article {pmid42631411, year = {2026}, author = {Elwakil, BH and Helal, AM and El-Khatib, M and Abdelnaser, A and Darwish, AA and Shehata, NS and Akl, SH and Moneer, EA and Bakr, BA and El Wakil, A}, title = {Multilayered Silica-Core/Chitosan-Coated Nanostructures Co-Delivering Tamoxifen and Quercetin Mitigate LPS-Associated Neurodegenerative and Alzheimer's Disease-Like Alterations.}, journal = {Journal of biomedical materials research. Part B, Applied biomaterials}, volume = {114}, number = {8}, pages = {e70150}, doi = {10.1002/jbm.b.70150}, pmid = {42631411}, issn = {1552-4981}, support = {PUP-24-8//Pharos University in Alexandria/ ; }, mesh = {Animals ; *Alzheimer Disease/drug therapy/metabolism/pathology/chemically induced ; *Chitosan/chemistry/pharmacology ; *Quercetin/pharmacology/chemistry/pharmacokinetics ; *Lipopolysaccharides/toxicity ; *Silicon Dioxide/chemistry/pharmacology ; *Tamoxifen/pharmacology/chemistry/pharmacokinetics ; Rats ; Mice ; Male ; }, abstract = {Cholinergic dysfunction, oxidative stress, neuroinflammation, and proteinopathies are among the major hallmarks of Alzheimer's disease (AD). This study aimed to develop and evaluate the therapeutic potential of multilayered silica-based/chitosan-coated nanoparticles (Si@CsNPs) co-loaded with quercetin (QUR) and tamoxifen (TAM) in an LPS-induced neuroinflammatory murine model exhibiting AD-like neuropathological alterations associated with bacterial endotoxin exposure. Molecular docking and target prediction analyses suggested that TAM may exert partial cholinesterase inhibitory activity and potentially interact with muscarinic receptor- and epidermal growth factor receptor (EGFR)-associated pathways, which are implicated in neuroinflammation and oxidative stress regulation. The resulting silica-based/chitosan-coated nanoparticles (Si@CsNPs) co-loaded with QUR and TAM (QUR/TAM-Si@CsNPs) were spherical in shape, exhibited a core-shell architecture, and demonstrated high loading efficiencies for QUR (93.1% ± 2.56) and TAM (84.27 ± 3.66), with a mean particle diameter of approximately 135 nm as determined by TEM. Behavioral assessment using Morris Water Maze revealed that lipopolysaccharide (LPS) administration impaired spatial learning and memory in rats; these effects were significantly ameliorated by QUR/TAM-Si@CsNPs treatment, to a greater extent than Si@CsNPs loaded individually with QUR or TAM. Biochemical, apoptotic, and histopathological analyses further demonstrated that treatment with QUR/TAM-Si@CsNPs normalized acetylcholinesterase activity, Tau protein level, β-amyloid accumulation, pro-inflammatory mediators, and apoptotic indices while preserving hippocampal architecture. Collectively, these findings demonstrate that QUR/TAM-Si@CsNPs exert combined anti-inflammatory and neuroprotective effects, highlighting their promise as a multifunctional nanotherapeutic strategy against LPS-associated neurodegenerative and AD-like neuropathological alterations.}, } @article {pmid42631497, year = {2026}, author = {Gopal, RK and Pathoor, NN and Ganesh, PS}, title = {Eubiosis and dysbiosis in periodontitis-related systemic diseases.}, journal = {Journal of periodontology}, volume = {}, number = {}, pages = {}, doi = {10.1002/jper.70188}, pmid = {42631497}, issn = {1943-3670}, abstract = {BACKGROUND: This narrative review examines the eubiosis-dysbiosis spectrum in periodontitis and its systemic implications. Evidence is drawn from the literature through 2026; as a narrative review, some selection bias cannot be excluded. Periodontitis, affecting 10%-15% of adults globally, drives systemic health disorders through microbial dysbiosis.

OBJECTIVES: This narrative review examines microbial ecological shifts in periodontitis and their implications for cardiovascular disease (CVD), diabetes mellitus (T2D), neurodegenerative disorders, rheumatoid arthritis (RA), and other systemic conditions.

METHODS: We have synthesized the current evidence on oral microbiome transitions from eubiosis to dysbiosis, focusing on mechanistic pathways linking periodontal disease to systemic health outcomes.

RESULTS: Periodontal dysbiosis may influence systemic health through mechanisms including bacteremia, chronic inflammation, molecular mimicry, and microbiome axis interactions. Individuals with periodontitis show 1.5 to 2-fold increased cardiovascular risk, bidirectional relationships with diabetes (HbA1c reductions of 0.3%-0.5% following periodontal treatment), and associations with Alzheimer's disease, rheumatoid arthritis, and inflammatory bowel disease. Key pathogens including Porphyromonas gingivalis, Aggregatibacter actinomycetemcomitans, and Fusobacterium nucleatum have been proposed as keystone species capable of remodeling microbial communities and potentially contributing to systemic effects.

CONCLUSIONS: Understanding the eubiosis-dysbiosis spectrum provides crucial insights into oral-systemic health connections and offers therapeutic targets for managing both periodontal and systemic diseases. Integrated medical-dental care approaches, precision medicine strategies, and microbiome-based therapeutics represent promising future directions.}, } @article {pmid42631776, year = {2026}, author = {Dineshbhai, TK and Rafaliya, D and Singh, A and Maheshwari, S and Lalan, M and Chakraborthy, GS}, title = {Emerging diagnostic biomarkers and therapeutic targets in Alzheimer's disease.}, journal = {Inflammopharmacology}, volume = {}, number = {}, pages = {}, pmid = {42631776}, issn = {1568-5608}, abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disease and is the most common cause of dementia in the world. Cognitive decline, memory problems, behavioral disturbances, and, finally, loss of functional independence characterize it. AD has risen and continues to increase globally, especially among aging people. A team of researchers at the University of Alberta says that we need faster, better diagnosis and treatment of AD. It elaborates on the progressive understanding of AD pathophysiology, biomarkers, emergent targets, and the latest delivery solution. The paper covers and discusses various disease-causing mechanisms like plaque formation, tau hyperphosphorylation, etc., which causes AD. Research is also being undertaken on the role of genetic and epigenetic factors in the pathogenesis and evolution of diseases, including but not limited to APOE polymorphisms, DNA methylation, modifications of histones, and non-coding RNAs. Researchers have discovered biomarkers relevant to AD, particularly those found in CSF and blood. The biomarkers include Aβ42, phosphorylated tau, neurofilament light chain, GFAP, and TREM2. Other biomarkers include salivary, urinary, neuroimaging, and digital. Next come the therapeutic strategies targeting amyloid aggregation, tau pathology, and other types of dysfunctions. Recent developments in monoclonal antibodies, kinase inhibitors, anti-inflammatory agents, neurotrophic agents, and antioxidant therapies are stressed. Moreover, nanotechnology-based and targeted delivery systems being developed for drugs include, but are not limited to, liposomes, polymeric nanoparticles, dendrimers, nanoemulsions, and intranasal formulations to enhance blood-brain barrier permeability. A combination of biomarker-guided diagnostics with mechanism-based therapies might enable precision medicine approaches and improve clinical outcomes in AD.}, } @article {pmid42632150, year = {2026}, author = {Chenxi, D and Miaomiao, W and Jiahui, F and Hongming, Z and Lu, G and Lihua, W and Ying, Z and Xiaoqing, C and Jing, Z and Yanhong, S}, title = {Technological evolution of hyperthermia: From traditional moxibustion to nanomaterial-mediated platforms for inflammatory diseases.}, journal = {Journal of thermal biology}, volume = {140}, number = {}, pages = {104557}, doi = {10.1016/j.jtherbio.2026.104557}, pmid = {42632150}, issn = {0306-4565}, abstract = {Hyperthermia, a physical therapeutic modality with unique advantages in treating inflammatory diseases, has evolved rapidly from empirical practice to precision medicine. Technologically, it has expanded from whole-body hyperthermia and traditional moxibustion to localized approaches, including photothermal, magnetothermal, ultrasound, and implantable platforms. Traditional moxibustion acts through heat and near-infrared radiation, while nanomaterials and smart devices now enable precise control over temperature, spatial targeting, and treatment duration. these modalities converge on conserved mechanisms: TRPV channel activation, HSF1-HSP70 induction, and immune modulation, which collectively alleviate inflammation and promote tissue repair in inflammatory bowel disease, osteoarthritis, and Alzheimer's disease. This review summarizes technological evolution, mechanistic insights and therapeutic applications, thereby providing a framework for developing precision hyperthermia strategies and multifunctional platforms for inflammatory diseases.}, } @article {pmid42632510, year = {2026}, author = {Yi, F and Ma, J and Zhao, R and Xie, Q and Lu, S and Zhang, K and Zhong, Z and OuYang, H and Qin, Y and Xu, M and Xue, Q and Wang, X and Wei, W and Liu, Y}, title = {Zonisamide improves cognitive impairment and psychiatric symptoms related with SAPAP3 in mouse models of Alzheimer's disease.}, journal = {European journal of pharmacology}, volume = {1033}, number = {}, pages = {179279}, doi = {10.1016/j.ejphar.2026.179279}, pmid = {42632510}, issn = {1879-0712}, abstract = {BACKGROUND: Alzheimer's disease (AD) is characterized by pathological changes in Aβ&Tau, cognitive impairment, and may also manifest psychiatric symptoms. Zonisamide (ZNS) has been demonstrated its improvement of cognitive dysfunction in T2DM mice in our previous study. However, the efficacy and mechanism of ZNS in treating AD remain unclear.

AIM: We aims to investigate the therapeutic efficacy of ZNS for AD and its potential molecular mechanisms.

METHODS: Three-month-old 5xFAD mice were treated with ZNS (20 mg/kg, i.p.) for 12-week. The behavioral test assesses cognitive function and psychiatric symptoms. Aβ-PET/CT, immunofluorescence, and Thioflavine-S staining assessed the levels of Aβ plaques. Proteomics and Western blot analyses evaluated synapse-associated proteins, amyloid precursor protein (APP) related proteins and phosphorylated tau.

RESULTS: We discovered for the first time that ZNS significantly improved spatial learning and memory, and also alleviated psychiatric symptoms in 5xFAD. Besides, ZNS increased PSD95, SYP, BDNF, and SAP90/PSD-95-related protein 3 (SAPAP3), which plays a crucial role in compulsive-like behaviors. Importantly, siRNA-mediated knockdown of SAPAP3 in N2A/APP cells inhibited the regulatory effect of ZNS on PSD95 and NMDAR2A (NR2A). In addition, ZNS treatment reduced Aβ deposition in the brain. It also downregulated APP, p-APP (Thr668), BACE1, and PS1, and attenuated tau phosphorylation at Ser396 by inhibiting its upstream kinase ERK1/2 activity.

CONCLUSION: ZNS exerts neuroprotective effects in 5xFAD mice and improves AD-related cognitive impairment and AD-like lesions, which establishes ZNS as a promising therapeutic avenue for AD and its associated psychiatric symptoms.}, } @article {pmid42633398, year = {2027}, author = {Chen, H and Si, Y and Cheng, Q and Yu, Q and Cui, Z and Yu, S and Zhao, X and Jin, Y and Wang, Y and Li, M and Lu, Z}, title = {Therapeutic potential and underlying mechanisms of engineered young plasma-derived exosomes in Alzheimer's disease.}, journal = {Bioactive materials}, volume = {67}, number = {}, pages = {497-523}, pmid = {42633398}, issn = {2452-199X}, abstract = {Exosomes (EXOs) derived from the plasma of young individuals are believed to have the potential to ameliorate aging-related memory deficits. However, their specific roles and mechanisms in Alzheimer's disease (AD) therapy have not yet been systematically investigated. In this study, the rabies virus glycoprotein-targeting peptide (RVG-29) was conjugated to the surface of young plasma-derived EXOs to construct RVG-engineered EXOs (RVG-EXOs), and their therapeutic potential and underlying mechanisms in AD models were systematically evaluated. In 3×Tg AD model mice, exogenous administration of young plasma-derived EXOs and their engineered product (RVG-EXOs) revealed that RVG-EXOs could more efficiently enter brain tissue and target neurons, significantly reduce Aβ plaque and phosphorylated Tau (P-Tau) pathological deposition, restore synaptic structure, promote neuronal survival, and improve cognitive behavior. Mechanistic studies demonstrated that RVG-EXOs inhibited RPTOR expression, thereby activating the autophagy pathway and promoting the clearance of pathological proteins. Both in vitro and in vivo experiments confirmed that overexpression of RPTOR significantly suppressed the therapeutic effects of RVG-EXOs. single-cell transcriptomic profiling further revealed that RVG-EXOs not only increased neuronal proportion and modulated excitatory/inhibitory neuronal balance but also reshaped the microglial landscape by reducing deleterious disease-associated while increasing homeostatic surveillant microglia. In summary, this study not only reveals for the first time the potential value of young plasma-derived EXOs in AD treatment but also, through RVG engineering strategies and the elucidation of the RPTOR-autophagy mechanism, provides new insights for targeted therapy of neurodegenerative diseases.}, } @article {pmid42633943, year = {2026}, author = {Fujita, S and Fushimi, Y and Otsuka, Y and Murata, K and Buonincontri, G and Koerzdoerfer, G and Nittka, M and Fukunaga, I and Takabayashi, K and Hagiwara, A and Motoi, Y and Nakajima, M and Murakami, K and Shima, A and Kubota, M and Bilgic, B and Kamagata, K and Sawamoto, N and Abe, O and Nakamoto, Y and Aoki, S}, title = {Brain Amyloid Burden Mapping Using MR Fingerprinting Aided by Deep Learning.}, journal = {Magnetic resonance in medical sciences : MRMS : an official journal of Japan Society of Magnetic Resonance in Medicine}, volume = {25}, number = {4}, pages = {}, doi = {10.2463/mrms.mp.2026-0112}, pmid = {42633943}, issn = {1880-2206}, mesh = {Humans ; Positron-Emission Tomography ; *Deep Learning ; *Magnetic Resonance Imaging/methods ; *Brain/diagnostic imaging/metabolism ; Prospective Studies ; *Amyloid beta-Peptides/metabolism ; Reproducibility of Results ; Female ; Male ; *Brain Mapping/methods ; Alzheimer Disease/diagnostic imaging ; }, abstract = {PURPOSE: To develop and externally validate a non-invasive framework for quantifying brain amyloid-β (Aβ) deposition using magnetic resonance fingerprinting (MRF) and neural network-based decoding, with positron emission tomography (PET) as the reference standard.

METHODS: This prospective multi-site study included 44 participants from 2 sites who had undergone, or were scheduled to undergo, Aβ PET within 1 year. MRF was performed on a 3T MR system using a 2D fast imaging with steady-state precession sequence with B1 correction, covering the whole brain in 9.5 min. PET images were co-registered to the MRF space, and regional amyloid load was calculated using an automated template-based pipeline. An inverse mapping function was implemented to convert MRF signals into amyloid burden maps. Repeatability, agreement with PET-based centiloid values, and associations with cognitive scores were evaluated.

RESULTS: The generated amyloid maps were visually similar to PET images. Test-retest analysis showed high repeatability, with a coefficient of variation of 1.8 ± 1.3% and an intraclass correlation coefficient of 0.84. In the external test set, MRF-based measurements correlated significantly with PET centiloid scores (Spearman's ρ = 0.589, P = 0.015) and Montreal Cognitive Assessment scores (ρ = -0.543, P = 0.020).

CONCLUSION: The proposed framework enables non-invasive Aβ mapping using a clinically feasible MRI protocol and may support repeated assessment for monitoring during anti-amyloid treatment.}, } @article {pmid42634203, year = {2026}, author = {Khan, MS and Ashesh, AM and Mammen, MV and Alhusaini, A and Jawaid, T and Akhtar, MS and Orayj, K and Ansari, I and Kumar, D and Kumar, A}, title = {Targeting NMDA Receptor Pathways in Alzheimer's Disease, From Cellular Mechanisms to Treatment Strategies.}, journal = {Current neuropharmacology}, volume = {}, number = {}, pages = {}, doi = {10.2174/011570159X474645260731070203}, pmid = {42634203}, issn = {1875-6190}, abstract = {The Alzheimer's Disease (AD) lacks effective disease-modifying therapy, even though amyloid-targeting immunotherapies have recently been applied clinically. N-methyl-D-Aspartate Receptors (NMDARs) play a central yet mechanistically complicated role in the pathophysiology of AD, where they are convergence points of amyloid-beta (Aβ) oligomer toxicity, tau-dependent excitotoxicity, and progressive synaptic failure. This critical review examines NMDAR dysfunction across the AD spectrum, with a focus on subunit-regulated signalling, subcellular localisation, and subsequent pathological cascades. The effects of Aβ oligomers on NMDAR activity involve multiple mechanisms that disrupt their function, including glutamate dysregulation mediated by GLT-1, redistribution of GluN2B to extrasynaptic areas, and inhibition of JAK2-CREB via activation of extrasynaptic receptors. Tau enhances excitotoxic injury throughdendritic mislocalization, and the tau-Fyn-GluN2B complex, which propels pro-death signalling by DAPK1. This conceptually important prevailing synaptic-extrasynaptic dichotomy is fiercely criticised here, given evidence that synaptic receptors containing GluN2A also mediate pathological signalling during sustained Aß exposure, and that tri-heteromeric receptor populations are problematic for subunit-selective targeting. Neuroinflammation, dysfunction of the blood-brain barrier, and excitotoxic amplification via GluN2C/D-enriched receptor pools in neurons, astrocytes, microglia, oligodendrocytes, and endothelial cells are underexplored therapeutic targets for neurodegenerative disease (non-neuronal NMDARs). Memantine is the only approved NMDAR-targeting agent for AD. Subunit-selective antagonists have not been translated into clinical use, and the positive allosteric modulator dalzanemdor (SAGE-718) did not pass its randomised Phase 2 trial in 2024. The most mechanistically justified approach is to advance subunit-selective, compartment-specific, or protein-complexdisrupting strategies. Although it is not established whether any single NMDAR-targeting intervention will suffice as a disease-modifying therapy, the convergence of molecular, genetic, and clinical evidence positions NMDAR dysfunction as a tractable , if therapeutically demanding , node in the AD pathogenic network, warranting continued, mechanism-informed drug discovery.}, } @article {pmid42634340, year = {2026}, author = {Cui, H and Li, Q and Yao, Y and Wang, X and Tian, S}, title = {Physicochemical Characterization and Biological Activity of Ethanol- Extracted Residue of Saussurea involucrata.}, journal = {Combinatorial chemistry & high throughput screening}, volume = {}, number = {}, pages = {}, doi = {10.2174/0113862073470898260602093207}, pmid = {42634340}, issn = {1875-5402}, abstract = {INTRODUCTION: Saussurea involucrata's ethanol-extracted residue (ROSI), a byproduct of its oral liquid preparation, nevertheless holds significant therapeutic promise. To evaluate its potential as a treatment for neurodegenerative illnesses, this study investigates its physicochemical properties and biological activity.

MATERIALS AND METHODS: UV-Vis, IR spectroscopy, UHPLC-Q Exactive HFX systems, microscopy, powder characterisation, and thermogravimetric analysis were used to examine the physical and chemical characteristics of ROSI. Antioxidant activities and pancreatic lipase inhibition were assessed. Its therapeutic targets for neurodegenerative disorders were predicted by network pharmacology and molecular docking analyses.

RESULTS: ROSI demonstrated high organic acid content, a uniform porous structure, consistent particle size, and high thermal stability, meeting industrial flowability standards. While showing modest pancreatic lipase inhibition, it exhibited potent antioxidant activity. Pharmacomics analysis suggests ROSI may target multiple pathways involved in neurodegenerative diseases.

DISCUSSION: Despite its modest pancreatic lipase inhibitory effect, ROSI exhibits potent antioxidant activity and stable physicochemical properties suitable for industrial applications. Network pharmacology and molecular docking analyses reveal therapeutic potential for ROSI in neurodegenerative diseases such as Alzheimer's and Parkinson's. Consequently, ROSI serves as a natural antioxidant and a raw material for the development of functional foods and pharmaceuticals.

CONCLUSION: ROSI holds promise as an adjunctive treatment for neurodegenerative diseases, particularly for its antioxidant effects and industrial applicability. Further research should optimize its use in chronic disease management and explore its broader medicinal potential.}, } @article {pmid42634351, year = {2026}, author = {Patnaik, S and Patra, PK and Patra, CN and Panda, KC}, title = {Biomarkers, Diagnostics, and Emerging Therapies in Alzheimer's Disease: A Comprehensive Systematic Review (2015-2025).}, journal = {Central nervous system agents in medicinal chemistry}, volume = {}, number = {}, pages = {}, doi = {10.2174/0118715249427154260531181405}, pmid = {42634351}, issn = {1875-6166}, abstract = {INTRODUCTION: The underlying association between multiple risk factors like age, preexisting diseases, infections, traumatic brain injuries, and certain genetic factors makes the diagnosis and treatment a challenge in AD. Identification of biomarkers and proper diagnosis of AD could make its management easier. Advances in diagnostic techniques like Positron Emission Tomography (PET) imaging have greatly improved the ability to identify, detect early, monitor disease progression, and manage its therapy.

METHODS: The recent therapeutic advancements in treatments encompass immunotherapies aimed at amyloid-beta (Aβ) and tau proteins, novel drug delivery systems, non-pharmacological methodologies, and personalised medicine techniques, combination therapies, and non-invasive brain stimulation are important in the management of AD. Cholinesterase inhibitors, such as galantamine, rivastigmine, and donepezil, are used to enhance cognitive performance and reduce confusion. Moderate to severe AD, memantine, a N-methyl-D-aspartate receptor (NMDA) receptor antagonist, is prescribed. Researchers are looking into both active and passive vaccines to get antibodies to Aβ plaques, and monoclonal antibodies, such as Lecanemab and Donanemab, which are used to treat early-stage AD.

RESULTS: Ongoing research is focused on identifying new biomarkers and therapeutic targets, advancing gene therapy, and refining immunotherapeutic approaches for AD.

DISCUSSION: There is growing interest in comprehending the influence of lifestyle and environmental factors on the mitigation of AD risk. Ongoing research is essential to elucidate the complexity of AD pathophysiology and to create effective therapies.

CONCLUSION: This review highlights the critical need for future AD research to bridge identified gaps in early detection, focus on improving early diagnosis, developing more effective treatments, refining existing drugs and therapies, and understanding the underlying disease progression mechanisms.}, } @article {pmid42634372, year = {2026}, author = {Tong, Y and Hu, G and Liu, L and Zhang, Y and Jiang, N and Hou, Y and Zhang, M}, title = {Dynamic Entropic Mapping of Alzheimer's Neuropathology: Eyes-Open and Eyes-Closed EEG Biomarkers through Wavelet Entropy Analysis.}, journal = {Current Alzheimer research}, volume = {}, number = {}, pages = {}, doi = {10.2174/0115672050450560260119050625}, pmid = {42634372}, issn = {1875-5828}, abstract = {BACKGROUND: Alzheimer's Disease (AD) is characterized by amyloid-β plaques and tau tangles, while current diagnostic tools are often invasive and costly. Electroencephalography (EEG) offers a non-invasive alternative, with alpha rhythm abnormalities as key features. Impaired alpha reactivity during the transition from Eyes-Closed (EC) to Eyes-Open (EO) reflects early thalamocortical dysfunction.

OBJECTIVE: This study employs EO/EC wavelet entropy analysis to assess neurodynamic features across frequency bands, aiming to explore entropy-based EEG markers for early AD detection.

METHODS: This cross-sectional study enrolled 60 participants (30 AD and 30 controls). EEG was recorded during 60-second EC and Eyes-Open (EO) states using a 20-channel system. Continuous Wavelet Transform (CWT) and multiscale entropy were used to assess complexity differences across bands and regions between groups.

RESULTS: AD patients showed reduced alpha entropy differences between EC and EO states. Multiscale entropy difference (ΔEN α) analysis revealed weaker modulation in β-α and θ-δ bands compared with HC. Occipital ΔEN α correlated significantly with MMSE, with the strongest association in the alpha band (r = 0.9000, P < 0.001).

DISCUSSION: This study applies dual-state wavelet entropy analysis to reveal impaired neural reactivity in AD during eyes-open and eyes-closed transitions. The ΔEN α metric distinguishes AD from controls and correlates with cognitive decline, reflecting reduced neural flexibility and disrupted frequency-specific network dynamics.

CONCLUSION: This study shows that dual-state wavelet entropy analysis, especially ΔEN α, is a noninvasive tool for detecting neurodynamic abnormalities in AD. It reflects loss of state-dependent responsiveness and neural complexity, with potential for early screening and objective evaluation of treatment.}, } @article {pmid42634511, year = {2026}, author = {Mishra, R and Chauhan, N and Agrawal, KK}, title = {Current Targeted Nanoparticle Therapy for Alzheimer's Disease: Current Advances and Future Prospects.}, journal = {Current neurovascular research}, volume = {}, number = {}, pages = {}, doi = {10.2174/0115672026471444260724103751}, pmid = {42634511}, issn = {1875-5739}, abstract = {BACKGROUND: The effects of Alzheimer's disease (AD) on society are profound. The blood-brain barrier selectively permits the penetration of specific forms of molecules through the blood circulation into the CNS, which can restrict the effectiveness of medications supplied systemically. The therapeutic targets are located in the CNS. However, local administration channels to the CNS are rather intrusive, which can lead to patient discomfort and limit the feasibility of repeated treatments.

METHODOLOGY: This article has evaluated treatment methodologies for AD that use nanoparticles to target the brain and the pathological features of the illness. The material that is currently available has been categorized based on the aspect of AD that is discussed: targeted medication and neurodegeneration.

RESULT: The use of nanoparticles in the targeted delivery of medications intended to alleviate the symptoms of AD or halt the disease's progression has yielded positive results. Because of their multivalence, nanoparticles can target the treatment site, pass through the blood-brain barrier, and be functionalized with various targeting groups. Intravenous administration, rather than more intrusive techniques, has enhanced drug bioavailability in the CNS. Furthermore, the development of vaccinations and medication formulations for intranasal delivery has utilized nanoparticles.

DISCUSSION: This study focused on the advancement of AD treatment. Nanoparticles are designed to enhance drug bioavailability through intravenous and intranasal routes for quicker brain access with fewer side effects. Nanoparticles also aid in targeting disease features like amyloid- beta plaques and tau tangles. While results in animal models are positive, transitioning to human clinical trials requires a more profound understanding of AD mechanisms and biomarker identification.

CONCLUSION: Research employing animal models suggests that targeted nanoparticles can enhance the effectiveness of AD treatments. A deeper understanding of AD mechanisms will lead to more successful targeted nanoparticle applications.}, } @article {pmid42631247, year = {2026}, author = {Chen, X and Boey, J and Wei, K and Ding, C and Malagón, P and Hong, JP and Zhou, Z}, title = {The Use of Dynamic Neck Lymphaticovenous Anastomosis in the Adjunctive Treatment of Alzheimer's Disease: A Retrospective Case Series.}, journal = {Archives of plastic surgery}, volume = {53}, number = {4}, pages = {352-360}, pmid = {42631247}, issn = {2234-6163}, abstract = {BACKGROUND: Lymphovenous anastomosis (LVA) has recently emerged as a potential method for the symptomatic management of Alzheimer's disease (AD). Building on this, we conceptualize the "dynamic neck lymphovenous anastomosis" (DN-LVA) to illustrate the versatility of our technique. DN-LVA utilizes a vein graft that traverses through the sternocleidomastoid muscle to facilitate the drainage of lymphatic fluid from the deep cervical lymphatic vessels to the external jugular vein.

METHODS: This study presents a retrospective analysis of patients who underwent DN-LVA between November 2024 and January 2025. The clinical outcome was evaluated through positron emission tomography/computed tomography (PET/CT) imaging and cognitive assessment tools, which included Mini-Mental State Examination (MMSE), Montreal Cognitive Assessment (MoCA), Neuropsychiatric Inventory (NPI), and Clinical Dementia Rating (CDR). The vein graft was harvested from the lower limb.

RESULTS: Five subjects were recruited into this study. Postoperative PET/CT scans revealed up to a 6.9% increase in glucose metabolism in patient 3, a decrease of 12.3% in amyloid deposits, and a 4.7% reduction in tau deposits in patient 5 and patient 4, respectively. Clinically, MMSE and MoCA scores were improved by 1.8 and 1.4, respectively. NPI scores decreased by 5.8 across five overall, and the CDR remained unchanged in all subjects. All grafts demonstrated vessel patency, and no postoperative complications were observed.

CONCLUSION: DN-LVA appears to be a safe, minimally invasive procedure with potential cognitive and metabolic benefits in AD. Further studies with larger cohorts and longer follow-up are warranted to confirm these preliminary findings.}, } @article {pmid42631306, year = {2026}, author = {de Oliveira, GLDS and Bertollo, AG}, title = {Non-pharmacological strategies for the management of Alzheimer's disease.}, journal = {Dementia & neuropsychologia}, volume = {20}, number = {}, pages = {e20250290}, pmid = {42631306}, issn = {1980-5764}, abstract = {Alzheimer's disease (AD) is a multifactorial neurodegenerative disease affecting various cognitive domains, requiring a holistic and integrated therapeutic approach. The treatment of AD goes beyond pharmacological interventions, also necessitating non-pharmacological therapies that can act synergistically, both with each other and with emerging pharmacological treatments, including new anti-amyloid therapies. These therapies aim to improve patients' quality of life and alleviate behavioral symptoms, such as agitation and depression, and delay disease progression. Current clinical and meta-analytic evidence suggests that these approaches can be effectively integrated with conventional treatment, offering a valuable alternative to enhance patients' overall well-being. However, further research is needed to deepen the understanding of the ideal combination of the new anti-amyloid therapies, to address the limitations of current evidence, and to robustly establish their effectiveness in the clinical context of AD, aiming to generate a broader and more lasting impact on disease treatment. This narrative review aims to synthesize the evidence on diverse non-pharmacological therapies for managing AD and discuss their practical implications for clinical care.}, } @article {pmid42625393, year = {2026}, author = {Okafor, NI and Abdelgader, A and Abobaker, M and Choonara, YE}, title = {A Review of the Therapeutic Potential of Stem Cell-Derived Nanocarriers to Treat Neurological Disorders.}, journal = {ChemistryOpen}, volume = {15}, number = {9}, pages = {e202500425}, pmid = {42625393}, issn = {2191-1363}, support = {//National Research Foundation (NRF) of South Africa/ ; }, mesh = {Humans ; *Nervous System Diseases/therapy/drug therapy ; Animals ; *Stem Cells/cytology/metabolism ; *Nanoparticles/chemistry ; Blood-Brain Barrier/metabolism ; *Drug Carriers/chemistry ; Stem Cell Transplantation ; }, abstract = {Neurological disorders (NDs) are characterized by substantial loss of specific neurons, with Alzheimer's and Parkinson's diseases being the most frequent NDs and nearly 99% of all "foreign substances" are prohibited from entering the brain by the blood-brain barrier (BBB) and the blood-cerebrospinal fluid barrier (CFB). These barriers, while crucial for brain protection, pose significant challenges for drug delivery, as they restrict the entry of many therapeutic agents into the brain, and this represents the primary manifestation of the absence of pathogenesis-targeting therapeutics. With significant success across multiple cell transplantation research efforts, stem cell therapy has been utilized for decades to treat neurological disorders. They work by replacing injured or lost cells directly, releasing proliferation and neurotrophic factors through autocrine and paracrine actions, suppressing neurological inflammation, and activation of endogenous brain progenitor cells. Nanocarriers derived from stem cells represent an innovative and promising therapeutic strategy for combating neurological diseases, combining faculties of regeneration of stem cells with the precision of nanotechnology. These nanocarriers possess natural biocompatibility and can efficiently cross the BBB to transport the therapeutic agents directly to affected neural tissues, thereby promoting enhanced treatment efficacy while reducing off-target effects. However, key challenges remain in large-scale production, standardization, and long-term safety. Thus, this review has examined the potential applications of stem cell extracellular vesicle (EV)-nanocarriers, mainly exosomes and recent development in the treatment of neurological diseases.}, } @article {pmid42626026, year = {2026}, author = {Mehta, V and Singh, D and Kelman, J and Nimma, S and Lutz, H and Schnee, A and Weisman, D and Rosenbloom, MH}, title = {Real-world determinants of time to initiation of anti-amyloid treatments: comparative data from private and academic practice settings.}, journal = {Alzheimer's & dementia (Amsterdam, Netherlands)}, volume = {18}, number = {3}, pages = {e70436}, pmid = {42626026}, issn = {2352-8729}, abstract = {INTRODUCTION: Earlier anti-amyloid therapy (AAT) initiation results in improved clinical outcomes in Alzheimer's disease (AD). We sought to identify demographic, clinical, and disease-related factors impacting door-to-treatment times (DTTs).

METHODS: A retrospective review of AAT data was conducted at private and academic neurological practices.

RESULTS: A total of 329 patients (53.2% from private versus 46.8% academic practices), mean age 73.5 ± 7.2 (55.3% female), with most being non-Hispanic White were treated with lecanemab (81.2%) or donanemab (18.2%). DTTs were significantly reduced (p < 0.05) in both practices when diagnosis was confirmed with blood-based biomarkers (BBBs) as well as with greater clinic experience dosing AATs. DTT increased in patients with non-Medicare insurance and was not impacted by diagnosis, referral source, apolipoprotein E genotype status, or clinic distance.

DISCUSSION: Patients with private insurance may experience greater delay in DTT, whereas BBBs may reduce DTT relative to traditional confirmatory biomarkers. DTT improves with clinic experience.}, } @article {pmid42627514, year = {2026}, author = {Cao, Q and Shen, M and Liu, Y and Li, C and Liu, L and Zhou, J and Yue, R and Niu, D and Ren, Y and Pan, L and Yao, J and Zhang, G}, title = {The role of microglia glucose metabolism reprogramming in Alzheimer's disease treatment.}, journal = {Journal of Alzheimer's disease : JAD}, volume = {}, number = {}, pages = {13872877261478594}, doi = {10.1177/13872877261478594}, pmid = {42627514}, issn = {1875-8908}, abstract = {Alzheimer's disease (AD) is a neurodegenerative disorder characterized by progressive cognitive impairment, and there remains a lack of effective treatments capable of reversing or significantly slowing disease progression. Accumulating evidence indicates that the immune function of microglia, the resident immune cells of the central nervous system, is a critical factor in regulating AD pathogenesis. Emerging research in immunometabolism further reveals that glucose metabolic reprogramming serves as a central driver of microglial phenotypic and functional differentiation. This review systematically outlines the fundamental characteristics of microglial glucose metabolism and focuses on how the dynamic metabolic reprogramming it undergoes during AD progression regulates microglial immune behavior and inflammatory responses. Building on this, we further summarize key regulatory targets within the "metabolism-immune axis" and corresponding pharmacological intervention strategies. Finally, this article discusses current challenges and future research directions in the field of microglial immunometabolism. This review aims to provide a theoretical foundation for AD intervention strategies targeting the "metabolism-immune axis" and to offer insights for the development of novel disease-modifying therapeutics.}, } @article {pmid42627571, year = {2026}, author = {Wang, Q and Wei, Y and Shen, C and Kang, W and Wang, L}, title = {CT1812 Attenuates Surgery-Induced Cognitive Impairment and Modulates TMEM97- and PGRMC1-Associated Hippocampal Stress Responses in Aged Mice.}, journal = {Neurochemical research}, volume = {51}, number = {5}, pages = {}, pmid = {42627571}, issn = {1573-6903}, support = {82201549//National Natural Science Foundation of China/ ; }, mesh = {Animals ; *Membrane Proteins/metabolism ; *Hippocampus/drug effects/metabolism ; Male ; Mice, Inbred C57BL ; Mice ; *Aging/drug effects/metabolism ; *Cognitive Dysfunction/metabolism/drug therapy/etiology ; *Postoperative Cognitive Complications/metabolism/drug therapy ; Receptors, Progesterone ; }, abstract = {Postoperative neurocognitive disorders (PND) are common complications in older surgical patients, but druggable mechanisms linking surgical trauma to hippocampal synaptic and cognitive vulnerability remain poorly defined. The σ-2 receptor (σ-2R), encoded by transmembrane protein 97 (TMEM97), and progesterone receptor membrane component 1 (PGRMC1) intersect membrane lipid biology and synaptic stress signaling; CT1812, a pharmacological σ-2R complex modulator, has shown target engagement in early Alzheimer's disease trials, but whether this pathway participates in postoperative hippocampal injury is unknown. This study examined whether surgery-induced hippocampal stress in aged mice is associated with TMEM97 and PGRMC1 signaling and whether early CT1812 treatment can attenuate this response. Young adult (2-3 months) and aged (18-20 months) male C57BL/6J mice underwent sham operation or laparotomy; aged mice were further treated with vehicle or CT1812 (3 mg/kg, intravenous injection, days 0-3). Hippocampal molecular changes were assessed by western blotting and immunofluorescence on day 3, and behavior was evaluated by open field test (OFT) and Morris water maze (MWM) on days 6-10. Laparotomy increased hippocampal TMEM97 and PGRMC1 expression and induced anxiety-like and spatial-memory deficits preferentially in aged mice, without evidence that locomotor impairment explained the behavioral phenotype. TMEM97 and PGRMC1 were detected in neuronal nuclei (NeuN)-positive neurons, ionized calcium-binding adapter molecule 1 (Iba-1)-positive microglia, and glial fibrillary acidic protein (GFAP)-positive astrocytes in hippocampal cornu ammonis 1 (CA1), supporting multicellular pathway involvement. In aged surgical mice, CT1812 significantly reduced upregulation of TMEM97 and PGRMC1, improved OFT center-zone occupancy and MWM performance, and restored the synaptic markers postsynaptic density protein 95 (PSD95) and synaptophysin. CT1812 also normalized lipid-handling proteins, including apolipoprotein E (ApoE), ATP-binding cassette transporter A1 (ABCA1), cholesterol 24-hydroxylase (CYP46A1), and low-density lipoprotein receptor (LDLR), and reduced perilipin 2 (PLIN2) accumulation in neurons and microglia. In parallel, CT1812 attenuated a selective endoplasmic reticulum (ER) stress response involving binding immunoglobulin protein (BIP) and protein kinase R-like endoplasmic reticulum kinase (PERK)-eukaryotic initiation factor 2α (eIF2α) signaling in hippocampal neurons, and suppressed microglial nuclear factor κB (NF-κB)/NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammatory activation, whereas C/EBP homologous protein (CHOP) was not significantly changed. These findings support a model in which postoperative injury in the aged hippocampus engages a lipid-proteostatic and inflammatory stress program associated with TMEM97 and PGRMC1, and suggest that CT1812 attenuates cognitive vulnerability by restraining this coupled response.}, } @article {pmid42627656, year = {2026}, author = {Meiselbach, MK and Xu, J and Brown, T and Polsky, D}, title = {Medicare Advantage Beneficiary Enrollment Decisions Following New Complex Conditions.}, journal = {JAMA health forum}, volume = {7}, number = {8}, pages = {e262843}, doi = {10.1001/jamahealthforum.2026.2843}, pmid = {42627656}, issn = {2689-0186}, mesh = {Humans ; *Medicare Part C/statistics & numerical data ; United States ; Female ; Male ; Aged ; Chronic Disease/epidemiology ; Aged, 80 and over ; Cohort Studies ; Insurance, Medigap/statistics & numerical data ; }, abstract = {IMPORTANCE: Prior research has demonstrated higher rates of disenrollment from Medicare Advantage (MA) among people with greater health care needs. Yet, less is known about how disenrollment responds to changes in medical complexity, whether disenrollment varies by the degree of complexity, and how these patterns differ by state Medigap protections and MA plan characteristics.

OBJECTIVE: To examine changes in MA plan disenrollment following the development of new complex medical conditions and assess heterogeneity by number of conditions, state Medigap policy, and plan characteristics.

This cohort study used Medicare enrollment and claims data from 2016 to 2021. The study population included beneficiaries continuously enrolled in MA in 2016 without complex medical conditions from 2016 through 2018. A treatment group developed a new complex condition in 2019; a comparison group did not develop a complex condition through 2021. Data were analyzed from December 1, 2025, to March 1, 2026.

EXPOSURE: Development of 1 or more new complex medical conditions in 2019, including acute myocardial infarction, Alzheimer disease and related dementia, atrial fibrillation, chronic kidney disease, chronic obstructive pulmonary disease, depression, congestive heart failure, or stroke.

MAIN OUTCOMES AND MEASURES: Annual disenrollment from the prior year MA plan, which included disenrollment to traditional Medicare (TM) or switching to another plan within MA. Difference-in-differences models with beneficiary and year fixed effects were estimated and converted to differences in percentage points.

RESULTS: The analytic sample included 1 054 926 beneficiaries, including 219 942 (mean [SD] age, 75.3 [6.3] years; 54.6% female) who developed new complex conditions in 2019 and 834 984 (mean [SD] age, 73.8 [5.6] years; 56.7% female) who did not develop a new complex condition in 2019. Developing any new complex condition was associated with an increase of 3.3 (95% CI, 3.1-3.5) percentage points (pp) in MA disenrollment, including an increase of 2.8 (95% CI, 2.7-2.9) pp in disenrollment to TM. The number of new complex conditions was associated with increased disenrollment, from 1.4 (95% CI, 1.3-1.6) pp for 1 condition to 12.8 (95% CI, 11.6-13.9) pp for 4 or more conditions. Disenrollment to TM was 1.5 (95% CI, 0.9-2.1) pp higher among beneficiaries residing in states with Medigap guaranteed issue and community rating protections.

CONCLUSIONS AND RELEVANCE: In this study, development of new complex medical conditions was associated with higher MA disenrollment, particularly to TM and in states with Medigap protections, and the magnitude increased with medical complexity. These findings highlight how changes in health status and state policy may shape Medicare coverage decisions.}, } @article {pmid42627738, year = {2026}, author = {Chang, Y and Kim, HJ and Kim, Y and Park, A and Nam, S and Banerjee, DR and Hasenour, CM and Young, JD and Brooks, GA and Wolfe, RR and Kim, IY}, title = {Exogenous lactate ameliorates Aβ-induced energy deficit and neurotoxicity with increased mitochondrial TCA cycle carbon flux in SH-SY5Y cells.}, journal = {American journal of physiology. Cell physiology}, volume = {}, number = {}, pages = {}, doi = {10.1152/ajpcell.00268.2026}, pmid = {42627738}, issn = {1522-1563}, support = {2021R1A2C3005801//National Research Foundation of Korea (NRF)/ ; GCU-202106260001//Gachon University/ ; //Myocare Inc/ ; }, abstract = {A growing body of evidence has demonstrated the existence of metabolic dysfunction in neurodegenerative diseases, including Alzheimer's disease (AD), suggesting that deprivation of energy substrates impairs cellular dynamics. As the glucose utilization declines in AD patients, the need for alternative energy sources becomes crucial to sustain neuronal activities and prevent cell death induced by neurotoxic proteins, such as amyloid beta (A(?)) aggregates. In this context, lactate has been investigated as a potential alternative brain energy substrate in several studies, yet its impact on neuronal cells under A(?)-induced toxicity remains unclear. We confirmed significant suppression of energy production-related biological pathways by analyzing brain transcriptomic data of AD patients. In subsequent in vitro studies, exogenous lactate treatment ameliorated neuron-like cell death caused by A(?) aggregates. Using a [13]C stable isotope tracer, we verified cellular lactate uptake and its incorporation into TCA cycle in neurons under the neurotoxic condition. [13]C metabolic flux analysis further supported these findings by revealing that lactate treatment restored Aβ-suppressed mitochondrial TCA cycle fluxes. These metabolic improvements were accompanied by increased expression of mitochondrial proteins. These findings support lactate shuttling as a mechanism for supplying lactate-derived carbon to mitochondrial energy metabolism, which may improve neuronal resilience under Aβ-induced metabolic stress.}, } @article {pmid42628381, year = {2026}, author = {Quan, YS and Liu, JY and Liu, H and Sun, YX and Wang, YL and Liu, Z and Quan, ZS and Shen, QK}, title = {Design synthesis and evaluation of usnic acid derivatives as multi-target drugs for Alzheimer's disease.}, journal = {Bioorganic chemistry}, volume = {181}, number = {}, pages = {110398}, doi = {10.1016/j.bioorg.2026.110398}, pmid = {42628381}, issn = {1090-2120}, abstract = {The pathogenesis of AD is complex, and existing clinical drugs only alleviate symptoms and are difficult to block the course of the disease. Although UA has neuroprotective activities such as antioxidant and anti-inflammatory properties, its anti-AD activity is severely restricted by drug defects such as a single target and insufficient blood-brain barrier permeability. Therefore, this study takes UA as the lead compound, designs and synthesizes 38 UA derivatives, systematically evaluates their anti-AD biological activity, and aims to screen for multifunctional anti AD lead compounds. Among them, the lead compound S12 exhibited exceptional activity, with an EC50 value of 1.24 μM representing a 17.9-fold improvement in potency relative to the parent compound. Furthermore, WB assays were conducted to elucidate the underlying mechanism of action of this compound. The results revealed that compound S12 exerts anti-AD activity through the synergistic modulation of multiple signaling pathways: it inhibits activation of the MAPK and NF-κB pathways, as well as aberrant phosphorylation of tau protein; concurrently, it downregulates BACE1 expression to reduce Aβ production, and suppresses activation of the Bax/Bcl-2 pathway thereby inhibiting caspase-1 activation and ultimately confers neuroprotective, anti-AD effects. The apparent permeability coefficient of compound S12 across an in vitro (BBB) model was determined to be 7.66 × 10[-6] cm/s, confirming its ability to effectively cross the BBB. Further pharmacological evaluation demonstrated that S12 exerted a potent ameliorative effect on learning and memory deficits in an AD mouse model. In vivo toxicity assessment, no gross or histopathological abnormalities were observed in the major organs, including the heart, liver, spleen, and kidneys. Moreover, S12 significantly attenuated neuronal pathological injury in the hippocampus of Aβ-induced AD model mice, underscoring its robust neuroprotective activity. In conclusion, compound S12 demonstrates robust efficacy in ameliorating learning and memory deficits, enhancing blood-brain barrier permeability, and exerting anti-AD activity. Accordingly, it represents a highly promising multifunctional therapeutic candidate for the treatment of AD.}, } @article {pmid42630070, year = {2026}, author = {Alsharayri, S and Knox, S and Cutty, M and Mollalo, A}, title = {Dual eligibility and neuropsychiatric symptoms and treatment disparities among Medicare Part D beneficiaries with Alzheimer's disease and related dementias.}, journal = {Journal of Alzheimer's disease : JAD}, volume = {}, number = {}, pages = {13872877261478140}, doi = {10.1177/13872877261478140}, pmid = {42630070}, issn = {1875-8908}, abstract = {BackgroundNeuropsychiatric symptoms (NPS) are common and clinically consequential in Alzheimer's disease and related dementias (ADRD), yet their recognition and treatment may vary across socioeconomic groups. Dual-eligible Medicare-Medicaid beneficiaries represent a vulnerable population, but differences in NPS documentation and management remain unclear.ObjectiveTo examine whether dual eligibility is associated with differences in (1) documented NPS and (2) prescription fills among Medicare beneficiaries with ADRD who received home health (HH) care.MethodsWe conducted a cross-sectional study of 167,484 Medicare Part D beneficiaries with ADRD who received HH care and were identified using the Chronic Conditions Warehouse flag. Dual eligibility was the primary exposure. NPS were identified using diagnosis codes from medical claims. Prescription fills for NPS-related medications were identified using Medicare Part D prescription drug event data (≥2 prescription fills for anxiety-related medications and antidepressants). Logistic regression models estimated associations of dual eligibility with NPS documentation and prescription fills, adjusting for demographic characteristics, original Medicare entitlement, and comorbidity burden.ResultsDual-eligible beneficiaries comprised 30.7% of the cohort. Documented confusion and anxiety were the most prevalent symptoms. Dual-eligible beneficiaries had a higher prevalence of confusion (83.5% versus 82.0%) and anxiety (57.0% versus 53.2%) compared with Medicare-only beneficiaries. After adjustment, dual eligibility was associated with higher odds of documented confusion (aOR 1.18, 95% CI 1.14-1.22) and anxiety (aOR 1.19, 95% CI 1.15-1.22). Dual eligibility was also associated with slightly higher odds of anxiety-related prescription fills (aOR 1.21, 95% CI 1.17-1.26), whereas antidepressant prescription fills did not differ (aOR 1.00, 95% CI 0.95-1.05).ConclusionsDual eligibility was associated with modest differences in NPS documentation and prescription fills, suggesting differences in recognition and management of NPS among beneficiaries with ADRD.}, } @article {pmid42630294, year = {2026}, author = {Shafi, S and Ansari, GA}, title = {Developing artificial intelligence-based techniques for brain MRI image segmentation.}, journal = {Frontiers in neuroscience}, volume = {20}, number = {}, pages = {1894751}, doi = {10.3389/fnins.2026.1894751}, pmid = {42630294}, issn = {1662-4548}, abstract = {INTRODUCTION: Brain MRI image segmentation is essential for the accurate diagnosis and treatment of neurological disorders, including brain tumors, Alzheimer's disease, and multiple sclerosis. Artificial intelligence (AI), particularly deep learning, has emerged as an effective approach for improving the precision and efficiency of medical image segmentation while reducing manual effort.

METHODS: This study utilized a publicly available Kaggle brain MRI dataset containing labeled images for supervised learning. A Convolutional Neural Network (CNN)-based framework was developed for automatic brain MRI segmentation. The methodology incorporated preprocessing techniques, including noise removal, normalization, and data augmentation, to improve image quality and model performance. The proposed model was evaluated using Accuracy, Dice Score, and Intersection over Union (IoU).

RESULTS: Experimental results demonstrated that the proposed AI-based segmentation framework achieved high segmentation accuracy and effectively distinguished normal brain tissue from abnormal regions. The model outperformed conventional image-processing methods by providing improved segmentation precision, reducing manual intervention, and enhancing the reliability of medical image analysis.

DISCUSSION: The findings demonstrate the potential of AI-based deep learning techniques for automated brain MRI segmentation in clinical applications. The proposed framework can support clinicians by improving diagnostic accuracy and reducing processing time. Future work will focus on implementing more advanced deep learning architectures and expanding the dataset to further improve segmentation performance and clinical applicability.}, } @article {pmid42622750, year = {2026}, author = {Fu, C and Li, Q and Yang, Y and Gu, S and Zhao, W and Yao, X and Liu, H}, title = {Discovery of novel RIPK3 inhibitors by virtual screening and bioactivity evaluation.}, journal = {Molecular diversity}, volume = {}, number = {}, pages = {}, pmid = {42622750}, issn = {1573-501X}, support = {0012/2025/ASJ and 0043/2023/AFJ//the Science and Technology Development Fund of Macao SAR/ ; }, abstract = {As the most common chronic neurodegenerative disease, Alzheimer's disease (AD) has limited effective treatment options, highlighting the critical urgency of developing new therapeutic drugs. Receptor-interacting protein kinase 3 (RIPK3) is a key regulatory protein in the process of cell necroptosis and is also a potential target for AD. Existing inhibitors are not suitable for clinical treatment of AD due to problems such as insufficient activity, high toxicity, and poor selectivity. Therefore, the discovery of novel RIPK3 inhibitors is necessary and urgent. This study proposes and applies an integrated virtual screening strategy based on molecular fingerprint similarity, pharmacophore models, molecular docking, and molecular dynamics (MD) simulation. Using this workflow, we selected 54 compounds from approximately 9.7 million compounds for in vitro biological validation. In vitro kinase activity assays showed that three compounds (8019 - 0682, STK930700, and T72029) exhibited good inhibitory activity against RIPK3, with IC50 values of 1.684 µM, 3.002 µM, and 7.592 µM. Among them, 8019 - 0682 and T72029 demonstrated good cytoprotective effects in the TNF-α-induced L929 cell necroptosis model, with EC50 values of 2.135 µM and 15.891 µM. Finally, MD simulations and binding free energy calculations for the three compounds revealed a crucial hydrogen bond interaction with the M97 residue in the RIPK3 hinge region. In summary, this study proposes a combined virtual screening strategy and offers three promising lead compounds targeting RIPK3 for AD treatment.}, } @article {pmid42622822, year = {2026}, author = {Zhang, H and Lai, J and Wang, T and Li, T and Liu, S and Sun, DL and Chen, W and Kuang, W and Li, X and Zhang, M and Liao, Z and Xiang, X and Tuerxun, M and Zhang, X and Zhang, N and Xiao, S and Jessen, F and Yu, E and Yu, X and Wang, H}, title = {Adaptation and feasibility of the International Registry for Alzheimer's Disease and Other Dementias real-world datasets in old-age mental healthcare practice in China.}, journal = {Journal of Alzheimer's disease : JAD}, volume = {}, number = {}, pages = {13872877261478137}, doi = {10.1177/13872877261478137}, pmid = {42622822}, issn = {1875-8908}, abstract = {BackgroundAnti-amyloid disease-modifying therapies (DMTs) for early Alzheimer's disease (AD) are entering routine care, increasing the need for harmonized, registry-ready real-world data. The International Registry for Alzheimer's Disease and Other Dementias (InRAD) proposed a minimum dataset (MDS) and extended dataset (EDS), but their applicability to psychiatry-led old age mental healthcare practices in China is uncertain.ObjectiveTo adapt the InRAD dataset for real-world AD DMT practice across multiple psychiatry institutions in China and assess the feasibility of routine data capture for the proposed MDS/EDS.MethodsWe conducted a modified Delphi consensus study and a multicenter feasibility survey. Forty-nine experts classified domains/items into the MDS or EDS using predefined agreement thresholds. Thirty-five DMT-initiating mental healthcare teams reported the routine availability of the proposed data elements.ResultsHighly consistent with InRAD, ten domains were included in the China-adapted MDS/EDS, covering patient profiles and lifestyle, diagnostic work-up and biomarkers, treatment, outcomes, safety, treatment-monitoring examinations, and registry discontinuation. However, item prioritization reflected local practice, emphasizing diagnostic traceability, functional and neuropsychiatric outcomes, caregiver burden, and structured safety capture. Feasibility results revealed that many MDS elements were collected, but the consensus-defined MDS exceeded what is currently captured in a standardized, analysis-ready format; most EDS items were moderately feasible, while WHO-5 (patient version) and DAT-scan were least feasible.ConclusionsAn InRAD-aligned dataset is broadly acceptable for psychiatry-led AD DMT practices in China, but implementation gaps remain. A phased registry approach with standardized definitions and workflow-supported capture may improve the completeness and comparability of real-world DMT evidence.}, } @article {pmid42622974, year = {2026}, author = {Talebi, A and Nabili, S and Alaei, M and Koohsarian, P and Doostmohammadi, A and Dadashpour, M}, title = {Exosome-derived biomarkers as non-invasive tools in stroke, Parkinson's disease, and Alzheimer's disease.}, journal = {Metabolic brain disease}, volume = {41}, number = {1}, pages = {}, pmid = {42622974}, issn = {1573-7365}, mesh = {Humans ; *Exosomes/metabolism ; Biomarkers/metabolism ; *Alzheimer Disease/metabolism/diagnosis ; *Parkinson Disease/metabolism/diagnosis ; *Stroke/metabolism/diagnosis ; Animals ; MicroRNAs/metabolism ; }, abstract = {Neurological disorders, including stroke, Parkinson's disease (PD), and Alzheimer's disease (AD), are among the most prevalent and debilitating neuropathological conditions, affecting over 50 million people globally. Effective prevention and treatment strategies require a comprehensive understanding of reliable and disease-specific biomarkers. Such insights can enhance diagnostic precision, enable early detection, and support the development of targeted therapeutic approaches. In this review, we focus on exosome-derived proteins and small non-coding RNAs as promising non-invasive biomarkers for stroke, PD, and AD, given the accessibility and stability of exosomes in biological fluids. Furthermore, we examine their potential diagnostic and therapeutic relevance, emphasizing their functional roles, specificity, and sensitivity. Finally, we discuss current limitations, emerging challenges, and future research directions to guide the advancement of exosome-based biomarker discovery and clinical translation in neurological disorders. However, we emphasize that the comparative effectiveness of exosomal microRNAs (miRNAs) versus protein biomarkers requires direct validation in future head‑to‑head cohort studies.}, } @article {pmid42623143, year = {2026}, author = {Chen, Y and Ge, L and Lazarovici, P and Zheng, W}, title = {Artemisinin Attenuates Aβ1-42 Aggregation via the CaMK IV/PKA-CREB-Ace-H4 Cascade in Neuronal Cultures and 3xTg-AD Models.}, journal = {The American journal of Chinese medicine}, volume = {}, number = {}, pages = {1-23}, doi = {10.1142/S0192415X26500667}, pmid = {42623143}, issn = {1793-6853}, abstract = {Alzheimer's disease (AD), a progressive neurodegenerative disease with a rising global prevalence, is characterized by amyloid-β (Aβ) aggregation, tau hyperphosphorylation, inflammation, oxidative damage, and neuronal apoptosis. Studies have increasingly recognized epigenetic modifications as key regulators in the development of AD. Epigenetic modifications, particularly histone acetylation, are increasingly recognized as critical regulators of cell survival and AD pathogenesis. Although artemisinin (ART) exhibits potent anti-oxidative, anti-inflammatory, and neuroprotective properties, its impact on histone acetylation in AD remains uncharacterized. This study investigated whether ART regulates histone acetylation to confer neuroprotection and rescue behavioral deficits in Alzheimer's disease models. Using SH-SY5Y cells, primary neurons, and 3xTg-AD mice, we found that ART restores histone acetylation homeostasis by enhancing histone H4 acetylation. Mechanistically, this effect is driven by the activation of the CaMK IV/PKA-CREB signaling cascade. Treatment with ART reduced ROS, improved mitochondrial function, decreased Aβ1-42 deposition, and suppressed neuronal apoptosis. However, these beneficial effects were abolished by PKA or CaMK IV inhibitors. Consequently, ART treatment significantly reduced reactive oxygen species (ROS) generation, restored mitochondrial function, decreased Aβ1-42 deposition, suppressed neuronal apoptosis, and alleviated AD-like neuropathology and cognitive deficits. Crucially, the neuroprotective and epigenetic benefits of ART were entirely abolished by pharmacological inhibitors of PKA or CaMK IV. This study is the first to demonstrate that artemisinin ameliorates AD pathology and behavioral impairments via the CaMK IV/PKA-CREB-Ace-H4 axis, establishing ART as a promising therapeutic candidate for epigenetic intervention in AD.}, } @article {pmid42623762, year = {2026}, author = {Wang, X and Liu, Y and Liu, J and Wang, R and Zheng, J and Deng, Z and Song, K and Zhang, D and Wang, C and Zhu, K and Zhang, J and Wu, C and Hou, G and de Vries, EFJ and Wang, Y}, title = {Translational imaging evidence for rapid reversal of amyloid and myelin pathology following deep cervical lymphatic-venous anastomosis in Alzheimer's disease.}, journal = {Nuclear medicine and biology}, volume = {160-161}, number = {}, pages = {109675}, doi = {10.1016/j.nucmedbio.2026.109675}, pmid = {42623762}, issn = {1872-9614}, abstract = {BACKGROUND: Recently, microsurgical restoration of extracranial lymphatic outflow through lymphatic-venous anastomosis (LVA) has been explored as a potential, albeit controversial, therapeutic strategy to enhance glymphatic clearance in Alzheimer's disease (AD); however, its impact on AD-related neuropathology has not yet been quantitatively or longitudinally evaluated. In this study, we performed translational PET imaging to determine whether restoring extracranial lymphatic outflow can rapidly and reversibly modulate cerebral glucose metabolism, myelin integrity, and amyloid burden in relation to cognitive improvement.

METHODS: A cervical lymphatic obstruction model was established in rats, followed by longitudinal [[18]F]FDG-PET and [[11]C]MeDAS-PET to assess cerebral glucose metabolism and myelin integrity before and after LVA, with imaging findings further validated by immunohistochemistry. A cohort of eight AD patients underwent LVA and received [[11]C]PIB and [[11]C]MeDAS PET imaging at baseline and follow-up. The imaging results were correlated with cognitive performance.

RESULTS: In Sprague-Dawley rats, cervical lymphatic obstruction led to significantly elevated cerebral glucose metabolism and reduced myelin integrity, both of which were largely restored to near-normal levels following LVA treatment, as further validated by immunohistochemical analyses. Similarly, in AD patients, LVA produced a 36.0 ± 2.1% decrease in cortical amyloid burden on [[11]C]PIB-PET (p < 0.001) and a 59.8 ± 29.0% increase in [[11]C]MeDAS uptake (p = 0.005). Subsequent correlation with MMSE scores demonstrated that short-term cognitive improvement was associated with greater myelin restoration and greater amyloid reduction.

CONCLUSION: These preliminary findings provide initial evidence that restoration of extracranial lymphatic outflow may modulate core neuropathological processes in AD, justifying further investigation in larger cohorts with appropriate control groups and randomized controlled designs to validate and extend these observations.

TRIAL REGISTRATION: The study was registered on the Chinese Clinical Trial website on April 21, 2025 (Registration No. ChiCTR2500101149).}, } @article {pmid42624382, year = {2026}, author = {Yenkoyan, K and Davtyan, T and Torosyan, H and Galstian, S and Chavushyan, V}, title = {Bone marrow remodeling and brain-bone marrow crosstalk in Alzheimer's disease-like neurodegeneration.}, journal = {Brain, behavior, and immunity}, volume = {}, number = {}, pages = {106968}, doi = {10.1016/j.bbi.2026.106968}, pmid = {42624382}, issn = {1090-2139}, abstract = {Alzheimer's disease (AD) is increasingly recognized as a systemic disorder involving not only central neurodegeneration but also alterations in peripheral immune regulation and systemic homeostasis. Among these, the bone marrow represents a critical yet underexplored interface between the brain and systemic homeostasis. In the present study, we investigated whether AD-like neurodegeneration induces functional and structural remodeling of the bone marrow and whether these changes can be modulated through central neural stimulation and treatment with embryonic proteoglycans (PEG). An AD-like model was induced in adult male rats by intracerebroventricular administration of aggregated amyloid-β (Aβ1-42). Bone marrow alterations were assessed using ELISA for insulin-like growth factor-1 (IGF-1) and nerve growth factor (NGF), Western blot analysis of c-Fos and NF-κB, high-performance liquid chromatography for GABA determination, flow cytometry of hematopoietic and niche-associated cell populations, and morphological evaluation using hematoxylin and eosin and Giemsa staining. Additional modulation was performed by sequential electrostimulation of the hypothalamic supraoptic and paraventricular nuclei and by administration of embryonic proteins. Amyloid exposure significantly increased bone marrow IGF-1 levels, c-Fos expression, and NF-κB activation, accompanied by marked remodeling of marrow architecture characterized by reduced adiposity, increased hematopoietic cellularity, megakaryocytic abnormalities, and altered expression of progenitor-, neuronal-, and apoptosis-associated markers. Flow cytometry revealed shifts in specific CD3[+]CD3[+] T-cell subpopulations and increased apoptotic signaling, indicating dynamic reorganization of the hematopoietic niche. Hypothalamic stimulation and PEG treatment partially normalized these alterations, reducing inflammatory activation and restoring trophic and cellular balance. These findings demonstrate that AD-like neurodegeneration is associated with coordinated bone marrow remodeling and support the existence of a functional brain-bone marrow axis. The reversibility of these changes suggests that the bone marrow represents a biologically active and therapeutically accessible component of systemic responses to neurodegeneration, with potential relevance for future Alzheimer's disease interventions.}, } @article {pmid42624557, year = {2026}, author = {Halder, D and Prajapati, D and Banerjee, T and Biswas, S and Ghosh, B}, title = {Epigenetic modulators as therapeutics for neurodegenerative disorders/Alzheimer's disease.}, journal = {Methods in enzymology}, volume = {733}, number = {}, pages = {163-222}, doi = {10.1016/bs.mie.2026.06.010}, pmid = {42624557}, issn = {1557-7988}, mesh = {Humans ; *Alzheimer Disease/drug therapy/genetics/metabolism ; *Epigenesis, Genetic/drug effects ; Animals ; *Histone Deacetylase Inhibitors/pharmacology/therapeutic use ; DNA Methylation/drug effects ; *Neurodegenerative Diseases/drug therapy/genetics ; Histone Deacetylases/metabolism ; }, abstract = {Epigenetic dysregulation is recognized as a primary contributor to the pathogenesis of neurodegenerative disorders, especially Alzheimer`s disease (AD). Epigenetic mechanisms, including DNA methylation, histone modifications, and non-coding RNA regulation, govern gene expression without altering the DNA sequence, which plays a crucial role in neuronal development, synaptic plasticity, and memory formation. In AD, abnormal epigenetic alterations disrupt neuronal homeostasis, promote Aβ aggregation, tau hyperphosphorylation, and neuroinflammation, which leads to cognitive impairment. This chapter explores the assays performed and their processes using epigenetic modulators, along with their therapeutic potential in neurodegenerative diseases, especially AD. HDAC inhibitors, DNMT inhibitors, and emerging approaches, such as PROTACs for selective degradation of epigenetic enzymes, were discussed in the context of neurocognitive disorders. Preclinical and clinical evidence suggest that targeting specific HDAC isoforms (HDAC3, HDAC6, etc) can restore synaptic plasticity and improve cognitive function. This chapter further discusses recent advances, challenges in drug specificity, BBB permeability, and off-target epigenetic effects, which remain barriers to clinical translation. Case studies highlighting successful epigenetic interventions in AD models were presented to demonstrate therapeutic feasibility. Overall, epigenetic modulators present a promising therapeutic approach for neurodegeneration, and continued research integrating various assays like DNA methylation analysis, histone modification analysis, non-coding RNA analysis, neuroinflammation analysis, and functional and behavioral assays in AD models is significant in harnessing the full potential for AD treatment.}, } @article {pmid42613627, year = {2026}, author = {Jamali, MC and Shafie, A and Alqahtani, AJ and Al-Samawi, RI and Alyami, HM and Ashour, AA and Felemban, MF and Mansuri, N and Tayeb, FJ and Ahmad, I and Mudhafar, M and Sheweita, SA}, title = {Advances in the clinical application of mesenchymal stem cells for neurological disorders.}, journal = {Stem cell research & therapy}, volume = {17}, number = {1}, pages = {}, pmid = {42613627}, issn = {1757-6512}, mesh = {Humans ; *Mesenchymal Stem Cell Transplantation/methods ; *Mesenchymal Stem Cells/cytology/metabolism ; *Nervous System Diseases/therapy/pathology ; Animals ; Amyotrophic Lateral Sclerosis/therapy/pathology ; Alzheimer Disease/therapy/pathology ; }, abstract = {Therapeutic approaches employing mesenchymal stem cells (MSCs) have emerged as a promising avenue for investigating treatments for neurological disorders. This strategy aims to capitalize on the biological properties of MSCs to support the repair of damaged neural tissue and modulate pathological processes. This review provides a comprehensive overview of the current clinical evidence regarding MSC applications in major neurological disorders, including Parkinson's disease (PD), Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), stroke, spinal cord injury (SCI), and other pertinent disorders. Across clinical studies, MSC administration has generally demonstrated a favorable safety profile and procedural feasibility. However, therapeutic efficacy remains variable and inconsistent across trials. Importantly, differences in MSC sources, manufacturing procedures, delivery routes, dosing strategies, and patient selection contribute substantially to the heterogeneity of reported outcomes. Therefore, the current body of evidence supports the safety of MSC-based interventions, but their clinical effectiveness has not yet been consistently demonstrated. Future progress will depend largely on the standardization of cell preparation and treatment protocols, improved biomarker-driven patient stratification, and rigorously designed large-scale randomized trials.}, } @article {pmid42613696, year = {2026}, author = {Abubakar, MD and Dahiya, R and Nama, L and Goyal, K and Ambawatiya, A and Bishnoi, M and Rai, A and Murti, K and Kumar, N}, title = {An Innovative Strategy for Treating Neurodegenerative Disorders through Exosome-based Smart Delivery Systems: A Comprehensive Review.}, journal = {CNS & neurological disorders drug targets}, volume = {}, number = {}, pages = {}, doi = {10.2174/0118715273453626260724060812}, pmid = {42613696}, issn = {1996-3181}, abstract = {Alzheimer's and Parkinson's diseases are devastating brain disorders. The complex pathophysiology of the diseases and the lack of effective treatments have left them almost unexplored and untreatable. One potential approach to PD and AD therapy development is through exosomes, a delivery system that can be translated from innovative delivery techniques into clinical use. These exosome-based therapeutics will require thorough testing, research-driven refinement of engineering methods, and collaboration among scientists, clinicians, and industry to develop exosome therapeutics for clinical use. This review explores the biological properties of exosomes, recent engineering advances to improve their therapeutic potential, and new methods to leverage their versatility for selective delivery of remedial agents to the brain. In addition, preclinical evidence demonstrates that exosomes can modulate amyloid-β aggregation, α-synuclein pathology, neuroinflammation, and mitochondrial dysfunction. Yet difficulties related to mass production, maintaining quality, and obtaining regulatory approvals to bring them into clinical practice remain significant limiting factors. The authors point out the therapeutic advantages and drawbacks of exosome-based drug delivery systems. Besides, it provides a roadmap for harnessing these methods effectively as medical interventions for Alzheimer's and Parkinson's disorders, thereby promoting more studies in the area. Finally, we outline a conceptual model for translating novel exosome-based delivery methods into clinically applicable treatment modalities for Alzheimer's and Parkinson's diseases, thereby encouraging continued exploration in this promising field of research.}, } @article {pmid42613698, year = {2026}, author = {Sharma, A and Singh, P}, title = {Synergistic Role of Caffeic Acid with Conventional Neuroprotective Drugs: Potential of Combination Therapy for Managing Alzheimer's Disease.}, journal = {Recent advances in inflammation & allergy drug discovery}, volume = {}, number = {}, pages = {}, doi = {10.2174/0127722708476112260728060133}, pmid = {42613698}, issn = {2772-2716}, abstract = {INTRODUCTION: Alzheimer's Disease (AD) is a complex neurodegenerative disease involving amyloid-β accumulation, formation of neurofibrillary tangles, oxidative stress, and inflammation. Current treatment options include symptomatic agents such as Acetylcholinesterase Inhibitors (AChEIs) and memantine. The present review discusses the therapeutic potential of Caffeic Acid (CA) as an adjunctive agent to conventional anti-Alzheimer's treatments, focusing particularly on its pharmacodynamics and pharmacokinetics.

METHODS: An extensive search of the literature was carried out from the years 2000 to 2025 using databases such as PubMed, Scopus, Web of Science, Science Direct, Embase, Medline, Google Scholar, and others. All in vitro, in vivo, and in silico studies that have evaluated CA alone or in combination with AChEIs and memantine were included.

RESULTS: The existing literature suggests that CA has antioxidant, anti-inflammatory, and weak cholinesterase inhibition properties, while AChEIs and memantine mainly target neurotransmission. The results suggest that CA, when combined with other anti-Alzheimer's agents, provides superior neuroprotective properties compared to monotherapy in various animal models. Nevertheless, current data support more additive rather than synergistic actions of CA with AD medications.

DISCUSSION: Pharmacokinetic issues associated with CA use are possible due to the drug's ability to interfere with cytochrome P450 and P-glycoprotein. Moreover, issues with CA pharmacokinetics, nanoparticle delivery systems, and patient compliance might affect the translation of these findings into clinical practice.

CONCLUSION: CA might be used as an auxiliary substance for treating AD. Further research on pharmacokinetic/pharmacodynamic interactions and synergy between these compounds is required.}, } @article {pmid42613699, year = {2026}, author = {Kulan, H}, title = {Proteomic Basis of Polypharmacological Cognitive Recovery in Down Syndrome and Alzheimer's Disease.}, journal = {Current Alzheimer research}, volume = {}, number = {}, pages = {}, doi = {10.2174/0115672050471158260716112026}, pmid = {42613699}, issn = {1875-5828}, abstract = {INTRODUCTION/OBJECTIVE: Down Syndrome (DS) is a genetic disorder caused by trisomy of human chromosome 21 and represents the most common genetic cause of intellectual disability. It is also associated with an increased risk of developing Alzheimer's Disease (AD). Although various pharmacological treatments have been shown to improve learning and memory in DS models, the underlying mechanisms of cognitive improvement remain poorly understood. This study aims to identify molecular signatures associated with pharmacological cognitive rescue across different brain regions using a machine learning-guided targeted proteomics approach.

METHODS: Gradient Boosting Tree (GBT)-based feature selection combined with Principal Component Analysis (PCA) was applied to identify reproducible proteomic signatures in cortical samples from memantine-treated mice and in hippocampal samples from RO4938581-treated mice.

RESULTS: GBT models achieved classification accuracies exceeding 80% across experimental groups, and PCA showed distinct group separation, with PC1 and PC2 accounting for more than 60% of the total variance. The consistently identified proteins across datasets include APP, RCAN1, S6/pS6, IL1B, BAX, TAU, AMPKA, BRAF, ERK, and ADARB1.

DISCUSSION: The identified proteins converge on interconnected networks linking synaptic signaling, metabolic regulation, and neuroinflammation, reflecting pathways involved in Excitation/İnhibition (E/I) imbalance and neurodegeneration. Their consistency across datasets implies that coordinated regulation of these networks, rather than isolated pathway effects, is associated with cognitive improvement. Specifically, the MAPK-ERK and AMPK-mTOR signaling pathways emerge as key integrative nodes connecting synaptic function, energy balance, and cellular stress responses. These results point to possible mechanistic overlap with Alzheimer's disease-related pathology and support a network-based, multi-target model of cognitive improvement in DS.

CONCLUSION: These results demonstrate that different pharmacological treatments converge on shared protein signatures associated with cognitive improvement in DS. This convergence supports a network- based, multi-target therapeutic approach, in which modulation of key regulatory nodes rather than single targets may underlie effective treatment strategies.}, } @article {pmid42614235, year = {2026}, author = {Meng, Z and Wu, H and Miao, Y and Qi, W and Sha, M}, title = {Association between different sodium-glucose co-transporter 2 inhibitors and the risk of dementia: a network meta-analysis.}, journal = {Frontiers in endocrinology}, volume = {17}, number = {}, pages = {1777151}, pmid = {42614235}, issn = {1664-2392}, mesh = {Humans ; *Sodium-Glucose Transporter 2 Inhibitors/therapeutic use ; *Dementia/prevention & control/epidemiology ; *Diabetes Mellitus, Type 2/drug therapy ; Benzhydryl Compounds/therapeutic use ; *Hypoglycemic Agents/therapeutic use ; Canagliflozin/therapeutic use ; Glucosides/therapeutic use ; }, abstract = {BACKGROUND: Sodium-glucose cotransporter 2 inhibitors (SGLT2i), as key therapeutic agents for type 2 diabetes, have in recent years been recognized as potentially exerting neuroprotective effects on the central nervous system. However, systematic comparative evidence remains lacking regarding whether different SGLT2i exhibit differential effects on dementia risk. By conducting a network meta-analysis to compare the association between different SGLT2i and the risk of dementia onset, the relative efficacy of each drug in reducing dementia risk is determined.

METHODS: A systematic search was conducted across databases including PubMed, Embase, Web of Science, and the Cochrane Library, from their inception to the search cutoff date of 1 December 2025. Randomized controlled trials and observational studies comparing SGLT2i with other antidiabetic medications or placebo, and reporting dementia outcomes, were included. A network meta-analysis employing a random-effects model was conducted. Pooled effect sizes were expressed as hazard ratios with 95% confidence intervals. Relative efficacy among different drugs was ranked using the probability of ranking, whilst heterogeneity and consistency were assessed.

RESULTS: Six cohort studies involving 845,433 patients were included in this analysis. The results of the network meta-analysis indicated that canagliflozin (HR = 0.75, 95% CrI: 0.59, 0.98), Dapagliflozin (HR = 0.75, 95% CrI: 0.59, 0.98), and Empagliflozin (HR = 0.69, 95% CrI: 0.55, 0.85) significantly reduced the risk of dementia onset. Empagliflozin had the highest probability of being ranked as the most effective treatment (81.2%). However, no statistically significant differences were observed between empagliflozin and dapagliflozin or canagliflozin in the network comparisons. For Alzheimer's disease, Dapagliflozin (HR = 0.68, 95% CrI: 0.48, 0.96) and Empagliflozin (HR = 0.62, 95% CrI: 0.45, 0.87) also demonstrated significant risk reduction, whilst direct comparisons between Empagliflozin and other agents showed no significant differences. For vascular dementia, Empagliflozin (HR = 0.63, 95% CrI: 0.46, 0.87) and Canagliflozin (HR = 0.71, 95% CrI: 0.48, 0.98) also demonstrated favorable outcomes.

CONCLUSIONS: The findings of this study indicate that dapagliflozin, empagliflozin, and canagliflozin, particularly empagliflozin, demonstrate significant potential in reducing the incidence of dementia and related cognitive impairments. Compared with DPP-4 inhibitors, these agents effectively lower the risk of dementia, Alzheimer's disease, and vascular dementia, offering an effective therapeutic option for diabetic patients, particularly the elderly.}, } @article {pmid42615643, year = {2026}, author = {Singh, SK and Dinodiya, H and Parihar, S and Korupalli, C and Vankayala, R}, title = {Engineering ApoE3-Targeted NIR-Responsive Liposomes for Multimodal Inhibition of Amyloid-β Aggregation and Acetylcholinesterase Activity.}, journal = {ACS chemical neuroscience}, volume = {17}, number = {16}, pages = {3094-3108}, doi = {10.1021/acschemneuro.6c00315}, pmid = {42615643}, issn = {1948-7193}, support = {BT/RLF/Re-entry/17/2018//Department of Biotechnology, Ministry of Science and Technology, India/ ; 191620102067//University Grants Commission/ ; CRG/2023/001189//Department of Science and Technology, Ministry of Science and Technology, India/ ; I/SEED/RRV/20200076//Department of Science and Technology, Ministry of Science and Technology, India/ ; }, mesh = {*Liposomes ; *Amyloid beta-Peptides/metabolism ; Humans ; *Cholinesterase Inhibitors/pharmacology/administration & dosage ; Donepezil/pharmacology/administration & dosage ; *Acetylcholinesterase/metabolism ; *Apolipoprotein E3/metabolism ; Alzheimer Disease/metabolism/drug therapy ; Cell Line, Tumor ; Blood-Brain Barrier/metabolism/drug effects ; Indocyanine Green ; Animals ; }, abstract = {Alzheimer's disease (AD) is characterized by progressive neurodegeneration and cognitive decline, largely driven by amyloid-β (Aβ) aggregation and dysregulated acetylcholinesterase (AChE) activity. While current pharmacological interventions utilize AChE inhibitors and Aβ antagonists, their efficacy is frequently hampered by monotherapeutic limitations, poor blood-brain barrier (BBB) permeability, and a lack of controlled release mechanisms. Herein, we report the engineering of the liposomal formulation coloaded with Donepezil (DNP) and the photothermal agent indocyanine green (ICG), followed by conjugation of ApoE3 protein (LIDA) designed for multimodal AD therapy. Surface-conjugated ApoE3 serves a bifunctional role by facilitating BBB penetration and actively inhibiting Aβ oligomerization. Upon 808 nm laser irradiation, ICG-mediated photothermal induction triggers the spatiotemporal release of DNP, significantly enhancing AChE inhibition. Furthermore, LIDA treatment effectively mitigates Aβ-induced cytotoxicity and mitochondrial dysfunction in SH-SY5Y cells. By integrating targeted delivery with NIR responsiveness, this study presents a novel, multivalent strategy to combat the complex pathological landscape of AD.}, } @article {pmid42615950, year = {2026}, author = {Hu, CJ and Huang, YH and Cho, S and Wang, BCM and Shen, SP and Newson, RS and Tang, CH}, title = {Epidemiology, Patient Characteristics, Treatment Patterns, and Costs of Mild Cognitive Impairment and Alzheimer's Disease in Taiwan.}, journal = {Value in health regional issues}, volume = {}, number = {}, pages = {101687}, doi = {10.1016/j.vhri.2026.101687}, pmid = {42615950}, issn = {2212-1102}, abstract = {OBJECTIVES: Alzheimer's disease (AD) with mild cognitive impairment (MCI) and AD are stages along the cognitive decline continuum and represent growing public health concerns. This study aimed to assess the diagnosed prevalence, claims-identified incidence, treatment patterns, healthcare costs, comorbidities, and observed mortality outcomes of individuals with AD with MCI, and AD with dementia in Taiwan claims data over a 10-year period.

METHODS: We conducted a retrospective cohort study using Taiwan's National Health Insurance Research Database. Individuals diagnosed with AD with MCI, or AD, between 2013 and 2022 were identified via ICD-9-CM and ICD-10-CM codes. Cross-sectional and longitudinal analyses examined epidemiology, treatment trends, costs, comorbidities, and mortality using descriptive statistics, survival analysis, and cost evaluations.

RESULTS: The estimated prevalence of AD with MCI, and AD from the claims database, increased from 109 379 cases in 2018 to 131 053 in 2022. Among pharmaceutical interventions, donepezil usage was predominant and increased over time, whereas nonpharmacologic therapies remained minimal. Healthcare costs rose with disease severity, with nonpharmacological inpatient care being the highest expense. Cardiovascular and metabolic comorbidities were prevalent and increased with severity. Observed cumulative mortality proportions increased with advancing disease severity; patients with AD with severe dementia had the highest mortality burden (41.98% at year 3).

CONCLUSION: AD with MCI and AD with dementia prevalence estimation is rising, demonstrating increasing costs and high comorbidity burdens. Disease severity is linked to higher mortality, reinforcing the need for integrated care and early cost-effective interventions to optimize outcomes in AD with MCI and AD with patients with dementia.}, } @article {pmid42618557, year = {2026}, author = {Jonsdotter, A and Leverin, AL and Svedin, P and Lindström, M and Ebefors, K and Carlsson, Y and Hagberg, H and Rocha-Ferreira, E}, title = {Exendin-4 improves neurodevelopmental outcome after neonatal germinal matrix hemorrhage.}, journal = {Cell death & disease}, volume = {17}, number = {1}, pages = {}, pmid = {42618557}, issn = {2041-4889}, support = {2023-02035//Vetenskapsrådet (Swedish Research Council)/ ; 2021-0056//Hjärnfonden (Swedish Brain Foundation)/ ; }, mesh = {Animals ; *Exenatide/pharmacology ; *Neuroprotective Agents/pharmacology/therapeutic use ; Rats ; Animals, Newborn ; Neurodevelopment/drug effects ; Caspase 3/metabolism ; *Peptides/pharmacology/therapeutic use ; Matrix Metalloproteinase 9/metabolism ; Rats, Sprague-Dawley ; *Venoms/pharmacology/therapeutic use ; Disease Models, Animal ; Microglia/drug effects/metabolism/pathology ; Tumor Suppressor Protein p53/metabolism ; Female ; }, abstract = {Germinal matrix hemorrhage (GMH) is a common complication in premature infants and is associated with a high risk of neurodevelopmental impairment and mortality. Currently, there are no specific neuroprotective treatments available. Exendin-4 is a drug used for the treatment of type 2 diabetes mellitus, and it has shown neuroprotective effects in several neurological disorders including Alzheimer's and Parkinson's disease. In this study, we used the preterm postnatal day 5 rat model of GMH to evaluate whether exendin-4 exerts neuroprotective effects in this setting. Our results show that in the acute phase, exendin-4 reduced microglial activation, caspase-3 activation, p53 expression, AIF-associated cell death, MMP-9 expression, and neutrophil infiltration into the hemorrhage site. Exendin-4 treatment improved neurodevelopmental outcomes in both negative geotaxis and eye-opening latency when compared to saline-treated GMH controls, and conferred gray and white matter protection as early as 48 h after injury, with persistent neuroprotection observed at 5, 11, and 35 days after GMH. Exendin-4-treated animals also showed significant recovery of motor function in the rotarod test. In summary, this study demonstrates that exendin-4 reduces brain injury in a rat model of GMH in both the short and long term and is associated with improved neurological outcome.}, } @article {pmid42619056, year = {2026}, author = {Oishi, K and Adams, R and Nowrangi, MA and Zandi, PP and Lyketsos, CG}, title = {Utilizing routinely acquired clinical neuroimaging and electronic health record data to advance precision medicine in dementia care.}, journal = {International review of psychiatry (Abingdon, England)}, volume = {}, number = {}, pages = {1-17}, doi = {10.1080/09540261.2026.2714142}, pmid = {42619056}, issn = {1369-1627}, abstract = {Alzheimer's disease (AD) exhibits significant clinical variability in symptom onset, progression rates, neuropsychiatric symptoms and treatment responses. This variability reflects a range of underlying biological, genetic and environmental factors. This review summarizes recent advances in leveraging real-world electronic health records (EHRs) and clinical brain MRI to enhance precision medicine in dementia care. Traditional MRI research has identified consistent subtypes of atrophy associated with AD. However, these models often struggle to apply to routine clinical imaging, which can vary widely in contrast, resolution and acquisition protocols. Recent technological developments now allow for reliable measurement of gray matter, white matter, brainstem and cerebellar structures from routine clinical scans, effectively overcoming long-standing limitations of conventional neuroimaging methods. Additionally, efforts in EHR analysis, including the use of natural language processing on unstructured clinical notes, have enabled large-scale extraction of cognitive scores, neuropsychiatric symptoms and treatment responses. By integrating structured EHR data with detailed imaging markers, researchers have enabled predictive modeling of cognitive decline and treatment responses, though generalizability across settings remains a challenge. Federated learning frameworks offer a privacy-preserving approach to collaboratively develop models across multiple institutions. Together, these strategies outline a practical, data-driven approach to individualized diagnosis, prognosis and treatment planning for dementia.}, } @article {pmid42619761, year = {2026}, author = {Copeland, MH and Youngstrom, DE and Konrad, KS and Diering, GH and Letsinger, AC and Aksu, LR and Yakel, JL and Cushman, JD}, title = {Diphenhydramine Disrupts Sleep Architecture in 5XFAD Alzheimer's Disease Model and Wild-Type Mice.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, doi = {10.64898/2026.07.22.739929}, pmid = {42619761}, issn = {2692-8205}, abstract = {Sleep disruption is common in Alzheimer's disease (AD). Diphenhydramine (DPH), a first-generation antihistamine with anticholinergic properties, is widely used as an over-the-counter sleep aid. We tested whether chronic DPH treatment alters sleep architecture in 5XFAD and wild-type mice. Female 5XFAD (n=16) and wild-type (WT) littermates (n=14) were implanted with wireless telemetry recording devices to measure electroencephalography (EEG), electromyography (EMG), temperature, and activity continuously. After a 24h baseline recording at 5 months of age, mice received oral DPH (10 mg/kg) or vehicle at ZT0 for one month. After this chronic treatment, sleep was recorded continuously for 48h during ongoing dosing. Sleep was scored as rapid eye movement (REM), non-rapid eye movement (NREM) 1, NREM2, or wake. A survival curve analysis was used to investigate the microarchitecture of sleep phases after chronic diphenhydramine treatment. At baseline, 5XFAD mice had more time in NREM1 than WT controls and had shorter REM and NREM2 bouts. Chronic DPH treatment fragmented NREM2 in both genotypes, reducing long NREM2 bouts. DPH increased total duration of NREM1 and REM during the active phase, which is analogous to daytime drowsiness in humans. DPH did not rescue 5XFAD sleep deficits; instead, DPH treatment exacerbated NREM2 fragmentation. Overall, chronic DPH use degrades sleep quality and increases fragmentation in both WT and AD-model mice, which questions the use of sedating anticholinergics as sleep aids, especially in AD.}, } @article {pmid42620159, year = {2026}, author = {Wander, PL and Doherty, L and Pan, Q and Carmichael, O and Turner, R and Kuo, S and Munshi, M and Wallia, A and Noble, JM and Shah, VO and Nadkarni, NK and Mudaliar, S and Dabelea, D and Temprosa, M and Knowler, WC and Nathan, DM and Luchsinger, JA and , }, title = {Randomized metformin and cognitive outcomes in the Diabetes Prevention Program Outcomes Study.}, journal = {medRxiv : the preprint server for health sciences}, volume = {}, number = {}, pages = {}, doi = {10.64898/2026.08.05.26359234}, pmid = {42620159}, abstract = {IMPORTANCE: Metformin may influence risk of dementia, with prior conflicting observations of protection or harm.

OBJECTIVE: To determine the association of randomization to metformin vs. placebo or intensive lifestyle intervention (ILS) in the Diabetes Prevention Program (DPP) with cognitive outcomes (cognitive impairment syndromes and trajectories of cognitive test performance) during the DPP Outcomes Study (DPPOS).

Prospective long-term follow-up of DPP/DPPOS participants at 27 U.S. centers among adults who were at high risk for type 2 diabetes (T2D) at baseline.

EXPOSURES: Randomization to metformin, placebo, or ILS (1996-1999) for 3.2 years followed by open-label metformin in the original randomized metformin group until 2021.

MAIN OUTCOMES & MEASURES: Cognitive impairment syndromes were adjudicated in 2022- 2024 in 1,483 participants (median age 74 [IQR 68, 80]) using the National Alzheimer's Coordinating Center Uniform Dataset version 3. Cognitive performance in executive and memory domains was ascertained with repeated cognitive tests between 2009 and 2024. Multinomial logistic regression and mixed-effects models were fit to examine associations of randomization to metformin with cognitive outcomes.

RESULTS: Total metformin exposure (mean ± SD) was 15.5 ±7.7 years/person in the metformin group. Persons in the placebo and ILS groups received out-of-study metformin usually after developing diabetes with mean metformin total exposure of 4.5 ±5.1 and 3.8 ±4.8 years/person in the placebo and ILS groups, respectively. Overall, the frequency distributions of the cognitive syndromes did not differ significantly by treatment group; however, randomization to metformin was associated with a 60% (OR 0.40 [95%CI 0.17, 0.97]) and 62% (OR 0.38 [95%CI 0.16, 0.89]) lower odds of dementia compared with placebo and ILS, respectively, after adjustment for demographics, education, income, and APOE-ε4 genotype. Randomization to metformin was also associated with significantly better memory performance over time (β=0.58; 95%CI: 0.09, 1.1; p=0.02; Cohen's d=0.1).

CONCLUSIONS AND RELEVANCE: Long-term metformin treatment is associated with a reduced risk of dementia and better memory performance among persons with pre-diabetes or T2D. Estimates were imprecise due to a limited number of dementia cases. Longer follow-up with more dementia cases is needed to confirm our findings.

KEY POINTS: Question: Is chronic metformin treatment related to the risk of dementia and cognitive impairment?Findings: Randomization to metformin in the Diabetes Prevention Program was associated with a lower risk of dementia in the Diabetes Prevention Program Outcomes Study compared with the randomization to placebo or randomization to intensive lifestyle intervention, but the overall distribution of cognitive impairment syndromes did not differ significantly by treatment group. Randomization to metformin was also related to modestly better longitudinal performance in a memory test.Meaning: Chronic metformin treatment may decrease the risk of dementia.}, } @article {pmid42620184, year = {2026}, author = {Falahati, M and Ramezannejad, E and Vaez-Gharamaleki, Y and Radnia, P and Shahba, S and Rasoulian, P and Rezaei, S and Dasmeh, N and Bemanalizadeh, M}, title = {Determining the metabolic profile measured using ultra-high pressure liquid chromatography associated with Beta Amyloid burden in the brain in individuals with mild cognitive impairment.}, journal = {Research square}, volume = {}, number = {}, pages = {}, doi = {10.21203/rs.3.rs-10065374/v1}, pmid = {42620184}, issn = {2693-5015}, abstract = {As the world's population ages, Alzheimer's disease (AD), a progressive neurodegenerative disorder, is becoming more common. The current diagnoses for AD are not precise enough to identify the disorder when it is possible to cure. An early indicator of Alzheimer's is the assessment of beta-amyloid by positron emission tomography (PET) score, a substantial decrease in the brain's metabolomics. Furthermore, Metabolomics can be detected by UPLC (ultra-high pressure liquid chromatography). This study investigates the link between metabolic profiles and beta-amyloid load in AD in order to shed light on possible biomarkers for disease progression. The data from 59 people who have been diagnosed with moderate cognitive impairment (MCI) is extracted from the Alzheimer's Disease Neuroimaging Initiative (ADNI). This study uses ultra-high-performance liquid chromatography (UPLC) to investigate the correlation between baseline metabolic data and changes in amyloid PET scores. Seven metabolites, including DOPA, Methionine Sulfoxide (Met.SO), Tryptophan Betaine, choline, leucine, valine, and FA (18:2), seem to have a substantial connection with amyloid PET scores. These can be used as early indications of AD progression, especially Met.SO is particularly relevant when considering time interaction. Understanding the metabolic alterations associated with amyloid load can pave the way for future research incorporating metabolites into a therapeutic treatment that can be identified as crucial to the illness's progression.}, } @article {pmid42620424, year = {2026}, author = {McGill, CJ and Christensen, A and Namvari, S and Thorwald, MA and Anson, H and Vermulst, M and Finch, CE and Benayoun, BA and Pike, CJ}, title = {17α-Estradiol Confers Limited Protection Against APOE4 Phenotypes in Middle-Aged Female Mice.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, doi = {10.64898/2026.08.06.743074}, pmid = {42620424}, issn = {2692-8205}, abstract = {Longevity-promoting interventions represent a promising strategy to mitigate brain aging and reduce Alzheimer's disease (AD) risk. The NIA Interventions Testing Program identified the weak estrogen 17α-estradiol (17αE2) as a compound that extends healthspan and lifespan in mice, with effects observed primarily in males. Our recent work demonstrated that 17αE2 healthspan benefits were modulated by human apolipoprotein E (APOE) genotype such that aging phenotypes were improved more strongly in middle-aged male mice with targeted-replacement of the AD-associated APOE4 allele compared to APOE3 , the risk neutral and most common APOE allele. Here, we tested whether APOE -dependent, AD-relevant benefits of 17αE2 observed in males extend to females. Specifically, we treated 12-month-old APOE3 and APOE4 targeted-replacement female mice for 6 months with chow containing 0 or 14.4ppm 17αE2. We find that relative to APOE3 , APOE4 genotype largely exhibits more robust systemic phenotypes associated with aging, including increased adiposity, impaired glucose tolerance, and reduced energy expenditure. Further, we observe that treatment with 17αE2 yields modest improvements in some outcomes, including decreased adiposity and increased lean mass, glucose tolerance, and energy expenditure, though significant benefits are found only in APOE4 females. In the CNS, we observed mixed effects of APOE genotype on behavioral performance and indices of brain aging, with APOE4 females performing worse in the Barnes Maze and having higher levels of the AD-related peptide soluble β-amyloid, but no APOE genotype differences in cortical lipid raft oxidative damage. In contrast to its systemic effects, 17αE2 did not significantly improve neural outcomes in APOE3 or APOE4 females. These findings address the impact of biological sex on established protective effects of a longevity-promoting intervention against APOE4 phenotypes, which have significant relevance to the prevention of age-related conditions including metabolic dysfunction, cognitive impairment and vulnerability to AD.}, } @article {pmid42621237, year = {2026}, author = {Xue, WY and Li, X and Li, WT and Qin, BZ and Wang, CZ and Liu, T and Wang, M}, title = {Post-marketing safety signals and report-level ARIA-E stratification for lecanemab and donanemab: an integrated FAERS and WHO-VigiAccess pharmacovigilance study.}, journal = {Therapeutic advances in drug safety}, volume = {17}, number = {}, pages = {20420986261473013}, pmid = {42621237}, issn = {2042-0986}, abstract = {BACKGROUND: Anti-β-amyloid monoclonal antibodies provide a disease-modifying treatment approach for Alzheimer's disease, but post-marketing safety concerns remain, particularly amyloid-related imaging abnormalities (ARIA). Real-world studies have mainly described adverse event spectra and disproportionality signals, whereas report-level amyloid-related imaging abnormalities with edema or effusion (ARIA-E) risk stratification remains less well characterized.

OBJECTIVES: To compare post-marketing adverse event profiles of lecanemab (LEC) and donanemab (DON), identify report-level factors associated with ARIA-E, and develop a machine learning model for ARIA-E risk stratification.

DESIGN: Retrospective pharmacovigilance study using spontaneous reporting databases.

METHODS: Adverse event reports for lecanemab and donanemab were analyzed using the Food and Drug Administration Adverse Event Reporting System (FAERS) and WHO-VigiAccess. FAERS disproportionality analyses were performed at the Preferred Term and System Organ Class levels using frequency-based and Bayesian methods. Time-to-onset and serious-outcome patterns were further explored. Multivariable logistic regression was used to examine factors associated with report-level ARIA-E. An extreme gradient boosting (XGBoost) model was developed using temporally split FAERS datasets with nested cross-validation and temporal external validation.

RESULTS: FAERS included 2961 lecanemab and 1542 donanemab primary suspect reports; WHO-VigiAccess included 2525 lecanemab- and 1450 donanemab-related reports. Across databases, adverse event profiles were dominated by neurological events, with ARIA-related events representing the central safety signals. Serious outcomes clustered mainly in the early treatment period and attenuated over time. In complete-case regression, no overall difference in ARIA-E reporting odds was observed between donanemab and lecanemab, whereas a significant donanemab-by-body weight interaction was identified. The XGBoost model showed modest discrimination, with area under the receiver operating characteristic curve values of 0.677 in internal validation and 0.630 in temporal external validation. Calibration was suboptimal, and decision curve analysis suggested limited net benefit mainly within low-threshold ranges.

CONCLUSION: ARIA-related and other neurological events remain the principal post-marketing safety concern for lecanemab and donanemab. The XGBoost model may support report-level risk prioritization, particularly during early treatment, but should not be used as a diagnostic substitute or a source of precise individualized risk estimates.}, } @article {pmid42622140, year = {2026}, author = {Greenberg, SM and Iadecola, C and Chou, SH and Cogswell, PM and Elkind, MSV and Hicks, WJ and Le, C and Levine, DA and Lipton, R and Massimo, L and Mohl, SM and Seshadri, S and Snyder, HM and Yaffe, K and Zachrison, KS and , }, title = {Amyloid-Related Imaging Abnormalities Summit Special Proceedings: Cardiovascular and Stroke Considerations for β-Amyloid Immunotherapy in Alzheimer Disease.}, journal = {Journal of the American Heart Association}, volume = {}, number = {}, pages = {e048108}, doi = {10.1161/JAHA.125.048108}, pmid = {42622140}, issn = {2047-9980}, abstract = {BACKGROUND: New antiamyloid therapies (AAT) for treating patients with early Alzheimer disease (AD) have become available in the past 3 years. Although AAT can be beneficial in slowing progression of AD, they also come with potentially serious side effects, particularly for patients requiring anticoagulation or thrombolysis for cardiovascular conditions. Given that most patients with AD are older and likely to have cardiovascular risk factors, there is urgent need for additional guidance for clinicians about potential risks and benefits associated with AAT for patients with cardiovascular comorbidities, best practices for management of these patients, and special considerations with respect to emergency evaluation and treatment of patients on AAT who develop acute neurological symptoms.

METHODS: The American Heart Association convened 75 multidisciplinary experts for the Amyloid-Related Imaging Abnormalities Summit: Cardiovascular and Stroke Considerations for β-Amyloid Immunotherapy in AD in July 2025. These experts were divided into 8 work groups to evaluate the current evidence related to AAT usage in patients with cardiovascular risk factors and conditions and develop consensus-based guidance for clinicians.

RESULTS: This statement outlines the outcomes of the Summit, including considerations for prescribers, primary care professionals, emergency personnel, and health care system stakeholders. These considerations are intended to improve identification of patients as appropriate candidates for AAT, management of patients with co-occurring AD and cardiovascular conditions, and their emergency evaluation and treatment. The statement also includes guidance for shared decision-making, implementation of system changes for improving dementia care, and recommendations for future research and data collection to add to the body of evidence for treating patients with concomitant AD and cardiovascular conditions.

CONCLUSIONS: Building on lessons learned from the establishment of stroke systems of care, the consensus-based considerations outlined in this document can serve as a foundation for AD systems of care aimed at ensuring optimal use of these ground-breaking therapies.}, } @article {pmid42611034, year = {2026}, author = {Dodart, CA}, title = {The locus coeruleus gateway hypothesis: Noradrenergic integrity as a candidate determinant of amyloid-β clearance efficiency in anti-amyloid immunotherapy for Alzheimer's disease.}, journal = {Journal of Alzheimer's disease : JAD}, volume = {}, number = {}, pages = {13872877261474020}, doi = {10.1177/13872877261474020}, pmid = {42611034}, issn = {1875-8908}, abstract = {Anti-amyloid immunotherapies (lecanemab, donanemab) produce statistically significant but clinically modest slowing of decline in early Alzheimer's disease (AD), with substantial inter-individual response variability that current covariates-antibody titer, baseline amyloid load, apolipoprotein E ε4 (APOE4) status, or tau burden-leave largely unexplained. We propose that a systematically unmeasured upstream variable contributes to this variability: the structural integrity of the locus coeruleus (LC), the principal source of brain norepinephrine (NE), framed as a candidate determinant of amyloid-β (Aβ) clearance efficiency rather than of overall clinical outcome. This hypothesis paper synthesizes three peer-reviewed lines of evidence and derives a hierarchy of falsifiable predictions; no new data are reported. First, tau pathology initiates in LC neurons before any cortical structure, reducing NE output from the earliest preclinical stage. Second, NE governs two complementary Aβ-clearance pathways: glymphatic flow, via aquaporin-4 dynamics driven by slow LC oscillations during non-REM sleep, and microglial phagocytosis, via β2-adrenergic receptor signaling. Third, in Parkinson's disease, the DTI-ALPS index mediates the relationship between LC integrity on neuromelanin-sensitive MRI and cognition. We term this the Locus Coeruleus Gateway Hypothesis (LCGH). Its mediation chain is testable now in ADNI, which holds research-grade diffusion-tensor imaging; its treatment-response prediction requires immunotherapy cohorts that acquire such imaging, not the existing CLARITY-AD or TRAILBLAZER-ALZ 2 archives, whose safety MRI used diffusion-weighted, not tensor, sequences. We state explicitly that Aβ clearance is only one contributor to clinical benefit, and that the LCGH predicts pharmacodynamic efficiency, not that NE restoration treats AD.}, } @article {pmid42611062, year = {2026}, author = {Biswas, B and Gabb, VG and Blackman, J and Morrison, H and Coulthard, E and Roudaut, A}, title = {"Like Taking Part in Star Wars": Qualitative Study Using Thematic Analysis to Explore the Acceptability and Experiences of Older Adults Participating in Remote Longitudinal Sleep and Dementia Research.}, journal = {Journal of medical Internet research}, volume = {28}, number = {}, pages = {e88094}, pmid = {42611062}, issn = {1438-8871}, mesh = {Humans ; Aged ; Female ; Male ; *Dementia/physiopathology ; *Sleep ; Cognitive Dysfunction/physiopathology ; Aged, 80 and over ; Longitudinal Studies ; Qualitative Research ; Remote Patient Monitoring ; Digital Health ; }, abstract = {BACKGROUND: Sleep disturbance is a common symptom of and potential risk factor for neurodegeneration and dementia. Remote monitoring technologies and increasing digital literacy offer promise for monitoring symptoms and treatment responses via sleep and cognitive assessments from patients' homes. However, the acceptability of remote sleep and circadian research in older adults with and without cognitive impairment is not known.

OBJECTIVE: This study aimed to explore and describe the barriers, facilitators, and user experience of older adults participating in longitudinal sleep and dementia research using remote monitoring technologies.

METHODS: Older adults with mild cognitive impairment (MCI) or dementia due to probable Alzheimer disease or Lewy body disease and age-matched controls participated in an 8-week remote study involving multimodal assessments of sleep and cognition, including actigraphy, wireless electroencephalography, web-based cognitive tasks, and serial saliva samples. Participants were asked for feedback via questionnaires during the study at 2 time points and purposively invited to complete end-of-study interviews about their experiences. The Capability, Opportunity, Motivation-Behavior model of behavior change, and the extended Unified Theory of Acceptance and Use of Technology, were used to guide questionnaire and interview topic guide development. Inductive reflexive thematic analysis was undertaken, with components from the models used as sensitizing concepts.

RESULTS: A total of 14 participants (9 with MCI or dementia, 5 controls) completed end-of-study interviews, and 28 participants (9 with MCI or dementia, 19 controls) completed questionnaires. Six key themes were identified: (1) "Perceived value as motivation," (2) "Trust and simplicity as cornerstones in user experience," (3) "Adjusting to study participation over time," (4) "Adherence, accuracy, and getting it right," (5) "Social support as a facilitator and a barrier," and (6) "Reflections, realities, and uncertainties around sleep."

CONCLUSIONS: Older adults with and without cognitive impairment were motivated to engage in longitudinal remote sleep research and provide good quality data. Acceptability was related to burden, usability, and reliability of devices, having sufficient support, and ability to build study tasks into a routine. In repeated cognitive tasks, varying task content and difficulty, and allowing flexibility in timing may avoid fatigue and frustration. Future studies should aim to identify effective strategies for recruiting diverse populations, particularly those with limited technology experience or from underserved communities, to ensure equitable participation and representation in research. Providing education on the importance of sleep for brain health and technology use may be beneficial.}, } @article {pmid42611282, year = {2026}, author = {Ahmad, S and Mei, J and Wang, C and Jia, M and Nouman, MF and Ai, H}, title = {Modulation Mechanisms of Transmembrane Domain Flexibility in Amyloid Precursor Protein and Notch: A Coarse-Grained Simulation Study on the Impact of Upper and Lower Leaflet Composition in Liquid-Ordered and Liquid-Disordered Ternary Bilayer Membranes.}, journal = {Langmuir : the ACS journal of surfaces and colloids}, volume = {42}, number = {32}, pages = {23197-23215}, doi = {10.1021/acs.langmuir.6c00533}, pmid = {42611282}, issn = {1520-5827}, support = {ZR2022MB073//Shandong Provincial Natural Science Foundation of China/ ; }, mesh = {*Lipid Bilayers/chemistry/metabolism ; *Receptors, Notch/chemistry/metabolism ; *Amyloid beta-Protein Precursor/chemistry/metabolism ; *Molecular Dynamics Simulation ; Protein Domains ; Cholesterol/chemistry ; Phosphatidylcholines/chemistry ; }, abstract = {Alzheimer's disease (AD) and Notch-related pathologies are linked to dysregulated γ-secretase cleavage of amyloid precursor protein (APP) and Notch transmembrane domains (TMDs). However, γ-secretase inhibitors for AD often disrupt Notch signaling, necessitating strategies to selectively modulate substrate cleavage. This study employs coarse-grained molecular dynamics simulations to investigate how lipid bilayer composition─specifically liquid-ordered (Lo) and liquid-disordered (Ld) phases with varying cholesterol (Chol), palmitoyl-sphingomyelin, and 1,2-dioleoyl-sn-phosphatidylcholine ratios─impacts the flexibility and stability of APP and Notch TMDs. Our key findings reveal that Chol-rich Lo phases enhance APP TMD flexibility, promoting γ-secretase cleavage and Aβ production, while Notch TMD stability is largely unaffected by Chol, favoring Ld phases, replicating perfectly the existing experimental observations and resolving several conflicting perspectives. A critical innovation lies in identifying asymmetric lipid compositions (e.g., Chol-enriched lower leaflets) as regulators of APP-Notch selectivity. These results highlight membrane microenvironment engineering as a promising therapeutic avenue to decouple APP and Notch processing. Future work should validate these findings experimentally and explore lipid-based modulators for AD treatment with reduced side effects.}, } @article {pmid42611390, year = {2026}, author = {Oria, RS and Akpang, KE and Ben, RB and Aneke, VO and Ushie, IE and Uchenna, MJ and Ikong, GB and Uket, JI and Woko, C and Ijomone, OM}, title = {Hesperidin attenuates aluminum chloride-induced cognitive impairment by modulating ERK/MAPK Signaling, tau protein immunoexpression, neuroinflammation, and microglial activation in mice.}, journal = {Metabolic brain disease}, volume = {41}, number = {1}, pages = {}, pmid = {42611390}, issn = {1573-7365}, mesh = {Animals ; *Hesperidin/pharmacology/therapeutic use ; Aluminum Chloride ; *Microglia/drug effects/metabolism ; Male ; *tau Proteins/metabolism/biosynthesis ; Mice ; *MAP Kinase Signaling System/drug effects ; *Cognitive Dysfunction/chemically induced/metabolism/drug therapy ; *Neuroinflammatory Diseases/metabolism/drug therapy/chemically induced ; *Neuroprotective Agents/pharmacology/therapeutic use ; Maze Learning/drug effects ; Aluminum Compounds ; }, abstract = {Aluminum chloride (AlCl3) is widely used to model Alzheimer's-related neurotoxicity and cognitive decline. Hesperidin, a citrus flavanone with antioxidant and anti-inflammatory properties, has unclear neuroprotective mechanisms against aluminum-induced neurodegeneration. This study investigated hesperidin's neuroprotective effects against AlCl3-induced cognitive impairment in mice, focusing on ERK/MAPK signaling, tau expression, neuroinflammation, and microglial activation. Mice received AlCl3 (100 mg/kg) daily for four weeks, hesperidin (100 mg/kg), both, or vehicle, with hesperidin administered during weeks 3 and 4 in the co-treated group. Cognitive function was assessed using the Morris water maze and Y-maze tests. TNF-α and IL-1β were quantified in brain tissue. IBA1-positive microglial density, ERK immunoreactivity, and tau expression were evaluated immunohistochemically in the hippocampal CA3 region and the prefrontal cortex. AlCl3 impaired spatial and working memory, elevated pro-inflammatory cytokines, increased microglial activation, and upregulated ERK and tau immunoexpression in both regions. Hesperidin co-treatment significantly rescued cognitive deficits, attenuated neuroinflammation, reduced microglial reactivity, modulated ERK signaling, and decreased tau overexpression. These findings demonstrate that hesperidin protects against AlCl3-induced neurodegeneration by concurrently modulating neuroinflammatory and kinase-dependent pathways, supporting its therapeutic potential in aluminum-related tauopathies.}, } @article {pmid42612268, year = {2026}, author = {Li, Z and Sun, T and Han, M and Xiao, B and Liu, S and Zhang, J and Ma, J and Ma, H and Yang, J and Zhang, Z}, title = {Deep learning-driven discovery and optimization of natural LSD1 inhibitors for the treatment of Alzheimer's disease.}, journal = {Bioorganic chemistry}, volume = {181}, number = {}, pages = {110396}, doi = {10.1016/j.bioorg.2026.110396}, pmid = {42612268}, issn = {1090-2120}, abstract = {Alzheimer's disease (AD) is a prevalent neurodegenerative disorder with limited effective disease-modifying treatments. Lysine-specific demethylase 1 (LSD1) has emerged as a promising target for AD therapy. However, current LSD1 inhibitors for AD still suffer from poor brain permeability, off-target toxicity, and chemical-scaffold scarcity. Herein, we developed a multimodal deep learning model (PLM-CAFT-DTA) for drug-target affinity (DTA) prediction. This model integrates ChemBERTa, ESM-2, graph attention, and cross-attention fusion to achieve high prediction precision. Using this model combined with virtual screening and molecular simulation, we identified silybin as a hit compound from a library of over 70,000 natural products. After rational modification, compound S3 was obtained with significantly improved LSD1 inhibition (IC50 = 2.30 μM), approximately 7-fold more potent than the silybin. In vitro assays showed that S3 exhibited favorable neuroprotective and antioxidant activities. In APP/PS1 mice, S3 upregulated hippocampal H3K9me2, suppressed neuroinflammation and Aβ deposition, and improved cognitive function. By addressing unmet demands for AI-assisted anti-AD lead discovery, this study provides a generalized DTA tool for early-stage drug development, and identifies S3 as a novel LSD1 inhibitor with potent anti-AD efficacy.}, } @article {pmid42612783, year = {2026}, author = {Yu, Z and Wang, Y and Yang, Y}, title = {Autophagy as a mechanistic link between physical exercise and Alzheimer's disease.}, journal = {Neuroscience}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.neuroscience.2026.08.026}, pmid = {42612783}, issn = {1873-7544}, abstract = {Alzheimer's Disease (AD), the most prevalent cause of dementia worldwide, is a neurodegenerative disorder that currently has no cure. A growing body of evidence suggests that physical exercise is a potential non-pharmacological strategy in the treatment of AD. Recent findings highlight the involvement of autophagy in the modulatory actions of physical exercise for AD. Here, we present a narrative review of the current knowledge on how exercise impacts AD, specifically focusing on its regulation of autophagic activity in animal models of Alzheimer's disease. Evidence from rodent studies further demonstrates that exercise may influence AD-related pathology through autophagy-lysosomal regulation, lysosomal homeostasis, and mitochondrial quality control, but direct human evidence remains limited. This review uniquely positions exercise-induced autophagy regulation as a central mechanistic hub, offering a novel paradigm for developing lifestyle-based interventions for AD.}, } @article {pmid42613144, year = {2026}, author = {Valverde, A and Blasco, H and Corcia, P and Herault, O and Magistretti, P and Herault, L and Cali, C and Bartesaghi, L and Stone, J and Mitrofanis, J}, title = {Exploring the effect of red and near-infrared light on neurodegenerative disease: A focus on amyotrophic lateral sclerosis, Charcot's devastating disease of the motor system.}, journal = {International review of neurobiology}, volume = {189}, number = {}, pages = {205-236}, doi = {10.1016/bs.irn.2026.01.013}, pmid = {42613144}, issn = {2162-5514}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/therapy/radiotherapy ; Animals ; *Infrared Rays/therapeutic use ; Red Light ; *Neurodegenerative Diseases/therapy ; }, abstract = {All neurodegenerative diseases, from Alzheimer's disease to amyotrophic lateral sclerosis (ALS), are characterised by a relentless and progressive degeneration of neurones. The degenerating neurones suffer from mitochondrial dysfunction, glutamate excitotoxicity, metabolic disorder and atypical protein aggregations; there is also widespread neuroinflammation and damage to the neurovascular unit across the nervous system. Unfortunately, there is no current treatment option that addresses all, if not many, of these striking abnormalities, one that stops or even slows the progression of the disease (ie neuroprotective). In this chapter, we explore the potential effectiveness of red and near infrared light (R-NIr) on ALS, one of the most devastating of all the neurodegenerative diseases. This condition impacts the motor system, from the cerebral cortex and brainstem to the spinal cord, as well as many skeletal muscles. Individuals suffer greatly and the survival period after onset of the first signs is often very short, averaging just over 2 years, as against 4-8 years in dementia. We outline two main reasons why R-NIr may have positive outcomes in ALS; (1) R-NIr has been shown to be neuroprotective in many other neurodegenerative diseases, improving cell function and survival, and; (2) unlike many other treatments attempted previously, R-NIr addresses many, if not all features of pathology associated with ALS. In summary, we suggest that R-NIr, with its multi-modal effect, could be a valuable treatment option for patients with ALS, particularly if the treatment is started early, before the development of excessive cellular damage.}, } @article {pmid42603633, year = {2026}, author = {Choi, HS and Jeon, SH and Liu, H and Kim, M and Yu, JS and Yoo, SS and Son, DJ and Han, SB and Yeo, IJ and Lim, SC and Hong, JT}, title = {p53 deficiency increases vulnerability to chronic stress-induced anxiety- and depression-like behaviors: Role of calcium dysregulation and BDNF signaling.}, journal = {Behavioural brain research}, volume = {}, number = {}, pages = {116437}, doi = {10.1016/j.bbr.2026.116437}, pmid = {42603633}, issn = {1872-7549}, abstract = {The tumor suppressor protein p53 is a known modulator of neurodegenerative disease (ND) processes. Although p53 expression is increased in the brains of patients with Alzheimer's disease, Parkinson's disease, and ischemic stroke, its role in mood disorders such as anxiety and depression remains unclear. To investigate the role of p53 in behavioral responses to chronic stress, we examined behavioral and molecular alterations in p53 knockout (p53[-/-]) mice and wild type mice. In p53[-/-] mice, increased vulnerability to chronic unpredictable mild stress (CUMS)-induced anxiety- and depression-like behaviors was observed following CUMS exposure. In parallel with these behavioral changes, BDNF expression was reduced, whereas glutamate levels were elevated in the prefrontal cortex of p53[-/-] mice. Increased calcium-associated staining and NMDAR2B expression were observed together with increased neuronal injury- and cell death-related markers. In primary cortical neurons derived from p53[-/-] mice, corticosterone treatment resulted in greater increases in glutamate levels, NMDAR2B expression compared to wild-type controls. Cell death markers (cleaved caspase-3, p-p38, p-JNK) were upregulated, while neuroprotective signals (BDNF, p-Akt, p-ERK, p-CREB) were suppressed in p53[-/-] mice, and corticosterone-treated primary neuronal cells from p53[-/-] mice. These findings indicate that p53 deficiency is associated with enhanced vulnerability to CUMS-induced anxiety- and depression-like behaviors and is accompanied by alterations in calcium handling, glutamate homeostasis, neuronal injury-related markers, and BDNF-associated neuroprotective signaling.}, } @article {pmid42604096, year = {2026}, author = {Bayly, H and Salvati, L and Lenio, S and Mez, J and Alosco, ML and Tripodis, Y}, title = {Evaluating inclusion of continuous multivariable cognitive scores for operational enrichment of preclinical Alzheimer's disease trials: a retrospective emulation study.}, journal = {JAR life}, volume = {15}, number = {}, pages = {100081}, pmid = {42604096}, issn = {2534-773X}, support = {R01 AG053509/AG/NIA NIH HHS/United States ; P30 AG072979/AG/NIA NIH HHS/United States ; R01 AG073235/AG/NIA NIH HHS/United States ; P30 AG013854/AG/NIA NIH HHS/United States ; P30 AG053760/AG/NIA NIH HHS/United States ; P20 AG068082/AG/NIA NIH HHS/United States ; R01 AG056258/AG/NIA NIH HHS/United States ; P30 AG066444/AG/NIA NIH HHS/United States ; R01 AG045571/AG/NIA NIH HHS/United States ; P30 AG072975/AG/NIA NIH HHS/United States ; U24 RR021382/RR/NCRR NIH HHS/United States ; U19 AG073153/AG/NIA NIH HHS/United States ; R01 AG043434/AG/NIA NIH HHS/United States ; P30 AG062428/AG/NIA NIH HHS/United States ; P30 AG066507/AG/NIA NIH HHS/United States ; P30 AG072946/AG/NIA NIH HHS/United States ; R01 DC008552/DC/NIDCD NIH HHS/United States ; P30 AG066518/AG/NIA NIH HHS/United States ; R01 AG019771/AG/NIA NIH HHS/United States ; R01 AG069453/AG/NIA NIH HHS/United States ; P50 AG005142/AG/NIA NIH HHS/United States ; R01 AG058724/AG/NIA NIH HHS/United States ; P20 AG068053/AG/NIA NIH HHS/United States ; P30 AG010133/AG/NIA NIH HHS/United States ; U01 AG057195/AG/NIA NIH HHS/United States ; P50 AG016574/AG/NIA NIH HHS/United States ; P30 AG066511/AG/NIA NIH HHS/United States ; P30 AG086404/AG/NIA NIH HHS/United States ; U24 AG072122/AG/NIA NIH HHS/United States ; P30 AG066512/AG/NIA NIH HHS/United States ; P30 AG066515/AG/NIA NIH HHS/United States ; I01 RX001534/RX/RRD VA/United States ; P30 AG062421/AG/NIA NIH HHS/United States ; P30 AG035982/AG/NIA NIH HHS/United States ; P50 AG008702/AG/NIA NIH HHS/United States ; S10 OD026738/OD/NIH HHS/United States ; R35 AG072262/AG/NIA NIH HHS/United States ; R01 AG077444/AG/NIA NIH HHS/United States ; U19 AG063911/AG/NIA NIH HHS/United States ; U24 AG067418/AG/NIA NIH HHS/United States ; R01 AG068338/AG/NIA NIH HHS/United States ; P30 AG066508/AG/NIA NIH HHS/United States ; P01 AG003991/AG/NIA NIH HHS/United States ; R01 AG062276/AG/NIA NIH HHS/United States ; P30 AG013846/AG/NIA NIH HHS/United States ; P30 AG072978/AG/NIA NIH HHS/United States ; P01 AG026276/AG/NIA NIH HHS/United States ; P50 AG047270/AG/NIA NIH HHS/United States ; P30 AG072980/AG/NIA NIH HHS/United States ; P30 AG062429/AG/NIA NIH HHS/United States ; P30 AG066519/AG/NIA NIH HHS/United States ; R01 AG053993/AG/NIA NIH HHS/United States ; R01 AG067781/AG/NIA NIH HHS/United States ; P50 AG005136/AG/NIA NIH HHS/United States ; P30 AG072973/AG/NIA NIH HHS/United States ; P30 AG062422/AG/NIA NIH HHS/United States ; U19 AG024904/AG/NIA NIH HHS/United States ; R01 AG079280/AG/NIA NIH HHS/United States ; P50 AG016573/AG/NIA NIH HHS/United States ; P30 AG086401/AG/NIA NIH HHS/United States ; P50 AG047266/AG/NIA NIH HHS/United States ; R01 NS075075/NS/NINDS NIH HHS/United States ; R01 EB009352/EB/NIBIB NIH HHS/United States ; P30 NS098577/NS/NINDS NIH HHS/United States ; P30 AG066462/AG/NIA NIH HHS/United States ; P30 AG010161/AG/NIA NIH HHS/United States ; R01 AG056531/AG/NIA NIH HHS/United States ; P30 AG066530/AG/NIA NIH HHS/United States ; P50 AG005133/AG/NIA NIH HHS/United States ; R01 AG021910/AG/NIA NIH HHS/United States ; P30 AG066509/AG/NIA NIH HHS/United States ; R01 AG056031/AG/NIA NIH HHS/United States ; P20 AG068077/AG/NIA NIH HHS/United States ; R01 AG061788/AG/NIA NIH HHS/United States ; P30 AG066546/AG/NIA NIH HHS/United States ; UL1 TR000448/TR/NCATS NIH HHS/United States ; P30 AG072977/AG/NIA NIH HHS/United States ; P30 AG062677/AG/NIA NIH HHS/United States ; I21 RX001381/RX/RRD VA/United States ; P50 AG047366/AG/NIA NIH HHS/United States ; U19 NS120384/NS/NINDS NIH HHS/United States ; P30 AG072958/AG/NIA NIH HHS/United States ; P30 AG062715/AG/NIA NIH HHS/United States ; P30 AG066506/AG/NIA NIH HHS/United States ; P30 AG066468/AG/NIA NIH HHS/United States ; P30 AG072976/AG/NIA NIH HHS/United States ; P30 AG010129/AG/NIA NIH HHS/United States ; P30 AG019610/AG/NIA NIH HHS/United States ; R56 AG045571/AG/NIA NIH HHS/United States ; P30 AG072947/AG/NIA NIH HHS/United States ; P30 AG072931/AG/NIA NIH HHS/United States ; P50 MH071616/MH/NIMH NIH HHS/United States ; P30 AG072972/AG/NIA NIH HHS/United States ; R01 AG054110/AG/NIA NIH HHS/United States ; R01 AG052560/AG/NIA NIH HHS/United States ; P30 AG066514/AG/NIA NIH HHS/United States ; P30 AG072959/AG/NIA NIH HHS/United States ; R01 AG055005/AG/NIA NIH HHS/United States ; P50 AG033514/AG/NIA NIH HHS/United States ; }, abstract = {BACKGROUND: Prevention trials for Alzheimer's Disease face significant challenges due to the slow and uncertain rate of cognitive decline in asymptomatic, amyloid-positive individuals. Biomarker positivity alone does not guarantee clinically meaningful progression, often leaving studies underpowered.

OBJECTIVES: Evaluate model-based operational trial enrichment within an amyloid-positive, cognitively normal subgroup.

METHODS: Trained on a small cohort from the National Alzheimer's Coordinating Center (N = 113), with external validation using baseline data of a similar small cohort from the Alzheimer's Disease Neuroimaging Initiative (N = 161). Gradient-boosted decision trees estimated progression risk and projected power under alternative enrollment strategies. Predictors included neuropsychological scores, demographics, medical history, and ApoE ε4 genotype. The primary outcome was clinical progression to cognitive impairment within 1- and 3-year follow-up windows.

RESULTS: In the independent testing set, the model successfully increased the effective prevalence of the outcome. The Positive Predictive Value for the 1-year window was 0.27 (a 35% relative increase over the 0.20 baseline prevalence) and 0.43 for the 3-year window (a 23% relative increase over the 0.35 baseline). Power simulations for an emulated trial (N = 500) demonstrated that this enrichment strategy consistently increased statistical power, potentially reducing the required sample size to achieve 80% power by up to 32% for small treatment effect sizes.

CONCLUSIONS: This operational methodology functions as a screening filter to optimize event rates within a highly specific, preselected trial population.}, } @article {pmid42605027, year = {2026}, author = {Duijkers, S and Ter Huurne, DBG and Blom, M and Bodde, HE and Dobbe, JHM and Van der Flier, W and Jansen, WJ and Olde Rikkert, M and Papma, JM and Verhey, FRJ and Ramakers, IHGB}, title = {Current Practice and Long-Term Developments in Multidisciplinary Dutch Memory Clinics.}, journal = {Journal of geriatric psychiatry and neurology}, volume = {}, number = {}, pages = {8919887261478290}, doi = {10.1177/08919887261478290}, pmid = {42605027}, issn = {1552-5708}, abstract = {ObjectivesMemory Clinics (MCs) have a central role in multidisciplinary diagnostics and care of cognitive disorders and dementia. This study describes current clinical practice and developments of Dutch MCs since their start in 1986.MethodsA survey was sent to all Dutch hospital-based MCs in 1998, 2004, 2009, 2017 and 2023. Topics included: organization, patient characteristics, scales and questionnaires, neuropsychological assessment, additional assessments, novel biomarkers, disclosure of diagnosis and treatment. 74 out of the total of 89 MCs completely or partially filled out the questionnaire.ResultsThe number of MCs increased to 89. The number of patients seen increased substantially (per MC/year: 1998: 130; 2023: 324; total: 1998: 1560; 2023: 28,848). The proportion of patients diagnosed with dementia decreased from 80% in 1998 to 47% in 2023. Most commonly available assessments were neuroimaging (100%), routine laboratory testing of blood (98%) and neuropsychological assessment (NPA; 98%). Thirty-one percent indicated infrastructure needed to be changed before prescribing monoclonal antibody treatments for Alzheimer's disease.ConclusionsMCs showed substantial development in number, number of patients and geographical distribution within the country. Nowadays, MCs are central care facilities for the timely and multidisciplinary diagnosis and treatment of people with cognitive disorders and dementia.}, } @article {pmid42605139, year = {2026}, author = {Javed, MN and Khan, SM and Mustafa, S and Mujtaba, A and Amin, H and Azhar, N and Hameed, A and Zayed, A and Khalid, M and Hussain, JM}, title = {Gantenerumab for Early Alzheimer's Disease: An Updated Systematic Review and Meta-Analysis.}, journal = {Brain and behavior}, volume = {16}, number = {8}, pages = {e71643}, doi = {10.1002/brb3.71643}, pmid = {42605139}, issn = {2162-3279}, mesh = {Humans ; *Alzheimer Disease/drug therapy ; *Antibodies, Monoclonal, Humanized/therapeutic use/pharmacology ; Randomized Controlled Trials as Topic ; Amyloid beta-Peptides ; }, abstract = {INTRODUCTION: Alzheimer's disease (AD) is a progressive neurodegenerative disorder with limited treatment options. Gantenerumab, a β-amyloid-targeting monoclonal antibody, has shown mixed clinical results. With new trial data available, this updated systematic review and meta-analysis re-evaluates its efficacy and safety in early AD.

METHODS: Registered on PROSPERO (CRD420251082463) under PRISMA guidelines, we searched PubMed, Cochrane Library, and Google Scholar from inception to October 2025 for randomized trials in early AD comparing gantenerumab with placebo. A random-effects model assessed pooled outcomes with heterogeneity (I[2]) and sensitivity analyses. Additionally, meta-regression and certainty of evidence using Gradepro were performed. Risk of bias was evaluated using the Cochrane tool. An Institutional Review Committee (IRC) and its Ethical Review Board (ERB) approval was not required.

RESULTS: Six trials (3103 participants: 1718 gantenerumab; 1385 placebo) were included. Gantenerumab showed no significant effect on CDR-SB (MD = -0.07; 95% CI: -0.34-0.20; p = 0.62; I[2] = 16%) but produced small improvements in FAQ (MD = -0.73; 95% CI: -1.30 to -0.17; p = 0.01; I[2] = 0%) and Amyloid-PET score (MD = -45.67; 95% CI: -88.09 to -3.24; p = 0.03; I[2] = 99%). While significant statistical improvement was seen in the ADAS-Cog13 score (MD = -0.95; 95% CI: -1.76 to -0.13; p = 0.02; I[2] = 0%), the effect sizes for both FAQ and ADAS-Cog13 fell below established MCID thresholds. MMSE and ADCS-ADL showed no significant differences. Safety analysis revealed higher risks of ARIA-E (RR = 5.51), ARIA-H (RR = 1.73), and injection site reactions (RR = 2.15), with no differences in other adverse events.

CONCLUSION: Gantenerumab significantly reduces amyloid and statistically improves select functional (FAQ) and cognitive (ADAS-Cog13) measures in early AD; however, these changes remain below accepted MCID thresholds, indicating a lack of true clinical meaningfulness. Combined with its failure to enhance global cognition and an increased ARIA risk, routine clinical use is not supported.}, } @article {pmid42606634, year = {2026}, author = {Cheng, L and Gong, P and Su, X and Fang, Y and Wang, T}, title = {miR-584-5p suppresses Aβ1-42-induced apoptosis in Alzheimer's disease cell model via targeting of HDAC1.}, journal = {Acta neurologica Belgica}, volume = {}, number = {}, pages = {}, pmid = {42606634}, issn = {2240-2993}, abstract = {BACKGROUND: Alzheimer's disease (AD) represents a profoundly detrimental neurodegenerative disorder, and early diagnosis coupled with effective treatment remains a major clinical challenge. MicroRNAs (miRNAs) have emerged as key regulators associated with pathological processes in AD.

AIM: This study aimed to explore the expression pattern and the likely diagnostic value of miR-584-5p in AD, as well as its molecular mechanism of action in regulating β-amyloid (Aβ)-induced apoptosis.

METHODS: Peripheral blood samples from 90 AD patients and age- and sex-matched controls were examined using RT-qPCR. Correlation analyses of miR-584-5p expression with key AD biomarkers (Aβ42, tTau, pTau) were performed in AD patients. Following exposure to 5 µM Aβ1-42, SH-SY5Y cells were employed in subsequent functional experiments. Bioinformatics analysis, a dual-luciferase reporter assay, and negative correlation analysis of plasma samples were conducted to verify the target gene of miR-584-5p.

RESULTS: miR-584-5p was significantly downregulated in AD patients, and its expression correlated with Aβ42 (r = 0.665), total tau (tTau, r = -0.642), phosphorylated tau (pTau, r = -0.576), and Mini-Mental State Examination (MMSE) scores (r = 0.618), yielding an AUC of 0.864 in this single-center cohort. miR-584-5p overexpression inhibited 5 µM Aβ1-42-induced apoptosis in SH-SY5Y cells, an effect that was reversed by concurrent HDAC1 overexpression. Mechanistically, by targeting HDAC1, miR-584-5p modulates p53 acetylation and the Bcl-2/Bax pathway at the protein level.

CONCLUSIONS: miR-584-5p exerted neuroprotective effects via the miR-584-5p/HDAC1 axis, offering new insights into AD pathogenesis and suggesting this axis as a candidate for further preclinical investigation.}, } @article {pmid42606694, year = {2026}, author = {Jaiswal, C and Singh, I and Singh, AK}, title = {Fisetin Attenuates Amyloid-Beta-Induced Neurotoxicity in Human Neuroblastoma SH-SY5Y Cells: Integrating In Silico Target Prediction and In Vitro Validation.}, journal = {Journal of biochemical and molecular toxicology}, volume = {40}, number = {9}, pages = {e71076}, doi = {10.1002/jbt.71076}, pmid = {42606694}, issn = {1099-0461}, support = {CRG/2022/006612//Anusandhan National Research Foundation/ ; }, mesh = {Humans ; Flavonols ; *Amyloid beta-Peptides/toxicity/metabolism ; *Flavonoids/pharmacology/chemistry ; *Neuroblastoma/metabolism/pathology/drug therapy ; Cell Line, Tumor ; *Peptide Fragments/toxicity ; *Neuroprotective Agents/pharmacology ; Oxidative Stress/drug effects ; Molecular Docking Simulation ; }, abstract = {The accumulation of amyloid beta (Aβ) and tau tangles in the brain leads to Alzheimer's disease (AD). Fisetin, a natural flavonoid, is an antioxidant molecule, and its neuroprotective effects are not clearly understood. Therefore, attempts have been made to evaluate the neuroprotective effects of fisetin using in silico methods and an Aβ1-42-induced neurotoxicity model in human neuroblastoma SH-SY5Y cells. In silico studies demonstrated that fisetin binds strongly and with high stability to different proteins, such as ULK1 (autophagy marker), p21 (senescence/cell cycle marker), and synaptophysin (synaptic marker), which are responsible for maintaining brain health and are implicated in AD. Moreover, Aβ1-42 was also found to bind to these protein targets, indicating that Aβ1-42 and fisetin both target common binding sites. In vitro studies on SH-SY5Y cells further confirmed that fisetin promotes cell survival under the toxic effects of Aβ1-42. It reduced oxidative stress and restored the activities of ion channels, which were impaired by Aβ1-42 treatment. Fisetin increased antioxidant defense and restored the activity of molecules that control brain signals. Overall, fisetin acts on multiple targets to protect neurons by reducing oxidative damage, supporting ion channel activity, and inducing the autophagy process.}, } @article {pmid42607896, year = {2026}, author = {Li, X and Chen, Z and Guan, J and Yu, H and Wang, J}, title = {Oral Administration of Melatonin Modulates Macrophage Polarization via Modulating the Vegf Signaling Pathway and Ameliorates Alzheimer's Disease in APP/PS1 Mice.}, journal = {Brain research bulletin}, volume = {}, number = {}, pages = {112088}, doi = {10.1016/j.brainresbull.2026.112088}, pmid = {42607896}, issn = {1873-2747}, abstract = {BACKGROUND: Alzheimer's disease (AD) is a neurodegenerative disorder with a global prevalence, currently lacking effective treatments and posing a major public health challenge due to the burden it places on healthcare systems while affecting millions of people. Melatonin is a hormone with considerable potential for treating various neurodegenerative disorders, including AD. The mechanisms responsible for melatonin's therapeutic benefits in Alzheimer's disease (AD) require further elucidation. This study was designed to investigate the mechanisms by which melatonin exerts its effects in APP/PS1 mice.

METHODS: The Morris water maze was used to assess the performance of melatonin-treated APP/PS1 mice. Haematoxylin&Eosin and Nissl staining were conducted to observe the integrity of hippocampal neurons. Transcriptomic sequencing of hippocampal tissue was performed to identify differentially expressed genes, which were subjected to Gene Ontology (GO) term and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses. Immunofluorescence analysis was used to detect the levels of Cd16, Cd32, Cd68 and Cd206 in APP/PS1 mice. Reverse transcription-quantitative polymerase chain reaction (RT-qPCR), immunoblotting, and immunohistochemistry were employed to validate the relative expression of Vegf, Flt1, and Kdr proteins.

RESULTS: In the Morris water maze, melatonin-treated APP/PS1 mice demonstrated a marked increase in platform crossings. Improved neuronal integrity in the hippocampus was observed through Haematoxylin&Eosin and Nissl staining. Transcriptomic sequencing of hippocampal tissue revealed 295 differentially expressed genes, which were significantly associated with 1091 GO terms and 30 KEGG pathways. Immunofluorescence analysis indicated that melatonin treatment notably reduced Cd16 and Cd32 levels while elevating Cd68 and Cd206 in APP/PS1 mice. Subsequent analyses via RT-qPCR, immunoblotting, and immunohistochemistry validated the increased relative expression of Vegf, Flt1, and Kdr proteins.

DISCUSSION: Melatonin attenuates AD pathogenesis in APP/PS1 mice by promoting macrophage polarization via the Vegf signaling pathway, revealing a novel mechanism for AD prevention and treatment.}, } @article {pmid42608531, year = {2026}, author = {Wu, YL and Xu, QQ and Qin, ZH and Wu, X and Hu, Z and Yang, W and Ren, PY and Tian, YY and Lin, ZX and Xian, YF}, title = {Oxyberberine-nanoparticle attenuates the cognitive deficits in a transgenic mouse model of Alzheimer's disease via modulating gut microbiota through suppressing CXCL10/CXCR3 pathway.}, journal = {Acta pharmacologica Sinica}, volume = {}, number = {}, pages = {}, pmid = {42608531}, issn = {1745-7254}, abstract = {Oxyberberine (OBB) has good potential neuroprotective effects. However, the poor water solubility of OBB poses a challenge to its therapeutic effects. In this study, OBB-hydroxypropyl-β-cyclodextrin (OBB-β-CD) was prepared to increase the water solubility and improve bioavailability of OBB. The neuroprotective effects of OBB-β-CD against AD were investigated using 3×Tg transgenic AD mouse model. OBB-β-CD exhibited dual regulatory capabilities in improving both behavioral deficits and pathological features of AD. OBB-β-CD was more effective than OBB in modulating the amyloid precursor protein (APP) processing and inhibiting the hyperphosphorylation of Tau protein. OBB-β-CD was effective in reducing both the concentration of beta-amyloid 42 (Aβ42) and the deposition of Aβ plaques in 3×Tg mouse models. OBB-β-CD also suppressed neuroinflammation by promoting microglial polarization from an M1-like to an M2-like phenotype. Furthermore, OBB-β-CD restored the gut dysbiosis and inhibited the activation of the C-X-C motif chemokine receptor 3 (CXCR3) and the level of C-X-C motif chemokine ligand 10 (CXCL10) in the brain and colon tissues of 3×Tg mice. Simultaneously, the effect of OBB that suppressed microglial M1 and promoted M2 polarization to improve the neuronal micro-environment was verified in vitro using BV-2 cells. Importantly, OBB-β-CD showed similar anti-AD effects of knockdown of CXCR3 in 3×Tg mice, but no synergistic effects were observed in the shCXCR3 + OBB-β-CD group compared to the shCXCR3 group. Furthermore, the results of molecular docking and surface plasmon resonance (SPR) assay indicated that CXCR3 could bind with OBB. Additionally, the fecal microbiota transplantation (FMT) of fecal microbiota from the OBB-β-CD-treated 3×Tg mice (OBB-β-CD-FMT) significantly alleviated the cognitive deficits in the pseudo-germ-free 3×Tg mice via markedly suppressing the hyperphosphorylation of Tau protein, Aβ level and the activation of CXCR3 in the brain of 3×Tg mice. OBB-β-CD has good potential for further development into a therapeutic agent for AD treatment.}, } @article {pmid42608660, year = {2026}, author = {Shinagawa, S and Nagata, T}, title = {Toward Precision Neuropsychiatry of Dementia: Neuropsychiatric Symptoms as Multidimensional Clinical Phenotypes.}, journal = {Psychogeriatrics : the official journal of the Japanese Psychogeriatric Society}, volume = {26}, number = {5}, pages = {e70209}, doi = {10.1111/psyg.70209}, pmid = {42608660}, issn = {1479-8301}, support = {24K10690//Japan Society for the Promotion of Science/ ; JP24wm0625505//Japan Agency for Medical Research and Development/ ; }, mesh = {Humans ; *Dementia/psychology/diagnosis ; Phenotype ; *Neuropsychiatry/methods ; *Precision Medicine/methods ; Sleep Wake Disorders ; }, abstract = {Neuropsychiatric symptoms (NPS) are the most clinically consequential manifestations of dementia, yet they are frequently underestimated as secondary behavioural complications. This review introduces a precision neuropsychiatry framework that conceptualises NPS-including apathy, agitation, psychosis, depression, and sleep disturbances-as multidimensional clinical phenotypes. These phenotypes bridge neurodegeneration, biological aging, brain network disruption, psychosocial context, functional decline, and caregiver burden. We trace the conceptual evolution from dementia to neurocognitive disorders, and from behavioural and psychological symptoms of dementia (BPSD) to NPS and mild behavioural impairment (MBI). Precision neuropsychiatry stratifies NPS based on disease background, clinical stage, neural networks, biological aging, physical vulnerability, and psychosocial context to optimise differential diagnosis, prognostic prediction, and targeted interventions. Although conventional symptom-based classification remains practically useful, it must be complemented by biological, functional, and contextual stratification; identical symptom labels often arise from distinct mechanisms and express differently based on personality, life history, environmental mismatch, and available resources. Emerging evidence from MBI, neuroimaging, brain-age paradigms, frailty, neuroinflammation, Alzheimer's disease (AD) biomarkers, and international consensus criteria supports this multidimensional shift. Future research should advance from cross-sectional symptom descriptions toward longitudinal, mechanism-informed, and context-sensitive models to translate these findings into real-world psychogeriatric care.}, } @article {pmid42608702, year = {2026}, author = {Swane, V and Biering-Sørensen, B}, title = {Posterior cortical atrophy with initial psychiatric presentation: a case report.}, journal = {Journal of medical case reports}, volume = {20}, number = {1}, pages = {}, pmid = {42608702}, issn = {1752-1947}, mesh = {Humans ; Male ; Aged ; Atrophy ; Magnetic Resonance Imaging ; *Cerebral Cortex/pathology/diagnostic imaging ; *Neurodegenerative Diseases/diagnostic imaging/psychology ; Electroencephalography ; Alzheimer Disease ; Neuropsychological Tests ; }, abstract = {BACKGROUND: Posterior cortical atrophy (PCA) is a rare neurodegenerative syndrome most commonly associated with atypical Alzheimer's disease. It is characterized by progressive visuospatial and visuoperceptual deficits with relative sparing of memory and language in early stages. Diagnosis is frequently delayed or missed due to clinical heterogeneity, subtle early symptoms, and limited sensitivity of routine cognitive screening tools. Psychiatric symptoms may further obscure the underlying neurological disorder. This case highlights the diagnostic challenges posed by PCA presenting in the context of prominent psychiatric symptoms, combined with a rapid clinical decline.

CASE PRESENTATION: A 68-year-old white Danish male presented with suicidal ideation and was initially admitted to a psychiatric ward. He had a remote history of a suicide attempt and a family history of suicide but no known neurodegenerative disease. Within a short period, severe cognitive and functional impairment became evident, dominated by visuospatial deficits, apraxia, simultanagnosia, optic ataxia, and features of Gerstmann and Balint syndromes, with relative preservation of memory and language. Neuroimaging revealed marked posterior cortical atrophy and parieto-occipitotemporal hypometabolism with sparing of the posterior cingulate cortex. Cerebrospinal fluid analysis showed mildly reduced amyloid-β1-42 and markedly elevated neurofilament light chain levels. Electroencephalography demonstrated focal posterior slowing without epileptiform activity. Extensive evaluation excluded autoimmune, epileptic, metabolic, and prion-related causes. Based on the clinical syndrome, characteristic neuroimaging findings, and supportive CSF biomarkers, a diagnosis of posterior cortical atrophy likely related to underlying Alzheimer's disease pathology was made. Disease-specific treatment was discussed but not initiated due to patient preference.

CONCLUSIONS: This case illustrates how posterior cortical atrophy may be overlooked, particularly when psychiatric symptoms dominate the initial presentation. It underscores the importance of considering neurodegenerative disorders in older patients with atypical psychiatric presentations or unexplained functional decline. Early recognition of PCA is crucial for accurate diagnosis, appropriate counseling, and tailored supportive care.}, } @article {pmid42608731, year = {2026}, author = {Long, W and Yuan, M and Wang, S and Tan, X and Gao, LC}, title = {The mitophagy-inflammasome axis: a shared pathological hub in Alzheimer's and Parkinson's diseases.}, journal = {Translational neurodegeneration}, volume = {15}, number = {1}, pages = {}, pmid = {42608731}, issn = {2047-9158}, support = {2025JJ80178//the Hunan Provincial Natural Science Foundation of China/ ; kq2502334//the Changsha Natural Science Foundation of China/ ; }, mesh = {Humans ; *Mitophagy/physiology ; *Inflammasomes/metabolism ; *Parkinson Disease/pathology/metabolism ; *Alzheimer Disease/pathology/metabolism ; Animals ; Mitochondria/metabolism/pathology ; alpha-Synuclein/metabolism ; Amyloid beta-Peptides/metabolism ; }, abstract = {Alzheimer's disease (AD) and Parkinson's disease (PD) represent the most prevalent chronic neurodegenerative disorders, characterized by progressive loss of neurons as a core pathological feature. Despite discrepancies in their clinical phenotypes and signature pathological proteins, accumulating evidence has validated a common molecular pathogenic mechanism: dysfunctional bidirectional crosstalk between mitophagy and inflammasomes. As the central hub of neuronal energy metabolism, mitochondrial impairment triggers the release of damage-associated molecular patterns such as reactive oxygen species and mitochondrial DNA, which in turn activate inflammasomes (e.g., NLRP3) to elicit chronic neuroinflammation. Conversely, excessive inflammasome activation suppresses mitophagy, exacerbating the accumulation of damaged mitochondria and pathological protein aggregates, and forming a pathological mitochondrial damage-inflammatory activation-autophagy inhibition cycle. Microglia and astrocytes, key immunocompetent cells of the central nervous system, act as a hub within this regulatory network. Therapeutic strategies targeting the mitophagy-inflammasome axis have achieved remarkable advancements, including mitophagy agonists, inflammasome inhibitors, and dual-target modulators. This review summarizes recent findings regarding the pathogenic roles of β-amyloid and α-synuclein in AD and PD, as well as the protective effects offered by regulating mitophagy and inflammasome activity. Furthermore, the major directions and potential hurdles in the development of targeted therapeutics are discussed, in the aim of providing insights into the novel therapeutic avenues for the treatment of both disorders.}, } @article {pmid42609487, year = {2026}, author = {Huang, J and Li, X and Zhou, K and Liu, B and Wei, Y and Guo, H and Wei, S and Xu, S and Liu, Y and Huang, J and Deng, D and Liang, L}, title = {High-frequency taVNS modulates olfaction-related brain activity in patients with subjective cognitive decline.}, journal = {Frontiers in human neuroscience}, volume = {20}, number = {}, pages = {1888005}, pmid = {42609487}, issn = {1662-5161}, abstract = {BACKGROUND: Subjective cognitive decline (SCD) is considered a high-risk factor for Alzheimer's disease and serves as a critical window of the prevention and treatment. Transcutaneous auricular vagus nerve stimulation (taVNS) has shown therapeutic effects on cognitive impairment, but there is a lack of research on its application in SCD.

PURPOSE: This study aimed to explore the immediate modulatory effects of taVNS at different frequencies on the brain function in patients with SCD.

METHODOLOGY: Seventy SCD and 49 healthy control (HC) were enrolled. Resting-state functional MRI data were collected at baseline and during taVNS with three stimulation conditions: 1 Hz-taVNS, 20 Hz-taVNS, and sham taVNS (staVNS), respectively. Regional homogeneity (ReHo) analysis was used to identify spontaneous neural activity changes in SCD; the abnormal brain regions were then used as seed for subsequent functional connectivity (FC) analysis. In addition, ReHo and FC analyses were performed to assess the immediate modulatory effects of taVNS in SCD.

RESULTS: Compared with HC, SCD showed abnormal ReHo and FC mainly involving olfaction-related brain regions, and the reduced value was positively associated with Shape Trail Test-part B. During taVNS, we found that 20 Hz-taVNS significantly increased ReHo in the bilateral olfactory cortex compared with baseline, and decreased FC between the left medial orbitofrontal cortex and the right precentral and postcentral gyri. No significant ReHo or FC changes were observed during 1 Hz-taVNS and staVNS.

CONCLUSION: These findings suggest that SCD exhibits reduced spontaneous activity and disrupted FC in the olfaction-related brain regions, which may reflect early functional alterations before objective impairment; 20 Hz-taVNS can modulate these cerebral functional abnormalities and may hold potential as a noninvasive neuromodulation strategy in SCD.}, } @article {pmid42610018, year = {2026}, author = {Umbria, M and Exposito, J and Gasol, M and Vallano, A}, title = {A regional registry ensures clinical guideline adherence and economic sustainability of Alzheimer's disease treatment: a 12-year population-based study in Catalonia.}, journal = {Frontiers in pharmacology}, volume = {17}, number = {}, pages = {1848809}, pmid = {42610018}, issn = {1663-9812}, abstract = {Population-based registries for Alzheimer's disease pharmacological treatment are essential tools for monitoring clinical guideline adherence and health system sustainability. This retrospective observational study analyzes 12 years of real-world data from the Catalan Registry of Pharmacological Treatment of Alzheimer's Disease (RTFMA) between 2012 and 2024. Analyzing a cohort of over 158,000 patients treated with acetylcholinesterase inhibitors or memantine, we found that the treated population increased by 24.5%, reaching 56,874 individuals in 2024. The implementation of a mandatory registration system was associated with high clinical appropriateness, with 81.9% of treatments initiated at recommended moderate stages (GDS 4-5), while only 8.6% began at mild stages. Despite the aging population and the impact of the COVID-19 pandemic-which caused a transient decline in treatment initiations in 2020-the system demonstrated resilience with a full recovery by 2023. Treatment discontinuation was primarily driven by mortality (95% of known reasons), indicating high persistence until end-of-life. From an economic perspective, Alzheimer's therapies represented a stable 1.9% of the total public pharmaceutical budget in 2023, reflecting effective cost containment through generic drug use. These findings suggest that a centralized, guideline-linked registry optimizes patient selection and maintains the economic viability of Alzheimer's care, providing a robust framework for the future integration of high-cost disease-modifying therapies.}, } @article {pmid42610081, year = {2026}, author = {Eldehna, WM and El-Damasy, AK and Lim, J and Hefny, SM and Al-Warhi, T and Elgohary, AS and El-Hamaky, AA and Paik, MJ and Elnagar, MR and Elimam, DM and Omar, YM and Kim, H and Tawfik, HO}, title = {Quinazolinone-triazole hybrids as multi-target-directed ligands for Alzheimer's disease: discovery of potent and selective MAO-B inhibitors with cholinesterase modulating activity.}, journal = {RSC advances}, volume = {}, number = {}, pages = {}, pmid = {42610081}, issn = {2046-2069}, abstract = {A new series of quinazolinone-triazole hybrids (QTHs, 5a-n) was designed, synthesized, and evaluated as potential multi-target-directed ligands for Alzheimer's disease. All synthesized compounds were screened against human monoamine oxidase A (MAO-A) and monoamine oxidase B (MAO-B). The obtained results revealed pronounced selectivity toward MAO-B, with IC50 values ranging from 0.65 to 7.51 µM, while exhibiting negligible MAO-A inhibition (IC50 > 40 µM). Compounds 5a, 5d, 5g, 5h, and 5m emerged as the most potent and selective MAO-B inhibitors and were subsequently evaluated for inhibition of acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE). Among them, compound 5h displayed the most favorable biological profile, showing potent inhibition of MAO-B (IC50 = 0.65 µM), AChE (IC50 = 0.084 µM), and BuChE (IC50 = 0.667 µM). In silico ADMET analysis indicated acceptable drug-like properties for the lead compounds. Furthermore, molecular docking studies against MAO-B and AChE revealed favorable binding interactions, while a 500 ns molecular dynamics simulation confirmed the stability of the 5h-MAO-B complex. Collectively, the present findings identify compound 5h as a promising lead candidate and highlight quinazolinone-triazole hybrids as attractive scaffolds for the development of selective MAO-B inhibitors with additional cholinesterase inhibitory activity for Alzheimer's disease treatment.}, } @article {pmid42610650, year = {2026}, author = {Hiruta, Y and Jin, Z and Adachi, M and Amer, L and Tjokro, NO and Trujillo, DF and Potempa, J and O'Donoghue, AJ and Chen, C and Jokerst, JV}, title = {Protease-Triggered Chromogenic Release From Peptide-Modified Calcium Carbonate Microspheres Enables Colorimetric Detection of Porphyromonas gingivalis Activity.}, journal = {Advanced science (Weinheim, Baden-Wurttemberg, Germany)}, volume = {}, number = {}, pages = {e77102}, doi = {10.1002/advs.77102}, pmid = {42610650}, issn = {2198-3844}, support = {//Shiley Foundation/ ; //National Nanotechnology Coordinated Infrastructure/ ; ECCS-2025752//National Science Foundation/ ; 22KK0234//Promotion of Joint International Research (Fostering Joint International Research/ ; 21K06495//Promotion of Joint International Research (Fostering Joint International Research/ ; //Japan Society for the Promotion of Science/ ; //Fukuzawa Memorial Fund/ ; }, abstract = {Porphyromonas (P.) gingivalis is a Gram-negative anaerobic bacterium with exceptionally high pathogenicity among periodontal pathogens. It is associated not only with periodontal disease but also with various systemic diseases, including Alzheimer's disease, rheumatoid arthritis, and atherosclerosis. Therefore, early detection of this bacterium is crucial for enabling subsequent treatment and prevention of such conditions. Herein, we report a chromogenic release-based assay system utilizing calcium carbonate microspheres and a dye-labeled peptide that is selectively cleaved by an Arg-specific protease called gingipain (RgpB) that is secreted by P. gingivalis. By utilizing the reactive anhydride functional groups of poly(isobutylene-alt-maleic anhydride), we simultaneously achieved the conjugation of the dye-labeled peptide and its immobilization onto calcium carbonate microspheres. Through optimization of the peptide sequence and the surface modification density on calcium carbonate microspheres, the assay of RgpB detection with the absorbance of supernatant exhibited a low limit of detection of 0.25 nM, as well as high storage stability and selectivity for P. gingivalis. The measurements obtained with this assay system for clinical gingival crevicular fluid samples showed a high correlation (Pearson's r = 0.79) with qPCR results. This assay system offers an on-site, visual means to monitor P. gingivalis activity without requiring specialized instrumentation.}, } @article {pmid42602177, year = {2026}, author = {Azimzadeh, M and Ababzadeh, S and Kahaki, AG and Babaei, SMH and Seyedebrahimi, R and Farsani, ME}, title = {The Gut-Brain Axis in Neurodegeneration: Mechanistic Links Between Dysbiosis and Neuropathology.}, journal = {Iranian journal of pathology}, volume = {21}, number = {4}, pages = {507-522}, pmid = {42602177}, issn = {1735-5303}, abstract = {BACKGROUND & OBJECTIVE: The gut-brain axis is essentially a two-way communication system that physically connects the brain and the intestinal tract. The connection is mediated through a series of pathways, including neural, endocrine, and immune pathways. Gut dysbiosis, which is explained as an imbalance in the microbial community, has been linked to the causation of various neurodegenerative disorders such as Alzheimer's disease, Parkinson's disease, and multiple sclerosis. However, the pathological mechanisms in the brain are only partially known. The present review outlines the process of gut dysbiosis and neurodegeneration, detailing the roles of protein aggregation, neuroinflammation, barrier disruption, and neuroglial dysfunction. Then, extending the comparison to a range of neurodegenerative diseases, we discuss the possibility of common pathway therapeutics and actual microbiome-based treatment options planning from the standpoint of microbiome-directed interventions.

CONTENT/FINDINGS: Gut dysbiosis triggers a definable cascade, starting with the disruption of the intestinal barrier and increased permeability (leaky gut), which allows bacterial products (lipopolysaccharides, bacterial amyloids) and pro-inflammatory cytokines to enter systemic circulation. Such peripheral changes weaken the blood-brain barrier and thus allow these factors to access the CNS, where they lead to neuroglial dysfunction (microglial priming, astrocytic reactivity, and oligodendrocyte injury) by disruption of glial homeostasis. CNS glial cell malfunction leads to the development of proteinopathies characteristic of each disease: amyloid and tau hyperphosphorylation in Alzheimer's disease through BACE1 upregulation and kinase activation; synuclein in Parkinson's disease via molecular mimicry, oxidative stress, and impaired clearance; and demyelination in multiple sclerosis through oligodendrocyte apoptosis. Oral bacteria such as Porphyromonas gingivalis aggravate this inflammatory loop through the direct invasion of the CNS and proteolytic cleavage of amyloid and tau. The vagus nerve is yet another pathway through which gut-derived inflammatory signals and pathological synuclein can be transmitted to the brain.

CONCLUSION: The gut microbiome is more than just a correlate of neurodegeneration; it actively promotes neurodegenerative diseases through pathways that can be mechanistically defined. Microbiome-targeted interventions such as dietary changes, precision probiotics, fecal microbiota transplantation, and anti-inflammatory agents offer a measure of hope for changing these pathological processes. Future studies need to be directed at determining the time sequence of cause and effect, finding dependable microbiota-based biomarkers, and formulating tailored strategies that can account for individual microbial composition variability, genetic susceptibility, and environmental exposures. A deeper understanding of the gut-brain axis from this mechanistic perspective could eventually lead to the prevention or postponement of neurodegeneration.}, } @article {pmid42602264, year = {2026}, author = {Tarbiat, S and Kantarci-Carsibasi, N}, title = {Dual inhibitory potential of N-methylcytisine against GSK-3β and AChE: implications for Alzheimer's disease treatment.}, journal = {Open life sciences}, volume = {21}, number = {1}, pages = {20251363}, pmid = {42602264}, issn = {2391-5412}, abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disease characterized by memory loss and irreversible cognitive decline. Glycogen synthase kinase 3β (GSK-3β) is significant in tau hyperphosphorylation and neurodegeneration. The cholinergic hypothesis of AD links cognitive impairment to reduced synaptic acetylcholine (ACh). Increased acetylcholinesterase (AChE) activity exacerbates this issue. To search for a potential dual GSK-3β/AChE inhibitor, we focused on N-methylcytisine. This natural cytisine-derived alkaloid has not been studied for its various biological effects on the prevention of AD. The in vitro results indicated that N-methylcytisine displayed promising activity against GSK-3β and AChE with IC50 values of 11 and 22.7 µM, respectively. GSK-3β kinetic study according to the varying substrate or ATP concentrations at different N-methylcytisine levels revealed mixed-type inhibition. The results of the integrated in silico workflow indicate that N-methylcytisine exhibited favorable binding to AChE (docking score -9.6 kcal/mol; MM-GBSA -70.2 kcal/mol), comparable to the reference inhibitor galantamine (-10.8 kcal/mol; -70.6 kcal/mol). In contrast, its interaction with GSK-3β was more moderate (-5.3 kcal/mol; -50.3 kcal/mol) relative to staurosporine (-8.5 kcal/mol; -82.6 kcal/mol), consistent with its smaller scaffold. Overall, the results support a flexible, mixed-type interaction profile and highlight N-methylcytisine as a promising dual-acting candidate for Alzheimer's disease.}, } @article {pmid42602524, year = {2026}, author = {Dwivedi, AK and Imbimbo, BP and Abanto, J and Espay, AJ}, title = {Comparison of double-blind and open-label decline rates in lecanemab and donanemab trials in Alzheimer's disease.}, journal = {BMJ neurology open}, volume = {8}, number = {2}, pages = {e001649}, pmid = {42602524}, issn = {2632-6140}, abstract = {BACKGROUND: Phase 3 trials of the anti-amyloid monoclonal antibodies lecanemab and donanemab in Alzheimer's disease demonstrated modest slowing of cognitive decline over 18 months. Subsequent open-label extensions (OLE) suggested greater long-term benefit based on comparisons with historical untreated cohorts, which are vulnerable to selection and attrition bias.

METHODS: We simulated longitudinal Clinical Dementia Rating-Sum of Boxes trajectories using mixed-effects models calibrated to reproduce published means, variances and attrition patterns from the Clarity-AD and TRAILBLAZER-ALZ 2 trials, separately for early- and delayed-start cohorts and in combined analyses. Observed annualised slopes were also directly compared between double-blind (DB) and OLE phases. Placebo effects were estimated by comparing DB placebo arms with matched untreated historical cohorts derived from published natural history data.

RESULTS: Simulations closely reproduced reported trajectories. In both trials, the early-start cohorts showed significantly faster annualised decline during OLE than during DB treatment (lecanemab ∆=0.53; 95% CI 0.40 to 0.66; donanemab ∆=0.66; 95% CI 0.41 to 0.91), whereas delayed-start cohorts showed no meaningful phase-related differences. OLE decline rates approximated those observed in DB placebo groups. In the lecanemab trial, DB placebo participants declined more slowly than matched untreated controls; decline in the donanemab trial varied by baseline severity.

CONCLUSIONS: Despite selective retention favouring slower progressors, both lecanemab and donanemab accelerated cognitive decline during OLE phases and paralleled placebo-level declines.}, } @article {pmid42602880, year = {2026}, author = {Murugadoss, K and Venkatakrishnan, AJ and Soundararajan, V}, title = {GLP-1-based incretin therapy is associated with lower incident Alzheimer's disease and cardiorenal events in adults with documented neuropsychiatric, cognitive, or sensory risk.}, journal = {Biology methods & protocols}, volume = {11}, number = {1}, pages = {bpag043}, pmid = {42602880}, issn = {2396-8923}, abstract = {Alzheimer's disease (AD) develops over years, creating an opportunity for interventions that target modifiable risk factors before the onset of clinical dementia. Here we applied a federated electronic health record (EHR) system encompassing over 29 million de-identified patients toward a target-trial emulation framework involving 153,412 adults aged 50 years or older with at least one documented AD risk factor. New users of glucagon-like peptide-1 (GLP-1)-based incretin therapy were compared with new users of non-GLP-1 antidiabetic medications after a 12-month washout, with 1:1 propensity-score matching on 30 baseline variables and additional exact matching on index year of therapy initiation and 5-year age band. In the primary matched cohort, 28,901 patients per arm, incretin initiation was associated with lower first recorded AD diagnosis (hazard ratio [HR] 0.46, 95% confidence interval [CI] 0.29-0.73, q = 0.003), all-cause dementia (HR 0.66 [0.55-0.79], q < 0.001), and all-cause mortality (HR 0.46 [0.37-0.58], q < 0.001), with directionally-lower Mild Cognitive Impairment (HR 0.76 [0.61-0.94], q = 0.135) and Alzheimer's-related medication initiation (HR 0.82 [0.65-1.03], q = 0.217). The AD diagnosis mitigation signal was independently reproduced for semaglutide (HR 0.56; N = 23,675 per arm; q = 0.02), with the directionally consistent tirzepatide point estimate (HR 0.60) not reaching significance. GLP-1 RA initiation was also associated with substantially lower (all q < 0.001) incidence of heart failure (HR 0.50 [0.45-0.55]), cardiomyopathy (HR 0.38 [0.31-0.47]), major adverse cardiovascular events (HR 0.74 [0.67-0.82]), acute kidney injury (HR 0.67 [0.67-0.74]), and chronic kidney disease (HR 0.68 [0.62-0.75]). Negative-control outcomes showed no significant separation (all q > 0.45), including allergic rhinitis (HR 0.96 [0.87-1.07]), hemorrhoids (HR 1.07 [0.95-1.21]), and inguinal hernia (HR 1.39 [0.89-2.18]). Stricter two-code ICD definitions supported lower first recorded AD diagnosis in the incretin arm (HR 0.51 [0.29-0.89], q = 0.018) and lower first recorded all-cause dementia diagnosis (HR 0.68 [0.54-0.85], q = 0.003). In 12-month landmark analyses among semaglutide initiators, ≥5% weight-loss responders had lower 3-year AD cumulative incidence than non-responders after matching (0.07% vs. 0.40%; incidence ratio 5.76; P = .036), although this was not significant in the hazard-ratio model (HR 0.54, P = .39). Sustained-dose stratification showed no comparable gradient (high-dose vs. low-dose 0.30% vs. 0.14%; HR 2.77; P = .38), with ≤12 AD events per group. The weight-loss-specific pattern did not extend to all-cause dementia: weight-loss responders and non-responders had similar 3-year cumulative incidence (1.54% vs. 1.70%; HR 0.87, P = .53). Initiation of GLP-1 receptor agonist therapy in adults with documented AD risk factors was associated with lower recorded incidence of AD, dementia, mortality, and multiple cardiovascular and renal outcomes in this observational target-trial emulation. These findings support the hypothesis that earlier incretin therapy may contribute to AD risk modification through upstream cardiometabolic pathways, while prospective randomized prevention studies will be required to determine causality, underlying biological mechanisms, and optimal treatment timing.}, } @article {pmid42603243, year = {2026}, author = {Anwer, T and Verma, A and Asiri, A and Alaklobie, M and Albaqami, A and Alshahrani, F and Aly, K and Sharma, M and Siddiqui, S and Alam, N and Alam, MF}, title = {Restoration of Neuronal Metabolism and Memory in Alzheimer's Disease by Reprogramming the Exosomal microRNA Network.}, journal = {Journal of molecular neuroscience : MN}, volume = {76}, number = {3}, pages = {}, pmid = {42603243}, issn = {1559-1166}, mesh = {Humans ; *Alzheimer Disease/metabolism/genetics ; *MicroRNAs/metabolism/genetics ; *Exosomes/metabolism/genetics ; Animals ; *Neurons/metabolism ; Neuronal Plasticity ; *Memory ; }, abstract = {Historically the development of amyloid-β plaques and tau neurofibrillary tangles have been used as the hallmarks of Alzheimer's disease (AD). However, there is increasing evidence suggests that these pathological hallmarks are secondary to deeper metabolic defect in the brain. AD is progressively being recognized as a metabolic synaptic disorder characterized by insulin resistance, impaired cellular energy homeostasis, mitochondrial dysfunction, and synaptic degeneration. Synaptic plasticity is closely linked to the insulin-sensitive system of glucose utilization, mitochondrial activity, and local protein synthesis that render the synapses highly sensitive to the malfunction of the metabolic system. Recent discoveries highlight the important role of exosomes in mediating communication between neural cells by transferring regulatory miRNAs across neuronal networks. Exosomal miRNAs regulate insulin signaling, synaptic gene expression, mitochondrial function, and neuroinflammation. In AD, exosomal miRNA profiles are significantly altered, with enrichment of miR-29, miR-34a, miR-146a, and miR-21, alongside depletion of synapse-supporting miR-132. These changes contribute to insulin resistance, impaired glucose transporter trafficking, dendritic spine destabilization, and reduced expression of synaptic proteins such as PSD-95 and synaptophysin, ultimately leading to cognitive decline. Importantly, neuron-derived exosomes can cross the blood-brain barrier, making their miRNA cargo promising biomarkers and therapeutic targets for early AD diagnosis and precision treatment.}, } @article {pmid42601176, year = {2026}, author = {Koh, H and Choi, S and Sung, JE}, title = {Verb-Semantic Feature Analysis for Alzheimer's Dementia in a verb-final language: evidence from Korean.}, journal = {Neuropsychological rehabilitation}, volume = {}, number = {}, pages = {1-25}, doi = {10.1080/09602011.2026.2715712}, pmid = {42601176}, issn = {1464-0694}, abstract = {This study examined the effects of Verb-Semantic Feature Analysis (Verb-SFA) on verb naming, noun retrieval, sentence comprehension, and discourse production in individuals with Dementia of the Alzheimer's Type (DAT). Given the lexical-semantic degradation characteristic of DAT and the central role of verbs in Korean, a verb-final language, this study evaluated whether Verb-SFA facilitates treatment, near-transfer, and far-transfer effects. Three male participants, aged 60 or older with 16 years of education, completed 17 sessions: pre-treatment (4 sessions), treatment (10 sessions), and post-treatment (3 sessions). Treatment effects were assessed using 45-item probe sets derived from the Korean Item Selection Naming Test. Results showed significant improvement in naming accuracy for treated verbs, with a robust interaction between treatment sessions and treated items. No significant near-transfer effects were found for untreated verbs in the probe set or on the Action Naming Test. However, significant near-transfer effects were observed for noun retrieval on the Korean-Boston Naming Test, although verbal fluency tasks showed no improvement. Far-transfer effects emerged in sentence comprehension, suggesting strengthened verb-semantic processing supports higher-level linguistic abilities. No measurable gains were observed in discourse production. Overall, Verb-SFA treatment enhanced verb naming and sentence comprehension in individuals with DAT.}, } @article {pmid42598237, year = {2026}, author = {Zhang, M and Zhang, Y and Zhang, Z and Jia, X and Lei, S and Bu, N and Wang, Y and Bai, Y and Wang, S}, title = {Effects of mindfulness-based exercise on Parkinson's disease and Alzheimer's disease: a systematic review and meta-analysis.}, journal = {Frontiers in neurology}, volume = {17}, number = {}, pages = {1860499}, pmid = {42598237}, issn = {1664-2295}, mesh = {Humans ; *Parkinson Disease/therapy/psychology ; *Alzheimer Disease/therapy/psychology ; *Mindfulness/methods ; *Exercise Therapy/methods ; Yoga ; Qigong ; Tai Ji ; }, abstract = {OBJECTIVE: Currently, there is a lack of robust evidence demonstrating the efficacy of mindfulness-based exercise (MBE) on motor and cognitive outcomes in individuals with Parkinson's disease (PD) and Alzheimer's disease (AD), resulting in the absence of standardized and effective MBE treatment protocols. This systematic review and meta-analysis summarizes the available evidence to evaluate the therapeutic effects of MBE on motor and cognitive function in PD and AD.

METHODS: For two common neurodegenerative diseases, PD and AD, we searched PubMed, Embase, Cochrane Library, and Web of Science to identify studies published from inception to January 30, 2026. Search terms included neurodegenerative diseases, Parkinson's disease, Alzheimer's disease, mindfulness, Tai Chi, yoga, and Qigong. Two independent reviewers assessed the risk of bias of included studies, performed data extraction, and evaluated the evidence. Treatment effects were assessed using the Unified Parkinson's Disease Rating Scale (UPDRS-III), Timed Up and Go Test (TUG), Berg Balance Scale (BBS), Montreal Cognitive Assessment (MoCA), Mini-Mental State Examination (MMSE), Beck Depression Inventory (BDI), Parkinson's Disease Sleep Scale (PDSS), Activities of Daily Living (ADL), and Parkinson's Disease Questionnaire-39 (PDQ-39). Data analysis was performed using Review Manager 5.4 software to evaluate effect sizes and 95% confidence intervals (CIs). Heterogeneity tests were conducted to assess differences in treatment effects among Tai Chi, yoga, and Qigong.

RESULTS: We screened 4,576 articles and identified 28 studies that met the inclusion criteria. Of the included studies, 23 focused on PD and 5 on AD. Only 7 reported adequate allocation concealment, and 2 implemented participant blinding. GRADE assessment indicated moderate certainty of evidence for UPDRS-III, TUG, BBS, MoCA, and MMSE. BDI, PDSS, ADL, and PDQ-39 were rated as low-quality evidence. The pooled results showed significant effects: UPDRS-III (MD: -4.74, 95% CI [-6.78, -2.70], p < 0.00001); TUG(MD: -1.63, 95% CI [-2.41, -0.85], p < 0.0001); BBS(MD:2.80, 95% CI [1.54, 4.06], p < 0.0001); MoCA (MD: 1.93, 95% CI [1.12, 2.74], p < 0.00001); MMSE (MD: 2.80, 95% CI [0.32, 5.29], p = 0.03); BDI (SMD: -0.18, 95% CI [-0.47, 0.12], p = 0.24); PDSS (SMD: -0.31, 95% CI [-0.91, 0.28], p = 0.30); ADL (MD: -0.59, 95% CI [-3.49, 2.31], p = 0.69); and PDQ-39 (MD: -2.85, 95% CI [-6.36, 0.67], p = 0.11).

CONCLUSION: MBE demonstrated statistically significant improvements in motor function and certain cognitive domains in PD patients, suggesting its potential as a beneficial adjunctive non-pharmacological intervention for ameliorating motor symptoms and delaying cognitive decline, whereas evidence for non-motor symptom improvement remains insufficient. Subgroup analysis further indicated a favorable signal of MBE on cognitive function in AD patients; however, the current evidence is preliminary and warrants validation through additional high-quality studies. Given the inherent challenges in implementing double-blinding due to the nature of MBE interventions, coupled with inadequate allocation concealment, the present findings should be interpreted with caution owing to the substantial risks of performance and selection bias.}, } @article {pmid42598748, year = {2026}, author = {Tonietto, M and Silvestri, E and Belder, CRS and Barkhof, F and Fox, NC and Smith, J and Klein, G}, title = {Volume change with gantenerumab: Impact of amyloid-related imaging abnormalities and amyloid removal.}, journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association}, volume = {22}, number = {8}, pages = {e71749}, pmid = {42598748}, issn = {1552-5279}, support = {//F. Hoffmann-La Roche/ ; }, mesh = {Humans ; *Antibodies, Monoclonal, Humanized/therapeutic use ; *Alzheimer Disease/drug therapy/diagnostic imaging/pathology ; *Amyloid beta-Peptides/metabolism ; *Brain/diagnostic imaging/pathology/drug effects ; Female ; Male ; Magnetic Resonance Imaging ; *Amyloid/metabolism ; White Matter/pathology/diagnostic imaging ; }, abstract = {INTRODUCTION: Amyloid-lowering antibodies are associated with neuroanatomical volume changes. This study aims to disentangle the contributions of amyloid-related imaging abnormalities (ARIA) and amyloid clearance to these changes.

METHODS: Data from the GRADUATE I and II trials of gantenerumab in early Alzheimer's disease were analyzed. Participants were grouped as placebo, gantenerumab-treated without ARIA, or gantenerumab-treated with ARIA.

RESULTS: Gantenerumab treatment was associated with greater parenchymal volume reduction than placebo, with no difference between ARIA and non-ARIA groups. The ARIA group exhibited greater ventricular enlargement which was offset by reduced external cerebrospinal fluid space expansion. Greater amyloid removal correlated with greater volume reduction, although volume changes also occurred in white matter, where amyloid is minimal. Furthermore, the ARIA group showed a flatter relationship between ventricular expansion and clinical decline.

DISCUSSION: ARIA are not associated with long-term parenchymal reduction; rather, they are linked to a fluid shift from the external space to the ventricles. Amyloid removal correlates with parenchymal changes, but white matter changes suggest additional mechanisms beyond local clearance. Neither phenomenon was associated with worse clinical outcomes.

TRIAL REGISTRATION NUMBER: NCT03444870 and NCT03443973.}, } @article {pmid42600000, year = {2026}, author = {Chae, H and Park, Y and Kim, Y and Yoon, E and Kim, KW and Yoo, S}, title = {Wearable transparent OLED glasses for cognitive stimulation: Enhancing brain connectivity through gamma entrainment.}, journal = {Science advances}, volume = {12}, number = {33}, pages = {eaee5504}, pmid = {42600000}, issn = {2375-2548}, mesh = {Humans ; *Wearable Electronic Devices ; *Cognition/physiology ; *Brain/physiology ; *Gamma Rhythm/physiology ; Cognitive Enhancement ; }, abstract = {Gamma wave entrainment is a promising approach for improving cognitive function, particularly in the early stages of Alzheimer's disease. However, for everyday treatment, a light source system that maintains visibility while delivering effective stimulation is essential for patient comfort and practicality. To address this need, we developed organic light-emitting diode (OLED) glasses with optimized large-area transparent OLEDs for gamma wave entrainment. The optimization involved all layers of the device, including encapsulation, to achieve high luminous transmittance (75%), uniformity (over 90%), and electrical performance, ensuring suitability for wearable applications. Under real-world conditions (see-through visibility and ambient light present), the transparent OLED glasses successfully induced gamma rhythm entrainment, enhancing brain connectivity between the occipital and frontal regions. They also notably reduced visual discomfort and showed a trend of enhanced connectivity compared to nontransparent OLEDs. These results highlight the potential of this noninvasive wearable technology for early cognitive intervention, providing comfortable therapeutic light stimulation.}, } @article {pmid42600466, year = {2026}, author = {Kumar, N and Khan, I and Singh, J and Kumar, K and Kushwaha, VK and Ojha, S and Raman, SK and Shankar, G}, title = {Recent developments in donepezil-based hybrid molecules as multi-target therapeutics for Alzheimer's disease: A paradigm shift beyond symptomatic treatment.}, journal = {Bioorganic chemistry}, volume = {181}, number = {}, pages = {110361}, doi = {10.1016/j.bioorg.2026.110361}, pmid = {42600466}, issn = {1090-2120}, abstract = {Alzheimer's disease (AD) is a progressive age-related neurodegenerative disorder characterized by the gradual loss of cholinergic neurons, leading to cognitive impairment, synaptic dysfunction, and irreversible neuronal degeneration. The multifactorial nature of AD, involving cholinergic deficits, amyloid-β (Aβ) aggregation, tau hyperphosphorylation, oxidative stress, mitochondrial dysfunction, neuroinflammation, and metal dyshomeostasis, has limited the clinical success of single-target therapeutic strategies. Although donepezil (DPZ), a clinically approved acetylcholinesterase (AChE) inhibitor, remains one of the most widely prescribed agents for symptomatic management, it does not alter the underlying neurodegenerative processes. Consequently, DPZ has emerged as an attractive medicinal chemistry scaffold for the development of multi-target-directed ligands (MTDLs) that simultaneously modulate multiple interconnected pathological pathways implicated in AD. This review provides a comprehensive and critically organized overview of recent advances in DPZ-based hybrid molecules, emphasizing rational design strategies, hybridization approaches, structure-activity relationships (SAR), molecular mechanisms, and pharmacological profiles. To facilitate a mechanistic understanding, the reported hybrids are systematically classified according to structural modifications of the indanone moiety, the benzylpiperidine moiety, or simultaneous modification of both pharmacophoric regions. Comparative analysis reveals how scaffold engineering, linker optimization, and strategic incorporation of complementary pharmacophores influence cholinesterase inhibition, anti-amyloid activity, antioxidant capacity, neuroprotection, metal chelation, monoamine oxidase inhibition, and blood-brain barrier permeability. Importantly, this review critically examines the current translational landscape, highlighting that despite encouraging in vitro and in vivo findings, no DPZ-based hybrid has yet advanced to clinical evaluation. Key challenges, including pharmacokinetic optimization, metabolic stability, safety, target engagement, and clinical translatability, are discussed together with future medicinal chemistry directions. Rather than presenting DPZ-based hybrids as established disease-modifying therapies, the available evidence supports their role as promising multifunctional lead compounds and valuable molecular platforms for the rational design of next-generation anti-Alzheimer agents. By integrating emerging SAR trends with critical translational perspectives, this review provides a contemporary framework to guide future development of clinically relevant multifunctional therapeutics for AD.}, } @article {pmid42600807, year = {2026}, author = {Fereidouni, A and Nematollahi, S and Mathew, KT and Favennec, V and Liceran, L and Aldenhoff-Kelly, C and Valdivieso, MA and Trent, S and Moradikor, N}, title = {Allosteric modulation of ionotropic and G protein-coupled receptors in Alzheimer's disease: A neuroprotective strategy and therapeutic implications.}, journal = {International journal of biological macromolecules}, volume = {}, number = {}, pages = {154063}, doi = {10.1016/j.ijbiomac.2026.154063}, pmid = {42600807}, issn = {1879-0003}, abstract = {Alzheimer's disease (AD) is the leading cause of dementia and still lacks an effective treatment that can slow or stop disease progression. In addition to amyloid-β and tau pathology, AD involves major disturbances in calcium balance, neurotransmission, and synaptic plasticity. Conventional orthosteric drugs provide limited symptomatic benefit and often interfere with physiological receptor function, underscoring the need for more selective therapeutic strategies. This review explores allosteric modulation of neurotransmitter receptors as a potential neuroprotective strategy in AD, with an emphasis on mechanisms that restore synaptic integrity, regulate calcium homeostasis, and engage disease-relevant intracellular signaling pathways. The review synthesizes preclinical and clinical evidence on allosteric modulators targeting key ionotropic receptors, including NMDA, AMPA, GABA-A, nicotinic acetylcholine, and P2X7 receptors, and G protein-coupled receptors (GPCRs) such as M1 muscarinic receptors, metabotropic glutamate receptors, and the calcium-sensing receptor. Particular attention is given to receptor selectivity, signaling bias, and translational relevance. Allosteric modulation of ionotropic receptors can influence excitability and synaptic plasticity and may preserve endogenous neurotransmission, with circuit-stabilizing effects reported mainly in preclinical studies. GPCR-directed allosteric modulators can affect AD-related processes, including amyloid- and tau-associated toxicity, excitotoxicity, and neuroinflammation, although evidence for these effects is largely preclinical and clinical translation remains challenging. Convergent pathways, such as Ca[2+]-dependent signaling, ERK/CREB, PI3K/Akt, and cAMP/PKA, may represent shared mediators of disease-relevant effects. Allosteric modulation may offer a more refined, receptor-specific framework for therapeutic investigation in AD. Ionotropic and GPCR-targeted agents may each produce symptomatic or preclinical disease-relevant effects, but their capacity to slow disease progression in patients remains unproven and will require current pharmacological and translational challenges to be addressed.}, } @article {pmid42600874, year = {2026}, author = {Xiao, J and Lan, Z and Zhang, R and Zhang, J and Hu, Z and Jia, B and Tang, H and Xu, T and Bao, X and Xu, Y and Yu, L and Ji, SL and Zhu, X}, title = {Novel natural inhibitor Rubimaillin targets NLRP3 R167/Y381 to ameliorate inflammatory and neurodegenerative diseases.}, journal = {Journal of ethnopharmacology}, volume = {}, number = {}, pages = {122293}, doi = {10.1016/j.jep.2026.122293}, pmid = {42600874}, issn = {1872-7573}, abstract = {Rubia cordifolia L. is traditionally used in Chinese medicine for treating arthritic and inflammatory conditions by cooling blood and activating circulation. Gouty arthritis, one of the disease models investigated in this study, falls within this traditional anti-arthritic application. This study investigates whether rubimaillin (Rub), a naphthoquinone from Rubia cordifolia, selectively inhibits NLRP3 inflammasome activation and exerts therapeutic effects in relevant disease models. The NLR family pyrin domain-containing 3 (NLRP3) inflammasome is a key driver of various inflammatory, metabolic, and neurodegenerative disorders; yet, no clinically approved inhibitor is currently available. Rubia cordifolia L. is a traditional medicinal herb, and Rubimaillin (Rub), a naphthoquinone isolated from this herb, has potential anti-inflammatory properties, but its role and mechanism in regulating NLRP3 activation remain unclear.

AIM OF STUDY: This study aimed to determine whether Rubimaillin (Rub), a naphthoquinone isolated from Rubia cordifolia L., can selectively inhibit NLRP3 inflammasome activation and yield therapeutic effects in relevant NLRP3-driven disease models.

MATERIALS AND METHODS: Mouse primary microglia, bone marrow-derived macrophages (BMDMs), and the human macrophage cell line THP-1 were primed with lipopolysaccharide (LPS) for 3 h, then stimulated with Nigericin or ATP to induce NLRP3 inflammasome assembly and pyroptosis. Caspase-1 activation, apoptosis-associated speck-like protein containing a CARD (ASC) speck formation, interleukin-1β (IL-1β) release, and lactate dehydrogenase (LDH) secretion were quantified. Mutagenesis studies were conducted to identify critical residues required for Rub's binding to NLRP3. The in vivo therapeutic potential of Rub was assessed in three murine models of NLRP3-driven inflammation: LPS-induced sepsis, monosodium urate crystal (MSU)-induced gouty arthritis, and the APP/PS1 double-transgenic Alzheimer's disease (AD) mouse model. Mice received intraperitoneal Rub or vehicle, and disease severity was evaluated by histopathology, cytokine profiling, and behavioral tests.

RESULTS: Rub significantly reduced pyroptosis and IL-1β release in mouse primary microglia, BMDMs, and THP-1 cells in a dose-dependent manner, without affecting Absent in melanoma 2(AIM2) or NLR family CARD domain containing 4 (NLRC4) pathways. Mechanistically, Rub directly bound to NLRP3, thereby blocking the oligomerization of both NLRP3 and ASC, as well as preventing caspase-1 activation and gasdermin D (GSDMD) cleavage. Furthermore, mutagenesis studies identified arginine 167 and tyrosine 381 as critical residues for Rub's binding to NLRP3. In vivo, Rub treatment significantly prolonged survival and attenuated lung injury in the sepsis model, reduced paw swelling and bone erosion in the gout model, and ameliorated cognitive deficits and neuroinflammation in the AD model, respectively.

CONCLUSION: Collectively, these findings demonstrate that Rub selectively targets the NLRP3 inflammasome and exerts therapeutic effects on NLRP3-driven diseases including sepsis, gout, and AD. This study provides a molecular basis for the traditional application of Rubia cordifolia L. and highlights Rub as a promising natural lead compound for the treatment of NLRP3-driven disorders.}, } @article {pmid42591325, year = {2026}, author = {Shin, J and Suh, SI and Park, YJ and Lee, S and Kang, J and Lee, ES and Jung, HN and Ryoo, I and Lee, S and Eo, JS and Oh, K and Koh, SB and Kang, SH}, title = {Real-world implementation of lecanemab in Korean patients at a tertiary memory clinic: Safety, ARIA risk, and early treatment patterns.}, journal = {Alzheimer's & dementia (Amsterdam, Netherlands)}, volume = {18}, number = {3}, pages = {e70447}, pmid = {42591325}, issn = {2352-8729}, abstract = {INTRODUCTION: Lecanemab has demonstrated clinical efficacy in early Alzheimer's disease (AD), but real-world data remain limited, particularly in Asian populations.

METHODS: We prospectively enrolled 127 patients across the AD continuum who initiated lecanemab at a tertiary memory clinic in Korea. Infusion-related reactions (IRRs), amyloid-related imaging abnormalities (ARIAs), and cognitive outcomes were evaluated through clinical assessments, serial magnetic resonance imaging (MRI), and longitudinal Mini-Mental State Examination (MMSE) follow-up.

RESULTS: Among 127 patients, 102 completed at least five infusions with follow-up MRI. IRRs occurred in 27 (21.3%) patients, primarily during the first infusion. ARIAs occurred in 9 of 102 (8.8%), including ARIAs with edema in 4 (3.9%) and ARIA with hemorrhage in 7 (6.9%); most events were mild or asymptomatic. Higher microbleed burden and white matter hyperintensity were associated with increased ARIA risk. MMSE scores remained stable over 6 months.

DISCUSSION: In this prospective Korean cohort, lecanemab was generally well tolerated. Longer term controlled studies are needed to clarify cognitive outcomes.}, } @article {pmid42593033, year = {2026}, author = {Değirmenci, S and Tırın, H and Arıkan, E and Andiç, K and Sezgin, E}, title = {Red cell distribution width and modified 5-item frailty index to predict short-term mortality in patients undergoing surgery for hip fracture.}, journal = {Ulusal travma ve acil cerrahi dergisi = Turkish journal of trauma & emergency surgery : TJTES}, volume = {32}, number = {8}, pages = {998-1007}, doi = {10.14744/tjtes.2026.20432}, pmid = {42593033}, issn = {1307-7945}, mesh = {Humans ; Female ; *Hip Fractures/surgery/mortality/blood ; Aged, 80 and over ; Male ; *Erythrocyte Indices ; Aged ; *Frailty/mortality ; Intensive Care Units/statistics & numerical data ; Hospital Mortality ; Prognosis ; Turkey ; }, abstract = {BACKGROUND: Hip fractures (HFs), which are common in the geriatric population and have a high mortality rate, are among the pathologies frequently encountered in emergency departments (EDs). The aim of this study was to investigate the prognostic value of red cell distribution width (RDW) and modified 5-item frailty index (mFI-5) scores in the prediction of short-term mortality and intensive care unit (ICU) admission in patients with HFs.

METHODS: Patients who presented to the ED due to HF between January 01, 2019, and December 31, 2023, were evaluated. Patients who underwent surgery for femoral neck, intertrochanteric, or subtrochanteric fractures were included in the study. Baseline demographics (age and sex), comorbidities, ICU admission status, and in-hospital and 30-day mortality rates were recorded. Univariate and multivariable logistic regression analyses were performed to identify independent predictors of ICU admission and 30-day mortality.

RESULTS: A total of 413 patients undergoing surgical treatment for HFs were included. The mean age of the patients was 80±11 years, and 271 (65.6%) were female. ICU admission was required for 43 patients (10%), while in-hospital and 30-day mortality rates were 7% (n=30) and 9.9% (n=41), respectively. Multivariable logistic regression analysis identified RDW as an independent predictor of both ICU admission (odds ratio [OR] 1.22, 95% confidence interval [CI] 1.05-1.41; p=0.009) and 30-day mortality (OR 1.20, 95% CI 1.03-1.39; p=0.016). Atrial fibrillation (AF) and Alzheimer's disease were also identified as independent predictors of ICU admission, while AF and age independently predicted 30-day mortality. The mFI-5 score did not reach statistical significance in univariate analysis for either outcome. A predictive model incorporating RDW and other covariates achieved area under the curve values of 0.74 for ICU admission and 0.70 for 30-day mortality.

CONCLUSION: RDW emerged as an independent predictor of ICU admission and 30-day mortality in surgically managed HF patients, with improved discriminatory performance when integrated into a multiparametric model. Advanced age, Alzheimer's disease, and AF further contribute to increased risk and should be closely monitored in clinical management. These findings support the incor-poration of RDW into routine emergency risk stratification for this vulnerable population.}, } @article {pmid42593551, year = {2026}, author = {Arriagada, J and Lantadilla, M and Lobos, P and Paz, AA and Herrera, EA and Muñoz, P and Paula-Lima, A}, title = {Metformin Enhances Antioxidant Defenses and Limits Lipid Peroxidation Through the Modulation of Nrf2/KEAP1 Pathway in Hippocampal Neurons Exposed to Amyloid-β Oligomers.}, journal = {Neurotoxicity research}, volume = {44}, number = {4}, pages = {}, pmid = {42593551}, issn = {1476-3524}, support = {Doctorate National Scholarship No. 2123 0993//Agencia Nacional de Investigación y Desarrollo/ ; FONDECYT Regular Grant No. 1241502//Agencia Nacional de Investigación y Desarrollo/ ; FONDECYT Regular Grants No. 1251980//Agencia Nacional de Investigación y Desarrollo/ ; FONDECYT Regular Grant No. 1261188//Agencia Nacional de Investigación y Desarrollo/ ; Universidad de Chile RS0925//Universidad de Chile/ ; Universidad de Chile RS0925//Universidad de Chile/ ; INACH 16-21//Institut chilien de l'Antarctique/ ; }, mesh = {Animals ; *NF-E2-Related Factor 2/metabolism ; *Amyloid beta-Peptides/toxicity ; *Metformin/pharmacology ; *Kelch-Like ECH-Associated Protein 1/metabolism ; *Hippocampus/drug effects/metabolism ; *Neurons/drug effects/metabolism ; *Lipid Peroxidation/drug effects/physiology ; Signal Transduction/drug effects ; *Antioxidants/metabolism/pharmacology ; Cells, Cultured ; Rats ; Peptide Fragments/toxicity ; Oxidative Stress/drug effects ; }, abstract = {Oxidative stress is an early and important feature of Alzheimer's disease (AD) that contributes to synaptic dysfunction and neurodegeneration. Soluble amyloid-β oligomers (AβOs) are major contributors to oxidative damage and have been shown to impair neuronal antioxidant defenses. The Nrf2/KEAP1 pathway is a central regulator of cellular redox homeostasis; however, its activity is compromised in AD, increasing neuronal vulnerability to oxidative stress. Metformin (Met), a widely used antidiabetic drug, has emerged as a potential modulator of antioxidant signaling pathways in the nervous system. In the present study, we investigated whether Met enhances antioxidant defenses in primary fetal rat hippocampal neurons exposed to AβOs. Neuronal cultures were treated with Met (2.5 mM for 24 h) prior to exposure to AβOs (500 nM for 6 h). We evaluated Nrf2 and KEAP1 protein levels, Nrf2 nuclear localization, antioxidant enzyme expression and activity, and lipid peroxidation. Met treatment promoted Nrf2 nuclear accumulation, preserved a favorable Nrf2/KEAP1 profile under amyloid stress, and enhanced the expression and activity of key antioxidant enzymes, including superoxide dismutase (SOD1 and SOD2), catalase (CAT), and glutathione peroxidase (GPx1/2). In addition, Met attenuated AβOs-induced lipid peroxidation, supporting its protective effects against amyloid-associated oxidative damage. Collectively, these findings indicate that Met strengthens neuronal antioxidant defenses and promotes redox resilience under amyloid-associated oxidative stress. Our results support modulation of the Nrf2/KEAP1 pathway as a mechanism contributing to the neuroprotective actions of Met and identify the coordinated enhancement of antioxidant defenses and reduction of lipid peroxidation as key components of neuronal redox resilience against AβOs-induced stress.}, } @article {pmid42594210, year = {2026}, author = {Reardon, S}, title = {Tau can wreak havoc in brain cells' energy factories.}, journal = {Science (New York, N.Y.)}, volume = {393}, number = {6812}, pages = {651}, doi = {10.1126/science.ael4194}, pmid = {42594210}, issn = {1095-9203}, mesh = {*Mitochondria/metabolism ; Humans ; *tau Proteins/metabolism ; *Brain/metabolism/cytology ; *Alzheimer Disease/metabolism/drug therapy ; Animals ; *Energy Metabolism ; *Neurons/metabolism ; }, abstract = {Study of mitochondria suggests new treatment strategy for Alzheimer's and other diseases.}, } @article {pmid42594414, year = {2026}, author = {Dinnerstein, E}, title = {The missing improvers: Tau pathology, neuroplasticity, and the case for tau-informed patient selection before amyloid immunotherapy.}, journal = {The journal of prevention of Alzheimer's disease}, volume = {13}, number = {9}, pages = {100653}, doi = {10.1016/j.tjpad.2026.100653}, pmid = {42594414}, issn = {2426-0266}, abstract = {Amyloid immunotherapy with lecanemab and donanemab has been approved on the basis of statistically significant slowing of cognitive and functional decline in early Alzheimer's disease (1,2). Yet clinicians treating individual patients face the everyday challenge of estimating whether a given patient is declining at the rate that would be expected for them, and whether their trajectory reflects a response to treatment. I argue that this difficulty arises in large part because the field cannot yet routinely stratify patients by tau pathology before treatment, even though tau burden is among the strongest available predictors of both the rate of progression and the magnitude of response to amyloid-targeting therapy. Post-hoc and open-label analyses of the Clarity AD and TRAILBLAZER-ALZ 2 programmes suggest that patients with absent, low, or medium tau burden may constitute a biologically distinct group in whom amyloid clearance is most likely to permit clinical stabilization or measurable functional gain. These observations remain hypotheses, generated largely from subgroup, open-label, and biomarker data rather than from prospective trials designed to test them I propose that tau status should be given strong consideration in patient selection, that tau-guided selection should be evaluated prospectively, and that the access, reimbursement, and standardization barriers to tau positron emission tomography (PET) - together with the promise of scalable plasma tau biomarkers - be addressed deliberately as the field moves toward tau-informed treatment. One tau PET tracer is currently approved by the US Food and Drug Administration, and a regulatory decision on a second is anticipated in 2026.}, } @article {pmid42594906, year = {2026}, author = {Koychev, I and Holman, RR}, title = {Semaglutide treatment fails but might prevent Alzheimer's disease.}, journal = {Lancet (London, England)}, volume = {408}, number = {10555}, pages = {602-603}, doi = {10.1016/S0140-6736(26)01647-8}, pmid = {42594906}, issn = {1474-547X}, } @article {pmid42595220, year = {2026}, author = {Liu, CW and Liu, YM and Li, WJ and Qu, QW and Shan, ZX and Dong, FX and Hou, XQ}, title = {Osthol Ameliorates Alzheimer's Disease-Associated Cognitive Impairment by Targeting the Estrogen-Cholinergic Axis in Age-Stratified Female 3×Tg-AD Mice.}, journal = {Neurochemistry international}, volume = {}, number = {}, pages = {106241}, doi = {10.1016/j.neuint.2026.106241}, pmid = {42595220}, issn = {1872-9754}, abstract = {Alzheimer's disease (AD) represents a devastating neurodegenerative disorder globally. It is clinically characterized by cognitive dysfunction, predominantly learning and memory impairments, and is closely associated with cholinergic system damage. Osthol (OST), a bioactive compound with well-documented neuroprotective properties, has been shown to enhance learning and memory functions. However, the precise molecular mechanisms underlying its therapeutic effects on AD-related cognitive impairment remain unclear. This study elucidates the critical interplay between estrogen-cholinergic system imbalance and AD progression across distinct temporal windows in female AD models. By focusing on this sex-specific regulatory axis, we aimed to address a key gap in understanding AD pathogenesis and OST's targeted efficacy. We employed age-stratified 3×Tg-AD mice as an experimental model and utilized comprehensive behavioral paradigms to assess learning and memory functions. An age-dependent gradient of cognitive impairment, accompanied by varying degrees of neuropathological damage, was observed in 3×Tg AD mice across different age groups. OST significantly improved learning and memory performance in 3×Tg AD mice of all age groups. Western blotting, ELISA, and immunofluorescence staining indicated that OST treatment effectively alleviated damage to the estrogen-cholinergic-NGF axis through multiple synergistic mechanisms: upregulation of Acetylcholine (ACh), Choline acetyltransferase (ChAT), Tyrosine kinase-A (TrkA), and Nerve growth factor (NGF) expression; downregulation of Acetylcholinesterase (AChE) activity; and increased expression of Estradiol (E2), Estrogen receptor-α (ERα), and Estrogen receptor-β (ERβ). In addition, OST improved synaptic plasticity (Postsynaptic density protein-95 (PSD95), Synuclein (SYN), and Brain-derived neurotrophic factor (BDNF)), inhibited neuronal apoptosis (B-cell lymphoma-2 (Bcl-2) and Bcl-2-associated X protein (BAX)), and enhanced neurotransmitter signaling cascades (γ-aminobutyric acid (GABA), Glutamic acid (Glu), Epinephrine (E), and ACh). These findings provide new insights into the mechanisms of AD and support OST as a promising candidate for targeted AD therapy.}, } @article {pmid42596624, year = {2026}, author = {Zhang, Z and Tan, H and Shi, F and Dai, J and Ding, W and Li, J and Wang, Y and Yang, R and Xu, X and Chen, C and Xiao, F and Huang, LA and Liu, X and Liao, R and Yan, L}, title = {A Novel Nogo-A Receptor Antagonist Peptide Impedes Alzheimer's Disease Pathology by Nogo-A/NgR/ROCK Signaling Pathway.}, journal = {CNS neuroscience & therapeutics}, volume = {32}, number = {8}, pages = {e71052}, doi = {10.1002/cns.71052}, pmid = {42596624}, issn = {1755-5949}, support = {82102690//National Natural Science Foundation of China/ ; 2026A1515011575//Basic and Applied Basic Research Foundation of Guangdong Province/ ; 20211128182437730//Guangdong Provincial Medical Science and Technology Research Fund/ ; 2024A03J0902//2024 Joint between City, University (College) and Enterprise/ ; 21626406//Fundamental Research Funds for the Central Universities/ ; 2025-WJHX-31//Horizontal Research from the Guangdong Provincial Health Economics Association/ ; }, mesh = {Animals ; *Alzheimer Disease/pathology/drug therapy/metabolism/genetics ; *Signal Transduction/drug effects/physiology ; *rho-Associated Kinases/metabolism ; Mice, Transgenic ; *Nogo Proteins/metabolism/antagonists & inhibitors ; Mice ; Amyloid beta-Peptides/metabolism ; *Nogo Receptor 1/antagonists & inhibitors/metabolism ; Humans ; Peptide Fragments/metabolism ; Amyloid beta-Protein Precursor/genetics ; Male ; Disease Models, Animal ; tau Proteins/metabolism ; Presenilin-1/genetics ; *Peptides/therapeutic use/pharmacology ; }, abstract = {AIMS: To evaluate the therapeutic effects of NAP2, a novel NgR1 antagonist peptide, on Alzheimer's disease (AD) pathology and to determine whether inhibition of the Nogo-A/NgR1/ROCK signaling axis can ameliorate neurodegenerative alterations in APP/PS1 mice.

METHODS: APP/PS1 transgenic mice received a three-month NAP2 intervention. Cognitive performance was assessed using standard learning and memory tests. Amyloid-β plaque burden, dendritic spine density, tau phosphorylation, and Aβ42 levels were examined by histological and biochemical analyses. Mitochondrial function and downstream ROCK signaling activity were also evaluated.

RESULTS: NAP2 treatment significantly improved cognitive performance in APP/PS1 mice. NAP2 reduced amyloid-β plaque deposition, decreased Aβ42 expression, and increased hippocampal dendritic spine density. Tau hyperphosphorylation was notably attenuated. In addition, NAP2 alleviated Aβ42-induced mitochondrial dysfunction. Mechanistic studies revealed that NAP2 interfered with ROCK signaling downstream of Nogo-A.

CONCLUSION: NAP2 ameliorates multiple AD-related pathological features, an effect accompanied by the inhibition of the Nogo-A/NgR1/ROCK pathway. These findings highlight the therapeutic potential of NAP2 to enhance resilience against Alzheimer's disease pathology.}, } @article {pmid42596762, year = {2026}, author = {Mokdad, AH and Dwyer-Lindgren, L and Murray, CJL}, title = {Chronic Disease and Disability in the United States: Trends, Inequities, and Imperatives for Policy Reform.}, journal = {The Milbank quarterly}, volume = {}, number = {}, pages = {}, doi = {10.1111/1468-0009.70109}, pmid = {42596762}, issn = {1468-0009}, abstract = {UNLABELLED: Policy Points Position Universal, High-Quality Education as a Foundational Public Health Strategy. Long-term health and life expectancy in the United States are shaped more by educational attainment than by any other single factor. Disparities in access to early childhood, K-12, and higher education perpetuate cycles of chronic disease, economic hardship, and shortened lifespan, particularly in marginalized communities. Policymakers must recognize education as a critical public health intervention and commit to providing universal access to high-quality education at every stage of life. This transformation requires shifting the focus from mere per-pupil spending toward the national scaling of high-impact instructional models, such as intensive, high-dosage tutoring and adaptive learning. Leveraging generative AI to provide personalized, real-time instruction tailored to individual student needs is essential to bridge the achievement gap at scale. Furthermore, achieving true educational equity requires decoupling school quality from local property taxes, integrating health literacy and nutrition into curricula, and ensuring higher education remains affordable and accessible for all. Transform the Food and Built Environment to Advance National Metabolic Resilience. The structure of America's food system and built environment directly fuels the escalating burden of obesity, diabetes, and related chronic diseases. Federal and state policies must fundamentally shift agricultural subsidies away from calorie-dense, nutrient-poor commodities toward specialty crops and fresh produce. To ensure these healthy choices are the default for every household, the federal government must finalize and enforce mandatory, interpretive front-of-package warning labels for ultra-processed foods. This shift, designed to move beyond the passive Nutrition Facts panel, will provide at-a-glance transparency and incentivize industrywide reformulation. Furthermore, metabolic health must be integrated into the K-12 experience through mandatory daily high-intensity physical activity to improve cardiorespiratory fitness and cognitive performance and minimally processed school meals. Finally, investments in active transportation infrastructure, including pedestrian greenways and safe routes to school, are essential to encourage movement as a default, closing the "convenience gap" that disproportionately burdens low-income and rural Americans. Normalize Chronic Obesity Management. Acknowledging that no nation has successfully reversed the obesity epidemic through behavioral advice alone, the United States must treat obesity as a chronic biological condition rather than a temporary lifestyle lapse. It is imperative that public and private payers guarantee universal, affordable access to evidence-based treatments, including next-generation pharmacotherapies (such as GLP-1 receptor agonists). These clinical strategies must be coupled with a modernized, real-time health data infrastructure to monitor outcomes and ensure equitable access at the neighborhood level.

CONTEXT: Over the past three decades, mortality from leading causes such as cardiovascular disease and cancer has declined in the United States, but the burden of chronic, disabling conditions, including musculoskeletal disorders, mental and substance use disorders, and obesity, has grown or stagnated, widening the gap between total years lived and years lived in good health. These shifts are accompanied by persistent and widening inequities in longevity by geography, race/ethnicity, and socioeconomic status.

METHODS: This analysis draws on the 2023 Global Burden of Disease Study, which estimates mortality, disability, and risk factor burden for 375 diseases and 88 risk factors nationally and at the state level, combined with findings from the US Health Disparities project. The latter uses small-area estimation to evaluate county-level life expectancy and mortality across five racial/ethnic groups and four educational strata, and the "Ten Americas" framework, which stratifies the population by race/ethnicity, geography, and socioeconomic context.

FINDINGS: In 2023, US life expectancy reached 78.5 years and healthy life expectancy 64.5 years, both still below prepandemic 2019 levels, with a persistent 13-14-year gap between life expectancy and healthy life expectancy. Ischemic heart disease remained the leading cause of death, but drug use disorders rose from the 26th to the leading cause of disability, a 562% increase since 1990, while Alzheimer disease and musculoskeletal disorders also climbed in rank. High systolic blood pressure remained the top mortality risk factor despite a large decline, while high body mass index and high fasting plasma glucose burdens grew substantially. State-level disparities widened, with West Virginia and Mississippi trailing Hawaii by wide and increasing margins. Life expectancy gaps by race/ethnicity, education, and place were large and growing, reaching 20.4 years across the "Ten Americas" by 2021, with county-level life expectancy spanning more than 27 years nationally.

CONCLUSIONS: US health trends reflect a shift from fatal to disabling disease, driven substantially by the obesity/metabolic and substance use epidemics, layered onto deep and widening structural inequities by race/ethnicity, place, and education. Reversing these trends requires a multidimensional policy agenda spanning universal, high-quality education; reform of the food and built environment; normalized clinical management of obesity; expanded, integrated substance use and mental health treatment; and modernized, real-time public health data infrastructure.}, } @article {pmid42597430, year = {2026}, author = {Powell, WJB and Schindler, SE and Jiménez-Mausbach, M and Oh, IY and Hofmann, A and Snider, BJ and Paczynski, M and Ghoshal, N and Payne, PRO and Lai, AM and Hofford, MR and Gupta, A}, title = {Medical comorbidities of patients receiving amyloid-targeting treatments in a memory clinic.}, journal = {Alzheimer's & dementia (Amsterdam, Netherlands)}, volume = {18}, number = {3}, pages = {e70445}, pmid = {42597430}, issn = {2352-8729}, abstract = {INTRODUCTION: Trials of amyloid-targeting treatments (ATTs) for early symptomatic Alzheimer's disease (AD) enrolled selected patients with minimal medical comorbidities. We investigated whether real-world memory clinic patients who received ATTs also had fewer comorbidities than the broader clinic population.

METHODS: We extracted data on demographics, comorbidities, and medications from patients who were seen at the Washington University Memory Diagnostic Center from July 1, 2023, through July 1, 2025. We compared the characteristics of patients by biomarker testing status and ATT treatment status.

RESULTS: Of 9938 unique patients, 1948 underwent AD biomarker testing and 335 received ATT infusions (304 lecanemab, 31 donanemab). The patients who underwent biomarker testing or received ATTs were more likely to be White individuals and to have fewer comorbidities than patients who did not undergo testing or receive ATTs.

DISCUSSION: Real-world ATT patients were healthier than the general clinic population and more similar to clinical trial participants.}, } @article {pmid42597443, year = {2026}, author = {Tolosa-Tort, P and Okorie, M and Chatterjee, A and Boeriu, AI and Sharma, RU and Andrews, SJ}, title = {Toward personalized medicine in AD/ADRD through genetic-exposome dementia risk assessments.}, journal = {NPJ dementia}, volume = {2}, number = {1}, pages = {70}, pmid = {42597443}, issn = {3005-1940}, abstract = {Genetic-Exposome Dementia Risk Assessments (GEDRA) integrate genomic and environmental risk factors into actionable, patient-centered tools for Alzheimer's disease and related dementias (AD/ADRD). By enabling midlife risk stratification before biomarker or cognitive changes, GEDRA supports personalized medicine through targeted screening, tailored interventions, treatment guidance, and proactive planning. Strategic investment in GEDRA will advance responsible risk communication and translate precision prevention strategies into equitable, clinically meaningful practice.}, } @article {pmid42597745, year = {2026}, author = {Martínez-Molina, N and Orte, S and Migliorelli, C and Ribas, V}, title = {Toward precision neuroscience in Alzheimer's disease: the role of multimodal AI.}, journal = {Frontiers in aging neuroscience}, volume = {18}, number = {}, pages = {1903637}, pmid = {42597745}, issn = {1663-4365}, abstract = {BACKGROUND: Alzheimer's disease (AD) is increasingly understood as a biologically defined and heterogeneous continuum, requiring models that move beyond symptom-based diagnosis toward individualized risk prediction, stratification, and intervention.

OBJECTIVE: This mini-review outlines how precision neuroscience frameworks may support the characterization of AD by integrating multimodal biomarkers, systems biology, systems neurophysiology, digital health markers, and artificial intelligence (AI).

METHODS: We synthesize recent developments across multi-omics profiling, neuroimaging and electrophysiological biomarkers, AI-based speech analysis, and multimodal machine learning approaches, with emphasis on their potential contribution to biologically informed disease staging and personalized clinical decision-making.

RESULTS: Omics and systems biology approaches are expanding the characterization of molecular pathways involved in AD susceptibility, progression, and treatment response. Systems neurophysiology, including multimodal neuroimaging, electrophysiology, and whole-brain modeling, provides complementary markers of large-scale network disruption across the AD continuum. Digital health technologies, particularly AI-based speech analysis, offer scalable and ecologically valid tools for early risk enrichment and longitudinal monitoring. Multimodal AI models further enable the integration of heterogeneous clinical, molecular, imaging, genetic, and behavioral data into probabilistic representations of disease burden and progression. However, clinical translation remains constrained by interpretability, harmonization, validation, fairness, and accessibility challenges.

CONCLUSION: Precision neuroscience offers a promising framework for reconceptualizing AD as a dynamically modeled and biologically stratified disorder. Future progress will depend on robust multimodal datasets, transparent AI methods, longitudinal validation, and equitable implementation strategies capable of supporting early detection, trial enrichment, and personalized prevention or treatment.}, } @article {pmid42583026, year = {2026}, author = {Erdal, M and Arı, A and Emekli, AS and Yılmaz, NÇ and Kürtüncü, M}, title = {Clinical Use of Interleukin-6 Blockade in Neuroimmunological Disorders.}, journal = {Noro psikiyatri arsivi}, volume = {63}, number = {}, pages = {482-494}, pmid = {42583026}, issn = {1300-0667}, abstract = {Interleukin-6 (IL-6) is a multifunctional cytokine that plays a critical role in immune regulation, host defense, and tissue repair. Within the central nervous system (CNS), IL-6 contributes to both neuroprotection and neuroinflammation, depending on the signaling pathway involved; classic signaling, trans-signaling, or trans-presentation. Dysregulation of IL-6, particularly through sustained overexpression, disrupts the blood-brain barrier (BBB) integrity, promotes glial activation, and amplifies chronic inflammation, thereby contributing to the pathophysiology of numerous neurological disorders. This review aims to evaluate the role of IL-6 in neuroinflammatory processes and its clinical implications across a spectrum of neurological diseases. It focuses on the therapeutic potential and safety profile of IL-6 inhibitors, particularly tocilizumab and satralizumab. Key conditions discussed include neuromyelitis optica spectrum disorder (NMOSD), myelin oligodendrocyte glycoprotein-associated disease (MOGAD), autoimmune encephalitis (AE), neuro-Behçet's disease (NBD), myasthenia gravis (MG), epilepsy, multiple sclerosis (MS), and Alzheimer's disease (AD). Clinical trials have demonstrated the efficacy of IL-6 receptor blockade in reducing relapse rates in NMOSD, leading to regulatory approvals. Promising off-label results have also been reported in treatment-resistant cases of MOGAD, epilepsy, and autoimmune conditions. However, IL-6 inhibition carries risks such as serious infections and paradoxical inflammatory reactions. Targeting the IL-6 pathway represents a significant advancement in neuroimmunology, offering new therapeutic opportunities for otherwise refractory conditions. Future research should focus on large-scale randomized controlled trials and the development of IL-6 inhibitors capable of crossing the BBB to enhance CNS-specific efficacy. Cost-related accessibility also remains a major challenge for broader clinical application.}, } @article {pmid42583837, year = {2026}, author = {Zhu, N and Xu, H and Garcia-Ptacek, S and Mitra, S and Eriksdotter, M}, title = {Oral anticoagulants, cognition, and clinical outcomes in atrial fibrillation and Alzheimer's disease: a Swedish nationwide study.}, journal = {European heart journal}, volume = {}, number = {}, pages = {}, doi = {10.1093/eurheartj/ehag584}, pmid = {42583837}, issn = {1522-9645}, support = {FoUI-1002840//Center for Innovative Medicine/ ; AF-1032116//Swedish Alzheimer's Foundation/ ; M24-0221//Åke Wiberg Foundation/ ; 2022-01428//Swedish Research Council/ ; 2022-01425//Swedish Research Council/ ; 2024-03599//Swedish Research Council/ ; M-2024-2526//Petrus and Augusta Hedlund Foundation/ ; 2024-1370//Magnus Bergvall Foundation/ ; //Swedish Kidney Foundation/ ; //Karolinska Institutet internal funds/ ; //Karolinska Institutet/ ; //Emil and Wera Cornell Foundation/ ; //Swedish Dementia Foundation/ ; //Stockholm County Council and Karolinska Institutet/ ; //New Innovative Roads Call/ ; //Leif Lundblad/ ; //Loo and Hans Osterman Foundation/ ; //Gun and Bertil Stohne Foundation/ ; //Swedish Dementia Foundation/ ; //Tore Nilson Foundation/ ; //Gamla Tjänarinnor Foundation/ ; //Lindhés Advokatbyrå Foundation/ ; //Mats Paulsson Foundation/ ; FO2024-0339//Swedish Brain Foundation/ ; 2021-02680//PREDEM/ ; }, abstract = {BACKGROUND AND AIMS: Use of non-vitamin K oral anticoagulants (NOACs) is associated with reduced dementia risk in patients with atrial fibrillation (AF), but their impact on cognitive function and clinical outcomes in AF patients with Alzheimer's disease (AD) remains unclear.

METHODS: Based on the Swedish Registry for Cognitive/Dementia Disorders, individuals with incident AD during May 2007-December 2020 and pre-existing AF were identified. Anticoagulant use at baseline was categorized as non-use, warfarin, or NOACs. Inverse probability of treatment weighting was employed to balance covariates. Mixed-effects models were used to assess the association between anticoagulant use and cognitive decline measured by the Mini-Mental State Examination (MMSE). Cox proportional hazards models were used to examine risks of all-cause mortality, ischaemic stroke/systemic embolism, major bleeding, and fracture.

RESULTS: Among 7308 eligible individuals (3341 non-users, 2277 warfarin users, and 1690 NOAC users), NOAC users exhibited significantly slower cognitive decline compared to non-users (difference in MMSE scores β = 0.23 points/year, 95% confidence interval [CI] 0.11-0.36) and warfarin users (β = 0.21 points/year, 95% CI 0.10-0.33). Compared to non-use of anticoagulants, NOAC use was associated with significantly lower rates of mortality (hazard ratio [HR] 0.81; 95% CI 0.72-0.91), ischaemic stroke/systemic embolism (HR 0.66; 95% CI 0.53-0.82), and fracture (HR 0.79; 95% CI 0.64-0.97), without an increased rate of major bleeding (HR 1.05; 95% CI 0.84-1.32); in contrast, warfarin use was associated with significantly lower rates of mortality (HR 0.88; 95% CI 0.80-0.97) and ischaemic stroke/systemic embolism (HR 0.85; 95% CI 0.72-1.00), but a higher rate of major bleeding (HR 1.31; 95% CI 1.09-1.56). Compared to warfarin, NOAC use was associated with lower rates of ischaemic stroke/systemic embolism (HR 0.78; 95% CI 0.62-0.98) and major bleeding (HR 0.80; 95% CI 0.64-1.01), and non-significant reductions in mortality and fracture.

CONCLUSIONS: In patients with AF and AD, NOAC use was associated with modestly slower cognitive decline and more favourable effectiveness and safety profiles, compared to warfarin or no anticoagulation.}, } @article {pmid42584743, year = {2026}, author = {Wani, OH and Dhaka, P and Pinky, and Choudhary, SS and Wani, AA and Iqbal, A and Parvez, S and Dar, TA}, title = {Majoon-e-Boolis as a neurotherapeutic agent: cognitive and neuronal restoration in alzheimer's disease model.}, journal = {Metabolic brain disease}, volume = {41}, number = {1}, pages = {}, pmid = {42584743}, issn = {1573-7365}, support = {3-67/2022-CCRUM/Tech//Central Council for Research in Unani Medicine/ ; }, mesh = {Animals ; *Alzheimer Disease/drug therapy/metabolism/chemically induced ; Rats ; Oxidative Stress/drug effects ; Male ; Disease Models, Animal ; *Neuroprotective Agents/pharmacology/therapeutic use ; Amyloid beta-Peptides ; *Cognition/drug effects ; *Neurons/drug effects/metabolism ; Antioxidants/pharmacology/therapeutic use ; Peptide Fragments ; Rats, Wistar ; }, abstract = {Majoon-e-Boolis (MB), a traditional Unani formulation, has been used for neurological conditions; however, its molecular mechanism remains largely unexplored. The current study was designed to explore the novel mechanistic insights between antioxidant activity, anti-inflammatory effects, dopaminergic support and anti-aggregation properties of the formulation for modulating the pathogenesis of Alzheimer's Disease (AD). Behavioral deficits were studied via Novel Object Recognition, Elevated Plus Maze and Open Field Test. In addition, the study looked at the immunohistochemistry of superoxide dismutase 2, tumor necrosis factor-alpha, tyrosine hydroxylase and α-synuclein (α-Syn) against Aβ1-42-induced AD model. Additionally, histopathological alterations were also performed against the AD model. The observed findings demonstrated that MB treatment in Aβ1-42-induced AD in rat models significantly improved their cognitive impairments and alleviated anti-anxiety behaviour with enhanced locomotor activity. Moreover, MB induced significant reduction in oxidative stress and neuroinflammation with enhanced dopaminergic neuronal activity. GC-MS analysis of MB revealed the presence of bioactive phytochemicals such as thiophene, guanidinopropionic acid, 5-hydroxymethylfurfural etc. The findings underscore the potential of MB as a promising therapeutic agent in mitigating the multifaceted pathology of Aβ1-42-induced AD in a rat model by exerting its neuroprotective effects, cognition restoration and overall maintenance of neuronal architecture through a combination of antioxidant, anti-inflammatory and anti-aggregation mechanisms, making it a multifaceted therapeutic candidate for AD.}, } @article {pmid42585344, year = {2026}, author = {Yuan, R and Liao, G and Su, S and Shan, J and Tang, S}, title = {Identification of B-cell senescence-related key genes and mechanisms in Alzheimer's disease through transcriptomic sequencing combined with Mendelian randomization analysis and experimental verification.}, journal = {Journal of Alzheimer's disease : JAD}, volume = {}, number = {}, pages = {13872877261477008}, doi = {10.1177/13872877261477008}, pmid = {42585344}, issn = {1875-8908}, abstract = {BackgroundAlzheimer's disease (AD) is a progressive neurodegenerative disorder and the leading cause of dementia. Currently, no treatment method can treat AD completely successfully.ObjectiveThis work seeks to uncover new genetic signatures linking B-cell senescence to AD, elucidate the immune-related pathological mechanisms of AD.MethodsThe GSE85426 and GSE168813 for AD were obtained from public databases. Differential analysis of expression matrix in GSE85426 was conducted to screen differentially expressed genes (DEGs), WGCNA was explored to obtain B cell and cell senescence related hub genes. Then the key genes for AD were screened by intersection, Mendelian randomization (MR), receiver operating characteristic (ROC) curve, and Wilcoxon test. Additionally, enrichment analysis, immune infiltration analysis, and molecular docking were performed to investigate the molecular mechanism of key genes and drug targets related to key genes, respectively.ResultsIn this study, CCDC86 and PARP9 were identified as key genes, genetic association analysis suggested CCDC86 correlates with higher AD susceptibility while PARP9 tends to correlate with lowered AD risk. We also found that these two key genes were highly correlated with B cells, and the abundance of B cells in AD increased significantly. Finally, our calculation revealed that the binding free energy between PARP9 and bisphenol A was -7.6 kcal/mol, implying a favorable simulated binding tendency between the two molecules.ConclusionsThese findings suggest that PARP9 may serve as a promising and reliable drug target for clinical therapy, which may represent a tentative candidate worthy of further experimental validation for subsequent biomarker and therapeutic target research in AD.}, } @article {pmid42585804, year = {2026}, author = {Sun, J and Yu, M and Li, H and Ma, L}, title = {Edaravone dexborneol alleviates neuronal senescence injury by mitigating the innate immune response.}, journal = {Tissue & cell}, volume = {104}, number = {Pt 1}, pages = {103821}, doi = {10.1016/j.tice.2026.103821}, pmid = {42585804}, issn = {1532-3072}, abstract = {Aging is a key risk factor for neurodegenerative diseases, contributing to progressive neuronal damage and closely linked to the onset and progression of conditions like Alzheimer's and Parkinson's diseases. However, the effect of edaravone dexborneol (EDB) on neuronal senescence remains unclear, which is an urgent scientific question to be addressed. In this study, we established models of neuronal senescence induced by oxidative stress and OGD/R. EDB treatment partially restored the proliferation inhibition of senescent cells. EDB treatment significantly decreased senescence markers, as indicated by reduced senescence-associated β-galactosidase staining and lower p16 and p21 protein expression. Subsequent research demonstrated that EDB improved mitochondrial membrane potential and replenished intracellular ATP levels. In the OGD/R-induced neuronal injury model, EDB treatment notably decreased the expression of senescence markers (p16/p21/p53). Mechanistic studies revealed that EDB not only alleviated oxidative stress but also inhibited the cGAS-STING-mediated innate immune signaling pathway. This study is the first to demonstrate that EDB mitigates mitochondrial damage to exert anti-neuronal senescence effects, offering a novel intervention strategy for aging-related neurodegenerative diseases.}, } @article {pmid42585890, year = {2026}, author = {Şenol, H and Demir, Y and Tokalı, P and Şenol, AM and Akyıldırım, O and Tokalı, FS}, title = {Development of novel diaryl ether-phenolic Mannich Base derivatives with potent cholinesterase inhibition and low neuronal toxicity.}, journal = {Bioorganic chemistry}, volume = {181}, number = {}, pages = {110354}, doi = {10.1016/j.bioorg.2026.110354}, pmid = {42585890}, issn = {1090-2120}, abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by cholinergic dysfunction, making acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) attractive therapeutic targets. In the present study, twelve novel phenolic Mannich base-derived hydrazones incorporating a diaryl ether scaffold were rationally designed, synthesized, and evaluated as cholinesterase inhibitors. All synthesized compounds exhibited potent nanomolar inhibition against both cholinesterases, with Ki values ranging from 24.27 to 98.56 nM for AChE and 28.68-148.41 nM for BChE. Compound 5 was identified as the most potent AChE inhibitor (Ki = 24.27 nM), whereas compound 6 showed the highest BChE inhibitory activity (Ki = 28.68 nM). Both compounds were considerably more potent than the reference inhibitors tacrine and donepezil. Enzyme kinetic studies revealed that all compounds acted as competitive inhibitors. Cytotoxicity evaluation against SH-SY5Y neuronal cells demonstrated low toxicity, with IC50 values ranging from 33.41 to 46.79 μM, indicating that effective cholinesterase inhibition occurred at concentrations far below those affecting neuronal cell viability. Molecular docking and MD simulations demonstrated stable binding of the most active compounds within the catalytic gorge of both enzymes through persistent hydrogen bonds, cation-π, and π-π interactions with key active-site residues. MM-GBSA and energy decomposition analyses further supported their favorable binding affinities. In addition, the synthesized compounds exhibited acceptable predicted pharmacokinetic properties, including favorable parameters related to blood-brain barrier permeability and oral absorption. These results identify phenolic Mannich base-derived hydrazones as promising lead compounds for the development of new cholinesterase inhibitors for the treatment of Alzheimer's disease.}, } @article {pmid42586290, year = {2026}, author = {Zhang, C and Cheng, C and Wang, L and Zhang, H and Yu, Y and Zhang, J and Zhang, J}, title = {Bibliometric analysis in the field of photobiomodulation in the last two decades: research trends and evolution of hot topics.}, journal = {Photodiagnosis and photodynamic therapy}, volume = {}, number = {}, pages = {105610}, doi = {10.1016/j.pdpdt.2026.105610}, pmid = {42586290}, issn = {1873-1597}, abstract = {BACKGROUND: Photobiomodulation (PBM) has evolved into a vibrant interdisciplinary field. Despite rapid research expansion, a comprehensive quantitative mapping of its knowledge structure, key contributors, and emerging trends remains lacking.

METHODS: We conducted a bibliometric analysis of PBM publications from the Web of Science Core Collection (2006-2025). Knowledge mapping utilized CiteSpace, VOSviewer, and the bibliometrix R package. Additionally, PubMed clinical trial data were extracted to cross-validate bibliometric trends with actual clinical practice.

RESULTS: We identified 4,907 publications, exhibiting a compound annual growth rate of 14.67%. Michael R. Hamblin was the most prolific author (n=100, h-index=54), and Lasers in Medical Science was the core journal (n=1,180). Brazil dominated global output (32.2%, n=1,579), led by the University of São Paulo (n=821). Thematic analysis highlighted "photobiomodulation" and "low-level laser therapy" as fundamental themes, while "Alzheimer's disease" emerged as a specialized, rapidly growing niche.

CONCLUSIONS: Over two decades, PBM has matured into a promising mainstream therapeutic modality. Future research must prioritize the standardization of treatment parameters, alongside deeper exploration of biological mechanisms and long-term clinical validation. This 20-year mapping provides a strategic roadmap to guide evidence-based PBM practice.}, } @article {pmid42587009, year = {2026}, author = {Barnett, EJ and Hess, JL and Hou, J and Escott-Price, V and Fennema-Notestine, C and Kremen, W and Lin, SJ and Zhang, C and Demontis, D and Børglum, AD and Gaiteri, C and Elman, J and Holmans, P and Faraone, SV and Glatt, SJ}, title = {A novel method to disentangle tightly linked risk and resilience genes for brain disorders: application to Alzheimer's disease.}, journal = {Molecular psychiatry}, volume = {}, number = {}, pages = {}, pmid = {42587009}, issn = {1476-5578}, abstract = {Genetic risk factors for neuropsychiatric disorders are well documented. However, some individuals with high genetic risk remain unaffected, and the mechanisms underlying such resilience remain poorly understood. The presence of protective resilience factors that mitigate risk could help explain the disconnect between predicted risk and reality, particularly when genetic contributions are substantial but incompletely understood. Identifying and studying resilience factors could improve our understanding of pathology, enhance risk prediction, and inform preventive measures or treatment strategies. However, such efforts are complicated by the difficulty of identifying resilience that is separable from low risk. We developed a novel adversarial multi-task neural network model to detect genetic resilience markers. The model learns to separate high-risk unaffected individuals from affected individuals at similar risk while "unlearning" patterns found in low-risk groups using adversarial learning. In simulated and existing Alzheimer's disease (AD) datasets, we identified markers of resilience with a feature-importance-based approach that prioritized specificity, generated resilience scores, and analyzed associations with polygenic risk scores (PRS). In simulations, our model had high specificity and sensitivity in identifying resilience markers, significantly outperforming traditional approaches. Applied to AD data, the model generated genetic resilience scores protective against AD and independent of PRS. We identified five resilience-associated SNPs, including known AD-associated variants, underscoring their potential involvement in resilience. Our findings support the utility of resilience scores in modifying risk predictions, particularly for high-risk groups. Expanding this method could aid in understanding resilience mechanisms, potentially improving diagnosis, prevention, and treatment strategies for AD and other brain disorders.}, } @article {pmid42588443, year = {2026}, author = {Sun, L and Zhu, X and Fan, C and Wang, Y and Chen, Q and Zhang, L and Zhang, Y and Liu, Y}, title = {Pharmacological Effects and Molecular Mechanisms of Lignans in the Treatment of Alzheimer's Disease.}, journal = {Molecules (Basel, Switzerland)}, volume = {31}, number = {15}, pages = {}, doi = {10.3390/molecules31152594}, pmid = {42588443}, issn = {1420-3049}, support = {82404834//National Natural Science Foundation of China/ ; 2024XJJ-QNCX022, 2024KYYWF-1391//the Youth Science and Technology Innovation Capacity Cultivation Project of Heilongjiang University of Chinese Medicine/ ; CYQN24014//Heilongjiang Chunyan Innovation Team Program/ ; TD2024H002//Heilongjiang Provincial Natural Science Foundation Team Project/ ; LJGXCG2022-096//Heilongjiang Province "Double First-Class" Discipline Collaborative Innovation Achievements Construction Project/ ; }, mesh = {*Lignans/pharmacology/chemistry/therapeutic use ; Humans ; *Alzheimer Disease/drug therapy/metabolism ; Animals ; *Neuroprotective Agents/pharmacology/therapeutic use/chemistry ; Signal Transduction/drug effects ; Oxidative Stress/drug effects ; }, abstract = {Alzheimer's disease (AD) is a complex, multifactorial neurodegenerative disorder whose core pathological hallmarks include Aβ aggregation, tau hyperphosphorylation, chronic neuroinflammation, oxidative stress, mitochondrial dysfunction, and gut microbiota dysbiosis. Lignans, a class of naturally occurring polyphenolic dimers widely distributed in medicinal plants and diet, exhibit multi-target neuroprotective effects with low toxicity. This review provides a systematic synthesis of the anti-AD pharmacological mechanisms underlying nine structurally distinct lignan subtypes-dibenzocyclooctadiene, tetrahydrofuran, bisepoxy, benzofuran, and biphenyl types-emphasizing scaffold-dependent structure-activity relationships. Key mechanistic pathways encompass direct inhibition of Aβ aggregation and tau phosphorylation, activation of the Nrf2 antioxidant signaling axis and PI3K/Akt pro-survival pathways, suppression of NF-κB-mediated neuroinflammation, restoration of cholinergic function, protection of mitochondria via SIRT3, inhibition of ferroptosis through Gsk3β/Nrf2/GPX4 signaling, and modulation of the gut-brain axis via microbiota-mediated conversion to enterolactone. This review addresses key pharmacokinetic limitations such as low oral bioavailability, rapid metabolism, and limited brain exposure, alongside strategies including structural modification, brain-targeted delivery systems, and gut microbiota modulation. Despite promising preclinical evidence, clinical translation remains limited. Future research priorities should focus on direct target validation, network pharmacology, optimized formulations, and well-designed clinical trials to develop lignans into next-generation anti-aging and anti-AD therapeutics.}, } @article {pmid42589213, year = {2026}, author = {Badawy, AAB and Dawood, S and Clanchy, FIL and Williams, RO and Stone, TW}, title = {Docking Analysis of Drugs Used in the Treatment of Alzheimer's Disease, Using Cell Membrane Receptors and Enzymes of the Kynurenine Pathway: A Pilot Study.}, journal = {International journal of molecular sciences}, volume = {27}, number = {15}, pages = {}, doi = {10.3390/ijms27156555}, pmid = {42589213}, issn = {1422-0067}, mesh = {*Alzheimer Disease/drug therapy/metabolism ; *Kynurenine/metabolism ; *Molecular Docking Simulation ; Humans ; Pilot Projects ; Cholinesterase Inhibitors/chemistry/pharmacology ; Indoleamine-Pyrrole 2,3,-Dioxygenase/metabolism/chemistry ; }, abstract = {Molecular docking in silico techniques were used to assess the interactions between several drugs used in the treatment of Alzheimer's disease (AlzD) with neuronal receptors and with tryptophan and glycolytic pathway enzymes. AlzD drugs believed to act by inhibiting acetylcholinesterase (AChE) docked to that enzyme, whereas other drugs did not. No docking was observed to the nicotinic acetylcholine receptor (α-7-nAChR). All the drugs tested docked to the kainic acid receptor for glutamate, whereas donepezil, galantamine, tropisetron and N-acetylcysteine docked to the glutamate-NMDA receptor, but none docked to the glutamate-AMPA receptor. Two compounds docked to GABA receptors. Since the kynurenine pathway of tryptophan metabolism has been linked to AlzD, docking was examined with its various enzymes. Docking to tryptophan-2,3-dioxygenase (TDO2), indoleamine-2,3-dioxygenase-1 (IDO1) and 2-amino-3-carboxymuconic acid-6-semialdehyde decarboxylase was seen with most of the AlzD drugs. Donepezil docked to kynurenine monooxygenase, while rivastigmine, memantine and tropisetron docked to kynurenine aminotransferase-2. There was limited docking to the aryl hydrocarbon receptor and glycolytic enzymes, whereas most drugs docked to phosphoenolpyruvate carboxykinase (PEPCK). Despite their strong docking ability to IDO1 and TDO, none of the compounds tested inhibited their enzyme activity in an assay of kynurenine production. This pilot study highlights the varied pharmacological profile of drugs used in AlzD and suggests that a detailed examination of their functional effects should be considered to assist understanding of their different profiles at on- and off- target sites in human treatment.}, } @article {pmid42589253, year = {2026}, author = {Forbes-Hernández, TY and Quiles-Ramírez, C and Giampieri, F and Godos, J and Grosso, G and Rodríguez-Velasco, CL and Xiao, J and Ding, M and Battino, M and Rivas-García, L and Sánchez-González, C}, title = {Integrative Metabolomic Evidence of Bioactive Food-Derived Compounds Targeting Alzheimer's Disease: A Cross-Study Analysis in Caenorhabditis elegans.}, journal = {International journal of molecular sciences}, volume = {27}, number = {15}, pages = {}, doi = {10.3390/ijms27156591}, pmid = {42589253}, issn = {1422-0067}, support = {PID2019-106778RB-I00//Government of Spain/ ; Visiting Scholars 2022//Universidad de Granada/ ; }, mesh = {Animals ; *Caenorhabditis elegans/metabolism/drug effects ; *Alzheimer Disease/metabolism/drug therapy ; *Metabolomics/methods ; Antioxidants/pharmacology ; Flavonoids/pharmacology ; Oxidative Stress/drug effects ; Neuroprotective Agents/pharmacology ; Amyloid beta-Peptides/metabolism ; *Metabolome ; Cholinesterase Inhibitors/pharmacology ; Disease Models, Animal ; Polyphenols/pharmacology ; }, abstract = {Alzheimer's disease (AD) is a major neurodegenerative condition with limited treatment options. Applications of food-derived products rich in bioactive compounds have emerged as promising strategies, yet comparative evidence across different matrices remains scarce. Here, we present an integrative metabolomic analysis of eleven food extracts previously tested in Caenorhabditis elegans models of AD. By combining chemical fingerprints and functional bioassay data-including oxidative stress resistance, β-amyloid-induced paralysis, and tau-associated locomotion-we employed multivariate statistics to uncover common patterns and correlations. Principal Component Analysis, PLS-DA, and hierarchical clustering revealed distinct groupings of extracts based on metabolite profiles and neuroprotective effects. Polyphenols, flavonoids, and iridoids were consistently associated with beneficial outcomes, while antioxidant capacity and acetylcholinesterase inhibition emerged as key functional traits. Correlation heatmaps highlighted extract-specific strengths, suggesting potential for rational combinations targeting complementary bioactivities. This work underscores the value of integrating metabolomics and functional biology to inform the design of food-based interventions for neurodegenerative diseases, paving the way for evidence-based innovation in brain health.}, } @article {pmid42589276, year = {2026}, author = {Kanagawa, H and Kawahara, A and Mikawa, N and Sugihara, K and Ueda, M and Nitta, A and Egi, M and Oda, R and Nonaka, S and Tozaki-Saitoh, H and Oda, K and Nakanishi, H}, title = {Candidalysin Inhibits Porphyromonas gingivalis Lipoprotein-Induced IL-1β Production in BV-2 Microglia via Hydrophobic Microbial Interactions.}, journal = {International journal of molecular sciences}, volume = {27}, number = {15}, pages = {}, doi = {10.3390/ijms27156614}, pmid = {42589276}, issn = {1422-0067}, support = {JP24K09808 (S.N.) and JP24K09787 (K.O.).//JSPS KAKENHI/ ; }, mesh = {*Interleukin-1beta/metabolism/biosynthesis ; *Microglia/metabolism/drug effects/microbiology ; *Porphyromonas gingivalis/metabolism/pathogenicity ; Hydrophobic and Hydrophilic Interactions ; Animals ; *Lipoproteins/metabolism ; Lipopolysaccharides/pharmacology ; Mice ; NF-kappa B/metabolism ; Cell Line ; }, abstract = {In postmortem Alzheimer's disease (AD) brains, Porphyromonas gingivalis (Pg), a major periodontal pathogen, and Candida albicans, one of the most common fungal pathogens, have been detected. Although it is important to better understand the effects of their co-infection in the brain for elucidating the pathogenesis of AD, little is known about the neuropathological significance of such co-infection. In the present study, we aimed to elucidate the effects of co-exposure to virulence factors derived from Pg and C. albicans on microglial inflammatory responses. We demonstrated, for the first time, that both candidalysin dissolved in dimethyl sulfoxide (CLd) and water (CLw) significantly suppressed Pg lipopolysaccharide (LPS)-induced interleukin-1β (IL-1β) production by 35-60% and nuclear factor-κB (NF-κB) activation by 20-40%. It should be noted that contaminating Pg outer membrane lipoproteins in Pg LPS were mainly responsible for IL-1β production. To examine the possible hydrophobic interactions between lipoproteins contaminating the Pg LPS preparation and CL, we used 8-anilino-1-naphthalenesulfonic acid sodium salt (ANS-Na), which can be excited to emit fluorescence by binding of hydrophobic molecules. The mean fluorescence intensity of ANS-Na was significantly reduced by approximately 26% following co-treatment with CLw and Pg LPS compared with CLw alone. Furthermore, we generated a mutant form of CL with reduced hydrophobicity (GRAVY index: 1.106 vs. 0.874) while preserving its predicted structural properties. This mutant CLd no longer inhibited Pg LPS-induced IL-1β production. Taken together, these findings indicate that hydrophobic interactions between lipoproteins contaminating the Pg LPS preparation and CL mediate the inhibitory effect of CL on Pg LPS-induced inflammatory responses. The present findings suggest that interactions between polymicrobial virulence factors in the brain may modulate microglia-mediated inflammatory responses during AD progression.}, } @article {pmid42589569, year = {2026}, author = {Tan, CL and Zheng, XM and Zhu, YF and Xiong, QQ and Li, H and Meng, XL}, title = {CellSwarm-AD: A Multi-Scale Agent-Based Framework for Virtual Alzheimer's Disease Trials.}, journal = {International journal of molecular sciences}, volume = {27}, number = {15}, pages = {}, doi = {10.3390/ijms27156915}, pmid = {42589569}, issn = {1422-0067}, support = {32400068//National Natural Science Foundation of China/ ; 2025T180738//China Postdoctoral Science Foundation/ ; 2024M750284//China Postdoctoral Science Foundation/ ; }, mesh = {*Alzheimer Disease/drug therapy/metabolism/pathology ; Humans ; Computer Simulation ; Amyloid beta-Peptides/metabolism ; Donepezil/therapeutic use/pharmacokinetics ; Memantine/therapeutic use/pharmacokinetics ; }, abstract = {Computational models of Alzheimer's disease (AD) rarely connect cellular heterogeneity, spatial tissue organization, pathology cascades, and pharmacological intervention within one auditable workflow. We present CellSwarm-AD, a four-layer framework comprising five cell agent classes, a spatial Aβ diffusion environment, an Aβ-Ca[2+]-tau-NF-κB-viability cascade with repository PK/PD models, and an optional experiment orchestration interface. Layer 3 was demonstrated with reproducible prompt templates and deterministic mock outputs; no live large language model was used to generate or modify the quantitative simulation outputs or statistical results. In a prespecified 78-week virtual trial (n = 200 per arm), patient-level repeated measurements were analyzed with Gaussian generalized estimating equations. Week-78 mean (SEM) MMSE-like changes were -1.747 (0.071) for the placebo, -1.368 (0.076) for lecanemab, -1.428 (0.067) for donepezil, and -1.369 (0.065) for independently simulated donepezil plus memantine. The corresponding single-trial Cohen's d values versus the placebo were 0.395, 0.354, and 0.426. Across 20 independent n = 200-per-arm trials, the mean d values were 0.337, 0.359, and 0.326, respectively; replicates were not pooled. Ablation removed most of the treatment contrast when PK/PD was disabled, and fixed-domain grid testing showed decreasing relative L2 error from 6.20% (100 × 100) to 1.49% (200 × 200) against a 400 × 400 reference. These results establish a reproducible proof-of-concept while identifying calibration dependence, weak cross-layer coupling, and the absence of individual-level external validation as current limitations.}, } @article {pmid42590850, year = {2026}, author = {Pascual-Lucas, M and Lacosta, AM and Montañés, M and Canudas, J and Loscos, J and Monleón, I and Allué, JA and Sarasa, L and Fandos, N and Romero, J and Sarasa, M and Torres, M and Whyms, D and Terencio, J and Piñol-Ripoll, G and Boada, M}, title = {Long-term safety and immunogenicity of ABvac40 active immunotherapy in mild cognitive impairment and very mild Alzheimer's disease: Results from AB1601 phase 2 extension study.}, journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association}, volume = {22}, number = {8}, pages = {e71746}, doi = {10.1002/alz.71746}, pmid = {42590850}, issn = {1552-5279}, support = {//Araclon Biotech-Grifols./ ; }, mesh = {Humans ; *Alzheimer Disease/therapy/immunology/drug therapy ; Female ; Male ; Amyloid beta-Peptides/immunology ; Aged ; *Cognitive Dysfunction/therapy/immunology/drug therapy ; *Immunotherapy, Active/methods/adverse effects ; Peptide Fragments/immunology ; Double-Blind Method ; Treatment Outcome ; *Alzheimer Vaccines/therapeutic use/adverse effects ; Aged, 80 and over ; }, abstract = {INTRODUCTION: ABvac40 is an active immunotherapy targeting Aβ40, the main component of cerebrovascular deposition in Alzheimer's disease (AD). A 24-month randomized, placebo-controlled phase 2 study (Part A) showed favorable safety and robust immunogenicity, with exploratory signals of clinical efficacy. Here, we report results from Part B, an 18-month extension evaluating long-term safety and immunological memory.

METHODS: Participants treated with ABvac40 in Part A received placebo plus a delayed booster, whereas previous placebo participants received ABvac40. Exploratory endpoints included safety, tolerability, and immunogenicity.

RESULTS: Seventy-seven participants entered Part B. Treatment-emergent adverse events (TEAEs) occurred in 75.0% of participants in placebo + booster group and 81.1% in ABvac40 group; serious TEAEs were 5.0% and 16.2%, respectively. No ARIA-E or meningoencephalomyelitis were observed, with one ARIA-H event. ABvac40 induced robust antibody responses following delayed booster, with detectable anti-Aβ40 antibodies in CSF.

DISCUSSION: ABvac40 showed favorable long-term safety and durable immunogenicity, supporting further clinical development.

TRIAL REGISTRATION: ClinicalTrials.gov: NCT03461276, registered March 2, 2018. EudraCT: 2016-004352-30, registered March 10, 2017.}, } @article {pmid42577341, year = {2026}, author = {Chattopadhyay, T and Kush, R and Ankarath, RH and Senthilkumar, P and Gleave, EJ and Patterson, C and Owens-Walton, C and Thomopoulos, SI and Johnson, SC and Mormino, EC and Tosun, D and Hohman, TJ and Thompson, PM}, title = {Multi-modal deep learning and explainable AI for predicting multiple dementia-related neuropathologies from brain MRI, clinical, and genetic data.}, journal = {Frontiers in neurology}, volume = {17}, number = {}, pages = {1839071}, pmid = {42577341}, issn = {1664-2295}, abstract = {Alzheimer's disease and related dementias (ADRD) typically involve multiple, overlapping pathologies-such as amyloid-β (Aβ), tau, cerebral amyloid angiopathy (CAA), TDP-43, hippocampal sclerosis, and alpha-synuclein-that complicate diagnosis and treatment. While PET and CSF biomarkers can detect abnormal levels of Aβ and tau, they are invasive, expensive, and not widely available. By contrast, structural magnetic resonance imaging (MRI) offers a non-invasive and scalable alternative, one that is now showing promise for neuropathological prediction when combined with artificial intelligence methods. Prior efforts have largely focused on inferring single pathologies such as abnormal Aβ; however, there is a pressing need for models that can jointly predict multiple co-occurring pathologies. In this work, we develop and evaluate a hybrid deep learning framework that integrates 3D T1-weighted brain MRI with demographic, clinical, and genetic covariates to make inferences, in living individuals, regarding the presence of six ADRD pathologies. The models are trained and tested using autopsy-confirmed neuropathology from individuals who were scanned while they were alive. Based on their strong performance on related tasks, we evaluate two machine learning models: (1) a deep learning algorithm based on a 3D convolutional neural network, a widely used model in computer vision applications, and (2) AutoGluon, an automated machine learning framework that automatically selects an approach for the problem. Each method can use both imaging and non-imaging covariates as inputs. To improve model transparency, we incorporate explainable AI methods-including occlusion sensitivity analysis (OSA), Grad-CAM, and Integrated Gradients (IG)-to interpret the spatial contribution of brain regions to model predictions. Finally, we compare the resulting feature importance maps ('salience maps') with traditional voxel-based morphometry (VBM) analyses to assess their biological plausibility. Our findings show the promise of multimodal, interpretable AI approaches for comprehensive, non-invasive profiling of dementia-related pathologies.}, } @article {pmid42577352, year = {2026}, author = {Lu, LC and Lan, SH and Lan, SJ and Hsieh, YP}, title = {Effectiveness of noninvasive brain stimulation techniques on cognitive function in individuals with Alzheimer's disease and MCI: a systematic review and meta-analysis.}, journal = {Frontiers in aging neuroscience}, volume = {18}, number = {}, pages = {1782521}, pmid = {42577352}, issn = {1663-4365}, abstract = {BACKGROUND: Noninvasive brain stimulation (NIBS) may alleviate cognitive impairments in individuals with Alzheimer's disease (AD). However, clinical findings remain inconsistent, highlighting the need for a systematic review and meta-analysis to clarify the efficacy of NIBS.

OBJECTIVE: To compare the effects of NIBS and sham stimulation on global cognition in individuals with AD.

METHODS: Randomized controlled trials were identified from PubMed, Web of Science, Scopus, and the Cochrane Central Register of Controlled Trials by using relevant search terms. Cognitive outcomes were assessed using objective scales, and pooled standardized mean differences with 95% confidence intervals (CIs) were calculated using a random-effects model.

RESULTS: NIBS was associated with significant improvements in global cognition in individuals with AD, as measured using the Mini-Mental State Examination (MMSE; standardized mean difference = 0.58, 95% CI = 0.32 to 0.84, p < 0.001) and Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog; standardized mean difference = -0.40, 95% CI = -0.68 to -0.13, p = 0.004). The subgroup analysis revealed that treatment is efficacious when patients are stable medication users for 3 months or less (MMSE scores), intervention is delivered for 6 weeks, and NIBS is administered singularly. Longer duration of pharmacological treatment was associated with reduced NIBS efficacy on MMSE scores in both the meta-regression and subgroup analyses. Cognitive gains based on MMSE outcomes were maintained at 4 and 8 weeks after treatment.

CONCLUSION: This meta-analysis provides evidence for the effects of NIBS on common cognitive outcomes in AD and explores potential moderators related to sample and intervention characteristics.

https://www.crd.york.ac.uk/PROSPERO/view/CRD420251065634.}, } @article {pmid42578020, year = {2026}, author = {Riccardi, C and Napolitano, E and Platella, C and Conte, A and Paladino, S and Musumeci, D and Montesarchio, D}, title = {Lipid-conjugated Ru(iii) complexes as inhibitors of pathological peptide aggregation in neurodegenerative disorders.}, journal = {RSC medicinal chemistry}, volume = {}, number = {}, pages = {}, pmid = {42578020}, issn = {2632-8682}, abstract = {Neurodegenerative diseases (NDs), characterized by the progressive loss of neuronal homeostasis and function, represent an increasing global health burden. Their severity and profound impact on quality of life highlight the urgent need for effective and targeted therapeutic strategies. Recent studies have drawn attention to the potential of certain Ru(iii) complexes, including NAMI-A and KP1019, as promising therapeutic candidates for NDs. Originally developed as anticancer agents, these compounds have demonstrated remarkable activity in inhibiting the aggregation of model misfolded proteins, which represent a common pathological feature of various neurological disorders. Herein, searching for Ru(iii) complexes which could be effective as anti-neurodegenerative agents, we selected AziRu - a NAMI-A-like compound - and some of its lipid-conjugated derivatives, previously explored as anticancer drug candidates, and tested them for their ability to interfere with the self-aggregation of selected model peptides involved in the pathogenesis of NDs, such as Alzheimer's disease (AD), Parkinson's disease (PD) and prion diseases. Among them, the Ru(iii) complexes we named MyriPyRu and PalmiPyRu, bearing myristic and palmitic acid-based tails, respectively, emerged as promising candidates. These complexes effectively modulated and inhibited the aggregation of amyloid peptides linked to AD pathogenesis with IC50 values in the low micromolar range (ca. 5 μM for both compounds). More detailed studies on their interaction with AD peptides revealed their capacity to be coordinated by histidine residues in the N-terminal region. Biological investigations on human neuroblastoma-derived cells indicated no relevant cytotoxicity at concentrations comparable to those that caused anti-aggregation effects. Overall, these findings are highly promising, as MyriPyRu or PalmiPyRu could be the starting compounds to evolve further modified derivatives functionalized with specific targeting moieties for amyloid peptides, potentially paving the way to a new generation of Ru(iii)-based anti-amyloid agents for the treatment of Alzheimer's disease.}, } @article {pmid42579351, year = {2026}, author = {Liu, S and Han, D and Bai, T and Chen, H and Li, JP}, title = {Interpreting Divergent Short-Chain Fatty Acid Effects in Alzheimer's Disease: A Seven-Axis Framework.}, journal = {Aging and disease}, volume = {}, number = {}, pages = {}, doi = {10.14336/AD.2026.0777}, pmid = {42579351}, issn = {2152-5250}, abstract = {Studies of short-chain fatty acids (SCFAs) in Alzheimer's disease (AD) report protective, neutral, and adverse findings, but the same class label often conceals non-equivalent exposures and endpoints. We propose an AD-specific interpretive framework that organizes this heterogeneity as a causal sequence: source or intervention → SCFA species, dose, and route → absorption and metabolic filtering → target-compartment exposure → host and disease state → responding cell type → endpoint. Seven interdependent axes-SCFA species, dose, route, compartment, exposure context, disease stage, and responding cell type-identify the coordinates needed to compare studies. This organization separates administered dose from achieved exposure, direct entry into the central nervous system from blood-brain barrier or peripheral gut-brain signaling, and stage-related disease biology from evidence of stage-specific treatment efficacy. It also requires symmetric interpretation of null findings according to exposure verification, target engagement, power, cellular resolution, and endpoint specificity. The framework integrates rather than replaces established microbiome, pharmacological, and neuroimmune principles and has not been validated as a predictor of effect direction. Its explanatory value can be tested by prespecified meta-regression, variance partitioning, interaction analysis, matched-exposure replication, and causal mediation. Persistent opposite effects under matched coordinates would indicate missing dimensions or failure of the framework. This Perspective therefore supports mechanism-linked, biomarker-informed research rather than nonspecific SCFA supplementation in unselected patients.}, } @article {pmid42579441, year = {2026}, author = {Sun, F and Liu, Y and Zhou, Q and Hu, Q and Wang, W and Xiao, Y and Su, J and Liu, G and Sun, M and Chen, L and Li, H and Yang, Y and Wang, JZ}, title = {A Small-Molecule DEPTAC Rescues Cognitive Deficits by Targeted Dephosphorylation of Pathological Tau.}, journal = {Advanced science (Weinheim, Baden-Wurttemberg, Germany)}, volume = {}, number = {}, pages = {e77088}, pmid = {42579441}, issn = {2198-3844}, support = {82571635//National Natural Science Foundation of China/ ; 82230041//National Natural Science Foundation of China/ ; 82371436//National Natural Science Foundation of China/ ; YCJJ20252412//Fundamental Research Funds for the Central Universities/ ; 241111310400//Key R&D Program of Henan Province/ ; }, abstract = {Accumulation of hyperphosphorylated Tau (p-Tau) is a central driver of neurodegeneration in Alzheimer's disease (AD). Addressing the limitations of current therapeutics, we developed TP2, a small-molecule DEPhosphorylation-TArgeting Chimera (DEPTAC). TP2 is engineered to physically tether endogenous PP2A to Tau, facilitating targeted dephosphorylation. Mechanistically, TP2 induces ternary complex formation and potently reduces p-Tau in neurons. Systemic administration of TP2 in distinct tauopathy mouse models (P301L and AAV-hTau-N368) significantly lowered brain p-Tau levels, oligomers, and neurofibrillary tangles without altering global PP2A activity. Crucially, by rebalancing the phosphorylation of Tau, TP2 restored Tau's physiological function, as evidenced by the preservation of neuronal morphology, synaptic integrity, and microtubule stability. TP2 also ameliorated the dysregulated neuroimmune microenvironment. Consequently, TP2 treatment robustly reversed cognitive deficits in multiple behavioral paradigms. These findings establish TP2 as a promising therapeutic candidate that targets upstream pathological phosphorylation to halt neurodegeneration and restore cognitive function.}, } @article {pmid42580389, year = {2026}, author = {Bu, J and Nie, X and Luo, H and Wang, J and Jiang, D and Xu, N and Zhuang, P and Zhang, Y and Yin, Q}, title = {Neuron-Derived Neuroinflammation in Neurodegenerative Diseases: Mechanisms and Intervention Prospects.}, journal = {Pharmacological research}, volume = {}, number = {}, pages = {108383}, doi = {10.1016/j.phrs.2026.108383}, pmid = {42580389}, issn = {1096-1186}, abstract = {Neurodegenerative diseases represent a major global public health challenge, imposing substantial societal and economic burdens. Their complex pathogenesis and limited therapeutic options underscore an urgent need for new paradigms. Emerging evidence indicates that dysregulation of the brain's immune microenvironment is a critical driver of disease progression. Conventional wisdom posits that peripheral immune cells and central glial cells serve as the primary initiators of neuroimmune responses, whereas neurons are regarded merely as passive recipients of inflammatory damage. Emerging evidence suggests that upon receiving pathological signals in the central nervous system, neurons may become more vulnerable and participate in the onset of neuroimmune processes, positioning them as potential targets for early intervention in neurodegenerative diseases. This article systematically reviews the contribution of neuron-derived immune-inflammatory responses in neurodegenerative diseases and potential intervention strategies. We first outline the capacity of neurons to regulate neuroimmune responses and detail the underlying molecular mechanisms. Then we compare the specific mechanisms by which neurons with different susceptibility drive and amplify neuroinflammation in various neurodegenerative diseases such as alzheimer's disease, parkinson's disease, amyotrophic lateral sclerosis, vascular cognitive impairment, and transformed these mechanisms into intervention strategies targeting neurons,. This article aims to break through the traditional concept of passive neuronal damage, systematically integrate intervention strategies that shift from targeting peripheral immune and glial cells to regulating neuron-derived immunity, thereby providing a new theoretical framework for overcoming current clinical limitations and identifying effective therapeutic targets for the prevention and treatment of neurodegenerative diseases.}, } @article {pmid42580438, year = {2026}, author = {Silva, AC}, title = {Current Clinical Evidence on Nose-to-Brain Drug Delivery.}, journal = {Drug discovery today}, volume = {}, number = {}, pages = {104765}, doi = {10.1016/j.drudis.2026.104765}, pmid = {42580438}, issn = {1878-5832}, abstract = {Intranasal delivery is increasingly recognised as a promising strategy for direct drug transport to the brain via the nose-to-brain pathway, bypassing the blood-brain barrier and improving therapeutic efficacy. This approach has shown potential in the treatment of neurological disorders, including Alzheimer's disease, Parkinson's disease, epilepsy, multiple sclerosis, and acute psychiatric conditions, as well as in emergencies such as anxiety attacks and migraine episodes. Recent clinical studies investigating intranasal formulations of rivastigmine, insulin, and olanzapine, among other drugs, have provided encouraging evidence supporting the clinical translation of this delivery strategy. In addition, FDA-approved intranasal products indicated for central nervous system disorders, including diazepam and midazolam for seizure management, and triptans for migraine, demonstrate the growing clinical relevance of intranasal drug delivery. Both preclinical and clinical studies have reported encouraging outcomes, particularly when intranasal delivery is combined with nanoformulations and specialised delivery devices designed to enhance olfactory deposition. Intranasal administration is non-invasive, painless, and may improve patient adherence while enhancing brain bioavailability. Nevertheless, further well-designed clinical studies are required to establish the long-term safety, efficacy, and clinical applicability of this delivery strategy.}, } @article {pmid42581224, year = {2026}, author = {Stefano, GB and Esch, T}, title = {Microbiome-Inflammation-Mitochondria Coupling in Neurodegeneration and Depression: An Integrative Opinion.}, journal = {Molecular neurobiology}, volume = {63}, number = {1}, pages = {}, pmid = {42581224}, issn = {1559-1182}, mesh = {Humans ; *Mitochondria/metabolism/pathology ; Animals ; *Inflammation/pathology/microbiology/metabolism ; *Depression/microbiology/metabolism/pathology ; *Neurodegenerative Diseases/microbiology/pathology/metabolism ; *Microbiota ; *Gastrointestinal Microbiome/physiology ; *Nerve Degeneration/pathology ; }, abstract = {There is increasing evidence that gut microbiome dysbiosis, systemic inflammation, and mitochondrial dysfunction interact in ways that influence psychiatric and neurodegenerative disease vulnerability. Recent findings indicate that microbial signaling, inflammatory activation, and mitochondrial stress responses form dynamic bidirectional networks that may influence neurotransmission, neuroplasticity, metabolism, and behavior. This integrative opinion article distinguishes major depressive disorder (MDD), Parkinson's disease (PD), and Alzheimer's disease (AD) as mechanistically distinct disorders while proposing that they may share overlapping upstream modulatory pathways involving inflammation, microbial dysregulation, and mitochondrial dysfunction. Importantly, the microbiome-inflammation-mitochondria axis is presented as a disease-modifying and vulnerability-associated framework rather than a singular unifying etiology. Current limitations including reverse causation, microbiome heterogeneity, and differences in treatment responsiveness are also discussed.}, } @article {pmid42581666, year = {2026}, author = {Williams, A and Reddy, ABS and Velayudhan, L}, title = {A Systematic Review of Effects of Cholinesterase Inhibitors and Memantine on Cognitive Domains in Alzheimer's Disease.}, journal = {Journal of geriatric psychiatry and neurology}, volume = {}, number = {}, pages = {8919887261470005}, doi = {10.1177/08919887261470005}, pmid = {42581666}, issn = {1552-5708}, abstract = {BackgroundAlzheimer's Disease (AD) is characterised by progressive cognitive decline. Cholinesterase inhibitors (ChEI) (donepezil, rivastigmine and galantamine) and memantine have been the mainstay treatment and have showed their effectiveness on total cognitive scores, but their effects on individual cognitive domains remain unclear. This systematic review examined their impact on individual cognitive domains.MethodPubMed, Cochrane, MEDLINE, Web of Science and PsycINFO were searched (1st January 1999 - 31st March 2025) for studies evaluating the effects of ChEI and memantine on cognitive domains using standardised cognitive scales in individuals with AD. The review followed PRISMA guidelines. Risk of bias was assessed using the Cochrane ROB1 tool and a narrative synthesis was used to report the main findings.ResultsSixteen studies were included. Rivastigmine demonstrated dose-dependent benefits across memory, language, and praxis domains, with higher-doses generally producing less cognitive decline and greater improvements than lower-dose patches or capsules. Donepezil yielded benefits in language, praxis, and visuospatial abilities. Galantamine showed significant improvements in memory, praxis, visuospatial function, and language, and was superior to donepezil in language in one comparative study. Memantine demonstrated benefits across memory, language, praxis, attention, and visuospatial domains, both as monotherapy and as an adjunct to donepezil, with adjunct therapy producing sustained improvements in language and praxis. Overall, higher treatment doses were consistently associated with greater preservation of cognitive function across domains.DiscussionChEIs and memantine provide domain-specific cognitive benefits beyond global cognitive improvement. Future studies should examine whether treatment tailored to domain-specific deficits improves patient outcome.PROSPEROCRD42024493998.}, } @article {pmid42582267, year = {2026}, author = {Winzell, F and Arvidsson, I and Overgaard, NC and Heyden, A and Åström, K and Karlsson, L and Vogel, JW and Hansson, O and Mattsson-Carlgren, N and , }, title = {Benchmarking privacy and utility in synthetic tabular cohorts for Alzheimer's disease research.}, journal = {Alzheimer's & dementia (Amsterdam, Netherlands)}, volume = {18}, number = {3}, pages = {e70430}, pmid = {42582267}, issn = {2352-8729}, abstract = {INTRODUCTION: The scarcity of large, clinically relevant cohorts is becoming a bottleneck in Alzheimer's disease (AD) research, as their sensitive nature makes open data sharing difficult. Privacy-preserving synthetic datasets generated with machine learning may help address this challenge.

METHODS: We compared five frameworks for generating synthetic tabular data from the Alzheimer's Disease Neuroimaging Initiative and Anti-Amyloid Treatment in Asymptomatic Alzheimer's Disease cohorts, with a set of empirical privacy and utility metrics. Two of the methods, DataSynthesizer and TableDiffusion, provide ε -differential privacy guarantees.

RESULTS: Methods with differential privacy achieved high privacy ratings but low levels of utility. Deep learning methods like Tabular Prior-data Fitted Network (TabPFN) and Conditional Generative Adversarial Network (CTGAN) also showed high privacy with limited utility. In contrast, non-private DataSynthesizer and Synthpop offered higher utility at a cost of lower privacy.

DISCUSSION: The evaluated methods demonstrated a clear trade-off between privacy and utility. High privacy was generally associated with insufficient utility, highlighting the need for further research into synthetic data generation for AD.}, } @article {pmid42573665, year = {2026}, author = {Mukim, RD and Xu, Y and Evola, V and Parmar, MS}, title = {Semaglutide as a potential neuroprotective agent for neurological and neurodegenerative disorders: Mechanisms, preclinical evidence, and translational challenges and opportunities.}, journal = {Molecular biology reports}, volume = {53}, number = {1}, pages = {}, pmid = {42573665}, issn = {1573-4978}, mesh = {Semaglutide ; Humans ; *Glucagon-Like Peptides/pharmacology/therapeutic use/metabolism ; *Neuroprotective Agents/pharmacology/therapeutic use ; *Neurodegenerative Diseases/drug therapy/metabolism ; Animals ; Biomarkers/metabolism ; Oxidative Stress/drug effects ; *Nervous System Diseases/drug therapy/metabolism ; }, abstract = {Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are established treatments for metabolic disease, with growing evidence suggesting neuroprotective potential in central nervous system (CNS) disorders. In preclinical models of Alzheimer's disease (AD), Parkinson's disease (PD), multiple sclerosis (MS), and stroke, semaglutide has been reported to reduce neuroinflammatory and oxidative stress markers and improve selected pathological or behavioral outcomes, although the specific effects vary by model and indication. However, significant translational challenges remain. The Phase 3 EVOKE and EVOKE+ trials in early symptomatic AD failed to meet primary cognitive endpoints, although biological target engagement was reported, with improvements in selected AD-related biomarkers including p-tau181, p-tau217, neurogranin, YKL-40, and plasma hsCRP. This dissociation between biomarker changes and clinical benefit may reflect treatment timing, advanced neurodegeneration, limited CNS exposure, endpoint sensitivity, or other factors. In contrast, observational studies suggest an association between semaglutide or GLP-1 RA exposure and lower dementia-related risk in at-risk populations, although preservation of cognitive reserve has not been directly demonstrated and causality has not been established. This review evaluates the current mechanistic, preclinical, and emerging clinical evidence for semaglutide across neurodegenerative and neuroinflammatory disorders, with emphasis on distinguishing semaglutide-specific findings from broader GLP-1 RA class effects and identifying key translational limitations. Collectively, current evidence supports continued investigation of semaglutide as a potential neuroprotective strategy, while highlighting the need for earlier intervention studies, improved understanding of CNS target engagement, and further clinical validation.}, } @article {pmid42573807, year = {2026}, author = {Maman, D and Steinfield, Y and Berkovich, Y}, title = {Factors associated with selection of total hip arthroplasty versus hemiarthroplasty for femoral neck fracture in older adults: a nationwide analysis of 99,084 cases.}, journal = {Archives of orthopaedic and trauma surgery}, volume = {146}, number = {1}, pages = {}, pmid = {42573807}, issn = {1434-3916}, mesh = {Humans ; *Femoral Neck Fractures/surgery ; *Hemiarthroplasty/statistics & numerical data ; *Arthroplasty, Replacement, Hip/statistics & numerical data ; Aged ; Male ; Female ; Retrospective Studies ; Aged, 80 and over ; United States ; *Patient Selection ; Comorbidity ; Proximal Femoral Fractures ; }, abstract = {BACKGROUND: Surgical management of displaced femoral neck fractures in older adults typically involves hemiarthroplasty or total hip arthroplasty (THA). Although clinical guidelines suggest that THA may be considered in selected healthier and cognitively intact patients, real-world procedure selection varies widely. This study evaluated patient factors associated with selection of THA versus hemiarthroplasty in a contemporary U.S.

METHODS: A retrospective cohort study was conducted using the 2022 Nationwide Readmissions Database (NRD). Patients ≥ 65 years hospitalized with femoral neck fracture were identified using ICD-10-CM codes. Those treated with internal fixation or non-arthroplasty procedures were excluded. Weighted analyses characterized demographics, comorbidities, and hospital utilization between THA and hemiarthroplasty groups. A multivariable logistic regression model identified factors independently associated with receiving THA. All analyses accounted for NRD survey design.

RESULTS: Among 142,013 operative cases, 99,084 met inclusion criteria (81.8% hemiarthroplasty; 18.2% THA). Patients receiving THA were younger (76.6 vs. 81.9 years), had shorter length of stay (6.06 vs. 7.24 days), and were more frequently discharged home (17.5% vs. 6.2%). Metabolic conditions were associated with increased odds of THA, including obesity (OR 1.17) and sleep apnea (OR 1.12). Frailty-related conditions were associated with markedly reduced THA likelihood, including Alzheimer's disease (OR 0.48), Parkinson disease (OR 0.55), chronic kidney disease (OR 0.78), chronic lung disease (OR 0.72), and congestive heart failure (OR 0.77). Each additional year of age decreased the odds of THA by approximately 9%.

CONCLUSION: In this nationwide cohort, selection of THA rather than hemiarthroplasty was associated with younger age and lower prevalence of frailty- and cognition-related comorbidities, while several metabolic comorbidities showed modest positive associations with THA use. These findings describe contemporary national selection patterns but do not establish treatment appropriateness, clinical benefit, or guideline concordance, as key factors such as pre-fracture mobility, functional independence, and living situation were not available in the dataset.

LEVEL OF EVIDENCE: Level III.}, } @article {pmid42574828, year = {2026}, author = {Lin, X and Wei, Z and Dong, X and Sun, Y}, title = {A sequential photodynamic-antioxidation therapy against Alzheimer's β-amyloid enabled by a dual‑carbon dots nanomotor.}, journal = {Journal of colloid and interface science}, volume = {724}, number = {Pt 3}, pages = {141317}, doi = {10.1016/j.jcis.2026.141317}, pmid = {42574828}, issn = {1095-7103}, abstract = {Abnormal accumulation of β-amyloid protein (Aβ) in the brain is considered as the primary hallmark of Alzheimer's disease (AD). Beyond inducing neuronal metabolic disorders and apoptosis, Aβ activates oxidative stress pathways, thereby exacerbating reactive oxygen species (ROS) toxicity. Therefore, the design of effective multi-target synergistic therapeutics targeting Aβ and excessive ROS has emerged as a critical strategy for AD prevention and treatment. Herein, we propose a "Sequential Photodynamic-Antioxidation Therapy (SPAT)" against Alzheimer's Aβ, and the SPAT strategy is enabled by the design of a sub-10nm dual‑carbon dots Janus composite (SeRCD) composed of a newly designed and synthesized selenium-doped high-efficiency antioxidant carbon dot (SeCD) and a previously reported near-infrared (NIR) carbon dot (RCD) possessing both thermogenic and photodynamic functionalities. The thermogenic property of RCD in SeRCD endows the Janus composite with photo-propelled autonomous motion powered by "self-thermophoretic force" under NIR irradiation. Thus, SeRCD shows potent inhibition of Aβ fibrillization at low concentrations (0.5 to 5 μg/mL) via photooxygenation and the nanomotor effect under NIR irradiation for only 10 min. Under the subsequent NIR-off condition, SeCD in SeRCD effectively mitigates the oxidative damage to cells by scavenging ROS. Thus, the lifespan of AD nematodes is prolonged by the SPAT strategy from 12 to 19 d at 2 μg/mL. The results collectively demonstrate the effectiveness of the dual-CDs composite design and great potential of the SPAT strategy for application in fighting against AD.}, } @article {pmid42574987, year = {2026}, author = {Liu, Z and Li, P and Cecarini, V and Eleuteri, AM and Nan, B and Piao, C}, title = {Ginsenoside Rg2 attenuates Alzheimer-like phenotypes in 3xTg-AD mice: Associations with gut microbiota and brain metabolomic profiles.}, journal = {Phytomedicine : international journal of phytotherapy and phytopharmacology}, volume = {160}, number = {}, pages = {158678}, doi = {10.1016/j.phymed.2026.158678}, pmid = {42574987}, issn = {1618-095X}, abstract = {BACKGROUND AND PURPOSE: Alzheimer's disease (AD) is the most common form of dementia. The microbiota-gut-brain axis represents a critical pathway bridging peripheral metabolic signals and central AD pathology. This study aimed to evaluate the effects of ginsenoside Rg2 on AD-like phenotypes in 3xTg-AD mice and to examine its associations with gut microbiota and brain metabolomic profiles.

STUDY DESIGN AND METHODS: A 3xTg-AD mouse model was used to assess the effects of Rg2 intervention in vivo. Behavioral performance was assessed using open field and water maze tests, Aβ and inflammatory factors were detected by ELISA, gut microbial changes were analyzed by 16S rRNA sequencing, and brain metabolic alterations were investigated using untargeted metabolomics.

RESULTS: The results showed that Rg2 improved behavioral performance in mice, reduced Aβ deposition in the brain, and decreased serum and brain tissue inflammatory factors. Rg2 treatment was associated with alterations in gut microbial community characteristics. Metabolomics indicated that Rg2 was associated with alterations in the brain metabolic profile, with differential metabolites mainly involved in energy and lipid metabolism as well as inflammation-related pathways. The correlation network further revealed a close relationship between microbiota, SCFAs and brain metabolites, inflammation and behavioral indicators.

CONCLUSION: Rg2 attenuated AD-related pathology and functional impairment in 3xTg-AD mice. These protective effects were accompanied by changes in gut microbiota composition, brain metabolic profiles, and the inflammatory microenvironment. This study provides multi-omics evidence supporting the potential of Rg2 as a natural product for AD intervention and highlights its associations with gut microbiota and brain metabolism.}, } @article {pmid42575412, year = {2026}, author = {Liu, Y and Peng, L and Li, M and Yan, W and Xiang, Q}, title = {Let-7d-5p improves mouse cognitive function by targeting bach1 in Alzheimer's disease.}, journal = {Experimental neurology}, volume = {}, number = {}, pages = {115957}, doi = {10.1016/j.expneurol.2026.115957}, pmid = {42575412}, issn = {1090-2430}, abstract = {BACKGROUND: MicroRNAs (miRNAs) have emerged as critical modulators in Alzheimer's disease (AD) pathogenesis. The lethal-7 (let-7) family functions as key regulators of cell apoptosis, differentiation, and immune response. Herein, we explore the functions and underlying mechanisms of let-7d-5p in AD progression.

METHODS: Eight-month-old male APP/PS1 transgenic mice and wild-type C57BL/6 J mice were assigned to the model and control groups, respectively. Model mice received intrahippocampal injections of either a negative control adenovirus (Ad-NC) or a let-7d-5p overexpression adenovirus (Ad-let-7d-5p). The Morris water maze test was conducted to assess cognitive function. Hippocampal histopathological changes were evaluated using hematoxylin and eosin staining. Aβ deposition was detected via immunohistochemical staining. SH-SY5Y cells were transfected with let-7d-5p mimics prior to treatment with 10 μM Aβ1-42. Cell viability and apoptosis were examined using MTT assays and flow cytometry. The expression levels of let-7d-5p and bach1 were measured using RT-qPCR. Western blotting was conducted to evaluate bach1, Bcl-2, and cleaved caspase-3 protein levels. The binding relationship between let-7d-5p and bach1 was verified using luciferase reporter assays.

RESULTS: In vitro, Aβ1-42 treatment induced the downregulation of let-7d-5p and decrease of cell viability. However, overexpression of let-7d-5p significantly increased let-7d-5p level, enhanced cell viability and inhibited cell apoptosis of Aβ1-42-treated SH-SY5Y cells. Moreover, overexpression of let-7d-5p upregulated Bcl-2 protein levels and downregulated cleaved caspase-3 protein levels in Aβ1-42-treated SH-SY5Y cells. Furthermore, let-7d-5p overexpression ameliorated oxidative stress injury in Aβ1-42-treated SH-SY5Y cells. Importantly, bach1 upregulation counteracted the inhibitory effects of let-7d-5p overexpression on Aβ1-42-induced cellular injury. In vivo, let-7d-5p overexpression mitigated cognitive deficits of AD mice, as indicated by reduced escape latency and increased platform crossings. Additionally, let-7d-5p overexpression attenuated hippocampal histopathological changes and Aβ deposition in APP/PS1 mice. At the molecular level, let-7d-5p targeted bach1 3'UTR and repressed its mRNA and protein expression in vitro and in vivo. Rescue assays further validated that bach1 overexpression restored the protective effect of let-7d-5p on cognitive deficits and pathological injuries.

CONCLUSION: Let-7d-5p alleviates cognitive deficits in AD by inhibiting Aβ deposition and neuronal apoptosis through targeting bach1.}, } @article {pmid42575718, year = {2026}, author = {Dzib, E and Hernández-Ayala, LF and Silva-Aguirre, S and Galano, A}, title = {Rational Design of Multifunctional Tacrine Derivatives as Candidates for the Treatment of Alzheimer and Parkinson Diseases.}, journal = {ChemMedChem}, volume = {21}, number = {15}, pages = {e70429}, doi = {10.1002/cmdc.70429}, pmid = {42575718}, issn = {1860-7187}, support = {CBF2023-2024-1141//SECIHTI/ ; }, mesh = {*Tacrine/chemistry/pharmacology/chemical synthesis/therapeutic use/analogs & derivatives ; *Alzheimer Disease/drug therapy/metabolism ; *Drug Design ; Humans ; Monoamine Oxidase/metabolism/chemistry ; Acetylcholinesterase/metabolism/chemistry ; *Parkinson Disease/drug therapy/metabolism ; *Cholinesterase Inhibitors/chemistry/pharmacology/chemical synthesis/therapeutic use ; Receptors, N-Methyl-D-Aspartate/antagonists & inhibitors/metabolism ; Structure-Activity Relationship ; *Monoamine Oxidase Inhibitors/chemistry/pharmacology/chemical synthesis ; Catechol O-Methyltransferase/metabolism ; Molecular Structure ; Molecular Docking Simulation ; Catechol O-Methyltransferase Inhibitors/chemistry/pharmacology/chemical synthesis ; }, abstract = {Alzheimer disease (AD) and Parkinson disease (PD) are multifactorial neurodegenerative disorders for which there is currently no therapy that prevents or slows their progress. Some drugs used to treat AD are inhibitors of acetylcholinesterase (AChE) and antagonists of N-methyl-D-aspartate receptor (NMDAr), while inhibitors of catechol-O-methyltransferase (COMT) and monoamine oxidase B (MAO-B) are used for PD. Tacrine was the first FDA (Food and Drug Administration) approved drug against AD. Although later withdrawn due to hepatotoxicity, it remains a pivotal scaffold for drug development. Herein, 1295 tacrine derivatives, meant to enhance therapeutic efficacy and safety of the parent compound, were designed through the CADMA-Chem protocol. The chemical space was screened using selection scores based on ADME properties, toxicity, and synthetic accessibility. Two derivatives with the best drug-like behavior were chosen for further investigation. Acid-base constants and reactivity descriptors were estimated for them. Our findings show that these derivatives are promising inhibitors of AChE, COMT, NMDAr, and MAO-B. Therefore, according to in silico predictions they are expected to be beneficial for AD and PD. One of the compounds investigated here is the first reported tacrine-derived compound with potential as COMT inhibitor.}, } @article {pmid42575772, year = {2026}, author = {Russo, AG and Hawkshaw, MJ and Sataloff, RT}, title = {Voice Disorders as Early Biomarkers of Cognitive Decline.}, journal = {Journal of voice : official journal of the Voice Foundation}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.jvoice.2026.07.037}, pmid = {42575772}, issn = {1873-4588}, abstract = {BACKGROUND: Dementia affects greater than 57 million people worldwide. With an aging population and limited disease-curing treatments available, early identification of biomarkers is crucial. The 2020 Lancet Commission identified hearing loss as the largest modifiable risk factor for dementia globally, and a randomized controlled trial found that hearing intervention reduced 3-year cognitive change in older adults who were at increased risk for cognitive decline. Similarly, studies have found that abnormalities in acoustic measures of voice are correlated with cognitive status and can potentially predict decline. The association between hearing loss and cognitive decline might have both social and neurological mechanisms. Dysphonia might pose similar problems. Socially, voice disorders may reduce engagement in social and cognitively stimulating activities. Neurologically, one example is in Parkinson's disease in which the vagus nerve is one of the earliest sites of Lewy body pathology in Braak staging, and dysphonia and dysarthria can precede motor symptoms by years. Voice changes have been associated with different neurological conditions such as amyotrophic lateral sclerosis, multiple system atrophy, and Alzheimer's disease. Despite this, no prior large-scale study has examined whether diagnosed voice disorders are associated independently with incident cognitive decline. Our study is the first to examine this potential association, using the TriNetX US Collaborative Health Network platform to compare patients with diagnosed voice disorders and matched controls, with a hearing loss cohort as a standard of comparison given that it is the largest established modifiable risk factor for dementia, as dysphonia is also a modifiable condition.

RESULTS: This study included 833,417 total patients in the voice disorders and control cohorts. Voice disorders were associated with a significantly elevated risk of incident cognitive decline compared to controls (HR=1.291, 95% CI 1.155-1.443, P<0.0001). Hearing loss alone was associated with a slightly lower risk of cognitive decline (HR=1.267, 95% CI 1.203-1.334, P<0.0001). Voice disorders without concurrent hearing loss were associated with an elevated risk of incident cognitive decline compared to hearing loss alone (HR=1.261, 95% CI 1.121-1.419, P=0.0001), while voice disorders with hearing loss were associated with the highest risk among all cohorts (HR=2.038 vs controls; HR=1.545 vs hearing loss). Both voice disorder subgroups did not differ when compared with each other (HR=1.088, P=0.376).

CONCLUSION: The results from our study indicate that voice disorders are associated with an elevated risk of incident cognitive decline and may represent a stronger early biomarker than hearing loss alone. These findings highlight otolaryngology and family medicine/internal medicine encounters as potential entry points for cognitive assessment, and early voice treatment needs to be investigated for possible beneficial cognitive effect.}, } @article {pmid42576199, year = {2026}, author = {Zheng, F and Guan, R and Yu, X and Yang, J and Zhao, H and Yang, F}, title = {ADAR-mediated RNA editing in CNS disorders: from pathogenic mechanisms to therapeutic opportunities.}, journal = {Cellular & molecular biology letters}, volume = {31}, number = {1}, pages = {}, pmid = {42576199}, issn = {1689-1392}, mesh = {Humans ; *RNA Editing/genetics ; *Adenosine Deaminase/metabolism/genetics ; *Central Nervous System Diseases/genetics/therapy/pathology/metabolism ; Animals ; *RNA-Binding Proteins/metabolism/genetics ; }, abstract = {The adenosine deaminases acting on RNA (ADAR) family of enzymes (ADAR1 and ADAR2) catalyze adenosine-to-inosine (A-to-I) RNA editing. This post-transcriptional change is remarkably prevalent in the central nervous system (CNS). ADAR-mediated editing is critical for proper brain development, synaptic plasticity, and immunological homeostasis in the central nervous system (CNS) via recoding neurotransmitter receptors and ion channels. Conversely, a wide range of CNS disorders, such as neurodegenerative diseases (Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis), neuropsychiatric conditions (schizophrenia, bipolar disorder, and major depression), cerebrovascular diseases, and gliomas, are now linked to dysregulation of ADAR activity, whether through loss-of-function mutations, altered expression, or mislocalization. To address the main question of whether altered RNA editing is a fundamental driver of pathogenesis, a compensatory response, or a context-dependent modulator, this review critically synthesizes existing evidence. The basic processes of ADAR enzymes and their regulation throughout neurodevelopment are first described. Next, we thoroughly assess the unique molecular fingerprints of ADAR dysregulation across several CNS disorders, emphasizing recurring themes such as Alu RNA hypo-editing, induction of innate immunity, and GRIA2 editing, which can cause excitotoxicity. Lastly, we examine new treatment approaches that use or reinstate ADAR activity, such as small-molecule modulators and site-directed RNA editing tools (leveraging endogenous ADAR for programmable editing of RNA [LEAPER], clustered ADAR-recruiting guide RNAs (gRNAs) for effective RNA editing [CLUSTER], and mimicking inverted repeats to recruit ADARs using engineered oligoribonucleotides [MIRROR]). We summarize by reviewing key obstacles to clinical translation, including crossing the blood-brain barrier, the risks of off-target editing, and the challenges of achieving spatiotemporal accuracy. We also list important open topics for further investigation.}, } @article {pmid42576501, year = {2026}, author = {Li, D and Li, Y and Yang, X and Wang, Y and Qu, Y}, title = {[Association between 473 gut microbiota and Alzheimer's disease: a Mendelian randomization mediation analysis of 233 circulating metabolites].}, journal = {Nan fang yi ke da xue xue bao = Journal of Southern Medical University}, volume = {46}, number = {8}, pages = {1926-1935}, doi = {10.12122/j.issn.1673-4254.2026.08.20}, pmid = {42576501}, issn = {1673-4254}, mesh = {*Alzheimer Disease/microbiology/genetics ; *Mendelian Randomization Analysis ; Humans ; *Gastrointestinal Microbiome ; Genome-Wide Association Study ; }, abstract = {OBJECTIVES: To investigate the causal associations between gut microbiota (GM) and Alzheimer's disease (AD) and the mediating role of circulating metabolites using Mendelian randomization (MR) analysis.

METHODS: A two-sample MR analysis was conducted based on genome-wide association study (GWAS) summary data. Valid instrumental variables for 473 GM taxa and 233 circulating metabolites were selected, and the inverse-variance weighted (IVW) method was used as the primary analytical approach, with MR-Egger regression and weighted median method as the complementary analyses. Multiple sensitivity analyses were conducted to assess the robustness of the results, and reverse MR analyses were used to verify the direction of causality. Mediation MR analyses were performed to determine the mediating effects of the circulating metabolites.

RESULTS: A positive causal association was identified between the abundance of Negativibacillus massiliensis and the risk of AD (OR=1.204, 95% CI: 1.020-1.421,P=0.028), and the results were stable and reliable as confirmed by sensitivity analyses (P>0.05). Reverse MR analysis revealed no significant causal effect of AD on the abundance of Negativibacillus massiliensis (P=0.678). Mediation MR analysis showed that the indirect effect mediated by free cholesterol to total lipid ratio in very small very-low-density lipoprotein (v-VLDL FC/TL) accounted for 6.63% of the total effect of Negativibacillus massiliensis on AD.

CONCLUSIONS: From a genetic causal inference perspective, Negativibacillus massiliensis is likely associated with an increased risk of AD, and v-VLDL FC/TL may partially mediate this association, suggesting their potential as targets for AD prevention and treatment.}, } @article {pmid42576561, year = {2026}, author = {Kara, S and Özandaç, S and Sencar, L and Akillioglu, K and Polat, S}, title = {Transforming Growth Factor Beta-1 Alleviates Neurodegeneration by Regulating Aβ42 and VDAC1 Expression in the Temporal Lobe and Cerebellum in an Alzheimer's Disease-Like Model.}, journal = {Current molecular medicine}, volume = {}, number = {}, pages = {}, doi = {10.2174/0115665240501722260724103809}, pmid = {42576561}, issn = {1875-5666}, abstract = {BACKGROUND: Alzheimer's Disease (AD) has a critical pathology that causes neurodegeneration and mitochondrial dysfunctions via the amyloid deposition. The temporal lobe plays a role in converting sensory input into derived meanings for appropriate processing of visual memory, language comprehension, and emotional association. The cerebellum plays a critical role in the control of motor systems, cognitive, and emotional functions. Aβ42 accumulates between nerve cells in the brain, disrupting synaptic functions and negatively affecting memory and other cognitive functions. VDAC1 is a protein located in the cell membrane that facilitates energy transport to the mitochondria. TGF-β1 is a cytokine that plays a role in many biological functions, including cell growth, differentiation, and tissue repair.

OBJECTIVE: The aim of the study was to investigate the effect of TGF-β1 on scopolamine-induced neurodegeneration of the temporal lobe and cerebellum in experimental AD.

METHODS AND RESULTS: The evaluation showed that, according to light and electron microscopic results, edema areas, cytoplasmic vacuolization, and cellular damage were increased in the scopolamine group, while these changes were significantly reduced in the treatment group. According to immunohistochemical findings, the expression levels of Aβ42 and VDAC1 were significantly higher in the scopolamine group than in the control and TGF-β1 groups, while in the treatment group, a low expression was observed compared to the scopolamine group.

CONCLUSION: When all these results are considered together, it has been concluded that TGF-β1 application may regulate the expression of Aβ42 and VDAC1 in critical control centers such as the temporal lobe and cerebellum in a Scopolamin-induced neurodegeneration model, potentially alleviating cellular damage.

DISCUSSION: Previous studies have reported that TGF-β1 exerts both antineurodegenerative and neuroprotective effects. In our study, evaluation of the effects of TGF-β1 demonstrated beneficial effects on both mitochondrial damage and amyloid accumulation. Nevertheless, further detailed investigations of these effects may provide valuable insights for future studies.}, } @article {pmid42576592, year = {2026}, author = {Jeeru, TR and Palathoti, N and Swaminathan, G}, title = {The Multifaceted Role of the P2X7 Receptor in Alzheimer's Disease: A Unifying Pathological Link.}, journal = {CNS & neurological disorders drug targets}, volume = {}, number = {}, pages = {}, doi = {10.2174/0118715273460900260724035926}, pmid = {42576592}, issn = {1996-3181}, abstract = {Alzheimer's Disease (AD) is a neurodegenerative disorder that characterizes depletion of memory, cognition, and a change in behavioural patterns. There is no standard treatment that completely cures this prevalent disease. This review delves into the existing pathologies of AD, which include the Aβ plaques accumulation, neurofibrillary tangles and Lewy bodies formation, and the influence of the P2X7 receptor on cellular mechanisms of neuronal cells like microglial cells, astrocytes and oligodendrocytes and also its influence on pathways such as JAK2/STAT3, NGF signalling, (Transactive response DNA binding protein) TDP-43 Proteinopathy, Wnt/β-Catenin signalling, and FGF7/FGFR2/PI3K/Akt causing AD. It discusses the unifying role of the P2X7 receptor mediating these pathways that link to the occurrence and progression of AD. The role of the Purinergic receptor (P2X7 receptor), a ligand-gated ion channel activated by extracellular ATP, was examined across existing cellular mechanisms and possible pathways involved in AD, as well as the co-pathologies encompassed and their hypothetical relationship with the P2X7 receptor. Additionally, the current P2X7 receptor antagonists treating neurotoxicity are discussed along with existing pre-clinical and clinical data. This may further advance drug development by targeting the P2X7 receptor to mitigate AD across multiple mechanisms.}, } @article {pmid42576595, year = {2026}, author = {Maghsoudlou, F and Esteki, A}, title = {Audio‒Visual Gamma Stimulation for Alzheimer's Disease: Current Evidence and Future Directions.}, journal = {Current Alzheimer research}, volume = {}, number = {}, pages = {}, doi = {10.2174/0115672050478693260720114427}, pmid = {42576595}, issn = {1875-5828}, abstract = {INTRODUCTION/OBJECTIVE: Alzheimer's Disease (AD) is characterized by progressive cognitive decline and disrupted neural oscillations. Recently, 40 Hz gamma stimulation has emerged as a potential non-invasive therapy. This review evaluates the safety, tolerability, and clinical outcomes of this intervention based on evidence from the past decade.

METHODS: A literature search was conducted across PubMed, Web of Science, Google Scholar, and ClinicalTrials.gov for studies published during the last ten years. Registered and ongoing studies were also identified through ClinicalTrials.gov. Extracted data included stimulation modality, stimulation parameters, safety and tolerability outcomes, and reported effects on functional connectivity, brain atrophy, cognitive performance, and sleep-related measures.

RESULTS: Thirty studies were identified, comprising eight sensory-based 40-Hz gamma stimulation approaches, 12 40-Hz transcranial Alternating Current Stimulation (tACS) protocols, and 10 ongoing clinical trials. Among the 20 completed studies, 40-Hz gamma stimulation was reported to be safe and well-tolerated. The synthesized evidence from these completed trials suggests potential beneficial effects on functional connectivity, brain atrophy progression, cognitive outcomes, and sleep-related measures.

DISCUSSION: Gamma stimulation may represent a promising approach for modulating neural network activity and cognitive function in AD. Nevertheless, current evidence remains limited by small sample sizes, methodological heterogeneity, differences in stimulation protocols, and short follow-up periods. These factors limit the ability to draw definitive conclusions regarding therapeutic efficacy.

CONCLUSION: 40-Hz gamma stimulation is a feasible and generally well-tolerated non-invasive intervention with potential relevance for AD treatment. Further large-scale, randomized, and controlled studies are required to establish standardized stimulation protocols, determine long-term efficacy, and clarify its clinical utility.}, } @article {pmid42576814, year = {2026}, author = {Singh, N and Guha, L and Kumari, A}, title = {Exosome-based nanomedicine for neurological disorders: mechanisms, engineering, and therapeutic potential.}, journal = {Therapeutic delivery}, volume = {}, number = {}, pages = {1-40}, doi = {10.1080/20415990.2026.2715878}, pmid = {42576814}, issn = {2041-6008}, abstract = {Exosomes are naturally occurring extracellular vesicles that have emerged as promising bio-inspired nanocarriers for the treatment of neurological disorders owing to their intrinsic biocompatibility, low immunogenicity, and ability to cross the blood-brain barrier. This review highlights recent advances in exosome biology, cargo-sorting mechanisms, and engineering strategies designed to enhance therapeutic delivery and targeting within the central nervous system. Particular emphasis is placed on the application of engineered exosomes in neurodegenerative diseases, stroke, spinal cord injury, neuropathic pain, and neuroinflammatory disorders. In addition, we discuss how exosomes compare with conventional delivery platforms and critically examine the major barriers limiting their clinical translation, including heterogeneity, scalability, reproducibility, purity, and regulatory standardization. By integrating mechanistic insights with translational perspectives, this review provides a framework for the rational design and future clinical implementation of exosome-based nanomedicines for neurological disorders. Relevant literature was identified through searches of PubMed, Scopus, Web of Science, and Google Scholar. Publications available from database inception through [Month Year] were screened using combinations of keywords including "exosomes," "extracellular vesicles," "neurological disorders," "brain-targeted delivery," "exosome engineering," "drug delivery," and "clinical trials." Additional relevant articles were identified through manual searches of reference lists from selected studies and recent reviews.}, } @article {pmid42577281, year = {2026}, author = {Dhapola, R and Sharma, P and Kumari, S and Vellingiri, B and HariKrishnaReddy, D}, title = {Neuroprotective effect of normal and modified mesenchymal stem cell-derived exosomes by mitigating Alzheimer's-related oxidative and inflammatory damage via Nrf2/HO-1 in SH-SY5Y cells.}, journal = {Ibrain}, volume = {}, number = {}, pages = {}, pmid = {42577281}, issn = {2769-2795}, abstract = {Exosome therapy is emerging as a promising neuroprotective strategy for Alzheimer's disease (AD). We evaluated and compared whether normal exosomes (NE) and modified exosomes (ME) derived from AD rat brain extract-treated rat bone marrow mesenchymal stem cells possess the potential to protect SH-SY5Y cells against streptozotocin (STZ) induced toxicity. The effect of exosomes on oxidative stress, inflammation and neuronal survival was evaluated. Further, antioxidant mechanism of exosomes by nuclear factor erythroid 2-related factor 2/heme oxygenase-1 (Nrf2/HO-1) signaling was explored. Cells were exposed to 5 mM STZ and treated with NE and ME at an equivalent concentration of 50 µg/mL. Exosomes were characterized by specific exosomal markers, CD63 and CD9. Cell viability was assessed using the MTT assay. Neuronal growth and survival were evaluated by measuring brain-derived neurotrophic factor (BDNF) using ELISA and neuronal nuclei (NeuN) expression using immunocytochemistry. Intracellular reactive oxygen species (ROS) levels were determined using H2DCFDA, while inflammatory mediators, including interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) were quantified by ELISA. Expression levels of Nrf2 and HO-1 were also determined. Exosome treatment improved cell viability, reduced ROS, and lowered IL-6 and TNF-α levels. Immunocytochemistry quantification showed increased nuclear Nrf2 and HO-1 expression in exosome-treated cells. Moreover, our data indicate that ME derived from AD rat brain extract-treated rat bone marrow mesenchymal stem cells are more potent in protecting SH-SY5Y cells from STZ-induced oxidative stress and inflammation, possibly via Nrf2/HO-1 signaling, as compared to NE. These in vitro results support further preclinical evaluation of exosome-based strategies for AD.}, } @article {pmid42565414, year = {2026}, author = {Ramirez-Contreras, LA and Camargo-Hernández, G and Sanchez-Enriquez, S and Silva-Jara, JM and Hernández Estrada, S and Hernández Villaseñor, LA and Anaya Esparza, LM}, title = {Bioinformatic Tools to Explore the Mechanisms and the Multitarget Recognition of Huperzine A in Alzheimer's and Parkinson's Diseases.}, journal = {Current drug targets}, volume = {}, number = {}, pages = {}, doi = {10.2174/0113894501499352260714060149}, pmid = {42565414}, issn = {1873-5592}, abstract = {INTRODUCTION: Considering the shared physiological mechanisms between Alzheimer's disease (AD) and Parkinson's disease (PD), it is plausible that certain compounds may exert therapeutic effects on both neurological disorders. This study aimed to employ in silico techniques to investigate the pharmacological mechanisms of huperzine A (HA) as an alternative treatment for PD and AD.

METHODS: Molecular targets of HA and genes associated with AD and PD were identified from public databases. Gene Ontology analysis, metabolic pathway analysis, and protein-protein interaction (PPI) network construction were performed to identify shared molecular targets. Molecular docking was performed to assess HA affinity for hub proteins and to compare it with that of drugs used to treat AD and PD.

RESULTS: The results suggested that HA interacts with 77 molecular targets common to both diseases. Enrichment analysis revealed that proteins from these targets were involved in biological functions, such as serotonin and amine binding. Hub proteins (SRC, TP53, AKT1, and CASP3) were identified from the PPI network. Furthermore, molecular docking simulations showed favorable binding of HA to the hub proteins and adequate binding to the targets of standard drugs (MAOB and ACHE). On the other hand, molecular dynamics analyses were performed to compare the binding characteristics of HA with those of the control targets.

DISCUSSION: HA may modulate SRC, CASP3, and AKT1, suggesting a pleiotropic mechanism underlying the association between AD and PD. These computational findings provide a rational basis for experimental validation by modulating signaling pathways implicated in inflammatory processes and inhibiting enzymes involved in neurotransmitter degradation.

CONCLUSION: This study contributes to the understanding of the neuroprotective activity of HA in AD and PD. However, further in vitro and in vivo investigations are required to confirm the dual therapeutic potential of HA in the treatment of AD and PD.}, } @article {pmid42568171, year = {2026}, author = {Lv, J and Cai, X and Yang, Z and Li, B and Zhou, Y and Li, F and Fu, H}, title = {A comprehensive assessment of cholinesterase inhibitors for the treatment of Alzheimer's disease based on drug selection recommendations for Chinese Medical Institutions.}, journal = {Expert review of pharmacoeconomics & outcomes research}, volume = {}, number = {}, pages = {}, doi = {10.1080/14737167.2026.2715983}, pmid = {42568171}, issn = {1744-8379}, abstract = {BACKGROUND: Cholinesterase inhibitors (ChEIs) are widely used to treat Alzheimer's disease (AD), yet the optimal choice remains unclear.

RESEARCH DESIGN AND METHODS: This study aimed to comprehensively evaluate the overall clinical value of seven ChEI formulations (donepezil tablets, rivastigmine capsules, rivastigmine patches, galantamine tablets, galantamine orally disintegrating tablets, and two huperzine A formulations) to provide evidence-based guidance for rational AD pharmacotherapy selection. The evaluation framework used in this study was derived from the Rapid Guide for Drug Evaluation and Selection in Chinese Medical Institutions (Second Edition). This framework integrates mini-health technology assessment (mini-HTA) with the System of Objectified Judgment Analysis (SOJA). Seven formulations were assessed across five weighted dimensions: pharmacological properties (28 points), efficacy (27 points), safety (25 points), economy (10 points), and other attributes (10 points). A systematic literature search was performed using PubMed, CNKI, Wanfang, and official regulatory databases.

RESULTS: Within this assessment framework, donepezil tablets achieved the highest score (74.86), followed by rivastigmine patches (73.50) and rivastigmine capsules (72.28). These three formulations are recommended as priority options for inclusion in Chinese hospital formularies. The remaining four drugs may be prescribed according to individual patient conditions and institutional available resources.

CONCLUSIONS: This evaluation provides evidence-based guidance for clinical and institutional decision-making in AD management and delivers a generalizable assessment framework adaptable to local real-world data for healthcare institutions globally.}, } @article {pmid42568632, year = {2026}, author = {Liu, J and Chen, W}, title = {Identification and validation of mitophagy and astrocyte-related molecular signature in the pathogenesis of Alzheimer's disease: evidence from ensemble learning-driven multi-omics and clinical validation.}, journal = {Frontiers in neuroscience}, volume = {20}, number = {}, pages = {1910621}, pmid = {42568632}, issn = {1662-4548}, abstract = {BACKGROUND: Alzheimer's disease (AD) is a progressive neurodegenerative disorder with limited diagnostic tools and therapeutic options. Dysregulated mitophagy in astrocytes plays a pivotal role in AD pathogenesis. This study aims to identify a mitophagy and astrocyte (MA)-associated molecular signature for AD diagnosis and therapeutic targeting.

METHODS: Limma, WGCNA, xCell, PPI network and integrated machine learning pipeline coupled with SHAP were deployed on AD patient hippocampal bulk profiles (GSE28146, GSE36980, GSE29378, GSE48350) for identification of MA-associated predictive model and hub gene. Next, astrocyte patten and MA-associated hub gene molecular performance were estimated in hippocampal single-cell profile of AD patients (GSE163577) via advanced analytical frameworks. In addition, active learning framework and molecular docking was deployed in GSE29378 for identification of therapeutic candidate for AD patients by targeting MA-associated hub gene. Furthermore, AD hippocampal tissues were collected, and then MA-associated hub gene expression was estimated.

RESULTS: A core 8-gene MA signature (ITSN1, VLDLR, CYP7A1, SREBF2, RASL12, TPMT, CYP4X1, ARHGEF) was identified, which can guide the molecular subgroup identification and predictive model construction for AD patients. ITSN1 can be considered as the MA-associated hub gene in AD pathogenesis, which was up-regulated and predominantly expressed in astrocytes. Drug repositioning identified BRD-K10008415 as the potential compound predicted to reverse the AD signature by targeting ITSN1.

CONCLUSIONS: This study identified ITSN1 as a MA-associated critical hub potential connecting mitophagy dysregulation and astrocyte dysfunction in AD. We also identified MA-associated molecular signatures that can potentially elaborate predictive effects on AD pathogenesis. BRD-K10008415 can be considered as potential candidate for AD treatment by targeting ITSN1.}, } @article {pmid42570085, year = {2026}, author = {Bu, Y and Fan, Z and Li, L}, title = {Bacterial outer membrane vesicles in oral diseases: from pathogenic mediators to theranostic platforms.}, journal = {Critical reviews in microbiology}, volume = {}, number = {}, pages = {1-19}, doi = {10.1080/1040841X.2026.2713518}, pmid = {42570085}, issn = {1549-7828}, abstract = {Bacterial outer membrane vesicles (bOMVs) are nanoscale structures derived from Gram-negative (G[-]) bacteria that play an important role in oral diseases. As key mediators of host-microbe interactions, bOMVs contribute to the pathogenesis of periodontitis, oral squamous cell carcinoma (OSCC), and oral lichen planus (OLP) by disrupting immune homeostasis and promoting tissue destruction. Beyond the oral cavity, bOMVs serve as critical vectors in the oral-systemic axis, disseminating virulence factors to distant organs and contributing to atherosclerotic cardiovascular diseases (ACVDs), Alzheimer's disease (AD), and gastrointestinal (GI) disorders. Concurrently, their inherent properties, including cargo-loading capacity, immunogenicity, and biofilm penetration, position them as promising platforms for noninvasive diagnostics and targeted therapeutics. This review systematically integrates current knowledge on bOMVs biogenesis, pathogenic mechanisms in oral and systemic diseases, and emerging applications in diagnosis and treatment. We also highlight key challenges and future directions for translating bOMVs-based strategies into clinical practice, emphasizing their potential as next-generation theranostic tools (combining therapeutic and diagnostic functions) for oral diseases.}, } @article {pmid42570437, year = {2026}, author = {Yan, Y and Tian, D and Yang, F and Zhao, R and Deng, L and Wang, Q and Xie, M}, title = {A brain-targeted biomimetic iron-porphyrin covalent organic framework nanoplatform for Alzheimer's disease: synergistic intervention via antioxidant, Aβ-regulating and immunomodulatory effects.}, journal = {Journal of colloid and interface science}, volume = {724}, number = {Pt 3}, pages = {141264}, doi = {10.1016/j.jcis.2026.141264}, pmid = {42570437}, issn = {1095-7103}, abstract = {The pathological progression of Alzheimer's disease (AD) involves multiple interconnected pathways, including β-amyloid (Aβ) deposition, oxidative stress, and microglial dysfunction, which together form a self-reinforcing vicious cycle. This complexity poses a major challenge to conventional single-target therapeutic strategies. To address this limitation, we developed a biomimetic nanoplatform integrating active brain targeting, multiple therapeutic bioactivities, and immunomodulatory function. The core of this platform was an iron-porphyrin-based covalent organic framework (COF) that possesses enzyme-mimetic antioxidant activity, metal-ion-chelating capability, and Aβ-modulating properties. The COF core was cloaked with a BV2 microglial membrane (BM) to enhance biocompatibility and further functionalized with Angiopep-2 peptide to enable efficient blood brain barrier (BBB) penetration. In vitro studies demonstrated that the platform effectively scavenged various reactive oxygen species, achieved a copper-ion chelation rate of 41.78%, inhibited Aβ aggregation, and depolymerized pre-formed fibrils. At the cellular level, the nanoplatform not only protected neurons from β-amyloid-induced toxicity but also improved the redox status and mitochondrial function of microglia. Furthermore, it promoted the polarization of microglia from the pro-inflammatory M1 phenotype toward the neuroprotective M2 phenotype, which was correlated with enhanced β-amyloid phagocytic capacity. In APP/PS1 (APPswe/PSEN1dE9) transgenic mice, treatment with this nanoplatform markedly reduced cerebral Aβ plaque deposition, attenuated neuroinflammation and oxidative stress, and improved BBB integrity, ultimately leading to the remarkable recovery of spatial learning, memory, and spontaneous exploration abilities in mice. In summary, this integrated nano-strategy, which combines delivery, clearance, and modulation, represents an effective multi-target approach for intervening in the complex pathological network of AD.}, } @article {pmid42570467, year = {2026}, author = {Lin, CH and Hung, PH and Chung, MC and Wu, LY and Chung, CJ}, title = {Risk of Dementia after initiation of GLP-1 RA versus long-acting insulin in patients with type 2 Diabetes mellitus.}, journal = {The journal of prevention of Alzheimer's disease}, volume = {13}, number = {9}, pages = {100645}, doi = {10.1016/j.tjpad.2026.100645}, pmid = {42570467}, issn = {2426-0266}, abstract = {BACKGROUND: Recent studies suggest a decreased risk of dementia in patients treated with glucagon-like peptide-1 receptor agonist (GLP-1 RA). In this study, we compare the risk of dementia associated with GLP-1 RA versus long-acting insulin in adults aged over 50 years with type 2 diabetes (T2DM) using real-world administrative data from a large Taiwan cohort DESIGN: A population-based retrospective cohort study SETTING: We analyzed 10,783 propensity score-matched pairs of adults with T2DM who initiated either GLP-1 RA or long-acting insulin from Taiwan's National Health Insurance Research Database (2011-2021).

MEASUREMENTS: Primary outcome was new-onset dementia; secondary outcomes included dementia requiring treatment and specific dementia subtypes (Alzheimer's disease, vascular dementia, and unspecified dementia). Hazard ratios (HRs) were estimated using Cox models.

RESULTS: Analysis of matched pairs identified 375 cases of newly diagnosed dementia. The incidence rate was 4.86 per 1,000 person-years in GLP-1 RA users versus 7.56 in insulin users. GLP-1 RA use was associated with significantly lower risk of overall dementia (HR 0.64, 95% CI 0.46-0.89, P=0.0072) and unspecified dementia (HR 0.41, 95% CI 0.24-0.68, P=0.0006), but not for Alzheimer's disease (HR 1.48, 95% CI 0.61-3.63, P=0.3867) or vascular dementia (HR 1.66, 95% CI 0.21-13.03, P=0.6324). Among GLP-1 RAs, both liraglutide (HR 0.40, 95% CI 0.20-0.80, P=0.0091) and dulaglutide (HR 0.42, 95% CI 0.19-0.92, P=0.0311) showed significant protective effects against unspecified dementia.

CONCLUSIONS: GLP-1 RA use was associated with lower dementia risk versus long-acting insulin in T2DM patients, especially with liraglutide and dulaglutide. As observational, causality requires confirmation from randomized controlled trials.}, } @article {pmid42571862, year = {2026}, author = {Ding, F and Yang, L and Qiao, S and Lam, TKY and Su, Z and He, Y and Chen, Z and Cui, X and Chan, Y and Zhang, W and Xu, J and Cai, Z and Lyu, A and Li, F}, title = {Targeting transthyretin tetramer with a novel blood-brain barrier-penetrating small-molecule stabilizer for the treatment of Alzheimer's disease.}, journal = {International journal of biological macromolecules}, volume = {}, number = {}, pages = {153998}, doi = {10.1016/j.ijbiomac.2026.153998}, pmid = {42571862}, issn = {1879-0003}, abstract = {The stability of the transthyretin (TTR) tetramer is critical for regulating cerebral amyloid-β (Aβ) homeostasis in Alzheimer's disease (AD). Stable TTR tetramer can directly bind Aβ and promote its clearance from the brain. However, current TTR tetramer stabilizers lack blood-brain barrier (BBB) penetration, limiting their clinical translation. Therefore, to fully realize the therapeutic potential of TTR in AD, novel TTR tetramer stabilizers with superior BBB penetration must be discovered. Here, we aim to identify TTR tetramer stabilizers with BBB penetration via a multidimensional virtual screening workflow, and perform preliminary validation of their biological activities. Finally, Z1097086893 was identified as the lead compound. In vitro, the compound exhibited significant BBB penetration and robust TTR tetramer stabilization activity. In vivo, Z1097086893 also crossed the BBB. MSI showed localization to the choroid plexus within the ventricular system, the principal site of TTR synthesis and secretion in the brain. In the 5xFAD mouse model, the compound significantly reduced hippocampal Aβ plaque burden, alleviated neuronal injury, and rescued spatial learning and recognition memory deficits. Safety assessments confirmed that Z1097086893 was well tolerated at therapeutic doses, with no detectable drug-induced organ toxicity or abnormalities in liver and kidney function. Our findings validate cerebral TTR tetramer stabilization as a promising therapeutic strategy for AD, and provide a lead compound for further clinical translation. Furthermore, the BBB-first screening workflow established in this work offers a generalizable technical framework for the development of brain-targeted therapeutics for AD.}, } @article {pmid42572565, year = {2026}, author = {Song, Z and Xie, Y and Zhu, H and Li, J and Yang, C and Guo, Y and Nong, X and Zhu, Z and Chen, Z and Wang, Z}, title = {Evaluating the cognitive efficacy of marine-derived drugs in Alzheimer's disease: A systematic review and Bayesian network meta-analysis.}, journal = {Therapeutic advances in neurological disorders}, volume = {19}, number = {}, pages = {17562864261476868}, pmid = {42572565}, issn = {1756-2856}, abstract = {BACKGROUND: In recent years, marine-derived drugs for Alzheimer's disease (AD) have attracted growing attention, but their comparative cognitive efficacy and safety remain uncertain because of inconsistent findings across studies.

OBJECTIVES: To compare the efficacy and safety of marine-derived interventions for Alzheimer's disease.

DESIGN: Systematic review and Bayesian network meta-analysis of randomized controlled trials conducted in accordance with PRISMA 2020.

DATA SOURCES AND METHODS: We systematically searched PubMed and the Cochrane Library for randomized controlled trials (RCT) of marine-derived drugs in patients with AD. Continuous outcomes were synthesized as mean differences (MD) in change-from-baseline, and dichotomous outcomes were synthesized as odds ratios (OR), each with 95% credible intervals (CI).

RESULTS: A total of 16 eligible RCTs involving 4,158 patients were included. For the Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog), GV-971 (vs placebo; MD -1.85, 95% CI -2.89 to -0.82) and tramiprosate (vs placebo; MD -0.83, 95% CI -1.63 to -0.02) significantly improved cognitive function. For the Mini-Mental State Examination (MMSE), rifampicin (vs placebo; MD 1.90, 95% CI 0.25 to 3.56) was associated with greater improvement in MMSE scores, whereas tramiprosate (vs placebo; MD -2.40, 95% CI -4.67 to -0.09) was associated with poorer cognitive performance. No statistically significant differences among drugs were observed for the Clinical Dementia Rating-Sum of Boxes (CDR-SB) or for the incidence of adverse events. Overall, treatment effects were outcome-dependent, with significant benefits observed mainly in ADAS-Cog and MMSE, whereas no intervention demonstrated consistent superiority across all cognitive outcomes.

CONCLUSION: Marine-derived drugs showed generally acceptable safety and potential cognitive benefits in selected outcomes. GV-971 and tramiprosate improved ADAS-Cog scores, while rifampicin therapy showed a possible MMSE benefit. However, no intervention was consistently superior across cognitive outcomes, and the antibiotic finding was based on a single small trial. Current evidence is therefore insufficient to identify the optimal marine-derived therapy for AD, highlighting the need for larger, adequately powered RCTs.}, } @article {pmid42573081, year = {2026}, author = {Saffour, S and Gul, TS and Gul, HI}, title = {Rational drug design for Alzheimer's disease: from approved therapies to next-generation clinical candidates and AI-guided innovation.}, journal = {Future medicinal chemistry}, volume = {}, number = {}, pages = {1-19}, doi = {10.1080/17568919.2026.2714022}, pmid = {42573081}, issn = {1756-8927}, abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by multifactorial pathology, including amyloid-β (Aβ) aggregation, tau hyperphosphorylation, oxidative stress, neuroinflammation, and synaptic dysfunction. Despite extensive research, currently approved treatment provides only symptomatic relief, while recently approved disease-modifying monoclonal antibodies have shown limited benefits. Ongoing clinical investigations have shifted toward multi-target directed ligands (MTDLs), RNA-based therapies, immunotherapies, and vaccines. Some approved drugs that have established safety profiles are being repurposed to address the disease's neuropsychiatric symptoms or modulate AD pathological changes. Integrating diverse pharmacophores, such as curcumin, resveratrol, chromone, and indole, within a single skeleton is anticipated to exert multi-modal modifying properties. In parallel, optimization of ADME properties, particularly blood-brain barrier (BBB) permeation and efflux modulation, remains a major obstacle in AD drug design. The incorporation of artificial intelligence (AI) and machine learning (ML) is expected to enhance the prediction of pharmacokinetic, pharmacodynamic, and toxicity parameters.}, } @article {pmid42573418, year = {2026}, author = {Norevik, CS and Huuha, AM and Kobro-Flatmoen, A and Lydersen, S and Røsbjørgen, RN and Bækkerud, FH and Scrimgeour, N and Tari, AR}, title = {Effects of Intravenously Administered Plasma from Exercise-Trained Donors on Mitochondrial Respiration in a Rat Model of Alzheimer's Disease.}, journal = {Medicine and science in sports and exercise}, volume = {58}, number = {9}, pages = {1901-1913}, doi = {10.1249/MSS.0000000000004018}, pmid = {42573418}, issn = {1530-0315}, mesh = {Animals ; *Alzheimer Disease/therapy/metabolism ; Male ; *Mitochondria/metabolism ; Disease Models, Animal ; *Physical Conditioning, Animal/physiology ; Oxidative Phosphorylation ; Rats ; Hippocampus/metabolism ; Rats, Transgenic ; *Plasma ; Proteomics ; Blood Donation ; Cell Respiration ; }, abstract = {PURPOSE: Dysfunction of mitochondria is observed early in Alzheimer's disease (AD), possibly driving the pathogenesis of the disease. This study aims to assess whether plasma from exercise-trained donors can enhance mitochondrial function in a transgenic AD model and to gain insight into the proteomic profile of the donor plasma.

METHODS: Male McGill-R-Thy1-APP rats (n = 3 per treatment group) were treated at either an early preplaque stage (2.2 months) or a later stage (5.2 months) with plasma from exercise-trained donors (ExPlas), sedentary donors (SedPlas), or saline. The rats received 14 transfusions over 6 wk. Mitochondrial respiration was assessed in cornu ammonis (CA), dentate gyrus (DG), gastrocnemius, and left ventricle using high-resolution respirometry. Proteomic analyses were performed in donor blood using mass spectrometry.

RESULTS: In early-stage AD rats, ExPlas improved hippocampal mitochondrial respiration. Compared with saline, CA oxidative phosphorylation (OXPHOS) capacity for complex I increased by +30.8 pmol O2·s-1·mg-1 (P < 0.001) and CI+II by +37.8 pmol O2·s-1·mg-1 (P < 0.001). Compared with SedPlas, CA OXPHOS for CI increased by +16.9 pmol O2·s-1·mg-1 (P = 0.01) and CI+II by +23.8 pmol O2·s-1·mg-1 (P = 0.007). In DG, similar improvements were only seen compared with saline. In CA, but not DG, of later-stage rats, ExPlas produced smaller but significant increases in CI and CI+II OXPHOS compared with saline, but no significant differences compared with SedPlas. No changes were observed in muscle or heart. Proteomics revealed enrichment of complement and platelet-related pathways in ExPlas.

CONCLUSIONS: This proof-of-concept study shows that exercise-trained donor plasma enhances hippocampal mitochondrial respiration in early-stage AD rats and, to a lesser extent, in later-stage AD rats. The proteomic profile of the exercise-trained donor plasma indicates a role of altered complement and platelet functions.}, } @article {pmid40903964, year = {2026}, author = {Wu, S and Guo, T and Zheng, X and Gu, C and Hu, Y and Gu, X and Zhou, X}, title = {Integrated machine learning-based RNA sequencing and single-cell analysis reveal RNA methylation regulation patterns in the immune microenvironment of Alzheimer's disease.}, journal = {Neural regeneration research}, volume = {21}, number = {8}, pages = {3754-3768}, pmid = {40903964}, issn = {1673-5374}, abstract = {Alterations in RNA methylation may affect the initiation and development of Alzheimer’s disease. However, the exact nature of the relationship between RNA methylation and Alzheimer’s disease remains unclear. In this study, RNA methylation levels were analyzed by bulk transcriptomic and single-cell RNA sequencing. The expression levels of RNA methylation regulators were confirmed using molecular biology techniques. Co-expression network analysis was used to identify relevant long non-coding RNAs. Molecular subtypes related to RNA methylation were classified, and variations in clinical characteristics, biological behavior, and immune signatures between subtypes were assessed. Machine learning approaches were applied to identify methylation-associated long non-coding RNAs, which were used to construct a risk model and nomogram for Alzheimer’s disease. Potential therapeutic agents for different risk groups were predicted, and in vitro experiments were conducted to identify key RNA methylation events. Single-cell analysis demonstrated enhanced RNA methylation in patients with Alzheimer’s disease, particularly within T cells, B cells, and NK cells. Quantitative reverse transcription-polymerase chain reaction and western blot confirmed alterations in RNA methylation regulators in neurons treated with amyloid-β oligomers in vitro. This evidence supported the classification of patients with Alzheimer’s disease into heterogeneous subtypes. Specifically, subtype 1 was identified as the immune-active subtype, while subtype 2 was characterized by a metabolic phenotype. Machine learning algorithms identified five significant methylation-associated long non-coding RNAs —LINC01007, MAP4K3-DT, MIR302CHG, VAC14-AS1, and TGFB2-OT1—that accurately predict clinical outcomes for patients with Alzheimer’s disease. These patients were classified into low- and high-risk categories; the latter group displayed higher immune infiltration, upregulated immune regulatory gene expression, and elevated immune scores and responded better to treatment with arachidonic-trifluoroethane. These findings suggest that dysregulated RNA methylation alters the immune microenvironment in Alzheimer’s disease and is closely associated with its progression. This phenomenon provides novel insights into potential therapeutic strategies for Alzheimer’s disease that target RNA methylation.}, } @article {pmid42565262, year = {2026}, author = {Collins, EC and Lu, M and Beck, R and Hendrix, J and Hodsdon, ME and Hansson, O}, title = {Plasma P-tau217 for detecting amyloid clearance after donanemab in Alzheimer's disease.}, journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association}, volume = {22}, number = {8}, pages = {e71740}, pmid = {42565262}, issn = {1552-5279}, support = {//Eli Lilly and Company/ ; }, mesh = {Humans ; *Alzheimer Disease/drug therapy/blood/diagnostic imaging ; *tau Proteins/blood ; Positron-Emission Tomography ; Biomarkers/blood ; Phosphorylation ; Female ; Male ; Aged ; *Amyloid beta-Peptides/metabolism ; *Amyloid/metabolism ; ROC Curve ; Antibodies, Monoclonal, Humanized ; }, abstract = {INTRODUCTION: This analysis of the phase 3 TRAILBLAZER-ALZ 2 trial examined whether plasma tau protein phosphorylated at threonine 217 (p-tau217) level can reliably monitor treatment-related amyloid clearance (TRAC) after donanemab treatment in early symptomatic Alzheimer's disease (AD).

METHODS: Amyloid positron emission tomography (PET) and plasma p-tau217 levels were assessed at baseline and longitudinally during study treatment. The diagnostic performance of p-tau217 in detecting post-treatment TRAC (< 24.1 Centiloids [CL]) was evaluated by receiver operating characteristic (ROC) analysis.

RESULTS: Plasma p-tau217 showed suboptimal performance in detecting TRAC by PET in donanemab-treated participants (N = 830), with an area under the ROC curve of 0.61 at 52 weeks.

DISCUSSION: Despite reductions in plasma p-tau217 with donanemab treatment, this biomarker cannot currently be used to accurately detect TRAC by PET (< 24.1 CL) in individuals with early symptomatic AD.}, } @article {pmid42562385, year = {2026}, author = {Gauch, M and Ablinger, I and Corsten, S and Dörr, F and Flöel, A and Grewe, T and Foede, J and Heinrich, I and Knels, C and Köb, AL and Meinzer, M and Rosenkranz, A and Schmischke, A and Unger, N and Volkmer, A and Wuttke, T and Rysop, AU}, title = {Mapping PPA Care: Results of a Survey Study on Speech and Language Therapy for People With Primary Progressive Aphasia Across Germany.}, journal = {Dementia (London, England)}, volume = {}, number = {}, pages = {14713012261473983}, doi = {10.1177/14713012261473983}, pmid = {42562385}, issn = {1741-2684}, abstract = {Background: Primary Progressive Aphasia (PPA) is a rare condition characterised by a gradual loss of language due to neurodegenerative processes including frontotemporal lobar degeneration and Alzheimer's disease. Speech and language therapy is one of the main treatment options for people with PPA (PwPPA). International survey studies among speech and language therapists (SLTs) have revealed considerable shortcomings in treatment options for this patient group. To date, there has been no survey on speech and language therapy for PwPPA in Germany. Methods: We translated a survey that was originally developed to describe speech and language therapy for PPA in the UK into German and adapted it to the German healthcare system. The final 32-item survey covering demographics of SLTs and PwPPA, referral patterns, as well as diagnostic and therapeutic procedures, was distributed online. Results: Data from 46 SLTs, from 10 of Germany's 16 federal states with experience in treating PwPPA were included. These 46 SLTs had treated 158 PwPPA in the last 24 months and reported working with PwPPA for >20 sessions on average. PwPPA were most frequently referred to speech and language therapy 2-3 years after symptom onset with word finding difficulties. Qualitative content analysis revealed barriers on multiple levels to access speech and language therapy. Informal assessments, including analysis of spontaneous speech, interviews with PwPPA and/or carers and screening of language and communication skills were reported as most frequently used. SLTs rated life story work, activity and participation-focused therapy and symptom-focused therapy. for language disorders as the most commonly used for PwPPA. Discussion: This study provides an overview of the current state of speech and language therapy for PwPPA in Germany. It shows that there is currently no clear pathway for PPA care that covers all levels of the International Classification of Functioning Disability and Health and encompasses both assessment and treatment approaches. A comparison of the results obtained from this survey study with those from other similar studies in the UK, Turkey and Italy revealed both similarities and differences. Our findings underscore the need for further research, the development of standardized, evidence-based assessment and intervention tools, and targeted professional training.}, } @article {pmid42564239, year = {2026}, author = {Cretin, B and Philippi, N and Bousiges, O and Dibitonto, L and Blanc, F}, title = {The impact of long-term antiseizure treatment on cognitive decline in late-onset epileptic prodromal Alzheimer's disease: an exploratory study.}, journal = {Frontiers in aging neuroscience}, volume = {18}, number = {}, pages = {1786247}, pmid = {42564239}, issn = {1663-4365}, abstract = {BACKGROUND: The well-documented bidirectional relationship between Alzheimer's disease (AD) and epilepsy suggests that seizures are not merely a complication of AD but may also contribute to disease progression. Emerging evidence indicates that antiseizure medications (ASMs) could potentially slow the disease course and act as disease-modifying agents if initiated early.

OBJECTIVES: We investigated the long-term cognitive and functional effects of ASMs when introduced at the prodromal stage of AD.

METHODS: Twenty-two sporadic epileptic prodromal AD patients (epADs) and 21 matched subjects without epilepsy (nepADs) were followed for a median of 7 years. Baseline cognition, daily functioning, clinical/paraclinical features, and pharmacological profiles were compared. Annual assessments included cognition, pharmacological burden, and functional impairment.

RESULTS: At the final follow-up, epADs evidenced more preserved cognition than nepADs, reflecting a significantly slower annual rate of cognitive decline (-1.2 ± 0.9 vs. -2.7 ± 2.4 points/year on the MMSE score, respectively; p = 0.01). They were also less likely to require neuroleptics (9.1% vs. 47.6%, p < 0.01) or memantine (0% vs. 28.6%, p < 0.01). However, epADs and nepADs had the same proportion of Alzheimer's dementia at the final follow-up visit (90.9% vs. 90.5%, p = 0.96). Despite being significant, these results had low statistical power due to our small sample size and should be considered exploratory.

CONCLUSION: Our findings support the idea that early ASM treatment may attenuate cognitive decline in sporadic prodromal AD patients with comorbid epilepsy. However, these benefits were not accompanied by a lower dementia rate at the final follow-up visit, suggesting that ASMs alone are insufficient for sustained disease modification. Combinatorial therapeutic strategies may be needed to achieve long-term neuroprotection in AD.}, } @article {pmid42564398, year = {2026}, author = {Shi, P and Wang, S and Zang, Z and Wang, D and Yang, C and Tao, J and Liu, J and Sun, J and Shen, W and Wang, R and Sun, M}, title = {Barrier-to-Autointegration Factor 1: a key regulator of nuclear envelope integrity, genome stability, and disease progression.}, journal = {Frontiers in immunology}, volume = {17}, number = {}, pages = {1870828}, pmid = {42564398}, issn = {1664-3224}, mesh = {Humans ; *Genomic Instability ; *DNA-Binding Proteins/genetics/metabolism ; Animals ; *Nuclear Envelope/metabolism/genetics ; *Nuclear Proteins/genetics/metabolism ; Disease Progression ; Neoplasms/genetics/pathology/metabolism ; DNA Repair ; Neurodegenerative Diseases/genetics/metabolism ; cGAS-STING Signaling Pathway ; }, abstract = {Barrier-to-Autointegration Factor 1 (BANF1) is a self-associating protein encoded within the q13.1 locus of chromosome 11. It is integral to multiple cellular processes, including cell cycle regulation, chromatin organization, gene expression modulation, nuclear envelope (NE) repair, DNA damage repair (DDR), innate immune function, and viral infection control. While prior investigations have provided preliminary phenotypic and bioinformatic characterizations of BANF1 across various disease states, comprehensive analyses detailing its functional roles and mechanistic underpinnings in diverse pathological contexts remain scarce. In cancer, BANF1 is frequently upregulated, with cancer cells leveraging its functions to preserve NE integrity, inhibit activation of the cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) immune pathway, and facilitate epithelial-mesenchymal transition (EMT). These activities contribute to enhanced genomic stability and promote tumor cell proliferation and migration, thereby conferring oncogenic properties. In neurodegenerative diseases, BANF1 is implicated in disease pathogenesis, exemplified by its mediation of glutamate-induced oxidative stress and apoptosis in neuronal cells, as observed in Alzheimer's disease (AD). Additionally, rare mutations in BANF1 are associated with hereditary conditions: the recessive Ala12Thr (A12T) variant causes Néstor-Guillermo progeria syndrome (NGPS), whereas the dominant Gly16Arg (G16R) mutation results in dominant motor neuronopathy. This review further synthesizes recent progress in exploring BANF1 as a therapeutic target, encompassing the development of small-molecule inhibitors, immunomodulatory approaches, and its potential applications in cancer treatment. Overall, this article provides a comprehensive overview of BANF1's structural features, cellular functions, and involvement in disease initiation and progression, with particular emphasis on its expression profiles in malignancies and the therapeutic promise of BANF1-directed interventions.}, } @article {pmid42564518, year = {2026}, author = {Park, J}, title = {Druggable Pathophysiologic Targets in Alzheimer Disease: From Amyloid and Tau to Biomarker-Guided Multimodal Therapy.}, journal = {Dementia and neurocognitive disorders}, volume = {25}, number = {3}, pages = {152-163}, pmid = {42564518}, issn = {2384-0757}, abstract = {Alzheimer disease (AD) is no longer viewed only as a clinical syndrome of memory impairment but as a biological disease continuum driven by interacting amyloid-β, tau, glial, vascular, metabolic, and synaptic mechanisms. This shift has practical therapeutic consequences. Symptomatic agents such as cholinesterase inhibitors and memantine remain useful for selected patients, but they do not directly modify the core neurodegenerative process. In contrast, amyloid-β monoclonal antibodies have provided proof that biomarker-confirmed early AD can be slowed, although the magnitude of clinical benefit is modest, treatment is restricted to carefully selected patients, and amyloid-related imaging abnormalities require structured monitoring. Tau pathology, neuroinflammation, blood-brain barrier dysfunction, mitochondrial and oxidative stress, and impaired proteostasis are therefore increasingly important druggable axes rather than secondary background phenomena. A staged, biomarker-guided druggability framework can evaluate each target by biological proximity to clinical decline, biomarker measurability, therapeutic modifiability, implementation feasibility, and suitability for sequencing or combination therapy. Validated and emerging targets are summarized with emphasis on how biomarkers reshape patient selection and outcome assessment and how anti-amyloid therapy can be integrated with stage-specific interventions targeting tau propagation, glial activation, vascular injury, clearance failure, and metabolic vulnerability. The central conclusion is that AD drug development should move from a single-target rescue model toward biomarker-guided, mechanism-matched, and combination-ready strategies that can be tested earlier in the disease course while maintaining realistic safety and implementation standards.}, } @article {pmid42565151, year = {2026}, author = {Ramireddy, VVS and Shaikh, RG and Pednekar, AR and Tripathi, D and Munde, CT and Wagh, K}, title = {A Systematic Literature Review of Emerging Advances in Neurological Disorders: Diagnostic Innovations, Therapeutic Strategies, and Future Directions.}, journal = {Cureus}, volume = {18}, number = {7}, pages = {e112202}, pmid = {42565151}, issn = {2168-8184}, abstract = {Neurological disorders remain a major clinical burden because they affect cognition, movement, vascular function, behavior, psychological health, and long-term independence. Recent advances in imaging, biomarkers, artificial intelligence, regenerative therapy, immunotherapy, and targeted pharmacology have expanded diagnostic and therapeutic possibilities, yet the evidence remains dispersed across different neurological conditions and study designs. This review aimed to synthesize emerging advances in neurological disorders, focusing on diagnostic innovations, therapeutic strategies, and future clinical directions. A systematic literature review approach was applied using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA)-based screening principles. Eleven studies were included, covering ischemic stroke, glioblastoma, Alzheimer's disease, multiple sclerosis, Parkinson's disease, motor neuron disease, episodic migraine, transient ischemic attack, and postoperative delirium. Data were extracted on study design, condition, intervention or diagnostic method, comparator, outcomes, and key findings. Risk of bias was assessed using the Risk of Bias 2 (RoB 2) tool for randomized trials, the Risk of Bias in Non-randomized Studies of Interventions (ROBINS-I) for nonrandomized, uncontrolled, post hoc, feasibility, and biomarker-monitoring studies, and the Quality Assessment of Diagnostic Accuracy Studies-2 (QUADAS-2) for diagnostic and radiomics studies. Findings showed increasing use of radiomics, circulating tumor DNA, rhythm monitoring, vascular imaging, inflammatory markers, biologics, cell therapy, psychological intervention, and lipid-lowering therapy. Several studies reported promising clinical or biomarker signals, while others clarified treatment limitations in specific disease subtypes. Overall, the findings suggest an emerging shift toward precision-oriented neurology, but larger controlled trials, prospective biomarker validation, standardized outcomes, and longer follow-up are required before routine implementation.}, } @article {pmid42557932, year = {2026}, author = {Wu, H and Chen, Q and Fang, M and Tang, H and Liu, H and Liu, J and Zhang, J and Chi, L and Liu, S and Xin, J and Leng, L and Wang, P and Chi, S and Li, Y and Chen, J and Zhang, L and Zhang, J and Ma, Q and Wang, X and Meng, X and Nao, J and Li, X and Lv, Y and Jia, Y and Zhao, Q and Liu, C and Gan, J and Zhu, J and Song, Y and Li, H and Fei, M and Guo, X and Liu, J and Peng, G and Chen, X and Ji, Y}, title = {Lecanemab use in Chinese patients with Alzheimer's disease: a 12-month multicenter real-world study.}, journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association}, volume = {22}, number = {8}, pages = {e71702}, pmid = {42557932}, issn = {1552-5279}, support = {TJYXZDXK-3-014B//Tianjin Key Medical Discipline Construction Project/ ; }, mesh = {Aged ; Aged, 80 and over ; Female ; Humans ; Male ; *Alzheimer Disease/drug therapy/blood/diagnostic imaging ; Amyloid beta-Peptides/blood ; Biomarkers/blood ; China ; Treatment Outcome ; *Antibodies, Monoclonal, Humanized/therapeutic use ; }, abstract = {INTRODUCTION: We evaluated lecanemab's safety and cognitive outcomes in Chinese patients with Alzheimer's disease (AD) and the utility of blood-based biomarkers (BBMs) for treatment guidance.

METHODS: A multicenter, real-world cohort enrolled 1042 patients receiving lecanemab, with 453, 359, 97 patients followed up at 3, 6, 12 months, respectively. Safety outcomes included amyloid-related imaging abnormalities (ARIA) and infusion-related reactions (IRRs), and the main clinical outcome was Clinical Dementia Rating Scale-Sum of Boxes (CDR-SB) score change.

RESULTS: Of 1,042 patients, ARIA occurred in 7.87%, and IRRs in 16.12%. Discontinuation was 16.51%, mainly due to financial burden. CDR-SB did not change at 12 months overall or in any subgroup. High-accuracy BBMs were the sole AD biomarker assay in 5.28%, with comparable outcomes.

DISCUSSION: Lecanemab exhibited favorable 12-month safety, with no clear evidence of cognitive decline, and BBMs hold potential for treatment guidance. Further studies using a control group are now warranted.}, } @article {pmid42559122, year = {2026}, author = {, and Boquet-Pujadas, A and Anagnostakis, F and Yang, Z and Tian, YE and Duggan, MR and Erus, G and Srinivasan, D and Joynes, CM and Bai, W and Patel, PJ and Walker, KA and Zalesky, A and Davatzikos, C and Wen, J}, title = {Multi-organ AI endophenotypes chart the heterogeneity of brain, eye and heart pan-disease.}, journal = {Nature. Mental health}, volume = {4}, number = {2}, pages = {203-230}, pmid = {42559122}, issn = {2731-6076}, support = {RF1 AG054409/AG/NIA NIH HHS/United States ; RF1 AG092412/AG/NIA NIH HHS/United States ; }, abstract = {Disease heterogeneity and commonality pose significant challenges to precision medicine, as traditional approaches frequently focus on single disease entities and overlook shared mechanisms across conditions. Inspired by pan-cancer and multi-organ research, we introduce the concept of "pan-disease" to investigate the heterogeneity and shared etiology in brain, eye, and heart diseases. Leveraging individual-level data from 129,340 participants, as well as summary-level data, curated from the MULTI consortium, we applied a weakly-supervised deep learning model (Surreal-GAN) to multi-organ imaging, genetic, proteomic, and RNA-seq data, identifying 11 AI-derived biomarkers, called Multi-organ AI Endophenotypes (MAEs), for the brain (Brain 1-6), eye (Eye 1-3), and heart (Heart 1-2), respectively. We found Brain 3 to be a risk factor for Alzheimer's disease (AD) progression and mortality, whereas Brain 5 was protective against AD progression. Crucially, in data from an anti-amyloid AD drug (solanezumab), heterogeneity in cognitive decline trajectories was observed across treatment groups. At week 240, patients with lower brain 1-3 expression had slower cognitive decline, whereas patients with higher expression had faster cognitive decline. A multi-layer causal pathway pinpointed Brain 1 as a mediational endophenotype linking the FLRT2 protein to migraine, exemplifying novel therapeutic targets and pathways. Additionally, genes associated with Eye 1 and Eye 3 were enriched in cancer drug-related gene sets with causal links to specific cancer types and proteins. Finally, Heart 1 and Heart 2 had the highest mortality risk and unique medication history profiles, with Heart 1 showing favorable responses to antihypertensive medications and Heart 2 to digoxin treatment. The 11 MAEs provide novel AI dimensional representations for precision medicine and highlight the potential of AI-driven patient stratification for disease risk monitoring, clinical trials, and drug discovery.}, } @article {pmid42560467, year = {2026}, author = {Brimson, S and Thitilertdecha, P and Kumaree, KK and Brimson, JM}, title = {Sigma-1 Receptor Ligand Blarcamesine (ANAVEX 2-73) for Alzheimer's Disease: A Systematic Review.}, journal = {CNS drugs}, volume = {}, number = {}, pages = {}, pmid = {42560467}, issn = {1179-1934}, abstract = {BACKGROUND AND OBJECTIVES: Alzheimer's disease (AD) remains a major cause of dementia, and currently available therapies provide only modest clinical benefit or are limited by intravenous administration and treatment-related adverse effects. Blarcamesine (ANAVEX 2-73) is an orally administered sigma-1 receptor (S1R) agonist that has demonstrated neuroprotective effects in preclinical studies and has progressed through Phase I, Phase II and Phase IIb/III clinical trials. This systematic review evaluated the current clinical evidence for the efficacy and safety of blarcamesine in early-stage and mild-to-moderate AD.

METHODS: A systematic literature search was conducted in PubMed (including MEDLINE), Scopus, and Google Scholar, together with clinical trial registries, with the final search performed in September 2025. Reference sections of manuscripts were searched, and authors were contacted for additional data. Studies investigating only blarcamesine in participants with mild-to-moderate AD were included. Blarcamesine for other diseases or severe AD were excluded. Data were summarised descriptively in accordance with PRISMA guidelines. The risk of bias was assessed using version 2 of the Cochrane Risk of Bias tool (RoB2) for randomised, placebo-controlled trials, and an adapted version of RoB2 for cross-over trials.

RESULTS: One Phase I first-in-human study in healthy volunteers and ten reports describing two randomised clinical trials (NCT02244541, a randomised open-label study, and NCT03790709, a randomized placebo-controlled study) and their associated open-label extension studies (NCT02756858 and NCT04314934) were identified, including two peer-reviewed manuscripts, two preprints, and six conference abstracts. Thirty-two participants were enrolled in the Phase IIa open-label dose-finding study, where outcome measures were compared to baseline (NCT02244541). In the extended open-label study exploring the cognitive effect for another 52 weeks, 21 of 32 remained in the study (NCT02756858). The randomised placebo-controlled trial (NCT03790709) enrolled 509 participants and randomised them into three groups: 167 treated with 30 mg blarcamesine, 168 treated with 50 mg blarcamesine and 168 treated with placebo (for 30 mg blarcamesine, 112 completed the study; for 50 mg blarcamesine, 90 completed the study; and for placebo, 136 completed the study). Subsequently, 300 of 509 participants remained in the open-label extension (NCT04314934). Across these two studies, blarcamesine was generally well tolerated, with adverse events that were predominantly mild, transient, and dose-related. Treatment was associated with slower cognitive and functional decline, improvements in multiple clinical outcome measures, and reduced brain atrophy in genetically defined subgroups. Participants carrying the SIGMAR1 and COL24A1 wild-type genotypes were associated with greater therapeutic benefit, supporting the potential value of pharmacogenomic patient stratification.

CONCLUSIONS: Current clinical evidence suggests that blarcamesine is a promising orally administered therapeutic candidate for early-stage AD with an acceptable safety profile and encouraging efficacy, particularly in genetically defined populations. However, the available evidence is derived from a limited number of clinical studies, including secondary analyses and conference reports. Additional independent randomised clinical trials are required to confirm these findings and further define the role of blarcamesine in the treatment of AD.

PROSPERO REGISTRATION: CRD420251142826.}, } @article {pmid42561582, year = {2026}, author = {Kumari, P and Lipton, RB and Aschenbrenner, AJ and Sperling, R and Donohue, MC and Grober, E}, title = {Stages of objective memory impairment (SOMI) as a predictor of clinical progression in the A4 study.}, journal = {The journal of prevention of Alzheimer's disease}, volume = {13}, number = {8}, pages = {100641}, doi = {10.1016/j.tjpad.2026.100641}, pmid = {42561582}, issn = {2426-0266}, abstract = {BACKGROUND: About one third of amyloid positive, cognitively normal individuals develop mild cognitive impairment or clinical Alzheimer dementia (AD) over 5 years of follow-up. Sensitive cognitive measures, in addition to biomarkers of amyloid pathology, add to the efficiency of secondary prevention trials by identifying cognitively normal individuals at greatest risk of clinical progression. The Stages of Objective Memory Impairment (SOMI) system, based on the picture version of the Free and Cued Selective Reminding Test with immediate recall (pFCSRT+IR), predicted clinical progression in two observational studies.

OBJECTIVE: Our objective was to extend SOMI's findings to clinical trials using participants from the Anti-Amyloid Treatment in Asymptomatic Alzheimer's(A4) study.

METHODS: Eligible participants were cognitively normal, had a Clinical Dementia Rating (CDR) =0, an elevated amyloid level, the pFCSRT+IR, pTau217, and longitudinal data on the CDR. Cox proportional hazards model was used to assess the association of baseline SOMI stage for clinical progression defined by time to the first of 2 consecutive CDRs > 0 or CDR>0 at last assessment. The sample was censored at 4.5 years of follow-up.

RESULTS: Of the 911 eligible participants, mean age was 72 years, 59% were female, 62% were APOE ε4 carriers, and 37% progressed over 4.5 years. Hazard ratios (HR) for progression were estimated with follow-up time as the timescale and the SOMI 0 group as the reference. The HRs for progression across SOMI stage increased from 1.48(1.15-1.92 p=.003) for SOMI-1, to 1.83 (1.32-2.54, p ≤ 0.001) for SOMI-2, and to 3.04 (1.97-4.68, p ≤ 0.001) for SOMI 3/4. SOMI remained an independent and significant predictor when pTau217 was added to the model.

CONCLUSION: SOMI's risk profile in A4 was similar to prior findings in observational cohorts. SOMI provides a low-cost, non-invasive enrichment tool for identifying individuals at risk for early cognitive decline in secondary prevention trials.}, } @article {pmid42561665, year = {2026}, author = {Tyagi, P and Kumari, S and Sharma, P and Dhapola, R and Paidlewar, M and Medhi, B and HariKrishnaReddy, D}, title = {HMGB1 signalling in Alzheimer's disease: pathogenic roles and therapeutic prospects.}, journal = {International immunopharmacology}, volume = {187}, number = {}, pages = {117204}, doi = {10.1016/j.intimp.2026.117204}, pmid = {42561665}, issn = {1878-1705}, abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative condition marked by the gradual loss of neurons, especially in the hippocampus and cerebral cortex. This neuronal loss results in cognitive decline, memory problems, and changes in behaviour. It accounts for roughly 90% of all cases, making it the most common reason for dementia worldwide, with a marked rise in its occurrence as one ages. AD is pathologically marked by the presence of intracellular neurofibrillary tangles composed of hyperphosphorylated tau protein and the formation of extracellular amyloid-β plaques. Along with these defining characteristics, oxidative stress and chronic neuroinflammation, which are triggered by prolonged astrocyte and microglia activation and excessive reactive oxygen species production, play crucial roles in the development of the illness. The majority of cases of AD are sporadic late-onset illness, but the less common familial variant is linked to mutations in the APP, PSEN1, and PSEN2 genes that cause aberrant amyloid-β formation. High mobility group box 1 (HMGB1) is a crucial modulator of neuroinflammation in AD, according to new research. By activating the receptor for advanced glycation end products (RAGE) and Toll-like receptor 4 (TLR4), HMGB1, especially in its pro-inflammatory disulfide state, hinders memory and learning. RAGE/CaMKKβ-AMPK, ERK1/2, GSK-3β, NF-κB, MAPKs, and NLRP3 inflammasome cascades are among the overlapping downstream signalling pathways that these receptors initiate. Together, these pathways induce tau hyperphosphorylation, amyloid-β buildup, and persistent inflammatory responses. Therefore, a viable treatment approach for reducing neuroinflammation and associated pathologies with AD. is to target HMGB1-mediated signalling networks.}, } @article {pmid42561776, year = {2026}, author = {Chen, W and Zhan, K and Xu, C and Sun, S and Yang, X and Lei, H}, title = {Structure-based identification of novel indole-fused polycyclic derivatives as potent acetylcholinesterase inhibitors.}, journal = {Bioorganic & medicinal chemistry}, volume = {142}, number = {}, pages = {118765}, doi = {10.1016/j.bmc.2026.118765}, pmid = {42561776}, issn = {1464-3391}, abstract = {The pathogenesis of Alzheimer's disease (AD) is closely associated with cholinergic neuronal impairment, which is induced by excessive degradation of acetylcholine (ACh) mediated by acetylcholinesterase (AChE). In this study, a series of novel indole-fused polycyclic derivatives (1-28) were designed, synthesized, and assessed for their AChE inhibitory activities. The biological evaluation results demonstrated that most of the compounds exhibited moderate to excellent AChE inhibitory activities. Among them, compounds 8, 9, 21, and 26 showed leading AChE inhibitory activity with IC50 values of 0.29 μM, 1.5 μM, 1.2 μM, and 1 μM, respectively, which were superior to the positive control galantamine (IC50 = 2.2 μM). Furthermore, favorable drug-likeness profiles and optimal pharmacokinetic properties were confirmed for compound 8 through ADME analysis. Stable binding interactions between compound 8 and AChE were validated by the results of 100 ns molecular dynamics simulations. Overall, compound 8 was characterized as a potent and well-qualified AChE inhibitor, and further systematic investigations are warranted for its application in the treatment of AD-related diseases.}, } @article {pmid42552384, year = {2026}, author = {Klimmt, J and Cardoso Gonçalves, C and Montgomery, JV and Müller, SA and Bublitz, M and Filser, S and Paeger, L and Nuscher, B and Dannert, A and Roeber, S and Pravata, V and Schifferer, M and Shrouder, JJ and Schulz, N and González-Gallego, J and Cappello, S and Misgeld, T and Plesnila, N and Beltrán, E and Herms, J and De Domenico, E and Beyer, MD and Schultze, JL and Haass, C and Lichtenthaler, SF and Carraro, C and Paquet, D}, title = {A reproducible three-dimensional model of human brain tissue to investigate physiological and disease-associated microglia phenotypes.}, journal = {Nature neuroscience}, volume = {}, number = {}, pages = {}, pmid = {42552384}, issn = {1546-1726}, support = {ADR AD2019604S//BrightFocus Foundation (BrightFocus)/ ; 16LW047//Bundesministerium für Bildung und Forschung (Federal Ministry of Education and Research)/ ; }, abstract = {Stem-cell-based in vitro models offer promising potential to elucidate human brain cell functions and interactions, but limitations in reproducibility, maturation and cell-type diversity persist. Especially, prolonged incorporation of mature microglia and studies of neuroinflammation have proven challenging. Here, we developed a human induced pluripotent stem cell-based three-dimensional cortical brain tissue model (3BTM) containing neurons, astrocytes and microglia with high reproducibility, maturity and viability. 3BTMs show morphological, functional and proteomic maturation of all cell types, leading to high similarity to their in vivo counterparts. Incorporated microglia survive for over 6 months and display mature morphology, functions and gene expression. Importantly, when engineered to model Alzheimer's disease pathology, 3BTMs recapitulate key disease hallmarks, including amyloid deposition, increased phospho-tau levels and neuroinflammation, with microglia shifting their transcriptional landscape to disease-relevant signatures. Treatment of Alzheimer's disease 3BTMs with anti-Aβ immunotherapy cleared deposits and largely reversed disease signatures in glia. Together, our microglia-containing model provides a platform for studying physiological and pathological states of human brain tissue.}, } @article {pmid42552421, year = {2026}, author = {Liao, K and Xie, M and Ibáñez, CF}, title = {p75 neurotrophin receptor signaling through the RhoA/ROCK pathway contributes to Tau-mediated neurodegeneration.}, journal = {Molecular psychiatry}, volume = {}, number = {}, pages = {}, pmid = {42552421}, issn = {1476-5578}, support = {X2026t/77//Royal Swedish Academy of Sciences (Kungl. Vetenskapsakademien)/ ; }, abstract = {Therapeutic development in Alzheimer's Disease (AD) has for the most part been focused on reducing β-amyloid load. Nevertheless, neurofibrillary tangles (NFTs), produced by aggregation of hyper-phosphorylated Tau protein, correlate with neurodegeneration and cognitive impairment significantly better than amyloid accumulation in AD patients. Here we report that P301S mice, a model of Tau-mediated neurodegeneration, carrying mutant variants of the p75 neurotrophin receptor (p75[NTR]) deficient in RhoA/ROCK signaling are protected from neurodegeneration and cognitive impairment. Both p75[∆DD], lacking the death domain, and triple mutant p75[KKEA], unable to interact with RhoGDI, decreased insoluble Tau species, reduced gliosis, neurodegeneration and synapse loss, and improved spatial learning and memory in P301S mice. Intriguingly, p75[C259A], a variant unresponsive to neurotrophins but still competent for RhoA signaling induced by myelin-derived ligands, did not afford any neuroprotection. P301S neurons expressing p75[∆DD] or p75[KKEA], but not p75[C259A], showed reduced phospho-Tau and ROCK and GSK3β activity, the two main kinases responsible for Tau phosphorylation. In line with this, treatment with myelin-associated glycoprotein (MAG) enhanced Tau phosphorylation and ROCK activity in P301S neurons expressing wild type p75[NTR] or p75[C259A], but not p75[∆DD] or p75[KKEA]. Together, these results indicate that p75[NTR] contributes to AD Tauopathy by enhancing the activity of the RhoA-ROCK pathway.}, } @article {pmid42552845, year = {2026}, author = {Wang, X and Li, Y and Ye, J and Lian, H and Li, T and Wang, J}, title = {Lymphedema and Alzheimer's Disease: Connecting Through the "Peripheral-Central Lymphatic System".}, journal = {Lymphatic research and biology}, volume = {}, number = {}, pages = {15578585261471251}, doi = {10.1177/15578585261471251}, pmid = {42552845}, issn = {1557-8585}, abstract = {The connection between the peripheral lymphatic system (PLS) and the central lymphatic system (CLS) plays a crucial role for the overall circulatory system. Notably, there are several similarities between lymphedema and Alzheimer's disease (AD). Accumulating evidence suggests that lymphedema might be associated with AD, potentially influencing its progression through mechanisms related to the peripheral-central lymphatic circulation. This review summarizes the lymphatic system's structure, function, and drainage pathways, emphasizing how aging and blockage of the CLS can exacerbate the progression of AD. Additionally, we discuss the relationship between lymphedema and AD, highlighting the significance of the PLS-CLS and exploring lymphaticovenous anastomosis as a promising treatment for both lymphedema and AD.}, } @article {pmid42553297, year = {2026}, author = {Li, Q and You, M}, title = {Targeting mitochondria for the treatment of neurodegenerative diseases.}, journal = {Frontiers in neuroscience}, volume = {20}, number = {}, pages = {1835506}, pmid = {42553297}, issn = {1662-4548}, abstract = {Mitochondria are central regulators of cellular metabolism, redox balance, calcium signaling, and cell survival, making them essential for neuronal function. Because neurons rely heavily on mitochondrial oxidative phosphorylation to meet their high energetic demands, mitochondrial dysfunction has emerged as a key pathogenic driver in major neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis. Defects in mitochondrial bioenergetics, excessive reactive oxygen species production, impaired mitochondrial dynamics, disrupted mitophagy, and dysregulated calcium handling collectively contribute to neuronal damage, synaptic dysfunction, and neuroinflammation. These insights have prompted growing interest in therapeutic strategies that directly target mitochondria to restore organelle homeostasis. Recent advances in chemical biology and nanomedicine have enabled the development of mitochondria-targeted ligands, peptide-based targeting systems, and carrier or nanotechnology-enabled delivery platforms designed to overcome biological barriers and selectively deliver therapeutic cargos to mitochondria within the central nervous system. In this Review, we summarize mitochondrial pathological mechanisms in neurodegenerative diseases and discuss emerging mitochondria-targeted therapeutic strategies, highlighting delivery technologies, therapeutic modalities, and translational challenges. Although most strategies remain at the preclinical or proof-of-principle stage, these advances are beginning to shape a conceptual framework for precision mitochondrial medicine, with the longer-term goal of developing disease-modifying interventions for neurodegenerative disorders.}, } @article {pmid42554972, year = {2026}, author = {Wang, X and Tao, Y and Li, Q and Yang, J and Liu, Q and Xu, A}, title = {The Therapeutic Efficacy of Gold Needle "Regulating Spirit" Acupuncture for Amnestic Mild Cognitive Impairment: Protocol for a Randomized Controlled Trial.}, journal = {JMIR research protocols}, volume = {15}, number = {}, pages = {e96326}, pmid = {42554972}, issn = {1929-0748}, mesh = {Humans ; *Cognitive Dysfunction/therapy ; *Acupuncture Therapy/methods/instrumentation ; *Needles ; *Gold/therapeutic use ; Aged ; Female ; Male ; Middle Aged ; Treatment Outcome ; Biomarkers/blood ; }, abstract = {BACKGROUND: Amnestic mild cognitive impairment (aMCI), the predominant subtype of mild cognitive impairment, carries the highest risk of progression to Alzheimer disease among all mild cognitive impairment subtypes. Currently, clinical practice lacks an established, authoritative treatment method for this condition. Prior clinical evidence indicates acupuncture may enhance cognitive function in individuals with mild cognitive impairment. Further clinical evidence suggests Gold Needle therapy demonstrates significant therapeutic effects for challenging and refractory conditions; however, a critical gap exists: no clinical trials currently ascertain whether Gold Needle therapy surpasses conventional acupuncture in treating aMCI. This trial aims to rigorously evaluate the therapeutic efficacy and safety of the Gold Needle "Regulating Spirit" method for clinical symptoms in patients with aMCI, alongside investigating its underlying imaging and biochemical mechanisms.

OBJECTIVE: This proposed study aims to identify imaging and laboratory biomarkers for the early diagnosis of aMCI, thereby providing a theoretical foundation for clinical practice.

METHODS: This randomized controlled trial will recruit 90 patients diagnosed with aMCI from the Beijing Hospital of Traditional Chinese Medicine, affiliated with Capital Medical University, alongside 20 healthy volunteers. The 90 patients with aMCI will be randomly allocated to 1 of 3 groups: the Gold Needle "Regulating Spirit" group uses gold-based needles, the general acupuncture "Regulating Spirit" group, or a sham acupuncture control group. The Gold Needle "Regulate Spirit" group uses gold-based needles, the general acupuncture "Regulate Spirit" group uses standard needles, and the sham acupuncture group administers Park needles. Participants will undergo 3 sessions per week of their assigned acupuncture or placebo treatment over a continuous 12-week period.

RESULTS: This study was initiated on September 1, 2023. As of October 30, 2025, 110 eligible participants had been enrolled, and data collection had been completed in full. Data analysis is currently underway, and the preliminary results are expected to be available by June 2025. We hypothesize that, compared with the filiform needle-based mind-regulating acupuncture group, the golden needle-based mind-regulating acupuncture group will demonstrate superior efficacy in improving cognitive impairment. This superiority will be reflected in multiple key outcome measures, including Montreal Cognitive Assessment and Mini-Mental State Examination scores, plasma biomarkers, and functional magnetic resonance imaging findings.

CONCLUSIONS: We anticipate that by the end of the trial, we will be able to definitively ascertain whether the gold acupuncture needle technique for "regulating spirit" offers a significant advantage in treating aMCI, and further investigate the nature of this therapeutic benefit, to offer a more efficacious intervention for the clinical management of aMCI and the prevention of Alzheimer disease.}, } @article {pmid42555876, year = {2026}, author = {Shir, D and Corriveau-Lecavalier, N and Jones, DT and Ramanan, VK and Lachner, C and Knopman, DS and Petersen, RC and Josephs, KA and Day, GS and Graff-Radford, J and Graff-Radford, NR}, title = {Eligibility for Anti-Amyloid Therapies in Patients With Biomarker-Confirmed Atypical Alzheimer Disease Phenotypes.}, journal = {Neurology}, volume = {107}, number = {5}, pages = {e218347}, doi = {10.1212/WNL.0000000000218347}, pmid = {42555876}, issn = {1526-632X}, mesh = {Humans ; *Alzheimer Disease/drug therapy ; Female ; Phenotype ; Aged ; Male ; Retrospective Studies ; Biomarkers ; Aged, 80 and over ; *Patient Selection ; Middle Aged ; *Eligibility Determination ; }, abstract = {BACKGROUND AND OBJECTIVES: Clinical trials of anti-amyloid therapies (AATs) for Alzheimer disease (AD) primarily enrolled patients with mildly symptomatic, amnestic predominant presentations. The applicability of eligibility criteria to atypical AD phenotypes, including posterior cortical atrophy (PCA), logopenic variant primary progressive aphasia (lvPPA), dysexecutive AD (dAD), and corticobasal syndrome because of AD (CBS-AD), is unknown.

METHODS: We conducted a retrospective eligibility analysis of patients with atypical AD evaluated at Mayo Clinic. Theoretical eligibility for AAT was assessed at initial clinical evaluation by applying inclusion and exclusion criteria from landmark clinical trials (Study to Confirm Safety and Efficacy of Lecanemab in Participants With Early Alzheimer's Disease [CLARITY-AD] and the Study of LY3002813 (Donanemab) in Participants With Early Symptomatic Alzheimer's Disease [TRAILBLAZER-ALZ2]) and appropriate use criteria for lecanemab and donanemab. Eligibility percentages and reasons for exclusion were compared across phenotypes.

RESULTS: The cohort included 184 patients (61.4% female) with biomarker-confirmed atypical AD: PCA (n = 98, 53.3%), lvPPA (n = 42, 22.8%), dAD (n = 37, 20.1%), and CBS-AD (n = 7, 3.8%). Age at onset (p = 0.039) and presentation (p < 0.001) differed, with patients with lvPPA oldest (median age at onset, presentation: 63.1, 66.9 years) and patients with dAD youngest (onset, presentation: 55.1, 57.3). Functional impairment differed by phenotype (p = 0.005), with lvPPA more often diagnosed at the mild cognitive impairment/very mild stage (Clinical Dementia Rating [CDR] 0.5; 71.4%), whereas PCA and dAD more frequently presented with mild dementia, although time from symptom onset to diagnosis did not differ (p = 0.634). Mini-Mental State Examination (MMSE) scores differed (p = 0.036), with lower scores in PCA and lvPPA (median 21 and 21, respectively) compared with CBS-AD (median 27). Depending on the eligibility framework applied, 70%-85% of patients would not meet treatment criteria. Bedside cognitive thresholds were the primary drivers of ineligibility (50%-67% of exclusions), despite most patients having early symptomatic disease (global CDR 0.5-1; 82%). Imaging-based exclusions (22%-27%) and severity thresholds (moderate or severe dementia, 19%-23%) were also frequent. Reasons for ineligibility were similar across phenotypes.

DISCUSSION: Most patients with atypical AD would not meet eligibility criteria for AAT, typically because of MMSE-based exclusion rather than measures of cognitive function. Eligibility rates are broadly similar across atypical phenotypes. These findings highlight the need for phenotype-sensitive staging and patient selection for treatment in atypical AD.}, } @article {pmid42555976, year = {2026}, author = {Xu, T and Zhang, C and Yang, Y and Shen, Z and Zhong, Z}, title = {Esketamine alleviates neuroinflammation and cognitive impairment in male 3xTg-AD mice by regulating the TAOK1/IL-17 axis.}, journal = {Canadian journal of physiology and pharmacology}, volume = {}, number = {}, pages = {}, doi = {10.1139/cjpp-2025-0340}, pmid = {42555976}, issn = {1205-7541}, abstract = {Beyond its antidepressant effects, esketamine (ESK) has the potential to enhance neuroplasticity, facilitating the reconnection with emotional and cognitive processes, improving social cognition, and promoting resilience. However, not much is known about its role in Alzheimer's disease (AD). This study aims to explore the potential mechanism of ESK in AD treatment. The potential targets of ESK were predicted by bioinformatics analysis, and 3xTg-AD male mice were subjected to adeno-associated virus and ESK treatment. Cognitive ability, neuronal damage, and proinflammatory factors in 3xTg-AD mice were evaluated. An inflammatory model was established by inducing mouse cortical neurons with mouse IL-17A protein. Neuronal viability was assessed after treatment with different concentrations of ESK. TAOK1 knockdown or IL-17RA knockdown was performed on 3xTg-AD mice and neurons. TAOK1 was highly expressed in the cerebral cortex of ESK-treated 3xTg-AD mice. ESK improved IL-17-induced neuronal inflammation and DNA damage in a TAOK1-dependent manner. TAOK1 interacted with IL-17RA. IL-17RA knockdown improved DNA damage and inflammatory responses in cells and alleviated cognitive impairment and neuroinflammation in AD mice. Overall, ESK protects against DNA damage-mediated neuroinflammation by promoting TAOK1 and inhibiting IL-17 signaling, thereby improving cognitive dysfunction in 3xTg-AD mice.}, } @article {pmid42556030, year = {2026}, author = {Rodriguez, A and Judge, B and Shelley, N and Mehta, V and Friedrichsen, K and Strain, J and Benzinger, TL and Schindler, SE and Holtzman, DM and Cross, AH and Brier, MR}, title = {Clinical features of older MS patients with and without Alzheimer disease biomarkers.}, journal = {Multiple sclerosis and related disorders}, volume = {114}, number = {}, pages = {107406}, doi = {10.1016/j.msard.2026.107406}, pmid = {42556030}, issn = {2211-0356}, abstract = {Multiple sclerosis (MS) is a neurodegenerative disease characterized by inflammatory demyelination and axonal injury. Magnetic resonance imaging (MRI) plays a central role in MS diagnosis. Recent work suggests that biomarkers indicative of Alzheimer's disease (AD) are markedly reduced in people with MS. Whether differences in AD biomarkers are related to different features of MS, including MRI characteristics or treatment history, is unclear. In this study, 100 MS patients from Washington University in St. Louis underwent review of their most recent MRI as well as their prior and present MS disease-modifying treatment (DMT) exposures. We then ascertained the relation of MRI features and DMT to plasma AD biomarker measurements, with only a small subset (N=7) demonstrating APS2+ biomarker evidence of AD. Lesion distribution across MS topographies and total white matter lesion (WML) burden were both similar across MS patients with and without biomarker evidence of AD. Central vein sign (CVS), a recently integrated imaging biomarker of MS, was highly prevalent across the MS cohort and did not differ by AD biomarker status or MS clinical typicality at diagnosis, supporting the MS diagnoses even for people with atypical initial presentations. DMT exposure history showed associations with AD biomarkers: longer exposure to B cell-depleting anti-CD20 monoclonal antibody therapies (BCDT) corresponded to lower levels of amyloid pathology as measured by plasma biomarkers, and longer exposure to interferon-beta corresponded to a less pathological Aβ42/40 ratio. These findings indicate that structural MRI features do not explain differences in AD biomarker profiles in MS, whereas treatment-related immunologic effects may contribute to variation in AD pathology risk in MS patients.}, } @article {pmid42556278, year = {2026}, author = {Shi, Z and Cheng, X and Zhang, C and Hu, J and He, X and Chen, S and Wu, H and Tian, M and Yan, C and He, L}, title = {Vorinostat ameliorates cognitive impairment and Tau pathology in an AAV-P301L-Tau-induced tauopathy mouse model: insights into neuroinflammation and PI3K/AKT/GSK3β signaling.}, journal = {International immunopharmacology}, volume = {187}, number = {}, pages = {117216}, doi = {10.1016/j.intimp.2026.117216}, pmid = {42556278}, issn = {1878-1705}, abstract = {Alzheimer's disease (AD) is a neurodegenerative disorder with significant sex-related differences, exhibiting a higher incidence rate in elderly women. Tau pathology has been implicated in sex-associated differences in AD susceptibility and disease progression, contributing to differential pathological burden between males and females. Vorinostat (SAHA), a histone deacetylase inhibitor (HDACi) used in cancer treatment, has shown potential therapeutic effects in various neurological and psychiatric disorders; however, the mechanisms underlying its regulation of tau-associated pathology remain poorly understood, with limited evidence regarding its effects in tau-related neurodegenerative conditions. In this study, we investigated the effects of SAHA treatment on an AAV-P301L-Tau-induced tauopathy model. In vivo, we observed that SAHA administration significantly improved p-Tau levels in the hippocampus and cortex of mice, reduced microglial activation and neuronal damage, and alleviated tauopathy-associated cognitive impairments. Our findings revealed sex-associated differences in Tau-related pathological alterations, with female mice exhibiting greater pathological changes and differential responses to SAHA treatment in several molecular and histological indicators. Further combined in vivo and in vitro experiments revealed that SAHA was associated with modulation of the PI3K/AKT/GSK3β signaling pathway, suppression of NF-κB activation, and attenuation of neuroinflammatory responses, including reductions in experimentally measured inflammatory markers such as interleukin-6 (IL-6) and tumour necrosis factor alpha (TNF-α). These molecular alterations may represent important regulatory components contributing to the neuroprotective effects of SAHA, rather than acting as the sole determinants of its therapeutic efficacy. In summary, these results indicate that SAHA can improve Tau-associated pathological alterations in an AAV-P301L-Tau-induced tauopathy model. The potential mechanisms may involve coordinated regulation of multiple pathological processes, including modulation of Tau phosphorylation, neuroinflammatory responses, and aging-associated signaling pathways. The observed sex-dependent responses to SAHA provide additional insights into the potential influence of biological sex on HDACi-based therapeutic strategies, although the molecular mechanisms underlying these differences require further investigation.}, } @article {pmid42552038, year = {2026}, author = {Peter L, IR and Chatterjee, D and Chrishone, AF and Francis, D}, title = {Metabolic therapeutic targets in Alzheimer's disease.}, journal = {International review of neurobiology}, volume = {188}, number = {}, pages = {1-32}, doi = {10.1016/bs.irn.2026.05.010}, pmid = {42552038}, issn = {2162-5514}, mesh = {Humans ; *Alzheimer Disease/metabolism/drug therapy ; Animals ; *Energy Metabolism/physiology/drug effects ; *Brain/metabolism ; *Mitochondria/metabolism ; Glucose/metabolism ; }, abstract = {Alzheimer's disease (AD) is increasingly recognized as a disorder marked not only by amyloid-β and tau pathology, but also by profound disturbances in brain energy metabolism that arise early in disease progression. Accumulating evidence indicates that impairments in glucose utilization, insulin signaling, and mitochondrial function precede neurodegeneration and contribute directly to synaptic failure and cognitive decline. This chapter presents a comprehensive overview of Alzheimer's disease through the lens of metabolic dysfunction, highlighting disrupted neuronal bioenergetics as a central and unifying feature of pathogenesis. We examine key metabolic pathways implicated in AD, including cerebral glucose hypometabolism, brain insulin resistance, impaired glycolysis, mitochondrial oxidative phosphorylation deficits, oxidative stress, and altered mitochondrial dynamics. The chapter further discusses therapeutic strategies aimed at restoring metabolic homeostasis, such as insulin sensitization, enhancement of glucose transport, activation of mitochondrial biogenesis, modulation of the electron transport chain, and the use of mitochondria-targeted antioxidants. In parallel, alternative energy approaches-including ketone metabolism, fatty acid oxidation, and pentose phosphate pathway activation-are explored as promising avenues to bypass glucose-dependent energy deficits and reinforce neuronal resilience. Emerging directions in metabolic therapeutics are also highlighted, including combination treatment strategies, NAD[+]-sirtuin and AMPK signaling, and the expanding role of the gut microbiome-brain metabolism axis. By integrating insights from experimental models, neuroimaging studies, and clinical trials, this chapter underscores the potential of metabolic interventions to enable early, disease-modifying strategies for Alzheimer's disease.}, } @article {pmid42552040, year = {2026}, author = {Chaurasia, V and Das Modak, S and Singh, GK and Modi, G}, title = {A comprehensive review on therapeutics and diagnostic agents targeting acetyl and butyryl cholinesterases for AD.}, journal = {International review of neurobiology}, volume = {188}, number = {}, pages = {145-198}, doi = {10.1016/bs.irn.2026.05.017}, pmid = {42552040}, issn = {2162-5514}, mesh = {Humans ; *Alzheimer Disease/drug therapy/diagnosis/enzymology/metabolism ; *Butyrylcholinesterase/metabolism/drug effects ; *Cholinesterase Inhibitors/pharmacology/therapeutic use ; Animals ; *Acetylcholinesterase/metabolism/drug effects ; }, abstract = {Alzheimer's disease (AD) is a progressive, irreversible, and multifaceted neurodegenerative disorder characterized by cognitive decline, memory loss, and behavioral impairment, posing a major global health challenge. Its multifactorial pathology includes cholinergic dysfunction, amyloid-β deposition, tau hyperphosphorylation, oxidative stress, and neuroinflammation. Among these, impairment of the cholinergic system, characterized by reduced acetylcholine levels, plays a crucial role in cognitive deficits. The enzymes acetylcholinesterase (AChE) and butyrylcholinesterase (BChE), which hydrolyze acetylcholine, are closely involved in disease progression and serve as important therapeutic and diagnostic targets in AD. This book chapter provides a comprehensive overview of therapeutic and diagnostic agents targeting AChE and BChE in AD, and discusses small-molecule inhibitors, multifunctional ligands, and emerging strategies to modulate cholinesterase activity and restore cholinergic neurotransmission, alleviating disease symptoms. In addition, the chapter highlights advances in diagnostic approaches using fluorescent probes, particularly near-infrared (NIR) probes, for selective detection and imaging of AChE and BChE, including their molecular design, photophysical properties, enzyme selectivity, and mechanisms of action, all of which are critically examined. Targeting AChE and BChE offers a dual advantage in AD by enabling both symptomatic treatment and early-stage diagnosis. This chapter aims to present a clear and comprehensive overview of recent advances in therapeutic and diagnostic approaches, offering meaningful insights for researchers in developing effective strategies for the treatment and monitoring of AD.}, } @article {pmid42552042, year = {2026}, author = {Milmile, M and Singh, S and Pandey, A and Pawar, G and Petkar, P and Chander, Y and Mishra, R and Chawla, R}, title = {Brain energy crisis in Alzheimer's and Parkinson's disease: Nanotechnology as a therapeutic strategy.}, journal = {International review of neurobiology}, volume = {188}, number = {}, pages = {231-271}, doi = {10.1016/bs.irn.2026.05.016}, pmid = {42552042}, issn = {2162-5514}, mesh = {Humans ; *Parkinson Disease/metabolism/drug therapy/therapy ; *Energy Metabolism/physiology/drug effects ; *Alzheimer Disease/metabolism/drug therapy/therapy ; Animals ; *Brain/metabolism/drug effects ; *Nanotechnology/methods ; Mitochondria/metabolism ; Nanoparticles ; Oxidative Stress ; Drug Delivery Systems/methods ; }, abstract = {Alzheimer's disease and Parkinson's disease are increasingly recognized as disorders marked not only by protein aggregation but by a sustained failure of brain energy metabolism. Years before overt cognitive or motor symptoms emerge, neurons begin to experience impaired glucose utilization, mitochondrial dysfunction, and declining ATP production. Because the brain is highly energy-dependent, even subtle metabolic disturbances can disrupt synaptic function, impair neuronal signaling, and trigger oxidative stress. As mitochondrial efficiency declines, reactive oxygen species accumulate, inflammatory pathways become chronically activated, and damaged cellular components are insufficiently cleared, creating a vicious cycle that accelerates neurodegeneration. Conventional metabolic therapies, including antioxidants and mitochondrial cofactors, have produced limited clinical success, largely due to poor penetration across the blood-brain barrier and lack of specificity for vulnerable neuronal populations and intracellular targets such as mitochondria. Nanotechnology introduces a more precise therapeutic strategy by enabling targeted delivery of metabolic modulators directly to the brain. Engineered nanocarriers can be designed to cross biological barriers, enhance drug stability, and release therapeutic agents in a controlled or stimuli-responsive manner within diseased regions. Advanced systems including polymeric nanoparticles, lipid-based carriers, intranasal nano formulations, biomimetic vesicles, and catalytic nanozymes offer the ability to simultaneously modulate oxidative stress, restore mitochondrial function, and regulate neuroinflammation. By integrating delivery precision with metabolic intervention, neuro-nanomedicine shifts the therapeutic focus from symptomatic management toward addressing the underlying bioenergetic crisis. Although challenges remain in safety validation, scalability, and clinical translation, targeted nanotherapeutic strategies hold significant promise for transforming the treatment landscape of these debilitating neurodegenerative disorders.}, } @article {pmid42552043, year = {2026}, author = {Jain, V and Bharti, S}, title = {The potential of HDAC inhibitors for Alzheimer's disease.}, journal = {International review of neurobiology}, volume = {188}, number = {}, pages = {273-298}, doi = {10.1016/bs.irn.2026.01.005}, pmid = {42552043}, issn = {2162-5514}, mesh = {Humans ; *Alzheimer Disease/drug therapy/metabolism ; *Histone Deacetylase Inhibitors/pharmacology/therapeutic use ; Animals ; *Histone Deacetylases/metabolism ; Epigenesis, Genetic/drug effects ; *Neuroprotective Agents/pharmacology ; }, abstract = {Alzheimer's disease is a progressive neurodegenerative condition characterized by cognitive deterioration, memory loss, and persistent neuroinflammation. Notwithstanding considerable scientific advancements, current therapy strategies predominantly address symptoms and are ineffective in arresting illness progression. Recent studies have demonstrated the crucial role of epigenetic changes, especially histone modifications, in the pathophysiology of Alzheimer's disease. Removal of the acetyl group from histones and non-histone proteins by histone deacetylases (HDACs) plays a pivotal role in the regulation of gene expression, synaptic plasticity, and neuronal survival. Such changes lead to dysregulated HDAC activity, which is further associated with significant clinical characteristics of Alzheimer's disease, including amyloid-beta accumulation, tau hyperphosphorylation, oxidative stress, and neuroinflammation. In Alzheimer's disease and other neurodegenerative diseases, the histone acetylation equilibrium is markedly disrupted, resulting in a shift towards hypoacetylation, which further inhibits the production of neuroprotective genes. Pharmacological inhibition of HDACs can reinstate hyperacetylation, therefore facilitating neuroprotective effects. This chapter explores the therapeutic potential of HDAC inhibitors in relation to Alzheimer's disease. This chapter also focuses on various HDAC isoforms associated with disease progression and explores the detailed mechanism by which HDAC inhibitors affect the epigenetic regulation and neuronal function. Preclinical investigations focusing on the role of HDAC inhibitors in mitigating neuroinflammation and Alzheimer's diseases, with a special focus on HDAC inhibitors in clinical trials, present intriguing opportunities for therapeutic advancement. The chapter further explores various challenges such as off-target effects, restricted isoform specificity, and inadequate blood-brain barrier permeability. To address these constraints, various strategies such as isoform-selective inhibitors, targeted delivery methods, and combination treatments are also explored. Thus, the chapter provides in-depth information on the role of HDAC inhibitors, which hold significant potential as disease-modifying agents in the treatment of Alzheimer's disease.}, } @article {pmid42552044, year = {2026}, author = {Singh, AK and M R, S and P S, A and Krishnamoorthi, S and Iyaswamy, A and Durairajan, SSK}, title = {The Tau-mitochondria connection and its impact on cellular energy metabolism in Alzheimer's disease.}, journal = {International review of neurobiology}, volume = {188}, number = {}, pages = {299-361}, doi = {10.1016/bs.irn.2026.06.002}, pmid = {42552044}, issn = {2162-5514}, mesh = {Humans ; *Alzheimer Disease/metabolism/pathology ; *Energy Metabolism/physiology ; *Mitochondria/metabolism ; *tau Proteins/metabolism ; Animals ; }, abstract = {Alzheimer's disease (AD) is a complex multifactorial neurodegenerative disease process resulting in progressive cognitive deterioration and synaptic dysfunction. The primary research approach in AD has traditionally focused on amyloid- pathology however an increasingly evidence suggests that tau protein is a key mediator of neuronal damage via a direct action on mitochondrial bioenergetics. In this chapter we look at the nature of the tau-mitochondrial interface, and propose a paradigm of tau-induced energy failure in AD. Physiologically tau provides stability to the microtubules and is involved in transport mechanisms within cells. In AD, tau is excessively post-translationally modified hyperphosphorylated and truncated tau species form toxic oligomers that incorrectly translocate to mitochondria, interacting pathologically with critical proteins such as voltage-dependent anion channel 1 (VDAC1) and adenine nucleotide translocase (ANT), impeding the mitochondrial ATP/ADP exchange and reducing oxidative phosphorylation efficiency. Tau also further damages mitochondria by excessive fission, inhibition of axonal transport and Inhibition of mitophagy by interrupting PINK1-Parkin signaling. In turn, the build-up of dysfunctional mitochondria leads to ROS production, mtDNA damage and calcium imbalance creating a vicious cycle toward oxidative stress and tau pathology. At the cellular level they cause an energy depletion of the synapse and at the systems level cause glucose hypometabolism and activation of neuroinflammation. The chapter additionally discusses novel therapeutic approaches that target both tau and mitochondrial abnormalities, namely antisense oligonucleotides (ASO), mitochondria targeted compounds and mitophagy modifiers, stressing that it would be more effective to utilize a cocktail of these inhibitors. As a whole, in the context of decreased bioenergetics, the tau-mitochondria axis is an important factor to consider in the successful treatment of AD.}, } @article {pmid42552046, year = {2026}, author = {Yadav, N and Banerjee, J and Tiwari, M and Dixit, A}, title = {Brain lipid dysregulation as a driver of energy metabolism failure in Alzheimer's disease.}, journal = {International review of neurobiology}, volume = {188}, number = {}, pages = {363-396}, doi = {10.1016/bs.irn.2026.02.004}, pmid = {42552046}, issn = {2162-5514}, mesh = {Humans ; *Alzheimer Disease/metabolism ; *Energy Metabolism/physiology ; Animals ; *Lipid Metabolism/physiology ; *Brain/metabolism ; Mitochondria/metabolism ; }, abstract = {Alzheimer's Disease (AD) is becoming more widely recognized as a condition of brain energy metabolism, wherein lipid dysregulation plays a crucial, although unrecognized, role. In addition to functioning as structural elements of neuronal membranes, lipids such as phospholipids, sphingolipids, and cholesterol play a crucial role in regulating mitochondrial bioenergetics, synaptic activity, and membrane-associated signaling pathways. In AD, modifications in lipid composition, distribution, and turnover compromise membrane fluidity, disturb mitochondrial dynamics, and obstruct lipid-mediated transport of energy substrates. These alterations intensify oxidative stress, impair glucose and ketone utilization, and stimulate neuroinflammatory pathways that further diminish metabolic capacity. Progress in lipidomics has uncovered disease-specific lipid signatures, providing a fresh understanding of the relationship between lipid homeostasis and neuronal energy loss. Despite extensive focus on amyloid and tau, lipid-mediated bioenergetic failure remains underrepresented in integrative AD models; this chapter addresses this gap and consolidates existing information connecting lipid modifications to metabolic dysfunction in AD, emphasizing molecular pathways and prospective treatment strategies aimed at lipid metabolism to re-establish bioenergetic equilibrium.}, } @article {pmid42552066, year = {2025}, author = {Liu, Y and Poon, CH and Tse, LSR and Roy, J and So, CT and Tong, BC and Yao, KM and Tipoe, GL and Steinbusch, H and Aquili, L and Kalueff, A and Cheung, KH and Fung, ML and Lim, LW}, title = {Homeostatic DNMT3a Activity Is Required to Restore Cognition and Hippocampal DNA Methylation in the 5xFAD Model of Alzheimer's Disease.}, journal = {Aging and disease}, volume = {17}, number = {5}, pages = {2710-2739}, doi = {10.14336/AD.2025.0283}, pmid = {42552066}, issn = {2152-5250}, mesh = {Animals ; *Alzheimer Disease/genetics/metabolism/drug therapy ; DNA Methyltransferase 3A ; *Hippocampus/metabolism ; *DNA Methylation/drug effects ; Disease Models, Animal ; Mice ; *DNA (Cytosine-5-)-Methyltransferases/metabolism/genetics ; *Cognition/drug effects/physiology ; Mice, Transgenic ; Methionine/pharmacology ; Spatial Memory/drug effects ; Homeostasis ; Male ; Neuronal Plasticity/drug effects ; }, abstract = {Dysregulation of DNA methylation has been implicated in Alzheimer's disease (AD), making the manipulation of DNA methylation processes a promising therapeutic strategy. DNA methyltransferase 3a (DNMT3a), one of the two de novo DNMTs, is involved in learning and memory. However, it remains elusive whether and how alterations in DNMT3a expression contributes to AD pathogenesis. In this study, we investigated the consequences of DNA methylation dysregulations in the hippocampus of 5xFAD mouse model of AD and explored the use of L-methionine (MET) supplement to restore DNA methylation dysregulations. The 5xFAD model exhibited spatial memory impairments accompanied by global DNA hypomethylation and dysregulated hippocampal expression of DNA methyltransferases (DNMT) and demethylases. Prolonged treatment with MET rescued memory deficits, reduced amyloid-β load, decreased neuroinflammation, restored the expression of plasticity-regulating genes and proteins, and enhanced serotonergic neurotransmission. DNMT3a knockdown diminished the pro-cognitive effects of MET and independently impaired spatial memory and hippocampal neuroplasticity in both wildtype and 5xFAD mice. Interestingly, DNMT3a overexpression also had detrimental effects on spatial memory and hippocampal neuroplasticity in both genotypes. Our findings demonstrate that methyl supplementation can be a promising therapeutic strategy for AD patients with brain DNA hypomethylation and that maintaining DNMT3a homeostasis is crucial for normal cognitive functions and the pro-cognitive effects of MET.}, } @article {pmid42541636, year = {2026}, author = {Yang, F and Gao, W and Wang, J and Li, H}, title = {The Glial Autophagy-Lysosomal-Inflammation Axis in Alzheimer's Disease: a Unifying Mechanistic Framework.}, journal = {Molecular neurobiology}, volume = {63}, number = {1}, pages = {}, pmid = {42541636}, issn = {1559-1182}, mesh = {Humans ; *Alzheimer Disease/pathology/metabolism ; *Autophagy/physiology ; *Neuroglia/pathology/metabolism ; Animals ; *Lysosomes/metabolism/pathology ; *Inflammation/pathology/metabolism ; Signal Transduction ; }, abstract = {Recent studies suggest that impairment of the glial autophagy-lysosomal pathway (ALP) critically contributes to the sustained neuroinflammatory response and neurodegenerative processes in Alzheimer's disease (AD). Glial cells, comprising microglia, astrocytes, oligodendrocytes, and ependymal cells, serve as key immune regulators in the central nervous system, where they are essential for maintaining ALP homeostasis, promoting proteostasis, and modulating neuroinflammatory responses. Here, we systematically review the regulatory roles of glial ALP in AD pathology, emphasizing its involvement in amyloid accumulation, tau hyperphosphorylation, synaptic impairment, white matter damage, and mitochondrial as well as other organelle dysfunction, and provide an in-depth analysis of key signaling pathways including TFEB, mTOR, and NLRP3. Furthermore, we outline therapeutic strategies aimed at restoring lysosomal function, regulating autophagic flux, and suppressing inflammation, along with a discussion of the multi-target regulatory potential of acupuncture and natural bioactive agents. We also highlight emerging ALP-associated biomarkers and their potential utility in early diagnosis and treatment response assessment. The objective of this review is to uncover the mechanistic interplay between glial ALP dysregulation and the pathological cascade of AD, offering a conceptual framework for the development of novel therapeutics that integrate neuroprotection with immune modulation.}, } @article {pmid42541674, year = {2026}, author = {Kewal, A and Rajput, MS and Shah, J and Gandhi, D}, title = {Valorization of 2-aminoethoxydiphenyl borate as a neurotherapeutic agent: modulation of calcineurin, TRPC1 and MARK2/GSK-3β signaling in scopolamine-triggered tauopathy.}, journal = {Inflammopharmacology}, volume = {}, number = {}, pages = {}, pmid = {42541674}, issn = {1568-5608}, support = {(IP/2023-24/68)//Nirma University Funded Minor Research Project Scheme. Directorate of Research, Nirma University, Ahmedabad, India/ ; }, abstract = {In Alzheimer's disease (AD), amyloid beta (Aβ) plaques and hyperphosphorylated tau tangles drive neurodegeneration and cognitive decline. Disrupted calcium homeostasis-particularly via transient receptor potential canonical-1 (TRPC1) channels-contributes to tauopathy and disease progression. This study investigated the therapeutic potential of 2-aminoethoxydiphenyl borate (2-APB), a modulator of TRP channels, in a scopolamine-induced rat model of AD. Adult Wistar rats were assigned to six groups: normal control, disease control (scopolamine 2.5 mg/kg), three 2-APB treatment groups (2.5, 5.0 and 10.0 mg/kg) and a donepezil group (5.0 mg/kg), each with six animals. Treatments lasted three weeks. Cognitive performance was assessed using the Morris water maze, memory consolidation and open field tests. Biochemical assays measured acetylcholinesterase (AChE), calcineurin, oxidative stress markers (GSH, MDA) and inflammatory cytokines (TNF-α, IL-6, IL-1β). Protein and gene expression analyses (Western blot, qRT-PCR) evaluated tau, GSK-3β, TRPC1, MARK2, and calcineurin A/PPP3CA, alongside histopathological and immunohistochemical studies. 2-APB treatment significantly reduced pro-inflammatory cytokines, alleviated neuroinflammation, and decreased oxidative stress. Cognitive function improved, correlating with normalized AChE activity and preserved neuronal structure. At the molecular level, 2-APB reduced tau hyperphosphorylation at Ser396 and Thr231, likely through suppression of TRPC1-associated calcium entry and consequent modulation of calcium-dependent kinases (MARK2) and phosphatases (calcineurin), as well as the GSK-3β pathway. However, given that 2-APB is a broad-spectrum calcium signaling modulator - known to act on IP3 receptors, SOCE/ORAI pathways, and multiple TRPC subtypes in addition to TRPC1-the present findings provide supportive evidence linking TRPC1 modulation to the observed neuroprotective effects. Although, the involvement of additional interconnected signaling mechanisms cannot be excluded and these findings should be interpreted within the context of 2-APB's pleiotropic pharmacological profile. Downregulation of TRPC1 and calcineurin A/PPP3CA gene expression supported 2-APB's role in restoring calcium balance and mitigating tau pathology. These results highlight 2-APB's potential in addressing key AD features-tauopathy, oxidative stress, neuroinflammation and cognitive impairment-warranting further preclinical and clinical research as a potential therapeutic for AD and related tauopathies.}, } @article {pmid42542289, year = {2026}, author = {Rodrigues, ES and Gomes, J and Comis-Neto, AA and Arena, RVP and Meus, SS and Evangelista, HC and Luzardo, BFS and Ávila, DS and Rosa, SG and Pinton, S}, title = {Differential effects of Lactobacillus casei in probiotic and paraprobiotic forms on behavioral performance, oxidative stress, neuroinflammation, and cholinergic dysfunction in a streptozotocin-induced model of sporadic Alzheimer's disease.}, journal = {Progress in neuro-psychopharmacology & biological psychiatry}, volume = {149}, number = {}, pages = {111865}, doi = {10.1016/j.pnpbp.2026.111865}, pmid = {42542289}, issn = {1878-4216}, abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by cognitive decline, oxidative stress, neuroinflammation, and cholinergic dysfunction. Increasing evidence suggests that gut microbiota disturbances contribute to AD progression, encouraging the investigation of microbiota-modulating approaches such as probiotics and paraprobiotics. This study evaluated the effects of Lactobacillus casei probiotic and its thermally inactivated paraprobiotic on cognitive, behavioral, oxidative, cholinergic, and inflammatory alterations in a sporadic AD model induced by intracerebroventricular streptozotocin (STZ-ICV; 3 mg/3 μL/site) in female rats. From day 4, animals received daily oral treatment with probiotic L. casei (1 × 10[9] CFU), paraprobiotic (100 mg/kg), or saline for 14 days. Behavioral assessments of memory and exploratory activity were performed alongside biochemical analyses of oxidative stress markers, antioxidant defenses, acetylcholinesterase (AChE) activity, and neuroinflammatory parameters in central and peripheral tissues. STZ-ICV administration induced impairments in working and long-term memory, increased oxidative stress and neuroinflammation, elevated AChE activity, and promoted intestinal and behavioral alterations. Both probiotic and paraprobiotic treatments attenuated memory deficits, reduced lipid peroxidation, inhibited AChE activity, and decreased inflammatory markers. However, their effects differed in magnitude and tissue specificity. The probiotic mainly improved peripheral antioxidant defenses, whereas the paraprobiotic exerted broader neuroprotective effects, reducing cerebral oxidative stress, restoring non-enzymatic antioxidant levels in the hippocampus and colon, improving jejunal catalase activity, and attenuating hippocampal astrogliosis. These findings demonstrate that modulation of the gut-brain axis through L. casei-based interventions mitigates key pathological features of sporadic AD, with paraprobiotics emerging as a promising and stable alternative with enhanced neuroprotective potential independent of bacterial viability.}, } @article {pmid42542440, year = {2026}, author = {Wang, J and Huang, L and Li, B and Guo, Q and Xie, F}, title = {Advancing Alzheimer's disease research in China: insights, innovations, and future directions from the chinese preclinical Alzheimer's disease study (CPAS).}, journal = {Molecular psychiatry}, volume = {}, number = {}, pages = {}, pmid = {42542440}, issn = {1476-5578}, abstract = {This review delves into the advancements in Alzheimer's Disease (AD) research in China, focusing on insights, innovations, and future directions derived from the Chinese Preclinical Alzheimer's Disease Study (CPAS). With an aging population, AD prevalence has risen, increasing societal and economic burdens. CPAS, initiated in 2019, aims to identify early Alzheimer's pathology using plasma biomarkers and PET imaging. The study includes participants across the cognitive spectrum, including cognitively unimpaired individuals, patients with mild cognitive impairment (MCI), and patients with dementia, undergoing comprehensive assessments. Key findings include the impact of Aβ-PET on diagnosis and management, risk factors for amyloid pathology, and the expansion of biomarkers to include synaptic and other PET imaging markers. Future directions involve exploring disease-modifying therapies and applying multi-omics approaches to enhance the understanding and treatment of AD. These efforts are crucial for advancing personalized medicine and improving therapeutic outcomes in China and globally.}, } @article {pmid42545731, year = {2026}, author = {Maiese, K}, title = {Oxidative stress, aging, metabolism, SIRT1, and the gut microbiota: the neurocardiac basis of cognitive loss.}, journal = {Medical gas research}, volume = {}, number = {}, pages = {}, pmid = {42545731}, issn = {2045-9912}, abstract = {FactsCardiovascular disease, Alzheimer's disease, and multiple sclerosis share a neurocardiac basis linked by cellular metabolism and diabetes, indicating the presence of common pathological pathways.Current care remains symptomatic and prevention focused, and interventions targeting shared pathways such as oxidative stress, senescence, and autophagy are lacking.Apolipoprotein E (APOE), glucagon-like peptide-1 (GLP-1) agonism, silent mating type information regulation 2 homolog 1 (Saccharomyces cerevisiae) (SIRT1), mitochondrial dynamics, and the gut microbiome are key modulators of the neurocardiac axis and are highly interdependent.Understanding the interactions among ferroptosis, pyroptosis, and apoptosis under comorbid conditions is essential for clinical translation.Open questionsIs oxidative stress a primary driver or a consequence of autophagy dysregulation that links cardiac dysfunction to cognitive decline?Are GLP-1 receptor agonists neuroprotective independent of glycemic control, and what is the optimal timing and disease stage?Which microbial metabolites influence mitochondrial dynamics and senescence, and can microbiome targeting improve both cardiac and cognitive outcomes?Is combined inhibition of ferroptosis and pyroptosis superior to single-pathway blockade, and how can strategies for different comorbidity profiles be chosen?How can APOE genotypes and individual metabolic states guide personalized therapies that simultaneously reduce cardiovascular risk and neurodegeneration? Cardiovascular disease and cognitive loss have a neurocardiac basis. Poor vascular perfusion can impair cognitive function in both Alzheimer's disease and multiple sclerosis. However, a treatment gap exists because current approaches do not adequately address the shared underlying cellular mechanisms responsible for cognitive dysfunction in these conditions. Current treatments for cognitive impairment in diseases such as cardiovascular disease, Alzheimer's disease, multiple sclerosis, and diabetes often fail to fully address the shared underlying cellular mechanisms. Consequently, the prevailing precision treatment strategy, which focuses on managing symptoms and preventing disease progression, is insufficient. This highlights the urgent need for innovative approaches capable of targeting these common cellular pathways across these diverse conditions. Novel investigations into oxidative stress, cellular senescence, programmed cell death with apoptosis, ferroptosis, pyroptosis, and autophagy, cellular metabolism with apolipoprotein E and glucagon-like peptide-1 receptor agonism, silent mating type information regulation 2 homolog 1 (Saccharomyces cerevisiae), mitochondrial dynamics, and the gut microbiome offer the potential to address the risk factors and clinical treatments for cardiovascular disease and cognitive loss. These pathways are exquisitely dependent upon one another and require in-depth knowledge of the modulatory cellular mechanisms for effective translation to clinical care.}, } @article {pmid42547074, year = {2025}, author = {Mimenza-Alvarado, AJ and Vazquez-Guajardo, M and Martínez-Bravo, LE and Aguilar Navarro, SG}, title = {The state of Alzheimer's disease in Mexico: current challenges and directions for diagnosis and treatment.}, journal = {Gaceta medica de Mexico}, volume = {161}, number = {6}, pages = {558-568}, doi = {10.24875/GMM.25000128}, pmid = {42547074}, issn = {0016-3813}, mesh = {Humans ; *Alzheimer Disease/diagnosis/therapy/epidemiology ; Mexico/epidemiology ; Biomarkers/blood ; tau Proteins ; Disease Progression ; }, abstract = {Alzheimer's disease (AD) is a major public health challenge in Mexico, with cases expected to rise significantly by 2050. For years, AD lacked major medical advances, but the emergence of plasma biomarkers and disease-modifying therapies has shifted the paradigm from symptomatic treatment to altering disease progression. While these advances are promising, they present substantial challenges for developing countries such as Mexico. The availability and interpretation of new biomarkers must be carefully managed, ensuring their use only in individuals with cognitive impairment rather than for asymptomatic screening. Furthermore, the presence of core biomarkers such as phosphorylated tau 217 in asymptomatic individuals should be considered, indicating "at-risk" status rather than biological AD. Although plasma biomarkers offer new opportunities, cerebrospinal fluid remains the only validated tool in Mexico for confirming amyloid pathology. In addition, two disease-modifying therapies are now approved in Mexico, but defining appropriate candidates, balancing potential benefits against risks, and monitoring treatment response remain significant challenges, especially in the absence of amyloid positron emission tomography imaging. Addressing these issues is critical to ensuring that new diagnostic and therapeutic strategies are effectively and equitably integrated into Mexico's healthcare system. Accordingly, there is an urgent need for the development of public policies and diagnostic infrastructure to ensure the safe, affordable, and sustainable implementation of these advances in countries such as Mexico.}, } @article {pmid42547584, year = {2026}, author = {Phénix, J and Sarty, I and Katz, MS and Vázquez Cobá, A and Marure Rojano, AE and Nie, H and Kerksiek, A and Jerry, I and Berger, CS and Kiss, RS and Lütjohann, D and Pastor, WA and Poirier, J and Munter, LM and , }, title = {Reducing CETP activity prevents memory decline in an Alzheimer's disease mouse model.}, journal = {EMBO molecular medicine}, volume = {}, number = {}, pages = {}, pmid = {42547584}, issn = {1757-4684}, support = {PJT-162302//Canadian Institutes of Health Research (CIHR)/ ; PJT-175306//Canadian Institutes of Health Research (CIHR)/ ; PJT-186080//Canadian Institutes of Health Research (CIHR)/ ; PJT 153287//Canadian Institutes of Health Research (CIHR)/ ; PJT-178210//Canadian Institutes of Health Research (CIHR)/ ; RR172187//WFF | Weston Brain Institute (WBI)/ ; 32565//Canada Foundation for Innovation (CFI)/ ; 17-02//ASC | Alzheimer Society Research Program (ASRP)/ ; RGPIN-2015-04645//Natural Sciences and Engineering Research Council of Canada (NSERC)/ ; 356162//FRQ | Santé (FRQS)/ ; 1017734//Secretaría de Ciencia, Humanidades, Tecnología e Innovación (Secihti, Conacyt), Ciudad de México, México/ ; }, abstract = {Epidemiological studies have shown that lower activity of the cholesteryl ester transfer protein (CETP) correlates with reduced Alzheimer's disease (AD) risk. While small-molecule CETP inhibitors like evacetrapib have previously been assessed for cardiovascular diseases, their involvement in AD has not been investigated. Here, we establish CETP as a novel pharmacological target for AD treatment. Using CETP transgenic mice crossed to a mouse model of amyloidosis and administering evacetrapib, we provide evidence that CETP inhibition maintained memory independent of classic AD markers, likely through maintained vascular health, while increasing hippocampal cholesterol and altering plasma lipoproteins. Using proteomic data of cerebrospinal fluid (CSF) from cognitively unimpaired individuals at risk for AD in the PResymptomatic EValuation of Experimental or Novel Treatments for AD (PREVENT-AD) cohort, we confirm that our mouse model reflects physiological changes in pre-symptomatic human subjects. We propose the repurposing of CETP inhibitors as an effective therapeutic strategy to delay or prevent cognitive impairment in AD.}, } @article {pmid42549172, year = {2026}, author = {Liu, BB and Wang, HC and He, YL and Zhang, LJ and Meng, DL and Fu, Y and Wang, MY and Zhang, W}, title = {Inhibition of amyloid β aggregation by venetoclax: a computational and in vitro experimental approach.}, journal = {RSC advances}, volume = {}, number = {}, pages = {}, pmid = {42549172}, issn = {2046-2069}, abstract = {The aggregation of amyloid β-protein (Aβ) plays a key role in the pathological progression of Alzheimer's disease (AD). Given the current absence of effective therapeutic strategies, the drug repurposing approach provides novel insights into the treatment of AD. Venetoclax, a B-cell lymphoma 2 (BCL-2) inhibitor, has demonstrated remarkable efficacy in the treatment of hematological malignancies, characterized by well-defined pharmacokinetic properties and a favorable safety profile. However, its effects and molecular mechanisms in the treatment of AD remain unexplored. Here, we investigated the potential of venetoclax in the inhibition of Aβ aggregation and elucidated its underlying mechanism. The inhibitory effect of venetoclax on Aβ aggregation was assessed using thioflavin T (ThT) fluorescence assays, transmission electron microscopy (TEM), and circular dichroism (CD) spectroscopy. Cellular assays were performed to evaluate the neuroprotective effects of venetoclax against Aβ42-induced neurotoxicity and oxidative stress. Molecular dynamics (MD) simulations were conducted to explore the molecular interactions between venetoclax and Aβ42 peptides. Venetoclax significantly inhibited Aβ aggregation, reduced fibril formation, and decreased β-sheet content at molar ratios of 2 : 1 and 1 : 1 (Aβ : venetoclax). Cellular assays showed that venetoclax attenuated Aβ42-induced neurotoxicity and oxidative stress. MD simulations revealed that venetoclax stabilized Aβ peptides via hydrogen-bonding networks, increasing solvent accessibility and reducing hydrophobic interactions. Venetoclax inhibited Aβ aggregation and mitigated Aβ-induced neurotoxicity by stabilizing Aβ peptide dynamics. These findings support the potential of venetoclax as a repurposed therapeutic candidate for AD.}, } @article {pmid42549510, year = {2026}, author = {Silva, A and Silva, S and Macedo, J and Moreira, P and Baptista, D and Bicker, J and Fortuna, A and Liberal, J and Rodrigues, B and Resende, R and Vitorino, I and Santos, AE and Neves, BM and Pereira, C and Cruz, MT}, title = {Intranasal Administration of Isoeugenol Improves Memory Deficits in APP/PS1 Old Mice-A Role Beyond Nrf2 Activation?.}, journal = {FASEB journal : official publication of the Federation of American Societies for Experimental Biology}, volume = {40}, number = {15}, pages = {e72186}, doi = {10.1096/fj.202601575R}, pmid = {42549510}, issn = {1530-6860}, support = {LA/P/0058/2020//MEC | Fundação para a Ciência e a Tecnologia (FCT)/ ; UID/04539/2025//MEC | Fundação para a Ciência e a Tecnologia (FCT)/ ; UID/PRR/4539/2025//MEC | Fundação para a Ciência e a Tecnologia (FCT)/ ; }, mesh = {Animals ; *NF-E2-Related Factor 2/metabolism ; *Eugenol/analogs & derivatives/administration & dosage/pharmacology ; Mice ; Administration, Intranasal ; *Memory Disorders/drug therapy/metabolism ; *Alzheimer Disease/drug therapy/metabolism ; Humans ; Mice, Transgenic ; *Amyloid beta-Protein Precursor/genetics/metabolism ; *Presenilin-1/genetics/metabolism ; Male ; Disease Models, Animal ; Microglia/metabolism/drug effects ; }, abstract = {Alzheimer's disease (AD), a neurodegenerative disorder and the most common cause of dementia, has no cure or effective treatment; thus, identification of disease-modifying therapeutics is crucial. Nrf2 is a master controller of homeostatic functions whose activity is compromised in AD. Most pharmacological Nrf2 activators are electrophilic molecules that covalently modify cysteine residues in the thiol-rich Keap1, and many are Michael acceptors, such as low-molecular-weight (LMW) skin allergens. However, LMW allergens-induced Nrf2 activation in a pharmacological setting has only recently attracted attention, exemplified by the clinical success of Dimethyl Fumarate. Hence, we investigated, for the first time, the potential of the skin allergen Isoeugenol to activate Nrf2 and reverse selected AD hallmarks, both in vitro and in vivo, in AD-specific models. In vitro studies were performed using microglia cells exposed to LPS and neuronal cells overexpressing human APP with Swedish mutation, to evaluate Isoeugenol's potential in decreasing neuroinflammation and activating the Nrf2 pathway, respectively. In vivo studies were conducted in 10-month-old AD double-transgenic mice (APP/PS1), which were intranasally administered Isougenol. Isoeugenol's pharmacokinetic and pharmacodynamic profile, and its effect on mice cognition were evaluated. The results showed that Isoeugenol (1) activated Nrf2 in AD neuronal cells (likely involving AKT signaling); (2) exhibited antioxidant and Nrf2-dependent anti-inflammatory activity, which was abolished after Nrf2 silencing; (3) exhibited good pharmacokinetic and pharmacodynamic profiles; (4) reduced the levels of Aβ peptides in vitro and in vivo; (5) reduced triglyceride and LDL cholesterol levels in treated mice; and (6) improved the memory deficits in old mice. This is the first study reporting Isoeugenol's intranasal administration, and on specific AD mice models. Overall, the results reinforce Isoeugenol as a pleiotropic molecule, with great potential for AD treatment.}, } @article {pmid42551683, year = {2026}, author = {Gao, J and Xu, Y and Jiang, W and Wang, Z and Wang, L and Zhang, H}, title = {Adenosine monophosphate-activated protein kinase: A golden mediator of exercise in metabolic dysfunction-associated diseases (review).}, journal = {International journal of biological macromolecules}, volume = {}, number = {}, pages = {153885}, doi = {10.1016/j.ijbiomac.2026.153885}, pmid = {42551683}, issn = {1879-0003}, abstract = {Metabolic diseases represent a major threat to human health and are largely associated with excessive energy intake and insufficient energy expenditure. Increasing evidence indicates that obesity, diabetes, metabolic dysfunction-associated fatty liver disease, sarcopenia, Alzheimer's disease, and cancer are closely associated with metabolic dysfunction. Extensive clinical studies and therapeutic strategies have been developed for the prevention and treatment of these disorders. Among these approaches, targeted regulation of cellular energy homeostasis has emerged as a widely recognized strategy, with adenosine monophosphate-activated protein kinase (AMPK) identified as an important therapeutic target for metabolic disease intervention. With the growing development of sports medicine, exercise has become a preferred non-pharmacological approach for the prevention and management of metabolic dysfunction-related diseases, with its beneficial effects largely mediated through AMPK activation. However, the mechanisms by which exercise modulates AMPK and its subtypes in different tissues and diseases remain incompletely understood. Therefore, this narrative review retrieved English-language literature published up to May 2026 from the PubMed, Web of Science, and Scopus databases. A search strategy was constructed using the terms "AMPK", "exercise", "obesity", "diabetes", "NAFLD/MASLD", "sarcopenia", and "Alzheimer's disease" and the corresponding tissues associated with these metabolic diseases. A comprehensive analysis was conducted focusing on AMPK and its subtypes. In this narrative review, we synthesize current research on how exercise modulates AMPK in different tissues and subtype-specific functions, summarizing and analyzing existing evidence that may provide a theoretical basis for subtype-targeted therapeutic strategies (including exercise therapy and pharmacological therapy) for metabolic dysfunction-related diseases.}, } @article {pmid42541418, year = {2026}, author = {Zhang, J and Wang, C and Liang, C and Peng, T and Chang, K and Bu, J and Wang, Z and Wang, X and Hua, Q and Tan, Y}, title = {Neurolymphatic formula restores meningeal and peripheral lymphatic function via VEGFR3 activation: Mechanistic validation of coptisine as a key anti-Alzheimer's compound.}, journal = {Journal of Alzheimer's disease : JAD}, volume = {}, number = {}, pages = {13872877261470114}, doi = {10.1177/13872877261470114}, pmid = {42541418}, issn = {1875-8908}, abstract = {BackgroundAlzheimer's disease (AD) is characterized by amyloid-β (Aβ) accumulation with impaired lymphatic clearance, yet therapies targeting lymphatic dysfunction remain underexplored. The Neurolymphatic Formula (NLF), a traditional Chinese medicine, demonstrates lymphatic modulation potential, but its mechanistic role in AD remains unknown.ObjectiveThis study aimed to elucidate NLF's therapeutic efficacy in AD and investigate whether it enhances central and peripheral lymphangiogenesis via VEGF receptor 3 (VEGFR3) activation.MethodsWe evaluated NLF's pharmacological effects on behavior and AD pathology in APP/PS1 mice, including sunitinib-induced lymphatic impairment models. Underlying mechanisms were explored using network pharmacology, molecular docking, and in vitro assays on human lymphatic endothelial cells (HLECs).ResultsIn APP/PS1 mice, 4-week NLF treatment reduced Aβ plaque burden by 43% (p < 0.01) and improved spatial memory latency by 35% (p < 0.05). NLF restored meningeal and mesenteric lymphatic density in sunitinib-treated mice to 82% and 133% of baseline, respectively (p < 0.01), while upregulating serum VEGFR3 2.3-fold (p < 0.01). To validate NLF's molecular basis, coptisine was identified as a representative VEGFR3 ligand (-7.1 Kcal/mol). In vitro, coptisine (25 μM) enhanced HLEC viability by 60%, accelerated wound closure 2.5-fold, and increased tube junctions by 75% (all p < 0.01) alongside VEGFR3 upregulation.ConclusionsNLF alleviates AD pathology by promoting Aβ clearance through VEGFR3-mediated dual modulation of central and peripheral lymphatic systems. The in vitro efficacy of its constituent, coptisine, mechanistically validates this pro-lymphangiogenic pathway, highlighting NLF's therapeutic potential as a holistic lymphatic-targeted AD treatment.}, } @article {pmid42541425, year = {2026}, author = {Jodlowska-Siewert, E and Liu, L and Yang, K and Ostroushko, D and Lutsey, PL and Chekouo, T and Safo, SE and , }, title = {A score based on MRI imaging variables can predict time to moderate progression in mild cognitive impairment: Multimodal data integration study.}, journal = {Journal of Alzheimer's disease : JAD}, volume = {}, number = {}, pages = {13872877261469162}, doi = {10.1177/13872877261469162}, pmid = {42541425}, issn = {1875-8908}, abstract = {BackgroundMild cognitive impairment (MCI) is an intermediate stage between normal aging and Alzheimer's disease (AD). Because there is no treatment for AD, it is vital to establish which patients are at a higher risk of disease progression, and might benefit from early intervention.ObjectiveThis study investigates whether a score based on clusters of MRI and lipidomic variables can predict the time to moderate progression in MCI.MethodsWe analyzed MRI and lipidomics data from 480 individuals with MCI (mean age 72.14 years, range 55-90 years). Moderate progression was defined as a ≥ 2.5-point increase in the Clinical Dementia Rating Scale Sum of Boxes (baseline mean CDR-SB of 1.2, range 0-10 points). Multi-source data integration and clustering methods were used to derive predictive scores.ResultsThe MRI-based score outperformed the lipidomics score (c-index: 0.754 versus 0.666). A 1-unit increase in the MRI score was linked to a 13% higher risk of moderate progression. Individuals in the top 25% of MRI scores had a 3-fold greater risk of decline.ConclusionsAn MRI-based score offers a simple, effective tool to predict moderate MCI progression and identify high-risk individuals for AD.}, } @article {pmid42541586, year = {2026}, author = {Du, X and Shen, Z and Xu, Y and Song, W and Guo, Y and Kou, J and Gong, S and Ren, Q}, title = {Research progress of traditional Chinese medicine interventions for aging-related nervous system diseases.}, journal = {Biogerontology}, volume = {27}, number = {4}, pages = {}, pmid = {42541586}, issn = {1573-6768}, support = {82574744//National Natural Science Foundation of China/ ; JSTJ-2025-490//The Youth Science and Technology Talent Support Program of Jiangsu Association for Science and Technology/ ; YJQN2025005//Research Project Funding from Affiliated Jiangning Hospital of Chinese Medicine, China Pharmaceutical University/ ; }, mesh = {Humans ; *Medicine, Chinese Traditional/methods ; *Aging/drug effects ; Animals ; *Nervous System Diseases/drug therapy ; *Drugs, Chinese Herbal/therapeutic use ; Oxidative Stress/drug effects ; }, abstract = {Aging-related neurological disorders, including stroke, Alzheimer's disease (AD), Parkinson's disease (PD), epilepsy, and various neuroinflammatory conditions, affect over three billion individuals worldwide and constitute leading causes of morbidity, disability, and socioeconomic burdens. Aging contributes not only to the increased incidence of these disorders but also to their progression through interconnected mechanisms, including endothelial dysfunction, oxidative stress, chronic inflammation, mitochondrial dysfunction, cellular senescence, metabolic imbalance, and gut microbiota dysbiosis. These processes collectively impair neuronal survival, synaptic plasticity, and cognitive and motor functions. Traditional Chinese medicine (TCM), with its characteristic multi-component and multi-target therapeutic strategies, has emerged as a promising approach to counteract age-associated neurological decline. Accumulating preclinical studies suggest that TCM interventions may exert neuroprotective, anti-inflammatory, and antioxidant effects, modulate autophagy, restore metabolic homeostasis, and potentially delay cellular senescence. However, high-quality clinical evidence on safety and efficacy remains limited. This review summarizes current insights into the molecular interplay between aging and neurological disorders and highlights the therapeutic potential of TCM in targeting hallmarks of aging, providing perspectives for integrative prevention and treatment strategies for neurodegenerative and neurovascular diseases.}, } @article {pmid42444063, year = {2026}, author = {Zhang, L and He, K and Zhang, H and Wu, L and Gao, C and Liu, A and Qiu, S and Sun, Q and Gao, Q}, title = {Ultrasound enhances glymphatic-associated solute transport via Piezo1-related mechanotransduction in 5xFAD mice.}, journal = {Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism}, volume = {}, number = {}, pages = {271678X261470064}, pmid = {42444063}, issn = {1559-7016}, abstract = {Glymphatic dysfunction contributes to impaired clearance of neurotoxic proteins (e.g. Aβ) and AD progression. Low-intensity transcranial focused ultrasound (LITFUS) is a noninvasive mechanomodulation strategy that can enhance glymphatic CSF transport via acoustic radiation force. However, its therapeutic efficacy in promoting glymphatic Aβ clearance to alleviate cerebral amyloid burden and cognitive decline remains to be established. 5xFAD mice underwent bilateral hippocampal LITFUS for 4 weeks. Glymphatic transport was assessed using fluorescent tracers administered via intracisternal or intrahippocampal injection, followed by ex vivo imaging. Soluble Aβ levels in the deep cervical lymph nodes (dCLNs) were also measured to evaluate downstream drainage. Immunohistochemistry was used to assess Aβ1-42 deposition and Iba1 immunoreactivity, and cognitive function was evaluated using behavioral tests. Piezo1 involvement was examined using pharmacological inhibition with GsMTx4 together with qPCR and Western blot analyses of isolated brain vascular fractions. Safety was evaluated by blood-brain barrier permeability assays and H&E staining. Compared with sham treatment, LITFUS significantly increased brain-wide cerebrospinal fluid tracer influx and enhanced hippocampal interstitial solute transport in 5xFAD mice. LITFUS also increased soluble Aβ levels in the dCLNs, reduced Aβ deposition in the hippocampus and prefrontal cortex, decreased Iba1 immunoreactivity, and improved learning and memory performance. These effects were accompanied by increased Piezo1 expression in isolated brain vascular fractions and enhanced CaMKII/eNOS signaling. Pharmacological inhibition with GsMTx4 attenuated the LITFUS-induced improvements in glymphatic transport, reduction of Aβ burden, and downstream signaling. LITFUS did not induce detectable blood-brain barrier disruption or histological injury. LITFUS noninvasively enhances glymphatic transport, reduces cerebral Aβ burden, and improves cognitive function in 5xFAD mice. The findings support a role for Piezo1-related mechanotransduction in mediating these effects and highlight the translational potential of LITFUS as a noninvasive therapeutic approach for AD.}, } @article {pmid42531071, year = {2026}, author = {Le Bars, S and Soudy, M and Glaab, E}, title = {XYomics: detecting sex-dependent molecular mechanisms in omics data.}, journal = {Nucleic acids research}, volume = {54}, number = {14}, pages = {}, pmid = {42531071}, issn = {1362-4962}, support = {//Luxembourg Fondation Wivine/ ; INTER/JPND23/17999421/AD-PLCG2//Luxembourg National Research Fund/ ; INTER/22/17104370/RECAST//Luxembourg National Research Fund/ ; INTER/EJP RD22/17027921/PreDYT//Luxembourg National Research Fund/ ; C24/BM/18865990/AsynIntact//Luxembourg National Research Fund/ ; }, mesh = {Humans ; *Software ; Male ; *Sex Characteristics ; *Alzheimer Disease/genetics/metabolism ; Female ; *Computational Biology/methods ; Genomics/methods ; Single-Cell Analysis ; }, abstract = {Understanding sex-dependent differences in disease risk, manifestation, and treatment response is essential for precision medicine. While funding agencies now mandate consideration of Sex as a Biological Variable (SABV), existing bioinformatics tools lack systematic approaches to characterize sex-related molecular mechanisms. Current practices frequently treat sex as a confounding variable, which may obscure important biological differences such as sex-specific alterations, sex-dimorphic changes (opposite effects between sexes), and sex-modulated changes (different effect magnitudes). We present XYomics, an open-source R package for systematic analysis of sex-dependent alterations in biomedical omics data. The software identifies sex-specific, sex-dimorphic, and sex-modulated changes at both individual feature and systems levels. XYomics implements dual analytical modes: sex-disease interaction term modeling for adequately powered datasets and sex-stratified analysis with robust non-significance filtering for smaller sample sizes. Using single-cell RNA sequencing data from Alzheimer's disease patients, we demonstrate how XYomics identifies sex-dimorphic genes largely undetected by standard sex-averaged analyses. By integrating statistical categorization with pathway enrichment and network analysis using a curated hormone signaling interactome, the software facilitates discovery of sex-specific biomarkers and disease mechanisms frequently obscured in sex-aggregated analyses.}, } @article {pmid42532399, year = {2026}, author = {Yildirim, C and Bekerecioglu, S and Akyıldız, S and Bingol, B and Ulusal, H and Yilmaz, SG and Bal, R}, title = {Naringin preserved cognitive function through modulation of cholinergic dysfunction, oxidative stress, and synaptic proteins in scopolamine-induced cognitive impairment.}, journal = {Progress in neuro-psychopharmacology & biological psychiatry}, volume = {}, number = {}, pages = {111868}, doi = {10.1016/j.pnpbp.2026.111868}, pmid = {42532399}, issn = {1878-4216}, abstract = {INTRODUCTION: Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by memory loss and cognitive decline. The cholinergic hypothesis remains central to its framework, suggesting that the degeneration of cholinergic neurons and resulting neurotransmission disruption play a major role in cognitive impairment. Naringin, a potent polyphenolic compound abundant in citrus fruits, has gained attention for its antioxidant, anti-inflammatory, and neuroprotective properties. This study aims to investigate naringin's neuroprotective potential in a scopolamine-induced amnesia model, focusing on the BDNF/GAP-43 signaling pathway and markers of synaptic plasticity.

MATERIALS AND METHODS: A total of 42 male Wistar albino rats were divided into six groups: Saline, Scopolamine (Sco; 1 mg/kg/day), Sco + Naringin (50, 100, and 200 mg/kg), and Sco + Donepezil (3 mg/kg). Following a 21-day treatment period, cognitive and emotional behaviors were assessed using the Morris Water Maze (MWM) and Elevated Plus Maze (EPM) tests. Hippocampal tissues were analyzed for acetylcholinesterase (AChE) activity and oxidative/nitrosative stress markers (MDA, Peroxynitrite, NO, NOS). BDNF and GDNF mRNA expression was quantified by RT-qPCR, and the protein levels of BDNF, GAP-43, PSD-95, SYP, GFAP, SIRT1, KEAP1, Nrf2, and HO-1 were evaluated by Western blot. PSD-95, SYP, GFAP, and NeuN were further examined by confocal imaging.

RESULTS: Scopolamine administration induced significant impairments in spatial learning and memory, alongside anxiogenic-like behaviors. Biochemical analyses revealed a marked increase in AChE activity and oxidative/nitrosative stress in the Sco group. Additionally, scopolamine caused a profound reduction in BDNF, GDNF, GAP-43, PSD-95, and SYP levels, while increasing GFAP expression. Naringin treatment effectively attenuated these deficits by lowering AChE activity, reducing oxidative damage, and suppressing neuroinflammation. Notably, naringin preserved the expression of synaptic proteins, in association with upregulation of the BDNF/GAP-43 pathway and maintaining pre- and post-synaptic protein levels (SYP and PSD-95).

CONCLUSION: These findings demonstrate that naringin exerts significant neuroprotective effects against scopolamine-induced cholinergic amnesia. These findings are consistent with the possibility that naringin preserves synaptic plasticity, enhances neurotrophic support, and mitigates inflammatory responses, suggesting that it may represent a promising natural therapeutic candidate for Alzheimer-like neurodegeneration.}, } @article {pmid42534606, year = {2026}, author = {Wen, J and Zhao, M and Xiao, Y and Li, S and Hu, W}, title = {Correction: OATP1A2 mediates Aβ1-42 transport and may be a novel target for the treatment of Alzheimer's disease.}, journal = {Frontiers in pharmacology}, volume = {17}, number = {}, pages = {1903977}, doi = {10.3389/fphar.2026.1903977}, pmid = {42534606}, issn = {1663-9812}, abstract = {[This corrects the article DOI: 10.3389/fphar.2024.1443789.].}, } @article {pmid42535277, year = {2026}, author = {Kang, SH and Park, YJ and Lee, S and Kang, J and Lee, S and Lee, ES and Jung, HN and Ryoo, I and Hwang, H and Choi, K and Eo, JS and Suh, SI and Oh, K and Koh, SB}, title = {Heterogeneity in plasma p-tau217 response and its association with cognitive trajectories under lecanemab treatment.}, journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association}, volume = {22}, number = {8}, pages = {e71705}, pmid = {42535277}, issn = {1552-5279}, support = {RS-2025-16066879//National Research Foundation of Korea (NRF) grant funded by the Korea government (MSIT)/ ; K2615351//Korea University Guro Hospital (Korea Research-Driven Hospital) and grant funded by Korea University Medicine/ ; RS-2023-00273685//Starting Growth Technological R&D Program (TIPS Program) funded by the Ministry of SMEs and Startups, Korea/ ; BT240027//Seoul R&BD Program through the Seoul Business Agency funded by the Seoul Metropolitan Government/ ; }, mesh = {Humans ; *tau Proteins/blood ; *Alzheimer Disease/drug therapy/blood ; Female ; Biomarkers/blood ; Male ; Aged ; Disease Progression ; Phosphorylation ; Prospective Studies ; Longitudinal Studies ; Treatment Effect Heterogeneity ; Aged, 80 and over ; *Cognition/drug effects ; }, abstract = {INTRODUCTION: Plasma phosphorylated tau 217 (p-tau217) is a promising biomarker for monitoring treatment response in Alzheimer's disease (AD), but its longitudinal dynamics and clinical relevance remain unclear.

METHODS: In this prospective real-world study, 153 patients with early AD receiving lecanemab were analyzed. Longitudinal changes in plasma p-tau217 were assessed, and trajectory patterns were identified using clustering and slope-based approaches. Associations with baseline factors and cognitive outcomes were evaluated.

RESULTS: Plasma p-tau217 levels decreased significantly from 3 months, with the greatest decline between 3 and 6 months, followed by a plateau. Two distinct trajectory groups were identified. Patients in the greater reduction group showed more favorable cognitive trajectories, particularly slower progression in Clinical Dementia Rating-Sum of Boxes (CDR-SB) scores. Hypertension was associated with a diminished biomarker response.

DISCUSSION: These findings support plasma p-tau217 as an early pharmacodynamic biomarker and highlight its potential role in guiding individualized treatment strategies in routine clinical practice.}, } @article {pmid42536296, year = {2026}, author = {Li, YQ and Chen, DX and Zhu, XT and Li, W and Wu, JL and Fang, LM and Li, MQ}, title = {Therapeutic Potential of Jiedu Yizhi Formula for Alzheimer's Disease: A Randomized Controlled Trial.}, journal = {Chinese journal of integrative medicine}, volume = {}, number = {}, pages = {}, pmid = {42536296}, issn = {1993-0402}, abstract = {OBJECTIVE: To observe the clinical effect and safety of Jiedu Yizhi Formula (JYF) in Alzheimer's disease (AD) patients.

METHODS: Eligible patients with mild to moderate AD and Chinese medicine (CM) syndrome of Pi (Spleen)-Shen (Kidney) deficiency with phlegm-turbidity obscuring orifices were collected from the Third Affiliated Hospital of Changchun University of Chinese Medicine between December 2022 and December 2023. Patients were randomly assigned to JYF and donepezil groups at a 1:1 ratio by using a random number table and received a total of 24 weeks of continuous treatment. Both groups were given AD cognitive behavior training and health education at the same time. The Mini Mental State Examination (MMSE), Montreal Cognitive Assessment (MoCA), AD Assessment Scale-Cognitive (ADAS-cog), Activity of Daily Living (ADL), and Hamilton Depression (HAMD) scale scores were measured before treatment, 12 and 24 weeks after treatment. The cognitive domain scores and the total effective rates were also compared between groups. During the study period, any adverse reactions were recorded and compared between groups.

RESULTS: Totally 62 participants completed the study, with 31 in each group. The MMSE, MoCA, ADAS-cog, ADL, and HAMD scores significantly improved after 12 and 24 weeks of treatment in both groups (P<0.05 or P<0.01). Moreover, significant improvements in the ADL and HAMD scores were observed in the JYF group at 12 or 24 weeks than in the donepezil group (P<0.05 or P<0.01). Meanwhile, the cognitive domain scores of orientational and abstraction abilities and the total effective rate (64.52% vs. 45.16%) in the JYF group were significantly higher (P<0.05). No significant difference was found in the incidence of adverse reactions between groups (9.68% vs. 6.45%, P>0.05).

CONCLUSION: JYF can improve the cognitive dysfunction of mild to moderate AD patients with CM syndrome of Pi-Shen deficiency with phlegm-turbidity obscuring orifices, and its safety is good. (Trial registration No. NCT06393413).}, } @article {pmid42537728, year = {2026}, author = {Zhang, Y and Ge, P and Mao, J and Wang, T and Yuan, H}, title = {Role of auricular vagus nerve stimulation in alleviating neuronal apoptosis and cognitive dysfunction in male rats with vascular dementia.}, journal = {Journal of stroke and cerebrovascular diseases : the official journal of National Stroke Association}, volume = {}, number = {}, pages = {108716}, doi = {10.1016/j.jstrokecerebrovasdis.2026.108716}, pmid = {42537728}, issn = {1532-8511}, abstract = {BACKGROUND AND PURPOSE: Vascular dementia (VD) is characterized by cognitive impairment resulting from cerebrovascular damage. Prior studies have shown that vagus nerve stimulation improves learning and memory in patients with Alzheimer's disease. This study, therefore, investigated whether auricular vagus nerve stimulation (aVNS) ameliorates cognitive dysfunction in a rat model of VD through activation of the adenosine A2A receptor (A2AR) and nuclear factor erythroid 2-related factor 2 (Nrf2)/heme oxygenase-1 (HO-1) signaling pathways.

METHODS: Fifty male rats were randomly assigned to five groups by a computer-generated sequence: control (A), sham-operated (B), VD model (C), aVNS-treated (D), and aVNS combined with the A2AR antagonist SCH 58261 (E). Rats in the aVNS group received stimulation (0.6 mA, 40 Hz, 0.5 ms square pulses) for 4 weeks. Spatial learning and memory were evaluated using the Morris water maze test. Rat brain microvascular endothelial cells were cultured and treated with an A2AR agonist and/or a protein kinase A (PKA) inhibitor to verify the involvement of the A2AR-Nrf2/HO-1 pathway. Expression levels of inflammatory cytokines (IL-1β and IL-6), key signaling proteins (A2AR, p-PKA, p-Nrf2, and HO-1), and phosphorylated tau (p-tau) were measured using western blot or enzyme-linked immunosorbent assays.

RESULTS: Compared with Groups C and E, Group D exhibited improved spatial learning and memory. aVNS markedly increased the p-PKA and p-Nrf2/HO-1 levels while reducing p-tau and proinflammatory cytokine levels. In vitro experiments showed that A2AR agonist treatment upregulated p-PKA and p-Nrf2/HO-1 expression; however, this effect was abolished by PKA inhibition.

CONCLUSION: aVNS ameliorates cognitive impairments in VD rats and attenuates neuronal apoptosis, p-tau accumulation, and neuroinflammation, and these effects are associated with activation of the A₂AR/PKA/Nrf2/HO-1 signaling pathway. These findings suggest that aVNS may represent a promising therapeutic strategy for cognitive impairment associated with VD.}, } @article {pmid42537824, year = {2026}, author = {Abouali, O and Mokabber, A and Naderpour, S and Vojoudi, E and Sefat, F and Saeinasab, M and Rahimzadegan, M and Nosrati, R}, title = {Chitosan-based hydrogel for intranasal drug delivery; current advances in the brain diseases treatment.}, journal = {International journal of pharmaceutics}, volume = {}, number = {}, pages = {127259}, doi = {10.1016/j.ijpharm.2026.127259}, pmid = {42537824}, issn = {1873-3476}, abstract = {Neurodegenerative diseases represent a growing health concern that is projected to become more prevalent and affect more people in the upcoming decades. One of the most complicated components of recent neurodegenerative disease therapies is the penetration and delivery of therapeutics to the central nervous system (CNS), which are hindered via the blood-brain barrier (BBB). In response, innovative treatment approaches leveraging noninvasive techniques including nanosized drug delivery systems and intranasal (IN) administration with higher treatment efficacy and patient satisfaction are developing as potential options. IN administration delivers medications directly to the brain through both the olfactory and trigeminal pathways, with the olfactory pathway representing the primary route for nose-to-brain transport. Among various IN platforms, chitosan (CS)-based hydrogels have attracted considerable attention because of their excellent biocompatibility, biodegradability, mucoadhesive properties, and ability to enhance drug permeation by prolonging nasal residence time and transiently modulating epithelial tight junctions. This review critically summarizes recent advances in CS-based hydrogels for IN drug delivery for the treatment of brain diseases including Alzheimer's disease (AD), Parkinson's disease (PD), depressive manifestations, ischemia,brain tumors,epilepsy, seizures, and schizophrenia. In addition, the review discusses the relationships between hydrogel design and therapeutic performance, highlights current translational challenges, and outlines future perspectives for the clinical development of CS-based IN hydrogel systems.}, } @article {pmid42538765, year = {2026}, author = {Sun, H and Huang, D and Yang, F and Zhang, P and Yang, D and Zeng, C}, title = {Metabolomic Discoveries for Traditional Chinese Medicine Efficacy in Alzheimer's Disease.}, journal = {BioMed research international}, volume = {2026}, number = {1}, pages = {e2455800}, pmid = {42538765}, issn = {2314-6141}, support = {2023008//Scientific Research Projects of Medical and Health Institutions of Longhua District, Shenzhen/ ; 82270940//The National Natural Science Foundation of China/ ; }, mesh = {Humans ; *Alzheimer Disease/metabolism/drug therapy ; *Medicine, Chinese Traditional/methods ; *Metabolomics/methods ; *Drugs, Chinese Herbal/therapeutic use ; Animals ; Brain/metabolism ; Metabolic Networks and Pathways/drug effects ; }, abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by cognitive decline, memory impairment, and behavioral alterations. However, the complex etiology and pathogenesis of AD have thus far precluded the development of satisfactory therapeutic agents. Traditional Chinese medicine (TCM) has garnered increasing recognition for its potential in AD management due to its multicomponent, multitarget therapeutic strategy. Metabolomics, an advanced analytical methodology for investigating metabolic alterations in biological systems, has yielded significant insights into both the therapeutic efficacy and mechanistic underpinnings of TCM interventions for AD. This review synthesizes recent metabolomic findings associated with TCM approaches to AD treatment, identifying key metabolic pathways across diverse biological specimens, including brain tissue, blood, urine, and feces. Through systematic elucidation of these metabolic networks, metabolomics offers substantial potential to facilitate the advancement of TCM-derived therapeutics for AD, potentially enhancing global patient outcomes.}, } @article {pmid42538997, year = {2026}, author = {Krunic, A and Umesh Ganesh, N and Coskun, U and Brennan, W and Patel, C and Joshi, O and Lee, J and Gu, TS and Caruso, J and O'Connell, A and Lisboa, C and Crossland, N and Kurkela, M and Julia, T and Fowler, A and Tay, TL and Fischer, A and Delalle, I and Blusztajn, JK and Mellott, TJ}, title = {MicroRNA-223 Enhances Microglia-Dependent Clearance of Amyloid Beta Plaques and Ameliorates Behavioral Deficits in a Mouse Model of Alzheimer's Disease.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, doi = {10.64898/2026.07.20.738977}, pmid = {42538997}, issn = {2692-8205}, abstract = {The Alzheimer's disease (AD) brain is characterized by dysregulated expression of multiple microRNAs (miRNA), positioning them as promising diagnostic and therapeutic targets. The levels of glia-enriched miR-223 are abnormal in the brains and plasma of AD patients and miR-223 is neuroprotective in models of stroke. However, whether miR-223 can be beneficial in AD is not known. Here, we report that intracerebroventricular (ICV) injection of miR-223 oligonucleotide mimic alleviated cognitive impairment, reduced amyloid beta (Aβ) pathology, and ameliorated the defects in synaptic marker expression in App [NL-G-F] AD model mice. Mechanistically, miR-223 induced microglial clustering around Aβ plaques with a concomitant upregulation of microglial phagocytic receptors AXL, TREM2 and CD11c, while pharmacological microglial depletion abolished the plaque-clearance phenotype. Moreover, in human iPSC-derived microglia miR-223 directly targeted multiple genes in the endo-lysosomal pathway, including AD risk gene SPPL2A , indicating that it acts as a major regulator of microglial phenotype. Lastly, long-term AAV-mediated overexpression of miR-223 recapitulates its beneficial effects on cognition, pathology, and synaptic marker expression. Our study demonstrates a novel approach for the treatment of AD using miR-223 and highlights the potential of RNAi-based therapeutics in neurodegenerative disease.}, } @article {pmid42539626, year = {2026}, author = {Han, J and Zhao, W and Deng, R and Wang, Y and Gong, W and Wang, Z and Sun, G and Liu, H and Geng, M and Zhang, Y}, title = {Sodium oligomannate reduces cerebral infarction and improves neurological function through microbiota remodeling in MCAO/R rats.}, journal = {Frontiers in pharmacology}, volume = {17}, number = {}, pages = {1880590}, doi = {10.3389/fphar.2026.1880590}, pmid = {42539626}, issn = {1663-9812}, abstract = {BACKGROUND: Ischemic stroke is the second leading cause of death worldwide, characterized by high mortality and a narrow therapeutic window for thrombolysis. Gut microbiota dysbiosis and gliosis following ischemic stroke are key drivers of post-stroke neurological impairment. Sodium oligomannate (GV-971) is a low-molecular-weight acidic oligosaccharide that targets the gut-brain axis. It alleviates gliosis and improves cognitive dysfunction by remodeling gut microbiota in Alzheimer's disease. However, it is still unknown whether GV-971 has pharmacological activity against ischemic stroke.

METHODS: Here, we explore the efficacy of GV-971 on infarct volume, gliosis, blood-brain barrier integrity, gut microbiota composition, and post-stroke cognitive impairment (PSCI) using a middle cerebral artery occlusion/reperfusion (MCAO/R) model in male Sprague-Dawley rats.

RESULTS: Administer medication before surgery for 4 consecutive days and once after surgery, after stroke 24-hour triphenyltetrazolium chloride (TTC) staining revealed that 0.3 mg/kg GV-971 significantly reduced infarct volume in ischemic brain tissue from 37.81±2.391% to 13.30±4.801% and neurological impairment score of GV-971 treatment significantly decreased from 11.50±0.54 to 7.29±1.47. After stroke 24-hour immunofluorescence analysis of glial activation confirmed that GV-971 significantly reduced central inflammatory responses. Western blot combined with Evans blue staining collectively demonstrated that after stroke 24-hour, GV-971 exerts a significant protective effect on the blood-brain barrier. In the gut, GV-971 reversed microbial dysbiosis, as revealed by shotgun metagenomics, enhanced intestinal barrier integrity, and suppressed colonic inflammation. Antibiotic depletion abolished GV-971's neuroprotective effect, while fecal microbiota transplantation from GV-971-treated donors restored protection, supporting a microbiota-dependent contribution. Furthermore, GV-971-treated rats subjected to MCAO/R exhibited significant improvements in motor and cognitive function. For example, on day 35, Y-maze test results indicated that GV-971 administered either before MCAO/R (pre-treatment) or during the perioperative period (co-treatment) increased spontaneous alternation rate from 60.95±4.91% to 85.60±6.32% and 85.64±5.027%. On day 32, novel object recognition assay results indicated that GV-971 treatment increased new-object exploration from 0.2039±0.03752 to 0.3991±0.1122 (pre-treatment) and 0.5066±0.06982 (co-treatment). On day 42, Barnes maze test results indicated that GV-971 treatment reduced the time required to locate the target hole from 76.45±17.41s to 31.03±20.75 s and 33.37±19.30 s for pre- and co-treatment, respectively.

CONCLUSION: Taken together, GV-971 demonstrated neuroprotective potential in experimental ischemic stroke.}, } @article {pmid42541080, year = {2026}, author = {Espinosa, PS and Li, S and Preisler, J and Hennekens, CH}, title = {Donanemab Infusion and Recurrent Seizures in a Patient With Alzheimer's Disease and Epilepsy in the Absence of Amyloid-Related Imaging Abnormalities (ARIA).}, journal = {Cureus}, volume = {18}, number = {7}, pages = {e111911}, doi = {10.7759/cureus.111911}, pmid = {42541080}, issn = {2168-8184}, abstract = {Donanemab is an immunoglobulin G1 (IgG1) monoclonal antibody that was recently approved by the United States Food and Drug Administration for the treatment of early symptomatic Alzheimer's disease (AD). The drug was approved with boxed warnings for amyloid-related imaging abnormalities (ARIA). While seizures are recognized adverse events, they are predominantly characterized in the context of ARIA and accompanied by edema (ARIA-E) or hemosiderin deposition (ARIA-H). The precise epileptogenic mechanisms of anti-amyloid immunotherapies independent of macroscopic ARIA remain poorly understood. We report the case of a 90-year-old man with mild cognitive impairment due to AD and a history of well-controlled focal epilepsy on levetiracetam, who experienced two generalized tonic-clonic seizures. Each paroxysmal event occurred within two hours of completing his fifth and sixth monthly donanemab (1,400 mg intravenous) infusions. Inter-ictal magnetic resonance imaging (MRI), including fluid-attenuated inversion recovery (FLAIR) and susceptibility-weighted imaging (SWI) sequences, demonstrated no evidence of ARIA-E or ARIA-H. Routine electroencephalography (EEG) revealed no interictal epileptiform discharges. Seizure recurrence necessitated an escalation of his levetiracetam dosage to 750 mg twice daily and the immediate discontinuation of donanemab therapy, after which he remained seizure-free. The temporal proximity of the seizures to the infusions, the positive rechallenge, and the absence of identifiable structural, metabolic, or infectious precipitants raise the possibility of an association with donanemab. However, causality cannot be established from a single case report. Several biologically plausible mechanisms may explain this temporal association, including rapid amyloid-beta (Aβ) clearance, microglial activation, neuroinflammatory responses, and transient blood-brain barrier dysfunction, which may lower the seizure threshold in a patient with pre-existing epileptogenic networks. However, these mechanisms remain hypothetical and were not directly demonstrated in this patient. Clinicians should maintain a high index of suspicion for acute post-infusion seizures in patients receiving donanemab, particularly those with a history of epilepsy, even in the absence of radiographically detectable ARIA. Clinicians should be aware of this potential safety signal in patients with pre-existing epilepsy. Additional studies are needed before specific monitoring or treatment recommendations can be established.}, } @article {pmid42524328, year = {2026}, author = {Miaja, P and Martinez-Baños, M and Martin-Bermejo, MJ and Moreno, I and Dominguez, M and Bovolenta, P}, title = {Pharmacodynamic and stage-dependent therapeutic efficacy of SFRP1 neutralization in a mouse model of Alzheimer's disease.}, journal = {Alzheimer's & dementia (New York, N. Y.)}, volume = {12}, number = {3}, pages = {e70301}, pmid = {42524328}, issn = {2352-8737}, abstract = {INTRODUCTION: Alzheimer's disease (AD) is characterized by early synaptic dysfunction followed by progressive amyloid beta (Aβ) accumulation, neuroinflammation, and cognitive decline. We previously identified secreted frizzled-related protein 1 (SFRP1) as a multifactorial contributor to AD pathogenesis and provided initial evidence that its neutralization ameliorates pathological AD-like traits in mice. Here we evaluate the pharmacodynamics, biodistribution, and therapeutic window of an anti-SFRP1 monoclonal antibody (α-SFRP1) in double transgenic amyloid precursor protein (APP) and presenilin-1 (PS1) mice (APP/PS1).

METHODS: Pharmacokinetics and target engagement of α-SFRP1 were assessed in groups of both male and female APP/PS1 mice using biotinylated or Zirconium-89 labeled ([89]Zr) antibodies, with tissue distribution and α-SFRP1 levels quantified by in-house enzyme-linked immunosorbent assay (ELISA) or positron emission tomography/computed tomography (PET/CT). Therapeutic efficacy was evaluated by administering α-SFRP1 or the SFRP1 inhibitor WAY-316606 at different stages of disease progression via retro-orbital injection, followed by analysis of AD-like pathology using ELISA and quantitative immunofluorescence assays and statistical analysis.

RESULTS: Using [89]Zr-labeled antibodies, we show that intravenously administered α-SFRP1 engages its target systemically and reaches the brain, although at substantially lower levels and with a rapid 24-h clearance. Treatment with α-SFRP1 had no apparent systemic side effects or sex-dependent differences, but its therapeutic efficacy against AD-like brain pathology was strongly dependent on disease stage. Although early administration reduced amyloid pathology in previous studies, treatment initiated at intermediate or advanced stages showed minimal benefit at standard doses. Higher antibody doses reduced amyloid burden and dystrophic neurites but were associated with increased mortality. Pharmacological inhibition of SFRP1 using a small-molecule inhibitor similarly failed to ameliorate pathology at intermediate stages.

DISCUSSION: Together, these findings demonstrate that SFRP1 remains a relevant therapeutic target in AD, but its effective modulation is constrained by limited brain exposure and a narrow therapeutic window, underscoring the importance of early intervention and prompting the search for improved brain-targeted delivery strategies.}, } @article {pmid42524884, year = {2026}, author = {Sa, Y and Yuan, H and Ma, J and Yang, Z and Wang, M and Wang, W and Yang, L and Ma, F and Zhang, W and Mening'oo, GW and Chen, G and Ma, X}, title = {Innovative Test Strip-Based Colorimetric Sensors Integrated With Affinity Chromatography: Acetylcholinesterase Inhibitor Screening Breakthrough in Lycium Barbarum Leaves.}, journal = {Advanced science (Weinheim, Baden-Wurttemberg, Germany)}, volume = {}, number = {}, pages = {e76863}, pmid = {42524884}, issn = {2198-3844}, support = {2023BEG02014//Key Research and Invention Program of Ningxia/ ; 82360684//National Natural Science Foundation of China/ ; 2024AAC02043//Natural Science Foundation of Ningxia/ ; 2026AAC030216//Natural Science Foundation of Ningxia/ ; XJKF240324,XJKF240330//Key Research Projects of Ningxia Medical University/ ; }, abstract = {Current Alzheimer's drugs exhibit limited effectiveness, highlighting the necessity for multi-target treatments. This study developed an innovative and efficient screening platform combining hydrogen peroxide test strip-based colorimetric sensing with affinity chromatography for rapid identification of acetylcholinesterase (AChE) inhibitors from complex herbal medicines. Applying this strategy, from Lycium barbarum leaves, we identified three potent inhibitors: chlorogenic acid, N-acetyl-N'-caffeoylputrescine (NANCP), and N-caffeoylputrescine (NCP), with IC50 ranging from 55.7 to 143.2 µm. Molecular analyses confirmed their stable binding to AChE. In a D-galactose and AlCl3-induced Alzheimer's disease (AD) mouse model, NCP treatment significantly rescued cognitive deficits in AD mice, with the spontaneous alternation rate in the Y-maze test improved by up to 50%. It markedly reduced cerebral Aβ levels (by 54%) and pro-inflammatory cytokines, including TNF-α, IL-1β, and IL-6, alleviated oxidative stress, and attenuated hippocampal neuronal damage. Mechanistically, NCP modulated glycerophospholipid metabolism, reshaped gut microbiota, and targeted the proteasome-autophagy pathway, revealing a multi-faceted synergistic mechanism. The research offers a new screening tool for AChE inhibitors and highlights a promising natural multi-target candidate, NCP, for AD therapy.}, } @article {pmid42527713, year = {2026}, author = {Jiang, M and Lin, Y and Wang, L and Ou, K}, title = {LncRNA DLX6-AS1 Regulates the Pathological Process Related to Alzheimer's Disease via miR-204-5p.}, journal = {Neuromolecular medicine}, volume = {28}, number = {1}, pages = {}, pmid = {42527713}, issn = {1559-1174}, mesh = {Humans ; *Alzheimer Disease/pathology/genetics/blood/metabolism ; *MicroRNAs/physiology/genetics/biosynthesis/blood ; tau Proteins/metabolism ; Female ; Male ; Amyloid beta-Peptides/pharmacology/toxicity ; Phosphorylation ; *RNA, Long Noncoding/physiology/blood/genetics ; Cell Line, Tumor ; Aged ; Animals ; *Homeodomain Proteins/physiology/genetics ; Peptide Fragments/pharmacology/toxicity ; Aged, 80 and over ; Mice ; Brain/pathology ; }, abstract = {Alzheimer's disease (AD) is a neurodegenerative disorder causing progressive neuronal damage. Incidence rises with age, and early diagnosis is difficult. This study examined DLX6-AS1 clinical relevance and regulatory mechanism in AD, and its interaction with miR-204-5p in AD pathology. It offers new insights into early diagnosis and treatment. A total of 133 AD patients and 105 healthy controls were selected. Their serum levels of DLX6-AS1 and miR-204-5p were analyzed using quantitative polymerase chain reaction. β-amyloid (Aβ)1-42-induced SH-SY5Y neuronal injury and okadaic acid (OA)-induced Neuro-2a tau abnormal phosphorylation models were constructed. The role/function of DLX6-AS1/miR-204-5p axis was then investigated using cell counting kit-8, flow cytometry, western blotting, enzyme-linked immunosorbent assay and a dual-luciferase reporter gene assay. AD patients had higher serum DLX6-AS1 and lower miR-204-5p levels. DLX6-AS1 showed an AUC of 0.838 for AD diagnosis. DLX6-AS1 levels were negatively associated with cognitive function, brain structural integrity, and benign pathology-and positively associated with disease severity, functional impairment, and pathological markers. In AD cell models, DLX6-AS1 was upregulated. Silencing it promoted cell proliferation, reduced apoptosis and oxidative stress, improved mitochondrial and synaptic function, decreased tau phosphorylation, and enhanced microtubule stability and axonal transport. Dual-luciferase assays confirmed direct binding between DLX6-AS1 and miR-204-5p. Co-inhibition reversed the protective effects of DLX6-AS1 silencing. Serum DLX6-AS1 is a potential biomarker for early diagnosis and assessment of AD. It regulates Aβ-induced neuronal damage and tau phosphorylation by targeting miR-204-5p, offering a new mechanism target for AD molecular therapy.}, } @article {pmid42529533, year = {2026}, author = {Kummer, N and Cihova, M and Nirmalraj, PN}, title = {Antiamyloid Antibody Effects on Aβ-42 Protein Aggregates Profiled Using Nanospectroscopy.}, journal = {Chemical & biomedical imaging}, volume = {4}, number = {7}, pages = {1379-1389}, pmid = {42529533}, issn = {2832-3637}, abstract = {Anti-amyloid-β (Aβ) monoclonal antibodies are designed to selectively target protein biomarkers and promote amyloid clearance in Alzheimer's disease. Yet the effects of antibodies on individual Aβ protein aggregates remain to be fully clarified. The work presented here employs nanospectroscopy (atomic force microscopy combined with infrared spectroscopy) to resolve morphological and secondary structural changes in Aβ-42 protein aggregates upon treatment with aducanumab and lecanemab antibodies (biosimilars). The treatment of Aβ-42 peptides with aducanumab resulted in reduction of oligomer prevalence and formation of larger-diameter fibril bundles confirmed from the AFM height maps and infrared spectral readouts recorded at nanometer-scale spatial resolution. Conversely, lecanemab treatment of Aβ-42 peptides did not suppress oligomer generation but was observed to preferentially bind along the full length of the nodular-shaped protofibril surface. Importantly, neither aducanumab nor lecanemab was observed to induce any surface adsorption-driven disassembly of Aβ-42 protofibrils or elongated mature fibrils. Thus, nanospectroscopy enables direct characterization of antibody-amyloid interfacial interactions and provides insights into the distinct modes of action of emerging anti-Aβ therapeutics through label-free chemical imaging.}, } @article {pmid42530040, year = {2026}, author = {Shi, Q and Pradhan, AK and Dong, S and Rammes, G and Wang, X}, title = {Sevoflurane and Aβ1-42 Oligomers Synergistically Induce Morphological Changes of Astrocytes in the Hippocampus of Male Mice.}, journal = {Journal of integrative neuroscience}, volume = {25}, number = {7}, pages = {50442}, doi = {10.31083/JIN50442}, pmid = {42530040}, issn = {0219-6352}, support = {2024MZFS003//Open Fund Program of the Key Laboratory of Anesthesiology and Resuscitation, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, China/ ; }, mesh = {Animals ; *Amyloid beta-Peptides/pharmacology ; *Sevoflurane/pharmacology ; *Peptide Fragments/pharmacology/administration & dosage ; *Astrocytes/drug effects/pathology/metabolism ; Male ; *Hippocampus/drug effects/pathology/metabolism ; Glial Fibrillary Acidic Protein/metabolism/drug effects ; *Anesthetics, Inhalation/pharmacology/administration & dosage ; Mice ; }, abstract = {BACKGROUND: Reactive gliosis serves as a characteristic feature of the pathophysiology of Alzheimer's disease (AD). Nevertheless, the influence of anesthetics on the morphological dynamics of astrocytes remains ambiguous.

METHODS: Employing ex vivo hippocampal slices, in this study, we explored the impacts of sevoflurane and Amyloid-β peptide 1-42 (Aβ1-42) oligomers on astrocytic morphology. The primary outcomes encompassed the fluorescence intensity of glial fibrillary acidic protein (GFAP), the levels of a 38-kDa GFAP breakdown product (a marker of astroglial injury), and quantitative morphometric analyses (cell volume, surface area, branch complexity, and Sholl intersections).

RESULTS: Co-exposure to sevoflurane and Aβ1-42 led to an elevation of the 38-kDa GFAP breakdown product and a significant reduction in the mean fluorescence intensity of GFAP. Moreover, it resulted in a decrease in astrocytic volume, surface area, branch complexity, and Sholl intersections. These synergistic alterations were not observed when either treatment was administered alone.

CONCLUSIONS: These findings imply that sevoflurane aggravates Aβ1-42-induced astrocytic dysfunction, which has implications for perioperative management in patients with AD or those at risk of developing AD.}, } @article {pmid42521490, year = {2026}, author = {Jung, WH and Oh, ST and Choe, MS and Kwon, YJ and Kim, SJ and Jeon, YS and Baek, KM and Chang, W and Lim, KS and Kim, JS and Yun, SP and Lee, MY}, title = {A Cerebral Organoid Model of Familial Alzheimer's Disease Using Amyloid Precursor Protein Mutation, Val669Leu (APP[Seoul]).}, journal = {International journal of stem cells}, volume = {}, number = {}, pages = {}, doi = {10.15283/ijsc25044}, pmid = {42521490}, issn = {2005-3606}, abstract = {Various animal and cellular Alzheimer's disease (AD) models harboring familial AD (fAD) mutations have been developed and widely used for AD research. In this study, we established an AD cerebral organoid (CO) model using a novel Val669Leu (APP[Seoul]) mutation in the APP gene. We generated a human embryonic stem cell (hESC) line overexpressing APP[Seoul], referred to as the fAD-S hESC line. Using this line, we produced COs and confirmed robust AD-associated pathologies, including amyloid-β (Aβ) accumulation and tau phosphorylation. In addition, increased expression of β-secretase was observed in this model. Based on these findings, we investigated the effects of BACE1 inhibitor IV, a β-secretase inhibitor, in the CO model. Treatment with BACE1 inhibitor IV significantly reduced Aβ levels and tau phosphorylation. Furthermore, we differentiated the fAD-S hESC line into cortical neurons (fAD-S neurons) to establish a 2D cellular AD model. Consistent with the CO results, fAD-S neurons exhibited elevated levels of Aβ and phosphorylated tau, which were also significantly attenuated by BACE1 inhibitor IV treatment. Collectively, these results demonstrate the successful establishment of hESC-derived 2D and 3D AD models based on the APP[Seoul] fAD mutation.}, } @article {pmid42521537, year = {2026}, author = {da Silva, AMP and Haddad-Santos, D and de Siqueira Lima, DV and Cardoso, LJC and Moura, CB and Høilund-Carlsen, PF and Perry, G and Kishi, T and Barbosa, BJAP and Anghinah, R}, title = {Bayesian Reanalysis of a Pilot Randomized Clinical Trial of Low-Dose Lithium in Mild Cognitive Impairment: A Probabilistic Re-Expression of the LATTICE Trial.}, journal = {The American journal of geriatric psychiatry : official journal of the American Association for Geriatric Psychiatry}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.jagp.2026.06.014}, pmid = {42521537}, issn = {1545-7214}, abstract = {OBJECTIVE: The LATTICE pilot randomized clinical trial found no statistically significant effect of low-dose lithium on 6 coprimary outcomes in mild cognitive impairment (MCI). We aimed to re-express these results in Bayesian terms and estimate the probability of benefit, negligible difference, or harm across cognitive, neuroimaging, biomarker, and safety outcomes.

METHODS: We conducted a Bayesian reanalysis of published aggregate data from LATTICE, a single-site, randomized, double-blind, placebo-controlled 2-year trial of low-dose lithium carbonate versus placebo. The trial randomized 83 older adults with MCI, of whom 80 initiated treatment. Outcomes included verbal and visuospatial delayed recall, Preclinical Alzheimer Cognitive Composite, hippocampal and cortical volume measures, brain-derived neurotrophic factor, and serious adverse events. Posterior means, 95% credible intervals (CrI), and posterior probabilities were estimated using weakly informative priors.

RESULTS: Lithium was associated with a posterior mean standardized effect of 0.38 SD for CVLT-II delayed recall (95% CrI, -0.03 to 0.80), corresponding to a 96.5% probability of benefit and an 80.6% probability of exceeding 0.20 SD. The raw between-group difference was 1.47 points (95% CrI, 0.18-2.75). Bayesian re-expression of the intention-to-treat model showed an annualized CVLT-II treatment-by-time effect of 0.69 points per year (95% CrI, 0.02-1.35). BVMT-R remained near null. Hippocampal outcomes were directionally favorable but imprecise. Other cognitive, biomarker, imaging, and safety outcomes showed no robust signal.

CONCLUSIONS: This Bayesian reanalysis supports an inconclusive interpretation of LATTICE, while identifying a probabilistic signal for verbal delayed recall-not seen in the other outcomes-that warrants testing in adequately powered trials.}, } @article {pmid42521539, year = {2026}, author = {Bassiouni, W and Ye, E and Colson, TL and Ferguson, SSG and Abd-Elrahman, KS}, title = {M1 muscarinic receptor modulation drives sex-specific alterations of Alzheimer's pathophysiology in APPswe/PSEN1ΔE9 mice.}, journal = {The Journal of pharmacology and experimental therapeutics}, volume = {}, number = {}, pages = {104980}, doi = {10.1016/j.jpet.2026.104980}, pmid = {42521539}, issn = {1521-0103}, abstract = {Alzheimer's disease (AD) is a neurodegenerative disorder marked by cognitive decline, where females account for 60% of diagnosed cases. AD is featured by β-amyloid deposition, which influences the activity of M1 muscarinic acetylcholine receptors (M1 mAChRs) that are essential for memory and learning. We previously demonstrated that VU0486846, a M1 mAChR positive allosteric modulator, improves cognitive function in AD mice by ameliorating β-amyloid pathology. However, it remains unclear how changes in M1 mAChR signaling and subcellular localization in AD brain influences its mechanism and how this differs between sexes. Nine-month-old male and female APPswe/PSEN1ΔE9 (APP/PS1) and wild-type mice were treated with VU0486846 (10 mg/kg/day) or vehicle via drinking water for 8 weeks. Elevated extracellular signal-regulated kinase 1/2 signaling, a plausible driver for β-amyloid pathology, was observed in female but not male APP/PS1 mice cortices, whereas VU0486846 mitigated this change. Additionally, VU0486846 enhanced the phosphorylation of the neuronal transcription factor cAMP response element-binding protein and increased the level of c-Fos, which regulate neuronal survival, in female wild-type and APP/PS1 mice only. In contrast, only male APP/PS1 mice exhibited increased levels of p62/SQSTM1 and decreased glycogen synthase kinase-3β activity, indicative of impaired autophagic flux, a change that was ameliorated by VU0486846 treatment. In subcellular fractions obtained from mice cortices, VU0486846 only increased cytosolic M1 mAChR level in female wild-type and APP/PS1 mice but not in males. Our findings indicate that M1 mAChR signaling is disrupted in APP/PS1 mice in a sex-dependent manner. VU0486846 enhances prosurvival signaling in females, potentially by increasing the cytosolic pool of M1 mAChRs, while modulating autophagy pathways in males, highlighting a sex-specific mechanism of action and underscoring its therapeutic potential. SIGNIFICANCE STATEMENT: The study highlights the sex-specific role of M1 muscarinic acetylcholine receptor (M1 mAChR) in Alzheimer's disease (AD) pathophysiology, providing evidence that the ability of M1 mAChR positive allosteric modulation to alleviate β-amyloid pathology occurs through distinct mechanisms. It rescues neuronal activity in females, which could be linked to enhanced cytosolic receptor pooling, while restoring autophagic flux in males. The study also reinforces the therapeutic potential of M1 mAChR positive allosteric modulators and supports the development of sex-tailored interventions for AD.}, } @article {pmid42522301, year = {2026}, author = {Ishak, NI and Siran, R and Mohamad Zain, WNIW and Azme, N}, title = {Endothelial-to-mesenchymal Transition at the Blood-brain Barrier: Molecular Mechanisms and Pathological Roles Across Brain Diseases.}, journal = {CNS & neurological disorders drug targets}, volume = {}, number = {}, pages = {}, doi = {10.2174/0118715273485479260721072747}, pmid = {42522301}, issn = {1996-3181}, abstract = {Endothelial-to-Mesenchymal Transition (EndMT) is a significant contributor to Blood- Brain Barrier (BBB) dysfunction in various brain diseases. The majority of current therapies, aimed at reducing BBB dysfunction, focus on preventing inflammation or stabilizing tight junctions. In most cases, these therapies do not provide adequate or long-lasting vascular protection. Endothelial cells undergo phenotypic programming, losing their barrier-forming capacity and developing features of mesenchymal and extracellular matrix-producing cells as the disease progresses. The change leads to chronic vascular leakage, neuroinflammation, microvascular fibrosis, and dysfunctional neurovascular coupling. Several upstream stimuli, including inflammatory cytokines, TGF-β/BMP-Smad signaling, and oxidative damage, converge to drive EndMT within the distinctive, specialized environment of the brain endothelium. Ischemic stroke, multiple sclerosis, cerebral cavernous malformations, arteriovenous malformations, glioblastoma, brain metastasis, and Alzheimer's disease indicate that EndMT is not a rare or unique process but a shared and common pathologic process that may result in disease progression and eventual resistance to treatment. Recent single-cell and spatial transcriptomic data have shown that partial EndMT states exist and may be precursors to irreversible microvascular remodeling. It is necessary to identify therapeutic approaches that go beyond short-term stabilization of the BBB and target the molecular programs underlying the loss of endothelial identity. This review synthesizes mechanistic, disease-related, and therapeutic evidence indicating that EndMT is a leading cause of BBB failure and highlights therapeutic opportunities for targeting this endothelial plasticity in brain diseases.}, } @article {pmid42523519, year = {2026}, author = {Chen, X and Munoz-Mayorga, D and Lyu, X and Jati, S and Zhang, J and Rossitto, LA and Tao, Y and Zhao, S and Hui, E and Kauffman, A and Zhu, B}, title = {A non-canonical androgen signaling pathway drives microglial activation and tau pathology in females.}, journal = {Research square}, volume = {}, number = {}, pages = {}, pmid = {42523519}, issn = {2693-5015}, abstract = {Alzheimer's disease (AD) disproportionately affects women, who exhibit greater vulnerability to Tau pathology and neuroinflammation. The precise mechanisms underlying this vulnerability remain elusive, although sex hormones are thought to play a pivotal role. Here, we report that supplementation with the non-aromatizable androgen dihydrotestosterone (DHT) exacerbates Tau pathology in female tauopathy models, with microglia as the main driver of this effect. DHT treatment upregulates proinflammatory gene expression in microglia and promotes the disease-associated microglia (DAM) phenotype in a Trem2-dependent manner. Surprisingly, these effects are independent of the canonical androgen receptor (AR) and instead depend on the orphan nuclear receptor TR4, which mediates DHT-driven effects by transcriptionally regulating Trem2 in microglia. Moreover, TR4 protein levels are elevated in postmortem brain tissue from Braak stage 6 female AD patients and correlate with p-Tau levels. Together, our findings uncover a non-canonical DHT-TR4- Trem2 signaling axis in microglia and identify TR4 as a key regulator of neuroinflammation in female neurodegeneration, providing mechanistic insight into female-specific vulnerability to AD.}, } @article {pmid42523541, year = {2026}, author = {Ambekar, A and Zielinski, R and Eloyan, A}, title = {TRAECR: A Tool for Preprocessing Positron Emission Tomography Imaging for Statistical Modeling.}, journal = {ArXiv}, volume = {}, number = {}, pages = {}, pmid = {42523541}, issn = {2331-8422}, abstract = {Positron emission tomography (PET) imaging is widely used in a number of clinical applications, including cancer and Alzheimer's disease (AD) diagnosis, monitoring of disease development, and treatment effect evaluation. Statistical modeling of PET imaging is essential to address continually emerging scientific questions in these research fields, including hypotheses related to evaluation of effects of disease modifying treatments on amyloid reduction in AD and associations between amyloid reduction and cognitive function, among many others. In this paper, we provide background information and tools for statisticians interested in developing statistical models for PET imaging to pre-process and prepare data for analysis. We introduce our novel pre-processing and visualization tool TRAECR (Template registration, MRI-PET co-Registration, Anatomical brain Extraction and COMBAT/RAVEL harmonization) to facilitate data preparation for statistical analysis.}, } @article {pmid42523631, year = {2026}, author = {Ding, X and Hu, X and Xue, W and An, Y and Cheng, W and Zhang, S and Lei, A and Zhang, J}, title = {Anti-inflammatory CAR-microglia targeting Aβ for Alzheimer's disease therapy.}, journal = {Frontiers in immunology}, volume = {17}, number = {}, pages = {1820099}, pmid = {42523631}, issn = {1664-3224}, mesh = {*Alzheimer Disease/therapy/metabolism/immunology ; Animals ; *Microglia/metabolism/immunology/transplantation ; *Amyloid beta-Peptides/metabolism/immunology ; Humans ; Mice ; Axl Receptor Tyrosine Kinase ; Receptor Protein-Tyrosine Kinases/genetics/metabolism ; Disease Models, Animal ; *Induced Pluripotent Stem Cells/metabolism ; c-Mer Tyrosine Kinase/genetics/metabolism ; Efferocytosis ; Mice, Transgenic ; Proto-Oncogene Proteins/genetics/metabolism ; Phagocytosis ; Cytokines/metabolism ; Anti-Inflammatory Agents ; }, abstract = {Alzheimer's disease (AD) is characterized by the accumulation of amyloid-β (Aβ) plaques and chronic neuroinflammation, which together drive progressive neuronal loss and cognitive decline. In recent years, monoclonal antibodies targeting Aβ have demonstrated encouraging clinical benefits in Alzheimer's disease (AD). However, their therapeutic efficacy remains limited by insufficient and unsustained clearance of Aβ, as well as treatment-associated neuroinflammatory responses. These limitations highlight the need for alternative strategies that can achieve efficient Aβ elimination while maintaining immune homeostasis. To overcome these challenges, we developed a novel anti-inflammatory CAR-Microglia (CAR-Mic) incorporating a construct based on the TAM receptor family (TYRO3, AXL, and MERTK), which are key regulators of efferocytosis and anti-inflammatory responses. The resulting Aβ-targeted CAR-Mics showed enhanced Aβ engulfment and reduced proinflammatory cytokines release. Among the constructs tested, AXL-CAR demonstrated the most favorable overall performance and was therefore selected for the generation of human induced pluripotent stem cell (iPSC)-derived CAR microglia-like cells (CAR-iMGLs). In an AD mouse model, AXL-CAR-iMGLs exhibited enhanced Aβ clearance without evidence of severe adverse effects. Collectively, these findings establish TAM receptor-based CAR-iMGLs as a promising cell therapy model for AD and potentially other neurodegenerative disorders characterized by chronic neuroinflammation and defective pathological protein clearance.}, } @article {pmid42508295, year = {2026}, author = {Lu, W and Caulfield, TR and Lee, E and Jeevaratnam, S and Wang, N and Bu, G and Kanekiyo, T and Li, Y}, title = {Discovery of a CI-994 derivative as a dual modulator of class I histone deacetylases and Wnt/β-catenin signaling for Alzheimer's disease therapy.}, journal = {Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics}, volume = {23}, number = {5}, pages = {e00974}, doi = {10.1016/j.neurot.2026.e00974}, pmid = {42508295}, issn = {1878-7479}, abstract = {Alzheimer's disease (AD) is a multifactorial disease with mixed pathologies. Consequentially, drugs targeting multiple pathological processes may offer synergistic benefits. While histone deacetylase (HDAC) inhibitors have demonstrated efficacy in alleviating AD-related pathologies in animal models, the neuroprotective Wnt/β-catenin signaling pathway remains compromised in AD brain. CI-994 is a class I HDAC inhibitor containing N-(2-aminophenyl)-benzamide. Our recent studies indicate that CI-994 is also an activator of Wnt/β-catenin signaling by stabilizing Wnt co-receptor LRP6. We herein use CI-994 as a scaffold to develop novel potent dual modulators of class I HDACs and Wnt/β-catenin signaling for AD therapy. Our lead compound, W2A-28, selectively inhibits class I HDAC1, 2 and 3 with IC50 values of 0.51 μM, 0.68 μM and 0.22 μM, respectively, and shows no inhibitory activities on other HDACs. Furthermore, W2A-28 potently activates Wnt reporter activity with an EC50 value of 1.61 μM in Wnt-3A-expressing HEK293 cells. As expected, activation of Wnt/β-catenin signaling by W2A-28 is associated with elevated LRP6 protein level. Importantly, W2A-28 displays excellent microsomal stability in both mouse and human liver microsomal stability assays, alongside high permeability and a lack of active efflux in MDR1-MDCKII models. Critically, W2A-28 treatment significantly enhances histone acetylation, activates Wnt/β-catenin signaling, suppresses tau phosphorylation, and reduces Aβ levels in AD patient-specific cerebral organoids carrying APOE ε4/ε4 or APOE ε3/ε4 with PSEN1 M146V mutation. Our findings position W2A-28 as a promising multi-target drug candidate for AD therapy.}, } @article {pmid42508316, year = {2026}, author = {Wang, D and Huang, W and Wang, X and Zhang, L and Tao, X and Qin, F and Guo, S and Han, G and Zhang, Z}, title = {Fluorescence lifetime imaging of G-quadruplex RNA dynamics in Alzheimer's disease using a novel nucleic acid-sensitive probe.}, journal = {Talanta}, volume = {312}, number = {Pt A}, pages = {130351}, doi = {10.1016/j.talanta.2026.130351}, pmid = {42508316}, issn = {1873-3573}, abstract = {Real-time monitoring of G-quadruplex (G4) RNA dynamics is vital for understanding their biological roles in the progression and treatment of Alzheimer's disease. However, this remains challenging due to two key difficulties. First, current fluorescent probes lack sufficient selectivity for G4 RNA over G4 DNA and other non-G4 secondary structures in live-cell competitive environments. Second, fluorescence intensity-based imaging cannot detect subtle changes in G4 RNA because of variations in fluorophore uptake and photobleaching. Herein, we report a novel thiazole orange derivative (TOGR) for fluorescence lifetime imaging of G4 RNA in living cells. Structural modifications of thiazole orange enhance RNA-binding affinity and G4 selectivity. TOGR exhibits a unique fluorescence lifetime when bound to G4 structures, enabling sensitive detection of G4 formation independent of local probe concentration via FLIM. FLIM imaging reveals that TOGR primarily colocalizes with RNA in the cytoplasm and nucleoli. Due to its preferential RNA-binding affinity in competitive cellular environments, TOGR enables selective monitoring of G4 RNA dynamics, facilitating the exploration of novel roles of G4 RNA in cells without interference from G4 DNA. Importantly, the dynamic behavior of G4 RNA during Alzheimer's disease pathology and the effects of glucocorticoids on G4 RNA dynamics were successfully revealed using this lifetime-sensitive and RNA-selective imaging probe. This research not only paves the way for advanced probe design for detailed G4 RNA imaging but also lays the foundation for exploring G4 RNA-related pathological mechanisms in Alzheimer's disease.}, } @article {pmid42508392, year = {2026}, author = {Kumar, V and Jang, S and Choi, Y and Kim, S and Nam, Y and You, M and Moon, M}, title = {Targeting the Microbiota-Butyrate-BHB Axis As a Potential Metabolic Therapeutic Strategy for Alzheimer's Disease.}, journal = {Aging and disease}, volume = {}, number = {}, pages = {}, doi = {10.14336/AD.2026.0606}, pmid = {42508392}, issn = {2152-5250}, abstract = {Alzheimer's disease (AD) is increasingly linked to metabolic and microbial dysregulations, with butyrate and β-hydroxybutyrate (BHB) identified as key modulators. BHB is a ketone body primarily produced by the liver during periods of low glucose availability, and BHB levels are reduced in the AD brain and peripheral blood. Butyrate, a microbiota-derived short-chain fatty acid, is also reduced in the peripheral blood in association with gut microbiota dysbiosis. The reduction of butyrate and BHB, together with gut microbiota dysbiosis, is commonly observed in AD patients and correlates with cognitive decline and AD-related pathologies. Reduced levels of butyrate and BHB may impair energy metabolism, exacerbating amyloid-beta (Aβ) and tau pathologies. In contrast, preliminary evidence from interventional and ketogenic studies suggests that increasing butyrate and BHB levels may attenuate AD-related pathologies, such as Aβ and tau abnormalities, while improving cognitive function. Emerging evidence suggests that both butyrate and BHB can cross the blood-brain barrier (BBB), suppressing oxidative stress and pro-inflammatory cytokines and potentially mitigating Aβ aggregation and tau hyperphosphorylation. Accordingly, therapeutic strategies targeting the microbiota-butyrate-BHB axis represent a promising and biologically plausible approach that warrants further rigorous clinical investigation for the prevention and treatment of AD. This review comprehensively examines the roles of butyrate and BHB in ameliorating key AD-related pathologies, including Aβ aggregation, tau hyperphosphorylation, neuroinflammation, and neurodegeneration. Additionally, the review explores the bidirectional association between butyrate/BHB and gut dysbiosis in AD, including how dysbiosis reduces butyrate/BHB levels while elevating them may reverse dysbiosis and improve gut-brain axis function. Collectively, these findings suggest that butyrate and BHB emerge as promising candidates for potential novel adjunctive therapies for AD, although supporting human evidence remains preliminary and heterogeneous.}, } @article {pmid42509698, year = {2026}, author = {Wang, X and Li, J and Wei, Z and Rong, C and Zhao, D and Wang, Y}, title = {Integrating Multi-Omics and Mendelian Randomization Reveals the Role of Epstein-Barr Virus Infection in Alzheimer's Disease and the Therapeutic Potential of Resveratrol.}, journal = {Current Alzheimer research}, volume = {}, number = {}, pages = {}, doi = {10.2174/0115672050463115260708111634}, pmid = {42509698}, issn = {1875-5828}, abstract = {INTRODUCTION: The pathogenesis of Alzheimer's disease (AD) is complex, with immune system dysregulation playing a critical role. However, the specific molecular mechanisms linking peripheral immune responses to central pathologies in AD remain unclear. This study aims to systematically screen for reliable plasma biomarkers of AD by integrating transcriptomics, Mendelian randomization (MR) of plasma proteomics, and bioinformatics analyses, and to explore their potential pathogenic mechanisms and therapeutic drugs.

MATERIALS AND METHODS: Transcriptomic sequencing of plasma samples from three AD patients and three healthy controls was first performed to identify differentially expressed genes (DEGs) and perform functional enrichment analyses. The aim of this study is to provide a preliminary indication of gene expression changes based on real patient samples for subsequent MR and bioinformatics analyses, rather than serving as confirmatory evidence. Following this, two-sample MR was performed to explore the potential causal relationship between plasma proteins and AD in genetic prediction, and MR-positive results were intersected with transcriptome DEGs to identify highconfidence targets. After that, protein-protein interaction (PPI) analysis, functional enrichment (GO/KEGG), and transcription factor (TF) target network analysis were conducted. Based on the KEGG pathway analysis, the causal association between antibodies related to Epstein-Barr virus and AD in genetic prediction was further evaluated. In the end, the diagnostic power of core biomarkers was validated in the GEO dataset. Potential therapeutic drugs were screened in the CTD database, followed by verification through molecular docking and molecular dynamics simulation.

RESULT: Our transcriptomic enrichment analysis of DEGs indicates that AD is significantly correlated with viral infection and immune and inflammatory pathways. According to the results of MR analyses, 36 plasma proteins have a causal effect on AD in genetic prediction. Among these 36 targets, two pathways are identified as enriched: "EBV Infection" and "Efferocytosis". Seven core targets are CR2, ICAM1, TAPBP, TNFAIP3, THBS1, SCARF1, and SIRPG. Also, the concentration of antibodies against EBV EBNA-1 and VCA p18 was confirmed by MR analyses to be risk factors for AD. According to drug predictions, molecular docking, and molecular dynamics simulations, resveratrol can stabilize CR2.

DISCUSSION: This study systematically identifies major plasma immune biomarkers associated with AD and proposes a mechanism by which EBV infection regulates plasma proteins CR2, TNFAIP3, and THBS1, which may affect AD risk. Resveratrol is thought to have preventive and protective effects, as predicted computationally.

CONCLUSION: This study systematically identified key plasma markers associated with AD. Resveratrol is likely to become a potentially effective preventive and protective drug in the prevention and treatment of AD, providing new ideas and targets for immune intervention of AD.}, } @article {pmid42509706, year = {2026}, author = {Shen, Z and Cheng, J and Wang, L and Hou, Q}, title = {Molecular Mechanisms and Therapeutic Strategies in Parkinson's Disease: From Pathogenic Signaling to Drug Development.}, journal = {Current neuropharmacology}, volume = {}, number = {}, pages = {}, doi = {10.2174/011570159X457429260706102249}, pmid = {42509706}, issn = {1875-6190}, abstract = {Parkinson's Disease (PD) is the second most common neurodegenerative disease after Alzheimer's Disease (AD), yet no effective disease-modifying therapy is currently available. Its pathogenesis is highly complex, involving multiple interacting pathological processes, which poses substantial challenges for therapeutic intervention. Moreover, PD often has a prolonged prodromal phase and lacks sufficiently sensitive and specific diagnostic methods for early-stage detection, further limiting timely identification and treatment. Current pharmacological therapies mainly provide symptomatic relief, but their long-term use is frequently associated with reduced efficacy and motor complications. Therefore, the development of novel therapeutic strategies and potential disease-modifying agents remains an urgent priority. This review systematically summarizes the molecular mechanisms and biomarkers associated with PD, outlines current symptomatic treatments, and discusses emerging therapeutic candidates in clinical development, with particular emphasis on disease-modifying strategies. By integrating pathogenic mechanisms, diagnostic advances, and therapeutic progress, this review aims to provide a comprehensive perspective to support the development of more effective interventions for PD.}, } @article {pmid42509708, year = {2026}, author = {Liu, Y and Zhang, Y and Zheng, W and Shi, X and Yao, W and Zhang, J and Bai, F}, title = {Cortico-white Matter Functional Coupling as a Biomarker of Alzheimer's Disease Progression and rTMS Therapeutic Efficacy.}, journal = {Current neuropharmacology}, volume = {}, number = {}, pages = {}, doi = {10.2174/011570159X470892260706231913}, pmid = {42509708}, issn = {1875-6190}, abstract = {INTRODUCTION: Alzheimer's disease (AD) spectrum disorders are characterized by progressive cognitive decline, with white matter degeneration and disrupted cortico-cortical connectivity as early features. Cortico-white matter functional coupling integrates neuronal activity with axonal conduction, yet its natural trajectory across the AD spectrum and ability to be modulated by repetitive transcranial magnetic stimulation (rTMS) remain unclear.

METHODS: Longitudinal resting-state fMRI from the ADNI cohort (n = 160: 59 cognitively normal, CN; 65 mild cognitive impairment, MCI; 36 AD) was used to assess baseline and 1-year changes in mean Fisher's z-transformed coupling between 82 cortical seeds (AAL-90 atlas, excluding subcortical nuclei) and a probabilistic group white matter mask. Specifically, 54 patients with amnestic MCI (aMCI) from the rTMS cohort were allocated to active (n = 40) or sham (n = 14) groups and received four weeks of neuronavigated rTMS targeting the left angular gyrus. Cortico-white matter functional coupling was calculated identically in both cohorts. Changes in coupling strength and their associations with changes in neuropsychological performance were examined across all cortical seeds.

RESULTS: At baseline, mean cortico-white matter functional coupling followed a nonlinear pattern (MCI > AD and CN). One-year follow-up revealed that the CN group exhibited a slight decrease in coupling, and the MCI and AD groups showed a pathological increase. Compared with the sham group, active rTMS significantly attenuated this increase in coupling. After adjusting for covariates, coupling changes were strongly correlated with cognitive decline. The AD group demonstrated the most significant associations (n = 104), whereas the active rTMS group showed 71 associations, predominantly linked to objective memory improvement.

DISCUSSION: This abnormal overcoupling, leading to compensation and decompensation, is associated with the progression of Alzheimer's disease. rTMS effectively moderates this pathological surge by enhancing neural efficiency and stabilizing large-scale network integration. Our findings position cortico-white matter functional coupling as an effective indicator of disease intensity and a measurable link in the chain of rTMS effectiveness for early-stage AD.

CONCLUSION: Overall, cortico-white matter functional coupling may serve as a novel scan-based biomarker for tracking AD progression and evaluating rTMS treatment efficacy in patients with MCI.}, } @article {pmid42509854, year = {2026}, author = {Alessio, M and Giulia, N and Annagrazia, A and Francesco, A and Raffaele, M and Massimo, C and Giacinto, B and Carlo, N and Romano, E and Rossella, R}, title = {Lithium as a Potential Neuroprotective Strategy in Glaucoma: Mechanisms and Therapeutic Perspectives.}, journal = {Biomolecules}, volume = {16}, number = {7}, pages = {}, doi = {10.3390/biom16071062}, pmid = {42509854}, issn = {2218-273X}, abstract = {Glaucoma is a major global health concern, identified as the foremost cause of irreversible blindness, affecting nearly 95 million individuals. It is characterized by the progressive degeneration of retinal ganglion cells (RGCs), leading to significant vision-related disabilities and an extensive socio-economic impact. The concept that glaucoma should be viewed not solely as an ocular condition but also as a neurodegenerative disorder, sharing pathophysiological features with diseases like Alzheimer's and Parkinson's, is now widely accepted. This review examines the convergence of molecular mechanisms, including the roles of amyloid precursor proteins and neuroinflammation, that contribute to RGC loss. Notably, lithium, traditionally used as a mood stabilizer, has emerged as a potential neuroprotective agent for the treatment of Alzheimer's disease. In light of the common neurodegenerative mechanisms linking glaucoma with central neurodegenerative diseases, here, we review the current evidence supporting lithium's therapeutic potential in glaucoma, emphasizing the need for further clinical studies to determine its effectiveness in preserving optic nerve health and improving patient outcomes.}, } @article {pmid42510665, year = {2026}, author = {Mitroshina, EV and Strelkova, PL and Korokozova, MV and Vedunova, MV}, title = {HIF1 Stabilization by Roxadustat Improves Cognition and Prevents Neuron Loss in Alzheimer's Diseases In Vivo.}, journal = {Biology}, volume = {15}, number = {14}, pages = {}, doi = {10.3390/biology15141118}, pmid = {42510665}, issn = {2079-7737}, support = {22-15-00178-p//Russian Science Foundation/ ; }, abstract = {Alzheimer's disease (AD) is one of the most prevalent neurodegenerative disorders worldwide and is characterized by progressive memory impairment, cognitive decline, and behavioral dysfunction. The brain's high energy demand makes it vulnerable to hypoxia, which can trigger AD pathology. Hypoxia-inducible factor (HIF) is a transcription factor that mediates cellular and tissue adaptation to low oxygen levels. HIF-1 plays a dual role in AD: on the one hand, it is considered a potential neuroprotective target; on the other hand, its activation may exacerbate disease pathogenesis by promoting amyloid plaque formation. Given this ambiguity, further studies are needed. This study investigated the HIF prolyl hydroxylase inhibitor Roxadustat in 6-month-old male 5xFAD mice. Stabilization of the HIF-1 complex exerted a positive effect on learning ability and the retention of long-term spatial memory in 6-month-old male 5xFAD mice. Four-week treatment with Roxadustat significantly reduced pathological morphological alterations in cells of the prefrontal cortex. In addition, animals treated with Roxadustat exhibited significantly increased expression of the brain-derived neurotrophic factor (BDNF) in the cerebral cortex. Our findings suggest that stabilization of the HIF-1 complex through inhibition of HIF prolyl hydroxylase may represent a promising strategy for neuroprotection in AD.}, } @article {pmid42510722, year = {2026}, author = {Avitabile, A and Rusciano, D and Amato, R and Cannizzaro, L and Gagliano, C}, title = {Sex-Dependent Brain Plasticity in Neurological Disease: From Biological Variability to Adaptive, Compensatory, and Maladaptive Trajectories.}, journal = {Biology}, volume = {15}, number = {14}, pages = {}, doi = {10.3390/biology15141176}, pmid = {42510722}, issn = {2079-7737}, abstract = {Brain plasticity is often described as the capacity of the nervous system to change in response to development, experience, injury, disease, or treatment. That definition is useful, but it can obscure two clinically important points: plasticity is biologically constrained, and change is not always beneficial. This narrative review examines sex-dependent brain plasticity as a context-sensitive process rather than as a simple male-female contrast. We distinguish four operational outcomes of plasticity: (i) reparative plasticity, which restores structure or function; (ii) compensatory plasticity, which preserves performance through alternative or more costly strategies; (iii) insufficient plasticity, in which reorganization is too weak or unstable to sustain function; and (iv) maladaptive plasticity, in which plastic change reinforces dysfunction, pain, excitability, rigidity, or decline. We also define adaptive reserve as the integrated capacity of neural, glial, vascular, immune, metabolic, endocrine, and gene-regulatory systems to support useful reorganization under stress. The review evaluates endocrine, synaptic, neuroimmune, mitochondrial, vascular, stress-related, and epigenetic mechanisms, indicating where evidence for sex-dependent effects is relatively strong and where it remains indirect, inconsistent, or context-dependent. Disease examples include autism spectrum disorder, attention-deficit/hyperactivity disorder, epilepsy, intellectual disability, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, Huntington's disease, traumatic and ischemic injury, multiple sclerosis, chronic pain, aging, and systemic metabolic or inflammatory disorders. Throughout, biological sex is separated from gender-related social, diagnostic, and health-care determinants. We conclude that therapeutic strategies should not aim simply to enhance plasticity, but to guide it by matching intervention, timing, dose, biological readiness, and monitoring to the patient's adaptive state.}, } @article {pmid42511504, year = {2026}, author = {Post, WM and Widomska, J and Oosterwijk, E and De Witte, W and Tiemessen, DM and Klemann, CJHM and Ruisch, IH and Coenen, MJH and Janssen, DAW and Martens, F and Carnes, MU and Marks, JA and Page, GP and Richter, HE and Cartwright, R and Minassian, VA and Thomas, LF and Skogholt, AH and Stafne, SN and Hveem, K and Kluivers, KB and Poelmans, G}, title = {Amyloid Precursor Protein Processing Links Female Urgency Urinary Incontinence with Alzheimer's Disease: Implications for Treatment.}, journal = {International journal of molecular sciences}, volume = {27}, number = {14}, pages = {}, pmid = {42511504}, issn = {1422-0067}, support = {PROJ00787 (DIABIP)//European Fund for Regional Development (EFRD)/ ; }, abstract = {Urgency urinary incontinence (UUI) and Alzheimer's disease (AD) are highly comorbid conditions in women, but the underlying molecular mechanisms are largely unknown. Therefore, we used network enrichment analyses and an elaborate literature search to integrate the most significant genes from four genome-wide association studies (GWASs) and other genetic, expression and functional evidence into a molecular landscape of female UUI. This molecular landscape centers around local, i.e., bladder-based, processing of the AD-associated amyloid precursor protein (APP). To further elucidate how APP processing is implicated in the comorbidity between UUI and AD, we conducted polygenic risk score (PRS)-based analyses, which showed that genetic risk factors associated with AD and a decreased amyloid beta 42/40 blood level ratio (also) contribute to UUI susceptibility. In conclusion, APP processing constitutes a putative molecular link between UUI and AD, adding further weight to their clinical comorbidity and having implications for the treatment (and prevention) of both traits.}, } @article {pmid42512037, year = {2026}, author = {Bagda, V and Farooz, ZH and Knuckey, NW and South, SM and Gribble, SK and Tomar, M and Bharadwaj, P and Ariyath, A and Taddei, K and Martins, RN and Meloni, BP}, title = {The Poly-Arginine Peptide R18D Inhibits Amyloid-Beta (Aβ) Aggregation and Aβ-Induced Cytotoxicity, Reduces Intracellular Tau Aggregation, and Exhibits Oral Bioavailability.}, journal = {Biomedicines}, volume = {14}, number = {7}, pages = {}, doi = {10.3390/biomedicines14071564}, pmid = {42512037}, issn = {2227-9059}, support = {N/A//Perron Institute for Neurological and Translational Science/ ; N/A//Argenica Therapeutics/ ; }, abstract = {Background/Objectives: Effective disease-modifying therapies targeting pathogenic proteins associated with Alzheimer's disease (AD) remain limited. This study investigated the therapeutic potential of the neuroprotective, cationic arginine-rich peptide R18D to mitigate the pathogenic effects of amyloid-beta (Aβ) and tau associated with AD. Methods: R18D was examined for its ability to inhibit Aβ aggregation in a cell-free assay, attenuate Aβ-induced cytotoxicity in MC65 cells, and suppress intracellular tau aggregation in two neural cell models. Intracellular tau aggregation was quantified using a homogeneous time-resolved fluorescence assay. Additionally, a pilot pharmacokinetic study of R18D was conducted in mice following oral gavage administration. Results: In the cell-free assay, R18D inhibited Aβ aggregation by up to 65%. In human MC65 cells induced to overexpress APP-C99 and accumulate Aβ, treatment with R18D inhibited cellular toxicity by as much as 100%. Preformed tau seeds were applied to human SH-SY5Y cells and rat primary cortical neurons to induce intracellular tau aggregation, and tau levels were quantified after 48 h. Exposure to tau seeds induced robust tau aggregation in both cellular models, which was significantly attenuated by R18D treatment, reducing aggregation by 34.8% in SH-SY5Y cells and 49.9% in cortical neurons. Pharmacokinetic studies demonstrated that R18D was detectable in plasma at 30 and 60 min following oral administration in mice. Conclusions: Together, these results demonstrate that R18D can modulate both Aβ and tau pathologies in vitro and is orally bioavailable, supporting its further evaluation as a therapeutic candidate for AD and other tau-associated neurodegenerative disorders.}, } @article {pmid42512450, year = {2026}, author = {Yogi, S and Singh, A}, title = {Molecular Mechanisms of Neurodegenerative Diseases: Emerging Biomarkers and Therapeutic Targets.}, journal = {Brain sciences}, volume = {16}, number = {7}, pages = {}, doi = {10.3390/brainsci16070675}, pmid = {42512450}, issn = {2076-3425}, abstract = {Neurodegenerative diseases (NDs), such as Alzheimer's disease (AD), Parkinson's disease (PD), Amyotrophic lateral sclerosis (ALS), and Huntington's disease (HD), involve the gradual loss of structure or function of neurons in the nervous system and are an increasing threat to the aging population worldwide. Although these disorders have different clinical features which affect cognition, movement and other vital body functions, they share key underlying molecular and cellular processes. This starts with protein misfolding and aggregation, mitochondrial dysfunction, oxidative stress, dysregulated protein homeostasis, neuroinflammation, and disrupted cell death pathways. Recent findings have added disease-specific processes, like amyloid-β and tau aggregates in AD, α-synuclein aggregation and mitophagy failure in PD's, TDP-43-related impaired RNA metabolism in ALS, and mutant huntingtin causing transcription aberrations in HD. Protein interactome network analysis showed mechanistic crosstalk between pathogenic proteins of AD and PD. New evidence highlights how lysosomal dysfunction, endoplasmic reticulum stress, and microglial activation, act as a common axis in neurodegeneration. Advancements in genomics and epigenomics have found shared genetic risk loci and regulatory processes that affect how diseases develop and progress. Simultaneously, new biomarkers like circulating microRNAs, exosome-related pathological proteins, neurofilament light chain, inflammatory cytokines, and microglial activation markers are powering early diagnosis tools and disease variations. New imaging techniques also allow for the identification of protein aggregations before symptoms appear. Overall, these findings are accelerating targeted treatments and personalized medicine aimed at disease progression. This review highlights current insights into the molecular mechanisms of NDs and discusses new biomarkers and treatment targets that help future diagnostic and treatment strategies.}, } @article {pmid42512462, year = {2026}, author = {Siarkos, K and Politis, AM and Politis, AA and Smyrnis, N and Papageorgiou, C and Prentakis, A and Gournellis, R and Katirtzoglou, E and Theleritis, C}, title = {Non-Pharmacological Interventions for Managing Apathy in Older Adults with Neurocognitive Disorders: A Systematic Review of Randomized Controlled Trials.}, journal = {Brain sciences}, volume = {16}, number = {7}, pages = {}, doi = {10.3390/brainsci16070687}, pmid = {42512462}, issn = {2076-3425}, abstract = {BACKGROUND/OBJECTIVES: Apathy is among the most common neuropsychiatric features of late-life neurocognitive disorders and predicts functional decline and greater caregiver burden. As no treatment is formally established, identifying effective interventions is a priority. We systematically reviewed non-pharmacological randomized controlled trials (RCTs) targeting apathy in older adults with neurocognitive disorders.

METHODS: We searched PubMed/MEDLINE, PsycInfo, the Cochrane Library, and Google Scholar (final search 23 March 2026). Eligible studies were non-pharmacological RCTs reporting an apathy outcome. Evidence levels were graded with OCEBM and quality with PEDro; two reviewers mapped PEDro items onto Cochrane risk-of-bias domains. Reporting followed PRISMA 2020.

RESULTS: Sixty-two RCTs were included. Physical exercise and music-based interventions showed the most consistent benefit, whereas technology-based and brain stimulation approaches remained experimental. Only 30 trials (48%) showed a significant between-group effect on apathy-most were null, within-group, or had apathy as a secondary outcome. Marked heterogeneity precluded meta-analysis. Most trials were of moderate to high quality, though near-universal performance bias arose from the inability to blind participants and providers.

CONCLUSIONS: Managing apathy in these populations remains challenging, and the certainty of the evidence is limited. Purpose-built, apathy-focused trials reporting effect sizes and durability are needed before disease-specific recommendations can be made.}, } @article {pmid42512531, year = {2026}, author = {Phutirat, A and Culevski, KA and Mach, H and Kwon, J and Tan, H and Koh, G and Marzban, C and Mourad, PD}, title = {Low-Intensity Focused Ultrasound Alters Alzheimer's Disease Pathology, In Vivo, as a Function of Ultrasound Dose and Age.}, journal = {Brain sciences}, volume = {16}, number = {7}, pages = {}, doi = {10.3390/brainsci16070757}, pmid = {42512531}, issn = {2076-3425}, support = {W81XWH-20-1-0479//Congressionally Directed Medical Research Programs/ ; }, abstract = {BACKGROUND/OBJECTIVES: Alzheimer's Disease (AD) and vascular dementia contribute up to ~75% of dementia cases, as determined via autopsy. AD arises in part due to the buildup of aberrant proteins (amyloid beta (Aβ) and Tau); vascular dementia is caused by reduced cerebral blood flow. Each dementia mechanisms damages brain. Bobola et al. found that their low-intensity focused ultrasound (FUS) protocol applied to the brains of the 5XFAD mouse model of AD reduced Aβ by 50% through activation of microglia. Eguchi et al. found that their own FUS protocol applied to the brains of the same mouse model reduced Aβ by 15% and increased cerebral blood flow by 50% through an increase in endothelial nitric oxide synthase (eNOS). Here, we sought to test a combined version of those two FUS protocols, expecting both a decrease in Aβ burden and an increase in eNOS.

METHODS: Using a diagnostic ultrasound probe, we applied our combined FUS protocol primarily to the left hippocampus of anesthetized 5XFAD mice, for an hour a day, for three days for younger mice and for five days for older mice. On day three or five, respectively, we harvested their brains and performed histological analysis to assess Aβ burden, microglial activation and their co-localization with Aβ, as well as the burden of eNOS within neuronal nuclei (here called intra-neuronal eNOS) and outside of neurons.

RESULTS: Relative to untreated mice, the treated younger mice had more activated microglia co-localized with Aβ and reduced Aβ burden for large plaques, as well as no change in each measure of eNOS. In contrast, the treated older AD mice had no change in activated microglia co-localized with Aβ, and no change in Aβ burden. However, relative to untreated older AD mice, FUS decreased total and extra-neuronal eNOS and increased intra-neuronal eNOS.

CONCLUSIONS: The ability of our FUS protocol to reduce Aβ burden and alter the eNOS distribution depends critically upon the age of the AD mice (more Aβ plaques for a comparable number of microglia for older mice relative to younger mice) and duration of the treatment. The observed decrease in extra-neuronal eNOS distribution in older AD mice caused by FUS raises the concern that our protocol may increase ischemia, while the increase in intra-neuronal eNOS may counteract that effect via protection of synaptic function. These findings also identify two candidate therapeutic windows for our FUS treatment protocol, each requiring more research before translation to humans. One window is early intervention to maximize Aβ plaque removal via activation of microglia. The second is later intervention to protect synaptic function if it is possible to mitigate the potential ischemic risk caused by the differential effects of FUS on eNOS.}, } @article {pmid42512898, year = {2026}, author = {Kannenieks, D and Priede, Z and Millers, A and Velins, KK}, title = {Development and External Validation of a Machine Learning Model for Classification of Mild Cognitive Impairment and Dementia Using Clinical Data.}, journal = {Medicina (Kaunas, Lithuania)}, volume = {62}, number = {7}, pages = {}, doi = {10.3390/medicina62071356}, pmid = {42512898}, issn = {1648-9144}, abstract = {Background and Objectives: As society ages, the number of patients with cognitive impairment is increasing. Machine learning methods that use structured clinical and cognitive-assessment data during routine diagnostic work-up may support and monitor structured classifications of cognitive status. This kind of approach can improve early screening, reduce physicians' workload and develop greater support for personalized treatment. To develop an XGBoost-based machine learning model using the National Alzheimer's Coordinating Center (NACC) dataset and to evaluate the model's precision with clinician-assigned diagnosis in a Latvian retrospective cohort study. Materials and Methods: The research was designed as a retrospective external validation cohort study that used two data sources. Firstly, the National Alzheimer's Coordination Center (NACC) longitudinal dataset was used to train the ML model. Secondly, medical records gathered from Pauls Stradins Clinical University Hospital dating from 2020 to May 2025 were used to evaluate the algorithm's precision. Results: In the NACC study, the weighted four-class model achieved an overall accuracy of 84.0% and a balanced accuracy of 70.9%, but the SCD class remained poorly classified. After reframing the model to a three-class model the performance grew stronger for normal cognition, mild cognitive impairment (MCI) and dementia. Class distribution in the Latvian cohort consisted of dementia (n = 138); MCI (n = 13); and subjective cognitive decline (SCD) (n = 2). Dementia was identified most strongly-124/138 (sensitivity-89.9%). MCI was correct in 9/13 cases (sensitivity-69.2%). SCD cases were excluded. Overall, the model agreed with the neurologist-assigned diagnoses in 88.1% of the cases (133/151). Conclusions: The ML classification model has high precision when comparing with neurologist-assigned diagnoses, but it struggles to separate adjacent early-stage diagnoses, meaning that it did not reliably identify SCD. These findings support further methodological development and the implementation of prospective research. Nevertheless, this technology has high potential for being integrated in the future to aid triage and early screening, especially when advanced diagnostics are limited.}, } @article {pmid42513614, year = {2026}, author = {Çetinkaya, K and Ünsal, Y}, title = {The Glymphatic System and Neurosurgery: A Comprehensive Narrative Review of Current Concepts and Future Directions.}, journal = {Journal of clinical medicine}, volume = {15}, number = {14}, pages = {}, pmid = {42513614}, issn = {2077-0383}, abstract = {The glymphatic system is a recently defined perivascular waste elimination pathway responsible for the efficient clearance of metabolic waste and neurotoxic proteins in the central nervous system. This system facilitates the entry of cerebrospinal fluid (CSF) into the brain parenchyma via arterial perivascular spaces and its interaction with interstitial fluid (ISF) via glial cell-associated aquaporin-4 (AQP4) channels. It functions particularly actively during sleep. Impairment of glymphatic flow contributes to nerve cell damage and neuroinflammation in various pathologies such as Alzheimer's disease, Parkinson's disease, traumatic brain injury, subarachnoid hemorrhage, and neurological tumors. In neurosurgical practice, surgical positioning, anesthesia regimen, and intracranial pressure changes play a decisive role in glymphatic function, and perioperative modulation of the system can affect postoperative recovery and cognitive outcomes. Today, non-invasive imaging techniques and molecular biological approaches are deepening our understanding of the functioning of the glymphatic system in humans, and this system is emerging as a potential target in the diagnosis and treatment of neurological diseases. This review comprehensively addresses the basic anatomical and physiological principles of the glymphatic system, its role in pathological processes, and its clinical significance in neurosurgical applications.}, } @article {pmid42514879, year = {2026}, author = {Osmanlioglu Dag, SR and Alagoz, MA}, title = {Dual Targeting of AChE Inhibition and GPX4 Binding by Plant-Derived Compounds for the Treatment of Alzheimer's Disease: Insights from Molecular Docking and Molecular Dynamics Simulations.}, journal = {Pharmaceutics}, volume = {18}, number = {7}, pages = {}, doi = {10.3390/pharmaceutics18070798}, pmid = {42514879}, issn = {1999-4923}, support = {TSA-2025-4366.//Inonu University/ ; }, abstract = {Background/Objectives: Alzheimer's disease (AD) is primarily characterized by cholinergic dysfunction, for which acetylcholinesterase (AChE) inhibition remains the mainstay of symptomatic treatment. However, additional hypotheses such as ferroptosis-an iron-dependent form of regulated cell death-have gained prominence in explaining disease progression. Glutathione peroxidase 4 (GPX4), a critical antioxidant enzyme, plays a protective role by suppressing ferroptotic pathways. In this context, identifying phytochemicals capable of inhibiting AChE and exhibiting activator-like binding toward GPX4 may provide a dual therapeutic benefit. This study aimed to identify such dual-acting compounds through a structure-based virtual screening approach. Methods: A total of 3014 natural compounds were collected from three curated databases: NPACT, HIT, and HIM. Molecular docking was performed against GPX4 (7U4I) and AChE (7D9Q). Compounds demonstrating high affinity for both targets were shortlisted. Z-score normalization and statistical ranking were used to select the best two dual-target compounds. Results: Out of 3014 compounds, 68 showed dual-binding potential. Among these, NPACT00189 (docking scores: -6.720 kcal/mol for GPX4; -8.983 kcal/mol for AChE) and NPACT01210 (docking scores: -5.813 kcal/mol for GPX4; -9.640 kcal/mol for AChE) were identified as top candidates based on docking scores. Molecular dynamics (MD) simulations were conducted for both compounds for 250 ns on the AChE binding site and the allosteric site of GPX4. The results indicated that NPACT00189 maintained stable interactions throughout the simulation period at both targets, indicating its dual-targeting potential. Conclusions: NPACT00189 represents a promising dual-target candidate for further investigation in AD therapy. Its potential requires confirmation through comprehensive in vitro and in vivo studies.}, } @article {pmid42514962, year = {2026}, author = {Chen, C and Leung, C and Zhai, Z and Wang, G and Yang, R and Hu, Q and Yue, X and Yao, Z and Zhao, Z and Zhang, X}, title = {Feasibility Study of Nose-to-Brain Delivery of Galantamine for Alzheimer's Disease: Enhancing Olfactory-Region Deposition to Improve Therapeutic Efficacy.}, journal = {Pharmaceutics}, volume = {18}, number = {7}, pages = {}, doi = {10.3390/pharmaceutics18070885}, pmid = {42514962}, issn = {1999-4923}, support = {2025A1515010639//Natural Science Foundation of Guangdong Province/ ; }, abstract = {Background: Alzheimer's disease (AD) is the seventh leading cause of death worldwide, posing a substantial global health burden. Although galantamine (GNT) is a first-line clinical drug for AD treatment, its therapeutic efficacy is constrained by inefficient brain delivery across the blood-brain barrier (BBB). Nose-to-brain delivery represents a promising route to bypass the BBB. However, its efficiency remains limited by insufficient drug deposition in the anatomically restricted olfactory region. In this study, we developed a galantamine nasal spray (GNT-NS) with enhanced olfactory region deposition and evaluated its feasibility for nose-to-brain delivery in AD treatment. Methods: We optimized the formulation by systematically investigating the cascade relationship among formulation physicochemical properties, spray performance, and olfactory region deposition. Nasal deposition distribution was quantitatively evaluated using a physiologically realistic 3D-printed human nasal cavity model reconstructed from clinical magnetic resonance imaging (MRI) data. Further, the in vivo biodistribution and therapeutic efficacy of GNT-NS were evaluated in AD rats. Results: The optimized formulation P3 achieved an olfactory region fraction of 23.85%, markedly exceeding that of the unoptimized formulation P0. Subsequent in vivo biodistribution studies showed that P3 produced higher brain drug exposure than both intranasally administered P0 and the commercial oral formulation. Further pharmacodynamic studies demonstrated that GNT-NS significantly improved cognitive and behavioral deficits in AD rats, exhibiting superior therapeutic efficacy over commercially available oral galantamine tablets. Conclusions: Collectively, this study proposes a cascade regulation strategy linking formulation physicochemical properties, spray performance, and olfactory region deposition and demonstrates that optimizing nasal spray properties can enhance olfactory deposition, increase brain exposure and improve therapeutic efficacy. These findings provide a useful reference for the design of nose-to-brain delivery formulations for AD and other central nervous system diseases.}, } @article {pmid42515707, year = {2026}, author = {Mella, J and Vega-Muñoz, A and Soto, M and Moraga, D and Campanini-Salinas, J and Sandoval-Obando, E and Contreras-Barraza, N and Salazar-Sepúlveda, G and Salas-Guzmán, N and Carabantes-Silva, R and Mellado, M}, title = {Evolution of Multitarget Strategies for Alzheimer's Disease: From Cholinergic Inhibition to Network-Oriented Therapeutic Design (2006-2025).}, journal = {Pharmaceuticals (Basel, Switzerland)}, volume = {19}, number = {7}, pages = {}, doi = {10.3390/ph19071024}, pmid = {42515707}, issn = {1424-8247}, support = {Puente de Investigación UCEN Convocatoria Año 2025 grant CIPPTE202505//Central University of Chile/ ; }, abstract = {Background: Alzheimer's disease (AD) is a complex neurodegenerative disorder and a major global health challenge. The traditional "one drug-one target" paradigm has shown limitations in addressing its multifactorial nature. Multitarget-directed ligands (MTDLs), designed to modulate multiple pathological pathways, have emerged as a promising therapeutic strategy. Objectives: To examine the structural, thematic, and temporal evolution of multitarget strategies for AD treatment between 2006 and 2025. Methods: A total of 1184 Web of Science-indexed articles were analyzed. Publication growth, h-index, author productivity, institutional and national contributions, and keyword co-occurrence networks were evaluated using VOSviewer. Bibliometric laws (Price, Bradford, Zipf, and Lotka) were applied to characterize productivity patterns and thematic organization. Results: Multitarget research shows exponential growth, suggesting a consolidation of the MTDL paradigm. China, India, the United States, Italy, and Spain were the most productive countries. Early studies focused on cholinesterase inhibition, particularly acetylcholinesterase-based hybrids. The field expanded to include β-amyloid aggregation, oxidative stress, metal chelation, and blood-brain barrier permeability. Recent trends emphasize integration of computational approaches, including molecular docking, molecular dynamics, virtual screening, and network pharmacology, alongside targets such as BACE1 and GSK-3β. Conclusions: Multitarget strategies have evolved toward a systems-oriented framework. Despite advances, challenges remain in reducing cholinesterase dependency and improving translational validation. This study provides a framework to interpret therapeutic evolution and guide future network-based drug design.}, } @article {pmid42515891, year = {2026}, author = {Jia, J}, title = {Glycogen Synthase Kinase-3β in Alzheimer's Disease: Targets for Therapy and Imaging.}, journal = {Current topics in medicinal chemistry}, volume = {}, number = {}, pages = {}, doi = {10.2174/0115680266497019260720045602}, pmid = {42515891}, issn = {1873-4294}, abstract = {Glycogen synthase kinase-3β (GSK-3β) is a key regulator of the pathogenesis of Alzheimer's disease (AD), capable of simultaneously modulating core pathological processes such as amyloid-β (Aβ) deposition, tau protein hyperphosphorylation, synaptic damage, and neuroinflammation. Therefore, it has become one of the core druggable molecular nodes for AD intervention. This review is mainly divided into two parts. The first part focuses on the GSK-3β inhibitors that have been validated in AD-related cell and animal models. These inhibitors are specifically classified into four categories: metal ion-based compounds, adenosine triphosphate (ATP)-competitive inhibitors, non-ATP-competitive inhibitors, and multi-target inhibitors. The second part focuses on GSK-3β-specific positron emission tomography (PET) radioligands, which can non-invasively monitor GSK-3β enzyme activity in vivo, providing quantitative in vivo molecular imaging tracers for the study of AD pathogenesis and quantitative assessment of treatment effects. This review systematically summarizes GSK-3β-related inhibitors and PET radioligands in AD, thereby providing key references for the rational design of next-generation AD therapeutic drugs and diagnostic agents.}, } @article {pmid42515916, year = {2026}, author = {Saini, M and Hooda, T and Dar, MO and Kumar, S and Khatri, R and Lather, A}, title = {Network Pharmacology-guided Target Evaluation of Nefopam for Alzheimer's Disease: Insights from Docking and Molecular Dynamics Simulations.}, journal = {Current computer-aided drug design}, volume = {}, number = {}, pages = {}, doi = {10.2174/0115734099474093260712091739}, pmid = {42515916}, issn = {1875-6697}, abstract = {INTRODUCTION: Amyloid-β accumulation, aberrant tau protein, neuroinflammation, and oxidative stress are some of the main pathogenic characteristics of Alzheimer's disease (AD), a degenerative illness characterized by cognitive deterioration. The majority of current AD therapies provide symptomatic alleviation with significant adverse effects, highlighting the urgent need for novel therapeutic approaches.

OBJECTIVE: This study examines nefopam, a centrally acting analgesic with NMDA antagonist and monoaminergic properties, as a potential treatment for AD using in silico methods like Network Pharmacology, Docking, and Molecular Dynamics Simulation studies.

RESULTS: Using network pharmacology, 90 molecular targets shared by the AD and nefopam pathways were identified. Following the selection of important hub proteins for further analysis, eight proteins with accessible 3D structures were put through molecular docking and MMGBSA computations. Nefopam demonstrated significant binding affinities, especially to 5HTR2A, GRIN1, 5HTR2C, SLC6A4, SLC6A3, and MAOB, whereas OPRM1 displayed weaker interactions, consistent with its lower MM-GBSA value (-37.04 kcal/mol) and docking score (-2.963). Molecular dynamics simulations of particular complexes over 100 ns revealed stable contacts and minimal structural changes for SLC6A3, SLC6A4, and 5HTR2A, suggesting strong and long-lasting binding.

DISCUSSION: The findings suggest that nefopam exhibits significant multi-target interactions with several proteins involved in AD pathogenesis, particularly those associated with neurotransmission, neuroprotection, and neuroinflammatory pathways. Its stable binding behavior and favorable interaction profiles support its potential role in modulating disease progression beyond symptomatic management.

CONCLUSION: Overall, this computational analysis confirms that nefopam can target multiple proteins linked to AD. These results show that more experimental research is necessary to validate nefopam's therapeutic potential and provide positive support for its repositioning in AD treatment.}, } @article {pmid42516031, year = {2026}, author = {Snyder, HM and Tampi, MP and Aisen, PS and Allegri, R and Apostolova, LG and Atri, A and Aurora, S and Caramelli, P and Crivelli, L and Cummings, J and de Strooper, B and Fox, NC and Grinberg, LT and Hardy, J and Lamb, BT and Levey, A and Lopez, O and Mummery, C and Nitrini, R and Pahlke, S and Petersen, RC and Pike, KJ and Porsteinsson, AP and Rabinovici, GD and Rafii, M and Raman, R and Sabbagh, MN and Salloway, SP and Scheltens, P and Schott, JM and Selkoe, DJ and Sevlever, G and Sperling, R and Tansey, MG and van Dyck, C and Zetterberg, H and Carrillo, MC}, title = {Recent Cochrane review has serious flaws: A perspective of clinicians and researchers from around the world.}, journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association}, volume = {22}, number = {7}, pages = {e71696}, pmid = {42516031}, issn = {1552-5279}, abstract = {In response to a Cochrane review (published in April 2026) on the clinical trials of monoclonal antibodies targeting beta amyloid, this perspective outlines a number of critiques. The scientists, methodologists, subject-matter experts, and clinicians on this perspective strongly recommend that the Cochrane editorial board consider a call for editorial response, correction of press materials, or commissioned reply to this review for four overarching reasons: (1) decision to pool antibodies that do and do not clear beta amyloid, (2) decision to include studies from a time when biomarkers of Alzheimer's disease were not available, (3) analytical and methodological limitations of the approach used, (4) conflating the distinct roles and methodological processes of systematic review and guideline methodologies, (5) contextualizing the present critique within the existing evidence-synthesis literature, and (6) mechanistic inference beyond the scope of the presented analyses. Conclusions that may not accurately reflect treatment-specific effects could cause significant downstream clinical and psychosocial harm to those currently undergoing treatment and their family members as well as individuals considering participation in Alzheimer's clinical trials.}, } @article {pmid42516875, year = {2026}, author = {Tropea, MR and Aceto, G and Trovato, RC and Nicitra, E and Santuccio, N and Intili, G and D'Ascenzo, M and Puzzo, D}, title = {Dopamine D3 receptor blockade restores hippocampal synaptic plasticity and rescues memory deficits in Alzheimer's disease mouse models.}, journal = {Frontiers in aging neuroscience}, volume = {18}, number = {}, pages = {1840697}, pmid = {42516875}, issn = {1663-4365}, abstract = {INTRODUCTION: Early synaptic failure is widely considered a primary driver of cognitive decline in Alzheimer's disease (AD), and previous studies have suggested that dopaminergic signaling may contribute to hippocampal synaptic dysfunction. Among dopaminergic receptors, dopamine D3 receptors (D3Rs) have emerged as important modulators of synaptic plasticity and cognitive processes, but their role in AD-related synaptic impairment remains unclear. The aim of this study was to determine whether pharmacological blockade of D3Rs could restore memory deficits and hippocampal synaptic dysfunction in preclinical models of AD.

METHODS: Behavioral studies, including novel object recognition (NOR), novel object location (NOL), and open-field tests, were performed to evaluate recognition memory, spatial memory, locomotor activity, and anxiety-related behavior in two mechanistically distinct mouse models of AD: triple-transgenic 3xTg-AD mice and α7 nicotinic acetylcholine receptor knockout (α7KO) mice. Electrophysiological recordings in hippocampal slices were used to assess AMPA/NMDA ratio, basal synaptic transmission, and long-term potentiation (LTP). qPCR and western blot analyses were performed to evaluate hippocampal D3R mRNA and protein expression, respectively. Pharmacological treatments included the selective D3R antagonist NGB-2904 and cariprazine, a clinically approved antipsychotic with high affinity for D3Rs.

RESULTS: Recognition and spatial memory deficits were rescued by NGB-2904 and cariprazine in both AD models, without affecting locomotor activity or anxiety-related behavior. No sex-dependent differences were observed in the behavioral response to treatment. Electrophysiological recordings revealed a reduced AMPA/NMDA ratio and impaired LTP in both models, while basal synaptic transmission was selectively reduced in 3xTg-AD mice. D3R-targeting compounds restored synaptic transmission and plasticity. Inhibition of PKA prevented the rescue of LTP induced by D3R blockade, suggesting the involvement of the cAMP/PKA signaling pathway. Both models displayed reduced hippocampal D3R mRNA expression and protein levels, suggesting that the residual population of D3Rs might represent a viable target.

CONCLUSION: Together, these findings demonstrate that D3R-targeting compounds rescue synaptic plasticity and memory deficits in two mechanistically distinct AD models. These results support a role for dopaminergic signaling in early synaptic dysfunction and highlights D3R modulation as a relevant pathway for further investigation in AD-related cognitive impairment.}, } @article {pmid42517615, year = {2026}, author = {Ya, J and Liu, M and Ji, Y and Tong, Z and Luo, B and Bai, J and Ren, J and Qu, X}, title = {Diazonium-Enabled Post-Synthetic Construction of Enantiomeric Single-Atom Nanoagents Used for Alzheimer's Disease Treatment.}, journal = {Small (Weinheim an der Bergstrasse, Germany)}, volume = {}, number = {}, pages = {e74610}, doi = {10.1002/smll.74610}, pmid = {42517615}, issn = {1613-6829}, support = {T2495262//National Natural Science Foundation of China/ ; 22437006//National Natural Science Foundation of China/ ; 22237006//National Natural Science Foundation of China/ ; 2025ZD0617100//National Science and Technology Major Project/ ; }, abstract = {Alzheimer's disease (AD) is driven by a self-amplifying interplay between oxidative stress and neuroinflammation, in which mitochondrial DNA (mtDNA) leakage-induced activation of the cGAS-STING pathway plays a central role. Strategies that solely eliminate reactive oxygen species (ROS) are insufficient to suppress downstream inflammatory cascades. Here, we report a pair of chiral dual-functional single-atom nanoagents that can simultaneously scavenge ROS and sequester leaked mtDNA. A diazonium-enabled post-synthetic modification strategy is employed to graft benzoic acid linkers onto a single-atom catalyst, enabling covalent conjugation of nona-arginine peptides with opposite chirality (L-/D-R9). The resulting constructs are further encapsulated by KLVFFAED peptides and tannic acid to yield L-/D-TKRM, conferring blood-brain barrier permeability and mitochondrial targeting. Both L- and D-TKRM effectively scavenge ROS and preserve mitochondrial function in Aβ-stimulated microglia, while D-TKRM exhibits enantioselectively prolonged mtDNA capture, more efficient suppression of cGAS-STING signaling, enhanced M2 microglial polarization, and superior neuroprotection. In vivo studies have demonstrated that these two nanoagents rescue cognitive function in 3 × Tg-AD mice, with D-TKRM showing better efficacy accompanied by reduced amyloid pathology, microglial activation, and neuronal loss. This work highlights diazonium chemistry as a new, versatile single-atom functionalization strategy and underscores that chirality is important for developing effective therapeutic agents for AD treatment.}, } @article {pmid42517781, year = {2026}, author = {Scerri, A and Scerri, K and Scerri, C}, title = {Global trends in Alzheimer's and dementia research (2019-2024): A machine learning-based bibliometric analysis.}, journal = {Journal of Alzheimer's disease : JAD}, volume = {}, number = {}, pages = {13872877261471922}, doi = {10.1177/13872877261471922}, pmid = {42517781}, issn = {1875-8908}, abstract = {BackgroundDementia, including Alzheimer's disease, represents one of the fastest-growing global health challenges. To coordinate research priorities, the World Health Organization (WHO) introduced the Blueprint for Dementia Research in 2022. This framework outlines six research themes spanning disease mechanisms, diagnosis, treatment development, risk reduction, epidemiology and health economics, and care and support. However, empirical evidence assessing whether global research activity aligns with these priorities remains limited.ObjectiveTo analyse global trends in dementia and Alzheimer's disease research and examine how research output is distributed across the thematic priorities defined in the WHO Blueprint for Dementia Research.MethodsA total of 206,636 unique peer-reviewed primary care studies published between 2019 and 2024 were retrieved from databases on the EBSCOhost platform. A machine-learning-assisted natural language processing pipeline classified publications into the six WHO research themes. Temporal trends were assessed and differences in thematic distributions before and after publication of the WHO blueprint were evaluated.ResultsAnnual dementia research output increased from 27,248 publications in 2019 to 39,147 in 2024. Research activity was consistently dominated by studies on disease mechanisms and diagnosis. Risk reduction and drug development demonstrated the strongest growth. Research related to dementia care and support, epidemiology and health economics increased more slowly and declined following publication of the WHO blueprint.ConclusionsGlobal dementia research continues to expand but remains unevenly distributed across research priorities. While progress in biomedical discovery is substantial, comparatively limited growth in care-related research highlights the need for stronger investment in studies addressing implementation and real-world dementia care.}, } @article {pmid42518426, year = {2026}, author = {Gohar, N and Abbas, M and Masaud, SM and Zulfiqar, I and Jabeen, H and Malik, NS and Nadeem, H}, title = {"Behavioral and Neuroinflammatory Evaluation of a Novel Isoxazole-5-One Derivative in Animal Models of Alzheimer's Disease via TNF-α, COX-2, IL-6, and NF-κB Modulation".}, journal = {ACS omega}, volume = {11}, number = {27}, pages = {39910-39921}, doi = {10.1021/acsomega.6c01108}, pmid = {42518426}, issn = {2470-1343}, abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by cognitive decline, cholinergic dysfunction, and neuroinflammation. Multitarget-directed ligands (MTDLs) are increasingly recognized as promising therapeutic approaches for such multifactorial pathological disorders. Isoxazole-5-one derivatives represent a novel scaffold with potential neuroprotective activity. In current study, the cognitive and anti-inflammatory properties of a newly synthesized isoxazole-5-one derivative, (E)-3-((benzylamino)-methyl)-4-(3,4,5-trimethoxybenzylidene) isoxazol-5-(4H)-one (M5), were evaluated using scopolamine-induced mice models of AD and biochemical analysis, respectively. Behavioral performance was assessed using the Morris Water Maze (MWM) and Y-maze paradigms. Scopolamine administration significantly impaired spatial learning, memory consolidation, and spontaneous alternation behavior, while treatment with M5 produced dose-dependent memory improvements. At the highest dose (10 mg/kg), M5 markedly reduced escape latency and enhanced target quadrant occupancy in the MWM, as well as restored alternation rates in the Y-maze (p < 0.001 vs scopolamine), with effects comparable to donepezil, a standard cholinesterase inhibitor. Biochemical analyses further demonstrated that M5 significantly reduced hippocampal levels of TNF-α and IL-6, while downregulating COX-2 and NF-κB expression, confirming its potent anti-inflammatory action. Taken together, these findings suggest that M5 ameliorates memory impairment potentially through its anti-inflammatory actions. Therefore, M5 may represent might be a promising multitarget-directed ligand for Alzheimer's disease.}, } @article {pmid42518955, year = {2026}, author = {Zhu, CW and Schneider, LS and Elder, GA and Soleimani, L and Neugroschl, J and Schimming, C and Sano, M}, title = {Neuropsychiatric symptom profile in neurocognitive disorders and their relationship with functional decline.}, journal = {Frontiers in neurology}, volume = {17}, number = {}, pages = {1805908}, doi = {10.3389/fneur.2026.1805908}, pmid = {42518955}, issn = {1664-2295}, abstract = {INTRODUCTION: Neuropsychiatric symptoms (NPS) are common in neurocognitive disorders (NCD) and are known to negatively impact patient's functional abilities. However, our understanding of the relationship between individual NPS and functional decline in patients with NCD across the spectrum of cognitive impairment is limited. Here we examine the relationship between specific NPS to characterize their effects on patient's function within and across different etiologies.

METHOD: Longitudinal observational study using the National Alzheimer's Coordinating Center Uniform Data Set (NACCUDS). We examined NPS as characterized by expert clinicians and report its impact on the outcome of functional decline, measured by the Functional Assessment Questionnaire (FAQ), a standardized assessment of activities of daily living, by dementia etiology (Alzheimer's disease (AD, N = 11,044), Lewy Body Disease (LBD, N = 921), and behavioral variant frontal temporal lobe dementia (bvFTD, N = 933)).

RESULTS: We find apathy was the most commonly endorsed and the most persistent symptom across dementia types in all groups and was associated with more rapid functional decline in AD and bvFTD. On the contrary, depression, occurring in 40% or more of all groups, was not associated with worsening functional impairment in any group. We identified patterns that indicated higher rates of disinhibition and persistent disinhibition in bvFTD compared to AD and LBD. Psychosis had unique impact on functional decline in AD and LBD as did agitation in AD.

DISCUSSION: Differential impact of individual NPS across dementia etiologies and their impact on functional decline may have important consequences for clinical trial designs for the treatment of these symptoms.}, } @article {pmid42519716, year = {2026}, author = {Labounek, R and Matheson, MJ and Strong, CA and Petersen, A and Hill, A and Robertson, AJ and Hansen, A and Block, AD and Henderson, JN and Nestrasil, I and Lenglet, C and Mantyh, WG}, title = {Reduced Effect of APOE4 on White Matter Microstructure in an American Indian Community.}, journal = {Neurology. Genetics}, volume = {12}, number = {4}, pages = {e200418}, doi = {10.1212/NXG.0000000000200418}, pmid = {42519716}, issn = {2376-7839}, abstract = {BACKGROUND AND OBJECTIVES: Apolipoprotein E4 (APOE4) is central to Alzheimer disease (AD) personalized medicine, yet its link to AD is highly ancestry-dependent. Emerging evidence suggests an attenuated risk of APOE4 on brain health in American Indian (AI) participants. This study examines white matter microstructure, an early indicator of brain health deterioration, among tribal Elders carrying the APOE4 allele.

METHODS: We performed a cross-sectional, community-based study in partnership with the Bois Forte Band of Chippewa. Tribal Elders (>54 years of age) were evaluated at the Tribal Nation's health clinic or urban office and were recruited via radio, health fairs, social media, and flyers. We preselected 7 MRI white matter tracts that prior work has shown to be consistently associated with APOE4 status and AD in non-Hispanic white (NHW) participants. We compared microstructural integrity between AI and NHW APOE4 carriers vs noncarriers while controlling for age, sex, and hypertension status.

RESULTS: Sixty-two tribal Elders were included. The mean age was 65 years, and the mean Mini-Mental State Examination score was 29. Forty-nine (79%) participants were female, 33 (53%) had hypertension, and 10 (16%) were APOE4 heterozygotes. In contrast to NHW Alzheimer Disease Neuroimaging Initiative participants, tribal Elders had consistently attenuated associations of APOE4 on white matter microstructure.

DISCUSSION: Tribal elders have an attenuated effect of APOE4 on a neuroimaging measure of brain health. This finding parallels volumetric and neuropsychological findings in other AI populations. Caution is required when interpreting APOE4 for AI patients in clinical settings, where APOE4 status is increasingly used for prognostic, diagnostic, and treatment eligibility purposes.}, } @article {pmid42520518, year = {2026}, author = {Han, M and Liao, Q and He, S and Guo, L and Lu, Z and Wang, X and Sun, W and Duan, Y and Lyu, W and Li, Q}, title = {Regulation of different kinases for Alzheimer's disease therapy: progresses and perspectives.}, journal = {Bioorganic chemistry}, volume = {181}, number = {}, pages = {110300}, doi = {10.1016/j.bioorg.2026.110300}, pmid = {42520518}, issn = {1090-2120}, abstract = {Alzheimer's disease (AD) is clinically characterized by extracellular amyloid plaques caused by β-amyloid (Aβ) aggregation and intracellular neurofibrillary tangles (NFTs) formed by hyperphosphorylation of tau protein. Plaques and tangles attract microglia to their periphery, causing them to adopt the proinflammatory M1 type. In the central nervous system (CNS), activated microglia are a major source of inflammatory molecules, which trigger a positive feedback mechanism that activates more microglia, which further aggravates the neuroinflammatory response. In this procedure, many kinases are involved in the main signaling pathways of microglia activation. Kinases phosphorylate different substrate proteins, thereby regulating various processes of AD occurrence and development. Therefore, many researchers have developed kinase modulators to reduce the phosphorylation process of downstream substrates, in order to achieve the effect of AD treatment.}, } @article {pmid42520782, year = {2026}, author = {Persson, J and Voss, G}, title = {Anti-Amyloid Therapies for Early Alzheimer's Disease: Evidence-Based Recommendations.}, journal = {South Dakota medicine : the journal of the South Dakota State Medical Association}, volume = {79}, number = {1}, pages = {35-39}, pmid = {42520782}, issn = {0038-3317}, abstract = {BACKGROUND: Alzheimer's disease (AD) is the most common cause of dementia in older adults and represents a growing public health burden. Traditional therapies offer only symptomatic relief without modifying disease progression. Recently approved anti-amyloid monoclonal antibodies, donanemab and lecanemab, represent a shift toward disease-modifying treatment in patients with mild cognitive impairment (MCI) or mild AD with confirmed amyloid pathology.

METHODS: This review synthesizes current evidence from key clinical trials, real-world safety considerations, and expert-driven appropriate use recommendations (AURs) to guide the safe and effective use of donanemab and lecanemab.

RESULTS: Both agents demonstrate statistically significant and clinically meaningful slowing of cognitive and functional decline in early symptomatic AD. Key differences exist in their mechanisms of action, dosing schedules, and treatment duration. Safety monitoring, particularly for amyloid-related imaging abnormalities (ARIA) and apolipoprotein E (APOE) ε4 genotyping, is an essential component of care.

CONCLUSION: Anti-amyloid therapies offer a meaningful step forward in AD management, but their use requires careful patient selection, biomarker confirmation, and adherence to safety protocols. As long-term outcomes and comparative effectiveness remain uncertain, continued surveillance, patient education, and equitable access will be important in optimizing the clinical impact of anti-amyloid therapies.}, } @article {pmid42521309, year = {2026}, author = {Moncion, K and Rodrigues, L and Bon, A and Sutoski, A and Sikorska, K and Allison, EY and Abreu, J and Golchi, S and Arbour, N and Gauthier, C and Paquette, C and Rosa-Neto, P and Leppert, I and Rowley, C and Tardiff, CL and Thiel, A and Al-Khazraji, B and Tang, A and Roig, M}, title = {Protecting the brain from post-stroke cognitive impairment and dementia with multimodal exercise training: study protocol for a Bayesian adaptive trial (PROTECT).}, journal = {BMJ open}, volume = {16}, number = {7}, pages = {e123336}, doi = {10.1136/bmjopen-2026-123336}, pmid = {42521309}, issn = {2044-6055}, abstract = {INTRODUCTION: Stroke triggers acute vascular and inflammatory mechanisms that predispose the brain to rapid neurodegeneration. Up to 52% of stroke survivors develop cognitive impairment within 6 months and 20% receive a clinical diagnosis of dementia within 5 years. The subacute phase (<6 months) represents a critical window in which the brain may be most responsive to neuroprotective interventions. Multimodal aerobic and resistance training improves cognition in chronic stroke, but whether it improves cognition, neuroimaging markers and blood biomarkers of dementia risk when delivered during this early window remains unknown. The PROTECT trial will compare the effects of 12 weeks of multimodal exercise (moderate-to-high-intensity resistance and aerobic training) versus a low-intensity exercise comparator on cognition, neuroimaging outcomes, blood biomarkers of cognitive decline and dementia risk in people with subacute stroke.

METHODS AND ANALYSIS: The PROTECT trial is a 12-week, Phase 3, assessor-blinded, multisite Bayesian adaptive randomised controlled trial (RCT) following a two-arm parallel group sequential design with 6-month and 12-month follow-up (NCT07445841). Participants will be randomised to multimodal training or the comparator using concealed allocation with permuted blocks of varying sizes. The primary outcome is cognition, measured using the 13-item Alzheimer's Disease Assessment Scale-Cognitive assessment (ADAS-Cog-13). Secondary outcomes include ADAS-Cog-Plus, structural and perfusion neuroimaging and blood biomarkers of inflammation and neurodegeneration. Tertiary outcomes include cardiorespiratory fitness, functional mobility, muscle strength, body composition, neuropsychological status, patient-reported cognition, quality of life, fatigue and healthcare utilisation. Outcomes will be assessed at baseline, post-intervention (primary endpoint) and at 6-month and 12-month follow-up. Sample size was estimated via 20 000 Monte Carlo simulations using an ADAS-Cog effect size of Cohen's d=0.63 from a previous exercise RCT. The target was ≥80% power to detect this treatment effect at a one-sided type I error rate of 2.5%, using a weakly informative prior centred at zero with a variance of 100. The minimum required was 45 completers per arm (N=90) and accounting for 25% attrition, up to 120 participants (60 per arm) will be enrolled. Pre-planned adaptive features include: (1) two interim analyses at 50% and 75% of completers; (2) early stopping for efficacy and futility; and (3) sample size re-estimation.

ETHICS AND DISSEMINATION: Ethical approval to conduct this study has been granted by the Centre de recherche interdisciplinaire en réadaptation du Montréal métropolitain (CRIR MP-50-2025-2294) and Hamilton Integrated Research Board (HIREB 19222). Any protocol amendments will be submitted to the appropriate ethics boards. Written informed consent to participate in this study will be obtained from all participants by study coordinators or assistants. Study results will be published and reported in peer-reviewed journal following Adaptive Designs Consolidated Standards of Reporting Trials extension guidelines.

TRIAL REGISTRATION NUMBER: NCT07445841.}, } @article {pmid42502360, year = {2026}, author = {Houmani, A and Parul, FNU and Saeed, M and Skowronek, R and Katkoori, V and Pikuleva, IA and Grant, MB and Busik, JV and Yavari, M and Abela, GS}, title = {Cholesterol crystal formation and embolism in the central nervous system and their potential role in Alzheimer's disease.}, journal = {American heart journal plus : cardiology research and practice}, volume = {69}, number = {}, pages = {100826}, pmid = {42502360}, issn = {2666-6022}, abstract = {The brain and nervous tissues are very rich in cholesterol with local sterol biosynthesis being the primary source. The production of cholesterol in the brain may also lead to cholesterol crystal formation that in turn can cause inflammation which potentially can contribute to Alzheimer's disease. In this review we provide examples of cholesterol crystals (CCs) in human brains of Alzheimer patients. Moreover, cholesterol in the arterial circulation is also a major contributor to brain pathology. Specifically, CCs embolization released during plaque rupture may lead to reduced cognitive function, transient ischemic attacks, and ischemic strokes. Ischemic strokes can be caused by either thrombotic emboli from atrial fibrillation or CC emboli and platelets from ruptured plaques in the carotid arteries and aortic arch. CC emboli can cause blood flow obstruction, localized inflammation, and vasospasm of the local arterial vasculature, all contributing to ischemia and brain injury. Prevention and treatment of CC emboli with statins and aspirin has been found to be effective. Moreover, previous studies have demonstrated that both statins and aspirin can dissolve CCs. Thus, preventing formation and/or dissolving CCs could potentially be effective in reducing end organ injury induced by both CCs formation and emboli. Although further investigation with human studies remain lacking, recent studies have demonstrated prevention of thrombus formation induced by CCs may also provide another approach to inhibiting end-organ ischemic injury.}, } @article {pmid42502675, year = {2026}, author = {Yu, L and Alhoqail, WA and Mickymaray, S and Li, F}, title = {Cnicin Attenuates Aluminium Chloride-Induced Neurodegeneration Through Antioxidant and Anti-Inflammatory Mechanisms.}, journal = {Dose-response : a publication of International Hormesis Society}, volume = {24}, number = {3}, pages = {15593258261471150}, pmid = {42502675}, issn = {1559-3258}, abstract = {BACKGROUND: Alzheimer's disease (AD) is a progressive neurodegenerative disorder with limited disease-modifying therapies. Aluminium chloride (AlCl3)-induced neurotoxicity mimics key pathological features of AD, including oxidative stress, neuroinflammation, and cholinergic dysfunction.

OBJECTIVE: This study aimed to evaluate the neuroprotective effect of cnicin in an AlCl3-induced rat model of Alzheimer-like neurodegeneration.

METHODS: Rats were divided into five groups: normal control, AlCl3 control (75 mg/kg/day, p.o.), AlCl3 with cnicin (20 and 40 mg/kg/day, p.o.), and AlCl3 with donepezil (5 mg/kg/day, p.o.) for 30 days. Behavioral performance was assessed using hanging wire and beam walking tests. Biochemical parameters, including acetylcholinesterase (AChE), antioxidant enzymes (SOD, CAT, GSH), malondialdehyde (MDA), and inflammatory cytokines (TNF-α, IL-1β) were analyzed, along with histopathology.

RESULTS: AlCl3 administration induced significant behavioral deficits, increased AChE activity, oxidative stress, neuroinflammation, and neuronal damage. Cnicin treatment dose-dependently improved motor function, reduced AChE activity, restored antioxidant levels, decreased lipid peroxidation, and suppressed inflammatory markers. Histological analysis confirmed preservation of neuronal architecture, comparable to that of donepezil.

CONCLUSION: Cnicin exhibits significant neuroprotective effects against AlCl3-induced neurodegeneration by modulating cholinergic activity, oxidative stress, and inflammation, suggesting its potential as a therapeutic agent for AD.}, } @article {pmid42503498, year = {2026}, author = {Lee, YS and Roh, S and Han, J and Moon, I and Stone, ST and Warne, DK}, title = {Alzheimer's Disease Knowledge Among American Indians: The Role of Social Determinants of Health.}, journal = {Dementia (London, England)}, volume = {}, number = {}, pages = {14713012261471592}, doi = {10.1177/14713012261471592}, pmid = {42503498}, issn = {1741-2684}, abstract = {American Indian populations experience a disproportionately high prevalence of risk factors for Alzheimer's disease and related dementias. This study assessed Alzheimer's disease knowledge across seven domains and identified factors associated with overall and domain-specific Alzheimer's disease knowledge among American Indian adults. Guided by the social determinants of health framework, we conducted a cross-sectional survey of American Indian adults residing in South Dakota. A total of 227 participants completed a self-administered survey questionnaire measuring Alzheimer's disease knowledge across seven domains. Multivariable regression analyses were performed to examine factors associated with overall Alzheimer's disease knowledge and each domain. Participants demonstrated 63.5% accuracy in overall Alzheimer's disease knowledge (M = 18.7, SD = 4.1), indicating a moderate level of knowledge. Knowledge varied across domains: participants were most knowledgeable about the life impact of Alzheimer's disease and least knowledgeable about risk factors and symptoms. Four domains were found to be statistically significant: disease course, treatment and management, risk factors, and caregiving. Higher educational attainment and employment status were significantly associated with greater overall Alzheimer's disease knowledge. Education was the most consistent factor associated with greater knowledge across all four domains, whereas other social determinants of health variables (e.g., social support from significant others, lower depressive symptoms, health status, exercise) showed domain-specific associations. Findings highlight the need for educational outreach and culturally tailored interventions grounded in the social determinants of health and responsive to American Indian community contexts. Notable gaps in knowledge-particularly regarding risk factors and symptoms-suggest priority areas for Alzheimer's disease prevention efforts. Health initiatives should address key social determinants, including education, employment, social support, health/mental health status, and health behaviors. Interventions must be developed in partnership with Indigenous leaders and health professionals to ensure culturally relevant, community-driven, and holistic approaches that improve Alzheimer's disease knowledge and support Alzheimer's disease prevention in American Indians.}, } @article {pmid42504206, year = {2026}, author = {Zhang, Y and Qin, G and Lian, Q and Sun, Y and Liu, Z and Chen, B and Li, Z and Li, N and Song, R and Wang, Y}, title = {Deciphering the Multi-Target Therapeutic Mechanisms of Traditional Chinese Medicine Against Alzheimer's Disease: A Network Pharmacology Perspective.}, journal = {Drug design, development and therapy}, volume = {20}, number = {}, pages = {597886}, pmid = {42504206}, issn = {1177-8881}, mesh = {Humans ; *Alzheimer Disease/drug therapy/metabolism ; *Medicine, Chinese Traditional ; *Network Pharmacology ; *Drugs, Chinese Herbal/therapeutic use/pharmacology/chemistry ; Signal Transduction/drug effects ; Animals ; }, abstract = {Alzheimer's disease (AD) poses a growing threat to global health, with no disease-modifying therapies currently available to cure or reverse its progression. Given its favorable safety profile and multi-target nature, Traditional Chinese Medicine (TCM) has attracted increasing attention as a potential strategy for AD prevention and treatment. In recent years, network pharmacology (NP) has emerged as a valuable predictive and analytical tool in TCM research, offering insights into the potential mechanisms underlying AD interventions. This review aims to systematically outline the methodology and commonly used databases in TCM NP, summarize the main TCM monomers and compounds studied for AD over the past decade, and identify five core signaling pathways, namely, the PI3K/Akt signaling pathway, the MAPK signaling pathway, the JAK-STAT signaling pathway, the AGE-RAGE signaling pathway, and the Nrf2 signaling pathway, implicated in pathogenesis and TCM action. To guide further exploration of TCM's role in AD management and to support subsequent research on its disease mechanisms and therapeutic strategies.}, } @article {pmid42504849, year = {2026}, author = {Kumar, S and Burhan, AM and Colman, S and Chu, L and Davies, S and Derkach, P and Elmi, S and Gerretsen, P and Graff-Guerrero, A and Greenway, K and Hussain, M and Ismail, Z and Kim, D and Krisman, L and Ma, C and Moghabghab, R and Mulsant, BH and Pollock, BG and Rej, S and Rostas, A and Schoer, N and Streiner, DL and Van Bussel, L and Rajji, TK and , }, title = {Standardizing care for agitation in Alzheimer's disease, results from a randomized controlled trial of an integrated care pathway versus usual care - the StaN trial.}, journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association}, volume = {22}, number = {7}, pages = {e71610}, doi = {10.1002/alz.71610}, pmid = {42504849}, issn = {1552-5279}, support = {//Centre for Aging and Brain Health Innovation/ ; //Brain Canada Foundation through the Canada Brain Research Fund/ ; }, mesh = {Humans ; Female ; Male ; Double-Blind Method ; *Psychomotor Agitation/therapy/drug therapy/etiology ; *Alzheimer Disease/complications/therapy/drug therapy ; Aged ; Aged, 80 and over ; Polypharmacy ; Canada ; Treatment Outcome ; Long-Term Care ; Psychotropic Drugs/therapeutic use ; }, abstract = {BACKGROUND: Adherence to treatment guidelines for agitation in dementia is suboptimal and inconsistent. We designed and evaluated an Integrated Care Pathway (ICP) for the management of agitation in dementia.

METHODS: This was a double-blind randomized controlled trial at 12 inpatient units and long-term-care homes (LTCHs) across Canada. Participants were randomized 1:1 to the ICP or treatment-as-usual (TAU). Primary outcomes were Cohen Mansfield Agitation Inventory (CMAI) and psychotropic polypharmacy at 12 weeks.

RESULTS: We randomized 185 participants (93 inpatients, 92 in LTCHs). For CMAI, there were no significant time-by-treatment-group interactions among inpatients (F4, 299.3 = 1.7, p = 0.14) or LTCH residents (F4, 296.0 = 0.87, p = 0.48). For polypharmacy, there were significant time-by-treatmentgroup interactions among both inpatients (χ 7 2 = 15.3, p = 0.032) and LTCH residents (χ 7 2 = 30.0, p < 0.001), with lower rates of polypharmacy in the ICP group at certain time points, but not at week 12.

CONCLUSIONS: Standardizing care for agitation in dementia may result in lesser polypharmacy without affecting efficacy. Future studies should assess the ICP in the broader community and outpatients.}, } @article {pmid42505964, year = {2026}, author = {Galizzi, G}, title = {Omega-3 Fatty Acids and Alzheimer's Disease: Toward a New Understanding of Neuroprotective Mechanisms and Intervention Strategies.}, journal = {Marine drugs}, volume = {24}, number = {7}, pages = {}, doi = {10.3390/md24070224}, pmid = {42505964}, issn = {1660-3397}, mesh = {Humans ; *Alzheimer Disease/drug therapy/metabolism ; Animals ; *Neuroprotective Agents/pharmacology/therapeutic use ; *Fatty Acids, Omega-3/pharmacology/therapeutic use ; Docosahexaenoic Acids/pharmacology ; Dietary Supplements ; Brain/drug effects/metabolism ; Eicosapentaenoic Acid/pharmacology ; }, abstract = {Alzheimer's disease (AD) is a multifactorial neurodegenerative disorder characterized by amyloid-β (Aβ) deposition, tau hyperphosphorylation, neuroinflammation, mitochondrial dysfunction, and oxidative stress. Despite recent advances, current therapies offer little benefit, and AD remains a significant challenge. Polyunsaturated fatty acids (PUFAs), particularly eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), have attracted attention for their neuroprotective effects primarily through anti-inflammatory and antioxidant properties, but also for their ability to influence membrane fluidity and neuronal function. DHA is the predominant omega-3 PUFA in nerve cell membranes and is critical for synaptic plasticity and cognitive function. Some evidence has demonstrated that marine omega-3 supplementation reduces Aβ deposition, modulates microglial activation, and prevents cognitive decline in animal models. Even with heterogeneous results, preclinical and clinical studies suggest that long-term DHA/EPA supplementation can improve cognitive function in subjects with mild cognitive impairment (MCI) and reduce neuroinflammation markers. However, individual variability and brain bioavailability pose significant challenges. This review summarizes and discusses the current knowledge on the importance of PUFAs for human health, exploring novel mechanistic hypotheses, such as the effect of omega-3 fatty acids on brain iron homeostasis, the microbiota-gut-brain axis, the glymphatic system, and miRNAs. Furthermore, it focuses on the therapeutic potential of PUFAs in the treatment of AD and proposes future directions for translational research.}, } @article {pmid42506306, year = {2026}, author = {Vamanu, A and Mastaleru, A and Schreiner, TG and Popescu, G and Roceanu, AM and Cucu, AI and Patrascu, A and Vulpoi, GA and Bilcu, RV and Cozma, RS and Olariu, R and Bistriceanu, CE and Covali, R and Cuciureanu, DI and Ciubotaru, A}, title = {Pharmacological and Clinical Heterogeneity of Anti-Amyloid Monoclonal Antibodies in Early Alzheimer's Disease: A Systematic Review and Meta-Analysis of Randomized Trials.}, journal = {Medical sciences (Basel, Switzerland)}, volume = {14}, number = {3}, pages = {}, doi = {10.3390/medsci14030337}, pmid = {42506306}, issn = {2076-3271}, mesh = {Humans ; *Alzheimer Disease/drug therapy ; Randomized Controlled Trials as Topic ; *Antibodies, Monoclonal/therapeutic use/pharmacology ; *Amyloid beta-Peptides/antagonists & inhibitors/immunology ; Antibodies, Monoclonal, Humanized/therapeutic use ; Biomarkers ; }, abstract = {Background: Anti-amyloid monoclonal antibodies represent the first disease-modifying therapeutic strategy targeting amyloid-β pathology in early Alzheimer's disease (AD). Although several agents have demonstrated the ability to reduce cerebral amyloid burden, their clinical efficacy and safety remain subjects of substantial scientific and regulatory debate. This study aimed to synthesize randomized evidence evaluating the benefit-risk profile of anti-amyloid monoclonal antibodies in biomarker-confirmed early AD. Methods: A systematic review and classical pairwise meta-analysis of randomized controlled trials (RCTs) was conducted following the PRISMA 2020 guidelines. PubMed/MEDLINE, Embase, and the Cochrane Central Register of Controlled Trials were searched for phase III placebo-controlled trials evaluating lecanemab, donanemab, aducanumab, and gantenerumab in patients with mild cognitive impairment due to AD or mild AD dementia with biomarker confirmation of amyloid pathology. The primary outcome was change from baseline in the Clinical Dementia Rating-Sum of Boxes (CDR-SB) at the longest available follow-up. Safety outcomes included amyloid-related imaging abnormalities with edema or effusion (ARIA-E), amyloid-related imaging abnormalities with hemorrhage (ARIA-H), serious adverse events, and treatment discontinuation. Random-effects meta-analyses were performed. Results: Six randomized comparisons derived from four phase III trials involving 7695 participants met the eligibility criteria. Anti-amyloid monoclonal antibodies were associated with a statistically significant slowing of clinical progression compared with placebo (pooled mean difference in CDR-SB: -0.42 points; 95% CI -0.59 to -0.25; I[2] = 78%). The observed effect was primarily driven by trials of lecanemab and donanemab, whereas aducanumab demonstrated discordant results across trials and gantenerumab showed no clinically meaningful benefit. Despite statistical significance, the magnitude of the pooled effect approached the lower boundary of the minimal clinically important difference reported for CDR-SB in early AD. Treatment was associated with a markedly increased risk of ARIA-E (pooled risk ratio 10.1; 95% CI 7.8-13.0), with moderate heterogeneity across studies. Most ARIA-E events were asymptomatic and detected through protocol-mandated MRI monitoring. Conclusions: In biomarker-confirmed early Alzheimer's disease, anti-amyloid monoclonal antibodies produce a statistically significant but modest slowing of clinical decline accompanied by a substantially increased risk of ARIA. The benefit-risk profile appears heterogeneous across individual antibodies and may reflect pharmacological differences in amyloid targeting and clearance mechanisms. These findings support cautious, individualized use of anti-amyloid therapies and highlight the need for longer-term studies to determine whether short-term slowing of decline translates into clinically meaningful disease modification.}, } @article {pmid42506779, year = {2026}, author = {Talwar, A and Sherer, J and Abughosh, S and Chatterjee, S and Aparasu, RR}, title = {Cumulative Anticholinergic Burden and Risk of Delirium Among Older Adults with Alzheimer's Disease.}, journal = {Pharmacy (Basel, Switzerland)}, volume = {14}, number = {4}, pages = {}, doi = {10.3390/pharmacy14040089}, pmid = {42506779}, issn = {2226-4787}, abstract = {Delirium is a transient neuropsychiatric condition that is a severe and prevalent condition affecting 2.6 million older adults each year. Alzheimer's disease (AD) and anticholinergic medication use are risk factors for delirium. This study evaluated the association between cumulative anticholinergic burden (CAB) and risk of delirium among older adults with AD initiating cholinesterase inhibitors (ChEIs). This retrospective cohort study used 2013-2017 Medicare claims data, and included adults 65 years and older with AD who initiated any of the ChEIs (donepezil, rivastigmine, and galantamine) after a 12-month washout period. CAB, as the primary exposure, was measured on the index date and calculated as the monthly total standardized daily dose of anticholinergic medications. A multivariable Cox proportional hazards regression model with inverse probability of treatment weighting (IPTW) generated using generalized boosted models was used to evaluate the risk of delirium associated with the CAB. This study identified 143,320 older adults with AD who initiated ChEIs. Most patients were in the low/no burden (62.73%) group, followed by high burden (21.12%) and moderate burden (16.14%). Overall, delirium diagnosis was observed in 19.11% of the cohort. The Cox regression model with IPTW found that moderate (aHR, 1.56; 95% CI, 1.52-1.61; p < 0.0001) and high CAB (aHR, 1.45; 95% CI, 1.42-1.49; p < 0.0001) were associated with an increased risk of delirium compared to low/no burden. Among older adults with AD initiating ChEIs, moderate and high CAB were associated with an increased risk of delirium compared with low/no CAB. These findings highlight the need to carefully reduce the CAB, especially dose and duration, along with utilizing anticholinergic alternatives in older adults with AD.}, } @article {pmid42506943, year = {2026}, author = {Periyasamy, TS and Sekar, N and Lakshmanan, H}, title = {Integration of multi-omics and artificial intelligence for therapeutic insights in Alzheimer's disease: A comprehensive review.}, journal = {Journal of Alzheimer's disease : JAD}, volume = {}, number = {}, pages = {13872877261471812}, doi = {10.1177/13872877261471812}, pmid = {42506943}, issn = {1875-8908}, abstract = {Alzheimer's disease (AD) is a progressively worsening type of brain disorder that damages the nerve cells. It is marked by the buildup of amyloid-β plaques outside the cells, tau neurofibrillary tangles inside the cells, and overall molecular-level dysfunction. The therapies currently available mainly cater to alleviating the symptoms, whereas the newly approved disease-modifying antibodies, such as lecanemab and donanemab, bring out only limited clinical improvements. Being complicated and involving many factors, AD requires sophisticated computer-based methods to combine different biological data and find suitable therapy targets. In this review, we discuss how artificial intelligence (AI)-powered multi-omics data integration can be a catalyst in discovering drug targets, identifying biomarkers, and stratifying patients for AD. By utilizing machine learning techniques like random forests, graph neural networks, and deep learning, AI-led multi-omics methods have helped uncover new therapeutic targets. Models that were built using federated learning across various institutions outperformed single-center models with a higher area under the curve score (0.84, 0.94 versus 0.76, 0.85). AI-guided patient stratification lessened the clinical trial's sample size needs by 40, 55% while still retaining 80, 90% statistical power. Multi-omics analyses further pointed out that it is the downstream molecular pathways, and not amyloid pathology alone, that are significantly involved in disease progression, thereby questioning the effectiveness of single-target anti-amyloid therapies and endorsing combination treatment strategies. AI and multi-omics data combination can be a game-changer in facilitating new target discovery, making clinical trial design more efficient, and ushering in precision medicine in AD.}, } @article {pmid42507054, year = {2026}, author = {Otomi, Y and Shinya, T and Otsuka, H and Kasai, H and Matsushita, T and Takaoka, Y and Hiroshima, Y and Matsubara, T and Fujita, K and Tomioka, Y and Nakataki, M and Numata, S and Izumi, Y and Harada, M}, title = {Serial amyloid PET demonstrates marked reduction in amyloid burden following donanemab treatment: a real-world cohort study.}, journal = {Japanese journal of radiology}, volume = {}, number = {}, pages = {}, pmid = {42507054}, issn = {1867-108X}, support = {JP24K15767//Japan Society for the Promotion of Science/ ; }, abstract = {PURPOSE: To evaluate changes in amyloid burden on serial amyloid PET before and after donanemab treatment in a real-world clinical cohort.

METHODS: This retrospective study included 20 consecutive patients who underwent serial amyloid PET before and after donanemab treatment. Quantitative analysis was performed using Centiloid values and tracer-specific standardized uptake value ratios (SUVr). Visual assessment was also performed to determine amyloid-positive or amyloid-negative status before and after treatment.

RESULTS: Centiloid values significantly decreased from 52.3 ± 23.4 at baseline to - 5.6 ± 16.5 at follow-up, with a mean change of - 58.0 (p < 0.001). All patients showed a reduction in Centiloid values. In the flutemetamol group (n = 12), pons-referenced SUVr significantly decreased, while in the florbetapir group (n = 8), cerebellar-referenced SUVr also showed significant reductions (both p < 0.001). On visual assessment, 17 of 20 patients (85%) converted from amyloid-positive to amyloid-negative status after treatment.

CONCLUSION: Serial amyloid PET demonstrated a substantial reduction in amyloid burden following donanemab treatment in this real-world cohort. Quantitative amyloid PET, particularly using Centiloid scaling, may be a useful tool for monitoring treatment response in clinical practice.}, } @article {pmid42507235, year = {2026}, author = {Stites, SD and Lee, K and Kuz, C and Mandell, D and Bogner, HR and Brown, R}, title = {Worry and Anxiety in the Era of Early Diagnosis and Disease Modifying Treatment for Alzheimer's Disease.}, journal = {Current psychiatry reports}, volume = {28}, number = {1}, pages = {}, pmid = {42507235}, issn = {1535-1645}, mesh = {Humans ; *Alzheimer Disease/diagnosis/psychology/therapy ; Early Diagnosis ; *Anxiety/psychology/diagnosis ; }, abstract = {PURPOSE OF REVIEW: Psychologists and psychiatrists are well-positioned to be at the forefront of addressing the challenges posed by anxiety in early diagnosis and treatment of Alzheimer's disease (AD) dementia that are unfolding in primary care settings. The present article provides a summary of emerging areas in Alzheimer's disease testing and research to guide clinical decisions and research pursuits.

RECENT FINDINGS: The present article provides an overview of how anxiety is understood in early diagnosis of dementia due to AD, its influence in AD-related mechanisms, and the implications of these findings on current research practices. We conducted focused literature reviews between January and June 2026 and synthesized the information to provide a narrative review. Overall, the clinical roles of anxiety in AD dementia are expanding- from being viewed primarily as reactions to cognitive decline to serving as informative features of the diagnostic process and clinical course of the disease.}, } @article {pmid42507320, year = {2026}, author = {Wang, C and Han, X and Lin, Y and Pan, Y and Miao, Q and Wang, Y and Wang, SQ and Zhang, Z and Wang, L and Tang, ZR and Peng, Y and Yung, KK and Ma, N and Lu, D and Zhang, S and Shi, L}, title = {Betulinaldehyde Ameliorates Aβ-Induced Neurotoxicity and Cognitive Deficits by Modulating the eEF2K/eEF2 Pathway.}, journal = {CNS neuroscience & therapeutics}, volume = {32}, number = {7}, pages = {e71050}, doi = {10.1002/cns.71050}, pmid = {42507320}, issn = {1755-5949}, support = {2022YFA1104900//National Key Research and Development Program of China/ ; 2022ZD0214400//The Brain Science and Brain-like Intelligence Technology-National Science and Technology Major Project/ ; 82371175//National Natural Science Foundation of China/ ; U24A20804//National Natural Science Foundation of China/ ; 2023A1515030012//Guangdong Basic and Applied Basic Research Foundation/ ; 2022B1515130007//Guangdong Basic and Applied Basic Research Foundation/ ; 2023B1515040015//Guangdong Basic and Applied Basic Research Foundation/ ; 202102070001//The Science and Technology Projects in Guangzhou/ ; 2023A0505050121//International Science and Technology Projects of Guangdong Province/ ; 20261073//The Research Project of Guangdong Provincial Bureau of Traditional Chinese Medicine/ ; }, mesh = {Animals ; *Amyloid beta-Peptides/toxicity ; *Elongation Factor 2 Kinase/metabolism ; Mice ; *Peptide Fragments/toxicity ; *Triterpenes/pharmacology/therapeutic use ; Signal Transduction/drug effects ; Humans ; *Neuroprotective Agents/pharmacology/therapeutic use ; Neurons/drug effects ; *Cognition Disorders/drug therapy/chemically induced ; Mice, Inbred C57BL ; }, abstract = {BACKGROUND: Alzheimer's disease (AD), the most common form of dementia, remains without effective therapies. Dysregulated eukaryotic elongation factor 2 kinase/eukaryotic elongation factor 2 (eEF2K/eEF2) pathway leads to aberrant protein synthesis and impaired neuronal function in AD, positioning this axis as a promising therapeutic target. However, effective pharmacological modulators of eEF2K/eEF2 remain limited. Betulinaldehyde (Betu), an active ingredient derived from traditional Chinese medicine, remains to be thoroughly evaluated as a potential neuroprotective agent.

PURPOSE: This study aims to investigate the therapeutic effects of Betu on AD and determine whether its activities are mediated through the eEF2K/eEF2 pathway.

METHODS: Neuronal cell models were used to assess the effects of Betu on β-amyloid 42 (Aβ42)-induced neuronal death, dendritic spine damage, protein synthesis inhibition, and eEF2 hyperphosphorylation. The eEF2K agonist nelfinavir (NFV) and the protein synthesis inhibitors cycloheximide (CHX) and anisomycin (AS) were used to investigate the involvement of the eEF2K/eEF2 pathway and its regulated protein synthesis in the action of Betu. The cellular thermal shift assay (CETSA) was used to detect potential interactions between Betu and eEF2K. Additionally, the effects of Betu on reactive oxygen species (ROS) levels and the associated pathways were evaluated. An Aβ42-induced mouse model of AD was used to evaluate the in vivo effects of Betu on cognitive decline, hippocampal neuropathological damage, and eEF2 hyperphosphorylation.

RESULTS: Betu significantly ameliorated the Aβ42-induced neuronal death and dendritic spine damage, restored protein synthesis, and reversed eEF2 hyperphosphorylation. The neuroprotective effects of Betu were effectively inhibited by the CHX, AS, or NFV treatment, and CETSA supported a potential interaction between Betu and eEF2K. Furthermore, Betu reversed Aβ42-induced ROS accumulation and upregulated nuclear factor-like 2 and heme oxygenase-1, potential downstream effectors of the eEF2K pathway. In an Aβ42-induced AD mouse model, Betu treatment markedly ameliorated cognitive decline, concomitant with attenuated neuropathological damage and restored eEF2 phosphorylation in the hippocampus.

CONCLUSION: These findings demonstrate that Betu protects against Aβ42-induced neurotoxicity by modulating the eEF2K/eEF2 pathway, highlighting its potential as a lead compound for AD.}, } @article {pmid42507332, year = {2026}, author = {Liao, C and Sun, D and Wang, X}, title = {Disease mechanisms and translational barriers guide nanocarrier design for nose to brain delivery in Alzheimer's disease.}, journal = {Discover nano}, volume = {21}, number = {1}, pages = {}, pmid = {42507332}, issn = {2731-9229}, support = {82572661//National Natural Science Foundation of China/ ; }, abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder with limited disease-modifying treatment options, partly because many therapeutic agents show insufficient brain exposure and dose-limiting systemic adverse effects after conventional administration. Nose-to-brain (N2B) delivery has emerged as a non-invasive strategy to transport therapeutics to the central nervous system through the olfactory and trigeminal pathways, thereby partially bypassing the blood-brain barrier. Recent advances in nanomedicine and biomaterial engineering have further improved this approach by enhancing drug stability, nasal residence, mucosal transport, and brain-targeting efficiency. This review examines nanocarrier-enabled N2B delivery strategies for AD from a mechanism-guided perspective, highlighting how AD-related pathological processes shape the selection of therapeutic cargos and formulation designs. We discuss recent progress in the intranasal delivery of repurposed small molecules, natural products, insulin-related agents, peptides and proteins, extracellular vesicles, antibodies, and nucleic acid-based therapeutics. We further summarize major nanocarrier and formulation platforms, including lipid-based systems, polymeric nanoparticles, micelles, extracellular vesicles, in situ gels, and device-assisted delivery technologies. Particular attention is given to the design parameters that influence N2B performance, including particle size distribution/PDI, surface charge, mucus interaction, cargo protection, targeting modification, biodistribution, and deposition reproducibility. Finally, we critically evaluate the translational challenges that continue to limit clinical application, including species differences in nasal anatomy, dose-volume restrictions, device-dependent variability, limited human pharmacokinetic evidence, manufacturing complexity, long-term safety, and regulatory requirements. By integrating disease mechanisms, nanocarrier design, and translational considerations, this review provides a structured perspective for developing more rational and clinically feasible N2B nanodelivery systems for AD.}, } @article {pmid42499619, year = {2026}, author = {Li, PS and Liu, Y and Zhao, MR and Zhu, YQ and Shi, YX and Jing, MD and Hu, XW and Jiang, CH and Liu, XD and You, YL and Wu, CJ and Bie, NN and Liu, XM}, title = {Zizybeoside II From Jujube Fructus Prolongs Lifespan and Mitigates Alzheimer's Disease Progression in Caenorhabditis elegans Through HSF-1/HSP-16.2 Pathway.}, journal = {Food science & nutrition}, volume = {14}, number = {7}, pages = {e72151}, pmid = {42499619}, issn = {2048-7177}, abstract = {Jujube (Ziziphus jujuba Mill.) has been consumed as a nutraceutical and medicinal food in China for millennia. Recent studies have highlighted the nutritional and bioactive properties of jujube fruit extracts, with potential to mitigate Alzheimer's disease (AD) progression through longevity-enhancing effects. Our previous study explored the lifespan-extending mechanisms of Jujube Fructus extract (JE) in Caenorhabditis elegans (C. elegans). Here, we evaluated the efficacy of zizybeoside II (ZB), separated from JE through HPLC, in extending lifespan and ameliorating AD pathology in C. elegans. The results showed that ZB treatment significantly prolonged C. elegans lifespan while maintaining reproductive capacity, with concurrent enhancements in normal activity and stress resistance during aging. Additionally, we found that ZB effectively alleviated various β-Amyloid (Aβ)-induced neurotoxic phenotypes in AD worms, including paralysis and behavioral deficits. Mechanistic investigations in N2a/APP695 cells demonstrated that ZB reduced the accumulation of Aβ and phosphorylated tau (p-Tau) proteins, diminished oxidative stress levels through the HSF-1/HSP16.2 pathway, and thereby slowed the progression of AD. This study provides a theoretical basis for the subsequent clinical trials of ZB in delaying AD.}, } @article {pmid42499998, year = {2026}, author = {Ruesga Mundo, S}, title = {Neuroinflammation as a failure of allostatic integrity: a hierarchical-circular model of biological memory for pathogenesis in neurodegenerative and neuropsychiatric diseases.}, journal = {Frontiers in systems neuroscience}, volume = {20}, number = {}, pages = {1888548}, pmid = {42499998}, issn = {1662-5137}, abstract = {INTRODUCTION: Chronic neuroinflammation is a hallmark of neurodegenerative diseases (Alzheimer's disease, Parkinson's disease) and neuropsychiatric disorders (major depression, schizophrenia). However, current models fail to explain why some individuals develop persistent neuroinflammation while others maintain homeostasis, nor why similar inflammatory pathology produces such diverse clinical phenotypes.

HYPOTHESIS: We propose that pathological neuroinflammation emerges from a failure of allostatic integrity-the capacity of the organism to maintain adaptive circular information flow across five interconnected levels: (1) genetic architecture and morphogenetic programming, (2) epigenetic molecular memory, (3) allostatic load and systemic physiological adaptation, (4) the psychoneuroimmuneendocrine (PINE) network, and (5) interoceptive-neuronal integration. When this circular flow is disrupted, maladaptive stable states become entrenched, perpetuating chronic inflammation.

DEVELOPMENT OF THE HYPOTHESIS: Synthesizing evidence from longitudinal and mechanistic studies (with foundational older works cited where necessary), we discuss how: (a) early-life stress epigenetically programs inflammatory reactivity; (b) elevated allostatic load predicts chronic neuroinflammation; (c) PINE network dysregulation perpetuates pro-inflammatory signaling; and (d) interoceptive dysfunction may prevent the downregulation of inflammation. Allostatic integrity is introduced as a dynamic systems-level property hypothesized to moderate the relationship between inflammatory pathology and clinical expression.

TESTABLE PREDICTIONS: The framework generates falsifiable predictions: (1) composite indices of allostatic integrity will outperform single biomarkers in predicting transition to chronic neuroinflammation; (2) multidomain interventions targeting multiple levels will produce multiplicative (synergistic) effects; (3) patients with similar inflammatory profiles but contrasting allostatic integrity will show markedly different clinical trajectories; and (4) improvements in allostatic integrity will correlate with reduced neuroinflammation independent of direct anti-inflammatory therapies.

CONCLUSION: The Hierarchical-Circular Model reframes chronic neuroinflammation not as a linear cascade but as a potential systemic failure of biological memory and allostatic integrity. Pending empirical validation, this framework may offer a conceptual basis for biomarker development, multidomain prevention, and personalized treatment strategies.}, } @article {pmid42502037, year = {2026}, author = {Montano, CB and Chumki, SR and Wang, D and Palma, AM and Zhang, Z and Porsteinsson, AP}, title = {Brexpiprazole With Antidepressants for Agitation in Alzheimer's Dementia: Post Hoc Analysis.}, journal = {The American journal of geriatric psychiatry : official journal of the American Association for Geriatric Psychiatry}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.jagp.2026.06.015}, pmid = {42502037}, issn = {1545-7214}, abstract = {OBJECTIVE: To analyze the efficacy and safety of brexpiprazole versus placebo on agitation symptoms in participants with Alzheimer's dementia, with and without concomitant antidepressants.

METHODS: Data were pooled from two Phase 3, 12-week, randomized, double-blind, placebo-controlled trials of brexpiprazole (ClinicalTrials.gov identifiers: NCT01862640, NCT03548584). Post hoc, participants were stratified by antidepressant use. Efficacy was assessed using the Cohen-Mansfield Agitation Inventory (CMAI) and safety using treatment-emergent adverse events (TEAEs).

RESULTS: Brexpiprazole 2 or 3 mg/day improved CMAI Total score versus placebo in participants with concomitant antidepressant (n = 97; least squares mean difference at Week 12, -12.1 [95% confidence interval, -19.1 to -5.05]; t(77) = -3.4, p = 0.001; Cohen's d = 0.72) and without concomitant antidepressant (n = 513; -2.93 [-5.49 to -0.37]; t(487) = -2.2, p = 0.025; Cohen's d = 0.20). Falls were the only TEAE reported for ≥5% of participants with concomitant antidepressant (brexpiprazole, 6.5%; placebo, 5.7%).

CONCLUSION: In this exploratory post hoc analysis, brexpiprazole improved agitation symptoms and was generally well tolerated in participants with Alzheimer's dementia with and without concomitant antidepressants.}, } @article {pmid42498669, year = {2026}, author = {McDiarmid, A}, title = {Sustaining Drug Discovery Amid the Limits of Alzheimer's Disease Immunotherapies.}, journal = {eNeuro}, volume = {13}, number = {7}, pages = {}, doi = {10.1523/ENEURO.0112-26.2026}, pmid = {42498669}, issn = {2373-2822}, mesh = {Humans ; *Alzheimer Disease/therapy/immunology/drug therapy ; *Immunotherapy/methods ; *Drug Discovery ; Animals ; Amyloid beta-Peptides/metabolism ; }, abstract = {Accumulation of insoluble extracellular amyloid-β (Aβ) plaques and intraneuronal fibrillary hyperphosphorylated tau fibrils in the brain are widely believed to contribute to the progressive neurodegeneration and neuronal loss characteristic of the Alzheimer's disease and the associated dementia. Anti-amyloid immunotherapies that reduce cerebral Aβ burden in affected individuals have been approved based on biological outcomes from clinical trials. However, the extent to which Aβ clearance translates into improved meaningful clinical, cognitive, and functional benefit versus risk and cost is unclear based on available data. Here, the critical barriers that limit the impact of anti-amyloid immunotherapies, including aducanumab, lecanemab, and donanemab, are discussed. Treatment slows cognitive decline by ∼20-30% in certain patient subsets, but absolute improvements in cognitive and functional outcomes remain modest. Independent analyses of how treatment impacts health span suggests statistically significant trial results may not translate into significant real-world benefit. Response is most significant in cases of early-stage disease where levels of copathology tau are low. Edema and brain hemorrhage occur frequently, particularly in carriers of APOE-e4 alleles, an established genetic risk factor for Alzheimer's disease, raising safety concerns which led to some regulators banning treatment in this patient group. Strict clinical trial eligibility criteria, high treatment costs relative to patient benefit, intensive during-treatment monitoring, and the absence of population-level screening programs further limit treatment accessibility and generalizability. Emerging evidence of accelerated brain atrophy and immunotherapy tolerance further complicates benefit-risk consultation. Sustaining drug- discovery pipelines by exploring combination therapies, tau-targeted approaches, drug repositioning, and novel small molecules through will be essential to provide comprehensive treatment options and personalized treatment plans for affected patients.}, } @article {pmid42498697, year = {2026}, author = {Makhaeva, GF and Astakhova, TY and Grishchenko, MV and Shteinberg, TS and Kovaleva, NV and Boltneva, NP and Rudakova, EV and Pronkin, PG and Timokhina, EN and Radchenko, EV and Shchegolkov, EV and Burgart, YV and Saloutin, VI and Charushin, VN and Richardson, RJ}, title = {Influence of N-Functionalization of Amiridine on the Biological Activity of Its Conjugates as Multitarget Agents for Potential Treatment of Alzheimer's Disease.}, journal = {ChemMedChem}, volume = {21}, number = {14}, pages = {e70392}, doi = {10.1002/cmdc.70392}, pmid = {42498697}, issn = {1860-7187}, support = {24-63-00016//Russian Science Foundations/ ; }, mesh = {*Alzheimer Disease/drug therapy/metabolism ; Amyloid beta-Peptides/metabolism/antagonists & inhibitors ; *Cholinesterase Inhibitors/chemistry/pharmacology/chemical synthesis ; Acetylcholinesterase/metabolism ; Butyrylcholinesterase/metabolism ; Humans ; Peptide Fragments/metabolism/antagonists & inhibitors ; Structure-Activity Relationship ; Molecular Structure ; Molecular Docking Simulation ; Imines/chemistry ; }, abstract = {The goal of this mechanistic study was to elucidate the influence of N-functionalization of amiridine on the biological properties of its conjugates. We synthesized conjugates of amiridine and salicylimine/amine 9, 10 with linkers containing an N-acyl group at the amiridine fragment as analogs of our previously obtained hybrids 1, 2 containing an N-aminohexamethylene spacer. A comparative study of selected biological activities of N-acylalkylene conjugates 9, 10 with conjugates 1, 2 showed substantial decreases in anti-butyrylcholinesterase (BChE) activity (35-fold for the imine and 8-fold for the amine), loss of anti-acetylcholinesterase (AChE) activity, and disappearance of the ability to block amyloid beta (1-42) (Aβ42) self-aggregation. Similar effects were observed for the model compound N-hexylamiridine 3 and its N-acyl derivative 11. However, N-acyl functionalization at the amiridine pharmacophore did not reduce the ability of the conjugates to block AChE-induced β-amyloid aggregation and only slightly decreased their antiradical activity, maintaining the higher activity of amines compared to imines. These effects were consistent with results from quantum mechanical calculations and molecular docking, showing that N-acylation of amiridine decreased the proton affinity of its endocyclic N-atom. Consequently, the amiridine pharmacophore was essentially unprotonated, thereby diminishing the anticholinesterase activity of conjugates 9 and 10 and their ability to block Aβ42 self-aggregation.}, } @article {pmid42498936, year = {2026}, author = {Poffenberger, CN and Taylor, MM and Larson, K and Mufson, EJ and Dixon, KJ}, title = {Inhibition of Soluble TNF Mitigates Traumatic Brain Injury as a Risk Factor for the Development of Amyloidogenic Proteins and Functional Deficits in 3xTg-AD Mice.}, journal = {Journal of neurotrauma}, volume = {}, number = {}, pages = {8977151261469044}, doi = {10.1177/08977151261469044}, pmid = {42498936}, issn = {1557-9042}, abstract = {Traumatic brain injury (TBI) is a well-known risk factor for dementia with Alzheimer's disease (AD), and there are no known therapies that can mitigate this risk. Pre-clinical studies demonstrate a temporary upregulation of amyloid beta (Aβ) and corresponding neurological dysfunction following TBI with little-to-no studies developing interventions to prevent this pathophysiology. The pro-inflammatory cytokine tumor necrosis factor (TNF) has been shown to promote the development of AD, and here we investigate whether a clinically relevant biologic known as XPro1595 that neutralizes soluble TNF (solTNF) can mitigate TBI as a risk factor for the development of amyloidogenic proteins and corresponding neurological dysfunction. Following a single controlled cortical impact model of TBI or sham-injury, adult male 3xTg-AD mice were treated acutely with either XPro1595, a dominant-negative protein that neutralizes soluble TNF (10 mg/kg, S.C.), or vehicle solution. Between 6 h and 1 month post-injury (MPI), levels of cytokines, inflammatory markers, and AD-related proteins were evaluated in the ipsilateral hippocampus. Additionally, animals were behaviorally tested for deficits in cognition (learning and memory), as well as hindpaw mechanical hypersensitivity. TBI induced a significant increase in TNF (ELISA, 6 h) and TNFR1 (Western blot, 3 days post-injury [DPI]) expression, which correlated with an increase in BACE1, Aβ42, and caspase-3 at 3 and 7 DPI. Significant deficits in cognition and mechanical hypersensitivity were found at 7 DPI with similar trends at 1 MPI. In comparison, injured mice treated with XPro1595 had improvements in cognition and mechanical hypersensitivity (cf. vehicle-treated injured mice) and did not have these same increases in BACE1, Aβ42, and caspase-3 (levels were similar to sham-injured mice), likely by increasing NF-κB deactivation (pNF-κB [p65; Ser468]), indicative of a reduced inflammatory response. Overall, treatment with XPro1595 following TBI prevented the development of amyloidogenic proteins and corresponding neurological dysfunction. Clinically, these data support the use of XPro1595 as a clinically relevant therapeutic for patients with TBI to mitigate the risk of increased Aβ levels and neurological decline subacutely post-injury.}, } @article {pmid42499341, year = {2026}, author = {Singh, B and Pigazzani, F and Manfredini, R}, title = {Circadian rhythms and chronotherapy in Alzheimer's disease: Mechanisms and therapeutic implications.}, journal = {Neuroprotection (Chichester, England)}, volume = {}, number = {}, pages = {}, pmid = {42499341}, issn = {2770-730X}, abstract = {Alzheimer's disease (AD), the most prevalent form of dementia, has been increasingly associated with disruptions in circadian rhythms and sleep-wake regulation. This narrative review synthesizes recent literature on how circadian dysfunction may contribute to AD pathogenesis, biomarker profiles, and treatment response. Mechanistic studies suggest important interactions between core clock genes and neurodegenerative cascades involving oxidative stress, neuroinflammation, glial reactivity, and proteostasis. Disruptions in circadian-regulated molecular pathways, including brain and muscle ARNT-like 1 (BMAL1)-sirtuin 1 (SIRT1), nuclear factor kappa B (NF-κB)-NOD-like receptor family pyrin domain containing 3 (NLRP3), and period circadian regulator 2 (PER2)-antioxidant signaling pathways, may compromise neuronal resilience and worsen AD-related pathology. Emerging evidence also suggests distinct circadian patterns in AD-relevant biomarkers, including melatonin, cortisol, orexin, core body temperature, blood-brain barrier permeability, and glial marker oscillations. These rhythmic patterns may have diagnostic and prognostic relevance and support the need for time-aware biomarker interpretation. Chronotherapeutic strategies targeting circadian biology, including melatonin receptor agonists, light therapy, time-restricted feeding, and circadian-aligned drug delivery systems, may help improve targeted clinical endpoints in AD. This review also discusses chronoepigenetics as an emerging area in which clock-regulated epigenetic modifications may influence neurodegenerative trajectories. Future directions include next-generation chronotherapeutic targets, such as glial clocks, clock-gated inflammatory mechanisms, and systemic comorbidities with circadian modulation, including diabetes and hypertension. Overall, the available evidence supports a close association between circadian disruption and both AD pathology and therapeutic response, while also highlighting important gaps in large-scale clinical trials. This time-oriented perspective may support the development of personalized, biomarker-guided, and rhythm-informed approaches to AD care. By bridging chronobiology and neurodegeneration, this review highlights how circadian precision medicine may refine future approaches to understanding and managing AD.}, } @article {pmid42499414, year = {2026}, author = {Mohammed, W and Al Ameri, M and Al Marzooqi, S and Alsafar, H and Olbrich, R and Mousa, M and Barayan, D and Magalhaes, T and Quilez, J and Reche, J and Alkaf, B and Shatila, A and Marzouka, NAD and Iqbal, I and Yousif, A and Rahma, A and Al Mannaie, A}, title = {Landscape of Apolipoprotein (APOE) in the Emirati Population and Recommendations for a Genotyping Approach for Amyloid-Beta Monoclonal Antibodies (Aβ-mAbs) in Alzheimer's Disease Patients.}, journal = {Cureus}, volume = {18}, number = {7}, pages = {e113196}, pmid = {42499414}, issn = {2168-8184}, abstract = {BACKGROUND: Apolipoprotein E (APOE) genotyping is increasingly recognized as a biomarker to support treatment decisions for Alzheimer's disease (AD) with the introduction of anti-amyloid monoclonal antibodies as promising therapeutic options. Although not yet incorporated into formal pharmacogenomic guidelines, regulatory authorities acknowledge its potential role in advancing precision medicine approaches.

METHODS: We reviewed AD cases diagnosed in 2024 from the Department of Health - Abu Dhabi records and assessed monoclonal antibody prescribing patterns. APOE genotypes were determined using the two defining variants, APOE rs429358 and rs7412, using whole-genome sequencing data from 506,734 participants enrolled in the Emirati Genome Program.

RESULTS: In 2024, 1,285 individuals were diagnosed with AD. Aducanumab was prescribed to eight patients between 2022 and 2024. In the Emirati Genome Program cohort, the allele frequencies of rs429358 and rs7412 were 8.3% and 4.2%, respectively. The most prevalent APOE genotype was ε3/ε3 (77.9%). The APOE ε4 risk allele was observed in 14.7% of participants, including 0.9% who were homozygous for ε4, while the protective APOE ε2 allele was present in 7.5%.

CONCLUSION: APOE profiling supports genotype-informed treatment strategies for anti-amyloid therapies. These findings establish a population-specific framework for integrating genetic information into the Emirati Genome Program pharmacogenomic report, enhancing precision medicine approaches for AD management in the UAE.}, } @article {pmid42491022, year = {2026}, author = {Yao, W and Lv, T and Zheng, W and Liu, Y and Shi, X and Zhang, Y and Song, Y and Bai, Y and Bai, F}, title = {Associations between neuronavigated rTMS-mediated functional connectome plasticity and neurotransmitter receptors in Alzheimer's disease.}, journal = {Alzheimer's & dementia (New York, N. Y.)}, volume = {12}, number = {3}, pages = {e70294}, pmid = {42491022}, issn = {2352-8737}, abstract = {INTRODUCTION: Cognitive improvement is mediated by repetitive transcranial magnetic stimulation (rTMS) in Alzheimer's disease (AD), and connectome gradient analysis has important potential to explore more comprehensive information for treatment efficacy. However, it remains unclear whether and how rTMS mediates connectome gradient reconstruction and its spatial neurotransmitter associations in subjects on the AD spectrum.

METHODS: A total of 84 subjects on the AD spectrum underwent 4 weeks of conventional neuronavigated rTMS targeting the left angular gyrus (20 Hz, 20 sessions over 4 weeks, 20 minutes per session), including 60 subjects with true stimulation and 24 with sham stimulation. This study identified functional connectome gradients and investigated their neuroplasticity between pre- and post-rTMS intervention. A support vector regression model was subsequently used to explore the cognitive prediction value of baseline measures. Finally, connectome‒neurotransmitter association analysis was used to investigate neurotransmitter profiles related to rTMS therapeutic efficacy.

RESULTS: These findings showed that rTMS treatment mainly mediated the decreased gradient values in the somatomotor regions and such baseline values of these regions showed preliminary predictive value for memory improvement after treatment (R [2]: 0.40-0.63, mean absolute error: 1.54-3.19, root mean square error: 1.98-3.94, p = 0.0002). Moreover, connectome-neurotransmitter association analysis suggested spatial associations between these gradient changes and normative metabotropic glutamate receptor 5 (mGluR5) and 5-hydroxytryptamine receptor 2A (5HT2a) receptor distributions.

DISCUSSION: rTMS mediates plasticity in high-order metric levels in the brain and is linked to the spatial distributions of specific neurotransmitter receptors in subjects on the AD spectrum.}, } @article {pmid42492268, year = {2026}, author = {Luo, S and Guo, J and Xu, J and Song, J and Dai, Y and Xu, S}, title = {Natural polysaccharides as multi-target therapeutic candidates for Alzheimer's disease: Mechanisms, structure-activity relationships, and translational perspectives.}, journal = {Phytomedicine : international journal of phytotherapy and phytopharmacology}, volume = {159}, number = {}, pages = {158585}, doi = {10.1016/j.phymed.2026.158585}, pmid = {42492268}, issn = {1618-095X}, abstract = {BACKGROUND: Alzheimer's disease (AD) is increasingly recognized as a systems-level disorder involving amyloid-β (Aβ) deposition, tau pathology, oxidative stress, mitochondrial dysfunction, neuroinflammation, synaptic impairment, and microbiota-gut-brain axis dysregulation. Although previous reviews have summarized the anti-AD effects of natural polysaccharides according to individual pathological pathways, an integrated framework linking polysaccharide structure, gut microbial metabolism, peripheral immune regulation, and central AD pathology remains insufficiently developed.

PURPOSE: This review aims to provide an updated and integrative synthesis of natural polysaccharides as multi-target therapeutic candidates for AD, with particular emphasis on their mechanistic networks, structure-activity relationships, and translational potential.

METHODS: A systematic PubMed search was performed for studies published from January 1, 2016, to June 7, 2026. Eligible studies investigated natural polysaccharides as primary therapeutic interventions in in vivo AD models. Reviews, editorials, purely in vitro studies, studies using polysaccharides solely as drug-delivery carriers, synthetic derivatives, and inseparable compound formulations were excluded. Seventy-four original studies were included for mechanistic and structure-activity analyses.

RESULTS: Natural polysaccharides were found to regulate multiple interconnected AD-related processes, including Aβ production, aggregation, and clearance, tau phosphorylation, redox homeostasis, glial activation, inflammasome signaling, synaptic plasticity, cholinergic function, intestinal barrier integrity, gut microbiota composition, and short-chain fatty acid production. Unlike earlier pathway-based summaries, this review proposes a structure-microbiota-metabolite-barrier-inflammation-redox-brain pathology framework to explain how polysaccharide structural features may determine microbial utilization, metabolite generation, immune modulation, and downstream neuroprotective effects.

CONCLUSION: Natural polysaccharides represent promising multi-target candidates for AD prevention and treatment. Future studies should prioritize structurally defined polysaccharide fractions, causal microbiota validation, pharmacokinetic/pharmacodynamic profiling, biomarker-guided assessment, and rigorously designed clinical trials.}, } @article {pmid42493137, year = {2026}, author = {Cardoso, E and Serra, AC and Coelho, JFJ and Pereira, P}, title = {Glycopolymers as emerging modulators of Amyloid-β aggregation: structure-activity relationships and therapeutic potential.}, journal = {Carbohydrate polymers}, volume = {388}, number = {}, pages = {125572}, doi = {10.1016/j.carbpol.2026.125572}, pmid = {42493137}, issn = {1879-1344}, mesh = {Humans ; *Amyloid beta-Peptides/metabolism/chemistry/antagonists & inhibitors ; *Alzheimer Disease/drug therapy/metabolism/pathology ; Structure-Activity Relationship ; Animals ; Protein Aggregates/drug effects ; *Protein Aggregation, Pathological/drug therapy/metabolism ; }, abstract = {Despite ongoing debate about the "amyloid hypothesis", the imbalance between the production and clearance of β-amyloid (Aβ) peptides in the brain remains one of the most compelling explanations for the progression of Alzheimer's disease. Current strategies therefore focus on discovering clinically relevant therapeutic agents that target Aβ peptides and amyloid structures. Because of their unique and attractive properties - biocompatibility, non-immunogenicity, non-toxicity, and ease of functionalization and production - the use of glycopolymers as amyloid inhibitors has generated interest in therapeutic research for Alzheimer's disease. This review provides a comprehensive and critical overview of the literature on glycopolymers in the treatment of Alzheimer's disease. It begins with a description of the disease's neuropathological mechanisms and the formulations approved by the FDA or currently in clinical trials. The second part discusses the use of glycopolymers as amyloid inhibitors, which prevent the formation of neurotoxic soluble oligomers and subsequent plaques observed in Alzheimer's disease. This is achieved by binding to monomers, blocking self-aggregation, and interrupting toxic interactions, offering a therapeutic strategy to halt disease progression. Finally, the main conclusions and perspectives on the use of glycopolymers as amyloid inhibitors are presented.}, } @article {pmid42494775, year = {2026}, author = {Lavigne, SB and Hromas, G and LaRoche, A and Parker, AS and Abdullah, MS and Fernandez, RA and Wang, CP and de Erausquin, G and Salardini, A and Tanner, J and Kautz, TF and Castro, J and Mendoza, C and Seshadri, S and Sullivan, AC}, title = {Frontotemporal dementia in Hispanic populations: Regional and national comparisons.}, journal = {Alzheimer's & dementia (Amsterdam, Netherlands)}, volume = {18}, number = {3}, pages = {e70396}, pmid = {42494775}, issn = {2352-8729}, abstract = {INTRODUCTION: Although Hispanic/Latine populations experience higher dementia rates, they remain underrepresented in frontotemporal dementia (FTD) research. This study examines clinical manifestations of FTD within a South Texas Hispanic/Latine cohort compared to national data.

METHODS: Participants diagnosed with FTD were included from (1) our FTD clinic, the South Texas Alzheimer's Disease Research Center, and local Advancing Research and Treatment in Frontotemporal Lobar Degeneration-Longitudinal Evaluation of Familial Frontotemporal Dementia Subjects Longitudinal Frontotemporal Lobar Degeneration cohort (Hispanic: n = 17; White non-Hispanic: n = 22), and (2) the National Alzheimer's Coordinating Center dataset (Hispanic: n = 24; White non-Hispanic: n = 407; National Institute on Aging/National Institutes of Health Grant U24 AG072122). Clinical, neuroimaging, and neuropsychological data were harmonized for cross-cohort comparisons.

RESULTS: Hispanic participants presented with more movement-related symptoms and advanced cognitive impairment at diagnosis than non-Hispanic Whites. Diagnostic delays averaged 4 years from symptom onset. Educational disparities significantly contributed to health-care access differences.

DISCUSSION: Findings underscore diagnostic severity and systemic barriers faced by Hispanic populations with FTD, emphasizing the need for culturally sensitive diagnostic tools and interventions for equitable dementia care.}, } @article {pmid42495050, year = {2026}, author = {Jannati, A and Toro-Serey, C and Ciesla, M and Chen, E and Showalter, J and Bates, D and Pascual-Leone, A and Tobyne, S}, title = {Streamlining eligibility assessment for Alzheimer's disease-modifying therapies: Prediction of MMSE scores using the digital clock and recall.}, journal = {Frontiers in digital health}, volume = {8}, number = {}, pages = {1799372}, pmid = {42495050}, issn = {2673-253X}, abstract = {INTRODUCTION: The eligibility of anti-amyloid disease-modifying therapies (DMTs) and their integration into clinical practice in some institutions requires a specific range of Mini-Mental State Examination (MMSE) scores. Reliance on this pencil-and-paper psychometric instrument imposes operational burdens and risks of perpetuating health disparities, given the test's known educational and cultural biases. This study evaluates the efficacy of the Digital Clock and Recall (DCR™)-a rapid, FDA-listed digital cognitive assessment-to crosswalk to MMSE scores using machine learning, thereby offering a faster, scalable, and equitable mechanism for patient triage.

METHODS: We conducted a retrospective analysis using data from the multi-site Bio-Hermes-001 (BH) study (NCT04733989, N = 945). Participants were clinically classified as cognitively unimpaired, mild cognitive impairment, or probable Alzheimer's dementia. We trained a Poisson elastic net regression model on 70% of the sample, using age and multimodal digital features derived from the DCR (including drawing kinematics and voice acoustics) to predict MMSE scores. The model was validated using the remaining 30% of Bio-Hermes-001 and an independent external validation cohort from the Apheleia study (NCT05364307, N = 238).

RESULTS: The machine learning model predicted MMSE scores with a root-mean-squared error (RMSE) of 2.43 in the BH test set. This error margin falls within the established test-retest reliability range of the manual MMSE itself (∼4.0-4.2 points at short inter-test intervals), providing evidence that the predicted score is of comparable precision to a repeat human administration of the MMSE. External validation in the Apheleia cohort demonstrated robust generalizability (RMSE = 2.62). In the BH held-out test set, the model showed comparable performance across Race (White RMSE = 2.46; Non-White RMSE = 2.25) and Ethnicity (Hispanic RMSE = 2.19; Non-Hispanic RMSE = 2.45), a balanced pattern also observed in the Apheleia-001 external cohort. Exploratory demographic analyses on prediction errors, including Age, Sex, Race, and Ethnicity, yielded significant differences only for Sex and Age in Apheleia, with signed errors becoming progressively more negative (i.e., increasing under-prediction) at older ages for the latter. This scarcity of statistical differences across cohorts suggested that our predictions were fair.

DISCUSSION: Machine learning can leverage multimodal features from the DCR to accurately and equitably crosswalk to MMSE scores in support of current guidelines, transforming a time-intensive manual test into a rapid, automated assessment. By deploying this "digital triage" engine, where traditional assessments are still used for DMT eligibility, healthcare systems can streamline the identification of DMT-eligible patients, reduce specialist referral bottlenecks, and ensure that access to life-altering therapies is determined by pathology rather than demography.}, } @article {pmid42495562, year = {2026}, author = {Pujar, KG and Purohit, D and Shetty, RP and S, P and Kolachi, KY and Bharathi H M, A and Achar, PG and P, P}, title = {Pharmacophore-driven design and biological evaluation of heterocyclic PDE4B inhibitors for Alzheimer's disease.}, journal = {RSC advances}, volume = {}, number = {}, pages = {}, pmid = {42495562}, issn = {2046-2069}, abstract = {Alzheimer's disease (AD) is a complex neurodegenerative condition marked by a gradual loss of cognitive function, impaired synaptic signalling, and sustained neuroinflammatory responses. Among the molecular pathways associated with disease progression, cyclic adenosine monophosphate (cAMP) signalling, plays a crucial factor in disruption of cellular homeostasis. Phosphodiesterase-4 (PDE4), especially the PDE4B isoform, controls intracellular cAMP levels in neuronal and glial cells, which affects inflammatory signalling and synaptic plasticity in the brain. Therefore, selectively targeting PDE4B is a novel approach to identify the small molecule's therapeutic activity to restore the cAMP signalling, with parallel regulation of the dose-limiting side effects. GSK356278 and Rolipram are the known PDE4B modulators, which have been considered for the current study to generate significant pharmacophoric features and execute drug design as CNS-active PDE4B inhibitors. Six heterocyclic derivatives were designed and synthesised by altering the core scaffold in order to maximise hydrophobicity, CNS permeability, and Q-pocket engagement without depending on direct Zn[2+] or Mg[2+] coordination. Among these, molecule VCHH-19 and VCPH-19 demonstrated significant CNS compatibility and good binding stability. PC12 cell lines were chosen to verify the in vitro neuroprotective response, and the Drosophila model for in vivo for AD assessment. All of these results indicated the significance of pyridine-based heterocycles molecules as potential candidates for PDE4B-targeted AD treatment.}, } @article {pmid42496756, year = {2026}, author = {Sahu, SK and Nayak, M and Samal, A and Jena, S and Pradhan, J and Dandapat, J and Samanta, L and Jena, S}, title = {T3 and curcumin regulates collagen-IV and collagen-VI expression: role in suppression of amyloid-β via TGFβ1-Sp1 signaling in hypothyroid mice brain.}, journal = {Metabolic brain disease}, volume = {41}, number = {1}, pages = {}, pmid = {42496756}, issn = {1573-7365}, support = {26913/HED/HE-PTC-WB-02-17//OHEPEE and S&T Department, Government of Odisha/ ; 584/83/OSHEC//OURIIP, OSHEC, Government of Odisha/ ; }, mesh = {Animals ; *Curcumin/pharmacology/therapeutic use ; *Hypothyroidism/metabolism/drug therapy ; *Amyloid beta-Peptides/metabolism/antagonists & inhibitors ; *Triiodothyronine/pharmacology/therapeutic use ; Signal Transduction/drug effects ; Mice ; *Transforming Growth Factor beta1/metabolism ; *Collagen Type IV/metabolism/biosynthesis ; Male ; *Brain/metabolism/drug effects ; Mice, Inbred BALB C ; Sp1 Transcription Factor/metabolism ; }, abstract = {Hypothyroidism has been associated with cognitive disorders and high risk of neurodegenerative disorders like Alzheimer's disease (AD), which is caused by amyloid-β (Aβ) accumulation in brain. The aim of the study is to examine the therapeutic ability of triiodothyronine (T3) and curcumin in regulating two key extracellular matrix proteins (ECM), collagen IV and collagen VI in brain since both drugs have neuroprotective and anti-fibrotic effects. The study further explored the possible role of signaling molecules such as transforming growth factor β1 (TGFβ1) and specificity protein 1 (Sp1) in regulating the effects of T3 and curcumin on Aβ accumulation and ECM protein expression. Experiment was carried on Balb/c mouse model by inducing hypothyroidism with 0.05% PTU followed by treatment of T3, curcumin and a combination of both. The study revealed a significant increase in the expression of collagen IV and VI, along with elevated levels of TGFβ1 and Sp1 signalling proteins, in hypothyroid conditions in response to increased Aβ expression in both the cortex and hippocampus. Western blot and RT-PCR analysis showed that T3 and curcumin treatment downregulate the levels of ECM proteins, the APP gene, Aβ protein, and the signaling factors. The study found that T3 and curcumin treatment downregulates the collagen IV and VI expression by negatively regulating TGFβ1 and Sp1 when expression of APP and Aβ are low. T3 and coadministration of T3 with curcumin more effectively regulate thyroid function and ECM protein expression in both the cortex and hippocampus. Whereas curcumin alone exhibits limited impacts under the experimental conditions in our study, this may due to bioavailability, dosage or treatment duration which need to further investigation. Our results indicate a novel therapeutic approach for understanding Aβ pathology associated with hypothyroidism, emphasizing the potential association between thyroid hormone and nature-based compounds, such as curcumin, in modulating ECM dynamics and neuroprotection.}, } @article {pmid42497640, year = {2026}, author = {Malcangio, M and Sideris-Lampretsas, G}, title = {Chronic pain in Alzheimer disease and the role of neuroimmune interactions.}, journal = {Pharmacological reviews}, volume = {78}, number = {5}, pages = {100149}, doi = {10.1016/j.pharmr.2026.100149}, pmid = {42497640}, issn = {1521-0081}, abstract = {Chronic pain conditions affect a large proportion of the global population and pain has tremendous personal and economic impact, affecting quality of life and ability to work while imposing a significant burden on families and health care systems. Neurological disorders and painful conditions are frequently accompanied by chronic pain, which is often jointly diagnosed with age-related neurodegenerative diseases, however, many patients do not receive adequate treatment. This review aims to create a working framework around the issue of under-recognized/undertreated chronic pain in Alzheimer disease by offering an in-depth overview of the mechanisms driving chronic pain and how we can leverage this knowledge to advance therapeutics approaches for these patients with an emphasis on the immune system. SIGNIFICANCE STATEMENT: Chronic pain conditions are prevalent among the aging population, and they positively associate with dementia. The incidence of chronic pain is associated with neuropsychiatric symptoms of dementia and pain management should aim for effective treatments regardless of cognitive status.}, } @article {pmid42497811, year = {2026}, author = {Tağraf, B and Kaygusuz, D and Yerlikaya, D and Oğul, ÖE and Hanoğlu, L}, title = {The effect of simultaneous application of plant-rich ketogenic diet and intermittent fasting on early-to-mid-stage Alzheimer's disease: a randomised controlled trial.}, journal = {The journal of nutrition, health & aging}, volume = {30}, number = {9}, pages = {100930}, doi = {10.1016/j.jnha.2026.100930}, pmid = {42497811}, issn = {1760-4788}, abstract = {INTRODUCTION: This study evaluates the effect of simultaneous application of plant-rich ketogenic diet and intermittent fasting as an individualized adjunct to standard treatment on cognitive function in early/mid-stage Alzheimer's patients.

METHODS: This assessor-blinded, randomized controlled trial enrolled 60 Alzheimer's disease (AD) patients (CDR 1-2; aged 55-85), randomized to intervention (n = 30; intervention + standard care) or control (n = 30; standard care). Cognition and brain structure were assessed at baseline and 6 months. Individual cognitive changes were analyzed using Reliable Change Index (RCI).

RESULTS: Cognitive change scores differed significantly between groups (p < 0.001). The mean Mini Mental State Examination (MMSE) score increased by +0.9 in the intervention group, while a decrease of -1.5 points was observed in the control group. RCI analysis indicated stability in 93% of intervention and 70% of control participants, with cognitive improvement in 7% and 3.3%, respectively.

DISCUSSION: The intervention method has the potential to stabilize cognitive decline in AD and promote improvement at the individual level. The response to the intervention is closely related to the individual's metabolic phenotype and structural brain integrity.

ETHICAL APPROVAL: Istanbul Medipol University Non-Interventional Clinical Research Ethics Committee on March 6, 2025, under number 242 and the study was carried out in accordance with the Declaration of Helsinki and its later amendments.

CLINICALTRIALS: gov ID: NCT06898424.}, } @article {pmid42484409, year = {2026}, author = {Tulloch, R and Gaffiero, D}, title = {Menopause, brain health and hormone replacement therapy: gaps in knowledge and policy solutions from a Scottish perspective.}, journal = {Post reproductive health}, volume = {32}, number = {1}, pages = {77-81}, doi = {10.1080/20533691.2026.2631221}, pmid = {42484409}, issn = {2053-3705}, mesh = {Humans ; Female ; Scotland ; *Menopause/physiology/psychology ; Women's Health ; *Health Policy ; *Brain/physiology ; *Hormone Replacement Therapy ; Health Knowledge, Attitudes, Practice ; Alzheimer Disease/prevention & control ; Primary Health Care ; Quality of Life ; }, abstract = {PURPOSE: This commentary argues for the systematic integration of brain health into menopause care and policy in the United Kingdom (UK). Using Scotland as a strategically bounded case study, it examines persistent knowledge gaps among women and primary care professionals and their implications for equitable menopause care.

KEY ISSUES: Menopause involves significant neuroendocrine changes that affect brain metabolism, structure, and cognition, contributing to women's disproportionate Alzheimer's disease risk. Although hormone replacement therapy may alleviate neurological and cognitive symptoms - and may offer neuroprotective benefits when initiated early - clinical uncertainty, stigma, and inconsistent guidance continue to delay recognition, support, and treatment. These gaps translate into avoidable cognitive decline, reduced quality of life, and marked inequities in access to menopause care.

IMPLICATIONS: Targeted primary care training, coherent public communication, and UK-specific investment in evidence-based menopause services are urgently required. This programme of research is situated within Scotland as a strategically bounded, devolved health system, allowing for a focused examination of how brain health is addressed within menopause policy and practice. By embedding brain health within Scotland's Women's Health Plan, the findings will inform future comparative and UK-wide research and contribute to the development of equitable, person-centred, and brain-health informed menopause care across the lifespan.}, } @article {pmid42484748, year = {2026}, author = {Abroumand Gholami, A and Ghadiminia, N and Akhrorova, S and Kubaev, A and Agamurodov, S and Salomova, F}, title = {Correspondence: Erythrina caffra in cadmium-induced Alzheimer's-like pathology: A new candidate or a familiar pattern?.}, journal = {Molecular biology reports}, volume = {53}, number = {1}, pages = {}, pmid = {42484748}, issn = {1573-4978}, mesh = {*Alzheimer Disease/drug therapy/chemically induced/pathology/metabolism ; Animals ; *Cadmium/toxicity ; *Plant Extracts/pharmacology/therapeutic use ; *Erythrina/chemistry/metabolism ; *Neuroprotective Agents/pharmacology/therapeutic use ; Humans ; Rats ; Oxidative Stress/drug effects ; Disease Models, Animal ; }, abstract = {Cadmium neurotoxicity has been increasingly linked to neurodegenerative processes, and plant-derived compounds are being explored for their protective potential. The recent study by Ed-Day and colleagues investigated the neuroprotective effects of Erythrina caffra seed extract in a cadmium-induced Alzheimer's-like model in rats, reporting improvements in memory, cholinergic function, oxidative stress, and neuroinflammation. Four principal concerns are identified: (1) treatment protocol ambiguity, use of young rats to model an age-related disease, and unclear prevention-versus-therapy distinction; (2) memantine as positive control, mechanistically mismatched with cadmium toxicity pathways; (3) claim of Alzheimer's-like pathology without measuring Aβ plaques and tau tangles; and (4) no cadmium quantification in tissues or biofluids, leaving the mechanism, direct neuroprotection versus reduced bioavailability, unresolved. While the study offers promising preliminary evidence for the neuroprotective potential of E. caffra, its translational significance is constrained by these methodological and interpretative limitations. Addressing these concerns in future investigations would strengthen the evidence base for this medicinal plant's therapeutic potential.}, } @article {pmid42485607, year = {2026}, author = {Chen, Y and Chen, A and Power, MC and Grodstein, F and Kapasi, A and Capuano, AW and Lange-Maia, BS and Moghtaderi, A and Stapp, EK and Bhattacharyya, J and Shah, RC and Barnes, LL and Bennett, DA and James, BD}, title = {Associations of Alzheimer Disease and Related Dementia Neuropathologies With Timely Diagnosis of Dementia in Healthcare Settings.}, journal = {Neurology}, volume = {107}, number = {3}, pages = {e218352}, doi = {10.1212/WNL.0000000000218352}, pmid = {42485607}, issn = {1526-632X}, mesh = {Humans ; Female ; Male ; *Alzheimer Disease/pathology/diagnosis ; Aged, 80 and over ; Retrospective Studies ; *Dementia/diagnosis/pathology ; Aged ; *Brain/pathology ; United States ; Cohort Studies ; Medicare ; }, abstract = {BACKGROUND AND OBJECTIVES: A timely diagnosis of dementia may provide valuable time for treatment and planning, yet underdiagnosis is common. This study investigated the relationship between presence of dementia pathologies and timeliness of dementia diagnosis by healthcare providers.

METHODS: This was a retrospective study using 5 cohorts at Rush Alzheimer's Disease Center. We included participants who met all of the following criteria: (1) incident dementia based on annual cohort assessments, (2) linkage to Medicare records, and (3) a completed postmortem brain autopsy. Postmortem neuropathologic examinations identified the presence of AD, limbic-predominant age-related TDP-43 encephalopathy neuropathologic change (LATE-NC), vascular pathologies, and neocortical Lewy bodies (LBs). In linked Medicare data, we defined timely diagnosis as the presence of claims with dementia diagnoses within 3 years before or 1 year after the cohort-based dementia onset. We used logistic regressions to quantify associations of neuropathology markers with timely diagnosis vs underdiagnosis.

RESULTS: Of the 500 eligible participants (71% female, 95% non-Latino White, mean [SD] age at cohort dementia onset = 88 [7] years, mean [SD] years from onset to death = 4 [3]), only 54% received a timely diagnosis. After controlling for demographics, time to death, and other neuropathologies, a pathologic diagnosis of AD (OR = 1.91, 95% CI 1.21-3.00) and moderate/severe LATE-NC pathologies (OR = 1.83, 95% CI 1.25-2.68) were independently associated with higher odds of timely diagnosis. Moderate/severe vascular pathologies (OR = 0.94, 95% CI 0.55-1.59) and neocortical LB pathologies (OR = 1.00, 95% CI 0.64-1.55) were not significantly associated with receipt of a timely diagnosis. In a separate multivariable logistic regression, we found that participants with 3 or 4 neuropathologies present had an over 2-fold increase in odds of timely diagnosis (OR = 2.24, 95% CI 1.32-3.82), compared with those with 1 or no neuropathology.

DISCUSSION: In deceased older adults with cohort-determined incident dementia, the healthcare system was twice as likely to capture those with pathologic diagnosis of AD, moderate/severe LATE-NC, and more than 3 copathologies in a timely manner. While findings from this predominantly White and highly educated sample warrant replication in broader population, this study is an important initial step toward understanding biological correlates of timely diagnosis of dementia.}, } @article {pmid42486010, year = {2026}, author = {Li, X and Li, S and Su, J and Zheng, F and Li, S and Zhao, X and Chen, D and Yan, J and Xia, C}, title = {Merocyanine derivatives as theranostic agents for cognitive improvement and real-time imaging of amyloid-β in APP/PS1 transgenic mice.}, journal = {Spectrochimica acta. Part A, Molecular and biomolecular spectroscopy}, volume = {363}, number = {Pt 1}, pages = {128458}, doi = {10.1016/j.saa.2026.128458}, pmid = {42486010}, issn = {1873-3557}, abstract = {Amyloid-β (Aβ) is widely recognized as a biomarker for the diagnosis and treatment of Alzheimer's Disease (AD). In our previous work, a series of merocyanine fluorescent probes were designed, synthesized and evaluated for the imaging of Aβ plaques. Here, we further identified the representative probe D4, which not only demonstrates the characteristics of a highly sensitive fluorescent probe for real-time imaging of Aβ content in the brain of APP/PS1 mice, but also exhibited the ability to treat AD, including inhibition of Aβ aggregation (inhibition rate: 89.5%), antioxidant activity (3.4 times that of Trolox); AChE inhibitory activity (IC50 = 0.5 ± 0.0 μM) and the capacity to cross the BBB (Pe = 8.6 ± 0.7). Additionally, D4 dramatically attenuates Aβ-induced SH-SY5Y cell death by preventing the generation of ROS, and intravenous administration of 0.5 mg/kg D4 for 15 days significantly improved the cognitive ability of 7-month-old APP/PS1 mice by protecting hippocampal and cortex neurons from necrosis, attenuating oxidative stress in the hippocampus and cortex, and reducing Aβ burden deposition. These findings strongly suggest that D4 owns a high theranostic potential for treating AD.}, } @article {pmid42486320, year = {2026}, author = {Dilip, PI and Daksh, R and Sharma, P and Khanna, S and Bojja, SL and Singh, AK and Nampoothiri, M}, title = {Repressor Element 1 Silencing Transcription Factor as a central regulator of autophagy and neuroinflammation in Alzheimer's disease.}, journal = {European journal of pharmacology}, volume = {}, number = {}, pages = {179168}, doi = {10.1016/j.ejphar.2026.179168}, pmid = {42486320}, issn = {1879-0712}, abstract = {Repressor element-1 silencing transcription factor (REST) is a critical epigenetic regulator involved in multiple cellular processes, including apoptosis, autophagy, and neuronal survival. By modulating the expression of neuronal and stress-response genes, REST contributes significantly to neuroprotection. REST is predominantly localised in the nucleus; however, in Alzheimer's Disease (AD), nuclear REST is reduced, leading to transcriptional dysregulation and contributing to AD pathology. The low levels of REST are associated with defective autophagy flux, including mitochondrial dysfunction and enhanced vulnerability to toxic protein aggregates, causing AD and other neurodegenerative disorders. Recent research shows that REST suppresses several apoptotic genes, modulating neuroinflammatory signalling and regulates autophagy. The specific regulatory mechanism of REST suggests new strategies for the prevention and treatment of AD and ageing. Despite REST's unique functions and importance in AD, its precise role and the molecular mechanisms underlying REST-mediated signalling pathways have not been comprehensively reviewed. The purpose of this review is to provide an overview of the structural and functional characteristics of REST, explore the mechanisms underlying REST-mediated autophagy, neuroinflammation and apoptosis in AD and discuss the emerging therapeutic implications of targeting REST.}, } @article {pmid42487022, year = {2026}, author = {Xu, W and Chen, J and Zhou, Y and Liu, C and Han, Y and Zheng, K}, title = {Comparative efficacy and safety of photobiomodulation, transcranial direct current stimulation, and repetitive transcranial magnetic stimulation in Alzheimer's disease: a network meta-analysis of randomized controlled trials.}, journal = {Lasers in medical science}, volume = {41}, number = {1}, pages = {}, pmid = {42487022}, issn = {1435-604X}, support = {82371442//National Natural Science Foundation of China/ ; 2020YFC2004803//National Key Research and Development Program of China/ ; }, mesh = {Humans ; *Alzheimer Disease/therapy ; *Transcranial Direct Current Stimulation/adverse effects/methods ; *Transcranial Magnetic Stimulation/adverse effects/methods ; Randomized Controlled Trials as Topic ; *Low-Level Light Therapy/adverse effects/methods ; Treatment Outcome ; Cognition ; Cognitive Enhancement ; Bayes Theorem ; }, abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder for which current pharmacological therapies provide only modest and transient benefits, underscoring the need for effective non-pharmacological interventions. Non-invasive brain stimulation (NIBS), including photobiomodulation (PBM), transcranial direct current stimulation (tDCS), and repetitive transcranial magnetic stimulation (rTMS), is a promising approach. This study compared the efficacy, feasibility, and safety of PBM, tDCS, and rTMS in AD. We conducted a Bayesian network meta-analysis (NMA) of randomized controlled trials (RCTs), prospectively registered in PROSPERO (CRD420251006868) and reported according to PRISMA-NMA. The primary outcome was global cognitive performance, assessed by the Mini-Mental State Examination (MMSE) and the Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog). Secondary outcomes were feasibility and safety, evaluated by dropout rates and adverse events, respectively. A total of 34 studies, comprising 35 RCTs (n = 1,559), were included, with one study contributing two independent randomized controlled trials. All three interventions improved global cognitive performance compared with control. PBM showed the highest estimated effects on both MMSE (MD = 3.14, 95% CrI: 1.71 to 4.60) and ADAS-Cog (MD = - 8.01, 95% CrI: -12.82 to - 3.13). In indirect comparisons, PBM was superior to rTMS for ADAS-Cog (MD = - 5.24, 95% CrI: -10.23 to - 0.12), while the MMSE comparison narrowly missed statistical significance (MD = 1.57, 95% CrI: -0.02 to 3.18). These findings were generally consistent across subgroups stratified by baseline cognition and intervention duration. PBM tended to rank highest for cognitive improvement with feasibility and safety comparable to tDCS and rTMS in AD. These findings support the therapeutic potential of PBM, and large-scale RCTs are needed to guide individualized treatment strategies, with implications for clinical decision-making in geriatric care.}, } @article {pmid42487544, year = {2026}, author = {Zhou, J and Li, S and Liu, H and Sun, Y and Wang, Z}, title = {The Effectiveness of Animal-Assisted Interventions for People Living With Dementia: An Overview of Systematic Reviews and Meta-Analysis.}, journal = {International journal of nursing practice}, volume = {32}, number = {4}, pages = {e70172}, doi = {10.1111/ijn.70172}, pmid = {42487544}, issn = {1440-172X}, support = {72274007//National Natural Science Foundation of China/ ; LJRC22YB03//Incubation Fund for Scientific Research and Innovation of Leading Talents of Unnamed Nursing of Peking University/ ; XJRC-2025-JY-YJ-GX-QNQZ-068//Xinjiang Talent Development Fund/ ; }, mesh = {*Dementia/therapy/psychology ; Humans ; *Animal Assisted Therapy ; Animals ; Quality of Life ; Systematic Reviews as Topic ; Activities of Daily Living ; }, abstract = {AIMS: This overview aims to provide high-quality evidence synthesis of animal-assisted interventions (AAIs) among people living with dementia.

BACKGROUND: Dementia has become the seventh leading cause of death in the world. Unfortunately, currently effective pharmacological interventions remain elusive. As a non-pharmacological treatment, AAI is gaining more attention while the effectiveness of AAI for people living with dementia remains unclear.

METHODS: EMBASE, PubMed, Cochrane Library, CINAHL, CNKI, VIP, CBM and Wanfang databases were searched from inception to March 2026. The AMSTAR2 was used to assess the methodological quality of the included reviews. Meta-analysis was conducted using STATA 16 for the original studies identified from the included reviews. Evidence quality of main outcomes was assessed according to the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) guidelines.

RESULTS: Sixteen systematic reviews were included in the overview. A significant improvement was found in depression among dementia patients, but not in agitation, quality of life (QOL), cognition and activities of daily living (ADL).

CONCLUSIONS: There is moderate evidence that AAI has positive effects on depression for people living with dementia. Despite searches, no sufficient evidence has been found to substantiate the positive effects of AAI on other outcomes in people living with dementia. Due to the small number of studies, small sample sizes and significant heterogeneity, more randomised controlled trials with large samples are needed.}, } @article {pmid42487594, year = {2026}, author = {Lonlab, K and Nitjapol, A and Thummayot, S and Tiyaboonchai, W and Jumnongprakhon, P}, title = {Targeting Aβ25-35-Induced Neuronal Senescence-Like Features Using Curcumin-Loaded Solid Self-Emulsifying Drug Delivery Systems.}, journal = {Current aging science}, volume = {}, number = {}, pages = {}, doi = {10.2174/0118746098440081260430205824}, pmid = {42487594}, issn = {1874-6128}, abstract = {INTRODUCTION: Curcumin is widely recognized for its anti-neurodegenerative properties. However, its clinical utility is hindered by poor aqueous solubility and low bioavailability. To address these limitations, Curcumin-loaded Solid Self-Emulsifying Drug Delivery Systems (C-SSEDDS) have been formulated to improve pharmacokinetics and neuronal targeting. Despite these advancements, the molecular mechanisms underlying curcumin in Alzheimer's Disease (AD)-related neuronal senescence remain poorly understood. Therefore, this study provides novel molecular insights into the therapeutic potential of C-SSEDDS for targeting neuronal senescence- like features in the AD context.

METHODS: An in vitro model of neuronal senescence-like features was established by exposing SK-N-SH cells to 0.075 μM Aβ25-35 for 24 hours, resulting in a 20-30% decline in cell viability. Subsequently, cells were post-treated with C-SSEDDS at optimized non-toxic concentrations (0.1, 1, and 10 μg/mL curcumin equivalent) and 10 μg/mL commercial curcumin for 24, 48, and 72 hours in Aβ25-35-free media. The study comprehensively assessed cell viability, morphological alterations, and key biomarkers associated with neuronal senescence-like features, including senescence- associated beta-galactosidase (SA-β-gal) positive cells, Reactive Oxygen Species (ROS) levels, NLRP3, Sirt-1, and synaptophysin expression.

RESULTS: C-SSEDDS post-treatment significantly improved cell viability, reduced apoptotic cells, and decreased SA-β-gal positive cells in Aβ25-35-induced senescence-like SK-N-SH cells compared to the untreated Aβ25-35 group. It also effectively decreased intracellular ROS level and NLRP3 expression, and markedly upregulated Sirt-1 and synaptophysin expression. Notably, CSSEDDS demonstrated therapeutic efficacy superior to commercial curcumin and comparable to N-acetylcysteine (NAC).

DISCUSSION: In SK-N-SH cells exhibiting senescence-like features, the C-SSEDDS formulation effectively counteracts Aβ25-35-induced damage. It mitigates key drivers of cellular stress, including oxidative stress, inflammation-related markers, and apoptosis, while also enhancing Sirt-1 activity and promoting synaptic plasticity.

CONCLUSION: C-SSEDDS demonstrates significant potential as a promising therapeutic strategy against Aβ25-35 -induced neuronal stress and senescence-like changes in AD.}, } @article {pmid42488183, year = {2026}, author = {Singhal, M and Lin, J and Delehanty, M and Karimi, A and Rittner, L and Bento, M}, title = {Geographic and demographic gaps in publicly available Alzheimer's disease datasets: A large language model-based discovery and analysis.}, journal = {Digital health}, volume = {12}, number = {}, pages = {20552076261470698}, pmid = {42488183}, issn = {2055-2076}, abstract = {INTRODUCTION: Alzheimer's disease (AD) affects millions worldwide, and researchers heavily rely on datasets for diagnosis and treatment. Identifying relevant datasets is challenging due to data gaps and bias related to the demographics and geographic origin.

METHOD: We investigated AD data gaps by identifying and manually curating publicly accessible AD datasets containing imaging and/or tabular data. We also extracted key information such as data availability, geographic location, and participant demographics. We used five Large Language Models (LLMs) to identify AD datasets, allowing us to explore potential datasets while also evaluating retrieval consistency across models.

RESULT: We identified 24 publicly accessible AD datasets (open access or controlled access via registration). These datasets enabled us to emphasize three critical gaps: (1) variability in AD dataset retrieval, as observed through differences in LLM outputs, related to dataset visibility and accessibility; (2) geographical imbalance, with North America contributing 55.6% of datasets, US alone 66.7%, followed by Europe at 36.1%, and smaller shares from South America 11.1%, Asia 8.3%, and Africa 2.8%; and (3) demographic deficits, with the majority of datasets predominantly White, as 9 of 24 had over 80% White participants. Among the seven datasets that reported any Black participant representation, the proportion of Black participants ranged from 15.3% to 18.8%.

CONCLUSION: These findings reveal significant disparities in the availability and retrieval of AD datasets, with most data concentrated in Western countries and critical gaps in demographic representation. LLMs show inconsistent retrieval, particularly for newer, smaller, or region-specific datasets, which may perpetuate existing biases.}, } @article {pmid42489438, year = {2026}, author = {Saadawy, M and Majeed, M and Saadawy, E and , }, title = {APOE4-specific glymphatic effects on clinical progression in the Alzheimer's Disease Neuroimaging Initiative with pathological correlates in the A4 study.}, journal = {Journal of Alzheimer's disease : JAD}, volume = {}, number = {}, pages = {13872877261469565}, doi = {10.1177/13872877261469565}, pmid = {42489438}, issn = {1875-8908}, abstract = {BackgroundThe APOE ε4 allele is the strongest genetic risk factor for late-onset Alzheimer's disease (AD). However, some carriers show "clinical resilience", maintaining their cognition despite high risk.ObjectiveWe hypothesized that the glymphatic system, the brain's waste clearance pathway, may attenuate APOE ε4-mediated neurodegeneration, and tested this in two independent cohorts.MethodsWe analyzed 625 cognitively normal older adults from the Alzheimer's Disease Neuroimaging Initiative (ADNI) discovery cohort and 447 amyloid-positive participants from the preclinical Anti-Amyloid Treatment in Asymptomatic Alzheimer's (A4) validation cohort. Glymphatic function was estimated using the analysis of diffusional kurtosis imaging along the perivascular space (DTI-ALPS) index in ADNI and choroid plexus (CP) [18]F-Flortaucipir PET uptake in the A4 study. Primary outcomes were clinical conversion to dementia (ADNI) and hippocampal tau pathology (A4).ResultsIn the discovery cohort, we observed a trend toward ALPS × APOE4 interaction (p = 0.057, not reaching conventional statistical significance). Carriers with preserved function (high ALPS) showed a reduced conversion risk (hazard ratio = 0.52, 95% CI: 0.27-0.99) compared to those with low function. In the validation cohort, glymphatic interface dysfunction (higher CP tau) strongly predicted hippocampal tau burden (p < 0.0001). However, the gene-specific interaction was not replicated (p = 0.928); clearance failure predicted pathology regardless of genotype. Exploratory fluid biomarker analyses in ADNI did not reveal significant interactions.ConclusionsThese findings suggest that preserved glymphatic function is associated with clinical resilience in APOE ε4 carriers, though the interaction was borderline (p = 0.057) and should be considered hypothesis-generating. The strong pathological associations with clearance integrity highlight a biologically plausible mechanism in AD pathogenesis that warrants further investigation.}, } @article {pmid42489531, year = {2026}, author = {Farzeen, I and Nazir, MM and Jaan, Z and Ghaffar, W and Masood, A and Yasmeen, M and Ashraf, A and Różański, H}, title = {Biochemical modulators of synaptic plasticity: New horizons in Alzheimer's disease treatment.}, journal = {Journal of Alzheimer's disease : JAD}, volume = {}, number = {}, pages = {13872877261469864}, doi = {10.1177/13872877261469864}, pmid = {42489531}, issn = {1875-8908}, abstract = {Synaptic dysfunction is the earliest and most critical pathological feature of Alzheimer's disease (AD), directly contributing to cognitive decline. This review provides an integrative overview of the molecular and biochemical modulators governing synaptic plasticity and their disruption in AD. We discuss how the collective impairment of Aβ aggregation, tau pathology, calcium imbalance, oxidative stress, and neuroinflammation affects dendritic spine morphology and synaptic connectivity. Particular attention is given to neurotrophins such as brain-derived neurotrophic factor and TrkB signaling, hormonal influences, likewise glucocorticoids, estrogens, testosterone, endocannabinoid pathways, lipid and cholesterol regulators like ApoE and lipid rafts, and epigenetic mechanisms that modulate synaptic resilience. We further evaluate the therapeutic potential of pharmacological agents, including cholinesterase inhibitors, NMDA receptor modulators, and multi-target directed ligands alongside nutraceuticals such as resveratrol, curcumin, omega-3 fatty acids, Withania somnifera, and Bacopa monnieri. Emerging technologies, including iPSC-derived neuronal models, optogenetics, and advanced neuroimaging biomarkers like SV2A PET, cerebrospinal fluid/plasma neurogranin, are also highlighted for their role in elucidating and monitoring synaptic integrity. Ultimately, targeting the biochemical modulators of synaptic plasticity offers a promising avenue for AD therapy, especially through combinatorial and precision-medicine strategies aimed at restoring synaptic function and cognitive performance.}, } @article {pmid42489536, year = {2026}, author = {Costa, T and Sensi, SL and Høilund-Carlsen, PF and Robakis, NK and Vissel, B and Espay, AJ}, title = {Do anti-amyloid therapies demonstrate clinically meaningful benefit? A Bayesian reappraisal.}, journal = {Journal of Alzheimer's disease : JAD}, volume = {}, number = {}, pages = {13872877261469870}, doi = {10.1177/13872877261469870}, pmid = {42489536}, issn = {1875-8908}, abstract = {BackgroundRecent anti-amyloid trials have been interpreted as evidence of clinical benefit in Alzheimer's disease, although their relevance remains debated.ObjectiveTo reinterpret pooled randomized evidence on anti-amyloid therapies within a Bayesian framework focused on benefit and harm.MethodsPooled estimates from a recent Cochrane review were reanalyzed using posterior probability estimation with clinically relevant thresholds.ResultsThe probability that treatment effects reached clinically meaningful thresholds was generally low, whereas the probability of substantial harm, particularly amyloid-related imaging abnormalities, was high.ConclusionsCurrent randomized evidence suggests that statistically significant anti-amyloid effects may not translate into clinically meaningful benefit.}, } @article {pmid42489967, year = {2026}, author = {Søraas, A and Engvig, A and Alnæs, D and Karim, LN and Danilova, E and Istre, MS and Nygaard, S and Utgård, TR and Ceprnjic, S and Reiakvam, O and Edvardsen, E and Westlye, LT and Nygaard, AB and Dahl, JA and Nissen-Meyer, LSH and Ihle-Hansen, H and Holland, P}, title = {Interstitial fluid rejuvenation through young-donor plasma exchange in cognitively impaired patients: a pilot safety and feasibility study.}, journal = {GeroScience}, volume = {}, number = {}, pages = {}, pmid = {42489967}, issn = {2509-2723}, abstract = {Heterochronic parabiosis improves physiological and cognitive function in aging rodents; these benefits appear to be derived from the removal of aged blood plasma components and the addition of younger ones. In humans, removing plasma from older individuals with Alzheimer's disease (AD) and replacing it with saline and albumin delayed cognitive deterioration in a large clinical trial. However, mimicking heterochronic parabiosis in humans by removing large volumes of a patient's blood plasma and replacing it with plasma from young and healthy donors has not been tested. Here, we have performed a pilot study to characterize the feasibility and safety of such a procedure, replacing between 16 and 26 L of patient blood plasma with young (ages 18-24) donor blood plasma for twelve patients who recently received a diagnosis of mild cognitive impairment with biomarker evidence of AD. The dose and time interval between plasma exchanges was tailored to maximize equilibration of donor plasma components into the interstitial fluid, with the aim of achieving what we term interstitial rejuvenation. We explored three permutations of a plasma exchange protocol with different treatment intensities and doses, each performed on three to five patients. We present data on safety, feasibility, patient burden, resource use of the treatments, preliminary measurements of clinical variables, and short-term cognitive trajectories in the patients. The procedures were feasible, and the adverse events observed were consistent with known risks of plasma exchange, supporting further investigation of treatment efficacy in a larger controlled trial. This safety and feasibility study was first registered 22 December 2023 at ClinicalTrials.gov and given the identifier NCT06234436.}, } @article {pmid42490036, year = {2026}, author = {Just, C and Seibert, K and Chan, C and Maldonado-Correa, C and Jones, D}, title = {Considerations in Alzheimer's Disease in Women.}, journal = {Current neurology and neuroscience reports}, volume = {26}, number = {1}, pages = {}, pmid = {42490036}, issn = {1534-6293}, mesh = {Humans ; *Alzheimer Disease/diagnosis/metabolism ; Female ; *Sex Characteristics ; Biomarkers ; tau Proteins/metabolism ; }, abstract = {PURPOSE OF REVIEW: To examine sex differences in Alzheimer's disease and cognition with a focus on hormonal transitions, biomarker trajectory, and implications for diagnosis and treatment.

RECENT FINDINGS: Women account for nearly two-thirds of individuals with Alzheimer's disease and demonstrate important biological and clinical differences compared with men. APOE ε4 confers greater risk in women, while menopause, depression, chronic stress, adverse pregnancy outcomes, and metabolic dysfunction may further increase vulnerability. Biomarker studies suggest that amyloid trajectories are broadly similar between sexes, but women exhibit earlier or greater tau accumulation once amyloid pathology is present. Women may maintain verbal memory performance longer than men despite underlying pathology, potentially delaying diagnosis. Emerging plasma biomarkers, particularly p-tau217, may improve early detection, monitoring, and treatment. Alzheimer's disease in women reflects a complex interaction between sex-specific biology, hormonal transitions, psychosocial factors, and neurodegenerative processes. Recognizing these differences has important implications for cognitive assessment, biomarker interpretation, diagnosis, and application of disease-modifying therapies.}, } @article {pmid42490707, year = {2026}, author = {Cossette-Lefebvre, M and Bergeron, N}, title = {[Cooccurrence of catatonia, delirium and dementia in an elderly woman: A case report].}, journal = {Sante mentale au Quebec}, volume = {51}, number = {1}, pages = {95-104}, pmid = {42490707}, issn = {1708-3923}, mesh = {Humans ; Female ; *Catatonia/complications/diagnosis ; *Dementia/complications/diagnosis ; *Delirium/complications/diagnosis ; Aged ; }, abstract = {Catatonia is a severe but underrecognized neuropsychiatric syndrome that is frequently misdiagnosed as delirium or dementia in older adults, resulting in delayed and potentially inappropriate treatment. A 79-year-old woman was admitted for rapid cognitive decline, significant weight loss, and social withdrawal. Initial evaluations suggested major depressive disorder or dementia. Neurological investigations were inconclusive. Following the initiation of psychotropic medication, psychiatric assessment revealed mutism, posturing, and marked psychomotor retardation, fulfilling DSM-5 criteria for catatonia. A lorazepam challenge test confirmed the diagnosis. Psychotropic medications were discontinued, and lorazepam was titrated to 2 mg 4 times daily, resulting in significant clinical improvement. Subsequent brain positron emission tomography (PET) imaging along with clinical evidence supported the presence of an underlying Alzheimer's disease. However, the emergence of superimposed delirium required gradual benzodiazepine tapering. Memantine was subsequently introduced, allowing lorazepam withdrawal and full symptomatic remission. The patient was discharged home. During outpatient follow-up, recurrence of partial symptoms prompted consideration of alternative therapeutic strategies. This case underscores the importance of recognizing catatonia in older adults presenting with cognitive impairment. It highlights the diagnostic and therapeutic challenges posed by the coexistence of catatonia, delirium, and neurodegenerative disease, and emphasizes the need for early identification and a multidisciplinary approach to optimize outcomes.}, } @article {pmid42490986, year = {2026}, author = {Kim, GH and Yoon, HJ and Kim, EH and Kim, JY and Yeom, J and Kang, SY and Lee, B and Jeong, JH}, title = {Six-month real-world amyloid PET outcomes after lecanemab: Greater amyloid reduction at the MCI stage than in dementia.}, journal = {Alzheimer's & dementia (New York, N. Y.)}, volume = {12}, number = {3}, pages = {e70300}, doi = {10.1002/trc2.70300}, pmid = {42490986}, issn = {2352-8737}, abstract = {INTRODUCTION: Evidence from routine clinical practice regarding stage-dependent responses to lecanemab remains limited. We examined early amyloid positron emission tomography (PET) and clinical trajectories according to disease stage in a real-world cohort.

METHODS: Among 89 patients who received lecanemab, 50 individuals with baseline amyloid positivity and follow-up amyloid PET were included in the primary amyloid PET efficacy analysis. Amyloid burden was quantified using the Centiloid scale. Longitudinal Centiloid trajectories were analyzed using linear mixed-effects models including disease stage, time from baseline amyloid PET, and the disease stage × time interaction, with adjustment for cumulative dose exposure, age, sex, and apolipoprotein E (APOE) ε4 carrier status. Cognitive and functional outcomes were assessed using mixed-effects models.

RESULTS: Amyloid burden decreased substantially during follow-up. After adjustment for cumulative dose exposure, age, sex, and APOE ε4 carrier status, the disease stage × time interaction was significant (β = +1.62 Centiloid/month; 95% confidence interval, 0.80 to 2.43; p < 0.001), indicating a faster rate of Centiloid reduction in patients with mild cognitive impairment (MCI) than in those with dementia (estimated -2.34 vs. -0.72 Centiloid/month). Conversion to amyloid-negative status (full treatment-related amyloid clearance) occurred in 9 of 50 patients (18.0%) and was more frequent at the MCI stage (p = 0.022). Patients treated at the MCI stage also showed more favorable short-term cognitive and functional trajectories than those treated at the dementia stage.

DISCUSSION: In real-world clinical practice, lecanemab treatment was associated with substantial amyloid reduction, with faster amyloid clearance observed at the MCI stage. These findings support the potential value of earlier intervention with anti-amyloid therapy, although longer follow-up and controlled comparisons are needed to determine whether early biomarker changes translate into sustained clinical benefit.}, } @article {pmid42479714, year = {2026}, author = {Buard, G and Verny, M}, title = {[Focus on limbic-predominant age-related TDP-43 encephalopathy (LATE)].}, journal = {Geriatrie et psychologie neuropsychiatrie du vieillissement}, volume = {24}, number = {3}, pages = {0}, doi = {10.1684/pnv.2026.1294}, pmid = {42479714}, issn = {2115-7863}, abstract = {In 2019, an international working group described a new clinicopathological entity: limbic-predominant age-related TDP-43 encephalopathy (LATE). Neuropathologically, LATE is characterized by the abnormal accumulation of TDP-43 protein in limbic structures, particularly the hippocampus and parahippocampal regions. Clinically, LATE presents as a slowly progressive, isolated mesiotemporal amnestic syndrome, typically affecting individuals aged over 75 years. Brain MRI usually reveals marked hippocampal atrophy, while FDG-PET may demonstrate medial temporal hypometabolism. A diagnosis of probable LATE requires the exclusion of underlying amyloid pathology, although concomitant Alzheimer's disease pathology is common in older adults. To date, no symptomatic or disease-modifying pharmacological treatment has demonstrated efficacy in LATE. However, its clinical course appears to differ from that of typical Alzheimer's disease, with potentially slower progression and longer preservation of functional independence. LATE therefore represents a common and likely underrecognized cause of memory impairment in older adults, and its identification has important implications for diagnosis, prognosis, and therapeutic decision-making.}, } @article {pmid42479987, year = {2026}, author = {Ghorbani, E and Hajihashemi, S and Fahanik-Babaei, J and Nazari, M}, title = {Chronic 40-Hz Light-Emitting Diode (LED) Therapy Attenuates Cognitive and Behavioral Deficits and Modulates BDNF and Caspase-3 Expression in a D-galactose/Aluminum Chloride-Induced Sporadic Alzheimer's-Like Rat Model.}, journal = {The International journal of neuroscience}, volume = {}, number = {}, pages = {1-17}, doi = {10.1080/00207454.2026.2706611}, pmid = {42479987}, issn = {1563-5279}, abstract = {INTRODUCTION: Alzheimer's disease (AD) is a progressive neurodegenerative condition marked by gradual deterioration of cognition, synaptic integrity, and neuronal viability. Experimental exposure to D-galactose (D-gal) combined with aluminum chloride (AlCl3) produces oxidative and inflammatory damage within the brain, closely resembling AD-related neuropathology. Photobiomodulation therapy (PBMT) has recently gained attention as a safe, non-pharmacological approach with neuroprotective potential; however, the impact of sustained 40-Hz light-emitting diode (LED) stimulation in this context remains insufficiently explored.

METHODS: In the present study, rats received D-gal (60 mg/kg, i.p.) and AlCl3 (200 mg/kg, oral) for six weeks to induce AD-like changes. The treatment group was exposed to 40-Hz pulsed LED light (425-550 nm, 15 min/session, three times weekly). Behavioral analyses were performed using the elevated plus maze (EPM), novel object recognition (NOR), and passive avoidance (PA) paradigms. Western blotting quantified brain-derived neurotrophic factor (BDNF) and cleaved-caspase-3 expression in whole brain tissue.

RESULTS: D-gal/AlCl3 administration produced anxiety-like behavior, recognition deficits, and impaired memory retention, accompanied by decreased BDNF and elevated caspase-3. Remarkably, 40-Hz LED exposure reversed these alterations, up-regulating BDNF and suppressing caspase-3, in parallel with improvements in cognitive and emotional outcomes.

CONCLUSION: These data suggest that 40-Hz LED stimulation confers neuroprotection in the D-gal/AlCl3-induced AD model, potentially through enhancement of neurotropic signaling and inhibition of apoptosis, supporting its promise as a non-invasive strategy against neurodegenerative decline.}, } @article {pmid42479989, year = {2026}, author = {Magee, RG and Xie, SX and Ohm, DT and Rhodes, E and Massimo, L and Van Deerlin, VM and Wolk, DA and Lee, EB and Mcmillan, CT and Irwin, DJ}, title = {Association Between Postmortem Pathologic Burden and the Rate of Clinical Progression in Patients With Frontotemporal Lobar Degeneration.}, journal = {Neurology}, volume = {107}, number = {3}, pages = {e218278}, doi = {10.1212/WNL.0000000000218278}, pmid = {42479989}, issn = {1526-632X}, mesh = {Humans ; Female ; *Frontotemporal Lobar Degeneration/pathology ; *Disease Progression ; Male ; Middle Aged ; Retrospective Studies ; Aged ; tau Proteins/metabolism ; *Brain/pathology ; DNA-Binding Proteins/metabolism ; Longitudinal Studies ; Autopsy ; }, abstract = {BACKGROUND AND OBJECTIVES: Histopathologic staging of Alzheimer disease has led to validation of imaging techniques that guide diagnosis and treatment. We previously constructed preliminary phases of the sequential progression of TDP-43 and tau to guide similar efforts in behavioral-variant frontotemporal dementia (bvFTD). In this article, we expand this work using digital pathology and longitudinal clinical data to more comprehensively model the relationship between clinical progression and the distribution and severity of postmortem frontotemporal lobar degeneration (FTLD) pathology.

METHODS: In this retrospective cohort study, 101 patients (42% female, median age at symptom onset = 63 years) were selected from the Penn Integrated Neurodegenerative Disease Database and had both longitudinal assessments and primary neuropathologic diagnosis of FTLD-Tau or FTLD-TDP. We used validated methods to quantify the burden of primary pathology from up to 6 cortical regions across hemispheres. FTLD-TDP pathologic phase was constructed from diagnostic pathology data based on published criteria. We tested the association between pathologic metrics and (1) disease duration or (2) the rate of clinic progression measured by 2 independent global measures (Clinical Dementia Rating Scale-Sum of Boxes [CDR-SB] and Mini-Mental State Examination [MMSE]). Linear regression and linear mixed-effects models were adjusted for hemisphere sampled, sex, age at onset, pathogenic variant status, and pathologic subtype.

RESULTS: Disease duration did not associate with pathologic burden in multiple regression (FTLD-TDP β = 0.01 [-0.06, 0.09]; p = 0.7; FTLD-Tau β = 0.1 [-0.4, 0.7]; p = 0.7). By contrast, mean TDP-43 burden, but not FTLD-Tau burden, was associated with both worse relative CDR-SB (β = 0.1 [0.06, 0.2]; p = 0.0001) and MMSE (β = -0.1 [-0.2, -0.03]; p = 0.009) among all FTLD-TDP patients. TDP-43 phase also associated with worse CDR-SB (β = 0.07 [0.02, 0.1]; p = 0.005) and MMSE (β = -0.2 [-0.3, -0.1]; p = 0.000005). TDP-43 burden (CDR-SB (β = 0.1 [0.03, 0.2]; p = 0.005 and MMSE (β = -0.2 [-0.4, -0.05]; p = 0.009)), but not phase (CDR-SB (β = 0.02 [-0.03, 0.08]; p = 0.4 and MMSE (β = -0.04 [-1, 0.07]; p = 0.5)), associated with relative decline in sensitivity analyses limited to bvFTD.

DISCUSSION: Greater TDP-43 burden was most closely associated with antemortem clinical decline rather than cumulative aggregation through the disease course. These human data suggest that the temporal dynamics of protein aggregation may differ among FTLD proteinopathies, with implications for the interpretation of FTLD-Tau and FTLD-TDP‑specific biomarkers as these are developed.}, } @article {pmid42482244, year = {2026}, author = {Bonnì, S and Esposito, R and Mencarelli, L and Di Lorenzo, F and Ricci, F and Di Iulio, F and Savastano, E and Candeo, F and De Masi, F and Coletta, A and Vinci, AC and Ferraresi, M and Mancini, M and Casula, EP and Borghi, I and Spampinato, DA and Maiella, M and Cinnera, AM and Assogna, M and Bruno, M and Nocilli, M and Ferrara, M and Russo, M and Tagliamonte, NL and Ferrari, C and Bertino, S and Calabrò, RS and Maggio, MG and De Luca, R and Burrascano, R and Gjonaj, E and Mirabile, A and De Pasquale, P and d'Avella, A and Quartarone, A and Koch, G}, title = {Personalized non-invasive combined magnetic and electrical stimulation of the default mode network in mild AD patients (CMES-AD): a multicentric randomized sham-controlled trial protocol.}, journal = {Alzheimer's research & therapy}, volume = {}, number = {}, pages = {}, doi = {10.1186/s13195-026-02145-x}, pmid = {42482244}, issn = {1758-9193}, support = {PNRR- MCNT2-2023-12377518//Ministero della Salute/ ; }, abstract = {BACKGROUND: Patients with Alzheimer's disease (AD) exhibit early alterations in the Default Mode Network (DMN), a key brain network involved in episodic memory where the precuneus plays a central role. Precision-targeted, non-invasive brain stimulation represents a promising strategy to improve cognitive function in individuals with dementia. The DMN can be modulated through personalized non-invasive electromagnetic stimulation, a therapeutic approach that enhances neural plasticity and stabilizes network connectivity. This trial implements an innovative therapeutic protocol based on precision delivery of personalized electromagnetic stimulation targeting the precuneus, the main hub of the DMN.

METHODS: This phase 2 multicenter, randomized, double-blind, sham-controlled, three-arm trial evaluates the safety and efficacy of combined repetitive transcranial magnetic stimulation (rTMS) and transcranial alternating current stimulation (tACS) targeting the precuneus in AD patients. rTMS will be applied using the intermittent theta burst stimulation (iTBS) protocol, while tACS will be delivered at gamma frequency (70 Hz). Personalization of iTBS-tACS treatment is established using neuronavigated TMS with electroencephalography (TMS-EEG). The 24-week intervention starts with a 2-week intensive course of daily combined treatment over the precuneus (5 sessions per week), followed by a 22-week maintenance phase with weekly stimulation. The primary outcome measure is the change in the integrated Alzheimer Disease Rating Scale (iADRS) between baseline and week 24. Secondary outcomes include score changes in the Alzheimer's Disease Cooperative Study - Activities of Daily Living (ADCS-ADL) scale, Clinical Dementia Rating Scale-Sum of Boxes (CDR-SoB), the Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog13), the Mini-Mental State Examination (MMSE), the Montreal Cognitive Assessment (MoCA), the Frontal Assessment Battery (FAB), the Face-Name Association Task (FNAT), the Neuropsychiatric Inventory (NPI), and the Apathy Motivation Index (AMI). Exploratory outcomes will include changes in cortical activity and connectivity (assessed through TMS-EEG, MRI), in blood based biomarkers of neurodegeneration, synaptic activity and neural inflammation, and sensorimotor functions in virtual environments. Evaluation at week 12 and a follow-up assessment at week 32 will be conducted to assess short-term and follow-up treatment effects, respectively.

SIGNIFICANCE: This trial aims to provide evidence that personalized combined electrical and magnetic stimulation of the DMN may slow functional and cognitive decline in AD patients, contributing to the development of personalized interventions for AD treatment.

TRIAL REGISTRATION: ClinicalTrials.gov, NCT07075770, registered 10 July 2025.}, } @article {pmid42482583, year = {2026}, author = {Yang, SM and Guo, WQ and Dong, WG and Huang, JY and Huang, ST and Huang, Y and Zhan, SJ and Lin, L and Wang, F and Liu, LL}, title = {[Effects of electroacupuncture on motor function and PGC-1α/FNDC5/BDNF pathway in muscle and brain of SAMP8 mice].}, journal = {Zhen ci yan jiu = Acupuncture research}, volume = {51}, number = {7}, pages = {887-895}, doi = {10.13702/j.1000-0607.20250437}, pmid = {42482583}, issn = {1000-0607}, mesh = {Animals ; *Electroacupuncture ; *Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha/metabolism/genetics ; *Brain-Derived Neurotrophic Factor/metabolism/genetics ; Mice ; *Muscle, Skeletal/metabolism ; Male ; *Fibronectins/metabolism/genetics ; Humans ; *Brain/metabolism ; *Alzheimer Disease/genetics/metabolism/therapy/physiopathology ; Signal Transduction ; Motor Activity ; Acupuncture Points ; }, abstract = {OBJECTIVES: To observe the effect of electroacupuncture (EA) on motor function and skeletal muscle morphology in SAMP8 mice, and to explore the mechanisms of EA improving motor dysfunction in Alzheimer's disease from the peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α)/fibronectin type Ⅲ domain-containing protein 5 (FNDC5)/brain-derived neurotrophic factor (BDNF) pathway.

METHODS: SAMP8 mice were randomly divided into model and EA groups, with 9 mice in each group. Nine anti-aging SAMR1 mice were used as control group. In the EA group, "Baihui"(GV20), "Dazhui"(GV14) and "Shenshu"(BL23) were needled with EA for 20 min every day, 8 d as a course of treatment, with an interval of 2 d between courses. A total of 3 courses was proceeded. The motor function of mice was detected by grasping test, swimming test, suspension test and hind limb clamping test. The morphological structure of gastrocnemius muscle was observed by HE staining. The positive expressions of PGC-1α, FNDC5 and BDNF in gastrocnemius muscle were observed by immunohistochemical staining. The expression levels of PGC-1α, FNDC5 and BDNF mRNAs in gastrocnemius muscle and cerebral motor cortex were detected by real-time fluorescence quantitative PCR. The expression levels of PGC-1α, FNDC5 and BDNF proteins in gastrocnemius muscle and cerebral motor cortex were detected by Western blot.

RESULTS: Compared with the control group, the peak grip strength, average and maximum swimming speed, and suspension test score of the model group were significantly decreased (P<0.01), and the hind limb clamping test score was significantly increased (P<0.01). The gastrocnemius muscle fibers were loose and irregularly arranged, the spacing was widened and the cytoplasmic staining was uneven. The positive expression area ratios of PGC-1α, FNDC5 and BDNF in gastrocnemius muscle were significantly decreased (P<0.01), and the relative expression levels of PGC-1α, FNDC5 and BDNF mRNAs and proteins in gastrocnemius muscle and cerebral motor cortex were significantly decreased (P<0.01). Compared with the model group, the peak grip strength, average and maximum swimming speed, and suspension test score of the EA group were significantly increased (P<0.01), and the hind limb clamping test score was significantly decreased (P<0.01). The muscle fibers were intact and arranged regularly, the spacing was narrowed, and the cytoplasmic staining was uniform.The positive expression area ratios of PGC-1α, FNDC5 and BDNF were significantly increased (P<0.01), and the relative expression levels of PGC-1α, FNDC5 and BDNF mRNAs and proteins in gastrocnemius muscle and cerebral motor cortex were significantly increased (P<0.01, P<0.05). The correlation analysis results of PGC-1α, FNDC5 and BDNF mRNA expression in gastrocnemius and cerebral motor cortex showed a highly positive correlation (r>0.70, P<0.01).

CONCLUSIONS: EA can improve motor dysfunction and skeletal muscle morphology in SAMP8 mice, and its mechanism may be related to up-regulation of PGC-1α, FNDC5 and BDNF expressions in gastrocnemius and cerebral motor cortex.}, } @article {pmid42483783, year = {2026}, author = {Wen, Y and Zhan, S and Duan, Y and Pang, M and Yan, J and Deng, M and Fan, H}, title = {Efficacy and Safety of Mesenchymal Stem Cell Therapy for Alzheimer's Disease: A Systematic Review and Meta-Analysis.}, journal = {Stem cells and development}, volume = {}, number = {}, pages = {15473287261468404}, doi = {10.1177/15473287261468404}, pmid = {42483783}, issn = {1557-8534}, abstract = {Alzheimer's disease (AD) is the leading cause of dementia, and effective disease-modifying therapies remain limited. Mesenchymal stem cells (MSCs) have shown therapeutic potential because of their neuroprotective and immunomodulatory properties, but clinical evidence remains inconclusive. We systematically evaluated the efficacy and safety of MSC therapy in AD. Following the PRISMA 2020 guidelines and a PROSPERO-registered protocol (CRD420261329891), we searched PubMed, the Cochrane Library, Embase, Web of Science, CNKI, and Wanfang from inception to March 1, 2026. Clinical studies of patients with primary AD treated with MSCs were included. Outcomes covered cognition, daily function, neuropsychiatric symptoms, biomarkers, imaging findings, and adverse events. Standardized mean differences (SMDs) with 95% confidence intervals (CIs) were pooled using R. Risk of bias was assessed with the RoB 2 tool, and evidence certainty was assessed with GRADE. Six studies involving 196 patients were included. Overall analyses showed no significant improvement in Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog) or Mini-Mental State Examination (MMSE) at 12-16 weeks or 24-26 weeks after MSC treatment versus placebo, with substantial heterogeneity. Dose-stratified analyses suggested significant benefits of low-dose MSCs on ADAS-Cog (SMD = -1.33, 95% CI: -2.35 to -0.31) and MMSE (SMD = 2.59, 95% CI: 0.52-4.66). MSC therapy significantly improved Alzheimer's Disease Cooperative Study-Activities of Daily Living (ADCS-ADL; SMD = 3.27, 95% CI: 1.79-4.75), but not Neuropsychiatric Inventory (NPI) or Quality of Life in Alzheimer's Disease (QOL-AD) scale. Biomarker analyses showed no significant overall effects on Aβ42 or total tau, although subgroup analyses suggested possible increases in Aβ42 and reductions in total tau at certain doses. Imaging data from two studies indicated potential protective effects on hippocampal atrophy. MSC therapy was generally well-tolerated, although intracerebroventricular administration was associated with more transient adverse events. Evidence certainty was low to very low for most outcomes. MSC therapy for AD appears feasible and relatively safe, with potential cognitive and disease-modifying effects. However, current clinical evidence remains insufficient to confirm its efficacy.}, } @article {pmid42483925, year = {2026}, author = {Li, W and Guo, C and Jin, Y and Ji, H and Zhang, L and Li, W and Zhang, W and Fu, L}, title = {Ganoderma sinense Polysaccharides Improve Cognition in a Mouse Model of Alzheimer's Disease by Modulating Gut Microbiota and Short-Chain Fatty Acid Metabolism.}, journal = {Current Alzheimer research}, volume = {}, number = {}, pages = {}, doi = {10.2174/0115672050473800260622054102}, pmid = {42483925}, issn = {1875-5828}, abstract = {INTRODUCTION: The number of patients with Alzheimer's Disease (AD) worldwide is expected to reach 152 million by 2050, but developing an effective AD treatment remains challenging. This study purified two polysaccharides (GSP1 and GSP2) from Ganoderma sinense, a traditional Chinese medicine, and investigated their potential therapeutic effects against AD.

MATERIALS AND METHODS: GSP1 and GSP2 were purified and characterized for key physicochemical properties, including monosaccharide composition and molecular weight. In vitro neuroprotective efficacy was evaluated using glutamate-challenged SH-SY5Y cells. For in vivo assessment, an AlCl₃/D-galactose induced AD mouse model was established to quantify cognitive/memory enhancement. Multiomic analysis of the gut microbiota, Short-Chain Fatty Acid (SCFAs) metabolomics, and behavioural tests were conducted to elucidate the therapeutic mechanisms of GSP1.

RESULTS: Both GSP1 and GSP2 conferred neuroprotection against toxin-induced damage. Notably, GSP1 demonstrated superior efficacy compared with GSP2, significantly enhancing cognitive/ memory performance and reducing amyloid-β plaque deposition. Furthermore, GSP1 changed gut microbial diversity and SCFA metabolic profiles. Critical genus-level correlations emerged: Turicibacter, Jeotgalicoccus, and Staphylococcus were positively associated with therapeutic outcomes, whereas Odoribacter was negatively associated.

DISCUSSION: Natural polysaccharides, particularly GSP1, demonstrate therapeutic potential against AD by modulating gut microbiota. Mechanistically, this effect is linked to reshaping microbial communities and affecting the production of neuroprotective SCFAs. Although these findings position GSP1 as a promising AD therapeutic candidate, deeper exploration of gut-brain axis mechanisms remains essential for clinical translation.

CONCLUSION: GSP1 emerges as a promising therapeutic candidate for AD, offering a new approach to developing AD-targeted pharmaceuticals and nutraceuticals.}, } @article {pmid42475614, year = {2026}, author = {Jarrell, L and Vanhoy, S}, title = {Doll therapy: Innovative treatment for patients with Alzheimer disease to improve patient and staff safety in a hospital setting.}, journal = {Nursing}, volume = {56}, number = {8}, pages = {56-61}, doi = {10.1097/NSG.0000000000000419}, pmid = {42475614}, issn = {1538-8689}, mesh = {Humans ; *Alzheimer Disease/therapy/psychology ; Female ; Male ; *Patient Safety/standards ; Aged ; *Play Therapy/methods ; Accidental Falls/prevention & control ; Aged, 80 and over ; }, abstract = {BACKGROUND: Patients with Alzheimer disease may display negative neuropsychiatric symptoms that can pose patient safety risks.. Doll therapy is described in the literature as a successful diversional activity for these patients.

PURPOSE: This project aimed to provide doll therapy to patients with Alzheimer disease at their facility to reduce neuropsychiatric symptoms, improve patient safety, patient outcomes, and the patient and family experience, and to positively impact the health care team's experience when caring for this patient population.

METHODS: A total of 55 patients with a diagnosis of Alzheimer disease participated in the doll therapy program. Quantitative and qualitative data were collected and analyzed. These included patient's behavior prior to doll therapy and the patient's response to doll therapy.

RESULTS: Patients experienced a sense of purpose and comfort, as well as decreased risk for falls, physical workplace violence events, and being placed in restraints as a result of doll therapy.}, } @article {pmid42476460, year = {2026}, author = {Fowler, CF and Osipyan, E and Devenyi, GA and Madularu, D and Breitner, J and Near, J}, title = {Early treatment with naproxen alters hippocampal metabolites in the TgF344-AD rat model of Alzheimer's disease.}, journal = {Neurochemistry international}, volume = {}, number = {}, pages = {106226}, doi = {10.1016/j.neuint.2026.106226}, pmid = {42476460}, issn = {1872-9754}, abstract = {Alzheimer's disease (AD) is characterized by the appearance of brain pathology decades prior to clinical symptoms. The pre-symptomatic phase of AD provides opportunity for early detection and intervention. One early intervention that has been proposed is the use of non-steroidal anti-inflammatory drugs (NSAIDs), such as naproxen. However, evidence suggests that effects of naproxen intervention differ with stage of the disease, and the optimal intervention time is not clear. Accordingly, in this study, we investigated the impact of the timing of naproxen treatment in a rat model of AD. We used the TgF344-AD rat model of AD which develops characteristic pathological features of human AD, including abundant amyloid plaque pathology, astrogliosis, and microgliosis by 6 months of age, and neurofibrillary tangles and neuronal loss by 16 months of age. We examined the effects of naproxen treatment beginning at 1, 4, and 10 months of age in transgenic (Tg) animals and their wild-type (WT) littermates. We used longitudinal in vivo magnetic resonance spectroscopy (MRS) to study the impact of naproxen treatment on hippocampus neurochemistry. Previous studies have used MRS to non-invasively characterize the trajectory of altered hippocampal neurochemistry across the lifespan in the TgF344-AD rat model. In the current study, we employed MRS at 4, 10, and 16 months, i.e. prior to or after the appearance of amyloidosis and gliosis (6 months) and tau pathology (16 months), respectively, in Tg animals. Naproxen treatment altered neurochemistry in Tg animals only if administered beginning at 1 or 4 months of age, mitigating an otherwise observed increase in total choline and decrease in taurine. A more subtle effect was observed on the otherwise-expected increase in myo-inositol. These results highlight the possibility that earlier naproxen intervention could have distinct neurochemical effects compared to delayed treatment, though mechanistic implications remain to be clarified. Moreover, these findings support the use of MRS as a useful non-invasive method of monitoring treatment-related changes in neurochemistry in transgenic animal models.}, } @article {pmid42477703, year = {2026}, author = {Yang, Y and Kwak, YT}, title = {Associations of Ginkgo biloba extract exposure with 12-month cognitive trajectories in amyloid PET-positive mild cognitive impairment and Alzheimer's disease: a pooled retrospective cohort study.}, journal = {BMC complementary medicine and therapies}, volume = {}, number = {}, pages = {}, doi = {10.1186/s12906-026-05469-1}, pmid = {42477703}, issn = {2662-7671}, support = {HI22C0667//Korea Health Industry Development Institute/Republic of Korea ; }, abstract = {BACKGROUND: Alzheimer's disease (AD) and mild cognitive impairment (MCI) show considerable heterogeneity in treatment response, underscoring the need for individualized therapeutic approaches. Ginkgo biloba extract is commonly used in cognitive disorders, but its efficacy in amyloid biomarker-confirmed populations remains unclear. To evaluate the association between Ginkgo biloba extract exposure and 12-month cognitive and functional change patterns in amyloid PET-positive MCI/AD, and to assess whether baseline plasma MDS-OAβ (amyloid oligomerization tendency) is associated with cognitive trajectory subgroup membership.

METHODS: In this 12-month retrospective study, 165 drug-naïve amyloid PET-positive patients (83 with documented Ginkgo biloba extract use in routine care and 82 without documented Ginkgo use) were assessed for changes in Korean Mini-Mental State Examination (K-MMSE-2), Clinical Dementia Rating-Sum of Boxes (CDR-SB), Korean Instrumental Activities of Daily Living (K-IADL), and plasma MDS-OAβ levels. K-means clustering was used to define three cognitive trajectory subgroups, and exploratory one-vs-rest adjusted logistic regression analyses were performed to examine baseline variables associated with trajectory group membership.

RESULTS: Three cognitive trajectories were identified: Improver (n = 36), Stabler (n = 113), and Decliner (n = 16). Compared with patients without documented Ginkgo use, patients with documented Ginkgo exposure showed significantly greater cognitive gains (ΔK-MMSE-2 + 1.42 vs. - 0.30, p = 0.012), less IADL decline (p < 0.001), and greater reductions in MDS-OAβ levels (p < 0.001). Baseline plasma MDS-OAβ did not significantly differ among the trajectory groups and was not interpreted as a robust independent predictor of trajectory membership. Ginkgo use differed significantly across trajectory groups and was least frequent in the Decliner group.

CONCLUSIONS: In this amyloid PET-positive MCI/AD cohort, Ginkgo biloba extract exposure was associated with more favorable 12-month cognitive, functional, and plasma MDS-OAβ changes. However, baseline MDS-OAβ should be regarded as an exploratory biomarker rather than a validated predictor of improvement or Ginkgo-related benefit.}, } @article {pmid42478598, year = {2026}, author = {Martens, CR and Decker, KP and DeConne, TM and Sanjana, F and Horvat, F and Rizzi, NA and Awad, C and Habash, E and Hobson, JC and Kramer, MK and Armstrong, ML and Reisdorph, N and Pohlig, RT and Lanzi, AM and Johnson, CL and Cohen, ML and Ellison, JM}, title = {A phase-II randomized controlled pilot study of nicotinamide riboside supplementation in older adults with amnestic mild cognitive impairment.}, journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association}, volume = {22}, number = {7}, pages = {e71605}, doi = {10.1002/alz.71605}, pmid = {42478598}, issn = {1552-5279}, support = {K01AG054731/AG/NIA NIH HHS/United States ; P20GM113125/GM/NIGMS NIH HHS/United States ; }, mesh = {Humans ; Pilot Projects ; *Cognitive Dysfunction/drug therapy/diagnostic imaging ; Aged ; Double-Blind Method ; Female ; *Niacinamide/analogs & derivatives/therapeutic use/administration & dosage ; Male ; *Dietary Supplements ; Cerebrovascular Circulation/drug effects ; Pyridinium Compounds ; Neuropsychological Tests ; Cognitive Enhancement ; NAD/blood ; *Amnesia/drug therapy ; Blood Pressure/drug effects ; Treatment Outcome ; Aged, 80 and over ; }, abstract = {INTRODUCTION: Declining nicotinamide adenine dinucleotide (NAD[+]) may elevate risk of Alzheimer's disease.

METHODS: We conducted a 12-week double-blind, randomized, placebo-controlled pilot study to evaluate the safety, tolerability, and preliminary efficacy of the NAD[+] precursor, nicotinamide riboside (NR), for enhancing cognitive function and cerebral blood flow (CBF) in adults with amnestic mild cognitive impairment (aMCI).

RESULTS: 42 participants completed the study (NR = 22, placebo = 20). Adherence was similar between groups with no serious adverse effects. Blood NAD[+] increased twofold in the NR group. There were no improvements in cognitive function (primary outcome), total CBF, or blood pressure (secondary outcomes). Exploratory analyses revealed potential increases in regional CBF, particularly in the hippocampus.

DISCUSSION: NR effectively raises NAD[+] in people with MCI but does not improve cognitive function, total CBF, or blood pressure over 12 weeks. Future studies should investigate regional effects on CBF over longer treatment durations.}, } @article {pmid42478899, year = {2026}, author = {Zhang, N and Chen, W and Wang, M}, title = {The liver-brain axis: A multidimensional regulatory network implicated in Alzheimer's disease pathogenesis and clinical implications.}, journal = {Animal models and experimental medicine}, volume = {}, number = {}, pages = {}, doi = {10.1002/ame2.70262}, pmid = {42478899}, issn = {2576-2095}, support = {Seed Program (YYZZ202409)//Capital Medical University Affiliated Beijing Friendship Hospital/ ; }, abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by amyloid-β (Aβ) deposition. The liver-brain axis underscores the central role of the liver in modulating cognitive function through multidimensional regulatory mechanisms. As a core metabolic and detoxification organ, the liver also helps maintain cerebral homeostasis via pathways including the urea cycle, antioxidant systems, ketone body metabolism, and bile acid regulation. Dysfunction of these processes may lead to ammonia accumulation, exacerbated oxidative stress, and Aβ clearance, thereby accelerating the pathological progression of AD. Liver-derived factors such as apolipoprotein E (APOE), C-reactive protein (CRP), fibroblast growth factor 21 (FGF21), and insulin-like growth factor 1 (IGF-1) significantly increase the risk of AD through dual mechanisms-inhibiting Aβ clearance and activating neuroinflammation, thereby directly affecting cognitive function via modulation of inflammation, metabolism, and blood-brain barrier (BBB) integrity. Neural interfaces formed by the hypothalamic-pituitary-target gland axis and the vagus nerve enable communication from the liver to the brain, with emerging evidence also supporting a reverse influence from the brain to the liver. Emerging technologies such as molecular tracing and nanocarriers provide new tools for deciphering dynamic interactions within the liver-brain axis. Liver-targeted metabolic interventions show potential for reversing cognitive impairment. Unlike previous reviews that mainly focused on single pathways, this review conceptualizes the liver-brain axis as a multidimensional regulatory network in AD. By clearly linking network nodes to potential therapeutic interventions, it provides us with a novel framework that not only describes the various mechanisms but also focuses on identifying actionable targets for disease prevention and treatment.}, } @article {pmid42479540, year = {2026}, author = {Zhang, J and Yu, P and Xu, M and Liang, F and Chen, Y and Dong, Y and Zhang, Y and Yu, S and Hua, F and Otu, HH and Libermann, TA and Inouye, SK and Marcantonio, ER and Yang, G and Xie, Z}, title = {Anesthesia and surgery induce sex-dependent Tau phosphorylation and behavior changes in aged mice.}, journal = {Anesthesiology}, volume = {}, number = {}, pages = {}, doi = {10.1097/ALN.0000000000006261}, pmid = {42479540}, issn = {1528-1175}, abstract = {BACKGROUND: Preoperative blood Tau phosphorylated at threonine 217 (Tau-PT217), a newly identified blood biomarker of Alzheimer's disease, is associated with postoperative delirium in patients. Anesthesia/surgery is also associated with postoperative increased blood Tau-PT217 amounts in patients. Moreover, in female aged mice, anesthesia/surgery increases Tau-PT217 in lungs, blood and brain tissues, leading to behavioral changes. However, whether these effects are sex-dependent remain largely undetermined.

METHODS: Eighteen-month-old female and male mice (C57BL/6J) underwent abdominal surgery under general anesthesia (1.4% isoflurane and 40% oxygen). Levels of Tau-PT217, inflammatory markers, and GSK3β activity were measured in lungs, blood, and brain tissues of aged mice using nanoneedle technology, Western blot, immunohistochemistry, RT-PCR and others. Postoperative delirium-like behavior was assessed using a battery of behavioral tests (buried food, open filed and Y maze). To explore causality, we performed orchiectomy and administered androgen receptor antagonist enzalutamide in aged male mice. Finally, testosterone was delivered via inhalation to aged female mice.

RESULTS: Anesthesia/surgery increased the amounts of Tau-PT217 in lungs (2.29±0.16 fold versus 1.15±0.71 fold, P<0.01), blood, and brain tissues of aged female, but not male, mice compared to control condition, leading to postoperative delirium-like behavior, as evidenced by increases in the composite Z score (3.74±1.46 versus 0.60±1.17, P<0.01), in the aged female, but not male, mice. Anesthesia/surgery elevated inflammatory markers and GSK3β activity in aged female mice, which exhibited lower baseline testosterone levels and androgen receptor expression in lungs compared to males. Both orchiectomy and enzalutamide treatment in male mice reduced testosterone levels and androgen receptor expression, leading to elevation of Tau-PT217 amounts and behavior changes following anesthesia/surgery. Conversely, testosterone inhalation in aged female mice mitigated the anesthesia/surgery-induced elevation of Tau-PT217 amounts and behavior changes.

CONCLUSIONS: Testosterone and androgen receptor signaling may contribute to the sex-dependent differences in Tau phosphorylation and postoperative behavior changes in aged mice.}, } @article {pmid42472492, year = {2026}, author = {Damirchi, EK and Barani, A and Hamidi, SM and Ebrahimzadeh, MA}, title = {Melatonin hybrids as multifunctional therapeutic agents: A comprehensive review.}, journal = {European journal of medicinal chemistry}, volume = {318}, number = {}, pages = {119156}, doi = {10.1016/j.ejmech.2026.119156}, pmid = {42472492}, issn = {1768-3254}, abstract = {Compound hybridization has received attention due to its potential to address several diseases, including neurological disorders, cancer, infectious diseases, and others. Melatonin is a hormone with antioxidant, anti-inflammatory, and neuroprotective effects. Some drug design research has focused on synthesizing hybrid molecules in which melatonin is hybridized with other pharmacologically active compounds to increase therapeutic efficacy and reduce toxicity. These hybrids demonstrate improved binding affinity, selectivity, and pharmacokinetic characteristics compared to their separate components. This review shows the pharmacological assessment and therapeutic potential of diverse melatonin-based hybrids. These hybrids have exhibited significant efficacy in the treatment of complex diseases such as Alzheimer's disease, cancer, and inflammatory disorders. Hybridization leads to the synthesis of a new generation of structures that represent a promising therapeutic approach for disease treatment.}, } @article {pmid42472573, year = {2026}, author = {Yanagisawa, D and Ohgita, T and Kawashima, H and Yoshikawa, H and Saito, H and Tooyama, I and Takata, K}, title = {Neurotheranostics in Alzheimer's Disease: Current concepts and experimental strategies.}, journal = {Pharmacology & therapeutics}, volume = {}, number = {}, pages = {109084}, doi = {10.1016/j.pharmthera.2026.109084}, pmid = {42472573}, issn = {1879-016X}, abstract = {In Alzheimer's disease (AD), pathological changes start decades before symptoms appear; by the time cognitive issues are noticeable, widespread neuronal and glial dysfunction and significant neuronal loss have already occurred. Recent regulatory approvals of monoclonal antibodies targeting aggregated amyloid-β (Aβ) species, including oligomers and fibrils, represent a major advance in disease-modifying therapy. However, therapeutic efficacy is strongly dependent on intervention at the earliest pathological stages, underscoring the importance of early diagnosis and treatment. Early diagnosis requires biomarkers that accurately reflect the initiation and progression of AD pathology as well as the development of methodologies capable of capturing these pathological states in vivo. Effective early treatment necessitates strategies that suppress the formation, activation, or toxicity of molecules that trigger downstream neurodegenerative cascades, thereby interrupting disease progression at its source. In parallel, advances in targeted brain delivery technologies are essential to enable sensitive detection and effective therapeutic modulation of central nervous system targets. Neurotheranostics is an integrated conceptual framework that aims to achieve early diagnosis and targeted therapy either simultaneously or in a coordinated manner using shared molecular targets and biological readouts. By unifying molecular imaging, biomarker analysis, and disease-modifying intervention, neurotheranostics aims to overcome the limitations of conventional diagnostic and therapeutic paradigms in neurodegenerative disorders, including AD. In this review, we summarize recent advances in neurotheranostic approaches for AD and highlight emerging molecular probes, low-molecular-weight compounds, and delivery technologies, including contributions from our studies.}, } @article {pmid42472714, year = {2026}, author = {Khan, M and Khan, T and Tariq, A}, title = {From biomarker expansion to equitable implementation in mild cognitive impairment.}, journal = {Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology}, volume = {47}, number = {8}, pages = {}, pmid = {42472714}, issn = {1590-3478}, mesh = {Humans ; *Cognitive Dysfunction/diagnosis/cerebrospinal fluid ; *Biomarkers/cerebrospinal fluid ; *Alzheimer Disease/diagnosis/cerebrospinal fluid ; }, abstract = {The expanding role of cerebrospinal fluid (CSF) biomarkers in Alzheimer's disease diagnosis represents a major shift toward biologically driven dementia care. In response to the article by Poli et al., we discuss important considerations regarding the broader implementation of CSF biomarker testing in patients with mild cognitive impairment (MCI), particularly in the era of emerging anti-amyloid therapies. While biomarker-guided approaches may improve identification of atypical or non-amnestic Alzheimer's disease presentations, widespread adoption remains limited by disparities in diagnostic infrastructure, standardized testing availability, expertise in lumbar puncture procedures, and longitudinal monitoring capacity across healthcare systems. In addition, expanded eligibility for anti-amyloid therapies introduces challenges related to patient selection, treatment accessibility, and equitable allocation of healthcare resources. Ethical considerations surrounding biomarker disclosure and prognostic uncertainty also warrant continued discussion. We emphasize the need for future studies evaluating accessibility, cost-effectiveness, and standardized patient selection frameworks to support equitable integration of biomarker-guided dementia care into routine neurological practice.}, } @article {pmid42473218, year = {2026}, author = {Keskin, A and Mogulkoc, R and Baltaci, AK}, title = {Relationship Between miRNA and Neurodegenerative Diseases Such as Alzheimer's disease, Parkinson's, Huntington's disease, Amyotrophic Lateral Sclerosis.}, journal = {Mini reviews in medicinal chemistry}, volume = {}, number = {}, pages = {}, doi = {10.2174/0113895575484348260702044851}, pmid = {42473218}, issn = {1875-5607}, abstract = {The regulatory roles of miRNAs on CNS homeostasis, neuronal differentiation, and synaptic plasticity make these molecules indispensable for healthy brain functions. miRNA dysregulation, by triggering abnormal neurodevelopment, has a critical impact on the etiology and progression of neurodegenerative diseases. MicroRNAs (miRNAs) are short, single-stranded, non-coding ribonucleic acid (RNA) molecules, 18 to 24 nucleotides long. They play a role in posttranscriptional gene regulation by binding to complementary sequences on messenger RNA (mRNA), thereby promoting mRNA degradation or preventing translation into protein. MiRNAs are essential regulators of the genome because they bind targets and alter gene expression. MiRNA biogenesis and functions are tightly regulated, and their dysregulation is associated with various diseases, including cancer, cardiovascular diseases, and neurodegenerative disorders. In particular, disruption of the Blood-Brain Barrier in neurodegenerative diseases allows molecules to leak into the bloodstream, enabling the detection of miRNAs in other body fluids and making these fluids potential biomarker sources. In this context, miRNAs can be measured in blood, cerebrospinal fluid, and other biological samples. It has significant potential for early diagnosis, disease progression monitoring, and evaluation of treatment efficacy. In this review, the relationship between MiRNAs and neuronal degeneration diseases was evaluated. In this review, prepared in light of the current literature scanned through the PubMed database, we examined data from the last 5 years (2021-2026) on neurodegenerative diseases associated with miRNA dysregulation, including Alzheimer's Disease (AD), Parkinson's Disease (PD), Amyotrophic Lateral Sclerosis (ALS), and Huntington's Disease (HD).}, } @article {pmid42473227, year = {2026}, author = {Rodrigues, JFR and Rodrigues, LP and Rodrigues, FCP and Cavalcante, LL and Payão, SLM and Tavares, AR and Forlenza, OV and de Godoy, MF and Filho, GMA}, title = {Cardiovascular Comorbidities with Alzheimer's Disease: A Systematic Review and Meta-analysis.}, journal = {Current Alzheimer research}, volume = {}, number = {}, pages = {}, doi = {10.2174/0115672050468989260629094050}, pmid = {42473227}, issn = {1875-5828}, abstract = {INTRODUCTION: Alzheimer's disease stands as the most prevalent form of dementia, characterized by a progressive decline in cognitive function and memory. Numerous risk factors have been linked to its development, creating a complex interplay of influences. In this study, we aim to delve into the relationship between cardiovascular disease and Alzheimer's disease, exploring how conditions affecting heart health may impact the onset and progression of this debilitating neurological disorder. Through this research, we could find potential connections that inform prevention strategies and therapeutic approaches.

MATERIALS AND METHODS: We adopted the PRISMA guidelines and defined the PECOS framework as follows: Population (P) = individuals; exposure (E) = cardiovascular disease; comparison (C) = without cardiovascular disease; outcome (O) = Alzheimer's disease; and study design(S) = all kinds of studies with an association between cardiovascular disease and Alzheimer's disease without time limits. A meta-analysis was conducted using case-control, cohort, and genetic studies to estimate Odds Ratios (ORs) or Hazard Ratios (HRs).

RESULTS: The pooling of data in meta-analysis demonstrated that a person with any Cardiovascular Disease (CVD), Heart Failure (HF), Coronary Artery Disease (CAD), Atrial Fibrillation (AF), Hypertension (HTN), and Myocardial Infarction (MI) had more risk of developing Alzheimer's disease [CVD: HR = 1.30 (CI: 1.27-1.33) / HF: HR = 1.63 (CI: 1.37-1.94) / CAD: HR = 1.43 (CI: 1.40-1.46) / AF: HR = 1.38 (CI: 1.34-1.42) / HTN: HR = 1.22 (CI: 1,10-1.35) / MI: HR = 1.07 (CI: 1,01-1.13)]. Cross-sectional studies demonstrated an association between cardiovascular diseases and Alzheimer's disease [OR = 1.29 (CI: 1.23-1.35)]. Mendelian randomization meta-analysis did not demonstrate a causal relation between cardiovascular disease and Alzheimer's disease [AF: OR = 1.03 (CI: 1.00-1.01) / HF: OR = 1.00 (CI: 0,79-1.36)]. A Mendelian randomization meta-analysis demonstrated that a person with AD had a higher risk of developing myocardial infarction [OR = 1.07 (CI: 1.03-1.10)].

DISCUSSION: This review examines the connection between AD and CVD, noting that HF increases the risk of developing AD with a hazard ratio of 1.63. It suggests that altered brain perfusion and hypoxia appear to be one important neurodegenerative factor. Some genetic changes in individuals with CVD made them more vulnerable to AD. Effective prevention and treatment of CVD can help reduce the risk of AD.

CONCLUSION: HF, AF, and CAD were the CVDs with the highest risk of developing AD. The results suggest that changes in cerebral blood perfusion are a principal neuropathological event that leads to genetic alterations that end in AD.}, } @article {pmid42474014, year = {2026}, author = {Yu, Y and Zhao, H and He, Y and Zhao, J and Yang, X and Liu, X and Cheng, X}, title = {Therapeutic Effects of the Traditional Chinese Formula Qifuyin on Cognition, Lipid Metabolism, and Gut Microbiota in ApoE4 Mice.}, journal = {Combinatorial chemistry & high throughput screening}, volume = {}, number = {}, pages = {}, doi = {10.2174/0113862073453341260621182306}, pmid = {42474014}, issn = {1875-5402}, abstract = {INTRODUCTION: Apolipoprotein E4 (ApoE4) is the strongest genetic risk factor for sporadic Alzheimer's disease (AD). Qifuyin is a promising herbal formula used clinically for cognitive decline, but its effects on ApoE4-associated cognitive and systemic phenotypes remain unclear. This study aimed to evaluate the effects of Qifuyin on cognitive performance in ApoE4 transgenic mice and to preliminarily explore its associations with lipid metabolism and gut microbiota alterations.

METHODS: Ten-month-old ApoE4 transgenic mice were treated with Qifuyin by gavage for 321 days, once daily for the first 123 days and once every two days thereafter. Cognitive function was assessed using the step-down test, novel object recognition test (NORT), and Morris water maze test (MWM). Aging- and frailty-related phenotypes were evaluated using senescence grading scores. Serum triglyceride (TG), high-density lipoprotein cholesterol (HDL-C), and apolipoprotein B (ApoB) levels were measured to assess lipid metabolism. Gut microbiota composition and functional profiles were analyzed by 16S rRNA and metagenomic sequencing.

RESULTS: Qifuyin treatment significantly reduced error counts and prolonged latency in the stepdown test, increased the 24h preference index in the NORT, shortened escape latency, and increased platform crossings in the MWM in ApoE4 transgenic mice. High-dose Qifuyin reduced aging scores in males and in all doses in females and in the pooled dataset. Qifuyin decreased serum TG and ApoB levels, and increased serum HDL-C levels. 16S rRNA sequencing indicated that Qifuyin increased alpha diversity and shifted beta diversity toward the control profile. At the phylum level, Qifuyin altered the relative abundances of Firmicutes, Bacteroidota, Cyanobacteria, and Synergistota. At the family and genus levels, Qifuyin treatment was associated with increased abundances of Helicobacteraceae, Bacteroidaceae, Helicobacter, and Bacteroides, and a reduced abundance of Ruminococcaceae. Metagenomic annotation analysis showed altered abundances of K02003, K06147, COG1961, CBM37, and GH35-related features.

DISCUSSION: These findings suggest that Qifuyin may benefit ApoE4-associated cognitive and systemic dysfunction through its integrated effects on lipid metabolism and gut microbiota alterations. The microbiota-related changes observed in this study may provide a potential link between peripheral metabolic regulation and cognitive improvement, although their mechanistic significance requires further validation.

CONCLUSIONS: Qifuyin improved cognitive performance and lipid metabolism, and was associated with alterations in gut microbiota composition in ApoE4 transgenic mice. These findings suggest that Qifuyin may exert beneficial effects on cognitive and systemic phenotypes in this model, while the biological significance of specific microbial changes warrants further investigation.}, } @article {pmid42474555, year = {2026}, author = {Singh, P and Rath, SL}, title = {Neural network-enhanced investigation of ferroptosis and druggability in early-onset alzheimer's disease.}, journal = {Metabolic brain disease}, volume = {41}, number = {1}, pages = {}, pmid = {42474555}, issn = {1573-7365}, mesh = {*Ferroptosis/physiology/genetics/drug effects ; *Alzheimer Disease/metabolism/drug therapy/genetics ; Humans ; Biomarkers/metabolism ; MicroRNAs/genetics/metabolism ; Oxidative Stress/physiology ; *Neural Networks, Computer ; Machine Learning ; }, abstract = {Alzheimer's disease (AD) is a complex neurodegenerative disorder which is multifactorial in nature. Some of its characteristics are slow cognitive decline, memory problems and behavioral changes. AD patient brains show a progressive synaptic toxicity, autophagy, neuroinflammation, excess generation of reactive oxygen species (ROS), neuronal death and oxidative stress, which occurs due to disrupted metal homeostasis along with tau and amyloid-β protein deposition. Notably, lipid peroxidation, iron buildup and elevated oxidative stress in AD brains suggest a possible molecular connection between ferroptosis and AD neurodegeneration. This study explores the genetic and bioinformatics perspective on the relationship between ferroptosis and AD aiming to identify potential therapeutic potential biomarkers using Neural network (NN) and Machine learning models. Six ferroptosis related genes were found to be differentially expressed in AD. Further machine learning analysis shortlisted four key biomarker genes. An NN-based diagnostic prediction model was developed and validated using AUC-ROC anaysis, which gave high diagnostic values (AUC- 0.92) in the analysis. The findings highlight a strong correlation between ferroptosis and altered metabolic functions in AD. miRNA-gene interaction analysis revealed that two biomarker genes, CYBB and ACSL4 can be regulated by several regulatory miRNAs i.e., hsa-miR-146-5p, hsa-miR-106b-5p, hsa-miR-223-3p, hsa-miR-155-5p, hsa-miR-34a-5p, hsa-miR-125b-5p and hsa-miR-27a-3p suggesting their potential as early diagnostic potential biomarkers. Immune microenvironment analysis revealed strong neuroinflammatory responses in AD with increased infiltration of macrophages (M0, M1 and M2), monocytes and multiple T cell subsets. This heightened immune activity may be driven by ferroptosis-induced oxidative stress contributing to neuronal death. Furthermore, druggability of these targets was evaluated and several drugs were identified that may be potentially repurposed for therapeutic intervention in AD pathogenesis. This study presents a diagnostic predictive model integrating gene expression, miRNA regulation and immune infiltration analysis, offering a novel perspective on early AD detection. The identified ferroptosis-related potential biomarkers and regulatory miRNAs could serve as valuable tools for clinical diagnosis and targeted therapeutic intervention, advancing personalized treatment strategies for Alzheimer's disease.}, } @article {pmid42474734, year = {2026}, author = {Zheng, Y and Bhalala, OG and Chin, KS and Watson, R and Yassi, N}, title = {Use of blood-based neurofilament light chain as an endpoint in clinical trials of neurodegenerative conditions: a scoping review.}, journal = {Journal of neurology}, volume = {273}, number = {8}, pages = {}, pmid = {42474734}, issn = {1432-1459}, mesh = {Humans ; *Neurofilament Proteins/blood ; *Neurodegenerative Diseases/blood/diagnosis ; Biomarkers/blood ; *Clinical Trials as Topic ; }, abstract = {INTRODUCTION: Neurofilament light chain (NfL) is a structural axonal protein measurable in CSF and blood, increasingly investigated as a biomarker of neuroaxonal injury in clinical and research contexts. This review aims to explore the use of blood-based NfL as an endpoint in clinical trials of neurodegenerative conditions.

METHOD: A database search of MEDLINE and EMBASE was conducted to identify interventional clinical trials and/or related post hoc analyses for neurodegenerative diseases, published between 2013 and 2024 that reported the use of serum or plasma NfL as an endpoint. Additional studies from reference lists of included trials were manually considered for inclusion where relevant. Data were charted descriptively by disease type and summarised.

RESULTS: 49 studies were included, 29 in multiple sclerosis (MS), eight in amyotrophic lateral sclerosis (ALS), six in Alzheimer's disease (AD), and six in other diseases. Across studies, reductions in NfL often paralleled improvements in primary efficacy outcomes, supporting its use as a biomarker of disease activity and treatment response. However, several studies demonstrated a lack of concordance between change in NfL and in clinical outcomes, some of which may be related to the non-disease-modifying mechanisms of the interventions studied. This necessitates careful consideration when applying blood-based NfL as a biomarker endpoint for studies involving such interventions.

CONCLUSION: Blood NfL is a promising biomarker with potential utility as a surrogate endpoint in neurological clinical trials, particularly for diseases with active axonal injury. Further validation, particularly around disease- and intervention-specific interpretation, is needed before blood NfL can be incorporated more routinely as a clinical endpoint.}, } @article {pmid42474786, year = {2026}, author = {Kale, D and Dcunha, BV and Lakshmi, S and Raghu, SV and Elumalai, P}, title = {Neuroprotective potential of marine-derived polysaccharide against Aβ42-induced toxicity in a Drosophila Alzheimer's disease model.}, journal = {Molecular biology reports}, volume = {53}, number = {1}, pages = {}, pmid = {42474786}, issn = {1573-4978}, support = {ICMR (2021 - 11092 No. 52/08/2022 BIO/BMS//ICMR/ ; }, mesh = {Animals ; *Polysaccharides/pharmacology/metabolism ; *Alzheimer Disease/metabolism/drug therapy ; *Amyloid beta-Peptides/metabolism/genetics/toxicity ; Oxidative Stress/drug effects ; *Neuroprotective Agents/pharmacology ; Drosophila melanogaster/metabolism ; Disease Models, Animal ; Humans ; Reactive Oxygen Species/metabolism ; Animals, Genetically Modified ; *Peptide Fragments/metabolism ; Antioxidants/pharmacology ; }, abstract = {BACKGROUND: Alzheimer's disease (AD) is a neurodegenerative condition caused by amyloid β (Aβ42) accumulation, neuroinflammation, oxidative stress and cholinergic dysfunction, resulting in neuronal death and cognitive decline. Excessive Aβ42 accumulation disrupts redox equilibrium, increases reactive oxygen species (ROS), and activates inflammatory and apoptotic pathways. Natural bioactive compounds with immunomodulatory and antioxidant properties are increasingly being explored as possible multi-target therapies. Alkylglycerol (AKG), a lipid-derived immunomodulator, and fucoidan, a sulfated polysaccharide found in brown algae, have both shown neuroprotective properties. This study examines the effectiveness of Fucoidan and AKG in preventing Aβ42-induced diseases in a Drosophila melanogaster model, both individually and in combination.

METHODOLOGY: Transgenic Drosophila expressing human Aβ42 in the brain were divided into control, Aβ42, Fucoidan-treated, AKG-treated, and combination-treated groups. Oxidative stress indicators such as nitric oxide (NO), hydrogen peroxide (H2O₂), malondialdehyde (MDA), and total ROS were measured using biochemical tests. To evaluate redox reactions, the activity of the antioxidant enzymes glutathione (GSH), catalase (CAT), and superoxide dismutase (SOD) were evaluated. Cholinergic function was assessed by measuring acetylcholinesterase (AChE) activity. The analysis of gene expression focused on genes linked with oxidative stress (SOD, CAT, PHPGx, TRx1), inflammatory markers (TNFα, TNFαR), apoptotic regulator p53, and neurogenesis-related genes (Wnt pathway, SOX2, Nanog).

RESULTS AND DISCUSSION: Aβ42 expression disrupted neurogenic signaling and cholinergic balance while markedly increasing oxidative markers and inflammatory mediators. Although AKG and fucoidan separately decreased inflammation and oxidative stress, the combination treatment yielded the biggest results. Dual therapy increased the activity of antioxidant enzymes, decreased the activity of AChE, downregulated TNFα and p53, and restored the expression of Wnt, SOX2, and Nanog. These results demonstrate the translational potential of Fucoidan and AKG act for AD care by showing that their combined treatment helps to restore redox stability, suppress inflammation, boost neurogenesis, and mitigate Aβ42-induced neurotoxicity.}, } @article {pmid42475384, year = {2026}, author = {Ma, L and Wang, D and Li, Z and Ye, G and Chen, M}, title = {Exosomal gene-based predictive model and therapeutic target identification for Alzheimer's disease: A bioinformatics analysis.}, journal = {PloS one}, volume = {21}, number = {7}, pages = {e0354014}, doi = {10.1371/journal.pone.0354014}, pmid = {42475384}, issn = {1932-6203}, mesh = {*Alzheimer Disease/genetics/drug therapy/metabolism ; Humans ; *Computational Biology/methods ; Molecular Docking Simulation ; *Exosomes/genetics/metabolism ; Gene Regulatory Networks ; Gene Expression Profiling ; Databases, Genetic ; }, abstract = {BACKGROUND: Alzheimer's disease (AD) is a degenerative central nervous system disorder characterized by progressive cognitive and behavioral impairment. As nanoscale intercellular communication vesicles that carry AD-related pathological molecules, exosomes are promising biomarkers and therapeutic carriers for AD. In this study, we downloaded AD-related gene expression profiles and clinical data from the Gene Expression Omnibus (GEO) database (datasets GSE138260, GSE29378, GSE36980, and GSE5281). Through a series of bioinformatics analyses, clinical predictive model construction, pharmacological network analysis, and molecular docking simulations, we developed an exosomal gene-based predictive model for AD pathogenesis and identified potential pharmacological networks and molecular docking targets for AD treatment.

MATERIALS AND METHODS: AD-related gene expression and clinical data were retrieved from the GEO database. Bioinformatics analyses, clinical model construction, drug-gene network analysis, and molecular docking were subsequently performed to explore exosomal gene models for predicting AD pathogenesis, as well as potential pharmacological networks and molecular docking targets for AD therapy.

RESULTS: A five-exosomal-gene predictive model was established, comprising CD44, CXCR4, TUBB, PSMA5, and PSMB3. Pharmacological network analysis of these five genes revealed their significant associations with chelidonine, 2-chloro-1,4-dinitrobenzene, oxazolone, phencyclidine, thioridazine, and etodolac. Further molecular docking simulations identified key binding targets, including R41, Y42, R78, Y79, C77, I88, C97, A98, I96, I72, L70, E67, G103, I91, and T102.

CONCLUSIONS: Our comprehensive analyses successfully established a reliable exosomal gene-based model for predicting AD pathogenesis, and identified relevant pharmacological networks and core molecular docking targets, providing novel insights for AD diagnosis and targeted therapy.}, } @article {pmid42471071, year = {2026}, author = {Hu, K and Gao, W and Pan, J and Xu, X and You, P and Li, K and Yang, G and Wang, D and Jiang, M and Wang, X and Zhao, Y and Xu, Y}, title = {Ginkgo biloba Extract 50 alleviates memory and synaptic plasticity deficits by inhibiting neuroinflammation via the blockage of ATP-P2X7R axis in presenilin 1/2 conditional double knockout mice.}, journal = {Journal of ethnopharmacology}, volume = {}, number = {}, pages = {122199}, doi = {10.1016/j.jep.2026.122199}, pmid = {42471071}, issn = {1872-7573}, abstract = {Ginkgo biloba L. has been widely utilized in traditional Chinese medicine for its potential to enhance memory-related functions. In traditional medical practices, it is also commonly prescribed for conditions associated with cognitive decline and age-related disorders. These ethnopharmacological uses are closely linked to neurodegenerative disorders, in which neuroinflammation plays a central role. Ginkgo biloba has shown anti-inflammatory and neuroprotective properties, yet its underlying mechanisms in modulating neuroinflammation are still not fully understood.

AIM OF THE STUDY: Neuroinflammation is critically involved in cognitive impairment and neurodegenerative diseases, while therapeutic options remain limited. Ginkgo biloba extract 50 (GBE50) is a standardized formulation with potential neuroprotective properties. This study aimed to assess its effects on neuroinflammation-associated cognitive dysfunction and to clarify the mechanisms involved.

METHODS: Presenilin 1/2 conditional double knockout mice served as a cognitive impairment model, with behavioral tests used to evaluate cognitive function. The constituents of GBE50 were identified by UPLC-Q-TOF-MS, and ATP content was quantified using biochemical assays. The expression of P2X7 receptor, NLRP3 inflammasome-related proteins, inflammatory cytokines, and synaptic markers was determined at both mRNA and protein levels using qRT-PCR and Western blotting. Microglial activation and P2X7R distribution were assessed via immunofluorescence, and hippocampal synaptic plasticity was examined using LTP recordings.

RESULTS: Using UPLC-Q-TOF-MS, 51 compounds were characterized in GBE50, mainly flavonoids and terpene lactones, which are likely responsible for its biological activities. Treatment with GBE50 markedly alleviated cognitive impairment in PS cDKO mice. It downregulated P2X7R and key components of the NLRP3 inflammasome (NLRP3, NEK7, Caspase-1, and ASC), while also reducing the transcription of pro-inflammatory cytokines including Il-1β, Il-18, and Tnf-α. In parallel, GBE50 restored synaptic protein levels and improved long-term potentiation deficits.

CONCLUSION: Collectively, our findings suggest that modulation of the ATP-P2X7R-NLRP3 axis contributes to the neuroprotective effects of GBE50 in AD, highlighting this pathway as a promising therapeutic target for preventing AD-related neurodegeneration.}, } @article {pmid42471087, year = {2026}, author = {Yao, M and Liu, A and Xing, L and Song, J and Yang, Y and Yue, X and Li, H}, title = {Neurovascular unit senescence as a driver of blood-brain barrier dysfunction in Alzheimer's disease：mechanisms, consequences, and therapeutic implications.}, journal = {Ageing research reviews}, volume = {}, number = {}, pages = {103260}, doi = {10.1016/j.arr.2026.103260}, pmid = {42471087}, issn = {1872-9649}, abstract = {Alzheimer's disease (AD) is a common age-related neurodegenerative disorder (NDD), with ageing as its primary risk factor. Cellular senescence, characterized by permanent cell-cycle arrest, apoptosis resistance and acquisition of the senescence-associated secretory phenotype (SASP), is the cellular hallmark of ageing. Recent evidence indicates that blood-brain barrier (BBB) dysfunction precedes cognitive decline and pathological protein deposition, representing an early event in AD, with the neurovascular unit (NVU) providing the structural and functional basis of the BBB. Mounting evidence shows that the core NVU cells-brain microvascular endothelial cells (BMECs), pericytes and astrocytes-enter senescence under AD-related conditions. SASP factors released by these cells disrupt BBB junction proteins and trans-BBB transport systems, and propagate senescence within the NVU via paracrine signaling. Peripheral inflammatory mediators and immune cells then traverse the compromised BBB, aggravating AD pathology, while accumulating Aβ, tau and reactive oxygen species (ROS) reciprocally accelerate NVU senescence, constituting a proposed vicious cycle. At the molecular level, the cGAS-STING pathway concurrently drives senescence maintenance, SASP induction and type I interferon (IFN-I)-mediated downregulation of BBB junction proteins, serving as a key convergence point linking NVU senescence to BBB injury. From the NVU perspective, this review systematically examines how cellular senescence drives BBB dysfunction and AD progression, clarifies the role of cGAS-STING as a molecular node, and discusses therapeutic strategies targeting NVU senescence to preserve BBB integrity, aiming to offer new insights into AD mechanisms and treatment.}, } @article {pmid42471719, year = {2026}, author = {Yamada, K and Ishida, K and Sakamoto, A and Shimada, H and Watanabe, M and Shimojo, M and Igarashi, H and Iwatsubo, T}, title = {AQP4-dependent enhancement of glymphatic function attenuates tau pathology and neurodegeneration in PS19 mice.}, journal = {Molecular neurodegeneration}, volume = {}, number = {}, pages = {}, doi = {10.1186/s13024-026-00977-7}, pmid = {42471719}, issn = {1750-1326}, support = {JP23wm0625001//AMED/ ; 23H0279//Japan Society for the Promotion of Science/ ; 25K10766, 20K21568, 18H02762//Japan Society for the Promotion of Science/ ; 2023-23012//Niigata University/ ; }, abstract = {BACKGROUND: The glymphatic system facilitates cerebrospinal fluid-interstitial fluid exchange and contributes to the clearance of pathogenic proteins from the brain. Glymphatic dysfunction has been associated with Alzheimer's disease and related tauopathies; however, whether impaired glymphatic transport causally drives tau accumulation and neurodegeneration, and whether its enhancement confers therapeutic benefit, remains unclear.

METHODS: Glymphatic water dynamics in PS19 tau transgenic mice were assessed using JJVCPE, a novel MRI-based approach for evaluating brain water exchange. The effect of pharmacological activation of aquaporin-4 (AQP4) with TGN-073 on glymphatic cerebrospinal fluid influx was examined in wild-type mice using dynamic contrast-enhanced MRI. Tau pathology, neurodegeneration, and cerebrospinal fluid tau levels were analyzed in PS19 mice following chronic TGN-073 treatment. AQP4-deficient PS19 mice were examined to determine target specificity.

RESULTS: PS19 mice exhibited significant impairment of glymphatic water exchange at early disease stages, which progressively worsened with ageing. Pharmacological activation of AQP4 with TGN-073 robustly enhanced glymphatic-related tracer influx, reduced tau accumulation, neuronal loss, and gliosis, and was accompanied by increased cerebrospinal fluid tau levels. TGN-073 also restored perivascular AQP4 enrichment without significantly altering overall AQP4 abundance. Importantly, these beneficial effects were abolished in AQP4-deficient PS19 mice, demonstrating that both glymphatic enhancement and suppression of tau pathology and neurodegeneration are AQP4-dependent.

CONCLUSIONS: Our findings support a mechanistic contribution of impaired glymphatic function to tau accumulation and neuronal vulnerability in tauopathy. Pharmacological activation of AQP4 enhances glymphatic function, restores perivascular AQP4 organization, and ameliorates tau pathology, neurodegeneration, and gliosis. These findings identify AQP4-mediated glymphatic modulation as a disease-relevant and therapeutically tractable pathway for tau-related neurodegenerative disorders.}, } @article {pmid42471753, year = {2026}, author = {Travison, TG and Davis-Plourde, K and Goldfeld, KS and Li, F and Lou, Y and Monin, JK and Taljaard, M and Turner, J and Vranceanu, AM and Allore, HG}, title = {The design of embedded pragmatic clinical trials: methodological developments and statistical lessons learned from the first cycle of the NIA IMPACT collaboratory.}, journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association}, volume = {22}, number = {7}, pages = {e71660}, doi = {10.1002/alz.71660}, pmid = {42471753}, issn = {1552-5279}, support = {U54AG063546/NH/NIH HHS/United States ; }, mesh = {Humans ; *Pragmatic Clinical Trials as Topic/methods ; *Research Design ; United States ; National Institute on Aging (U.S.) ; *Alzheimer Disease/therapy ; }, abstract = {INTRODUCTION: The National Institute on Aging-funded IMbedded Pragmatic Alzheimer's disease and AD-Related Dementias Clinical Trials (IMPACT) Collaboratory was established to build capacity for conducting embedded pragmatic clinical trials (ePCTs) within healthcare systems for people living with dementia and their care partners. Here we present methodology and describe lessons learned from the first five years of IMPACT's Design and Statistics Core (DSC).

METHODS: The DSC assembled a multidisciplinary team focused on advancing the design, analysis, and implementation of ePCTs.

RESULTS: The DSC developed and disseminated methods for design and sample size of cluster randomized designs with complex correlation structures; guidance for pilot ePCTs; approaches to patient-care partner ePCTs; approaches to testing health-equity-relevant hypotheses; and guidance for training quantitative and clinical scientists developing ePCTs.

DISCUSSION: Key gaps remain in applying dyadic designs and when studying heterogeneity of treatment effects, which will be major priorities for the next funding cycle.}, } @article {pmid42471754, year = {2026}, author = {Xia, CA and Salarian, M and Gartshore, CJ and Scaglione, A and Hayes, T and Liu, S and Tsai, HM and Echavarren, J and Cid, JM and Matzeu, A and Szardenings, AK}, title = {Development and characterization of a novel TDP-43 positron emission tomography tracer: [[18]F]JNJ-TDP43-1.}, journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association}, volume = {22}, number = {7}, pages = {e71675}, doi = {10.1002/alz.71675}, pmid = {42471754}, issn = {1552-5279}, support = {//Johnson & Johnson/ ; }, mesh = {Animals ; *Positron-Emission Tomography/methods ; *DNA-Binding Proteins/metabolism ; *Brain/diagnostic imaging/metabolism ; Rats ; Mice ; Humans ; Male ; Disease Models, Animal ; TDP-43 Proteinopathies/diagnostic imaging ; *Radiopharmaceuticals/pharmacokinetics ; Fluorine Radioisotopes ; }, abstract = {INTRODUCTION: Neurodegenerative disorders, including amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), limbic-predominant age-related TDP-43 encephalopathy (LATE), and Alzheimer's disease (AD) are associated with TAR DNA-binding protein 43 (TDP-43) pathology. A positron emission tomography (PET) tracer targeting TDP-43 aggregates could improve early diagnosis and guide treatment development for TDP-43-related conditions.

METHODS: Specific binding was evaluated using fluorescent labeling of compound, surface plasmon resonance (SPR), and autoradiography (ARG). Brain PET imaging in rats, nonhuman primate (NHP), and a disease mouse model was performed to characterize tracer pharmacokinetics and in vivo target binding.

RESULTS: JNJ-TDP43-1 exhibited high binding affinity for pathological TDP-43 (Kd = 7.1 nM) and remarkable selectivity over other proteinopathies. PET imaging demonstrated robust brain uptake and rapid washout in rodents and NHP. In vivo target engagement was confirmed in an AAV-hTDP43 disease model.

DISCUSSION: [[18]F]JNJ-TDP43-1 is a promising PET ligand for early diagnosis and evaluating therapies in TDP-43-related diseases.}, } @article {pmid40536954, year = {2026}, author = {Hu, M and Yi, H and Wang, S and Kang, X and Liu, Y and Liu, Z and Huang, H and Qin, Q and Yuan, L and Cai, W and Qiu, W and Lu, Z and Liu, S}, title = {Bone marrow mesenchymal stem cells protect against cerebral amyloid angiopathy by enhancing neutrophil mitocytosis.}, journal = {Neural regeneration research}, volume = {21}, number = {7}, pages = {3178-3186}, pmid = {40536954}, issn = {1673-5374}, abstract = {Current treatments for cerebral amyloid angiopathy are mainly symptomatic and have limited efficacy, and there is a lack of targeted therapies. Mesenchymal stem cell transplantation improves cognitive and motor function in conditions such as Alzheimer’s disease, acute ischemic stroke, and Parkinson’s disease. In addition, mesenchymal stem cell therapy modulates the immune system, reduces neuroinflammation, and improves resolution of brain lesions by cells of the macrophage lineage. Cerebral amyloid angiopathy and Alzheimer’s disease share similar pathologic changes involving amyloid-beta deposition, which contributes to the progression of both diseases and exacerbates cognitive deficits through impaired vascular integrity and neuroinflammation. Therefore, we hypothesized that mesenchymal stem cell therapy could also ameliorate the pathological changes seen in cerebral amyloid angiopathy by modulating the immune response. In this study, we show that bone marrow mesenchymal stem cells have a protective effect in a mouse model of cerebral amyloid angiopathy (Tg-SwDI/B). Bone marrow mesenchymal stem cell treatment improved cognitive function, reduced neuroinflammation, and maintained blood–brain barrier integrity in Tg-SwDI/B mice. Mechanistically, bone marrow mesenchymal stem cell treatment enhanced the expulsion of damaged mitochondria from neutrophils via migrasomes, in a process known as mitocytosis, thereby preserving mitochondrial quality within the neutrophils. Mitochondrial damage in neutrophils leads to cellular injury, including the generation of reactive oxygen species and the formation of neutrophil extracellular traps. Neutrophils activate mitocytosis to promote mitochondrial renewal, which further enhances their own clearance by macrophage lineage cells. Our findings demonstrate that bone marrow mesenchymal stem cells are a promising therapeutic candidate for cerebral amyloid angiopathy, as they play a significant role in migrasome-dependent mitochondrial quality control in neutrophils.}, } @article {pmid42468111, year = {2026}, author = {Bittner, T and Lopera, F and Rios-Romenets, S and Schiffman, C and Clayton, D and Hibar, D and Kollmorgen, G and Dolton, M and Poon, V and Nguyen, J and Giraldo-Chica, M and Acosta-Baena, N and Espinosa, A and Villegas, G and Muñoz, C and Serna, L and Alvarez, S and Protas, H and Luo, J and Sohankar, J and Chen, Y and Ghisays, V and Malek-Ahmadi, M and Ashton, NJ and Denkinger, MN and Cai, Y and Xu, YR and Ostaszewski, B and Selkoe, DJ and Alexander, RC and Quiroz, YT and Su, Y and Chen, K and Doody, RS and Langbaum, JB and Tariot, PN and Sink, KM and Reiman, EM}, title = {Baseline and placebo-related imaging, cerebrospinal fluid, plasma biomarker, and cognitive findings in unimpaired PSEN1 E280A mutation carriers and non-carriers in the Alzheimer's Prevention Initiative Autosomal Dominant Alzheimer's Disease Colombia Trial.}, journal = {EBioMedicine}, volume = {130}, number = {}, pages = {106390}, doi = {10.1016/j.ebiom.2026.106390}, pmid = {42468111}, issn = {2352-3964}, abstract = {BACKGROUND: The Alzheimer's Prevention Initiative Autosomal Dominant Alzheimer's Disease (ADAD) Colombia Trial evaluated the biological, cognitive, and clinical effects of crenezumab, an anti-oligomeric and monomeric amyloid-beta (Aβ) monoclonal antibody, in 30-60-year-old PSEN1 E280A mutation carriers without cognitive impairment from the world's largest ADAD kindred, finding no significant treatment effects on Alzheimer's disease progression. This article describes baseline biomarker, cognitive, and clinical measurements and placebo-related longitudinal changes in the randomised prevention trial's mutation carrier and non-carrier groups.

METHODS: Crenezumab and placebo-treated mutation carriers and placebo-treated non-carriers were assessed using amyloid and fluorodeoxyglucose positron emission tomography (PET), magnetic resonance imaging, plasma, and optional tau PET and cerebrospinal fluid (CSF) biomarker, cognitive, and clinical measurements over 5-8 years.

FINDINGS: 94% of the 252 kindred members (85 crenezumab-treated mutation carriers, 84 placebo-treated carriers, and 83 placebo-treated non-carriers) completed the trial. 55% of the carriers had baseline PET evidence of substantial Aβ plaques. 32.9% and 6.8% of amyloid PET-positive and PET-negative carriers, respectively, 36.5%, 13.2%, and 0% of pTau217-positive, pTau217-intermediate, and pTau217-negative carriers, respectively, and no non-carriers became cognitively impaired over the next 5 years. Carriers were distinguished from non-carriers by several baseline and longitudinal Aβ, tau, neurodegenerative, and inflammatory biomarker measures, but not by CSF oligomeric Aβ measurements.

INTERPRETATION: Despite the absence of significant treatment effects, these findings and the trial itself continue to inform the course of preclinical ADAD, advance Alzheimer's disease prevention research, and provide a shared resource of data and samples for the field (ClinicalTrials.gov ID: NCT01998841; trial completed).

FUNDING: National Institute on Aging, Banner Alzheimer's Institute, Genentech, Inc., and F. Hoffmann-La Roche Ltd.}, } @article {pmid42468644, year = {2026}, author = {Li, M and Zhao, Y and Xu, B and Wang, L and Luo, W and Tan, R and Zhang, X and Jiang, H}, title = {Polygonatum sibiricum polysaccharides and Alzheimer's disease: A review of preparation, structure, mechanisms, and application.}, journal = {Fitoterapia}, volume = {}, number = {}, pages = {107393}, doi = {10.1016/j.fitote.2026.107393}, pmid = {42468644}, issn = {1873-6971}, abstract = {Polygonatum sibiricum is a well-established botanical resource with dual medicinal and edible applications. Polygonatum sibiricum polysaccharides (PSP), the principal bioactive constituent of P. sibiricum, have long attracted research interest due to their structural diversity and broad spectrum of biological activities. Beyond its well-documented antioxidant, antibacterial, anti-inflammatory, antitumor, and anti-aging properties, PSP has recently demonstrated promising therapeutic potential in alleviating Alzheimer's disease (AD). However, current research findings on PSP remain fragmented, and a comprehensive framework elucidating the specific mechanisms by which it ameliorates AD is lacking. Based on this, this review begins with the extraction, isolation, purification, and structural characterization of PSP, systematically summarizes the multiple mechanisms by which PSP ameliorates AD, and provides an overview of its structural modification, toxicological studies, and multi-domain applications, aiming to offer theoretical support for the further development and translational application of PSP in the prevention and treatment of AD.}, } @article {pmid42469568, year = {2026}, author = {Kaushik, S and Fatima, JE and Raheem, A and Barbhuiya, MA and Thirupathi, AT and Singh, LP and Khan, PA and Aparna, TN and Pramanik, S and Shahid, MAA}, title = {Nanomedicine targeting neuroinflammatory pathways in Alzheimer's disease: a new frontier in inflammopharmacology.}, journal = {Inflammopharmacology}, volume = {}, number = {}, pages = {}, pmid = {42469568}, issn = {1568-5608}, abstract = {Alzheimer's disease (AD) is a multifactorial neurodegenerative illness characterized by progressive cognitive impairment, synaptic compromise, and relentless neuroinflammation. Increasing evidence suggests that neuroinflammatory cascades orchestrated by microglial activation, astrocytic malfunction, cytokine hyperproduction, and inflammasome signalling are at the core of AD pathogenesis. Conventional anti-amyloid and cholinergic treatments are only symptomatic and neglect the inherent neuroimmune dysregulation. Nanomedicine is a revolutionary frontier in inflammopharmacology, which enables the accurate modulation of neuroinflammatory circuits and enhanced brain delivery of medicines. Nanocarriers designed by engineering, including liposomes, polymeric nanoparticles, dendrimers, and exosomes, allow for targeted delivery across the BBB, increase drug bioavailability, and provide controlled release. The nano-systems are capable of inhibiting pro-inflammatory signalling, such as NF-κB and MAPK pathways, reducing oxidative stress, and enhancing microglial M2 polarization and thus restoring neuronal homeostasis. Recent developments in surface-functionalized and stimuli-responsive nanoplatforms further enable active targeting through receptor-mediated pathways and theranostic imaging in real-time. Comparative studies show that interventions based on nanocarrier-based therapies enhance therapeutic efficacy and safety profiles in preclinical AD models. Future directions include integrating AI-driven nano-design, gene and siRNA delivery, and precision neuropharmacology to enable personalized anti-inflammatory therapies. Substantial progress, translational challenges remain regarding long-term biocompatibility, large-scale production, and clinical validation. Nanomedicine against neuroinflammatory pathways represents a new paradigm for Alzheimer's treatment, linking molecular pharmacology and sophisticated nanotechnology to next-generation neuroinflammatory medicine.}, } @article {pmid42470923, year = {2026}, author = {Aydoğdu, GS and Ağagündüz, D and Roviezzo, F and Romano, B and Capasso, R}, title = {Therapeutic potential of curcumin in Alzheimer's disease: Multi-target mechanisms of action, experimental and clinical evidence, safety aspects.}, journal = {Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie}, volume = {202}, number = {}, pages = {119776}, doi = {10.1016/j.biopha.2026.119776}, pmid = {42470923}, issn = {1950-6007}, abstract = {Alzheimer's disease is a neurodegenerative disorder characterized by memory loss and impaired cognitive functions; its prevalence is increasing with the growth of the global elderly population. Unfortunately, early diagnostic and treatment methods developed by modern medicine have limited effectiveness for this disease. This situation has increased interest in natural ingredients, such as curcumin, which have beneficial effects on health. Some preclinical studies evaluating the efficacy of curcumin in Alzheimer's disease suggest that it may have preventive, protective, and therapeutic effects through various mechanisms, including anti-amyloidogenic effects, improvement of tau pathology, cholinesterase inhibition, anti-inflammatory and antioxidant effects, metal chelation, microbiota modulation, and epigenetic regulation. Similarly, some preclinical studies indicate that curcumin-based probes may offer a promising approach to the diagnosis of Alzheimer's disease. However, inconsistencies exist between preclinical and clinical studies. Curcumin's low bioavailability and high systemic elimination may be among the most significant causes of these inconsistencies. It is also thought that this situation may be related to differences and limitations in preclinical and clinical study designs. There is a need for preclinical studies that follow comprehensive, standardized protocols and for larger-scale, long-term, well-designed clinical trials to evaluate the effectiveness of curcumin in the early diagnosis, prevention, and treatment of Alzheimer's disease. In addition, potential risks, such as the toxicological effects of curcumin with increased bioavailability and curcumin-drug interactions in Alzheimer's patients, should be evaluated.}, } @article {pmid42462262, year = {2026}, author = {Liang, S and Lapane, KL and Ott, BR and Tjia, J and Baek, J and Yuan, Y and Alcusky, M}, title = {Comparing Effectiveness of Antidepressants for Nursing Home Residents With Dementias and Depressive Symptoms.}, journal = {Journal of the American Geriatrics Society}, volume = {}, number = {}, pages = {}, doi = {10.1111/jgs.70582}, pmid = {42462262}, issn = {1532-5415}, support = {5R01AG068450/AG/NIA NIH HHS/United States ; }, abstract = {BACKGROUND: Alzheimer's disease and related dementias (ADRD) are frequently accompanied by depressive symptoms, which may accelerate cognitive decline and increase mortality. Antidepressants, particularly selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs), are commonly prescribed, yet comparative effectiveness evidence in nursing home residents with ADRD is scarce.

METHODS: We conducted a retrospective cohort study using linked CMS data (2011-2018) of long-stay nursing home residents aged ≥ 65 years with ADRD and baseline depressive symptoms who newly initiated an SSRI or SNRI. Depressive symptoms were measured with the Patient Health Questionnaire-9 (PHQ-9; self-report or observed) at baseline and 60-120 days after initiation. Outcomes were the change in PHQ-9 scores (continuous) and clinically meaningful improvement. Analyses used overlap propensity score and inverse probability of censoring weighted linear and log-binomial models with generalized estimating equations to account for clustering of nursing home residents. Intention-to-treat (ITT) analyses, as-treated, and subgroup analyses were conducted.

RESULTS: Among 19,397 SSRI initiators and 2581 SNRI initiators, 66.9% had mild depressive symptoms at baseline. Median time from initiation to follow-up assessment was 85 days. In ITT analyses, mean PHQ-9 change was -2.38 for SSRIs and -2.24 for SNRIs (adjusted difference: -0.15; 95% CI, -0.42 to 0.11); clinically meaningful improvement occurred in 55.2% versus 56.9% (risk difference: -1.57; 95% CI, -3.66 to 0.52). As-treated analyses yielded similar results, and findings were consistent across subgroups defined by baseline depression severity, cognitive function, dementia type, and sensitivity analyses.

CONCLUSIONS: SSRIs and SNRIs were similarly effective for depressive symptoms in nursing home residents with ADRD. Given this and modest improvement rates, antidepressant selection should be individualized, emphasizing safety and resident characteristics. Additional research is needed to inform the decision to treat or not to treat, specific medication selection, and when to stop treatment in this population.}, } @article {pmid42462433, year = {2026}, author = {Bernardes, LMM and Marquez, AS and do Prado Mascarenhas, FNA and de Freitas, LF and Ferreira, DC and Malta, SM and Moreira, AS and Mendonça, TP and Bernardo de Sousa, JN and Silva, ÍF and Correia, LIV and Martins, MM and Ferreira, RB and Zhu, A and Zhang, H and Adebiyi, O and Leung, AK and Espindola, FS and Leite, ML and Ueira-Vieira, C and Mendes-Silva, AP}, title = {Acetonic extract of Saskatoon berry attenuates amyloid-associated neurotoxicity in cellular and Drosophila melanogaster Alzheimer's disease models.}, journal = {Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie}, volume = {202}, number = {}, pages = {119774}, doi = {10.1016/j.biopha.2026.119774}, pmid = {42462433}, issn = {1950-6007}, abstract = {Saskatoon berry (Amelanchier alnifolia) is rich in polyphenols known to modulate oxidative stress and neuroinflammation, key mechanisms involved in Alzheimer's disease (AD), yet its neuroprotective potential in this context remains unexplored. Here, we investigated two Saskatoon berry extracts, acetonic and ethanolic, using integrated chemical, computational, cellular and in vivo approaches. Antioxidant activity was confirmed in multiple assays, with stronger radical scavenging and moderate reducing capacity. Chemical profiling revealed solvent-dependent differences in phenolic and flavonoid content. In neuroglial models, the ethanolic extract showed mild-cytotoxicity, whereas the acetonic extract exhibited a favorable safety profile. In an amyloid-beta-induced cellular model, the acetonic extract produced only modest effects on viability. Furthermore, fibroblasts assays showed increased total ATP under non-inflammatory conditions, whereas in the LPS-stimulated inflammatory model the extract increased mitochondrial membrane potential. In contrast, in vivo studies using Drosophila melanogaster AD models showed protective effects of the acetonic extract, including reduced ThT-reactive fluorescence and increased retinal thickness, while improved survival was observed in w[1118] flies. Gene expression analysis of flies' brain tissue showed altered expression of selected mitochondrial- and immune-related genes. The AD-like model showed increased expression of co1, nd1, tfam and dipt, which were significantly reduced following treatment. Overall, these findings identify Saskatoon berry as a novel natural source of bioactive compounds with anti-Alzheimer's potential and suggest that the in vivo protective effects may involve mitochondrial homeostasis and immune-related processes, warranting future mechanistic studies and neuronal-specific validation in more complex organisms.}, } @article {pmid42463411, year = {2026}, author = {Shi, Y and Liao, X and Yu, G}, title = {Advances in Tricyclic Compounds for the Treatment of Alzheimer's Disease.}, journal = {ChemMedChem}, volume = {21}, number = {14}, pages = {e70384}, doi = {10.1002/cmdc.70384}, pmid = {42463411}, issn = {1860-7187}, mesh = {Humans ; *Alzheimer Disease/drug therapy/metabolism ; *Neuroprotective Agents/chemistry/pharmacology/therapeutic use ; Structure-Activity Relationship ; Animals ; *Cholinesterase Inhibitors/chemistry/pharmacology ; Molecular Structure ; Oxidative Stress/drug effects ; }, abstract = {Alzheimer's disease (AD) is a complex neurodegenerative disorder involving interconnected pathological pathways, including cholinergic dysfunction, Aβ deposition, tau hyperphosphorylation, neuroinflammation, oxidative stress, and dysregulation of metal ion homeostasis. Recently, the "one drug, one target" paradigm has faced certain clinical limitations, driving a paradigm shift toward multi-target therapeutic strategies. In this context, tricyclic scaffolds, characterized by rigid fused-ring skeletons, excellent structural tunability, and favorable neuropharmacological properties, have emerged as promising scaffolds for developing multi-target AD therapeutics. These molecules can interact with multiple AD-related targets through stable π-π stacking and hydrophobic interactions. Some tricyclic scaffolds, such as tetrahydrocarbolines, share structural similarity with endogenous neurotransmitters, suggesting potential involvement in modulating cognitive and mood-related pathways, along with favorable BBB permeability and neuro-compatibility. Accordingly, this review begins by outlining the distinct pathological mechanisms underlying AD, followed by a summary of recent progress on tricyclic compounds, encompassing both single-target and multi-target-directed molecules, with an emphasis on structure-activity relationships and mechanisms of action, aiming to offer new insights and strategies for combating this devastating disease.}, } @article {pmid42464289, year = {2026}, author = {Zhan, X and Liu, C and Yu, C and Lindblom, N and Deierborg, T and Kobro-Flatmoen, A and Gouras, GK and Wen, G}, title = {Passive amyloid-β immunotherapy in Alzheimer's disease: a multicellular clearance system beyond plaque removal.}, journal = {Molecular neurodegeneration}, volume = {21}, number = {1}, pages = {}, pmid = {42464289}, issn = {1750-1326}, mesh = {*Alzheimer Disease/therapy/immunology ; Humans ; *Amyloid beta-Peptides/immunology/metabolism ; Animals ; *Plaque, Amyloid/immunology/therapy ; *Immunotherapy/methods ; *Immunization, Passive/methods ; Brain/metabolism ; }, abstract = {Passive immunotherapy targeting amyloid-β (Aβ) has emerged as a major therapeutic strategy for Alzheimer's disease (AD), yet its clinical benefits remain modest and are frequently accompanied by vascular adverse events such as amyloid-related imaging abnormalities (ARIA). While the removal of extracellular Aβ plaques is associated with therapeutic efficacy, accumulating evidence suggests that additional cellular and vascular mechanisms may also contribute to complementary therapeutic outcomes alongside plaque removal. Recent studies show that Aβ antibodies are broadly distributed within the brain and interact with multiple neural and immune cell populations, rather than being limited to Aβ plaques. These observations support an expanded view of passive Aβ immunotherapy as a multicellular coordinated clearance process. Aβ antibodies engage diverse cellular and anatomical compartments, including neurons, glial cells, perivascular macrophages, peripheral immune cells, and meningeal lymphatic pathways, thereby influencing Aβ dynamics across intracellular and extracellular pools. Within this framework, therapeutic outcomes are influenced not only by plaque clearance but also by interactions between Aβ antibodies and cellular and anatomical compartments that regulate Aβ clearance and treatment-associated vascular response. This perspective may help explain variability in clinical efficacy and the emergence of vascular side effects, while also providing additional considerations for optimizing Aβ antibody design and therapeutic strategies.}, } @article {pmid42465724, year = {2026}, author = {Zhang, C and Song, D}, title = {Implications of autolysosome- astrocyte-associated signature in the pathogenesis of Alzheimer's disease: evidence from artificial intelligence and multi-omics and clinical validation.}, journal = {Frontiers in neuroscience}, volume = {20}, number = {}, pages = {1867831}, pmid = {42465724}, issn = {1662-4548}, abstract = {BACKGROUND: Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by amyloid-beta plaques and neurofibrillary tangles. Dysfunctional cellular clearance mechanisms, particularly autophagy-lysosomal pathways, and reactive astrocytosis are prominent pathological features, yet their interrelationship remains poorly defined.

OBJECTIVE: This study aimed to decipher a novel co-expression molecular signature linking autolysosomal dysfunction and astrocyte reactivity in AD pathogenesis.

METHODS: We performed Limma, WGCNA and Xcell algorithms in AD patient hippocampus bulk profiles for enrichment of astrocyte and autolysosome (AA)-associated DEGs. Next, explainable machine learning and consensus clustering enables the identification of AA-associated diagnostic model and molecular subgroups for AD patients at bulk level. Besides, AA-associated central pathogenic factor was identified, and its corresponding biological implications for AD were assessed at AD patient hippocampus single-cell level in temporal and spatial manners. Next deep learning algorithm (Drugreflector) and molecular docking enriched natural compounds for the treatment of AD by targeting AA-associated hub gene. Finally, AD clinical peripheral blood samples were collected for estimation of hub gene expression patterns.

RESULTS: 5 AA-associated shared DEGs can elaborate diagnostic and patient stratification capacity for AD patients. HMGCR can be considered as astrocyte-distributed central pathogenic and Berberine-oriented therapeutic target for AD patients.

CONCLUSION: Our findings unveil AA-associated diagnostic model and molecular subgroups coupled with HMGCR center pathogenic and druggable role in AD, which represents an actionable clinical target for AD patients.}, } @article {pmid42466122, year = {2026}, author = {Liang, X and Ning, T and Wang, Y and Zhan, L}, title = {Integrating serum pharmacology, network pharmacology, and molecular biology analysis to reveal the mechanisms of Baihe Dihuang decoction in treating Alzheimer's disease.}, journal = {Frontiers in microbiology}, volume = {17}, number = {}, pages = {1765044}, pmid = {42466122}, issn = {1664-302X}, abstract = {AIM: This study aimed to evaluate the potential neuroprotecive effects of Baihe Dihuang Decoction (BDD) in APP/PS1 double-transgenic (TG) mice and to investigate the role of the gut-brain axis (GBA) using an integrated approach combining serum pharmacology, network pharmacology, and molecular biology.

MATERIALS AND METHODS: The blood-borne bioactive components of BDD were initially identified using UPLC-Q-Orbitrap HRMS. Subsequently, network pharmacology was employed to prioritize key therapeutic targets and elucidate the primary pathways underlying the anti-Alzheimer's disease (AD) effects of BDD. The neuroprotective efficacy of BDD in TG mice was systematically evaluated using the morris water maze (MWM) test, histopathological observation (HE staining), transmission electron microscope (TEM) test, and ELISA-based inflammatory cytokine assays. The potential mechanisms were further elucidated by integrating network pharmacology with 16S ribosomal RNA (16S rRNA) sequencing. Finally, molecular docking and Western blotting (WB) were performed to validate the interactions within the identified pathways.

RESULTS: A total of 49 BDD-derived compounds were identified in serum samples. Network pharmacology revealed 116 common targets of BDD against AD. Remarkably, KEGG analysis highlighted 57 signaling pathways potentially involved in the anti-AD effects of BDD. Pharmacodynamic analysis showed that BDD ameliorated cognitive impairment in TG mice, mitigated pathological damage, and suppressed the release of IL-6, IL-1β, and TNF-α in the colon, brain, and serum. Moreover, 16S rRNA sequencing indicated that BDD modulated gut microbiota (GM) structure and restored intestinal flora imbalance in TG mice. Integrative analysis of network pharmacology and GM analysis identified several Key pathways (FoxO, MAPK, PI3K-Akt, HIF-1, Th17, IL-17, and Toll/Imd) and core anti-AD targets (TLR4, PTGS2, SIRT1, BDNF, NF-κB, STAT3, JAK2, EGFR, GSK3β, and CD86). Molecular docking results showed that the five complexes with the lowest docking scores (TLR4-salidroside, NF-κB-glabranin, TRKB-alantolactone, PTGS2-3'_4'_dihydroxyflavone, and SIRTI-abietic acid) exhibited strong binding affinity. QSAR and WB analyses further demonstrated the modulatory effects of BDD on these five core targets.

CONCLUSION: This study demonstrated that BDD effectively restored GM structure and ameliorated cognitive impairment in TG mice, thereby exerting therapeutic effects against AD. These findings support BDD as a potential traditional Chinese medicine (TCM) strategy for AD treatment.}, } @article {pmid42467190, year = {2026}, author = {Siriwattanasathien, Y and Yotmanee, P and Lehboon, K and Chokchaisiri, R and Nunparn, K and Chunglok, W and Suksamrarn, A}, title = {Isolation, modification, structure-activity relationship (SAR) and molecular docking studies of isoflavones from Derris scandens as potent dual AChE/BuChE inhibitors.}, journal = {Medicinal chemistry research : an international journal for rapid communications on design and mechanisms of action of biologically active agents}, volume = {}, number = {}, pages = {}, pmid = {42467190}, issn = {1554-8120}, support = {Contract No. 10/2025//Walailak University Graduate Scholarship/ ; DBG6180030//The Thailand Research Fund/ ; }, abstract = {The stems of Derris scandens are rich sources of isoflavonoids including a new isoflavone and nine known isoflavones. Some isolated isoflavones exhibited considerable acetyl cholinesterase (AChE) and butyryl cholinesterase (BuChE) inhibitory activities. Preliminary SAR studies have indicated that one of the essential structural requirements for a 5,7,4'-trioxygenated isoflavone to exhibit high ChE inhibitory activities is the presence of prenyl group(s). Structural modifications of the isoflavone 5 to ester and ether derivatives did not enhance the ChE inhibitory potential. Molecular docking studies have indicated that, if the isoflavone structure is more flexible, the better binding of isoflavone molecule to the receptor should be achieved. The more flexible dihydro analog of the prenyl moiety was therefore prepared from the isoflavone 5 to give corresponding dihydro analog 19 and the tetrahydro analog 20. It was found that the dihydro analog 19 was the most active analog for AChE and BuChE inhibitions, with the IC50 values of 0.41 ± 0.07 µM and 0.64 ± 0.01µM, respectively. It was 3.3- and 4.8-fold, respectively, more active than galanthamine. In addition, the dihydro analog 19 exhibited lower cytotoxicity toward Vero and RAW 264.7 cells than the isoflavone 5. Molecular docking studies indicated that 19 could simultaneously interact with the PAS, AS and CT of AChE and BuChE. The presence of an isopentyl group on isoflavone ring B is necessary for the dihydro analog to exhibit anti-ChE activity. Hence, an isoflavone with an isopentyl group on ring B, a prenyl group on ring A and suitable hydroxy groups on the aromatic ring could be a possible lead candidate for a dual-target-directed ligand for the treatment of Alzheimer's disease.}, } @article {pmid42467293, year = {2026}, author = {Hassan, MA and Al Amin, M and Sweilam, SH and Abohassan, M and Krishnan, K and Gupta, JK and Jahnavi, P and Vodeti, R and Radha, R and Gupta, PS and Reddy, KTK}, title = {Resveratrol and neuroprotection: modulation of cellular dynamics and signaling networks in neurodegenerative diseases.}, journal = {Inflammopharmacology}, volume = {}, number = {}, pages = {}, pmid = {42467293}, issn = {1568-5608}, abstract = {Progressive loss of neurons, oxidative stress, neuroinflammation, and mitochondrial dysfunction are hallmarks of neurodegenerative diseases (NDs), such as Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), and amyotrophic lateral sclerosis (ALS). Resveratrol, a polyphenolic phytoalexin mainly found in grapes and red wine, is a promising treatment candidate due to its diverse biological effects and neuroprotective properties. This review demonstrates the regulatory effects of resveratrol on cellular signaling pathways linked to NDs and its neuroprotective mechanisms. Resveratrol enhances neuronal survival, boosts mitochondrial biogenesis, and mitigates oxidative stress by affecting key molecular pathways, including SIRT1/AMPK, PI3K/Akt, MAPK, and Nrf2/ARE. The PI3K/Akt and ERK1/2 pathways promote neuronal regeneration by modulating pro-apoptotic and anti-apoptotic factors. Resveratrol inhibits NF-κB, reducing cytokine release and microglial activation, thereby exhibiting anti-inflammatory properties. It improves cognitive function, synaptic plasticity, and neuronal survival. Despite an increasing pharmacological profile, its practical applicability is limited by inadequate bioavailability, rapid metabolism, and restricted brain penetration. This review demonstrates resveratrol's effect on interconnected signaling networks related to neurodegeneration. We critically compare evidence from preclinical and clinical studies, demonstrating both therapeutic potential and translational limitations. Emerging nanotechnology-based delivery strategies are demonstrated to overcome bioavailability and blood-brain barrier penetration challenges. These insights provide a translational perspective for the future development of resveratrol-based interventions in NDs.}, } @article {pmid42467931, year = {2026}, author = {Kim, Y and Lee, G and An, S and Park, H and Kim, H and Kim, J and Kang, S and Kim, S and Kwon, D and Park, J and Hwang, Y and Kim, S and Yuan, X and Jeong, J and Lee, H and Kim, HK and Kim, J}, title = {Therapeutic Gene Editing of APOE4 in Sporadic Alzheimer's Disease via Prime Editor 7.}, journal = {Advanced science (Weinheim, Baden-Wurttemberg, Germany)}, volume = {}, number = {}, pages = {e76658}, doi = {10.1002/advs.76658}, pmid = {42467931}, issn = {2198-3844}, support = {NRF-2022R1A6A1A03053343//Ministry of Education, Republic of Korea/ ; RS-2025-02223734//Korea Health Industry Development Institute (KHIDI)/ ; RS-2024-00433755//Ministry of Science and ICT and Ministry of Health and Welfare, Republic of Korea/ ; }, abstract = {The apolipoprotein E4 (APOE4) allele is the strongest genetic risk factor for sporadic Alzheimer's disease (AD), driving Aβ accumulation, tau pathology, and synaptic dysfunction. Allele-specific correction of APOE4 represents a promising therapeutic strategy to mitigate disease progression. In this study, we developed an APOE4-specific prime editing strategy based on an optimized APOE4-targeting pegRNA, enabling precise and efficient conversion of the APOE4 allele to the lower-risk APOE3 variant. We found that PE7 targeting the APOE4 allele achieved robust and specific editing without detectable off-target effects. This correction reduced ApoE4 protein levels and attenuated key AD-related pathologies, including Aβ42 accumulation, tau phosphorylation, and activation of the ERK1/2 pathway in APP/APOE4 knock-in (KI) mice. Notably, PE7 treatment enhanced neuronal survival and improved cognitive performance in these mice. Furthermore, in human induced neurons derived from APOE3/4 heterozygous AD patient fibroblasts, PE7 consistently corrected the APOE4 allele and suppressed both amyloid- and tau-associated pathologies. These findings establish PE7-mediated APOE4 correction as a precise and efficient therapeutic genome-editing strategy with translational potential for sporadic AD.}, } @article {pmid42456960, year = {2026}, author = {Yang, F and Zhao, Y}, title = {Di(2-ethylhexyl) phthalate exposure aggravates amyloid-beta-induced toxicity in transgenic AD Caenorhabditis elegans via lysosomal dysfunction and oxidative stress.}, journal = {Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association}, volume = {}, number = {}, pages = {116276}, doi = {10.1016/j.fct.2026.116276}, pmid = {42456960}, issn = {1873-6351}, abstract = {Di(2-ethylhexyl) phthalate (DEHP) is a widely used plasticizer and environmental contaminant. DEHP exposure has been linked to neurotoxicity in Alzheimer's disease (AD), yet the underlying mechanisms remain unclear. Here we found that DEHP exacerbated amyloid-beta (Aβ)-induced toxicity in transgenic AD Caenorhabditis elegans (C. elegans) models. Meanwhile the accumulation of SQST-1 was increased, indicating that the autophagic flux was impaired. Consistently, Aβ deposition was elevated in DEHP-treated AD C. elegans. Further investigation revealed that DEHP treatment resulted in lysosomal dysfunction accompanied by a significant decrease in lysosome number. The expression of hlh-30, a key transcription factor involved in lysosomal biogenesis, as well as its downstream lysosome-related genes, including cup-5, vha-17, and lmp-1, was reduced by DEHP. Moreover, hlh-30 RNAi abolished the exacerbation of Aβ toxicity by DEHP, indicating that the modulation of hlh-30 was a critical mechanism underlying the effects of DEHP. Additionally, DEHP aggravated oxidative stress in AD C. elegans, while the antioxidant N-acetylcysteine alleviated lysosomal impairment and reduced Aβ deposition, suggesting that the elevated oxidative stress was a key contributor to DEHP-induced lysosomal dysfunction and autophagy impairment. These findings highlight lysosomal impairment as a key mechanism contributing to DEHP-exacerbated toxicity in AD models, and suggest the possibility of using antioxidants to prevent DEHP-induced toxicity.}, } @article {pmid42458012, year = {2026}, author = {Croese, T and Mummery, CJ and Bregman, N and Bracha, D and Baruch, K and Kertser, A and Raveh, S and Shochat, E and Schwartz, M}, title = {Immunotherapy with a short-lived anti-PD-L1 antibody in Alzheimer's disease: a phase 1b, randomized, double-blind trial.}, journal = {Nature medicine}, volume = {}, number = {}, pages = {}, pmid = {42458012}, issn = {1546-170X}, support = {5R01AG071810-02//U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; PTCG-20-701033/ALZ/Alzheimer's Association/United States ; }, abstract = {While Alzheimer's disease (AD) is initiated by amyloid plaque accumulation, its progression involves local neuroinflammation that the brain cannot resolve when age-related dysfunction of the systemic immune system limits peripheral immune support. Preclinical studies using rodent models showed that transient systemic blockade of programmed death-ligand 1 is associated with reduced neuroinflammation, neuroprotection and attenuation of disease progression. Based on the underlying mechanism, a new short-lived anti-programmed death-ligand 1 antibody with Fc-effector silencing and reduced FcRn binding (IBC-Ab002) was engineered. Here, we report a randomized, double-blind, phase 1b first-in-human trial in early AD, with safety and tolerability as the primary endpoint. Forty participants were enrolled across five ascending dose cohorts (1-30 mg kg[-1]), with dosing administered four times at 3-month intervals. Treatment was well tolerated, with no treatment-related serious adverse events or evidence of amyloid-related imaging abnormalities. Exploratory analyses at week 48 showed directional changes in cerebrospinal fluid biomarkers of neuronal and synaptic damage favoring the 30 mg kg[-1] dose, although no doses reached statistical significance given the limited sample size. The safety and tolerability profile supports further clinical development of systemic, intermittently administered IBC-Ab002 in early AD. ClinicalTrials.gov registration: NCT05551741 .}, } @article {pmid42458104, year = {2026}, author = {Suma Narayanappa, T and Ananthanarayana, V and Chinnathambi, S}, title = {Tau-mediated Mechanisms in Alzheimer's Disease Pathogenesis.}, journal = {Molecular neurobiology}, volume = {63}, number = {1}, pages = {}, pmid = {42458104}, issn = {1559-1182}, mesh = {Humans ; *tau Proteins/metabolism ; *Alzheimer Disease/metabolism/pathology ; Animals ; Amyloid beta-Peptides/metabolism ; }, abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by the accumulation of extracellular amyloid-β plaques and intracellular neurofibrillary tangles of Tau. It is clinically accompanied by progressive cognitive impairment and behavioral deficits. Despite extensive AD research involving amyloid-β, pharmacological strategies targeting Aβ have shown limited clinical efficacy or adverse effects in clinical trials, while lecanemab and donanemab have shown to modestly but significantly slow cognitive decline in phase III clinical trials. However, the overall limited success of Aβ-directed therapies has shifted the attention to Tau protein. Therefore, understanding the pathology and pathogenesis of Tau in the contribution to AD is important for early diagnosis and effective treatment. Under physiological conditions, Tau stabilizes microtubules, axonal transport, and synaptic integrity. However, pathological post-translational modifications have been shown to disrupt Tau-microtubule interactions, promoting its aggregation and release into the extracellular region. Increasing evidence suggests the prion-like propagation of extracellular Tau drives the disease progression across the neuronal and glial cells leading to synaptic dysfunctions. The recent diagnostic approaches involving Tau-PET and Tau-based biofluid biomarkers have improved the detection of AD pathology. Therefore, effective clearance of Tau in AD requires understanding the molecular and cellular mechanisms regulating the pathological Tau degradation. This review explains the mechanistic contribution of extracellular Tau in AD pathogenesis and the cellular consequences. This will provide a foundation for understanding the influence of Tau on AD, the discovery of potential therapeutic strategies and new treatment methods for AD.}, } @article {pmid42459068, year = {2026}, author = {Nooreen, Z}, title = {A Comprehensive Review on Compounds and Herbal Approaches against Amyloid Beta Aggregation in Alzheimer's Disease.}, journal = {Central nervous system agents in medicinal chemistry}, volume = {}, number = {}, pages = {}, doi = {10.2174/0118715249416202251209125536}, pmid = {42459068}, issn = {1875-6166}, abstract = {Alzheimer's disease is a neurodegenerative disorder that affects brain cells over time, progressively reducing cognitive function, interfering with memory retention, and making daily tasks more difficult. The development of amyloid-beta (Aβ) plaques plays an important role in the progression of the disease, contributing to neurological swelling and cognitive impairment. Aβ induces oxidative damage and produces anti-inflammatory cytokines while reducing the association with vascular RAGE and acetylcholine. This article aims to present the latest and relevant research on treatment approaches targeting amyloid beta, including synthetic compounds, phytomolecules, and plant extracts. Novel delivery approaches are also covered. Memantine, latrepirdine, somatostatin, diosgenin, cirsiliol, amentoflavone, luteoloside, and many other synthetic compounds have been reported to generally inhibit Aβ aggregation, thereby reducing plaque development. Phytomolecules such as brazilin, (+)-catechin, ginnalin A, bacoside-A, bakuchiol, curcumin, homotaurine, icariin, genistein, fucosterol, and quercitrin also alleviate symptoms via various mechanisms. Additionally, plant extracts from Annona atemoya, Lycium barbarum, Humulus lupulus, Oroxylum indicum, Salvia macilenta, Trichosanthis Semen, Camellia sinensis, Betula utilis, Cirsium japonicum, Elaeagnus glabra, Orthosiphon aristatus, Metasequoia glyptostroboides, Zizania latifolia, and Benincasa hispida are discussed briefly with their mechanisms of action. The present review also addresses the pathogenesis, risk factors, symptoms, and diagnosis of amyloid beta aggregation. Data were collected from PubMed, ScienceDirect, SciFinder, Scopus, and Google Scholar.}, } @article {pmid42459149, year = {2026}, author = {Panza, F and Dibello, V and Daniele, A and Lozupone, M}, title = {Do sigma-1 receptor agonists offer therapeutic promise for Alzheimer's disease?.}, journal = {Expert opinion on pharmacotherapy}, volume = {}, number = {}, pages = {}, doi = {10.1080/14656566.2026.2706070}, pmid = {42459149}, issn = {1744-7666}, abstract = {INTRODUCTION: Alzheimer's disease (AD) remains a major unmet medical need despite recent advances in amyloid-targeting therapies. The modest efficacy, safety concerns, and limited accessibility of monoclonal antibodies highlighted the need for alternative/complementary therapeutic strategies. The sigma-1 receptor (σ-1 R), a ligand-operated chaperone involved in cellular stress responses, has emerged as a promising target in neurodegeneration.

AREAS COVERED: The present Special Report provided a focused overview of σ-1 R agonists in AD, emphasizing their mechanistic role in modulating calcium homeostasis, mitochondrial function, autophagy, and neuroinflammation. We discussed clinical-stage compounds, including blarcamesine, evaluating their potential effects on both cognitive decline and neuropsychiatric symptoms. In addition, we highlighted emerging precision medicine approaches, including biomarker development and patient stratification.

EXPERT OPINION: σ-1 R agonists represented a novel therapeutic class that may enhance neuronal resilience rather than directly targeting specific pathological aggregates. This mechanism positions them as attractive candidates for combination strategies and for broader patient populations, including those ineligibles for biologic therapies. However, challenges remained, including incomplete understanding of receptor biology in aging and disease, variability in clinical response, and the need for robust biomarkers of target engagement. Future research should prioritize well-designed clinical trials and integrative biomarker strategies to define their role in AD treatment paradigms.}, } @article {pmid42459821, year = {2026}, author = {Campbell, LM and Aghamoosa, S and Horn, O and Fleischmann, HH and Lopez, J and Rbeiz, KS and Madden, K and Antonucci, M and Revuelta, G and McTeague, LM and Benitez, A}, title = {Feasibility of Interleaving Computerized Cognitive Training With Repetitive Transcranial Magnetic Stimulation: Pilot Studies in Mild Cognitive Impairment Due to Alzheimer's Disease and Stroke.}, journal = {JMIR neurotechnology}, volume = {5}, number = {}, pages = {e81437}, pmid = {42459821}, issn = {2817-092X}, abstract = {BACKGROUND: Repetitive transcranial magnetic stimulation induces neural plasticity, which may be maximized via adjunctive interventions.

OBJECTIVE: This study aimed to examine the feasibility and acceptability of interleaving computerized cognitive training (CCT) with accelerated intermittent theta burst (iTBS) repetitive transcranial magnetic stimulation in 2 open-label phase I trials of amnestic mild cognitive impairment (aMCI; NCT04503096) and poststroke mild cognitive impairment (psMCI; NCT04655963).

METHODS: Participants (aMCI: n=21; and psMCI: n=14) received 24 sessions of accelerated iTBS over 3 days (8 sessions per day). During the 10- to 15-minute intervals between iTBS sessions, participants engaged in CCT via the BrainHQ platform. During the 4-week follow-up period, participants were asked to complete 20 minutes daily of BrainHQ. Both studies offered identical compensation for daily practice, but the aMCI group received weekly reminders, whereas the psMCI group did not. Study-specific questionnaires assessed BrainHQ acceptability (administered post-treatment and at follow-up).

RESULTS: During in-laboratory treatment, the groups completed similar amounts of BrainHQ (aMCI: median 107, IQR 92-121 min; and psMCI: median 111, IQR 93-137 min; P=.51). However, engagement differed during the unmonitored follow-up (aMCI: median 450, IQR 167-581 min,; and psMCI: median 142, IQR 0-477 min); practice time increased in the aMCI group but decreased in the psMCI group over the 4 weeks (P=.001). Both groups generally rated BrainHQ positively at both time points in terms of their experience with the platform, exercises, and perceived benefit for their mood and functioning.

CONCLUSIONS: Combined treatment with CCT and accelerated iTBS is feasible and acceptable in people with mild cognitive impairment. Standardized dosing of CCT is feasibly achieved when interleaved with iTBS sessions and completed in-laboratory, but ecological adherence to CCT in an unmonitored, self-directed context likely requires additional supports and may be influenced by patient characteristics.}, } @article {pmid42459872, year = {2026}, author = {Munawwar, R and Sarfaraz, S and Ikram, R and Anser, H}, title = {The Therapeutic Potential of Phaseolus vulgaris in Alzheimer's Disease: Insights From Experimental Rodent Model.}, journal = {Scientifica}, volume = {2026}, number = {}, pages = {6739059}, pmid = {42459872}, issn = {2090-908X}, abstract = {Alzheimer's disease (AD) is a devastating neurological ailment affecting millions of people worldwide. For this neurological disease, there are numerous pharmacological and supportive treatments available. Several organic products are currently being investigated for AD. In a recent study, a variety of methods were used to conduct research and evaluate this advantageous effect, including passive avoidance tests, histopathology, biogenic amine assessment, and GC-MS analysis. For this study, three groups were made of albino rats of both genders. Group I was the negative control group (administered standard diet), Group II was treated with 500 mg/kg beans, and Group III was given 1000 mg/kg. All three groups were induced Alzheimer's by giving 2.5 mg/kg diazepam prior to the start of the treatment. The results showed that a significantly higher dosage level of 1000 mg/kg was most effective at preventing dementia in AD-induced rats as compared to the lower dose evaluated. Passive avoidance tests, GC-MS analysis, which revealed acetylcholine activity and other beneficial compounds like squalene, isoglutamine, and pyrrolizine, as well as histopathological analysis, all supported the effectiveness of this nutritional option. The findings unmistakably demonstrated that 1000 mg/kg red beans are very helpful in reducing dementia in AD-induced rats.}, } @article {pmid42461977, year = {2026}, author = {Zhu, C and Song, L and Mao, S and Li, K and Lin, X}, title = {Receptor-Ligand-Mediated Anchoring of Polyphenol Quantum Dots to Membrane Fragments for Precision Delivery in Alzheimer's Disease Therapy.}, journal = {ACS applied materials & interfaces}, volume = {}, number = {}, pages = {}, doi = {10.1021/acsami.6c10322}, pmid = {42461977}, issn = {1944-8252}, abstract = {Polyphenol-based carbon dots (PCDs) hold great promise for Alzheimer's disease (AD) treatment owing to their inherent antioxidant activity, ultrasmall size, and favorable blood-brain barrier (BBB) permeability. Nevertheless, rapid immune clearance and poor lesion targeting severely hinder their clinical translation. Conventional cell membrane coating is poorly compatible with ultrasmall PCDs, causing incomplete encapsulation, active site masking, and membrane protein inactivation. Herein, we fabricated a novel biomimetic nanostructure (MQCM) by anchoring mannose-modified quercetin nanodots (MQNDs) onto BV2 cell membrane fragments (CMFs) via specific mannose-CD206 receptor-ligand interactions. This unique binding strategy endowed MQCM with a high anchoring efficiency (84.3%) and improved structural stability. Distinct from conventional nonspecific membrane coating that shields active sites and impairs nanoparticle functionality, this design avoids such drawbacks and completely preserves the intrinsic bioactivity of MQNDs and membrane proteins. The optimized MQCM displays high BBB permeability (42.35%), precise BV2 targeting, and lesion-responsive drug release. BV2-derived CMFs prolong blood circulation and lesion retention of MQNDs, while the released MQNDs exert multiple anti-AD effects by regulating ROS homeostasis, inhibiting Aβ fibrillation, and promoting Aβ autophagy. Collectively, this integrated biomimetic system offers a precise AD therapeutic strategy and advances the clinical translation of PCD-based nanomedicines.}, } @article {pmid42448048, year = {2026}, author = {Waseem, A and Ghosh, S and Kumari, M and Raza, SS and Verma, S}, title = {Modulation of Inflammasome Biology in Age-Associated Neurodegenerative Diseases: Therapeutic Potential of Endogenous Gasotransmitters and Synthetic Molecules.}, journal = {Ageing research reviews}, volume = {}, number = {}, pages = {103257}, doi = {10.1016/j.arr.2026.103257}, pmid = {42448048}, issn = {1872-9649}, abstract = {Inflammasomes, particularly the NLRP3 complex, play a central role in coordinating innate immune activation and neuroinflammatory responses within the cytosol. Persistent or dysregulated nucleotide-binding domain, leucine-rich-containing family, pyrin domain-containing-3 (NLRP3) activation promotes caspase-1-dependent maturation of interleukin (IL)-1β and IL-18 and triggers gasdermin D (GSDMD)-mediated pyroptosis, thereby contributing to the pathogenic cascades underlying Alzheimer's disease (AD) and Parkinson's disease (PD). Endogenous gasotransmitters, including hydrogen sulfide (H2S) and nitric oxide (NO), have emerged as critical modulators of redox homeostasis, mitochondrial function, and inflammatory signaling pathways that directly or indirectly regulate NLRP3 inflammasome activity. Accumulating evidence suggests that these gaseous mediators exert potent neuroprotective effects by attenuating inflammasome activation, limiting oxidative and nitrosative stress, and preserving neuronal integrity. Despite their therapeutic potential, the pleiotropic and concentration-dependent actions of gasotransmitters pose substantial challenges for precise delivery and controlled bioavailability. However, donors or hybrid molecules, such as peptide conjugates, provide a suitable platform for sustained, controlled release of these gaseous molecules, overcoming their dose-dependent toxicity and facilitating protective biological effects. To date, the most advanced therapeutic strategies have focused on pharmacological inhibition of the NLRP3 inflammasome using synthetic compounds. Preclinical and emerging clinical studies demonstrate that such agents significantly modulate inflammasome-associated downstream signaling events through diverse molecular mechanisms. This review integrates current insights into NLRP3 inflammasome-driven pathology in age-associated neurodegenerative disorders, highlights the regulatory roles of endogenous gasotransmitters, and evaluates the therapeutic prospects of synthetic inflammasome-targeting agents for the treatment of neurodegenerative diseases in the aging population.}, } @article {pmid42448200, year = {2026}, author = {Murugan, AK}, title = {Oral disease-associated proteins implicated in neuronal disorders: Emerging roles in diagnosis and treatment.}, journal = {International journal of biological macromolecules}, volume = {}, number = {}, pages = {153500}, doi = {10.1016/j.ijbiomac.2026.153500}, pmid = {42448200}, issn = {1879-0003}, abstract = {Oral health plays a crucial role in maintaining cognitive functions, reflecting a complex interplay between the oral cavity and brain health. Emerging evidence indicates that various oral disease-associated protein molecules are implicated in the pathogenesis of diverse neuronal disorders, including neurodegenerative diseases. This review comprehensively summarizes oral disease-related protein molecules implicated in several neuronal disorders, including Alzheimer's disease, Parkinson's disease, neurodegeneration, neuroinflammation, dementia, cognitive decline, and brain fog in two different contexts. Firstly, it describes protein molecules under the classical oral disease condition [Aβ42, total-Tau, phosphorylated-Tau, α-synuclein, DJ-1, lactoferrin, MMP-2/8/9, IL-6, IL-1β, TNF-α, CRP, S100A8, S100A9, S100B, RAGE, LCN2, cathepsin B/L, HSP70/90, NfL, CXCL2/8, C3/4, defensins (α and β), and lysozyme]. Secondly, in COVID-19 context [ACE2, TMPRSS2, furin-1, NRP1, spike, T1R, and T2R]. It explores oral proteins implicated in neuronal disorders, highlighting their roles in activating inflammatory pathways, contributing to memory impairment, and mediating taste dysfunction in the context of COVID-19. Furthermore, the review delineates the mechanisms underlying the oral-brain axis, highlighting the roles of systemic inflammation, microbial interactions, and blood-brain barrier dysfunction in mediating these effects. It also highlights the innovative diagnostic potential of oral disease-associated proteins as non-invasive biomarkers for early detection and monitoring of neuronal disorders in both classical and COVID-19 contexts. In addition, the emerging therapeutic significance of these proteins is discussed, emphasizing their potential as molecular targets for the prevention and treatment of neurological diseases. Understanding oral disease-associated protein molecules provides novel insights into early diagnosis and progression of neuronal disorders.}, } @article {pmid42449057, year = {2026}, author = {Bukar, AM and Che Mohd Nassir, CMN and Ayuba, M and Manoharan, SD and Usman, AS and Umar, BI and Hein, ZM and Mohd Moklas, MA and Mehat, MZ and Abdul Hamid, H}, title = {Ficus deltoidea Preserves Hippocampal Neuronal Integrity and Redox Balance in Oxidative Stress-Driven Alzheimer's Disease-Like Rat Model.}, journal = {Molecular neurobiology}, volume = {63}, number = {1}, pages = {}, pmid = {42449057}, issn = {1559-1182}, mesh = {Animals ; *Oxidative Stress/drug effects ; *Alzheimer Disease/pathology/drug therapy/metabolism ; Male ; Rats, Wistar ; *Ficus/chemistry ; *Hippocampus/pathology/drug effects/metabolism ; Disease Models, Animal ; *Neurons/drug effects/metabolism/pathology/ultrastructure ; Oxidation-Reduction/drug effects ; Aluminum Chloride ; *Plant Extracts/pharmacology/therapeutic use ; Galactose ; Neuroprotective Agents/pharmacology/therapeutic use ; Antioxidants/pharmacology ; Rats ; Maze Learning/drug effects ; }, abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder and the leading cause of dementia worldwide, with oxidative stress playing a central role in its pathogenesis. Ficus deltoidea (FD), a medicinal plant rich in flavonoids vitexin and isovitexin, possesses potent antioxidant and anti-inflammatory properties, yet its neuroprotective efficacy in AD remains incompletely characterized. This study investigated the protective effects of FD in a D-galactose- and aluminum chloride (AlCl3)-induced oxidative stress-driven AD-like rat model using behavioral, histological, ultrastructural, and biochemical approaches. Fifty-four male Wistar rats were assigned to six groups: control, AD-like model, donepezil (1 mg/kg), and FD-treated groups (50, 100, and 200 mg/kg) for 10 weeks. Anxiety-like behavior and spatial working memory were assessed using the elevated plus maze (EPM) and T-maze tests, respectively. Hippocampal neuronal integrity was evaluated by hematoxylin and eosin (H&E) staining and transmission electron microscopy (TEM), while oxidative stress biomarkers (MDA, CAT, T-SOD, CuZn-SOD, and HO-1) were quantified using ELISA. FD treatment, particularly at 200 mg/kg, significantly improved spatial working memory and normalized anxiety-related behavior, with treatment responses approaching those observed in the donepezil-treated group. Histological analyses revealed preservation of pyramidal neurons across CA1, CA2, CA3, and dentate gyrus subregions, while ultrastructural studies demonstrated marked protection of mitochondrial integrity, myelin sheath organization, and smooth endoplasmic reticulum morphology. Biochemically, FD significantly reduced lipid peroxidation and enhanced endogenous antioxidant defenses. In conclusion, FD exerted significant neuroprotective effects characterized by preservation of hippocampal structure, maintenance of neuronal ultrastructure, and restoration of redox homeostasis in an oxidative stress-driven AD-like model. These findings demonstrate that FD mitigates oxidative stress-associated neuronal injury and cognitive impairment in a D-galactose and AlCl3-induced AD-like rat model, supporting its potential as a phytotherapeutic candidate for oxidative stress-related neurodegeneration. However, further studies are required to determine its effects on canonical Alzheimer's disease pathologies, including amyloid and tau abnormalities.}, } @article {pmid42449395, year = {2026}, author = {Jang, H and Kim, JW and Hwang, JW and Jeong, DW and Ka, J and Kang, DM and Suh, CH and Choi, Y and Oh, M and Kim, JS and Lim, JS and Lee, JH}, title = {Real-world safety and implementation challenges of lecanemab therapy for Alzheimer's disease in South Korea: a single-center experience.}, journal = {Alzheimer's research & therapy}, volume = {}, number = {}, pages = {}, doi = {10.1186/s13195-026-02141-1}, pmid = {42449395}, issn = {1758-9193}, support = {RS-2022-KH125667//Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health & Welfare and Ministry of science and ICT, Republic of Korea/ ; 2022-IF-0022//Asan Institute for Life Sciences/ ; }, abstract = {BACKGROUND: Lecanemab, an amyloid-targeting monoclonal antibody, was recently approved for early symptomatic Alzheimer's disease in South Korea. Asians were underrepresented in prior trials, and real-world data from Korea remain scarce, particularly regarding treatment settings, adverse events, and barriers to scalability. We assessed the feasibility and safety of lecanemab among Korean patients in a real-world tertiary hospital.

METHODS: A total of 112 patients initiated lecanemab treatment between December 2024 and October 2025 at Asan Medical Center. Prevalence of infusion-related reactions (IRRs), Amyloid-Related Imaging Abnormalities (ARIA), treatment discontinuation, and factors limiting implementation were evaluated.

RESULTS: Among 112 patients (mean age 71 years; 59% female), IRRs occurred in 41 (37%) and were generally mild or moderate under active surveillance. Among 105 at-risk patients who received at least four infusions and had at least one monitoring MRI, ARIA developed in 20 (19%): ARIA-E/H in 6 (5.7%) and isolated ARIA-H in 14 (13.3%). Only 1 patient with isolated ARIA-H presented with transient confusion. Patients with ARIA-E/H were younger, whereas those with ARIA-H were older and more likely to have baseline microhemorrhages. Eleven out of 105 were APOE ε4/ε4 homozygotes, of whom 5 developed ARIA. The rapid increase in treatment demand exceeded outpatient infusion capacity, resulting in progressively longer waiting times-up to 20 weeks 9 months after program initiation.

CONCLUSION: This single-center experience from a tertiary referral hospital in Korea demonstrates that lecanemab treatment was feasible and generally well-tolerated, with manageable adverse events including ARIA and IRRs; however, limited infusion capacity, lack of reimbursement, and patient concentration in tertiary centers highlight the need for referral networks and system-level strategies to improve nationwide accessibility.}, } @article {pmid42449771, year = {2026}, author = {Sotoudeh, H and Alizadeh, M}, title = {The Centiloid Scale in Amyloid PET Imaging: Current Role in Alzheimer's Disease Diagnosis, Treatment Planning, and Monitoring During Anti-Amyloid Therapy: A Clinical Perspective.}, journal = {Diagnostics (Basel, Switzerland)}, volume = {16}, number = {13}, pages = {}, doi = {10.3390/diagnostics16131989}, pmid = {42449771}, issn = {2075-4418}, abstract = {Amyloid positron emission tomography (PET) has become a critical tool in the diagnosis and treatment of Alzheimer's disease (AD). The Centiloid (CL) scale, a tracer/scanner-independent, standardized quantification unit introduced in 2015, transforms tracer- and scanner-specific standardized uptake value ratios (SUVRs) into a common metric anchored at 0 CL in young cognitively unimpaired individuals and 100 CL in patients with mild-to-moderate AD. This review synthesizes current evidence on the clinical role of the CL scale across three domains: (1) diagnostic classification, with established thresholds of <10 CL for amyloid negativity and >30 CL for high-certainty amyloid positivity; (2) treatment eligibility, where a 2024 Alzheimer's Association Research Roundtable consensus of global experts recommended a 24-30 CL threshold for initiating lecanemab or donanemab therapy in patients with mild cognitive impairment (MCI) or mild AD dementia; and (3) longitudinal therapy monitoring, in which serial CL measurements provide objective evidence of amyloid clearance. We also review the emerging 'gray zone' (10-30 CL) as a distinct clinical entity with elevated progression risk, the critical role of CL quantification in complementing visual reads in borderline cases, technical limitations, and the future integration of CL in clinical practice. This review also critically addresses the ongoing debate on whether amyloid clearance represents a reliable surrogate for clinical benefit, strategies for managing discordant biomarker findings, and the practical feasibility of serial amyloid PET in routine care. With FDA approval of both lecanemab and donanemab, familiarity with the CL scale as a functional treatment biomarker is increasingly relevant for neuroradiologists and nuclear medicine physicians in the modern AD care pathway. As with all imaging modalities, the CL has physiologic and technical limitations. Although the CL scale was designed to reduce heterogeneity across tracers and scanner platforms, the impact of different commercial quantification software packages on CL output remains incompletely characterized. Consistent use of a single software platform for longitudinal monitoring in individual patients is therefore recommended.}, } @article {pmid42449980, year = {2026}, author = {Li, Y and Zhao, H and Wu, J and Hu, Y and Pan, J and Frimpong, AO and Xie, B and Yang, W and Sun, M and Chen, W and Wang, P and Shao, C}, title = {Vitamin K2 Promotes Mitochondrial Structural and Functional Homeostasis to Ameliorate Alzheimer Pathology by Targeting the EGFR-Ras-ERK Signaling Axis.}, journal = {International journal of molecular sciences}, volume = {27}, number = {13}, pages = {}, doi = {10.3390/ijms27135708}, pmid = {42449980}, issn = {1422-0067}, mesh = {Animals ; *Alzheimer Disease/metabolism/drug therapy/pathology ; *Mitochondria/drug effects/metabolism/ultrastructure ; ErbB Receptors/metabolism ; Homeostasis/drug effects ; *Vitamin K 2/pharmacology ; Humans ; *MAP Kinase Signaling System/drug effects ; Drosophila melanogaster ; *ras Proteins/metabolism ; Signal Transduction/drug effects ; Disease Models, Animal ; Reactive Oxygen Species/metabolism ; Membrane Potential, Mitochondrial/drug effects ; Amyloid beta-Peptides/metabolism ; }, abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by β-amyloid (Aβ) accumulation and a breakdown of mitochondrial homeostasis. Vitamin K2 (VK2) has emerged as a potential neuroprotective agent, yet the specific molecular cascades linking its intervention to the restoration of mitochondrial integrity remain poorly understood. This study utilizes an AD Drosophila model to investigate the efficacy of VK2 and elucidates its multidimensional regulatory mechanisms. Behavioral analysis showed that VK2 significantly rescued locomotor impairments, improving both vertical climbing and horizontal walking performance. Crucially, VK2 intervention achieved a systemic rescue of mitochondrial health: transmission electron microscopy (TEM) confirmed the preservation of mitochondrial ultrastructure and cristae density, while biochemical assays demonstrated a robust recovery of bioenergetic markers, including ATP levels and the NAD[+]/NADH ratio. Furthermore, VK2 treatment stabilized the mitochondrial membrane potential (MMP) and effectively attenuated the accumulation of reactive oxygen species (ROS). To identify the molecular drivers of this recovery, an unbiased integration of human clinical transcriptomic data and network pharmacology prioritized the EGFR-Ras-ERK signaling axis as a central hub. In vivo validation confirmed that VK2 suppresses the pathological overactivation of this cascade. VK2 reduced EGFR phosphorylation in parallel with the effects observed for the EGFR inhibitor Gefitinib. Collectively, our findings show that VK2 ameliorates locomotor deficits and mitochondrial dysfunction in Aβ42-expressing flies and that these effects are associated with suppression of the EGFR-Ras-ERK signaling axis. Further studies are required to establish direct target engagement and pathway causality.}, } @article {pmid42450004, year = {2026}, author = {Petrov, W and Ślebioda, D and Kozińska, R and Kukla, K and Petrov, P and Sroka, M and Tesyna, J and Puźniak, G and Kudliński, M and Rejda, T and Skowron, I and Chłopaś-Konowałek, A}, title = {Analysis of the Efficacy of Acetylcholinesterase Inhibitors in the Treatment of Alzheimer's Disease, Literature Review.}, journal = {International journal of molecular sciences}, volume = {27}, number = {13}, pages = {}, doi = {10.3390/ijms27135733}, pmid = {42450004}, issn = {1422-0067}, mesh = {Humans ; *Cholinesterase Inhibitors/therapeutic use/pharmacology ; *Alzheimer Disease/drug therapy/metabolism ; Animals ; Acetylcholinesterase/metabolism ; Rivastigmine/therapeutic use ; }, abstract = {The term 'dementia' encompasses a diverse group of progressive neurodegenerative disorders, the common feature of which is the deterioration of higher cortical functions. This process not only involves memory deficits and language communication disorders, but also executive dysfunction and loss of emotional control, which ultimately leads to a complete loss of the patient's independence. Within this group of disorders, Alzheimer's disease (AD) presents the most serious clinical challenge, characterized by a unique neuropathological triad: the presence of extracellular β-amyloid plaques, intracellular neurofibrillary tangles of tau protein, and widespread dysfunction of cholinergic transmission. The cholinergic hypothesis remains the cornerstone of the current understanding of cognitive impairment in AD. It posits that progressive dementia is caused by the selective degeneration of neurons in the anterior basal forebrain, resulting in a drastic reduction in acetylcholine (ACh) levels in the synaptic cleft. In the absence of a causal treatment, acetylcholinesterase inhibitors (AChEIs) remain the standard of care. Their pharmacological action is based on the inhibition of the AChE enzyme, which allows neurotransmission deficits to be compensated for by prolonging the half-life of acetylcholine at the synapse. This literature review presents a synthesis of the efficacy and safety of classic and novel AChEIs. A comprehensive search of the PubMed, Scopus, and Cochrane Library databases was conducted for clinical data published up to 2026. Evidence from key trials indicates that standard AChEIs induce significant cognitive stabilization compared to placebo, with rivastigmine maximizing daily living parameters via transdermal delivery. However, their therapeutic impact remains strictly symptomatic without arresting neurodegeneration. Conversely, emerging agents like huperzine A and the translation-blocker Posiphen demonstrate disease-modifying potential by modulating CSF biomarkers associated with amyloid and tau proteins. Clinically, while traditional regimens are limited by gastrointestinal toxicities, transitioning toward innovative multi-target structures represents a necessary shift to address both cognitive decline and neurodegeneration.}, } @article {pmid42450155, year = {2026}, author = {Untiveros, G and St Germain, R and Barrington, B and Kujawa, SA and Prakapenka, AV and Strizzi, L}, title = {Presenilin-1 Affects Melanoma Cell Behavior in an Amyloid Precursor Protein-Rich, Alzheimer's Disease-like, Microenvironment.}, journal = {International journal of molecular sciences}, volume = {27}, number = {13}, pages = {}, doi = {10.3390/ijms27135885}, pmid = {42450155}, issn = {1422-0067}, mesh = {*Presenilin-1/metabolism/genetics ; Humans ; Animals ; *Amyloid beta-Protein Precursor/metabolism/genetics ; *Melanoma/metabolism/pathology ; *Tumor Microenvironment ; *Alzheimer Disease/metabolism/pathology ; Mice ; Cell Line, Tumor ; Amyloid beta-Peptides/metabolism ; Cell Movement ; }, abstract = {Recent studies report inverse relationships between the incidence of Alzheimer's Disease (AD) and certain malignancies, including melanoma. This has encouraged research into factor(s) in AD that can exert antitumor effects. Presenilin-1 (PS-1) is part of the enzymatic complex that cleaves amyloid precursor protein (APP) into amyloid-beta (Aβ) products that are linked to the neuronal damage seen in AD. PS-1 can also degrade β-catenin and reduce the effectiveness of the "wingless-related integration" (WNT) signaling pathway. Little is known about the relationship between the AD microenvironment, PS-1, and melanoma. We hypothesize that melanoma growth in AD depends on the degree of PS-1-dependent processing of APP into cytotoxic Aβ by melanoma cells. To determine how melanoma reacts to an APP-rich, AD-like microenvironment, PS-1-high (WM1552C) and PS-1-low (C8161) melanoma cells were treated with soluble recombinant human APP (rhAPP). We found that rhAPP treatment significantly reduced cellular activity in WM1552C but not in C8161 cells. Moreover, Aβ products were significantly higher in conditioned media from rhAPP-treated WM1552C compared to controls. Treatment with PS-1 inducing DAPT or PS-1 function inhibiting MRK-560 reversed the effects of rhAPP treatment, respectively in C8161 and WM1552C cells. Furthermore, we found that migration of WM1552C was significantly reduced in the presence of either soluble rhAPP or mouse AD brain tissue, compared to C8161, suggesting that in WM1552C the combination of PS-1 activity and the presence of APP/Aβ in the microenvironment interferes with cell migration. In summary, PS-1 function may predict how melanoma will grow in an APP/Aβ-rich microenvironment, such as AD.}, } @article {pmid42450355, year = {2026}, author = {Arendash, GW}, title = {Neuronal Microtubules and Radiofrequency Waves: The Quantum Core of Human Consciousness, Memory, and Pathway to Memory Enhancement/Recovery.}, journal = {International journal of molecular sciences}, volume = {27}, number = {13}, pages = {}, doi = {10.3390/ijms27136090}, pmid = {42450355}, issn = {1422-0067}, support = {AG025711, 1R43NS090653-01A, and 9R44AG073096-02A1//NIA-designated Florida Alzheimer's Disease Research Center/ ; }, mesh = {Humans ; *Microtubules/metabolism ; *Memory/physiology/radiation effects ; *Consciousness/physiology ; *Radio Waves ; Animals ; *Neurons/metabolism ; Quantum Theory ; }, abstract = {A unifying theory of both human consciousness and memory is presented that is based on neuronal microtubules (MTs) being central to both, and different populations of pyramidal cells in neocortex and hippocampus being responsible for consciousness or memory. First, two quantum theories of consciousness are presented-the Orchestrated Objective Reduction (Orch OR) theory of Penrose/Hameroff and the Environmental-Induced Decoherence Theory (EID) theory of Neven. A Hybrid (MT/EID) theory is proposed in the context of "consciousness"-dedicated pyramidal cells in Layer V of the cerebral cortex. This MT/EID theory involves the MT vibrations of the Orch OR Theory, along with the continual superposition qubit (SPQ) formation and SPQ entanglement of the EID Theory to collectively induce SPQ formation/entanglement in Layer V of the cerebral cortex. Orch OR's objective reduction (collapse of the waveform) is not included in this Hybrid theory because the system of SPQs themselves continuously collapses due to EID. For memory, it is proposed that Orch OR forms its basis with three specific modifications: (1) presenting "endogenous" radiofrequency (RF) vibrations generated by neuronal microtubules as forming a microtubule/RF wave "vibrational fabric" involving microtubular crystalline water cores, (2) refining Orch OR for memory by proposing SPQ formation for short-term memory and objective reduction of those qubits primarily in "memory-dedicated" pyramidal cells within cortical Layers II/III for long-term memory storage through "Quantum Darwinism" (SPQ/OR), and (3) integrating SPQ/OR with the ability of "externally" applied RF waves at 1 GHz to beneficially influence human memory through microtubule-enhancing mechanisms. It is proposed that a vibrational fabric consisting of MTs, RF waves, and generated photons provides the Photonic/RF-wave quantum coherence necessary for brain memory processing. Strong evidence for beneficial effects of exogenous RF wave treatment on memory is provided by a new bioengineered technology-Transcranial Radiofrequency Wave Treatment (TRFT; also known as TEMT). This evidence is presented in both pre-clinical and clinical studies involving normal and Alzheimer's Disease (AD) transgenic mice, and AD patients bearing memory loss. In support of MT involvement in memory, TRFT would appear to be an ideal non-pharmacologic technology to beneficially modulate the microtubule/RF wave vibrational fabric-an intraneuronal fabric that may be at the deep core of human memory, and thus the key to Alzheimer's Disease memory rescue.}, } @article {pmid42451691, year = {2026}, author = {Singh, AA and Arukha, AP and Song, M}, title = {Indole-Derived Compounds as Redox-Modulators: Antioxidant Mechanisms in Neuronal Protection.}, journal = {Molecules (Basel, Switzerland)}, volume = {31}, number = {13}, pages = {}, doi = {10.3390/molecules31132323}, pmid = {42451691}, issn = {1420-3049}, mesh = {Humans ; *Antioxidants/pharmacology/chemistry ; *Indoles/chemistry/pharmacology ; Animals ; *Neuroprotective Agents/pharmacology/chemistry ; Oxidation-Reduction/drug effects ; *Neurodegenerative Diseases/drug therapy/metabolism ; *Neurons/drug effects/metabolism ; Oxidative Stress/drug effects ; Signal Transduction/drug effects ; Reactive Oxygen Species/metabolism ; }, abstract = {Neurodegenerative diseases, such as Alzheimer's, Parkinson's, and Amyotrophic lateral sclerosis, are distinguished by progressive neuronal dysfunction caused primarily by oxidative stress, mitochondrial impairment, neuroinflammation, and redox imbalance. Growing evidence suggests that indole-derived compounds have significant neuroprotective potential due to their antioxidant, anti-inflammatory, and redox-modulating properties. This review summarizes the structural and biological significance of indole scaffolds, focusing on the mechanisms by which natural, endogenous, microbiota-derived, and synthetic indole compounds protect neuronal networks. Indole-3-carbinol, 3,3'-diindolylmethane, indole-3-propionic acid, and melatonin are major indole derivatives that control important neuroprotective pathways like Nrf2/ARE signaling, mitochondrial bioenergetics, neurotrophic factor expression, apoptotic regulation, and suppression of proinflammatory mediators. These compounds also maintain synaptic plasticity, reduce reactive oxygen species production, and improve neuronal survival in neurodegenerative disease models. Additionally, updated information from translational and clinical research indicates that indole-based compounds may have promising therapeutic applications; however, obstacles like low bioavailability, metabolic instability, and blood-brain barrier penetration continue to be major obstacles to clinical application. Development in nanoparticle delivery systems, microbiome-targeted interventions, and rational structural optimization may improve therapeutic efficacy and translational potential. Overall, indole-derived compounds are a versatile class of redox modulators with potential applications in the prevention and treatment of neurodegenerative diseases via integrated antioxidant and neuroprotective mechanisms.}, } @article {pmid42453339, year = {2026}, author = {Thapa Magar, TB and Kim, M and Kim, Y and Choi, EY and Choi, YK and Kim, DE and Kim, KB and Park, JE}, title = {Pharmacokinetics, Target Engagement of an Immunoproteasome Subunit Low-Molecular-Mass Polypeptide‑2 (LMP2) Inhibitor AR-01, and Its Anti-Alzheimer's Effects in Rodents.}, journal = {ACS pharmacology & translational science}, volume = {9}, number = {7}, pages = {1869-1880}, pmid = {42453339}, issn = {2575-9108}, abstract = {Previously, we reported that AR-01, an irreversible macrocyclic peptide epoxyketone, selectively inhibits the immunoproteasome catalytic subunit LMP2 (low-molecular mass polypeptide-2). We also showed that LMP2 inhibition produces anti-Alzheimer's effects in animal models of Alzheimer's disease (AD) by suppressing microglia-mediated inflammation. As such, AR-01 is being developed as a potential treatment for AD. Typically, CNS drugs with peptide backbones face significant challenges due to unfavorable properties for crossing the blood-brain barrier. In this report, we evaluated the pharmacokinetic properties of AR-01, including brain permeability (i.e., brain-to-plasma partition coefficient), in healthy mice and rats as part of early stage drug development. We also verified AR-01 target engagement in the brain using two alternative approaches: (i) LMP2 activity assay and (ii) LMP2 band shift on Western blotting, which is caused by the formation of an irreversible LMP2:AR-01 adduct. The results confirmed that a single intravenous administration of AR-01 inactivates LMP2 in the mouse brain in a dose-dependent manner. Multiple doses of AR-01 led to cumulative LMP2 adduct formation in the mouse brain and improved cognitive function in 5xFAD mice, a widely used model of amyloidogenesis. Taken together, the results suggest that AR-01 has promising pharmaceutical properties as an AD therapeutic.}, } @article {pmid42453526, year = {2026}, author = {Varinthra, P and Ibiayo, AG and Liu, CH and Pakaprot, N and Paromi, IN and Do, TT and Raza, M and Liu, IY}, title = {Therapeutic advances in Alzheimer's disease: Current strategies and future possibilities.}, journal = {Tzu chi medical journal}, volume = {38}, number = {3}, pages = {263-274}, pmid = {42453526}, issn = {2223-8956}, abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder causing memory, cognitive, and behavioral impairments in older adults and poses a major worldwide health challenge. The pathophysiology of AD is highly complex and multifactorial, arising from interrelated processes such as amyloid-β (Aβ) aggregation, tau hyperphosphorylation, synaptic dysfunction, neuroinflammation, mitochondrial impairment, and oxidative stress. In addition, both genetic predisposition and environmental or lifestyle factors play critical roles in disease susceptibility and progression. Despite decades of investigation, therapeutic options with robust disease-modifying potential remain limited. Based on published studies from 2021 to 2025, current treatments primarily focus on symptomatic management with cholinesterase inhibitors, N-methyl-D-aspartate receptor antagonists, and combined therapies, complemented by nonpharmacological interventions to support cognition and quality of life. Recently, advances in disease-modifying strategies, particularly monoclonal antibodies targeting Aβ, tau-directed therapies, and approaches modulating neuroinflammation, have generated cautious optimism for shifting the treatment paradigm. Importantly, emerging evidence suggests that specific herbal extracts with antioxidant, anti-inflammatory, and neuroprotective properties may serve as promising adjuncts to conventional therapy. Effective long-term management of AD may ultimately require multimodal strategies that integrate pharmacological, herbal, and lifestyle interventions with precision medicine approaches guided by biomarkers and neuroimaging. This minireview summarizes current therapeutic strategies, emerging advances, and persistent challenges, while highlighting future directions to enable earlier intervention and more effective modulation of disease progression.}, } @article {pmid42453713, year = {2026}, author = {Arachchige, ASPM and Schmiliver, B and Alves, GAM}, title = {Alzheimer's disease: A comprehensive review of epidemiology, pathophysiology, diagnosis, and treatment.}, journal = {AIMS neuroscience}, volume = {13}, number = {2}, pages = {208-243}, pmid = {42453713}, issn = {2373-7972}, abstract = {Alzheimer's disease (AD) is the most common cause of dementia, representing a major global public health challenge as populations age. It accounts for roughly 60%-80% of all dementia and is characterized by progressive cognitive decline, memory impairment, and eventual loss of independence in daily functioning. The disease unfolds over decades, with neuropathological alterations preceding the onset of clinical symptoms by many years. Alzheimer's disease is closely linked to the accumulation and deposition of cerebral amyloid-β (Aβ) and represents the most common cerebral amyloid deposition disorder. Recent advances in molecular biology, neuroimaging, and biomarker science have revealed a complex, multifactorial pathogenesis involving protein misfolding, neuroinflammation, synaptic dysfunction, vascular factors, and network-level propagation of pathology. This review synthesizes current knowledge on AD terminology, epidemiology and risk factors, clinical phenotypes and natural history, pathophysiological mechanisms, diagnostic approaches (including imaging and fluid biomarkers), and established as well as emerging therapeutic strategies, while also outlining key challenges and future directions.}, } @article {pmid42454694, year = {2026}, author = {Zakaria, FN and Baharuldin, MTH and Mat Taib, CN and Hamid, HA and Hamid, HA and Chiroma, SM and Moklas, MAM}, title = {Delta-9-tetrahydrocannabinol delineates D-galactose and aluminium chloride-induced cognitive dysfunction and neurodegeneration in the hippocampus of the Wistar rat model.}, journal = {Journal of biosciences}, volume = {51}, number = {}, pages = {}, pmid = {42454694}, issn = {0973-7138}, mesh = {Animals ; Aluminum Chloride/toxicity ; Galactose/toxicity ; Rats ; Male ; Rats, Wistar ; *Dronabinol/pharmacology ; Neurogenesis/drug effects ; Disease Models, Animal ; *Alzheimer Disease/drug therapy/chemically induced/pathology/genetics ; Doublecortin Protein ; Hippocampus/drug effects/pathology/metabolism ; *Cognitive Dysfunction/chemically induced/drug therapy/pathology/genetics/metabolism ; tau Proteins/genetics/metabolism ; Dentate Gyrus/drug effects/pathology/metabolism ; Calbindins/genetics/metabolism ; Chlorides/toxicity ; Aluminum Compounds/toxicity ; Glial Fibrillary Acidic Protein/genetics/metabolism ; Amyloid beta-Protein Precursor/genetics/metabolism ; Maze Learning/drug effects ; Cognition/drug effects ; Nerve Tissue Proteins ; Antigens, Nuclear ; }, abstract = {Alzheimer's disease (AD) is a neurodegenerative disorder characterised by neurodegeneration and a decline in cognition and memory. D-galactose (D-gal) and aluminium chloride (AlCl3) have been used to induce cognitive deterioration in rat models that mimic the alterations observed in AD. This study assessed the neurotherapeutic effect of Δ9-tetrahydrocannabinol (Δ9THC) on cognitive abilities, brain morphology, neurogenesis activity and neuropathological markers in Wistar rats induced by D-gal plus AlCl3. Male albino Wistar rats received D-gal (60 mg/kg, intraperitoneally) and AlCl3 (200 mg/kg, orally) daily for 10 weeks. The rats were then treated with increasing concentrations of Δ9THC (0.75, 1.5 and 3.0 mg/kg) for 28 days. Cognitive performance was evaluated using the novel object recognition and modified elevated plus maze tests. Dentate gyrus viable granule cells, neurogenesis markers, amyloid precursor protein and phosphorylated tau (p‑tau Thr231) were assessed histologically and molecularly. Δ9THC treatment improved cognitive performance, prevented granule cell loss in the dentate gyrus, increased neurogenesis-related markers (GFAP+, DCX+, calbindin+ and NeuN immunoreactivity), and reduced amyloid precursor protein and p‑tau Thr231 expression. These findings suggest that Δ9THC possesses promising therapeutic potential against Alzheimer's disease.}, } @article {pmid42454751, year = {2026}, author = {Biessels, GJ and Debette, S and Elahi, FM and Geranmayeh, F and Hansra, G and Hughes, TM and Ihara, M and Isaacs, J and Jokinen, H and Nott, A and Pendlebury, S and Peters, R and Schneider, J and Smith, C and Smith, EE and Vemuri, P and Wardlaw, J and Webb, A and Wilcock, DM and Hainsworth, AH}, title = {The Vascular Contribution to Dementia. World Stroke Organisation Scientific Statement.}, journal = {International journal of stroke : official journal of the International Stroke Society}, volume = {}, number = {}, pages = {17474930261470506}, doi = {10.1177/17474930261470506}, pmid = {42454751}, issn = {1747-4949}, abstract = {Alzheimer's disease (AD) and cerebrovascular pathology are the two most common causes of dementia, frequently co-occurring in older people. Community-based neuropathology studies indicate that vascular disease accounts for approximately one third of the population attributable risk of dementia, controlling for other pathologies (including AD). The proportion with vascular disease as co-pathology is likely to be higher (50-70%).The most common vascular substrate is cerebral small vessel disease, which includes small artery fibrosis (arteriolosclerosis), vascular amyloid deposits (cerebral amyloid angiopathy) and monogenic forms of small vessel disease, the commonest being Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL). Post-stroke cognitive impairment following both ischaemic stroke and intracerebral haemorrhage also contribute. In this World Stroke Organisation (WSO) scientific statement we assembled a multi-disciplinary international group of experts to review the vascular contribution to dementia, encompassing both vascular and neurodegenerative dementia. This statement has been reviewed and approved by the WSO executive.We summarize the epidemiology, neuropathology, cognitive profile, clinical impact and management of vascular disease in dementia, and discuss the recent VasCog-2-WSO diagnostic criteria. We consider the substantial overlap with clinical stroke and with AD dementia. We catalogue transcriptomic and proteomic studies that have revealed novel candidate molecules (COL4A1/4A2, HTRA1, TRIM47, FOXF2) as possible treatment targets. We appraise imaging-based biomarkers relevant to vascular disease, and potential biochemical markers (VEGF-A, PLGF, IL-6, MMP9, CTSB). We highlight the potential for vascular interventions to treat not only vascular dementia, but also the vascular component of neurodegenerative dementia. We review recent clinical trials targeting multiple pathways, including nitric oxide signalling, high blood pressure, the GABAergic system, angiogenic activity, microglial inhibition, PDE3 and PDE5 inhibition, as well as dietary supplementation with omega-3-fatty acid, s-equol and vitamin E. Finally, we consider upcoming opportunities and challenges relevant to vascular disease in dementia.}, } @article {pmid42455917, year = {2026}, author = {Kirac-Aydin, A and Pandey, BP and Mohanty, S and Mondal, R and Biswas, A and Pattnaik, AK and Mondal, S and Basavanakatti, VN and Bayrak, N and Jayaprakash, V and Kim, H and TuYuN, AF}, title = {Discovery of a Potent and Selective MAO-B Inhibitor From a Donepezil-Linked Chalcone Library With Promising Antiparkinsonian Activity.}, journal = {Drug development research}, volume = {87}, number = {5}, pages = {e70349}, doi = {10.1002/ddr.70349}, pmid = {42455917}, issn = {1098-2299}, support = {FDK-2024-40841//The Scientific Research Projects Coordination Unit of Istanbul University/ ; RS-2024-00347522//The National Research Foundation of Korea (NRF) funded by the Korean Government/ ; }, mesh = {*Monoamine Oxidase Inhibitors/pharmacology/chemistry ; Animals ; Monoamine Oxidase/metabolism ; Humans ; *Donepezil/chemistry/pharmacology ; Cholinesterase Inhibitors/pharmacology/chemistry ; *Chalcones/chemistry/pharmacology ; Rats ; Structure-Activity Relationship ; Molecular Docking Simulation ; Drug Discovery ; }, abstract = {A focused library of 19 donepezil-linked chalcones (DLCs) was efficiently synthesised through microwave-assisted Claisen-Schmidt condensation and subsequently profiled for their inhibitory activities against cholinesterases (AChE and BuChE) as well as monoamine oxidases (MAO-A and MAO-B). The DLCs exhibited potent and selective inhibition of MAO-B, with IC50 values ranging from 0.019 to 18.98 μM, whereas activity toward MAO-A was moderate to low (IC50 = 0.81 to > 20 μM). Among the tested DLCs, DLC9 and DLC14 showed the highest MAO-B inhibitory potential with IC50 values of 0.054 ± 0.004 μM and 0.019 ± 0.0015 μM, respectively, and high selectivity indexes (> 370 and > 1052, respectively), whereas DLC12 displayed notable MAO-A inhibition (IC50 = 0.81 ± 0.035 μM). Kinetic and reversibility studies revealed that the selected two lead DLCs (DLC9 and DLC14) acted as mixed-type reversible MAO-B inhibitors, with Kᵢ values of 20.0 ± 2.83 nM and 10.0 ± 2.82 nM, respectively. Furthermore, IC50 values of AChE inhibitory activities ranged from 5.40 to > 40 µM, whereas those of BuChE inhibitory activity range from 4.30 to > 40 µM. DLC6 showed the best AChE inhibitory potential with IC50 values of 5.40 ± 0.29 µM, while DLC13 revealed effective BuChE inhibitory potential with an IC50 value of 4.30 ± 0.89 µM. Molecular docking studies performed on hMAO-A and hMAO-B revealed that DLC14 establishes favourable π-π stacking within the aromatic cage of hMAO-B and maintains complementary hydrophobic contacts along the substrate cavity, whereas DLC6 lacks this key interaction due to steric interference of the ethoxy substituent. Among the three most potent MAO-B inhibitors (DLC2, DLC9, and DLC14), DLC2 exhibited the most favourable microsomal stability with the longest half-life and lowest intrinsic clearance, whereas DLC14 showed comparable metabolic profiles in rat and human liver microsomes. Experimental BBB permeability assays were hindered by compound-membrane interactions; however, in silico predictions indicated satisfactory oral bioavailability and brain penetration for all three candidates. In the MPTP-induced rat model of parkinsonism, the selective MAO-B inhibitor DLC14 and the non-selective inhibitor DLC6 significantly improved motor deficits and behavioural impairments across open field, pole, bar, rotarod, and forced swim tests, with progressive improvements observed up to Day 28. Notably, DLC14 consistently outperformed DLC6 and demonstrated an efficacy profile comparable to that of Selegiline, highlighting its therapeutic potential as an antiparkinsonian agent. These results indicate that DLC14 is potent and selective MAO-B inhibitor and could serve as promising candidate for the treatment of neurodegenerative disorders, such as Parkinson's disease.}, } @article {pmid42456348, year = {2026}, author = {Hashim, KN and Matsuba, Y and Hashimoto, S}, title = {Thioredoxin-dependent redox homeostasis modulates tau-seeded aggregation in HEK293 TauRD biosensor cells.}, journal = {Biochemical and biophysical research communications}, volume = {830}, number = {}, pages = {154297}, doi = {10.1016/j.bbrc.2026.154297}, pmid = {42456348}, issn = {1090-2104}, abstract = {Tau aggregation is a central pathological feature of Alzheimer's disease (AD) and other tauopathies. Although oxidative stress has been implicated in AD pathogenesis, the effects of intracellular redox perturbation on tau-seeded aggregation remain incompletely understood. In this study, we investigated the role of thiol redox homeostasis in tau-seeded aggregation using HEK293 TauRD fluorescence resonance energy transfer biosensor cells. Intracellular redox conditions were manipulated using the glutathione synthesis inhibitor l-buthionine-(S,R)-sulfoximine (BSO) and through overexpression or knockdown of thioredoxin (TXN), a key regulator of cellular thiol redox balance. BSO treatment significantly reduced intracellular glutathione levels without causing overt cytotoxicity, confirming successful redox alteration. However, BSO treatment failed to significantly alter tau-seeded aggregation. By contrast, TXN knockdown resulted in a modest but reproducible reduction in seeded aggregation efficiency without affecting total tau reporter expression. These findings indicate that acute glutathione depletion alone is insufficient to modulate tau-seeded aggregation in this cellular model. Furthermore, disruption of the TXN system inluences tau seeding in a manner that cannot be explained simply by increased oxidative stress. Together, our results suggest that thiol redox homeostasis contributes to the regulation of tau-seeded aggregation through mechanisms beyond a simple shift toward an oxidizing intracellular environment.}, } @article {pmid42443082, year = {2026}, author = {Li, J and Zhou, B and Yang, Y and Wang, J and Cheng, L and Zhu, C and Zhou, T and Yang, Y and Yin, W and Zhang, Y and Liu, R and Wang, L and Pu, Y and Li, Z}, title = {[Effects of moxibustion at the acupoints of governor vessel on cognitive function and gut microbiota in Alzheimer's disease model mice based on brain-gut axis].}, journal = {Zhongguo zhen jiu = Chinese acupuncture & moxibustion}, volume = {46}, number = {7}, pages = {1115-1124}, doi = {10.13703/j.0255-2930.20250414-k0003}, pmid = {42443082}, issn = {0255-2930}, mesh = {Animals ; *Moxibustion ; *Alzheimer Disease/therapy/microbiology/psychology/physiopathology/metabolism/genetics ; Mice ; Male ; *Cognition ; Humans ; Disease Models, Animal ; Mice, Inbred C57BL ; *Acupuncture Points ; *Gastrointestinal Microbiome ; Amyloid beta-Peptides/metabolism/genetics ; Tumor Necrosis Factor-alpha/metabolism/genetics ; Interleukin-6/metabolism/genetics ; *Brain/metabolism/physiopathology ; *Brain-Gut Axis ; Hippocampus/metabolism ; }, abstract = {OBJECTIVE: To observe the effects of moxibustion at the points of governor vessel on cognitive function and gut microbiota in Alzheimer's disease (AD) model mice, and explore the mechanism of moxibustion at governor vessel in treatment of AD.

METHODS: Eighteen APP/PS1 mice were randomly divided into a model group and a moxibustion group, with 9 mice in each group; and the other 9 C57BL/6J mice were collected as a blank group. In the moxibustion group, mild-warm moxibustion was operated at "Baihui" (GV20), suspended moxibustion was at "Fengfu" (GV16) and "Dazhui" (GV14), 20 min in each intervention. Moxibustion was delivered once daily for 2 weeks. The water maze test and the novel object recognition experiment were employed to evaluate the cognitive function of mice, and the contents of β-amyloid 40 (Aβ40), β-amyloid 42 (Aβ42), tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) in the hippocampus of mice were detected by ELISA, the morphology of hippocampal tissues was observed by HE staining, and the structure of fecal gut microbiota in mice was analyzed by 16S rRNA gene sequencing. The correlation of gut microbiota with the hippocampal Aβ40, Aβ42, TNF-α and IL-6 contents was analyzed.

RESULTS: Compared with the blank group, in the model group, the escape latency was extended (P<0.01), the number of platform crossings decreased (P<0.01), the target quadrant residence time ratio was reduced (P<0.01); the preference index in the novel object experiment increased (P<0.001), and the discrimination coefficient decreased (P<0.001). The contents of Aβ40, Aβ42, TNF-α and IL-6 in the hippocampus rose (P<0.05), the hippocampal neuron structure was imcomplete, with irregular size and arrangement, the neurons were vacuolar and some showed pyknosis and were reduced in number. ACE, Chao1 and Shannon indexes decreased (P<0.001) and the Simpson index rose (P<0.001). The relative abundance of Proteobacteria and Deferribacteres was reduced (P<0.001), that of Lactobacillus and Pasteurella was elevated (P<0.01), while that of Alistipes decreased (P<0.01). Compared with the model group, in the moxibustion group, the escape latency was shortened (P<0.05), the number of crossing the platform increased (P<0.05), and the target quadrant residence time ratio was higher (P<0.05); the preference index decreased (P<0.001), and the discrimination coefficient increased (P<0.001). The contents of Aβ40, Aβ42, TNF-α and IL-6 in the hippocampus decreased (P<0.01). Hippocampal tissue injury was attenuated. ACE, Chao1 and Shannon indexes increased (P<0.05), and Simpson index decreased (P<0.05). The relative abundance of Proteobacteria and Deferribacteres increased (P<0.05), that of Lactobacillus decreased (P<0.001). The correlation was presented between gut microbiota and the contents of hippocampal Aβ40, Aβ42, TNF-α and IL-6 in the moxibustion group.

CONCLUSION: Moxibustion at governor vessel points can improve cognitive function in AD mice, reduce Aβ accumulation, inhibit neuroinflammation, which may be related to the recovery of gut microbiota homeostasis.}, } @article {pmid42443567, year = {2026}, author = {Muratori, BG and Caetano, CR and da Veiga, IET and Soliani, AG and E Silva, SMS and Gava, JP and Ceridório, LF and Caselli, L and Ureshino, RP and Prado, CM and Cerutti, SM}, title = {Standardized Extract of Ginkgo biloba L. Reverses Memory Impairment in Older Female Mice with Basal Forebrain Cholinergic Dysfunction.}, journal = {Neurochemical research}, volume = {51}, number = {4}, pages = {}, pmid = {42443567}, issn = {1573-6903}, mesh = {Animals ; Female ; Ginkgo biloba ; *Plant Extracts/therapeutic use/pharmacology ; *Memory Disorders/drug therapy/metabolism ; Ginkgo Extract ; Amyloid beta-Peptides/metabolism ; Mice ; Aging/drug effects ; tau Proteins/metabolism ; Vesicular Acetylcholine Transport Proteins/genetics/metabolism ; *Prosencephalon/drug effects/metabolism ; Mice, Inbred C57BL ; Peptide Fragments ; }, abstract = {Aging induces neurochemical changes, particularly in the dentate gyrus (DG), that impair memory. In late-onset Alzheimer's disease (LOAD), neuronal loss in regions like the entorhinal cortex (EC) and hippocampus proper (HP), along with amyloid-β (Aβ) plaques, tau tangles, and reduced cholinergic signaling, accelerates cognitive decline. Building on our group's previous findings of cognitive benefits and neuroprotection from Ginkgo biloba L. leaf extract (EGb), and considering the limited success of current therapies, EGb has emerged as a promising multi-target strategy for reversing memory impairments. This study evaluates the effects of chronic EGb treatment on memory, anxiety-like behaviors, and motor activity in older female wild-type and VAChT knockdown KD[HET] and KD[HOM] mice, which show 45% and 65% reductions in VAChT expression, respectively. We assessed the impact of EGb on Aβ1-42 peptide and phosphorylated tau (pTauT231) by quantifying Aβ IR[+] and pTau IR[+] cells in the dCA1, dCA3, and dDG, via immunohistochemistry. Results showed that aging led to short- and long-term memory deficits, which were exacerbated in the VAChT KD[HOM] mice. However, EGb treatment reversed these deficits in a dose-dependent manner by modulating Aβ and pTau-IR[+] cells in the dCA1, and dDG regions. In vitro, EGb significantly inhibited Aβ aggregation through interactions with Aβ and the POPC monolayer. These findings suggest that EGb may provide a promising therapeutic strategy for AD, improving cognition and offering neuroprotection by targeting key neuropathological features like Aβ plaques and phosphorylated tau.}, } @article {pmid42443606, year = {2026}, author = {Akbari, V and Bahramikia, S}, title = {Tau physiology and pathology: impacts on cellular structures and neurodegenerative diseases.}, journal = {Inflammopharmacology}, volume = {}, number = {}, pages = {}, pmid = {42443606}, issn = {1568-5608}, abstract = {This review explores the crucial roles of the tau protein in neuronal integrity and its dysregulation in neurodegenerative diseases (NDs), particularly tauopathies. Key features include abnormal tau phosphorylation, leading to insoluble aggregates and neuronal dysfunction. Various therapeutic strategies, such as reducing tau phosphorylation, inhibiting aggregation, and enhancing clearance through autophagy and immunotherapies, are discussed. Promising candidates such as anle138b and methylene blue display efficacy in preclinical models. The interplay between tau and Aβ pathology is also highlighted, emphasizing the complexity of therapeutic approaches. A thorough understanding of tau functions is essential for developing targeted treatments to combat tau-related neurotoxicity and advance therapies for Alzheimer's disease (AD). This article examines the dual role of tau in physiology and pathology, highlighting its effects at both the cellular and subcellular levels. These findings underscore the critical importance of the tau protein in preventing NDs and suggest that a deeper understanding of its functions could improve treatment strategies for tau-related disorders.}, } @article {pmid42444486, year = {2026}, author = {Li, Q and Fan, B and Xiao, Y and Zhang, Z and Zhao, S and Liao, B and Zeng, J and Shan, X and Ye, H and Wen, Y and Zhang, L and Guo, H and Xiao, F and Zhu, H}, title = {Branched-chain amino acids and gut microbiota: coregulation and impact on neurological function via the gut-brain axis.}, journal = {Gut microbes}, volume = {18}, number = {1}, pages = {2698204}, doi = {10.1080/19490976.2026.2698204}, pmid = {42444486}, issn = {1949-0984}, mesh = {*Amino Acids, Branched-Chain/metabolism ; Humans ; *Gastrointestinal Microbiome/physiology ; Animals ; *Brain/metabolism/physiology ; *Nervous System Diseases/metabolism/microbiology ; *Gastrointestinal Tract/microbiology/metabolism ; }, abstract = {Diseases that cause neurological dysfunction, such as Parkinson's disease (PD), Alzheimer's disease (AD), and maple syrup urine disease (MSUD), among others, are characterized by complex and multifaceted etiologies. There is growing evidence that branched-chain amino acids (BCAAs), regulated by the gut microbiota, play a critical role in the development of the central nervous system (CNS) disorders. This review focuses on the potential role of branched-chain amino acid metabolism in regulating brain function and gut microbiota. First, we summarize the current understanding of BCAAs, encompassing their biochemical metabolism, function, and systemic metabolic mechanisms. Subsequently, we delve into the mechanisms through which the gut microbiota regulates branched-chain amino acid metabolism, along with its mechanistic insights and recent evidence of its impact on neurological disorders. Finally, we discuss future research directions and challenges regarding gut BCAAs metabolism as a potential treatment for brain and gastrointestinal dysfunction.}, } @article {pmid42444499, year = {2026}, author = {Sellitepe, HE and Aksel, AB and Zıvalı, H and Pehlivanlar Yavrucu, E and Sağlık Özkan, BN and Doğan, İS and Özcan Kosif, K}, title = {Structure-Guided Optimization of 1,2,4-Triazole-Thione-Based Mannich Derivatives as Dual-Target Modulators: AChE/MAO-B.}, journal = {Chemical biology & drug design}, volume = {108}, number = {1}, pages = {e70347}, doi = {10.1111/cbdd.70347}, pmid = {42444499}, issn = {1747-0285}, mesh = {*Triazoles/chemistry/metabolism ; *Acetylcholinesterase/metabolism/chemistry ; *Cholinesterase Inhibitors/chemistry/metabolism/pharmacology/chemical synthesis ; *Monoamine Oxidase/metabolism/chemistry ; Humans ; Molecular Docking Simulation ; *Monoamine Oxidase Inhibitors/chemistry/metabolism/pharmacology ; Butyrylcholinesterase/metabolism/chemistry ; Structure-Activity Relationship ; Animals ; Alzheimer Disease/drug therapy ; Binding Sites ; }, abstract = {Diseases such as Alzheimer's, Parkinson's, and depression result from neurotransmitter imbalances. In particular, for AD, it is critical to inhibit AChE to preserve the decline in acetylcholine levels and to block excessive MAO-B activity, which leads to nerve damage and cognitive impairment. As current scientific research has moved away from the "one drug for one target" approach toward a "multi-target" strategy, dual-acting inhibitors that simultaneously inhibit both AChE and MAO-B enzymes are considered the most promising new drug candidates for the treatment of Alzheimer's disease. In this study, we investigated the inhibition of AChE, BChE, MAO-A, and MAO-B in the pathophysiology of AD as a working group. Within the scope, 10 new compounds (5a-j) were synthesized, consisting of a phenolic ring, a secondary or tertiary amine tail, and a 1,2,4-triazole core. The cholinesterase and MAO inhibitory profiles of the compounds were investigated using both in vitro and in silico methods. Compound 5b exhibited dual inhibitory activity against AChE and MAO-B enzymes, with IC50 values of 0.136 ± 0.006 μM and 0.108 ± 0.005 μM, respectively. In accordance with 5b, it interacted with crucial amino acids of the hAChE and hMAO-B enzymes in the docking studies. These results suggest that 5b is a dual-target inhibitor of AChE and MAO-B and represents a promising therapeutic option for the treatment of Alzheimer's disease.}, } @article {pmid42444751, year = {2026}, author = {Zivko, C and Sagar, R and Ahmed, W and Xydia, A and Farinelli, F and Ostlund, I and Das, D and Maher, BJ and Lyketsos, CG and Mahairaki, V}, title = {Heterogeneous responses to memantine in Alzheimer's disease: A precision medicine approach using iPSC models.}, journal = {Alzheimer's & dementia (New York, N. Y.)}, volume = {12}, number = {3}, pages = {e70271}, pmid = {42444751}, issn = {2352-8737}, abstract = {INTRODUCTION: Alzheimer's disease (AD) is a complex neurodegenerative disorder characterized by progressive cognitive and functional decline. Memantine, a commonly prescribed N-methyl-D-aspartate receptor antagonist, appears to slightly delay symptom progression in moderate or advanced stages of AD. Clinical response is highly variable across patients with some benefiting but others not. Induced pluripotent stem cell (iPSC)-derived neurons can provide a donor-dependent model to predict the therapeutic efficacy of memantine.

METHODS: We generated iPSC-derived cortical neurons from 19 individuals (12 AD and 7 cognitively unimpaired [CU]). Assays for calcium influx and oxidative stress were developed and optimized for neurons. Memantine was tested under different treatment conditions. Neurons were exposed to glutamate/glycine to induce calcium influx and menadione to generate oxidative stress. Memantine treatment was applied either acutely (1 hour) or as a 24-hour pre-treatment to evaluate its neuroprotective effects.

RESULTS: Peripheral blood mononuclear cell-derived iPSCs were successfully differentiated into functional neurons, exhibiting comparable electrophysiological properties between AD and CU lines. Calcium influx assays revealed a heterogeneous response among AD and CU neurons, with AD neurons generally displaying higher baseline fluorescence. Memantine treatment for 24 hours significantly reduced calcium influx, with a -9.85% average reduction and a range of -0.39% to -39%. Similarly, reactive oxygen species assays showed menadione-induced oxidative stress was attenuated by 24-hour memantine pre-treatment for a mean -26.05% reduction and a range of -4.23% to -72.21%. The observed variability indicates differential susceptibility to excitotoxicity reduction and or oxidative stress mitigation across lines.

DISCUSSION: This exploratory study establishes a robust in vitro platform to test memantine efficacy using iPSC-derived neurons to model calcium dysregulation and oxidative stress in AD. The observed variability in response highlights the importance of personalized approaches in AD treatment, emphasizing the potential for iPSC-based platforms in precision medicine.}, } @article {pmid42444752, year = {2026}, author = {Ding, Z and Gibson, KA and Nascari, DG and Tallant, LE and Bouchal, SM and Dickson, DW and Fryer, JD}, title = {Anti-amyloid nanobody-Fc fusion protein drives potent amyloid clearance through microglial recruitment.}, journal = {Alzheimer's & dementia (New York, N. Y.)}, volume = {12}, number = {3}, pages = {e70269}, pmid = {42444752}, issn = {2352-8737}, abstract = {INTRODUCTION: Anti-amyloid beta (Aβ) monoclonal antibodies are effective at lowering amyloid in Alzheimer's disease (AD). However, whether Fc-mediated effector function is absolutely required for efficacy is not completely understood. This is important for optimizing therapeutic efficacy and mitigating side effects such as amyloid-related imaging abnormalities (ARIA). Antibodies lacking Fc effector function, like single-domain antibodies (nanobodies), offer a unique tool to dissect these mechanisms, as their small size facilitates blood-brain barrier (BBB) penetration and allows Fc-mediated functions to be studied independently.

METHODS: We immunized a llama with Aβ aggregates and constructed a phage display library to screen for aggregate-specific nanobodies. Lead candidates were characterized by epitope mapping and binding affinity to amyloid plaques in both murine and human AD brain tissues. We further assessed their BBB permeability and evaluated their efficacy in clearing pre-existing plaques in amyloid precursor protein (APP)/presenilin 1 (PS1) mice.

RESULTS: We identified two lead nanobodies, 3A11 and 2D10, that bind distinct epitopes and specifically bind Aβ plaques in murine and human AD brain tissues. Following systemic administration, the monovalent, unmodified (Fc-less) 2D10 nanobody, but not 3A11, successfully crossed the BBB and engaged amyloid plaques in APP/PS1 mice. However, despite robust target engagement, the Fc-less 2D10 failed to recruit microglia or reduce plaque burden. In contrast, an engineered 2D10-Fc fusion antibody potently cleared amyloid plaques, achieving a reduction in pathology comparable to aducanumab treatment. This efficacy was directly correlated with Fc-mediated microglial recruitment and activation, demonstrating that the Fc domain is essential for phagocytic plaque removal.

DISCUSSION: Our findings demonstrate that Fc effector function is indispensable for microglial-mediated amyloid clearance in vivo. By clarifying this fundamental mechanism, this study provides a framework for the rational design of next-generation immunotherapies. Furthermore, 2D10-Fc represents a promising therapeutic candidate, combining the high-affinity targeting of nanobodies with the effector power necessary for robust plaque clearance.}, } @article {pmid42445718, year = {2026}, author = {Kang, L and Salas-Hernandez, JL and Xu, R}, title = {Central neural circuits and their associated mechanisms of inter-organ crosstalk.}, journal = {Frontiers in cell and developmental biology}, volume = {14}, number = {}, pages = {1830768}, pmid = {42445718}, issn = {2296-634X}, abstract = {The central nervous system (CNS), which comprises the brain and spinal cord, serves as the core regulatory hub for maintaining homeostasis and coordinating diverse physiological functions. These functions include interoception, cognition, and social behavior. The intricate architecture and extensive connectivity of the CNS enable integration of multi-system responses, thereby ensuring bodily stability and adaptability. The CNS exerts profound regulatory influences on fundamental life-sustaining processes and higher-order cognitive and social functions. This is mediated by distinct neural circuits and molecular mechanisms. CNS dysfunction is strongly associated with the pathogenesis of neurological disorders (Alzheimer's disease, Parkinson's disease, stroke and epilepsy), metabolic diseases (obesity and diabetes), and cardiovascular conditions (hypertension and atherosclerosis). Given the pivotal role of the CNS in both physiological regulation and disease progression, a comprehensive understanding of CNS mechanisms is critical for identifying therapeutic targets. This review systematically examines the regulatory functions of the CNS in physiology and disease. Moreover, this review analyzes the underlying molecular and circuit-level mechanisms, and discusses potential therapeutic strategies. By elucidating the systemic interactions of the CNS, this study aims to highlight its potential as a target for innovative interventions in disease prevention, diagnosis, and treatment.}, } @article {pmid42445988, year = {2026}, author = {Delaney, HJ and Islam, S and Healy, D and Oglesby, R and Konda, M and Rietman, GM and Lynch, R and Nazmi, A and Murray, JT and Cunningham, MO and Cunningham, C}, title = {CSF1R inhibition exacerbates gamma oscillation disruption and induces network hyperexcitability in APP/PS1 mice.}, journal = {Brain : a journal of neurology}, volume = {}, number = {}, pages = {}, doi = {10.1093/brain/awag147}, pmid = {42445988}, issn = {1460-2156}, abstract = {Alzheimer's Disease is the most common neurodegenerative disease worldwide, but significant gaps in pathophysiological understanding have hampered development of disease-modifying therapies. In Alzheimer's disease, neurophysiological function is impaired, with gamma frequency oscillations - thought to be essential for higher-order cognitive processes - disrupted in both patients and animal models. However, the mechanisms driving these disruptions are unclear and, in particular, the role of neuroinflammation in these changes is poorly understood. In this study, we investigated neuronal network dynamics in acute brain slices from APP/PS1 transgenic mice. Gamma frequency oscillations had significantly reduced amplitude in APP/PS1 brain slices at 9-11 months, accompanied by an increase in beta frequency power and heightened epileptiform activity. This is suggestive of a slowing in neuronal oscillations, considered a neurophysiological hallmark of Alzheimer's disease. Immunohistochemical analysis revealed a reduction in parvalbumin- and somatostatin-positive inhibitory interneuron populations. Treatment with gabazine demonstrated increased network sensitivity to GABAA receptor antagonism, further indicating compromised inhibitory control in APP/PS1. As these altered oscillatory dynamics correlated with microglial reactivity, we hypothesised a causal role for microglia. Administration of the CSF1R inhibitor GW2580 reduced microglial proliferation, attenuated development of the disease-associated microglial phenotype and partially rescued synaptic loss; but, had no significant impact on amyloid plaque burden or cognitive deficits. Unexpectedly, GW2580 treatment exacerbated neuronal network hyperactivity and the incidence and complexity of epileptiform activity. Microglia in GW2580-treated mice showed reduced CD68 expression and decreased engulfment of synaptic elements, potentially facilitating the persistence of hyperexcitable synapses. These findings support a role of microglia in regulating neuronal network homeostasis and caution against indiscriminate suppression of microglial activity in Alzheimer's disease. Therapeutic strategies targeting microglia must account for their homeostatic functions to avoid adverse effects on neuronal network stability.}, } @article {pmid42446837, year = {2026}, author = {Hsu, CY and Raval, AD and Bainsal, N and Kaur, I and Baig, MR and Turakulov, R and Sapaev, I and Hjazi, A and Alghazali, T and Smerat, A}, title = {Molecular Regulation of Pyroptosis in Alzheimer's Disease: Linking Neuroinflammation, Cell Death, and Therapeutic Targeting.}, journal = {Molecular neurobiology}, volume = {63}, number = {1}, pages = {}, pmid = {42446837}, issn = {1559-1182}, mesh = {Humans ; *Pyroptosis/physiology/drug effects ; *Alzheimer Disease/pathology/metabolism/therapy ; Animals ; *Neuroinflammatory Diseases/pathology/metabolism ; *Cell Death/physiology ; *Molecular Targeted Therapy ; Inflammasomes/metabolism ; }, abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by profound cognitive decline, wherein chronic neuroinflammation plays a pivotal pathogenic role. Central to this inflammatory milieu is pyroptosis, a highly inflammatory form of programmed lytic cell death mediated by gasdermin proteins. This comprehensive review provides an in-depth synthesis of the cellular and molecular mechanisms underlying pyroptosis in AD. We detail the distinct roles of microglia as primary initiators responding to amyloid-beta (Aβ) and tau aggregates, alongside the specific vulnerabilities of neurons facing oxidative stress, astrocytes impacting metabolic support, and endothelial cells whose pyroptotic death contributes directly to blood-brain barrier disruption. At the molecular level, the priming and activation of the NLRP3 and NLRP1 inflammasomes by diverse triggers, including classical markers like Aβ, environmental neurotoxicants and metabolic stressors, converge on caspase-1 and caspase-8 activation. This cascade culminates in gasdermin D (GSDMD) and gasdermin E (GSDME) pore formation, leading to cellular lysis and the massive release of pro-inflammatory cytokines such as IL-1β and IL-18. Furthermore, this paper explores the emerging and critical concept of PANoptosis, highlighting the intricate crosstalk between pyroptosis, apoptosis, and necroptosis within PANoptosome complexes triggered by mitochondrial dysfunction. We evaluate current and prospective therapeutic strategies, ranging from multi-target natural and traditional herbal remedies to advanced nanomedicine, synthetic small molecules, and epigenetic gene therapies. By integrating insights from blood-based pyroptosis-associated molecular signatures and advanced targeted drug delivery systems, we emphasize the critical need for personalized, multi-targeted approaches to successfully harness pyroptosis modulation in the clinical management and treatment of AD.}, } @article {pmid42446992, year = {2026}, author = {Wong, DYK and Fu, WY and Uhm, H and Jiang, Y and Yip, YCC and Mok, VCT and Kwok, TCY and Ouyang, L and Fu, AKY and Ip, NY}, title = {Repurposing trazodone for Alzheimer's disease to modulate soluble ST2 levels and alleviate Alzheimer's pathology.}, journal = {Proceedings of the National Academy of Sciences of the United States of America}, volume = {123}, number = {29}, pages = {e2536489123}, doi = {10.1073/pnas.2536489123}, pmid = {42446992}, issn = {1091-6490}, support = {the Theme-Based Research Scheme [T13-605/18 W] the General Research Fund HKUST16104624 HKUST16102824//the Research Grants Council of Hong Kong/ ; AoE/M-604/16//the Areas of Excellence Scheme of the University Grants Committee/ ; NA//the InnoHK initiative of the Innovation and Technology Commission of the Hong Kong Special Administrative Region Government/ ; Joint Laboratory Funding Scheme [JLFS/M-604/24]//the SIAT-HKUST Joint Laboratory for Brain Science/ ; 2023B1212120004//the Guangdong-Hong Kong Joint Laboratory for Psychiatric Disorders/ ; ITCPD/17-9//the Innovation and Technology Fund for State Key Laboratory/ ; }, mesh = {*Alzheimer Disease/drug therapy/pathology/metabolism ; Animals ; *Drug Repositioning ; Humans ; Mice ; *Trazodone/pharmacology/therapeutic use ; Microglia/metabolism/drug effects/pathology ; *Interleukin-1 Receptor-Like 1 Protein/metabolism/genetics ; Amyloid beta-Peptides/metabolism ; Mice, Transgenic ; Amyloid beta-Protein Precursor/genetics ; Male ; Female ; Disease Models, Animal ; }, abstract = {Alzheimer's disease (AD) is a multifactorial disorder involving various pathological mechanisms, such as amyloidosis, immune dysfunctions, and synaptic impairments, which are important therapeutic targets. Repurposing drugs to target these mechanisms offers a promising approach to reduce the costs and duration of drug development. Genetic studies underscore the critical role of microglial clearance of amyloid-beta (Aβ) in AD pathogenesis. Specifically, soluble ST2 (sST2)-one of the two major isoforms of the ST2 protein encoded by the IL1RL1 (interleukin-1 receptor-like 1) gene-acts as a decoy receptor isoform that interferes with IL-33/ST2 signaling and has been identified as a disease-modifying factor that impairs microglial Aβ clearance functions. In this study, we investigated drug repurposing opportunities to modulate sST2 levels and alleviate AD pathologies. Unbiased screening of commonly used medications in AD patients, followed by validation in model systems, identified trazodone-an antidepressant used to treat major depressive disorder-as a leading negative regulator of sST2. Trazodone primarily suppresses sST2 expression through its antagonistic effects on adrenergic signaling. In the APP/PS1 transgenic mouse model of AD, trazodone treatment enhanced microglial interaction with Aβ and alleviated Aβ pathology. Furthermore, trazodone reduced neurodegeneration and rescued synaptic deficits in APP/PS1 mice. Comprehensive molecular profiling of APP/PS1 mouse brains showed that trazodone restored the expression of synaptic proteins critical for synaptic integrity and plasticity. Overall, these findings demonstrate that trazodone is a promising repurposing candidate for AD that targets underlying immune dysfunctions and synaptic impairment.}, } @article {pmid42447924, year = {2026}, author = {Nitrini, R and Takada, LT and Brucki, SMD}, title = {The past, present, and future of Alzheimer's disease-part 3: the future.}, journal = {Arquivos de neuro-psiquiatria}, volume = {84}, number = {6}, pages = {1-10}, doi = {10.1055/s-0046-1824435}, pmid = {42447924}, issn = {1678-4227}, abstract = {Predicting future advances in science is practically impossible because unexpected discoveries can radically change the march of ongoing processes. Predicting the nearest future may have a slightly greater chance of success. First, the diagnosis of risk factors for Alzheimer's disease (AD), based on the preponderant role of genetics, will be made very early. Diagnosis will be made with biomarkers prior to clinical manifestations. Furthermore, the prevention of AD and of dementia due to AD will be possible with better control of the many risk factors for dementia, healthier lifestyles, multi-target drugs, and genetic therapy. The relationship between AD and aging will be better understood, opening possibilities for intervention in aging itself. As the pathophysiology of AD is not unique, treatment will be individualized, according to the stage and characteristics of the disease. Most clinical trials will have surrogate markers as primary outcomes. Treatments to decrease the velocity or arrest the evolution of mild cognitive impairment (MCI) and mild dementia caused by AD will be available. Additionally, artificial intelligence (AI) will aid in the diagnosis and selection of the best treatments. Access to the new methods for diagnosing and treating AD is currently limited to a small parcel of the population, especially in low- and middle-income countries, because of their high costs. Due to the high prevalence of AD, it is possible these will become less expensive in the future. The possibility of reversing dementia once it has set in will probably have to wait for longer.}, } @article {pmid42435703, year = {2026}, author = {Ghose, A and Paidesetty, SK and Prusty, SK and Satapathy, BS and Panda, PK and Pakeeraiah, K and Mishra, A and Dandela, R}, title = {Rationally designed phytochemical-derived carbamate hybrids unveiling potent inhibition of cholinesterase and amyloid-β peptides.}, journal = {Bioorganic chemistry}, volume = {180}, number = {}, pages = {110242}, doi = {10.1016/j.bioorg.2026.110242}, pmid = {42435703}, issn = {1090-2120}, abstract = {Alzheimer's disease (AD) is most likely to be caused by the accumulation of Aβ and dysfunction of the cholinergic pathology. Oxidative damage, alterations of brain glucose metabolism, and cognitive impairment are all demonstrated in the STZ models. In order to overcome such effects, a new set of phenolic-carbamate conjugates (5a-5h) was synthesized, and their structures were elucidated using FTIR, UV, and NMR spectroscopy. The in silico studies confirmed excellent binding capabilities against AChE and Aβ targets. In vitro antioxidant assays depicted a significant free radical scavenging ability, with compound 5c exhibiting the enhanced effect. Cell line study with SH-SY5Y and PC12 cells showed greater % cell viability. AChE activity demonstrated compound 5c has significant effectiveness (IC50 = 1.98 uM). Neurobehavioral activity showed an improvement in learning and memory during behavioural assessments. In vivo antioxidant study showed greater scavenging activity (SOD, CAT, GSH), reduced of oxidative stress (MDA, NO), and the improvement in total antioxidant activity. Overall, the compound 5c has demonstrated significant results comprising decreased cholinesterase and Aβ inhibition deciphering enhanced cholinergic restoration. Hippocampal integrity was preserved, as it was confirmed by histopathological examination. It concludes that bromo-vanillyl carbamate derivative 5c (30 mg/kg) has potent antioxidant, anti-amyloid, and neuroprotective characteristics, rendering it a promising multitarget lead that warrants further investigation for the treatment of AD.}, } @article {pmid42436821, year = {2026}, author = {Shan, G and Zhang, Y and Ding, AA}, title = {Statistical inference for saved time based on disease progression curves in Alzheimer's disease research.}, journal = {Contemporary clinical trials communications}, volume = {52}, number = {}, pages = {101664}, pmid = {42436821}, issn = {2451-8654}, abstract = {Saved time is an easy interpretation metric that provides information to patients on how long a new treatment can delay the disease progression in time as compared to the placebo. The frequently used projection approach for saved time estimation utilizes limited information from the available data. To address that limitation, the area above the disease progression curve was proposed to estimate saved time by using more information from data. However, it is a challenge to derive the closed-form statistical inference (e.g., confidence interval of saved time) as area above the curve is quadratic relative to visit time and saved time based on the curves is nonlinearly related to the area above the curve. In this article, we derived the closed-form variance of saved time based on the area above curve approach by using Taylor expansion. We then compared the performance of the closed-form method and the existing simulation-based method to construct the confidence interval for saved time based on the area above curve approach with regard to coverage probability and interval width under various scenarios. The simulation results indicate that the proposed closed-form method has similar performance as compared to the existing method, while the closed-form method can be computationally easy in practice without additional simulations in the existing method. Data from the completed phase 2 donanemab trial were used to illustrate the application of the proposed method.}, } @article {pmid42437499, year = {2026}, author = {Brown, CA and Robinson, JL and Das, SR and McGrew, E and Suh, E and Van Deerlin, VM and Irwin, DJ and Nasrallah, IM and Mechanic-Hamilton, D and Yushkevich, PA and Wolk, DA and Lee, EB}, title = {Clinicopathologic Evaluation of Amyloid Clearance in Alzheimer Disease.}, journal = {JAMA}, volume = {}, number = {}, pages = {}, doi = {10.1001/jama.2026.13058}, pmid = {42437499}, issn = {1538-3598}, abstract = {IMPORTANCE: The long-term efficacy of amyloid-targeting therapies hinges on their ability to slow downstream neuropathologic change, but little is known about the influence of amyloid clearance on tau pathology and neurodegeneration.

OBJECTIVE: To determine the postmortem and in vivo association between amyloid levels and downstream neuropathology after treatment with aducanumab in a patient with patchy areas showing minimal residual amyloid levels.

This clinicopathologic case report from a single academic memory center includes a male carrier of the p.R47H TREM2 variant, which is associated with a higher risk of Alzheimer disease, who was in his 50s, had mild cognitive impairment, and received aducanumab while participating in a randomized clinical trial. Fourteen untreated controls, who were matched by age or presence of the TREM2 variant, also are included.

EXPOSURES: The male carrier of the p.R47H TREM2 variant had received 30 doses of aducanumab (cumulative dose of 280 mg/kg) over 4.5 years.

MAIN OUTCOMES AND MEASURES: Neuropathologic evaluation at autopsy, positron emission tomography to measure standardized uptake value ratio as a measure of amyloid and tau levels, and magnetic resonance imaging to determine longitudinal change in cortical thickness.

RESULTS: Four years after receiving the final dose of aducanumab, the patient died. An autopsy showed variable levels of amyloid pathology, including brain regions with very low levels of amyloid juxtaposed with brain regions that had typically high levels of amyloid in the deep cortical layers and only low levels of amyloid in the superficial cortical layers. Compared with the brain regions of the untreated controls, the brain regions of the patient after treatment with aducanumab showed low levels of amyloid that were preferentially found in the gyral crests, were associated with less tau pathology at autopsy, and were associated with slower longitudinal atrophy on in vivo magnetic resonance imaging (β = -0.50 [95% CI, -0.62 to -0.37]; t = -7.96 and P < .001). In contrast, the patient's brain regions with high amyloid burden were preferentially found in the sulcal depths and had similar levels of tau pathology as seen at autopsy in the untreated controls.

CONCLUSIONS AND RELEVANCE: In this case report, areas of extensive amyloid clearance after amyloid-targeting therapy were associated with less downstream neuropathologic change. In addition, amyloid clearance appears to preferentially occur in the gyral crests. Future studies should evaluate the differential mechanisms involved in amyloid clearance from superficial and deep cortical layers and in gyri and sulci because extensive amyloid clearance may be necessary to achieve downstream neuropathologic benefit after removal of amyloid.}, } @article {pmid42438228, year = {2026}, author = {Oh, JM and Jeong, WK and Son, HJ and Kim, SY and Oh, TW and Ji, M and Nam, JW and Baek, M and Park, JH and Shin, WH and Kim, HJ and Choi, B and Paik, MJ and Kim, H}, title = {Ameliorative Effects of a Naphthoquinone Derivative With β-Amyloid Aggregation Inhibitory Activity on Cognitive Impairment and Metabolite Analysis of the Blood and Brains of Mice.}, journal = {Drug development research}, volume = {87}, number = {5}, pages = {e70345}, doi = {10.1002/ddr.70345}, pmid = {42438228}, issn = {1098-2299}, support = {RS-2024-00347522//National Research Foundation of Korea (NRF)/ ; }, mesh = {Animals ; *Amyloid beta-Peptides/metabolism/antagonists & inhibitors ; Mice ; Brain/metabolism/drug effects ; Male ; *Naphthoquinones/pharmacology/chemistry/therapeutic use ; Humans ; *Cognitive Dysfunction/drug therapy/metabolism ; Peptide Fragments/metabolism ; Alzheimer Disease/drug therapy/metabolism ; Scopolamine ; Madin Darby Canine Kidney Cells ; *Neuroprotective Agents/pharmacology ; Cognitive Enhancement ; }, abstract = {Accumulation of amyloid-β (Aβ) plaques is an important cause of Alzheimer's disease (AD) pathogenesis. In this study, we evaluated Aβ aggregation inhibitory activity of synthesized naphthoquinone derivatives as well as improvement in cognitive functions and metabolite profiling of brain tissues using scopolamine (SCO)-induced mice. Compound 888 (2-(4-(2,3,4-trimethoxybenzyl)piperazin-1-yl)naphthalene-1,4-dione, [TPN]) showed the highest Aβ aggregation inhibitory activity (IC50 = 0.14 μM), and was more potent than the reference compound curcumin (IC50 = 1.63 μM). Compound TPN showed effective monoamine oxidase (MAO)-A, MAO-B, acetylcholinesterase, and butyrylcholinesterase inhibitions at 10 μM, likely as candidates for multitarget-directed ligands. TPN was permeable through the blood-brain barrier, and non-toxic to MDCK and SH-SY5Y cells. TPN displayed prolonged and stable interactions with Aβ42 during molecular dynamics simulations, in contrast to the short-lived contacts observed for curcumin. Cognitive impairment was significantly improved by TPN-treatment in behavioral tests. TPN treatment attenuated Aβ-related protein expression, inflammatory responses, oxidative stress-related changes, and apoptosis-related alterations, while preserving hippocampal pyramidal neurons and their typical morphology. In metabolite profiling, TPN modulated a narrower set of pathways mainly related to amino acid and kynurenine metabolism, whereas donepezil induced broader adjustments involving amino acid, mitochondrial/energy, and lipid-related pathways compared to those in the serum and cortex of the SCO group, in contrast to those in the hippocampus. Collectively, a potent Aβ aggregation inhibitor TPN showed significant cognitive improvement, accompanying by neuroprotective effects, decreasing inflammation, and retaining neuron structures, exhibiting changed metabolic profiles compared to the control treatments. These findings suggest that TPN has cognitive-protective and neuroprotective potential under scopolamine-induced impairment conditions and warrants further validation in AD-relevant models.}, } @article {pmid42438861, year = {2026}, author = {Liu, X and Lin, T and Jiang, Y and Luo, S and Chen, S and Chai, Y and Yang, Z and Wei, Y and Wang, H and Li, X and Xiang, YT and Sha, F and Tang, J}, title = {Antidepressant use and dementia, cognitive measures, and neuroimaging outcomes: A population-based cohort study.}, journal = {Psychological medicine}, volume = {56}, number = {}, pages = {e225}, doi = {10.1017/S0033291726104942}, pmid = {42438861}, issn = {1469-8978}, support = {82404371//National Natural Science Foundation of China/ ; 72304267//National Natural Science Foundation of China/ ; }, mesh = {Humans ; *Antidepressive Agents/therapeutic use/adverse effects ; Female ; Male ; *Dementia/epidemiology/diagnostic imaging ; Aged ; Neuroimaging ; Prospective Studies ; *Cognition/drug effects ; United Kingdom/epidemiology ; Middle Aged ; Magnetic Resonance Imaging ; Brain/diagnostic imaging ; Cohort Studies ; UK Biobank ; }, abstract = {BACKGROUND: Prior observational studies have reported conflicting results regarding whether antidepressant treatment reduces long-term dementia risk, likely due to confounding by indication and reverse causation. We aimed to investigate the association between baseline antidepressant use and incident dementia, incorporating cognitive and neuroimaging outcomes.

METHODS: We conducted a prospective cohort study using UK Biobank participants free of dementia at baseline. Antidepressant use was self-reported at baseline (2006-2010). Incident dementia was identified through linked electronic health records until December 19, 2022. Cox proportional hazards models estimated hazard ratios (HRs) for all-cause dementia, Alzheimer's disease (AD), and vascular dementia (VD), adjusting for sociodemographic, lifestyle, health-related, antidepressant indication factors, and co-medication of other anticholinergics. In subsamples, cognitive performance (n = 57,330) and structural brain imaging (n = 42,276) were examined as intermediate outcomes.

RESULTS: Among 461,464 participants, 33,721 (7.3%) reported baseline antidepressant use. Over a mean follow-up of 13.4 years, 7,922 (1.7%) developed incident dementia. Baseline antidepressant use was associated with higher risks of all-cause dementia (adjusted HR: 1.47, 95% CI 1.36-1.60), AD (1.53, 1.36-1.73), and VD (1.44, 1.23-1.70). Users performed worse on fluid intelligence and prospective memory tasks and showed lower total and gray matter volume, regional reductions in the hippocampal gray matter and basal nucleus, and greater white matter hyperintensity volume.

CONCLUSIONS: Baseline antidepressant use was linked to a higher risk of dementia, poorer cognitive performance, and adverse brain structural changes. These findings underscore the importance of judicious prescribing, regular cognitive monitoring, and consideration of non-pharmacological approaches in clinical care.}, } @article {pmid42439335, year = {2026}, author = {Singh, S and Singh, S and Khandelwal, V and Bharti, U and Singh, PK}, title = {Gut Microbiota in Neuroinflammation, Neurodegenerative Disorders, and Neuropsychiatric Disorders: A Comprehensive Narrative Review.}, journal = {CNS & neurological disorders drug targets}, volume = {}, number = {}, pages = {}, doi = {10.2174/0118715273455874260702045636}, pmid = {42439335}, issn = {1996-3181}, abstract = {Neurodegenerative and neuropsychiatric illnesses are characterized by neuroinflammation, which is driven by microglial activation, cytokine production, and breakdown of the blood-brain barrier (BBB). It is currently known that the gut microbiota plays an important role in modulating neuroimmune signaling, which in turn may trigger anxiety-like behaviors and depressive phenotypes through the microbiota-gut-brain axis. This review aims to integrate the most recent mechanistic knowledge on treatment strategies targeting the gut microbiota to modulate neuroinflammation. This review article discusses preclinical and clinical studies that investigated microbial composition, metabolite profiles, and host-microbe interactions involved in neuroinflammatory processes. However, special attention was given to signaling via the vagus nerves and bile acids, as well as to tryptophankynurenine metabolism and short-chain fatty acids (SCFAs). To examine the potential connection between the two, researchers used animal models such as germ-free animals and antibiotic-injected mice for fecal microbiota transplantation (FMT). This article defines dysbiosis as amplifying neuroinflammatory responses by altering microglial phenotypes, disrupting the blood-brain barrier, and triggering the production of pro-inflammatory cytokines. In contrast, microbiome diversity rehabilitation through the use of probiotics, prebiotics, synbiotics, and dietary modifications reduces neuroinflammatory markers and enhances cognitive and behavioral status. Clinical trials have shown considerable promise in diseases such as Alzheimer's disease (AD), Parkinson's disease (PD), autism spectrum disorder (ASD), and depression. However, variability in treatment protocols, treatment resistance, and host-specific factors continue to pose significant challenges. This narrative review integrates mechanistic insights into microglial activation, cytokine signaling, blood-brain barrier regulation, vagal pathways, tryptophan metabolism, and short-chain fatty acids with emerging clinical evidence and therapeutic strategies, including probiotics, prebiotics, dietary modulation, and personalized microbiome-based interventions. Despite promising therapeutic potential, microbiome engineering faces important challenges, including safety concerns, lack of standardized intervention protocols, and substantial inter-individual variability in host-microbiome responses, which currently limit clinical translation. This review focuses on both neurodegenerative and neuropsychiatric disorders, examining shared neuroinflammatory mechanisms mediated by the gut-brain axis and evaluating microbiotatargeted therapeutic strategies across these disease categories. The review discusses both preventive strategies, including dietary modulation, prebiotics, and lifestyle-based microbiome interventions, as well as therapeutic approaches such as microbiota-targeted treatments aimed at mitigating neuroinflammation and disease progression.}, } @article {pmid42439669, year = {2026}, author = {Robert, J}, title = {What Are the Potential Therapeutic Benefits of Targeting Blood-Borne Lipoproteins in the Treatment of Alzheimer's Disease?.}, journal = {Cells}, volume = {15}, number = {13}, pages = {}, doi = {10.3390/cells15131191}, pmid = {42439669}, issn = {2073-4409}, mesh = {Humans ; *Alzheimer Disease/drug therapy/blood/therapy ; *Lipoproteins/blood/metabolism ; Animals ; Amyloid beta-Peptides/metabolism ; Lipoproteins, HDL ; }, abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by cognitive decline, the deposition of amyloid-β (Aβ) plaques, the formation of neurofibrillary tangles, and cerebrovascular dysfunction. Evidence suggests that blood-borne lipoproteins play a role in the disease's pathophysiology by influencing the cerebrovasculature and amyloid metabolism. Low-density lipoprotein (LDL) and very-low-density lipoprotein (VLDL) can contribute to oxidative stress, endothelial dysfunction, vascular dysfunction, and the accumulation of amyloidogenic peptides, thereby exacerbating neurodegeneration. The role of lipoprotein(a) (Lp(a)) remains unclear, whereas high-density lipoprotein (HDL) is recognized for its cerebroprotective properties, including anti-inflammatory and vasoreactive functions. These properties help to maintain neuronal homeostasis and facilitate the clearance of Aβ from the brain. This review summarizes the current evidence regarding the role of lipoproteins in AD and discusses how therapeutic strategies targeting lipoprotein pathways, such as lipid-lowering agents and HDL mimetics developed for cardiovascular diseases, may benefit patients with AD.}, } @article {pmid42440180, year = {2026}, author = {Mohamadpour, M and Amandadi, M and Javan, M and Hosseinkhani, S}, title = {A Combination of Artemisinin, N-acetylcysteine, Resveratrol, and Hesperidin Ameliorates Hippocampal Damage and Pathological Features in an Experimental Model of Alzheimer's Disease.}, journal = {Neurochemical research}, volume = {51}, number = {4}, pages = {}, pmid = {42440180}, issn = {1573-6903}, mesh = {Animals ; *Resveratrol/therapeutic use/administration & dosage ; *Alzheimer Disease/drug therapy/pathology/chemically induced/metabolism ; *Hippocampus/drug effects/pathology/metabolism ; *Hesperidin/therapeutic use/administration & dosage ; *Acetylcysteine/therapeutic use/administration & dosage ; Male ; *Artemisinins/therapeutic use/administration & dosage ; *Neuroprotective Agents/therapeutic use/administration & dosage ; Rats ; Disease Models, Animal ; Drug Therapy, Combination ; Streptozocin ; Amyloid beta-Peptides/metabolism ; tau Proteins/metabolism ; Maze Learning/drug effects ; Rats, Sprague-Dawley ; }, abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by cognitive impairment and pathological accumulation of amyloid-β and tau proteins. This study investigated the potential neuroprotective effects of a combined treatment consisting of artemisinin, N-acetylcysteine, resveratrol, and hesperidin in a streptozotocin (STZ)-induced intracerebroventricular (ICV) rat model of AD. Twenty 8-week-old rats were divided into four groups: control, SHAM, STZ-ICV, and STZ-ICV receiving oral administration of the compound combination for 30 days. Cognitive performance was evaluated using the Morris water maze and passive avoidance tests. Neurodegenerative and molecular changes were assessed through Western blot analysis of phosphorylated tau, amyloid-β-related markers, and apoptosis- and inflammation-associated proteins. Histological analyses included Nissl staining and immunofluorescence for amyloid deposition and caspase-3 expression. Results demonstrated that STZ-ICV administration induced significant cognitive impairment, neuronal loss, and increased amyloid-β and phosphorylated tau levels. Treatment with the combined compounds partially improved behavioral performance and was associated with reductions in amyloid-β deposition, tau phosphorylation, and caspase-3 expression, along with improved neuronal preservation in the hippocampus. These findings suggest that the combined administration of artemisinin, N-acetylcysteine, resveratrol, and hesperidin exerts multi-target neuroprotective effects in an experimental AD model, potentially through modulation of oxidative stress, neuroinflammation, and apoptotic pathways. However, further studies are required to evaluate pharmacokinetics, safety, and translational relevance before clinical application.}, } @article {pmid42440193, year = {2026}, author = {Adiniaev, Y and Omar, M and Daniel, O and Timor, TM and Barash, Y and Brook, OR and Klang, E and Gorenshtein, A}, title = {Generative large language models in the clinical management of Alzheimer's disease and mild cognitive impairment.}, journal = {Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology}, volume = {47}, number = {8}, pages = {}, pmid = {42440193}, issn = {1590-3478}, mesh = {Humans ; *Alzheimer Disease/therapy/diagnosis ; *Cognitive Dysfunction/therapy/diagnosis ; *Large Language Models ; Generative Artificial Intelligence ; }, abstract = {BACKGROUND: Dementia affects over 55 million people worldwide. Mild cognitive impairment (MCI) often precedes Alzheimer's disease (AD). Clinical management requires integrating uncertain evidence from neuropsychological testing, neuroimaging, and biomarkers. Large language models (LLMs) also generate probabilistic outputs, but whether they can reliably support diagnostic, therapeutic, or educational tasks in AD and MCI has not been systematically examined.

METHODS: We searched PubMed, Scopus, and PubMed Central (January 2023 to April 2026) for studies evaluating generative LLMs on clinical tasks in Alzheimer's disease (AD) or mild cognitive impairment (MCI). Risk of bias was assessed using QUADAS-AI and AXIS. Narrative synthesis followed the SWiM guideline.

PROSPERO: CRD420261372436.

RESULTS: Eleven studies were included: diagnosis (n = 3), treatment guidance (n = 2), and patient/caregiver education (n = 8); two studies contributed to multiple domains. Diagnostic models achieved high internal accuracy (0.94-0.97) but declined on external validation; three-way classification accuracy dropped approximately 7% points, and MMSE-prediction R² collapsed from 0.90 to 0.25 on an external dataset. Treatment guidance approached but did not match structured clinical guidelines. Educational outputs were rated moderate to high quality but lacked source attribution and exceeded recommended reading levels; retrieval augmentation improved usability without improving accuracy. Hallucination was quantified in only 2 of 11 studies, and no study evaluated prospective clinical use.

CONCLUSIONS: Current evidence does not support the use of LLMs for diagnosis, treatment selection, or patient education in AD/MCI without clinician oversight. These findings reflect the specific model versions, prompting strategies, and evaluation conditions in place at the time of each study, and are further limited by small heterogeneous evaluations, sparse hallucination measurement, and absence of prospective clinical validation.}, } @article {pmid42440589, year = {2026}, author = {Huang, X and Xu, G and Zhou, Y and Wang, D and Ai, L and Liu, H and Fan, A and Wang, L and Zhang, P}, title = {P2-engineered exosomes encapsulating curcumin alleviate cognitive decline in AD-like mice by improving microglia-related neuropathology.}, journal = {Materials today. Bio}, volume = {39}, number = {}, pages = {103388}, doi = {10.1016/j.mtbio.2026.103388}, pmid = {42440589}, issn = {2590-0064}, abstract = {Natural exosomes, as drug carriers, can deliver anti-inflammatory agents across the blood-brain barrier (BBB) to lesion sites in the brain, thereby demonstrating immense potential in the treatment of brain inflammation-related diseases. However, the application of natural exosomes is constrained by their poor targeting ability. Herein, we report a novel drug delivery system (P2-Exo-Cur) constructed by engineering exosomes to display the P2 peptide on their surface, thereby enabling targeted delivery of curcumin to microglia. Our results revealed that P2-Exo-Cur possesses a nanoscale membrane structure and can efficiently deliver curcumin to microglia both in vitro and in vivo. This technology provides a microglia-targeted delivery approach for anti-inflammatory agents such as curcumin, while overcoming the undesirable off-target effects that limit their efficacy. Furthermore, treatment of lipopolysaccharide (LPS)-induced inflammatory BV2 cell models with P2-Exo-Cur significantly suppressed the polarization of BV2 cells toward the M1 phenotype, as well as the secretion of pro-inflammatory cytokines. Finally, we also validated the excellent therapeutic potential of this technology in the 5xFAD mouse model. In conclusion, in this study, we for the first time constructed engineered exosomes that can specifically bind to the NCAM protein on microglia to achieve precise delivery of curcumin by expressing the P2 peptide on their surface, exerting beneficial effects in AD treatment without causing significant adverse effects. This strategy may offer a non-invasive and innovative therapeutic method for the management of brain inflammation-related diseases.}, } @article {pmid42440665, year = {2026}, author = {Han, J and Sun, Y and Song, Y and Wu, Y and Wang, X}, title = {The latest research progress of ligustilide in the prevention and treatment of central nervous system disorders.}, journal = {Frontiers in pharmacology}, volume = {17}, number = {}, pages = {1843537}, doi = {10.3389/fphar.2026.1843537}, pmid = {42440665}, issn = {1663-9812}, abstract = {BACKGROUND: Ligustilide (LIG), a natural phthalide compound mainly isolated from Angelica sinensis and Ligusticum chuanxiong, has attracted increasing attention because of its diverse pharmacological activities, including anti-inflammatory, antioxidant, anti-apoptotic, and neuroprotective effects. Emerging studies suggest that LIG may have therapeutic relevance in central nervous system (CNS) disorders.

PURPOSE: This review systematically summarizes the pharmacological effects, molecular mechanisms, pharmacokinetic characteristics, metabolism, safety profile, and therapeutic potential of LIG in CNS disorders.

METHODS: Relevant studies published up to 26 October 2025 were retrieved from PubMed, Web of Science, and Scopus using keywords related to ligustilide, central nervous system disorders, pharmacokinetics, metabolism, and toxicity. After removing duplicate records and excluding reviews, editorials, and irrelevant articles, 55 eligible original studies were included in this review.

RESULTS: Current evidence indicates that LIG exerts neuroprotective effects in multiple CNS disorders, including ischemic stroke, cerebral ischemia-reperfusion injury, vascular dementia, Alzheimer's disease, Parkinson's disease, traumatic brain injury, and anxiety disorders. Its mechanisms mainly involve modulation of PI3K/Akt, MAPK, NF-κB, Nrf2/ARE, AMPK, and other signaling pathways, leading to reduced oxidative stress, inflammation, apoptosis, and mitochondrial dysfunction. In addition, available studies suggest that LIG can cross the blood-brain barrier and shows relatively favorable safety in preclinical models.

CONCLUSION: LIG demonstrates broad neuroprotective potential in preclinical studies and may represent a promising candidate for CNS disease intervention. However, its poor chemical stability, low oral bioavailability, limited toxicity evaluation, and lack of clinical evidence remain major challenges for translational application. Further studies are required to optimize delivery strategies and validate its efficacy and safety in clinical settings.}, } @article {pmid42440686, year = {2026}, author = {Feng, X and Bi, S and Shi, C and Chang, Q and Zhang, J and Zhuang, Y}, title = {Comparison of safety of lecanemab and donanemab: a real-world disproportionality analysis using the FDA adverse event reporting system.}, journal = {Frontiers in pharmacology}, volume = {17}, number = {}, pages = {1868789}, doi = {10.3389/fphar.2026.1868789}, pmid = {42440686}, issn = {1663-9812}, abstract = {BACKGROUND: Lecanemab and donanemab are anti-amyloid-β (Aβ) monoclonal antibodies recently approved for the treatment of Alzheimer's disease (AD). Although both agents have demonstrated therapeutic potential, their post-marketing adverse event reporting profiles remain insufficiently characterized and compared in spontaneous reporting systems. This study aimed to systematically compare adverse event signals associated with these two drugs using the FDA Adverse Event Reporting System database, with sex-stratified and sensitivity analyses performed to support the main findings.

METHODS: FAERS reports up to the fourth quarter of 2025 were retrospectively analyzed. Reports in which lecanemab or donanemab was recorded as the primary suspect drug were included. AEs were classified by system organ classes (SOCs) and preferred terms (PTs) according to the Medical Dictionary for Regulatory Activities (MedDRA). Signal detection was performed using four algorithms: reporting odds ratio (ROR), proportional reporting ratio (PRR), Bayesian confidence propagation neural network (BCPNN), and multi-item gamma Poisson shrinker (MGPS). Sex-stratified analysis, sensitivity analysis after excluding reports involving concomitant medications, and time-to-onset (TTO) analysis based on the Weibull shape parameter model were also conducted. False discovery rate (FDR) correction was applied to analyses involving multiple P values.

RESULTS: A total of 3,640 AE reports were identified, including 2,602 for lecanemab and 1,038 for donanemab. Nervous system disorders was the most frequently reported SOC and the only SOC meeting the positivity criteria across all four algorithms for both drugs. At the PT level, the frequently reported events for both drugs were mainly concentrated in amyloid-related imaging abnormality (ARIA)-related events, including ARIA with oedema/effusion (ARIA-E) and ARIA with microhaemorrhages/haemosiderin deposition (ARIA-H), headache, and infusion-related reactions. The strongest disproportionality reporting signals were mainly observed for ARIA-related preferred terms and cerebral microhaemorrhage. In separate FAERS-based disproportionality analyses, lecanemab showed stronger disproportionality reporting signals for ARIA-H, whereas donanemab showed stronger disproportionality reporting signals for ARIA-E. In addition, drug-specific PT signal distributions differed between the two agents. Several potential novel PT signals were also identified. Sex-stratified analysis suggested differences in the distribution of certain PT signals between female and male reports. Sensitivity analysis supported the stability of most core signals. The median TTO was 46 days for lecanemab and 31 days for donanemab, and Weibull analysis suggested different temporal patterns of AE occurrence.

CONCLUSION: Using four signal detection algorithms, this study compared real-world adverse event reporting profiles associated with lecanemab and donanemab. The two drugs showed both shared and distinct adverse event reporting profiles, particularly in ARIA subtype-related disproportionality signals, drug-specific PT signals, potential novel reporting signals, sex-stratified reporting patterns, and TTO characteristics. These findings provide pharmacovigilance evidence for targeted safety monitoring and hypothesis generation, but should not be interpreted as causal associations or true incidence estimates.}, } @article {pmid42440728, year = {2026}, author = {Badesso, S and Espelosín, M and Alonso, C and Montilla, A and Collantes, M and Cuadrado-Tejedor, M and García-Osta, A}, title = {Reprogramming lipid metabolism for cognitive restoration in Alzheimer's via PLA2G4E.}, journal = {Alzheimer's & dementia (New York, N. Y.)}, volume = {12}, number = {3}, pages = {e70285}, doi = {10.1002/trc2.70285}, pmid = {42440728}, issn = {2352-8737}, abstract = {INTRODUCTION: Growing evidence implicates dysregulated brain lipid metabolism in Alzheimer's disease (AD) pathogenesis, influencing membrane integrity, neuroinflammation, and amyloid beta and tau pathology, thereby representing a promising therapeutic target. However, therapeutic strategies targeting lipid pathways remain largely unexplored.

METHODS: The therapeutic potential of PLA2G4E, previously identified in our earlier work, was validated in the APP[NL-G-F] AD mouse model using a translational gene-delivery approach with a blood-brain barrier-penetrant adeno-associated vector (AAV) (AAVP31) to achieve widespread brain expression. Brain lipidomics was performed to investigate the molecular mechanisms underlying treatment effects.

RESULTS: PLA2G4E expression rescued memory deficits, reduced tau phosphorylation, and improved brain glucose metabolism and cognitive performance in AD models and aged wild-type mice. These effects were accompanied by partial normalization of disease-associated lipid metabolic alterations.

DISCUSSION: These findings support PLA2G4E as a promising therapeutic target in AD and provide mechanistic evidence linking modulation of lipid metabolic pathways to synaptic and cognitive rescue.}, } @article {pmid42440762, year = {2026}, author = {Xing, X and Wang, K and Feng, Y and Wu, C and Jia, L and Li, H and Wen, Z and Tang, Y and Wang, Z and Zhang, X and Li, X and Hua, Y and Zhang, L and Dong, X}, title = {Post-marketing safety of lecanemab: a real-world study based on FAERS database, multicenter cohort and network pharmacology.}, journal = {Frontiers in psychiatry}, volume = {17}, number = {}, pages = {1822543}, doi = {10.3389/fpsyt.2026.1822543}, pmid = {42440762}, issn = {1664-0640}, abstract = {INTRODUCTION: Lecanemab is a monoclonal antibody targeting amyloid-beta (Aβ) approved for treating Alzheimer's disease (AD) with mild cognitive impairment or mild dementia. Continuous monitoring of its real-world safety profile remains essential. This study aimed to analyze lecanemab-related adverse events (AEs) using the FDA Adverse Event Reporting System (FAERS) database and a multicenter cohort, and explored mechanisms via network pharmacology.

METHODS: We conducted an updated disproportionality analysis of FAERS data from 2023 to 2024 to identify disproportionate reporting signals (SDRs). A multicenter retrospective cohort study was performed, including lecanemab users from June 2024 to February 2025. Data were collected from electronic medical records of five tertiary hospitals. AEs were identified and influencing factors of AE occurrence were analyzed. Additionally, a drug-gene interaction network was constructed to explore potential mechanisms.

RESULTS: In the FAERS analysis of 2,764 AEs from 1,389 lecanemab users, 12 of 41 positive SDRs were prioritized, with 75% (9/12) being nervous system disorders, primarily amyloid-related imaging abnormalities (ARIA). In the cohort study, 29.05% (43/148) of patients experienced AEs, with infusion-related reactions being most common. Age was identified as a risk factor for AE occurrence [OR (95% CI): 1.109 (1.011-1.215), P = 0.028], while pre-treatment significantly reduced AE incidence. Gene enrichment analysis suggested potential links between lecanemab-related genes and AEs.

DISCUSSION: This study provides real-world evidence on the risk profile of lecanemab, highlighting the importance of continued safety monitoring. These findings may inform discussions about the risks associated with anti-amyloid treatments and warrant further confirmation in large-scale prospective studies.}, } @article {pmid42441396, year = {2026}, author = {Fleisher, AS and Munsie, L and Mancini, M and Cheng, YJ and Guo, J and Nuthall, H and Otero, DS and Kotari, V and Kielbasa, W and Hutton, M and Brys, M and Mergott, DJ and Mintun, M and Hansson, O}, title = {Ceperognastat in Early Symptomatic Alzheimer Disease: A Randomized Clinical Trial.}, journal = {JAMA}, volume = {}, number = {}, pages = {}, doi = {10.1001/jama.2026.12768}, pmid = {42441396}, issn = {1538-3598}, abstract = {IMPORTANCE: Inhibiting O-linked N-acetylglucosaminidase (OGA) is hypothesized to slow accumulation of aggregated, hyperphosphorylated tau and neurofibrillary tangle formation.

OBJECTIVE: To evaluate the efficacy and safety of the potent oral OGA inhibitor ceperognastat in early symptomatic Alzheimer disease (AD).

This double-blind, randomized, placebo-controlled phase 2 study was conducted at 72 sites in 5 countries from September 2021 to August 2024, with a posttreatment observational extension period through May 2025. The primary outcome population comprised participants with early symptomatic AD and biomarker evidence of tau pathology, including low to medium baseline tau levels (excluding individuals with high levels), as measured by positron emission tomography (PET) with flortaucipir F18.

INTERVENTION: Participants were randomized 1:1:1 to receive once-daily, oral ceperognastat at doses of 0.75 mg (n = 110) or 3 mg (n = 108) or placebo (n = 108).

MAIN OUTCOMES AND MEASURES: The primary outcome was change in Integrated AD Rating Scale (iADRS) score. The success criterion was a 60% or greater probability of achieving greater than or equal to 25% slower progression vs placebo using a bayesian probabilistic disease progression model. The 6 secondary outcomes were Alzheimer's Disease Assessment Scale-Cognitive Subscale, 13-item version; Alzheimer's Disease Cooperative Study-Activities of Daily Living scale; Clinical Dementia Rating-Sum of Boxes; Mini-Mental State Examination; tau PET; and volumetric magnetic resonance imaging.

RESULTS: Of the 327 randomized participants (mean age, 73.4 years; 201 [61.5%] females), 259 (87 receiving ceperognastat 0.75 mg, 86 receiving ceperognastat 3 mg, and 86 receiving placebo) with low to medium baseline tau levels were included in the primary outcome population (mean age, 74.3 years; 161 [62.2%] females). In this population, no clinically meaningful benefit vs placebo was observed for the primary end point (iADRS score) at 100 weeks: posterior mean change from baseline was -8.39 with ceperognastat 0.75 mg, -13.27 with ceperognastat 3 mg, and -10.07 with placebo. The disease progression ratio relative to placebo was 0.84 (95% credible interval [CrI], 0.66-1.04) for the ceperognastat 0.75 mg group and 1.32 (CrI, 1.10-1.58) for the ceperognastat 3 mg group, corresponding to 16% less and 32% greater progression, respectively. No benefits were demonstrated for secondary clinical end points. From baseline to 76 weeks, least-squares mean change in standardized uptake value ratio on PET showed a statistically significantly smaller increase (P = .04) vs placebo only for the ceperognastat 3 mg group in the lateral temporal lobe. Volumetric magnetic resonance imaging showed less whole brain volume loss in participants treated with ceperognastat vs placebo (43.2% [ceperognastat 0.75 mg] and 49.5% [ceperognastat 3 mg] less vs placebo; both P < .001). The ceperognastat 3 mg group had more serious (ceperognastat 0.75 mg: n = 13 [12.0%]; ceperognastat 3 mg: n = 29 [26.4%]; placebo: n = 17 [15.7%]) and severe (ceperognastat 0.75 mg: n = 7 [6.5%]; ceperognastat 3 mg: n = 15 [13.6%]; placebo: n = 7 [6.5%]) treatment-emergent adverse events.

CONCLUSIONS AND RELEVANCE: Ceperognastat did not slow disease progression of early symptomatic AD.

TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT05063539.}, } @article {pmid42441421, year = {2026}, author = {Wang, L and Cai, Q and Yang, Y and Zhou, Y and Liu, Y and Wu, P and Liu, J and Liu, Y}, title = {A Multitarget Nanosystem Loaded with Donepezil for Alzheimer's Disease Treatment by Activating Mitophagy and Reshaping the Inflammatory Microenvironment.}, journal = {ACS applied materials & interfaces}, volume = {}, number = {}, pages = {}, doi = {10.1021/acsami.6c05393}, pmid = {42441421}, issn = {1944-8252}, abstract = {A paradigm shift from single-target interventions toward multitarget synergistic actions is increasingly recognized as a promising therapeutic approach for Alzheimer's disease (AD). Given this, an oxidative stress-responsive nanocomposite, RuO2-TPP/Don@BSA (RDB), was developed to enable effective AD therapy via a "cocktail strategy". Utilizing bovine serum albumin (BSA), the system crosses the blood-brain barrier (BBB) through gp60 receptor-mediated endocytosis. Within the AD brain microenvironment, RDB undergoes disulfide bond cleavage in response to elevated H2O2 levels, thereby releasing donepezil (Don) and RuO2-TPP in a stimuli-responsive manner. Meanwhile, RuO2-TPP escapes from lysosomes, targets mitochondria, and interrupts the oxidative stress cascade, further repairing mitochondrial dysfunction and activating mitophagy. Moreover, RDB promotes the polarization of microglia from the pro-inflammatory M1 phenotype to the anti-inflammatory M2 phenotype, thereby reshaping the inflammatory microenvironment of AD. Finally, RDB demonstrated significant efficacy in APP/PS1 transgenic AD mice, markedly reducing hippocampal expression of GFAP and Iba-1, concomitant with a notable improvement in cognitive dysfunction. In summary, these findings establish RDB as a multitarget synergistic therapeutic system that offers a promising strategy for the treatment of AD.}, } @article {pmid42442404, year = {2026}, author = {Marsden, M and McLaren, JE and Bevan, RJ and Penn-Ripley, D and Somerville, M and Lauder, SN and Jones, MH and Maros, LB and McGurk, MR and Gallimore, A and Price, DA and Miners, KL and Ladell, K and Siebzehnrubl, FA and Hughes, TR and Humphreys, IR and Clement, M}, title = {Cytomegalovirus-induced T cell responses accelerate Alzheimer's disease progression in mice.}, journal = {Brain : a journal of neurology}, volume = {}, number = {}, pages = {}, doi = {10.1093/brain/awag043}, pmid = {42442404}, issn = {1460-2156}, support = {//Jane Hodge Foundation/ ; MR/X00922X/1/MRC_/Medical Research Council/United Kingdom ; 207503/Z/17/Z/WT_/Wellcome Trust/United Kingdom ; //Brain Tumour Charity/ ; MR/V000489/1//MRC/ ; MR/S07709/1//MRC/ ; MR/X018318/1//MRC/ ; }, abstract = {Infections have long been implicated as causative factors in Alzheimer's disease (AD). Multiple studies have further suggested a key role for herpesviruses, such as cytomegalovirus (CMV). Using transgenic 3xTg-AD mice, we demonstrate that systemic infection with the β-herpesvirus murine CMV (MCMV) accelerates the development of cognitive decline, tauopathy and synaptic loss in the hippocampus, all of which are key features of AD. Accelerated disease progression after infection was associated with substantial lymphocyte infiltration into the brain, dominated by MCMV-specific effector memory CD8+ T cells expressing CXCR3. T cell receptor analyses revealed that clonally diverse virus-specific CD8+ T cells were selectively recruited into the brain during the development of AD. T cell depletion or treatment with the antiviral drug valganciclovir during chronic infection reduced lymphocytic infiltrates in the brain and reversed cognitive decline. These data provide a mechanistic link between chronic viral infections and the development of AD.}, } @article {pmid42442677, year = {2026}, author = {Shu, XD and Liu, HF and Liao, YQ and Pu, WJ and Zhao, T and Pan, WD and Zhang, N and Li, JY}, title = {Saebias A-G, eudesmane sesquiterpenes from Salvia plebeia with potential for Alzheimer's disease prevention via anti-neuroinflammatory and neuroprotective effects.}, journal = {Phytochemistry}, volume = {}, number = {}, pages = {115024}, doi = {10.1016/j.phytochem.2026.115024}, pmid = {42442677}, issn = {1873-3700}, abstract = {Saebias A-G (1-7), seven previously undescribed eudesmane sesquiterpenoids compounds and seventeen known compounds were isolated from Salvia plebeia R.Br. Among them, compound 1 is a unique C16-type eudesmane sesquiterpenoid featuring a 6/6/5-membered scaffold, 2-3 are nor-eudesmane sesquiterpenoids and 5 contains a rare 6/6/3/5 tetracyclic skeleton. Their structures including absolute configurations were elucidated by extensive spectroscopic methods, single-crystal X-ray crystallographic and ECD calculation. All compounds were evaluated for their inhibitory effect on nitric oxide (NO) production induced by lipopolysaccharide (LPS) in BV-2 cells and neuroprotective effect induced by H2O2 in PC12 cells. The results showed that four compounds exhibited significant NO inhibitory effects, with IC50 values ranging from 0.76 to 3.72 μM. Among them, compound 2 showed significant inhibitory effect, which significantly suppressed the production of IL-6, IL-1β, and iNOS in a concentration-dependent manner. The PC12 cells damage induced by H2O2 was attenuated by compounds 2, 10, 11, 13, 15, and 23. Moreover, compounds 2 and 11 delayed H2O2 induced damage, stabilized reactive oxygen species (ROS), mitochondrial membrane potential (MMP) and apoptosis expression levels. Notably, compound 2 exerted dual anti-neuroinflammatory and neuroprotective activities, and its multi-target pharmacological profile makes it a promising candidate for the prevention and treatment of Alzheimer's disease. These studies provide new potential neuroprotective agents for the prevention and treatment of neurodegenerative diseases.}, } @article {pmid42442802, year = {2026}, author = {Robles, CV and Robles, CV and Revilla, APA and de Jesús Valencia Suárez, V and Santander, MAS}, title = {The Role of Genetic Alterations in the Emergence of Alzheimer's Disease in Down Syndrome: A Review.}, journal = {The European journal of neuroscience}, volume = {64}, number = {1}, pages = {e70623}, doi = {10.1111/ejn.70623}, pmid = {42442802}, issn = {1460-9568}, abstract = {Down syndrome (DS), the most common chromosomal disorder, is associated with an accelerated aging process, increasing the risk of early-onset Alzheimer's disease. This review examines genetic factors involved in the development of Alzheimer's disease (AD) in people with DS. A systematic search in major databases was conducted, and articles from 2020 to 2025 that met the predefined inclusion criteria were included. The results showed that the prevalence of AD was above 60% in people with DS older than 65 years, the mean age at diagnosis was 53 years, and the mortality occurred around 59 years. The main genetic factor identified was the overexpression of the APP gene, along with other genes such as DYRK1A, RCAN1, SOD1, APOEε4, and genes involved in the immune response, as well as posttranscriptional dysregulation. Diagnosis remains a challenge due to the pre-existent intellectual disability and the atypical clinical presentation of the disease; however, the development of adapted neuropsychological tests, biomarkers, and neuroimaging techniques is expected to facilitate early diagnosis. The connection between both diseases is the result of multiple genetic factors that lead to early onset and accelerated progression of AD. It is essential to achieve timely diagnosis and provide early treatment to improve quality of life of both patients and their caregivers.}, } @article {pmid42433215, year = {2026}, author = {Cai, L and Zhao, X and Liao, C and Liu, Q and Hu, S and Huang, M}, title = {Efficacy and predictors of cognitive stimulation therapy combined with pharmacotherapy for mild-to-moderate Alzheimer's disease: a randomized controlled trial.}, journal = {Frontiers in psychiatry}, volume = {17}, number = {}, pages = {1840039}, pmid = {42433215}, issn = {1664-0640}, abstract = {INTRODUCTION: Alzheimer's disease (AD) is associated with progressive cognitive decline, functional impairment, and reduced quality of life. Although pharmacological treatments such as cholinesterase inhibitors and memantine are commonly used, their clinical benefits remain limited and heterogeneous. Cognitive stimulation therapy (CST) may provide additional benefits when combined with standard pharmacotherapy. This randomized controlled trial (RCT) aimed to evaluate the clinical efficacy of modified CST combined with standard drug therapy on cognitive function, activities of daily living, and quality of life in patients with mild-to-moderate AD and to explore key predictors of CST efficacy using a multivariate regression model.

METHODS: This evaluator-blinded randomized controlled trial enrolled 80 patients with mild-to-moderate Alzheimer's disease (AD), who were randomly assigned in a 1:1 ratio to either the modified CST plus standard pharmacotherapy group (study group, n = 40) or the standard pharmacotherapy-alone group (control group, n = 40).The modified CST program comprised 14 weekly 45-minute sessions. The primary endpoint was the change in the Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog) score from baseline to post-intervention. Secondary measures included the Activities of Daily Living (ADL) scale and the Quality of Life in Alzheimer's disease (QOL-AD) questionnaire. Data were analyzed using an intention-to-treat (ITT) approach. Independent predictors of treatment efficacy were identified using a two-stage screening strategy (univariate screening and stepwise regression).

RESULTS: A total of 75 patients completed the study, and 80 were included in the ITT analysis. After 14 weeks of intervention, baseline-adjusted ANCOVA showed that the study group had significantly better post-intervention ADAS-Cog scores than the control group. The adjusted mean difference in ADAS-Cog score was -3.28 points (95% CI: -3.72 to -2.83; P < 0.001), favoring the study group. Significant baseline-adjusted between-group differences were also observed for ADL (adjusted mean difference = -4.93, 95% CI: -8.39 to -1.47; P = 0.006) and QOL-AD (adjusted mean difference = 2.69, 95% CI: 1.01 to 4.37; P = 0.002), both favoring the study group. Higher years of education (β = -0.54, P < 0.001), regular physical activity (β = -0.28, P = 0.003), higher baseline Mini-Mental State Examination (MMSE) scores (β = -0.22, P = 0.001), and active hobbies (β = -0.20, P = 0.002) were significant independent predictors of CST efficacy.

DISCUSSION: Modified CST combined with medication significantly delays cognitive decline and improves QOL-AD in patients with mild-to-moderate AD. Educational attainment, lifestyle factors, and cognitive reserve are key determinants of CST efficacy. Relevant institutions should develop targeted enhancement protocols for patients with lower educational levels or insufficient cognitive reserves when implementing CST.

TRIAL REGISTRATION: Chinese Clinical Trial Registry, identifier ChiCTR2600118654, https://www.chictr.org.cn.}, } @article {pmid42435043, year = {2026}, author = {Dabas, A and Yadav, P and Singh, R}, title = {Exploring thiazole conjugates as cholinesterase inhibitors for Alzheimer's disease treatment.}, journal = {Future medicinal chemistry}, volume = {}, number = {}, pages = {1-15}, doi = {10.1080/17568919.2026.2699679}, pmid = {42435043}, issn = {1756-8927}, abstract = {Alzheimer's Disease (AD), a major global health concern, is marked by memory loss and cognitive decline, especially in the elderly. Cholinergic hypothesis is one of the leading hypotheses toward the treatment of AD, prompting the development of cholinesterase (ChE) inhibitors. Acetylcholinesterase (AChE) remains a vital therapeutic target due to its role in enhancing acetylcholine levels and neural function. The natural products, synthetic analogs, and hybrid molecules have been evaluated as inhibitors of ChEs. Recent studies highlight thiazole-fused heterocyclic scaffolds and their derivatives as promising ChE inhibitors with neuroprotective potential. This article covers the synthesis of conjugates of thiazole with piperazine, benzimidazole, pyrazole, and other heterocyclic compounds, along with their potential as ChE inhibitors. This article will be useful to medicinal chemists and pharmaceutical industries to design and synthesize library of thiazole conjugates.}, } @article {pmid42429089, year = {2026}, author = {Zhang, Z and Li, D and Liu, J and Lu, L and Cai, W and Yu, G}, title = {[Mechanism of Bushen Yijing Formula in improving cognitive function in Alzheimer's disease model mice].}, journal = {Zhejiang da xue xue bao. Yi xue ban = Journal of Zhejiang University. Medical sciences}, volume = {}, number = {}, pages = {1-12}, doi = {10.3724/zdxbyxb-2025-0747}, pmid = {42429089}, issn = {1008-9292}, abstract = {OBJECTIVES: To explore the mechanism of Bushen Yijing Formula (BSYJF) in the treatment of Alzheimer's disease (AD) through an integrated approach combining transcriptomics, network pharmacology, and molecular docking.

METHODS: Twelve amyloid precursor protein/presenilin-1 (APP/PS1) transgenic mice were randomly divided into normal control, model, and BSYJF groups. The treated group received daily intragastric administration of BSYJF for 12 consecutive weeks. Cognitive function and hippocampal amyloid β-protein (Aβ) deposition were assessed using behavioral tests and immunohisto-chemistry. Hippocampal tissues were subjected to transcriptomic sequencing to identify differentially expressed genes (DEGs). Functional enrichment analyses were performed using Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and gene set enrichment analysis (GSEA). In parallel, active compounds of BSYJF were screened via the TCMSP and PubChem databases, and AD-related targets were retrieved from GeneCards and other disease databases. Core targets were identified by intersecting these targets with transcriptomic DEGs. Molecular docking and molecular dynamics simulations were employed to evaluate binding affinity between active compounds and core targets, and qPCR was used to validate expression changes of core target genes.

RESULTS: BSYJF treatment improved cognitive function and reduced hippocampal Aβ deposition in APP/PS1 mice. Transcriptomic analysis revealed 73 DEGs between the model and BSYJF groups. GO analysis identified enrichment in 281 biological processes, 104 cellular components, and 120 molecular functions. KEGG analysis highlighted 110 pathways, and GSEA supplemented 322 enriched gene sets, many related to the immune system, neurodegenerative diseases, and signaling pathways such as Th17 cell differentiation and NF-κB. Integrated analysis with network pharmacology prioritized 10 core targets. Molecular docking and molecular dynamics simulations indicated strong structural stability and binding affinity of BSYJF bioactive constituents to these core targets. qPCR results confirmed that BSYJF downregulated the expression of Aurkb, Nr1i3, and Ttk, while upregulating Apob and Ces1d, consistent with the transcriptomic findings.

CONCLUSIONS: Transcriptomics, bioinformatics analysis, and animal experiments suggest that BSYJF may regulate immune-inflammatory responses and alleviate neuronal damage through a multi-component, multi-target, and multi-pathway approach, thereby improving cognitive function in AD model mice.}, } @article {pmid42429504, year = {2026}, author = {Lu, K and Lu, Y and Tang, R and Dong, X and Zhuang, P and Gao, Y and Cheng, M and Wang, Y and Wang, Y}, title = {Mechanisms of autophagy-lysosome pathway impairment in Alzheimer's disease.}, journal = {Journal of Alzheimer's disease : JAD}, volume = {}, number = {}, pages = {13872877261460879}, doi = {10.1177/13872877261460879}, pmid = {42429504}, issn = {1875-8908}, abstract = {The autophagy-lysosomal pathway is key for the removal of harmful substances in cells. This article integrates evidence that highlights the role of lysosomal function and the autophagy-lysosomal pathway in maintaining intracellular homeostasis and the effects of their dysfunction on protein secretion and metabolic disorders, leading to the pathogenesis of Alzheimer's disease (AD) and other tau diseases. Dysfunction of the autophagy-lysosomal pathway is believed to be the main factor leading to the accumulation of amyloid-β and tau proteins, which are also pathological features of AD. This article also discusses why autophagy is indispensable in the early to mature stages of neuronal development and how damage to the function of autophagy can cause neurodevelopmental abnormalities and neurodegenerative diseases. We also summarized the potential role of oligodendrocytes. We believe that its relationship with lysosomes can provide a new perspective and research direction for future research on neurodegenerative diseases. Autophagy-lysosomal pathway damage is considered to be a key factor in the pathology and diagnosis of multiple sclerosis, but we believe that the challenge associated with its transformation into clinical treatment is enormous. These findings suggest that enhancing or improving autophagy function may be an effective treatment method to alleviate the condition of AD patients, which can provide new strategies for clinical treatment and intervention of AD in the future.}, } @article {pmid42430015, year = {2026}, author = {Khodaei, M and Bidabad, B and Shiri, ME and Sedaghat, MK}, title = {Ricci Flow-Based Approach for Early Diagnosis of Alzheimer's Disease.}, journal = {Neuroinformatics}, volume = {24}, number = {3}, pages = {}, pmid = {42430015}, issn = {1559-0089}, mesh = {*Alzheimer Disease/diagnostic imaging ; Humans ; *Magnetic Resonance Imaging/methods ; Early Diagnosis ; *Hippocampus/diagnostic imaging/pathology ; Female ; Aged ; Male ; Discriminant Analysis ; *Image Interpretation, Computer-Assisted/methods ; Aged, 80 and over ; Imaging, Three-Dimensional/methods ; }, abstract = {Early diagnosis of Alzheimer's disease (AD) is increasingly important due to its rising prevalence and significant impact on individuals, families, and healthcare systems. Hippocampal atrophy is a well-established and significant biomarker for AD. Advanced techniques like MRI imaging and surface parameterization have shown considerable promise in improving the accuracy and speed of AD diagnosis. This study aims to utilize the Ricci flow method to map the 3D hippocampal surface to a 2D sphere and extract relevant features for early AD detection. The process involves several key steps: inputting an MRI scan and preprocessing to isolate the hippocampal surface, applying the Ricci flow to map this surface to a sphere, constructing a feature vector using Linear Discriminant Analysis (LDA) and Kernel LDA, and employing various classifiers to diagnose AD, with model evaluation based on the ADNI dataset. Experimental results reveal that combining Ricci flow-based feature extraction with Kernel LDA significantly improves diagnostic accuracy. The model achieves classification accuracies of 97.28% (NC/AD), 96.14% (NC/EMCI), 96.45% (NC/MCI), 94.83% (EMCI/LMCI), 95.84% (MCI/AD), and 95.37% (LMCI/AD). Additionally, it attains 93.65% and 92.30% accuracy in three-way and four-way classification tasks, respectively. These results outperform most reviewed studies and are comparable to others. This research highlights the potential of merging advanced 3D imaging techniques with mathematical models to enhance diagnostic precision, emphasizing the critical role of early detection in the effective treatment and management of Alzheimer's disease.}, } @article {pmid42431348, year = {2026}, author = {Ma, Q and Ding, Z and Wang, R and Jin, J and Wang, H and Li, Y and Liu, Z and Wang, X and Yin, T}, title = {40 Hz-rTMS modulates spike-LFP coupling and improves cognitive function in 5xFAD mice.}, journal = {Experimental neurology}, volume = {}, number = {}, pages = {115909}, doi = {10.1016/j.expneurol.2026.115909}, pmid = {42431348}, issn = {1090-2430}, abstract = {OBJECTIVE: Spike-local field potential (LFP) coupling plays a pivotal role in mediating cross-scale neural communication. Although abnormal coupling has been reported in Alzheimer's disease (AD) models in vitro, in vivo evidence remains lacking. This study aimed to characterize in vivo spike-LFP coupling in 5XFAD mice and investigate whether 40 Hz repetitive transcranial magnetic stimulation (rTMS) can ameliorate related deficits.

METHODS: We performed chronic in vivo electrophysiological recordings of spikes and LFPs were performed in the hippocampal dentate gyrus (DG) via. Phase-locking and coherence analysis were employed to quantify spike-LFP coupling. Cognitive function was evaluated using the Y-maze, novel object recognition, and Morris water maze tasks. The correlation between spike-LFP coupling and cognitive performance was analyzed by the Spearman method.

RESULTS: In wild-type (WT) sham mice, DG spikes exhibited tightly confined phase preferences (θ oscillation: 108°-126°; high γ (Hγ) oscillation: 198°-216°). In contrast, 5XFAD mice displayed severely dispersed spike-phase distributions and reduced coupling intensity, with mean vector length decreasing by 19.90% (spike-θ) and 23.8% (spike-Hγ) compared with that in WT-sham controls. Following 14 consecutive days of 40 Hz rTMS intervention, 5XFAD mice exhibited significant increases in mean vector length (θ: +39.44%; Hγ: +31.47%) and normalized spike-LFP phase distributions. Notably, rTMS treatment also markedly rescued learning, memory, and cognitive flexibility in 5XFAD mice. Spike-LFP coupling strength was significantly correlated with learning and memory performance.

CONCLUSION: These preliminary findings suggest that 40 Hz rTMS modulates pathological spike-LFP coupling in 5XFAD mice, laying the groundwork for therapeutic exploration.}, } @article {pmid42431472, year = {2026}, author = {Kurz, CI and Tegethoff, P and Gelz, J and Gkempelsi, I and Hufnagel, A and Neziraj, F and Schuhbauer, P and Rahn, H and Boeck, M and Keidel, LF and Perneczky, R}, title = {The DECISION Study: Protocol for the Development and Internal Validation of a Multimodal Decision-Making Capacity Framework.}, journal = {Journal of clinical epidemiology}, volume = {}, number = {}, pages = {112417}, doi = {10.1016/j.jclinepi.2026.112417}, pmid = {42431472}, issn = {1878-5921}, abstract = {BACKGROUND: Decision-making capacity (DMC) is a prerequisite for valid informed consent, as well as being a key methodological requirement in clinical and epidemiological research. For individuals with neurocognitive disorders, DMC assessment is frequently based on subjective clinical judgement, with limited standardization and significant variability across settings. Current instruments are resource-intensive and not sufficiently adapted for stage-specific or real-world applications.

OBJECTIVE: To develop and internally validate a structured multimodal framework for assessing decision-making capacity in individuals across the Alzheimer's disease continuum.

METHODS: We propose a modular assessment framework that operationalizes the core domains of decision-making capacity: understanding, appreciation, reasoning and expression of choice. This is complemented by neuropsychological profiling, informant-based measures and structured decision scenarios. Internal validation will be performed against established functional reference standards, including the MacArthur Competence Assessment Tool for Treatment (MacCAT-T), while the Clinical Dementia Rating (CDR) will be used for disease characterization only. Primary analyses focus on feasibility, reliability, and criterion validity. Biomarkers and neuroimaging measures are examined as exploratory contextual correlates of decisional vulnerability and are not used to define decision-making capacity. The co-design approach thus integrates both patient and caregiver perspectives as well as clinician and expert input, with focus group interviews providing a complementary, structured format to capture interdisciplinary professional perspectives.

RESULTS: The protocol is designed to generate evidence regarding feasibility, reliability, and criterion validity of a multimodal DMC assessment framework. It provides standardized scoring and quantifiable outputs, as well as a basis for stage-sensitive interpretation. Exploratory analyses will further evaluate associations between functional decision-making capacity and markers of neurodegenerative disease burden. This methodological framework provides a standardized, reproducible approach to assessing decision-making capacity in cognitively vulnerable populations.

CONCLUSIONS: Developed within the German legal framework, it integrates cognitive, functional and contextual dimensions to support more transparent and quantifiable capacity assessment. Following external validation, the framework may inform future clinical studies, observational research, and ethically robust consent procedures in cognitively impaired populations.}, } @article {pmid42432671, year = {2026}, author = {Chen, F and Wang, L and Liu, H and Khan, Q and Tang, B and Bao, N}, title = {The role of AI-assisted drug repurposing in neurological disorders: a systematic review of validation strategies, challenges and opportunities.}, journal = {Journal of nanobiotechnology}, volume = {}, number = {}, pages = {}, doi = {10.1186/s12951-026-04551-7}, pmid = {42432671}, issn = {1477-3155}, abstract = {Neurological disorders refer to a diverse group of conditions that affect the brain, peripheral nerves, and spinal cord and impair socioemotional, cognitive, motor, and sensory functions. Alzheimer's disease (AD), Multiple Sclerosis (MS), Parkinson's disease (PD), Huntington's disease (HD), and Amyotrophic Lateral Sclerosis (ALS) are some of the well-known neurodegenerative diseases that affect millions of people worldwide. Despite the advanced technologies and nano-drug delivery systems, the success rate of developing drugs for neurological disorders is significantly low. Among several constraints, including gastrointestinal irritation, rapid metabolism, and low stability, the blood-brain barrier (BBB) emerges as one of the key challenges in the development and application of drugs against neurological disorders. These challenges necessitate innovative approaches to develop cost-effective therapeutic strategies. Drug repurposing, the discovery of new therapeutic benefits of existing drugs, is a promising drug discovery approach for discovering potential treatment options for complex neurological disorders. This review aims to explore the advanced and significant progress in drug repurposing for major neurological disorders, including MS, AD, PD, ALS, HD, stroke, and neuropsychiatric conditions. It places an explicit emphasis on discussing the potential role of artificial intelligence (AI)-assisted drug repurposing and understanding of the biological mechanisms in discovering new drugs for these neurological conditions. This also examines current challenges in drug repurposing and provides a critical review of the available opportunities and limitations in AI-assisted drug repurposing.}, } @article {pmid42426112, year = {2026}, author = {Kim, Y and Choudhary, A and Kim, H and Teale, P and McConnell, B and Al Borno, M}, title = {Comparing vibrotactile stimulation to combined visual and auditory stimulation for 40 Hz gamma entrainment.}, journal = {Scientific reports}, volume = {}, number = {}, pages = {}, doi = {10.1038/s41598-026-60911-1}, pmid = {42426112}, issn = {2045-2322}, abstract = {There is significant interest in combined visual and auditory stimulation to entrain 40 Hz gamma oscillations for the treatment of Alzheimer's disease and other neurological conditions such as stroke and insomnia. In this work, we compared another sensory modality-vibrotactile stimulation delivered with a glove-to visual and auditory stimulation in 15 healthy participants in terms of electroencephalogram (EEG) responses and subjective experience. We found that vibrotactile stimulation from the glove could evoke 40 Hz EEG responses in the central, frontal and, to a lesser extent, occipital cortices. We also observed distinct patterns of functional connectivity between the two stimulation modalities. Participants preferred the vibrotactile stimulation over the visual and auditory stimulation. Our study supports future investigations on vibrotactile stimulation for the treatment of neurological conditions.}, } @article {pmid42426158, year = {2026}, author = {Vöglein, J and Levin, J and Stögmann, E and Haass, C and Höglinger, GU and Frölich, L and Jessen, F}, title = {Attitudes of specialist memory-clinic patients with early symptomatic Alzheimer's disease towards lecanemab: results from a multicenter survey in Europe.}, journal = {Scientific reports}, volume = {16}, number = {1}, pages = {}, pmid = {42426158}, issn = {2045-2322}, mesh = {Humans ; *Alzheimer Disease/drug therapy/psychology/genetics ; Female ; Male ; Aged ; Europe ; Surveys and Questionnaires ; Cross-Sectional Studies ; Middle Aged ; Aged, 80 and over ; Memory ; }, abstract = {Lecanemab approval in the European Union (EU) was granted after a delay. This delay resulted in concerns from many stakeholders, but attitudes of patients with early symptomatic Alzheimer's disease receiving specialist memory-clinic care remained insufficiently assessed. Therefore, we evaluated attitudes of specialist memory-clinic patients with early symptomatic Alzheimer's disease towards lecanemab in Europe. In this anonymous, international, multicentre, cross-sectional survey conducted from October 14, 2024 to February 18, 2025, a standardized, expert-developed questionnaire assessed attitudes towards lecanemab treatment and EU approval. Before answering four binary questions, participants received brief explanatory information on expected clinical benefit, amyloid-related imaging abnormalities (ARIA), and the increased ARIA risk associated with APOE ε4 homozygosity. The survey was conducted in specialist memory clinics within the European Alzheimer's Disease Consortium (EADC), the German memory clinic network (DNG), and Austrian memory centers. Available recruitment-flow data were limited to completed questionnaires because the survey was anonymous and distributed locally. 281 patients with early symptomatic Alzheimer's disease completed the survey. Network-level sample sizes were EADC n = 202, DNG n = 60, and Austria n = 19; country-specific sample sizes within the EADC and response rates were not available. Endorsement was high for both individual treatment with lecanemab (81.9%, 95% confidence interval [CI] 76.8-86.2) and general EU approval (91.8%, 95% CI 87.9-94.7). Endorsement remained substantial, but was lower, in the context of APOE ε4 homozygosity (treatment: 61.2%, 95% CI 55.2-66.9; approval: 76.5%, 95% CI 71.1-81.3). Approval-related questions received higher endorsement than treatment-related questions (84% vs. 72%; p < 0.001). Support for approval for APOE ε4 homozygotes declined after regulatory recommendations excluded this group (from 87% to 73%; p = 0.025); this comparison reflects independent respondents completing the anonymous survey before versus after November 14, 2024. Network-level comparisons were descriptive and underpowered for geographic inference. High endorsement within this specialist memory-clinic sample suggests perceived value of access to lecanemab. Greater endorsement for approval than for individual treatment may reflect support for treatment access beyond personal treatment choice, but alternative explanations such as social desirability, acquiescence, misunderstanding, or effects of the survey information cannot be excluded. The findings should not be generalized beyond specialist memory-clinic patients and should be interpreted in view of potential selection and response biases, absent response-rate data, and the brief, non-validated binary questionnaire.}, } @article {pmid42426326, year = {2026}, author = {Wu, Q and Fan, D and Ren, J and Xing, Y and Chen, Z and Jin, H and Lu, Y and Wang, X and Zheng, H}, title = {SUMOylation in Mitochondrial Quality Control: Mechanisms and Implications for Neurodegenerative Disease.}, journal = {Molecular neurobiology}, volume = {63}, number = {1}, pages = {}, pmid = {42426326}, issn = {1559-1182}, mesh = {*Sumoylation/physiology ; *Neurodegenerative Diseases/metabolism/pathology ; Humans ; *Mitochondria/metabolism/pathology ; Animals ; Mitophagy ; }, abstract = {Mitochondria, as the primary energy-generating organelles in neurons, play a pivotal role in regulating cellular metabolism. Given the post-mitotic nature and long lifespan of neurons, they are particularly vulnerable to the cumulative burden of mitochondrial damage. In response to various physiological and stress signals, a sophisticated mitochondrial quality control (MQC) system has evolved, which encompasses mitochondrial biogenesis, dynamics (fission and fusion), and mitophagy. This coordinated network acts as a critical surveillance mechanism to eliminate damaged components and maintain a healthy mitochondrial pool. The small ubiquitin-like modifier (SUMO) pathway, involving reversible SUMOylation and deSUMOylation, has emerged as a key regulator of MQC by directly modifying its core components. Dysregulation of the SUMO pathway disrupts mitochondrial homeostasis, and the resulting mitochondrial dysfunction is increasingly recognized as a central pathogenic mechanism in neurodegenerative diseases. This review systematically examines the role of the SUMO pathway in regulating MQC and its implications in the pathogenesis of Alzheimer's disease, Parkinson's disease, and Huntington's disease. Finally, we discuss the therapeutic potential and translational challenges of targeting the SUMO pathway for the treatment of neurodegenerative diseases.}, } @article {pmid42427159, year = {2026}, author = {Bevins, EA and Léger, GC and Herman, MA and Ringman, JM and Roy, S and Shtrahman, M and Pa, J and Feldman, HH}, title = {Safety considerations of gene-based therapies for Alzheimer's disease.}, journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association}, volume = {22}, number = {7}, pages = {e71515}, doi = {10.1002/alz.71515}, pmid = {42427159}, issn = {1552-5279}, support = {//Epstein Family Alzheimer's Research Collaboration (EFARC)/ ; }, mesh = {Humans ; *Alzheimer Disease/therapy/genetics ; *Genetic Therapy/adverse effects/methods ; Gene Therapy Agents ; Animals ; Dependovirus/genetics ; Oligonucleotides, Antisense/therapeutic use ; }, abstract = {Gene-based therapies show increasing promise for the treatment of neurologic disease. In 2016, nusinersen, an RNA-based therapy, was approved for children with spinal muscular atrophy (SMA). Over 200 clinical trials have utilized gene therapy approaches for a host of neurodegenerative and neuromuscular disorders, including Alzheimer's disease (AD).[1] Delivering gene-based therapies to the central nervous system (CNS) has raised safety concerns. As clinical trials utilizing gene therapy paradigms are undertaken and as approved therapies translate into clinics, a better understanding of safety issues and monitoring parameters is needed. We describe current therapeutic approaches for AD using gene-based therapies such as adeno-associated virus gene therapy and RNA interference by antisense oligonucleotides (ASOs) and undertake a review of medical safety considerations for existing AD gene therapy trials. We identify challenges in analyzing medical safety data currently available and provide guidelines for making this information more accessible and interpretable for the future.}, } @article {pmid42427416, year = {2026}, author = {Cvek, B}, title = {Comment on "Disulfiram as an anti-inflammatory agent: mechanisms, nano-delivery strategies, and applications in non-oncologic diseases" by Q. Jiang, M. Jiang, Y. Lv, X. Zhang, S. Wang and J. Zhao, RSC Adv., 2025, 15, 36344.}, journal = {RSC advances}, volume = {}, number = {}, pages = {}, pmid = {42427416}, issn = {2046-2069}, abstract = {The referenced article reviews the purported anti-inflammatory properties of disulfiram, an anti-alcohol drug also known as Antabuse. However, the anti-inflammatory properties of disulfiram should be considered alongside a wealth of scientific research demonstrating its potential to treat various conditions, including cancers, Alzheimer's disease, sepsis, tuberculosis, blindness and heart conditions. I argue that almost all these results are unreliable using basic chemical knowledge. Most importantly, disulfiram has never been shown to be an active molecule in vivo. The authors of the referenced article did not address this fact at all. Testing disulfiram in vitro yields misleading and dangerous pseudoscientific "results", suggesting that it could be a potential treatment for an ever-growing list of diseases.}, } @article {pmid42427668, year = {2026}, author = {Pallerla, AV and Lucido, CC and Saito, K and Nolt, GL and Arbones-Mainar, JM and Funnell, JL and Satish, D and Smith, LM and Stephens, IO and Goulding, D and MacLean, SM and Olmsted, SM and Adreon, D and Hernandez, G and Golden, LR and Persohn, S and Macauley, SL and Territo, PR and Morganti, J and Johnson, LA}, title = {Anti-amyloid immunotherapy drives APOE4 specific increases in glial reactivity, perivascular immune activation, and ARIA-like events.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, doi = {10.64898/2026.06.26.734793}, pmid = {42427668}, issn = {2692-8205}, abstract = {Anti-amyloid antibodies represent the first disease modifying therapeutics for Alzheimers disease (AD). Adoption of these novel treatments has been slowed by the occurrence of amyloid related imaging abnormalities (ARIA) - treatment-associated edema (ARIA-E) or microhemorrhages (ARIA-H) that disproportionately affect carriers of the E4 allele of apolipoprotein E (APOE). With E4 carriers comprising nearly 70% of the AD population, there is a critical need to understand the unique vulnerability of E4 carriers to these events. To address this gap, we utilized the EFAD mouse model - which expresses human APOE isoforms on the 5xFAD background of amyloidosis - to directly compare the effects of anti-amyloid therapy across APOE genotypes. 9-month-old E2, E3, and E4FAD mice received weekly injections of chimeric Aducanumab (chAdu) or IgG control for 12 weeks, to assess APOE isoform-specific effects on amyloid dynamics, ARIA-H-like microhemorrhages, and underlying cellular and transcriptomic responses. E4FAD mice demonstrated plaque reductions with accompanying increases in microhemorrhages (measured on both MRI and histology), and increases in microglial and astrocyte reactivity - especially in the perivascular compartment. Additionally, vascular branching analysis and parallel single cell and spatial transcriptomics revealed a loss of vascular plasticity and increased inflammatory and immune signaling in the neurovascular units of E4FAD mice. Together, these findings suggest the cerebrovasculature of E4s is uniquely susceptible to antibody mediated vascular damage and provide immunological targets for the assessment or mitigation of ARIA risk in this highest need population.}, } @article {pmid42427890, year = {2026}, author = {Lin, F and Teng, Y}, title = {Magnolol mitigates neuroinflammation via NF-κB/IL-6/IL-1β pathways in AlCl3-induced Alzheimer's disease: insights from in-vivo and in-silico investigations.}, journal = {3 Biotech}, volume = {16}, number = {8}, pages = {314}, pmid = {42427890}, issn = {2190-572X}, abstract = {The neuroprotective effectiveness of natural substances against neuroinflammatory pathways linked to Alzheimer's disease (AD) is still not well understood. In this study, we used both in vivo and in silico methods to assess the therapeutic potential of magnolol at dosages of 25 and 50 mg/kg body weight in a rat model of AD produced by aluminium chloride (AlCl3). Significant cognitive impairments, elevated levels of malondialdehyde (MDA), and increased expression of important neuroinflammatory mediators, including nuclear factor kappa-B (NF-κB), interleukin (IL-6), and interleukin-1β (IL-1β), were all brought on by exposure to AlCl3. Magnolol treatment markedly reduced the levels of pro-inflammatory cytokines, lactate dehydrogenase (LDH), and nitric oxide (NO), improved cognitive function, and strengthened antioxidant defence systems as shown by increased glutathione (GSH), catalase (CAT), and superoxide dismutase (SOD) activities. Histopathological examination further validated Magnolol's neuroprotective properties, showing decreased neuronal degeneration. Magnolol has substantial binding affinities for NF-κB, IL-6, and IL-1β, according to molecular docking and dynamic modelling studies, indicating that it can directly influence neuroinflammatory signalling pathways. Overall, these results show that magnolol has important neuroprotective effects by reducing oxidative stress and inhibiting important inflammatory mediators, underscoring its potential as an effective treatment option for AD.}, } @article {pmid42428551, year = {2026}, author = {Li, W and Yu, X and Guo, C and Huang, Y and Wei, Z and Liu, Y and Wang, JZ and Liu, R and Ji, W and Duan, Q and Wang, J and Wang, G and Wang, X}, title = {Acylglycerol Kinase Inhibition Restores Mitophagy and Alleviates Alzheimer's Disease Pathology.}, journal = {MedComm}, volume = {7}, number = {7}, pages = {e70863}, pmid = {42428551}, issn = {2688-2663}, abstract = {Mitophagy is a conserved cellular process that removes dysfunctional or excess mitochondria. Increasing evidence suggests that impaired mitophagy plays a crucial role in AD development. Promoting mitophagy has been shown to be protective in models of AD, representing an important target of Alzheimer's disease (AD). However, the molecular mechanisms underlying impaired mitophagy in AD are still elusive. Here, we provide evidence that highly expressed acylglycerol kinase (AGK), a mitochondrial lipid kinase associated with mitochondrial protein transport, glycolysis, and platelet formation, is a key mediator of mitophagy in AD. We found that AGK promoted the binding of ATPase family AAA domain containing 3A to translocase of the inner mitochondrial membrane 23 and sequentially increased mitochondrial import of PTEN-induced putative kinase 1, leading to the decrease of mitophagy. Further investigations revealed that the AGK downregulation in neuronal cells and APP/PS1 mice enhanced mitophagy, increased mitochondrial membrane potential, decreased pathological Tau/Aβ and neuroinflammation, and alleviated cognitive dysfunctions in the mice. Altogether our findings indicate that AGK plays a critical role in mediating mitophagy defects in AD; furthermore, downregulation of AGK promotes mitophagy and the decrease of Aβ and pathological Tau, providing an encouraging therapeutic treatment for AD.}, } @article {pmid42419633, year = {2026}, author = {Cauzzi, E and Ficchì, S and De Paolis, ML and Saba, L and Montanari, M and Loffredo, G and La Barbera, L and Krashia, P and Nobili, A and D'Amelio, M}, title = {Midbrain dopamine loss drives parvalbumin interneuron vulnerability through tissue plasminogen activator-linked perineuronal-net breakdown and hippocampal disinhibition.}, journal = {Neurobiology of disease}, volume = {}, number = {}, pages = {107527}, doi = {10.1016/j.nbd.2026.107527}, pmid = {42419633}, issn = {1095-953X}, abstract = {Midbrain dopaminergic degeneration is an early feature of Alzheimer's Disease (AD), dementia with Lewy bodies (DLB), and AD-Parkinson's disease overlap (AD-PD). However, its direct contribution to the failure of hippocampal inhibitory-circuits, a pathological feature shared across these conditions, remains unresolved. Parvalbumin-positive interneurons (PV-INs) regulate hippocampal excitation-inhibition balance and are directly modulated by dopamine (DA). These neurons are protected by perineuronal nets (PNNs), extracellular-matrix structures supporting fast GABAergic signaling and neuronal resilience. We tested whether midbrain-derived DA loss is sufficient to destabilize hippocampal PV-IN function, potentially promoting their vulnerability or affecting PNN integrity. Through stereotaxic unilateral 6-hydroxy-dopamine lesion of the Ventral Tegmental Area/Substantia Nigra pars compacta in C57BL/6 N mice, we reduced the hippocampal DA tone and midbrain-derived synaptic input onto PV-INs. At 1-month post-lesion, PV-IN numbers were preserved, but the PNN integrity was reduced, accompanied by increased expression of tissue plasminogen activator (tPA), a PNN-remodeling protease. In CA1 pyramidal neurons, spontaneous inhibitory postsynaptic currents showed reduced frequency with faster decay, and bicuculline unmasked heightened population-spike excitability. By 6-months post-lesion, PV-IN numbers declined significantly, especially in CA1, demonstrating progressive vulnerability. D2/D3 receptor (D2/D3R) activation with quinpirole normalized tPA levels in PV-INs ex vivo, restored PNN integrity after sub-chronic treatment in vivo and increased inhibitory postsynaptic-event frequency, indicating functional recovery of GABAergic drive. These findings support the involvement of a DA-D2/D3R-tPA axis contributing to PV-IN extracellular-matrix integrity and hippocampal inhibitory tone. They also demonstrate that DA depletion is sufficient to trigger PNN breakdown, reduce GABAergic inhibition, network hyperexcitability, and cause progressive PV-IN loss independently of canonical protein aggregates like Aβ, tau or α-synuclein, characteristic of AD, DLB or AD-PD. This mechanism links midbrain degeneration to hippocampal circuit failure, highlighting D2/D3R signaling and extracellular proteolysis as actionable targets for early circuit stabilization across AD, DLB, and AD-PD.}, } @article {pmid42420256, year = {2026}, author = {He, CY and Wang, XY and Fan, J and Wang, YN and Masters, CL and Wang, YJ}, title = {Could the cognitive benefits of amyloid-beta clearance grow in time for Alzheimer's disease?.}, journal = {Translational psychiatry}, volume = {}, number = {}, pages = {}, doi = {10.1038/s41398-026-04188-y}, pmid = {42420256}, issn = {2158-3188}, support = {82588301//National Natural Science Foundation of China (National Science Foundation of China)/ ; 82120108010//National Natural Science Foundation of China (National Science Foundation of China)/ ; 82401695//National Natural Science Foundation of China (National Science Foundation of China)/ ; }, abstract = {Alzheimer's disease (AD) is characterized histologically by amyloid-β (Aβ) deposition in the brain. Immunotherapies targeting Aβ clearance have become a leading treatment strategy. Although these therapies effectively reduce cerebral Aβ burden, their cognitive benefits remain modest during the trial period. This review systematically assesses the extent of Aβ clearance by immunotherapies and its related cognitive outcomes, focusing on whether cognitive benefits increase over time. We refine a model of the "lag effect" between plaque clearance and cognitive benefit, which is potentially influenced by clearance rate, treatment duration, disease stage, genetic factors, and aging. We also discuss the underlying biological mechanisms and potential neuroprotective targets. Future research should prioritize long-term studies, early intervention, personalized therapies, and combination approaches addressing multiple pathological pathways. Given limited short-term cognitive gains, optimizing outcomes will require tailoring treatments to individual patient factors-including genetics, disease progression, and aging-to minimize side effects and enhance long-term cognitive function.}, } @article {pmid42420546, year = {2026}, author = {Nour, H and Mounadi, N and Samadi, A and Chtita, S}, title = {Stylopine as multi-target anti-Alzheimer agent.}, journal = {Scientific reports}, volume = {}, number = {}, pages = {}, doi = {10.1038/s41598-026-61364-2}, pmid = {42420546}, issn = {2045-2322}, support = {#12R282//Zayed Bin Sultan Center for Health Sciences, United Arab Emirates University/ ; }, abstract = {Alzheimer's disease is a complex neurodegenerative disorder involving multiple enzymes, such as acetylcholinesterase (AChE), butyrylcholinesterase (BuChE), monoamine oxidase B (MAO-B), and β-secretase (BACE-1). Currently available treatments are limited to acetylcholinesterase inhibitors, which offer purely symptomatic relief and do not halt disease progression. Consequently, the development of multi-target ligands represents a promising therapeutic approach. In this study, Alkaloids were evaluated using in silico approaches. Predictions of biological activity performed using the PASS software revealed stylopine as a promising candidate with potential anti-Alzheimer activity. Furthermore, this compound demonstrated strong binding affinity for key targets (Torpedo AChE, BuChE, and BACE-1), as well as a promising pharmacokinetic profile. Molecular dynamics simulations and MM-GBSA calculations have demonstrated the stability of stylopine-target interactions. Taken together, these studies suggest that stylopine could be a promising multitarget agent for the treatment of Alzheimer's disease, although further experimental data are needed to confirm its efficacy.}, } @article {pmid42421820, year = {2026}, author = {Brosch, JR and Wang, S and Apostolova, LG and Agarwal, A and Allen, JW and Gutmann, L and Tobar, M and Gonzalez, L and Johnson, D and Treadway, L and Connolly, J and Tang, A and Lettich, E and Davies, S and Kuhn, N and Hammers, DB and Clark, D and Farlow, M and Willis, DR and Fowler, N and Wilcock, DM}, title = {The Indiana University Brain Health Program to deliver amyloid-targeted therapy to Alzheimer's disease patients.}, journal = {Alzheimer's & dementia (New York, N. Y.)}, volume = {12}, number = {3}, pages = {e70291}, pmid = {42421820}, issn = {2352-8737}, abstract = {INTRODUCTION: The Indiana University Brain Health Program was developed to support safe implementation of amyloid-targeting therapies (ATTs) for early Alzheimer's disease (AD).

METHODS: We established Neurology Brain Health Navigators (neuroBHNs) to extend our Brain Health Navigator model into specialty care. NeuroBHNs pre-screen patients for ATT eligibility, coordinate biomarker and imaging evaluation, provide structured education, and guide treatment initiation and monitoring. The program includes a dedicated social worker and insurance pre-authorization specialist to streamline infusion access. Blood pressure is monitored at each visit, and infusions are deferred if readings exceed 140/90 mmHg.

RESULTS: Through December 16, 2025, 243 patients initiated lecanemab therapy. Apolipoprotein E (APOE) ε4 homozygotes were not excluded; 74% of treated patients carried at least one Apoε4 allele. The ARIA rate was 13.2%, and 40% of patients experienced infusion-related reactions.

CONCLUSIONS: A navigator-centered model can efficiently deliver ATT while supporting structured education, screening, and safety monitoring, potentially contributing to favorable safety outcomes.}, } @article {pmid42422111, year = {2026}, author = {Wang, J and Fu, X and Liu, J and Yang, Y}, title = {Non-invasive brain stimulation in frontotemporal dementia: syndrome-specific signals and priorities for future trials.}, journal = {Frontiers in aging neuroscience}, volume = {18}, number = {}, pages = {1842455}, pmid = {42422111}, issn = {1663-4365}, abstract = {Frontotemporal dementia is the second most common cause of young-onset dementia after Alzheimer's disease and lacks disease-modifying treatment. This narrative review summarizes human studies of non-invasive brain stimulation, including repetitive transcranial magnetic stimulation and theta-burst stimulation, transcranial electrical stimulation, and transcranial photobiomodulation, in frontotemporal dementia and primary progressive aphasia. We review stimulation targets, protocols, outcomes, and safety, and organize the evidence by clinical subtype and modality. Current data remain preliminary, but recurrent signals support prefrontal and cerebellar repetitive transcranial magnetic stimulation/theta-burst stimulation and prefrontal or temporoparietal transcranial direct current stimulation, particularly in primary progressive aphasia. By contrast, controlled evidence in behavioral-variant frontotemporal dementia is limited and heterogeneous. Future trials should be sham-controlled, multicenter, and syndrome-stratified; combine stimulation with symptom-relevant cognitive or language therapy; and incorporate biomarker-informed targeting, target-engagement measures, and longer follow-up to determine durability and clinical relevance.}, } @article {pmid42422228, year = {2026}, author = {Sukreet, S and Donohue, MC and Ngolab, J and Belsha, A and Salazar, J and Cohen, P and Jaiswal, S and Tan, V and Aggarwal, NT and Alber, J and Johnson, K and Jicha, GA and van Dyck, CH and Ramanan, S and Lah, JJ and Salloway, S and Verdooner, SR and Rafii, MS and Aisen, PS and Sperling, RA and Rissman, RA}, title = {Relationships between longitudinal retinal amyloid imaging and amyloid PET in the A4 Trial.}, journal = {Alzheimer's & dementia (Amsterdam, Netherlands)}, volume = {18}, number = {3}, pages = {e70422}, pmid = {42422228}, issn = {2352-8729}, abstract = {INTRODUCTION: Alzheimer's disease (AD) is associated with retinal amyloid-related changes, which may help identify amyloid positron emission tomography (PET) positive (+) individuals. Previously, in a small cross-sectional study, we reported higher retinal spot counts (RSCs) in preclinical amyloid PET (+) individuals screened for the Anti-Amyloid Treatment in Asymptomatic Alzheimer's Disease (A4) trial compared to control individuals enrolled in the Longitudinal Evaluation of Amyloid Risk and Neurodegeneration (LEARN) trial before drug treatment.

METHODS: Eligible volunteers had retinal scans 48 hours after consuming curcumin. Scans were processed and quantified via NeuroVision. Participants were grouped by amyloid status and treatment to assess the effect of solanezumab on RSC.

RESULTS: RSC did not differ significantly over time between groups and was not modified by treatment, diverging from the cross-sectional retinal amyloid findings observed in A4/LEARN.

DISCUSSION: Curcumin-based retinal amyloid labeling shows promise but needs standardized protocols and validation in larger cohorts to understand its relationship to amyloid PET.}, } @article {pmid42422260, year = {2026}, author = {Akhbari, M and Babaei, F and Navidi-Moghaddam, A and Ghafghazi, S and Khodabandehloo, F and Sarookhani, MR and Dargahi, L and Mohammadi, G and Nassiri-Asl, M}, title = {The effects of Saccharomyces boulardii on TLR4/NF-κB neuroinflammatory pathway in the hippocampus of LPS-induced rats.}, journal = {IBRO neuroscience reports}, volume = {21}, number = {}, pages = {199-206}, pmid = {42422260}, issn = {2667-2421}, abstract = {Saccharomyces boulardii (Sb), a probiotic yeast, is known for its positive effects on gastrointestinal and metabolic health. Recent research has explored its potential to influence neurological conditions by modulating neuroinflammatory responses via the gut-brain axis. Toll-like receptor 4 (TLR4) is recognized as a key molecular target in regulating neuroinflammation, particularly in disorders like Alzheimer's disease (AD). This study investigated whether Sb could alleviate downstream elements of the TLR4 neuroinflammatory pathway in a lipopolysaccharide (LPS)-induced rat model relevant to AD. Rats were randomly assigned to four groups: 1) control, 2) LPS, 3) Sb + LPS, and 4) Sb alone. All groups received either normal saline or Sb (a volume of 1 ml containing 10 [10] CFU) by oral gavage for four weeks. From day 14, LPS (250 μg/kg/day) or saline was administered intraperitoneally for nine days. Researchers assessed spatial memory, levels of TLR4 pathway-associated proteins in the hippocampus, pro-inflammatory cytokine expression, and neuronal survival using Nissl staining. The results showed that pre-treatment with Sb partially ameliorated spatial learning deficits, significantly reducing the LPS-induced elevation of nuclear factor kappa B (NF-κB) and interleukin-1β (IL-1β) in the hippocampus and protecting against neuronal loss in the hippocampal CA1 region. Sb mitigates LPS-induced neuroinflammation by modulating downstream elements of the TLR4 pathway-specifically NF-κB and IL-1β-rather than acting directly on the TLR4 receptor, likely through mechanisms involving the gut-brain axis.}, } @article {pmid42422549, year = {2026}, author = {Ruesga Mundo, S}, title = {Hierarchical-circular model of biological memory: a multilevel hypothesis for pathogenesis and allostatic integrity in Alzheimer's disease and related dementias.}, journal = {Frontiers in dementia}, volume = {5}, number = {}, pages = {1841647}, pmid = {42422549}, issn = {2813-3919}, abstract = {INTRODUCTION: Alzheimer's disease and related dementias remain largely resistant to disease-modifying therapies, despite decades of research focused on linear neuropathological pathways such as beta-amyloid and tau. Persistent paradoxes-including the dissociation between pathology burden and clinical expression, the impact of early-life stress, and the role of systemic factors-indicate the need for integrative theoretical frameworks. This article proposes a multilevel hypothesis conceptualizing dementias as disorders of biological memory and allostatic integrity rather than isolated brain pathologies.

HYPOTHESIS: The Hierarchical-Circular Model of Biological Memory posits that dementia emerges from progressive disruptions in a circular, multilevel system that encodes and stabilizes biological information across the lifespan. The model is organized around the unifying principle "Signal → Plasticity → Stable State" and integrates five interconnected levels: (1) morphogenetic programming and genetic architecture, (2) epigenetic molecular memory, (3) allostatic load and systemic physiological adaptation, (4) the Psychological-Neurological-Endocrine-Immunological (PNEI) network, and (5) interoceptive-neuronal integration. At any level, perturbation can propagate bidirectionally through the system, establishing maladaptive stable states that manifest clinically as dementia.

DEVELOPMENT OF THE HYPOTHESIS: Through a structured synthesis of longitudinal, mechanistic, and multisystem studies (2010-2025), the model specifies how gene-environment interactions, epigenetic modifications, cumulative allostatic load, neuroimmune dynamics, and altered interoceptive timescales jointly shape vulnerability and resilience. The concept of allostatic integrity is introduced as a dynamic systems-level property-distinct from allostatic load-that explains why similar neuropathological burdens may result in divergent clinical trajectories. Distinct dementia phenotypes are proposed to reflect different patterns of circular reinforcement across the five levels.

TESTABLE PREDICTIONS: This framework generates concrete, falsifiable predictions: (1) composite indices of allostatic integrity will outperform single biomarkers in predicting conversion from mild cognitive impairment to dementia; (2) multidomain interventions targeting more than one system level will have multiplicative, rather than additive, effects on slowing cognitive decline; (3) patients with similar amyloid/tau profiles but contrasting allostatic integrity will show markedly different trajectories of clinical progression; and (4) allostatic integrity moderates the protective effect of cognitive reserve, a pattern not predicted by reserve frameworks alone.

CONCLUSION: The Hierarchical-Circular Model of Biological Memory offers a unifying hypothesis for Alzheimer's disease and related dementias that bridges genetic, epigenetic, physiological, neuroimmune, and interoceptive processes across the lifespan. By reframing dementias as failures of biological memory and allostatic integrity, the model provides a conceptual roadmap for mechanistic research, multidomain prevention, and personalized treatment strategies.}, } @article {pmid42423023, year = {2026}, author = {Kim, S and Oda, H and Oyama, R and Makishi, R and Bade, S and Bade, S and Ally, I and Iijima, Y and Gibo, Y and Minami, K and Fukuzawa, F and Sanji, S and Inamine, K and Kishi, H and Huh, S and Tanifuji, T and Nagahiro, M and Watanabe, N}, title = {Efficacy, safety and policy implications of anti-amyloid monoclonal antibodies for Alzheimer's disease: protocol for a living systematic review and meta-analysis.}, journal = {BJPsych open}, volume = {12}, number = {4}, pages = {e182}, doi = {10.1192/bjo.2026.12044}, pmid = {42423023}, issn = {2056-4724}, abstract = {BACKGROUND: Dementia affects approximately 6-13% of adults aged 65 years and older, with Alzheimer's disease accounting for most cases. Established symptomatic therapies, including acetylcholinesterase inhibitors and memantine, provide limited benefit and do not modify disease progression. Multiple monoclonal antibodies (mABs) targeting different amyloid-β species have been developed as potential disease-modifying therapies; because some agents have entered clinical use whereas others remain investigational, a continuously updated synthesis of their efficacy and safety is needed.

AIMS: To evaluate the efficacy and safety of all anti-amyloid mABs for adults with Alzheimer's disease, using a living systematic review and meta-analysis.

METHOD: We will conduct a living systematic review and meta-analysis in accordance with the Cochrane Handbook, Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) 2020 and the PRISMA extension for living systematic reviews. Randomised controlled trials comparing any approved or investigational anti-amyloid mAB with placebo, standard care or active comparators will be included. Searches of Ovid MEDLINE, Embase, Cochrane Central Register of Controlled Trials, ClinicalTrials.gov and WHO International Clinical Trials Registry Platform will be updated every 6 months. Meta-analyses will be conducted separately for each antibody molecule using random-effects models. Critical outcomes include global clinical change and disease severity, cognitive abilities, functional ability and dependency, and safety (serious adverse events, treatment discontinuation and amyloid-related imaging abnormalities). Important outcomes include neuropsychiatric symptoms, quality of life and health system outcomes. Certainty of evidence will be assessed using the methodology Grading of Recommendations, Assessment, Development and Evaluation.

RESULTS: This article describes a protocol; therefore, no review findings are available at this stage.

CONCLUSIONS: This living systematic review will provide an up-to-date synthesis of the benefits and harms of anti-amyloid monoclonal antibodies to inform clinical decision-making and health-system planning in Alzheimer's disease.}, } @article {pmid42423667, year = {2026}, author = {Huang, Q and Zuo, Y and Xie, Y and Liu, Z and Wang, L and Xu, H and Yu, M and Liu, C}, title = {A nose-to-brain drug delivery system targeting mitochondrial dysfunction: application potential and future prospects of chitosan nanogels in Alzheimer's disease.}, journal = {Biomaterials science}, volume = {}, number = {}, pages = {}, doi = {10.1039/d6bm00624h}, pmid = {42423667}, issn = {2047-4849}, abstract = {Alzheimer's disease (AD) is a neurodegenerative disorder characterized by neuronal degeneration and cognitive impairment. One of its core pathologies involves energy metabolism disruption and oxidative stress resulting from mitochondrial dysfunction. Traditional drugs struggle to effectively cross the blood-brain barrier (BBB), while the nasal-brain drug delivery system offers a novel approach for achieving direct brain access. Chitosan, a biodegradable natural polymer with strong mucosal adhesion properties, has been extensively utilized in recent years to construct nanogel carriers. This approach enhances drug retention and absorption in the nasal epithelium, enabling targeted delivery to the brain via the olfactory or trigeminal nerve pathways. This paper provides a systematic review of research progress on chitosan nanogel-based naso-cerebral drug delivery systems targeting mitochondrial dysfunction, focusing on their molecular mechanisms in improving mitochondrial energy metabolism, scavenging excess reactive oxygen species (ROS), suppressing neuroinflammation, and regulating apoptosis. Additionally, this paper analyzes the design principles of various modification strategies-such as triphenylphosphine (TPP) modification, pH/ROS responsiveness, and drug-loaded nanozyme complexes-along with their efficacy validation in AD models. It further explores the future development trends of chitosan nanogel-mediated multi-target intervention and smart-responsive nasal-brain delivery systems, offering new directions for precision treatment of AD.}, } @article {pmid42423809, year = {2026}, author = {Yousef, AI and El-Twab, SMA and Khadrawy, SM and Abdel-Moneim, A and Khalil, RG}, title = {Polydatin inhibits hippocampal neurodegeneration in diabetic rats via modulation of oxidative stress and NF-kB/COX-2/IL-6 inflammatory pathway.}, journal = {Metabolic brain disease}, volume = {41}, number = {1}, pages = {}, pmid = {42423809}, issn = {1573-7365}, mesh = {Animals ; *Oxidative Stress/drug effects ; *Glucosides/pharmacology/therapeutic use ; *Stilbenes/pharmacology/therapeutic use ; *Hippocampus/drug effects/metabolism/pathology ; Male ; Rats ; Cyclooxygenase 2/metabolism ; *Diabetes Mellitus, Experimental/metabolism/drug therapy ; *NF-kappa B/metabolism ; Interleukin-6/metabolism ; Neuroprotective Agents/pharmacology/therapeutic use ; Signal Transduction/drug effects ; Molecular Docking Simulation ; *Neurodegenerative Diseases/metabolism/drug therapy ; }, abstract = {Impaired insulin function and persistent hyperglycemia damage the brain of diabetics and raise the risk of Alzheimer's disease (AD). Although polydatin (PLD) possesses promising biological effects, no major study has yet explored its anti-neurodegenerative efficacy in the hippocampus. This study therefore aims to investigate the probable protective effects of PLD against hippocampal neurodegeneration in diabetic rats, as well as explore its in-silico inhibitory activity against two key enzymes implicated in the progression of AD. Experimental diabetes was induced in male albino rats then PLD was administered orally to the diabetic rats (50 mg/kg b.wt.) daily for four weeks. In silico molecular docking was used to predict the interactions of PLD against BACE1 and AChE. PLD treatment significantly improved diabetic parameters, lowering blood glucose and raising serum insulin. Excitingly, PLD markedly alleviated oxidative stress by reducing lipid peroxidation and nitric oxide levels while enhancing antioxidant defenses (elevated GPx activity and GSH content) in the hippocampus of diabetic rats. PLD also suppressed neuroinflammation by down-regulating NF-κB, COX-2, and IL-6 mRNA expression. Furthermore, PLD significantly elevated the protein level of IDE while lowered Aβ1-42 level. In silico, PLD revealed potent binding affinity for BACE1 (-8.6 Kcal/mol) and AChE (-10.5 Kcal/mol), interacting with key residues, indicating its inhibition potential. Overall, PLD effectively reduced neurodegeneration in the hippocampus of diabetic rats via inhibiting oxidative stress, inflammation, and Aβ1-42 accumulation. PLD may act as a promising multi-target anti-neurodegenerative candidate, capable of simultaneously modulating multiple pathways and more experimental validation are needed in the future.}, } @article {pmid42424238, year = {2026}, author = {Tshimbombu, TN and Thurmann, KE and Decourt, B and Nyalundja, AD and Shardow, SB and Amoako, ME and Iragi, GM and Mwambali, JA and Sabbagh, MN}, title = {Autophagy in Alzheimer's disease: mechanisms, clinical trials, and horizons.}, journal = {Neuro-degenerative diseases}, volume = {}, number = {}, pages = {1-21}, doi = {10.1159/000553506}, pmid = {42424238}, issn = {1660-2862}, abstract = {BACKGROUND: Alzheimer's disease (AD) is an incurable progressive neurodegenerative disorder characterized by the pathological accumulation of amyloid beta (Aβ) plaques and neurofibrillary tangles in the brain. Recent findings have identified dysregulation of autophagy, a cellular mechanism for degradation and recycling, as a crucial contributor to the pathogenesis of AD. This narrative review examines the role of autophagy in the metabolism of Aβ and tau and evaluates current therapeutic strategies aimed at modulating autophagic pathways.

SUMMARY: Autophagy is governed by the key molecular regulators mammalian target of rapamycin, adenosine monophosphate-activated protein kinase, Beclin-1, and transcription factor EB, which collectively control the clearance of protein recycling, including aggregates, inside cells. Pharmacological agents such as rapamycin, resveratrol, and trehalose, alongside sigma-1 receptor agonists and gene therapy approaches, have demonstrated potential in modulating autophagy in preclinical and clinical studies. Despite these advances, significant challenges persist; namely, neuronal heterogeneity, optimal timing for therapeutic intervention, and the absence of reliable biomarkers to monitor autophagic activity and treatment efficacy.

KEY MESSAGES: Targeting autophagy offers a promising and potentially safe avenue for slowing AD progression. Future investigations should prioritize the development of selective autophagy modulators and personalized treatment strategies to restore autophagic flux and enhance clinical outcomes in patients with AD.}, } @article {pmid42424917, year = {2026}, author = {Lapmanee, S and Thonapan, N and Sriwong, S and Bhubhanil, S and Wongchitrat, P and Charoenphon, N and Ngernsutivorakul, T and Hooncharoen, K and Bunwatcharaphansakun, P and Khongkow, M and Namdee, K}, title = {RGD-functionalized cannabidiol lipid nanoparticles improve brain delivery and alleviate cognitive and metabolic dysfunction via gut-brain axis modulation in an Alzheimer's disease model.}, journal = {Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie}, volume = {201}, number = {}, pages = {119724}, doi = {10.1016/j.biopha.2026.119724}, pmid = {42424917}, issn = {1950-6007}, abstract = {BACKGROUND: Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by cognitive decline and neuronal loss. Evidence links gut-brain axis dysfunction and metabolic disturbances to AD. Although cannabidiol (CBD) has neuroprotective effects, its use is limited by poor bioavailability and brain delivery.

METHODS: Arginylglycylaspartic acid (RGD)-functionalized, CBD-loaded lipid nanoparticles (CBD/LNP-RGD) were developed to enhance targeted delivery across the blood-brain barrier (BBB) via integrin αvβ3-mediated transcytosis. Cellular uptake and BBB permeability were evaluated in vitro. Anti-inflammatory and antioxidant effects were assessed in Aβ/LPS-induced models. In vivo efficacy was examined using cognitive-behavioral tests, including the novel object recognition and the Morris water maze. Metabolic parameters, histopathology, synaptic protein expression, and gut barrier integrity were also evaluated.

RESULTS: CBD/LNP-RGD demonstrated a 3-fold increase in cellular uptake and a 65% enhancement in BBB transport compared to non-targeted formulations. Treatment significantly reduced pro-inflammatory cytokines (i.e., IL-6 and TNF-α, p < 0.001) and intracellular reactive oxygen species (p < 0.001). In vivo, CBD/LNP-RGD improved cognitive performance comparable to Donepezil (p < 0.001). Additionally, it normalized glycemic control, insulin resistance, and triglyceride levels without hepatic or renal toxicity. At the tissue level, CBD/LNP-RGD reduced Aβ and tau pathology, restored short-chain fatty acids, preserved hippocampal neuronal integrity, and upregulated synaptophysin and PSD-95 proteins. Enhanced intestinal barrier function was evidenced by increased expression of tight junction proteins ZO-1 and occludin.

CONCLUSIONS: CBD/LNP-RGD represents a multifunctional nanotherapeutic platform that improves brain delivery and exerts neuroprotective, anti-inflammatory, antioxidant, and metabolic regulatory effects. Its ability to modulate both central pathology and the gut-brain axis highlights its potential as a disease-modifying strategy for Alzheimer's disease.}, } @article {pmid42425064, year = {2026}, author = {Rudman, MD and Ulrich, JD and Holtzman, DM}, title = {Recent advances in Alzheimer's disease: From molecular mechanisms to therapeutic strategies.}, journal = {Cell}, volume = {189}, number = {14}, pages = {4193-4224}, doi = {10.1016/j.cell.2026.06.006}, pmid = {42425064}, issn = {1097-4172}, abstract = {Alzheimer's disease (AD) remains the leading cause of dementia worldwide and an escalating global health crisis. The hallmark amyloid plaques and neurofibrillary tangles (NFT) are now known to be accompanied by a complex array of pathologies that culminate in neurodegeneration and cognitive decline. New disease-modifying therapies for AD can now slow cognitive decline through the removal of amyloid plaques from the brain, but treatments to stop or prevent cognitive impairment remain elusive. In this review, we summarize the most recent updates in AD research on pathologic disease mechanisms and therapeutic strategies, highlighting advancements in apolipoprotein E (APOE) biology, neuroimmunology, biomarker discovery, and initial experience with new disease-modifying therapies. These important discoveries are revolutionizing AD diagnosis and treatment and provide hope for a future where AD is not only treatable but also preventable.}, } @article {pmid42425385, year = {2026}, author = {Thakkar, A and Mote, C and Gadade, A and Dighe, V and Kaur, G and Vora, A}, title = {Longifolene mitigates amyloid beta induced neurotoxicity by acting on PI3K/AKT/NFκB pathway: Comprehensive in vitro, in vivo pharmacokinetics and pharmacodynamic studies for Alzheimer's disease.}, journal = {European journal of pharmacology}, volume = {}, number = {}, pages = {179119}, doi = {10.1016/j.ejphar.2026.179119}, pmid = {42425385}, issn = {1879-0712}, abstract = {Alzheimer's disease (AD) is a multifactorial disease characterized with deposition of Amyloid-β peptide leading to oxidative stress and neuroinflammation. Terpenes are a broad class of natural compounds known to possess anti-oxidant and anti-inflammatory effects. Longifolene (LNF), a major constituent of pine resin is a non -polar sesquiterpene possessing promising anti-oxidant and anti-inflammatory activity. Oxidative stress and neuroinflammation are pathological drivers of AD. The current work is focused on evaluating the neuroprotective potential of LNF using in vitro cell line-based and in vivo animal-based model for AD. Pre-treatment with LNF at 1, 10 and 100 μM displayed significant neuroprotective potential in Aβ1-42 induced neurotoxicity in SH-SY5Y cell-line. Additionally, 0.5 and 1μM of LNF significantly prevented ROS generation, mitochondrial dysfunction and apoptosis in SH-SY5Y cell-line. Pharmacokinetic studies in rats showed that LNF achieved the therapeutic concentrations in brain. Further, in pharmacodynamic studies, 20 days pre-treatment and 30 days post-treatment with LNF at 10, 50 and 100 mg/kg resulted in dose-dependent improvements in behavioral, biochemical and histopathological parameters in Aβ1-42 induced AD in rats. Functional assays demonstrated that LNF brought about significant reduction in levels of AChE, TNF-α and IL-6 levels and elevation in BDNF in the rat brain. Histopathological examination of the cortex and hippocampus showed that LNF at doses of 50 and 100 mg/kg markedly attenuated neuronal swelling and cortical atrophic changes, while preserving the pyramidal layer thickness in the hippocampus. Protein expression studies using western blot analysis showed that LNF displays anti-AD activity by acting on PI3K/AKT/NFκB pathway. These findings highlight LNF as a potential neuroprotective agent for AD intervention.}, } @article {pmid42412302, year = {2026}, author = {Zhang, C and Ma, Y and Shi, Z and He, X and Hu, J and Chen, S and Wu, H and Tian, M and Yan, C and Xing, M and He, L}, title = {Study on the Effects and Mechanisms of Resveratrol in Improving Cognitive Impairment in Aβ1-42-Induced Alzheimer's Disease Model Mice.}, journal = {Journal of neuroimmune pharmacology : the official journal of the Society on NeuroImmune Pharmacology}, volume = {21}, number = {1}, pages = {}, pmid = {42412302}, issn = {1557-1904}, mesh = {Animals ; *Resveratrol/pharmacology/therapeutic use ; *Alzheimer Disease/chemically induced/drug therapy/metabolism ; *Amyloid beta-Peptides/toxicity ; Mice ; *Peptide Fragments/toxicity ; *Cognitive Dysfunction/drug therapy/chemically induced/metabolism ; Disease Models, Animal ; Male ; Autophagy/drug effects ; Mice, Inbred C57BL ; *Antioxidants/pharmacology/therapeutic use ; Oxidative Stress/drug effects ; }, abstract = {Aging is a major risk factor for neurodegenerative diseases, including Alzheimer's disease (AD). Targeting cellular senescence has therefore emerged as a promising therapeutic strategy. Resveratrol (RV), a natural polyphenolic compound, exhibits anti-aging properties through the regulation of autophagy and oxidative stress; however, its mechanisms in AD remain incompletely understood. In this study, we investigated the effects and underlying mechanisms of RV in an Aβ1-42-induced AD model. In vivo, RV administration significantly reduced the expression of aging-related markers and activated autophagy-associated signaling pathways. In vitro, RV treatment markedly attenuated Aβ1-42-induced cell viability loss and excessive reactive oxygen species (ROS) production. Further mechanistic analyses demonstrated that RV-induced autophagy activation was closely associated with the AMP-activated protein kinase/UNC-51-like kinase 1 (AMPK/ULK1) and silent information regulator 1/nuclear factor-kappaB (SIRT1/NF-κB) pathways. Collectively, these findings suggest that RV alleviates AD-related pathological processes by promoting autophagy and delaying cellular senescence, highlighting its potential as a therapeutic agent for age-related neurodegenerative diseases.}, } @article {pmid42412614, year = {2026}, author = {Duan, W and Xing, Y and Liu, W}, title = {Protocol for generating multiplexed prime-edited monoclonal cell lines in porcine fetal fibroblasts.}, journal = {STAR protocols}, volume = {7}, number = {3}, pages = {104691}, doi = {10.1016/j.xpro.2026.104691}, pmid = {42412614}, issn = {2666-1667}, abstract = {Porcine fetal fibroblasts (PFFs) serve as standard donor cells for generating cloned pigs, and prime editing (PE) enables precise genome modification. Here, we describe a protocol for generating multiplexed prime-edited monoclonal cell lines in PFFs. We describe steps for pegRNA/ngRNA design and screening, plasmid electroporation, nocodazole treatment, puromycin selection, and monoclonal isolation and genotyping. Although demonstrated by introducing three Alzheimer's disease-associated pathogenic mutations, the pipeline can be readily adapted to multiplex PE of other endogenous loci in porcine cells. For complete details on the use and execution of this protocol, please refer to Liu et al.[1].}, } @article {pmid42412645, year = {2025}, author = {Hidasi, Z and Fullajtár, M}, title = {[Special aspects of the treatment of Alzheimer's disease (Anti-amyloid therapies and management of BPSD)].}, journal = {Psychiatria Hungarica : A Magyar Pszichiatriai Tarsasag tudomanyos folyoirata}, volume = {40}, number = {3-4}, pages = {274-281}, pmid = {42412645}, issn = {0237-7896}, mesh = {Humans ; *Alzheimer Disease/drug therapy/psychology/therapy ; *Amyloid beta-Peptides/immunology ; Antibodies, Monoclonal, Humanized/therapeutic use ; Immunization, Passive ; }, abstract = {Due to its diverse symptomatology, Alzheimer's disease requires a complex therapeutic approach. Among the disease-modifying pharmacotherapeutic options, significant progress has recently been made in the field of anti-amyloid antibody therapies. These are generally costly procedures in which passive immunization targets various components of the beta-amyloid cascade. The individual agents differ significantly in terms of efficacy and potential side effects/complications. Considering the questionable degree of cognitive effectiveness, and the associated risks, the exact evaluation of the practical applicability of these agents is currently not possible; long-term data analysis is needed. The symptom cluster of behavioral and psychological symptoms of dementia (BPSD) is in itself complex, encompassing a wide range of clinical phenomena. These symptoms, which frequently occur in everyday patient care and often have multifactorial origins and pathomechanisms, require a complex therapeutic approach. The therapeutic benefit of pharmacological treatments applicable to specific symptom clusters is often difficult to determine due to potential side effects; therefore, individualized treatment supplemented with non-pharmacological methods is warranted. Keywords: Alzheimer's disease; anti-amyloid therapies; behavioral and psychological symptoms of dementia (BPSD).}, } @article {pmid42413499, year = {2026}, author = {Vear, A and Olsen, SA and Lange, ECH and Müller, MA and Svendsen, C and Clemmensen, C}, title = {Preventative semaglutide and tirzepatide treatment does not alter disease progression in the 5xFAD mouse model of Alzheimer's disease.}, journal = {Cell reports. Medicine}, volume = {}, number = {}, pages = {102906}, doi = {10.1016/j.xcrm.2026.102906}, pmid = {42413499}, issn = {2666-3791}, abstract = {There is growing evidence that long-acting mimetics of the gut-derived incretin hormones GLP-1 and GIP act as disease-modifying therapies for Alzheimer's disease (AD). Here, we temporally characterize the efficacy of the approved incretin receptor agonists semaglutide, a GLP-1R agonist, and tirzepatide, a GLP-1R/GIPR co-agonist, in preventing AD progression. In 5xFAD mice treated for 2 or 4 months, both incretin therapies lower body weight and improve glucose tolerance, yet neither compound produces measurable effects on memory or learning tasks, amyloid-β plaque deposition, or glial cell activation. In a non-amyloidogenic model, 3 days of incretin pre-treatment does not alter microglial activation or the expression of inflammatory markers following lipopolysaccharide (LPS) administration in mice. Our findings indicate that chronic semaglutide or tirzepatide treatment, even when initiated before overt pathology and delivered for a prolonged period, does not slow neuropathological progression in 5xFAD or LPS-treated mice.}, } @article {pmid42413719, year = {2026}, author = {Alameen, AAM and Al-Kuraishy, HM and Abdelaziz, AM and Al-Gareeb, AI and Albuhadily, AK and Batiha, GE}, title = {Targeting PARP1-dependent parthanatos in Alzheimer's disease: Mechanisms and therapeutic opportunities.}, journal = {Life sciences}, volume = {402}, number = {}, pages = {124578}, doi = {10.1016/j.lfs.2026.124578}, pmid = {42413719}, issn = {1879-0631}, abstract = {Alzheimer's disease (AD) is the predominant cause of dementia globally. This review clarifies the dual function of poly(ADP-ribose) polymerase 1 (PARP1) in AD pathogenesis, emphasizing its role in mediating parthanatos, a unique caspase-independent cell death mechanism. We analyze contemporary literature regarding PARP1 expression, parthanatos signaling, and pharmaceutical treatments in AD models. In addition, PARP1 exhibits context-dependent duality: its physiological nuclear expression in hippocampus neurons is essential for memory consolidation and decreases early in cognitive impairment, suggesting a correlative association with synaptic malfunction. In contrast, overactivity of PARP1 resulting from Aβ-induced oxidative stress and DNA damage induces neurodegeneration via multiple pathways, including NAD+/ATP exhaustion leading to metabolism collapse, creation of the AIF-MIF complex promoting parthanatos, NF-κB-induced neuroinflammation, dysregulation of mitophagy, and disruption of the neuroprotective SIRT1 signaling pathway. The overactivity contributes to a positive feedback loop, where PARP1 intensifies Aβ and tau protein accumulation while simultaneously disrupting the BBB. In preclinical models of AD, genetic knockout, pharmacologic agents such as PJ34 and MC2050, or precursors of NAD[+] such as nicotinamide and NMN attenuate Aβ deposition, normalize metabolism, and ameliorate cognitive decline. The PARP1/parthanatos pathway is at the center of the confluence of oxidative stress, DNA damage, metabolism disorder, and neuroinflammation in AD. Metformin and other PARP1 inhibitors offer intriguing treatment options. PARP1's cell-type- and intracellular location-dependent activity necessitates careful consideration of context, dose, and disease stage while developing therapies. The present understanding in this review could inform future research on PARP1 regulation in AD clinical practice.}, } @article {pmid42413935, year = {2026}, author = {Lee, S and Kao, CY and Li, Z and Dan, T and Wu, G and Hao, W}, title = {Optimal control for anti-abeta treatment in Alzheimer's disease using a reaction-diffusion model.}, journal = {Journal of the Royal Society, Interface}, volume = {23}, number = {240}, pages = {}, doi = {10.1098/rsif.2025.1158}, pmid = {42413935}, issn = {1742-5662}, support = {1R35GM146894/GF/NIH HHS/United States ; DMS-2533995//NSF/ ; DMS 2208373//NSF/ ; DMS 2513176//NSF/ ; //Huck Chair in AI Mathematical Modeling from Penn State University's Huck Institutes of the Life Sciences/ ; }, mesh = {*Alzheimer Disease/diagnostic imaging/metabolism/drug therapy/therapy ; Humans ; *Amyloid beta-Peptides/metabolism/antagonists & inhibitors ; *Models, Biological ; Positron-Emission Tomography ; }, abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder that severely impairs survival and quality of life. While anti-amyloid beta (Aβ) therapies can slow disease progression, their efficacy depends on personalized dosing that maximizes benefits and minimizes risks, such as amyloid-related imaging abnormalities (ARIA). Mathematical modelling offers a powerful tool for understanding AD dynamics and optimizing treatment, yet most models focus solely on temporal behaviour, overlooking spatial heterogeneity within the brain. In this study, we propose a spatially explicit reaction-diffusion model to describe Aβ plaque dynamics. We formulate an optimal control problem to minimize plaque concentration while balancing therapeutic efficacy and treatment risk. Under reasonable assumptions, we establish well-posedness and uniqueness of the optimal solution. A finite element method (FEM)-based numerical framework is developed to compute personalized treatment strategies. Our model is calibrated using longitudinal Aβ positron emission tomography (PET) data from the Alzheimer's Disease Neuroimaging Initiative (ADNI), enabling estimation of patient-specific parameters, such as growth rate and effective diffusivity. Results show that optimized treatment strategies consistently outperform constant dosing regimens across patient groups, achieving substantial reductions in cumulative amyloid burden while minimizing side effects. This integrated, data-driven framework advances personalized, spatially informed therapeutic optimization for AD.}, } @article {pmid42415176, year = {2026}, author = {Eom, JW and Kim, KR and Kim, DH and Song, JG and Han, C and Kim, HW and Ha, S and Song, WJ and Kim, YH}, title = {Zinc-mediated lysosomal activation by 1H10 enhances autophagy and attenuates tau pathology in Alzheimer's disease models.}, journal = {Molecular brain}, volume = {}, number = {}, pages = {}, doi = {10.1186/s13041-026-01328-9}, pmid = {42415176}, issn = {1756-6606}, support = {NRF-2020R1I1A1A01061724//National Research Foundation of Korea/ ; RS-2023-NF001356//National Research Foundation of Korea/ ; 2025-RISE-01-019-04//The seoul RISE centor/ ; }, abstract = {Impaired autophagic flux and lysosomal dysfunction contribute critically to the accumulation of pathological protein aggregates in Alzheimer's disease (AD). Emerging evidence suggests that intracellular zinc dynamics regulate lysosomal function by modulating processes such as acidification and lysosomal biogenesis. We previously identified 1H10 as an AMP-activated protein kinase (AMPK) inhibitor and subsequently demonstrated its zinc-binding capacity and ability to regulate intracellular zinc homeostasis. Building on our prior findings that intra-lysosomal zinc promotes acidification and activates transcription factor EB (TFEB), we investigated whether 1H10 enhances lysosomal function through zinc mobilization in neurons, thereby improving autophagy and reducing pathological protein accumulation. In primary cortical neurons, 1H10 increased lysosomal abundance and enhanced lysosomal degradative capacity in a zinc-dependent manner, as demonstrated by increased cathepsin B activity and DQ-BSA degradation. It alleviated lysosomal dysfunction induced by v-ATPase inhibition and promoted autophagic flux, leading to reduced accumulation of amyloid-β (Aβ) and tau in neuronal models. In 5XFAD mice, 1H10 treatment showed trends toward improved spatial learning in the Morris water maze, reduced tau phosphorylation at Thr205 and Ser214, normalized LC3-II levels, and restored autophagic-lysosomal homeostasis, without significant changes in extracellular amyloid plaque burden. These findings indicate that zinc-mediated lysosomal activation by 1H10 enhances the autophagy-lysosomal pathway and attenuates tau pathology in AD models, suggesting that targeting lysosomal function may represent a potential therapeutic strategy for neurodegenerative disorders characterized by impaired proteostasis.}, } @article {pmid42415281, year = {2026}, author = {Aldana, BI and Freude, K}, title = {Chemokines in Alzheimer's Disease: Early Defence, Late Damage and the Impact of Sex and Infection.}, journal = {Basic & clinical pharmacology & toxicology}, volume = {139}, number = {2}, pages = {e70273}, doi = {10.1111/bcpt.70273}, pmid = {42415281}, issn = {1742-7843}, support = {R434-2023-242//Lundbeck Foundation/ ; N/A//Alzheimersfonden/ ; }, mesh = {Humans ; *Alzheimer Disease/immunology/metabolism ; *Chemokines/metabolism/immunology ; Animals ; Female ; Male ; Sex Factors ; Signal Transduction ; Virus Diseases/immunology ; Neuroinflammatory Diseases/immunology ; COVID-19/immunology ; Receptors, Chemokine/metabolism ; Brain/immunology/metabolism ; Sex Characteristics ; }, abstract = {Chemokines constitute a versatile signalling network maintaining homeostasis and glia-neuron communication in the healthy brain but become progressively dysregulated during aging and Alzheimer's disease (AD). This review examines how chemokine systems transition from tightly regulated homeostatic signals to drivers of chronic neuroinflammation in AD. We describe the major chemokine families (CC, CXC, CX3C) and their dominant central nervous system (CNS) receptors (CCR2, CXCR3, CX3CR1), which activate canonical inflammatory pathways including NF-κB, JAK/STAT and PI3K-AKT. In AD, chemokine dysregulation occurs in a coordinated manner across multiple functional modules, including recruitment-associated (CCL2, CXCL1), interferon-inducible (CXCL10), loss-of-restraint (CX3CL1) and vascular-associated chemokines. These alterations shift the network from regulated immune communication to self-sustaining inflammatory circuits perpetuating chronic neuroinflammation. These networks reprogram microglia and astrocytes into disease-associated phenotypes, amplify peripheral immune cell infiltration and destabilise synaptic function. Biological sex profoundly influences neuroinflammatory trajectories, with females exhibiting enhanced microglial senescence and interferon signalling, while males show accelerated complement activation. Viral pathogens, particularly neurotropic viruses (HSV-1, HHV-6, VZV) and SARS-CoV-2, actively reprogram chemokine networks, linking infection to amyloid-β accumulation, tau pathology and neurodegeneration. Therapeutically, chemokine axes represent precision targets requiring stage-matched, sex-stratified interventions rather than broad anti-inflammatory approaches. Understanding chemokine network dynamics offers mechanistic insights into AD pathogenesis and could provide pointers for therapeutic strategies.}, } @article {pmid42415688, year = {2026}, author = {Hill, N and AlMuallim, HYO and Maddock, E and Hobbs, C and Clarke, E and Goncalves, MB and Corcoran, JPT}, title = {Treatment with KCL-286, a first-in-class retinoic acid receptor-β (RARβ) agonist, ameliorates neuronal DNA damage and inflammation in a mouse model of Alzheimer's disease.}, journal = {FEBS open bio}, volume = {}, number = {}, pages = {}, doi = {10.1002/2211-5463.70284}, pmid = {42415688}, issn = {2211-5463}, support = {110047/Z/15/Z/WT/WT_/Wellcome Trust/United Kingdom ; MR/R006466/1/MRC_/Medical Research Council/United Kingdom ; }, abstract = {Alzheimer's disease (AD) is a complex, multifactorial neurodegenerative disorder for which effective disease-modifying therapies remain limited. Accumulation of neuronal DNA double-strand breaks (DSBs) is an early pathological event that contributes to genomic instability and neuronal vulnerability in AD. Therapeutic strategies that enhance DNA repair may therefore be of considerable interest. Here, using the Tg2576 mouse model of AD, we show that treatment with KCL-286, a selective retinoic acid receptor-β (RARβ) agonist, reduces neuronal DNA damage. KCL-286 enhances DSB repair in neurons, in part through upregulation of the DNA repair factor BRCA1, while also attenuating neuroinflammatory activation. In addition, KCL-286 normalises microglial and astrocytic morphology, consistent with reduced pathological glial activation. Together, these findings demonstrate that selective RARβ activation ameliorates neuronal DNA damage and neuroinflammation in a mouse model of AD, supporting further investigation as a potential disease-modifying therapeutic strategy.}, } @article {pmid42415930, year = {2026}, author = {Wang, PJ and Yang, XY and Ji, L and Shi, JJ and Cai, XM and Sun, P and Liu, HX and Jiang, F and Yang, F}, title = {Peripheral metabolomic profiling reveals lipid and amino acid alterations associated with immuno-inflammatory responses in treatment-naïve late-onset Alzheimer's disease.}, journal = {Frontiers in aging neuroscience}, volume = {18}, number = {}, pages = {1858299}, pmid = {42415930}, issn = {1663-4365}, abstract = {BACKGROUND: Immuno-metabolic dysregulation contributes to Alzheimer's disease (AD) pathogenesis, yet the peripheral metabolic landscape and its interplay with neuroinflammation remain poorly characterized in treatment-naïve, late-stage patients. This study aimed to delineate plasma metabolic alterations and immuno-metabolic interactions in Chinese first-time outpatients with late-onset AD (CFTO-LOAD).

METHODS: Untargeted metabolomics and ELISA were applied to plasma from 35 CFTO-LOAD patients and 35 sex-matched cognitively healthy controls (CHCs) to quantify metabolites, cytokines (TNF-α, IL-17, IL-9), and soluble Aβ/Tau markers.

RESULTS: A total of 875 differentially abundant metabolites (DAMs) were identified in CFTO-LOAD, comprising 227 upregulated and 648 downregulated species (P < 0.05), predominantly lipids, fatty acids (e.g., dodecanoic acid, arachidonic acid), and amino acids (e.g., L-arginine, L-leucine). KEGG analysis revealed enrichment in fatty acid and amino acid metabolism, GABAergic synapse, and intestinal immune network pathways. CFTO-LOAD patients exhibited elevated pro-inflammatory cytokines TNF-α and IL-17 (P adj < 0.05), reduced IL-9 (P adj < 0.001), increased soluble p-Tau, p-Tau181, and p-Tau217 (P adj < 0.01), and decreased Aβ42/Aβ40 ratio (P adj < 0.001). Linear regression identified significant correlations between differential metabolites and immune/pathological markers, including positive associations of dodecanoic acid with TNF-α (r = 0.34, P adj < 0.05) and arachidonic acid with Aβ42/Aβ40 ratio (r = 0.30, P adj < 0.05), and negative associations of arachidonic acid with p-Tau217 (r = -0.43, P adj < 0.01) and sphinganine 1-phosphate with TNF-α (r = -0.28, P adj < 0.05).

CONCLUSION: These findings characterize the peripheral immuno-metabolic landscape in treatment-naïve late-onset AD, identifying metabolic mediators that may mechanistically link neuroinflammation to Aβ and Tau pathology. This provides a foundation for biomarker development and therapeutic targeting in late-stage disease, pending independent validation.}, } @article {pmid42416049, year = {2026}, author = {Yang, M and Liang, Z}, title = {GLP-1 receptor agonists in neurological diseases: mechanisms and therapeutic prospects from metabolism to neuroprotection.}, journal = {Frontiers in immunology}, volume = {17}, number = {}, pages = {1839620}, pmid = {42416049}, issn = {1664-3224}, mesh = {Humans ; *Glucagon-Like Peptide-1 Receptor Agonists ; Animals ; *Neuroprotective Agents/therapeutic use/pharmacology ; *Nervous System Diseases/drug therapy/metabolism ; Glucagon-Like Peptide-1 Receptor/metabolism ; *Neuroprotection/drug effects ; Oxidative Stress/drug effects ; }, abstract = {Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are widely used metabolic therapies for type 2 diabetes and obesity, with well-established cardiovascular benefits. Beyond glycemic control, accumulating experimental and clinical evidence suggests that GLP-1RAs exert pleiotropic actions relevant to neurological diseases. Metabolic dysfunction, chronic inflammation, oxidative stress, mitochondrial impairment, and neurovascular injury represent convergent mechanisms that contribute to neurodegeneration, cerebrovascular pathology, and metabolism-related brain disorders. Notably, these processes overlap with pathways modulated by GLP-1 signaling across systemic and central compartments. GLP-1 receptors are expressed in neurons, glial cells, and components of the neurovascular unit, providing a biological basis for possible neurological effects. Preclinical studies suggest that GLP-1RAs can reduce neuroinflammation and oxidative stress, support mitochondrial function, and help maintain blood-brain barrier integrity. Clinical findings, however, remain inconsistent. Studies in Parkinson's disease have reported encouraging signals, but biomarker evidence for disease modification is still limited. In Alzheimer's disease, clinical trials have produced mixed or negative results. These differences may reflect disease stage, patient selection, drug-specific pharmacology, central nervous system exposure, endpoint sensitivity, and treatment duration. Overall, GLP-1RAs may influence neurological disease through metabolic, inflammatory, and vascular pathways, but their clinical role remains unsettled. Future studies should use biomarker-informed designs, prespecified neurological endpoints, appropriate drug selection, and sufficiently long follow-up to determine which patients and disease stages are most likely to benefit.}, } @article {pmid42418270, year = {2026}, author = {Caselli, RJ and Geldmacher, DS and Schilling, TB}, title = {A Narrative Review of Amyloid-β Monoclonal Antibodies for Alzheimer Disease: How Amyloid Species Engagement May Affect Clinical Outcomes.}, journal = {The neurologist}, volume = {31}, number = {4}, pages = {129-135}, doi = {10.1097/NRL.0000000000000679}, pmid = {42418270}, issn = {2331-2637}, support = {//Eli Lilly and Company, Indianapolis, IN/ ; }, mesh = {Humans ; *Alzheimer Disease/drug therapy/diagnostic imaging/metabolism ; *Amyloid beta-Peptides/immunology/metabolism ; *Antibodies, Monoclonal/therapeutic use ; Plaque, Amyloid/drug therapy ; Animals ; }, abstract = {BACKGROUND: Alzheimer's disease (AD) is a leading cause of death worldwide, with growing prevalence as life expectancy increases. An important neurological hallmark of AD is the deposition of extracellular neuritic amyloid-β (Aβ) plaques that can disrupt synaptic transmission and cause neuronal death. More recent studies suggest that targeting Aβ species can slow the progression of cognitive decline in AD.

REVIEW SUMMARY: This narrative review examines the efficacy of monoclonal antibodies targeting the amyloid-β (Aβ) protein in the treatment of AD. It discusses the mechanisms by which these antibodies aim to mitigate amyloid pathology and explores their clinical outcomes in various trials. The review highlights the importance of amyloid plaque reduction to less than 25 Centiloids observed through amyloid positron emission tomography (PET) scans as a predictor of slowing cognitive decline. The findings suggest that targeting insoluble amyloid plaques is crucial for achieving clinical benefits in AD treatment. This review also discusses the phenomenon of amyloid-related imaging abnormalities (ARIA) that may be associated with monoclonal antibody therapy.

CONCLUSION: Monoclonal antibodies that target Aβ monomers, soluble oligomers and protofibrils, and insoluble fibrils/plaques were developed, and not all have provided clinical benefit. Emerging evidence suggests that it is important to reduce amyloid plaque burden to less than 25 Centiloids, consistent with a visually negative amyloid PET scan, in order to slow cognitive decline in early symptomatic AD.}, } @article {pmid42418504, year = {2026}, author = {Cai, Y and Wang, Y and Huang, W and Su, Y and Lei, M and Jia, R and Wu, C and Zhang, T and Sun, L and Peng, B and Cheng, J and Yu, J and Chen, X and Ye, Q and Yu, J and Xin, J}, title = {Lecanemab treatment improves B cell subpopulation immune homeostasis in patients with Alzheimer's disease.}, journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association}, volume = {22}, number = {7}, pages = {e71655}, doi = {10.1002/alz.71655}, pmid = {42418504}, issn = {1552-5279}, support = {82571602//National Natural Science Foundation of China/ ; 82371188//National Natural Science Foundation of China/ ; 2022ZD0211603//Brain Science and Brain-like Intelligence Technology-National Science and Technology Major Project/ ; ADB510200//Lingang Laboratory/ ; }, mesh = {Humans ; *Alzheimer Disease/drug therapy/immunology ; *Homeostasis/drug effects ; Female ; Male ; *B-Lymphocyte Subsets/drug effects/immunology ; Aged ; *Antibodies, Monoclonal/therapeutic use/pharmacology ; *B-Lymphocytes/drug effects/immunology ; Leukocytes, Mononuclear/drug effects ; }, abstract = {INTRODUCTION: Lecanemab, the first disease-modifying therapy for Alzheimer's disease (AD), mitigates pathology primarily by clearing amyloid plaques, but its impact on peripheral immunity remains unclear.

METHODS: To assess Lecanemab's immunological effects, we performed antibody array analysis of serum and single-cell RNA sequencing of peripheral blood mononuclear cells collected from healthy controls and patients with AD at baseline, 3, and 6 months post-treatment.

RESULTS: Lecanemab restored multiple serum chemokines to healthy levels in patients with AD. Compared to controls, baseline samples from patients with AD showed altered frequencies and functions of naïve and unswitched memory (UswM) B cells. Lecanemab treatment corrected the abnormal naïve and UswM B cell proportions and rebuilt their functional homeostasis by alleviating chronic inflammation and reversing the dysregulation of key pathways including immune response, NF-κB, RAGE, and cell adhesion.

DISCUSSION: These findings uncover a novel peripheral immunomodulatory mechanism of Lecanemab, offering new insights into AD therapeutics.}, } @article {pmid42410071, year = {2026}, author = {Suo, X and Wan, P and Yu, J and Zhu, X and Tian, C and Li, S and Sun, G and Liu, H and Liu, S and Geng, M and Tian, J and Yang, W and Zhang, Y}, title = {The Protective Effects of Small-Molecule Compound 0242 Against LPS-Induced Neuroinflammation and in P301S Tau Transgenic Mice.}, journal = {Neurochemical research}, volume = {51}, number = {4}, pages = {}, pmid = {42410071}, issn = {1573-6903}, support = {2024CXPT029, 2025CXPT011//Key R&D Program of Shandong Province, China/ ; SYS202205//Shandong Laboratory Program/ ; ZR2024QH615//Shandong Provincial Natural Science Foundation/ ; }, mesh = {Animals ; Lipopolysaccharides/toxicity ; Mice, Transgenic ; *tau Proteins/genetics/metabolism ; Female ; *Neuroinflammatory Diseases/chemically induced/metabolism/drug therapy/prevention & control ; Mice ; Microglia/drug effects/metabolism ; *Neuroprotective Agents/therapeutic use/pharmacology ; Alzheimer Disease/drug therapy/metabolism ; Hippocampus/drug effects/metabolism ; Mice, Inbred C57BL ; }, abstract = {Neuroinflammation and tau pathology are central drivers of Alzheimer's disease (AD) progression, necessitating multi-target therapeutic strategies. Here, we evaluated the efficacy and mechanisms of 0242, a novel small-molecule derivative optimized from the berberine scaffold. In lipopolysaccharide (LPS)-stimulated BV-2 microglia, 0242 treatment significantly inhibited cell activation and nitric oxide release without cytotoxicity, while downregulating the mRNA levels of pro-inflammatory cytokines IL-1β and TNF-α. Transcriptomic profiling revealed that 0242 modulated LPS-induced inflammatory gene signatures by enriched core signaling cascades, including NF-κB, TLR, and JAK-STAT and upregulating cytoprotective genes such as ceruloplasmin (Cp) and Bcl2a1b. In vivo, oral administration of 0242 attenuated hippocampal astrocyte and microglial activation in an LPS-induced acute neuroinflammatory mouse model. Furthermore, in female P301S tau transgenic mice, 0242 treatment significantly improved spontaneous locomotor activity and recognition memory. Histological and biochemical analyses confirmed that 0242 suppressed hippocampal glial activation and reduced total tau protein levels in the prefrontal cortex. Collectively, these findings suggest that 0242 may exert potent anti-neuroinflammatory effects by modulating multiple immune signaling cascades and uniquely alleviates tau pathology in AD.}, } @article {pmid42410083, year = {2026}, author = {Costello, H and Reeves, S and Glue, P and Young, AH and Howard, R}, title = {Depression in neurodegenerative disease: neurobiological mechanisms and emerging treatments.}, journal = {Molecular psychiatry}, volume = {}, number = {}, pages = {}, pmid = {42410083}, issn = {1476-5578}, abstract = {Depression is one of the most common and disabling neuropsychiatric complications of neurodegenerative diseases. In Alzheimer's disease (AD) and Parkinson's disease (PD), depressive syndromes affect more than one-third of patients and are associated with accelerated cognitive decline, reduced quality of life, and increased healthcare utilisation. Despite this burden, current antidepressant treatments show little or no efficacy in these populations, suggesting that depression arising in the context of neurodegeneration may reflect distinct underlying neurobiological mechanisms. Emerging evidence from molecular imaging, neuropathology, and cognitive neuroscience indicates disease-specific disruption of monoaminergic, glutamatergic, inflammatory, and reward-related circuits in AD and PD. These alterations may undermine the mechanisms of action of standard antidepressants and contribute to treatment resistance. Yet patients with cognitive impairment are routinely excluded from antidepressant trials, and few high-quality studies have evaluated novel therapies in neurodegenerative disease. In this narrative review, we synthesise current evidence on the neurobiological mechanisms underpinning depression in AD and PD and critically evaluate emerging pharmacological and neuromodulatory therapies targeting glutamatergic, serotonergic, dopaminergic, immune, and circuit-level dysfunction. Here, we highlight that depression in neurodegenerative disease offers a unique and underutilised model for mechanistically guided antidepressant development. We identify how interventions including glutamate modulators, dopaminergic agents, kappa opioid antagonists, immune-modulating therapies, and next-generation brain stimulation approaches may offer therapeutic promise. By aligning treatment development with disease-specific circuit and molecular pathology, this framework may improve outcomes for this neglected population while advancing precision psychiatry more broadly.}, } @article {pmid42410183, year = {2026}, author = {de Oliveira Portugal Couto, C and Hass das Eiras, ML and Juliao de Morais, JL and Leal Cordeiro Júnior, CW and Forlenza, OV and de Jesus Rodrigues de Paula, V}, title = {Chronic Lithium Exposure Reshapes PI3K-mTOR-linked Proteostatic Networks in the Hippocampus of an Alzheimer's Disease Mouse Model.}, journal = {Molecular neurobiology}, volume = {63}, number = {1}, pages = {}, pmid = {42410183}, issn = {1559-1182}, mesh = {Animals ; *Hippocampus/metabolism/drug effects/pathology ; *Alzheimer Disease/metabolism/drug therapy/pathology ; *Phosphatidylinositol 3-Kinases/metabolism ; Mice, Transgenic ; Disease Models, Animal ; *TOR Serine-Threonine Kinases/metabolism ; *Lithium/pharmacology/administration & dosage/therapeutic use ; Signal Transduction/drug effects ; Protein Interaction Maps/drug effects ; Proteomics ; Mice ; }, abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by amyloid-β deposition, tau pathology, and alterations in signaling pathways involved in neuronal survival and protein homeostasis. Lithium has been suggested as a potential neuroprotective treatment, but the molecular mechanisms associated with its long-term effects are still not fully understood. In this study, we investigated the effects of chronic lithium treatment on hippocampal proteins associated with PI3K-related signaling in triple-transgenic Alzheimer's disease (3xTg-AD) mice. Wild-type and transgenic animals received either a lower or higher lithium dose for eight months. Hippocampal samples were analyzed by LC-MS/MS proteomics followed by protein interaction and functional enrichment analyses. From a total of 7768 identified proteins, bioinformatic analyses identified 157 proteins shared between APP-, MAPT-, and PI3K-associated datasets. Further network analyses identified 18 proteins related to PI3K signaling, including seven proteins shared among all three datasets: FKBP1A, HSPA1B, HSPA8, RAS-related proteins, RPL13, RPL19, and RPL24. These proteins are associated with protein folding, translation regulation, cellular stress responses, and signaling pathways. Chronic lithium treatment was associated with changes in the expression of these proteins in both wild-type and transgenic animals. The observed effects differed between the two lithium concentrations tested and did not follow a simple linear pattern. Our findings suggest that long-term lithium exposure is associated with changes in molecular networks related to proteostasis and translational regulation in the hippocampus. Although additional studies are needed to better understand the mechanisms involved, these results provide a proteomic framework for investigating lithium-sensitive pathways that may be relevant to Alzheimer's disease.}, } @article {pmid42411221, year = {2026}, author = {Sharma, A and Kaur, A and Khan, J and Pandey, H}, title = {Phyto-Nanotherapeutics for Alzheimer's Disease: Current Progress and Future Perspectives.}, journal = {Central nervous system agents in medicinal chemistry}, volume = {}, number = {}, pages = {}, doi = {10.2174/0118715249455878260609100548}, pmid = {42411221}, issn = {1875-6166}, abstract = {Alzheimer's Disease (AD) is a prevalent neurodegenerative disorder characterized by progressive cognitive and behavioral impairment and represents a major cause of dementia worldwide. It primarily affects the elderly population. The disease is marked by progressive neuronal damage, leading to impairments in cognition, behavior, emotions, and communication. Although currently available therapies provide symptomatic relief, they fail to alter disease progression, necessitating the development of more effective therapeutic strategies. Phytoconstituents have gained considerable attention due to their neuroprotective properties and multitargeted mechanisms of action against pathways implicated in AD. However, their clinical application is limited by poor Blood-Brain Barrier (BBB) permeability, low bioavailability, and inadequate solubility. Nanotechnology offers a promising approach for brain-targeted drug delivery by enhancing the therapeutic efficacy of phytoconstituents through advanced nanocarrier systems. This review explores the synergistic potential of phytoconstituents and nanocarriers for the management of AD, aiming to improve therapeutic outcomes and overcome existing limitations. It further highlights the integration of medicinal plant-based compounds with nanotechnology as a novel strategy for AD treatment. The combination of nanocarriers and phytoconstituents may facilitate enhanced BBB penetration and improved neuroprotection. Notably, nanomedicine- based approaches, including phytoconstituent-loaded nanoparticles and liposomes, demonstrate significant potential to overcome delivery barriers and enable efficient drug transport to the brain.}, } @article {pmid42411440, year = {2026}, author = {Ye, T and Shuai, Y and Liu, Y and Liu, S and Tang, X and Tian, W and Zhang, Y and Kong, Y}, title = {Efficacy and Safety of Transcranial Direct Current Stimulation on Multiple Health Outcomes in Neurological Disorders: An Umbrella Review of Meta-Analyses of Randomized Controlled Trials.}, journal = {Journal of integrative neuroscience}, volume = {25}, number = {6}, pages = {47145}, doi = {10.31083/JIN47145}, pmid = {42411440}, issn = {0219-6352}, mesh = {*Transcranial Direct Current Stimulation ; Humans ; *Nervous System Diseases/therapy ; *Randomized Controlled Trials as Topic ; Meta-Analysis as Topic ; Systematic Reviews as Topic ; *Outcome Assessment, Health Care/statistics & numerical data ; }, abstract = {BACKGROUND: Neurological disorders are a leading cause of disability worldwide. Transcranial direct current stimulation (tDCS) is a promising therapeutic tool for neurological disorders. However, a consensus on clinical recommendations for using tDCS in patients with neurological disorders is lacking. In this umbrella review, we aimed to establish evidence-based guidance for using tDCS to treat neurological disorders.

METHODS: This study followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines 2020. PubMed/MEDLINE, Embase, the Cochrane Library, the Web of Science, and the Cumulative Index to Nursing and Allied Health Literature (CINAHL) were systematically searched to identify and evaluate existing systematic reviews and meta-analyses on the use of tDCS for neurological disorders. Quality was assessed using the Measurement Tool to Assess Systematic Reviews 2 (AMSTAR 2) and the Grades of Recommendations, Assessment, Development, and Evaluation (GRADE) tool. The Hartung-Knapp-Sidik-Jonkman random effects model was employed for reanalysis.

RESULTS: A total of 17 systematic reviews and meta-analyses encompassing 358 randomized controlled trials and 7160 participants were analyzed. tDCS demonstrated efficacy across seven distinct health conditions, including stroke, Parkinson's disease, Alzheimer's disease, cerebellar ataxia, fibromyalgia, disorders of consciousness, and migraine. Adverse effects were rarely reported, with the exception of mood changes associated with fibromyalgia. Our results indicated that tDCS significantly improved 34 distinct health outcomes related to these conditions.

CONCLUSIONS: We found that tDCS may be a promising treatment for neurological disorders, with mild and infrequent adverse effects. Further studies are warranted to validate the therapeutic potential of tDCS in the reported neurological conditions, investigate additional neurological health outcomes, and explore the underlying mechanisms of tDCS effects. The PROSPERO Registration: CRD42024589432, https://www.crd.york.ac.uk/PROSPERO/view/CRD42024589432.}, } @article {pmid42411945, year = {2026}, author = {Nakamura, Y and Tsushio, T and Tanahashi, M and Suganami, H and Omori, T and Nishiyama, K and Aoki, H and Nagakura, N}, title = {Post Hoc Subgroup Analysis by Disease Severity in a Non-Inferiority Trial of Donepezil 27.5 mg Transdermal Formulation in Japanese Patients With Mild-to-Moderate Alzheimer Disease.}, journal = {Alzheimer disease and associated disorders}, volume = {}, number = {}, pages = {}, doi = {10.1097/WAD.0000000000000738}, pmid = {42411945}, issn = {1546-4156}, support = {//Teikoku Seiyaku/ ; }, abstract = {BACKGROUND: The efficacy of cholinesterase inhibitors varies depending on the severity of Alzheimer disease. We examined the effects of the disease severity on the efficacy of donepezil 27.5 mg patches in Japanese patients with Alzheimer disease.

METHODS: A post hoc analysis of covariance using per-protocol set in a noninferiority study of donepezil 27.5 mg patches with donepezil hydrochloride 5 mg tablets (JapicCTI-194582) was conducted after imputation of missing data using multiple imputations.

RESULTS: No apparent imbalances in the extracted confounding factors were observed between the 2 treatment groups. The baseline value of the Alzheimer Disease Assessment Scale (Japanese version) cognitive subscale was adjusted using analysis of covariance. Least-squares mean of changes from baseline in the Alzheimer Disease Assessment Scale (Japanese version) cognitive subscale at week 24 for each group were -1.661 (-2.681 to -0.640) (donepezil patch) and 0.065 (-0.987 to 1.117) (donepezil hydrochloride tablet). The difference in the least-squares mean (95% CI) between 2 groups was -1.726 (-3.1913 to -0.2602, P=0.021).

CONCLUSIONS: A post hoc analysis of covariance using the per-protocol set suggested that donepezil patches may be more effective than donepezil tablets in slowing cognitive decline in patients with mild Alzheimer disease.}, } @article {pmid42412004, year = {2026}, author = {Zhang, J and Wang, Y and Lu, Z and Yang, Y and Wang, J and Zhao, L and Li, F and Miao, M and Chen, WM and Wu, SY and Sun, M}, title = {HbA1c trajectories after SGLT2 inhibitor initiation and the risk of dementia.}, journal = {Journal of Alzheimer's disease : JAD}, volume = {}, number = {}, pages = {13872877261462927}, doi = {10.1177/13872877261462927}, pmid = {42412004}, issn = {1875-8908}, abstract = {BackgroundType 2 diabetes mellitus (T2DM) is a major risk factor for dementia, yet the prognostic value of early dynamic glycemic changes following glucose-lowering therapy remains underinvestigated.ObjectiveTo determine whether early glycated hemoglobin (HbA1c) trajectories after initiating sodium-glucose cotransporter 2 inhibitors (SGLT2i) predict long-term dementia and mortality risks.MethodsThis retrospective new-user cohort study utilized electronic health records from the TriNetX Global Network. Adults with T2DM initiating their first SGLT2i were included. To mitigate immortal-time bias, a 1-year landmark design was applied. Patients were stratified by baseline HbA1c and classified into improved, stable, or worsened trajectories based on values 91-455 days post-initiation. Propensity-score matching was performed within strata. The primary outcome was all-cause dementia.ResultsAmong 172,050 matched patients, modest HbA1c worsening in those with Good baseline control (<7.0%) did not increase dementia risk (HR 0.93; 95% CI, 0.75-1.15). However, in patients with Fair baseline control (7.0-8.9%), worsening to Poor control significantly increased dementia (HR 1.39; 95% CI, 1.11-1.74) and mortality risks. Conversely, among those with Poor baseline control (≥9.0%), trajectory improvement conferred substantial neuroprotection, reducing the risk of dementia (HR 0.64; 95% CI, 0.51-0.79) and mortality (HR 0.71; 95% CI, 0.60-0.84). These findings provide clinically actionable evidence linking glycemic dynamics to neurodegenerative risk, particularly Alzheimer's disease and related dementias.ConclusionsDynamic HbA1c trajectories following SGLT2i initiation independently predict dementia risk. Integrating trajectory-based assessments into routine care provides an actionable, scalable biomarker to guide timely treatment intensification and mitigate diabetes-related neurocognitive decline.}, } @article {pmid42399403, year = {2026}, author = {Endrizzi, W and Ragni, F and Bovo, S and Chandra, A and Moroni, M and Jurman, G and Osmani, V}, title = {The landscape of artificial intelligence in neurodegenerative diseases: a systematic review.}, journal = {Communications medicine}, volume = {}, number = {}, pages = {}, doi = {10.1038/s43856-026-01669-5}, pmid = {42399403}, issn = {2730-664X}, abstract = {BACKGROUND: The rising global burden of neurodegenerative diseases underscores an urgent need for advanced research in diagnosis, prognosis, and treatment. Artificial Intelligence (AI) methods, particularly when applied to multimodal data, offer a powerful tool to address these challenges. However, a comprehensive overview and critique of the current landscape of AI methods is lacking.

METHODS: 4,685 records of peer-reviewed, primary research articles were screened and 1,956 articles reviewed in full text, yielding 1,186 included studies. For each included study, clinical objectives, disease focus, data modalities, modelling approach, evaluation strategy, and reporting practices were extracted.

RESULTS: Fewer than 5% of studies integrated pharmacological treatments into their predictive models, limiting the extent to which models can directly inform clinical decision-making. Neuroimaging was the predominant input modality, while integration of other clinically relevant data types was relatively rare. Reproducibility rates remain critically low at 35%, and external validation practices fail to use geographically and demographically diverse datasets.

CONCLUSIONS: Overall, AI research in neurodegenerative diseases suffers from significant limitations in reproducibility, data inclusivity, and clinical translatability. We provide a set of recommendations that can be adopted to address these issues and improve reliability and downstream clinical utility.}, } @article {pmid42401549, year = {2026}, author = {Liu, C and Zhang, T and E, ED and Xu, TY and Yang, FR and Li, JW and Shang, Q and Zhang, ZY and Shen, HW and Zhang, XQ}, title = {Maraviroc attenuates inflammation-exacerbated cognitive and amyloid pathology in an early-stage Alzheimer's disease mouse model.}, journal = {Translational psychiatry}, volume = {}, number = {}, pages = {}, doi = {10.1038/s41398-026-04215-y}, pmid = {42401549}, issn = {2158-3188}, support = {32201322//National Natural Science Foundation of China (National Science Foundation of China)/ ; LY24H090001//Natural Science Foundation of Zhejiang Province (Zhejiang Provincial Natural Science Foundation)/ ; }, abstract = {Alzheimer's disease (AD) is an age-related neurodegenerative disorder characterized by progressive cognitive decline, and increasing evidence indicates that systemic inflammation can accelerate disease progression. Maraviroc, a CCR5 antagonist approved for the treatment of human immunodeficiency virus (HIV) infection, has shown neuroprotective effects in several neurological contexts, but its role in AD-related pathology remains unclear. In this study, cognitive performance was assessed in 5 × FAD mice using the Y-maze, novel object recognition, novel location recognition, and social discrimination tests. Amyloid-related changes were evaluated by hippocampal APP/Aβ immunoblotting and plaque staining using 6E10 and Thioflavin S. Glial responses were examined by IBA1 and GFAP immunostaining, and inflammatory cytokines were quantified by ELISA. We found that 5 × FAD mice exhibited age-dependent cognitive impairments, with detectable deficits emerging at 3 months of age. Systemic administration of lipopolysaccharide (LPS) further exacerbated cognitive dysfunction, amyloid-related alterations, and neuroinflammatory responses in young 5 × FAD mice. Maraviroc treatment attenuated LPS-associated cognitive impairments, reduced amyloid-related measures, and dampened pro-inflammatory cytokine responses, with a trend toward reduced microglial cell density. Collectively, these findings demonstrate that systemic inflammation accelerates Alzheimer's-like pathology and cognitive decline, and suggest that pharmacological modulation of neuroinflammatory signaling by maraviroc may mitigate inflammation-driven disease exacerbation at early stages.Schematic diagram illustrating the effects of maraviroc on LPS-induced cognitive deficits in 3-month-old 5 × FAD mice. In this model, maraviroc is associated with modulation of glial inflammatory responses, reduced pro-inflammatory cytokine levels, and alleviation of amyloid pathology in the hippocampus, which together coincide with improved cognitive performance. Figure created with BioRender.com.}, } @article {pmid42402307, year = {2026}, author = {Chen, Z and Yang, K and Lin, F and Tang, W and Shi, Y and Zhou, S and Liu, J and You, Y}, title = {White matter abnormalities in Alzheimer's disease: Implications for pathophysiology, diagnosis, and treatment.}, journal = {Ageing research reviews}, volume = {}, number = {}, pages = {103229}, doi = {10.1016/j.arr.2026.103229}, pmid = {42402307}, issn = {1872-9649}, abstract = {White matter (WM) abnormalities have emerged as a critical element in Alzheimer's disease (AD) pathogenesis, shifting from their former status as a passive consequence to an active contributor to disease progression. Notably, microstructural WM alterations, detectable early via advanced neuroimaging techniques such as diffusion tensor imaging, frequently precede overt gray matter atrophy and cognitive decline, highlighting their potential as early contributors to AD pathogenesis. The origins of WM pathology are multifactorial, involving a complex interplay among β-amyloid (Aβ) and tau aggregation, energy dysmetabolism, neuroinflammation, vascular dysfunction, and cellular senescence. Importantly, we emphasize a paradigm-shifting perspective: WM degeneration acts not merely as a downstream outcome but as a key driver of AD pathogenesis, capable of accelerating protein aggregation, amplifying neuroinflammation, and compromising neural plasticity. Given its early manifestation and close association with symptom onset, WM integrity has emerged as a sensitive and reliable biomarker for early AD detection and progression monitoring. Moving beyond diagnostics, the growing understanding of WM pathophysiology has unveiled a new frontier of therapeutic interventions aimed at myelin regeneration and WM protection. Despite persisting translational challenges, targeting WM integrity represents a pivotal avenue for developing disease-modifying therapies capable of slowing disease progression and improving clinical outcomes in patients with AD.}, } @article {pmid42402880, year = {2026}, author = {, }, title = {[Standard operating procedure for pre-analytical blood biomarker processing in Alzheimer's disease (2026 edition)].}, journal = {Zhonghua yi xue za zhi}, volume = {106}, number = {25}, pages = {2568-2578}, doi = {10.3760/cma.j.cn112137-20260202-00363}, pmid = {42402880}, issn = {0376-2491}, support = {2023YFC3605400//National Key Research and Development Program of China/ ; 82588301//Natural Science Foundation of China/ ; 2024GGXM003//Joint Project of the Chongqing Science and Technology Bureau and the Health Commission/ ; }, mesh = {*Alzheimer Disease/blood/diagnosis ; Humans ; *Biomarkers/blood ; Amyloid beta-Peptides/blood ; tau Proteins/blood ; }, abstract = {Alzheimer's disease (AD) is a major health threat to the elderly. With the clinical application of disease-modifying therapeutic drugs, early and accurate diagnosis of AD has become increasingly essential. Given the ease of collection, blood biomarker detection has emerged as a crucial method for early screening, clinical diagnosis, and disease monitoring of AD. In recent years, substantial progress has been achieved in the research of AD blood biomarkers, and some indicators have been introduced into clinical practice. However, the detection of AD blood biomarkers, such as β-amyloid protein and phosphorylated tau protein, are highly susceptible to pre-analysis factors, which reduces the reliability of their clinical application and restricts the comparability among different blood biomarker studies. Currently, in China, there is a growing trend in the scientific research, testing product development, and clinical application of AD blood biomarkers. Therefore, it is necessary to standardize the AD blood biomarker detection in China. Based on this background, Cognitive Impairment Working Group of the National Medical Quality Control Center for Neurological Diseases established the "Standard operating procedure for pre-analytical blood biomarker processing in Alzheimer's disease (2026 edition)". This standard is developed in line with international recommendations, incorporating the practical experience of blood biomarker research in China and taking into consideration both clinical and research needs. It formulates a standardized operating procedure for the pre-treatment of blood samples, providing a quality control reference for the research and clinical application of AD blood biomarkers in China.}, } @article {pmid42403709, year = {2026}, author = {Fontán-Baselga, T and Cañeque-Rufo, H and Rivera-Illades, E and Gramage, E and Zapico, JM and de Pascual-Teresa, B and Ramos-Álvarez, MDP and Vicente-Rodríguez, M and Herradón, G}, title = {Chronic inhibition of receptor protein tyrosine phosphatase β/ζ reduces amyloid plaque load and modulates pleiotrophin-expressing glial cells, glial-plaque interactions and genes related to amyloid beta clearance.}, journal = {Frontiers in pharmacology}, volume = {17}, number = {}, pages = {1839516}, pmid = {42403709}, issn = {1663-9812}, abstract = {Alzheimer's disease (AD) is the most common cause of dementia. Pleiotrophin (PTN) is a neurotrophic factor relevant for central nervous system repair, neuron differentiation and survival. It is upregulated in different neuroinflammatory conditions. PTN is an endogenous inhibitor of Receptor Protein Tyrosine Phosphatase (RPTP) β/ζ. In a previous study, we showed that a short treatment with the RPTPβ/ζ inhibitor MY10 reduced amyloid beta (Aβ) plaque formation and glial activation in old APP/PS1 mice. Nevertheless, these preliminary data required new studies to prove the disease-modifying potential of RPTPβ/ζ inhibition by using younger animals and a longer treatment with MY10. Thus, we have now treated for 3 months five- to seven-month-old wild type (WT) and APP/PS1 mice with MY10. This treatment decreased Aβ plaque formation and increased the number of microglial cells in the dorsal subiculum of APP/PS1 mice. In addition, MY10 reduced the number of GFAP+, not Iba1+, cells surrounding Aβ plaques. As expected, PTN expression was upregulated in the brain of APP/PS1 compared to WT mice and it was mainly found in Iba1+ and GFAP+ cells. Interestingly, treatment with MY10 significantly decreased the expression of PTN and the number of PTN-expressing Iba1+ and GFAP+ cells. MY10 induced a significant decrease of Mmp9 expression in the hippocampus of APP/PS1 mice, a key enzyme in AD progression. In summary, chronic inhibition of RPTPβ/ζ in APP/PS1 mice reduces Aβ plaque deposition, modulating glial-plaque interactions and the expression of specific genes including Ptn and its receptor.}, } @article {pmid42403869, year = {2026}, author = {Tuleubayeva, A}, title = {Cardiovascular Biomarkers as a Primary Care Gateway to Early Alzheimer's Disease Detection: The Case for an Integrated Screening Approach.}, journal = {Cureus}, volume = {18}, number = {6}, pages = {e110287}, pmid = {42403869}, issn = {2168-8184}, abstract = {Alzheimer's disease (AD) affects millions of Americans and represents one of the leading causes of disability and healthcare expenditure in the United States. The vast majority of patients are diagnosed at the symptomatic stage, when substantial neuronal loss has already occurred and the therapeutic window for disease-modifying treatment has closed. Recently approved disease-modifying therapies have created an urgent clinical need for pre-symptomatic patient identification. The cardiovascular risk factors most commonly managed in primary care -- hypertension, dyslipidemia, type 2 diabetes, atrial fibrillation, and chronic heart failure -- are among the most powerful modifiable antecedents of AD pathology, operating through systemic inflammation, cerebral small vessel disease, impaired glymphatic clearance, and tau hyperphosphorylation. The biomarkers used to monitor these conditions -- C-reactive protein, cardiac troponin, NT-proBNP, and homocysteine -- reflect active neurodegeneration risk processes already measured routinely in primary care. This clinical perspective proposes a three-stage integrated neuro-cardiological screening protocol linking cardiovascular biomarker assessment to plasma P-tau217 blood testing for AD confirmation. This framework addresses the implementation gap identified in recent United States primary care literature and represents a practical step toward closing the AD diagnostic gap.}, } @article {pmid42404289, year = {2026}, author = {Larson, ST and Susman, JL}, title = {Navigating Alzheimer's Disease in Primary Care: Practical Strategies for Diagnosis and Management.}, journal = {International journal of general medicine}, volume = {19}, number = {}, pages = {603347}, pmid = {42404289}, issn = {1178-7074}, abstract = {Alzheimer's disease (AD), the most common form of dementia, is a neurodegenerative disorder that primarily affects older adults. Because the number of Americans 65 years of age and older living with AD is expected to increase and the availability of specialty physicians, such as neurologists and geriatricians, is limited, the role of primary care in diagnosing and managing patients with AD is expected to grow. Several guidelines for primary care providers are available for the evaluation, diagnosis, and treatment of patients with AD. However, there is no single concise and convenient reference tool for use in the primary care setting. In the primary care setting, clinicians are responsible for identifying patients at risk or demonstrating signs of cognitive impairment, administering cognitive tests, identifying appropriate referrals, and, in some cases, ordering blood-based biomarker testing. Although definitive testing and treatment identification may occur in the specialty care setting, in addition to serving as the hub to coordinate the multidisciplinary care team, primary care clinicians remain responsible for guiding patients and caregivers through shared decision-making regarding treatment, as well as the myriad responsibilities related to comorbidities, patient and caregiver psychological well-being, social support, and safety. This review aims to provide practical recommendations to primary care clinicians for the diagnosis, management, and long-term care of patients with AD.}, } @article {pmid42404421, year = {2025}, author = {Mansouri, Z and Motamedi, F and Khodagholi, F and Zahmatkesh, M}, title = {Histone Deacetylase Class IIb Inhibition Improves Amyloid-β-induced Learning and Memory Deficits in Male Rats.}, journal = {Basic and clinical neuroscience}, volume = {16}, number = {3}, pages = {583-594}, pmid = {42404421}, issn = {2008-126X}, abstract = {INTRODUCTION: Alzheimer's disease (AD) is a neurodegenerative disease associated with progressive impairment of cognitive function. The primary pathological features of AD include aggregation of amyloid-β (Aβ) and hyperphosphorylation of the tau protein. Histone deacetylases (HDACs) play a crucial role in the pathophysiology of neurodegenerative diseases. This study aimed to investigate the potential neuroprotective effects of HDAC6 and HDAC10 inhibition in a rodent model of AD.

METHODS: Learning and memory deficits were induced by bilateral intra-hippocampal Aβ injections in male Wistar rats. Tubacin (HDAC6 inhibitor) and bufexamac (HDAC6 and 10 inhibitors) were microinjected 30 minutes after Aβ injection. The possible molecular changes in the hippocampus following Aβ injection were also assessed by western blotting analysis of pCREB/CREB and Pp70/P70 ratios.

RESULTS: Our results revealed that bufexamac significantly recovered learning and memory impairments induced by Aβ in the Morris water maze (MWM) task. Tubacin improved memory decline without affecting learning. Bilateral intra-hippocampal injection of each of the HDAC inhibitors significantly increased the pCREB/CREB and Pp70/p70 ratios compared to the Aβ group, which was concurrent with behavioral alterations.

CONCLUSION: HDAC IIb treatment may be a promising strategy for improving learning and memory impairments in an animal model of AD, suggesting that HDAC targeting is a valuable strategy for further investigation.}, } @article {pmid42404899, year = {2026}, author = {Oh, SJ and Shin, OS and Hur, JY}, title = {From infection to dysfunction: viral triggers and antiviral immune factors in Alzheimer's disease pathology.}, journal = {Frontiers in immunology}, volume = {17}, number = {}, pages = {1839357}, pmid = {42404899}, issn = {1664-3224}, mesh = {Humans ; *Alzheimer Disease/immunology/pathology/virology ; Animals ; *Virus Diseases/immunology ; Brain/immunology/virology/pathology ; Host-Pathogen Interactions/immunology ; SARS-CoV-2/immunology ; }, abstract = {Neurodegenerative diseases and neurocognitive disorders increasingly appear to share a common and underappreciated contributor: the viral-immune axis in the brain. This review presents current evidence linking neurotropic viruses and host antiviral immunity to the onset and progression of neurodegeneration and neurocognitive dysfunction. We explore how viral infections, particularly by Herpesviruses, Severe Acute Respiratory Syndrome Coronavirus 2, and Human Immunodeficiency Virus, disrupt neural homeostasis through neuroinflammation, amyloidosis, tauopathy, and autophagy dysregulation in neurodegeneration including Alzheimer's disease (AD). Simultaneously, host antiviral mechanisms, including type I interferons and interferon regulatory factors, often amplify neuronal damage when dysregulated. By examining viral and immune interactions within the neurodegenerative diseases, this review aims to broaden our understanding of the viral-immune axis in the brain and inspire novel approaches to prevention and treatment.}, } @article {pmid42406171, year = {2026}, author = {Wu, H and Xia, J and Shi, Z and Zhang, C and Chen, S and Dai, L and He, L}, title = {Vorinostat Rescues Cognitive Deficits in a Neuroinflammatory Mouse Model: A Study of Sex Differences and the Underlying TLR4/NF-κB Mechanism.}, journal = {Neurochemical research}, volume = {51}, number = {4}, pages = {}, pmid = {42406171}, issn = {1573-6903}, mesh = {Animals ; *Toll-Like Receptor 4/metabolism ; Male ; *Vorinostat/therapeutic use/pharmacology ; Female ; *NF-kappa B/metabolism ; Mice, Inbred C57BL ; Mice ; *Neuroinflammatory Diseases/drug therapy/metabolism/chemically induced ; Lipopolysaccharides ; *Sex Characteristics ; *Cognitive Dysfunction/drug therapy/metabolism/chemically induced ; Signal Transduction/drug effects ; Microglia/drug effects/metabolism ; Neuroprotective Agents/therapeutic use/pharmacology ; Disease Models, Animal ; Hippocampus/drug effects/metabolism ; Histone Deacetylase Inhibitors/therapeutic use/pharmacology ; }, abstract = {With the acceleration of global aging, Alzheimer's disease (AD) poses a significant public health challenge, and effective treatments are still lacking. Neuroinflammation, particularly microglia-mediated inflammation, plays a central role in AD pathogenesis, with the Toll-like receptor 4 (TLR4)/nuclear factor-κB (NF-κB) signaling pathway being a key regulator. The histone deacetylase inhibitor (HDACi) Vorinostat (SAHA) has shown anti-inflammatory and neuroprotective potential in preclinical studies. Given the significant sex differences in AD incidence, pathology, and treatment response, this study aimed to systematically investigate the effects of SAHA on lipopolysaccharide (LPS)-induced neuroinflammation and cognitive dysfunction, analyzing its sex-specific effects and underlying mechanisms. An LPS-induced neuroinflammation model was established in male and female C57BL/6 mice via intraperitoneal injection (1 mg/kg) for 7 consecutive days, followed by SAHA (50 mg/kg) gavage intervention for 23 days. Cognitive function was assessed using Y-maze, novel object recognition, and passive avoidance tests. Hippocampal pathology was analyzed via hematoxylin-eosin (HE) staining and Nissl staining. Western blot and quantitative PCR (qPCR) were used to detect hippocampal expression of the TLR4/TRAF6/IKKα/NF-κB pathway, inflammatory factors (IL-6, IL-1β, TNF-α, iNOS), and neuroplasticity-related proteins (BDNF, p-CREB). In vitro experiments using LPS-stimulated BV2 microglia validated SAHA's anti-inflammatory mechanisms via CCK-8, Griess assay, qPCR, and Western blot. Results showed that LPS treatment significantly activated the TLR4/TRAF6/IKKα/NF-κB pathway, upregulated hippocampal pro-inflammatory factors, caused neuronal damage, and impaired learning and memory; these effects appeared more pronounced in female mice, though this observation is exploratory and requires cautious interpretation. SAHA treatment markedly alleviated LPS-induced inflammation, neuropathology, and cognitive deficits. Notably, SAHA appeared to produce differential effects across sexes: female mice showed potentially stronger and more comprehensive improvements in cognitive recovery, downregulation of inflammatory factors, and upregulation of BDNF and p-CREB compared to males, suggesting a possible sexually dimorphic response. In vitro experiments further confirmed that SAHA significantly reduced inflammation in LPS-stimulated BV2 microglia by inhibiting the TLR4/TRAF6/IKKα/NF-κB pathway. In conclusion, this study demonstrates that SAHA exerts neuroprotective effects by inhibiting the TLR4/NF-κB pathway, thereby improving cognitive impairment, and may have a more pronounced protective effect in females. These findings suggest SAHA is a promising drug for treating neuroinflammation-induced cognitive dysfunction and highlight the importance of considering sex as a biological variable in epigenetic therapy for precision medicine.}, } @article {pmid42406553, year = {2026}, author = {Wen, S and Gao, J and Wang, Z and Ma, Q and Xu, XL and Chen, J}, title = {EphB1-Mediated Transient Blood-Brain Barrier Opening Facilitates a Ferritin-Based Nanotherapeutic for Alzheimer's Disease.}, journal = {Advanced science (Weinheim, Baden-Wurttemberg, Germany)}, volume = {}, number = {}, pages = {e76480}, doi = {10.1002/advs.76480}, pmid = {42406553}, issn = {2198-3844}, support = {ZKJC2203//Zhejiang Rehabilitation Medical Center/ ; ZKXK02//Zhejiang Rehabilitation Medical Center/ ; 2021C03050//Development Program of Zhejiang Province/ ; 82372109//National Natural Science Foundation of China/ ; }, abstract = {The treatment of Alzheimer's disease (AD) is severely hampered by the blood-brain barrier (BBB), which limits the delivery of therapeutic agents like donepezil (DPZ), an acetylcholinesterase inhibitor. While DPZ has multi-faceted benefits, its clinical efficacy is constrained by poor BBB penetration, requiring high doses that lead to significant side effects. To overcome this, we developed a brain-targeted nanotherapeutic utilizing apoferritin (AFn) nanoparticles loaded with DPZ (AFn-DPZ). We demonstrate that this platform, by binding to the EphB1 receptor on the blood-brain barrier, enables transient and reversible opening of the blood-brain barrier, thereby facilitating efficient and targeted drug delivery. Following intravenous administration in an AD mouse model, AFn-DPZ exhibited enhanced brain accumulation and sustained release of DPZ. This targeted delivery inhibited acetylcholinesterase activity, reduced amyloid plaque burden, alleviated neuroinflammation, attenuated oxidative damage, restored mitochondrial function, and upregulated the expression of brain-derived neurotrophic factor (BDNF). Consequently, AFn-DPZ treatment significantly improved cognitive performance compared to free DPZ. Our findings establish EphB1-mediated facilitation of BBB traversal as a promising strategy for enhancing nanotherapeutic delivery to the brain, offering a potent approach to address the complex pathology of AD.}, } @article {pmid42406649, year = {2026}, author = {Zawadzki, S and Okła, E and Michlewska, S and Bednarek, R and Ortega López, P and de la Mata, FJ and Jansons, J and Skrastina, D and Kreišmane, M and Piļipenko, V and Jansone, B and Ionov, M and Bryszewska, M and Miłowska, K}, title = {Tiered Evaluation of Carbosilane Dendrimer-siRNA Nanoplatform from Single-Cell Biocompatibility to Blood-Brain Barrier Model Dynamics and Murine Alzheimer Model Behavior Assessment.}, journal = {ACS applied materials & interfaces}, volume = {}, number = {}, pages = {}, doi = {10.1021/acsami.6c06099}, pmid = {42406649}, issn = {1944-8252}, abstract = {Blood-brain barrier (BBB) transport remains a primary constraint on achieving predictable central nervous system exposure for Alzheimer's disease (AD) therapeutics, motivating the evaluation of delivery platforms with barrier-resolved and functionally relevant end points. We assessed a carbosilane dendrimer (G3Si PEG6000) and its siRNA dendriplex using a tiered, upstream strategy spanning cell internalization, DNA damage screening, BBB model integrity and permeability, and in vivo AD-relevant murine model learning. At the cellular level, the dendrimer enhanced intracellular siRNA-associated signal with predominantly cytoplasmic localization, and siRNA complexation attenuated genotoxicity relative to the noncomplexed carrier. In a BBB triculture model, barrier function was preserved without sustained transendothelial electrical resistance (TEER) loss, and complementary tracer flux readouts showed time- and formulation-dependent, nonmonotonic changes, including TEER-permeability decoupling consistent with nonuniform perturbation and time-dependent changes in barrier-associated paracellular responses. In APOE4 knock-in mice, dendriplex treatment increased platform-zone crossings in the Morris Water Maze probe trial, whereas target-quadrant time showed only a modest, nonsignificant trend. Collectively, these integrated results indicate that siRNA complexation improves the BBB-relevant safety-performance balance of G3Si PEG6000 and supports further studies that directly link brain exposure and target engagement to cognitive outcomes.}, } @article {pmid42398685, year = {2026}, author = {Tang, Y and Huang, L and Li, W and Gao, T and Shi, N and Zhu, Y and Wang, Y and Nan, J and Zhu, Y and Li, J and Ma, Y}, title = {Efficacy of Non-Invasive Brain Stimulation in Alzheimer's Disease: An Umbrella Review of Meta-Analyses.}, journal = {Neuroscience and biobehavioral reviews}, volume = {}, number = {}, pages = {106844}, doi = {10.1016/j.neubiorev.2026.106844}, pmid = {42398685}, issn = {1873-7528}, abstract = {This umbrella review integrates systematic reviews and meta-analyses to evaluate the efficacy of non-invasive brain stimulation (NIBS) in Alzheimer's disease (AD). We searched seven databases from inception to 20 June 2025 for relevant literature. Effect sizes and 95% confidence intervals were extracted using a structured approach and visualized through effect size heatmaps and evidence mapping. Methodological quality and evidence certainty were assessed using AMSTAR 2 and GRADE, respectively. A total of 42 publications, encompassing 130 primary studies and 5,771 patients, were included. NIBS yielded significant immediate improvements in global cognition, daily living, neuropsychiatric symptoms, memory, language, executive function, global impression, visuospatial function, and cholinergic transmission. Among 119 outcome associations, 57.1% were statistically significant (p < 0.05). Long-term benefits were sustained only in global cognition. Moreover, these techniques exhibited modality-specific effects on cognitive and clinical outcomes. Subgroup analysis identified repetitive transcranial magnetic stimulation (rTMS) as the most effective technique, supported by 16 moderate- to high-quality associations. Transcranial direct current stimulation (tDCS) showed inconsistent results with only three moderate-quality associations, while transcranial alternating current stimulation (tACS) demonstrated potential but limited evidence. Intermittent theta burst stimulation (iTBS) showed no significant cognitive benefits in the limited available evidence. Available safety evidence, though limited, suggests generally mild and transient adverse effects. NIBS, particularly rTMS, shows therapeutic potential for AD, though this is based on preliminary evidence. Future multicenter long-term studies and standardized protocols are needed to facilitate the precise application of NIBS in AD treatment.}, } @article {pmid42398193, year = {2026}, author = {Saumur, TM and Ashraf, H and Mathers, KE and Wagner, B}, title = {Pharmacotherapy for Alzheimer's Disease and Dementias in Long-Term Care: A Real-World EHR Study.}, journal = {Journal of the American Medical Directors Association}, volume = {27}, number = {9}, pages = {106293}, doi = {10.1016/j.jamda.2026.106293}, pmid = {42398193}, issn = {1538-9375}, abstract = {OBJECTIVES: To characterize contemporary pharmacologic medication order patterns for Alzheimer's disease (AD) and related dementias (ADRD) among US long-term care (LTC) residents and to examine facility- and resident-level factors associated with treatment.

DESIGN: Retrospective and observational study.

SETTING AND PARTICIPANTS: Electronic health record data from 1,675,873 LTC residents in the PointClickCare Life Sciences clinical database included 295,946 with a documented ADRD diagnosis in skilled nursing facilities in the United States who remained in facility at the end of the study window (January-April 2025).

METHODS: Residents were classified as treated/untreated based on the presence of ≥1 ADRD medication order as outlined by the Alzheimer's Association. Analyses incorporated demographics, comorbidities, medication burden, and facility characteristics. Multivariate logistic regression estimated the odds of having an ADRD medication order.

RESULTS: Overall, 82.0% of residents with ADRD had ≥1 order for ADRD medication. Treatment was most common among residents with Lewy body dementia (91.1%) and early onset AD (90.3%) and least frequent among Asian (72.3%), Native Hawaiian, or Other Pacific Islander (74.6%) and short-stay residents (75.6%). Treated residents exhibited a higher medication burden (mean, 8.6 vs 6.3). Diagnoses for other chronic conditions as well as specific ADRD subtypes strongly impacted probability of treatment; diabetes was associated with lower odds of treatment, whereas ADRD subtypes strongly predicted treatment.

CONCLUSIONS AND IMPLICATIONS: Approximately one-fifth of residents with ADRD did not have an ADRD medication order, and treatment varied significantly by nonclinical predictors. These findings underscore the need to investigate and understand possible treatment disparities, optimize polypharmacy management, and discover new ADRD treatments, and develop safer and more effective ADRD therapies.}, } @article {pmid42392701, year = {2026}, author = {Li, JY and Wang, XX and Wan, SF and Feng, TT and Guo, AJ and Liu, JY and Feng, K}, title = {[Research progress on role of PINK1/Parkin-mediated mitophagy in Alzheimer's disease and TCM interventions].}, journal = {Zhongguo Zhong yao za zhi = Zhongguo zhongyao zazhi = China journal of Chinese materia medica}, volume = {51}, number = {8}, pages = {2143-2152}, doi = {10.19540/j.cnki.cjcmm.20260113.701}, pmid = {42392701}, issn = {1001-5302}, mesh = {Humans ; PTEN-Induced Putative Kinase ; *Protein Kinases/metabolism/genetics ; *Alzheimer Disease/drug therapy/metabolism/genetics/physiopathology ; *Ubiquitin-Protein Ligases/metabolism/genetics ; *Mitophagy/drug effects ; Animals ; *Drugs, Chinese Herbal/administration & dosage ; Mitochondria/metabolism/drug effects ; }, abstract = {Alzheimer's disease(AD) is a neurodegenerative disorder characterized by progressive cognitive decline. Current treatment strategies mainly focus on symptomatic regulation of the neurotransmitter system, but their intervention effects on key pathological processes such as amyloid β(Aβ) deposition and abnormal phosphorylation of Tau protein remain limited. Therefore, it is urgent to explore new intervention targets from the perspective of the key mechanisms underlying the disease's occurrence and development. In recent years, mitochondrial dysfunction and imbalanced mitophagy have been recognized as closely related to the onset and progression of AD. The PTEN-induced putative kinase 1(PINK1)/E3 ubiquitin-protein ligase parkin(Parkin) pathway is a classic mechanism for the recognition, ubiquitination marking, and autophagic clearance of damaged mitochondria. Multiple studies have shown that under AD pathological conditions, the expression of this pathway is blocked, or its activity is reduced, leading to restricted mitophagy flux and obstacle clearance, which in turn exacerbate oxidative stress, energy metabolism disorders, and synaptic function damage, accelerating neuronal degeneration. Based on this, intervention strategies targeting PINK1/Parkin-mediated mitophagy have gradually attracted attention. Existing research indicates that single components and formulas of TCM, as well as some bioactive molecules, can reduce Aβ deposition, inhibit abnormal phosphorylation of Tau protein, and enhance synaptic plasticity by regulating PINK1/Parkin-mediated mitophagy, thereby exerting neuroprotective effects and improving cognitive function. However, the current evidence mainly comes from experimental studies, and the blood-brain barrier permeability, long-term safety, and clinical reproducibility of these interventions still need further verification. This article systematically reviewed the molecular mechanisms and upstream regulatory networks of PINK1/Parkin-mediated mitophagy, elaborated on the research evidence of its role in the pathological process of AD, and focused on summarizing the research progress of TCM interventions targeting this pathway, aiming to provide references for subsequent mechanism verification, evidence-based research design, and exploration of comprehensive intervention strategies.}, } @article {pmid42392719, year = {2026}, author = {Yuan, CB and Ju, YT and Liu, YM and Wang, BS and Zhang, L and Yu, CY and Yang, YL and Chen, WY and Leng, YJ and Cheng, MJ and Min, DY}, title = {[Quercetin improves cognitive impairment in mice with Alzheimer's disease by inhibiting inflammatory response and activating cAMP/PKA/CREB signaling pathway].}, journal = {Zhongguo Zhong yao za zhi = Zhongguo zhongyao zazhi = China journal of Chinese materia medica}, volume = {51}, number = {8}, pages = {2323-2334}, doi = {10.19540/j.cnki.cjcmm.20251210.801}, pmid = {42392719}, issn = {1001-5302}, mesh = {Animals ; *Alzheimer Disease/drug therapy/genetics/immunology/psychology/metabolism ; Male ; *Quercetin/administration & dosage ; Signal Transduction/drug effects ; Mice ; *Cyclic AMP Response Element-Binding Protein/genetics/metabolism ; Humans ; *Cyclic AMP/metabolism/genetics/immunology ; *Cyclic AMP-Dependent Protein Kinases/genetics/metabolism ; Mice, Inbred C57BL ; *Cognitive Dysfunction/drug therapy/genetics ; Mice, Transgenic ; Disease Models, Animal ; Hippocampus/drug effects ; }, abstract = {This study aimed to investigate the effects of quercetin on cognitive dysfunction in a mouse model of Alzheimer's disease(AD) and to explore its potential mechanisms. Network pharmacology was used to construct a "drug-core component-key target-pathways-disease" network to identify potential targets and related pathways associated with drug efficacy. Thirty 3-month-old male APP/PS1 transgenic mice were randomly divided into a model group, a quercetin group(100 mg·kg~(-1)), and a donepezil hydrochloride group(0.5 mg·kg~(-1)), while age-matched C57BL/6J mice from the same litter served as the control group. Each group consisted of 10 mice, and the treatment groups received the corresponding drug interventions for 24 weeks. The Morris water maze(MWM) test was used to assess memory performance, and the nest-building test was applied to evaluate daily living ability. hematoxylin-eosin(HE) staining, Nissl staining, and immunohistochemistry were used to assess pathological changes in hippocampal neurons. Western blot analysis was used to detect the expression levels of tau, phosphorylated(p)-tau, interleukin-1β(IL-1β), tumor necrosis factor-α(TNF-α), brain-derived neurotrophic factor(BDNF), cyclic adenosine monophosphate(cAMP), protein kinase A(PKA), p-PKA, cAMP response element-binding protein(CREB), and p-CREB-related signaling proteins in hippocampal tissue. Network pharmacology analysis identified 165 quercetin-related active component targets and 4 324 learning-and memory-related targets. Intersection analysis yielded 71 AD-related core genes. Protein-protein interaction(PPI) network analysis identified protein kinase B(Akt1), estrogen receptor 1(ESR1), epidermal growth factor receptor(EGFR), and non-receptor tyrosine kinase(SRC) as core target genes. Kyoto Encyclopedia of Genes and Genomes(KEGG) pathway analysis indicated that quercetin may regulate AD progression through the PI3K/Akt signaling pathway, cAMP signaling pathway, TNF signaling pathway, and EGFR tyrosine kinase inhibitor resistance-related pathways. Animal experiments showed that, compared with the control group, the model group exhibited significantly reduced nesting scores, prolonged escape latency(P<0.05), and fewer platform crossings(P<0.05). The number of neurons in the cortex and hippocampus was significantly decreased, and extracellular amyloid β(Aβ) deposition was significantly increased(P<0.01). In addition, the expression levels of p-tau/tau, IL-1β, TNF-α, cAMP, p-PKA/PKA, and p-CREB/CREB in hippocampal tissue were significantly elevated(P<0.01), whereas BDNF protein expression was significantly reduced(P<0.01). Compared with the model group, the quercetin and donepezil hydrochloride groups showed significantly increased nesting scores, shortened escape latency(P<0.05), and increased numbers of platform crossings(P<0.05). The number of neurons in the hippocampal CA1 region was significantly increased(P<0.01), and the expression levels of p-tau/tau, IL-1β, TNF-α, cAMP, p-PKA/PKA, and p-CREB/CREB in hippocampal tissue were significantly decreased(P<0.05, P<0.01). These results indicate that quercetin can significantly improve cognitive impairment in APP/PS1 transgenic mice, and its mechanism may be associated with activation of the cAMP/PKA/CREB signaling pathway and reversal of the upregulation of pro-inflammatory cytokines, including TNF-α and IL-1β.}, } @article {pmid42392731, year = {2026}, author = {Lyu, SY and Wang, XZ and Chen, XY and Guo, R}, title = {[Exploring mechanism of "treating different diseases with the same method" for depression and Alzheimer's disease based on "liver-spleen-kidney" axis and advances in traditional Chinese medicine intervention].}, journal = {Zhongguo Zhong yao za zhi = Zhongguo zhongyao zazhi = China journal of Chinese materia medica}, volume = {51}, number = {10}, pages = {2726-2738}, doi = {10.19540/j.cnki.cjcmm.20260108.302}, pmid = {42392731}, issn = {1001-5302}, mesh = {Humans ; *Alzheimer Disease/drug therapy/physiopathology/metabolism ; *Drugs, Chinese Herbal/administration & dosage/therapeutic use ; *Spleen/drug effects/physiopathology ; *Kidney/drug effects/physiopathology ; *Liver/drug effects/physiopathology ; Animals ; *Medicine, Chinese Traditional ; *Depression/drug therapy/physiopathology ; }, abstract = {Depression(major depressive disorder, MDD) and Alzheimer's disease(AD) are two highly prevalent neuropsychiatric disorders. With the aging population, their comorbidity rate continues to rise. The pathogenesis of MDD and AD is complex, and modern medicine still lacks strategies that can simultaneously intervene in the core processes of both diseases. The theory of "treating different diseases with the same method" in traditional Chinese medicine(TCM) is an important therapeutic principle, which means that different diseases showing identical syndromes during their development can be treated with the same approach. This provides a TCM perspective for the diagnosis and treatment of their comorbidity. Based on the theory of the "liver-spleen-kidney" axis, this study identified that MDD and AD shared common pathogenesis: liver dysfunction in free coursing, spleen dysfunction in transportation, and kidney essence deficiency. It further connected this pathogenesis with the dysregulation of the neuroendocrine-immune(NEI) network in modern medicine, revealing common pathological mechanisms in neuroinflammation, dysfunction of the "hypothalamic-pituitary-adrenal"(HPA) axis, and gut microbiota dysbiosis. Meanwhile, it also reviewed specific mechanisms of TCM herbs such as Bupleuri Radix(Chaihu), Paeoniae Radix Alba(Baishao), and Astragali Radix(Huangqi), as well as their active components, in treating MDD and AD by regulating the NEI network through multiple targets and pathways. This may provide evidence for the application of the "treating different diseases with the same method" theory and broaden the perspective for the treatment of MDD and AD.}, } @article {pmid42394931, year = {2026}, author = {Jeon, YH and Kim, JA and Kang, DY and Lee, S and Choi, NK and Park, JY}, title = {Ginkgo biloba extract for dizziness-related symptoms in central neurological disorders: a systematic review and meta-analysis.}, journal = {Frontiers in neurology}, volume = {17}, number = {}, pages = {1860538}, pmid = {42394931}, issn = {1664-2295}, abstract = {BACKGROUND AND PURPOSE: Dizziness associated with central neurological disorders-broadly defined as dizziness or vertigo attributable to central nervous system pathology affecting central vestibular processing-is a clinically challenging and heterogeneous condition with limited treatment options. Ginkgo biloba extract-through its microcirculatory, neuroprotective, and anti-inflammatory mechanisms-represents a biologically plausible intervention. However, its efficacy in this setting has not been comprehensively established. We evaluated the efficacy and safety of Ginkgo biloba extract through a systematic review and meta-analysis of randomized controlled trials (RCTs).

METHODS: Nine international and Korean databases were searched from January 1974 through November 2025. Studies were eligible if they were RCTs enrolling adults aged 18 years or older with cerebrovascular disease, neurodegenerative disease, or central vestibular dysfunction who had dizziness, vertigo, or balance-related symptoms or relevant outcome assessments. Cochrane RoB 2.0 tool and certainty of evidence was rated using the Assessment, Development and Evaluations (GRADE) approach. Prespecified subgroup analyses by underlying etiology and intervention type, together with leave-one-out sensitivity analyses, were performed to explore heterogeneity.

RESULTS: Nine RCTs (N = 2,394) were included; participants were predominantly drawn from dementia populations (71.6%), with smaller contributions from cerebral arteriosclerosis (23.0%) and vertebrobasilar or posterior circulation disorders (5.4%). Ginkgo biloba significantly reduced dizziness/vertigo severity on the 11-point box scale (MD - 0.76, 95% CI - 1.35 to -0.18; p = 0.01) and VAS (SMD - 0.38, 95% CI - 0.58 to -0.19; p = 0.0001). Moderate-certainty evidence suggested improvements in functional outcomes and quality of life, including the Alzheimer's Disease Activities of Daily Living International Scale (MD = -0.17, 95% CI: -0.22 to -0.13) and the Dementia Quality of Life - Proxy (MD = 2.00, 95% CI: 0.85 to 3.15). The intervention was generally well tolerated, with significantly lower risks of angina pectoris (OR 0.51, 95% CI 0.31 to 0.85) and tinnitus (OR 0.37, 95% CI 0.22 to 0.63) and no significant increase in other adverse events.

CONCLUSION: Ginkgo biloba extract may reduce dizziness severity and improve daily functioning in patients with central neurological disorders accompanied by dizziness or vertigo, with a favorable safety profile. However, given the small number of eligible trials, substantial clinical and statistical heterogeneity, and the predominance of dementia-derived data, these findings should be interpreted with caution. Well-designed RCTs in clearly defined central vestibular populations, ideally confirmed by neuroimaging or vestibular testing, are needed to confirm these results.

https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD420251229692, PROSPERO: CRD420251229692.}, } @article {pmid42394935, year = {2026}, author = {Leone, L and Kiernan, TJ and Kuwabara, S and Barnett, M and Devenney, E and Ahmed, RM and Lin, CS}, title = {A convergence of global epidemics: diabetes as a modulator of neurodegenerative and neuro-inflammatory disorders.}, journal = {Frontiers in neurology}, volume = {17}, number = {}, pages = {1824840}, pmid = {42394935}, issn = {1664-2295}, abstract = {Diabetes mellitus (DM) and neurological disorders are rapidly converging global health burdens, driven by population ageing, the growing prevalence of metabolic syndrome, and limited early detection and disease-modifying therapies for many neurological syndromes. Beyond its established role in diabetes-related peripheral neuropathy, DM is increasingly implicated as a modifier of risk, phenotype, and prognosis across a wide range of central and peripheral nervous system diseases. In this narrative review, we synthesize current epidemiological, clinical, genetic, and mechanistic evidence examining the relationship between DM and 10 clinically important neurological disorders: Alzheimer's disease (AD), vascular dementia (VaD), Parkinson's disease (PD), Huntington's disease (HD), amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), chronic inflammatory demyelinating polyradiculoneuropathy (CIDP), multiple sclerosis (MS), myasthenia gravis (MG), and neuromyelitis optica spectrum disorder (NMOSD). Across these conditions, DM acts as a context-dependent disease modifier, increasing risk in some disorders, appearing protective or delaying onset in others, and influencing disease phenotype, progression, and treatment response. We highlight potential areas of mechanistic convergence, such as insulin resistance, inflammation, disrupted energy homeostasis, and genetic predisposition, alongside important divergences shaped by disease-specific pathology. We also discuss the clinical and translational implications of this interface, including diagnostic challenges, opportunities for improved risk stratification, and growing interest in repurposing antidiabetic therapies, particularly metformin, glucagon-like peptide-1 receptor agonists, and sodium-glucose cotransporter-2 inhibitors, for neurological benefit. As the global burden of diabetes and neurological disease escalates, it is crucial to better understand the interplay between metabolic dysfunction, neurodegeneration, and neuro-immune pathways. The integration of insights across diseases may inform prevention strategies and support the development of therapeutic interventions at the metabolic-neurological interface.}, } @article {pmid42395049, year = {2026}, author = {Hofmann, A and Perneczky, R}, title = {Obstacles and solutions for implementing amyloid-targeting treatments in Europe.}, journal = {Alzheimer's & dementia (Amsterdam, Netherlands)}, volume = {18}, number = {3}, pages = {e70367}, pmid = {42395049}, issn = {2352-8729}, abstract = {Recent approvals of disease-modifying therapies by the European Medicines Agency mark a historic shift in the treatment landscape of Alzheimer's disease (AD) within the European Union that will challenge national health-care systems and require major adaptations and modernization. This Perspective article provides an overview of the major obstacles in Europe concerning successful implementation of amyloid-targeting treatments and offers potential solutions to overcome them. Major hurdles include a lack of recognition regarding the critical importance of an early, biomarker-based AD diagnosis; low acceptance of blood tests and digital cognitive screening tools; insufficient investment in magnetic resonance imaging capacities; and a fragmented infrastructure for clinical registries. We call on European clinicians, research institutions, and policy makers for a bold and coordinated action to urgently modernize diagnostic pathways and monitoring infrastructure to deliver novel AD treatments in a timely, safe, and equitable manner to all patients who may benefit.}, } @article {pmid42395345, year = {2026}, author = {Zhao, B and Zhou, R and Liu, P and Li, Q and Yan, Y and Du, J and Zhao, K and Liu, J and Wang, J and Qu, Q}, title = {FLOT1 and EEF1D: ac4C-related genes bridging Alzheimer's disease and sleep deprivation.}, journal = {Frontiers in aging neuroscience}, volume = {18}, number = {}, pages = {1825164}, pmid = {42395345}, issn = {1663-4365}, abstract = {BACKGROUND: Alzheimer's disease (AD) and sleep deprivation (SD), two common conditions in the elderly, share complex molecular connections and may mutually influence each other's pathogenesis. Current drugs only relieve symptoms with limited efficacy, making it urgent to explore the shared pathological mechanisms and potential intervention targets of the two conditions. This study used bioinformatics: first screening AD-related genes associated with SD and N4-acetylcytidine (ac4C) from relevant data; then identifying key genes via Mendelian randomization (MR) analysis and machine learning; finally screening AD-related key cells with single-cell RNA sequencing (scRNA-seq) data, to provide a basis for revealing the molecular and cellular regulatory mechanisms of AD-SD comorbidity.

METHODS: This study integrated bulk RNA sequencing (RNA-Seq) and scRNA-seq data from the Gene Expression Omnibus (GEO) database to identify AD-related key genes associated with SD and ac4C. Machine learning algorithms, including MR, were applied to screen these key genes. Additionally, gene set enrichment analysis (GSEA) was conducted to explore the pathways associated with the key genes, while ssGSEA was used to assess differences in immune cell infiltration. For the scRNA-seq data, key cells involved in AD pathology were further identified. Subsequently, the differential expression of the two key genes was validated using peripheral blood samples collected from AD and SD patients.

RESULTS: Through MR analysis, machine learning algorithms, and other analytical approaches, FLOT1 and EEF1D were identified as key genes. GSEA revealed that these key genes were enriched in multiple pathways, including the lysosome pathway, chemokine signaling pathway, and leukocyte transendothelial migration. Immune cell infiltration analysis suggested that myeloid-derived suppressor cells (MDSCs) might serve as key immune cells. Additionally, scRNA-seq analysis identified microglia, CD4 + T cells, CD8 + T cells, and natural killer (NK) cells as key cell types involved in AD pathogenesis. Critically, these key genes were successfully validated in peripheral blood samples from AD and SD patients, aligning with the above analysis.

CONCLUSION: Overall, FLOT1 and EEF1D were identified as key genes associated with SD and ac4C in AD. This finding provided new grounds for the clinical diagnosis and treatment of AD.}, } @article {pmid42395350, year = {2026}, author = {Van Skike, CE and Hernandez, SF and Hussong, SA and Miller, LR and Makhlouf, H and Muppala, AC and DeRosa, N and Jahrling, JB and Dineley, KT and Galvan, V}, title = {mTOR drives cerebrovascular dysfunction and blood-brain barrier breakdown in a model of Alzheimer's disease with cerebral amyloid angiopathy.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, doi = {10.64898/2026.06.23.733858}, pmid = {42395350}, issn = {2692-8205}, abstract = {Cerebral amyloid angiopathy (CAA) is characterized by the deposition of amyloid β fibrils (Aβ) within walls of the cerebrovasculature and contributes to intracerebral hemorrhage, ischemic stroke, and cognitive dysfunction in patients with Alzheimer's disease (AD) and in non-pathological aging. Previous studies have shown that mTOR drives cerebrovascular dysfunction and cognitive impairment observed in AD, vascular cognitive impairment, and normative aging. However, the mechanisms by which mTOR contributes to CAA are unknown. Here, we show that mTOR drives the accumulation of fibrillar vascular Aβ lesions in the Tg2576 Model of AD with CAA (using equal numbers of female and male mice), which directly impair endothelium-dependent cerebrovascular reactivity. Additionally, we found that blood-brain barrier (BBB) breakdown and remodeling of tight junction proteins, dependent on mTOR, are associated with increased cerebral microhemorrhages. Finally, we show that mTOR contributes to neurovascular uncoupling in Tg2576 AD mice through nNOS dysfunction and inhibition of non-nitric oxide synthase-dependent contributions to neurovascular coupling (NVC). Contextual memory impairments were ameliorated by the mTOR inhibitor rapamycin. Improvements in memory were associated with reduced cerebrovascular Aβ fibril accumulation, enhanced endothelium-dependent vasodilation, reduced fibrillar Aβ load, restoration of BBB integrity, attenuation of intracerebral microhemorrhage, and restoration of NVC. These data indicate that mTOR drives vascular accumulation of fibrillar Aβ, including those associated with brain vasculature, and mediates cerebrovascular dysfunction in a model of AD with CAA. Thus, mTOR inhibitors represent a promising treatment option for patients with CAA and AD.}, } @article {pmid42395404, year = {2026}, author = {Giorgio, J and Blazhenets, G and Landau, SM and Pezzoli, S and Yokoyama, JS and Soleimani-Meigooni, DN and Carrillo, MC and Grinberg, LT and Seeley, WW and Spina, S and Nudelman, KN and Apostolova, LG and Dickerson, BC and Jagust, WJ and Rabinovici, GD and Joie, R and , and , }, title = {Characterisation of Posterior Predominant Amyloid PET Binding Across Multiple Cohorts.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, doi = {10.64898/2026.06.17.733031}, pmid = {42395404}, issn = {2692-8205}, abstract = {The standard approach to quantify amyloid (Aβ) PET averages uptake within a single cortical mask that assumes no clinically relevant spatial heterogeneity in uptake patterns. Here, in a sample of 12,379 clinically impaired participants taken from four phenotypically diverse cohorts we use data-driven approaches to discover heterogeneous patterns of Aβ-PET binding, uncovering a reproducible and clinically relevant pattern of posterior predominant Aβ-PET binding. In particular, Aβ-PET positive participants who have posterior predominant binding are less likely to be APOE -ε4 carriers, more severely impaired, have thinner cortex in posterior regions, and greater posterior tau PET burden. Furthermore, in a subsample of participants with neuropathological assessment, participants with posterior predominant Aβ binding have a higher likelihood of having cerebral amyloid angiopathy at autopsy. These findings suggest that Aβ-PET accumulates along two orthogonal axes with biological and clinical relevance, indicating that the standard approach to assess Aβ-PET is insufficient to capture meaningful signal from Aβ-PET imaging. This work has implications for the diagnosis and treatment of Alzheimer's disease and extends our understanding of the mechanisms governing variable Aβ-PET distribution and its downstream effects.}, } @article {pmid42395537, year = {2024}, author = {Wang, R and Maloney, B and Nho, K and Beck, J and Counts, SE and Lahiri, DK}, title = {Human microRNA-153-3p targets specific neuronal genes and is associated with the risk of Alzheimer's disease.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, doi = {10.1101/2024.09.07.611728}, pmid = {42395537}, issn = {2692-8205}, abstract = {Alzheimers disease (AD) is a progressive degenerative disease characterized by a significant loss of neurons and synapses in cognitive brain regions and is the leading cause of dementia worldwide. AD pathology comprises extracellular amyloid plaques and intracellular neurofibrillary tangles. However, the triggers of this pathology are still poorly understood. Repressor element 1-silencing transcription/neuron-restrictive silencer factor (REST/NRSF), a transcription repressor of neuronal genes, is dysregulated during AD pathogenesis. How REST is dysregulated is still poorly understood, especially at the post-transcriptional level. MicroRNAs (miRNAs), a group of short non-coding RNAs, typically regulate protein expression by interacting with target mRNA transcript 3-untranslated region (UTR) and play essential roles in AD pathogenesis. Herein, we demonstrate that miR-153-3p reduces REST 3-UTR activities, mRNA, and protein levels in human cell lines, along with downregulating amyloid β precursor protein (APP) and α-synuclein (SNCA). We determine by mutational analyses that miR-153-3p interacts with specific targets via the seed sequence present within the respective mRNA 3-UTR. We show that miR-153-3p treatment alters the expression of these specific proteins in human neuronally differentiated cells and human induced pluripotent stem cells and that miR-153-3p is itself dysregulated in AD. We further find that single nucleotide polymorphisms (SNPs) within 5kb of the MIR153-1 and MIR153-2 genes are associated with AD-related endophenotypes. Elevation of miR-153-3p is associated with reduced AD probability, while elevated REST may associate with a greater AD probability. Our work suggests that a supplement of miR-153-3p would reduce levels of toxic protein aggregates by reducing APP, SNCA, and REST expression, all pointing towards a therapeutic and biomarker potential of miR-153-3p in AD and related dementias.}, } @article {pmid42396326, year = {2026}, author = {Ferreira-Atuesta, C and Schubert, KM and Noain, D and Draganski, B and Galovic, M and , }, title = {Association of antiseizure medication with lower amyloid and tau burden.}, journal = {medRxiv : the preprint server for health sciences}, volume = {}, number = {}, pages = {}, doi = {10.64898/2026.06.22.26356204}, pmid = {42396326}, abstract = {Network hyperexcitability is increasingly implicated in prodromal Alzheimer's disease and may be suppressed by antiseizure medications (ASMs). ASMs are widely prescribed to older adults, yet whether their use relates to Alzheimer's-disease biomarkers at the population level is unknown. In 52,537 participants in the National Alzheimer's Coordinating Center (NACC) study, we compared cerebrospinal-fluid biomarkers, amyloid and tau positron emission tomography (PET) between ASM users and non-users using inverse-probability-of-treatment weighting with gradient-boosted propensity scores. ASM users showed directionally lower amyloid across multiple brain regions, amplifying markedly in APOE ε4 carriers (Centiloid β = -25.7, p = 0.007). All three temporal tau-PET composites were significantly lower in users (META-temporal β = -0.05, p = 0.01). The amyloid finding replicated independently in the the Alzheimer's Disease Neuroimaging Initiative (ADNI) dataset (Centiloid β = -8.6, p = 0.01), whereas four comparator drug classes showed no amyloid signal. These convergent observational findings provide a quantitative framework for evaluating ASMs as candidate disease-modifying agents in Alzheimer's disease.}, } @article {pmid42385584, year = {2026}, author = {Kiprov, DD and Green, AP and Boyinapalli, P}, title = {Technological advances in selective plasma adsorption: The MTx.100 column and the emergence of subtractive precision medicine.}, journal = {Transfusion and apheresis science : official journal of the World Apheresis Association : official journal of the European Society for Haemapheresis}, volume = {65}, number = {4}, pages = {104484}, doi = {10.1016/j.transci.2026.104484}, pmid = {42385584}, issn = {1473-0502}, abstract = {Therapeutic plasma exchange (TPE) is well-established for autoimmune, hematological, and neurological disease but is intrinsically non-selective: protective immunoglobulins, coagulation factors, and albumin are depleted alongside pathogenic substances, and reliance on donor-derived replacement fluid carries logistical and immunological costs. The MTx.100 column (Marker Therapeutics AG) is a selective plasma adsorption device that addresses these limitations through hydrophobic-affinity adsorption. It targets pro-inflammatory cytokines, protein-bound metabolic waste, hydrophobic environmental contaminants, and microparticulates while preserving immunoglobulins, coagulation factors, electrolytes, and the patient's own signaling proteins. Plasma is treated and conserved, eliminating replacement-fluid dependency. Clinical experience encompasses approximately 1000 procedures globally. A prospective single-arm multicenter trial in 107 critically ill COVID-19 patients (424 procedures) demonstrated 28-day mortality of 37.4% against an FDA-agreed performance goal of 88.1% (p < 0.0001); propensity-matched analysis showed approximately three-fold higher survival odds versus standard of care (OR 3.0; 95% CI 1.56-5.85; p = 0.0008), with significant reductions in inflammatory and metabolic markers and no serious adverse events attributable to the column or procedure. Hospital case reports across polytrauma, post-LVAD implantation, and toxin-induced hepatitis demonstrated hemodynamic and electrolyte stability and favorable clinical trajectories. Across 114 elective outpatient procedures, vital signs and electrolytes remained stable throughout treatment, and third-party laboratory analyses confirmed measurable reduction of PFAS, microplastics, and persistent organic pollutants in treated patients. Within the emerging framework of subtractive precision medicine, selective plasma adsorption offers a complementary paradigm to additive pharmacotherapy for conditions characterized by inflammatory and toxic burden. A pilot trial in Alzheimer's disease is underway.}, } @article {pmid42385644, year = {2026}, author = {Luo, J and Rasmussen, IJ and Thomassen, JQ and Frikke-Schmidt, R}, title = {Causal insights of modifiable cardiovascular risk factors for dementia risk - potential for efficient prevention and improved brain health.}, journal = {Atherosclerosis}, volume = {419}, number = {}, pages = {120824}, doi = {10.1016/j.atherosclerosis.2026.120824}, pmid = {42385644}, issn = {1879-1484}, abstract = {BACKGROUND: The 2024 Lancet Commission report identifies 14 modifiable risk factors that may prevent half of dementia. The causal nature of these associations remains however unclear. We aimed to establish robust causal estimates for modifiable cardiovascular risk factors and dementia, offering tangible targets for effective dementia prevention.

METHODS: We selected independent variants from the largest genomic consortia to date (N = 439,214 to 3,037,499) for each modifiable risk factor and generated polygenic risk scores for participants of European ancestry in the UK Biobank (N = 408,788). We conducted univariable and multivariable linear Mendelian randomization, assessed genetic shapes by nonlinear approaches, and performed several sensitivity analyses, including sex stratification.

RESULTS: Genetic predisposition to high low-density-lipoprotein cholesterol (LDL-C) (1.12, 1.01-1.23), non-high-density-lipoprotein cholesterol (1.30, 1.26-1.35), triglycerides (1.19, 1.01-1.41), body mass index (1.04, 1.02-1.07), systolic (1.14, 1.09-1.20) and diastolic (1.10, 1.02-1.19) blood pressure, type 2 diabetes (1.04, 1.00-1.09) and smoking (1.18, 1.06-1.32), were associated with increased risk of all-cause dementia, while longer education was associated with a reduced risk (0.58, 0.33-0.99). Results for Alzheimer's disease and vascular dementia were directionally similar. Moreover, genetically predicted high physical activity level was associated with low risk of Alzheimer's disease (0.58, 0.33-0.99) only. Sensitivity analyses supported the main results, and no nonlinear shapes were detected.

CONCLUSION: These findings provide causal insights into modifiable cardiovascular risk factors for dementia and unfold a substantial potential for dementia prevention by timely treatment of high LDL-C, triglycerides, hypertension, and diabetes, alongside smoking cessation and maintenance of normal weight.}, } @article {pmid42386905, year = {2026}, author = {Chun, H and Youn, W and Lim, H and Harada, R and Ko, HY and Yoon, J and Oh, SJ and Seemann, P and Pepe, JG and Shoichet, BK and Lee, HW and Furumoto, S and Okamura, N and Yun, M and Lee, CJ}, title = {In-depth multimodal validation of [18]F-THK5351 for imaging monoamine oxidase-B-mediated reactive astrogliosis in Alzheimer's and related neurodegenerative diseases.}, journal = {Experimental & molecular medicine}, volume = {}, number = {}, pages = {}, pmid = {42386905}, issn = {2092-6413}, support = {RS-2025-16071448//National Research Foundation of Korea (NRF)/ ; RS-2022-00144475//National Research Foundation of Korea (NRF)/ ; RS-2025-00520546//National Research Foundation of Korea (NRF)/ ; RS-2022-00144475//National Research Foundation of Korea (NRF)/ ; RS-2024-00403076//Korea Basic Science Institute (KBSI)/ ; }, abstract = {[18]F-THK5351, initially developed as a positron-emission tomography (PET) tracer for tau pathology, was later shown to display high affinity for monoamine oxidase-B (MAO-B), raising uncertainty about the biological origin of its brain signals in neurodegenerative diseases. To resolve this ambiguity, we implemented a multi-scale validation framework integrating enzyme activity inhibition assays, molecular docking, biolayer interferometry, autoradiography, multiple transgenic and viral animal models, and human PET imaging. THK5351 selectively inhibited MAO-B while sparing MAO-A and exhibited reversible binding kinetics to recombinant MAO-B. Computational modelling localized THK5351 near the MAO-B substrate funnel, revealing moderate binding energy and weaker π-π stacking interactions compared with selective tau tracers. Autoradiographic analysis of human cortical tissue demonstrated that tracer binding was dominated by MAO-B-related signals, with a smaller contribution from tau aggregates, a difference insufficient to produce visually distinguishable patterns in clinical imaging. In APP/PS1 mice, [18]F-THK5351 uptake colocalized with regions of reactive astrogliosis and was abolished by MAO-B inhibition, whereas overexpression of P301L-hTau induced extensive tau deposition without affecting tracer retention. MAO-B knockout reduced both tracer binding and tau phosphorylation, and viral induction of astrogliosis elevated tracer uptake that was reversed by selective MAO-B blockade. In a patient with corticobasal syndrome, tracer signals decreased during selegiline treatment and reappeared after drug withdrawal, mirroring preclinical pharmacological responses. Collectively, these findings demonstrate that [18]F-THK5351 uptake primarily reflects MAO-B-mediated reactive astrogliosis rather than tau pathology, providing mechanistic insight into its signal origin and underscoring the value of cross-scale, multimodal validation in PET tracer development for neurodegenerative disease research.}, } @article {pmid42387856, year = {2026}, author = {Miles, N and McNamee, B and Zadikoff, C and Boiser, J and Shebley, M and Boinpally, R}, title = {Comparison of ABBV-552 Safety and Pharmacokinetics in Healthy Asian and Western Adults.}, journal = {Clinical pharmacology in drug development}, volume = {15}, number = {7}, pages = {e70072}, doi = {10.1002/cpdd.70072}, pmid = {42387856}, issn = {2160-7648}, support = {//AbbVie/ ; }, mesh = {Adult ; Female ; Humans ; Male ; Middle Aged ; Young Adult ; Administration, Oral ; *Alzheimer Disease/drug therapy/physiopathology ; Asian People ; Dose-Response Relationship, Drug ; Healthy Volunteers ; *Membrane Glycoproteins/agonists ; *Nerve Tissue Proteins/agonists ; White People ; }, abstract = {ABBV-552, a positive modulator of synaptic vesicle glycoprotein 2A (SV2A), was under investigation as a treatment for cognitive impairment related to Alzheimer's disease. This Phase 1, multicenter, open-label, parallel cohort study (NCT05686980) was conducted to examine the pharmacokinetics (PK), safety, and tolerability of ABBV-552 in healthy adult Japanese and Han Chinese participants and to compare PK and safety findings with healthy adult Western participants from previous studies. Japanese participants in Cohort 1 (N = 10) received three ascending single oral doses (5, 15, and 40 mg) of ABBV-552 with a washout of 7 days between doses. Han Chinese participants in Cohort 2 (N = 7) received a single oral dose of 40 mg ABBV-552. After a single oral dose of 40 mg ABBV-552, PK was comparable between both cohorts. Additionally, the range of individual ABBV-552 concentrations and mean 24-h profiles were comparable with historical data in healthy adult Western participants. In this small study population, single doses of ABBV-552 were well tolerated at all tested doses. Common adverse events reported were dizziness (39%), somnolence (11%), and fatigue (11%). No unique safety signals following single dose ABBV-552 administration were observed in the Japanese or Han Chinese populations examined compared with the previously examined Western population.}, } @article {pmid42388101, year = {2026}, author = {Lai, HY and Meng, LC and Ye, YJ and Chen, HM and Chen, LK and Hsiao, FY}, title = {Comparative risk of ventricular arrhythmia and sudden cardiac death among acetylcholinesterase inhibitors in dementia: A population-based cohort study.}, journal = {British journal of clinical pharmacology}, volume = {}, number = {}, pages = {}, doi = {10.1002/bcp.70656}, pmid = {42388101}, issn = {1365-2125}, support = {MOST 110-2634-F-010-001//Taiwan Ministry of Science and Technology/ ; NSTC111-2622-8-A49-019-IE//Taiwan National Science and Technology Council/ ; NSTC112-2923-B-A49-002-MY2//Taiwan National Science and Technology Council/ ; //Interdisciplinary Research Center for Healthy Longevity of National Yang Ming Chiao Tung University/ ; }, abstract = {BACKGROUND: Previous studies have suggested that acetylcholinesterase inhibitors (AChEIs) may be associated with an increased risk of ventricular arrhythmia or sudden cardiac death, potentially related to QTc prolongation. However, evidence comparing the real-world risk of severe cardiac conduction outcomes among the three AChEIs-donepezil, galantamine and rivastigmine-remains limited.

OBJECTIVE: This study aimed to compare the risk of ventricular arrhythmia or sudden cardiac death associated with the use of different AChEIs in older adults with dementia.

METHODS: We conducted a retrospective cohort study using Taiwan's National Health Insurance database. Older adults diagnosed with dementia who initiated AChEI therapy between 2010 and 2019 were identified and categorized according to the AChEI prescribed. Participants were followed until the end of 2020. Stabilized inverse probability of treatment weighting was applied to balance baseline characteristics, with rivastigmine serving as the reference group. Cox proportional hazards models were used to estimate hazard ratios for ventricular arrhythmia or sudden cardiac death.

RESULTS: A total of 66 589 older adults with dementia initiating AChEI therapy were included. Donepezil was the most frequently prescribed AChEI (64.8%), followed by rivastigmine (33.0%) and galantamine (2.3%). Compared with rivastigmine, IPTW-weighted analyses showed no significant association between donepezil use (HR 0.95, 95% CI, 0.82-1.09) or galantamine use (HR 1.40, 95% CI, 0.90-2.18) and the risk of ventricular arrhythmia or sudden cardiac death.

CONCLUSIONS: The risk of ventricular arrhythmia or sudden cardiac death was comparable among donepezil, galantamine and rivastigmine in older patients with dementia.}, } @article {pmid42388121, year = {2026}, author = {Schwartz, NU and Dietz, CD and Lin, Z and Tammewar, G and Bui, N and La Joie, R and Wang, Y and Sreekrishnan, A and Suhami, D and VandeVrede, L and Ljubenkov, PA and Rojas, JC}, title = {Reduced diffusion associated with amyloid-related imaging abnormalities in three patients treated with donanemab.}, journal = {Neurocase}, volume = {}, number = {}, pages = {1-6}, doi = {10.1080/13554794.2026.2695021}, pmid = {42388121}, issn = {1465-3656}, abstract = {Amyloid-related imaging abnormalities (ARIA) with edema (ARIA-E) and with hemorrhage (ARIA-H) are common adverse effects of amyloid-targeting therapies (ATT), characterized on MRI by T2/fluid-attenuated inversion recovery (FLAIR) hyperintensities and susceptibility-sensitive hypointensities, respectively. ARIA resulting from ATT is not commonly associated with reduced diffusion or acute infarcts. In this case series, we describe three patients with mild cognitive impairment due to Alzheimer's disease (AD) - a 75-year-old woman, a 74-year-old woman, and an 80-year-old man (APOE ε3/ε3, ε4/ε4, and ε3/ε4, respectively) - who developed ARIA accompanied by transient foci of reduced diffusion within the first six months of donanemab treatment, without permanent T2/FLAIR correlates. The diffusion-restricting lesions may represent ischemic infarcts, although the lack of permanent T2/FLAIR correlate is atypical. Clinicians should be aware that reduced diffusion may accompany ARIA. The course can be highly dynamic, and both the clinical presentation and management implications may vary.}, } @article {pmid42388698, year = {2026}, author = {Jannati, A and Toro-Serey, C and Ciesla, M and Chen, E and Bates, D and Showalter, J and Tobyne, S and Pascual-Leone, A}, title = {Initial specialist validation of clinical decision support recommendations from a machine learning-enabled digital cognitive assessment.}, journal = {Frontiers in neurology}, volume = {17}, number = {}, pages = {1806000}, pmid = {42388698}, issn = {1664-2295}, abstract = {INTRODUCTION: Disease-modifying therapies for Alzheimer's disease (AD) heighten demand for scalable tools enabling primary care providers (PCPs) to detect cognitive impairment and triage patients for appropriate evaluation. The brief tablet-based Linus Health Core Cognitive Evaluation (CCE) integrates the Digital Clock and Recall (DCR) and Life and Health Questionnaire (LHQ) to generate clinical decision support (CDS) and decision-tree pathways.

METHODS: We conducted a retrospective specialist content-validity study (June 15-27, 2023) using a modified RAND/UCLA Appropriateness Method. Five board-certified cognitive/behavioral neurologists independently rated CDS recommendations and nine predefined pathway parts for patients aged ≥55 across 21 de-identified reports. Items scored 1-9 were summarized as pooled medians with interquartile ranges; medians ≥7 indicated appropriateness. Agreement among experts was quantified using ICC [2,k] and ICC [2,1].

RESULTS: All cognitive-impairment recommendations met the threshold. All seven borderline/impaired-DCR pathways were appropriate (median 7-8). Two pathways fell below threshold: cognitively unimpaired individuals with Green DCR scores (median 6) and a preliminary anti-amyloid treatment referral pathway (median 5). Agreement was moderate per patient [median ICC(2,k) = 0.61] and lower for individual diagnostic-concern recommendations [median ICC(2,k) = 0.25], reflecting specialist heterogeneity on borderline non-cognitive items and ceiling effects on high-rated items.

CONCLUSION: Cognitive neurologists judged CCE-derived CDS appropriate for PCP workup and referral decisions in older adults with suspected cognitive impairment. Findings support initial content validity of assessment-linked CDS, identify refinement priorities in low-risk and emerging-therapy pathways, and motivate planned PCP appropriateness and prospective implementation studies.}, } @article {pmid42388902, year = {2026}, author = {Hao, Y and Yang, H and Zhong, J and Zhang, J and He, X and Dong, X}, title = {Examining of the mechanism by which Yin Huang Ge compound alleviates cognitive dysfunction in Alzheimer's disease mice through modulation of Aβ degrading enzymes and neurotrophic factors.}, journal = {Frontiers in aging neuroscience}, volume = {18}, number = {}, pages = {1821074}, pmid = {42388902}, issn = {1663-4365}, abstract = {BACKGROUND: Alzheimer's disease (AD) poses a significant threat to human health, and with the number of patients increasing annually, developing effective prevention and treatment strategies has become an urgent priority. Early intervention is a viable strategy for treating AD, as biomarker changes associated with β-amyloid (Aβ) can emerge 20 or more years before cognitive impairment becomes apparent. Traditional Chinese medicine (TCM) offers a potential avenue for treatment at this early stage.

OBJECTIVE: This study investigated the potential therapeutic effects of the Yin Huang Ge compound on cognitive function in a mouse model of AD and evaluated its efficacy in mitigating Aβ accumulation, a key pathological feature of AD.

METHODS: APP/PS1 mice were randomly assigned to the following groups: Controls (C57BL/6 J mice) group, the Model group, YHG group, and donepezil (DNP) group. The YHG group and the DNP group were administered their respective drugs through gastric gavage, whereas the normal group and the Model group were supplied with saline. Administration sustained for a period of 30 consecutive days. We assessed mouse learning, memory, and spatial cognition using the Morris water maze, novel object recognition, Y-maze spontaneous alternation, and novel arm tests. Western blotting quantified the protein levels of β-amyloid 1-42 (Aβ1-42), insulin-degrading enzyme (IDE), neprilysin (NEP), matrix metalloproteinase-2 (MMP-2), and matrix metalloproteinase-9 (MMP-9). ELISA measured IDE and NEP enzymatic activity, while immunohistochemistry evaluated the expression of brain-derived neurotrophic factor (BDNF) and neurotrophin-3 (NT-3).

RESULTS: In contrast to the Control group, mice in the Model group exhibited significant impairments in learning, memory, and spatial cognition. The protein expression levels of Aβ1-42, MMP-2, and MMP-9 were markedly elevated (p < 0.01), whereas the expression of IDE and NEP was significantly reduced (p < 0.05, p < 0.01). ELISA analysis further revealed a substantial decrease in IDE and NEP activity (p < 0.01). A concomitant reduction in the expression of NT-3 and BDNF was also observed (p < 0.01). Compared to the Model group, mice treated with YHG or DNP exhibited significantly improved learning, memory, and spatial cognition. The protein expression of Aβ1-42, MMP-2, and MMP-9 was reduced (p < 0.05, p < 0.01), whereas the expression of IDE and NEP was elevated (p < 0.05). ELISA results confirmed the increased activity of IDE and NEP (p < 0.05). These assays also revealed a marked upregulation in the expression of NT-3 and BDNF (p < 0.01).

CONCLUSION: The YHG compound reduces cerebral Aβ deposition via a bidirectional regulatory mechanism, upregulating IDE and NEP to promote clearance while downregulating MMP-2 and MMP-9 to mitigate associated damage. It also elevates the expression of the neurotrophic factors BDNF and NT-3, which enhances endogenous neuroprotection and ameliorates core Alzheimer's disease pathology. Consequently, this treatment markedly improves cognitive function in APP/PS1 mice.}, } @article {pmid42389265, year = {2026}, author = {Temelli Goceroglu, R and Hacimuftuoglu, A}, title = {Advances in the treatment of Alzheimer's disease.}, journal = {Frontiers in pharmacology}, volume = {17}, number = {}, pages = {1819165}, pmid = {42389265}, issn = {1663-9812}, abstract = {Alzheimer's Disease (AD) is a progressive neurodegenerative disease for which disease-modifying therapies remain limited. Despite extensive efforts targeting amyloid-β and tau, these approaches have not translated into clear clinical benefit, underscoring the need for a more integrated understanding of AD pathogenesis. This narrative review summarizes recent advances in the molecular mechanisms underlying AD and evaluates current and emerging therapeutic strategies. A literature search was conducted using PubMed, Google Scholar, Web of Science and Scopus, focusing on preclinical and clinical studies addressing AD pathophysiology and treatment development. Conclusion: We summarize key pathogenic pathways, including Aβ aggregation, tau hyperphosphorylation, neuroinflammation, synaptic dysfunction, and metabolic dysregulation, and discuss how these interconnected processes have informed drug development efforts. Particular attention is given to limitations of single-target approaches and the growing interest in multi-target and combination therapies. In conclusion, a better understanding of the pathological mechanisms underlying AD may contribute to the development of more effective pharmacological therapies and integrated therapeutic approaches targeting the multifactorial nature of the disease.}, } @article {pmid42389420, year = {2026}, author = {Filippi, M and Cecchetti, G and Ghirelli, A and Spinelli, EG and Rugarli, G and Pisano, S and Samanes Gajate, AM and Chiti, A and Agosta, F}, title = {From Target Engagement to Treatment Governance: The Evolving Role of Amyloid PET in Anti-Amyloid Therapy.}, journal = {The Lancet regional health. Europe}, volume = {67}, number = {}, pages = {101757}, pmid = {42389420}, issn = {2666-7762}, abstract = {The introduction of anti-amyloid monoclonal antibodies has shifted Alzheimer's disease care from diagnostic clarification alone to the problem of treatment governance. While lecanemab and donanemab have demonstrated amyloid reduction at the group level, routine clinical care raises a different question: how should treatment exposure be managed in individual patients within constrained healthcare systems? We suggest that amyloid positron emission tomography (PET) may support this task by providing a quantitative baseline reference for target engagement and by informing decisions on treatment continuation, switching, or discontinuation during follow-up. However, amyloid reduction on PET should not be equated with proven individual-level clinical benefit, and the potential role of longitudinal PET must be considered alongside unresolved questions regarding safety, treatment burden, feasibility, and health-system capacity. Drawing on real-world experience from a high-volume European memory clinic, we argue that amyloid PET may have an increasingly relevant role within structured anti-amyloid treatment pathways.}, } @article {pmid42389758, year = {2026}, author = {Hussain, A and Alam, I and Agrawal, DK}, title = {Limitations of Current Therapies and Barriers in Alzheimer's Disease.}, journal = {Archives of internal medicine research}, volume = {9}, number = {2}, pages = {136-144}, pmid = {42389758}, issn = {2688-5654}, abstract = {Alzheimer's disease (AD) remains a major global health crisis due to its complex pathophysiology and limited therapeutic effectiveness. Despite advances in understanding key mechanisms such as amyloid-beta accumulation, tau pathology and neuroinflammation, current therapies provide limited clinical benefit. Multiple factors contribute to limitations and highlight the difficulty of translating scientific advancements into meaningful improvement in patient outcomes. This article provides a comprehensive and critical review of therapeutic, biological, clinical, and systemic barriers to effective Alzheimer's disease management as well as showcasing emerging strategies aimed to improve early detection, treatment approaches, and overall disease prevention.}, } @article {pmid42390710, year = {2026}, author = {Medeiros, EB and de Oliveira Monteiro, I and Kluwe-Schiavon, B and Possamai, OL and Fenilli, GP and Keller, GS and Lidio, AV and Casagrande, DD and Souza, CSM and de Bem Silveira, G and de Almeida, RCS and Vicente, HB and Magenis, ML and Luiz, GP and Damiani, AP and de Andrade, VM and Budni, J}, title = {Effect of Probiotic Supplementation in Older Individuals with Mild Cognitive Impairment and Alzheimer's Disease: A Randomized, Placebo-Controlled, Triple-Blind Clinical Trial.}, journal = {Probiotics and antimicrobial proteins}, volume = {}, number = {}, pages = {}, pmid = {42390710}, issn = {1867-1314}, abstract = {Alzheimer's disease (AD) is the most common type of dementia in older adults and often precedes mild cognitive impairment (MCI). These conditions are associated with biological alterations involving chronic inflammation, neuronal dysfunction, and genomic instability. In parallel, growing evidence has suggested a role for the gut-brain axis in cognitive aging, and probiotics have been investigated as a potential strategy to modulate inflammatory and neurotrophic pathways. This randomized, triple-blind, placebo-controlled clinical trial evaluated the effects of 12 weeks of supplementation with a probiotic blend containing Lactobacillus and Bifidobacterium strains in older adults classified as cognitively unimpaired (CU), MCI, or AD. The study examined DNA damage, inflammatory cytokines, neurotrophic factors, and stool consistency before and after the intervention. Overall, probiotic supplementation showed limited and heterogeneous effects across outcomes. DNA damage analyses did not indicate increased alkaline or oxidative DNA damage after probiotic supplementation, supporting the absence of detectable genotoxicity over the intervention period. Changes in inflammatory and neurotrophic biomarkers were more strongly related to time and diagnostic subgroups than to treatment allocation. Exploratory findings suggested a possible subgroup-specific effect on neurotrophic markers, particularly an increase in NGF in the MCI probiotic arm, but this pattern was not consistent across the broader biomarker panel. Stool consistency did not show reliable pre- to post-intervention changes. These findings suggest that the probiotic formulation was safe from a genotoxic perspective but did not produce a generalized biological effect across inflammatory, neurotrophic, or gastrointestinal outcomes. Larger studies incorporating dietary monitoring and microbiota profiling are needed to clarify whether specific probiotic strains can influence biological pathways relevant to cognitive aging.}, } @article {pmid42391577, year = {2026}, author = {Bautista, JR and Goth, O and Anbari, AB and Powell, KR}, title = {Readability and Linguistic Characteristics of Alzheimer's Disease and Related Dementias Prevention, Symptom, and Treatment Information from Generative Artificial Intelligence Chatbots.}, journal = {Journal of gerontological nursing}, volume = {52}, number = {7}, pages = {7-11}, doi = {10.3928/00989134-20260608-03}, pmid = {42391577}, issn = {0098-9134}, mesh = {Humans ; *Alzheimer Disease/prevention & control/therapy ; Generative Artificial Intelligence ; *Comprehension ; *Linguistics ; *Dementia/prevention & control/therapy ; }, abstract = {PURPOSE: To examine the readability and linguistic characteristics of Alzheimer's disease and related dementias (ADRD) prevention, symptom, and treatment information from generative artificial intelligence (GenAI) chatbots.

METHOD: We analyzed 66 outputs from free-to-use GenAI chatbots. We extracted readability (word count, Fleisch Reading Ease, and Fleisch-Kincaid Grade Level) and linguistic scores (analytical thinking, clout, authenticity, and emotional tone) using Microsoft Word and the Linguistic Inquiry and Word Count software. Data were analyzed using descriptive statistics, t tests, analysis of variance, and multivariate analysis of variance.

RESULTS: ADRD information from GenAI chatbots, especially treatment information, had college-level readability. Linguistic analyses indicate a high analytical thinking score and low scores for clout, authenticity, and emotional tone.

CONCLUSION: Our sample of ADRD GenAI information exceeded recommended reading levels for patient education materials. Although the outputs exhibited logical thinking, they also included uncertain, inauthentic, and negative tones. ADRD caregivers should be aware of these characteristics when using GenAI chatbots for ADRD information-seeking.}, } @article {pmid42391744, year = {2026}, author = {Xin, Y and Sheng, J and Wang, L}, title = {A review of Alzheimer's disease diagnosis and prognosis models based on multimodal deep learning.}, journal = {Reviews in the neurosciences}, volume = {}, number = {}, pages = {}, pmid = {42391744}, issn = {2191-0200}, abstract = {Although some drugs have been approved for clinical treatment, early diagnosis and intervention remain the most effective strategies for managing Alzheimer's disease (AD) at present. With advances in deep learning and multimodal fusion, an increasing number of complex frameworks have been proposed. This paper systematically reviews multimodal deep learning-based models for AD diagnosis between 2020 and 2026. Beyond the technical survey, we explore how to deal with the heterogeneous modality integration and missing modality processing. From these experimental results, many models show impressive performance on public datasets. However, we have noticed a troubling problem that these "lab-perfect" results often falter when they face the chaos of the real-world. Because of the persistent black-box problem and the hidden traps of data leakage, the path to clinical use is still uphill. This work suggests that it is time to move beyond chasing tiny gains in accuracy and focus on building models that doctors can truly trust, understand, and use in real clinical settings.}, } @article {pmid42391923, year = {2026}, author = {Guo, H and Zheng, S and Shi, X and Wang, X and Ma, R and Li, G}, title = {VER155008 rescues cognitive impairment in P301S tauopathy mice by promoting HSPA8-mediated lipophagy.}, journal = {European journal of pharmacology}, volume = {1030}, number = {}, pages = {179107}, doi = {10.1016/j.ejphar.2026.179107}, pmid = {42391923}, issn = {1879-0712}, abstract = {Alzheimer's disease (AD) features tau accumulation and pathogenic lipid droplet (LD) buildup, driving neurodegeneration through oxidative stress and neuroinflammation. The chaperone heat shock protein family A member 8 (HSPA8) is upregulated in AD, which may have implications for impaired LD clearance via lipophagy. We investigated whether targeting HSPA8 with the small-molecule antagonist VER155008 alleviates tau pathology and cognitive deficits by activating lipophagy in P301S tauopathy models. P301S tau transgenic mice and HEK293T-P301S cells were utilized. Western blotting, immunohistochemistry, and immunofluorescence were performed to assess HSPA8 levels, lipophagy, tau proteins, and inflammatory markers. VER155008 or vehicle control was administered to P301S mice for four weeks, starting at seven months of age. Cognitive function was evaluated using the Morris water maze and novel object recognition tests. Synaptic density was assessed through Golgi staining and electron microscopy. HSPA8 was elevated in P301S mice, correlating with impaired lipophagy and suppressed AMP-activated protein kinase (AMPK) activity. VER155008 treatment restored cognitive function and synaptic density. Critically, it activated lipophagy and reduced hippocampal LDs and tau pathology. Moreover, HSPA8 overexpression suppressed lipophagy and increased both LD accumulation and tau pathology. Inhibition of HSPA8 by VER155008 activates AMPK-mediated lipophagy, concurrently reducing tau pathology, oxidative stress, and neuroinflammation in AD models. These beneficial effects were eliminated by treatment with the AMPK inhibitor Compound C. This identifies the HSPA8-lipophagy axis as a promising therapeutic target for tauopathies.}, } @article {pmid42391929, year = {2026}, author = {Wang, Y and Sang, J and Li, H and Ren, X and Chen, C and Zheng, N and Xiao, H and Wei, Y and Xu, L and Jiang, R and Zhang, W and Xu, Z and Ge, L and Zhu, J and Xiong, B and Chen, Y and Feng, F and Sun, H}, title = {Development of potent BChE/Nrf2 modulators for Alzheimer's disease treatment via dual suppression of ferroptosis.}, journal = {European journal of medicinal chemistry}, volume = {317}, number = {}, pages = {119093}, doi = {10.1016/j.ejmech.2026.119093}, pmid = {42391929}, issn = {1768-3254}, abstract = {Targeting multiple pathological mechanisms holds significant potential for Alzheimer's disease (AD) therapy. Here, we designed 50 hybrids combining the benzimidazole-aminofurazan scaffold of a BChE inhibitor (S06-1064) with the 1,2,4-oxadiazole moiety of an Nrf2 activator (6). After four optimization rounds, S27-1046 and S27-1047 emerged as potent, selective BChE inhibitors and Nrf2 activators (S27-1046: eqBChE IC50 = 2.51 ± 1.51 nM, hBChE IC50 = 128.30 ± 16.89 nM, FP IC50 = 188.20 ± 57.11 nM, 4.73-fold ARE induced fold at 20 μM; S27-1047: eqBChE IC50 = 7.16 ± 2.96 nM, hBChE IC50 = 296.10 ± 55.78 nM, FP IC50 = 36.87 ± 23.07 nM, 7.42-fold ARE induced fold at 20 μM). They directly bind Keap1, disrupt Keap1-Nrf2 interaction, enhance antioxidant enzyme expression, and activate the GSH-GPX4 axis to inhibit Aβ-induced ferroptosis. Both compounds also protect against oxidative stress and neuroinflammation. S27-1047 showed superior Nrf2 activation and Keap1 binding, thus was selected for in vivo evaluation. In an Aβ-induced AD mouse model, S27-1047 significantly improved cognition, outperforming mono- or combination therapies. It has 12.62% oral bioavailability and crosses the BBB. This work presents multi-target agents targeting BChE, Nrf2, and ferroptosis for effective AD therapy.}, } @article {pmid42391971, year = {2026}, author = {Ning, Y and Chen, M and Yang, H and Jia, J}, title = {Sotagliflozin improves cognitive deficits and attenuates neuroinflammation of Alzheimer's disease.}, journal = {Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics}, volume = {23}, number = {4}, pages = {e00946}, doi = {10.1016/j.neurot.2026.e00946}, pmid = {42391971}, issn = {1878-7479}, abstract = {Effective treatments for Alzheimer's disease (AD) are limited. Due to shared pathological mechanisms between AD and diabetes, antidiabetic drugs like sodium-glucose cotransporter-2 inhibitors (SGLT2is) are potential therapeutic options. Although SGLT2is have shown cognitive benefits in diabetes models, their effects in AD models are not fully established. This study aimed to evaluate the therapeutic effects of sotagliflozin (Sota), an SGLT2i, in both in vivo and in vitro AD models. The network pharmacology analysis was used to predict the potential targets and pathways of Sota. And we selected 6-month-old APP/PS1 transgenic mice to investigate the effects of Sota. Cognitive function was assessed using the Morris water maze test. Immunohistochemistry and immunofluorescence were employed to quantify amyloid-beta (Aβ) plaque deposition in the hippocampal or cortex and analyze neuronal loss. Additionally, amyloid β oligomers induction and microglial cells were used to evaluate the effects of Sota on the release of pro-inflammatory mediators and to investigate the underlying mechanisms. In vivo, Sota treatment improved cognitive impairments, reduced pro-inflammatory cytokines, inhibited microglial activation, and promoted neuronal survival. In vitro, Sota mitigated Aß oligomer-induced toxicity in microglial cells by decreasing reactive oxygen species and pro-inflammatory cytokine release. Mechanistically, Sota treatment was associated with suppression of extracellular signal-regulated kinase (ERK) signaling. Our findings suggest that Sota improved cognitive impairment and attenuates neuroinflammation in AD. Sota may be a promising candidate for the treatment of AD.}, } @article {pmid42392137, year = {2026}, author = {Chen, Y and Yan, F and Xiao, P and Li, X and Yu, L and Dong, S and Yao, C}, title = {Non-invasive nanosecond transcranial pulsed electric fields: a deep-penetrating, high-field stimulation that suppresses hippocampal β-amyloid and improves cognitive deficits in Alzheimer's disease model.}, journal = {Journal of neural engineering}, volume = {}, number = {}, pages = {}, doi = {10.1088/1741-2552/ae8579}, pmid = {42392137}, issn = {1741-2552}, abstract = {OBJECTIVE: Hippocampal β-amyloid (Aβ) pathology may induce early circuit dysfunction and memory impairment in Alzheimer's disease (AD), making it a key target for slowing disease progression. However, existing transcranial electrical stimulation approaches, while remaining within safety limits, are insufficient to non-invasively generate sufficiently strong electric fields in deep brain regions. Here, we investigated whether nanosecond transcranial pulsed electric field stimulation (ns-tPFS) could provide a non-invasive deep-target strategy for modulating hippocampal Aβ pathology in an AD model.

APPROACH: The 10-month-old 5xFAD mice were selected for delivering repeated ns-tPFS (500 ns, 500 V, 1 Hz). The intracranial electric field exposure was estimated using finite-element modeling (FEM). Treatment effects were evaluated using the Morris water maze, Y-maze, immunofluorescence of Aβ deposition in the hippocampus and cortex, and western blotting of Aβ-related proteins. In addition, the structural responses of Aβ oligomers to pulsed electric fields were examined by employing molecular dynamics simulations, and structural brain safety was assessed by 9.4 T small-animal MRI.

MAIN RESULTS: ns-tPFS generated transient hippocampal electric fields on the order of 104 V/m. It reduced the hippocampal Aβ burden and was associated with coordinated changes in Aβ-related pathways, including decreased amyloidogenic processing and modulated Aβ transport-related receptors. Molecular dynamics simulations further suggested that Aβ oligomers are structurally sensitive to nanosecond-scale electric field transients within the hippocampal field range estimated by FEM. These changes were accompanied by improved spatial and working memory in 5xFAD mice. In contrast, under the present stimulation regimen, healthy mice were observed with no detectable cognitive impairment, or macroscopic MRI abnormalities.

SIGNIFICANCE: ns-tPFS may be a promising non-invasive deep-target electric-field strategy for mitigating hippocampal Aβ pathology and improving cognitive performance in an AD mouse model.}, } @article {pmid42392515, year = {2026}, author = {Pandey, JK and Verma, SK and Kumar, J and Perwej, Y and Jha, DSK and Panchal, BY and Ferdouse, R and V, S and Banerjee, S and Tiwari, M and Badal, R and Mandal, P and Baghel, JS}, title = {Transformative Role of Advanced Neural Computation in Clinical Image Diagnostics: A Review of Key Concepts and Applications.}, journal = {Seminars in ultrasound, CT, and MR}, volume = {}, number = {}, pages = {}, doi = {10.1053/j.sult.2026.06.010}, pmid = {42392515}, issn = {1558-5034}, abstract = {Medical imaging plays a crucial role in modern diagnostic practices, but traditional techniques often face limitations in accuracy, efficiency, and scalability. The emergence of deep learning (DL) has led to significant improvements that are transforming this field. This review discusses how DL algorithms are enhancing diagnostic imaging by improving accuracy, enabling automated analysis, and supporting personalized treatment plans. It focuses on key deep learning (DL) frameworks, including convolutional neural networks (CNNs), recurrent neural networks (RNNs), and generative adversarial networks (GANs). The review examines their applications in important medical imaging tasks such as image classification, segmentation, reconstruction, and disease prediction. It also considers how DL techniques are integrated with tools like radiomics, data augmentation strategies, and predictive analytics models. DL methods have shown superior performance in detecting and classifying diseases like pneumonia, tuberculosis, and Alzheimer's. They also improve the quality and speed of imaging modalities such as MRI, CT, and ultrasound. Despite these advances, challenges remain in data availability, model interpretability, clinical validation, and ethical issues related to bias and privacy. Addressing these challenges is essential for the successful clinical use of DL in medical imaging. This review ends with suggestions for future directions and best practices for ethically and practically integrating DL technologies into routine healthcare.}, } @article {pmid42381088, year = {2026}, author = {Verberk, IMW and de Koning, LA and Coomans, EM and Trieu, C and Leeuwis, AE and Hunter, J and Honigberg, L and van der Flier, WM and Vijverberg, EGB and Ossenkoppele, R and van de Giessen, E and Teunissen, CE}, title = {The potential of key Alzheimer's plasma biomarkers to mimic tau PET MUBADA-based disease staging.}, journal = {Alzheimer's research & therapy}, volume = {}, number = {}, pages = {}, doi = {10.1186/s13195-026-02085-6}, pmid = {42381088}, issn = {1758-9193}, abstract = {BACKGROUND: Patients with Alzheimer's disease (AD) with a low to intermediate tau-PET burden might benefit most from anti-amyloid treatment. Staging tau burden with plasma biomarkers would offer a scalable alternative to staging with tau-PET. This study investigated whether key plasma biomarkers P-tau217, P-tau181, Aβ42/40, GFAP and NfL can be used to accurately stage amyloid status (A-/A+) and tau-PET burden, and evaluated the relation of such a plasma-based staging system with cognitive outcomes over time.

METHODS: We included 105 participants with subjective cognitive decline (n = 27 A-, n = 18 A+), A+ mild cognitive impairment (n = 10) or A + AD-dementia (n = 50) from the Amsterdam Dementia Cohort who underwent [[18]F]flortaucipir PET-burden assessment (Tlow, Tintermediate or Thigh; based on MUBADA SUVr) and longitudinal cognitive assessment (average follow-up: 4.1 ± 3.5 years). AD-related plasma biomarkers were measured with Simoa. Discriminative performance (AUC) of each marker was compared using ROC analysis, and combined utility was assessed with logistic regression. Subsequently, cutoffs were established aiming for 90%-specificity, to regroup participants into a plasma-based staging scheme. Age-, sex- and education-adjusted linear mixed models (LMM) were performed to compare associations of plasma versus PET-based staging with longitudinal cognition.

RESULTS: 27 participants were A-TPET_low, 22 A+TPET_low, 27 A+TPET_int and 29 A+TPET_high. To discriminate A-TPET_low participants from A+TPET_low/int participants, P-tau217 performed best among all measured markers P-tau217, P-tau181, Aβ42/40, GFAP and NfL (AUC = 0.92 [95% CI: 0.856-0.985]). To discriminate A+TPET_high participants from A+TPET_low/int participants, also P-tau217 performed best among all markers (AUC = 0.74 [95% CI: 0.618-0.862]). A combination of Wald's backward-selected plasma markers did not statistically improve discriminative performance (DeLong's p > 0.05; two-marker combinations selected). Applying two cutoffs for P-tau217 as well as for the two-marker combinations, at 90% specificity to discriminate subsequent groups, we derived two plasma-based staging schemes. While the tau-PET staging scheme significantly and consistently associated with cognitive performance and decline across cognitive domains in LMMs, the plasma staging schemes did not.

CONCLUSIONS: Performance of plasma-based staging approaches developed in this study were high when discriminating individuals without amyloid pathology, while this was moderate when discriminating amyloid positive individuals with a high tau-PET burden. Our LMM findings visualize that tau staging in amyloid-positive individuals remains optimally performed with tau-PET scans.}, } @article {pmid42381140, year = {2026}, author = {Li, Y and Xie, K and Qian, S and Wang, Z and Zhang, H and Si, L}, title = {Quantifying Short-Term Functional Changes After Lecanemab Treatment in Early Alzheimer's Disease: An Exploratory 3-Month Follow-Up Case Report Using Eye Movement and Gait Analysis.}, journal = {Current Alzheimer research}, volume = {}, number = {}, pages = {}, doi = {10.2174/0115672050471024260520113701}, pmid = {42381140}, issn = {1875-5828}, abstract = {INTRODUCTION: Lecanemab is a monoclonal antibody targeting amyloid-β (Aβ) and is currently used in clinical practice for the treatment of early Alzheimer's disease (AD). However, noninvasive biomarkers reflecting its early efficacy are still unclear. This exploratory case report aims to investigate the combination of eye movement and gait analysis to quantitatively monitor shortterm functional changes during lecanemab treatment.

CASE PRESENTATION: Two male patients, both diagnosed with mild Alzheimer's disease through amyloid- PET and both with the APOE ε3/ε3 genotype, received intravenous lecanemab (10 mg/kg, every two weeks) for three months. Cognitive assessments (Montreal Cognitive Assessment, Mini- Mental State Examination, Clinical Dementia Rating), eye movement tests (smooth pursuit, overlapping saccades, anti-saccades), and gait analysis under single-task and dual-task conditions were conducted at baseline and follow-up. Patient 1 (79 years old) showed stable cognitive function, significant improvement in multiple eye movement parameters, and partial improvement in gait under single-task conditions. Patient 2 (60 years old) did not follow up on cognitive function tests as scheduled and showed inconsistent changes in eye movement parameters, but improved selected gait measures under dual-task conditions, particularly a shorter turning time. Neither patient experienced Amyloid-Related Imaging Abnormalities or infusion-related adverse events during the infusion process.

CONCLUSION: This exploratory case report suggests that eye movement and gait analysis may be sensitive to short-term functional changes following lecanemab treatment, which were not consistently captured by traditional cognitive scales. These findings are hypothesis-generating and warrant further investigation in larger studies. Multimodal functional assessment may hold promise as a tool for monitoring early treatment effects in Alzheimer's disease.}, } @article {pmid42381141, year = {2026}, author = {Mehrabadi, S}, title = {The Role of Digital Health Technologies in Early Detection and Management of Alzheimer's Disease.}, journal = {Current Alzheimer research}, volume = {}, number = {}, pages = {}, doi = {10.2174/0115672050415800251226061142}, pmid = {42381141}, issn = {1875-5828}, abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by cognitive decline and functional impairment, posing significant challenges for early detection and management. In recent years, digital health technologies have emerged as promising tools to enhance the diagnosis, monitoring, and treatment of AD. This review paper explores the multifaceted role of digital health technologies in the early detection and management of Alzheimer's disease. We examine the use of wearable devices that monitor cognitive function and daily activities, as well as mobile health applications designed for cognitive training and symptom tracking. Additionally, we analyze the impact of telehealth services in providing remote care, particularly for underserved populations. The integration of artificial intelligence and machine learning for analyzing behavioral and cognitive data to support early diagnosis and risk assessment is also discussed. Furthermore, we explore the concept of digital biomarkers and their potential to complement traditional diagnostic methods. Ethical considerations surrounding privacy, data security, and informed consent are addressed to ensure responsible implementation of these technologies. Finally, we highlight gaps in current research and propose future directions for integrating digital health technologies into Alzheimer's care, emphasizing the potential for personalized interventions tailored to individual patient needs. This review underscores the transformative potential of digital health to reshape Alzheimer's disease management and improve patient outcomes.}, } @article {pmid42382036, year = {2026}, author = {Hofmann, A and Paczynski, M and Ponisio, MR and Saef, B and Roberts, JP and Powell, WJB and Gupta, A and Oh, I and Hofford, M and Posey, Z and Aldinger, M and Benzinger, TLS and Morris, JC and Snider, BJ and Schindler, SE}, title = {Performing multiple biomarker tests delays initiation of amyloid-targeting treatments.}, journal = {Alzheimer's & dementia (Amsterdam, Netherlands)}, volume = {18}, number = {3}, pages = {e70387}, pmid = {42382036}, issn = {2352-8729}, abstract = {INTRODUCTION: With the clinical availability of amyloid-targeting treatments (ATTs), accurate and timely biomarker-based diagnosis of Alzheimer's disease (AD) has become increasingly important. Three AD biomarker modalities are commonly available in clinical practice: amyloid positron emission tomography (PET), cerebrospinal fluid (CSF) tests, and blood tests.

METHODS: We investigated the use and agreement of different biomarker modalities in a memory clinic. Further, we calculated the time until ATT initiation for patients who underwent a single test versus multiple biomarker tests.

RESULTS: The blood test agreed with amyloid PET in nine of 11 patients and CSF tests in all 14 patients. The median time from first clinic visit to ATT initiation was 4.7 months in 209 patients who underwent a single test and 8.1 months in 12 patients who underwent multiple tests.

DISCUSSION: Performing multiple biomarker tests delays initiation of ATT and should be restricted to patients with uncertain amyloid status following the first biomarker test.}, } @article {pmid42382677, year = {2026}, author = {Siam, NH and Nasrin, N and Saiyara, S and Saha, H and Deb, DP and Islam, J}, title = {Medicinal Plants and Their Bioactive Phytochemicals as Emerging Therapeutic Strategies for Alzheimer's Disease: An Integrative Review of Preclinical and Clinical Evidence.}, journal = {Scientifica}, volume = {2026}, number = {}, pages = {6124916}, pmid = {42382677}, issn = {2090-908X}, abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by β-amyloid deposition, tau hyperphosphorylation, mitochondrial dysfunction, oxidative stress, neuroinflammation, and blood-brain barrier disruption, collectively leading to widespread cortical and subcortical atrophy. Current FDA-approved pharmacotherapies, including acetylcholinesterase inhibitors and memantine, provide only modest symptomatic relief and fail to halt disease progression, underscoring the urgent need for alternative therapeutic approaches. Growing evidence highlights medicinal plants and their bioactive phytoconstituents as promising candidates for AD prevention and treatment because of their multitarget mechanisms, favorable safety profiles, and long history of traditional use. This review synthesizes extensive in vitro, in vivo, and clinical studies demonstrating the neuroprotective potential of plant extracts and isolated compounds that exert antioxidant, anti-inflammatory, antiamyloidogenic, anti-tau, cholinesterase-inhibitory, and synaptic-modulating effects. Key medicinal species, including Abelmoschus esculentus, Brassica oleracea, Cannabis sativa, Citrus reticulata, Lantana camara, Launaea taraxacifolia, Lawsonia inermis, Marrubium vulgare, Markhamia lutea, Persicaria minor, Pithecellobium dulce, Salvia aristata, Trigonella foenum-graecum, and Withania somnifera, show significant cognitive and neuroprotective benefits in experimental AD models. Phytochemicals such as sulforaphane, nobiletin, trigonelline, diosgenin, verbascoside, withaferin A, and withanolides strongly modulate the amyloid, tau, oxidative, and inflammatory pathways. Clinical trials further support the therapeutic potential of several plant-derived interventions for mild cognitive impairment and AD-related dementia. Collectively, these findings highlight medicinal plants and their active constituents as compelling complementary or translational strategies for AD management, warranting further mechanistic and clinical validation. This review aims to evaluate the neuroprotective potential of medicinal plants and their bioactive compounds in preventing and managing AD by summarizing evidence from in vitro, in vivo, and clinical studies.}, } @article {pmid42382756, year = {2026}, author = {Xing, JF and Mu, K and Yan, X and Yang, X and Zhang, D and Gao, W and Zhang, T and Yang, S and Wang, R and Zhang, W and Zhu, Y}, title = {Calibrating microglia states in Alzheimer's disease: decoding immune-metabolic networks and nano-targeted multicomponent therapies.}, journal = {Frontiers in immunology}, volume = {17}, number = {}, pages = {1843978}, pmid = {42382756}, issn = {1664-3224}, mesh = {*Alzheimer Disease/metabolism/immunology/therapy/pathology ; Humans ; *Microglia/metabolism/immunology/pathology/drug effects ; Animals ; Amyloid beta-Peptides/metabolism ; Metabolic Networks and Pathways ; }, abstract = {Alzheimer's disease treatment is shifting from pathology removal to regulating the brain microenvironment. Anti-Aβ monoclonal antibodies, such as lecanemab and donanemab, provide statistically significant disease-modifying effects but offer only modest cognitive improvement and pose safety risks, including amyloid-related imaging abnormalities. These results show that amyloid clearance is clinically relevant but not sufficient for full restoration of neuroimmune, metabolic, synaptic, and neurovascular balance. Microglia are now seen as central to Alzheimer's disease susceptibility and progression, existing along dynamic, spatially organized, sex-influenced, and genetically determined continua beyond a simple pro- or anti-inflammatory state. This review calls out three key drivers of microglial dysfunction: the TREM2-APOE lipid-sensing axis, complement-mediated synaptic elimination, and immunometabolic reprogramming-including glycolysis, mitochondrial damage, autophagy failure, NAD+ depletion, and innate immune signaling. We examine natural bioactive compounds, metabolic modulators, and biomimetic nanodelivery as promising, yet currently unproven, strategies for adjusting microglial state. Future therapies should incorporate both pathology removal and microenvironment protection, tailored by disease stage, genetic profile, sex, vascular risk, and microglial state-associated biomarkers.}, } @article {pmid42384283, year = {2026}, author = {Mostafa, SS and Mohammed, RA and Abbas, AY and Othman, MA}, title = {The protective role of melatonin on the brain in a rat model of Alzheimer's disease.}, journal = {Metabolic brain disease}, volume = {41}, number = {1}, pages = {}, pmid = {42384283}, issn = {1573-7365}, mesh = {Animals ; *Melatonin/pharmacology/therapeutic use ; *Alzheimer Disease/chemically induced/drug therapy/metabolism/pathology/prevention & control ; Male ; Rats ; *Neuroprotective Agents/pharmacology/therapeutic use ; *Brain/drug effects/metabolism/pathology ; Disease Models, Animal ; Aluminum Chloride ; Maze Learning/drug effects ; Microglia/drug effects/metabolism ; Rats, Sprague-Dawley ; Tumor Necrosis Factor-alpha/metabolism ; }, abstract = {Alzheimer's disease is an age-related neurodegenerative disorder characterized by progressive cognitive decline and multiple biochemical and structural abnormalities in the brain. Accumulating evidence suggests that aluminum exposure may contribute to neurodegenerative process including those observed in AD and was linked to neuronal damage and cognitive impairment. Melatonin (Mel) is a neurohormone that regulates circadian rhythm and possesses antioxidant, anti-inflammatory and neuroprotective properties. The current study investigated the potential protective roles of Mel in a rat model of AD induced by aluminum chloride (AlCl3). Forty adult male rats were divided into 4 experimental groups: a control group, an AlCl3-treated group, an AlCl3+Mel-treated group, and a Mel-only group. AlCl3 was administered orally for four weeks. Cognitive performance and spatial learning were assessed using Morris water maze test. Plasma levels of the pro inflammatory cytokines; interleukin-6 (IL-6) and tumor necrosis factor alpha (TNF-α) were measured using enzyme linked immunosorbent assay. Histopathological examination of the frontal cortex was performed using hematoxylin and eosin staining, and immunohistochemistry was conducted using the neuronal marker NeuN, microglial marker Iba1, and inflammatory markers IL-6 and TNF-α. Mel treatment significantly improved learning and memory performance in the Morris water maze test. It also reduced plasma levels of IL-6 and TNF-α. Using immunohistochemistry, Mel increased NeuN expression, while reducing Iba1, IL-6 and TNF-α expression. These findings showed that Mel attenuated frontal cortical neurodegeneration and neuroinflammation in this model of AD, suggesting that Mel may represent a promising neuroprotective therapeutic strategy for AD.}, } @article {pmid42385118, year = {2026}, author = {Morrill, VN and Pike, JR and Hu, J and Fornage, M and Surapaneni, A and Walker, KA and Knopman, DS and Mosley, TH and Coresh, J and Schneider, ALC and Smith, JR and Gottesman, RF}, title = {Genetic Risk for Alzheimer Disease, Midlife Hypertension, and Dementia: The ARIC Neurocognitive Study.}, journal = {Neurology}, volume = {107}, number = {2}, pages = {e218280}, doi = {10.1212/WNL.0000000000218280}, pmid = {42385118}, issn = {1526-632X}, mesh = {Humans ; *Hypertension/genetics/epidemiology ; Female ; *Alzheimer Disease/genetics/epidemiology ; *Dementia/genetics/epidemiology ; Male ; Middle Aged ; Genetic Risk Score ; *Genetic Predisposition to Disease ; Risk Factors ; Prospective Studies ; White People/genetics ; Black or African American/genetics ; United States/epidemiology ; Incidence ; }, abstract = {BACKGROUND AND OBJECTIVES: Genetics represent a nonmodifiable risk factor for Alzheimer disease (AD), with 60%-80% heritability. Midlife hypertension is a modifiable risk factor for both dementia and death. Our primary objective was to determine how genetic risk for AD modifies the association between hypertension and dementia.

METHODS: The Atherosclerosis Risk in Communities Study is an ongoing community-based prospective cohort study of 4 US centers. We analyzed White and Black participants free of dementia at age 55 years with genotypes and blood pressure measured at visit 1 (1987-1989). Three genetic risk groups (low, medium, high) were defined based on tertiles of a race-specific AD polygenic risk score. Dementia was ascertained through cognitive testing, informant interviews, hospitalization, codes and death records. Death was ascertained through the National Death Index. We examined the association of midlife hypertension with incident dementia within 3 genetic risk groups using Cox proportional-hazards and cumulative incidence function estimations. We used age 55 years as the time origin, with left truncation to allow entry at ages older than 55 years; age on December 31, 2022, was the administrative censoring date.

RESULTS: Among 8,931 White and 2,666 Black participants, the median follow up time was 26.6 and 23.8 years, the mean age was 54.0/53.5 years, and 53.0%/62.5% were female, respectively. After adjusting for demographics, midlife hypertension was significantly associated with dementia incidence across all genetic risk groups among White participants (low risk hazard ratio [HR] 1.29; 95% CI 1.07-1.55, medium risk HR 1.34; 95% CI 1.13-1.58, high risk HR 1.19; 95% CI 1.03-1.38) and among Black participants at high genetic risk (HR 1.31; 95% CI 1.04-1.66). Associations for low and medium genetic risk Black participants were consistent but not statistically significant. There were no significant differences in association of hypertension with dementia by AD genetic risk group. Individuals with hypertension had a 0%-2% higher probability of developing dementia by age 80 and a 6%-13% lower probability of dementia-free survival to age 80 years vs those without hypertension, across race and genetic risk groups.

DISCUSSION: Genetic risk for AD does not modify the association between hypertension and dementia. These data support the fact that all individuals with hypertension are likely to benefit from antihypertensive treatment.}, } @article {pmid42376965, year = {2026}, author = {Akasaka, T and Watanabe, H and Ono, M}, title = {Bithiophene Scaffold for PET Imaging and Photosensitization as a Novel Theranostic Platform Targeting Amyloid-β Aggregates.}, journal = {ACS chemical neuroscience}, volume = {}, number = {}, pages = {}, doi = {10.1021/acschemneuro.6c00047}, pmid = {42376965}, issn = {1948-7193}, abstract = {Amyloid β (Aβ) aggregates are primary targets for the diagnosis and curative treatment of Alzheimer's disease (AD). While various theranostic agents targeting Aβ aggregates have been developed, most rely on fluorescent imaging, which has limited clinical translation. In contrast, nuclear medicine imaging, particularly positron emission tomography (PET), offers high sensitivity and deep tissue permeability suitable for clinical settings. Moreover, photosensitization has emerged as a promising strategy to attenuate Aβ toxicity. In this study, we designed and synthesized novel bithiophene derivatives as PET/photosensitization theranostic agents. Western blotting analysis and MALDI-TOF MS spectrometry demonstrated that FABT-2 selectively oxidized Aβ aggregates under light irradiation, leading to a significant reduction in Aβ-induced cytotoxicity, as demonstrated by CCK8 and LDH assays. Furthermore, [18]F-labeled FABT-2 showed blood-brain barrier permeability in normal mice. These results suggest that FABT-2 may be a promising lead compound for the development of theranostic agents targeting Aβ aggregates.}, } @article {pmid42377068, year = {2026}, author = {Cantoni, V and Grassi, M and Premi, E and Cupidi, C and Zummo, E and Cotelli, MS and Benussi, A and Borroni, B}, title = {Long-term effects of multisession gamma transcranial alternating current stimulation in Alzheimer's disease.}, journal = {Journal of Alzheimer's disease : JAD}, volume = {}, number = {}, pages = {13872877261461248}, doi = {10.1177/13872877261461248}, pmid = {42377068}, issn = {1875-8908}, abstract = {This study investigated the long-term clinical effects of multisession gamma transcranial alternating current stimulation (tACS) over the precuneus in early-stage Alzheimer's disease. Forty-six patients from a previous randomized, double-blind, sham-controlled trial with an open-label extension underwent follow-up at 36 and 72 weeks. Participants received either 8 or 16 weeks of gamma tACS. Both treatment durations showed comparable long-term outcomes. Alzheimer's Disease Assessment Scale-Cognitive Subscale did not significantly worsen at 36 weeks, and Face-Name Association Test remained stable at both follow-up time points, whereas Clinical Dementia Rating-Sum of Boxes and Alzheimer's Disease Cooperative Study-Activities of Daily Living worsened over time. These findings suggest relative preservation of selected cognitive measures, despite worsening in broader clinical and functional outcomes.}, } @article {pmid42377581, year = {2026}, author = {Terzioglu-Usak, S and Zaim, M and Beker, M and Isik, S and Elibol, B}, title = {Molecular links between reelin downregulation, topoisomerase IIβ alterations, and proteins involved in Alzheimer pathology in human SH-SY5Y neuroblastoma cell line.}, journal = {Experimental brain research}, volume = {244}, number = {8}, pages = {}, pmid = {42377581}, issn = {1432-1106}, support = {12.2016/7//Bezmialem Vakıf Üniversitesi/ ; }, mesh = {Reelin Protein ; Humans ; *Nerve Tissue Proteins/metabolism/genetics ; *Serine Endopeptidases/metabolism/genetics ; *Cell Adhesion Molecules, Neuronal/metabolism/genetics ; *Extracellular Matrix Proteins/metabolism/genetics ; Cell Line, Tumor ; *Down-Regulation/physiology ; *Alzheimer Disease/metabolism/pathology ; *DNA Topoisomerases, Type II/metabolism/genetics ; RNA, Small Interfering/metabolism/genetics ; tau Proteins/metabolism ; *DNA-Binding Proteins/metabolism/genetics ; RNA, Messenger/metabolism ; Amyloid beta-Protein Precursor/metabolism ; Neuroblastoma/pathology ; Transfection ; Aspartic Acid Endopeptidases/metabolism ; Poly-ADP-Ribose Binding Proteins ; }, abstract = {Reelin signaling regulates multiple pathways in neurodegenerative conditions, including neuronal migration, synaptic plasticity, tau phosphorylation, and amyloidogenic processing of amyloid precursor protein (APP). This study aimed to investigate the impact of reelin downregulation on the expression of topoisomerase IIβ (topo IIβ), given its crucial role in neuronal differentiation and its established association with neurodegenerative disorders such as Alzheimer's disease (AD). Furthermore, we sought to elucidate the potential relationship between reelin downregulation and proteins implicated in the pathophysiology of AD. Firstly, the optimum concentration of small interfering RNAs (siRNA) targeting reelin was transfected into SH-SY5Y cells using Lipofectamine RNAiMAX reagent. The downregulation of reelin was confirmed at the mRNA level by real-time quantitative polymerase chain reaction (qRT-PCR). Reelin-mediated molecular alterations at both the mRNA and protein levels were analyzed by qRT-PCR and Western blotting. Reelin downregulation led to a decrease in the number of viable cells as determined by the MTT assay. Consistent with the downregulation of reelin gene expression, topo IIβ, Psen1, and BACE1 expressions were also reduced, whereas tau and APP expressions were upregulated. Although siRNA treatment effectively decreased reelin mRNA levels and the proteolytic fragment of reelin protein, no significant change was observed in total full-length reelin protein levels, suggesting the involvement of post-transcriptional regulatory mechanisms. Moreover, pTAU and APP protein expressions were increased, while Nurr1 protein was decreased in reelin-silenced cells. These findings suggest that downregulation of reelin gene expression may contribute to neurodegeneration through alterations in topo IIβ and nurr1 expression, in addition to changes in proteins associated with AD pathology.}, } @article {pmid42377618, year = {2026}, author = {Saini, D and Mujeeb, M and Akhtar, M and Haque, SE and Najmi, AK}, title = {PPAR-γ modulation restores the adiponectin-AMPK-AKT axis to attenuate metabolic stress-associated alzheimer's pathology.}, journal = {Molecular biology reports}, volume = {53}, number = {1}, pages = {}, pmid = {42377618}, issn = {1573-4978}, mesh = {Animals ; *Alzheimer Disease/metabolism/drug therapy/pathology ; *PPAR gamma/metabolism ; Male ; Rats ; Proto-Oncogene Proteins c-akt/metabolism ; Rats, Wistar ; *AMP-Activated Protein Kinases/metabolism ; Signal Transduction/drug effects ; *Adiponectin/metabolism ; Telmisartan/pharmacology ; Disease Models, Animal ; Stress, Physiological/drug effects ; Insulin Resistance ; Neuroprotective Agents/pharmacology ; Lipopolysaccharides ; Isoflavones/pharmacology ; tau Proteins/metabolism ; }, abstract = {Background Increasing evidence links metabolic dysregulation, insulin resistance, and endotoxin-induced inflammation to sporadic AD. A disruption of the PPARγ-adiponectin-AMPK-insulin pathway leads to neuroinflammation, Aβ buildup, tau hyperphosphorylation, and cognitive impairments. This study examined the neuroprotective effects of telmisartan and formononetin alone and in combination in metabolically primed AD-like rats. Methodology A two-hit model was employed to simulate metabolic endotoxemia-related sporadic Alzheimer's disease in male wistar rats. The model utilised chronic HFD feeding and systemic administration of LPS (250 µg/kg, i.p.). The animals received telmisartan, formonoetin, their combination, or a PPARγ inhibitor/ blocker. We evaluated metabolic parameters, cognitive performance, insulin resistance, inflammatory cytokines, adiponectin concentrations, cholinergic function, histopathology, and immunohistochemical markers of Aβ, tau, IRS-1, AMPK, and AKT signalling. Results The outcomes of HFD + LPS encompass weight gain, insulin resistance, inflammation, cholinergic dysfunction, neurotoxicity, elevated Aβ and tau pathology, and cognitive impairment. The therapy with telmisartan and formononetin enhanced these alterations in a dose-dependent manner, with the combination regimen demonstrating greater efficacy. The treatment reinstated adiponectin levels, enhanced AdipoR1-AMPK-AKT signalling, diminished pathogenic IRS-1 serine phosphorylation, reduced pro-inflammatory cytokines, maintained neuronal structure, and augmented recognition memory. The co-administration of PPARγ inhibitor/blocker abolished these protective effects, showing mediation reliance on PPARγ. Conclusion Telmisartan and formononetin have significant metabolic and neuroprotective advantages against AD generated by HFD and LPS through the activation of the PPARγ-adiponectin-AMPK-IRS-1-AKT signalling pathway. Targeting metabolic-inflammatory pathways using natural PPARγ modulators may aid in delaying or preventing sporadic AD associated with obesity, insulin resistance, and endotoxemia.}, } @article {pmid42377668, year = {2026}, author = {Zhang, J and Zhang, Q and Jordan, JD and Zong, X}, title = {Near‑Infrared Photobiomodulation in White‑Matter Disease: From Microglial States to Measurable Endpoints.}, journal = {Neuromolecular medicine}, volume = {28}, number = {1}, pages = {}, pmid = {42377668}, issn = {1559-1174}, support = {R01AG082207 and R01AG081874//National Institute on Aging of the National Institutes of Health under/ ; 149251504A//U.S. Department of Defense/ ; 24CDA1269588//American Heart Association Career Development/ ; }, mesh = {Humans ; *Microglia/radiation effects/physiology ; Animals ; *Low-Level Light Therapy/methods ; *Leukoencephalopathies/radiotherapy/diagnostic imaging/pathology ; *White Matter/radiation effects/injuries ; *Infrared Rays/therapeutic use ; Oligodendroglia/radiation effects ; Oxidative Stress ; Astrocytes/radiation effects ; Remyelination/radiation effects ; Axons/radiation effects ; }, abstract = {White-matter (WM) injury contributes to disability across multiple sclerosis, traumatic brain injury, Alzheimer's disease and related dementias, and small-vessel disease. We use microglial state programs as an organizing axis for WM injury-to-repair logic, while emphasizing that WM outcomes are multicellular and involve oligodendrocyte-lineage cells, astrocytes, axons/neurons, and vascular factors. Microglia span an injury-repair continuum, from inflammatory programs that increase oxidative stress and debris burden to repair-competent programs that support debris handling, remyelination, and axonal integrity. Near-infrared photobiomodulation (PBM; ~800-1100 nm) is most consistently associated with modulation of mitochondrial redox/bioenergetic pathways and inflammatory tone. CCO-centered mechanistic framing is best established near ~ 800-850 nm, whereas longer wavelengths (e.g., ~ 1064-1070 nm) may involve additional initiating mechanisms with downstream convergence on shared redox/bioenergetic and inflammatory pathways. Across demyelination and spinal cord injury models, appropriately dosed PBM has been reported to reduce inflammatory glial readouts and to associate with improved myelin/axon-related endpoints and functional measures, although mechanistic certainty varies across models. Human evidence remains early but broadly supports safety; a randomized trial in moderate traumatic brain injury reported treatment-related changes in diffusion-MRI WM metrics, while small dementia and chronic-injury studies report heterogeneous cognitive and physiological signals. Given dose dependence and depth-limited transcranial delivery, we synthesize mechanism-informed, dose-aware reporting guidance and WM-anchored outcome frameworks that pair diffusion MRI/DTI with interpretable biomarkers (e.g., NfL, GFAP, sTREM2) and thermally controlled sham designs. We also note potential indirect/systemic contributions that could help reconcile depth-dose constraints with deeper WM effects.}, } @article {pmid42377826, year = {2026}, author = {Lachhab, S and Elmoussaoui, S and Rafya, M and El Mansouri, AE and Mehdi, A and Ramalhosa, RR and Costa, AR and Carreiro, EP and Andrei, G and Snoeck, R and Benkhalti, F and Sanghvi, YS and Ali, MA and Lazrek, HB}, title = {Discovery of novel perillyl and myrtenyl nucleobase conjugates as dual anti-Alzheimer and antimicrobial agents.}, journal = {Molecular diversity}, volume = {}, number = {}, pages = {}, pmid = {42377826}, issn = {1573-501X}, abstract = {Recent studies suggest that Alzheimer's disease may be influenced by microbial infections and may involve multiple microbial pathogens contributing to its development and progression. Based on this hypothesis, dual antimicrobial and anti-Alzheimer's agents may provide advantages such as improved therapeutic effectiveness, treatment of infection-related Alzheimer disease, and reduced toxicity compared with single-target drugs. To discover novel therapeutic agents, a series of terpene-substituted pyrimidine derivatives were synthesized and evaluated for their antiviral, antibacterial, antifungal and anti-Alzheimer's activities. All compounds were characterized by spectroscopic methods to support their structures. Among all compounds screened for their biological activity, compounds 11 and 32 displayed excellent IC50 values of 10.1 and 9.9 µM, respectively, against eqBChE in comparison with Food and Drug Administration (FDA)-approved drugs galantamine (IC50 = 20.6 µM) and donepezil (IC50 = 4.1 µM) for the treatment of Alzheimer's disease (AD). Additionally, compound 32 exhibited promising antifungal activity against C. tropicalis (MIC = 0.83 µmol/ml and MFC = 1.69 µmol/ml), showing two-fold greater potency than fluconazole and three-fold greater potency than 5-fluorocytosine. Moreover, terpene derivative 32 showed moderate antibacterial activity against Pseudomonas aeruginosa, Staphylococcus aureus, Escherichia coli, and Enterococcus faecalis, with MIC and MBC values ranging from 3.35 to 6.71 µmol/ml. The docking studies of 32 with eqBChE supported the observed in vitro results. This study provides a promising lead compound with dual antimicrobial and anti-Alzheimer activity that may be further developed as a potential therapeutic agent for the treatment of Alzheimer's disease.}, } @article {pmid42380069, year = {2026}, author = {Zhang, Y and Qiao, H and Lv, Z and Guo, R and Li, D and Song, W and Wang, D}, title = {Transcranial 810 nm Pulsed Photobiomodulation Improves Learning and Reduces Aβ42 Burden in APP/PS1 Mouse Model of Alzheimer's Disease.}, journal = {Photobiomodulation, photomedicine, and laser surgery}, volume = {}, number = {}, pages = {25785478261465371}, doi = {10.1177/25785478261465371}, pmid = {42380069}, issn = {2578-5478}, abstract = {BACKGROUND: Alzheimer's disease (AD) is a leading cause of dementia in older adults, and effective and widely applicable treatment options remain limited. Photobiomodulation (PBM) has shown promise for AD. However, reported estimates of the delivered dose after transcranial propagation vary widely, limiting translation from animal models to clinical settings.

OBJECTIVE: Building on our team's prior clinical findings, this study evaluated whether an 810 nm/10 Hz pulsed PBM regimen improves cognitive performance and reduces Aβ42 burden in APP/PS1 mice.

METHODS: APP/PS1 mice received PBM using an 810 nm LED pulsed at 10 Hz. Irradiation was delivered for 540 sec/day, 6 days/week, for 7 weeks, with a scalp-surface power density of 0.025 W/cm[2] and an energy density of 13.5 J/cm[2]. Cognitive function was evaluated using the Morris water maze, and Aβ42 burden was quantified by immunofluorescence.

RESULTS: Cortical and hippocampal Aβ42 plaque burden was reduced, p < 0.01. Exploratory correlation analyses suggested an association between hippocampal Aβ42 plaque number and reversal-learning performance in the histological subset, p = 0.02. The microglia-Aβ42 colocalization ratio increased by 7.53%, p = 0.03, indicating enhanced spatial association between microglia and Aβ42 after PBM.

CONCLUSIONS: These findings support further evaluation of this 810 nm/10 Hz pulsed PBM regimen in AD mouse models and highlight the value of standardized PBM parameter reporting in preclinical studies.}, } @article {pmid42380200, year = {2026}, author = {Kazmi, SA and Chandra, F and Wasney, M and Cheng, J and Lum, GR and Iyer, M and Di Blasi, D and Espinoza, AN and Lopez-Romero, A and Yang, X and Garud, N and Hsiao, EY}, title = {Select microbial metabolites promote tau aggregation in a murine tauopathy model.}, journal = {Nature communications}, volume = {}, number = {}, pages = {}, doi = {10.1038/s41467-026-74775-6}, pmid = {42380200}, issn = {2041-1723}, support = {2018-191860//Silicon Valley Community Foundation (SVCF)/ ; }, abstract = {The gut microbiome is emerging as a modifier of risk for neurodegenerative diseases, but underlying mechanisms remain poorly understood. Here, we show that the hTau.P301S mouse model for progressive tauopathy develops alterations in the composition and function of the gut microbiome that are not recapitulated in amyloid-based 5xFAD or 3xTg models for Alzheimer's disease. Disrupting the gut microbiome via chronic antibiotic treatment exacerbates cognitive deficits and tau pathology in hTau.P301S mice, demonstrating a causal influence of the microbiome on tau-driven disease progression. This corresponds with widespread alterations in microbiome-dependent metabolites in the sera and brains of hTau.P301S mice, including subsets that correlate with the severity of tau pathology. By screening against tau biosensor cells, we identify select microbial metabolites-trimethylamine-N-oxide, 3-indoxyl sulfate, phenol sulfate, thymidine, and 2'deoxyuridine-that promote tau seeding and aggregation. Systemic administration of these metabolites worsens cognitive impairment and tau pathology in hTau.P301S mice. These findings establish a mechanistic link between the gut microbiome, serum and brain metabolites, as well as tau aggregation, suggesting that select microbial metabolites could potentially serve as therapeutic targets for tau-driven diseases.}, } @article {pmid41900916, year = {2026}, author = {Papaliagkas, V and Kalinderi, K and Moschou, M and Arnaoutoglou, M and Koutsouraki, E and Kimiskidis, VK}, title = {The Role of Transcranial Magnetic Stimulation for the Treatment of Alzheimer's Disease: A Narrative Review.}, journal = {Life (Basel, Switzerland)}, volume = {16}, number = {3}, pages = {}, pmid = {41900916}, issn = {2075-1729}, abstract = {Alzheimer's disease (AD) is the most common neurodegenerative disease that accounts for 60-80% of all dementia cases and affects millions of people worldwide. At present, standard drug therapies provide only limited symptomatic relief. Therefore, the exploration of novel therapeutic approaches is crucial for improving patient outcomes. Transcranial magnetic stimulation (TMS) has emerged as a promising non-invasive neuromodulation technique that may provide benefit in AD management. This review discusses the pathophysiological mechanisms by which TMS operates, evaluates its clinical efficacy in AD patients, assesses its safety profile, and suggests future directions for research.}, } @article {pmid41901082, year = {2026}, author = {Kumari, A and Zeng, XA}, title = {Dietary Bioactives in Alzheimer's Disease: A Critical Appraisal of Clinical Trials and Future Nutritional Strategies.}, journal = {Nutrients}, volume = {18}, number = {6}, pages = {}, pmid = {41901082}, issn = {2072-6643}, support = {32172348//National Natural Science Foundation of China/ ; }, mesh = {Humans ; *Alzheimer Disease/diet therapy ; *Dietary Supplements ; *Phytochemicals/administration & dosage ; Clinical Trials as Topic ; Curcumin ; *Diet ; }, abstract = {Background: Alzheimer's disease (AD) remains a major public health challenge. Observational associations between dietary patterns and reduced dementia risk have prompted investigations of dietary bioactives (DBs) as cognitive nutraceuticals. Methods: This critical narrative review examines interventional trials for nine prominent DBs relevant to AD: docosahexaenoic acid (DHA), curcumin, resveratrol, epigallocatechin gallate (EGCG), nicotinamide riboside (NR), tricaprilin, vitamin E (α-tocopherol), cannabinoids, and NIC5-15 (D-pinitol). Trials were identified through ClinicalTrials.gov (search date: December 2024) and supplemented by PubMed searches for published results. Data were extracted on trial phase, design, cognitive/functional endpoints, biomarker outcomes, and development status. Findings are synthesized qualitatively; no formal meta-analysis or risk of bias assessment was conducted. Results: None of the nine bioactives demonstrated consistent cognitive efficacy in AD. Phase III trials of DHA, curcumin, and tricaprilin did not meet primary cognitive endpoints. Resveratrol reduced CSF Aβ40 without cognitive benefit. Cannabinoids improved behavioral symptoms but showed no measurable cognitive effects. High-dose vitamin E slowed functional decline, while cognition remained unchanged. In contrast, trials in preclinical or at-risk populations reported preliminary cognitive signals for EGCG and biomarker engagement for NR, suggesting potential for early intervention. Conclusions: Current clinical evidence does not support high-dose DBs supplementation as an effective treatment for AD. Predominantly negative late-phase findings highlight limitations, with potential contributors including limited bioavailability, late intervention, insufficient target engagement, and biological heterogeneity. Future research may benefit from early biomarker-defined populations, optimized formulations, multi-nutrient or dietary approaches, and precision nutrition strategies considering genetic risk and baseline nutrient status. DBs may be better positioned for prevention or early-stage intervention rather than late-stage therapy.}, } @article {pmid41901221, year = {2026}, author = {Watt, G and Olaya, J and Muench, G and Garner, B and Karl, T}, title = {Effects of Chronic 100 mg/kg Cannabidiol Treatment in Male Double Transgenic APPSwe/PS1∆E9 Mice.}, journal = {Pharmaceuticals (Basel, Switzerland)}, volume = {19}, number = {3}, pages = {}, pmid = {41901221}, issn = {1424-8247}, support = {n.a.//Alzheimer's Australia Dementia Research/ ; #1102012, #1141789, and #1095215//National Health and Medical Research Council/ ; }, abstract = {Background/Objectives: Alzheimer's disease (AD) is a neurodegenerative disease for which there are no highly effective treatments, which highlights the need for novel therapeutics. Cannabidiol (CBD) has demonstrated antioxidant, anti-inflammatory and neuroprotective properties. Chronic CBD treatment (20 mg/kg and 50 mg/kg) reverses social recognition memory deficits of APPSwe/PS1∆E9 (APP/PS1) transgenic mice; however, it does not produce effects on AD-relevant brain pathology. Methods: Here, we investigated whether chronic high-dose CBD treatment (i.e., 100 mg/kg intraperitoneally) in early symptomatic 7.5-month-old APP/PS1 males would reverse cognitive deficits while also influencing neuropathological markers relevant to AD. Mice were assessed for anxiety, recognition memory, and social and aggressive behaviours before carrying out neuropathological analyses of collected brain tissue. Results: Vehicle-treated APP/PS1 transgenic males demonstrated reduced aggressive behaviour and increased socio-positive behaviour. A moderate deficit in social recognition memory was restored by CBD. APP/PS1 mice also exhibited elevated cortical proBDNF levels under vehicle treatment, and hippocampal levels of TNF-α and IL-1β were reduced in all APP/PS1 mice. AD transgenic mice exhibited no changes in soluble or insoluble Aβ42 levels or PPARγ isoforms. Conclusions: This study found that high-dose CBD restored a moderate social recognition memory deficit. However, CBD did not have marked effects on AD-relevant neuropathological markers assessed, most likely because the AD transgenic mice were evaluated at a disease stage too early to detect significant pathological changes. Thus, the underlying mechanisms for CBD's effect on social recognition memory require further investigation.}, } @article {pmid41903051, year = {2026}, author = {Jiang, C and Krivinko, J and Yu, Z and Sweet, RA and Zeng, L and Wang, H and Ding, Y and Zeng, Z and Kofler, J and Wang, L}, title = {Comparative Mortality Risk of Aripiprazole, Olanzapine, Quetiapine, and Risperidone in Alzheimer's Disease: A Real‑World Retrospective Cohort Study with Treatment Effect Heterogeneity Analysis.}, journal = {CNS drugs}, volume = {40}, number = {6}, pages = {823-833}, pmid = {41903051}, issn = {1179-1934}, support = {P30 AG066468/AG/NIA NIH HHS/United States ; R01 MH116046/MH/NIMH NIH HHS/United States ; }, mesh = {Humans ; *Antipsychotic Agents/adverse effects/therapeutic use/administration & dosage ; Female ; Retrospective Studies ; *Aripiprazole/adverse effects/therapeutic use/administration & dosage ; *Alzheimer Disease/drug therapy/mortality ; *Olanzapine/adverse effects/therapeutic use ; *Quetiapine Fumarate/adverse effects/therapeutic use/administration & dosage ; *Risperidone/adverse effects/therapeutic use/administration & dosage ; Male ; Aged ; Treatment Effect Heterogeneity ; Aged, 80 and over ; Cohort Studies ; }, abstract = {BACKGROUND: Second-generation antipsychotics (SGAs) are frequently used off-label to manage behavioral symptoms in Alzheimer's disease (AD), despite ongoing concerns about their safety. Comparative evidence on mortality risk across specific SGAs remains limited. In this study, we aim to compare all-cause mortality among patients with AD treated with one of the commonly prescribed SGAs and to explore treatment effect heterogeneity using causal machine learning.

METHODS: We conducted a retrospective cohort study using deidentified electronic health records from the Truveta platform. Patients with incident AD initiating treatment with aripiprazole, risperidone, quetiapine, or olanzapine were identified using a new-user design. Exposure was modeled as a time-varying covariate in Cox proportional hazards models, with propensity score matching applied to control for confounding. Causal tree and targeted maximum likelihood estimation were used to identify subgroups with heterogeneous treatment effects.

RESULTS: Among 17,004 patients with AD, aripiprazole was associated with significantly lower mortality than olanzapine (adjusted hazard ratio [AHR] 0.667, 95% confidence interval [CI] 0.472-0.941) and quetiapine (AHR 0.677, 95% CI 0.462-0.990). Quetiapine was also associated with lower mortality than olanzapine (AHR 0.833, 95% CI 0.702-0.990) and risperidone (AHR 0.830, 95% CI 0.705-0.978). Causal tree analysis revealed treatment effect heterogeneity by clinical characteristics, particularly among patients using type 2 diabetes mellitus (T2DM) medications. In subgroup analyses, aripiprazole remained protective in T2DM users (AHR = 0.604 versus the combined group of quetiapine and risperidone, p = 0.002).

CONCLUSIONS: Mortality risks vary substantially across SGAs in patients with AD with single-medication usage. Aripiprazole and quetiapine were associated with lower mortality compared with olanzapine and risperidone. Treatment effect heterogeneity suggests the need for individualized prescribing based on patient characteristics such as comorbid T2DM.}, } @article {pmid41903678, year = {2026}, author = {Lee, ALY and Ang, CW and Yeong, KY}, title = {Antibiotic repurposing as alternative therapeutic strategies for cancer and Alzheimer's disease: A solution or conundrum?.}, journal = {Drug discovery today}, volume = {31}, number = {3}, pages = {104651}, doi = {10.1016/j.drudis.2026.104651}, pmid = {41903678}, issn = {1878-5832}, mesh = {Humans ; *Alzheimer Disease/drug therapy ; *Drug Repositioning/methods ; *Anti-Bacterial Agents/therapeutic use/pharmacology ; Animals ; *Neoplasms/drug therapy ; Antineoplastic Agents/therapeutic use ; }, abstract = {Traditionally, drugs targeting mammalian systems have been repurposed as antibacterials to combat antimicrobial resistance. This review highlights the reverse perspective - exploring the emerging potential of antibiotics in the treatment and management of cancer and Alzheimer's disease. Because antibiotics are fast losing their efficacy due to resistance, repurposing clinically approved antibiotics for other diseases presents an attractive strategy, offering a new avenue for antibiotic applications rather than allowing valuable research efforts to go to waste. This review provides an overview on antibiotic repurposing for crucial diseases such as cancer and Alzheimer's disease, while also exploring the challenges and limitations associated with this approach. Future prospects of antibiotic repurposing are also discussed.}, } @article {pmid41903830, year = {2026}, author = {He, S and Lin, Z and Zhou, X and Wang, Q and Fang, C and Jin, Q and Guan, L}, title = {The novel therapeutic strategy of myricetin/chitooligosaccharide/astaxanthin, as potent multi-target-directed ligands for the potential treatment of Alzheimer's disease with comorbid depression.}, journal = {European journal of pharmacology}, volume = {1021}, number = {}, pages = {178806}, doi = {10.1016/j.ejphar.2026.178806}, pmid = {41903830}, issn = {1879-0712}, mesh = {*Flavonoids/pharmacology/therapeutic use/chemistry ; Animals ; *Alzheimer Disease/drug therapy/complications ; Amyloid Precursor Protein Secretases/metabolism/antagonists & inhibitors ; Amyloid beta-Peptides/metabolism ; Mice ; *Depression/drug therapy/complications ; Xanthophylls/pharmacology/therapeutic use/chemistry ; Ligands ; Neuroprotective Agents/pharmacology/therapeutic use ; Aspartic Acid Endopeptidases/metabolism/antagonists & inhibitors ; Monoamine Oxidase/metabolism ; Cell Line ; Cholinesterase Inhibitors/pharmacology/therapeutic use ; Peptide Fragments/metabolism ; Protein Aggregates/drug effects ; *Antidepressive Agents/pharmacology/therapeutic use ; Cell Survival/drug effects ; Humans ; Molecular Docking Simulation ; *Oligosaccharides/pharmacology ; }, abstract = {OBJECTIVE: The mixed particles of Myricetin (MYR)/Chitooligosaccharide (COS)/Astaxanthin (AST) had not study to therapeutic effects on Alzheimer's disease (AD) combined with depression. In this study, the mixed particles of MYR/COS/AST were investigate the inhibitory activities against cholinesterase (ChE) and monoamine oxidase (MAO), possessing good activity were further assayed to inhibit β-amyloid1-42 (Aβ1-42) aggregation, beta-site amyloid precursor protein cleaving enzyme-1 (BACE-1), the neuroprotective activity and cytotoxicity.

MATERIALS AND METHODS: ChE and MAO inhibitory activities by Ellman and Holts method. Aβ aggregation were evaluated by thioflavin T assay, BACE1 inhibition used the fluorescence resonance energy transfer (FRET)-based. The protective effect were tested by against L-Glutamate (L-Glu)-induced HT22 cell damage, Cu[2+]- and Fe[3+]-induced neuronal damage, the cytotoxicity were measured by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) test. The antidepressant activities were measured by the forced swimming test (FST).

RESULTS: The results showed that the mass ratio of the mixed particles MYR/COS/AST was 10:10:3, which exhibited the best inhibitory activities on AChE, MAO, also exhibited inhibition against Aβ1-42 aggregation, BACE-1, Aβ1-42 disaggregation, exerted protective effects L-Glu-induced HT22 cell damage and on the cells against Cu[2+] and Fe[3+]-induced damage in BV-2 cells. In the FST, the mixed particles of MYR/COS/AST (10:10:1) exhibited good antidepressant effect. None of three substances showed cytotoxicity against L929 cells. The molecular docking revealed important interactions between the active three substances and amino acid residues.

CONCLUSIONS: These studies provide the technical data for ensuring potential treatment of AD combined with depression of the mixed particles of MYR/COS/AST (10:10:3).}, } @article {pmid41903861, year = {2026}, author = {Salas, YM and Kemper, KM and Shanmughapriya, S and Langford, D and Natarajaseenivasan, K}, title = {Lipid metabolism and neurodegeneration: Mechanistic insights and therapeutic targets.}, journal = {Ageing research reviews}, volume = {118}, number = {}, pages = {103114}, pmid = {41903861}, issn = {1872-9649}, mesh = {Humans ; *Lipid Metabolism/physiology ; *Neurodegenerative Diseases/metabolism/pathology/drug therapy ; Animals ; *Aging/metabolism ; Signal Transduction ; *Brain/metabolism/pathology ; Membrane Microdomains/metabolism ; }, abstract = {Lipid metabolism plays a crucial role in maintaining brain homeostasis, affecting energy balance, membrane structure, and signaling pathways essential for neuronal and glial health. Disruption of lipid pathways is linked to neuroinflammation and the progression of neurodegenerative diseases like Alzheimer's and Parkinson's, as well as aging. Changes in cholesterol trafficking, sphingolipid and ceramide metabolism, and phospholipid remodeling can compromise synaptic membrane integrity and signaling, thereby increasing oxidative stress and inflammatory responses. Advanced techniques such as single-cell RNA sequencing (scRNA-seq) and single-nucleus transcriptomics have revealed specific alterations in lipid metabolism across different cell types, indicating a metabolic shift that enhances microglial activation and astrocytic reactivity. This lipid dysregulation contributes to a cycle that heightens neuronal vulnerability. Lipid rafts also facilitate receptor-mediated signaling, tying lipid imbalances to immune activation. Consequently, therapeutic strategies targeting lipid pathways are gaining traction, including modulating apolipoprotein E, inhibiting ceramide synthesis, and supplementing fatty acids to enhance membrane fluidity. Moreover, lipidomics helps identify unique lipid signatures that could serve as biomarkers for early diagnosis and treatment monitoring. Understanding the connection between lipid metabolism, neuroinflammation, and neurodegeneration offers valuable insights for developing targeted interventions in neurodegenerative diseases.}, } @article {pmid41903899, year = {2026}, author = {Green, MC and Braun, DJ and Leibold, CT and Van Eldik, LJ and Bailey, CS}, title = {Specific inhibition of p38α MAPK dampens neuroinflammation during acute alcohol withdrawal in mouse BV2 microglial cell line and rat organotypic hippocampal slice cultures.}, journal = {Alcohol (Fayetteville, N.Y.)}, volume = {133}, number = {}, pages = {32-37}, pmid = {41903899}, issn = {1873-6823}, support = {T32 AA027488/AA/NIAAA NIH HHS/United States ; T32 AG078110/AG/NIA NIH HHS/United States ; }, mesh = {Animals ; *Hippocampus/drug effects/metabolism ; *Microglia/drug effects/metabolism/enzymology ; Rats ; *Ethanol/adverse effects ; *Substance Withdrawal Syndrome/drug therapy/metabolism ; Mice ; *Mitogen-Activated Protein Kinase 14/antagonists & inhibitors/metabolism ; Cell Line ; *Neuroinflammatory Diseases/prevention & control ; Organ Culture Techniques ; Tumor Necrosis Factor-alpha/metabolism ; Cytokines/metabolism ; Rats, Sprague-Dawley ; Female ; }, abstract = {Neuroinflammation is implicated in anxiety and negative affect in alcohol withdrawal, potentially contributing to relapse. The mitogen-activated protein kinase p38α (p38) is a critical driver of neuroinflammation in such excitatory neural contexts, and its inhibition reduces neuroinflammatory cytokine production in the context of various insults generally corresponding with improved cellular and synaptic health. Although heretofore unexamined, we hypothesized that inhibition of p38 by small-molecule MW150 would reduce neuroinflammation during the acute alcohol withdrawal period. Immortalized mouse BV2 and post-natal day 8 rat organotypic hippocampal slice cultures received 50mM ethanol in media for 24 h followed by 24 h withdrawal, or for 48 h continuously, with administration of 5 μM MW150 or saline for the final 24 h of treatment. Control tissue never received ethanol. Levels of cytokines in the culture media were analyzed after 48 h by MesoScale ELISA assays. Elevated CXCL1 and TNFα levels were ameliorated by MW150 during ethanol withdrawal in culture media from BV2 and female OHSC, respectively. Further, MW150 reduced TNFα, but increased IL6, across all conditions in the BV2 microglia. Preliminary evidence suggests that p38 inhibition during early ethanol withdrawal in vitro reduces select inflammatory cytokines. Given that MW150 is presently in clinical trials for neuroinflammation in Alzheimer's disease, its preclinical validation for use in alcohol withdrawal in vivo is crucial to determine its feasibility to modulate neuroinflammation and problem drinking in humans.}, } @article {pmid41904014, year = {2026}, author = {Sahu, S and Rangappa, N and Chinnathambi, S and Mishra, M}, title = {Tau-Cytoskeleton and their interaction with other neurodegenerative proteins.}, journal = {Advances in protein chemistry and structural biology}, volume = {150}, number = {}, pages = {489-517}, doi = {10.1016/bs.apcsb.2025.10.032}, pmid = {41904014}, issn = {1876-1631}, mesh = {Humans ; *tau Proteins/metabolism ; Animals ; *Cytoskeleton/metabolism/pathology ; *Tauopathies/metabolism/pathology ; *alpha-Synuclein/metabolism ; *Neurodegenerative Diseases/metabolism/pathology ; Brain/metabolism/pathology ; *Amyloid beta-Peptides/metabolism ; *Huntingtin Protein/metabolism ; *Alzheimer Disease/metabolism/pathology ; }, abstract = {A wide range of neurological conditions known as Tauopathies are distinguished by a peculiar accumulation of Tau protein and its effect on the central nervous system (CNS) and beyond. In Tauopathies, Tau aggregation has a primary role in the neurodegenerative process. Clinically, individuals exhibit various symptoms, such as cognitive or behavioural anomalies, mobility issues, memory loss, and language problems. The major Tau isoforms (3R, 4R, or an equal 3R:4R ratio) identified in the inclusion bodies of the brain are used to classify Tauopathies pathologically. We address various Tauopathies, differentiating between primary and secondary forms, the involvement of Tau isoforms, the affected brain areas, and the corresponding neuropathological features. This review emphasizes the pathological and physiological role of Tau protein, providing a comprehensive analysis of the molecular processes enabling Tau aggregation and its subsequent effect on neuronal structure and function. Additionally, the review highlights the complex interactions that exist between Tau and other neurodegenerative proteins, including amyloid-beta in Alzheimer's disease, alpha-synuclein in Parkinson's disease, huntingtin protein in Huntington's disease, and how these relationships worsen Tau pathology and advance neurodegeneration. The organ-specific impact of Tauopathy, including the brain and other peripheral organs, has been discussed. The significance of these findings for future treatment techniques aiming at addressing Tau disease and mitigating its organ-specific repercussions.}, } @article {pmid41904593, year = {2026}, author = {Merkel, J and Perneczky, R and Jessen, F and Frölich, L and Jansen, O and Peters, S and Berg, D and Schulz, JB and Bartsch, T}, title = {Amyloid-related imaging abnormalities (ARIA) in Alzheimer's disease: from pathophysiology to individualized risk assessment.}, journal = {Alzheimer's research & therapy}, volume = {18}, number = {1}, pages = {}, pmid = {41904593}, issn = {1758-9193}, mesh = {Humans ; *Alzheimer Disease/diagnostic imaging/physiopathology/metabolism ; *Amyloid beta-Peptides/metabolism ; *Brain/diagnostic imaging/metabolism ; Risk Assessment ; Cerebral Amyloid Angiopathy/diagnostic imaging ; Precision Medicine ; Neuroimaging ; }, abstract = {Monoclonal antibodies targeting amyloid-β are the first approved disease-modifying treatment for Alzheimer’s disease. While amyloid-targeting therapies mitigate the progression of cognitive decline in early-stage Alzheimer’s disease, they are associated with amyloid-related imaging abnormalities (ARIA), an imaging phenomenon presenting as cerebral edema/effusion and/or hemorrhage. Redistribution of parenchymal amyloid-β to perivascular drainage pathways and direct antibody-amyloid interactions within the cerebral vasculature are considered key players in ARIA pathophysiology by promoting inflammation and vascular disruption, thus mirroring hallmarks of inflammatory cerebral amyloid angiopathy. Although ARIA is commonly regarded as an undesired side effect of amyloid-targeting therapies, its association with amyloid-β clearance from the brain opens up the possibility of an alternative interpretation as a physiological reaction to target engagement of anti-amyloid antibodies.Understanding risk factors that promote the occurrence of ARIA and its transformation from asymptomatic imaging phenomenon to its serious and severe form are of great importance to clinical practice. ARIA risk and severity are influenced by apolipoprotein E4 status, microvascular damage, and cerebral amyloid angiopathy, but may be further modulated by antibody binding preferences and comorbidities such as arterial hypertension and ischemic strokes. Identifying individual risk profiles based on deeper insights into pathophysiological pathways may improve patient safety and lead to personalized treatment concepts in Alzheimer’s disease.In this review, we provide a comprehensive summary of ARIA pathophysiology, highlight important risk factors and discuss their relevance in clinical risk management.}, } @article {pmid41904723, year = {2026}, author = {Yang, Q and Ren, X and Jia, R and Zheng, L and Ou, R and Xu, Y and Luo, Y and Yang, G and Wang, X}, title = {Programmed cell death: a promising management for Alzheimer's disease.}, journal = {Apoptosis : an international journal on programmed cell death}, volume = {31}, number = {4}, pages = {}, pmid = {41904723}, issn = {1573-675X}, support = {ZRY2022J007//Seed Foundation of Zhejiang Provincial People's Hospital/ ; 82302918//National Natural Science Foundation of China/ ; 2024KY758//Medical and Health Research Project of Zhejiang province/ ; 2025HY0772//Medical and Health Research Project of Zhejiang province/ ; 2025HY0770//Medical and Health Research Project of Zhejiang province/ ; LQ24H160044//Natural Science Foundation of Zhejiang Province/ ; QN26H160024//Natural Science Foundation of Zhejiang Province/ ; 2024WJC187//Hangzhou Biomedical and Health Industry Development Support Science and Technology Special/ ; 2022WJC232//Hangzhou Biomedical and Health Industry Development Support Science and Technology Special/ ; 2024WJC072//Hangzhou Biomedical and Health Industry Development Support Science and Technology Special/ ; 2026ZL0638//Zhejiang Province Traditional Chinese Medicine Science and Technology Project/ ; LHZQN26H160006//Hangzhou Joint Fund of Zhejiang Provincial Natural Science Foundation of China/ ; }, mesh = {*Alzheimer Disease/pathology/therapy/diagnosis/metabolism/genetics ; Humans ; *Apoptosis/genetics ; Cuproptosis ; Autophagy/genetics ; Animals ; Disulfidptosis ; Biomarkers/metabolism ; Necroptosis/genetics ; Ferroptosis/genetics ; Pyroptosis/genetics ; Parthanatos ; }, abstract = {Epidemiological investigations have indicated that Alzheimer's disease (AD) has emerged as a predominant health challenge among older adults, with its mortality rate rising sharply each year. Nevertheless, measures capable of delaying or halting its clinical progression have remained largely unattained until recent years. Programmed cell death (PCD), defined as a genetically regulated and orderly mode of cellular demise, is pervasive throughout organismal development and essential for maintaining life homeostasis. As research on PCD in AD has expanded, accumulating evidence has shown that autophagy, ferroptosis, cuproptosis, pyroptosis, necroptosis, parthanatos, NETosis, disulfidptosis, and oxeiptosis are intimately linked to the onset, progression, and prognosis of AD. This review synthesizes recent advances regarding the application of PCD in biomarker identification and therapeutic innovation to enhance AD diagnosis and management. Additionally, challenges and emerging opportunities in employing PCD as novel management strategies are examined, with the overarching aim of transitioning from treatment toward prevention.}, } @article {pmid41905544, year = {2026}, author = {Simpson, D and Morrone, CD and Wear, D and Khani, A and Liu, F and Gutierrez, J and Yu, WH}, title = {Neurovascular large artery dilatation increases the risk for Alzheimer's disease pathology.}, journal = {Neurobiology of disease}, volume = {223}, number = {}, pages = {107368}, doi = {10.1016/j.nbd.2026.107368}, pmid = {41905544}, issn = {1095-953X}, support = {R01 AG066162/AG/NIA NIH HHS/United States ; }, mesh = {Animals ; *Alzheimer Disease/pathology/metabolism ; Mice ; Plaque, Amyloid/pathology ; Mice, Transgenic ; Dilatation, Pathologic/pathology ; Disease Models, Animal ; *Cerebral Arteries/pathology ; Male ; *Brain/pathology ; }, abstract = {Alzheimer's disease and related dementias are increasing globally, highlighting the urgent need to clarify disease mechanisms to improve diagnosis and treatment. Vascular alterations are a major pathological feature of Alzheimer's disease. Beyond the established contributions of small vessel disease and large artery atherosclerosis, our group has shown that dilatation of large cerebral arteries is associated with an increased risk of dementia and Alzheimer's pathology. The most severe manifestation of this non-atherosclerotic vascular phenotype is dolichoectasia, characterized by abnormal enlargement of large blood vessels. Despite consistent epidemiological evidence, the mechanisms linking arterial dilatation to Alzheimer's disease pathology remain poorly understood. To address this gap, we induced large artery dilatation in homozygous App[NL-G-F] mice, a model of amyloid pathology, by injecting elastase into the cisterna magna. Mice were euthanized at 9 months and brains were analyzed using biochemical and immunohistochemical approaches. Elastase-treated mice showed a significant increase in amyloid plaque burden in the hippocampus and cortex compared with vehicle-treated controls. Neuronal loss was observed in the CA1 region of the hippocampus, with a similar trend in CA3. Markers of impaired autophagic-lysosomal clearance were elevated in both hippocampal and cortical regions, while neuroinflammation and astrogliosis were unchanged. In contrast, matrix metalloproteinase-9 (MMP-9) levels were significantly increased. Overall, this study establishes a novel mixed vascular-neurodegenerative pathology model by inducing large artery dilatation in an amyloid mouse model. Our findings demonstrate that vascular dilatation accelerates Alzheimer's disease-related pathology and provide a platform to investigate underlying mechanisms and potential therapeutic targets for mixed dementia.}, } @article {pmid41905660, year = {2026}, author = {VanGilder, JL and Hooyman, A and Hakhu, S and Schilling, KG and Hu, LS and Zhou, Y and Caselli, RJ and Baxter, LC and Beeman, SC}, title = {Using diffusion MRI to relate hippocampal subfield microstructure to delayed verbal memory in cognitively intact individuals at genetic risk for developing Alzheimer's disease.}, journal = {Experimental gerontology}, volume = {218}, number = {}, pages = {113112}, pmid = {41905660}, issn = {1873-6815}, support = {P30 AG072980/AG/NIA NIH HHS/United States ; R01 AG069453/AG/NIA NIH HHS/United States ; }, mesh = {Humans ; *Alzheimer Disease/genetics/psychology/pathology ; *Hippocampus/pathology/diagnostic imaging ; Male ; Female ; Aged ; *Diffusion Magnetic Resonance Imaging/methods ; Apolipoprotein E4/genetics ; Genetic Predisposition to Disease ; *Cognition/physiology ; Middle Aged ; Neuropsychological Tests ; *Verbal Learning ; Heterozygote ; *Memory ; Risk Factors ; Diffusion Tensor Imaging ; }, abstract = {Intervention to delay the onset of Alzheimer's disease (AD) is an important treatment strategy but detecting at-risk individuals before significant disease progression remains challenging. This study evaluates the relationship between hippocampal microstructure and verbal cognition in cognitively intact older adults, focusing on the differences between APOΕ ε4 allele carriers and noncarriers. Participants (n = 41 noncarriers, 33 carriers) over 60 years old (mean ± SD: carriers 71 ± 6.6; noncarriers 71 ± 6.4 years) underwent diffusion-weighted magnetic resonance imaging (dMRI) and volumetric assessments. We assessed hippocampal structure, including microstructure, using Neurite Orientation Dispersion and Density Imaging (NODDI), diffusion tensor imaging (DTI), and volumetric measures. Regression analyses examined the relationship between these hippocampal measures and verbal and visuospatial cognition, as evaluated by the Rey delayed recall tests, i.e., the Auditory Verbal Learning Test (AVLT) and Complex Figure Test (CFT), respectively. Results indicated that while volumetric data showed no significant findings, microstructural measures, particularly orientation dispersion (ODI) in the left subiculum, were positively associated with verbal recall in APOΕ ε4 carriers (p = 0.0011; Bonferroni-corrected alpha = 0.005). These findings suggest that hippocampal microstructure, rather than volume, may provide insights into cognitive decline in individuals at genetic risk for AD.}, } @article {pmid41905824, year = {2026}, author = {Fremont, R and Karim, A and Estevez, TP and McDonough, C and LaBarbiera, A and Feder, A and Naasan, G and Delgado, A and Charney, DS and Murrough, JW}, title = {KET-MCI: A Pilot Safety and Tolerability Study of Single Infusion Intravenous Ketamine for Older Adults with Depression and Mild Cognitive Impairment.}, journal = {The American journal of geriatric psychiatry : official journal of the American Association for Geriatric Psychiatry}, volume = {34}, number = {7}, pages = {899-910}, doi = {10.1016/j.jagp.2026.02.005}, pmid = {41905824}, issn = {1545-7214}, mesh = {Humans ; *Ketamine/administration & dosage/adverse effects/pharmacology ; Pilot Projects ; *Cognitive Dysfunction/drug therapy/complications ; Infusions, Intravenous ; Aged ; *Major Depressive Disorder/drug therapy/complications ; Female ; Male ; *Antidepressive Agents/administration & dosage/adverse effects ; Aged, 80 and over ; }, abstract = {OBJECTIVE: This open-label clinical trial primarily examined the safety and tolerability of ketamine treatment in patients with mild cognitive impairment and Major Depressive Disorder (MCI-D). Preliminary efficacy was also explored.

METHODS: The trial was conducted between November 2023 and March 2025. Patients with MCI-D and moderate to severe symptom levels of depression received a single intravenous ketamine infusion (0.5 mg/kg). Safety and tolerability were evaluated. Antidepressant efficacy was also explored by evaluating change in the Montgomery-Asberg Depression Rating Scale (MADRS) scores from baseline to 24 hours after the infusion.

RESULTS: Thirteen eligible patients received treatment and completed study procedures. No serious adverse events were reported and all participants tolerated study procedures. The treatment was associated with large-magnitude improvement in depression symptom severity from baseline (mean MADRS = 27.4[SD = 6.4]) to 24 hours after the infusion (mean MADRS = 5.7[SD = 4.7]) in all patients with improvements in MADRS persisting for 8 individuals up to 1 month after treatment (mean MADRS = 12.1[SD = 6.9], ≥50% improvement).

CONCLUSIONS: Findings from this open-label clinical trial support the safety and tolerability of ketamine treatment is in individuals with MCI-D. Ketamine may also be effective for improving depression in this population. Large-scale randomized controlled trials are needed to determine the efficacy and potential cognitive effects of this promising treatment in this patient population.}, } @article {pmid41906135, year = {2026}, author = {Yang, R and He, Y and Pan, Y and Geng, A and Huang, F and Guo, K and Zhang, H}, title = {Multiparity exacerbates Aβ accumulation and promotes cellular senescence in a mouse model of amyloidosis.}, journal = {Immunity & ageing : I & A}, volume = {23}, number = {1}, pages = {}, pmid = {41906135}, issn = {1742-4933}, support = {82271472//the National Natural Science Foundation of China grants/ ; }, abstract = {BACKGROUND: Women have nearly twice the lifetime risk of Alzheimer’s disease (AD) as men. Hormonal and reproductive factors have been implicated; however, the role of parity, a female-specific experience, remains unknown. While epidemiological data suggest that high parity may increase the risk of dementia, the underlying biological mechanisms are unclear. METHODS: We investigated the impact of multiparity on AD pathology using 2-month-old female 5xFAD mice. Mice were assigned to a nulliparous (0x) or multiparous (4x) (four consecutive gestation cycles) group. Brain tissues were analyzed at 6.4 months of age for Aβ pathology, neuroinflammation, synaptic markers, and senescence. Proteomic profiling and in vitro hormone treatment identified the key mediators. The role of voluntary running was assessed in a separate cohort of nulliparous mice. RESULTS: Multiparous 5xFAD mice showed increased Aβ plaque burden, elevated BACE1 expression, synaptic loss, and activated senescence pathways compared to nulliparous controls. Proteomic analysis revealed sustained upregulation of the transcription factor FOSB. FOSB was found to drive BACE1 expression and Aβ production. In vitro co-treatment with estradiol and progesterone increased FOSB and BACE1 levels, supporting the presence of a hormone-responsive regulatory link. In nulliparous female 5xFAD mice, voluntary running from 2 to 6 months of age reduced Aβ deposition, fewer FOSB+ neurons, and microglial activation compared with those in the sedentary controls. CONCLUSIONS: Our findings identified the FOSB/BACE1 signaling axis as a link between reproductive history and AD pathology. Multiparity accelerates amyloid pathology and brain aging in female 5xFAD mice, mechanistically linked to hormone-driven FOSB upregulation. Physical activity downregulates this pathway in nulliparous animals. Whether exercise can mitigate parity-associated pathology remains to be investigated in multiparous animal models.}, } @article {pmid41906332, year = {2026}, author = {Park, I and Lee, D and Hong, RS and Kim, HY and Kim, Y}, title = {Small Molecule Therapeutics Targeting Amyloid-β in Alzheimer's Disease: Mechanisms, Clinical Progress, and Future Strategies.}, journal = {Experimental neurobiology}, volume = {35}, number = {2}, pages = {57-80}, pmid = {41906332}, issn = {1226-2560}, abstract = {Alzheimer's disease (AD) imposes a growing burden on global healthcare systems. Current therapeutic interventions primarily alleviate cognitive and functional symptoms but have limited impact on the underlying neurodegenerative processes driving disease progression. This underscores the urgent need for treatments that target the pathogenic mechanisms of the disease. Advances in monoclonal antibody therapies against amyloid-β (Aβ) provide encouraging evidence for disease modification, though challenges related to dosing, cost, and safety constrain their broader application. Small molecule therapeutics represent a compelling alternative owing to advantageous properties such as enhanced brain penetration, oral bioavailability, and suitability for long-term administration in elderly patients. Building on these attributes, this review evaluates small molecule therapeutics as promising candidates for AD treatment. It summarizes small molecule compounds targeting Aβ across mechanisms that include modulating production, inhibiting aggregation, disassembling aggregates, enhancing clearance, and mitigating neurotoxicity. A comprehensive assessment of current data emphasizes the importance of continued research to overcome ongoing challenges and fully leverage the potential of small molecules. The limited number of candidates in late-stage clinical trials indicates that substantial efforts are still required to identify and refine effective agents. Continued investigation into their mechanisms and optimization of compound profiles will advance the development of small molecule-based therapies for AD.}, } @article {pmid41908799, year = {2025}, author = {Feng, JX and Zheng, MQ and Tian, X and Zimmermann, A and Wang, AX and Meng, X}, title = {Ginkgo biloba extract EGb 761 in patients with dementia and a history of cerebral infarction-meta-analysis of pooled data from randomised clinical trials.}, journal = {Frontiers in neurology}, volume = {16}, number = {}, pages = {1658064}, pmid = {41908799}, issn = {1664-2295}, abstract = {INTRODUCTION: Ginkgo biloba leaf extracts belong to the most popular herbal medicines for the treatment of neurological disorders, including Alzheimer's disease (AD) or stroke. EGb 761, a proprietary ginkgo leaf extract, has been shown to improve brain cell energy supply, to enhance neurogenesis and neuroplasticity, to decrease blood viscosity and improve brain perfusion. Thereby it improves cognitive performance, neuropsychiatric symptoms and activities of daily living in patients with dementia or mild cognitive impairment. It has further been shown to be beneficial for patients after ischaemic stroke. Therefore, the aim of this meta-analysis was to evaluate the treatment effects of EGb 761 in patients who had developed dementia following a cerebral infarction.

METHODS: We performed a meta-analysis of pooled data from clinical trials with EGb 761 in mild to moderate dementia in the subgroup of patients who had a cerebral infarction. Four randomised, placebo-controlled trials with homogeneous patient selection and design were included. Previous stroke was diagnosed by neuroimaging. The analysis focused on the comparison of treatment effects in the domains of cognition, activities of daily living and global assessment.

RESULTS: The meta-analysis included data from 488 patients. Significant treatment effects of 240 mg EGb 761 daily versus placebo were found for cognition (p = 0.0467), activities of daily living (p = 0.0230), and global clinical impression (p = 0.0371). The rates of adverse events and adverse drug reactions in the EGb 761 group were like those in the placebo group.

CONCLUSION: The results of our meta-analysis of patients with mild to moderate dementia who had previously had a cerebral infarction verified by neuroimaging showed statistically significant and clinically relevant benefits of EGb 761. The drug was shown to be safe and well tolerated and is a promising treatment option for patients developing dementia after cerebral infarction. Further dedicated clinical trials are needed to confirm these results.}, } @article {pmid41909522, year = {2026}, author = {Salini Jancy Rani, A and Balamurugan, BJ}, title = {Novel Roman domination-based graph energies for QSPR analysis of neuroprotective herbal compounds in Alzheimer's disease treatment.}, journal = {Frontiers in chemistry}, volume = {14}, number = {}, pages = {1731656}, pmid = {41909522}, issn = {2296-2646}, abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder for which U.S. Food and Drug Administration (FDA)-approved drugs provide only temporary symptomatic relief and often cause adverse effects. Plant-derived bioactive phytochemicals are emerging as promising alternatives due to their multi-targeted neuroprotective properties and reduced toxicity. In this article, herbal anti-Alzheimer's compounds are analyzed using a novel graph molecular modeling. In chemical graph theory, molecular structures are represented as isomorphic molecular graphs G V , E , where V and E denote the set of vertices (atoms) and edges (chemical bonds) respectively. Classical graph matrices such as adjacency and Laplacian matrices capture the molecular connectivity but fail to account for hierarchical differences in atomic influence. To address this limitation, Roman domination is employed to represent the hierarchical dominance of atoms within molecular structures. A Roman domination function (RDF) on a graph G V , E is a mapping f : V → 0 , 1 , 2 such that every atom v with f v = 0 has at least one adjacent atom u with f u = 2 , reflecting the hierarchical dominance within the isomorphic molecular graph. Based on this principle, the Roman domination-based matrices and corresponding graph energies are introduced in this article. Quantitative Structure-Property Relationship (QSPR) graph models are developed using the Roman energies through linear, quadratic and cubic regression analysis. The results demonstrate superior performance compared to classical approaches, with the quadratic regression showing the strongest correlations and lowest standard error. Internal validation through the Y-randomization and Leave-One-Out Cross-Validation methods confirmed the stability of the models, while external validation on the herbal compound Kaempferol (r = 0.993) further supported their predictive reliability. These findings underscore the robustness of Roman energies, establishing them as powerful molecular descriptors that offer enhanced accuracy in the QSPR analysis and hold promise for applications in drug design, materials informatics and computational chemistry.}, } @article {pmid41910461, year = {2026}, author = {Kong, X and Han, R and Fan, X and Wei, K and Ma, Z and Yang, G and Zhao, Y and Yang, Y and Yang, Y and Hong, J and Liu, J and Zhang, D and Ma, X}, title = {Acupuncture as an adjunct therapy for mild Alzheimer's disease: A randomized clinical trial.}, journal = {Journal of Alzheimer's disease : JAD}, volume = {111}, number = {2}, pages = {757-767}, doi = {10.1177/13872877261435880}, pmid = {41910461}, issn = {1875-8908}, mesh = {Humans ; *Alzheimer Disease/therapy/psychology/drug therapy ; Female ; Male ; *Acupuncture Therapy/methods ; Single-Blind Method ; Aged ; Donepezil/therapeutic use ; *Cholinesterase Inhibitors/therapeutic use ; Treatment Outcome ; Aged, 80 and over ; Combined Modality Therapy ; Indans/therapeutic use ; Piperidines/therapeutic use ; Neuropsychological Tests ; }, abstract = {BackgroundPreclinical studies suggest acupuncture may offer symptomatic relief or modify disease progression in Alzheimer's disease (AD), yet clinical evidence remains limited.ObjectiveThis study evaluated whether adding acupuncture to cholinesterase inhibitors improves outcomes in patients with mild AD and whether any benefits persist after treatment ends.MethodsIn this randomized, single-blind trial, participants with mild AD received either active or sham acupuncture three times per week for 14 weeks in addition to ongoing donepezil therapy, followed by a 14-week washout phase during which acupuncture was discontinued while donepezil was maintained. The primary outcome was change in Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-cog12) from baseline.ResultsA total of 160 participants were enrolled, and 157 were included in the primary analysis (78 active, 79 sham). At week 14, the mean change in ADAS-cog12 was -1.20 for the active acupuncture group versus 0.36 for the sham acupuncture group, yielding a difference of -1.50 (p < 0.001). After washout, no significant difference remained (difference, -0.31; p = 0.54). Adverse events occurred in 37.2% of the active and 45.6% of the sham group. Donepezil-related adverse events were less frequent with active acupuncture (6.4% versus 16.5%; p < 0.05).ConclusionsAcupuncture, when added to donepezil, improved cognition during active treatment and was associated with fewer cholinergic side effects in patients with mild AD. The cognitive benefits did not persist after acupuncture was discontinued, suggesting that acupuncture serves as an adjunctive symptomatic therapy rather than a disease-modifying intervention.Trial registrationClinicalTrials.gov [NCT05078944].}, } @article {pmid41910814, year = {2026}, author = {Tripathi, P and Shah, J}, title = {Vitamin D3 Attenuates Alzheimer's Disease-Like Pathology via Remodeling Amyloid Protein Production and Clearance Pathway in Wistar Rats.}, journal = {Neurochemical research}, volume = {51}, number = {2}, pages = {}, pmid = {41910814}, issn = {1573-6903}, support = {GSBTM/MD/PROJECTS/SSA/4887/2016-17//Gujarat State Biotechnology Mission, Government of Gujarat, India/ ; }, mesh = {Animals ; *Alzheimer Disease/metabolism/drug therapy/pathology/chemically induced ; *Cholecalciferol/therapeutic use/pharmacology ; *Amyloid beta-Peptides/metabolism ; Rats, Wistar ; Male ; Rats ; tau Proteins/metabolism ; Peptide Fragments/metabolism ; Hippocampus/drug effects/metabolism/pathology ; }, abstract = {Alzheimer's disease widely affects millions of people worldwide, accounting for 60% of dementia cases. Clinically classified by the presence of cognition impairment, pathophysiological representation includes deposited senile plaques, neurofibrillary tangles, and neuroinflammation. The pathogenesis of Alzheimer's disease (AD) remains multifaceted and is governed by multiple hypotheses. However, it undeniably involves amyloid-β (Aβ) accumulation and hyperphosphorylated tau (p-tau) pathology as the crucial events in disease initiation. Substantial evidence has correlated Vitamin D3 as a vital supplementation for the prevention of dementia and delays the progression of AD. The presence of localized Vitamin D receptors (VDR) in the brain and their capacity to convert absorbed Vitamin D to its active form have established a robust link between Vitamin D3 and Alzheimer's disease. The current study aims to explore the role of Vitamin D3 on specific parameters related to Alzheimer's disease in the Streptozotocin ICV-induced sporadic AD rat model. The study protocol included a single bilateral ICV STZ intrahippocampal injection to induce AD, followed by 21 days of treatment with two different doses of Vitamin D3 or Calcitriol (1alpha,25-dihydroxyvitamin D3)i.e., 2.5 μg/kg and 5.0 μg/kg. Results demonstrated that Vitamin D3 attenuates AD-specific parameters of amyloid plaque (Aβ1-40 and Aβ1-42), p-tau, and BACE-1. Moreover, a significant increase in the levels of both neprilysin (NEP) and insulin-degrading enzyme (IDE) was observed, both of which play a crucial role in the clearance of senile plaques. Vitamin D3 treatment also demonstrated a significant improvement in cognitive performance, along with attenuation of neuroinflammatory and oxidative stress parameters. Conclusively, optimal levels of Vitamin D3 impart neuroprotection in AD by attenuating production and increasing clearance of amyloid proteins.}, } @article {pmid41910845, year = {2026}, author = {Nekabari, MK and Ben-Azu, B and Chijioke, BS and Esuku, DT and Chidebe, EO and Friday, FB and Usin, SG and Iwhiwhu, P and Moses, AS and Diakparomre, O and Onyeukwu, OB}, title = {Lipopolysaccharide-induced Neuroimmune Alteration and Memory Decline in Aging Mice: The Role of Augmented Cellular Senescence.}, journal = {Neurotoxicity research}, volume = {44}, number = {2}, pages = {}, pmid = {41910845}, issn = {1476-3524}, mesh = {Animals ; *Lipopolysaccharides/toxicity ; *Aging/drug effects/immunology/metabolism/psychology ; Male ; Mice ; *Memory Disorders/chemically induced/metabolism ; *Cellular Senescence/drug effects/physiology ; Oxidative Stress/drug effects ; Doxycycline/toxicity ; *Neuroinflammatory Diseases/chemically induced/metabolism ; Alzheimer Disease/metabolism/chemically induced ; Hippocampus/metabolism/drug effects ; }, abstract = {Alzheimer’s disease (AD) remains a complex neurodegenerative disorder with multifactorial etiologies, often eluding effective modeling in preclinical studies. However, whether neuroinflammation, exacerbated by accelerated cellular senescence, is central to AD pathology induced by lipopolysaccharide, an endotoxemia agent, remains unknown. This study investigated a combination of lipopolysaccharide (LPS)-induced AD-like neuroinflammation with doxycycline-induced conditioned cellular senescence in mice. Following a 21-day doxycycline (DOXY)-induced cellular senescence in mice, neuroinflammation was induced by LPS from days 15–21. AD-related cognitive decline was investigated through spatial and non-spatial memory tests, oxidative stress, molybdoenzymes, acetylcholinesterase activity, inflammation, amyloid-beta levels, hypoxia-inducible factor (HIF-α) and brain-derived neurotrophic factors (BDNF) in brain regions affected by AD pathology, such as the hippocampus and prefrontal cortex (PFC). Behavioral assessments revealed that both LPS and DOXY independently impaired spatial and non-spatial working memory, locomotor activity, social interaction, and recognition memory, with their interactive treatment exacerbating these deficits significantly. Biochemical analyses revealed synergistic increases in pro-inflammatory cytokines (IL-1β, TNF-α, but not IL-4), oxidative stress markers (malondialdehyde, nitrite), astrocyte activation (GFAP), and amyloid-beta levels, with decreases in antioxidant defenses (GSH, GST, SOD, catalase) in the hippocampus and PFC. The DOXY + LPS group showed higher serum corticosterone levels, increased sulphite-oxidase in the PFC, and increased xanthine-oxidase and acetylcholinesterase in both regions, indicating an amplified stress response and cholinergic dysfunction. Conversely, DOXY + LPS interaction lowered hippocampal-targeted BDNF and HIF-α levels. These findings validate the role of cellular senescence in enhancing LPS-induced neuroinflammation, mimicking complex AD features, and provide a model for testing disease mechanisms and therapeutics.}, } @article {pmid41910849, year = {2026}, author = {Akram, SW and K, C}, title = {Enhancing Parkinson's Disease Staging: An Integrative Deep Learning Framework for Multimodal Feature Selection.}, journal = {Journal of molecular neuroscience : MN}, volume = {76}, number = {2}, pages = {}, pmid = {41910849}, issn = {1559-1166}, mesh = {Humans ; *Parkinson Disease/diagnostic imaging/genetics/diagnosis/pathology ; *Deep Learning ; Neuroimaging/methods ; Multilayer Perceptrons ; Support Vector Machine ; Particle Swarm Optimization ; }, abstract = {Parkinson's disease (PD) affects 10 million globally, with accurate staging essential for personalized treatment planning. Current UPDRS assessments achieve < 93% accuracy due to subjective clinical judgment and unimodal data limitations, failing to capture complex genetic-neuroimaging-clinical interactions driving disease heterogeneity. This study introduces MAFNet, a novel deep learning framework pioneering Iterative Adaptive Vold-Kalman Filter (IAVKF) temporal denoising, Accelerated Binary Particle Swarm Optimization (ABPSO) swarm feature selection, Multilayer Perceptron-Lagrangian Support Vector Machine (MLP-LSVM) classification, and Graph-Attention Based Multimodal Fusion Network (GAMF). Applied to PPMI cohort (200 patients) with genetic SNPs (50), neuroimaging voxels (1,024), and UPDRS-III scores, the end-to-end pipeline delivers 97.6% accuracy, 98.2% precision, 96.8% recall, and 97.3% F1-score-outperforming CNN (92.4%), Autoencoder (90.8%), InceptoFormer (96.6%), and HCT (97.0%). IAVKF boosts SNR + 15.2dB (+ 2.9% accuracy vs. PCA/t-SNE); ABPSO reduces 1,276→340 features (73% reduction); regularization cuts overfitting gap to 0.9% (vs. 4.2% baseline). SHAP interpretability validates clinical plausibility (top predictors: LRRK2 SNPs, UPDRS-III tremor, hippocampal volume). Five-fold CV confirms stability with the Indian cohort external validation. Real-time inference (0.2s/patient, RTX 3090) enables clinical deployment. Future scope includes longitudinal temporal modelling, modality-agnostic fusion, edge deployment, federated learning, and extension to Alzheimer's/ALS. MAFNet transforms PD staging from subjective assessments to objective precision medicine, enabling biomarker discovery, progression forecasting, and personalized therapies across diverse global populations.}, } @article {pmid41910964, year = {2026}, author = {Banerjee, G and Mok, TH and Hyare, H and Cousins, O and Jaunmuktane, Z and Mead, S and Collinge, J}, title = {High-Level Alzheimer Disease Neuropathological Change Following Iatrogenic Exposure.}, journal = {JAMA neurology}, volume = {83}, number = {5}, pages = {435-441}, pmid = {41910964}, issn = {2168-6157}, mesh = {Humans ; *Alzheimer Disease/pathology/chemically induced ; Male ; *Iatrogenic Disease ; Middle Aged ; Amyloid beta-Peptides/metabolism ; *Human Growth Hormone/adverse effects ; Aged ; *Brain/pathology ; }, abstract = {IMPORTANCE: Alzheimer disease (AD) is pathologically characterized by the deposition of amyloid-β (Aβ) and hyperphosphorylated tau. Human transmission of Aβ pathology in a prion-like fashion has resulted in iatrogenic cerebral amyloid angiopathy. More recently, iatrogenic Alzheimer disease (iAD) was described in recipients of cadaveric pituitary-derived human growth hormone (c-hGH) contaminated with Aβ amyloid seeds.

OBJECTIVE: To describe the clinical and postmortem findings in iAD.

This case series describes 4 c-hGH recipients who were referred to the UK National Prion Clinic. Between February 2024 and February 2025, 14 c-hGH recipients had been referred to this service, with clinical assessments ongoing. The current study included 4 of 14 people treated with c-hGH who were referred since the original report. These data were analyzed during February and March 2025.

EXPOSURE: c-hGH contaminated with Aβ amyloid seeds.

MAIN OUTCOMES AND MEASURES: Clinical and histopathological description.

RESULTS: The study describes 4 males who developed dementia following confirmed or suspected c-hGH treatment in childhood (age at symptom onset between 47 and 60 years) with cognitive syndromes characterized by prominent language involvement. Results include clinical and postmortem findings for 1 patient (onset at age 47 years) in whom postmortem examination (at age 57 years) showed unequivocal neuropathological features of AD, including severe tauopathy. Brief descriptions of 3 additional patients with prominent language involvement are also provided.

CONCLUSIONS AND RELEVANCE: These results demonstrate that patients with iAD can have histopathological findings classically found in sporadic AD and that prominent language involvement might be an important phenotypic feature in this AD subtype.}, } @article {pmid41910973, year = {2026}, author = {Grill, JD and Raman, R and Wang, S and Ernstrom, K and Andrews, PS and Appleby, BS and Bhangu, J and Dhadda, S and Irizarry, M and Johnson, K and Lenio, S and MacDonald, S and Ramanan, VK and Rosenberg, PB and Weisman, D and Aisen, P and Sperling, R and Sultzer, D and Karlawish, J}, title = {Amyloid Imaging and APOE Genotype Disclosure and Short-Term Psychological Distress.}, journal = {JAMA network open}, volume = {9}, number = {3}, pages = {e263845}, pmid = {41910973}, issn = {2574-3805}, mesh = {Humans ; Female ; Male ; Aged ; *Alzheimer Disease/genetics/diagnostic imaging/psychology ; Middle Aged ; Return of Individual Research Results ; *Apolipoproteins E/genetics ; Genotype ; Aged, 80 and over ; *Stress, Psychological/psychology/etiology ; Biomarkers ; Positron-Emission Tomography ; Cohort Studies ; }, abstract = {IMPORTANCE: Alzheimer disease (AD) biomarker and genetic testing results are increasingly disclosed to cognitively unimpaired adults in research and could in the future inform clinical treatment decisions in this population.

OBJECTIVES: To assess psychological outcomes after returning 3 categories of amyloid biomarker results as well as apolipoprotein E (APOE) genotypes.

This cohort study was a secondary analysis of data collected as part of screening for the multisite AHEAD preclinical AD trial. Participants were individuals aged 55 to 80 years undergoing screening from July 14, 2020, to October 15, 2024.

EXPOSURE: Participants were informed whether they had not-detected, intermediate, or elevated amyloid positron emission tomography levels, as well as their APOE genotype, which were categorized as noncarrier, ε4 heterozygote, or ε4 homozygote.

MAIN OUTCOMES AND MEASURES: Impact of Events Scale (IES; 15 items to assess intrusive thoughts and avoidance; each item is scored as not at all [0], rarely [1], sometimes [3], or often [5]; total range, 0-75), collected 24 to 72 hours after disclosure, and change in a scale measuring concerns about AD dementia (adapted scale using 6 items in which participants indicated their level of agreement with statements related to their perceived probability of developing AD dementia; items scored as strongly disagree [1] through strongly agree [5]; total range, 6-30), calculated by subtracting the score collected before biomarker testing from 1 collected after biomarker and genetic test results disclosure.

RESULTS: Among 3414 included individuals, the mean (SD) age was 68.8 (6.0) years and 2116 (62%) were female. Group mean IES scores were below clinically significant thresholds. Nevertheless, across genetic groups, learning an elevated amyloid result (1184 participants) was associated with higher IES (mean [SD], 10.5 [10.9]) than intermediate amyloid (482 participants; mean [SD] IES, 8.8 [9.8]), and intermediate amyloid was associated with higher scores than not-detected amyloid (1748 participants; mean [SD] IES, 6.5 [8.4]). Across amyloid groups, learning APOE ε4 homozygosity (337 participants) was associated with higher mean (SD) IES (12.7 [11.6]) than heterozygosity (1609 participants; 9.1 [10.2]), and heterozygosity was associated with higher IES than noncarrier status (1468 participants; mean [SD] IES, 6.2 [8.1]). Both types of information were significant in an analysis of covariance model; no interaction effect was observed. In contrast, only biomarker disclosure was associated with differential change in concerns about AD dementia. Those with elevated amyloid showed a mean (SD) increase in concern (0.8 [3.5]), those with intermediate amyloid showed a smaller increase (0.4 [3.7]), and those with not-detected amyloid showed decreased concerns (-1.1 [4.2]).

CONCLUSIONS AND RELEVANCE: In this cohort study of cognitively unimpaired adults, associations with intrusive thoughts were observed to differ among genetic and biomarker subgroups; such associations were limited to biomarker subgroups for measures of perceived dementia risk.}, } @article {pmid41911040, year = {2026}, author = {Kaur, P and Kumari, S and Singh, AK and Koley, T and Rai, N and Samath, EA and Dey, S}, title = {Targeting GSK3β with a Synthetic Small Molecule Rescues Neurotoxicity in a Cellular Model of Alzheimer's Disease.}, journal = {ACS chemical neuroscience}, volume = {17}, number = {8}, pages = {1505-1515}, doi = {10.1021/acschemneuro.5c00772}, pmid = {41911040}, issn = {1948-7193}, mesh = {Humans ; *Glycogen Synthase Kinase 3 beta/metabolism/antagonists & inhibitors ; *Alzheimer Disease/metabolism/drug therapy ; Cell Line, Tumor ; tau Proteins/metabolism ; Amyloid beta-Peptides/metabolism ; *Neuroprotective Agents/pharmacology ; *Oligopeptides/pharmacology ; Molecular Docking Simulation ; }, abstract = {The neuropathological presentation of Alzheimer's disease (AD) constitutes amyloid-β plaques and Tau tangles. Activation of GSK3β contributes to neurodegeneration by directly promoting tau hyperphosphorylation and amyloid-β formation. An earlier study also reported the overexpression of GSK3β in AD patients. This work designed and synthesized tetrapeptides [VYS(p)W, AKS(p)F, and DKS(p)F] containing a phosphate group attached to the serine residue, which mimicked the primed phosphorylated substrate of GSK3β. According to the network study, through interaction with various proteins and alteration of the molecular pathway of AD, the DKS(p)F peptide may exhibit a wide range of effects. The binding study of the peptide was performed by label-free surface plasmon resonance. The rescue effect of peptide on neurotoxicity was measured by MTT assay in SH-SY5Y cells. The peptide DKS(p)F was found to have the best docking score and binding energy with GSK3β. The low dissociation constant, (9.58 × 10[-8] M), indicates strongest binding capacity with GSK3β. The reduction in neurotoxicity of SH-SY5Y cells was observed after treatment with DKS(p)F by suppressing the levels of amyloid-β, Tau, and p-Tau proteins. This peptide can be one of the promising molecules for ongoing efforts to develop therapeutic molecules for the neurodegenerative disorder of Alzheimer's disease.}, } @article {pmid41911320, year = {2026}, author = {Ali, S and Kuo, YF and Shan, Y and Tzeng, HM and Raji, MA}, title = {Impact of annual wellness visits on preventing falls and fractures for Alzheimer's disease and related dementias older adults.}, journal = {Age and ageing}, volume = {55}, number = {3}, pages = {}, pmid = {41911320}, issn = {1468-2834}, support = {R01 AG083102/AG/NIA NIH HHS/United States ; }, mesh = {Humans ; *Accidental Falls/prevention & control/statistics & numerical data ; Aged ; Female ; Male ; United States/epidemiology ; Aged, 80 and over ; *Fractures, Bone/prevention & control/epidemiology/etiology ; *Alzheimer Disease/complications ; Risk Factors ; Medicare/statistics & numerical data ; *Dementia/complications ; Risk Assessment ; }, abstract = {BACKGROUND: Falls and fractures are leading causes of disability and premature death among older adults with Alzheimer's Disease and Related Dementias (ADRD). Annual Wellness Visits (AWVs), which Medicare reimburses, can screen and manage fall/fracture-related risk factors. This study evaluates the association between AWV and falls/fractures prevention among Medicare beneficiaries with ADRD.

METHODS: We analysed a cohort of Medicare beneficiaries in 2017 aged ≥68 years with ADRD and continuous enrollment from 2014 to 2016 (n = 1 610 637). AWV recipients were stratified by the number of visits before 2017 (0, 1, 2 or ≥ 3). Kaplan-Meier methods estimated rates of falls and fractures. Patients were censored at end of study (12/31/2021), if they lost Medicare coverage, or switched to HMO. We used inverse probability treatment weighting (IPTW) with propensity score in Cox proportional hazards models to assess the effect of AWVs.

RESULTS: AWVs were associated with reduced risks for falls (HR: 0.976 for 2 AWVs; 0.936 for ≥3 AWVs) and fractures (HR: 0.978 for 1 AWV; 0.960 for 2 AWVs; 0.927 for ≥3 AWVs), with greater reductions observed with more AVWs. Time-dependent models revealed AWV in follow-up period had stronger effects on fall and fracture risk (HR: 0.921 and 0.929, respectively). In subgroup analyses, AWV risk reduction was weaker for falls in Black and rural residents with no significant fracture risk reduction.

CONCLUSIONS: Our studies indicate more AWVs are associated with greater risk reduction of falls/fractures in older adults with ADRD. This study emphasizes expanding awareness of AWVs to prevent falls/fractures in this population.}, } @article {pmid41911332, year = {2026}, author = {Zhu, Z and Song, H and Liu, W and Tian, M and Hoang, T and Reddiar, SB and Trevaskis, NL and Han, S and Hu, L}, title = {Cervical Lymph Duct-Cannulated Rat Model for Assessing Lymphatic Transport from the Head and Brain.}, journal = {Journal of visualized experiments : JoVE}, volume = {}, number = {229}, pages = {}, doi = {10.3791/70217}, pmid = {41911332}, issn = {1940-087X}, mesh = {Animals ; Rats ; *Brain/metabolism/physiology ; *Lymphatic Vessels/metabolism/physiology/surgery ; *Catheterization/methods ; *Head/physiology ; Neck ; *Lymph/metabolism ; Models, Animal ; }, abstract = {Lymph flows from the central nervous system (CNS) via a series of lymphatic vessels (LVs) and lymph nodes that converge at the cervical lymph ducts. In addition to maintaining fluid balance, these lymphatic ducts play a key role in transporting a wide array of substances, including endogenous metabolites, signaling molecules, immune cells, and small and macromolecular drugs. This is critical for physiological homeostasis and immune function in both intracranial (e.g., brain) and extracranial regions (e.g., nasal and oral cavities). Impaired lymphatic drainage from the brain has increasingly been linked to a range of neurological and neurodegenerative disorders. Cervical lymph duct cannulation enables the collection of lymph draining the head and brain, allowing the measurement of the concentration and transport rate of various substances via the lymphatic system. Changes in these factors in response to different challenges (e.g., drugs, stress, trauma) and diseases (e.g., stroke, infection, Alzheimer's disease) can also be determined. Here, we describe an anesthetized, deep cervical lymph duct cannulated rat model that enables lymph collection for several hours following surgery. The method may be combined with imaging and multi-omics technologies for the measurement of a wide range of parameters of interest in the lymph. This facilitates fundamental physiological and pathophysiological research of the head and neck region, as well as pharmacokinetic/pharmacodynamic studies of drugs, particularly for the treatment of CNS diseases.}, } @article {pmid41911661, year = {2026}, author = {Martínez, RF and Sánchez-Gallardo, M and Cintas, P}, title = {Memantine: A look ahead. Insights into structure, syntheses, receptor binding mechanisms, drug hybrids and formulations, and potential repurposing.}, journal = {European journal of medicinal chemistry}, volume = {310}, number = {}, pages = {118791}, doi = {10.1016/j.ejmech.2026.118791}, pmid = {41911661}, issn = {1768-3254}, mesh = {*Memantine/chemistry/pharmacology/chemical synthesis/therapeutic use ; Humans ; *Receptors, N-Methyl-D-Aspartate/metabolism/antagonists & inhibitors ; *Alzheimer Disease/drug therapy/metabolism ; *Drug Repositioning ; Molecular Structure ; Animals ; }, abstract = {Since its approval for clinical use more than two decades ago, memantine has become a blockbuster drug against Alzheimer's disease (AD). Unlike other FDA approved small molecules for the treatment of AD, essentially acetyl cholinesterase inhibitors, memantine behaves as N-methyl-d-aspartate (NMDA) receptor antagonist. However, it is a weak and non-specific NMDA receptor channel blocker that has shown to be safe in slowing the decline of moderate to advanced AD symptoms. In fact, those of us familiarized with AD, are aware of clinical protocols where memantine is usually prescribed to mitigate late stages of this neurological disorder, following previous treatment with donepezil and other inhibitors. The role of memantine for either preventing or disrupting amyloid formation, yet promising, remains unconclusive. The pharmacological basis and mode of action of memantine are well known and have been reviewed from different standpoints, often within the context of adamantane scaffolds. In recent times, further analyses combining experiment and computational simulation have disclosed subtle features of memantine-receptor interactions and previously unrecognized mechanistic insights, which are summarized herein. Likewise, there is a growing interest in memantine derivatives, not only against neurodegeneration, but also versus unrelated pathologies. Such studies arising from lab observations and preclinical assessments at most, point to memantine's repurposing and open the door to further explorations and translation. It is noteworthy that some structural aspects of memantine, including crystal packing and polymorphism, are usually overlooked. This review pays attention to such key elements and updates synthetic protocols, including the first preparation of memantine in continuous flow.}, } @article {pmid41912089, year = {2026}, author = {Hoveizi, E and Karimi, A and Khajehpour, L and Ghotbeddin, Z and Pyecroft, S}, title = {Astrocyte-derived exosomes in cognitive recovery: A comparative assessment of neurobehavioral, molecular, and electrophysiological dimensions.}, journal = {Behavioural brain research}, volume = {507}, number = {}, pages = {116196}, doi = {10.1016/j.bbr.2026.116196}, pmid = {41912089}, issn = {1872-7549}, mesh = {Animals ; *Astrocytes/metabolism ; *Exosomes/metabolism/transplantation ; *Alzheimer Disease/therapy/metabolism/physiopathology ; Male ; Rats ; Disease Models, Animal ; Hippocampus/metabolism ; Brain-Derived Neurotrophic Factor/metabolism ; Basal Nucleus of Meynert/metabolism ; Behavior, Animal/physiology ; *Cognition/physiology ; Mice ; Acetylcholine/metabolism ; }, abstract = {BACKGROUND: Despite the growing interest in cell- and exosome-based therapies for neurological diseases including Alzheimer's disease (AD), there is still a gap in the investigation of more effective treatments in terms of efficacy, safety, and durability of effect. This study aimed to compare the therapeutic potential of astrocyte cells and their derived exosomes (AS-Exos) in restoring cognitive function in a mouse model of AD.

METHODS: AD model was induced by bilateral electrical lesioning of the nucleus basalis of Meynert (NBM). Astrocytes were isolated from neonatal rat brains, and AS-Exos were harvested from astrocyte-conditioned media using an AnaCell extraction kit. Seven days after lesion induction, astrocytes and AS-Exos were stereotaxically injected into the NBM. Four weeks later, behavioral assessments (passive avoidance and locomotor activity), electrophysiological recordings (EEG), and biochemical measurements of hippocampal brain-derived neurotrophic factor (BDNF) and acetylcholine (ACh) levels were performed.

RESULTS: AS-Exos were confirmed as cup-shaped vesicles (30-150 nm) expressing the exosomal surface markers CD9, CD63, and CD81. NBM lesions significantly reduced step-through latency (STL), hippocampal BDNF and ACh levels, and disrupted EEG oscillatory patterns. Treatment with AS-Exos markedly improved STL and produced greater increases in hippocampal BDNF and ACh levels compared with AD and AD+saline groups. EEG analysis also revealed enhanced beta, alpha, and gamma power, with the most robust normalization observed in the AS-Exos group.

CONCLUSIONS: AS-Exos demonstrated superior biochemical and electrophysiological benefits compared with astrocyte transplantation and provided equal or greater improvement in behavioral outcomes. These findings highlight AS-Exos as a promising cell-free therapeutic strategy for alleviating cognitive deficits associated with AD.}, } @article {pmid41912358, year = {2026}, author = {Gai, J and Sharma, H and Kaskie, B and Jogerst, GJ}, title = {Evaluating the Effect of National Background Check Program on Nursing Home Deficiency Citations.}, journal = {Health services research}, volume = {61}, number = {2}, pages = {e70108}, pmid = {41912358}, issn = {1475-6773}, support = {R21 AG082047/AG/NIA NIH HHS/United States ; }, mesh = {*Nursing Homes/standards/statistics & numerical data/organization & administration ; Humans ; United States ; *Elder Abuse/prevention & control/statistics & numerical data ; Medical Neglect ; Nursing Home Residents ; }, abstract = {OBJECTIVE: To evaluate the impact of the National Background Check Program (NBCP) on nursing home (NH) health deficiencies and citations related to abuse, neglect, and exploitation.

STUDY SETTING AND DESIGN: This study uses the Callaway and Sant'Anna Difference-in-Differences (CSDID) quasi-experimental method to analyze data from US nursing homes from 2009 to 2016. The study includes nursing homes from 18 states that received NBCP grants as treatment group and nursing homes from 24 states that did not receive NBCP grants as control group. We exclude eight pilot NBCP states.

We used facility-level deficiency data from NH Care Compare (CC), NH characteristics data from Certification and Survey Provider Enhanced Reports (CASPER), and Alzheimer's Disease and Related Dementias diagnosis data from Minimum Data Set (MDS) assessments, covering 96,261 nursing home-year observations.

PRINCIPAL FINDINGS: Overall, NBCP implementation was associated with a significant reduction in health deficiencies (-0.760, p < 0.01) and a decrease in the probability and number of citations for abuse, neglect, and exploitation (-0.029, p < 0.01; -0.048, p < 0.01). Subgroup analyses showed that NBCP was associated with reductions in health deficiencies in nursing homes, regardless of whether they had a high or low census of residents with Alzheimer's Disease and Related Dementias, and in both metropolitan and nonmetropolitan areas. However, the effects varied across states depending on when they adopted NBCP.

CONCLUSIONS: Our findings suggest that NBCP is an effective regulatory tool for improving nursing home deficiencies and reducing incidents of abuse-related violations. We need more research to assess if background check programs improve nursing home quality using resident-level outcomes.}, } @article {pmid41912523, year = {2026}, author = {Yu, P and Liu, J and Xu, W and Peng, L and Li, Y and Shao, S and Wang, Y and Qiu, Z and Yang, H}, title = {Synaptic rescue in an Alzheimer's mouse model: low-temperature steam-derived black ginseng oligosaccharides remodel protein S-nitrosylation-NADPH oxidase axis.}, journal = {NPJ science of food}, volume = {10}, number = {1}, pages = {}, pmid = {41912523}, issn = {2396-8370}, support = {no. 20240305022YY//Science and Technology Development Planning Project of Jilin Province/ ; no. 2025ccyc01//Changchun Talents Technology Innovation Project/ ; }, abstract = {Synaptic loss and aberrant protein S-nitrosylation (SNO) are strongly linked to cognitive decline in both patients and animal models of Alzheimer's disease (AD). Our recent work in an AD mouse model has shed light on the role of oligosaccharides extracted from black ginseng (OSBG) in ameliorating cognitive impairment. However, the precise molecular mechanisms responsible for therapeutic efficacy of OSBG in AD are not well understood. In the present study, we employed an innovative SNOTRAP-based proteomic approach to quantify SNO proteins in the brain of APP/PS1 mice following OSBG intervention. The results revealed that differentially expressed SNO proteins, such as SNO-NOX1 and SNO- NOX5, confirmed by Western blot (WB), are significantly enriched in pathways related to oxidative stress, such as "Oxidative_stress activation of NADPH oxidase" and "Synaptic target recognition". OSBG treatment significantly alleviated oxidative stress via inhibition of NADPH oxidase activity in APP/PS1 mouse and PC12 cells by WB immunofluorescence (IF) assays. More importantly, upregulation of PSD-95 and SYN1 was detected in the hippocampal tissue of APP/PS1 mice after OSBG intervention, which was further validated by the corresponding mRNA expression levels. Consistently, histopathological analysis revealed the restoration of hippocampal cellular structure. Overall, our findings highlight the synapse-protective effect of OSBG in an AD model through regulating protein SNO levels and inhibiting NADPH oxidase activity, revealing a novel mechanism by which OSBG alleviated oxidative stress injury.}, } @article {pmid41913059, year = {2026}, author = {Macheda, T and Hawkins, MR and Johnson, CE and Lapid, MG and Whitlock, HR and Shepard, SM and Cox, MF and Roberts, KN and Bytyqi, L and Hash, HM and El-Ezz, OAA and El-Ezz, MA and Kohler, K and Sunderam, S and O'Hara, BF and Van Eldik, LJ and Murphy, MP and Duncan, MJ and Bachstetter, AD}, title = {Glial cytokine modulation improves sleep and circadian disruption in female SAA knock-in mice of Alzheimer's-related pathology.}, journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association}, volume = {22}, number = {4}, pages = {e71314}, pmid = {41913059}, issn = {1552-5279}, support = {T32 AG078110/AG/NIA NIH HHS/United States ; AG068215/AG/NIA NIH HHS/United States ; }, mesh = {Animals ; *Alzheimer Disease/pathology/genetics/metabolism ; Female ; *Cytokines/metabolism ; Mice ; Mice, Transgenic ; Disease Models, Animal ; *Circadian Rhythm/drug effects/physiology ; Amyloid beta-Peptides/metabolism ; *Sleep/drug effects/physiology ; *Neuroglia/metabolism/drug effects ; Male ; Gene Knock-In Techniques ; *Sleep Wake Disorders/drug therapy ; }, abstract = {INTRODUCTION: Sleep and circadian disturbances are early Alzheimer's disease (AD) features, yet mechanisms linking amyloid pathology, neuroinflammation, and sex differences remain unclear.

METHODS: We longitudinally assessed sleep, circadian rhythms, and cognition in female and male hAPP[SAA] knock-in and control mice from 2 to 19 months using piezoelectric monitoring. Aged mice (15 months) received MW151, a glial cytokine inhibitor (2.5 mg/kg, every other day, 6 weeks).

RESULTS: Only females exhibited midlife reductions in light-phase sleep, increased rhythm fragmentation, and reduced rhythm stability, coinciding with selective reversal learning deficits, effects independent of amyloid or cytokine burden. MW151 increased light-phase sleep and reduced cortical TNF-α without altering amyloid beta (Aβ) accumulation.

DISCUSSION: HAPP[SAA] mice recapitulate female-predominant non-cognitive AD features, including sleep fragmentation and circadian instability preceding memory deficits. Sleep improved within weeks of MW151 treatment without Aβ reductions, implicating neuroinflammatory signaling as a rapid, modifiable driver of AD-related sleep disruption.}, } @article {pmid41913175, year = {2026}, author = {Ito, K and Tsuda, S and Wake, T and Hatakeyama, A and Ogisawa, F and Ono, M and Nakayama, R and Wakui, T and Nagano, N and Iwata, A}, title = {Reframing dementia care in the era of disease-modifying therapies: informational, psychosocial, and systemic insights from Japan.}, journal = {BMC health services research}, volume = {26}, number = {1}, pages = {}, pmid = {41913175}, issn = {1472-6963}, support = {25K14240//Grants-in-Aid for Scientific Research/ ; 25GB0301//Health and Labor Sciences Research Grant/ ; }, mesh = {Humans ; Japan ; Female ; Qualitative Research ; Male ; Caregivers/psychology ; *Dementia/therapy ; Aged ; Interviews as Topic ; Social Support ; Aged, 80 and over ; Middle Aged ; }, abstract = {BACKGROUND: The introduction of disease-modifying therapies (DMTs) for Alzheimer’s disease has prompted major changes in diagnostic pathways, referral processes, and service coordination in dementia care. Japan, as an early adopter of DMTs within a nationally coordinated dementia-care framework, offers an opportunity to examine how health service structures respond to these changes. This study explored health service–related support needs emerging across the DMT pathway, focusing on patient and informal caregiver experiences, with complementary perspectives from service providers. METHODS: A qualitative study was conducted using semi-structured interviews with 48 participants, including nine patients who underwent DMT eligibility assessment, seven informal caregivers, 11 physicians, four nurses, five clinical psychologists, five social workers, and seven community-based dementia support providers. Data were analyzed using the Framework Method, an applied qualitative approach suitable for health services research. Patients’ and caregivers’ accounts were treated as the primary analytic focus, while provider perspectives were used to contextualize system-level factors influencing care delivery. RESULTS: Three interrelated themes were identified. First, informational support needs reflected inequitable access to trustworthy information, difficulties in sustaining understanding of complex medical explanations, and a lack of structured opportunities to revisit information over time, particularly during transitions such as ineligibility, treatment discontinuation, or completion. Second, psychosocial support needs were closely shaped by service processes, including stigma-related experiences across clinical and social contexts, family-related tensions around treatment decisions, fluctuating expectations regarding treatment effects, and limited support for adjustment when DMT was no longer an option. Third, systemic and collaborative support needs highlighted fragmented roles between primary care and DMT-designated institutions, unclear referral and handover pathways, insufficient psychosocial care capacity, and weak integration between DMT delivery systems and existing dementia-care services. CONCLUSIONS: The implementation of DMTs has amplified pre-existing gaps in dementia care systems, revealing previously underrecognized structural vulnerabilities across informational, psychosocial, and systemic domains. Findings indicate that DMTs should be embedded within coordinated care pathways that ensure continuity of information provision, access to psychosocial support, and clear allocation of follow-up responsibility regardless of treatment eligibility. Aligning pharmacological innovation with health service design is essential to support equitable, continuous, and person-centered dementia care.}, } @article {pmid41914305, year = {2026}, author = {Xie, JL and Hu, XH and Wu, CL and Jin, Q and Pan, JP}, title = {DHA Ameliorates Alzheimer's Disease by Attenuating Microglial Pyroptosis via Regulation of the HOXA9-NLRP3 Pathway.}, journal = {Frontiers in bioscience (Landmark edition)}, volume = {31}, number = {3}, pages = {46572}, doi = {10.31083/FBL46572}, pmid = {41914305}, issn = {2768-6698}, support = {20232BAB206049//Jiangxi Provincial Natural Science Foundation General Project/ ; }, mesh = {*NLR Family, Pyrin Domain-Containing 3 Protein/metabolism/genetics ; *Docosahexaenoic Acids/pharmacology ; Animals ; *Alzheimer Disease/drug therapy/metabolism/pathology ; *Pyroptosis/drug effects ; *Microglia/drug effects/metabolism/pathology ; Humans ; Mice ; Signal Transduction/drug effects ; Mice, Transgenic ; *Homeodomain Proteins/metabolism/genetics ; Male ; Disease Models, Animal ; Mice, Inbred C57BL ; }, abstract = {BACKGROUND: Alzheimer's disease (AD) involves a progressive deterioration of cognitive abilities, memory loss, and persistent brain inflammation. Emerging evidence indicates that pyroptosis mediated by the NOD-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome, contributes significantly to AD development. Docosahexaenoic acid (DHA) has demonstrated neuroprotective properties; however, the precise mechanisms by which it modulates pyroptosis in AD have yet to remained incompletely elucidated.

OBJECTIVE: To explore the role of DHA in modulating microglial pyroptosis via the HOXA9-NLRP3 pathway in an AD model.

METHODS: Effects of DHA on Aβ25-35-induced pyroptosis were assessed in human microglial clone 3 (HMC3) human microglial cells using CCK-8, western blotting, immunofluorescence, and Enzyme-linked Immunosorbent Assay (ELISA) assays. The role of homeobox A9 (HOXA9) in pyroptosis regulation was evaluated through overexpression and knockdown experiments. Dual-luciferase reporter assays together with chromatin immunoprecipitation (ChIP) were used to verify the interaction of HOXA9 to NLRP3 promoter. Amyloid precursor protein / Presenilin-1 double-transgenic (APP/PS1) transgenic AD mice underwent DHA treatment in vivo, and cognitive performance was assessed using the Morris water maze paradigm. Expression of HOXA9, NLRP3, and pyroptosis-related proteins were analyzed by Quantitative Real-time Reverse Transcription PCR (qRT-PCR), Western blotting, and immunofluorescence.

RESULTS: DHA treatment significantly reduced Aβ25-35-induced microglial pyroptosis, as indicated by decreased levels of p30-Gasdermin D (GSDMD), cleaved-caspase-1, IL-1β, and IL-18. HOXA9 overexpression reversed the protective effects of DHA, whereas NLRP3 inhibition by MCC950 enhanced DHA inhibition of pyroptosis. Dual-luciferase and ChIP assays confirmed that HOXA9 directly regulates NLRP3 transcription. In APP/PS1 mice, DHA administration enhanced cognitive performance while simultaneously decreasing the expression of pyroptosis-related markers and inflammatory mediators in brain. Inhibition of NLRP3 signaling by MCC950 further strengthened the neuroprotective actions of DHA.

CONCLUSION: DHA ameliorates AD-related cognitive decline and reduces microglial pyroptosis through suppressing the HOXA9-NLRP3 axis. These results offer novel insights into the molecular basis of DHA-mediated neuroprotection and highlight potential therapeutic targets for AD.}, } @article {pmid41914924, year = {2026}, author = {Stagge, F and Saylor, AK and Dallas, ON and Johnson, AL and Palmer, KM and Fromm, D and Lanzi, AM}, title = {Increasing Educator Resources for Mild Cognitive Impairment and Dementia Using a Knowledge-to-Action Framework: The Development of DementiaBank Grand Rounds.}, journal = {American journal of speech-language pathology}, volume = {35}, number = {3}, pages = {1149-1169}, pmid = {41914924}, issn = {1558-9110}, mesh = {Humans ; *Speech-Language Pathology/education ; *Cognitive Dysfunction/diagnosis/psychology/therapy ; Focus Groups ; *Dementia/diagnosis/psychology ; *Communication Disorders/etiology/diagnosis ; Health Knowledge, Attitudes, Practice ; *Alzheimer Disease/diagnosis/psychology ; Curriculum ; *Teaching Rounds ; }, abstract = {PURPOSE: An educational gap exists in content knowledge and clinical education for speech-language pathologists concerning the treatment and assessment of cognitive-communication disorders from mild cognitive impairment (MCI) or dementia due to Alzheimer's disease (AD). This gap may result in less effective speech-language pathology services for this population. The overarching goal of this project was to enhance graduate speech-language pathology education about MCI and dementia due to AD to improve the quality of future service providers.

METHOD: To achieve this goal, this project had two objectives: first, to conduct a survey to understand speech-language pathology graduate school education practices in clinical and classroom settings regarding cognitive-communication disorders from MCI or dementia due to AD and, second, to conduct focus groups to guide the development of an online educational resource, informed by speech-language pathology graduate school educators. A knowledge-to-action (KTA) conceptual framework provided guidance to translate findings from the survey and focus groups into a highly implementable educational resource.

RESULTS: Educators of graduate speech-language pathology students reported a crucial need for additional accessible resources to assist them in teaching or supervising cognitive-communication disorders from MCI or dementia due to AD. The existing TalkBank educational resource, Grand Rounds, was explored through educator focus groups, and feedback directly informed the creation of a new educational resource tailored for this population.

CONCLUSIONS: Overall, an educational resource, DementiaBank Grand Rounds, was successfully developed for cognitive-communication disorders associated with MCI and dementia due to AD, utilizing the KTA framework. DementiaBank Grand Rounds may serve as a resource to support learners and educators and address the current gap in content knowledge and clinical education.

SUPPLEMENTAL MATERIAL: https://doi.org/10.23641/asha.31839664.}, } @article {pmid41915038, year = {2026}, author = {Xia, Y and Johnson, K and Fakhri, GE and Guehl, NJ and van de Giessen, E and Coomans, EC and Pijnenburg, YAL and Ossenkoppele, R and Groot, C}, title = {Bayesian modelling demonstrates clinically relevant heterogeneity in Tau PET patterns in Alzheimer's disease.}, journal = {European journal of nuclear medicine and molecular imaging}, volume = {53}, number = {7}, pages = {4664-4676}, pmid = {41915038}, issn = {1619-7089}, support = {10510022110010/ZONMW_/ZonMw/Netherlands ; WE.03-2024-06//Alzheimer Nederland/ ; 949570//H2020 European Research Council/ ; }, mesh = {Humans ; *Alzheimer Disease/diagnostic imaging/metabolism ; *Positron-Emission Tomography ; *tau Proteins/metabolism ; Bayes Theorem ; Female ; Male ; Aged ; }, abstract = {BACKGROUND: Traditionally, subgroups have been used to explore the effects of tau heterogeneity on cognition. However, categorization into rigid, exclusive subtypes, each with their own tau pattern, may overlook the fact that individual tau patterns are complex, and most individuals express features of multiple patterns. Mapping tau patterns in all their complexity has important clinical implications, as it may enable more accurate prognostication and support the development of personalized therapeutic strategies tailored to an individual’s unique tau profile. METHODS: We applied a data-driven Bayesian model using Latent Dirichlet Allocation (LDA) to identify four covarying tau PET patterns in amyloid-positive individuals with symptomatic Alzheimer’s disease (AD) from the Amsterdam Dementia Cohort (ADC, N = 93, mean age = 65.3). The four latent tau spatial patterns identified via LDA were designated as follows: Limbic (Factor 1), characterized by predominant involvement of the limbic regions; Left TPC (Factor 2), centered on the left temporo-parietal cortex (TPC); Posterior (Factor 3), reflecting a posterior neocortical distribution; and MTL-sparing (Factor 4), showing relative sparing of limbic regions with diffuse neocortical tau deposition. Associations between individual loadings on each of these factors and cognitive domain scores were assessed using linear regression analyses. We then applied the ADC-derived model to an independent validation sample from the Alzheimer’s Disease Neuroimaging Initiative (ADNI, N = 162, mean age = 72.7) to extract individual factor loadings. Associations between factor loadings and contemporaneous cognitive performance were again tested using linear regression, and linear mixed-effects models were used to additionally explore associations with cognitive decline. All analyses were adjusted for age, sex, education, and clinical diagnosis. RESULTS: In both the discovery and validation cohort, we identified distinct associations between tau factor loadings and cognitive performance. Higher loading on Factor 1: limbic tau was generally associated with relatively better baseline cognition and slower cognitive decline. Factor 2: left TPC tau was linked to worse baseline scores and faster decline in memory, MMSE and language scores but only in the ADNI cohort. Factor 3: posterior tau was associated with worse baseline MMSE in the ADC cohort and to worse visuospatial performance both cross-sectionally and longitudinally in the ADNI cohort. Factor 4: MTL-sparing tau was related to better longitudinal memory in the ADNI cohort. CONCLUSION: This data-driven approach identified overlapping tau patterns that relate to distinct cognitive domains. The findings highlight the value of continuous factor modeling in understanding heterogeneity in Alzheimer’s disease. Such a refinement of quantifying tau heterogeneity may improve patient stratification, refine prognostic accuracy, and ultimately guide the development of individualized treatment strategies.}, } @article {pmid41915110, year = {2026}, author = {Asl, AD and Naeimzadeh, F and Yonjali, RM and Mohammadpour, A and Khankandi, PG and Afkhami, A and Mahmoodpoor, A and Sanaie, S and Naseri, A}, title = {Selenium and probiotics co-supplementation: A scoping review of clinical evidence.}, journal = {Inflammopharmacology}, volume = {34}, number = {5}, pages = {3625-3635}, pmid = {41915110}, issn = {1568-5608}, support = {74645//Student Research Committee, Tabriz University of Medical Sciences/ ; }, mesh = {Humans ; *Selenium/administration & dosage/pharmacology ; *Probiotics/administration & dosage/pharmacology ; *Dietary Supplements ; Oxidative Stress/drug effects ; Antioxidants/administration & dosage/pharmacology ; Randomized Controlled Trials as Topic/methods ; Inflammation/drug therapy/metabolism ; Female ; }, abstract = {BACKGROUND: Selenium and probiotics have been individually recognized for their antioxidant, anti-inflammatory, and immune-modulating properties. However, the potential synergistic effects of their co-supplementation in human health remain minimally investigated. This scoping review aimed to summarize the current evidence on the impact of co-supplementation with selenium and probiotics. METHODS: A comprehensive literature search was conducted across PubMed, Scopus, Embase, and Web of Science databases to identify clinical trials investigating the effects of selenium and probiotics co-supplementation. Eligible studies included randomized controlled trials (RCTs) and non-randomized clinical trials assessing clinical, metabolic, inflammatory, oxidative stress, and immune-related outcomes. RESULTS: Ten clinical studies met the inclusion criteria, including populations with polycystic ovary syndrome, Alzheimer’s disease, schizophrenia, leukemia, gestational diabetes, elderly nursing home residents, and ICU patients with stage I–II bedsores. Co-supplementation was associated with changes in glycemic indices (fasting plasma glucose, insulin, HOMA-IR, QUICKI), selected lipid parameters (triglycerides, total cholesterol, LDL cholesterol), oxidative stress markers (total antioxidant capacity, glutathione, malondialdehyde), and inflammatory markers, particularly high-sensitivity C-reactive protein. Studies also reported improvements in mental health scores, cognitive function (MMSE), and immune-related markers including adhesion molecules. Gene expression changes, including TNF-α and PPAR-γ, were reported in limited studies. Overall, co-supplementation was well tolerated, with no serious adverse events reported. CONCLUSIONS: Selenium and probiotics co-supplementation may provide beneficial effects on metabolic regulation, oxidative stress, and inflammation-related conditions. However, heterogeneity in study design, probiotics’ strains, selenium dosage, and treatment duration limits firm conclusions. Larger, well-designed randomized controlled trials with long-term follow-up are needed.}, } @article {pmid41915579, year = {2026}, author = {Ashchi, A and Lachapelle, AA and Nassirou, S and Huston, J}, title = {Leqembi (Lecanemab) in Early Alzheimer's Disease: A Review of Clinical Trial Evidence and Therapeutic Implications.}, journal = {Reviews on recent clinical trials}, volume = {}, number = {}, pages = {}, doi = {10.2174/0115748871418305260224075827}, pmid = {41915579}, issn = {1876-1038}, abstract = {Lecanemab is an IgG1 monoclonal antibody that has emerged as the first FDAapproved drug to slow the progression of Alzheimer's disease by targeting amyloid plaques, with the potential to serve as a disease-modifying therapy. Ongoing clinical studies are evaluating the efficacy and safety of the medication; however, much of the current literature remains mixed regarding the clinical effectiveness of lecanemab. The results from the Clarity AD study, the largest clinical study regarding the effectiveness of lecanemab to date, revealed a statistically significant 27% reduction in the progression of cognitive decline and favorable secondary endpoints in patients with mild cognitive impairment or mild dementia, particularly in male patients as well as heterozygous APOE4 carriers. However, approximately 21% of participants who received lecanemab treatment developed amyloid-related imaging abnormalities, with a higher incidence in homozygous APOE4 carriers. These findings highlight the need to thoroughly screen patients to confirm amyloid pathology with an amyloid PET scan or CSF biomarkers, and to determine APOE4 status before treatment. Additional barriers to care include the financial cost of the medication as well as the need to administer the drug intravenously at a healthcare facility to ensure proper management. Additional studies must continue to explore the clinical impact and safety of the medication and increase its accessibility. Future research may also include analyzing the utilization of the drug in combination therapies to optimize patient outcomes. This paper aims to provide a comprehensive review of current data on lecanemab, its clinical implications, and potential future directions for the use of lecanemab.}, } @article {pmid41916100, year = {2026}, author = {Gong, H and Liu, J and Wang, Y and Lin, X and Wu, G and Ou, Y and Zhou, M and Yang, L and Peng, J and Ye, X and Wang, Y and Xu, F and Zhou, H and Feng, Z}, title = {Semaglutide treatment reverses HFD induced hippocampal microglia activation and improves cognitive dysfunction.}, journal = {Tissue & cell}, volume = {101}, number = {}, pages = {103495}, doi = {10.1016/j.tice.2026.103495}, pmid = {41916100}, issn = {1532-3072}, mesh = {Animals ; Semaglutide ; *Microglia/drug effects/pathology/metabolism ; *Hippocampus/pathology/drug effects ; *Glucagon-Like Peptides/pharmacology/therapeutic use ; Mice ; *Diet, High-Fat/adverse effects ; *Cognitive Dysfunction/drug therapy/pathology ; Mice, Inbred C57BL ; Male ; Alzheimer Disease/drug therapy/pathology ; Phosphatidylinositol 3-Kinases/metabolism ; Proto-Oncogene Proteins c-akt/metabolism ; }, abstract = {Long-term high-fat diets (HFD) induce obesity, neuroinflammation, and cognitive decline, increasing Alzheimer's disease (AD) risk. This study explores whether Semaglutide, a GLP-1 receptor agonist, mitigates these effects by modulating microglia via IGFBPL-1 and the PI3K/AKT pathway. In HFD-fed C57/BL6 mice, Semaglutide improved cognitive function, reduced hippocampal microglia activation, and decreased AD-like pathology (phospho-Tau, Aβ). IGFBPL-1, a neuroprotective factor downregulated by HFD and restored by Semaglutide. Direct IGFBPL-1 supplementation replicated Semaglutide's benefits, while PI3K/AKT inhibition blocked them. These findings reveal IGFBPL-1 as a key mediator of Semaglutide's neuroprotection, offering novel insights into combating obesity-linked neurodegeneration.}, } @article {pmid41916153, year = {2026}, author = {Wang, C and Xu, X and Zhu, H and Wu, D and Liang, J and Wang, X and Song, R and Shen, L and Hu, Y and Wang, D and Zhu, H and Cheng, X and Qi, Y}, title = {Acori tatarinowii Rhizoma-Curcumae Radix herbal pair ameliorates cognitive impairment and suppresses neuro-inflammation via Ca[2+]/CaMKKβ/AMPK/mTOR pathway in Alzheimer's disease.}, journal = {Journal of ethnopharmacology}, volume = {365}, number = {}, pages = {121606}, doi = {10.1016/j.jep.2026.121606}, pmid = {41916153}, issn = {1872-7573}, mesh = {Animals ; *Alzheimer Disease/drug therapy ; *Drugs, Chinese Herbal/pharmacology/therapeutic use ; Calcium-Calmodulin-Dependent Protein Kinase Kinase/metabolism ; Male ; *Neuroprotective Agents/pharmacology/isolation & purification ; AMP-Activated Protein Kinases/metabolism ; TOR Serine-Threonine Kinases/metabolism ; Mice ; Signal Transduction/drug effects ; *Cognitive Dysfunction/drug therapy ; *Acorus/chemistry ; Maze Learning/drug effects ; Rhizome ; Calcium/metabolism ; *Neuroinflammatory Diseases/drug therapy ; Autophagy/drug effects ; }, abstract = {Effective activation of neuronal autophagy and clearance of amyloid-beta (Aβ) represents a promising therapeutic strategy in the treatment of Alzheimer's disease (AD). The Acori Tatarinowii Rhizoma-Curcumae Radix Herbal pair (ACHP), derived from the traditional Changpu Yujin Decoction, has a long history in Traditional Chinese Medicine for addressing conditions related to cognitive function. However, the precise mechanisms underlying its role in autophagic dysfunction-related dementia remain unclear.

AIM OF THE STUDY: This study aims to investigate the neuroprotective effects of ACHP and the underlying mechanisms in AD.

MATERIALS AND METHODS: Analysis of prototype constituents in drug-containing serum was performed using UHPLC-Triple-TOF/MS. The neuroprotective effects of ACHP were evaluated in APP/PS1 mice using behavioral tests, including the Y-maze and Morris water maze. Transcriptomic analysis was conducted to identify potential neuroprotective pathways activated by ACHP. Neuronal damage and structural recovery were assessed through HE and Nissl staining. In addition, the anti-inflammatory and autophagy-regulating effects of ACHP were further investigated in N2a/APP cells. The molecular mechanisms were further elucidated using Western blot, immunofluorescence, ELISA, and qRT-PCR in both in vivo and in vitro models.

RESULTS: Twenty-five compounds in ACHP-treated mouse serum were identified. ACHP improved spatial learning and memory performance, increased intracellular Ca[2+] levels and downregulated the expressions of proinflammatory cytokines, including TNF-α, IL-1β, and IL-6, while significantly promoting autophagy. ACHP increased CaMKKβ protein expression and activated the AMPK signaling pathway (elevated p-AMPK/AMPK ratio), as well as those of autophagy-related proteins, while improving neuronal morphology.

CONCLUSION: These findings indicate that ACHP alleviates neuro-inflammatory damage and cognitive impairment potentially through modulation of the Ca[2+]/CaMKKβ-AMPK-mTOR signaling pathway involved in autophagy.}, } @article {pmid41916976, year = {2026}, author = {Parent, O and Alasmar, Z and Osborne, S and Bussy, A and Costantino, M and Fouquet, JP and Quesada, D and Pastor-Bernier, A and Fajardo-Valdez, A and Pichet-Binette, A and McQuarrie, A and Maranzano, J and Devenyi, GA and Steele, CJ and Villeneuve, S and , and , and Dadar, M and Chakravarty, MM}, title = {Characterizing spatiotemporal white matter hyperintensity pathophysiology in vivo to disentangle vascular and neurodegenerative contributions.}, journal = {Nature communications}, volume = {17}, number = {1}, pages = {}, pmid = {41916976}, issn = {2041-1723}, mesh = {*White Matter/diagnostic imaging/physiopathology/pathology ; Humans ; Magnetic Resonance Imaging/methods ; Female ; Male ; *Alzheimer Disease/diagnostic imaging/physiopathology/pathology ; Aged ; Aged, 80 and over ; Neurodegenerative Diseases/diagnostic imaging/physiopathology ; Dementia/diagnostic imaging/physiopathology ; Brain/diagnostic imaging/physiopathology ; }, abstract = {White matter hyperintensities (WMHs) are neuroimaging markers widely interpreted as caused by cerebral small vessel disease, yet emerging evidence suggests that a subset may have a neurodegenerative etiology. Current imaging methods have lacked the specificity to disentangle biological processes underlying WMHs in vivo. Here, we used voxel-level normative modeling and seven microstructural MRI markers with complementary biophysical sensitivities to generate single-subject high-resolution WMH pathophysiology maps in a large cohort (n = 32,526). We calculated data-driven spatial patterns of similar WMHs, revealing distinct periventricular, posterior, and anterior clusters. We identified a reproducible WMH signature linked to dementia and Alzheimer's disease, characterized by a posterior predominance and a pathophysiological pattern indicative of selective fiber degeneration. Posterior WMHs connected cortical regions vulnerable to tau pathology. Our framework helps parsing vascular and neurodegenerative contributions of WMHs in vivo, which could alter the course of treatment strategies and provide nuanced interpretations of research findings.}, } @article {pmid41918005, year = {2026}, author = {Singh, S and Sharma, Y and Bhardwaj, P and Kothari, D and Chhikara, A and Gupta, V and Kumar, D and Choudhary, N and Kondaveeti, SB}, title = {Next generation preventive neurology: how artificial intelligence and machine learning are reshaping Alzheimer's disease research.}, journal = {Behavioral and brain functions : BBF}, volume = {22}, number = {1}, pages = {}, pmid = {41918005}, issn = {1744-9081}, mesh = {Humans ; *Alzheimer Disease/prevention & control/diagnosis ; *Machine Learning/trends ; *Artificial Intelligence/trends ; Convolutional Neural Networks ; *Neurology/methods/trends ; Neuroimaging/methods ; Federated Learning ; Data Analytics ; }, abstract = {A neurological condition that worsens over time, Alzheimer’s disease (AD) is typified by memory loss, cognitive decline, and functional degradation. Traditional diagnostic techniques such as neuroimaging, cerebrospinal fluid biomarkers, and neuropsychological testing are often intrusive, costly, or insensitive in the early stages. Recent years have seen the emergence of AI and ML as game-changing technologies for AD risk assessment, early detection, and customized prevention. Using sophisticated models such as deep learning, convolutional neural networks (CNNs), and graph-based algorithms, AI-driven methods achieve high performance: CNNs, for example, have reached diagnostic accuracies of 94–99% for early AD and mild cognitive impairment using multimodal MRI and PET data. However, most reported performance metrics are derived from retrospective analyses and internal validation cohorts, with limited external validation across diverse populations. These methods include multimodal data integration from neuroimaging, genetics, and clinical records. Years before symptoms appear, AI-based frameworks can predict disease progression, identify modifiable risk factors, and guide individualized treatment plans. Future developments in federated learning and explainable AI (XAI) are promising, although data privacy, algorithmic bias, and ethical ramifications are concerns. Overall, AI and ML have a great deal of promise to transform the prevention of AD, enabling precision therapy and enhancing the lives of those who are at risk.}, } @article {pmid41918193, year = {2026}, author = {Behrouzfar, H and Mortazavi, P and Hassani, S and Aghebat Bekheir, S}, title = {Exploring the Effects of Empagliflozin Administration and Physical Training on Cognitive Functions in an Amyloid Beta-Induced Alzheimer's Rat Model.}, journal = {Current medicinal chemistry}, volume = {}, number = {}, pages = {}, doi = {10.2174/0109298673434008260121111535}, pmid = {41918193}, issn = {1875-533X}, abstract = {INTRODUCTION: Alzheimer's disease (AD) is a widely prevalent and neurodegenerative disorder that leads to dementia and mortality worldwide. Previous investigations have reported the beneficial effects of physical exercise on brain function, linked to anti-inflammatory effects in the brain vasculature and elevated BDNF production. Empagliflozin, a conventional antidiabetic agent, has shown potential neuroprotective properties in the central nervous system, evidenced by its ability to elevate BDNF and mitigate oxidative stress and inflammation.

MATERIALS AND METHODS: In the present investigation, AD was induced in control, exercise, empagliflozin (10 mg/kg BW, PO), and combined intervention groups using intrahippocampal injections of an amyloid-beta (Aβ) prepared solution via stereotaxic surgery. The therapeutic effects of each treatment, exercise alone, empagliflozin alone, and exercise plus empagliflozin, were studied. After 28 days, spatial memory tests were used to assess memory and learning. Furthermore, histopathological (H&E and Congo red) and immunohistochemical (GFAP) analyses were performed, and the ADP/ATP ratio in isolated brain mitochondria was measured by HPLC.

RESULTS: Our results showed that the combined program of physical training and empagliflozin treatment in the Aβ-induced AD model drastically improved cognitive functions and neurological parameters, including target-finding time, traveled distance, time spent in the target quadrant, and ADP/ATP ratios in brain mitochondria. Additionally, it diminished necrotic cell death and reduced Aβ plaques but did not notably affect astrocyte activity.

DISCUSSION: Exercise and empagliflozin, by affecting mitochondrial energy balance and reducing amyloid deposition, play key roles in mitigating AD pathophysiology.

CONCLUSION: The combined effects of the treatments used in this experimental method yielded significant improvements in cognitive functions. These findings provide a basis for further clinical studies for the exploration of the synergistic impact of the aforementioned therapeutic methods.}, } @article {pmid41918201, year = {2026}, author = {Sharma, S and Sharma, D and Sharma, A}, title = {Targeting Vascular Dementia: Pharmacological Mechanisms and Therapeutic Strategies.}, journal = {CNS & neurological disorders drug targets}, volume = {}, number = {}, pages = {}, doi = {10.2174/0118715273440657260226125023}, pmid = {41918201}, issn = {1996-3181}, abstract = {INTRODUCTION: Vascular dementia is a leading cause of cognitive deterioration worldwide, caused by a complex interplay of pathological mechanisms such as disrupted cerebral blood flow, oxidative stress, neuroinflammation, and endothelial dysfunction. A clear knowledge of these mechanisms is crucial for developing efficient treatment strategies. Various drug classes, including statins, cholinesterase inhibitors, anti-diabetic drugs, leukotriene antagonists, and nootropics, offer promising approaches by addressing different facets of this multifaceted condition. This review's objective is to offer a comprehensive analysis of the functional mechanisms of diverse pharmacological agents in curing vascular dementia. It further aims to identify their therapeutic potential, limitations, and areas requiring future research.

METHODOLOGY: A review of the literature was conducted to examine evidence from preclinical and clinical research. Pharmacological chemicals were evaluated for their effects on key pathological pathways, including oxidative stress, inflammation, endothelial dysfunction, and impaired neurotransmission.

RESULT AND DISCUSSION: Each class of drugs reviewed demonstrates distinct benefits in addressing specific aspects of vascular dementia. Statins primarily mitigate vascular risk factors and neuroinflammation, while cholinesterase inhibitors enhance neurotransmitter availability to support cognitive function. Anti-diabetic drugs exhibit neuroprotective properties through metabolic regulation and antiinflammatory effects, and leukotriene antagonists show potential in reducing oxidative damage and inflammation. Nootropics, on the other hand, focus on enhancing synaptic plasticity and memory. Despite these promising mechanisms, limitations such as inconsistent clinical outcomes, potential adverse effects, and the absence of individualized treatment protocols remain significant challenges.

CONCLUSION: This review emphasizes the need for developing integrated therapeutic strategies that target the diverse pathological mechanisms underlying vascular dementia. While current pharmacological approaches show considerable potential, there is a desperate need for long-term clinical validation and the development of personalized medicine frameworks. Advances in diagnostic tools, biomarkers, and imaging technologies will be crucial for early diagnosis and effective disease monitoring, paving the way for improved patient results and a more profound understanding of vascular dementia's complexity.}, } @article {pmid41918343, year = {2026}, author = {Lopes, SP and Emídio, JJ and Duarte, ABS and Orhan, IE and Deniz, FSS and Salmas, RE and de Sousa, DP}, title = {Synthesis of p-Coumarates With Potential Anti-Alzheimer's Action: Enzyme Inhibition and In Silico Studies.}, journal = {Chemistry & biodiversity}, volume = {23}, number = {4}, pages = {e03857}, pmid = {41918343}, issn = {1612-1880}, support = {306661/2016-0//Conselho Nacional de Desenvolvimento Científico e Tecnológico/ ; //Coordenação de Aperfeiçoamento de Pessoal de Nível Superior/ ; }, mesh = {*Cholinesterase Inhibitors/chemical synthesis/pharmacology/chemistry ; *Butyrylcholinesterase/metabolism ; *Alzheimer Disease/drug therapy/metabolism ; *Acetylcholinesterase/metabolism ; *Coumaric Acids/chemical synthesis/chemistry/pharmacology ; Humans ; Structure-Activity Relationship ; Molecular Docking Simulation ; Molecular Structure ; *Propionates/chemistry/chemical synthesis/pharmacology ; Dose-Response Relationship, Drug ; }, abstract = {Alzheimer's disease (AD) is a fatal neurodegenerative disorder that affects cognition, memory, and behavior. Such a disease is considered the most common cause of dementia and affects a large portion of the elderly population worldwide. Currently, cholinesterase inhibitors are used to reduce the symptoms and rate of progression of this disease. Thus, the present study evaluated the acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibitory activities of a set of 22 p-coumarate derivatives using the spectrophotometric method. The inhibitory activity of the compounds against AChE and BChE was measured using the adapted Ellman spectrophotometric method; the reported inhibition percentages were determined at a final concentration of 100 µM. The structures of the synthesized compounds were characterized by FTIR, [1]H-NMR, [13]C-NMR, and HRMS spectroscopy. Among the compounds tested, three showed moderate inhibitory activity against AChE and good activity against BChE: (E)-4-chlorobenzyl 3-(4-hydroxyphenyl)acrylate (14) (56.36%; 75.17%), (E)-4-bromobenzyl 3-(4-hydroxyphenyl)acrylate (15) (61.11%; 76.09%), and (E)-naphthalene 3-(4-hydroxyphenyl)acrylate (18) (59.18%; 65.39%), respectively. Compound 15 had an IC50 of 22.22 ±1.50 mM against BChE, which is notably better than galantamine's BChE inhibition. The in silico analysis suggested that compounds 14, 15, and 18 interact with AChE and BChE. Thus, p-coumaric acid derivatives represent promising prototypes for the search for new drug candidates for the treatment of AD.}, } @article {pmid41919006, year = {2026}, author = {Buchanan, TJ and Ewen, C and Rebollo Mesa, I and Germani, M and Watanabe, S and Jose, J and Famodimu, O and Colson, AO and De Bruyn, S}, title = {Two phase 1 randomised studies investigating the safety and pharmacokinetics of bepranemab in healthy participants of different ethnicities.}, journal = {BMJ neurology open}, volume = {8}, number = {1}, pages = {e001395}, pmid = {41919006}, issn = {2632-6140}, abstract = {BACKGROUND: Bepranemab is a recombinant, humanised, full-length IgG4 monoclonal antibody targeting a mid-region tau epitope. Two phase 1 studies assessed the safety, tolerability, pharmacokinetics (PK) and pharmacodynamics (PD) of bepranemab.

METHODS: UP0047 (NCT03464227) and UP0065 (NCT03605082) were phase 1, double-blind, placebo-controlled, single-dose, dose-escalation studies of intravenous bepranemab in healthy participants (Caucasian and Japanese descent, respectively). Primary endpoint: safety and tolerability of single ascending doses of bepranemab. PK were assessed in serum and cerebrospinal fluid (CSF); PD (levels of free tau) in CSF. A physiologically based PK/PD (PBPK/PD) model was developed to predict dose response.

RESULTS: UP0047: Caucasian participants (N=52) were randomised to bepranemab 0.3 mg/kg, n=2; 1 mg/kg, n=6; 3 mg/kg, n=6; 10 mg/kg, n=6; 30 mg/kg, n=6; 60 mg/kg, n=6; 120 mg/kg, n=6; placebo, n=14). UP0065: participants of Japanese descent (N=24) were randomised to bepranemab 30 mg/kg, n=6; 60 mg/kg, n=6; 120 mg/kg, n=6; placebo, n=6). No serious treatment-emergent adverse events (TEAEs) or discontinuations due to TEAEs were observed. One participant (bepranemab 60 mg/kg) experienced treatment-related TEAEs of headache (moderate intensity), nausea and vomiting (mild intensity). There was no effect of ethnicity on PK parameters. A dose-response effect of bepranemab on free tau levels was observed. Data applied to a PBPK/PD model supported a dose of 90 mg/kg of bepranemab every 4 weeks to achieve a reduction in mean change from baseline in free tau levels of up to 90%.

CONCLUSIONS: Safety, PK and PD data support continued investigation of bepranemab for the treatment of tauopathies.}, } @article {pmid41919455, year = {2026}, author = {Fujioka, S and Nagaishi, Y and Imamura, T and Minagawa, H and Uwatoko, K and Yukitake, M and Kira, JI and Tsuboi, Y}, title = {Amyloid PET-guided anti-amyloid therapy in corticobasal syndrome associated with clinical improvement.}, journal = {Neurologia i neurochirurgia polska}, volume = {}, number = {}, pages = {}, doi = {10.5603/pjnns.110307}, pmid = {41919455}, issn = {0028-3843}, abstract = {AIM OF THE STUDY: Corticobasal syndrome (CBS), a heterogeneous clinical phenotype, can be associated with various underlying pathologies. Although neuropathological studies show that CBS cases can be attributed to Alzheimer's disease (AD), in vivo confirmation and subsequent disease-modifying therapy remain rarely reported. In our patients presenting with clinical features consistent with CBS, amyloid positron emission tomography (PET) facilitated the diagnosis of underlying AD pathology and enabled the initiation of anti-amyloid therapy.

MATERIAL AND METHODS: We retrospectively reviewed patients with probable corticobasal degeneration from two tertiary centers who underwent amyloid PET confirming AD, systematically collecting clinical, imaging, and treatment data.

RESULTS: Two patients were identified who fulfilled the inclusion criteria. In both patients, episodic memory was impaired, which was inconsistent with a typical corticobasal syndrome phenotype. Amyloid PET demonstrated widespread cortical and subcortical amyloid deposition, confirming underlying AD pathology. Based on these findings, anti-amyloid therapy was initiated, and clinical improvement was observed in both patients, although causality cannot be inferred from this uncontrolled retrospective observation.

CONCLUSIONS: Corticobasal syndrome may be an atypical clinical presentation of AD pathology. Importantly, molecular imaging allowed an in vivo diagnosis of AD and facilitated the timely initiation of anti-amyloid therapy.

CLINICAL IMPLICATIONS: This novel report documents the clinical implementation of amyloid PET guided anti-amyloid therapy in patients presenting with CBS.}, } @article {pmid41920507, year = {2026}, author = {Lan, H and Zhang, J and Zhao, Z and Liu, X and Rao, C}, title = {Focal-DenseNet: A Risk Assessment Framework for Alzheimer's Disease in Heterogeneous MRI Data.}, journal = {Interdisciplinary sciences, computational life sciences}, volume = {}, number = {}, pages = {}, pmid = {41920507}, issn = {1867-1462}, support = {S202410497177//National Undergraduate Innovation and Entrepreneurship Training Program/ ; 25YJAZH138//Planning Fund Project of the Ministry of Education's Humanities and Social Sciences Research/ ; }, abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disease of the nervous system, which has become an important public health issue attracting global attention. However, its exact causes and pathogenesis have not been fully elucidated, and the existing treatment methods and intervention measures have limited efficacy. Therefore, how to establish a scientific and efficient risk assessment mechanism has become the key to the prevention and treatment of AD. Aiming at this problem, this paper optimizes the convolutional neural network structure of DenseNet and proposes a Focal-DenseNet model that integrates the focal loss function for the risk assessment and diagnostic prediction of AD. First of all, preprocess the collected data to ensure the data quality for subsequent analysis. Secondly, establish the Focal-DenseNet model. Finally, use the model for training and testing. The test results show that the test set accuracy of the model reaches 98.98%, indicating that the model performs well. In addition, this paper also compares the proposed model with the DenseNet model without using the focal loss function and other common deep learning models (such as VGG16, ResNet, etc.). The results show that the model in this paper exhibits superiority in multiple performance indicators. In particular, it has achieved high scores in key indicators such as accuracy, AUC (the area under the receiver operating characteristic curve), precision, and recall. This study provides an efficient technical support for the early risk assessment of AD, and holds significant clinical application value and academic reference significance for improving the prevention and treatment level of AD and reducing the global public health burden.}, } @article {pmid41920573, year = {2026}, author = {Pathak, US and Mehralizade, A and Goldberg, TE and Zoghbi, AW}, title = {Dementia in Severe Schizophrenia.}, journal = {JAMA psychiatry}, volume = {83}, number = {6}, pages = {590-600}, pmid = {41920573}, issn = {2168-6238}, mesh = {Humans ; Female ; Male ; *Dementia/genetics/epidemiology/etiology/diagnosis ; Retrospective Studies ; Middle Aged ; *Schizophrenia, Treatment-Resistant/complications/epidemiology/genetics ; Aged ; *Schizophrenia/complications ; Lewy Body Disease ; Severity of Illness Index ; }, abstract = {IMPORTANCE: Dementia develops in individuals with schizophrenia 4- to 20-fold more frequently than in the general population, but its etiology remains unexplained.

OBJECTIVE: To characterize the cognitive, clinical, and genetic features of dementia in individuals with severe, extremely treatment-resistant schizophrenia (SETRS).

This retrospective cohort study among individuals with SETRS was conducted at New York state hospitals from December 2017 through July 2019. All participants met DSM-5 schizophrenia criteria and were continuously hospitalized for 5 years or more. Exclusion criteria included forensic hospitalization, known medical causes of psychosis, or recent substance abuse. Cognitive, clinical, and genetic data were compared to data from individuals from the National Alzheimer Coordinating Center dataset, including those with Alzheimer disease (AD), frontotemporal dementia (FTD), Lewy body dementia (LBD), or vascular dementia (VD), along with healthy controls. Data were analyzed from January 2025 through December 2025.

MAIN OUTCOMES AND MEASURES: Multiple regression was used to analyze the effects of demographic, clinical, and genetic factors on the Montreal Cognitive Assessment (MoCA).

RESULTS: In this study's cohort of 155 individuals with SETRS (mean [SD] age, 59.3 [10.3] years; 56 female participants [36.1%]), 153 of 155 (98.7%) scored below the cutoff of 26 for mild cognitive impairment, and 73 of 155 (47.1%) scored below the cutoff of 10 for severe dementia (mean [SD] MoCA score, 9.8 [6.4]). At the item level, the MoCA profile of SETRS differed from those of AD and FTD but paralleled that of community-dwelling individuals with schizophrenia (Pearson r = 0.86; P < .001). No participants carried pathogenic variants in mendelian dementia genes; APOE4 allele frequency was significantly lower in SETRS (14.4%) than in AD (33.6%; odds ratio [OR], 0.33; 95% CI, 0.20-0.53; P < .001) or LBD (24.7%; OR, 0.51; 95% CI, 0.29-0.89; P = .01). Cognitive impairment was not attributable to premorbid intellectual disability, poor effort, medications, cardiometabolic risk factors, or institutionalization.

CONCLUSIONS AND RELEVANCE: In this cohort study of 155 individuals with SETRS, none of the commonly proposed explanations for schizophrenia dementia (eg, comorbid Alzheimer disease or cardiovascular risk factors) proved viable. The pattern of cognitive impairments differed from those of Alzheimer disease, frontotemporal dementia, and Lewy body dementia, but recapitulated and intensified that of community-dwelling schizophrenia.}, } @article {pmid41921123, year = {2026}, author = {Bukhbinder, AS and Ling, Y and Jhin, L and He, E and Harris, K and Rodriguez, M and Thomas, J and Cruz, G and Phelps, K and Kim, Y and Chen, L and Jiang, X and Schulz, PE}, title = {Risk of Alzheimer Dementia After High-Dose vs Standard-Dose Influenza Vaccination.}, journal = {Neurology}, volume = {106}, number = {8}, pages = {e214782}, pmid = {41921123}, issn = {1526-632X}, support = {R01 AG082721/AG/NIA NIH HHS/United States ; R01 AG084637/AG/NIA NIH HHS/United States ; }, mesh = {Humans ; *Alzheimer Disease/epidemiology/prevention & control ; Female ; Male ; Aged ; *Influenza Vaccines/administration & dosage ; Retrospective Studies ; Aged, 80 and over ; *Vaccination ; *Influenza, Human/prevention & control ; Cohort Studies ; }, abstract = {BACKGROUND AND OBJECTIVES: Previous studies, including large cohort analyses comparing vaccinated and unvaccinated adults, suggest that routine immunizations such as inactivated influenza vaccines (IIVs) may reduce Alzheimer dementia (AD) risk. Whether AD risk differs after high-dose IIV (H-IIV) vs standard-dose IIV (S-IIV) remains unexamined. We hypothesized that AD risk would be lower among adults ≥65 years after H-IIV compared with S-IIV.

METHODS: This retrospective cohort study analyzed data spanning 2014-2019 from IQVIA PharMetrics Plus for Academics, a US health care claims database. Eligible participants were ≥65 years with ≥2 years of continuous medical and pharmaceutical coverage and no previous diagnostic or pharmacotherapeutic indicators of cognitive impairment. Vaccinations were identified by name and Current Procedural Terminology codes. Participants were followed for up to 3 years postvaccination. Incident AD was defined using International Classification of Diseases codes and AD medication dispenses (anticholinesterase inhibitors, memantine). We emulated a target trial using sequential nested trials to align eligibility, treatment assignment, and time-zero with vaccination dates, preventing immortal time bias. Inverse probability weighting adjusted for measured confounding, emulated randomization, and mitigated selection bias. Effects were estimated as risk difference, number needed to treat (NNT), risk ratio; 95% CIs were obtained via bootstrapping. Secondary analyses examined potential effect modifiers such as sex.

RESULTS: The H-IIV group included 120,775 unique participants (185,183 person-trials; mean age 74.4 years, SD 5.5; 57.3% female), and the S-IIV group included 44,022 participants (53,918 person-trials; mean age 73.0, SD 6.1; 56.4% female). H-IIV was associated with significantly lower AD risk during months 1-25 postvaccination (minimum NNT = 185.2 at 25 months). After sex stratification, risk reduction persisted longer among women (months 1-13, minimum NNT = 416.7) than men (months 17-24, significant only in intention-to-treat analysis, minimum NNT = 232.6).

DISCUSSION: High-dose influenza vaccination is associated with reduced AD risk compared with standard-dose vaccination in adults ≥65 years, with a stronger effect among women. Significant study limitations included duration of follow-up (≤3 years) and lack of sociodemographic, lifestyle, biomarker, and mortality data. Further research is needed to clarify whether the observed difference reflects protection against influenza infection or non-infection-related mechanisms.

CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that treatment with H-IIV vs S-IIV was associated with decreased incident dementia in individuals ≥65 years of age captured in this US health care claims database.}, } @article {pmid41921847, year = {2026}, author = {Dong, YR and Wang, JR and Yang, Y and Chen, QZ and Jiang, YQ and Yang, X and Zhou, MC and Cao, SP and Zeng, SX and Zang, CX and Li, FF and Bao, XQ and Zhang, D}, title = {Unveiling the UFMylation Pathway: Implications in Neurodegenerative Diseases.}, journal = {Journal of molecular biology}, volume = {438}, number = {12}, pages = {169772}, doi = {10.1016/j.jmb.2026.169772}, pmid = {41921847}, issn = {1089-8638}, mesh = {Humans ; *Neurodegenerative Diseases/metabolism ; *Protein Processing, Post-Translational ; Ubiquitination ; Animals ; alpha-Synuclein/metabolism ; tau Proteins/metabolism ; *Proteins/metabolism ; }, abstract = {UFMylation is a recently characterized post-translational modification (PTM) system that conjugates Ubiquitin-Fold Modifier 1 (UFM1) to target proteins via a dedicated enzymatic cascade. This modification system regulates critical cellular processes by controlling protein subcellular localization, modulating protein-protein interactions, and coordinating with ubiquitination to regulate protein stability. Emerging evidence highlights UFMylation as a critical modifier of pathological proteins, including tau and α-synuclein, while impaired UFMylation pathways are observed in the brains of individuals with neurodegenerative disorders. In this review, we summarize the current role and mechanism of UFMylation in the pathogenesis of neurodegenerative diseases, offering the first comprehensive framework for targeting UFMylation in the treatment of neurodegenerative diseases.}, } @article {pmid41922490, year = {2026}, author = {Holmes, SE and Smith, GS}, title = {Trajectories of late-life depression: insights from molecular imaging.}, journal = {Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology}, volume = {}, number = {}, pages = {}, pmid = {41922490}, issn = {1740-634X}, support = {R01 AG059390/AG/NIA NIH HHS/United States ; R01AG059390//U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; R01NS125482//U.S. Department of Health & Human Services | NIH | National Institute of Neurological Disorders and Stroke (NINDS)/ ; }, abstract = {Late-life depression is associated with greater disability, suicide risk and mortality than depression in mid-life, and is a risk factor/prodrome for neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease. Many depressed, older adults fail to respond to first line antidepressant treatment, experience relapse and exhibit persistent symptoms, including anxiety, apathy and cognitive impairment, that may reflect underlying neurodegenerative processes. Advances in molecular imaging, particularly positron emission tomography (PET) allow direct in-vivo investigation of neurobiological mechanisms underlying late-life depression symptom trajectories, treatment response and the potential links to neurodegenerative disease. Molecular imaging studies in late-life depression have revealed alterations across neurotransmitter systems and Alzheimer's disease pathology (beta-amyloid and Tau) and a potential role of neuroinflammation. In late-life depression, variability in symptom presentation and treatment response arises from interacting neurotransmitter, inflammatory, and neurodegenerative processes and potentially other molecular mechanisms that impair synaptic plasticity. Future directions include the application of next-generation PET tracers targeting glutamatergic signaling, mitochondrial function, histone deacetylase activity, and cell-type-specific inflammation, along with multi-modal image analysis methods to test mechanistic models . Molecular imaging holds significant promise for guiding the development of targeted, mechanism-based treatments that reduce the burden of late-life depression and its associated vulnerability to neurodegenerative disease.}, } @article {pmid41922883, year = {2026}, author = {Shah, D and Akarte, K and Patel, S and Patel, A and Kushwaha, N and Panjwani, D and Patel, V and Ahlawat, P and Shah, A}, title = {Recent Progress on Selenium Nanoparticles: Synthesis and Neuroprotective Effects for the Treatment of Alzheimer's Disease.}, journal = {Molecular neurobiology}, volume = {63}, number = {1}, pages = {}, pmid = {41922883}, issn = {1559-1182}, mesh = {*Alzheimer Disease/drug therapy ; Humans ; *Nanoparticles/chemistry/therapeutic use ; Animals ; *Neuroprotective Agents/therapeutic use/chemical synthesis/chemistry/pharmacology ; *Selenium/therapeutic use/chemistry ; Blood-Brain Barrier/metabolism/drug effects ; }, abstract = {Alzheimer's disease (AD) is the most prevalent cause of dementia, affecting over 50 million individuals worldwide, with projections suggesting a tripling of cases by 2050. Current Food and Drug Administration (FDA)-approved treatments, including cholinesterase inhibitors, N-Methyl-D-aspartic acid (NMDA) receptor antagonists, and monoclonal antibodies, provide only modest symptomatic relief or partial disease modification. Their limitations include poor blood-brain barrier penetration, systemic side effects, and reduced efficacy in advanced stages. This has caused the exploration of novel nanotechnology-based interventions. This review synthesizes recent evidence from preclinical and translational studies on SeNPs for AD therapy. Also covering their synthesis methods (physical, chemical, and biological), surface engineering approaches, drug loading strategies, and mechanisms of action were systematically examined. SeNPs exhibit dual functionality as therapeutic agents and drug carriers. Functionalized SeNPs have shown the ability to cross the BBB, but this efficiency depends on particle size (typically < 100 nm) and surface ligands such as transferrin, rabies virus glycoprotein 29-peptide (RVG29), or transferrin-guiding peptide (TGN). Studies using ligand-modified SeNPs demonstrate improved BBB transport and enhanced modulation of oxidative stress, amyloid-β (Aβ) aggregation, and neuroinflammation. SeNPs exhibit neuroprotective activity in several preclinical models, primarily attributed to antioxidant and anti-inflammatory mechanisms. Although encouraging preclinical data support their promise, systematic toxicological assessment and optimization of stability are required. With advances in green synthesis, surface engineering, and theranostic applications, SeNPs may represent a new Framework in precision nanomedicine for Alzheimer's disease.}, } @article {pmid41922909, year = {2026}, author = {Dai, Q and Lin, Q and Chen, J and Deng, Z and Jin, W and Ye, P and Zuo, Y and Yang, Y and Xiao, S and Tang, Y}, title = {Prevalence and burden of neurological diseases in the Chinese mainland: An analysis from the Global Burden of Disease Study 2021.}, journal = {Chinese medical journal}, volume = {}, number = {}, pages = {}, pmid = {41922909}, issn = {2542-5641}, abstract = {BACKGROUND: Neurological diseases represent a growing challenge to the Chinese public health system. However, a comprehensive analysis of neurological diseases in China is lacking. This study aimed to analyze disease burden and risk factors of neurological diseases in the Chinese mainland to identify priorities for disease control and prevention.

METHODS: Disease burden and risk factors in the Chinese mainland were analyzed for 12 neurological disorders using data from the Global Burden of Diseases 2021 study and the Chinese Center for Disease Control and Prevention. Prevalence, deaths, years of life lost, years lived with disability (YLDs), and disability-adjusted life years (DALYs) were used as metrics.

RESULTS: Intracerebral hemorrhage (ICH) (1930.3 [95% uncertainty interval (UI): 1605.3-2296.7] per 100,000), ischemic stroke (1646.8 [95% UI: 1400.0-1893.1] per 100,000), Alzheimer's disease and other dementias (dementia) (708 [95% UI: 347.7-1561.7] per 100,000) made the greatest contributions to DALY rates in the Chinese mainland in 2021. The fastest growing contributors to DALY rates were dementia (208.2% [95% UI: 166.4-255.7%]), Parkinson's disease (160.7% [95% UI: 121.8-208.3%]), and ischemic stroke (95.2% [95% UI: 56.9-140.6%]). Migraine was the leading contributor to DALY rates among populations aged 10-39 years, ICH for those aged 40-74 years, ischemic stroke for those aged 75-89 years, and dementia for those aged >90 years. Ischemic stroke accounted for the highest age-standardized DALY rates in North and Northeast China, whereas ICH ranked first in other regions. High systolic blood pressure had the highest attributable DALYs for all diseases combined. Metabolic risk factors, alcohol use, secondhand smoke, and low physical activity contributed to higher YLDs in females, whereas alcohol use, smoking, and a high-sodium diet contributed to higher YLDs in males.

CONCLUSIONS: Neurological diseases present a growing public health challenge, characterized by significant disparities in their prevalence and presentation across age, sex, and geographic regions. Addressing these disparities requires coordinated strategies encompassing prevention, treatment, rehabilitation, and supportive care at the national level.}, } @article {pmid41923420, year = {2026}, author = {Luzzi, S and Snowden, JS}, title = {Low Sensitivity of Neuropsychological Scales Hinder Detection of Potential Benefit of Treatments in Alzheimer's Disease: A Position Paper.}, journal = {European journal of neurology}, volume = {33}, number = {4}, pages = {e70590}, pmid = {41923420}, issn = {1468-1331}, mesh = {Humans ; *Alzheimer Disease/diagnosis/therapy/drug therapy ; *Neuropsychological Tests/standards ; Cognitive Dysfunction/diagnosis ; Sensitivity and Specificity ; }, abstract = {BACKGROUND: Despite the advent of Disease Modifying Therapies (DMTs) for Alzheimer's Disease (AD), the approval and commercialization of anti-amyloid monoclonal antibodies has been slow and contentious, particularly in Europe. The primary source of debate is the discrepancy between robust biological effects-namely, effective β-amyloid clearance-and modest clinical improvements, which, although statistically significant, often fail to reach the minimal clinically important difference (MCID) compared to placebo.

METHODS: This paper highlights a confounding factor in the interpretation of the results of clinical trials: limited sensitivity of neuropsychological outcome measures. These tools, developed in the 1980s and only marginally updated, are not suited to detect subtle but meaningful cognitive changes in early disease stages.

RESULTS: The ADAS-Cog, the most commonly used cognitive endpoint, suffers from a substantial ceiling effect, impairing its ability to capture cognitive decline over short durations in prodromal populations. Likewise, functional scales such as the CDR-SB are inherently insensitive in mild cognitive impairment (MCI), as functional independence is, by definition, preserved. Moreover, the use of composite multidomain scales with high baseline scores may mask domain-specific improvements, further limiting a drug's capacity to reach MCID thresholds.

CONCLUSION: Methodological limitations risk undervaluing the therapeutic impact of treatment, particularly in trials targeting early or preclinical phases where changes are subtle and domain-specific. Urgent reconsideration of outcome measures is necessary to ensure accurate assessment of clinical efficacy and to avoid prematurely discarding potentially beneficial therapies.}, } @article {pmid41924980, year = {2026}, author = {Chaulagain, B and Gothwal, A and Mahanta, AK and Jarajapu, YPR and Singh, J}, title = {Cannabidiol and pBDNF Cotreatment Attenuates Pathological Symptoms and Improves Cognition in 3 month-Old 5XFAD Mice.}, journal = {ACS chemical neuroscience}, volume = {17}, number = {8}, pages = {1555-1565}, doi = {10.1021/acschemneuro.5c01009}, pmid = {41924980}, issn = {1948-7193}, support = {R01 AG068034/AG/NIA NIH HHS/United States ; R01 AG083981/AG/NIA NIH HHS/United States ; RF1 AG068034/AG/NIA NIH HHS/United States ; }, mesh = {Animals ; *Brain-Derived Neurotrophic Factor/administration & dosage/genetics/metabolism ; *Cannabidiol/pharmacology/administration & dosage ; *Alzheimer Disease/pathology/drug therapy/metabolism ; Mice ; Mice, Transgenic ; *Cognition/drug effects ; Disease Models, Animal ; Cognitive Enhancement ; Plaque, Amyloid/pathology ; Brain/drug effects/metabolism/pathology ; Humans ; }, abstract = {The marginal efficiency observed with the existing therapies in Alzheimer's Disease (AD) can be attributed to the timing of the treatment. The beneficiaries of symptomatic or disease-modifying therapy for AD are mild-cognitive-impairment (MCI) or late-stage dementia patients. At this stage, the pathological features are already advanced and irreversible, as the shift in biomarker levels starts in a continuum 15-20 years prior. Early intervention, therefore, is a plausible solution to this issue. Consequently, we selected 3 month-old 5XFAD AD mice as an early intervention model. We administered cannabidiol (CBD) and plasmid brain-derived neurotrophic factor (BDNF) encapsulated in liposome nanoparticles, functionalized with penetratin and mannose for brain-targeting, as a therapy. Neuroinflammation is emerging as a key driver of AD progression by its interaction with amyloid plaques and phosphorylated tau. Therefore, CBD, which is anti-inflammatory and neuroprotective, was used. BDNF, a synaptic modulation and cognitive maintenance agent, is declined and, thus, aggravates pathology and cognition in AD. BDNF expressed from the liposome nanoparticles supplements the reduced BDNF and aids in ameliorating AD pathology. We found four weekly doses of our formulation reduced the amyloid burden by 3.04-fold (p-value < 0.0001), declined pro-inflammatory cytokines TNF-α by 2.51-fold (p-value < 0.0001), IL-1β by 2.34-fold (p-value < 0.0001) and microglial activation by 2.15-fold (p-value < 0.0001) than saline controls. In addition, it increased the synaptic markers level and promoted adult hippocampal neurogenesis, eventually improving cognitive functions. These findings suggest the use of CBD and pBDNF has a potential therapeutic combination for AD management if intervened early.}, } @article {pmid41925793, year = {2026}, author = {Ramanan, S and Johnson, GVW}, title = {A Bioinformatic Analysis of BAG Protein Interactors and Pathways in Alzheimer's and Parkinson's Disease.}, journal = {Journal of molecular neuroscience : MN}, volume = {76}, number = {2}, pages = {}, pmid = {41925793}, issn = {1559-1166}, support = {R01 AG073121/AG/NIA NIH HHS/United States ; R01AG073121/GF/NIH HHS/United States ; }, mesh = {Humans ; *Parkinson Disease/metabolism/genetics ; *Alzheimer Disease/metabolism/genetics ; Animals ; *Transcription Factors/metabolism/genetics ; *DNA-Binding Proteins/metabolism/genetics ; Signal Transduction ; Computational Biology/methods ; Adaptor Proteins, Signal Transducing/metabolism/genetics ; Apoptosis Regulatory Proteins/metabolism/genetics ; }, abstract = {Alzheimer's disease (AD) and Parkinson's disease (PD) are the two most common neurodegenerative disorders. Within the scope of neurodegenerative disorders, the Bcl-2 associated athanogene (BAG) family proteins and associated interactors have been a key area of focus. The BAG family is a group of proteins that contain at least one evolutionarily conserved BAG domain. Despite this similarity, their interactions and functions can vary widely. So far, research has predominantly scrutinized individual BAG proteins, rather than explore potential cooperative actions among family members. Some BAG family members may function together thereby indicating potential interactions within this family. Although connections among BAG members have been observed, their role in neurodegenerative disorders, such as AD and PD, remains largely uncharacterized. This mini review explores the common pathways, intersections, and differences within these interactions as well as their link to AD and PD. Using computational techniques to mine transcriptomic data, several groupings of pathways that these BAG family members are involved in were identified in the context of AD and PD. Understanding these pathways and their relationships may uncover potential gaps in current research and help identify novel therapeutic targets for the treatment of these neurodegenerative diseases.}, } @article {pmid41925947, year = {2026}, author = {Patwekar, F and Patwekar, M and Wei, LS and Sharma, R and Varghese, R and Mohammed, A}, title = {Advancing diagnostic biomarkers in Alzheimer's disease: interdisciplinary innovations and technological frontiers.}, journal = {Human cell}, volume = {39}, number = {4}, pages = {}, pmid = {41925947}, issn = {1749-0774}, mesh = {*Alzheimer Disease/diagnosis/diagnostic imaging ; Humans ; *Biomarkers/analysis ; Precision Medicine ; Biosensing Techniques ; Digital Health ; Nanotechnology ; Early Diagnosis ; Machine Learning ; Artificial Intelligence ; *Interdisciplinary Research/trends ; Multiomics ; }, abstract = {Developing diagnostic biomarkers for Alzheimer's disease (AD) is at the cutting edge of interdisciplinary research and technical advancement. This comprehensive analysis investigates potential options for improving diagnostic accuracy and early detection of AD. Identifying biomarkers other than Aβ and tau proteins, such as synaptic dysfunction markers and metabolic indicators, is a novel technique. Integrating multi-omics data provides a comprehensive picture of AD pathophysiology, assisting in the discovery of biomarkers and treatment targets. Advances in technology, notably nanotechnology and biosensors, show promise for highly sensitive and specific platforms capable of identifying AD-related biomarkers in physiological fluids. AI and machine learning algorithms are critical in analyzing large datasets, improving pattern identification, and increasing diagnostic accuracy. Predictive models based on various biomarkers and clinical data open the way for personalized medicine methods in the treatment of AD. More advancements in PET and MRI tracers are required for targeted and sensitive imaging of specific AD-related clinical alterations. Wearing gadgets and seeing digital health signs have helped us to find diseases early and track them over time. They even allow monitoring from afar and all the time. This comprehensive review brings together new developments and teamwork across different fields. In this way, it guides to enhance how to identify AD. By mixing these new methods, we aim to change the diagnosis of AD early and accurately. This allows us to focus on treatments and push forward new cures for AD.}, } @article {pmid41925951, year = {2026}, author = {Feng, JQ and Yang, LL and Luo, YX and Yao, XQ}, title = {Alzheimer's disease: from molecular pathways to therapies.}, journal = {Molecular biomedicine}, volume = {7}, number = {1}, pages = {}, pmid = {41925951}, issn = {2662-8651}, support = {No.82371427//National Natural Science Foundation of China/ ; No.82401656//National Natural Science Foundation of China/ ; CSTB2023NSCQ-MSX0323//Natural Science Foundation of Chongqing Municipality/ ; 2025MSXM044//Joint project of Chongqing Health Commission and Science and Technology Bureau/ ; CYB240199//Postgraduate Research and Project of Chongqing Province/ ; }, mesh = {Humans ; *Alzheimer Disease/therapy/metabolism/pathology ; Animals ; Amyloid beta-Peptides/metabolism ; tau Proteins/metabolism ; Immunotherapy/methods ; Signal Transduction ; Molecular Targeted Therapy ; }, abstract = {Alzheimer disease (AD) is the most common neurodegenerative disorder and a leading cause of dementia worldwide. With accelerating population aging, its incidence continues to rise, imposing a substantial burden on public health systems and society. Despite extensive advances in research, currently available therapies remain largely symptomatic and have limited capacity to halt or reverse disease progression. Recent progress in understanding the molecular and cellular mechanisms underlying AD has driven the development of targeted therapeutic strategies, particularly immunotherapies directed against amyloid-β (Aβ) and tau pathology. However, the pathogenesis of AD is highly complex and multifactorial, underscoring the need for a more integrated understanding of the interactions among diverse pathological processes and the identification of additional therapeutic targets. Here, we provide a systematic synthesis of the core pathological mechanisms of AD and their interconnected molecular pathways, together with a comprehensive overview of current targeted therapeutic strategies. We highlight recent advances in Aβ- and tau-directed immunotherapies and further examine emerging interventions targeting neuroinflammation, metabolic dysregulation, the gut microbiota, lifestyle-related factors, and neurogenesis, evaluating their potential based on evidence from both clinical and preclinical studies. By integrating mechanistic insights with therapeutic developments, this review outlines key opportunities and challenges in the evolving landscape of AD treatment. These perspectives may inform the development of next-generation disease-modifying therapies and contribute to a more comprehensive framework for understanding the pathogenesis and treatment of AD.}, } @article {pmid41926104, year = {2026}, author = {Devanand, DP and Wei, R and Qian, M}, title = {Treatment of Early Symptomatic Alzheimer Disease With Valacyclovir-Reply.}, journal = {JAMA}, volume = {335}, number = {17}, pages = {1536-1537}, doi = {10.1001/jama.2026.1105}, pmid = {41926104}, issn = {1538-3598}, } @article {pmid41926105, year = {2026}, author = {Kosaka, M and Kami, M}, title = {Treatment of Early Symptomatic Alzheimer Disease With Valacyclovir.}, journal = {JAMA}, volume = {335}, number = {17}, pages = {1536}, doi = {10.1001/jama.2026.1102}, pmid = {41926105}, issn = {1538-3598}, } @article {pmid41926304, year = {2026}, author = {Senwar, KR and Dhillon, A and Yadav, M}, title = {Small Molecule Inhibitors Targeting Pathogenic Protein Aggregation in Neurodegenerative Diseases: Medicinal Chemistry and Mechanistic Insights.}, journal = {Current topics in medicinal chemistry}, volume = {}, number = {}, pages = {}, doi = {10.2174/0115680266439510260223082224}, pmid = {41926304}, issn = {1873-4294}, abstract = {A hallmark of Neurodegenerative Diseases (NDs) is protein misfolding, aggregation, and accumulation in specific brain regions. The accumulation of insoluble, misfolded protein aggregates is usually referred to as amyloid formation. This process leads to cellular dysfunction, destruction of neurons, loss of neuronal connections in specific brain areas, and brain damage. Despite the involvement of distinct pathogenic proteins, the underlying mechanisms of misfolding and aggregate formation are remarkably similar across various NDs. In this review, we present a comprehensive overview of the medicinal chemistry and mechanistic insights into phytochemicals and synthetic small molecules with potential for the treatment of neurodegenerative disorders. Various small molecules have been reported to have therapeutic effects by inhibiting the misfolding, aggregation, and accumulation of pathogenic proteins, such as amyloid-β, tau, and α- synuclein. This review mainly covers natural product-derived small molecules, notably polyphenols (including flavonoids and non-flavonoid polyphenols), as well as other phytochemical classes, such as quinones and alkaloids, along with their possible mechanisms of action. In addition, synthetic small molecules, osmolytes, metal chelators, and repurposed drugs for neurodegenerative disorders are thoroughly discussed.}, } @article {pmid41926844, year = {2026}, author = {Beyrer, J and Sheff, Z and Payakachat, N and Chandler, JM and Chen, YF and Kubisiak, J and Lee, A and Holdridge, KC and Yaari, R and Aisen, P and Rafii, MS and Sperling, RA and , }, title = {Increase in healthcare utilization and Medicare payment with progression of preclinical Alzheimer's disease.}, journal = {The journal of prevention of Alzheimer's disease}, volume = {13}, number = {6}, pages = {100547}, pmid = {41926844}, issn = {2426-0266}, mesh = {Aged ; Aged, 80 and over ; Female ; Humans ; Male ; *Alzheimer Disease/economics/therapy ; Disease Progression ; Health Care Costs ; *Medicare/economics/statistics & numerical data ; *Patient Acceptance of Health Care/statistics & numerical data ; Retrospective Studies ; United States ; Observational Studies as Topic ; Randomized Controlled Trials as Topic ; Multicenter Studies as Topic ; }, abstract = {BACKGROUND: Alzheimer's disease (AD) begins with the preclinical stage (Stages 1 and 2) where individuals are cognitively unimpaired but have AD pathology. Healthcare utilization and medical cost of cognitively unimpaired (preclinical) AD have not been previously evaluated.

OBJECTIVES: To describe healthcare resource utilization (HRU) and Medicare payments among cognitively unimpaired individuals with and without elevated amyloid and to evaluate the association of AD progression with HRU and Medicare payments.

DESIGN: Retrospective cohort analysis of the randomized controlled trial (Anti-Amyloid Treatment in Asymptomatic AD [A4]) and companion observational study (Longitudinal Evaluation of Amyloid Risk and Neurodegeneration [LEARN]) linked with Medicare.

SETTING: Clinical trials sites in the United States PARTICIPANTS: 246 cparticipants with cognitively unimpaired AD in A4 and 121 amyloid-negative participants in LEARN Medicare cohorts.

MEASUREMENTS: Measures from Medicare claims included medical conditions (diagnosis codes), HRU (inpatient, emergency room, outpatient, professional, skilled nursing facility, home health), and Medicare payments. AD progression (or cognitive or functional decline) was measured using Clinical Dementia Rating Scale-Global Score (CDR-GS) in A4/LEARN and diagnosis codes for cognitive impairment, AD, and JEN Frailty Index (JFI) of ≥6 (high frailty) in Medicare data.

RESULTS: HRU and payments were overall similar between A4 and LEARN Medicare. Claims indicators suggesting AD progression in A4 Medicare were associated with higher inpatient, outpatient, emergency room, and home health utilization (any utilization) and increased number of inpatient stays. Payments were significantly greater in A4 Medicare with AD progression vs without progression: 45% payment increase for cognitive impairment (p=0.035) with a mean incremental cost of $140 per person per month (PPPM) (95% confidence interval [CI] $125-$155), 66% payment increase for AD (p=0.011) with a mean incremental cost of $207 PPPM (95% CI $188-$226), and 103% payment increase for high frailty (p<0.001) with a mean incremental cost of $303 PPPM (95% CI $283-$323).

CONCLUSIONS: Overall, individuals with cognitively unimpaired AD in A4 Medicare did not have increased utilization and payments vs LEARN. HRU and payments were significantly greater in A4 Medicare participants with AD progression indicators in claims vs those without progression. These results highlight the need for additional research on both health and economic impacts of progression in a real-world (routine care) cohort of individuals with cognitively unimpaired AD and the potential cost savings associated with effective therapy that delays AD progression in cognitively unimpaired AD.

NCT02008357, NCT02488720.}, } @article {pmid41928210, year = {2026}, author = {Leelahavarong, P and Prawjaeng, J and Angkab, P and Wongkom, N and Scheltens, P and Srinonprasert, V and Senanarong, V}, title = {Cost-utility analysis of cerebrospinal fluid versus blood biomarkers for early detection of Alzheimer's disease and mild cognitive impairment in Thailand: a modeling study.}, journal = {BMC health services research}, volume = {26}, number = {1}, pages = {}, pmid = {41928210}, issn = {1472-6963}, mesh = {Humans ; Thailand ; Biomarkers/blood/cerebrospinal fluid ; *Alzheimer Disease/diagnosis/blood/cerebrospinal fluid ; Cost-Benefit Analysis ; *Amyloid beta-Peptides/blood/cerebrospinal fluid ; Cost-Effectiveness Analysis ; *Cognitive Dysfunction/diagnosis/blood/cerebrospinal fluid ; Markov Chains ; Aged ; Quality-Adjusted Life Years ; Early Diagnosis ; Decision Trees ; Peptide Fragments/blood ; Male ; Sensitivity and Specificity ; Female ; }, abstract = {OBJECTIVE: To evaluate the cost-utility of cerebrospinal fluid (CSF) and blood-based amyloid beta biomarkers for early detection of Alzheimer’s disease and mild cognitive impairment among older Thai adults at high risk of dementia. METHODS: We constructed a decision tree with Markov models from a societal perspective, using a 1-year cycle over a lifetime horizon and applying a 3% annual discount. Amyloid beta (Aβ)1–42 was used for CSF, while Aβ40 and Aβ42 were used for blood. Sensitivity and specificity data were primarily derived from Thai patients at Siriraj Hospital, and nonpharmacological treatment efficacy was obtained from the FINGER study. Epidemiological data, transition probabilities, and costs were collected from the literature and Siriraj Hospital; direct nonmedical costs and utility values were also obtained from Siriraj. We calculated lifetime costs, quality-adjusted life years (QALYs), and incremental cost-effectiveness ratios (ICERs), evaluating cost-effectiveness against THB160,000 (USD4,370) per QALY. Parameter uncertainty was explored via sensitivity analyses. This is non-clinical trail study. RESULTS: Compared with no testing, the CSF strategy yielded 0.011 additional life-years and 0.019 additional QALYs for an extra cost of THB2,589 (USD71), resulting in an ICER of THB132,961 (USD3,632) per QALY. Blood-based testing provided 0.009 additional life-years and 0.017 QALYs for an extra cost of THB15,467 (USD422), leading to an ICER of THB907,057 (USD24,776) per QALY. CONCLUSIONS: CSF biomarker testing is cost-effective in Thailand, whereas blood-based biomarkers are not. Reducing the cost of Simoa (the technology used to measure blood biomarkers) by approximately 83% would improve the cost-effectiveness of blood-based biomarkers. Future research should enhance blood biomarker accuracy.}, } @article {pmid41928225, year = {2026}, author = {Kato, M and Isazawa, A and Ohki, A and Fujita, A and Araki, M and Yanaizu, M and Kino, Y}, title = {Functional sQTLs regulating PTK2B exon 31 splicing uncover an RNA-dependent modulation of its kinase activity and cellular phenotype.}, journal = {Cell communication and signaling : CCS}, volume = {24}, number = {1}, pages = {}, pmid = {41928225}, issn = {1478-811X}, support = {19J15024//Ministry of Education, Culture, Sports, Science and Technology/ ; 19K07982//Ministry of Education, Culture, Sports, Science and Technology/ ; }, mesh = {*Focal Adhesion Kinase 2/genetics/metabolism ; Humans ; Animals ; *Exons/genetics ; *Alternative Splicing/genetics ; Phenotype ; Mice ; Alzheimer Disease/genetics ; Cell Movement ; Polymorphism, Single Nucleotide/genetics ; }, abstract = {BACKGROUND: Genome-wide association studies have shown that polymorphisms in PTK2B (Protein Tyrosine Kinase 2 Beta), encoding the calcium-sensitive tyrosine kinase PYK2 (Proline-rich tyrosine kinase 2), are associated with an increased risk of Alzheimer’s disease (AD). However, it remains unclear which genetic variants of PTK2B are functionally important. A recent transcriptome-wide association study has identified alternative splicing of exon 31 in PTK2B as being associated with AD, and proposed rs2251430 as the relevant splicing quantitative trait locus (sQTL). Here, we aimed to elucidate the regulatory mechanisms and functional significance of exon 31 splicing. METHODS: Alternative splicing of exon 31 was evaluated using publicly available RNA-seq data. To investigate the regulation of exon 31 splicing, we performed RT-PCR, RNA pull-down assays, Liquid Chromatography–Tandem Mass Spectrometry, and RNA immunoprecipitation. Western blotting, immunofluorescence, and co-immunoprecipitation analyses were conducted to examine the effects of exon 31 and its polymorphisms on PYK2 protein expression and function. The impact of exon 31 on cellular phenotypes was further assessed using antisense oligonucleotide (ASO) treatment in HeLa and HMC3 cells. RESULTS: We detected exon 31 skipping in certain human cell types, but not in mice, and observed its increase in microglia during AD progression. We then identified rs751019 and rs751018, both located near rs2251430, as sQTLs that affect exon 31 splicing, with rs751019 having a greater impact. Among RNA-binding proteins that interact with the surrounding sequence of rs751019, PCBP1 and PCBP2 were found to redundantly regulate exon 31 inclusion. PYK2 lacking exon 31 exhibited reduced protein expression and kinase activity, which in turn resulted in diminished phosphorylation of its substrate, GSK3β, with little change in calmodulin binding and intracellular localization. Moreover, ASO-induced exon 31 skipping decreased cell migration in a wound healing assay. It also increased multinucleation in human microglia-like HMC3 cells, a process recently identified in protective microglia. CONCLUSIONS: Our study validates rs751019 and rs751018 as functional sQTLs that influence PTK2B exon 31 splicing. It also identifies species-specific alternative splicing of exon 31 as a modulator of PYK2 expression and kinase activity, thereby linking sQTL-associated genetic variants to molecular and cellular changes that may underlie AD pathogenesis.}, } @article {pmid41928631, year = {2026}, author = {Huang, Y and Zhu, X and Yang, S and Zhang, Y and Tan, Z and Han, S}, title = {Digital Technology in Cognitive Decline: Bibliometric and Visualization Study.}, journal = {Current Alzheimer research}, volume = {}, number = {}, pages = {}, doi = {10.2174/0115672050420571260126043841}, pmid = {41928631}, issn = {1875-5828}, abstract = {With an increasing prevalence of cognitive decline diseases around the world, digital technologies are becoming an important tool for their prevention, diagnosis, and treatment. In this study, we present a comprehensive bibliometric study on the application of these digital technologies in the field of cognitive decline. This study intends to examine the trends of development and research hotspots of digital technology in cognitive decline field by bibliometric analysis. The literature has been analyzed in a systematic way. Bibliometrix R-package and VOSviewer were used to investigate publication tendency, country contribution, scholar influence, and research hotspots. A total of 1661 articles from 2006 to 2023 were analyzed. Results show an exponential increase in the number of annual publications on digital technologies applications and cognitive decline. The top journals, by volume of publication, are Alzheimer's & Dementia, the Journal of Alzheimer's Disease, and Neurology. The US is the dominant contributor of literature to this field, and the key countries for author impact include Greece, the USA, and Italy. Current research hotspots include virtual reality, machine learning, and artificial intelligence, based on analysis of keywords. This study characterizes the overall research progress and reveals research hotspots, trends, and the collaboration status among countries, on the utilization of digital technologies for cognitive decline. Moving forward, we call on researchers to increase developed/developing countries collaboration, to further implement digital technologies to counteract the public health burden of cognitive decline.}, } @article {pmid41928975, year = {2026}, author = {Ma, X and Koppelmans, V and Akcicek, H and Akcicek, EY and Shen, J and Chen, L and Balu, N and Yuan, C and King, JB}, title = {SNAP MRI Reveals Association Between Distal Cerebral Arterial Flow and Cognitive Function in an Aging Population.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {41928975}, issn = {2692-8205}, abstract = {OBJECTIVE: Impaired blood flow has recently been recognized as a critical contributor to cognitive impairment and dementia. It was reported that cerebral distal arterial flow measured from Simultaneous Non-contrast Angiography and Intraplaque Hemorrhage (SNAP) MRI is associated with post-treatment cognitive function improvement in carotid atherosclerosis patients. In this study, we aim to evaluate the value of SNAP-based measurements in assessing cerebrovascular function in an aging population.

MATERIALS AND METHODS: Neurovascular MRI data were collected on 36 aging participants (22 cognitively unimpaired and 14 impaired; 9 mild cognitive impairment (MCI) and 5 Alzheimer's Disease (AD)). Neurovascular MRI measurements, including white matter hyperintensities (WMH) volumes, cerebral blood flow (CBF), and SNAP-based distal cerebral arterial flow (dCAF) index, were quantified. Cognitive function was assessed using the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS).

RESULTS: Significant differences in the dCAF index were observed between cognitively unimpaired and impaired groups, and the dCAF index was significantly correlated with the RBANS total score. While CBF was significantly associated with dCAF index, there is no significant correlation of CBF or WMH with the RBANS score in this population.

CONCLUSION: Our findings suggest that the dCAF measured with SNAP MRI is valuable for evaluating the cognition-related cerebrovascular condition in an aging population.}, } @article {pmid41929577, year = {2026}, author = {Kandasamy, K and Narasimhamoorthi, SP and Arulselvan, P and Jaganathan, D}, title = {Protective effects of the natural polyphenol garcinol from Garcinia indica mitigates aluminium chloride-induced Alzheimer's-like neurodegeneration in Drosophila melanogaster.}, journal = {3 Biotech}, volume = {16}, number = {4}, pages = {154}, pmid = {41929577}, issn = {2190-572X}, abstract = {UNLABELLED: Alzheimer's disease (AD) is a devastating neurodegenerative condition that affects millions of people affected in worldwide. Natural resources such as medicinal plants have been utilized for the treatment of various memory disorders like amnesia, dementia, Alzheimer's, and Parkinson's for a long time. This study aimed to investigate plants with therapeutic bioactivities for a range of scientific investigations focused on the neuroprotective effects of garcinol from Garcinia indica against the Aluminium chloride (AlCl3)-induced AD in the Drosophila melanogaster model. Polar and non-polar solvents were active on the G. indica fruit rind and subjected to phytochemical investigation. Garcinol was extracted from the EtOH extract of G. indica fruit rind using TLC, column chromatography, GC-MS, UV-visible, and FT-IR. In vitro free radical scavenging effect of the EtOH extract of G. indica fruit rind was studied to determine its antioxidant properties. The effect of garcinol on the interaction and predicted binding interaction of the AD-associated enzymes Amyloid-β, Acetylcholinesterase (AChE), and β-secretase was studied by the in-silico analysis. AD condition was initiated in D. melanogaster by challenging them with AlCl3, and they were pre-treated with garcinol, which is isolated from the EtOH extract of G. indica fruit rind. The effect of garcinol on the AChE activity, oxidative stress markers, and pro-inflammatory cytokines was studied using the respective assay kits. The apoptotic proteins were studied using the RT-PCR analysis. The findings of the phytochemical analysis. In silico garcinol effectively interacts with and inhibits the intermolecular Amyloid-β, AChE, and β-secretase enzymes. AD, garcinol treatment successfully moderated the amendments in behavioural and cognitive impairments, regulated the oxidative stress markers, decreased AChE activity, and reduced the pro-inflammatory cytokine levels. The RT-PCR method proved that garcinol regulated the pro- and anti-apoptotic protein expressions in the AD-induced D. melanogaster. The findings suggested that garcinol from EEGIFR acts against AlCl3-induced AD in D. melanogaster because of its anti-inflammatory, antioxidant, and apoptosis-modulating capabilities, and it may develop as a capable therapeutic agent in treating AD.

SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s13205-026-04763-6.}, } @article {pmid41929929, year = {2025}, author = {Tang, Y and Zhuo, E and Li, P and Wang, C and Hu, X and Liu, X and Xu, G and Shen, Q}, title = {MANF improves cognitive function and attenuates neuroinflammation in APP/PS1 transgenic mice through the TLR4/MYD88/NF-κB signaling pathway.}, journal = {Journal of anesthesia and translational medicine}, volume = {4}, number = {4}, pages = {241-254}, pmid = {41929929}, issn = {2957-3912}, abstract = {BACKGROUND: Alzheimer's disease (AD) is the most prevalent neurodegenerative disorder, characterized by progressive cognitive decline, as well as pathological features such as β-amyloid (Aβ) plaque deposition, tau hyperphosphorylation, synaptic dysfunction, and neuronal loss. Growing evidence suggests that neuroinflammation, oxidative stress, and apoptosis play critical roles in the pathogenesis of AD, thereby contributing to neuronal damage and cognitive decline. Mesencephalic astrocyte-derived neurotrophic factor (MANF), an endoplasmic reticulum stress-inducible protein, has been shown to exert neuroprotective effects by modulating immune responses, alleviating oxidative stress, and suppressing apoptosis in various neurological disease models. These properties suggest that MANF could serve as a promising therapeutic candidate treating AD. This study investigated the therapeutic potential of MANF in improving cognitive function and ameliorating pathological changes in APP/PS1 transgenic (Tg) mice by modulating neuroinflammation and enhancing neural plasticity.

METHODS: Beginning at 10 months of age, male APP/PS1 transgenic mice received daily intraperitoneal injections of recombinant human MANF (rhMANF) at a dose of 1 μg/g for a duration of one month. Behavioral assessments, including the Morris water maze, open field, and fear conditioning tests, were conducted to evaluate cognitive function. Brain tissue was analyzed for β-amyloid (Aβ) deposition, neuroinflammation, oxidative stress, and neuronal apoptosis using immunofluorescence, immunohistochemistry, western blotting, and enzyme-linked immunosorbent assay. RNA sequencing (RNA-seq) and a BV2 microglial/HT22 neuronal co-culture system were used to further elucidate the mechanisms underlying MANF's effects.

RESULTS: rhMANF treatment significantly improved cognitive function in APP/PS1 Tg mice by reducing Aβ deposition, inhibiting microglial activation, and suppressing inflammatory cytokines (TNF-α, IL-1β, and IL-6). MANF also mitigated oxidative stress, reduced neuronal apoptosis, and restored synaptic protein levels, including those of Postsynaptic density protein-95(PSD95) and synaptophysin (SYN). In vitro studies confirmed that MANF effectively counteracts Aβ1-42-induced toxicity in the BV2/HT22 co-culture system. Transcriptomic analysis identified that MANF exerts its protective effects by regulating the TLR4/MYD88/NF-κB signaling pathway, thereby reducing inflammation and promoting synaptic plasticity.

CONCLUSIONS: This study demonstrates the protective role of MANF in AD and establishes MANF as a promising therapeutic candidate for AD and aging-related neurodegenerative disorders.}, } @article {pmid41929945, year = {2026}, author = {Yang, Y and Meng, Y and Li, M and Xu, Z and Wu, H and Zhang, Q and Zhang, S and Kong, F and Wang, Z and Li, X and Zhu, Y}, title = {Identification of potential short-chain fatty acid biomarkers in Alzheimer's disease through bioinformatics analysis.}, journal = {Journal of Alzheimer's disease reports}, volume = {10}, number = {}, pages = {25424823261424808}, pmid = {41929945}, issn = {2542-4823}, abstract = {BACKGROUND: Alzheimer's disease (AD) is a highly prevalent neurodegenerative disorder. Accumulating evidence suggests that short-chain fatty acids (SCFAs) can regulate the central nervous system, thereby affecting cognitive and behavior function.

OBJECTIVE: This study aimed to investigate the association between the AD development and SCFA metabolism via bioinformatic analysis.

METHODS: Gene expression profiles were obtained from the GEO database. 1243 genes related to SCFA were screened from Genecards database. Through weighted gene co-expression network analysis (WGCNA) and differential analysis, 10 SCFA hub genes were screened. Machine learning algorithms, including support vector machine recursive feature elimination (SVM-RFE) and least absolute shrinkage and selection operator (LASSO) regression models, were used to identify candidate biomarkers. The CIBERSORT algorithm was utilized to evaluate the infiltration of immune cells and its relationship with the potential biomarkers. The candidate biomarker chemicals were identified in the Comparative Toxicogenomics Database as underlying targeted drugs for treating AD.

RESULTS: Five genes-EZR, SNCA, GFAP, NFKBIA, and SST-were identified as potential biomarkers for AD through LASSO and SVM-RFE analyses. These genes can also be used to predict the risk of AD and have good diagnostic effects. The candidate biomarkers are associated with plasma cells, activated dendritic cells, M1 macrophages and resting natural killer cells. Notably, valproic acid and tretinoin were found to target these candidate genes, suggesting a new treatment approach for AD.

CONCLUSIONS: This study identified EZR, SNCA, GFAP, NFKBIA, and SST as potential key SCFA-related genes associated with the progression of AD, providing new insights into the prevention and treatment of AD.}, } @article {pmid41929949, year = {2026}, author = {Zhang, Q and Almanie, L and Ouyang, Y and Cheng, Z and Zhang, H}, title = {From routine periodontal therapy to Alzheimer's disease early detection: A scoping review.}, journal = {Journal of Alzheimer's disease reports}, volume = {10}, number = {}, pages = {25424823261421629}, pmid = {41929949}, issn = {2542-4823}, abstract = {An epidemiological association has been observed between periodontitis and Alzheimer's disease (AD); however, salivary and blood assays often show low specificity. Periodontal tissues and fluids, which are routinely removed and discarded during periodontal treatment, may be collected to offer matrices useful for the early detection of AD. This study aimed to map current preclinical and clinical evidence on biomarkers measured in periodontal tissues and fluids for the early detection of AD and organize them within an AD-specificity pyramid anchored to brain-relevant endpoints. Following PRISMA-ScR (Preferred Reporting Items for Systematic Reviews and Meta-Analyses-Extension for Scoping Reviews) guidance, we searched PubMed, Scopus, and Web of Science (January 1, 2015-August 31, 2025) for preclinical and clinical studies measuring AD-relevant biomarkers in periodontal matrices. The protocol was pre-registered (OSF DOI: 10.17605/OSF.IO/EDVU9; August 20, 2025). Two reviewers extracted the data, and other two independently verified them. The findings were organized using a four-tier AD-specificity pyramid. Results: Fourteen studies met the inclusion criteria. The biomarkers from the included studies were clustered into microbiome features, molecular signals, and genetic/transcriptomic findings. Evidence ranged from Tier-1 contextual inflammation/pathogens to Tier-4 core-pathology adjacency; five studies incorporated clinical/biological anchoring, with cerebrospinal fluid amyloid-β positivity providing the most brain-relevant anchor. Periodontal matrices are practicable, high-signal sources for AD-relevant biomarkers. However, translational validation linking periodontal biomarkers to brain endpoints is needed to assess the feasibility of multi-tier and chairside panels for early AD detection as part of routine periodontal care.}, } @article {pmid41929950, year = {2026}, author = {Lin, F and Yang, X and Xie, X and Qiu, L and Zheng, C and Zheng, X and Li, Z and Nie, B}, title = {The causal association between the new gut microbiota and Alzheimer's disease: A Mendelian randomization study.}, journal = {Journal of Alzheimer's disease reports}, volume = {10}, number = {}, pages = {25424823261422629}, pmid = {41929950}, issn = {2542-4823}, abstract = {BACKGROUND: There is a need for more studies to validate the role of gut microbiota in Alzheimer's disease (AD).

OBJECTIVE: This study aims to explore the causal association between new gut microbiota and AD using Mendelian randomization.

METHODS: Using genome-wide association study (GWAS) of 473 gut microbiota species and AD in IEU Open GWAS database, independent genetic loci related to gut microbiota were extracted as instrumental variables. The inverse variance weighting method was employed as the main indicator for evaluation. The stability and reliability of the results were further verified by heterogeneity test, outlier detection, horizontal pleiotropy test and leave-one-out analysis.

RESULTS: Following a thorough screening process, a total of 14 intestinal microbiota were included in the final analyses. The elevated abundance of Agathobacter, Citrobacter A, Clostridium E sporosphaeroides, Eubacterium R, Megamonas funiformis, and Pseudomonas aeruginosa can reduce the risk of AD. Higher abundance of Bifidobacterium, Holdemania massiliensis, Hydrogenophaga, Intestinimonas massiliensis, Megasphaera, Paenibacillus J, Prevotella, and Raoultella could increase the risk of AD. The MR-Egger analyses at 14 "genus" levels showed no horizontal pleiotropy and the p values were all more than 0.05. The leave-one-out analysis showed that results were relatively stable.

CONCLUSIONS: This study revealed a causal relationship between 14 specific gut microbiota and the risk of AD occurrence. Some bacteria are protective, while others increase the risk of AD. These findings are of clinical significance for the treatment and prevention strategies in clinical practice, and it also provides new perspectives for related research on the "gut-brain axis".}, } @article {pmid41929952, year = {2026}, author = {Huang, S and Guo, Y}, title = {Network meta-analysis of the efficacy of nine drugs for cognitive function in patients with Alzheimer's disease.}, journal = {Journal of Alzheimer's disease reports}, volume = {10}, number = {}, pages = {25424823261422205}, pmid = {41929952}, issn = {2542-4823}, abstract = {BACKGROUND: Alzheimer's disease (AD) remains a global challenge, and the comparative cognitive efficacy of emerging pharmacotherapies is still unclear.

OBJECTIVE: To compare and rank nine pharmacological agents against placebo in AD with respect to key cognitive outcomes using a network meta-analysis.

METHODS: We systematically searched randomized controlled trials published up to May 2025 that evaluated aducanumab, lecanemab, donanemab, gosuranemab, semorinemab, tilavonemab, zagotenemab, masupirdine, or sodium oligomannate in AD. The primary outcomes were Clinical Dementia Rating-Sum of Boxes (CDR-SB) and Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-cog); Mini-Mental State Examination (MMSE) was a secondary outcome. Treatments were ranked using the Surface Under the Cumulative Ranking curve (SUCRA).

RESULTS: Fifteen randomized trials encompassing 33 treatment arms were included. No drug demonstrated statistically robust superiority over placebo in primary outcomes. Semorinemab and tilavonemab achieved highest SUCRA rankings, but without significant pairwise advantage. For MMSE, aducanumab showed a modest mean difference versus placebo (1.98, 95% CI 0.03-3.93), though evidence of publication bias reduced confidence.

CONCLUSIONS: Current pharmacological treatments do not consistently outperform placebo in AD. Tau-targeted antibodies (semorinemab, tilavonemab) display modest but non-significant promise, whereas aducanumab's apparent benefit is likely confounded by publication bias. Further large, rigorous randomized controlled trials and improved preclinical models are essential.}, } @article {pmid41929955, year = {2026}, author = {Qiu, Q and Qian, W and Zhao, W and Xie, H and Cao, L and Ye, L and , }, title = {P-tau217 and %p-tau217 exhibited superior diagnostic accuracy over other blood biomarkers in the initial assessment of individuals being diagnosed with mild cognitive impairment and Alzheimer's disease dementia.}, journal = {Journal of Alzheimer's disease reports}, volume = {10}, number = {}, pages = {25424823261439687}, pmid = {41929955}, issn = {2542-4823}, abstract = {BACKGROUND: High-performance blood tests may improve diagnostic accuracy and support personalized treatment for Alzheimer's disease (AD), but validation at the time of initial clinical diagnosis remains limited.

OBJECTIVE: To assess whether plasma biomarkers can aid diagnostic decision-making at first clinical assessment, particularly as tools to triage patients for confirmatory testing in routine practice.

METHODS: We analyzed 241 cognitively normal (CN) controls, 211 patients with mild cognitive impairment (MCI), and 59 patients with AD dementia from the Alzheimer's Disease Neuroimaging Initiative. Plasma aliquots underwent analysis with the C2N Diagnostics PrecivityAD2[®] and Roche Diagnostics Elecsys[®] assays.

RESULTS: The AD group showed a lower Aβ42/Aβ40 ratio than the CN group (p < 0.01) and a mild decrease compared to the MCI group (p < 0.05). The AD group had significant increases in p-tau181, p-tau217, and %p-tau217 (p < 0.001) versus both MCI and CN groups. Glial fibrillary acidic protein (GFAP) and neurofilament light chain (NfL) were also significantly elevated in AD. The MCI and CN groups only differed in p-tau217 and %p-tau217 (p < 0.05). The AD versus CN AUCs for p-tau181, p-tau217, and %p-tau217 were 0.84, 0.87, and 0.87; for AD versus MCI, they were 0.79, 0.80, and 0.81. The p-tau181, p-tau217, and %p-tau217 showed a moderate correlation with the Alzheimer's Disease Assessment Scale-cognitive subscale. %p-tau217 demonstrated a strong correlation with the p-tau181/Aβ42 ratio in CSF (R = 0.72, p < 0.001).

CONCLUSIONS: In the setting of first-presentation diagnosis of clinically defined MCI and AD, p-tau217, and %p-tau217 outperformed other plasma biomarkers and may help triage patients for further confirmatory evaluation.}, } @article {pmid41929956, year = {2026}, author = {Rahman-Filipiak, A and Lesniak, M and Burgei, A and Sadaghiyani, S and Roberts, JS and Lichtenberg, PA and Iordan, A and Mozersky, J and Hampstead, BM}, title = {Qualitative insights into participant and care partner perspectives on research-based Alzheimer's disease biomarker testing and disclosure.}, journal = {Journal of Alzheimer's disease reports}, volume = {10}, number = {}, pages = {25424823261429997}, pmid = {41929956}, issn = {2542-4823}, abstract = {BACKGROUND: There is strong desire for the return of individual results, including biomarker testing, among participants in Alzheimer's disease and related dementias (ADRD) studies. However, it is not known whether participants accurately understand the utility, limitations, benefits and risks of biomarker disclosure, nor how they weigh these factors to inform their decision to undergo testing and learn results. Furthermore, little is known about how factors like participant race or diagnosis influence a desire to learn biomarker results.

OBJECTIVE: This mixed-methods study explored how clinically and racially diverse participant-care partner dyads perceive and plan to use AD biomarker testing in the context of research studies.

METHODS: 57 participants (Age: M = 74.28 ± 5.98; Race: n = 22 Black, n = 35 White; Diagnosis: n = 23 with mild cognitive impairment; n = 34 cognitively healthy) and care partners were recruited from AD studies wherein the participant completed amyloid-β and tau positron emission tomography without receiving results. Each completed an independent interview about their perspectives on learning the participant's results.

RESULTS: Responses suggested strong interest in learning results, driven by perceived benefits (e.g., informing treatment, lifestyle changes, and social support). Risks were rarely discussed, though some respondents cited concerns about psychological burdens of a positive result. Few nuanced differences in perceived risks or benefits were observed across race and diagnosis.

CONCLUSIONS: The decision to learn the results of biomarker testing is motivated by highly varied perceived benefits and minimal consideration of risks. Testing should be preceded by individualized counseling that carefully reviews potential benefits and risks.}, } @article {pmid41929964, year = {2026}, author = {Zhao, X and Wu, L and Li, P}, title = {TARDBP gene mutation in a Chinese family with frontotemporal dementia: A case report and literature review.}, journal = {Journal of Alzheimer's disease reports}, volume = {10}, number = {}, pages = {25424823251412416}, pmid = {41929964}, issn = {2542-4823}, abstract = {BACKGROUND: Mutations in the transactive response DNA binding protein (TARDBP) have never been reported in the population of familial frontotemporal dementia (FTD) in Chinese mainland.

OBJECTIVE: This study reports for the first time a familial FTD carrying TARDBP mutations in Chinese mainland and summarizes the genetic and clinical features of TARDBP mutant families.

METHODS: Case report of comprehensive clinical, genetic and neuroimaging examinations on a 68-year-old male patient diagnosed with behavioral variant FTD (bvFTD). A literature review was also conducted and clinical and genetic features of families with TARDBP mutations were summarized.

RESULTS: We reported the bvFTD patient in Chinese with heterozygous mutation of TARDBP. Brain MRI revealed bilateral frontal and temporal atrophy, predominant in the right side. FDG-PET demonstrated frontal and temporal hypometabolism. [18]F-DPA714-PET showed focally elevated bilateral temporal tracer uptake, and [18]F-MNI-1126-PET revealed a reduction in synaptic uptake throughout the brain, especially in the bilateral temporal lobes. In the literature, we found 68 patients from 24 families with 6 different TARDBP mutations in an exon 6. Nine patients presented with symmetrical atrophy involving the frontal, temporal, and parietal lobes, 11 with asymmetrical atrophy, and 5 without atrophy. More than 60.3% of the patients had an onset age earlier than 65 years old and there was a predominance of men.

CONCLUSIONS: Our discovery confirmed a pedigree of FTD families and expanded the pedigree mutation spectrum of TARDBP in China. The establishment between phenotype and genotype will aid the diagnosis and treatment of FTD.}, } @article {pmid41929976, year = {2026}, author = {Parmar, H and Walden, E and , }, title = {Towards practical application of deep learning in diagnosis of Alzheimer's disease.}, journal = {Journal of Alzheimer's disease reports}, volume = {10}, number = {}, pages = {25424823261415808}, pmid = {41929976}, issn = {2542-4823}, abstract = {BACKGROUND: Accurate diagnosis of Alzheimer's disease (AD) is both challenging and time consuming. With a systematic approach to diagnosis, steps can be taken toward improved treatment and prevention of the disease.

OBJECTIVE: This study explores the practical application of deep learning models for the diagnosis of AD across different disease stages.

METHODS: Due to computational complexity, long training times, and limited availability of labeled datasets, full brain three-dimensional (3D) convolutional neural networks (CNNs) are not commonly used, and many studies rely on two-dimensional (2D) variants. In this work, full brain 3D versions of well-known 2D CNN architectures were designed, trained, and tested for the diagnosis of multiple stages of AD. More than 1500 full brain volumes were used for model training and evaluation.

RESULTS: The proposed deep learning approach demonstrated good performance in differentiating various stages of AD. In addition to classification, the models were able to extract discriminative features relevant to disease stage. These features aligned with meaningful anatomical landmarks that are currently considered important for AD identification by clinical experts. An ensemble of all algorithms was also evaluated and achieved superior performance compared to individual models, with a maximum classification accuracy of 87.4%.

CONCLUSIONS: The trained 3D CNNs and their ensemble show strong potential for assisting in the diagnosis of AD. These models may be incorporated into clinical software tools to support physicians and radiologists in improved diagnostic decision making.}, } @article {pmid41929977, year = {2026}, author = {Kasuga, K and Yuzawa, C and Nakamura, K and Shimizu, Y and Hara, N and Ikeuchi, T and Sekijima, Y}, title = {A novel PSEN2 missense variant in a Japanese woman with hereditary Alzheimer's disease.}, journal = {Journal of Alzheimer's disease reports}, volume = {10}, number = {}, pages = {25424823261424532}, pmid = {41929977}, issn = {2542-4823}, abstract = {Hereditary Alzheimer's disease (hAD) and PSEN2 variants are rare, and the benefit of anti-amyloid β-directed monoclonal antibody (mAb) therapy is unknown. We encountered a 51-year-old Japanese woman with PSEN2-associated hAD. A molecular diagnosis revealed a novel uniallelic missense variant (NM_000447:c.356T > G, p.Leu119Arg) in PSEN2. Intravenous mAb therapy was initiated at age 50, and serial amyloid positron emission tomography showed intense Pittsburgh compound B accumulation and a reduction in amyloid-β deposits in the cerebral cortex after 6 months. Our results suggest that treatment with mAbs has the potential to reduce amyloid deposits in the brain, even in patients with symptomatic hAD.}, } @article {pmid41929981, year = {2026}, author = {Zupanic, E and Stegnar, G and Rakuša, M and Rus Prelog, P and Švab, I and Gregoric Kramberger, M}, title = {Estimates of current capacity for diagnosing and implementation of new treatment Alzheimer's disease in Slovenia.}, journal = {Journal of Alzheimer's disease reports}, volume = {10}, number = {}, pages = {25424823261424524}, pmid = {41929981}, issn = {2542-4823}, abstract = {BACKGROUND: The limited efficacy of current symptomatic treatments for Alzheimer's disease (AD) leads many patients to forgo medical help. However, new disease-modifying treatments (DMTs), such as donanemab and lecanemab, show potential to change this.

OBJECTIVE: To model the impact of these treatments on Slovenia's healthcare system by analyzing patient flow under both current and enhanced capacities, assuming DMT availability.

METHODS: The study estimates 76,923 potential DMT candidates aged 65 years and older with mild cognitive impairment or mild AD. Using data from Slovenia's three specialized centers for cognitive disorders, a Markov model simulated five five-year scenarios: baseline, real-life, real-life with capacity enhancement, biomarker integration, and biomarker integration with capacity enhancement.

RESULTS: Waiting times for specialist evaluation would increase from the current 3-12 months to 1.8 years. The primary bottleneck is lumbar puncture with cerebrospinal fluid (CSF) analysis, during which 64% of patients would become ineligible for DMT. The shortest waiting time to receive DMT occurs in the biomarker integration with capacity enhancement scenario, at 4 years, reducing ineligibility to 7%.

CONCLUSIONS: Current specialized outpatient facilities are limited, causing significant bottlenecks, especially in CSF analysis. Severe waiting times under current capacities mean many patients would progress to moderate or severe dementia or die before receiving treatment. Plasma biomarkers offer a promising triage approach to guide patients toward lumbar puncture or other confirmatory diagnostics, potentially easing this critical bottleneck. Substantial infrastructure and workforce improvements are essential to ensure timely and equitable access to DMTs in Slovenia.}, } @article {pmid41929983, year = {2026}, author = {Paez, K and Kopachik, C and Yilmaz, A and Vishweswaraiah, S and Ashrafi, N and Saiyed, N and Monacelli, N and Kerseviciute, I and Gordevicius, J and Ruff, S and Pai, A and Khaled, I and Maddens, ME and Graham, SF}, title = {Unraveling the impact of common medications on biomarker patterns in Alzheimer's disease and mild cognitive impairment.}, journal = {Journal of Alzheimer's disease reports}, volume = {10}, number = {}, pages = {25424823251387281}, pmid = {41929983}, issn = {2542-4823}, abstract = {BACKGROUND: The aging global population faces significant challenges from Alzheimer's disease (AD). Metabolomics offers a non-invasive, cost-effective diagnostic alternative. Researchers identified significant variations in the level of salivary and urinary metabolites between AD patients and cognitively healthy controls. However, it's unclear whether differences in metabolites between AD patients and healthy controls are due to the disease or medications.

OBJECTIVE: This study aims to investigate the impact of common AD medications (cholinesterase inhibitors) and hypertension medications (ARBs) on the AD patient metabolome.

METHODS: A retrospective metabolomics analysis was conducted to elucidate whether observed metabolic perturbations were attributable to AD pathology or polypharmacy, with a specific focus on cholinesterase inhibitors and ARBs.

RESULTS: Linear models revealed that cholinesterase inhibitors did not significantly modulate potential urinary and salivary biomarkers for AD. However, these inhibitors were associated with significant changes in urinary metabolite concentrations, including increased isovaleric acid and L-leucine and decreased formate and L-histidine (q = 0.027 for all). Analysis of ARB treatment revealed significantly reduced urinary tryptophan levels (q = 0.001) in AD patients and increased salivary acetone and isopropyl alcohol concentrations (q = 0.028) across all groups. Further analysis of saliva metabolite ratios revealed notable differences in asymmetric arginine methylation between the AD group and the control group (q = 0.021). Additionally, variations in citrate synthesis were observed between the mild cognitive impairment group and the control group on ARBs (q = 0.024).

CONCLUSIONS: Our research confirms that distinct biomarker profiles characteristic of AD remain present regardless of cholinesterase inhibitor and ARB treatment, providing a foundation for future clinical studies and therapeutic development by providing better diagnostic tools.}, } @article {pmid41930591, year = {2026}, author = {Qin, J and Xu, X and Zou, Y}, title = {Herpes zoster, antiviral therapy, and Alzheimer's disease: Turning association into an actionable prevention pathway.}, journal = {Journal of Alzheimer's disease : JAD}, volume = {111}, number = {3}, pages = {988-990}, doi = {10.1177/13872877261438524}, pmid = {41930591}, issn = {1875-8908}, mesh = {Humans ; *Alzheimer Disease/prevention & control/epidemiology ; *Antiviral Agents/therapeutic use ; *Herpes Zoster/prevention & control/drug therapy/complications/epidemiology ; }, abstract = {Yang and Jiang synthesize evidence linking varicella-zoster virus exposure to Alzheimer's disease risk and lay out a clinically intuitive pathway from infection to intervention, spanning antiviral treatment and herpes zoster vaccination. The review is timely because it highlights potentially modifiable touchpoints in routine care for older adults. Building on their work, this commentary raises one pragmatic question: what additional evidence would most efficiently translate these associations into targeted, implementable prevention strategies-clarifying when risk is most actionable, which intervention features matter most, and which subgroups may benefit most?}, } @article {pmid41930592, year = {2026}, author = {Vijverberg, EGB and Scharre, DW and Woodward, M and Catalano, S and Hamby, ME and Grundman, M and Morgan, RE and Iaci, J and Devins, T and Caggiano, AO}, title = {Randomized, double-blind study of zervimesine in mild to moderate Alzheimer's disease.}, journal = {Journal of Alzheimer's disease : JAD}, volume = {111}, number = {2}, pages = {897-908}, doi = {10.1177/13872877261437145}, pmid = {41930592}, issn = {1875-8908}, support = {1R01AG058660-01/AG/NIA NIH HHS/United States ; }, mesh = {Humans ; *Alzheimer Disease/drug therapy/blood ; Double-Blind Method ; Female ; Aged ; Male ; Treatment Outcome ; Aged, 80 and over ; tau Proteins/blood ; Middle Aged ; Amyloid beta-Peptides ; Dose-Response Relationship, Drug ; }, abstract = {BackgroundZervimesine (CT1812) is a first-in-class, brain-penetrant sigma-2 receptor ligand that prevents binding and displaces Aβ42 oligomers from receptors on neuronal synapses.ObjectiveThis study evaluated the safety and efficacy of zervimesine in mild to moderate Alzheimer's disease (AD).MethodsThis was a Phase 2, randomized, double-blind, placebo-controlled study. Participants were randomized to zervimesine 100 mg or 300 mg or placebo. In addition to ADAS-Cog11, outcomes were evaluated from baseline plasma p-tau217 in prespecified subgroups.ResultsOf 153 adults randomized, 150 were included in the mITT population. Adverse events occurred in 70.6% with zervimesine 100 mg, 82.4% with zervimesine 300 mg, and 78.0% with placebo. At Day 182, the ADAS-Cog 11 increased from baseline (indicating a decline in cognitive function) with the LS mean (SE) change of 2.69 (0.81) points in the placebo group versus 1.66 (0.60) points in the pooled zervimesine group [δ = -1.03 (-3.01, 0.96), p = 0.310]. For participants with baseline plasma p-tau217 levels below the median (1.0 pg/mL), the pooled zervimesine group showed greater improvement on the ADAS-Cog 11 at Day 182 relative to placebo (δ = -2.66; p = 0.080).ConclusionsThis phase 2 study indicated that zervimesine was safe and well tolerated and showed consistently favorable numerical treatment differences versus placebo. More robust treatment differences were observed in the below median baseline plasma p-tau217 group suggesting potentially greater efficacy of zervimesine in less advanced AD. These results support larger pivotal trials with zervimesine.Registered at clinicaltrials.gov: NCT03507790.}, } @article {pmid41930760, year = {2026}, author = {Patel, S and Sood, R and Shrivastava, S and Jeengar, MK}, title = {Neuroprotective Mechanisms of Erucin: Therapeutic Pathways in Neurodegenerative Disorders.}, journal = {Current neuropharmacology}, volume = {}, number = {}, pages = {}, doi = {10.2174/011570159X385491251208144807}, pmid = {41930760}, issn = {1875-6190}, abstract = {Neurodegenerative Disorders (NDDs), including Alzheimer's Disease (AD), Parkinson's Disease (PD), Huntington's Disease (HD), Amyotrophic Lateral Sclerosis (ALS), Multiple Sclerosis (MS), and other less prevalent conditions, represent a growing challenge in medical science due to their progressive nature and the absence of curative treatments. Cruciferous vegetables, such as those from the Brassicaceae family and other species in the Brassicales order, have been reported to offer potential benefits for treating and preventing NDDs. Their neuroprotective effects have been attributed to secondary metabolites, glucosinolates (GLs), and their hydrolytic products, isothiocyanates (ITCs). One of these ITCs is Erucin (ERU), chemically known as 4-isothiocyanatobutane, which is a specific type of ITC. ERU is the isothiocyanate derivative of erucic acid and is structurally related to sulforaphane (SFN), another well-known ITC. This review aims to synthesize current scientific knowledge on ERU's mechanisms of action in neurodegeneration, highlighting preclinical evidence supporting its neuroprotective effects in diseases such as AD and PD, and suggesting its potential as a treatment strategy for NDDs. Preliminary studies suggest that ERU may confer neuroprotection through antioxidative stress pathways, modulation of neuroinflammatory responses, and upregulation of neurotrophic factors. This article discusses ERU's chemical properties, pharmacokinetics, and observed impacts on neurodegenerative models, suggesting potential therapeutic pathways it may influence, thereby highlighting its promise as a future component of neuroprotective strategies against NDDs.}, } @article {pmid41930762, year = {2026}, author = {Singh, A and Mazumder, A and Das, S and Kumar, R and Kanda, A}, title = {Synergistic Anti-dementia Effects of Symplocos racemosa Nanoemulsion: Isolation, Molecular Docking, and In Vivo Evaluation.}, journal = {Current neurovascular research}, volume = {23}, number = {3}, pages = {187-204}, doi = {10.2174/0115672026421409260119050357}, pmid = {41930762}, issn = {1875-5739}, mesh = {Animals ; *Molecular Docking Simulation ; Male ; Emulsions ; Scopolamine/toxicity ; *Plant Extracts/therapeutic use/isolation & purification/pharmacology/chemistry ; *Dementia/drug therapy ; Maze Learning/drug effects ; Mice ; *Neuroprotective Agents/therapeutic use/pharmacology ; Cholinesterase Inhibitors ; Acetylcholinesterase/metabolism ; Oleanolic Acid/analogs & derivatives ; Drug Synergism ; Donepezil ; Disease Models, Animal ; Brain/drug effects ; }, abstract = {INTRODUCTION: Dementia, marked by a decline in mental abilities like memory that interferes with daily life, is primarily caused by Alzheimer's Disease (AD). Symplocos racemosa, rich in acetyl oleanolic acid, serves as a neuroprotective agent by lowering amyloid β levels in the brain. This study aims to develop a nanoemulsion for the targeted delivery of S. racemosa phytoconstituents to enhance therapeutic efficacy against dementia. The study also aims to find out the mechanism of the responsible molecules via molecular docking studies.

METHODS: S. racemosa bark was ultrasonically extracted with methanol and ethyl acetate, yielding six phytoconstituents: ellagic acid, betulinic acid, acetyl oleanolic acid, salireposide (from methanol), oleanolic acid, symlocoside (from ethyl acetate), isolated by column chromatography. Molecular docking against AChE and BACE-1 was conducted using CB Dock-2. A chitosan- based nanoemulsion containing all six compounds was prepared to enhance brain delivery and was physically characterized. All isolated phytoconstituents and nanoemulsions were evaluated for their in vitro enzyme inhibition (AChE and BACE-1) potential. Its anti-dementia efficacy was evaluated in scopolamine-induced rodent models using Hebb-Williams and Elevated Plus Maze tests, complemented by histopathological analysis of the brain cortex to assess therapeutic effects.

RESULTS: Docking studies showed acetyl oleanolic acid had stronger binding to BACE-1 and AChE than donepezil. This was further supported by an in vitro enzyme inhibition assay. Nanoemulsion at 200 and 400 mg/kg significantly reduced the time taken by memory-impaired mice to complete the Hebb-Williams Maze and transfer latency in the Elevated Plus Maze. Histopathological analysis showed a significant recovery of cortical damage. This indicates that the nanoemulsion has strong potential for the treatment of Alzheimer 's-related neurodegeneration.

DISCUSSION: The neuroprotective action of S. racemosa nanoemulsion (SRMN) is attributed to the large-scale presence of its phytoconstituents, which reportedly exhibit a better binding affinity and inhibitory action against AChE and BACE-1 than donepezil. Additionally, the nanoemulsion enhanced bioavailability, stability, and blood-brain barrier penetration, which in turn improved therapeutic outcomes. From behavioral and histological studies, we observed that SRMN performed well in terms of memory improvement and cortical protection, suggesting that it is a very good multi-target approach for dementia.

CONCLUSION: The prepared nanoemulsion from S. racemosa's isolated phytoconstituents is reported to exhibit synergistic action, thereby effectively managing dementia through BACE-1 and AChE inhibition.}, } @article {pmid41930767, year = {2026}, author = {Parashar, AK and Saraogi, GK and Sethi, VA and Yasin, HKA}, title = {Nanocarriers in Alzheimer's Therapy: A Comprehensive Review on Nanoparticulate Drug Delivery Systems.}, journal = {Current neurovascular research}, volume = {23}, number = {3}, pages = {160-173}, doi = {10.2174/0115672026435071260129105648}, pmid = {41930767}, issn = {1875-5739}, mesh = {Humans ; *Alzheimer Disease/drug therapy ; Animals ; *Drug Delivery Systems/methods ; Blood-Brain Barrier/drug effects/metabolism ; *Nanoparticles/administration & dosage ; *Nanoparticle Drug Delivery System ; *Drug Carriers/administration & dosage ; }, abstract = {INTRODUCTION: Neurodegenerative disorders, particularly Alzheimer's Disease (AD), pose a major global health challenge, characterized by progressive neuronal degeneration and cognitive decline. The blood-brain barrier (BBB) significantly limits the efficacy of conventional therapeutics, preventing adequate drug delivery to the central nervous system. Nanoparticulate Drug Delivery Systems (NPDDS) have emerged as a promising approach to overcome these limitations and enhance the therapeutic potential of AD interventions.

METHODS: This review comprehensively examines recent advancements in NPDDS for AD therapy. Various nanoparticle classes, including polymeric nanoparticles, solid lipid nanoparticles, gold nanoparticles, liposomes, microemulsions/nanoemulsions, dendrimers, and hydrogels, are evaluated with respect to their physicochemical characteristics, drug-loading capacities, BBBpenetrating strategies, and potential for targeted cerebral delivery. Relevant preclinical and clinical studies were analyzed to summarize the pharmacokinetic and pharmacodynamic benefits of these systems.

RESULTS: The reviewed NPDDS demonstrate enhanced drug solubility, stability, and controlled release profiles. Multiple strategies, such as surface functionalization, intranasal administration, and receptor-mediated transcytosis, facilitate BBB penetration and site-specific drug delivery. Nanocarriers improve drug accumulation at pathological sites, potentially enhancing therapeutic efficacy while reducing systemic side effects. Each nanoparticle class offers distinct advantages: polymeric and lipid-based systems provide controlled release and biocompatibility, while metallic and dendrimeric platforms offer theranostic capabilities and high drug-loading potential.

DISCUSSION: Despite their promise, challenges remain in translating NPDDS to clinical applications. Efficient and reproducible BBB crossing, potential cytotoxicity, long-term biocompatibility, and scalable manufacturing processes require further optimization. Multifunctional and hybrid nanocarriers, stimuli-responsive systems, and biomimetic designs are emerging to address these limitations. Continuous advancements in nanotechnology offer tunable physicochemical properties to tackle the complex pathogenesis of AD, enabling more precise, effective, and patient- compliant therapies.

CONCLUSION: NPDDS represent a transformative frontier in Alzheimer's disease management, offering targeted, efficient, and adaptable drug delivery solutions. Strategic development and rigorous evaluation of these systems may improve CNS bioavailability of therapeutic agents, enhance clinical outcomes, and potentially shift the paradigm in the treatment of neurodegenerative disorders. Future research should focus on overcoming translational challenges to realize the full potential of nanocarrier-based AD therapy.}, } @article {pmid41930874, year = {2026}, author = {Xiao, S and Han, Y and Yan, J and Wu, L and Lin, H and Yuan, C and Song, C and Ye, J}, title = {Salvianolic acid a inhibits neuroinflammation and ameliorates Alzheimer's disease pathology via the p38 MAPK/NF-κB pathway based on network pharmacology and experimental validation.}, journal = {International immunopharmacology}, volume = {178}, number = {}, pages = {116594}, doi = {10.1016/j.intimp.2026.116594}, pmid = {41930874}, issn = {1878-1705}, mesh = {Animals ; *Alzheimer Disease/drug therapy/pathology/metabolism ; *p38 Mitogen-Activated Protein Kinases/metabolism ; *NF-kappa B/metabolism ; *Caffeic Acids/therapeutic use/pharmacology ; Humans ; Mice ; *Lactates/therapeutic use/pharmacology ; *Anti-Inflammatory Agents/therapeutic use/pharmacology ; Network Pharmacology ; Signal Transduction/drug effects ; Mice, Transgenic ; Disease Models, Animal ; Male ; Amyloid beta-Peptides/metabolism ; Cell Line ; Cytokines/metabolism ; Molecular Docking Simulation ; *Neuroinflammatory Diseases/drug therapy ; }, abstract = {Alzheimer's disease (AD) represents the most prevalent form of neurodegenerative disorder, characterized by progressive cognitive impairments and a scarcity of effective treatments. Salvianolic acid A (SalA), a natural phytochemical endowed with antioxidative, antiapoptotic, and anti-inflammatory properties, emerges as a promising therapeutic candidate for AD. This study explored the therapeutic efficacy and underlying mechanisms of SalA in mitigating AD-related pathologies. Through integrative network pharmacology, molecular docking, and pathway enrichment analysis, p38 MAPK and NF-κB were identified as potential targets of SalA in the context of AD. SalA treatment inhibited the activation of the p38 MAPK/NF-κB pathway via targeting p38 MAPK, leading to decreased levels of IL-1α and IL-1β in lipopolysaccharide (LPS)-stimulated HMC3 cells. In an in vivo 3 × Tg-AD mouse model, SalA administration ameliorated cognitive decline associated with AD, decreased tau protein hyperphosphorylation in the hippocampus and cortex, and reduced amyloid-β (Aβ) accumulation and β-site amyloid precursor protein cleaving enzyme 1 (BACE1) levels. Furthermore, SalA attenuated the activation of the p38 MAPK/NF-κB pathway and the expression of related inflammatory cytokines in the brains of 3 × Tg-AD mice. In conclusion, this study elucidates the promising ameliorative effects of SalA on improving AD pathology, primarily through the modulation of the p38 MAPK/NF-κB signaling pathway.}, } @article {pmid41931192, year = {2026}, author = {Du, M and Ma, S and Bai, L and Mou, X and Gao, Y and Zhang, J and Chen, Y}, title = {Olfactory Dysfunction Exacerbates Hippocampal Aβ Accumulation, Tau Phosphorylation and Memory Deficits in Mice.}, journal = {Neurochemical research}, volume = {51}, number = {2}, pages = {}, pmid = {41931192}, issn = {1573-6903}, support = {202401AU070130//Natural Science Foundation of Yunnan Province/ ; 202301AT070430//Natural Science Foundation of Yunnan Province/ ; 202305AS350011//innovation team of stress and disorder in nervous system in Yunnan Province/ ; 82201597//the National Natural Science Foundation of China/ ; KUST-KH2022001Y//the Joint Medical Specialization of Kunming University of Science and Technology/ ; }, mesh = {Animals ; *tau Proteins/metabolism ; *Hippocampus/metabolism/drug effects ; Phosphorylation/physiology ; *Memory Disorders/metabolism/chemically induced ; *Amyloid beta-Peptides/metabolism ; Male ; *Olfaction Disorders/metabolism/chemically induced/complications ; Mice ; Mice, Inbred C57BL ; Maze Learning/drug effects/physiology ; Zinc Sulfate/toxicity ; Alzheimer Disease/metabolism ; Aspartic Acid Endopeptidases ; Amyloid Precursor Protein Secretases ; }, abstract = {Olfactory dysfunction is a frequent feature in patients with neurodegenerative disorders such as Alzheimer’s disease (AD). However, whether olfactory impairment is the cause or consequence of AD is unknown. We previously found that olfactory dysfunction impairs learning and memory in mice in multiple experimental paradigms, but whether olfactory dysfunction increases AD-related neuropathological changes such as Aβ deposition and tau protein phosphorylation is not clear. In this study, mice were treated with bilateral intranasal zinc sulfate (ZnSO4) solution infusion, which resulted in olfactory dysfunction for about 1 month in mice. 1, 3, 6, and 9 months after that, the Y-maze learning and memory, as well as hippocampal Aβ deposition, tau and p-tau expression were tested. We found that olfactory dysfunction leads to a long period and irreversible learning and memory impairment in mice. Olfactory dysfunction also increased Aβ deposition, Aβ42 level, and increased p-tau expression in hippocampus (HPC), which were accompanied by increased beta-site amyloid precursor protein cleaving enzyme 1 (BACE1) and decreased presenilin-1 (PS1) expression. Compared with one time of ZnSO4 treatment, repetitive ZnSO4 treatment (three times, a month apart) resulted in more significant increases in tau phosphorylation in mice hippocampus. These results suggest that olfactory dysfunction lead to behavioral and pathological changes associated with AD in mice, which suggest that olfactory dysfunction can contribute to the development of AD.}, } @article {pmid41931967, year = {2026}, author = {Sun, X and Xi, Y and Chen, Y and Zhou, J and Ni, J and Ding, Y and Zhang, H}, title = {Dysfunctional microglia-targeted nanoscavenger synergistically accelerates Aβ clearance and inhibits inflammatory cascade.}, journal = {Biomaterials}, volume = {333}, number = {}, pages = {124163}, doi = {10.1016/j.biomaterials.2026.124163}, pmid = {41931967}, issn = {1878-5905}, mesh = {Animals ; *Microglia/drug effects/metabolism/pathology ; *Curcumin/administration & dosage/chemistry/therapeutic use/pharmacology ; *Amyloid beta-Peptides/metabolism ; *Alzheimer Disease/drug therapy/pathology/metabolism ; *Inflammation/drug therapy/pathology/metabolism ; Administration, Intranasal ; Mice ; Mice, Transgenic ; Chitosan/chemistry ; Brain/metabolism/drug effects/pathology ; Male ; Humans ; }, abstract = {Amyloid-β (Aβ) clearance holds promise in Alzheimer's disease (AD) treatment, but the clinical application is limited by poor clearance efficacy and microglial inflammatory cascade caused by overloaded Aβ degradation. In this study, a polymeric lipoprotein-curcumin nanoscavenger (CP/[Man]Disc-Cur) with dysfunctional microglia-specific targeting capability is designed to synergistically promote Aβ clearance and inhibit microglial inflammatory cascade. For preparation, curcumin is post-encapsulated into mannose-modified Disc ([Man]Disc-Cur), followed by assembly with chitosan derivatives (CP) to obtain CP/[Man]Disc-Cur. After intranasal administration and triggered by the nasal acidic microenvironment, CP/[Man]Disc-Cur is depolymerized into [Man]Disc-Cur and protonated CP that adheres to reversibly open the tight junctions, promoting [Man]Disc-Cur penetration into the brain via the olfactory pathway. Thereafter, [Man]Disc-Cur captures Aβ oligomer with a high binding affinity (KD = 5.90 × 10[-8] M) and selectively targets dysfunctional microglia where Aβ catabolism is accelerated with inflammation inhibition by curcumin. After nasal treatment of CP/[Man]Disc-Cur for 4 weeks, Aβ burden, microglial inflammation, and memory deficits of APPswe/PS1dE9 transgenic AD mice are significantly attenuated without the obvious side effects. Collectively, this study provides a promising strategy for synergistically improving Aβ clearance and inhibiting microglial inflammatory cascade for enhanced AD treatment.}, } @article {pmid41931990, year = {2026}, author = {Gao, J and Yi, Y and Ran, W and Cheng, Y and Deng, W and Duan, S and Shi, F and Wei, Y and Zhang, Y and Gong, Q}, title = {Targeting astrocytic Nrf2 by Trilobatin alleviates lipopolysaccharide-induced depressive-like behaviors and cognitive impairment in mice: Mechanistic insights into gut microbiota and metabolites modulation.}, journal = {Phytomedicine : international journal of phytotherapy and phytopharmacology}, volume = {155}, number = {}, pages = {158118}, doi = {10.1016/j.phymed.2026.158118}, pmid = {41931990}, issn = {1618-095X}, mesh = {Animals ; *NF-E2-Related Factor 2/metabolism ; *Gastrointestinal Microbiome/drug effects ; Mice ; Lipopolysaccharides ; Male ; *Cognitive Dysfunction/drug therapy/chemically induced ; Mice, Inbred C57BL ; *Astrocytes/drug effects/metabolism ; Neuroprotective Agents/pharmacology ; *Depression/drug therapy/chemically induced ; Disease Models, Animal ; Behavior, Animal/drug effects ; *Disulfides/pharmacology ; Alzheimer Disease/drug therapy ; Oxidative Stress/drug effects ; Major Depressive Disorder/drug therapy ; Flavonoids ; Polyphenols ; }, abstract = {BACKGROUND: Clinical and preclinical evidence links major depressive disorder (MDD) and Alzheimer's disease (AD), suggesting MDD treatment could prevent some AD. Dysfunction within the microbiota-gut-brain axis contributes to MDD and AD pathogenesis via dysregulated microbial metabolites. Trilobatin (TLB) functions as a neuroprotective agent modulating gut microbiota. However, its capacity to alleviate depressive-like behavior and cognitive deficits through restoration of gut microbial ecology and metabolite profiles requires clarification.

OBJECTIVE: The present research was designed to examine the impact of TLB on depressive-like behavior and cognitive impairments, and the role of the gut microbiota and metabolites.

METHODS: Neuroprotective effects of TLB on MDD and AD were evaluated using an LPS mouse model exhibiting depressive-like behavior and memory impairment. The principal molecular target of TLB was identified through a combination of single-cell sequencing, surface plasmon resonance, and gene knockout approaches. Mechanistic insights into gut microbiota and metabolites were gained through 16S rRNA sequencing and fecal microbiota transplantation (FMT).

RESULTS: TLB attenuated LPS-induced depressive-like behaviors manifested as lowered sucrose preference, extended immobility, and improved cognitive deficits as reflected by Y-maze and novel object recognition. Mechanistically, TLB directly bound Nrf2, enhanced Nrf2-ARE activity, and suppressed neuroinflammation and oxidative stress. TLB restored gut microbiota homeostasis, elevated Akkermansia muciniphila (AKK) abundance and short-chain fatty acids, and strengthened intestinal tight junction proteins. FMT from TLB-treated mice replicated these benefits in wild-type but not Nrf2-knockout mice. AKK supplementation similarly ameliorated behavioral and cognitive deficits via Nrf2 activation.

CONCLUSION: Our findings reveal that TLB mitigates neuropsychiatric deficits by activating Nrf2, remodeling restructuring gut microbiota and fortifying intestinal barrier function. The Nrf2-mediated microbiota-gut-brain axis is suggested as a potential therapeutic target for MDD and AD, positioning TLB as a promising natural Nrf2 activator.}, } @article {pmid41931996, year = {2026}, author = {Liu, XY and Wang, K and Zhong, JJ and Lin, CL and Zhu, JR and Wang, PP and Guo, R and Shao, SS and Lim, HSD and Siow, KL and Shan Kek, R and Ng, YH and Chen, M and Han, RC and Yao, H and Zheng, GQ and Wen, L}, title = {Modified Kai-Xin-San ameliorates cognitive impairment in Alzheimer's disease model mice by regulating neuroinflammation and synaptic dysfunction.}, journal = {Phytomedicine : international journal of phytotherapy and phytopharmacology}, volume = {155}, number = {}, pages = {158102}, doi = {10.1016/j.phymed.2026.158102}, pmid = {41931996}, issn = {1618-095X}, mesh = {Animals ; *Drugs, Chinese Herbal/pharmacology/chemistry ; *Alzheimer Disease/drug therapy ; Disease Models, Animal ; Mice ; *Cognitive Dysfunction/drug therapy ; Male ; Amyloid beta-Peptides/metabolism ; Maze Learning/drug effects ; Neuronal Plasticity/drug effects ; Hippocampus/drug effects ; *Neuroinflammatory Diseases/drug therapy ; Mice, Inbred C57BL ; Synapses/drug effects ; }, abstract = {BACKGROUND: Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by debilitating cognitive decline. Despite its escalating global prevalence, effective disease-modifying therapies remain limited. Modified Kai-Xin-San (MKXS), a derivative of a classic Chinese herbal formula, has shown promise in AD management; however, its precise pharmacological mechanisms require further elucidation.

PURPOSE: This study aimed to evaluate the therapeutic effects of MKXS and identify the molecular mechanisms underlying its impact on cognitive function in an AD mouse model.

METHODS: The chemical profile of MKXS was characterized using HPLC-Q-TOF-MS, with 24 major constituents quantified via UPLC-PDA. MKXS was administered intragastrically to 5 × FAD mice daily for two consecutive months. Cognitive performance was evaluated using Morris water maze, T-maze, and Y-maze tests. Neuropathological changes, including β-amyloid (Aβ) deposition and neuronal loss, were analyzed via immunostaining, Nissl staining, ELISA, and Western blotting. Synaptic plasticity was assessed through Golgi staining and electrophysiological recordings. Furthermore, network pharmacology and experimental validation were conducted to identify core therapeutic targets with the application of GEO database.

RESULTS: Chemical analysis identified 125 constituents in MKXS, with 24 validated against reference standards. In 5 × FAD mice, MKXS treatment significantly ameliorated cognitive impairment, reduced hippocampal Aβ plaque burden, and attenuated neuronal loss. Network pharmacology highlighted neuroinflammation and synaptic regulation as core therapeutic mechanisms. Subsequent validation demonstrated that MKXS suppressed glial overactivation and lowered pro-inflammatory cytokine levels, effectively restoring synaptic plasticity and dendritic spine integrity within the hippocampus. Notably, MKXS significantly upregulated the CaMKIIα/CREB signaling pathway in the hippocampus of 5 × FAD mice. Crucially, pharmacological inhibition of CaMKIIα with KN93 significantly abolished these beneficial effects on synaptic function and memory, confirming the essential role of this signaling axis in MKXS-mediated neuroprotection.

CONCLUSION: MKXS alleviated cognitive impairment in 5 × FAD mice by attenuating neuroinflammation and restoring synaptic integrity. These neuroprotective effects were mediated, at least in part, by the activation of the CaMKIIα/CREB signaling pathway. Collectively, these findings underscore the potential of MKXS as a promising multi-target therapeutic intervention for AD.}, } @article {pmid41932135, year = {2026}, author = {Lin, WJ and Li, CY and Shi, WP and Liu, TA and Wang, YJ and Li, YJ}, title = {Ferulic acid inhibits Tau-441 liquid-liquid phase separation to restore glycolytic metabolism.}, journal = {International journal of biological macromolecules}, volume = {358}, number = {}, pages = {151806}, doi = {10.1016/j.ijbiomac.2026.151806}, pmid = {41932135}, issn = {1879-0003}, mesh = {*Coumaric Acids/pharmacology/chemistry ; *Glycolysis/drug effects ; Humans ; *tau Proteins/chemistry/metabolism ; Phase Separation ; Hexokinase/metabolism ; Molecular Docking Simulation ; Cell Survival/drug effects ; }, abstract = {Alzheimer's disease (AD) is one of the most common neurodegenerative diseases, and effective clinical treatment currently remains lacking. Ferulic acid (FA) has shown clinical effects in the treatment of AD, but the underlying mechanism of action remains unclear. Here, we showed that FA significantly enhances glycolytic metabolism by inhibiting Tau-441 liquid-liquid phase separation (LLPS). Through molecular docking and solution experiments, we demonstrated that FA binds to Tau-441 via hydrogen bonds, significantly reducing its β-sheet content, thereby effectively preventing the formation of Tau-441 droplets and their transition into solid aggregates. Immunofluorescence staining further confirmed that FA inhibits Tau-441 LLPS formation and reduces the recruitment of hexokinase (HK) during droplet formation. Metabolomic and network analyses revealed that FA significantly alters cellular metabolic profiles, particularly enhancing glycolytic pathway activity. Consistently, FA markedly increased the activities of three key enzymes (HK, PFK, and PK) in the glycolytic pathway, thereby elevating cellular ATP levels and cell viability. These results demonstrate that FA significantly improves glycolytic metabolic efficiency by inhibiting Tau-441 LLPS, thus providing critical experimental and theoretical support for the potential application of FA in treating AD. Overall, this study offers new molecular targets and natural compound intervention strategies for AD treatment.}, } @article {pmid41932344, year = {2026}, author = {Geldenhuys, WJ and Mersch, J and Cicala, D and Sarker, R and Roknuzzaman, ASM and Maghareh, M and Carerra, EM and Lade, DM and Menze, MA and Konkle, ME and Huber, JD}, title = {Medicinal Chemistry Review of the NEET Protein Family.}, journal = {ChemMedChem}, volume = {21}, number = {7}, pages = {e202500969}, pmid = {41932344}, issn = {1860-7187}, support = {P20 GM103434/GM/NIGMS NIH HHS/United States ; }, mesh = {Humans ; *Mitochondrial Proteins/metabolism/antagonists & inhibitors/chemistry ; Animals ; *Iron-Sulfur Proteins/metabolism/antagonists & inhibitors/chemistry ; }, abstract = {Members of the NEET family of proteins are of interest as drug targets in several age-related diseases, including cancer, diabetes, obesity, Alzheimer's and Parkinson's disease, stroke, and traumatic brain injury. These proteins share a CDGSH motif and redox-active [2Fe-2S] clusters. MitoNEET (CDGSH iron-sulfur domain-containing protein 1) is an outer mitochondrial membrane protein that was recently discovered as an off-target of the antidiabetic drug pioglitazone, and plays an essential role in mitochondrial bioenergetics, mitophagy, and iron metabolism. CDGSH iron-sulfur domain-containing protein 2 (nutrient-deprivation autophagy factor 1) is located on the endoplasmic reticulum and is found to be antiaging and associated with Wolfram Syndrome 2, while CDGSH iron-sulfur domain-containing protein 3 (mitochondrial inner NEET protein) is present in the mitochondrial matrix. In this review, we will evaluate the state of the field in the development of NEET protein interacting ligands, which can serve as pharmacological tools to study the biology/biochemistry of NEET family proteins in disease. The NEET family represents a novel class of drug targets, enabling the development of novel treatment modalities to modulate disease progression in various human disorders.}, } @article {pmid41933174, year = {2026}, author = {Cummings, JL and Agadjanyan, MG and Barry, M and Corey, L and Doody, R and Hendrix, S and Mattke, S and Mattsson-Carlgren, N and McDade, E and Menetski, JP and Mohs, RC and Partrick, KA and Petrovsky, N and Selkoe, DJ and Silva, D and Sperling, RA and Tiede, B and Vradenburg, G}, title = {Target product profiles for treatments to delay or prevent symptomatic Alzheimer's disease.}, journal = {Nature medicine}, volume = {32}, number = {4}, pages = {1223-1232}, pmid = {41933174}, issn = {1546-170X}, mesh = {Humans ; *Alzheimer Disease/prevention & control/drug therapy ; Biomarkers/metabolism ; Clinical Trials as Topic ; }, abstract = {Despite advances in understanding the mechanisms, risk factors and treatment strategies for Alzheimer's disease (AD), no approved therapies exist to prevent or delay onset in at-risk individuals or those with elevated biomarkers who do not yet show symptoms. Multiple candidate interventions are now being evaluated in clinical trials in these settings, raising key questions around which populations are most appropriate and what criteria should guide regulatory and clinical decision-making. Data are expected within 1-2 years, underscoring the need for stakeholder alignment on clinically meaningful and acceptable characteristics of preventative therapies or other products. To address this need, the Global CEO Initiative on Alzheimer's Disease convened an international group of experts to develop target product profiles for therapies designed to delay or prevent the onset of clinical symptoms in AD. These target product profiles outline minimum and preferred characteristics, including intended use, target populations, safety expectations and efficacy benchmarks. This effort provides a foundational framework to accelerate therapeutic development and guide researchers, regulators and patients in the evaluation of emerging therapies for preventing symptomatic AD.}, } @article {pmid41933339, year = {2026}, author = {Huang, N and Hong, R and Cui, X and Cao, L and Shi, L and Chen, B and Su, Y and Xu, X and Hua, C and Ying, T}, title = {Targeting the HDAC4-NHE6-endosomal pH axis restores amyloid-β clearance and cognitive function in Alzheimer's disease mice.}, journal = {Journal of nanobiotechnology}, volume = {24}, number = {1}, pages = {}, pmid = {41933339}, issn = {1477-3155}, support = {82272018//the National Natural Science Foundation of China/ ; ynnkxzd202404//Shanghai Sixth People's Hospital Institutional Brain Science and Brain-Inspired Research Project/ ; }, mesh = {Animals ; *Alzheimer Disease/metabolism/drug therapy ; *Amyloid beta-Peptides/metabolism ; *Histone Deacetylases/metabolism ; Mice ; Histone Deacetylase Inhibitors/pharmacology/chemistry ; Endosomes/metabolism/drug effects ; Mice, Transgenic ; *Cognition/drug effects ; Humans ; Vorinostat/pharmacology/chemistry ; Blood-Brain Barrier/metabolism/drug effects ; Hydrogen-Ion Concentration ; Nanoparticles/chemistry ; Male ; Disease Models, Animal ; Microglia/metabolism ; }, abstract = {BACKGROUND: Impaired clearance of amyloid-β (Aβ) is a major pathological hallmark of Alzheimer's disease (AD). Although histone deacetylase (HDAC) inhibitors show therapeutic potential, their clinical translation for AD is hampered by poor blood brain barrier (BBB) penetration and an incomplete understanding of their mechanism in Aβ clearance. Here, angiopep2-conjugated nanoparticles (SAHA@LIPO-ANG2) for efficient BBB translocation and delivery of the HDAC inhibitor vorinostat (SAHA) was developed and its underlying mechanisms were validated.

RESULTS: Our result demonstrates that SAHA@LIPO-ANG2 potently inhibits HDAC4 nuclear translocation, which was identified as a key upstream event responsible for the transcriptional repression of sodium-hydrogen exchanger 6 (NHE6). Restoration of NHE6 expression rectifies endosomal hyperacidification, thereby rescuing the trafficking and plasma membrane expression of the Aβ clearance receptor, low-density lipoprotein receptor-related protein 1 (LRP1). Furthermore, this HDAC4-NHE6-pH axis modulates the neuroimmune microenvironment to enhance Aβ clearance through multiple synergistic mechanisms: it upregulates phagocytic receptors and recruit microglial to phagocytize Aβ plaques, while concurrently reactivating autophagy-lysosomal function in astrocytes by increasing LAMP2 expression. Consequently, treatment with SAHA@LIPO-ANG2 in 5xFAD mice significantly reduced Aβ burden, suppressed neuroinflammation, rescued synaptic loss, and ultimately reversed cognitive deficits.

CONCLUSIONS: Our study not only elucidates a HDAC4-NHE6-pH regulatory axis in AD pathogenesis but also establishes a multifaceted nanotherapeutic strategy for restoring Aβ homeostasis. Our findings may provide therapeutic strategies for treating amyloid-related diseases.}, } @article {pmid41933799, year = {2026}, author = {Huang, Q and Lv, Y and Ye, X and Xia, X and Chen, Y and Wang, X and Tong, F and Yang, W and Bozorov, K and Shevtsov, M and Li, H and Gao, H and Ye, B}, title = {Engineered microglial membrane-coated polydopamine-based nanomedicine for precise treatment of Alzheimer's disease.}, journal = {Journal of controlled release : official journal of the Controlled Release Society}, volume = {394}, number = {}, pages = {114896}, doi = {10.1016/j.jconrel.2026.114896}, pmid = {41933799}, issn = {1873-4995}, mesh = {Animals ; *Polymers/administration & dosage/chemistry ; *Microglia/metabolism ; *Alzheimer Disease/drug therapy/pathology/metabolism ; *Indoles/administration & dosage/chemistry ; Mice, Transgenic ; *Nanoparticles/chemistry/administration & dosage ; *Rivastigmine/administration & dosage/pharmacokinetics/therapeutic use ; Humans ; Cell Membrane/metabolism ; Nanomedicine ; Mice ; Blood-Brain Barrier/metabolism ; Brain/drug effects/metabolism/pathology ; }, abstract = {Multimodal treatment for Alzheimer's disease (AD) is a pivotal option because of its complex pathogenesis. The major challenge of pharmacotherapies is effective drug delivery to the diseased brain and reduction of associated toxicity. Here, we propose a dual-target nanomedicine (PDA@R@M/K) for the management of AD by coating engineered microglial cell membrane (M/K) onto polydopamine (PDA) cores encapsulated with rivastigmine. M/K conferred nanoparticles (NPs) with reduced circulation clearance, pathological blood-brain barrier recognition, and enhanced brain inflammation chemotaxis. PDA cores not only acted as potent ROS scavengers to alleviate neuroinflammation but also piggybacked rivastigmine and implemented responsive release. After applying PDA@R@M/K in preclinical transgenic mouse models, amyloid plaque deposition, neurologic changes, and cognitive decline were largely rescued. These results provide the possibility of directly using NPs as therapeutics rather than merely as nanocarriers, and demonstrate the feasibility of engineered microglia membrane-coated NPs to improve the pharmacokinetics and efficacy of anti-AD drugs.}, } @article {pmid41933986, year = {2026}, author = {Patel, S and Reisch, A and Narapareddy, BR}, title = {Frontal variant Alzheimer's disease presenting as late-onset psychiatric illness: A case series highlighting diagnostic challenges on inpatient psychiatric units.}, journal = {Journal of the National Medical Association}, volume = {118}, number = {3}, pages = {446-450}, doi = {10.1016/j.jnma.2026.03.005}, pmid = {41933986}, issn = {1943-4693}, mesh = {Humans ; *Alzheimer Disease/diagnosis/psychology ; Female ; Aged ; Male ; Neuropsychological Tests ; Diagnosis, Differential ; Positron-Emission Tomography ; Magnetic Resonance Imaging ; Antipsychotic Agents/therapeutic use ; Middle Aged ; *Mental Disorders/diagnosis ; Psychiatric Department, Hospital ; }, abstract = {BACKGROUND: Neurocognitive disorders are classified within psychiatric nosology and may present with prominent behavioral, mood, or psychotic symptoms that resemble other psychiatric illnesses. This overlap can lead to diagnostic ambiguity, delayed recognition of neurodegeneration, and unnecessary or harmful treatments. Frontal variant Alzheimer's disease (fvAD) is particularly prone to misdiagnosis because behavioral symptoms may precede memory impairment.

OBJECTIVE: To describe three cases of fvAD initially diagnosed as other psychiatric illnesses and to highlight strategies for improving diagnostic accuracy on inpatient psychiatric units.

METHODS: Three adults hospitalized for late-onset psychiatric syndromes refractory to standard treatment underwent systematic cognitive assessment, neuropsychological evaluation, and neuroimaging. Diagnoses were subsequently clarified as fvAD.

RESULTS: All patients initially received antipsychotic medications; two developed extrapyramidal symptoms. Cognitive assessment, collateral history, neuropsychological testing, and FDG-PET/MRI demonstrated patterns consistent with fvAD, enabling diagnostic clarification, discontinuation of ineffective treatments, and engagement of appropriate dementia care.

CONCLUSION: Late-onset psychiatric syndromes resistant to treatment may represent early manifestations of neurocognitive disorders rather than other psychiatric conditions. Systematic assessment facilitates accurate diagnosis, reduces unnecessary interventions, and supports timely referral to multidisciplinary dementia care.}, } @article {pmid41934898, year = {2026}, author = {Zhong, J and He, X and Yang, H and Zhang, J and Liu, J and Yang, J and Dong, X}, title = {Icariin, astragaloside IV and puerarin mixture salvages synaptic loss by enhancing mitochondrial biogenesis: A multi-target strategy for Alzheimer's disease therapy.}, journal = {Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie}, volume = {198}, number = {}, pages = {119320}, doi = {10.1016/j.biopha.2026.119320}, pmid = {41934898}, issn = {1950-6007}, mesh = {Animals ; Male ; *Alzheimer Disease/drug therapy/metabolism/pathology ; *Saponins/pharmacology ; *Triterpenes/pharmacology ; *Mitochondria/drug effects/metabolism/ultrastructure ; Mice, Inbred C57BL ; *Organelle Biogenesis ; *Flavonoids/pharmacology ; *Isoflavones/pharmacology ; *Synapses/drug effects/metabolism/ultrastructure/pathology ; Glycogen Synthase Kinase 3 beta/metabolism ; Mice ; Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha/metabolism ; Mice, Transgenic ; Hippocampus/drug effects/metabolism ; Disease Models, Animal ; Signal Transduction/drug effects ; }, abstract = {OBJECTIVE: This study aimed to elucidate the potential mechanism by which the Icariin, astragaloside IV and puerarin (Ying-Huang-Ge, YHG) mixture regulates mitochondrial-synaptic homeostasis in Alzheimer's disease (AD) MOD mice through the Glycogen Synthase Kinase-3β (GSK-3β)/Peroxisome Proliferator-Activated Receptor γ Coactivator-1α (PGC-1α) signaling axis.

METHODS: Thirty 5-month-old male APP/PS1 mice were randomly divided into the MOD group, the YHG treatment group (YHG), and the Donepezil treatment group (DNP) (n = 10 per group). Ten age-matched male C57BL/6 J mice served as the CON group. Following two months of continuous administration, cognitive function was assessed using the Morris Water Maze (MWM) and Novel Object Recognition (NOR) tests. Dendritic spine density in the hippocampal CA1 region was evaluated via Golgi staining, and ultrastructural changes were examined using transmission electron microscopy (TEM). Hippocampal levels of adenosine triphosphate (ATP), malondialdehyde (MDA), and superoxide dismutase (SOD) were measured using biochemical assay kits. Protein expression levels of GSK-3β, p-GSK-3β (Ser9), PGC-1α, mitochondrial functional proteins (NRF-1, TFAM), and synaptic plasticity-related proteins (PSD95, SYN) were determined by Western blot.

RESULTS: Compared with the CON group, the MOD group exhibited significantly impaired learning and memory capabilities, reduced dendritic spine density in the hippocampal CA1 region, and disrupted synaptic ultrastructure. Mitochondria displayed pathological changes, including swelling and vacuolization. Furthermore, ATP and SOD levels were significantly decreased, while MDA content was elevated. Western blot analysis revealed increased total GSK-3β expression and significantly decreased expression of p-GSK-3β (Ser9), PGC-1α, downstream mitochondrial biogenesis proteins (NRF-1, TFAM), and synaptic proteins (PSD95, SYN). Intervention with YHG significantly ameliorated these cognitive deficits, mitigated pathological damage to mitochondria and synapses, and reversed the abnormal molecular expression profiles.

CONCLUSION: The YHG ameliorates cognitive dysfunction and attenuates synaptic impairment in APP/PS1 mice. The underlying mechanism may involve the inhibition of GSK-3β activity, which subsequently activates PGC-1α-mediated mitochondrial biogenesis, enhances mitochondrial quality, and mitigates oxidative stress, ultimately leading to the restoration of synaptic structural integrity.}, } @article {pmid41934929, year = {2026}, author = {Yao, M and Guo, H and Fang, Y and Chen, Y and Liu, Y and Liu, S and Guo, J and Guo, Z and Qian, J and Ma, Q}, title = {Microplastics released from dental materials induce oral inflammatory bone resorption and apoptosis via mitochondrial dysfunction.}, journal = {Environment international}, volume = {210}, number = {}, pages = {110226}, doi = {10.1016/j.envint.2026.110226}, pmid = {41934929}, issn = {1873-6750}, mesh = {*Apoptosis/drug effects ; Humans ; *Mitochondria/drug effects ; Animals ; *Microplastics/toxicity ; *Bone Resorption/chemically induced ; *Dental Materials/toxicity ; Mice ; Inflammation/chemically induced ; }, abstract = {Microplastics (MPs) are emerging pollutants that are associated with many diseases including atherosclerosis, inflammatory bowel disease (IBD), and Alzheimer's. The oral cavity is the primary point for the uptake of MPs by human, where MPs could pose risks to oral and even system health. Various polymer-based materials have been used as dental materials in oral treatment, however, the assessment of MPs in dental treatments remains limited and the processes and mechanisms by which MPs affect human health through the oral route are elusive. Here, we report the assessment of the risks and sources of MPs in dental clinics, the establishment of the relationship between MPs and oral inflammatory disorders, and also the elucidation of underlying mechanisms. Our results showed that commonly used therapeutic dental materials could generate MPs in dental clinics with proportions significantly higher than those in office areas and outdoors. As a representative, polymethyl methacrylate (PMMA) MPs showed significant toxicity to human oral keratinocytes (HOK), human periodontal ligament stem cells (hPDLCs), and THP-1-derived macrophages. Mechanistic investigations of apoptosis and inflammation processes revealed that MPs could lead to mitochondrial stress and autophagy and trigger the Notch signaling pathway and the JAK-STAT signaling pathway. Mice experiments showed that prolonged high-dose MPs exposure induced periodontal inflammatory reactions and even led to inflammatory bone resorption. This study provides a scientific basis for the oral health risks by MPs in dental practice and addresses the need for the development of dental materials with higher biocompatibility and environmentally sustainability.}, } @article {pmid41935066, year = {2026}, author = {Shou, R and Wang, Z and Han, Z and Li, A and Shang, J and Lou, H and Zhang, F and Zhan, Y and Shen, G and Lu, X and Jiang, H and Fan, X}, title = {Dietary silver nanoparticle supplementation induces Alzheimer-like lesions through Bifidobacterium deficiency-dominated gut microbiota dysbiosis and neuroinflammation.}, journal = {NPJ science of food}, volume = {10}, number = {1}, pages = {}, pmid = {41935066}, issn = {2396-8370}, support = {No. LY23B070004//Zhejiang Provincial Natural Science Foundation of China/ ; No. 82374136//National Natural Science Foundation of China/ ; No.2024SDXT001-7//Key R&D Program of Zhejiang/ ; }, abstract = {Dietary supplement silver nanoparticles have recently drawn attention following reports of hazards associated with long-term use. However, their biosafety, especially their effects on the gut-brain axis, remains largely unexplored. This study demonstrated that dietary supplement silver nanoparticles can accumulate in the intestines, brain, and liver of mice. Chronic exposure to these nanoparticles leads to Alzheimer-like lesions, primarily by disrupting gut microbiota balance. Specifically, this exposure depletes Bifidobacterium and Ruminococcaceae, resulting in reduced intestinal metabolites such as sphingomyelin (d18:1/20:0), tryptophan, and indole. Consequently, this disruption causes neuroinflammation, cognitive impairment, and amyloid-β deposition in mice. Moreover, Bifidobacterium was identified as a key microbial group contributing to Alzheimer-like lesions after exposure, whereas supplementation with Bifidobacterium breve MCC1274 effectively alleviated these lesions. Therefore, the potential risks of silver nanoparticles in dietary supplements should be carefully evaluated. This study provides a promising new direction for the prevention and treatment of Alzheimer-like lesions through microbial interventions.}, } @article {pmid41935801, year = {2026}, author = {Kong, L and Wu, Y and Zeng, H and Wu, R and Xu, X and Lu, Z and Zhang, W and Ma, C}, title = {The preclinical evidence and clinical translational prospects of medicarpin.}, journal = {Pharmacological research}, volume = {227}, number = {}, pages = {108183}, doi = {10.1016/j.phrs.2026.108183}, pmid = {41935801}, issn = {1096-1186}, mesh = {Humans ; Animals ; Translational Research, Biomedical ; }, abstract = {Medicarpin (MED) is an isoflavonoid compound derived from traditional Chinese medicine (TCM). Numerous preliminary experimental studies have shown that MED has significant pharmacological effects in the treatment of cancer, osteoporosis, osteoarthritis, Alzheimer's disease (AD), arthritis, and other diseases. However, the clinical application of MED has not yet been reported. Summarizing the preclinical drug research of MED is helpful for clarifying its pharmacological activities and evaluating its research prospects. In this review, we search for the preliminary experimental research of MED, encompassing pharmaceutics, pharmacodynamics, pharmacology, pharmacokinetics, clinical studies, and toxicology. A comprehensive review of the chemical synthesis and biosynthesis, biological activities, mechanisms, bioavailability, and clinical research of MED is conducted to systematically evaluate its safety, efficacy, and druggability. Ultimately, our work promotes the understanding of MED and facilitates its clinical translation and application.}, } @article {pmid41936348, year = {2026}, author = {Shimasaki, R and Kurihara, M and Bannai, T and Hatano, K and Suzuki, F and Tokumaru, AM and Ishii, K and Ihara, R and Iwata, A}, title = {Amyloid-related imaging abnormalities in Japanese patients with Alzheimer's disease treated with Lecanemab: A real-world study.}, journal = {The journal of prevention of Alzheimer's disease}, volume = {13}, number = {6}, pages = {100562}, pmid = {41936348}, issn = {2426-0266}, mesh = {Humans ; Female ; *Alzheimer Disease/drug therapy/diagnostic imaging ; Japan ; Male ; Aged ; Magnetic Resonance Imaging ; Aged, 80 and over ; *Antibodies, Monoclonal, Humanized/adverse effects/therapeutic use ; *Brain/diagnostic imaging/drug effects ; East Asian People ; }, abstract = {BACKGROUND: Although clinical trials have suggested a lower incidence of adverse events associated with Lecanemab in Asian populations compared to global cohorts, longitudinal real-world data across broader clinical indications are necessary to confirm these findings in routine practice.

OBJECTIVES: This study aimed to provide real-world evidence regarding the safety profile of Lecanemab in Japanese patients in a clinical setting.

DESIGN: A real-world observational study with a follow-up period of up to 18 months.

SETTING: A single center in Japan.

PARTICIPANTS: We included 120 Japanese patients who received Lecanemab between December 2023 and November 2025 and underwent at least one brain MRI before the fifth infusion.

MEASUREMENTS: Safety outcomes included amyloid-related imaging abnormalities (ARIA), infusion-related reactions (IRRs), and treatment discontinuation.

RESULTS: The mean age was 74.2 ± 7.9 years, and 89 (74%) were female. The majority of patients (88%) had a baseline CDR global score of 0.5. During follow-up, 81 patients completed the 12-month assessment. ARIA occurred in 24 patients (20%); ARIA-E with or without ARIA-H occurred in 5 patients (4%), and isolated ARIA-H occurred in 19 patients (16%). Crucially, no patients experienced symptomatic ARIA. All patients with ARIA-E who had available APOE data were ε4 carriers. Patients with ARIA had significantly lower baseline MMSE scores (p = 0.04), alongside non-significant trends toward higher plasma GFAP levels (p = 0.11) and higher deep white matter Fazekas scores (p = 0.05). IRRs occurred in 34 patients (28%), all of which were mild. Treatment was discontinued in 19 patients (16%), mainly due to disease progression (n = 8).

CONCLUSION: In this Japanese AD cohort, Lecanemab demonstrated a manageable safety profile in a real-world setting. In exploratory analyses, potential trends toward a higher frequency of ARIA were observed in patients with lower MMSE scores, higher plasma GFAP levels, and higher Fazekas scores, underscoring the importance of individualized risk assessment prior to therapy.}, } @article {pmid41936874, year = {2026}, author = {Wang, YX and Zhou, XW and Du, WR and Qin, SH and Zhang, CY and Ma, ZY}, title = {Novel 2-aminopyrimidine carboxamide derivatives as potential anti-Alzheimer's disease agents: Design, synthesis, biological activity and computational simulation evaluation.}, journal = {Bioorganic & medicinal chemistry letters}, volume = {137}, number = {}, pages = {130650}, doi = {10.1016/j.bmcl.2026.130650}, pmid = {41936874}, issn = {1464-3405}, mesh = {*Cholinesterase Inhibitors/chemical synthesis/chemistry/pharmacology ; *Alzheimer Disease/drug therapy/metabolism ; *Drug Design ; Acetylcholinesterase/metabolism/chemistry ; Butyrylcholinesterase/metabolism/chemistry ; Structure-Activity Relationship ; *Pyrimidines/chemistry/chemical synthesis/pharmacology ; Molecular Docking Simulation ; Humans ; Antioxidants/chemistry/chemical synthesis/pharmacology ; Molecular Structure ; Dose-Response Relationship, Drug ; Biphenyl Compounds/antagonists & inhibitors ; Picrates/antagonists & inhibitors ; }, abstract = {In this study, a series of 2-amino-5-formamidopyrimidine derivatives were designed and synthesized. Their potential as cholinesterase inhibitors (ChEIs) for the treatment of Alzheimer's disease (AD) were evaluated by the Ellman method. Meanwhile, the antioxidant activity of these compounds were assessed by the DPPH (2,2-diphen-yl-1-picrylhydrazyl) free radical scavenging assay. The cholinesterase (ChE) inhibition test showed that most compounds exhibited excellent to moderate inhibitory effects on acetylcholinesterase (AChE), while most of them did not show significant inhibitory effects on butyrylcholinesterase (BuChE), demonstrating significant selectivity. Among them, compound 9 s (AChE: IC50 = 1.60 μM) whose AChE inhibitory activity is superior to the positive control galantamine (AChE: IC50 = 5.10 μM) is the most promising representative compound. Meanwhile, compound 9 s has high selectivity with a SI (IC50 ratio of BuChE to AChE) value of 29.85. The results of enzyme kinetics study determined that compound 9 s was a mixed-type inhibitor. Additionally, the molecular docking studies results indicated that compound 9 s could simultaneously interact with the catalytic active site (CAS) and the peripheral anionic site (PAS) of AChE, which was consistent with the results of the enzyme kinetics experiments. Molecular dynamics (MD) simulation study further verified the stability of the 9 s-AChE complex. In addition, the DPPH radical scavenging assay indicated that these compounds also possessed relatively weak antioxidant activities. Among them, compound 9p exhibited the best antioxidant activity with an IC50 value of 113.93 μM, which was lower than that of the positive control ascorbic acid (IC50 = 41.17 μM). Overall, these experimental results suggested that compound 9 s as AChE inhibitor had potential value for further research.}, } @article {pmid41936993, year = {2026}, author = {Lizard, G and Sassi, K and Mackrill, JJ and Ghzaiel, I and Meziane, S and Hassen, E and Abdelkarim, M and Masmoudi-Kouki, O and Ghrairi, T and Brahmi, F and Gargouri, A and Rezig, L and Benkalifa, R and Khallouki, F and El Midaoui, A and Pincemail, J and Atanasov, AG and Vejux, A and Millot, N}, title = {7-ketocholesterol as a theranostic target: Potential applications and future perspectives.}, journal = {Chemistry and physics of lipids}, volume = {276-277}, number = {}, pages = {105588}, doi = {10.1016/j.chemphyslip.2026.105588}, pmid = {41936993}, issn = {1873-2941}, mesh = {Humans ; *Ketocholesterols/metabolism/antagonists & inhibitors ; *Theranostic Nanomedicine ; Alzheimer Disease/drug therapy/metabolism ; Animals ; *Cardiovascular Diseases/drug therapy/metabolism ; Oxidative Stress/drug effects ; }, abstract = {7-Ketocholesterol (7KC) is mainly formed by cholesterol autoxidation and is a pro-oxidant and pro-inflammatory bioactive lipid that also induces different types of cell death, including oxiapoptophagy. It is frequently associated with major age-related diseases, such as cardiovascular diseases, age-related macular degeneration, and Alzheimer's disease. 7KC can therefore be considered a biomarker for these diseases, offering the possibility of developing theranostic strategies combining diagnosis and treatment. Currently, all the elements are in place to develop tools for the design of theranostic therapies targeting 7KC in diseased organs: antibodies, nanoparticles used as nanoplatforms, molecules that neutralize 7KC such as enzymes which degrade it, as well as natural or synthetic compounds that inhibit the cytotoxic signaling pathways associated with oxidative stress, inflammation and cell death activated by 7KC. Identifying and neutralizing 7KC biological activities using a theranostic approach could also be of interest for growing medical fields such as space medicine widely concerned by oxidative stress, aging and age-related diseases, driven by microgravity. This review supports that most of key tools are now available to develop theranostic treatments targeting 7KC in age-related pathologies, especially in cardiovascular diseases associated with atheroma, but also in age-related macular degeneration and Alzheimer's disease. Discovery of effective treatments for these diseases is a major challenge and will answer an important need for both patients and caregivers.}, } @article {pmid41937403, year = {2026}, author = {Borda, MG and O'Hara-Veintimilla, K and Aarsland, D}, title = {Older Adults, Anti-Amyloid Therapy, and Frailty: What Oncology Can Teach Us.}, journal = {European journal of neurology}, volume = {33}, number = {4}, pages = {e70567}, pmid = {41937403}, issn = {1468-1331}, support = {//Helse Vest/ ; //Nasjonalforeningen for Folkehelsen/ ; }, mesh = {Humans ; *Frailty/diagnosis ; Aged ; *Alzheimer Disease/drug therapy ; *Geriatric Assessment/methods ; *Medical Oncology/methods ; }, abstract = {BACKGROUND: Anti-amyloid therapies, such as lecanemab or donanemab, represent the first disease-modifying treatments approved for early Alzheimer's disease (AD) in individuals with confirmed amyloid pathology. Their implementation in routine care raises important challenges, particularly in older adults with heterogeneous functional reserve and multimorbidity. We address the role of frailty in refining clinical decision-making for anti-amyloid therapies.

METHODS: This short communication presents a conceptual discussion informed by geriatric oncology, where frailty assessment and comprehensive geriatric assessment (CGA) are routinely used to individualize treatment in heterogeneous older populations. We describe how similar principles may be applied to anti-amyloid monoclonal antibodies once regulatory eligibility has been established, and outline a frailty-informed conceptual framework to support clinical decision-making in routine care.

RESULTS: This conceptual analysis proposes a stepwise, frailty-informed clinical framework that integrates regulatory eligibility assessment with brief frailty screening and targeted comprehensive geriatric assessment. The framework defines differentiated clinical pathways for robust, pre-frail, and frail individuals, linking frailty status to specific decisions regarding treatment initiation, need for prehabilitation, intensity of monitoring, and consideration of treatment deferral. By embedding frailty assessment within routine clinical workflows, the framework operationalizes evaluation of physiological reserve, anticipates treatment burden and monitoring feasibility, and provides a structured approach to individualized risk-benefit appraisal for anti-amyloid therapies.

CONCLUSIONS: Frailty-informed frameworks may offer a pragmatic and ethically grounded approach to support real-world implementation of anti-amyloid therapies, guiding treatment selection as well as longitudinal decisions on monitoring, continuation, and reassessment over time.}, } @article {pmid41937689, year = {2026}, author = {Helphrey, JH and Hart, J and McClintock, SM and Peters, ME and Thakkar, VJ and LoBue, C}, title = {A scoping review of frontal cortex tDCS on neuropsychological functioning in older adults with mild cognitive impairment and Alzheimer's Clinical Syndrome.}, journal = {International review of psychiatry (Abingdon, England)}, volume = {}, number = {}, pages = {1-17}, doi = {10.1080/09540261.2026.2647921}, pmid = {41937689}, issn = {1369-1627}, abstract = {Mild cognitive impairment (MCI) and Alzheimer's Clinical Syndrome (ACS) are prevalent, incurable, and are expected to increase in incidence over the next 30 years. Finding new treatments to address the cognitive and behavioral problems in MCI and ACS represent an urgent need. Brain circuitry disruption can cause cognitive dysfunction and neuropsychiatric symptoms (NPS) in both MCI and ACS. Therefore, one promising avenue of treatment is non-invasive brain stimulation through transcranial direct current stimulation (tDCS). This scoping review examined the current knowledge base for the potential neuropsychological and neuropsychiatric effects of frontal cortex tDCS in older adults with MCI and ACS. Of the 17 randomized controlled trials reviewed, treatment parameters such as session length, current intensity, number of treatments, and time between treatments varied widely across studies, which restricted identification of optimal tDCS treatment protocols. Mixed findings on neuropsychological outcomes were observed, though significant improvements were most commonly seen in studies measuring global cognition (10) followed by executive function (6). Only three studies yielded clinically significant cognitive improvement, and few studies assessed NPS outcomes. Additional rigorous research is indicated to enhance our understanding of tDCS as a treatment for cognitive and neuropsychiatric symptoms in older adults with MCI and ACS.}, } @article {pmid41937703, year = {2026}, author = {Salim, MW and Zhang, W and Collins-Praino, L and Wang, Y and Care, A}, title = {Small Extracellular Vesicles from Neural Cells: Physiological and Pathological Roles, and Potential in Neurodegenerative Therapy.}, journal = {Advanced healthcare materials}, volume = {15}, number = {21}, pages = {e04608}, pmid = {41937703}, issn = {2192-2659}, support = {//Higher Education Commission/ ; //International Macquarie University Research Excellence Scholarship/ ; FT210100737//ARC Future Fellowship/ ; //Dementia Australia Research Foundation/ ; //Mason Foundation/ ; //National Foundation for Medical Research & Innovation/ ; }, mesh = {Humans ; *Extracellular Vesicles/metabolism/pathology ; Animals ; *Neurodegenerative Diseases/therapy/pathology/metabolism ; *Neurons/metabolism/pathology ; Brain/metabolism/pathology ; }, abstract = {Small extracellular vesicles (sEVs) have emerged as central mediators of intercellular communication in the central nervous system (CNS) and are increasingly recognized for their dual roles in the pathogenesis and treatment of neurodegenerative diseases (NDDs). In disease contexts, sEVs facilitate the intercellular dissemination of pathogenic proteins and nucleic acids, thereby contributing to the propagation of Alzheimer's disease (AD) and Parkinson's disease (PD) pathology. Conversely, their intrinsic biocompatibility, capacity to traverse brain barriers, and inherent organotropic properties position sEVs as highly promising nanocarriers for CNS drug delivery. While mesenchymal stem cell-derived sEVs have been widely investigated in preclinical NDD models, accumulating evidence suggests that sEVs derived from neural cells, including neural stem cells, neurons, astrocytes, microglia, oligodendrocytes, and brain endothelial cells may offer superior brain targeting, disease relevance, and functional efficacy. This review provides a comprehensive and critical analysis of current knowledge on neural cell-derived sEVs, encompassing their physiological roles in brain homeostasis, their involvement in AD and PD pathogenesis, and their emerging therapeutic applications. We discuss cell-type-specific sEV cargo profiles, mechanisms underlying blood-brain and blood-cerebrospinal fluid barrier traversal, and recent advances in endogenous and exogenous engineering strategies that enhance cargo loading, targeting precision, and therapeutic performance. Importantly, we address key translational challenges that currently limit clinical implementation. By integrating mechanistic insights with therapeutic and engineering perspectives, this review highlights neural cell-derived sEVs as a biologically informed and versatile platform, underscoring their potential to advance next-generation neuro-nanomedicine for NDDs.}, } @article {pmid41940797, year = {2026}, author = {Rus Prelog, P and Kores Plesničar, B and Zupan, M and Frol, S and Kramberger, MG}, title = {The value and risks of antidepressant therapy in Alzheimer's disease: a field update and its clinical implications.}, journal = {Expert review of neurotherapeutics}, volume = {26}, number = {6}, pages = {523-537}, doi = {10.1080/14737175.2026.2653170}, pmid = {41940797}, issn = {1744-8360}, mesh = {Humans ; *Alzheimer Disease/drug therapy/complications/psychology ; *Antidepressive Agents/therapeutic use/adverse effects ; *Depression/drug therapy/etiology ; }, abstract = {INTRODUCTION: Depression is one of the most frequent and disabling neuropsychiatric syndromes in Alzheimer's disease (AD), yet antidepressant use is still largely extrapolated from late‑life depression and is poorly aligned with emerging evidence on 'neurodegenerative depression' and disease‑modifying therapies. This article critically re‑examines the clinical value and risks of antidepressants in AD.

AREAS COVERED: Drawing on a narrative search of PubMed/MEDLINE and Embase (January 2000-December 2025) and targeted review of recent guidelines and anti‑amyloid trials, the article synthesizes randomized and observational data on efficacy and safety across antidepressant classes, highlighting modest and inconsistent benefits alongside adverse outcomes such as falls, hyponatremia, bleeding, mortality and possible acceleration of cognitive decline. It integrates mechanistic work on synaptic loss, neuroinflammation and network disruption, discusses the exclusion of depressed patients from anti‑amyloid trials, and reviews rapid‑acting, neuromodulatory and psychosocial strategies within a proposed precision‑prescribing framework based on biomarkers, vascular burden and symptom dimensions.

EXPERT OPINION: Monoaminergic antidepressants in AD should not be abandoned but repositioned as time‑limited, closely monitored options for clearly defined, functionally impairing depressive syndromes, embedded in multimodal care rather than used as default, long‑term treatment for non‑specific distress. Future priorities include biomarker‑stratified AD depression trials, evaluation of interactions with anti‑amyloid therapies and rigorous testing of non‑monoaminergic interventions.}, } @article {pmid41940869, year = {2026}, author = {Sharif-Askari, Z and Atoui, K and El Zein, W and Rizk, M and Sharif Askari, E}, title = {From periodontitis to neurodegeneration: Can probiotics modulate the P. gingivalis-amyloid pathway in Alzheimer's disease?.}, journal = {Journal of Alzheimer's disease : JAD}, volume = {111}, number = {2}, pages = {471-488}, doi = {10.1177/13872877261432686}, pmid = {41940869}, issn = {1875-8908}, mesh = {Humans ; *Probiotics/therapeutic use ; *Alzheimer Disease/microbiology/metabolism ; *Porphyromonas gingivalis/metabolism ; Animals ; *Periodontitis/metabolism/microbiology ; *Amyloid beta-Peptides/metabolism ; }, abstract = {Alzheimer's disease (AD) is a neurodegenerative disorder characterized by the gradual destruction of cognitive and behavioral functions. Despite the continuous research efforts, there is still no cure for this disease. In recent years, researchers have investigated Porphyromonas gingivalis (P. gingivalis) as a potential cause of AD. P. gingivalis-lipopolysaccharides (LPS) and gingipains have been implicated in neuroinflammatory cascades relevant to AD. The gut-brain axis provides a pathway for microbial migration, immune activation, and regulation of the central nervous system function. Emerging evidence suggests that selected probiotics may modulate these pathways by restoring microbial balance, reinforcing epithelial barrier function, and regulating innate and adaptive immunity. Importantly, much of the evidence and mechanistic support for these effects derives from preclinical and animal studies, whereas human data remain limited to associative findings and early-stage clinical trials. Early clinical trials report modest improvements in cognitive scores and systemic inflammatory markers. Strain selection, dose, and treatment duration make direct comparisons challenging. This review integrates the literature on the links between P. gingivalis and AD, suggesting that probiotics may be used as neuroprotective agents. Taken together, current preclinical signals are consistent with the potential of probiotics as feasible adjuncts, pending confirmatory trials with standardized formulations.}, } @article {pmid41941206, year = {2026}, author = {Andrews, SJ and Yaffe, K}, title = {Advancing Precision Dementia Care With Genetic-Exposome Risk Assessment.}, journal = {JAMA neurology}, volume = {}, number = {}, pages = {}, doi = {10.1001/jamaneurol.2026.0573}, pmid = {41941206}, issn = {2168-6157}, } @article {pmid41941234, year = {2026}, author = {Oo, WJ and Sia, WT and Lee, JY and Chen, CH and Chang, WL and Chye, SM}, title = {The Role of Presynaptic Cytomatrix Protein Bassoon (BSN) in Tau Pathology and Propagation.}, journal = {CNS & neurological disorders drug targets}, volume = {}, number = {}, pages = {}, doi = {10.2174/0118715273400895251129055504}, pmid = {41941234}, issn = {1996-3181}, abstract = {Neurodegenerative disorders have become a global health threat following a prolonged lifespan, with the majority involving the accumulation and propagation of pathological tau. Tau oligomers can migrate to presynaptic terminals and interact with surrounding proteins, among which Bassoon (BSN) is one that selectively binds to and colocalises with misfolded tau. Studies have reported numerous implications of BSN mutations in tau pathology, including promoting tau seeding activity, hyperphosphorylation, misfolding, and aggregation. These eventually lead to the formation of neurofibrillary tangles in tauopathies. Given the BSN's physiological role in maintaining synapses, its mutation also impairs synaptic integrity. These abnormalities are consistently attenuated by downregulating BSN levels. However, BSN downregulation can lead to tau hyperphosphorylation via an alternative pathway, CDK5 hyperactivity. Current findings hypothesize that BSN reduces tau clearance by inhibiting proteasome activity. It is also suggested that BSN can impair dopaminergic pathways prior to the detection of tau pathological features. Tunnelling nanotubes also emerge as a potential interneuronal route for BSN-mediated tau spread. Despite a lack of clinical evidence, findings from postmortem samples, in vitro, and preclinical models highlight BSN as a potential candidate for tau-targeting therapies, indicating its role in the pathological development of tau. The involvement of BSN in tau seeding might also resolve challenges posed by tau-targeting drugs during clinical trials. Hence, this article aims to provide new insights into recent findings on BSN and tau with reference to previous studies. We will discuss the possible mechanisms involved, along with the future therapeutic value of BSN in the treatment of tauopathies.}, } @article {pmid41941239, year = {2026}, author = {Wang, N and Wen, H and Sun, Y and Xu, W and Shen, X and Wang, R}, title = {Effects of Hesperetin Early Intervention on Brain Neurons and Microglia in APPswe/PS1dE9 Mice.}, journal = {CNS & neurological disorders drug targets}, volume = {}, number = {}, pages = {}, doi = {10.2174/0118715273418623251203072424}, pmid = {41941239}, issn = {1996-3181}, abstract = {INTRODUCTION: Neuroinflammation and microglial dysfunction play central roles in the pathogenesis of Alzheimer's disease (AD). This study investigated whether early intervention with hesperetin, a citrus flavonoid, could attenuate neuroinflammation and modulate microglial polarization in both wild-type (WT) and APPswe/PS1dE9 transgenic (TG) mice.

METHODS: Three-month-old male C57BL/6J WT and APPswe/PS1dE9 TG mice were administered hesperetin (10 or 20 mg/kg/day for WT; 20, 40, or 80 mg/kg/day for TG) or vehicle for six months. Neuronal morphology was assessed using thionine staining. Microglial polarization was evaluated via CD11b/iNOS and CD11b/Arginase-1 immunofluorescence. Protein expression of CD11b, iNOS, Arginase-1, and TREM2 was measured by Western blot, and cytokine levels (TNF-α, IL-10) were quantified by ELISA.

RESULTS: In WT mice, hesperetin improved neuronal integrity, reduced M1 markers (CD11b⁺/ iNOS⁺ cells, iNOS, TNF-α), and enhanced M2 markers (CD11b⁺/Arginase-1⁺ cells, Arginase-1, TREM2). TG mice exhibited exacerbated neuroinflammation and neuronal loss compared to WT controls, which was significantly mitigated by hesperetin treatment. All hesperetin doses in TG groups reduced pro-inflammatory markers and increased anti-inflammatory and repair-associated factors.

DISCUSSION: These results indicate that hesperetin shifts microglial polarization toward the protective M2 phenotype, potentially via TREM2 upregulation, thereby reducing neuroinflammation and neuronal damage. This effect was observed in both age-related and Aβ-driven pathology, suggesting a dual role for hesperetin in immunomodulation and neuroprotection.

CONCLUSION: Early hesperetin intervention exerts neuroprotective effects by rebalancing microglial polarization and enhancing TREM2 expression, highlighting its potential as a preventive strategy against AD-related neuroinflammation.}, } @article {pmid41941282, year = {2026}, author = {Agrawal, MM and Mittal, P}, title = {Emerging Therapies and Research in Alzheimer's Disease: A Critical Review.}, journal = {Central nervous system agents in medicinal chemistry}, volume = {}, number = {}, pages = {}, doi = {10.2174/0118715249403872251208145159}, pmid = {41941282}, issn = {1875-6166}, abstract = {Alzheimer's disease, an extremely prevalent neurological illness and the leading cause of dementia globally, is an extremely prevalent neurological illness and is the leading cause of dementia globally. There are a few treatment options for AD, and those that do exist only slightly reduce symptoms, even after several clinical studies. The formation of Aβ plaques, neuroinflammation, and hyperphosphorylated tau neurofibrillary tangles are the characteristics of AD. While monoclonal antibodies such as lecanemab, donanemab, and aducanumab have demonstrated potential in addressing Aβ, their clinical efficacy and safety over an extended period of time remain uncertain. Novel avenues for tackling the underlying genetic causes of AD have been made possible by developments in genome editing tools, most notably CRISPR-Cas9. In preclinical animals, CRISPR-Cas9 has effectively edited genes relevant to AD, such as APP and PSEN1, leading to decreased levels of Aβ and enhanced cognitive function. Additionally, base and prime editing, two precision gene-editing techniques, have increased the medicines' selectivity and decreased their offtarget effects. However, before clinical applications are deployed, challenges related to technology, ethics, and safety must be resolved. This review highlights how monoclonal antibodies, neuroinflammation research, and CRISPR-Cas9 have the potential to revolutionize therapy choices for AD by examining the most current developments in the field.}, } @article {pmid41941989, year = {2026}, author = {Sun, Z and Peng, Q and Qiu, C and Jia, X and Wang, H and Wu, S and Tao, W}, title = {A specific pilose antler peptide LVLVEAELRE ameliorates cognitive deficits in SAMP8 mice via Celsr2.}, journal = {Journal of ethnopharmacology}, volume = {366}, number = {}, pages = {121649}, doi = {10.1016/j.jep.2026.121649}, pmid = {41941989}, issn = {1872-7573}, mesh = {Animals ; *Peptides/pharmacology/therapeutic use/chemistry ; Mice ; *Cadherins/metabolism/genetics ; Male ; *Cognitive Dysfunction/drug therapy/metabolism ; Amyloid beta-Peptides/metabolism ; *Alzheimer Disease/drug therapy/metabolism ; Molecular Docking Simulation ; Neuronal Plasticity/drug effects ; tau Proteins/metabolism ; Humans ; Disease Models, Animal ; Hippocampus/drug effects/metabolism ; }, abstract = {Pilose antler peptide (PAP), an extract derived from the traditional Chinese medicinal material Pilose antler, has shown promise in the treatment of neurodegenerative diseases. However, the precise molecular mechanisms underlying its anti-Alzheimer's disease (AD) effects remain to be fully elucidated.

AIM OF THE STUDY: This study focuses on a specific PAP monomer with a defined sequence (LVLVEAELRE), herein referred to as PAP, to explore its potential role and molecular mechanisms in AD treatment.

MATERIALS AND METHODS: Senescence-accelerated mouse prone 8 (SAMP8) mice were employed to evaluate the effects of PAP on cognitive function, classical AD pathologies (Aβ and p-Tau), and synaptic plasticity. To further elucidate the causal role of Cadherin EGF LAG seven-pass G-type receptor 2 (Celsr2), bidirectional viral manipulations (AAV-shCelsr2 for knockdown and AAV-OECelsr2 for overexpression) were performed in vivo. Furthermore, cellular thermal shift assays (CETSA), molecular docking, and microscale thermophoresis (MST) were utilized to validate the direct interaction between PAP and Celsr2.

RESULTS: PAP administration significantly improved cognitive impairment, mitigated Aβ deposition and Tau hyperphosphorylation, and enhanced synaptic plasticity in SAMP8 mice. Mechanistically, PAP upregulated Celsr2 expression, restored AMPA receptor subunits, and inhibited neuronal senescence. Crucially, Celsr2 knockdown abolished these neuroprotective benefits, whereas Celsr2 overexpression synergistically amplified the therapeutic efficacy of PAP. Finally, MST and docking analyses confirmed that PAP possesses a high and specific binding affinity for WT Celsr2.

CONCLUSIONS: This study demonstrates that PAP ameliorates AD-like pathology by regulating Celsr2, highlighting its potential as a promising preclinical drug candidate. The research findings provide a theoretical basis for the development of PAP-based therapeutic strategies for Alzheimer's disease.}, } @article {pmid41942439, year = {2026}, author = {Ohya, T and Arakawa, R and Sakayori, T and Nogami, T and Uchiyama, S and Tateno, A}, title = {Tau accumulation increases the susceptibility to effective seizures of electroconvulsive therapy.}, journal = {Translational psychiatry}, volume = {16}, number = {1}, pages = {}, pmid = {41942439}, issn = {2158-3188}, mesh = {Humans ; *Electroconvulsive Therapy/adverse effects ; *Seizures/metabolism/etiology/diagnostic imaging ; *tau Proteins/metabolism ; Female ; Positron-Emission Tomography ; Male ; Middle Aged ; Aged ; *Mood Disorders/therapy/metabolism/diagnostic imaging ; }, abstract = {Electroconvulsive therapy (ECT) is a very valuable treatment for mood disorders. While previous studies have examined predictors of ECT responsiveness, there is a scarcity of neuroimaging studies examining these predictors. In previous studies, it has been reported that epilepsy is significantly more common in patients with Alzheimer's disease, and it has been suggested that tau accumulation is related to the susceptibility to seizures. Positron emission tomography (PET) with florzolotau (18 F) ([[18]F]PM-PBB3) allows accurate quantification of tau in the brain cortex. We therefore performed tau PET with florzolotau (18 F) in 14 patients with mood disorders undergoing ECT to determine whether there is a relationship between tau accumulation and susceptibility to ECT. As a result, we found that the more tau accumulates, the more likely it is to produce effective seizures in ECT. Although our study has some limitations, it is suggested that ECT would be the first choice for treatment of depression associated with degenerative pathology such as Alzheimer's disease because tau accumulation might enhance the therapeutic efficacy of ECT.}, } @article {pmid41942585, year = {2026}, author = {Jahanbani, P and Hosseinzadeh, L and Mahmoudi, M and Jalilian, F and Eftekhari, M and Modarresi, M}, title = {Beyond the root: licorice (Glycyrrhiza glabra L.) fruit extract modulates oxidative stress and apoptotic markers in PC12 cells.}, journal = {Scientific reports}, volume = {16}, number = {1}, pages = {}, pmid = {41942585}, issn = {2045-2322}, support = {4020639//Kermanshah University of Medical Sciences/ ; }, mesh = {Animals ; *Oxidative Stress/drug effects ; PC12 Cells ; *Plant Extracts/pharmacology/chemistry ; *Glycyrrhiza/chemistry ; Rats ; *Apoptosis/drug effects ; *Fruit/chemistry ; Hydrogen Peroxide/toxicity/pharmacology ; *Neuroprotective Agents/pharmacology/chemistry ; Cell Survival/drug effects ; Antioxidants/pharmacology/chemistry ; Membrane Potential, Mitochondrial/drug effects ; Plant Roots/chemistry ; Flavonoids/pharmacology ; }, abstract = {The rising global prevalence of neurodegenerative disorders underscores the urgent need for novel therapeutic strategies. Oxidative stress is a well-established central driver in the pathogenesis of conditions like Alzheimer's and Parkinson's disease. While the root of Glycyrrhiza glabra L. (licorice) is a renowned source of natural antioxidants, its fruit remains a largely unexplored reservoir of bioactive compounds with potential neuroprotective properties. This in vitro study aimed to systematically evaluate the neuroprotective potential of different licorice fruit extracts and elucidate the underlying mechanisms against hydrogen peroxide (H2O2)-induced oxidative damage in PC12 neuronal cells. Different licorice fruit extracts were prepared sequentially with n-hexane, chloroform, ethyl acetate, methanol, and water by the maceration method. The protective effects of these extracts against H2O2-induced cytotoxicity were assessed using the MTT assay. Phytochemical profiling of the active ethyl acetate extract (EA extract) was performed using TLC, total flavonoid assay, and HPLC-DAD. EA extract exhibited the strongest protective activity. Pre-treatment with non-toxic concentrations of EA extract (12.5 and 25 µg/mL) significantly increased cell viability against H2O2 (IC50 = 70 µg/mL approximately 2.06 mM) by 33% and 38%, respectively. This extract possessed the highest total flavonoid content (50.08 ± 0.31 mg of quercetin equivalents per gram of dry extract) among all extracts, and HPLC-DAD analysis confirmed the presence of glabridin 27.75 ± 0.01 mg per gram of dry EA extract. EA extract also notably restored mitochondrial membrane potential, reduced caspase-3 activity, and decreased ROS production in H2O2-stressed cells. Our findings indicate that the ethyl acetate extract of licorice fruit attenuates H2O2-induced oxidative stress in PC12 cells, and its neuroprotective effect is likely associated with its high flavonoid content. Further research on licorice fruit may facilitate the discovery of novel therapeutic agents for oxidative stress-related disorders.}, } @article {pmid41943055, year = {2026}, author = {Di Caro, V and Cho, E and Thiel, J and Lizama, BN and Koel-Simmelink, MJA and Pandey, K and Duong, D and Seyfried, NT and Grundman, M and Teunissen, CE and Zetterberg, H and Blennow, K and Caggiano, AO and Hamby, ME}, title = {Impact of zervimesine on the neuroinflammatory biomarker GFAP and related proteomic molecular correlates in plasma of participants from a phase 2 clinical trial in Alzheimer's disease.}, journal = {Alzheimer's research & therapy}, volume = {18}, number = {1}, pages = {}, pmid = {41943055}, issn = {1758-9193}, support = {1R01AG058660/AG/NIA NIH HHS/United States ; }, mesh = {Humans ; *Alzheimer Disease/drug therapy/blood ; Biomarkers/blood ; Male ; Female ; Double-Blind Method ; Proteomics ; *Glial Fibrillary Acidic Protein/blood ; Aged ; Amyloid beta-Peptides/blood ; *Neuroinflammatory Diseases/blood/drug therapy ; }, abstract = {BACKGROUND: Zervimesine (CT1812) is an investigational brain-penetrant small molecule modulator of the sigma-2 receptor (S2R/TMEM97), currently in clinical development for the treatment of Alzheimer’s disease (AD) and dementia with Lewy bodies (DLB) that selectively prevents and displaces the binding of amyloid beta (Aβ) and α-synuclein oligomers from neuronal synapses. Given the mechanism of action, it was hypothesized that zervimesine might be more effective in patients with lower levels of AD pathology. Indeed, in the SHINE trial, a completed Phase 2, randomized, double-blind, clinical trial conducted in participants with AD, a robust, 95%, slowing of cognitive decline, as assessed via ADAS-Cog11, was observed in a pre-specified subgroup of participants with lesser AD pathology (i.e., low p-tau217 subgroup) compared to a 38% slowing in the overall modified intent-to-treat (mITT)) population. METHODS: In SHINE, exploratory plasma biomarkers were assessed using both a targeted and an unbiased, proteomics discovery approach in plasma from participants at baseline and end of study. Treatment effects of zervimesine relative to placebo were assessed in both the mITT population and in a low p-tau217 subgroup, who entered the study with lower (< 1pg/ml) plasma p-tau217 concentrations. Plasma biomarkers Aβ40, Aβ42, GFAP, NfL and BD-tau were assessed using clinically validated targeted assays, along with untargeted TMT-mass spectrometry (MS)-based discovery proteomics followed by bioinformatic, pathway and correlation analyses. RESULTS: Collectively, plasma biomarker findings in the low p-tau217 subgroup were more robust than in the mITT population. Levels of GFAP were significantly decreased and NfL, Aβ42 and Aβ40 levels trended towards a decrease with zervimesine compared to placebo. Proteomics analyses identified candidate pharmacodynamic biomarkers of zervimesine, and gene ontology and pathway analyses pointed to an impact on amyloid biology, trafficking, lipid metabolism, and immune response. Bioinformatics and correlation analyses with GFAP identified biomarkers that may reflect pathway engagement of S2R and/or decreased neuroinflammation. CONCLUSIONS: Exploratory plasma biomarker findings align with the degree of clinical benefit in SHINE mITT and low p-tau217 populations, and support future trial enrichment with patients with lower levels of pathology as defined by lower baseline plasma levels of p-tau217. TRIAL REGISTRATION: July 20th, 2018 ClinicalTrials.gov Identifier NCT03507790 https://clinicaltrials.gov/study/NCT03507790 .}, } @article {pmid41944296, year = {2026}, author = {Gong, W and Hui, W and Qiao, S and Ji, Q and Liu, M and Zhang, B and Liu, D and Wu, Y and Zhou, S}, title = {Brain and Liver Dual-Targeting Oridonin Nanoparticles to Enhance Aβ Clearance for Alzheimer's Disease Therapy.}, journal = {Advanced science (Weinheim, Baden-Wurttemberg, Germany)}, volume = {13}, number = {36}, pages = {e23458}, doi = {10.1002/advs.202523458}, pmid = {41944296}, issn = {2198-3844}, support = {2023-ZDYJSY-001//Shaanxi Administration of Traditional Chinese Medicine/ ; 2023JSYX16//Research Project from Air Force Medical University/ ; //Key Laboratory of New Drug Delivery System and New Technology for Formulation/ ; 82073775//National Natural Science Foundation of China/ ; 82071515//National Natural Science Foundation of China/ ; SZY-KJCYC-2025-ZY-013//Scientific Research Project of Shaanxi Administration of Traditional Chinese Medicine/ ; }, mesh = {*Diterpenes, Kaurane/pharmacology/administration & dosage/therapeutic use ; Animals ; *Alzheimer Disease/drug therapy/metabolism ; *Brain/metabolism/drug effects ; *Amyloid beta-Peptides/metabolism ; *Nanoparticles/administration & dosage ; *Liver/metabolism/drug effects ; Mice ; Humans ; Disease Models, Animal ; }, abstract = {The brain and liver are both critical organs involved in the pathogenesis of Alzheimer's disease (AD), particularly in the modulation of amyloid-beta (Aβ) metabolism and neuroinflammation. Based on this, a multifunctional nanodrug delivery system, termed OAF, was developed by encapsulating oridonin (ORI) into apoferritin (ApoFn), enabling simultaneous targeting of both brain and the liver through transferrin receptor 1 (TfR1). OAF upregulated the expression of low-density lipoprotein receptor-related protein 1 (LRP1) in cerebral capillary endothelial cells and hepatic parenchymal cells to promote Aβ clearance from the brain and subsequent hepatic degradation. In AD mice, OAF treatment markedly reduced Aβ deposition, neuroinflammation, and cognitive impairment, while ameliorating inflammation, oxidative stress, and mitochondrial dysfunction in both brain and liver. Overall, OAF synergistically combined Aβ clearance, anti-inflammatory, and antioxidant mechanisms, offering a novel therapeutic strategy for AD.}, } @article {pmid41944966, year = {2026}, author = {Riaz, M and Qadir, H and Noman, M and Ahmed, S and Shah, FA and Malik, MU and Bashir, K and Farooq, U and Irshad, N}, title = {Mechanistic Insights into Bergapten by Modulation of Filamin A and GSK3β in STZ Induced Alzheimer's Disease: An Integrated In Silico, In Vitro and In Vivo Study.}, journal = {Neurochemical research}, volume = {51}, number = {2}, pages = {}, pmid = {41944966}, issn = {1573-6903}, mesh = {Animals ; *Alzheimer Disease/drug therapy/chemically induced/metabolism ; *Glycogen Synthase Kinase 3 beta/metabolism ; Streptozocin/toxicity ; Male ; *Filamins/metabolism ; Mice ; Brain/metabolism/drug effects ; }, abstract = {Alzheimer’s disease (AD) is a progressive neurodegenerative disorder characterized by amyloid-β (Aβ) aggregation, tau hyperphosphorylation, synaptic dysfunction and neuroinflammation. The study investigates bergapten (BGN) as a potential AD treatment. Computational analysis revealed strong binding affinity of BGN with Filamin A (FLNA) and glycogen synthase kinase-3β (GSK3β). In vitro assays demonstrated acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibition suggesting cholinergic modulation. In intracerebroventricular (i.c.v) streptozotocin (STZ) induced AD mice model, BGN (25 mg/kg, 50 mg/kg and 100 mg/kg i.p) was administered daily for 23 days. The blood and brain tissues samples were collected for biochemical and histopathological analysis. BGN showed dose-dependent cognitive improvements, with biochemical tests indicating renal and hepatic safety. Reduced C-reactive protein and lactate dehydrogenase levels suggested minimal systemic toxicity and neuroinflammation. Histology revealed preserved neurons, decreased amyloid deposits, and improved brain structure. Immunohistochemical analyses indicated BGN was associated with lower Tau, NF-κB, TLR4, and Caspase-3 expression and restored redox homeostasis. Critically, ELISA confirmed reduced FLNA along with Aβ and GSK-3β levels and thus highlights BGN novel modulation of this unexplored AD target. RT-PCR analysis showed downregulated expression of amyloid precursor protein, tau, discs large scaffold protein 4 and glial fibrillary acidic protein, while enhanced synaptic plasticity markers. Collectively, these findings suggest BGN as a promising multi-target neuroprotective and safer agent for AD.}, } @article {pmid41945082, year = {2026}, author = {Falangola, MF and Voltin, J and Cole, M and Nietert, PJ and Liu, F and Iqbal, K and Jensen, JH}, title = {Corrigendum to Diffusion MRI measures detect brain microstructure changes due to early treatment with neurotrophic peptide mimetic P021 in the 3xTg-AD mouse model of Alzheimer's disease. Magn Reson Imaging. 2026 Jun;129:110641 Page: 9.}, journal = {Magnetic resonance imaging}, volume = {130}, number = {}, pages = {110677}, doi = {10.1016/j.mri.2026.110677}, pmid = {41945082}, issn = {1873-5894}, } @article {pmid41945111, year = {2026}, author = {Lai, Z and Zhang, B and Fu, Z and Li, R and Qian, Y and Zhang, Y and Xu, P and Du, Y}, title = {Research advances on Cordyceps sinensis and its components in relation to omics biomarkers for the neurological disorders.}, journal = {Die Naturwissenschaften}, volume = {113}, number = {3}, pages = {}, pmid = {41945111}, issn = {1432-1904}, support = {2026ZL0010//Zhejiang Traditional Chinese Medicine Science and Technology Program of China/ ; 82202605//National Natural Science Foundation of China/ ; 2023, DU YAOQIANG//Zhejiang Provincial Special Support Program for Cultivation of High-Level Innovative Health Talents of China/ ; }, mesh = {*Cordyceps/chemistry ; Animals ; *Nervous System Diseases/drug therapy ; Humans ; Biomarkers/analysis ; Multiomics ; Neuroprotective Agents/pharmacology ; }, abstract = {Cordyceps is a traditional medicinal fungus belonging to the species Ophiocordyceps sinensis. It grows in the alpine ecological zone of the Tibetan Plateau and exhibits dual characteristics of both insects and fungi. The primary species include Cordyceps sinensis and Cordyceps militaris. Rich in bioactive components such as cordycepin, polysaccharides, adenosine, and peptides, cordyceps demonstrates broad applications in immune regulation, anti-tumor activity, anti-inflammatory, and neuroprotection. Cordyceps sinensis and its components show great therapeutic potential in neurological diseases such as epilepsy, Alzheimer’s disease and Parkinson’s disease through multi-level and multi-target actions However, current research faces challenges including unclear mechanisms of action and insufficient clinical translation. In this review, we analyze the molecular mechanisms underlying cordyceps’ neuroprotective effects, including the regulating of apoptosis, improvement of mitochondrial function, and promoting of nerve repair. Utilizing network pharmacology, we explore the multi-targeted actions of cordyceps and predict the key pathways. Further we summarize the research progress in the integrated multi-omics analyses (genomics, transcriptomics, proteomics and metabolomics), to reveal the synergistic roles of cordyceps components in treating neurological disorders and identify potential molecular biomarkers. Additionally, we highlight the findings from preclinical experiments and animal models on cordyceps-based drugs, discussing their advantages and challenges for clinical application. Future studies should prioritize systematic exploration of standardized drug development, advanced multi-omics integration, and rigorous clinical trials. This will provide a more robust scientific foundation and practical guidance for the treatment of neurological diseases with cordyceps.}, } @article {pmid41946054, year = {2026}, author = {Tang, S and Peng, Y and Li, Y and Li, Y and Sun, H and Piao, S and Liu, Z and Wu, Y and Hou, Z and Liu, Z and Liu, S and Wang, R}, title = {Congming decoction alleviates Alzheimer's Disease induced by Aβ25-35 in rats via the microbiota-metabolism-inflammation axis, demonstrating its formulation advantages.}, journal = {Phytomedicine : international journal of phytotherapy and phytopharmacology}, volume = {155}, number = {}, pages = {158139}, doi = {10.1016/j.phymed.2026.158139}, pmid = {41946054}, issn = {1618-095X}, mesh = {Animals ; *Alzheimer Disease/drug therapy/chemically induced/metabolism ; *Drugs, Chinese Herbal/pharmacology ; Male ; Rats ; Amyloid beta-Peptides ; *Gastrointestinal Microbiome/drug effects ; Rats, Sprague-Dawley ; Peptide Fragments ; Inflammation/drug therapy/metabolism ; Feces/chemistry ; Brain/drug effects/metabolism/pathology ; Disease Models, Animal ; Chromatography, High Pressure Liquid ; }, abstract = {BACKGROUND: Congming decoction (CMD) is a traditional Chinese herbal formulation traditionally employed for enhancing memory. Despite its historical use, the specific mechanisms and advantages of CMD in the context of Alzheimer's disease (AD) remain inadequately understood.

PURPOSE: This study seeks to elucidate the therapeutic effects of CMD on AD in rats induced by Aβ25-35 and to clarify its underlying process through a multi-perspective approach.

STUDY DESIGN AND METHODS: Cognitive function and pathological alterations were assessed using behavioral tests, hematoxylin and eosin (HE) staining, and immunohistochemistry. Fecal metabolomics analysis, conducted via ultra-high-performance liquid chromatography coupled with quadrupole Orbitrap mass spectrometry (UHPLC-Q-Orbitrap-MS), was utilized to investigate CMD's impact on metabolic disorders. The structure of the gut microbiota was analyzed through 16S rRNA sequencing. Short-chain fatty acids (SCFAs) and bile acids (BAs) in feces, serum, and brain tissue were quantified using gas chromatography-mass spectrometry (GC-MS) and ultra-high-performance liquid chromatography-tandem quadrupole mass spectrometry (UHPLC-TQ-MS). To establish causal relationships, experiments involving antibiotic-induced microbiota depletion (ABX) and fecal microbiota transplantation (FMT) were performed. Network pharmacology and molecular docking techniques were also employed to identify potential active components and targets. Inflammatory markers were evaluated using enzyme-linked immunosorbent assay (ELISA) kits, immunohistochemistry, and immunofluorescence in brain tissue.

RESULTS: CMD markedly enhanced learning and memory, mitigated pathological changes in the brain and colon, and reestablished gut microbiota equilibrium. It regulated 45 endogenous metabolites involved in BAs, α-linolenic acid, and linoleic acid metabolism. CMD also modulated the levels of SCFAs and BAs in fecal matter, serum, and brain tissue. Strong correlations were identified among gut microbiota, metabolites, and AD-related indicators. Antibiotic treatment inhibited the neuroprotective benefits of CMD, whereas FMT from CMD-treated donors successfully replicated its therapeutic benefits. Network pharmacology analysis indicated that the active components of CMD might target inflammatory pathways. Additionally, CMD exhibited a significant restorative impact on markers associated with the AKT/NF-κB signaling pathway.

CONCLUSION: CMD exerts anti-AD effects by modulating the microbiota-gut-brain axis through remodeling gut microbiota, regulating metabolic homeostasis, and reducing brain inflammation. Notably, CMD demonstrated superior efficacy compared to single herbs or herb pairs.}, } @article {pmid41946775, year = {2026}, author = {Phemphunananchai, K and Waiwut, P and Phetcharaburanin, J and Poonsawas, P and Boonyarat, C}, title = {Repurposing FDA-approved drugs as multi-target neuroprotective agents for Alzheimer's disease via computational screening and experimental validation.}, journal = {Scientific reports}, volume = {16}, number = {1}, pages = {}, pmid = {41946775}, issn = {2045-2322}, support = {67-2(7)/2567//Faculty of Pharmaceutical Sciences, Khon Kaen University, Thailand/ ; RA2567-M109//The Research Assistant Program, Khon Kaen University, Thailand/ ; }, mesh = {*Alzheimer Disease/drug therapy/metabolism/pathology ; *Neuroprotective Agents/pharmacology/chemistry/therapeutic use ; *Amyloid Precursor Protein Secretases/antagonists & inhibitors/metabolism/chemistry ; *Drug Repositioning ; Humans ; *Aspartic Acid Endopeptidases/antagonists & inhibitors/metabolism/chemistry ; Molecular Docking Simulation ; Molecular Dynamics Simulation ; Amyloid beta-Peptides/metabolism ; Animals ; Butyrylcholinesterase/metabolism ; Drug Evaluation, Preclinical ; }, abstract = {β-site APP-cleaving enzyme 1 (BACE1, a β-secretase) is a key aspartyl protease that initiates the proteolytic processing of the amyloid precursor protein (APP) to form the amyloid-β (Aβ) peptide. Given that Aβ aggregation and plaque formation are a central pathological feature of Alzheimer’s disease (AD), BACE1 remains a critical therapeutic target. Furthermore, the complexity of AD pathology necessitates the identification of novel multi-target agents. This study employed a structure-based virtual screening, targeting the BACE1 approach to identify the potential BACE1 inhibitors from FDA-approved drug scaffolds derived from the ZINC database. Top-ranked candidates were subsequently validated through extensive 500 ns molecular dynamics (MD) simulations and in vitro assays of BACE1 inhibition activity. Furthermore, multi-AD-related target profiling of candidates was conducted using molecular docking and a series of in vitro assays. Among them, ZINC000019796155 emerged as a promising multi-target compound. Biochemical analysis revealed that ZINC000019796155 exhibited moderate inhibitory effects against BACE1. Subsequent assays confirmed its capacity to inhibit butyrylcholinesterase (BuChE) action and Aβ aggregation, function as a free radical scavenger, and provide neuroprotection against H2O2-induced oxidative stress in cellular models. Furthermore, western blot analysis elucidated the mechanism of neuroprotection, indicating that ZINC000019796155 inhibits the apoptotic pathway while simultaneously suppressing the formation of Aβ plaques and neurofibrillary tangles (NFTs). These findings highlight ZINC000019796155 as a validated scaffold with a known safety profile for AD. While further structural optimization and preclinical in vivo studies are necessary, this study underscores the potential of ZINC000019796155 as a multi-target neuroprotective agent for AD treatment.}, } @article {pmid41948063, year = {2026}, author = {Yang, SO and Ahn, J and Jung, YH and Jang, H and Na, DL and Kim, H and Kim, JP and Seo, SW and Kwak, K}, title = {Deep learning-based detection of cerebral microbleeds on 2D T2*-weighted GRE MRI: toward ARIA-H risk assessment in Alzheimer's treatment.}, journal = {Frontiers in aging neuroscience}, volume = {18}, number = {}, pages = {1729422}, pmid = {41948063}, issn = {1663-4365}, abstract = {BACKGROUND: Amyloid-related imaging abnormalities with hemorrhage (ARIA-H) are a key safety concern in anti-amyloid therapies for Alzheimer's disease, as they are radiologically indistinguishable from cerebral microbleeds (CMBs). Accurate detection of CMBs is therefore essential for both treatment eligibility assessment and post-treatment safety monitoring. However, manual identification on 2D T2*-weighted gradient-recalled echo (GRE) MRI is labor-intensive and subject to variability.

OBJECTIVE: To develop and validate an artificial intelligence (AI)-based model for automated CMB detection using only 2D T2*-weighted GRE MRI, which is widely used in clinical settings.

METHODS: We implemented a YOLOv11-based deep learning model, preceded by a novel multi-channel preprocessing pipeline that enhances CMB visibility. The model was trained and tested using a dataset of 758 participants, with expert consensus used as the reference standard.

RESULTS: Using the optimized basic preprocessing with super-resolution (BP + SR) pipeline, the model achieved a lesion-level sensitivity of 0.694, precision of 0.705, and F1-score of 0.699. In patient-level analysis for detecting elevated CMB burden (≥4), the system demonstrated sensitivity of 0.933 and specificity of 0.935, supporting reliable stratification of CMB severity. Regional analysis showed sensitivity of 0.625 for lobar CMBs and 0.627 for deep structures.

CONCLUSION: This study demonstrates the feasibility of robust CMB detection using only 2D T2*-weighted GRE MRI. Based on current performance, we position this system as a decision-support tool for GRE-based CMB screening, in which lesion-level detections may be aggregated to inform patient-level CMB burden relevant to ARIA-H risk stratification, while final ARIA grading and clinical decisions require expert neuroradiological confirmation.}, } @article {pmid41948065, year = {2026}, author = {Oh, H and Kim, H and Kang, H and Kwon, D and French, L and Park, YH and Youn, YC and An, SS and Kim, S and Kang, S}, title = {Systemic proteomic and organ aging signatures associated with plasma Aβ oligomerization in a Korean cohort: a cross-sectional study.}, journal = {Frontiers in aging neuroscience}, volume = {18}, number = {}, pages = {1620991}, pmid = {41948065}, issn = {1663-4365}, abstract = {BACKGROUND: Alzheimer's disease (AD) is characterized by the accumulation of amyloid-beta (Aβ) in the brain, which begins decades before the appearance of clinical symptoms. Blood from AD patients, when spiked with synthetic Aβ, exhibited a higher Aβ oligomerization tendency (OAβT) than the non-AD subjects. OAβT reflected early pathological changes of AD and is considered as a promising blood-based biomarker. However, the mechanism underlying OAβT remained elusive. This study aimed to identify proteomic signatures associated with OAβT and explore its role in AD diagnosis.

METHODS: Forty AD and non-AD subjects from a Korean cohort were divided into four groups based on the disease diagnosis, OAβT values (thresholded at 0.78 ng/mL), and amyloid PET status (A-PET): A-PET-positive AD patients with high or low OAβT values, A-PET-negative non-AD subjects with high or low OAβT values. Using aptamer-based proteomics, 7,288 proteins from plasma samples were quantified, and the group differences were assessed in protein levels and the enrichment of gene sets associated with annotations from the Gene Ontology database. Further, we assessed whether OAβT-PET mismatched cases (A-PET-positive but OAβT-low or A-PET-negative but OAβT-high) exhibited distinct blood proteome signatures in comparison to typical AD cases. Aging signatures for 11 organs were analyzed to explore systemic factors linked to OAβT-PET discrepancies. Additionally, the pharmacological influences on the OAβT-related proteome were investigated by comparing OAβT-correlated proteins with a database of drug-induced proteomic changes.

RESULTS: Elevated OAβT values, regardless of AD diagnosis, correlated with increased immune response and decreased cellular metabolism. Dementia-predicting proteins were enriched in non-AD individuals with high OAβT. Accelerated muscle aging was associated with high OAβT values and worse cognitive function. Furthermore, several potential pharmacological modulators of OAβT, including Minocycline and Anamorelin, were identified.

CONCLUSION: Our findings demonstrated OAβT as a reflection of systemic changes linked to early AD pathology. Moreover, the influence of medications and systemic aging on OAβT values pointed to the potential avenues for intervention and emphasized the importance of considering systemic factors in AD pathogenesis and treatment.}, } @article {pmid41948540, year = {2026}, author = {Khorsand, B and Ghanbarian, E and Rabin, LA and Sajjadi, SA and Ezzati, A}, title = {Incremental value of plasma biomarkers in predicting clinical decline among cognitively unimpaired older adults: Results from the A4 trial.}, journal = {Alzheimer's & dementia (Amsterdam, Netherlands)}, volume = {18}, number = {2}, pages = {e70321}, pmid = {41948540}, issn = {2352-8729}, support = {K23 AG063993/AG/NIA NIH HHS/United States ; R01 AG080635/AG/NIA NIH HHS/United States ; R01 AG095017/AG/NIA NIH HHS/United States ; }, abstract = {INTRODUCTION: Alzheimer's disease (AD) heterogeneity complicates early detection and trial design. Scalable predictors may aid risk stratification. We assessed whether scalable baseline plasma biomarkers and neuropsychological measures predict 5‑year cognitive and functional decline in cognitively unimpaired older adults.

METHODS: We analyzed 866 amyloid-positive participants from the Anti-Amyloid Treatment in Asymptomatic Alzheimer's Disease (A4) trial and 343 amyloid-negative individuals from the Longitudinal Evaluation of Amyloid Risk and Neurodegeneration (LEARN) study. Decline was defined as a ≥0.5 increase in Clinical Dementia Rating-Global Score over 240 weeks. The separate and joint value of demographics, apolipoprotein E (APOE) ε4, amyloid positron emission tomography (PET) standardized uptake value ratio (SUVR), plasma phosphorylated tau-217 (p-tau217), and Preclinical Alzheimer's Cognitive Composite (PACC) were assessed. A sub-study of 656 participants evaluated added value of plasma amyloid beta (Aβ)42/Aβ40, glial fibrillary acidic protein (GFAP), and neurofilament light chain (NfL).

RESULTS: The p-tau217 and PACC significantly improved prediction. Full models achieved areas under the curve (AUCs) of 0.78-0.80 across cohorts. Additional plasma biomarkers offered modest AUC gains (1%-3%).

DISCUSSION: The p-tau217 and PACC enhanced prediction of preclinical decline, supporting their utility in early identification and trial enrichment in AD.}, } @article {pmid41948553, year = {2026}, author = {Sólyomvári, C and Makkai, G and Capelo-Carrasco, N and Strac, DS and Zelena, D and Farkas, S}, title = {Time-dependent histological characterization of amyloid-β induced cholinergic and glial alterations and their modulation by dehydroepiandrosterone sulfate (DHEAS).}, journal = {Frontiers in endocrinology}, volume = {17}, number = {}, pages = {1764298}, pmid = {41948553}, issn = {1664-2392}, mesh = {Animals ; *Amyloid beta-Peptides/toxicity ; Male ; *Dehydroepiandrosterone Sulfate/pharmacology ; Mice ; *Cholinergic Neurons/drug effects/pathology/metabolism ; *Neuroglia/drug effects/pathology/metabolism ; Mice, Inbred C57BL ; *Peptide Fragments/toxicity ; Time Factors ; Microglia/drug effects/pathology/metabolism ; *Alzheimer Disease/pathology/metabolism/drug therapy ; Astrocytes/drug effects/metabolism/pathology ; }, abstract = {INTRODUCTION: Alzheimer's disease (AD) is a multifactorial neurodegenerative disorder characterized by predominant - but not exclusive - pathological accumulation of amyloid-β (Aβ) in the brain. This process affects not only neurons (particularly cholinergic) but also glial cells, contributing to progressive neuronal loss and neuroinflammation. Dehydroepiandrosterone (DHEA) and dehydroepiandrosterone sulfate (DHEAS) are endogenous steroids that are hypothesized to exert neuroprotective and anti-inflammatory effects. This study aims to histologically characterize the in vivo temporal progression of Aβ-induced alterations in cholinergic neurons and glial morphology. Our secondary aim was to evaluate whether DHEAS protects cholinergic integrity and, if so, whether this effect is mediated through glial activation.

METHODS: Aβ1-42 was injected into the cholinergic nucleus basalis magnocellularis (NBM) region of C57BL6/J male mice and one hour later 10 mg/kg DHEAS or vehicle (0.9% saline) was applied intraperitoneally. After 3, 12 or 33 days, the mice were transcardially perfused and immunohistochemical staining was used to investigate cholinergic cell (ChAT) and fiber (AChE) loss, as well as microglia (IBA1) and astrocyte (GFAP) morphology.

RESULTS: Our findings confirmed that Aβ peptide exerted neurotoxic effects on the cholinergic system and triggered time-dependent activation in both glia cell types. Microglial cells initiated their response by day 3, adopting an amoeboid morphology, whereas delayed astrocytic reactivity was observed between days 3 and 12, demonstrated by increased ramification. DHEAS treatment preserved cholinergic fiber density, without effecting the number of cell bodies and modulated the inflammatory responses of glia cells, by decreasing the area occupied and number of microglia in a time dependent manner.

DISCUSSION: Aβ toxicity exerts time-dependent effects on both cholinergic neurons and glia cells, while DHEAS shows therapeutic promise, though its efficacy and exact mechanism require further investigation.}, } @article {pmid41948610, year = {2026}, author = {Naim, A and Farooqui, AM and Badruddeen, and Khan, MI and Akhtar, J and Ahmad, A and Ashique, S and Islam, A}, title = {Nanoengineered phytochemicals overcome blood-brain barrier constraints in neurodegenerative disorders.}, journal = {Frontiers in neurology}, volume = {17}, number = {}, pages = {1792829}, pmid = {41948610}, issn = {1664-2295}, abstract = {Neurodegenerative disorders represent a growing global health burden and remain largely incurable, with current therapies providing only symptomatic relief and limited disease modifications. A major obstacle to effective treatment is the inability of many neuroprotective agents to reach the brain at therapeutically relevant concentrations due to poor bioavailability and the restrictive nature of the blood-brain barrier. Plant-derived phytochemicals possess well-documented antioxidant, anti-inflammatory, anti-apoptotic, and neuromodulatory activities; however, their clinical translation has been hindered by physicochemical instability, rapid metabolism, and insufficient brain exposure. This review critically examines nanoengineered delivery systems as a strategy to overcome these limitations and enable the effective brain targeting of neuroprotective phytochemicals. By integrating mechanistic insights with preclinical and emerging clinical evidence, we compared lipid-based, polymeric, vesicular, and dendritic nanocarriers, highlighting how particle size, surface chemistry, and ligand functionalization govern blood-brain barrier transport and intracerebral distribution. Particular emphasis is placed on rational design principles that consistently enhance brain bioavailability and therapeutic efficacy across models of Alzheimer's disease, Parkinson's disease, multiple sclerosis, and related disorders. Beyond efficacy, we analyzed key translational challenges, including nanocarrier-associated neurotoxicity, standardization of herbal activities, and regulatory gaps unique to herbal nanomedicines. Collectively, this synthesis reframes nano-phytomedicine not as an incremental formulation upgrade but as a design-driven strategy capable of unlocking the therapeutic potential of phytochemicals for neurodegenerative disease management.}, } @article {pmid41949026, year = {2026}, author = {Boyd, RJ and Dong, D and Sagar, R and Iliuk, A and Ahmed, W and Androni, X and Porsteinsson, AP and Rosenberg, PB and Lyketsos, CG and Witwer, KW and Mahairaki, V}, title = {Proteomic profiling of brain organoids and extracellular vesicles identifies early Alzheimer's disease biomarkers and drug response heterogeneity.}, journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association}, volume = {22}, number = {4}, pages = {e71273}, pmid = {41949026}, issn = {1552-5279}, support = {//The Richman Family Precision Medicine Center of Excellence in Alzheimer's Disease/ ; R44 AG063589/AG/NIA NIH HHS/United States ; AGR01071522/AG/NIA NIH HHS/United States ; 1RF1AG083801/GF/NIH HHS/United States ; R43 AG063589/AG/NIA NIH HHS/United States ; AGR01046543/AG/NIA NIH HHS/United States ; AGR01050515/AG/NIA NIH HHS/United States ; AGR01054771/AG/NIA NIH HHS/United States ; }, mesh = {*Alzheimer Disease/metabolism/drug therapy/pathology ; Humans ; *Extracellular Vesicles/metabolism ; *Organoids/metabolism ; *Proteomics/methods ; *Brain/metabolism/pathology ; Biomarkers/metabolism ; Induced Pluripotent Stem Cells/metabolism ; Selective Serotonin Reuptake Inhibitors/pharmacology ; Treatment Effect Heterogeneity ; }, abstract = {INTRODUCTION: Alzheimer's disease (AD) exhibits high genetic and clinical heterogeneity that limits therapeutic success. Patient-derived brain organoids and their extracellular vesicles (EVs) provide physiologically relevant models to study disease mechanisms and individualized drug responses.

METHODS: We generated the largest brain organoid cohort to date, derived from 30 independent induced pluripotent stem cell (iPSC) lines from AD and control individuals. Comparative proteomic profiling was performed on both organoids and their secreted EVs to capture molecular diversity and treatment effects.

RESULTS: Organoids and EVs consistently recapitulated neuronal proteomic signatures and revealed early alterations in AD-related pathways, including synaptic and neurotransmitter dysfunction. Distinct proteomic responses mirrored individual variability in selective serotonin reuptake inhibitor sensitivity.

DISCUSSION: Integrating organoid and EV data provides a systems-level view of AD pathophysiology and treatment response, positioning this dual-platform model as a cost-effective tool for precision medicine and drug discovery.}, } @article {pmid41950049, year = {2026}, author = {Robb, WH and Kaur, G and Huang, S and Martinez, F and Nguyen, B and Shin, CH and Yang, M and Conyers, CT and Grilli, CB and Upjohn, DP and Ortega, VE and Hohman, TJ and Keegan, RM and Parent, EE and Cogswell, PM and Graff-Radford, J and Johnson, DR and Ramanan, VK and Koran, ME}, title = {Health system patterns of imaging and fluid biomarker testing in the era of anti-amyloid therapies.}, journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association}, volume = {22}, number = {4}, pages = {e71343}, pmid = {41950049}, issn = {1552-5279}, support = {//Alzheimer's Association Clinician Scientist Fellowship (MEK)/ ; K76AG088554/AG/NIA NIH HHS/United States ; }, mesh = {Humans ; Female ; Biomarkers/cerebrospinal fluid ; *Alzheimer Disease/drug therapy/diagnostic imaging/cerebrospinal fluid ; *Amyloid beta-Peptides/cerebrospinal fluid ; Retrospective Studies ; Male ; Positron-Emission Tomography ; Apolipoproteins E/genetics ; Aged ; Aged, 80 and over ; tau Proteins/cerebrospinal fluid/blood ; Brain/diagnostic imaging ; Electronic Health Records ; }, abstract = {INTRODUCTION: Anti-amyloid-β (Aβ) therapies are reshaping Alzheimer's disease (AD) management. Understanding changes in real-world patterns of diagnostic testing and infusion chair usage is essential for optimizing access to care.

METHODS: Retrospective analysis of Mayo Clinic enterprise electronic health records (Jan 2019-Mar 2025) assessed trends in AD-relevant brain imaging, fluid biomarkers, apolipoprotein E (APOE) testing, and lecanemab infusions. Rates of amyloid-beta (Aβ) positivity by sex and age, APOE genotype frequencies, and lecanemab treatment initiation and discontinuation were evaluated.

RESULTS: Following national insurance coverage changes, lecanemab infusions grew by 110 infusions per quarter to 605 in Q1 2025. Aβ positron emission tomography scans increased (+22/quarter), cerebrospinal fluid biomarker orders declined (-25/quarter), and plasma p-tau217 orders rapidly increased (+238/quarter). Females were more likely to be Aβ positive (p < 0.006). APOE-ε4 homozygotes were less likely to initiate lecanemab (HR = 0.11, p < 0.001).

DISCUSSION: The adoption of anti-Aβ therapies coincided with a rapid shift in diagnostic workflows.}, } @article {pmid41951598, year = {2026}, author = {Zhao, S and Ye, R and Tang, QY and Attaallah, B and Toniolo, S and Saleh, Y and Rouse, MA and Garrard, P and Broulidakis, MJ and Thompson, S and Manohar, SG and Irani, SR and Ang, YS and Lockwood, P and Apps, MAJ and Hu, P and Wang, K and Rowe, JB and Le Heron, C and Husain, M}, title = {The social dimension of apathy: evidence for a distinct domain from 11,243 individuals across health and neurocognitive disorders.}, journal = {Translational psychiatry}, volume = {16}, number = {1}, pages = {}, pmid = {41951598}, issn = {2158-3188}, support = {226645/Z/22/Z//Wellcome Trust (Wellcome)/ ; 220258/WT_/Wellcome Trust/United Kingdom ; 82171917//National Natural Science Foundation of China (National Science Foundation of China)/ ; 82471271//National Natural Science Foundation of China (National Science Foundation of China)/ ; MR/V007173/1//RCUK | Medical Research Council (MRC)/ ; MC_UU_00030/14//RCUK | Medical Research Council (MRC)/ ; SUAG/092 G116768//RCUK | Medical Research Council (MRC)/ ; 02/2019//Canterbury Medical Research Foundation (CMRF)/ ; }, mesh = {Humans ; *Apathy ; Female ; Male ; Aged ; Middle Aged ; Adult ; *Neurocognitive Disorders/psychology/physiopathology ; Alzheimer Disease/psychology ; Frontotemporal Dementia/psychology/physiopathology ; Adolescent ; *Social Behavior ; Young Adult ; Parkinson Disease/psychology/physiopathology ; Aged, 80 and over ; }, abstract = {Apathy is a highly prevalent and disabling neuropsychiatric syndrome, but its multi-dimensional structure is a challenge for progress towards better identification and treatment. A crucial unresolved question is whether social disengagement reflects a distinct deficit in social motivation or a by-product of diminished initiative or emotional blunting. Previous studies have been constrained by modest sample sizes and limited use of apathy-specific instruments or phenotypically narrow cohorts. Here, we analysed item-level data from 11,243 individuals recruited across multiple centres, including 1154 neurological patients with Alzheimer's disease, Parkinson's disease, frontotemporal dementia, autoimmune encephalitis and small vessel disease, alongside people with depression and healthy adults. Across exploratory and confirmatory factor analyses, symptom-level network modelling, and lifespan analyses, social apathy consistently emerged as a coherent and separable dimension. This pattern was preserved across health, psychiatric, and neurocognitive cohorts, from adolescence through late life. Recognising social apathy as an independent domain reframes a central aspect of mental health-the motivation to connect, care, and act for others-and provides a foundation for more precise assessment and for interventions targeting both social and neurobiological mechanisms.}, } @article {pmid41951832, year = {2026}, author = {Islam, N and Akçesme, B}, title = {Single nucleotide polymorphisms affecting galantamine binding to acetylcholinesterase in Alzheimer's disease: a structural bioinformatics study.}, journal = {Journal of computer-aided molecular design}, volume = {40}, number = {1}, pages = {}, pmid = {41951832}, issn = {1573-4951}, mesh = {*Galantamine/chemistry/metabolism ; Humans ; *Alzheimer Disease/drug therapy/genetics/enzymology ; *Polymorphism, Single Nucleotide ; *Acetylcholinesterase/chemistry/genetics/metabolism ; *Cholinesterase Inhibitors/chemistry/pharmacology/metabolism ; Molecular Dynamics Simulation ; Molecular Docking Simulation ; Protein Binding ; Binding Sites ; Computational Biology ; Mutation, Missense ; Catalytic Domain ; Ligands ; }, abstract = {Galantamine, an acetylcholinesterase (AChE) inhibitor used for symptomatic treatment of Alzheimer's disease (AD), shows substantial inter-individual variability in clinical response. Missense single nucleotide polymorphisms (SNPs) within the AChE active-site gorge may modulate inhibitor recognition. In this computational study, binding residues were defined from human AChE inhibitor co-crystal structures and cross-referenced with dbSNP missense variation, followed by in-silico predictions of variant impact, evolutionary conservation and folding stability, and assessment of ligand engagement by docking and molecular dynamics (MD) with MM/GBSA binding-energy estimation. Using complexes containing galantamine (GNT) and a donepezil-like ligand (E20), 11 of 807 AChE missense variants overlapped binding-site residues, highlighting Phe294 (UniProt Phe326) and His447 (UniProt His479). ConSurf classified His447 as highly conserved, and MUpro predicted decreased folding stability for His447 substitutions. SwissDock docking indicated that His447Gln retains a plausible GNT binding pose and yielded the least favourable docking score among the tested variants, consistent with a potential reduction in binding strength. MD simulations (200 ns) of wild-type and His447Gln AChE-GNT complexes supported preserved global structural integrity of the complex over the simulated timescale, while indicating local remodelling of the GNT binding microenvironment. MM/GBSA estimates from terminal snapshots suggested a modestly less favourable theoretical binding free energy for His447Gln relative to wild-type (approximately 2.0 kcal mol[-1]). Given that His447 is the catalytic triad histidine, such substitutions may have consequences for catalysis in addition to inhibitor binding; these in-silico findings require experimental validation using site-directed mutagenesis with kinetic and binding assays.}, } @article {pmid41953054, year = {2026}, author = {Zhuang, YY and Yan, JM and Wu, TC and Xu, WS and Wu, B and Xie, X and Wang, WJ and Lin, HW and Jian, JW and Wang, JZ and Jiang, T and Chen, LM and Qiu, YX and Hu, ZY and Zhou, YH and Yang, T and Yang, MG and Zhu, JF and Tao, J and Chen, LD and Li, WG and Yan, K and Liu, WL}, title = {tDCS improves early Alzheimer's disease by synaptic vesicle fusion and release.}, journal = {Military Medical Research}, volume = {13}, number = {1}, pages = {100003}, pmid = {41953054}, issn = {2054-9369}, mesh = {Animals ; *Alzheimer Disease/therapy/physiopathology ; *Synaptic Vesicles/physiology/metabolism ; Mice ; Mice, Transgenic ; *Transcranial Direct Current Stimulation/methods/standards ; Disease Models, Animal ; Memory, Short-Term/physiology ; Male ; Prefrontal Cortex ; Humans ; }, abstract = {BACKGROUND: Working memory deficits, one of the earliest hallmarks of Alzheimer's disease (AD), are closely linked to abnormal neural activity in the dorsolateral prefrontal cortex (DLPFC). Transcranial direct current stimulation (tDCS), a non-invasive neuromodulation therapy, has been shown to ameliorate early AD working memory deficits by modulating excitatory activity in the DLPFC, yet the underlying mechanisms remain incompletely understood.

METHODS: This investigation was structured around 3 experimental phases. We initially applied tDCS to stimulate the left prefrontal cortex (PFC) of transgenic mice with 5 familial AD (5×FAD) 5 d per week for 4 weeks. Subsequently, we employed optogenetic (Opt) techniques to modulate left PFC glutamatergic neurons. Finally, we inhibited soluble N-ethylmaleimide-sensitive factor attachment receptor (SNARE) expression in the left PFC to elucidate the essential function of SNARE complex assembly with chaperone molecules in orchestrating synaptic vesicle release.

RESULTS: tDCS treatment improved working memory deficits in early-stage AD mice. This was accompanied by increased cerebral blood flow, enhanced neuronal excitability, amelioration of neurochemical metabolic disorders, and reduced amyloid β-protein (Aβ) deposition in the left PFC. Opt stimulation of PFC glutamatergic neurons similarly improved working memory, indicating the association between tDCS's therapeutic effects and synaptic plasticity of excitatory neurons. Crucially, tDCS facilitated synaptic vesicle fusion and release, evidenced by increased vesicle numbers, enhanced release probability, improved synaptic transmission efficacy, and upregulation of the SNARE complex, Snap25, and Syt1. Inhibiting SNARE expression in the left PFC attenuated the tDCS-induced improvements in synaptic vesicle release and working memory.

CONCLUSION: These findings collectively demonstrate that left PFC-targeted tDCS modulates interactions between the SNARE complex and chaperone molecules, thereby promoting synaptic vesicle fusion and release. This mechanism underlies the amelioration of early AD-like working memory impairment by tDCS.}, } @article {pmid41954680, year = {2026}, author = {Youssef, B and Ibrahim, EA and Moselhy, SS and ElShebiney, S and ELabd, WK}, title = {Nano-magnolol enhances the modulatory effects of magnolol on cognitive performance and BACE1-related biochemical changes in an STZ-induced rat model of Alzheimer's disease.}, journal = {Discover nano}, volume = {21}, number = {1}, pages = {}, pmid = {41954680}, issn = {2731-9229}, abstract = {BACKGROUND: The Late-onset Alzheimer's disease (LOAD) is progressive cognitive deficits associated with different abnormalities as cholinergic dysfunction, amyloid accumulation, inflammation, and oxidative stress. Magnolol is a polyphenolic compound that abrogated the neurodegenerative disease. The application of nanoparticles in medicine showed high bioavailability and low side effects for development of novel effective therapies. This study evaluated the neuroprotective potential of magnolol nanoparticles against streptozotocin (STZ) injected in intracerebroventricularly (ICV) induced Alzheimer's disease (AD) in rats.

METHODS: In current study, six groups of male Wister rats (10 rats/ group) were injected with STZ (2 mg/kg) in ICV bilaterally for induction of pathological features similar to AD. Rats were then treated with either magnolol or nano-magnolol or donepezil (p.o). Behavioral analysis was evaluated as the Morris Water Maze (MWM), Y-Maze, Novel Object Recognition (NOR), Passive Avoidance (PA), Elevated plus Maze (EPM), and Open Field Test (OFT). In addition, biochemical markers including brain acetylcholinesterase (AChE), glutathione-S-transferase (GST), B-secretase1 (BACE1) activities and nuclear factor kappa-B (NF-κB) were analyzed in hippocampal tissue.

RESULTS: Data obtained showed that nano-magnolol significantly showed a neuroprotective effect in LOAD rat model by restoring GST activity and effectively decreased the activities of AChE, BACE1 and level of NF-κB compared to both donepezil and magnolol. Molecular docking studies indicated strengthen the affinity of magnolol to the BACE-1 active site.

CONCLUSION: Nano-magnolol is promising in developing a new agent targeting cholinergic function, amyloidogenesis, neuro-inflammation, and oxidative stress reflecting its potent neuroprotective efficacy in AD treatment.}, } @article {pmid41954847, year = {2026}, author = {Ma, X and Wang, M and Yang, J and Li, G and Wang, Y and Fang, H and Zhang, S}, title = {Integrated Single-Cell and System Network Analysis: Exploring Cellular Communication Network Complexity and Signal Transmission Dysregulation in Down Syndrome Brain.}, journal = {Neuroinformatics}, volume = {24}, number = {2}, pages = {}, pmid = {41954847}, issn = {1559-0089}, support = {No. 2022D03052; No. XJNUBS202419; Grant Numbers. 82270417//This research was supported by the Special Natural Science Foundation of Xinjiang Uygur Autonomous Region Special Training Programme for Ethnic Minorities (No. 2022D03052), the Doctoral (Postdoctoral) Research Start-up Fund Project of Xinjiang Normal University (No. XJNUBS202419) and the National Natural Science Foundation of China (Grant Numbers. 82270417)./ ; }, mesh = {*Down Syndrome/pathology/metabolism/genetics/physiopathology ; Humans ; *Cell Communication/physiology ; *Brain/metabolism/pathology ; *Signal Transduction/physiology ; Neurons/metabolism/pathology ; Middle Aged ; Aging/pathology ; Female ; Single-Cell Analysis/methods ; Male ; }, abstract = {Down syndrome (DS) is a widespread chromosomal disorder primarily associated with cognitive impairment and progressive neurodegenerative changes. Clinically, age 50 years is considered a pivotal turning point in the health trajectory of individuals with DS. Before this age, they primarily face developmental challenges including significant cognitive deficits and difficulties in social interaction. However, as they age, they increasingly exhibit more severe neurodegenerative changes, including Alzheimer's disease (AD)-like cognitive decline and dementia symptoms. This study aimed to dissect intricate gene expression patterns in key neuronal cell types within the DS cerebral cortex and to examine how these patterns evolve with age. We conducted a detailed gene expression analysis of key neuronal cells, including inhibitory neurons, excitatory neurons, microglia, and oligodendrocyte progenitor cells, in individuals with DS. Additionally, the bioinformatics tool NeuronChat was employed to investigate the intercellular communication networks in the DS brain. Individuals with DS were divided into younger and older groups, with age 50 years as the boundary. Through comparative analysis, our findings indicated that aging in DS is associated with exacerbated neuronal dysfunction, decreased energy metabolism in microglia, and increased neurodegenerative traits in oligodendrocyte progenitor cells. Notably, compared to the control group, the DS brain showed increased complexity in cellular communication networks, reflecting an effort to maintain adaptability during syndrome progression. However, this increased complexity does not translate into effective signal transmission, suggesting significant disruptions in the function and structure of the neural network. This study provides a deeper understanding of cell function abnormalities and signal transmission irregularities in DS. By integrating single-cell and systemic network analyses, we revealed complex pathophysiological mechanisms, laying a foundational framework for developing new treatment methods. Our comprehensive analysis emphasizes the necessity for targeted strategies to address the multifaceted nature of DS pathogenesis and improve treatment outcomes.}, } @article {pmid41955600, year = {2026}, author = {Krupa, J and Malinowski, M and Krasowski, M and Kalinowska, A and Pietras, W and Kozieł, A and Kurek, Z and Jentkiewicz, A and Obeid, EH and Ulrych, J}, title = {The role of the MIND diet in prevention and treatment of Alzheimer's disease: A literature review.}, journal = {Wiadomosci lekarskie (Warsaw, Poland : 1960)}, volume = {79}, number = {2}, pages = {390-398}, doi = {10.36740/WLek/217286}, pmid = {41955600}, issn = {0043-5147}, mesh = {Humans ; *Alzheimer Disease/prevention & control/diet therapy ; *Diet ; }, abstract = {OBJECTIVE: Aim: Recent research increasingly point to modifiable risk factors, especially dietary patterns, as potential tools to prevent or delay neurodegeneration. This review evaluates the impact of the MIND diet on the prevention and progression of AD and compares it with other dietary interventions.

PATIENTS AND METHODS: Materials and Methods: A literature search was conducted using the PubMed and Google Scholar databases for articles published from January 2015 to January 2025, focusing on the influence of the MIND diet, as well as other dietary patterns, on AD progression and cognitive performance.

CONCLUSION: Conclusions: While the MIND diet shows promise as a feasible non-pharmacological strategy, current evidence is largely observational and limited by population heterogeneity and inconsistent adherence definitions. Short-term randomized controlled trials are less conclusive. Long-term clinical trials are needed to establish causality. Despite these limitations, the MIND diet remains a practical and potentially effective approach to reducing cognitive decline and delaying the onset of AD.}, } @article {pmid41956136, year = {2026}, author = {More, PS and Rangari, SW and Lade, SN and Unidrwade, DS and Burle, SS and Umekar, MJ and Lohiya, RT and Zanwar, AS}, title = {Drug repurposing in Alzheimer's disease: Emerging therapeutic strategies and promising candidates.}, journal = {Ageing research reviews}, volume = {118}, number = {}, pages = {103113}, doi = {10.1016/j.arr.2026.103113}, pmid = {41956136}, issn = {1872-9649}, mesh = {Humans ; *Alzheimer Disease/drug therapy/metabolism ; *Drug Repositioning/methods ; Animals ; *Neuroprotective Agents/therapeutic use ; }, abstract = {Alzheimer's disease is a progressive neurodegenerative disorder, and the most common cause of dementia, which causes 60-70 % of cases worldwide, and its prevalence is increasing by more than 55 million people globally, with an expected increase of 139 million cases by 2050. AD is characterized by Amyloid-β plaque deposition, tau hyperphosphorylation, synaptic dysfunction, neuroinflammation, and oxidative stress, which makes the pathophysiology multifactorial and complex in terms of the development of therapeutic treatment. Existing approved therapies, such as cholinesterase enzyme inhibitors and NMDA receptors antagonists, are merely symptomatic, whereas novel anti-amyloid monoclonal antibodies approved recently have low clinical efficacy with safety and cost issues. The low success rates of clinical trials highlight the necessity of alternative approaches. Drug repurposing of drugs has proved to be a promising solution, which uses drugs with know safety profiles to speed up the discovery of therapeutic solutions. These repurposed agents are used targeting diverse pathologic pathways, including amyloid aggregation, tau pathology, neuroinflammation, and synaptic dysfunction, with antidiabetic agents (metformin, GLP-1 receptor agonists) and anti-hypertensives (candesartan), anti-inflammatory ones (NSAIDs, pioglitazone), and neuroprotective ones (minocycline, sildenafil). Notably, mitochondrial dysfunction is becoming a significant early and essential cause of AD development, and mitochondria-targeted therapeutics like SS-31, Mdivi-1, MitoQ, DDQ, and SkQ1 are currently considered promising disease-modifying options. The development of artificial intelligence, multi-omics, and precision medicine also improves drug repurposing plans. Overall possibility to integrate multi-target repurposed therapies with novel technologies is a promising prospect to overcome the available shortcomings and improve clinical outcomes in AD.}, } @article {pmid41956234, year = {2026}, author = {Alves, SS and Manzine, PR and Dos Santos, FM and Migliaccio, MM and de Carvalho Alves, LV and da Silva Junior, RMP and Becerra-Hernández, LV and González-Acosta, CA and Buriticá-Ramírez, E and Cominetti, MR and Camins, A and Garcia-Cairasco, N}, title = {From comorbidity to continuum: Alzheimer's disease and epilepsy are connected-now what?.}, journal = {Neuroscience and biobehavioral reviews}, volume = {186}, number = {}, pages = {106682}, doi = {10.1016/j.neubiorev.2026.106682}, pmid = {41956234}, issn = {1873-7528}, mesh = {Humans ; *Epilepsy/epidemiology/physiopathology/metabolism ; *Alzheimer Disease/epidemiology/physiopathology/metabolism/complications ; Comorbidity ; Animals ; Brain/physiopathology/metabolism ; }, abstract = {Alzheimer's disease (AD) and epilepsy are increasingly recognized not merely as comorbid conditions but as disorders lying along a shared pathophysiological continuum, characterized by overlapping clinical features, network hyperexcitability, and convergent molecular mechanisms. Although bidirectional interactions between AD and epilepsy are now well established, critical questions remain regarding how this knowledge can be translated into improved risk prediction, prevention, and treatment. Classical mechanisms such as amyloid-β and tau pathology, neuroinflammation, and synaptic dysfunction, together with less explored processes including brain insulin resistance, converge on shared downstream effects that promote both neurodegeneration and epileptogenesis. However, marked mechanistic heterogeneity across individuals, limits standardized therapeutic approaches and complicates the prediction of seizure risk in AD and dementia risk in epilepsy. In this review, we synthesize evidence supporting the AD-epilepsy continuum, integrating molecular pathways, genetic and metabolic modifiers, fluid biomarkers, and neuroimaging signatures that may enable earlier identification of vulnerable trajectories. We critically examine pharmacological strategies with dual effects on neuroprotection and seizure control and discuss how targeting shared mechanisms may shift interventions from symptomatic management toward disease modification. Importantly, we highlight current gaps and emerging hypotheses that define the next steps for the field, including patient stratification, early biomarker-guided trial design, and precision-based therapeutic strategies. By moving beyond descriptive associations, this review outlines a framework for translating mechanistic insight into actionable approaches aimed at early detection, personalized intervention, and improved outcomes in individuals at risk across the AD-epilepsy spectrum.}, } @article {pmid41956992, year = {2026}, author = {Papapanagiotou, O and Cotton, K and Edwards, C and Michod, D and Crompton, L and Craig, T and Niklison-Chirou, MV}, title = {Lipid droplets in neurodegenerative diseases: pathological drivers and therapeutic vulnerabilities.}, journal = {Cell death discovery}, volume = {12}, number = {1}, pages = {}, pmid = {41956992}, issn = {2058-7716}, abstract = {Lipid droplets (LDs) are dynamic intracellular organelles traditionally associated with energy storage, which have become increasingly recognised for their versatile roles in cellular metabolism and signalling. In the brain, LDs have emerged as critical regulators in neurodegenerative diseases (NDDs) such as Alzheimer's disease (AD), Parkinson's disease (PD), and Hereditary Spastic Paraplegia (HSP). LDs contribute to neurodegeneration by influencing lipid metabolism, oxidative stress, and inflammatory responses. For instance, in AD, dysregulated lipid metabolism and impaired Apolipoprotein E 4 (ApoE4) function lead to LD accumulation associated with neuroinflammation and amyloid plaque formation. In PD, interactions between LDs and α-synuclein suggest a potential link between lipid dysregulation and neurotoxicity. Mutations in LD-associated proteins, such as spastin and DDH2 in HSP, highlight the importance of proper LD regulation for neuronal health. While LD accumulation can be protective by mitigating lipotoxicity, prolonged dysregulation can exacerbate NDD pathology. Targeting LD metabolism, through enhancing lipophagy or modulating LD-associated proteins, represents a promising therapeutic avenue. This review highlights the dual roles of LDs in the brain, acting both neuroprotectively and neurotoxically, and the therapeutic potential of targeting LD dynamics for NDD treatment.}, } @article {pmid41957314, year = {2026}, author = {Park, Y and Chae, H and Yoon, E and Kim, Y and Han, JW and Woo, SJ and Yoo, S and Kim, KW}, title = {Restoration of gamma center frequency via personalized entrainment marks cognitive preservation in early Alzheimer's disease.}, journal = {GeroScience}, volume = {}, number = {}, pages = {}, pmid = {41957314}, issn = {2509-2723}, support = {NRF-2017R1A5A1014708//National Research Foundation of Korea/ ; RS-2025-02223212//Korea Health Industry Development Institute/Republic of Korea ; }, abstract = {Gamma entrainment shows promise for Alzheimer's disease (AD) treatment in preclinical models, but human trials have yielded heterogeneous results. We hypothesized that the clinical efficacy of gamma entrainment depends on individual neurophysiological receptivity, specifically the capacity for neural circuit plasticity. In this open-label pilot study, we screened 37 individuals and enrolled 16 participants with early AD (CDR 0.5-1.0, amyloid-positive) who completed 12 weeks of home-based flickering light stimulation at individually optimized gamma frequencies (32-40 Hz). Pre- and post-intervention assessments included 64-channel EEG recordings and MMSE. Participants demonstrated dichotomous neurophysiological responses: 43.8% showed center frequency (CF) increase (increased CF [ICF+]) while 56.3% showed no change/decrease (non-increased CF [ICF-]). CF restoration was significantly associated with cognitive preservation (r = 0.52, p = 0.039). Notably, future responders exhibited distinct baseline signatures of "neural reserve," characterized by higher temporal gamma power (Cohen's d = 0.70-0.92) and stronger frontotemporal connectivity (Cohen's d = 1.11-1.47). Almost 30% of screened candidates failed to show baseline entrainment, highlighting a distinct "non-responsive" biological subtype. CF restoration following personalized gamma entrainment identifies a neurophysiological subtype capable of meaningful plasticity. Rather than a universal remedy, gamma entrainment appears to act on specific neural substrates preserved in a subset of patients. These findings suggest that baseline electrophysiological profiling could unlock gamma entrainment's therapeutic potential by stratifying likely responders for precision neuromodulation.}, } @article {pmid41957960, year = {2022}, author = {Li, CT and Fuh, JL and Yang, BH and Hong, CJ and Chang, CW and Tu, PC and Jeng, JS and Chen, MH and Tsai, SJ and Bai, YM and Su, TP and Lee, H and Huang, WS}, title = {Global cognitive dysfunction and β-amyloid neuropathology in late-life and treatment-resistant major depression.}, journal = {Psychological medicine}, volume = {52}, number = {16}, pages = {4116-4126}, doi = {10.1017/S0033291721001070}, pmid = {41957960}, issn = {1469-8978}, abstract = {BACKGROUND: Cognitive impairment is common in late-life depression, which may increase Alzheimer disease (AD) risk. Therefore, we aimed to investigate whether late-life major depressive disorder (MDD) has worse cognition and increases the characteristic AD neuropathology. Furthermore, we carried out a comparison between treatment-resistant depression (TRD) and non-TRD. We hypothesized that patients with late-life depression and TRD may have increased β-amyloid (Aβ) deposits in brain regions responsible for global cognition.

METHODS: We recruited 81 subjects, including 54 MDD patients (27 TRD and 27 non-TRD) and 27 matched healthy controls (HCs). Neurocognitive tasks were examined, including Mini-Mental State Examination and Montreal Cognitive Assessment to detect global cognitive functions. PET with Pittsburgh compound-B and fluorodeoxyglucose were used to capture brain Aβ pathology and glucose use, respectively, in some patients.

RESULTS: MDD patients performed worse in Montreal Cognitive Assessment (p = 0.003) and had more Aβ deposits than HCs across the brain (family-wise error-corrected p < 0.001), with the most significant finding in the left middle frontal gyrus. Significant negative correlations between global cognition and prefrontal Aβ deposits existed in MDD patients, whereas positive correlations were noted in HCs. TRD patients had significantly more deposits in the left-sided brain regions (corrected p < 0.001). The findings were not explained by APOE genotypes. No between-group fluorodeoxyglucose difference was detected.

CONCLUSIONS: Late-life depression, particularly TRD, had increased brain Aβ deposits and showed vulnerability to Aβ deposits. A detrimental role of Aβ deposits in global cognition in patients with late-onset or non-late-onset MDD supported the theory that late-life MDD could be a risk factor for AD.}, } @article {pmid41959105, year = {2026}, author = {Burberry, A and Benchek, P and Lowe, M and Shin, W and McCourt, B and Beamon, Q and Chakrabarti, S and Ramaiah, S and Woidke, E and Khrestian, M and Maecker, H and Bekris, LM and Rao, S and Ontaneda, D and Leverenz, JB and Bush, W and Pillai, JA}, title = {Early peripheral immune signaling precedes tau elevation and blood-brain barrier disruption in Alzheimer's disease.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, doi = {10.64898/2026.04.02.716122}, pmid = {41959105}, issn = {2692-8205}, abstract = {Neuroinflammation, along with amyloid beta (Aβ) deposition, phospho-tau (ptau) accumulation, blood-brain barrier (BBB) disruption, and cognitive decline are recognized components of Alzheimer's disease (AD). However, the timing and nature of peripheral immune changes across AD biological and clinical stages remain poorly understood. Here we performed mass cytometry profiling of whole blood and cerebrospinal fluid (CSF) immune cells from 351 human samples across two independent clinical cohorts spanning the AD continuum. We identify coordinated peripheral immune signaling signatures that emerge during preclinical stage of AD and precede significant elevation of plasma ptau217, CSF ptau181 and BBB disruption measured by dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI). AD-enriched immune features, including increased phospho-Akt signaling in naï ve T killer cells and phospho-PLCγ2 signaling in granulocytes, were not observed in patients with Frontotemporal lobar degeneration or treatment-naï ve multiple sclerosis. Furthermore, these immune signaling states could be induced in healthy donor immune cells following exposure to plasma or CSF from individuals with AD, indicating that circulating factors can drive these peripheral immune alterations. Together, our findings demonstrate that dynamic peripheral immune state changes arise early in AD and precede canonical biomarker and vascular changes, highlighting immune signaling pathways as potential targets for early therapeutic intervention.}, } @article {pmid41959530, year = {2026}, author = {Pandey, S and Talo, M and Siderovski, DP and Sumien, N and Bozdag, S}, title = {From General-Purpose to Disease-Specific Features: Aligning LLM Embeddings on a Disease-Specific Biomedical Knowledge Graph for Drug Repurposing.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {41959530}, issn = {2692-8205}, support = {R35 GM133657/GM/NIGMS NIH HHS/United States ; }, abstract = {Identifying new therapeutic uses for existing drugs is a major challenge in biomedicine, especially for complex neurodegenerative conditions such as Alzheimer disease and related dementias (ADRD), where treatment options remain limited and relevant data are often sparse, heterogeneous, and difficult to integrate. Although general-purpose Large Language Model (LLM) embeddings encode rich semantic information, they often lack the task-specific biomedical context needed for inference tasks such as computational drug repurposing. We introduce Contextualizing LLM Embeddings via Attention-based gRaph learning (CLEAR), a multimodal representation-fusion framework that aligns LLM embeddings with the topological structure of a context-specific Knowledge Graph (KG). Across five benchmark datasets, CLEAR achieved state-of-the-art results, improving predictive performance (e.g., F1 score) by up to 30% over prior methods. We further applied CLEAR to identify FDA-approved drugs with potential for repurposing for ADRD, including Parkinson disease-related dementia and Lewy Body dementia. CLEAR learned a biologically coherent embedding space, prioritized leading ADRD drug candidates, and accurately summarized known therapeutic relationships for FDA-approved Alzheimer disease drugs. Overall, CLEAR shows that grounding biomedical LLM embeddings with context-specific KG signals can improve drug repurposing in data-sparse, real-world settings. GitHub: https://github.com/bozdaglab/CLEAR.}, } @article {pmid41959743, year = {2026}, author = {Guo, Y and Jiang, Q and Gu, Z and Cao, H and Zuo, C and Huang, Y and Song, Y and Chen, X and Wang, F}, title = {ACSL4 in Alzheimer's disease: Pathogenetic mechanisms and potential therapeutic targets.}, journal = {Genes & diseases}, volume = {13}, number = {4}, pages = {101858}, pmid = {41959743}, issn = {2352-3042}, abstract = {Iron metabolism plays a vital role in maintaining physiological homeostasis, and its dysregulation is implicated in a range of pathological consequences and illnesses, including Alzheimer's disease (AD). Prior studies have demonstrated that Tau protein and amyloid precursor protein are involved in iron homeostasis disorder. Ferroptosis, an iron-dependent form of regulated cell death, has emerged as a key contributor to AD pathogenesis and a promising therapeutic target. Acyl-CoA synthetase long-chain family 4 (ACSL4) is a lipid metabolizing enzyme that enhances ferroptosis sensitivity by promoting the incorporation of oxidizable polyunsaturated fatty acids into membrane phospholipids. Beyond ferroptosis, ACSL4 also plays crucial roles in neuroinflammation and oxidative stress, which are implicated in AD progression. Therefore, targeting ACSL4 is fantastic and has a lot of promise for treating AD. Nevertheless, the precise mechanisms through which ACSL4 contributes to AD pathology have yet to be fully elucidated. This review reveals a potentially vital role of ACSL4 in AD, focusing on its involvement in ferroptosis, oxidative stress, and neuroinflammation. Additionally, we describe some natural and synthetic compounds targeting ACSL4 with therapeutic potential in AD. Building on the theoretical findings of earlier studies about focused interventions of the ACSL4 path, our evaluation provided a broad basis for the clinical transformation in the treatment of AD strategies.}, } @article {pmid41961243, year = {2026}, author = {Porsteinsson, AP and Chumki, SR and Wang, D and Such, P and Palma, AM and Zhang, Z and Shah, A and Kalu, U and Montano, CB}, title = {Short-Term and Long-Term Safety Analyses of Brexpiprazole for Agitation Associated with Dementia due to Alzheimer's Disease: Timing and Duration of Adverse Events.}, journal = {Drug safety}, volume = {}, number = {}, pages = {}, pmid = {41961243}, issn = {1179-1942}, abstract = {INTRODUCTION: Agitation symptoms are a common and burdensome aspect of Alzheimer's dementia. Historically, agitation has been managed using off-label treatments such as atypical antipsychotics, but this approach is associated with safety concerns in older, more vulnerable patients. Brexpiprazole is an atypical antipsychotic that has been recently approved in several countries for the treatment of agitation associated with dementia due to Alzheimer's disease. Previous analyses show that brexpiprazole was efficacious and generally well tolerated for up to 24 weeks. Building upon previous work, this post hoc analysis aimed to evaluate the timing and duration of treatment-emergent adverse events (TEAEs) during brexpiprazole treatment.

METHODS: In a 12-week analysis, data were pooled from three phase 3, randomized, double-blind, placebo-controlled trials of brexpiprazole in participants with agitation associated with dementia due to Alzheimer's disease. In a separate 24-week analysis, brexpiprazole data were combined from a 12-week randomized trial and a 12-week active-treatment extension trial. The median time from starting treatment to first reporting a TEAE and the median duration of all TEAEs were determined.

RESULTS: A total of 1043 participants received at least one dose of trial medication. Over 12 weeks, brexpiprazole 2 or 3 mg/day (the approved therapeutic dosages in the United States, N = 366) compared to placebo (N = 388) had similar time to first TEAE (32 days and 28 days, respectively), similar duration of all TEAEs (6 days and 4 days), and longer time to discontinuation due to adverse events (47 days and 30 days). Over 24 weeks (N = 163), the time to first TEAE on brexpiprazole 2 or 3 mg/day was 52 days, and the duration of all TEAEs was 3 days. Among participants who did not report a TEAE in the 12-week parent trial, TEAEs were rare throughout the 12-week extension trial.

CONCLUSIONS: These exploratory analyses reinforce that brexpiprazole is generally well tolerated over 12 weeks, and also over 24 weeks among patients who tolerated the first 12 weeks of treatment. The results provide a practical clinical insight into the safety of brexpiprazole over time in patients with agitation associated with dementia due to Alzheimer's disease.

TRIAL REGISTRATION: Post hoc analysis of NCT01862640, NCT01922258, NCT03548584, NCT03594123 (ClinicalTrials.gov).}, } @article {pmid41961641, year = {2026}, author = {Yang, L and Zhao, W and Zhao, J and Chen, S and Qin, X and Yang, Z and Kong, D and Zhang, W}, title = {Effects of ononin on cognitive and learning-memory functions in mild cognitive impairment.}, journal = {Neuroreport}, volume = {37}, number = {8}, pages = {308-318}, doi = {10.1097/WNR.0000000000002264}, pmid = {41961641}, issn = {1473-558X}, mesh = {Animals ; *Cognitive Dysfunction/drug therapy/physiopathology/psychology ; Male ; Mice, Transgenic ; Mice ; *Memory/drug effects ; *Cognition/drug effects ; Cognitive Enhancement ; Neurons/drug effects ; Maze Learning/drug effects ; *Learning/drug effects ; Disease Models, Animal ; }, abstract = {OBJECTIVE: This study aimed to investigate the potential of ononin in alleviating mild cognitive impairment (MCI) and to determine whether its effects depend on the functional recovery of neurons in the nucleus tractus solitarius (NTS).

METHODS: Four-month-old APP/PS1 mice were treated with 30-mg/kg ononin via oral gavage for 8 consecutive days. Cognitive behavior was assessed using the novel object recognition test, Y-maze test, and open field test. Cortical perfusion was measured by laser speckle contrast imaging. The activation of NTS neurons was detected using c-Fos immunofluorescence staining, while dendritic complexity and neuronal firing frequency were evaluated via Golgi staining and patch-clamp electrophysiology, respectively.

RESULTS: Ononin treatment significantly improved the novel object recognition index and spontaneous alternation rate in the Y-maze test in APP/PS1 mice. It also enhanced cerebral blood flow perfusion and increased the number of c-Fos-positive cells in the NTS, hippocampal CA1 region, and cortex. Furthermore, ononin increased dendritic intersections and restored dendritic spine density in NTS neurons to normal levels, along with significantly elevating their firing frequency.

CONCLUSION: Ononin may ameliorate MCI-like cognitive deficits in APP/PS1 mice by activating NTS neurons, restoring synaptic plasticity, and improving cerebral perfusion. These findings suggest that the NTS could serve as a potential target for early intervention in Alzheimer's disease.}, } @article {pmid41962111, year = {2026}, author = {Sobiech, L and Wójcik, L and Jankowska, N and Turżańska, K}, title = {Periodontitis as a systemic inflammatory disorder - implications for cardiovascular and neurodegenerative diseases.}, journal = {Wiadomosci lekarskie (Warsaw, Poland : 1960)}, volume = {79}, number = {3}, pages = {646-650}, doi = {10.36740/WLek/218274}, pmid = {41962111}, issn = {0043-5147}, mesh = {Humans ; *Neurodegenerative Diseases/etiology ; *Cardiovascular Diseases/etiology ; *Periodontitis/complications ; *Inflammation/complications ; Oxidative Stress ; }, abstract = {OBJECTIVE: Aim: Periodontitis is a chronic inflammatory condition associated with oral microbiome dysbiosis and the dominance of Gram-negative bacteria such as Porphyromonas gingivalis. It is characterized by progressive destruction of the supporting tissues of the tooth, leading to loss of connective tissue attachment, resorption of the alveolar bone, and, consequently to tooth loosening and loss. If left untreated, it leads to recurrent bacteremia and persistent systemic inflammation. The aim of this study is to discuss the mechanisms linking periodontitis to cardiovascular and neurodegenerative diseases.

PATIENTS AND METHODS: Materials and Methods: A comprehensive literature review was conducted examining clinical studies, systematic reviews, and meta-analyses assessing the impact of periodontal disease on the development of cardiovascular and neurodegenerative diseases.

CONCLUSION: Conclusions: Chronic activation of the immune response, oxidative stress, and lipid metabolism disorders promote endothelial dysfunction and the progression of atherosclerosis, increasing the risk of cardiovascular events. At the same time, systemic inflammation can affect the permeability of the blood-brain barrier and exacerbate neuroinflammatory processes, promoting β-amyloid accumulation and the progression of Alzheimer's disease. Analysis of the literature indicates the significant, albeit complex, nature of these relationships, emphasizing the importance of prevention and treatment of periodontal disease as part of comprehensive patient care. The key in the approach to periodontal patients is an interdisciplinary perspective, integrating dentistry, cardiology, neurology, and geriatrics.}, } @article {pmid41962274, year = {2026}, author = {Dong, Y and Wang, Y and Chen, K and Sun, G and Cao, X and Li, X and Lu, W and Dai, X and Huang, B and Chen, Y}, title = {Engineering versatile nanoplatforms for calcium homeostasis modulation and broad-spectrum disease therapies.}, journal = {Biomaterials}, volume = {333}, number = {}, pages = {124207}, doi = {10.1016/j.biomaterials.2026.124207}, pmid = {41962274}, issn = {1878-5905}, mesh = {Humans ; *Homeostasis ; *Calcium/metabolism ; Animals ; *Nanoparticles/chemistry ; Drug Delivery Systems ; Neoplasms/metabolism ; Calcium Signaling ; }, abstract = {Calcium ions (Ca[2+]) serve as a pivotal intracellular second messenger, participating in core physiological processes including cell proliferation, neurotransmission, and apoptosis. The maintenance of calcium homeostasis depends on the precise interplay of plasma membrane channels and intracellular organelle stores. Dysregulation of calcium signaling is implicated in the pathogenesis of multiple diseases, including Alzheimer's disease, cancer, and cardiovascular disorders. Conventional pharmacological interventions are limited by off-target effects, insufficient bioavailability, and a lack of temporal and spatial control. Ca[2+]-regulated nanoplatform achieves spatiotemporally controlled drug release and responsive calcium level modulation through advanced surface engineering and stimulus-responsive design, substantially improving therapeutic precision and efficacy. Furthermore, nanoprobes permit real-time monitoring of calcium dynamics with high sensitivity and resolution. This comprehensive review systematically summarizes and highlights significant advances in engineering versatile nanoplatforms for calcium homeostasis modulation, focusing on constructed nanocarriers for drug delivery, functional nano-regulators for calcium flux intervention, and sensitive nanoprobes for real-time calcium imaging and quantification. Current challenges and future directions are also discussed to inspire the development of next-generation nanotheranostic platforms for precise diagnosis and treatment of calcium homeostasis-related diseases.}, } @article {pmid41962336, year = {2026}, author = {Kumar, A and Khan, MN and Tiwari, AK and Islam, MM and Judder, MI}, title = {Targeting GPX4 in neurodegenerative disorder: Unlocking ferroptosis as a therapeutic frontier.}, journal = {Tissue & cell}, volume = {101}, number = {}, pages = {103523}, doi = {10.1016/j.tice.2026.103523}, pmid = {41962336}, issn = {1532-3072}, mesh = {*Ferroptosis/drug effects ; Humans ; *Phospholipid Hydroperoxide Glutathione Peroxidase/metabolism ; *Neurodegenerative Diseases/enzymology/pathology/drug therapy/therapy ; Animals ; Iron/metabolism ; Lipid Peroxidation ; Oxidative Stress ; Glutathione/metabolism ; }, abstract = {Ferroptosis is a regulated form of cell death characterized by iron-dependent lipid peroxidation and disruption of cellular redox homeostasis. Among the key regulators of this process, glutathione peroxidase 4 (GPX4) plays a central role in maintaining membrane lipid integrity by reducing phospholipid hydroperoxides using glutathione as a cofactor. Impairment of GPX4 activity leads to the accumulation of toxic lipid peroxides, ultimately triggering ferroptotic cell death. Increasing evidence suggests that dysregulation of GPX4-mediated antioxidant defense contributes to the pathogenesis of several neurodegenerative disorders, including Alzheimer's disease, Parkinson's disease, and other neurodegenerative conditions characterized by oxidative stress and iron imbalance. In recent years, targeting GPX4 and its associated metabolic pathways has emerged as a promising therapeutic strategy for modulating ferroptosis. This review summarizes the molecular mechanisms governing GPX4 regulation, including its interaction with glutathione metabolism, lipid peroxidation pathways, and iron homeostasis. Furthermore, we discuss emerging pharmacological modulators of GPX4 and ferroptosis, highlighting their potential applications in the treatment of neurological diseases. Understanding the regulatory network surrounding GPX4 may provide new insights into ferroptosis-based therapeutic interventions and facilitate the development of targeted strategies for the management of neurodegenerative disorders.}, } @article {pmid41962454, year = {2026}, author = {Fin, S and Moayedikia, A and Wiil, UK}, title = {Dual-model deep learning for Alzheimer's prognostication.}, journal = {Computers in biology and medicine}, volume = {208}, number = {}, pages = {111672}, doi = {10.1016/j.compbiomed.2026.111672}, pmid = {41962454}, issn = {1879-0534}, mesh = {Aged ; Aged, 80 and over ; Female ; Humans ; Male ; Middle Aged ; *Alzheimer Disease/cerebrospinal fluid/diagnosis ; Biomarkers/cerebrospinal fluid ; *Decision Support Techniques ; *Deep Learning ; Follow-Up Studies ; Longitudinal Studies ; *Predictive Learning Models ; Prognosis ; Proportional Hazards Models ; Random Forest ; Time Factors ; United States ; }, abstract = {Disease-modifying therapies for Alzheimer's disease demand precise timing decisions, yet current predictive models require longitudinal clinical observations and provide no uncertainty quantification-rendering them impractical at the critical first-visit encounter when treatment decisions must be made. We developed PROGRESS (PRognostic Generalization from REsting Static Signatures), a dual-model deep learning framework that transforms a single baseline cerebrospinal fluid (CSF) biomarker assessment into actionable prognostic estimates without requiring prior clinical history. The framework addresses two complementary clinical questions: a probabilistic trajectory network predicts individualized cognitive decline parameters with calibrated uncertainty bounds that achieve near-nominal coverage, enabling honest prognostic communication rather than false precision; and a deep survival model estimates time-to-conversion from mild cognitive impairment to dementia. Using data from over 3000 participants across 43 Alzheimer's Disease Research Centers in the National Alzheimer's Coordinating Center database, PROGRESS substantially outperforms existing approaches including Cox proportional hazards, Random Survival Forests, and gradient boosting methods for survival prediction. Risk stratification identifies patient groups with seven-fold differences in conversion rates, enabling clinically meaningful treatment prioritization. Leave-one-center-out validation demonstrates robust generalizability, with survival discrimination remaining strong across all held-out clinical sites despite heterogeneous measurement conditions spanning four decades of assay technologies. By combining superior survival prediction with trustworthy trajectory uncertainty quantification, PROGRESS bridges the gap between biomarker measurement and personalized clinical decision-making-providing the prognostic timeline that current staging approaches cannot offer.}, } @article {pmid41963454, year = {2026}, author = {Malakar, V and Roy, D and Dugar, N and Mali, PC and Malakar, CC and Gautam, M and Poddar, NK}, title = {Computational investigation of biochanin a targeting DEPTOR in Alzheimer's disease with in vitro cellular validation of neuroprotective activity.}, journal = {Scientific reports}, volume = {16}, number = {1}, pages = {}, pmid = {41963454}, issn = {2045-2322}, mesh = {*Genistein/pharmacology/chemistry ; *Alzheimer Disease/drug therapy/metabolism ; *Neuroprotective Agents/pharmacology/chemistry ; Humans ; Molecular Docking Simulation ; Molecular Dynamics Simulation ; }, abstract = {Trifolium pratense (TP) L. contains active phytoconstituents such as biochanin A are known to prevent oxidative stress–induced neuronal death in Alzheimer’s disease (AD). This study explored the molecular mechanism of TP phytoconstituents in AD therapy by network pharmacology and computational modelling. Common targets were analyzed via protein–protein interaction (PPI) in STRING and Cytoscape, followed by Gene Ontology (GO). Based on topological parameters DEPTOR (DEP domain–containing mTOR-interacting protein) was selected as a key target. Subsequently, molecular docking, molecular dynamics (MD) simulations, MM-PBSA free energy calculations, and DFT analyses were performed. It revealed that Biochanin A exhibited the highest MM/PBSA energy (− 150.04 kJ/mol) compared to the standard drug (− 24.01 kJ/mol) and formed stable interactions with key residues (Lys131 and Arg138). Moreover, the currently available therapy targeting the cholinesterase enzyme-related pathways is inadequate, as it displays only symptomatic treatment and fails to address the underlying neurodegenerative molecular mechanisms related to AD. In addition to computational analyses, in vitro validation was performed to confirm the neuroprotective effect of biochanin A. Using the MTT assay, increasing concentrations of Aβ1–42 (0.625–20 µM) were shown to reduce SH-SY5Y cell viability in a dose-dependent manner, with 10 µM Aβ1–42 causing ~ 48% reduction. Pretreatment with biochanin A (6.25–100 µM) significantly improved cell survival, with 100 µM restoring viability to ~ 82% of control levels (P < 0.01), indicating a dose-dependent neuroprotective effect without marked cytotoxicity below 100 µM. Overall, this integrative study reveals that biochanin A may target DEPTOR and stabilize mTOR regulatory interactions, suggesting a promising computationally supported and experimentally validated neuroprotective mechanism for Alzheimer’s disease therapy.}, } @article {pmid41963962, year = {2026}, author = {Li, Y and Wu, H and Yang, J and Weedor, JG and Ding, H and Cui, W and Cui, B and He, Z and Zhang, W and Xing, Y and Zeng, F and Huang, X and Zheng, K and Shen, Y and Yu, Y and Pan, W and Yang, X}, title = {Clostridium butyricum ameliorates Toxoplasma gondii-induced neuropsychiatric disorders by attenuating glial-mediated synaptic pruning via the gut-brain axis.}, journal = {Journal of neuroinflammation}, volume = {23}, number = {1}, pages = {}, pmid = {41963962}, issn = {1742-2094}, support = {Nos. 202310313083Y//the Training Programs of innovation and Entrepreneurship for College Students in Jiangsu Province/ ; Nos. X202510313020//the Training Programs of innovation and Entrepreneurship for College Students in Jiangsu Province/ ; Nos. X202510313017//the Training Programs of innovation and Entrepreneurship for College Students in Jiangsu Province/ ; No. JC20250007//the Faculty Development Grant of Basic Medical Sciences in Xuzhou Medical University/ ; Nos. 82372283//the National Natural Science Foundation of China/ ; No. QL-YB022//the XZHMU-QL Joint Research Fund/ ; No. 2022M710120//China Postdoctoral Science Foundation/ ; }, mesh = {Animals ; *Clostridium butyricum ; Mice ; *Neuroglia/metabolism ; *Neuronal Plasticity/physiology ; Toxoplasma ; *Brain-Gut Axis/physiology ; *Gastrointestinal Microbiome/physiology ; *Toxoplasmosis/psychology ; Mice, Inbred C57BL ; Male ; *Mental Disorders/microbiology ; Humans ; Fecal Microbiota Transplantation/methods ; *Brain ; Dysbiosis/microbiology ; }, abstract = {Gut microbiota dysbiosis contributes to Toxoplasma gondii (T. gondii)-induced neuropsychiatric disorders (TNDs); however, the underlying mechanisms remain largely elusive. Here, we identified the critical role of butyrate-producing bacteria in TNDs in mice. Decreased abundance of butyrate-producing bacteria was consistently observed in patients with Alzheimer’s disease and T. gondii-infected mice. Dietary supplementation with Clostridium butyricum (C. butyricum), a gut commensal butyrate-producing bacterium, reversed gut microbiota dysbiosis, ameliorated intestinal barrier disruption and inflammation, and reduced endotoxemia. Coincidentally, C. butyricum administration suppressed microglial and astrocytic activation, rescued synaptic ultrastructure damage and synaptic loss, thus alleviating cognitive impairment and anxiety/depression-like behaviors. Mechanistically, C. butyricum treatment mitigated the abnormal synaptic pruning mediated by glial cells and C1q to prevent the neuropathology induced by T. gondii infection. Importantly, fecal microbiota transplantation from C. butyricum-supplemented mice into antibiotic-treated recipients recapitulated the therapeutic effects on gut and brain pathology observed in infected mice. Together, our findings suggest that C. butyricum ameliorates TNDs by modulating glial cell-mediated abnormal synaptic pruning via the gut-brain axis, highlighting the therapeutic potential efficacy of butyrate-producing bacteria against TNDs.}, } @article {pmid41963989, year = {2026}, author = {Digma, LA and Young, CB and Winer, JR and Cody, KA and Younes, K and Sheng, J and Insel, PS and Rissman, RA and Sperling, R and Mormino, EC}, title = {Continuum of Core 1 biomarkers in preclinical Alzheimer's disease.}, journal = {Alzheimer's research & therapy}, volume = {18}, number = {1}, pages = {}, pmid = {41963989}, issn = {1758-9193}, support = {K99AG071837/NH/NIH HHS/United States ; U24 AG074855/AG/NIA NIH HHS/United States ; AARFD-21-849349/ALZ/Alzheimer's Association/United States ; }, mesh = {Humans ; *Alzheimer Disease/diagnostic imaging/blood/pathology ; *tau Proteins/blood ; Positron-Emission Tomography ; Biomarkers/blood ; Female ; Male ; Disease Progression ; Aged ; Longitudinal Studies ; Brain/diagnostic imaging/pathology/metabolism ; Atrophy ; Amyloid beta-Peptides/metabolism ; }, abstract = {BACKGROUND: Biological Staging for Alzheimer’s disease (AD) in clinically unimpaired (CU) individuals is critical for early detection efforts. In this study, we evaluated whether Core 1 biomarkers (plasma p-tau217 and amyloid-PET) within Biological Stage A, the earliest biological stage of AD, predict progression of downstream biomarkers and cognition. METHODS: We used baseline plasma p-tau217 and amyloid-PET, and longitudinal tau-PET, atrophy, and cognition data from the recently completed Anti-Amyloid Treatment in Asymptomatic Alzheimer’s (A4) Study. PET data were used to identify participants within AD Biological Stage A (amyloid-PET positive and medial temporal tau-PET negative). Within these Stage A participants, linear mixed effects models were used to examine associations between baseline levels of plasma p-tau217 and amyloid-PET burden with longitudinal regional tau-PET, atrophy, and cognition. We additionally evaluated whether p-tau217 and amyloid-PET burden within this group were associated with higher risk of progression to Biological Stage B+ (tau-PET positive in the medial temporal lobe). In our statistical models, we included covariates for age, sex, and APOE4 carriage. RESULTS: Of 335 A4 participants with complete biomarker data, 222 were identified as being in Biological Stage A. Among Biological Stage A CU, baseline plasma p-tau217 and amyloid-PET burden were associated with faster tau-PET accumulation and atrophy in AD-relevant regions (mean [SD] follow-up time for tau-PET: 4.2 [2.1] years and MRI: 4.2 [1.9] years), as well as faster cognitive decline (mean [SD] follow-up time for PACC: 5.7 [1.6] years) (all p < 0.05). Plasma p-tau217 and amyloid-PET burden were also associated with higher risk of progression to Biological Stage B+. DISCUSSION: In CU individuals in the initial stage of AD (Biological Stage A), early changing AD biomarkers provide prognostic information of downstream markers of disease. Evaluation of the utility of these measures in a real-world setting is warranted. TRIAL REGISTRATION: The A4 study was submitted for registration to clinicaltrials.gov on December 6th, 2013. The study is registered with ID NCT02008357. Screening and data collection for the study began in April 2014.}, } @article {pmid41964075, year = {2026}, author = {Andreozzi, E and Yagi, T and Wildsmith, K and Rawal, S and Horie, K and Boyd, P and Takahashi, E and Barthélemy, NR and Aluri, J and Charil, A and Reilhac, A and Gordon, BA and Flores, S and Verbel, D and Sauter, N and Benzinger, TLS and McDade, E and Mummery, C and , and , and Zhou, J and Bateman, RJ and Reyderman, L}, title = {Etalanetug (E2814) in dominantly inherited Alzheimer's disease: an open-label phase 1b/2 study to assess safety and target engagement in participants with mild to moderate cognitive impairment.}, journal = {Alzheimer's research & therapy}, volume = {18}, number = {1}, pages = {}, pmid = {41964075}, issn = {1758-9193}, mesh = {Humans ; Female ; Male ; *Alzheimer Disease/drug therapy/genetics/diagnostic imaging/cerebrospinal fluid ; tau Proteins/cerebrospinal fluid/metabolism ; Aged ; *Cognitive Dysfunction/drug therapy/diagnostic imaging/cerebrospinal fluid/genetics ; Middle Aged ; Positron-Emission Tomography ; Biomarkers/cerebrospinal fluid ; Brain/diagnostic imaging/drug effects/metabolism ; Treatment Outcome ; Dose-Response Relationship, Drug ; }, abstract = {INTRODUCTION: Etalanetug (E2814) is designed to delay the clinical progression of Alzheimer's disease (AD) by binding to the microtubule binding region (MTBR) of tau implicated in seeding and spreading of tau pathology. Dominantly inherited Alzheimer's disease (DIAD) is a rare form of the disease (< 1%), having similar changes in the tau distribution and pathology to sporadic AD. Herein, we report the safety, pharmacology and biomarker results of the etalanetug Study 103 in DIAD patients.

METHODS: Study 103 enrolled participants with mild-to-moderate cognitive impairment due to DIAD who received etalanetug intravenously every 4 weeks escalating from 750 mg, 1500 mg, 3000 mg, to 4500 mg. After ascending to 4500 mg, patients received 4500 mg for up to 108 weeks. Tau pathology biomarkers, ptau217 and MTBR-tau243 were measured in CSF. Additional assessments included tau PET ([[18]F]MK-6240) and MRI. Pharmacodynamic effects of etalanetug on biomarkers were evaluated. Untreated participants from the DIAN Observational and DIAN-TU studies trial served as natural history controls.

RESULTS: Overall, 8 participants enrolled in Study 103. Etalanetug reduced concentrations of ptau217 30.4% after 12 weeks (n = 7), 48.6% at 36 weeks (n = 5), and 57.9% at 108 weeks (n = 2). Etalanetug treatment reduced concentrations of MTBR-tau243 by 50.6% in DIAD participants (n = 7) after 12 weeks of treatment. Maximal reduction in MTBR-tau243 levels (71.6%) was observed at week 36 (n = 4) and was sustained to 108 weeks (n = 2). In healthy volunteers who lack tau pathology, etalanetug had no effect on MTBR-tau243 or ptau217 after 12 weeks of treatment. Three DIAD patients had tau PET acquired at week 60 and week 108. The data indicate that the tau PET SUVr signal remains stable overall, with a trend towards decrease over time. At 108 weeks, no tau accumulation was observed via tau PET in any of the 3 patients. Three participants experienced treatment-related adverse events (AEs) with the 3000 mg dose; additionally, 5 serious AEs total were reported in 3 participants.

DISCUSSION: Etalanetug treatment in these symptomatic participants with DIAD was tolerated across dose levels, and immunogenicity was found to be minimal. Etalanetug demonstrated effects on both hyperphosphorylated tau and tau tangle pathology. Taken together, the data support continued evaluation of etalanetug as an AD disease-modifying therapy.

TRIAL REGISTRATION: NCT04971733 (registration date: 2021-07-20).}, } @article {pmid41964934, year = {2026}, author = {Ghosh, N and Pathak, S and Bera, R and Sharma, A and Kakkar, D and Kurmi, BD and Srivasatava, P and Ghosh, M and Karwasra, R and Ansori, ANM and Das, S and Sharma, N}, title = {Biomimetic nanocarriers as advanced drug delivery strategies in neurological disorders.}, journal = {Expert opinion on drug delivery}, volume = {}, number = {}, pages = {1-20}, doi = {10.1080/17425247.2026.2659924}, pmid = {41964934}, issn = {1744-7593}, abstract = {INTRODUCTION: Neurological disorders represent a major and growing global health challenge due to complex central nervous system pathology and limited drug penetration across the blood-brain barrier. Conventional therapies are largely symptomatic and often fail to achieve sufficient brain bioavailability or disease modification. Biomimetic nanocarriers have emerged as a promising strategy to improve brain targeting and therapeutic efficacy.

AREAS COVERED: This review discusses recent advances in biomimetic nanocarriers for the treatment and diagnosis of neurological disorders. We summarize the pathological mechanisms underlying central nervous system diseases and discuss how cell membrane-coated nanocarriers derived from red blood cells, platelets, immune cells, stem cells, and cancer cells can enhance BBB penetration, immune evasion, and targeted delivery. A comprehensive literature search was conducted using PubMed, Scopus, Web of Science, and Google Scholar to evaluate therapeutic and diagnostic applications in Alzheimer's disease, Parkinson's disease, multiple sclerosis, autism spectrum disorder, ischemic stroke, and glioblastoma.

EXPERT OPINION: Biomimetic nanocarriers offer a promising strategy to overcome biological barriers and improve central nervous system drug delivery. However, clinical translation remains challenged by membrane source standardization, scalability, and safety concerns. Future research should focus on reproducible manufacturing, regulatory frameworks, and long-term toxicity evaluation to accelerate clinical adoption.}, } @article {pmid41964958, year = {2026}, author = {Fukui, M and Kaise, T and Masaki, T and Sakamoto, T and Kageyama, R}, title = {Activation of neurogenesis improves amyloid-β pathology and cognitive function through AMP kinase signaling in Alzheimer's disease model mice.}, journal = {Cell reports}, volume = {45}, number = {4}, pages = {117250}, doi = {10.1016/j.celrep.2026.117250}, pmid = {41964958}, issn = {2211-1247}, abstract = {Adult hippocampal neurogenesis declines with aging and in neurological disorders, leading to cognitive impairment. We previously showed that inducing Plagl2 and antagonizing Dyrk1a (iPaD) rejuvenates aged neural stem cells (NSCs), enhancing neurogenesis and cognition in aged mice. Here, we found that NSC-specific iPaD treatment activates neurogenesis, reduces amyloid-β deposition, and improves cognition in Alzheimer's disease model mice. Transcriptomic analysis revealed widespread changes in gene expression in the hippocampus after iPaD treatment. The upregulated genes include those associated with astrocyte and microglial activation involved in amyloid-β clearance, while several genes upregulated in Alzheimer's disease are downregulated. Among the latter genes, knockdown of Prkag2 in the hippocampus most effectively enhances neurogenesis and reduces amyloid-β accumulation. Notably, both iPaD treatment and Prkag2 knockdown activate AMP-activated protein kinase signaling, upregulating genes involved in autophagy and cellular homeostasis. These results suggest that Prkag2 may represent a promising therapeutic target for neurodegenerative diseases, including Alzheimer's disease.}, } @article {pmid41965633, year = {2026}, author = {Mansel, CO and Ghisays, V and Mahnken, JD and Swerdlow, RH and Reiman, EM and Karnes, JH and Denny, JC and Veatch, OJ}, title = {Downward bias in the association between APOE and Alzheimer's disease using prevalent and by-proxy disease sampling in the All of Us research program.}, journal = {BMC medical genomics}, volume = {19}, number = {1}, pages = {}, pmid = {41965633}, issn = {1755-8794}, support = {R01 HL156993/HL/NHLBI NIH HHS/United States ; OT2 OD026549/OD/NIH HHS/United States ; P30 AG035982/NH/NIH HHS/United States ; 1OT2OD026549/NH/NIH HHS/United States ; R01 HL158686/HL/NHLBI NIH HHS/United States ; OT2 OD036485/OD/NIH HHS/United States ; P30 AG072973/NH/NIH HHS/United States ; ZIA HG200417/NH/NIH HHS/United States ; }, mesh = {Humans ; *Alzheimer Disease/genetics/epidemiology ; *Apolipoproteins E/genetics ; Female ; Genome-Wide Association Study ; Middle Aged ; Prevalence ; United States/epidemiology ; Genotype ; *Genetic Predisposition to Disease ; Aged ; Bias ; }, abstract = {BACKGROUND: Recent genome-wide association studies for Alzheimer’s Disease and related dementias (ADRD) have increased statistical power via larger analysis datasets from biobanks by (1) including non-age-matched controls and prevalent cases, and/or (2) including individuals who report a family history of ADRD as proxy cases. However, these methods have the potential to increase noise and distort genetic associations which are important for genomic-informed prevention and treatment of ADRD. Here, we sought to understand how the effect sizes of genetic associations in ADRD could be sensitive to these methodological choices, using APOE genotypes as an example. METHODS: Participants in the All of Us Research Program over the age of 49 at enrollment (n = 229,722) were assigned one of four categories: incident ADRD (developed after enrollment in All of Us), prevalent ADRD (present on enrollment), proxy ADRD (participant noted a family history of ADRD), and control (no history or diagnosis of ADRD). ADRD diagnoses were determined using available electronic health records and APOE genotype was determined using whole-genome sequencing. Effect sizes for the associations between APOE risk alleles and ADRD diagnoses were compared using polychotomous logistic regression and presented as adjusted generalized ratios (AGR). RESULTS: The mean age of the cohort was 64 ± 9 years, and it was 57% female; 65% clustered predominantly with European genetic reference populations. Among the participants, 733 (0.3%) had prevalent ADRD, 684 (0.3%) had incident ADRD, and 19,186 (8.4%) reported a family history of ADRD (proxy ADRD). The effect size for APOE ε4 heterozygote was similar for proxy ADRD (AGR [95% CI]: 2.10 [1.96–2.24]) but attenuated for prevalent ADRD (1.38 [1.17–1.63]) compared to incident ADRD (2.13 [1.81–2.50]). For APOE ε4 homozygotes, the effect sizes were significantly attenuated in both proxy (3.53 [2.93–4.26]) and prevalent (3.12 [2.20–4.45]) ADRD. Furthermore, APOE and ADRD association effect sizes increased when restricting the control (no ADRD) group to older age brackets. CONCLUSIONS: Our study highlights how genetic associations with ADRD can be sensitive to how cases are defined in biobanks like All of Us, with effect sizes downwardly biased when using prevalent or by-proxy cases compared to incident cases.}, } @article {pmid41965638, year = {2026}, author = {Khan, AJ and Rahman, I and Beg, HA and Akter, S and Haque, R and Monsur, DT and Rani, H and Dom, TNM}, title = {Association of periodontitis and tooth loss with cognitive decline in the older adults - a systematic review.}, journal = {BMC oral health}, volume = {26}, number = {1}, pages = {}, pmid = {41965638}, issn = {1472-6831}, mesh = {Humans ; *Tooth Loss/complications ; *Periodontitis/complications ; *Cognitive Dysfunction/etiology ; Aged ; }, abstract = {BACKGROUND: The increasing global burden of dementia highlights the importance of identifying factors that may contribute to cognitive decline in later life. Growing evidence suggests that chronic oral conditions, particularly periodontitis (PD) and tooth loss, may be associated with Alzheimer's disease (AD) and related dementias. This study synthesizes current observational evidence on the association between PD, tooth loss, and cognitive impairment (CI) among older adults.

METHODS: A comprehensive literature search was conducted in PubMed, the Cochrane Library, Embase, Scopus, and Google Scholar for English-language studies published between 2010 and 2025. Cross-sectional and longitudinal cohort studies examining associations between PD, tooth loss, and CI were included. Study selection, data extraction, and quality assessment were performed in accordance with PRISMA 2020 guidelines.

RESULTS: Thirteen studies met the inclusion criteria, with sample sizes ranging from 40 participants to over 500,000 individuals in large population-based cohorts. Most studies focused on adults aged ≥ 50 years, particularly those aged 60 years and above. Periodontal status, tooth loss, and cognitive outcomes were assessed using heterogeneous diagnostic methods. Most studies reported significant associations between PD or tooth loss and CI, dementia, or AD. Periodontal treatment appeared protective in several studies, although some associations weakened after adjustment for confounders.

CONCLUSIONS: The findings support PD and tooth loss are consistently associated with adverse cognitive outcomes, although causal relationships cannot be established due to methodological heterogeneity and residual confounding. Integrating oral health care into geriatric and dementia-prevention strategies may help preserve cognitive function and improve quality of life among older adults.}, } @article {pmid41965687, year = {2026}, author = {Hamed, FM and Mady, MS and Elgayed, SH and Mansour, YE and Mahgoub, S and Lai, KH and Lin, CY and Elsayed, HE and Moharram, FA}, title = {Carpoxylon macrospermum leaf extract and its phenolic compounds: a multi-targeted therapeutic remedy for Alzheimer's disease.}, journal = {BMC complementary medicine and therapies}, volume = {26}, number = {1}, pages = {}, pmid = {41965687}, issn = {2662-7671}, support = {MOST 111-2320-B-038-040-MY3, 113-2628-B-038-009-MY3, and 113-2321-B-255-001//National Science and Technology Council of Taiwan/ ; }, mesh = {*Plant Extracts/pharmacology/chemistry ; *Alzheimer Disease/drug therapy ; Plant Leaves/chemistry ; Mice ; Animals ; Humans ; *Phenols/pharmacology/chemistry ; Molecular Docking Simulation ; RAW 264.7 Cells ; Cholinesterase Inhibitors/pharmacology ; *Anti-Inflammatory Agents/pharmacology/chemistry ; }, abstract = {BACKGROUND: Alzheimer’s disease (AD) is a progressive, neurodegenerative disorder with a significant impact, especially on elderly people. Although no current treatment is available for AD, several studies have been conducted to discover alternative remedies capable of managing its symptoms and slowing the progression. Accordingly, herein we analysed the phenolic composition and investigated the defatted aqueous methanol extract (DAE) of Carpoxylon macrospermum H.Wendl. & Drude (Family Arecaceae) leaves against key enzymes in addition to oxidative and inflammatory markers involved in AD progression. METHODS: NMR and mass spectrometry elucidated the phenolic compounds. Human carbonic anhydrase (hCA), human acetyl cholinesterase (AChE), and cyclo-oxygenase 2 (COX-2) inhibitor screening kits were used to assess the enzyme-inhibitory potential. Lipo-poly saccharide (LPS)-induced murine macrophage (RAW 264.7) in vitro model was used to test the anti-inflammatory effect. Molecular docking studies were conducted using AutoDock Vina. RESULTS: Chlorogenic acid (1), rutin (2), hesperidin (3), vanillic acid (4), and p-hydroxybenzoic acid (5) have been isolated. The DAE and compounds 2 and 4 significantly inhibited hCA enzyme with IC50 equivalent to 0.160 ± 0.008, 0.243 ± 0.012, and 0.290 ± 0.015 µg/mL, and AChE enzyme with an IC50 corresponding to 3.732 ± 0.13, 0.868 ± 0.03, and 0.597 ± 0.02 µg/mL, respectively. Additionally, they demonstrated potent anti-inflammatory activity by inhibiting the COX-2 enzyme with IC50 values of 4.602 ± 0.17, 2.806 ± 0.10, and 0.849 ± 0.03 µg/mL, respectively. The DAE, 2 and 4 reduced IL-2 to 3.49 ± 0.12—7.018 ± 0.24 pg/mL; IL-4 to 6.019 ± 0.21–12.07 ± 0.41 pg/mL, and TNF-α to 323.65 ± 11.10–501.88 ± 17.21 pg/mL, respectively. Western blotting revealed a decrease in iNOS protein expression. Rutin showed improved docking scores (-8.92 and -7.92 kcal/mol) with AChE and hCA, while 100 ns Molecular Dynamc Simulations (MDS) showed that rutin maintained stable interactions with the proteins throughout the simulations. CONCLUSION: C. macrospermum extract and its phenolics are promising candidates for AD management, though additional in vivo and clinical studies are needed.}, } @article {pmid41965896, year = {2026}, author = {Wang, J and Chen, L and Wang, Z and Chen, XY and Zhang, S and Ding, D and Zhou, Y and Rager-Aguiar, R and Lin, G and Zhang, H and Boda, VK and Ortyl, TC and Nelson, PT and Bezprozvanny, I and Zhou, FM and Du, J and Wu, Z and Li, W and Liao, FF}, title = {Pyrazole-derived TRPC3 antagonist ameliorates synaptic dysfunctions and memory deficits in Alzheimer's disease models.}, journal = {Molecular psychiatry}, volume = {}, number = {}, pages = {}, pmid = {41965896}, issn = {1476-5578}, abstract = {Transient receptor potential canonical (TRPC) channels are widely expressed in the brain; however, their precise roles in neurodegenerative diseases, such as Alzheimer's disease (AD), remain elusive. We found that TRPC3 expression is upregulated in excitatory neurons of brains with AD. We tested a selective inhibitor (JW-65) for TRPC3 over TRPC6 to investigate the potentially distinct role of TRPC3 in AD. JW-65 treatment significantly restored impaired synaptic plasticity and learning memory in acute and chronic experimental AD models. JW-65 treatment of late symptomatic 5XFAD transgenic mice reversed the impaired LTP, correlating with their significantly corrected synaptic gene expression based on hippocampal RNA-seq data analysis. JW-65 also provided synaptic protection in primary rat hippocampal neurons against soluble β-amyloid oligomers (AβOs), primarily via restoring the AβOs-impaired Ca[2+]/calmodulin-mediated signaling pathways. JW-65 treatment also significantly prevented Ca[2+] overload induced by AβOs. These findings suggest that aberrantly upregulated TRPC3, as a novel non-selective ion channel, significantly contributes to Ca[2+] dyshomeostasis in AD. Our work identifies TRPC3 as a potential therapeutic target for treating or preventing synaptic dysfunction of AD.}, } @article {pmid41966037, year = {2026}, author = {Qudoos, MA and Elliott, DP}, title = {Review of Donanemab and Lecanemab in Mild Dementia Stage of Alzheimer's Disease: Progress and Challenges.}, journal = {The Senior care pharmacist}, volume = {41}, number = {3}, pages = {98-108}, doi = {10.4140/TCP.n.2026.98}, pmid = {41966037}, issn = {2639-9636}, mesh = {Humans ; *Alzheimer Disease/drug therapy ; *Antibodies, Monoclonal/therapeutic use/adverse effects ; Amyloid beta-Peptides/metabolism ; Female ; *Antibodies, Monoclonal, Humanized/therapeutic use/adverse effects ; }, abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder marked by cognitive decline and functional impairment, primarily driven by the accumulation of amyloid-beta (Aβ) plaques and tau tangles. Historically, treatments have focused on symptomatic relief; however, recent therapeutic advances have focused on disease-modifying monoclonal antibodies (mAbs), notably lecanemab and donanemab, which target Aβ pathology in early-stage AD. This review explores the clinical efficacy, safety profile, and limitations of lecanemab and donanemab, emphasizing key findings from the CLARITY-AD and TRAILBLAZER-ALZ 2 trials. In these studies, lecanemab was shown to slow cognitive decline by 27% over 18 months, while donanemab achieved a 28.9% reduction over 76 weeks, with the greatest benefits observed in patients presenting with lower baseline tau pathology.Despite these promising outcomes, challenges remain, including possible reduced efficacy in women based on subgroup analyses of trial data, racial disparities in trial representation, adverse effects such as amyloid-related imaging abnormalities (ARIA), and substantial cost and accessibility barriers. This review underscores the need for more inclusive research, personalized treatment strategies, and continued exploration of AD's complex pathology beyond amyloid clearance.}, } @article {pmid41966346, year = {2026}, author = {Matuszewska, M and Cieślik, M and Sulejczak, D and Wilkaniec, A and Czapski, GA}, title = {BET protein inhibitor JQ1 reduces inflammationand hippocampal amyloid-β level without altering Tau phosphorylation in LPS-challenged adult wild-type mice.}, journal = {Brain research}, volume = {1884}, number = {}, pages = {150318}, doi = {10.1016/j.brainres.2026.150318}, pmid = {41966346}, issn = {1872-6240}, mesh = {Animals ; *Azepines/pharmacology ; *Triazoles/pharmacology ; Lipopolysaccharides/pharmacology ; Male ; *Hippocampus/metabolism/drug effects ; *Amyloid beta-Peptides/metabolism ; Mice ; Mice, Inbred C57BL ; Phosphorylation/drug effects ; *Inflammation/metabolism/drug therapy ; *tau Proteins/metabolism ; Alzheimer Disease/metabolism ; }, abstract = {A growing body of evidence highlights the role of infection and inflammation in the progression of Alzheimer's disease (AD). In this study, we aimed to analyze the impact of JQ1, an inhibitor of bromodomain and extraterminal domain (BET) proteins, which are key readers of the epigenetic acetylation code, on AD-related gene expression changes and biochemical alterations in the hippocampus during a lipopolysaccharide (LPS)-induced systemic inflammatory response in mice. JQ1 and LPS were administered intraperitoneally to adult male wild-type C57BL/6J mice. Changes in selected general and brain-specific parameters were measured for up to 12 h. Our results demonstrated that inhibition of BET proteins reduced LPS-induced sickness behavior and time-dependent elevation of proinflammatory signaling. LPS did not significantly alter amyloid-β (Aβ) levels; however, a significant reduction in Aβ load was observed in JQ1-treated animals overall, suggesting that BET proteins play a crucial role in regulating Aβ levels in the brain. At the same time, JQ1 treatment did not affect LPS-induced increases in phospho-Tau levels. Our results suggest that inhibiting BET proteins, in addition to their anti-inflammatory action, may be an effective strategy for reducing Aβ levels in the brain. However, a mechanistic explanation of this phenomenon requires further investigation.}, } @article {pmid41966670, year = {2026}, author = {Kaur, N and Gupta, S and Bansal, G and Bansal, Y}, title = {BACE-1 inhibitors as potential drug candidates for treatment of Alzheimer's disease: a systematic review.}, journal = {Molecular diversity}, volume = {}, number = {}, pages = {}, pmid = {41966670}, issn = {1573-501X}, abstract = {Over the past two decades, intensive research efforts have focused on the discovery and optimization of BACE-1 inhibitors for Alzheimer’s disease treatment, and the development of potent and selective BACE-1 inhibitors remains a central goal. The current review provides an in-depth and systematic analysis of BACE-1 inhibitors with particular emphasis on the mechanistic role of β-secretase in AD. Both 2D and 3D structural features, size, and physicochemical characteristics of the binding pocket of BACE-1 enzyme have been comprehensively examined. The types of molecular interactions required for the development of high-affinity inhibitors within the active-site were analyzed to accommodate diverse chemical scaffolds. Existing therapeutic approaches targeting BACE-1 include monoclonal antibodies and synthetic small-molecule inhibitors at various clinical trial stages. Numerous studies describing the development of new small-molecule inhibitors have also been reported in the literature. A systematic review based on PRISMA guidelines was conducted on these inhibitors, and SAR patterns along with molecular docking studies have been critically analysed. QSAR and ML approaches reported for BACE-1 inhibition are also compiled to highlight the contribution of integrated approaches for accurate activity prediction. Thus, the review provides insights that may accelerate rational lead optimization for novel BACE-1 inhibitors and can assist medicinal chemists in advancing Alzheimer’s therapeutics.}, } @article {pmid41966729, year = {2026}, author = {Stinson, SE and Shadrin, AA and Rahman, Z and Rødevand, L and Broce, IJ and Selbæk, G and Stefansson, H and Haavik, J and Parker, N and Koch, E and Frei, O and O'Connell, KS and Smeland, OB and Djurovic, S and Dale, AM and van der Meer, D and Andreassen, OA}, title = {Distinct metabolic signatures of Alzheimer's and Parkinson's disease revealed through genetic overlap.}, journal = {EBioMedicine}, volume = {127}, number = {}, pages = {106254}, pmid = {41966729}, issn = {2352-3964}, mesh = {Humans ; *Alzheimer Disease/metabolism/genetics ; *Parkinson Disease/metabolism/genetics ; Genome-Wide Association Study ; *Metabolome ; Genetic Predisposition to Disease ; Polymorphism, Single Nucleotide ; Metabolomics/methods ; Mendelian Randomization Analysis ; Linkage Disequilibrium ; }, abstract = {BACKGROUND: Metabolic dysfunction is a major risk factor for neurodegeneration, yet the genetic architecture linking systemic metabolism to Alzheimer's disease (AD) and Parkinson's disease (PD) remains unclear.

METHODS: We integrated genome-wide association data for 249 circulating metabolites and proglucagon with summary statistics for AD, PD, and cardiometabolic traits. Genetic correlations, polygenic overlap, causal relationships, and shared genetic loci were quantified using linkage disequilibrium score regression, high-definition likelihood, bivariate mixture modelling, Mendelian randomisation, and conjunctional false discovery rate analyses, followed by functional and tissue-specific enrichment analyses.

FINDINGS: AD displayed a metabolic-genetic profile aligned with body mass index, type 2 diabetes, coronary artery disease, and stroke, whereas PD exhibited largely opposing patterns (Spearman's rs = -0.26). Mendelian randomization analyses supported causal effects of lipoprotein subclasses, glutamine, and proglucagon on AD risk, with opposite or null effects in PD. Shared loci between metabolites and AD were enriched for lipid metabolism and cholesterol transport, whereas PD-associated loci were enriched for mitochondrial function, vesicle trafficking, and stress-response signalling.

INTERPRETATION: AD and PD are shaped by fundamentally distinct metabolic-genetic architectures. Metabolically targeted interventions, particularly those modulating lipid, amino acid, and proglucagon pathways, may require disease-specific and genetically informed strategies for prevention and treatment of neurodegenerative diseases.

FUNDING: Novo Nordisk Foundation (NNF23OC0099658), Marie Skłodowska-Curie Actions (801133), the Research Council of Norway (334920, 351751, 296030, 324252, 324499, 326813), the National Institutes of Health (U24DA041123, R01AG076838, U24DA055330, OT2HL161847, 5R01MH124839-02), NordForsk (164218), South-Eastern Norway Regional Health Authority (2020060), and the European Union's Horizon 2020 (847776, 964874, 101057454).}, } @article {pmid41966804, year = {2026}, author = {Tejero, A and Benito-Patón, V and Griñán-Ferré, C and Pallás, M and León-Navarro, D and Martín, M}, title = {Resveratrol induces molecular changes in cholesterol homeostasis in SAMP8 mice cerebellum.}, journal = {Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie}, volume = {198}, number = {}, pages = {119319}, doi = {10.1016/j.biopha.2026.119319}, pmid = {41966804}, issn = {1950-6007}, mesh = {Animals ; *Resveratrol/pharmacology ; *Cholesterol/metabolism ; *Cerebellum/drug effects/metabolism ; *Homeostasis/drug effects ; Mice ; Male ; *Stilbenes/pharmacology ; Aging/metabolism ; Mitochondria/drug effects/metabolism ; Alzheimer Disease/metabolism/drug therapy ; Receptors, LDL/metabolism ; *Neuroprotective Agents/pharmacology ; Disease Models, Animal ; Hydroxymethylglutaryl CoA Reductases/metabolism ; }, abstract = {Resveratrol (Rsv) is a natural polyphenol with neuroprotective properties that modulates several pathways implicated in Alzheimer's disease (AD). Cholesterol homeostasis is disrupted in AD patients, and this imbalance plays a key role in amyloid precursor protein (APP) processing, β-amyloid aggregation and membrane stability. The effect of Rsv on the cerebellum, an emerging structure in cognitive networks and AD pathology due to its high connectivity with other brain regions, remains largely unexplored. This study aims to characterize the effects of Rsv on the cerebellum of SAMP8 mice, an animal model of AD, at different ages (5- and 7-month-old mice) and to investigate how it act as a neuroprotective polyphenol in this structure via modulation of cholesterol metabolism. Aging caused a significant increase in cerebellar membrane free cholesterol levels, which were reversed by Rsv treatment. HMG-CoA reductase levels were significantly reduced by Rsv treatment in 5-month-old mice, suggesting that this polyphenol modulates cholesterol synthesis. Parameters related to cholesterol trafficking were also modulated, with increased LDL receptor levels, but without affecting ApoE. Mitochondrial electron transport chain complexes were also upregulated by Rsv treatment in 5-month-old animals, without affecting mitochondrial dynamics. Collectively, these data demonstrate-for the first time-that Rsv modulates key aspects of cholesterol metabolism and mitochondrial function in the cerebella of SAMP8 mice.}, } @article {pmid41968216, year = {2026}, author = {Zhu, S and Li, Y and Lin, C and Liu, X and Luo, Y and Qian, H and Tang, Z}, title = {Combined with network pharmacology, the therapeutic effect and mechanism of coumarins from Chimonanthus praecox extract in the treatment of Alzheimer's disease were investigated.}, journal = {Naunyn-Schmiedeberg's archives of pharmacology}, volume = {}, number = {}, pages = {}, pmid = {41968216}, issn = {1432-1912}, support = {grant number 82360873//National Natural Science Foundation General Project/ ; No: Qiankeheji-ZK [2022]- General 471//Guizhou Provincial Department of Science and Technology Project/ ; Contract No.: YCXKYB2023017//Construction Task of Graduate Education Innovation Plan Project of Guizhou University of Traditional Chinese Medicine/ ; }, abstract = {The objective of this study is to investigate the therapeutic potential and underlying mechanisms of Chimonanthus praecox-derived coumarins in Alzheimer's disease (AD)-related neuroinflammatory and cognitive impairments. Network pharmacology was employed to identify active components and targets of Chimonanthus praecox-derived coumarins, followed by intersection analysis with AD-related genes. A protein-protein interaction (PPI) network was constructed and subjected to functional enrichment analysis. Molecular docking was performed to validate the binding affinity between key compounds and core targets. An AD-like rat model characterized by aging-related cognitive impairment and neuroinflammation was established using D-galactose and aluminum chloride, and therapeutic effects of coumarin treatment were evaluated via behavioral testing, HE staining, immunohistochemistry, Western blotting, and electroencephalography (EEG). Four active compounds, 58 drug targets, and 19 AD-related intersecting targets were identified, primarily enriched in neuroinflammation-related pathways including NF-κB p65, NLRP3, and Alzheimer's disease-related pathways. Molecular docking showed strong binding of key coumarin derivatives to amyloid precursor protein (APP), apolipoprotein E4 (APOE4), NF-κB p65, and prostaglandin-endoperoxide synthase 2 (PTGS2). In vivo, Chimonanthus praecox-derived coumarin treatment improved aging-associated cognitive deficits, alleviated hippocampal neuronal injury, inhibited APP and APOE4 expression, and significantly downregulated NF-κB p65, PTGS2, IL-6, and NLRP3 levels. EEG analysis further confirmed attenuation of abnormal neural activity. Chimonanthus praecox-derived coumarins exert neuroprotective and anti-inflammatory effects through multi-target modulation, supporting their potential as candidate agents for AD-related neuroinflammatory and cognitive dysfunction.}, } @article {pmid41968555, year = {2026}, author = {Kaur, K and Goel, H and Chawla, PA and Chawla, V}, title = {Trends and Perspectives in the Targeting of Brain Through Ethosomal Formulations.}, journal = {Recent advances in drug delivery and formulation}, volume = {}, number = {}, pages = {}, doi = {10.2174/0126673878418338251203100909}, pmid = {41968555}, issn = {2667-3886}, abstract = {Neurological diseases such as Alzheimer's disease, Schizophrenia, anxiety, Parkinson's disease, and migraine are serious conditions that continue to threaten mankind. The cases of brainrelated disorders are increasing worldwide and are closely related to physiological, genetic, and environmental factors. Direct drug delivery to the brain is crucial for the effective treatment and prevention of these conditions. However, due to the presence of a lipophilic barrier, i.e., the bloodbrain barrier, the entry of therapeutic agents into the brain is restricted, resulting in a lower concentration at the targeted site. As a solution to this problem, the direct nose-to-brain connection is attracting attention for its effective, precise, non-invasive delivery of drugs via the olfactory and trigeminal pathways. However, there are some limitations, like permeability across the nasal mucosa and mucociliary clearance. Therefore, to overcome these restrictions, the use of nanocarriers, particularly ethosomes, is being attempted. This review paper delves into recent research papers and reports on ethosomes developed for intranasal delivery towards the management of neurological conditions. Ethosomes demonstrated an exceptional capacity to facilitate drug accumulation at targeted sites, owing to their ability to bypass first-pass metabolism, their flexible nature, and the presence of penetration enhancers. The high ethanol content in the composition significantly increases the fluidity of the lipid bilayer, allowing for better interaction of this vesicular system with the blood-brain barrier. Furthermore, the functionalization of ethosomes can enhance the specific delivery of drugs, increase patient compliance, and minimize side effects. However, no intranasal ethosomes for direct brain delivery have progressed from preclinical testing to the bedside of patients. They are still in the experimental phase, particularly in animals or in vivo lab models. The possibilities of toxic effects, the use of high amounts of ethanol, and irregular nasal absorption are a few concerns that need to be addressed. The increasing demand for intranasal delivery suggests that ethosomes may play a pivotal role in the management and treatment of brain-related conditions, but this will only occur after a substantial number of clinical trials confirm their safety and efficacy for human consumption. This review explores such possibilities and highlights current trends and future perspectives in targeting the brain with ethosomal formulations.}, } @article {pmid41969035, year = {2026}, author = {Shum, CK and Shea, YF and Au Yeung, TW and Chan, CCY and Chan, WC and Cheng, WK and Cheung, NYF and Cho, DHY and Chow, TK and Fong, GCY and Ip, BYM and Kwok, JSH and Lai, BMH and Lam, LCW and Lee, ATC and Lok, CM and Mok, KY and Ng, DKK and Siu, DYW and Yeung, PY and Tam, SKF}, title = {Consensus statement on the use of Alzheimer's disease biomarkers and anti-amyloid therapies in Hong Kong.}, journal = {Hong Kong medical journal = Xianggang yi xue za zhi}, volume = {32}, number = {2}, pages = {144-154}, doi = {10.12809/hkmj2514198}, pmid = {41969035}, issn = {1024-2708}, mesh = {Humans ; *Alzheimer Disease/diagnosis/drug therapy ; *Biomarkers/cerebrospinal fluid ; Hong Kong ; Neuroimaging/methods ; Amyloid beta-Peptides/cerebrospinal fluid ; Delphi Technique ; }, abstract = {Alzheimer's disease (AD) is the most common aetiology of cognitive impairment worldwide and in Hong Kong. There have been rapid advances in the use of biomarkers for the diagnosis of AD and in the availability of anti-amyloid therapies (AAT) to slow cognitive and functional decline. At present, there is no consensus in Hong Kong regarding the application of AD biomarkers or the use of AAT. A multidisciplinary group of 20 medical specialists from five professional societies discussed issues related to the application of biomarkers for the diagnosis of AD pathology and the use of AAT, and reviewed the evidence in the context of local experience to inform recommendations. A modified Delphi approach was adopted to finalise the recommendations. Consensus was defined as ≥75% agreement on a 9-point Likert scale among panellists. The panel finalised 26 consensus statements addressing the use of AD biomarkers, including neuroimaging and fluid biomarkers, as well as the use of AAT, including inclusion criteria, serial neuroimaging monitoring during treatment, and management of infusion reactions. These recommendations are relevant to the Hong Kong healthcare setting and may serve as guidance for doctors across specialties to facilitate appropriate management of AD.}, } @article {pmid41969962, year = {2026}, author = {İlhan, N and Keskin, E and Şahin, E and Alaylıoğlu, M and Samancı, B and Çamoğlu, T and Yurttaş, Z and Sordu, P and Ildız, S and Ayaz, G and Yediel, BŞ and Azzouz, SS and Bilgiç, B and Hanağası, HA and Gürvit, İH and Ak, DG and Dursun, E}, title = {The mRNA Expression Levels of General Transcription Factors Altered in Alzheimer Cases Possibly Due to Amyloid Beta 1-42 Exposure.}, journal = {Noro psikiyatri arsivi}, volume = {63}, number = {}, pages = {341-349}, pmid = {41969962}, issn = {1300-0667}, abstract = {INTRODUCTION: Given the global gene expression alterations associated with amyloid beta (Aβ), a hallmark of Alzheimer's disease (AD) pathology, this study aimed to investigate its potential role in modulating gene expression through the regulation of specific transcription factors (TFs).

METHODS: Using a combination of protein-protein interaction prediction tools and transcriptional regulatory interaction databases, we identified JUN, FOS, ATF2, ATF4, RELA, NF-κB, SMAD3, STAT1, STAT3, and SP1 as potential candidate TFs that might be involved in Aβ1-42 related pathways. We then conducted in vitro studies to demonstrate a direct effect of Aβ on these TFs and a case-control study to investigate any alterations of selected TFs in human samples. In vitro studies included HEK293 T cells treated with 0.09 µM and 10 µM Aβ1-42. The expression levels of the TFs were assessed by qRT-PCR. The mRNA expression levels of selected target transcription factors that have the highest PPI scores, namely JUN, FOS, and RELA, were also investigated in blood samples from core Alzheimer's disease (AD) cerebrospinal fluid (CSF) biomarker-confirmed AD cases and plasma ALZpath pTau217-confirmed healthy subjects.

RESULTS: In vitro studies indicated that the mRNA expression of most of the TFs was altered due to either the dose of Aβ or the period of treatments. JUN, FOS, NFKB, and SP1 mRNA expression were increased, while STAT1 and ATF2 were decreased within 24 hours of at least one dose of Aβ treatment. At 48 hours of treatment, FOS, STAT1, STAT3, ATF2, and SP1 were higher, whereas RELA, SMAD3, and NFKB were lower in Aβ-treated groups. At 72h of treatments, the ATF4 and NFKB expressions were high, whereas JUN FOS, RELA, STAT1, STAT3, ATF2, and SP1 were low in Aβ treated groups. Human samples showed that the mRNA levels of JUN and RELA were significantly higher in blood samples from AD cases compared to those from healthy individuals.

CONCLUSION: Alterations in the expression levels of TFs in response to Aβ exposure may explain the alterations of the expression levels of genes that these TFs regulate. Given that, understanding the transcriptional effects of Aβ and its regulatory role on TFs may provide a perspective for the physiological roles of Aβ and the molecular pathways underlying AD pathogenesis.}, } @article {pmid41970152, year = {2026}, author = {Lourdel, C and Launay, A and Couteau, A and Bomia, D and Pointereau, S and Bulteau, S and Tessier, F and Thevenet, S and Ahoure, C and Belloeil, V and Robert, G and Taudin, N and Manivel, L and Daucé-Fleuret, L and Richomme, C and Camus, V and Brit, S and Léger, J and Desmidt, T}, title = {The I-Learn Cognition and Behavior program for non-pharmacological treatment of agitation in nursing home residents with neurocognitive disorders: A cluster randomized trial.}, journal = {Alzheimer's & dementia (New York, N. Y.)}, volume = {12}, number = {2}, pages = {e70232}, pmid = {41970152}, issn = {2352-8737}, abstract = {INTRODUCTION: The "I-Learn Cognition and Behavior" program, integrating e-learning and simulation, aims to equip long-term care facility staff with non-pharmacological approaches for managing agitation in residents with neurocognitive disorders. This study evaluated the program's effectiveness.

METHOD: In this multicenter cluster-randomized trial, long-term care facilities served as the randomization units for a population of residents with neurocognitive disorders and agitation who underwent blinded assessments at baseline, 3, 6, and 10 months. Assessments included the Cohen-Mansfield Agitation Inventory (CMAI) as the primary outcome, the Neuropsychiatric Inventory-Nursing Home (NPI-NH), the Quality of Life in Alzheimer's Disease questionnaire, the Maslach Burnout Inventory (MBI), psychotropic use, and hospitalizations. Mixed-effects models analyzed changes in outcomes.

RESULTS: Twelve long-term care facilities were randomized to receive the I-Learn program (intervention) or usual care (control). One hundred sixty-nine residents were enrolled. There were no significant differences in total CMAI score changes between groups. The intervention group demonstrated significant reduced CMAI non-aggressive verbal agitation, MBI depersonalization, and psychotropic medication use (higher withdrawal rates and lower dosage increases) compared to the control group. NPI-NH scores decreased less in the intervention group.

DISCUSSION: The I-Learn program demonstrated potential for improving specific aspects of agitation in residents and well-being in caregivers while significantly reducing psychotropic medication use. "I-Learn Cognition and Behavior" is an easily accessible program with the potential for widespread distribution, contributing to improved well-being and quality of care in long-term care facilities for managing agitation in residents with neurocognitive disorders.}, } @article {pmid41970809, year = {2026}, author = {Kherachi, R and Daoud, I and Melkem, N and Chelihi, A and Al-Shuhaib, MBS and Hamouda, S and Meawad, SB and El-Arabey, AA and Abdalla, M}, title = {In silico investigation of 4-(Trifluoromethyl)benzohydrazide derivatives as potential anti-Alzheimer's agents by targeting acetylcholinesterase and butyrylcholinesterase.}, journal = {In silico pharmacology}, volume = {14}, number = {1}, pages = {111}, pmid = {41970809}, issn = {2193-9616}, abstract = {UNLABELLED: Alzheimer's disease (AD) is a condition that mostly affects individuals in the latter stages of life. Due to the importance of inhibiting acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) in improving cholinergic transmission in the brain, both enzymes were targeted to provide a direct therapeutic approach against AD. In this study, we examined a novel set of derivatives of 4-(Trifluoromethyl)benzohydrazide, which have been identified for their potential to prevent the progression of the aforementioned illness. In this study, various computational techniques, including molecular docking, molecular dynamics (MD) simulations, bioisosteric replacement, and ADMET predictions, were utilized to discover potential inhibitors of AChE and BuChE from a set of twenty-five compound derivatives. The most promising inhibitors for each target, namely 2 s for AChE (- 7.674 kcal/mol) and 2r for BuChE (- 6.144 kcal/mol), along with their isosteres, were identified based on their high docking scores. Furthermore, the stability of these inhibitors was confirmed through MD simulation, and they exhibited favorable drug-likeness properties and safety profiles. Hence, it is essential to do more research to advance their potential as pharmaceutical agents for the treatment of AD.

SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s40203-026-00605-8.}, } @article {pmid41971324, year = {2026}, author = {Wang, B and Deng, F and Liu, Z and Tian, J and Li, Y and Mao, Y and Song, H}, title = {Clinical application of fecal microbiota transplantation and its influencing factors.}, journal = {Frontiers in microbiology}, volume = {17}, number = {}, pages = {1807071}, pmid = {41971324}, issn = {1664-302X}, abstract = {Fecal microbiota transplantation (FMT) is an emerging therapy that has received significant attention in recent years, although its origins can be traced back to 4th-century China. In modern medicine, FMT has been incorporated into clinical guidelines for the treatment of recurrent Clostridioides difficile infection. By re-establishing a healthy gut microbiota and regulating the immune system, FMT has potential therapeutic effects on various diseases, such as gastrointestinal diseases, diabetes, tumors, Alzheimer's disease, and liver disease. However, its efficacy varies based on the type of disease and individual differences. The clinical application of FMT is influenced by multiple factors, including fecal matter processing, administration route, dosage, donor screening, and recipient detection. Currently, FMT faces numerous challenges, including the need to verify the stability and durability of its efficacy, standardize donor screening criteria, and optimize fecal processing and administration. Future research is expected to reveal the mechanisms of action of FMT, optimize treatment protocols, and refine its safety, efficacy, and convenience, thereby bringing hope for patients with complex and challenging diseases.}, } @article {pmid41971579, year = {2026}, author = {Gu, S and Yin, W and Xie, M and He, C and Bian, Y and Li, L and Lu, W and Wang, Q}, title = {Isoquinoline alkaloids in Coptis chinensis to treat Alzheimer's disease through promoting growth of Bifidobacterium breve inhibiting abnormal autophagy using a novel AI high-content intelligent imaging system.}, journal = {Chinese herbal medicines}, volume = {18}, number = {2}, pages = {405-419}, pmid = {41971579}, issn = {2589-3610}, abstract = {OBJECTIVE: Coptis chinensis has been shown to increase beneficial intestinal bacteria and treat Alzheimer's disease (AD). Bifidobacterium breve can effectively treat AD through the gut-brain axis. Therefore, this study aimed to study the joint effects of C. chinensis and B. breve in the treatment of AD.

METHODS: 16S rRNA was used to test the abundance of bacterial flora in APPswe/PS1ΔE9 mice after C. chinensis administration. To determine the efficacy of C. chinensis combined with B. breve on AD, pathological section staining, Barnes maze, Western blotting and ELISA were utilized to confirm the improvement of cognitive dysfunction in AD mice after administration. In order to elucidate the pharmacodynamic components of monomers in C. chinensis, network pharmacology was used to screen the components related to autophagy and confirm the pharmacodynamic effects by artificial intelligence (AI) high-content intelligent imaging.

RESULTS: The results of 16S rRNA sequencing indicated that C. chinensis could modulate the abundance of B. breve in AD mice. Pathological assessments, Barnes maze testing, and additional experiments have shown that C. chinensis combined with B. breve can improve the memory and learning ability of AD mice by reducing neuronal apoptosis and amyloid-β (Aβ) peptide deposition. Network pharmacology combined with AI high-content intelligent imaging technology and Western blotting experiments demonstrated that magnoflorine, 13-methylberberine and palmatrubine in C. chinensis could exert neuroprotective effects in AD mice by up-regulating p62 protein expression while down-regulating Beclin-1 and microtubule-associated protein 1 light chain 3 II (LC3II) protein levels, thereby modulating autophagy-related pathways.

CONCLUSION: C. chinensis can enhance the abundance of beneficial bacteria in the gut and ameliorate cognitive dysfunction in AD mice by interacting with B. breve. Moreover, magnoflorine, 13-methylberberine, and palmatrubine within C. chinensis can also mitigate excessive autophagy and oxidative stress in nerve cells.}, } @article {pmid41972397, year = {2026}, author = {Schurman, CA and Kaur, G and Kaya, S and Bons, J and Aguirre, CG and Liu, Q and King, CD and Wilson, KA and Baker, HL and Hady, M and Luna, NM and Bieri, G and Villeda, SA and Ellerby, LM and Schilling, B and Alliston, T}, title = {Alzheimer's Disease Risk Factor APOE4 Exerts Dimorphic Effects on Female Bone.}, journal = {Advanced science (Weinheim, Baden-Wurttemberg, Germany)}, volume = {13}, number = {28}, pages = {e23511}, pmid = {41972397}, issn = {2198-3844}, support = {R01DE019284-14S1-Alzheimer's/DE/NIDCR NIH HHS/United States ; S10OD028654/AG/NIA NIH HHS/United States ; T32AG000266/AG/NIA NIH HHS/United States ; R01AG067740/AG/NIA NIH HHS/United States ; /NH/NIH HHS/United States ; R01AG077770/AG/NIA NIH HHS/United States ; P30 AR075055/AR/NIAMS NIH HHS/United States ; P01AG066591/AG/NIA NIH HHS/United States ; R01 DE019284/DE/NIDCR NIH HHS/United States ; P30AR075055/AR/NIAMS NIH HHS/United States ; Disease Supplement: R01DE01928-11A1/DE/NIDCR NIH HHS/United States ; }, mesh = {Animals ; Female ; *Alzheimer Disease/genetics/metabolism ; *Apolipoprotein E4/genetics/metabolism ; Mice ; Humans ; Osteocytes/metabolism ; Male ; Risk Factors ; Proteomics ; Disease Models, Animal ; Mice, Transgenic ; Hippocampus/metabolism ; *Bone and Bones/metabolism ; }, abstract = {Individuals with Alzheimer's disease (AD) are at an increased risk of bone fracture, while osteoporosis in women is one of the earliest predictors of AD. Yet the mechanisms linking cognitive decline and skeletal deterioration remain poorly defined. Proteomic analysis of cortical bone from aged 21-month-old mice revealed strong enrichment of neurodegeneration-associated proteins, including apolipoprotein E (Apoe) and amyloid precursor protein. Apoe localized specifically to osteocytes, with expression in aged female bone nearly twice that of young 4-month-old male bone. Because human APOE alleles confer different age-related AD risks, we examined their roles in bone using humanized APOE2, APOE3, and APOE4 knock-in mice and analyzed bone and hippocampus from the same animals. APOE4 produced marked sex-specific effects on the bone transcriptome and proteome compared with APOE2 or APOE3. Strikingly, APOE4-associated proteomic disruptions were stronger in female bone than in the hippocampus. Functionally, APOE4 caused bone fragility in females without altering cortical structure. These deficits stemmed from impaired osteocyte perilacunocanalicular remodeling. Our findings identify APOE4 as a molecular driver of early osteocyte dysfunction and reduced bone quality, disproportionately affecting females. These findings highlight osteocytes as potential targets for early diagnosis of age-related cognitive impairment and treatment for bone fragility, in females.}, } @article {pmid41972598, year = {2026}, author = {Travers-Lesage, V and Since, M and Wang, A and Davis, A and Fayolle, D and Bernay, B and Modeste, F and Nachon, F and Brazzolotto, X and Crouzier, L and Sopkova-De Oliveira Santos, J and Maurice, T and Dallemagne, P and Rochais, C}, title = {Rational Design and Evaluation of Rivastigmine-Based Pleiotropic Prodrugs for the Treatment of Alzheimer's Disease.}, journal = {ACS chemical neuroscience}, volume = {17}, number = {11}, pages = {2170-2189}, doi = {10.1021/acschemneuro.6c00170}, pmid = {41972598}, issn = {1948-7193}, mesh = {*Rivastigmine/pharmacology/chemistry/therapeutic use ; *Prodrugs/pharmacology/chemistry/therapeutic use/chemical synthesis ; *Alzheimer Disease/drug therapy ; Animals ; *Cholinesterase Inhibitors/pharmacology/chemistry/therapeutic use ; Drug Design ; Humans ; Structure-Activity Relationship ; Acetylcholinesterase/metabolism ; Carbamates ; Memantine/pharmacology ; Fluoxetine/pharmacology ; Neuroprotective Agents/pharmacology ; }, abstract = {The multifactorial origin of Alzheimer's disease (AD) is currently being addressed with the development of combination therapy or multitarget directed ligands. If the conventional approach of targeting acetylcholinesterase (AChE) for AD treatment has limitations, it could offer opportunities for a polypharmacological approach by designing covalent pseudoirreversible prodrugs inspired by rivastigmine's mechanism of action. This study focuses on introducing aminated drugs to the rivastigmine carbamate moiety, namely, fluoxetine and memantine, which have shown synergy with cholinesterase inhibition. These innovative carbamates target sustained drug release through covalent pseudoirreversible cholinesterase inhibition, strategically balancing inhibitory potency, selectivity, mechanism, and reactivation kinetics. This comprehensive approach demonstrates the potential of targeting ChE via a covalent mechanism and provides valuable insights into the structure-activity relationships of these derivatives. Interestingly, this study provides a useful biochemical toolbox for characterizing pseudoirreversible cholinesterase carbamate-type inhibitors. The most promising compound was evaluated in in cellulo and in vivo AD models, highlighting the potential of polypharmacological interventions as innovative and multifaceted anti-AD drugs.}, } @article {pmid41972916, year = {2026}, author = {Li, Y and Wang, G and Xiong, C and Shan, G and Cao, Y and Llibre-Guerra, J and Hassenstab, J and McDade, E and Bateman, RJ}, title = {Statistical models for Alzheimer's disease clinical trials: Lessons learned from the DIAN-TU Platform Trial.}, journal = {Journal of Alzheimer's disease : JAD}, volume = {111}, number = {3}, pages = {1192-1199}, doi = {10.1177/13872877261441645}, pmid = {41972916}, issn = {1875-8908}, support = {R01 AG053267/AG/NIA NIH HHS/United States ; R01 AG068319/AG/NIA NIH HHS/United States ; R56 AG053267/AG/NIA NIH HHS/United States ; U01 AG059798/AG/NIA NIH HHS/United States ; 1R21AG08405401/NH/NIH HHS/United States ; U01 AG042791/AG/NIA NIH HHS/United States ; R01 AG046179/AG/NIA NIH HHS/United States ; }, mesh = {*Alzheimer Disease/drug therapy ; Humans ; *Models, Statistical ; Disease Progression ; *Clinical Trials as Topic ; Proportional Hazards Models ; Double-Blind Method ; }, abstract = {BackgroundAlzheimer's disease (AD) clinical trials often involve uneven follow-up durations and long-term open-label extensions (OLE), yet conventional statistical models are typically designed for fixed schedules, limiting their efficiency in such settings.ObjectiveTo describe and illustrate alternative statistical modeling approaches developed and implemented in the Dominantly Inherited Alzheimer Network Trials Unit platform trial to optimally leverage data with irregular and extended follow-up.MethodsWe present three complementary models: (1) a Cox proportional hazards model for recurrent disease progression events that uses all observed worsening events rather than only the first event; (2) a parametric disease progression model based on estimated years from expected symptom onset that estimates proportional slowing or time delay in disease progression; and (3) piecewise linear mixed-effects models tailored to the "gap" period between the double-blind phase and OLE, accommodating variable off-treatment intervals and missing interim data. All methods are illustrated with hypothetical examples, and ready-to-use SAS code is provided in the Supplemental Material.ResultsThe proposed models successfully handle complex longitudinal data structures typical trials with OLE phases, offering greater statistical efficiency and more comprehensive capture of treatment effects over extended periods compared with traditional approaches.ConclusionsThese flexible, efficient statistical models are well-suited for rare disease and long-duration AD trials. Wider adoption and further validation of these approaches may enhance the power and interpretability of future neurodegenerative disease trials.}, } @article {pmid41972921, year = {2026}, author = {Harrington, EE and Bock, JE}, title = {Honor culture and cognitive aging: Honor endorsement and deficits in memory aging and Alzheimer's disease knowledge.}, journal = {Journal of Alzheimer's disease : JAD}, volume = {111}, number = {3}, pages = {1278-1290}, doi = {10.1177/13872877261441602}, pmid = {41972921}, issn = {1875-8908}, mesh = {Humans ; *Alzheimer Disease/psychology ; Male ; Female ; Aged ; *Memory Disorders/psychology ; *Cognitive Aging/psychology ; *Health Knowledge, Attitudes, Practice ; United States ; Aged, 80 and over ; Middle Aged ; *Culture ; Adult ; *Aging/psychology ; }, abstract = {BackgroundIdentifying deficits in the public's memory aging knowledge is a promising avenue for improving our understanding of Alzheimer's disease (AD) risk and developing effective education and intervention strategies. Yet, it is important to contextualize knowledge within culturally relevant frameworks that may not only contribute to the extent of individuals' knowledge, but also to the reception of developed educational and intervention programs.ObjectiveOne prominent culture within the United States (U.S.) that has largely been neglected within AD research is the culture of honor, or those that prioritize the defense and maintenance of reputation.MethodsUsing an online sample, the present study examined 998 U.S. adults' endorsement of honor culture norms and knowledge of normal and pathological memory aging knowledge, as well as AD specific knowledge. Hierarchical linear regression analyses (controlling for age, sex, race/ethnicity, educational attainment, and dementia experience) examined associations between honor endorsement and each type of memory aging knowledge.ResultsGreater honor endorsement was associated with worse knowledge of normal memory aging, pathological memory aging, and AD. Exploratory analyses that examined links to domains of AD knowledge revealed that greater honor endorsement was specifically linked with worse knowledge related to AD risk factors, symptoms, treatment and management, life impact, and caregiving.ConclusionsThe present research advances our understanding of deficits in the public's memory aging knowledge within the context of U.S. honor cultures and highlights a need for the developmental of culturally relevant education and intervention efforts.}, } @article {pmid41973126, year = {2026}, author = {Shinde, P and Sathiyanarayanan, A and Lohidasan, S}, title = {Exploration of potential neuroprotective agents from medicinal plants for the treatment of Alzheimer's disease-approach through in silico ADMET, network pharmacology, docking, and dynamics studies.}, journal = {Journal of molecular modeling}, volume = {32}, number = {5}, pages = {}, pmid = {41973126}, issn = {0948-5023}, mesh = {*Neuroprotective Agents/chemistry/pharmacology/pharmacokinetics/therapeutic use ; *Molecular Docking Simulation ; *Alzheimer Disease/drug therapy/metabolism ; *Molecular Dynamics Simulation ; Humans ; *Plants, Medicinal/chemistry ; Network Pharmacology ; *Phytochemicals/chemistry/pharmacology ; }, abstract = {CONTEXT: A degenerative brain disorder that causes memory loss is Alzheimer's disease (AD). Phytoconstituents represent a promising therapeutic strategy due to their diverse bioactivities and favourable safety profiles. This study aimed to identify potential neuroprotective phytoconstituents for AD by pharmacokinetic screening, network pharmacology, molecular docking and molecular dynamics simulation. Among 22 phytoconstituents analysed, the network revealed GSK3β, STAT3, MAOB, ESR1, and PTGS2 as key AD-associated targets. Docking results were supported by dynamic stability analysis. The combined computational results support rosmariquinone as a potential neuroprotective lead compound for AD treatment.

METHODS: Pharmacokinetic and toxicity profiling of 22 phytoconstituents was performed using Swiss ADME and ProTox III software. Target prediction and construction of the phytoconstituent-disease target-gene interaction network were conducted using Swiss Target Prediction, Gene Card and Cytoscape. Pathway enrichment was evaluated via KEGG and GO analysis. Molecular docking of all shortlisted phytoconstituents against AD-related targets was carried out using AutoDock Vina, while 500 ns molecular dynamics simulations were performed using the Desmond module of the Schrödinger Suite to assess complex stability, RMSD, RMSF and hydrogen-bond fluctuation.}, } @article {pmid41973520, year = {2026}, author = {Franco Rocha, OY and Janelsins, MC and Magnuson, A}, title = {Decision-making and treatment planning for older adults with pre-existing cognitive impairment and cancer.}, journal = {Current opinion in supportive and palliative care}, volume = {20}, number = {2}, pages = {106-111}, doi = {10.1097/SPC.0000000000000804}, pmid = {41973520}, issn = {1751-4266}, mesh = {Humans ; *Neoplasms/therapy/psychology ; *Decision Making ; Aged ; *Cognitive Dysfunction/epidemiology ; Geriatric Assessment/methods ; Caregivers/psychology ; *Patient Care Planning/organization & administration ; Communication ; }, abstract = {PURPOSE OF REVIEW: The review aims to synthesize the current evidence on decision-making and cancer treatment planning for older adults with pre-existing cognitive impairment, Alzheimer's disease, and other related dementias.

RECENT FINDINGS: Current decision-making practices are not standardized, and evidence suggests that oncology physicians conduct burden-benefit analyses to guide treatment planning. There was a consensus on the importance of involving caregivers into the decision-making process. However, caregivers experience feelings of anxiety, uncertainty, and extra burden when deciding between treatment options and providing care. Nursing home staffs were frequently excluded from the decision-making process and were perceived as unprepared to identify and manage cancer symptoms. The planning and provision of care for this population can be guided by a comprehensive geriatric assessment (CGA). CGA can inform the decision-making process based on the patient's functionality and caregiver's resources, facilitate management of cancer care, guide the identification and management of cancer symptoms, and assist communication with patients and their caregivers.

SUMMARY: Decision-making and treatment planning for older adults with cancer and pre-existing cognitive impairment lacks standardization. CGA offers a standardized approach to guide treatment decisions, manage symptoms, and coordinate care by highlighting the needs and resources of patients and caregivers.}, } @article {pmid41974642, year = {2026}, author = {Xing, L and Liu, A and Gao, W and Li, J and Yao, M and Song, J and Duan, P and Li, H}, title = {Beyond the neuron: Exosomes as intercellular modulators of mitochondrial networks in the pathogenesis and treatment of Alzheimer's disease.}, journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association}, volume = {22}, number = {4}, pages = {e71330}, pmid = {41974642}, issn = {1552-5279}, support = {82105035//National Natural Science Foundation of China/ ; LH2023H064//Nature Science Foundation of Heilongjiang Province/ ; ZHY2024-304//Research Project of the Traditional Chinese Medicine Administration of Heilongjiang Province/ ; }, mesh = {Humans ; *Exosomes/metabolism ; *Alzheimer Disease/metabolism/therapy/pathology ; *Mitochondria/metabolism ; Animals ; *Neurons/metabolism ; }, abstract = {Alzheimer's disease (AD) is a devastating neurodegenerative disorder characterized by β-amyloid deposition, hyperphosphorylated tau protein, and progressive neuronal loss. Mitochondria form a dynamic interconnected network within the central nervous system, and their dysfunction plays a central role in AD, involving oxidative stress, kinetic dysregulation, and impaired mitochondrial autophagy. As key mediators of intercellular communication, exosomes carry bioactive components that regulate mitochondrial function in recipient cells. This review summarizes advances in research on exosomes as coordinators of the mitochondrial network in the central nervous system, regulating mitochondrial quality control across different neuronal cell types. It systematically outlines the molecular mechanisms by which exosomes modulate mitochondrial function in AD through regulating mitochondrial biogenesis, fusion-fission dynamics, mitochondrial autophagy, and related signaling pathways. Furthermore, it explores the potential of engineered exosome-based targeted therapies for AD intervention, aiming to provide a theoretical foundation and research direction for developing novel therapeutic strategies targeting mitochondrial dysfunction.}, } @article {pmid41975292, year = {2026}, author = {Esmaeili, H and Mahdavi-Fikjvar, E and Poureshaghi, F and Moridi Farimani, M and Sonboli, A and Dastres, E and Behboudi, H and Mirjalili, MH}, title = {Variation in phytochemical profiles and anti-cholinesterase activity across wild Iranian populations of Leucojum aestivum L.: a conservation perspective.}, journal = {BMC plant biology}, volume = {26}, number = {1}, pages = {}, pmid = {41975292}, issn = {1471-2229}, mesh = {*Cholinesterase Inhibitors/pharmacology/chemistry/analysis ; Iran ; *Amaryllidaceae/chemistry ; Galantamine/analysis/pharmacology ; Antioxidants ; *Phytochemicals/analysis ; Phenols/analysis ; Flavonoids/analysis ; Amaryllidaceae Alkaloids/chemistry ; Phenanthridines/analysis ; Plant Extracts/chemistry/pharmacology ; Acetylcholinesterase/metabolism ; }, abstract = {BACKGROUND: Leucojum aestivum L. (Amaryllidaceae) is a perennial bulbous species of high pharmaceutical importance, primarily recognized as a natural source of the alkaloid galantamine for Alzheimer’s disease treatment. Iranian L. aestivum populations (LAPs) may contain unique alkaloids with strong acetylcholinesterase (AChE) inhibitory effects, making them a conservation priority. To investigate phytochemical diversity and bioactivity, eight natural populations including LAP1 (Chahar Deh, Astaneh Ashrafieh); LAP2 (Baz Kia Gurab, Lahijan); LAP3 (Sangar); LAP4 (Chomesghal, Ziabar); LAP5 (Pinchah, Astaneh Ashrafieh); LAP6 (Chaboksar); LAP7 (Valiseh, Rudsar); and LAP8 (Vali Abad, Tonkabon) were sampled during the flowering stage. Galantamine, lycorine, total phenolic content (TPC), total flavonoid content (TFC), antioxidant capacity (FRAP and DPPH), and AChE inhibitory activity were quantified in bulbs and leaves. RESULTS: The highest AChE inhibition was recorded in bulbs of LAP6 (IC50: 95.57 µg/ml) and LAP7 (IC50: 102.38 µg/ml), corresponding to elevated galantamine levels (20.31 and 24.92 mg/g dry extract, respectively), which showed a strong positive correlation (r = 0.880, p < 0.01). In contrast, LAP8 contained no detectable galantamine in bulbs but exhibited exceptionally high leaf lycorine content (107.91 mg galanthamine equivalent/g dry extract) and antioxidant capacity (FRAP: 90.71 µmol Fe[2+]/g DW; DPPH, IC50: 95.10 µg/ml), alongside moderate AChE inhibition (IC50: 150.80 µg/ml in bulbs, 231.63 µg/ml in leaves). Leaf TPC (8.57–13.39 mg GAE/g DW) consistently exceeded bulb TPC (0.18–7.59 mg GAE/g DW). Cluster analysis grouped populations into three distinct classes: balanced alkaloid levels and antioxidant power (LAP1, LAP5, LAP6), lower alkaloid levels (LAP2, LAP3, LAP4), and high phenolic content and antioxidant power with relatively elevated alkaloid levels (LAP7, LAP8). CONCLUSIONS: These findings demonstrated a strong linkage between alkaloid composition and bioactivity, highlighting the pharmaceutical potential of specific chemotypes and emphasizing the necessity of in situ conservation and ex situ cultivation for sustainable utilization and drug development targeting cholinesterase inhibition and antioxidant activity.}, } @article {pmid41975524, year = {2026}, author = {More, SA and Mundke, RN and Agrawal, YO and Awathale, SN and Goyal, SN and Nakhate, KT and Rathod, SS}, title = {Intracerebroventricular streptozotocin-induced animal model of Alzheimer's disease: revealing dose optimization, administration regimen, and molecular pathways.}, journal = {Laboratory animal research}, volume = {42}, number = {1}, pages = {}, pmid = {41975524}, issn = {1738-6055}, abstract = {Streptozotocin (STZ) is a commonly administered chemical via the intracerebroventricular (ICV) route in rodents to induce Alzheimer’s disease (AD)-like symptoms. Unfortunately, available research articles from different laboratories suggest inconsistency in doses, administration schedules, and target brain regions. For instance, ICV dose varies from 1.5 to 5 mg/kg either unilaterally or bilaterally, for 7 days to 21 days, as a single or multiple injections. Therefore, it is challenging for novice investigators to select the optimal doses, treatment durations, and targeted molecular pathways while employing STZ to induce AD-like conditions in experimental animals. In this background, the information related to the STZ-induced animal model of AD should be available on a single platform to aid researchers in selecting the suitable doses and regimens that suit their research objectives. The literature search was carried out by employing search engines such as PubMed and Google Scholar with keywords such as streptozotocin, intracerebroventricular, dosage optimization, Alzheimer’s disease, neuroinflammation, and oxidative stress. The present review highlights the articles published up to May 2025, with predefined inclusion (ICV-STZ model, cognitive/biochemical outcomes) and exclusion criteria (non-peer-reviewed papers, studies lacking behavioral or molecular endpoints, and studies older than 20 years). We have attempted to present the optimal dose, administration regimen, and biological process for inducing ICV-STZ AD models based on their advantages and limitations. According to the comparative quantitative evaluation of preclinical investigations, bilateral ICV administration of STZ at a cumulative dose of 3 mg/kg (1.5 mg/kg on days 1 and 3) displays the most reliable and physiologically relevant regimen. Studies also demonstrated that between 14 and 21 days after injection, this regimen reliably causes oxidative stress, neuroinflammation, cholinergic dysfunction, and progressive cognitive impairments, offering a balanced picture of physiological, histological, and behavioral alterations. However, unlike transgenic models, the ICV-STZ paradigm generally fails to develop extensive amyloid-beta plaque deposition or well-formed neurofibrillary tangles. Hence, more quantitative investigations are necessary to validate this optimization.}, } @article {pmid41975594, year = {2026}, author = {Xu, L and Cheng, G and Hu, F and Duan, T and Han, M and Meng, H and Sun, Y and Zeng, D and Zheng, W and Yang, X and Wang, X and Tan, W and Zeng, Y}, title = {Molecular subtypes of the Alzheimer's disease spectrum: Multimodal biomarker integration, mechanistic validation, and adaptive clinical translation.}, journal = {Neural regeneration research}, volume = {}, number = {}, pages = {}, doi = {10.4103/NRR.NRR-D-25-00911}, pmid = {41975594}, issn = {1673-5374}, abstract = {Alzheimer's disease exhibits considerable heterogeneity in its clinical progression, neuropathological features, and underlying etiological mechanisms. However, current clinical diagnosis and treatment primarily rely on positron emission tomography and evidence-based cerebrospinal fluid biomarkers, with less emphasis on molecular subtypes, thereby limiting meaningful subtype stratification and personalized therapeutic interventions. Given advances in large-scale multi-omics technologies, single-cell genomics, and molecular imaging, research on the molecular subtypes of Alzheimer's disease is gradually increasing. In this review, we evaluate the growing body of studies on molecular subtypes of Alzheimer's disease through a comparative analysis of multimodal biomarkers, including cerebrospinal fluid proteomic profiles, single-nucleus transcriptomic architectures, neuroimaging endophenotypes, and adaptive clinical translation. We also analyze phenotypic variations across the Alzheimer's disease continuum to bridge molecular discoveries with clinical manifestations. Findings include proteomics-driven investigations that have identified five distinct cerebrospinal fluid proteomic subtypes. These subtypes are associated with divergent genetic backgrounds, survival rates, and cortical atrophy patterns, and are mechanistically linked to aberrant neuronal hyperproliferation, dysregulated innate immune activation, abnormalities in RNA splicing and processing, choroid plexus dysfunction, and blood-brain barrier impairment. Parallel progress in single-cell technologies, such as single-nucleus RNA sequencing, single-cell ATAC sequencing, and single-cell RNA sequencing applied to postmortem brain tissues, has enabled precise mapping of pathological cellular states across various brain regions. These approaches have revealed that molecular alterations in Alzheimer's disease exhibit high cell-type specificity and have uncovered novel disease-associated vascular-glial-neuronal co-expression modules, as well as vasculature-specific mechanisms correlated with APOE4 genetic risk. Tau- positron emission tomography neuroimaging studies have delineated four distinct spatiotemporal trajectories of tau accumulation, including temporo-lateral, occipital, hippocampal-sparing, and limbic subtypes, each associated with unique clinical phenotypes. From a genetic perspective, large-scale genome-wide association studies have identified approximately 75 risk loci implicated in Alzheimer's disease pathogenesis, including 42 previously unreported genomic regions, highlighting biological processes such as microglial activation, lipid metabolism, and synaptic function. Multi-omics analyses have further defined three hierarchical subtypes of Alzheimer's disease, which are primarily distinguished by dysregulation in either metabolic pathways, astroglial activation, or vascular and leptomeningeal function. Despite these advances in delineating heterogeneity, the field continues to face significant challenges. Key among these are the lack of cross-cohort reproducibility, standardized subtyping criteria, and evidence-based clinical validation.}, } @article {pmid41975601, year = {2026}, author = {Wei, L and Ren, H and Lin, Y and Sun, J and Nie, S and Gao, X and Huang, Y}, title = {Cultivation and transplantation of engineered stem cells: A new strategy for promoting repair of central nervous system injury.}, journal = {Neural regeneration research}, volume = {}, number = {}, pages = {}, doi = {10.4103/NRR.NRR-D-25-01121}, pmid = {41975601}, issn = {1673-5374}, abstract = {Due to the complex pathological microenvironment of nerve injury, the ability for self-repair is extremely limited, posing a major challenge for clinical treatment. Stem cell therapy has brought hope for nerve regeneration; however, natural stem cells have limitations such as low survival rates, poor directional differentiation efficiency, and insufficient secretion of neurotrophic factors. In recent years, the development of engineered stem cells through gene editing, biomaterial co-culture, or pretreatment has emerged as a promising new strategy. This review systematically describes the current application status of engineered stem cells in the repair of nerve injury. It summarizes the pathological mechanisms of nerve injury and the biological processes of endogenous neurogenesis and regeneration, providing a theoretical basis for engineering interventions. It details the engineering strategies used, including engineering methods, cell sources, cell processing technologies, cell delivery vehicles, and cell function regulation. Additionally, it discusses the multiple mechanisms of engineered stem cells, highlighting that their therapeutic effect is not solely dependent on differentiation into neurons or glial cells for replacement. Instead, their therapeutic effects primarily arise from the strong paracrine effects of engineered stem cells: they secrete neurotrophic factors to support the survival of host neurons, regulate the immune microenvironment, release exosomes to deliver repair-related miRNA or proteins, and promote angiogenesis and axon myelination, thereby facilitating the reconstruction of neural circuits. This review provides insights into the application of engineered stem cells in preclinical research, highlighting significant functional improvements in various neurological disease models such as spinal cord injury, stroke, Alzheimer's disease, and Parkinson's disease. Finally, this paper discusses the key challenges facing the clinical translation of this technology, including the risks of tumorigenicity, the long-term survival and safety of transplanted cells, the need for standardized preparation processes, and ethical and regulatory considerations. In summary, engineered stem cells demonstrate therapeutic potential beyond that of natural stem cells through synergistic multi-mechanism effects, providing more precise and efficient strategies for nerve injury repair. This review not only outlines the technological systems and theoretical advancements in this field but also establishes an important academic foundation for promoting the transition from basic research to clinical application. It systematically summarizes the mechanisms and applications of engineered stem cells in neural repair, emphasizing their potential and existing bottlenecks in translational medicine, thus providing a theoretical basis and directional guidance for future research.}, } @article {pmid41975605, year = {2026}, author = {Luo, L and Yan, T and Liu, W and Gao, Y and Tang, X and Yang, L and Zhao, M}, title = {Homoplantaginin regulates various pharmacological pathways: Candidate drugs for multi-target relief of cognitive decline and pathological changes in Alzheimer's disease.}, journal = {Neural regeneration research}, volume = {}, number = {}, pages = {}, doi = {10.4103/NRR.NRR-D-25-00660}, pmid = {41975605}, issn = {1673-5374}, abstract = {Alzheimer's disease is an age-associated neurodegenerative disorder with a complex pathogenesis. As a result, multi-target drug strategies have emerged in the development of anti- Alzheimer's disease medications. Natural compounds exhibit various pharmacological effects and low toxicity, making them beneficial for multifaceted intervention. Considering that NOD-like receptor protein 3 inflammasome-mediated inflammation is crucial for the treatment of Alzheimer's disease, we identified natural NOD-like receptor protein 3 inhibitors using molecular docking and a lipopolysaccharide/adenosine triphosphate-induced J774A.1 cell inflammation model. We found that homoplantaginin stably bound to NOD-like receptor protein 3, and surface plasmon resonance experiments further demonstrated that its binding affinity was 86.30 μM. Moreover, homoplantaginin effectively inhibited inflammation mediated by NOD-like receptor protein 3 inflammasome activation in J774A.1 cells by reducing the levels of interleukin-1β, interleukin-18, mature interleukin-1β (p17), and active caspase-1 (p20). Additionally, homoplantaginin treatment inhibited apoptosis and oxidative damage in L-glutamate-induced PC12 cells, as well as in aluminum chloride and D-galactose-induced Alzheimer's disease mice. The effects of homoplantaginin on Alzheimer's disease-like behavioral impairments were evaluated using the open field test, Y-maze, and Morris water maze. Results showed that there was no effect on control mice after administration of homoplantaginin once daily for 30 consecutive days, while locomotor and cognitive impairments in Alzheimer's disease mice were significantly alleviated, exhibiting superior efficacy compared with the positive drug donepezil. Importantly, consistent with the observations in J774A.1 cells, homoplantaginin inhibited the activation of the NOD-like receptor protein 3 inflammasome in the serum and brain tissues of Alzheimer's disease mice. NOD-like receptor protein 3 knockout hindered the improvement effect of homoplantaginin on cognitive deficits in Alzheimer's disease zebrafish induced by AlCl3 and D-gal, indicating that homoplantaginin enhances cognitive function by inhibiting activation of NOD-like receptor protein 3. Furthermore, homoplantaginin treatment reduced amyloid-beta deposition, oxidative stress, and apoptosis in Alzheimer's disease mice. Notably, aging is a major risk factor for Alzheimer's disease, and homoplantaginin prevented cellular senescence by regulating related biomarker levels in Alzheimer's disease mice. These results demonstrate that homoplantaginin may serve as a promising multifunctional candidate for the treatment of Alzheimer's disease.}, } @article {pmid41975609, year = {2026}, author = {Cao, K and Xie, J and Liang, X and Li, Y and Gong, H and Luo, H}, title = {Dendritic mesoporous silica nanoparticle-based nasal delivery carriers for passive immunotherapy of Alzheimer's disease.}, journal = {Neural regeneration research}, volume = {}, number = {}, pages = {}, doi = {10.4103/NRR.NRR-D-25-00917}, pmid = {41975609}, issn = {1673-5374}, abstract = {Hyperphosphorylation of tau is a key pathological hallmark of Alzheimer's disease and is closely associated with cognitive impairment. Passive immunotherapy targeting hyperphosphorylated tau is a promising approach to inhibit tau pathology. However, the blood-brain barrier restricts antibodies from reaching the central nervous system and exerting their therapeutic effects. Here, we developed an intranasal biomacromolecule delivery strategy for the treatment of Alzheimer's disease using dendritic mesoporous silica nanoparticles modified with hyaluronic acid as a drug carrier. Ten-month-old C57BL/6J mice, htau mice, and 5×FAD mice were intranasally administered 100 μg of hyaluronic acid-dendritic mesoporous silica nanoparticles@4B1 (antibody dose), and brain tissues were collected to evaluate antibody delivery efficiency. Using this delivery system, the anti-p-tau396,404 antibody 4B1 was efficiently delivered to the brains of 5×FAD mice, with an enrichment of 7.31% ± 0.18% ID/g. Entry of the 4B1 antibody into the brain ameliorated tauopathy in Alzheimer's disease model mice, reduced neuronal loss and neuroinflammation caused by tau pathology, and reversed cognitive dysfunction. These findings suggest that the nasal delivery strategy based on hyaluronic acid-responsive release is an effective method for delivering antibody biomacromolecules to the central nervous system, showing high efficiency of antibody entry into brain tissue and intracellular delivery. Our findings also demonstrate the role of p-tau396,404 in passive immunotherapy for Alzheimer's disease, suggesting that immunotherapy targeting p-tau396,404 is a promising strategy for ameliorating Alzheimer's disease pathology, inhibiting the aggregation of hyperphosphorylated tau, and alleviating neurological damage and cognitive dysfunction.}, } @article {pmid41975618, year = {2026}, author = {Chen, S and Li, J and Zhou, J and Xie, W and Li, H and Yang, L and Chen, G and Long, C}, title = {NeuroD1 gene therapy converts reactive astrocytes to functional new neurons in a mouse model of Alzheimer's disease.}, journal = {Neural regeneration research}, volume = {}, number = {}, pages = {}, doi = {10.4103/NRR.NRR-D-25-00721}, pmid = {41975618}, issn = {1673-5374}, abstract = {Alzheimer's disease is characterized by the presence of amyloid-beta plaques, neurofibrillary tangles, and chronic neuroinflammation. Effective therapies capable of restoring neuronal loss, a key pathological feature of Alzheimer's disease are lacking. Our previous studies have demonstrated that overexpression of neuronal differentiation 1 (NeuroD1) in astrocytes can convert astrocytes into neurons in Alzheimer's disease models and this astrocyte-to-neuron conversion technology can rescue pathological features in models of stroke and epilepsy. This study investigated whether NeuroD1-mediated in vivo reprogramming of reactive astrocytes into functional neurons could rescue neurodegeneration and cognitive decline in amyloid precursor protein/presenilin 1 transgenic Alzheimer's disease model mice. Using retro-orbital delivery of AAV-PHP.eB-GFAP-NeuroD1-GFP, we achieved broad astrocyte-to-neuron conversion throughout the brain of 7-month-old Alzheimer's disease mice. Three months post-treatment, immunostaining revealed significant neuronal regeneration in the cortex and hippocampus, accompanied by a marked reduction in neuroinflammatory markers. The converted neurons exhibited mature electrophysiological properties, including action potentials and synaptic activity, which correlated with increased neuronal density in the hippocampus. Morris water maze test demonstrated that NeuroD1-treated mice exhibited restored spatial learning and memory compared with control animals. These findings demonstrate that NeuroD1-driven neuroregeneration via gene therapy not only replenishes neuronal populations but also reduces key pathological features related to Alzheimer's disease, including neuroinflammation and amyloid plaque burden, ultimately reducing cognitive impairment. Our findings highlight in vivo astrocyte-to-neuron reprogramming through systemic astrocyte-to-neuron delivery as a promising and transformative strategy for treating Alzheimer's disease and related neurodegenerative disorders.}, } @article {pmid41977320, year = {2026}, author = {Toledano-Pinedo, M and Porro-Pérez, A and Schäker-Hübner, L and Diez-Iriepa, D and Iriepa, I and Siwek, A and Wolak, M and Satała, G and Bojarski, AJ and Doroz-Płonka, A and Handzlik, J and Godyń, J and Dallemagne, P and Rochais, C and Davis, A and Since, M and Pérez, B and Bellver-Sanchis, A and Irisarri, A and Pallàs, M and Solana-Manrique, C and López-Muñoz, F and Ismaili, L and Griñán-Ferré, C and Paricio, N and K Hansen, F and Więckowska, A and Marco-Contelles, J}, title = {Polyfunctionalized N-Arylsulfonyl Indoles: Identification of (E)-N-Hydroxy-3-{3-[(5-(3-(piperidin-1-yl)propoxy]-1H-indol-1-yl)sulfonyl]phenyl} acrylamide (MTP150) for the Epigenetic-Based Therapy of Parkinson's Disease.}, journal = {International journal of molecular sciences}, volume = {27}, number = {7}, pages = {}, pmid = {41977320}, issn = {1422-0067}, support = {PID2019-105813RB-C21//AEI (Government of Spain/ ; }, mesh = {Animals ; *Parkinson Disease/drug therapy/genetics/metabolism ; *Indoles/pharmacology/chemistry/therapeutic use ; Humans ; *Neuroprotective Agents/pharmacology/chemistry ; *Epigenesis, Genetic/drug effects ; Caenorhabditis elegans/drug effects/genetics ; Oxidative Stress/drug effects ; Disease Models, Animal ; *Acrylamides/pharmacology/chemistry ; }, abstract = {Herein, we have identified the polyfunctionalized 1-(phenylsulfonyl)-1H-indole-2-carboxylic acid derivative MTP150 for the treatment of neurodegenerative diseases owing to its efficacy in reducing protein aggregation, modulating matrix metalloproteinase activity, mitigating neuroinflammation, and enhancing DNA damage repair pathways across in vivo Caenorhabditis elegans models of Alzheimer's disease, Parkinson's disease (PD), and Huntington's disease. Further experiments in an in vivo Drosophila model of PD showed that MTP150 increased motor performance, reduced oxidative stress levels, and restored mitochondrial function in model flies. In addition, MTP150 exhibited neuroprotective effects in PD model cells, thereby supporting its therapeutic potential for this disease.}, } @article {pmid41977439, year = {2026}, author = {Bougea, A}, title = {Targeting Non-Coding RNAs as a Potential Therapeutic and Delivery Strategy Against Neurodegenerative Diseases.}, journal = {International journal of molecular sciences}, volume = {27}, number = {7}, pages = {}, pmid = {41977439}, issn = {1422-0067}, mesh = {Humans ; *Neurodegenerative Diseases/genetics/therapy ; Animals ; MicroRNAs/genetics ; *RNA, Untranslated/genetics ; Exosomes/metabolism/genetics ; CRISPR-Cas Systems ; RNA, Long Noncoding/genetics ; }, abstract = {Neurodegenerative diseases (NDs), including Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis (ALS), represent a growing global health challenge characterized by progressive neuronal loss and a lack of definitive disease-modifying treatments. This review explores the emerging potential of targeting non-coding RNAs (ncRNAs), such as microRNAs (miRNAs), long non-coding RNAs (lncRNAs), and exosomal RNAs, to modulate pathogenic molecular pathways and address the underlying molecular origins of neurodegeneration. We evaluate the integration of advanced computational techniques for RNA structure prediction and gene regulatory network analysis, alongside chemical engineering strategies-such as Locked Nucleic Acids (LNAs) and phosphorothioate modifications-aimed at enhancing the stability and specificity of RNA-based molecules. Furthermore, we analyze cutting-edge delivery and editing technologies, including nanotechnology-driven solutions for precise neuronal targeting and the CRISPR/Cas13 system for direct ncRNA manipulation.The findings indicate that while challenges in delivery efficiency and long-term efficacy persist, the synergy of chemical engineering and computational modeling significantly improves the therapeutic profile of ncRNAs, with exosomal pathways offering a novel route for intercellular signaling modulation and biomarker discovery. Therapeutic interventions directed at specific clinical targets, such as miR-34a and BACE1-AS, demonstrate the capacity to influence protein aggregation and neuroinflammatory cascades. Although ncRNA-based therapies are currently in nascent stages, ongoing technological advancements in RNA editing and nanotechnology offer a transformative framework that could redefine the future of ND treatment and successfully halt disease progression rather than merely managing symptoms.}, } @article {pmid41977460, year = {2026}, author = {Taboada-Jara, T and Ribalta, M and Romero-Becerra, F and Muixí, J and Bellver-Sanchis, A and Griñán-Ferré, C and Escolano, C and Pallàs, M}, title = {Usefulness of C. elegans Models of Alzheimer's and Huntington's Disease to Evaluate Novel Imidazoline I2 Receptor Ligands.}, journal = {International journal of molecular sciences}, volume = {27}, number = {7}, pages = {}, pmid = {41977460}, issn = {1422-0067}, support = {PDC2022-133441-I00//Ministerio de Ciencia, Innovación y Universidades/ ; 2021 SGR 00357//Agència de Gestió d'Ajuts Universitaris i de Recerca/ ; PID2022-138079OB-I00//Ministerio de Ciencia, Innovación y Universidades/ ; N° 19/2015//Ministerio de Economía y Finanzas and Programa Nacional de Becas "Don Carlos Antonio López"/ ; //Càtedra UB Dr. Antoni Esteve i Subirana de Recerca en Farmacologia/ ; }, mesh = {Animals ; *Caenorhabditis elegans/metabolism/genetics ; *Huntington Disease/drug therapy/metabolism/genetics ; *Imidazoline Receptors/metabolism ; *Alzheimer Disease/drug therapy/metabolism/genetics ; Disease Models, Animal ; Ligands ; Oxidative Stress/drug effects ; Humans ; Amyloid beta-Peptides/metabolism/genetics ; *Neuroprotective Agents/pharmacology ; Animals, Genetically Modified ; Caenorhabditis elegans Proteins/metabolism/genetics ; }, abstract = {Neurodegenerative diseases such as Alzheimer's (AD) and Huntington's (HD) remain major therapeutic challenges due to limited treatment efficacy. Imidazoline I2 receptor (I2-IR) ligands have recently emerged as promising neuroprotective agents, with reported roles in modulating oxidative stress, neuroinflammation, and protein aggregation. This study evaluates the therapeutic potential of several I2-IR ligands, including Idazoxan, CR4056, and novel compounds, using Caenorhabditis elegans (C. elegans) models of AD and HD. Transgenic strains CL2006 (expressing human Aβ1-42) and EAK103 (expressing Ht513) were employed to assess locomotor activity, oxidative stress tolerance, Aβ and Ht aggregation, and sod-1 gene expression. Several ligands significantly improved movement, reduced Aβ and Ht aggregates, and enhanced antioxidant gene expression, particularly Idazoxan, LSL42, and PIP01. Notably, some compounds exhibited prooxidant effects, highlighting the utility of C. elegans for early in vivo toxicity screening. Importantly, this study provides the first in vivo evidence of the efficacy of I2-IR ligands in HD models and reinforces their potential as therapeutic candidates for HD. Overall, these findings suggest a potential role for modulation of I2-IR-related pathways in neurodegeneration and support the utility of C. elegans as a rapid, cost-effective platform for preclinical drug evaluation.}, } @article {pmid41977473, year = {2026}, author = {Bivona, G and Ghersi, G}, title = {Microglia-Astrocyte Cooperation and Peripheral T Cells in Alzheimer's Disease: State-of-the-Art and Treatment Perspectives.}, journal = {International journal of molecular sciences}, volume = {27}, number = {7}, pages = {}, pmid = {41977473}, issn = {1422-0067}, mesh = {Humans ; *Alzheimer Disease/immunology/pathology/therapy/metabolism ; *Microglia/metabolism/immunology/pathology ; Animals ; *Astrocytes/metabolism/immunology/pathology ; *T-Lymphocytes/immunology/metabolism ; Amyloid beta-Peptides/metabolism ; Brain/pathology/immunology ; }, abstract = {Alzheimer's disease (AD) is a neurodegenerative disorder first described more than one century ago. Over this time, many features of the disease have been discovered and, consequently, many different approaches in the diagnosis and treatment of AD have been developed. A major assumption has guided research on AD in the past: this fatal form of cognitive decline is believed to have a pathogenic basis in the deposition of amyloid beta (Aβ) aggregates throughout the brain. Consequently, a main goal of AD therapy is to reduce Aβ load, and several monoclonal antibodies targeting amyloid are among the most recent approaches to AD treatment. However, the effectiveness of these drugs is limited, as they cannot block the progression of the disease; they only slow it down in certain conditions. Many other causative factors are known to promote the development of the disease, with immune system involvement being the most investigated. Indeed, it has been well documented that the microglial response enhances the deposition of other altered proteins, such as Tau, and induces a neurotoxic microenvironment that promotes neuronal loss. In this scenario, the interaction between microglia and astrocytes is known to accelerate pathogenic processes, and a possible role for peripheral T lymphocytes in AD pathology has also been described. An interesting hypothesis is that immune cells driving chronic inflammation might worsen AD progression and, therefore, could represent a target for treatment strategies in this disease. Thus, this review article aims to summarise the role of brain and peripheral immune molecules and cells in AD. Also, immune-based treatments for AD are described, including those targeting microglia and T cells.}, } @article {pmid41980328, year = {2026}, author = {Uti, DE and Alum, EU and Okpe, JM and Egbung, JE and Mbah, JO}, title = {Blood-brain barrier modulation for targeted central nervous system drug delivery in neurodegenerative and demyelinating disorders.}, journal = {Tissue & cell}, volume = {101}, number = {}, pages = {103524}, doi = {10.1016/j.tice.2026.103524}, pmid = {41980328}, issn = {1532-3072}, mesh = {Humans ; *Blood-Brain Barrier/metabolism/pathology/drug effects ; *Drug Delivery Systems/methods ; *Neurodegenerative Diseases/drug therapy/pathology ; Animals ; *Demyelinating Diseases/drug therapy/pathology ; *Central Nervous System/pathology/drug effects ; }, abstract = {The blood-brain barrier (BBB) plays an indispensable role in central nervous system homeostasis but it has remained a key barrier to successful treatment of neurodegenerative and demyelinating diseases. This review discusses the basis for BBB structural and functional regulation and critically discusses emerging strategies to improve therapeutic delivery in neurodegenerative diseases (Alzheimer's disease, Parkinson's disease, and multiple sclerosis). Across pharmacological, nanotechnological, physical and genetic platforms, comes a common thread of ideas; rational and temporally-controlled BBB modulation is the uniting theme that underlies effective and safe brain-targeted therapy. Approaches such as receptor-mediated transcytosis, ligand-engineered nanocartiers, focused ultrasound with microbubbles, osmotic disruption, and electroporation or molecular or viral engineering have expanded the therapeutic landscape, but potential translational application relies upon reversibility, spatial selection, and preservation of neurovascular integrity. The discipline is shifting past proof-of-concept research to clinically-incrementally actionable paradigms anchored on pharmacokinetic accuracy, biomarker-directed goal involvement, and safety strict examination. The growing body of evidence has implied that bio-modulation of the BBB can augment the delivery of neuroprotective, anti-amyloid, anti-a-synuclein, and remyelinating therapeutic treatment with minimal systemic exposure and off-target damage. Together, BBB modulation is transitioning to become an experimental strategy of delivery, but with great clinical potential as a precision therapeutic strategy.}, } @article {pmid41980337, year = {2026}, author = {Pattanaik, SK and Mohanty, D and Ray, A and Jena, S and Pattanaik, S and Rath, D}, title = {Phytotherapy for ageing-related multimorbidity: Systems-level insights into Centella asiatica in diabetes and Alzheimer's Disease.}, journal = {Phytomedicine : international journal of phytotherapy and phytopharmacology}, volume = {155}, number = {}, pages = {158026}, doi = {10.1016/j.phymed.2026.158026}, pmid = {41980337}, issn = {1618-095X}, mesh = {Humans ; *Alzheimer Disease/drug therapy ; *Centella/chemistry ; *Aging/drug effects ; *Phytotherapy ; *Diabetes Mellitus/drug therapy ; *Triterpenes/pharmacology ; Animals ; Plant Extracts/pharmacology ; Hypoglycemic Agents/pharmacology ; Neuroprotective Agents/pharmacology ; Signal Transduction/drug effects ; }, abstract = {BACKGROUND: The increasing burden of age-related illnesses underscores the urgent necessity for integrative treatment approaches that simultaneously address the complex connections between metabolic and neurodegenerative disorders. Diabetes mellitus (DM) and Alzheimer's disease (AD) are strongly interconnected through shared pathological mechanisms. Plant-based therapeutics with their rich diversity of multitarget bioactive compounds are able to compromise such a complex network. Centella asiatica (l.) Urb. (C. asiatica), A medicinal herb, it has garnered significant attention for its metabolic and neuroprotective activities in ethnopharmacology, as well as preclinical and clinical studies.

PURPOSE: In this study, we employ a computational approach to elucidate the key bioactive constituents of C. asiatica and their ability to modulate shared pathological mechanisms linking DM and AD. Provide a scientific rationale for its use as a multitarget phyto-therapeutic candidate against ageing-associated comorbidities.

METHODS: Relevant keywords were used to search databases Scopus, Science Direct, PubMed, Google Scholar and WOS. To gather the scientific evidence of its phytoconstituents, anti-diabetic activity and anti-Alzheimer's activity. Further, a network pharmacology-based approach was adopted.

RESULTS: From the identified phytoconstituents, fifty-four have favourable oral bioavailability, targeting 486 proteins. Venn interaction revealed 404 genes are cross-linked among C. asiatica, DM, and AD. Network pharmacology and enrichment analysis suggested that the PI3K-Akt signalling pathway is the key regulatory axis.

CONCLUSION: C. asiatica demonstrates potential as a multi-target phyto-therapeutic agent for managing interconnected ageing disorders, i.e., DM and AD, through modulation of the PI3K-Akt signalling pathway.}, } @article {pmid41980560, year = {2026}, author = {Hoffmann, D and Ahola, V and Huber, N and Natunen, T and Leskelä, S and Takalo, M and Martiskainen, H and Ballweg, S and Vorontsov, E and Selzer, S and Kallio, P and Pike, I and Sirviö, J and Haapasalo, A and Hiltunen, M}, title = {Lithium chloride alters Tau phosphorylation, kinase activity, and Rho GTPase signaling in cell models.}, journal = {Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie}, volume = {198}, number = {}, pages = {119347}, doi = {10.1016/j.biopha.2026.119347}, pmid = {41980560}, issn = {1950-6007}, mesh = {*Lithium Chloride/pharmacology ; *tau Proteins/metabolism ; Phosphorylation/drug effects ; Humans ; Animals ; *Signal Transduction/drug effects ; Mice ; *rho GTP-Binding Proteins/metabolism ; Glycogen Synthase Kinase 3 beta/metabolism ; Neurons/drug effects/metabolism ; Coculture Techniques ; Cell Line, Tumor ; }, abstract = {Hyperphosphorylation and intracellular aggregation of Tau are pathological hallmarks of several neurodegenerative diseases, including Alzheimer's disease (AD). Clinical trials involving protein kinase inhibitors to modulate Tau phosphorylation in AD patients have shown mixed outcomes. For clinical trials using lithium salts, this could be explained by sequestration of lithium by β-amyloid and might be circumvented by selection of lithium salts with low affinity to Aβ fibrils and oligomers, promoting improved therapeutic efficacy and positive outcomes in future clinical trials. Here, we assessed the effects of lithium chloride (LiCl), a potent inhibitor of the serine/threonine kinase GSK-3β, on Tau phosphorylation and kinase activity using two cell models: the U2OS cell line overexpressing human triple mutant Tau-tGFP and a mouse cortical neuron/BV-2 co-culture model with inflammation-induced Tau hyperphosphorylation. We show that in the co-culture model, induction of inflammation led to increased Tau phosphorylation at the assessed phosphosites. LiCl reduced Tau phosphorylation depending on the concentration and the targeted phosphosites. Proteomics data from the U2OS cell line showed that LiCl treatment led to decreased phosphorylation at most of the examined phosphosites, which was consistent with the biochemical data. Our data suggest that LiCl may affect other kinases beyond GSK-3β. Additionally, we observed changes in the phosphorylation status of several proteins belonging to different Rho GTPase cycles, known to play a role in AD pathogenesis. Taken together, our data expand the understanding of the effects of LiCl on Tau phosphosites, kinases, and other AD-relevant pathways, such as Rho GTPases.}, } @article {pmid41980692, year = {2026}, author = {Aslam, S and Tulain, UR and Zahid, F and Ali, Z and Erum, A and Alamri, AH and Al Fatease, A and Amin, M and Wan, G and Din, FU}, title = {Brain-targeted mucoadhesive in situ gel incorporating quercetin-PEG conjugate and rivastigmine-loaded chitosan nanoparticles for Alzheimer's therapy.}, journal = {International journal of biological macromolecules}, volume = {361}, number = {}, pages = {151998}, doi = {10.1016/j.ijbiomac.2026.151998}, pmid = {41980692}, issn = {1879-0003}, mesh = {*Rivastigmine/chemistry/pharmacokinetics/pharmacology/administration & dosage ; *Chitosan/chemistry ; *Quercetin/chemistry/pharmacokinetics ; *Polyethylene Glycols/chemistry ; *Nanoparticles/chemistry ; Animals ; *Alzheimer Disease/drug therapy/metabolism ; *Brain/metabolism/drug effects ; *Drug Carriers/chemistry ; Particle Size ; Gels/chemistry ; Rats ; Drug Liberation ; Adhesiveness ; }, abstract = {Alzheimer's dementia (AD) is a progressive neurodegenerative impairment driven by a pronounced cholinergic deficit. Quercetin (QUE) and rivastigmine (RVS) have been used in the treatment of AD, however, clinical translation of QUE and RVS is limited by poor solubility, and short half-life, respectively. To overcome these limitations, QUE was PEG-conjugated (Q-PEG) and co-encapsulated with RVS in chitosan nanoparticles (CNPs) and further incorporated in mucoadhesive in situ gel for nose-to-brain delivery. Q-PEG conjugation was confirmed by Fourier transform infrared spectroscopy (FTIR) and Proton nuclear magnetic resonance ([1]HNMR). The RVS-Q-PEG-CNPsG was optimized through systematic formulation development. The optimized formulation exhibited a mean particle size (134.7 ± 0.35 nm), narrow size distribution (0.213 ± 0.01), optimal zeta potential (+21.5 ± 0.45 mV) and suitable entrapment efficiency of QUE (92.3 ± 0.50%) and RVS (81.5 ± 0.81%). Structural characterization using Transmission electron microscopy (TEM), FTIR, X-Ray diffraction (XRD), and Differential scanning calorimetry (DSC) confirmed spherical morphology, components compatibility, amorphous nature and thermal stability, respectively. Moreover, the poloxamer based in situ gel demonstrated homogeneity, optimal viscosity and robust mucoadhesive strength, thereby markedly enhancing drug retention of CNPs at the administration site. Moreover, it depicted a sustained drug release profile in vitro, and enhanced nasal permeation, ex vivo. Additionally, histopathological evaluation validated the safety and mucosal compatibility of the formulation. Furthermore, pharmacokinetic studies demonstrated significantly enhanced brain bioavailability of RVS-Q-PEG-CNPsG (5.6 ∼ fold and 12.6 ∼ fold) compared to intranasal free RVS and QUE. These findings suggested that intranasally administered RVS-Q-PEG-CNPsG provides effective brain delivery, which may be a promising approach for the treatment of AD.}, } @article {pmid41981183, year = {2026}, author = {Belhaj, I and Åmellem, I and Tartanoglu, CH and Weidemann, HM and Vallenari, EM and Yang, M and Chaudhry, FA and Bjørås, M and Storm-Mathisen, J and Bergersen, LH}, title = {Lactate treatment improves brain biochemistry and cognitive function in transgenic Alzheimer's and wild-type mice.}, journal = {Scientific reports}, volume = {16}, number = {1}, pages = {}, pmid = {41981183}, issn = {2045-2322}, mesh = {Animals ; *Alzheimer Disease/drug therapy/metabolism/genetics ; Mice, Transgenic ; *Lactic Acid/pharmacology/administration & dosage ; *Brain/metabolism/drug effects ; Mice ; Female ; *Cognition/drug effects ; Male ; Disease Models, Animal ; Proteomics ; }, abstract = {Lactate, a well-known metabolite and signalling molecule, holds therapeutic potential for neurodegenerative diseases. Here, we investigated the effects of chronic lactate treatment on cognition and molecular biomarkers in the 5XFAD mouse model of Alzheimer’s disease (AD) and in wild-type (WT) controls using behavioural testing alongside proteomic and transcriptomic analyses. Mice received lactate or vehicle injections 4 days per week for 11 weeks, with behavioural testing before and after the treatment period. Lactate improved working memory in late-treated AD mice, without eliciting anxiety-like behaviour. At the molecular level, lactate reduced Il1b expression, and in a sex-dependent manner, normalised NEFL, and enhanced synaptic integrity proteins (OPCML, PPFIA2, STXBP3, SYT1, VGLUT2, VSNL1) in AD mice, while also augmenting mitochondrial regulators (ATP5G2, GRPEL1, SLC25A23) across genotypes. Notably, lactate upregulated low-abundance ionotropic glutamate receptor mRNAs (Grik3, Grin2c, Grid2ip) in female AD mice, indicating enhanced glutamatergic signalling. In WT mice, lactate increased expression of neurotrophic factors (Bdnf, Igf1, Vegfa), anti-inflammatory cytokines (Il4 and Il13), and the neuronal lactate transporter Mct2, suggesting promoted neuronal resilience. Together, these findings indicate that lactate treatment can mitigate cognitive decline and enhance molecular pathways of resilience in AD, warranting larger, age-stratified studies to validate its therapeutic potential and elucidate underlying mechanisms.}, } @article {pmid41981211, year = {2026}, author = {Zhu, TT and Liu, PM and Hashimoto, K and Yang, JJ}, title = {Clinical innovations and future directions of nanoparticles in the treatment of psychiatric and neurological disorders.}, journal = {Molecular psychiatry}, volume = {}, number = {}, pages = {}, pmid = {41981211}, issn = {1476-5578}, support = {82171189//National Natural Science Foundation of China (National Science Foundation of China)/ ; 81971020//National Natural Science Foundation of China (National Science Foundation of China)/ ; }, abstract = {Nanoparticles (NPs) provide a versatile toolkit for psychiatry and neurology by leveraging tunable size, surface chemistry, and payload control to overcome long-standing barriers in central nervous system (CNS) therapy. Lipid, polymeric, inorganic, and hybrid NPs can be engineered to traverse the blood-brain barrier (BBB) via receptor/transporter pathways, target specific cell types, and deliver sustained or stimuli-responsive release. Beyond drug delivery, NPs improve imaging, enable gene/RNA therapeutics, and support anti-inflammatory and neuroprotective strategies, advancing precision medicine. Preclinical studies in depression, schizophrenia, Alzheimer's disease, and Parkinson's disease show superior exposure, target engagement, and behavioral or cognitive benefits versus free drugs, including photothermal/photodynamic and nanobody-based approaches. Clinically, translation remains early: a handful of CNS-directed candidates (e.g., gold-based bioenergetic agents, intranasal lipid formulations, liposomal modulators) are in trials, while approvals largely lie outside CNS indications. Key hurdles include variable BBB integrity, immunogenicity and protein-corona effects, manufacturing and stability constraints, and limited effect-site exposure-response data in humans. This review outlines a translational playbook: model-informed development linking formulation to brain interstitial exposure; Quality-by-Design chemistry, manufacturing, and controls (CMC); stratified, adaptive trials with population PK/PD and harmonized biomarkers; and proactive safety monitoring with long-term registries. We also highlight NP strategies targeting the gut-brain axis-delivering probiotics, metabolites, or antimicrobials-as complementary routes to modulate neuroinflammation and circuit function. With rigorous clinical science, manufacturing quality, and safety governance embedded from the outset, nanotechnology is positioned to deliver safer, more effective, and potentially disease-modifying therapies for CNS disorders.}, } @article {pmid41981256, year = {2026}, author = {Shao, B and Zeng, Y and Ju, J}, title = {Dynamic collaboration between mitochondria and organelles: mechanisms, functions, and disease implications.}, journal = {Apoptosis : an international journal on programmed cell death}, volume = {31}, number = {4}, pages = {}, pmid = {41981256}, issn = {1573-675X}, support = {32572715//The National Natural Science Foundation of China/ ; }, mesh = {Humans ; *Mitochondria/metabolism/pathology ; Animals ; Neurodegenerative Diseases/metabolism/pathology ; Mitochondria Associated Membranes ; *Neoplasms/metabolism/pathology ; *Organelles/metabolism ; Oxidative Stress ; Alzheimer Disease/metabolism/pathology ; Cardiovascular Diseases/metabolism/pathology ; Metabolic Syndrome/metabolism/pathology ; }, abstract = {In recent years, numerous studies have revealed that dysregulation of mitochondria-organelle interactions is a common feature underlying various pathological processes and pathogen infections. For instance, in Alzheimer's disease (AD), dysfunction of mitochondrial-associated ER membranes (MAMs) leads to calcium overload and oxidative stress, while cancer cells enhance glycolysis by remodeling mitochondria-Golgi interactions. Targeting these key interacting nodes has shown significant therapeutic potential. Although technological advances have uncovered some underlying mechanisms, the spatiotemporal dynamics, tissue specificity, and causal role of organelle interactions in diseases remain unclear. In-depth understanding of these collaborative networks will provide new targets for the treatment of cancer, metabolic syndrome, and neurodegenerative diseases, and also create novel possibilities for elucidating pathogen-host interaction mechanisms and developing anti-infective therapies. Given the importance of dynamic mitochondria-organelle collaboration in disease treatment, this review first focuses on analyzing the molecular mechanisms underlying this crosstalk. Building on this, the dysregulation of mitochondria-organelle collaboration in diseases is discussed in depth, with a particular focus on cancer, cardiovascular diseases, metabolic syndrome, and neurodegenerative diseases. Finally, the potential therapeutic strategies targeting organelle interactions are summarized and analyzed. In conclusion, the information in this manuscript offers a new way to think about and treat several serious illnesses.}, } @article {pmid41981347, year = {2026}, author = {Sengupta, P and Mukhopadhyay, D}, title = {Nuclear Translocation of IGF1R Induces Cell Cycle Re-entry via Cyclin D1 Regulation in an Aβ-Driven Alzheimer's Disease Model.}, journal = {Molecular neurobiology}, volume = {63}, number = {1}, pages = {}, pmid = {41981347}, issn = {1559-1182}, mesh = {Humans ; *Alzheimer Disease/metabolism/pathology ; *Receptor, IGF Type 1/metabolism ; *Cyclin D1/metabolism ; *Amyloid beta-Peptides/toxicity ; *Cell Nucleus/metabolism/drug effects ; Cell Line, Tumor ; Active Transport, Cell Nucleus/drug effects ; *Cell Cycle/drug effects ; *Models, Biological ; Phosphorylation/drug effects ; Neurons/metabolism/drug effects ; }, abstract = {Alzheimer's disease (AD) involves progressive neurodegeneration, with abnormal receptor signaling and disrupted cell-cycle activity leading to neuronal loss. Here, we identify a previously unknown mechanism linking β-amyloid (Aβ) exposure to the nuclear translocation of the Insulin-like Growth Factor 1 Receptor (IGF1R) in differentiated SH-SY5Y neuronal cells. The differentiated cholinergic model induced by retinoic acid and BDNF expresses acetylcholinesterase (AChE) and indicates that under amyloidogenic stress, IGF1R may transition from homeostatic membrane and vesicular signaling to a nuclear-centric function. We show that prolonged Aβ treatment causes phosphorylation-dependent nuclear import of IGF1R, confirmed by confocal imaging and biochemical fractionation. IGF1R is conventionally located in the membrane and vesicular membranes; however, under amyloidogenic stress, we show here that it is imported to the nucleus and exerts transcriptional control. The buildup of nuclear IGF1R coincided with increased Cyclin D1 levels and redistribution of neurons into S and G2 phases, indicating abnormal cell-cycle re-entry. Chromatin immunoprecipitation demonstrated increased IGF1R binding at the CCND1 and JUN promoters after Aβ exposure, suggesting a direct role in gene transcription. Pharmacological blockade of IGF1R phosphorylation by PPP or SUMOylation by Ginkgolic acid significantly reduced Cyclin D1 elevation, implying that both post-translational modifications are involved in receptor nuclear trafficking. Co-immunoprecipitation and confocal imaging identified Nucleophosmin (NPM1) as a putative IGF1R interacting partner, potentially contributing to its nuclear transport and stabilizing receptor-chromatin complexes. These results establish IGF1R as a signaling-transcription connector linking extracellular amyloid stress to nuclear gene regulation, providing a mechanistic explanation for faulty neuronal cell-cycle re-entry in AD. We suggest that abnormal IGF1R-NPM1 interactions contribute to receptor mislocalization and cell-cycle failure, highlighting new targets for therapeutic intervention aimed at receptor trafficking and neuroprotection in Alzheimer's disease.}, } @article {pmid41981348, year = {2026}, author = {Abdellatif, AI and Elsharab, A and Moubarak, ES and Alsaadany, KR and Ayad, YW}, title = {Focused and unfocused transcranial ultrasound stimulation in Alzheimer's disease: a systematic review and meta-analysis of randomized controlled trials.}, journal = {Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology}, volume = {47}, number = {5}, pages = {}, pmid = {41981348}, issn = {1590-3478}, mesh = {Humans ; *Alzheimer Disease/therapy ; *Randomized Controlled Trials as Topic ; }, abstract = {BACKGROUND: Transcranial ultrasound stimulation (TUS) is a non-invasive method that allows deep brain structures to be targeted, and it may benefit individuals with Alzheimer'sdisease (AD). We conducted a systematic review and meta-analysis to assess the effect of TUS on global cognitive function in mild-to-moderate AD, comparing focused transcranial pulse stimulation (TPS) with unfocused low-intensity pulsed ultrasound (LIPUS). METHODS: We searched PubMed, Scopus, Cochrane, and Web of Science for randomized controlled trials (RCTs) comparing TUS with sham stimulation. The primary outcome was the change in global cognitive function. Secondary outcomes included functional status,depressive symptoms, and safety. RESULTS: Three RCTs (N=84) were included. Pooled analysis showed that TUS did not significantly improve global cognition compared with sham (SMD=0.31, p=0.54). However,subgroup analysis showed a significant difference between modalities (p=0.047):unfocused LIPUS had a larger effect size (SMD=0.73) than focused TPS (SMD=0.17).Notably, significant cognitive improvement was observed in patients <70 years. Active treatment showed higher disease stabilization rates ("responders"), reduced depressive symptoms (specifically TPS, p=0.008), and improved cerebral perfusion without amyloid-related imaging abnormalities (ARIA). CONCLUSION: While pooled analyses did not show a global cognitive benefit, the results favoured unfocused LIPUS over focused TPS; TUS had an excellent safety profile and higher disease stabilization rates; the potential benefits in younger populations and the biological effects suggest that TUS is a promising adjunct that should be further optimized for stimulation. REGISTRATION: This review was registered on PROSPERO (CRD420251276660).}, } @article {pmid41982209, year = {2026}, author = {Ubuka, T and Yuyama, K and Genjima, A and Nagakura, M and Kato, K and Hayashi, S and Makino, N and Yamane, T and Hirose, T and Yamane, Y}, title = {Mitigating cognitive decline in Alzheimer's disease dementia by enhancing cognitive reserve through neuroplasticity in addition to amyloid-β reduction.}, journal = {Frontiers in aging neuroscience}, volume = {18}, number = {}, pages = {1769431}, pmid = {41982209}, issn = {1663-4365}, } @article {pmid41984492, year = {2026}, author = {Chiu, PY and Chiu, HJ and Wei, CY and Tzeng, RC and Chang, HT and Chen, HM}, title = {Dementia with Lewy bodies clinical syndrome (DLBCS) questionnaire: A simple tool for the clinical screening of DLB.}, journal = {Journal of Alzheimer's disease : JAD}, volume = {111}, number = {3}, pages = {1073-1083}, doi = {10.1177/13872877261441187}, pmid = {41984492}, issn = {1875-8908}, mesh = {Humans ; *Lewy Body Disease/diagnosis/psychology ; Female ; Surveys and Questionnaires ; Male ; Aged ; Aged, 80 and over ; ROC Curve ; Taiwan ; Diagnosis, Differential ; Cognitive Dysfunction/diagnosis ; Sensitivity and Specificity ; Neuropsychological Tests ; }, abstract = {BackgroundDementia with Lewy bodies (DLB) remains underdiagnosed due to overlapping clinical features with Alzheimer's disease (AD) and vascular cognitive impairment (VCI). Early recognition is crucial, as DLB has distinct prognostic and therapeutic implications.ObjectiveThis study aimed to develop and validate a brief, clinically applicable screening instrument to improve bedside recognition of DLB and to compare its performance with established diagnostic approaches.MethodsWe designed the Dementia with Lewy Bodies Clinical Screening Questionnaire (DLBCSQ) and an extended version (DLBCSQ11) incorporating additional items to differentiate DLB from VCI. Clinical data were collected from a dementia registry in Taiwan, including patients with AD, VCI, and DLB. The diagnostic accuracy of DLBCSQ versions was evaluated using receiver operating characteristic (ROC) analyses across subgroups, including mild cognitive impairment with Lewy bodies (LB-MCI).ResultsBoth DLBCSQ and DLBCSQ11 demonstrated strong discriminatory ability, with area under the curve (AUC) values exceeding 0.84 for differentiating DLB from non-DLB syndromes. DLBCSQ11 showed greater specificity for distinguishing DLB from VCI, though about 20% of VCI patients still exhibited DLB-like features. Supplementary questions on visual hallucinations and tremors further improved detection of prodromal or mixed DLB cases.ConclusionsThe DLBCSQ9 and DLBCSQ11 represent practical and effective tools for clinical and bedside identification of DLB. By improving early recognition and differentiation from AD and VCI, these instruments may facilitate timely diagnosis, guide treatment decisions, and support future research on mixed dementia syndromes.}, } @article {pmid41984500, year = {2026}, author = {Shah, S and Tran, T and Wadhwa, SS and Huerta, GI and Ovalle-Eliseo, S and Martinez, A and Vossel, K and Campos, B and Bholat, M and Moreno, G and Diaz-Santos, M and Chang, TS}, title = {Increased dementia diagnosis and workup in primary care with a bilingual screening tool integrated in the electronic health record.}, journal = {Journal of Alzheimer's disease : JAD}, volume = {111}, number = {3}, pages = {1291-1300}, pmid = {41984500}, issn = {1875-8908}, support = {K08 AG065519/AG/NIA NIH HHS/United States ; T15 LM013976/LM/NLM NIH HHS/United States ; UH3 AG083254/AG/NIA NIH HHS/United States ; }, mesh = {Aged ; Aged, 80 and over ; Female ; Humans ; Male ; *Dementia/diagnosis ; *Electronic Health Records ; Hispanic or Latino ; Mass Screening/methods ; Mental Status and Dementia Tests ; *Multilingualism ; *Primary Health Care ; White ; Black or African American ; Asian ; Middle Aged ; }, abstract = {BackgroundAlzheimer's disease (AD) affects over 10% of adults aged 65 and older. Black and Hispanic/Latino individuals experience 1.5-2.0 times higher prevalence than White individuals, yet AD remains underdiagnosed, particularly in non-White populations. Common screening tools such as the Mini-Mental State Examination and Montreal Cognitive Assessment are limited by time burden and cultural sensitivity.ObjectiveTo evaluate the impact of integrating a brief dementia screening tool (DST) into the electronic health record (EHR) on diagnosis, evaluation, and treatment in primary care.MethodsThe DST, developed by the University of California Alzheimer's Disease Centers and the California Department of Public Health, takes under five minutes and includes a three-question patient form, optional informant questionnaire, and Mini-Cog. It was translated and culturally adapted for Spanish-speaking patients and embedded in the EHR. Patients aged ≥60 in a diverse Los Angeles County family medicine clinic completed the DST before annual wellness visits. We conducted a pre-post study comparing patients without prior dementia diagnoses during pre-intervention (February 2021-August 2022) and post-intervention (January 2023-June 2024) periods. Primary outcome was new dementia diagnosis; secondary outcomes included medications, referrals, labs, and imaging.ResultsAmong 1515 eligible patients post-intervention, 1249 completed screening. New dementia diagnoses increased from 0.75% pre-DST to 2.45% among those screening positive (adjusted OR 2.99; p = 0.01). Dementia medications, laboratory orders, and specialty referrals significantly increased; imaging did not.ConclusionsA brief, culturally adapted DST integrated into primary care improved dementia diagnosis, evaluation, and treatment.}, } @article {pmid41984564, year = {2026}, author = {Shavlovskaya, OA}, title = {[The effectiveness of citicoline in the treatment of cognitive disorders].}, journal = {Zhurnal nevrologii i psikhiatrii imeni S.S. Korsakova}, volume = {126}, number = {3}, pages = {136-140}, doi = {10.17116/jnevro2026126031136}, pmid = {41984564}, issn = {1997-7298}, mesh = {*Cytidine Diphosphate Choline/therapeutic use ; Humans ; *Nootropic Agents/therapeutic use ; Stroke/complications ; *Cognition Disorders/drug therapy/etiology ; *Cognitive Dysfunction/drug therapy/etiology ; }, abstract = {Randomized controlled trials, systematic reviews, and meta-analyses have shown that citicoline is highly effective in the treatment of vascular cognitive impairments (CI) of various origins (post-stroke, chronic cerebral ischemia (CCI)), post-traumatic CI, mild CI in neurodegenerative diseases (Alzheimer's disease, Parkinson's disease), and in patients with age-related memory impairments. Citicoline administration regimens: 1) post-stroke CI at a dose of 1000 mg/day. for a course of 4-12 months; 2) mild CI of vascular origin at a dose of 500 mg/day for a course of 3-9 months; 3) CI against the background of CCI at a dose of 500-2000 mg, the duration of the course depends on the severity of the symptoms; 4) non-demented CI at a dose of 1000 mg/day course of 9 months; 5) mild CI against Parkinson's disease at a dose of 1000 mg/day 12-18 months.}, } @article {pmid41985059, year = {2026}, author = {Du, JH and Shen, M and Mathys, H and Roeder, K}, title = {Uncovering causal relationships in single-cell omic studies with causarray.}, journal = {Briefings in bioinformatics}, volume = {27}, number = {2}, pages = {}, pmid = {41985059}, issn = {1477-4054}, mesh = {Humans ; *Single-Cell Analysis/methods ; Animals ; Mice ; *Genomics/methods ; *Alzheimer Disease/genetics ; Autistic Disorder/genetics ; Brain/metabolism ; }, abstract = {Advances in single-cell sequencing and Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR) technologies have enabled detailed case-control comparisons and experimental perturbations at single-cell resolution. However, uncovering causal relationships in observational genomic data remains challenging due to selection bias and inadequate adjustment for unmeasured confounders, particularly in heterogeneous datasets. To address these challenges, we introduce causarray, a robust causal inference framework for analyzing array-based genomic data at both pseudo-bulk and single-cell levels under unmeasured confounding. causarray integrates a generalized confounder adjustment method to account for unmeasured confounders and employs semiparametric inference with flexible machine learning techniques to ensure robust statistical estimation of treatment effects. Benchmarking results show that causarray robustly separates treatment effects from confounders while preserving biological signals across diverse settings. We also apply causarray to two single-cell genomic studies: (i) an in vivo Perturb-seq study of autism risk genes in developing mouse brains and (ii) a case-control study of Alzheimer's disease (AD) using three human brain transcriptomic datasets. In these applications, causarray identifies clustered causal effects of multiple autism risk genes and consistent causally affected genes across AD datasets, uncovering biologically relevant pathways directly linked to neuronal development and synaptic functions that are critical for understanding disease pathology.}, } @article {pmid41985900, year = {2026}, author = {Nonino, F and Minozzi, S and Sambati, L and Del Giovane, C and Baldin, E and Bassi, MC and De Santis, C and Gonzalez-Lorenzo, M and Vignatelli, L and Filippini, G and Richard, E}, title = {Amyloid-beta-targeting monoclonal antibodies for people with mild cognitive impairment or mild dementia due to Alzheimer's disease.}, journal = {The Cochrane database of systematic reviews}, volume = {4}, number = {4}, pages = {CD016297}, pmid = {41985900}, issn = {1469-493X}, mesh = {Humans ; *Alzheimer Disease/complications/drug therapy ; *Amyloid beta-Peptides/antagonists & inhibitors/immunology ; *Antibodies, Monoclonal/therapeutic use/adverse effects ; Randomized Controlled Trials as Topic ; *Cognitive Dysfunction/drug therapy/etiology ; *Dementia/drug therapy/etiology ; }, abstract = {RATIONALE: Alzheimer's disease is a neurodegenerative disorder and the most common cause of dementia. Aggregated amyloid-beta protein deposits are implicated in its pathogenesis. Amyloid-beta-targeting monoclonal antibodies (sometimes represented as Aβ-mAbs) are potentially disease-modifying for Alzheimer's disease: through the clearance of amyloid in the brain, they may slow cognitive and functional decline.

OBJECTIVES: To assess the clinical benefits and harms of amyloid-beta-targeting monoclonal antibodies aducanumab, bapineuzumab, crenezumab, donanemab, gantenerumab, lecanemab, ponezumab, remternetug, and solanezumab in people with mild cognitive impairment or mild dementia due to Alzheimer's disease.

SEARCH METHODS: We searched CENTRAL, MEDLINE (PubMed), Embase, and two clinical trials registries (Clinicaltrials.gov and WHO International Clinical Trials Registry Platform), and we undertook reference checking and citation research. The most recent search date was 7 August 2025.

ELIGIBILITY CRITERIA: We included randomised controlled trials (RCTs) that lasted at least 12 months and compared amyloid-beta-targeting monoclonal antibodies with placebo or no treatment in people with mild cognitive impairment or mild dementia due to Alzheimer's disease. We included both parallel-group and cluster designs.

OUTCOMES: Our outcomes of critical importance were: cognitive function; dementia severity; functional ability; any amyloid-related imaging abnormality (ARIA), which includes oedema (E) and haemorrhage (H); any symptomatic ARIA E and H; symptomatic brain haemorrhage; serious adverse events; and any-cause mortality. We analysed data at 12, 18, 24, and over 24 months of treatment.

RISK OF BIAS: We used the Cochrane risk of bias tool RoB 2 to assess the risk of bias in outcomes of critical importance.

SYNTHESIS METHODS: We meta-analysed results for each outcome within each comparison using the inverse variance method and the random-effects model. We used GRADE to assess the certainty of evidence for each outcome as very low, low, moderate, or high.

INCLUDED STUDIES: Overall, we included 17 studies with 20,342 participants. The mean age of participants in the studies ranged from 70 to 74 years. Seven studies enroled only participants with mild dementia, and one study enroled only participants with mild cognitive impairment. The remaining studies included a mixed population. The mean duration of participants' cognitive impairment ranged from 17 to 52 months. The 17 studies assessed seven different amyloid-beta-targeting monoclonal antibodies: aducanumab (n = 3), bapineuzumab (n = 4), crenezumab (n = 2), donanemab (n = 1), gantenerumab (n = 4), lecanemab (n = 1), and solanezumab (n = 2). All used placebo as a comparison. Eleven studies lasted 18 months, four lasted 24 months, and two lasted more than 24 months. All studies were funded by the pharmaceutical industry.

SYNTHESIS OF RESULTS: Below, we report the results of the studies at 18 months. Cognitive function Compared to placebo, amyloid-beta-targeting monoclonal antibodies probably result in little to no difference in cognitive function as measured by the ADAS-Cog (Alzheimer's Disease Assessment Scale-Cognitive) scale (standardised mean difference (SMD) -0.11, 95% confidence interval (CI) -0.16 to -0.06; 13 studies, 9895 participants; moderate certainty). Dementia severity Amyloid-beta-targeting monoclonal antibodies may result in little to no difference in dementia severity as measured by the CDR-SB (Clincal Dementia Rating Sum of Boxes) scale (SMD -0.12, 95% CI -0.24 to -0.00; 9 studies, 8053 participants; low certainty). Functional ability Amyloid-beta-targeting monoclonal antibodies probably result in little to no difference in functional ability as measured on the ADCS-ADL (Alzheimer's Disease Cooperative Study - Activities of Daily Living) scale (SMD 0.09, 95% CI 0.03 to 0.16; 3 studies, 3478 participants; moderate certainty) and may result in a small increase in functional ability if measured with the ADCS-iADL (Alzheimer's Disease Cooperative Study-Instrumental Activities of Daily Living) scale (SMD 0.21, 95% CI 0.10 to 0.32; 1 study, 1252 participants; low certainty) or ADCS-ADL-MCI (Alzheimer's Disease Cooperative Study - Activities of Daily Living for Mild Cognitive Impairment) scale (SMD 0.23, 95% CI 0.12 to 0.33; 4 studies, 2802 participants; low certainty). Adverse events Amyloid-beta-targeting monoclonal antibodies probably result in a small increase in the occurrence of any ARIA E (ARD (absolute risk difference) 107 more per 1000, 95% CI 77 more to 148 more; 11 studies, 13,595 participants; moderate certainty) and probably little to no difference in symptomatic ARIA E (ARD 29 more per 1000, 95% CI 22 more to 38 more; 2 studies, 3522 participants; moderate certainty) or symptomatic ARIA H (ARD 4 more per 1000, 95% CI 1 fewer to 31 more; 1 study, 1795 participants; moderate certainty). Three studies assessing any ARIA H showed heterogeneous results (I[2] = 81%), which prevented pooled analysis. At 18 months, amyloid-beta-targeting monoclonal antibodies do not increase serious adverse events (ARD 6 more events per 1000, 95% CI 10 fewer to 26 more; 9 studies, 11,904 participants; high certainty) or overall mortality (ARD 2 more events per 1000, 95% CI 3 fewer to 11 more; 7 studies, 9733 participants; high certainty). We judged the overall risk of bias as low for the outcomes of serious adverse events and mortality. We had some concerns about the overall risk of bias for efficacy outcomes, mainly due to the risk of functional unblinding (i.e. participants and investigators correctly guessing whether a participant is receiving the active drug or placebo because of noticeable side effects).

AUTHORS' CONCLUSIONS: The effect of amyloid-beta-targeting monoclonal antibodies on cognitive function and dementia severity at 18 months in people with mild cognitive impairment or mild dementia due to Alzheimer's disease is trivial, while on functional ability, it is small at best. Amyloid-beta-targeting monoclonal antibodies increase the risk of amyloid-related imaging abnormalities. Both desirable outcomes and adverse events were inconsistently reported in the studies included in the review. Successful removal of amyloid from the brain does not seem to be associated with clinically meaningful effects in people with mild cognitive impairment or mild dementia due to Alzheimer's disease. Future research on disease-modifying treatments for Alzheimer's disease should focus on other mechanisms of action.

FUNDING: This Cochrane review was funded in part by the Drug and Medical Devices Governance Area, Regione Emilia-Romagna, Bologna, Italy. The publication of this article was supported by "Ricerca Corrente" funding from the Italian Ministry of Health.

REGISTRATION: Protocol (2025): PROSPERO registration number CRD420251114325.}, } @article {pmid41986146, year = {2026}, author = {Ebani, EJ and Yadav, D and Knight-Greenfield, A and Gardella, J and Moirano, J and Intorcia, B and RoyChoudhury, A and Keil, SA and Nordvig, AS and Blum, S and Lin, M and Osborne, JR and Chiang, GC and Ivanidze, J}, title = {Cross-Platform Concordance of Quantitative Amyloid PET Z-Scores in a Real-World Clinical Cohort of Patients with Cognitive Impairment and Suspected Alzheimer Disease.}, journal = {AJNR. American journal of neuroradiology}, volume = {}, number = {}, pages = {}, doi = {10.3174/ajnr.A9354}, pmid = {41986146}, issn = {1936-959X}, abstract = {BACKGROUND AND PURPOSE: Normative modeling tools are FDA-approved clinical software applications that enable quantitative amyloid PET analysis in routine clinical practice, however implementation differences may yield non-interchangeable Z-scores, with implications for diagnosis and treatment eligibility for patients with cognitive impairment and/or suspected Alzheimer disease. This study evaluated the agreement of Z-scores derived from two widely used clinical software packages in a real-world cohort of patients with cognitive impairment/Alzheimer disease.

MATERIALS AND METHODS: Amyloid PET from 100 consecutive patients with cognitive impairment/Alzheimer disease obtained as part of standard-of-care evaluation at a single institution were retrospectively reviewed. Amyloid PET were post-processed using syngo.via MI Neurology (Siemens Healthineers) and MIMneuro (MIM Software/GE Healthcare). Regional Z-scores were obtained for the temporal, precuneus, posterior cingulate, parietal, frontal, and anterior cingulate cortices. Z-scores were compared per patient and stratified by Centiloid burden (low/intermediate/high: < 20/20-30/>30). Agreement was evaluated using Bland-Altman analysis and Deming regression.

RESULTS: Agreement between Syngo.via and MIMneuro varied by region. When regional Z-scores were averaged into a per-patient composite measure, overall bias was near-zero, with tight limits of agreement (slope = 0.97 [95% CI 0.93-1.02], intercept = 0.11 [95% CI -0.05-0.26]), indicating minimal proportional and constant bias between platforms. Bland-Altman analysis showed small bias and narrow limits of agreement (LoA) in the low-centiloid group (mean bias -0.19, 95% LoA -0.93 to +0.55) and the greatest divergence in the intermediate group (mean bias -0.44, LoA -2.02 to +1.14). In the high-centiloid group, bias remained small (+0.16) with wider LoA (-1.92 to +2.24). Temporal cortex Deming regression demonstrated proportional and constant bias (slope = 0.70 [95% CI 0.66-0.74], intercept = 0.34 [95% CI 0.07-0.61]), indicating systematic underestimation of high Z-scores by MIM relative to Syngo.via.

CONCLUSIONS: There was overall concordance between Syngo.Via and MIMneuro quantitative amyloid PET analysis software packages, however with significant region- and amyloid burden-dependent variability that increased in the intermediate-centiloid group. These differences may influence interpretation and determination of treatment eligibility in borderline cases, emphasizing that Z-scores from different commercial platforms should not be used interchangeably without cross-validation.}, } @article {pmid41986822, year = {2026}, author = {Hazar-Yavuz, AN and Ertas, B and Kaya, RK and Topal, F and Kabataş, GS and Altuntaş, C and Kabasakal, L and Yazir, Y and Cam, ME}, title = {Modulation of Amyloid and Tau Pathology by Empagliflozin in a High-Fat Diet and Streptozotocin-Induced Type 2 Diabetes-Associated Alzheimer's Model.}, journal = {The European journal of neuroscience}, volume = {63}, number = {8}, pages = {e70495}, doi = {10.1111/ejn.70495}, pmid = {41986822}, issn = {1460-9568}, support = {SAG-A-110618-0292//Marmara Üniversitesi/ ; }, mesh = {Animals ; *Glucosides/pharmacology/therapeutic use ; *Benzhydryl Compounds/pharmacology/therapeutic use ; *Alzheimer Disease/metabolism/drug therapy/pathology/etiology ; *tau Proteins/metabolism/drug effects ; *Diabetes Mellitus, Type 2/metabolism/complications/drug therapy ; Diet, High-Fat/adverse effects ; Male ; *Sodium-Glucose Transporter 2 Inhibitors/pharmacology ; Rats ; *Amyloid beta-Peptides/metabolism/drug effects ; *Diabetes Mellitus, Experimental/metabolism/complications/drug therapy ; Streptozocin ; Disease Models, Animal ; *Neuroprotective Agents/pharmacology ; Rivastigmine/pharmacology ; Brain/drug effects/metabolism/pathology ; }, abstract = {Type 2 diabetes mellitus (T2DM) contributes notably to the development and progression of Alzheimer's disease (AD) through overlapping pathological mechanisms such as insulin resistance, amyloid-β (Aβ) accumulation and tau hyperphosphorylation. Sodium-glucose cotransporter-2 (SGLT2) inhibitors have recently emerged as promising candidates for neuroprotection in metabolic disorders. The present work explored the potential therapeutic impact of the SGLT2 inhibitor empagliflozin (EMPA) compared with the acetylcholinesterase inhibitor rivastigmine (RIV) in a T2DM-induced AD rat model. The T2DM-AD model was established using a high-fat diet in combination with subsequent low-dose streptozotocin (35 mg/kg) administration. Metabolic, behavioural, biochemical, molecular and histopathological parameters were assessed to evaluate disease progression and treatment efficacy. EMPA significantly improved glucose metabolism, lowered nonfasting blood glucose, enhanced oral glucose tolerance and restored insulin levels in peripheral and central tissues. EMPA ameliorated short-term and spatial memory deficits and reduced Aβ and phosphorylated tau levels in the brain, serum and pancreas and normalized acetylcholinesterase and glycogen kinase-3β expression. Histological and immunohistochemical analyses corroborated these neuroprotective effects, revealing reduced neurodegeneration and proteinopathy in the cerebral cortex and hippocampus. EMPA exerts multifaceted neuroprotective and metabolic benefits in a T2DM-induced AD model, offering a therapeutic advantage over RIV by targeting both peripheral metabolic dysfunction and central neurodegeneration. By demonstrating that modulation of systemic glucose homeostasis can directly influence amyloid and tau pathology as well as cognitive outcomes, these findings provide important insight into the metabolic-neurodegenerative interface and highlight SGLT2 inhibition as a promising strategy for diabetes-associated cognitive decline and AD within the field of neuroscience.}, } @article {pmid41987015, year = {2026}, author = {Morales, MJ and Ricketts, S and Grudzen, CR and Brody, AA and Chodosh, J and Goldfeld, K and Shah, MN and , }, title = {Bridging the Gap Between the ED and Home: The Community Paramedic-Led Transitions Intervention for Persons Living With Dementia.}, journal = {Journal of the American Geriatrics Society}, volume = {}, number = {}, pages = {}, doi = {10.1111/jgs.70403}, pmid = {41987015}, issn = {1532-5415}, support = {P30 CA008748/CA/NCI NIH HHS/United States ; U19 AG078105/AG/NIA NIH HHS/United States ; U19 AG078105-01A1/AG/NIA NIH HHS/United States ; }, abstract = {More than 6 million persons living with dementia (PLWD) in the United States rely on the emergency department (ED) for unscheduled care, with up to half discharged home after treatment. The ED-to-home transition poses significant challenges for PLWD and their care partners (referred to as "dyads"), contributing to high rates of ED revisits and adverse outcomes. The Community Paramedic-led Transitions Intervention (CPTI) was developed to address these challenges by adapting the validated Care Transitions Intervention for the ED setting. Delivered by trained community paramedics, CPTI is a short-term 30-day program that includes one home visit and up to three follow-up phone calls. Using a coaching model, paramedic coaches work with members of the dyad to strengthen their knowledge, skills, and confidence to manage their health and successfully navigate the health care system. CPTI is being implemented as part of Emergency Departments LEading the Transformation of Alzheimer's and Dementia Care (ED-LEAD), a cluster-randomized pragmatic trial testing 3 interventions designed to improve outcomes for PLWD discharged home from the ED across 14 health systems and 79 EDs nationwide. This paper describes the CPTI model as implemented within ED-LEAD, detailing its theoretical foundation, structure, training curriculum, workflow integration, and implementation monitoring. This framework can provide a model for health systems, provider groups, and emergency medical service agencies interested in adopting this innovative approach and implementing the CPTI. Insights from its implementation within ED-LEAD will guide future efforts to improve post-ED outcomes and continuity of care for PLWD and their care partners.}, } @article {pmid41987849, year = {2026}, author = {Xu, Y and Chen, D and Ye, Q and Zhang, P and Shi, J and Li, S and Sun, Y and Zhao, Z and Tang, Y and Zhang, P and Tang, Z}, title = {Emerging Neural Recording and Neurostimulation Technologies Based on Brain-Computer Interface: A Promising Approach for Neuropsychiatric Disorders.}, journal = {MedComm}, volume = {7}, number = {}, pages = {e70739}, pmid = {41987849}, issn = {2688-2663}, abstract = {Neurological and psychiatric disorders, arising from disruptions in neural circuitry, pose a major and growing challenge to global healthcare systems. Brain-computer interface (BCI) technology has emerged as a promising approach, enabling direct communication between the brain and external devices. By facilitating bidirectional interaction with the nervous system, BCIs open new avenues for both diagnosis and treatment. In this review, we examine recent advances in recording and stimulation technologies within the BCI framework and evaluate their therapeutic potential across major neuropsychiatric disorders. We focus particularly on post-stroke motor rehabilitation as a representative paradigm, providing detailed analysis of the mechanisms, clinical evidence, and future prospects of endovascular BCI, BCI-integrated epidural spinal cord stimulation, and BCI-driven deep brain stimulation. We further extend the discussion to movement disorders such as Parkinson's disease and epilepsy, as well as cognitive and psychiatric conditions including Alzheimer's disease and depression, highlighting how BCI-based approaches enable symptom detection and closed-loop neuromodulation. Additionally, we address ethical and societal considerations accompanying clinical translation of these advanced neurotechnologies. By integrating current evidence, this review highlights a paradigm shift toward more active, precise, and personalized neural rehabilitation enabled by BCI systems, while outlining key challenges and future directions for research and clinical application.}, } @article {pmid41987879, year = {2026}, author = {Manganotti, P and Palacino, F and Pavan, S and Benussi, A}, title = {Epilepsy and EEG abnormalities in neurodegenerative dementias: toward a system epilepsy framework.}, journal = {Frontiers in aging neuroscience}, volume = {18}, number = {}, pages = {1806471}, pmid = {41987879}, issn = {1663-4365}, abstract = {Epilepsy and epileptiform activity represent underrecognized yet clinically significant features of neurodegenerative dementias, with emerging evidence suggesting they may contribute to disease progression rather than merely representing epiphenomena of neuronal loss. This comprehensive review examines the epidemiology, clinical presentation, electroencephalographic findings, and pathophysiological mechanisms underlying seizure activity in Alzheimer's disease (AD), dementia with Lewy bodies (DLB), and frontotemporal dementia (FTD). Meta-analytic data demonstrate elevated seizure prevalence across all three conditions, with cumulative probabilities of 13.4% for AD, 14.7% for DLB, and 3.0% for FTD, representing risk elevations of approximately 6- to 10-fold compared to age-matched controls. Critically, subclinical epileptiform activity detected through prolonged electroencephalographic monitoring affects up to 42-54% of AD patients and is associated with 1.5-fold accelerated cognitive decline. Each dementia subtype exhibits characteristic electroencephalographic signatures: AD demonstrates progressive spectral slowing with predominantly left temporal epileptiform discharges; DLB shows highly characteristic slowing of the dominant rhythm below 8 Hz with high diagnostic accuracy; and FTD displays relatively preserved background activity with frontal-temporal hypoconnectivity. We synthesize evidence from transcranial magnetic stimulation studies demonstrating distinct patterns of cortical excitability alterations across these conditions, with AD showing bilateral increases in cortical excitability and reduced GABAergic and cholinergic inhibition. Building upon these observations, dementia-associated epilepsy may be conceptualized within the framework of system epilepsies, arising from dysfunction of vulnerable neural networks rather than discrete lesions. This paradigm shift has profound therapeutic implications, supporting network-targeted interventions and the potential disease-modifying role of antiseizure medications. We conclude by presenting clinical recommendations for monitoring and treatment, emphasizing the need for prolonged electroencephalographic evaluation and consideration of empirical treatment for subclinical epileptiform activity associated with cognitive fluctuations.}, } @article {pmid41989792, year = {2026}, author = {Upadhyay, R and Jain, A and Karthik, T and Desavathu, M}, title = {Nanomedicines for neurodegenerative ageing: nasal delivery innovations for Alzheimer's and Parkinson's disease.}, journal = {Journal of drug targeting}, volume = {}, number = {}, pages = {1-20}, doi = {10.1080/1061186X.2026.2659210}, pmid = {41989792}, issn = {1029-2330}, abstract = {Alzheimer's disease and Parkinson's disease are progressive, age-related neurodegenerative disorders with increasing global prevalence, yet their treatment remains challenging despite the availability of multiple therapeutic agents. Conventional formulations are often limited by poor solubility, restricted blood-brain barrier penetration, extensive first-pass metabolism, short elimination half-life, low brain bioavailability, and systemic adverse effects. The nose-to-brain route has emerged as a promising strategy for delivering therapeutics directly to the brain. This approach offers non-invasive administration, rapid onset of action, direct brain targeting via olfactory and trigeminal pathways, bypassing of first-pass metabolism, improved bioavailability, and enhanced patient compliance. To exploit these advantages, a variety of biodegradable nanocarrier systems have been investigated, including lipid-based, Polymer-based, hybrid nanoparticles, nasal gel-based systems, nanoemulsions, nanosuspensions, and nasal sprays. This review provides a comprehensive synthesis of preclinical studies evaluating nose-to-brain nanocarrier-based delivery strategies for Alzheimer's and Parkinson's disease, with particular emphasis on their pharmacokinetic and pharmacodynamic performance. This indicates that nose-to-brain nanocarriers can effectively address key limitations. However, successful clinical translation will require addressing formulation-related challenges such as mucociliary clearance, nasal irritation, burst drug release, alongside well-designed clinical studies. Future research should focus on exploring emerging delivery platforms to advance nose-to-brain strategies for the management of neurodegenerative diseases.}, } @article {pmid41989985, year = {2026}, author = {Sun, M and Lu, Z and Chen, WM and Lv, S and Fu, N and Yang, Y and Wang, Y and Miao, M and Wu, SY and Zhang, J}, title = {N-Acetylcysteine and Dementia Risk in Elderly Patients.}, journal = {International journal of geriatric psychiatry}, volume = {41}, number = {4}, pages = {e70212}, doi = {10.1002/gps.70212}, pmid = {41989985}, issn = {1099-1166}, mesh = {Humans ; *Acetylcysteine/therapeutic use/administration & dosage ; *Dementia/epidemiology/prevention & control ; Aged ; Female ; Male ; Taiwan/epidemiology ; *Pulmonary Disease, Chronic Obstructive/drug therapy/complications ; Aged, 80 and over ; Risk Factors ; Proportional Hazards Models ; Dose-Response Relationship, Drug ; *Free Radical Scavengers/therapeutic use/administration & dosage ; Propensity Score ; Cohort Studies ; }, abstract = {OBJECTIVE: This study aimed to investigate the association between N-acetylcysteine (NAC) use and dementia risk in elderly individuals diagnosed with Chronic Obstructive Pulmonary Disease (COPD).

METHODS: Utilizing Taiwan's National Health Insurance Research Database (NHIRD), we conducted a population-based cohort study of 105,144 elderly COPD patients to investigate the association between NAC use and dementia risk. Propensity score matching (PSM) ensured balanced covariates between NAC users and nonusers. Cox regression analysis and Poisson Regression analysis were employed to assess dementia risk, considering NAC dosage, treatment duration, and comorbidities. Competing risk analysis and Kaplan-Meier method were used to account for mortality risk and estimate dementia incidence, respectively.

RESULTS: Elderly NAC users demonstrated a significant association with a lower dementia risk (adjusted hazard ratio [aHR]: 0.76, 95% confidence interval [CI]: 0.74-0.78). Higher daily NAC intake was associated with a dose-dependent decline in dementia risk, with optimal benefits observed at an average daily dose of 1.61 defined daily doses (DDD). Stratification by cumulative defined daily doses (cDDD) of NAC revealed a consistent dose-response relationship, with progressively diminished dementia risk across quartiles of cDDD. Notably, NAC use was associated with a lower risk of Alzheimer's dementia (aHR: 0.68, 95% CI: 0.66-0.70) compared to non-NAC antimucolytic users.

CONCLUSIONS: NAC use is associated with a dose-dependent reduction in dementia risk among elderly COPD patients, particularly for Alzheimer's dementia. Our findings underscore the potential of NAC as a potential protective factor against dementia in this vulnerable population, warranting further investigation and consideration in clinical practice.}, } @article {pmid41990984, year = {2026}, author = {Xu, G and Gao, J and Wang, T and Wu, H and Liu, S and Ji, Y and Wang, P and Guo, M}, title = {Differential modulation of EEG microstate spatiotemporal dynamics by rTMS and iTBS correlates with clinical improvement in Alzheimer's disease.}, journal = {Brain research}, volume = {1884}, number = {}, pages = {150323}, doi = {10.1016/j.brainres.2026.150323}, pmid = {41990984}, issn = {1872-6240}, mesh = {Humans ; *Alzheimer Disease/physiopathology/therapy ; *Transcranial Magnetic Stimulation/methods ; Female ; Male ; Electroencephalography/methods ; Aged ; Theta Rhythm/physiology ; Brain/physiopathology ; Treatment Outcome ; Aged, 80 and over ; }, abstract = {BACKGROUND: Transcranial magnetic stimulation (TMS) is an effective therapy for patients with Alzheimer's Disease (AD), potentially modulating aberrant functional connectivity. Electroencephalography (EEG) microstates represent transient large-scale resting networks and have emerged as candidate markers for AD. However, their modulation by repetitive TMS (rTMS) and intermittent theta burst stimulation (iTBS) protocols remains to be elucidated.

METHODS: Resting-state EEG was recorded from 28 AD patients at baseline and following the 1st, 7th, and 14th sessions of rTMS or iTBS treatment. Polarity-insensitive modified k-means clustering was used to segment EEGs into constituent microstates, which were then subjected to source localization to identify their corresponding cortical regions. Longitudinal changes within subjects in clinical status and microstate parameters (duration, occurrence, coverage, transition probability) were evaluated with one-way repeated-measures analysis of variance, and differences between rTMS and iTBS groups were assessed using t-tests.

RESULTS: Four microstates (MS A-D) were identified from EEG data. rTMS predominantly induced sustained suppression of MS-B, whereas iTBS elicited early-phase increases in MS-C activity. Clinical symptoms improvement following TMS correlated with increased MS-C and decreased MS-B activity. Source localization revealed rTMS predominantly modulated MS-B generators in the occipital cortex (impacting visual and dorsal attention networks), while iTBS preferentially engaged MS-C generators in the parietal cortex (affecting sensorimotor and frontoparietal networks).

CONCLUSIONS: We identified distinct EEG microstates and their underlying cortical generators associated with clinical improvement in AD following treatment with rTMS and iTBS protocols. The results demonstrate protocol-specific spatiotemporal modulation profiles and temporal dynamics, highlighting differential neural mechanisms of rTMS and iTBS.}, } @article {pmid41991301, year = {2026}, author = {Guo, SF and Wang, EL and Zeng, JX and Hou, YQ}, title = {[Research progress on the pathogenesis of Alzheimer's disease related to infectious pathogens].}, journal = {Zhonghua yu fang yi xue za zhi [Chinese journal of preventive medicine]}, volume = {60}, number = {4}, pages = {631-639}, doi = {10.3760/cma.j.cn112150-20250607-00522}, pmid = {41991301}, issn = {0253-9624}, support = {2024ZDXK0065//Key Discipline Project of Shanghai Municipal Health Commission/ ; 24SJYXZDA06//Key Discipline Project of Shanghai Songjiang District Municipal Health Commission/ ; 23ZR1457300//Project supported by the Shanghai Committee of Science and Technology/ ; 82401655//National Natural Science Foundation of China/ ; }, mesh = {Humans ; *Alzheimer Disease/microbiology/etiology ; }, abstract = {Alzheimer's disease (AD), one of the most prevalent neurodegenerative disorders, is clinically characterized by progressive memory decline and cognitive impairment, predominantly affecting the elderly population. The pathogenesis of AD remains incompletely elucidated, and effective curative treatments are currently lacking. Notably, China has become the country with the highest number of AD cases globally. Growing evidence suggests that infections may play a crucial role in the initiation and progression of AD, though the precise mechanisms remain unclear. This review systematically examines how infectious agents participate in AD pathogenesis through key pathways including: driving neuroinflammatory responses, disrupting the blood-brain barrier and mediating central nervous system invasion, programmed cell death, and modulating epigenetic regulation and gene expression. We focus on recent advances in understanding the associations between AD and diverse pathogens including viruses, bacteria, fungi, and parasites. Finally, we discuss current anti-infective therapeutic strategies and outline future research priorities, aiming to provide novel theoretical foundations and investigative approaches for AD prevention and treatment.}, } @article {pmid41991715, year = {2026}, author = {Wei, P and Zhu, T and Hashimoto, K and Jia, M and Yang, JJ}, title = {Exploring the lung-brain axis in perioperative neurocognitive disorders: a potential therapeutic target.}, journal = {Molecular psychiatry}, volume = {}, number = {}, pages = {}, pmid = {41991715}, issn = {1476-5578}, support = {82571352//National Natural Science Foundation of China (National Science Foundation of China)/ ; 82571374//National Natural Science Foundation of China (National Science Foundation of China)/ ; 2024M761822//China Postdoctoral Science Foundation/ ; }, abstract = {Perioperative neurocognitive disorders (PND), primarily including postoperative delirium (POD) and postoperative cognitive dysfunction (POCD), are common and serious complications in elderly surgical patients. However, the exact mechanisms underlying PND are not fully understood. The lung-brain axis has recently been recognized as an important pathway in neurodegenerative diseases such as Alzheimer's disease (AD). Given that PND shares pathological features with AD, such as amyloid-β (Aβ) accumulation, the lung-brain axis may also represent a plausible mechanistic contributor to PND. Furthermore, elderly surgical patients often receive inhalation anesthetics and undergo mechanical ventilation during general anesthesia, which directly affect the lungs and may alter the pulmonary microenvironment. Therefore, we hypothesize that the lung-brain axis plays a role in the development of PND. In this article, we discuss potential mechanisms by which surgery and anesthesia-especially inhalation anesthetics and mechanical ventilation-may influence cognitive function via the lung-brain axis. Potential mechanisms include changes in the pulmonary microbiota, secretion of brain-derived neurotrophic factor, and lung-derived inflammatory responses. These pathways may disrupt the blood-brain barrier, promote neuroinflammation, and exacerbate Aβ deposition, ultimately leading to cognitive impairment. Exploring the role of the lung-brain axis could provide new insights into PND pathophysiology and reveal potential targets for prevention and treatment of PND by targeting pulmonary-mediated cascades.}, } @article {pmid41991786, year = {2026}, author = {Flores-Melivilu, D and Carrazana, E and García, N and Alarcón, S and Caru-Ruiz, M and Chacón-Fuentes, M and Santos, N and Ahumada, M and Nova, E and Diaz-Espinoza, R and Sanhueza, M and Hormazábal, E and Salvadores, N}, title = {Aristotelia chilensis Fruit Extracts Exhibit Neuroprotective Properties Against Alzheimer's Disease Related Mechanisms.}, journal = {Molecular neurobiology}, volume = {63}, number = {1}, pages = {}, pmid = {41991786}, issn = {1559-1182}, mesh = {*Neuroprotective Agents/pharmacology/therapeutic use ; *Alzheimer Disease/pathology/drug therapy ; *Plant Extracts/pharmacology/therapeutic use ; *Fruit/chemistry ; Animals ; Amyloid beta-Peptides/metabolism ; Cell Survival/drug effects ; Glutamic Acid/toxicity ; Neurons/drug effects/pathology/metabolism ; Humans ; *Elaeocarpaceae/chemistry ; }, abstract = {Aristotelia chilensis (maqui) extracts have garnered interest for their potential bioactivity, yet their specific effects on Alzheimer's disease (AD) pathology remain understudied. This study evaluated the neuroprotective properties of white and black maqui fruit extracts against glutamate-induced excitotoxicity and β-amyloid (Aβ) fibrillogenesis in vitro. Pre-treatment with maqui extracts significantly mitigated glutamate toxicity, increasing cell viability from 26.8% in glutamate-treated cells to 49.9% and 48.8% for white and black maqui, respectively. Furthermore, the extracts reduced Fluorojade C-positive degenerating neurons by up to 86.4% compared to the glutamate control. The extracts also exhibited potent anti-fibrillogenic activity, suppressing Aβ fibril formation by up to 77% in the ThT assay. Electron microscopy confirmed this inhibitory effect by showing a reduction in fibrillar structures. In contrast, neither extract inhibited acetylcholinesterase nor butyrylcholinesterase activity. Together, these results indicate that maqui fruits contain compounds capable of modulating key pathological features of AD in vitro, supporting their potential for further investigation.}, } @article {pmid41992240, year = {2026}, author = {Bhargavan, B and Annadurai, N and Kanmogne, GD}, title = {Effects of HIV and azidothymidine on Alzheimer's-like pathology and amyloid beta transporters in hu-PBL-NSG mice, brain endothelial amyloid beta uptake and endothelial barrier integrity.}, journal = {Fluids and barriers of the CNS}, volume = {23}, number = {1}, pages = {}, pmid = {41992240}, issn = {2045-8118}, mesh = {Animals ; *Zidovudine/pharmacology ; *Amyloid beta-Peptides/metabolism/drug effects ; *Brain/metabolism/drug effects/pathology ; *Alzheimer Disease/metabolism/pathology ; Mice ; Receptor for Advanced Glycation End Products/metabolism/drug effects ; *Anti-HIV Agents/pharmacology ; Peptide Fragments/metabolism ; *HIV Infections/drug therapy/metabolism/complications ; tau Proteins/metabolism/drug effects ; Disease Models, Animal ; Nerve Tissue Proteins/metabolism/drug effects ; Male ; *Blood-Brain Barrier/drug effects/metabolism ; DNA-Binding Proteins ; Low Density Lipoprotein Receptor-Related Protein-1 ; }, abstract = {BACKGROUND: Despite increased life expectancy with antiretroviral therapy, people with HIV (PWH) have significantly higher prevalence of comorbid diseases, including neurocognitive impairment. PWH and neurocognitive impairment often show features of Alzheimer’s-like pathologies, including increased brain amyloid-beta (Aβ) and phospho-Tau; it is not known if antiretroviral drugs contribute to the development of these pathologies or potentiate HIV effects. We aimed to investigate whether azidothymidine (AZT), a drug still used by PWH in many resource-limited countries, alters or potentiates HIV-induced Alzheimer’s-like pathologies. METHODS: Hu-PBL-NSG mice plasma/serum and brain tissues were analyzed to investigate the effects of HIV-1 infection and AZT treatment on viremia, immunosuppression, phospho-Tau, Aβ42, neuronal NeuN, endothelial claudin-5, ZO-1, and Aβ transporters [low-density lipoprotein receptor–related protein-1 (LRP1) and receptor for advanced glycation end-products (RAGE)] transcription, expression, and proteolytic cleavage. In vitro, we assessed the effects of HIV-1 Tat and AZT on Aβ42 aggregation, endothelial LRP1 and RAGE expression, Aβ uptake and transport. RESULTS: HIV significantly increased brain phospho-Tau (serine199, threonine181, serine396), brain and plasma Aβ42, decreased LRP1, NeuN, claudin-5, ZO-1, and increased RAGE transcription and expression, increased soluble(s)LRP1 and decreased sRAGE. AZT treatment of infected animals decreased blood and brain viremia and reduced HIV-induced immunosuppression but had no effect on HIV-induced brain Aβ42, phospho-Tau, NeuN, claudin-5, ZO-1, LRP1 or RAGE transcription, expression, or cleavage. AZT treatment of non-infected animals significantly increased phospho-Tau in the brain somatosensory cortex, decreased LRP1, NeuN, claudin-5, and ZO-1, and increased RAGE transcription and expression, increased sLRP1 and decreased sRAGE. Tat decreased LRP1 and increased RAGE expression in brain endothelial cells, and AZT accentuated Tat-induced effects. AZT+Tat significantly increased Aβ aggregation and AZT significantly increased endothelial Aβ42 uptake/retention. CONCLUSIONS: HIV and AZT independently dysregulate NeuN, claudin-5, ZO-1, LRP1 and RAGE transcription, expression, and proteolytic cleavage in hu-PBL-NSG mice. Such dysregulation of neuronal nuclei, endothelial tight junction proteins, and Aβ transporters could contribute to increased neurovascular injury and altered Aβ clearance following HIV infection and/or AZT treatment. In the presence of Tat, AZT increased Aβ aggregation. AZT also increased endothelial Aβ uptake/retention, which suggests that AZT may contribute to brain endothelium impairment and dysfunction.}, } @article {pmid41992414, year = {2026}, author = {Micocci, S and Parisotto, S and Alberti, D and Lanfranco, A and Bitonto, V and Renzi, P and Salmi, M and Magnani, A and Bello, FD and Pagano, K and Ragona, L and Protti, N and Deagostino, A and Geninatti Crich, S}, title = {Carboranyl-Curcuminoids for the Neutron Capture-Based Treatment of Amyloid Aggregates in Alzheimer's Disease.}, journal = {Advanced science (Weinheim, Baden-Wurttemberg, Germany)}, volume = {}, number = {}, pages = {e21701}, doi = {10.1002/advs.202521701}, pmid = {41992414}, issn = {2198-3844}, support = {D13C22003520001//Dipartimenti di Eccellenza/ ; D13C25000220007)//Compagnia di San Paolo/ ; 964934//H2020 Future and Emerging Technologies/ ; }, abstract = {Alzheimer's disease (AD) is a neurodegenerative disorder characterized by progressive cognitive decline. The aggregation of amyloid-beta (Aβ) peptides into oligomers and fibrils is central to its pathogenesis. While oligomers represent the most neurotoxic species, larger aggregates serve as reservoirs, maintaining pathological Aβ levels. To our knowledge, this study is the first to investigate Boron Neutron Capture Therapy (BNCT) as a method to selectively destabilize Aβ aggregates. This is achieved by inducing structural modifications in the Aβ peptide, aiming to convert fibrils into innocuous species. The approach utilizes [10]B-enriched monocarbonyl analogs of curcumin (BMACs), a novel molecule that binds to Aβ fibrils and enables the site-specific release of high-linear-energy-transfer (LET) α particles and lithium ions upon neutron exposure. In vitro, Aβ aggregates were characterized using FESEM and Thioflavin T staining. The binding affinities of BMACs were determined through competition assays, with inhibition constants calculated using the Cheng-Prusoff equation. Post-irradiation analysis by [1]H-NMR and mass spectrometry demonstrated selective oxidation of histidine residues, a chemical modification capable of inducing fibril destabilization. This study provides proof of concept that not only offers future perspectives for Alzheimer's treatment but also enhances the understanding of radiation effects on proteins, particularly within the context of amyloidosis.}, } @article {pmid41992726, year = {2026}, author = {Evers, A and Watson, K and Abbasi, F and Haque, K and Verma, A and Eitan, E and Rasgon, N}, title = {Insights from changes in NDEV biomarkers of metabolism: Effects of PPARγ and GLP1 receptor agonists on brain metabolism.}, journal = {The Journal of clinical endocrinology and metabolism}, volume = {}, number = {}, pages = {}, doi = {10.1210/clinem/dgag176}, pmid = {41992726}, issn = {1945-7197}, abstract = {BACKGROUND: Insulin resistance (IR) is implicated in central nervous system disorders, including depression and Alzheimer's disease (AD).

METHODS: We analyzed biological samples from two cohorts of clinical trial participants: 1) participants with unremitted depression after six months of treatment as usual who received pioglitazone (PPARγ agonist, N = 12) or placebo and 2) middle-aged participants at genetic risk for AD who received liraglutide (glucagon-like peptide 1 [GLP1] receptor agonist, N = 15) or placebo. These cohorts, which previously showed treatment-related improvements in peripheral IR, were used to assess the effects of pioglitazone and liraglutide on CNS insulin signaling using neuron-derived extracellular vesicles (NDEVs) as biomarkers. We utilized biological samples to measure biomarkers of IR in NDEVs. Eleven Akt-mTOR pathway proteins were measured before and after 12 weeks of treatment in both groups.

RESULTS: Participants who received pioglitazone experienced broader changes, with significant increases in GSK3β (Ser9), mTOR (Ser2448), and RPS6 (Ser235/Ser236; all p ≤ 0.02) compared to placebo, and 77% of participants showed mTOR (Ser2448) response. Participants who received liraglutide demonstrated significantly increased NDEV-associated phosphorylated Akt (Ser473) and mTOR (Ser2448; p = 0.04 and p = 0.025, respectively) compared to placebo, with 40% and 30% of participants in the liraglutide group showing biomarker response in both Akt (Ser473) and mTOR (Ser2448), respectively. These effects appeared relatively independent from changes in fasting plasma insulin and glucose concentration at 120-minutes during the oral glucose tolerance test.

DISCUSSION: Our findings demonstrate CNS-specific biomarker responses to both PPARγ agonists and GLP1 receptor agonists.}, } @article {pmid41993246, year = {2026}, author = {Pattanashetty, SG and Serrano, PA and Rockwell, P and Xie, L and Figueiredo-Pereira, ME}, title = {Terazosin drives sex-dependent adrenergic-bioenergetic reprogramming to restore network function in Alzheimer's disease.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, doi = {10.64898/2026.04.02.716175}, pmid = {41993246}, issn = {2692-8205}, support = {R01 AG057555/AG/NIA NIH HHS/United States ; R33 AG083302/AG/NIA NIH HHS/United States ; }, abstract = {Alzheimer's disease (AD) has long been defined by amyloid-β plaques and hyperphosphorylated tau, yet disease-modifying therapies remain critically limited. Growing evidence reframes AD as a system-level failure driven by early dysregulation of synaptic, metabolic, and neuroimmune pathways, preceding overt protein aggregation and originating in selectively vulnerable circuits, including the locus coeruleus (LC)-hippocampal noradrenergic axis. This complexity underscores the need for therapeutic strategies that engage the disease at a network level, early in its trajectory. To this end, using a machine learning-based systems pharmacology framework for drug repurposing applied to human AD transcriptomic datasets, we identified terazosin (TZ) as a candidate predicted to reverse AD-associated molecular signatures. TZ is an FDA-approved α1-adrenergic receptor antagonist and phosphoglycerate kinase-1 activator. It was administered chronically via the diet (0.5 mg/kg bw/day) to male and female TgF344-AD rats and wild-type littermates from 5 to 11 months of age, preceding overt pathology. Bulk hippocampal RNA sequencing revealed sex-specific transcriptional remodeling in transgenic rats, strongly conserved with human AD datasets. Male TgF344-AD rats exhibited suppression of synaptic and transcriptional maintenance pathways with concurrent activation of metabolic, proteostatic, extracellular matrix, and vascular stress responses; females showed suppression of survival and vascular structural signaling alongside heightened DAM-like immune activation, amyloid-associated stress, and cell death programs. TZ reversed these signatures in a sex-dependent manner: males showed enhanced immune surveillance and reduced proteostasis burden, while females showed reinforcement of synaptic, survival, and metabolic pathways. TgF344-AD rats displayed selective LC-derived hippocampal noradrenergic axonopathy without global neuronal loss. TZ preserved fiber integrity preferentially in females and partially reversed LC vulnerability-associated transcriptional signatures in both sexes. TZ also reduced amyloid-β plaque burden in both sexes, attenuated hyperphosphorylated tau exclusively in females, and induced microglial morphological shifts in males. Finally, TZ restored wild-type spatial learning in transgenic animals, with females appearing to derive the greater cognitive benefit. Together, these findings demonstrate that TZ induced systems-level reprogramming of AD-relevant molecular pathways and preserved vulnerable noradrenergic circuitry in a sex-dependent manner. Moreover, TZ rescued spatial cognition in transgenic rats, with cognitive gains seemingly more pronounced in females. These results support adrenergic-bioenergetic modulation as a translational strategy for early-stage AD and underscore the necessity of sex as a biological variable in disease-modifying treatment development.}, } @article {pmid41993400, year = {2026}, author = {Kammala, AK and Tatiparthy, M and Sreenivasmurthy, SGS and Garza, KH and Budhwani, S and Richardson, L and Menon, R and Krishnan, B}, title = {Exofection as a Therapeutic Modality: Restoring P-gp Activity via Trophoblast-Derived EV in Neuroinflammatory Disorders.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, doi = {10.64898/2026.04.02.716001}, pmid = {41993400}, issn = {2692-8205}, abstract = {BACKGROUND: P-glycoprotein (P-gp/ABCB1) is a key efflux transporter that maintains barrier integrity by clearing xenobiotics and toxic metabolites. At the feto-maternal interface, trophoblast-derived extracellular vesicles (CTC-EVs) naturally and transiently transfer functional P-gp to maternal decidual cells, restoring lost and or reduced P-gp function (exofection) to sustain pregnancy homeostasis. A similar loss of P-gp at the blood brain barrier (BBB) contributes to impaired amyloid-β (Aβ) clearance and neuroinflammation in Alzheimer's disease. We investigated whether CTC-EV-mediated exofection could restore P-gp function in human brain endothelial cells (hBECs) and enhance Aβ clearance under inflammatory and neurodegenerative conditions.

METHODS: CTC-EVs were isolated and characterized by nanoparticle tracking analysis and western blotting for P-gp and EV markers. Transcriptomic profiling of CTC-EVs identified enrichment of transporter-related genes, including solute carriers and ABC transporters, along with inflammatory mediators. Network analysis revealed coordinated modules linking EV cargo to transporter regulation, endocytosis/trafficking pathways, and inflammatory remodeling processes converging on BBB efflux activity. hBECs were exposed to LPS (500 ng/mL, 48 h) with or without CTC-EVs. P-gp expression was assessed by immunofluorescence (mean fluorescence intensity, MFI) and western blotting, while functional efflux was measured using Calcein-AM assays. Aβ oligomer transport was evaluated using a transwell hBEC model. In vivo, 3xTg-AD mice received intravenous CTC-EVs (1×10L/day for 5 days), followed by assessment of P-gp expression, Aβ burden, and neuroinflammatory markers. Pharmacokinetic studies in P-gp knockout mice were conducted to confirm functional transporter recovery.

RESULTS: LPS exposure significantly reduced P-gp expression in hBECs (41.3% decrease in MFI, p=0.0084), which was restored by CTC-EVs (46.7% increase vs. LPS, p=0.0121). Exofection increased P-gp by a 2.1-fold following EV treatment as determined by western blot. Functional assays demonstrated enhanced efflux, with a 38.5% reduction in intracellular Calcein fluorescence (p<0.001). Network-informed mechanisms supported coordinated regulation of transporter and trafficking pathways. CTC-EVs improved Aβ transport across inflamed hBEC monolayers. In vivo, EV-treated 3xTg-AD mice exhibited increased P-gp expression in the frontal cortex (38.6%) and hippocampus (42.1%), reduced Aβ plaque burden (27.9%), and decreased inflammatory markers (IL-1β and TNF-α, p<0.05). In P-gp knockout mice, EVs reduced brain drug accumulation by 22.4% (p=0.032), confirming restoration of transporter function.

CONCLUSION: CTC derived EVs are natural carriers of functional transporter proteins and restore efflux capacity in compromised endothelial barriers. Integration of transcriptomic and network analyses highlights coordinated regulation of transporter, trafficking, and inflammatory pathways underlying exofection. This reproductive biology inspired strategy offers a promising therapeutic approach for enhancing Aβ clearance and mitigating neuroinflammation in Alzheimer's disease.}, } @article {pmid41993974, year = {2026}, author = {Han, H and Hou, L and Lu, J and Sun, H and Ning, W and Liang, Y and Gu, Y and Yin, H and Gao, Q}, title = {The intellectual landscape of cognitive impairment in type 2 diabetes: knowledge structure, research focuses and rising trends.}, journal = {Frontiers in endocrinology}, volume = {17}, number = {}, pages = {1809245}, pmid = {41993974}, issn = {1664-2392}, mesh = {*Diabetes Mellitus, Type 2/complications/psychology ; Humans ; *Cognitive Dysfunction/etiology/epidemiology/psychology ; Bibliometrics ; *Biomedical Research/trends ; }, abstract = {BACKGROUND: Type 2 diabetes mellitus (T2DM) is prevalent worldwide, with cognitive dysfunction emerging as a significant complication. Despite extensive research into its pathological mechanisms and clinical management, the knowledge structure, research priorities, and developmental trends within this field remain unsystematically integrated.

METHODS: To ensure comprehensive coverage and compatibility with bibliometric analysis tools, relevant publications on type 2 diabetes mellitus (T2DM) and cognitive dysfunction were primarily retrieved from the Web of Science Core Collection (WOSCC) database from its inception to November 5, 2025. Searches were also conducted in PubMed and Scopus to verify completeness, but the final dataset was derived mainly from WOSCC due to its optimal export format for CiteSpace (plain text with full records and cited references) and high overlap after deduplication. Employing bibliometric methods and tools such as CiteSpace (version 6.4 Advanced) and SCImago Graphica (version 1.0.39), we conducted visual analyses of publication trends, country/region collaboration, institutional distribution, author contributions, journal impact, co-cited references, and keywords.

RESULTS: A total of 1,752 publications were included. Annual publication volume exhibited a marked upward trend, accelerating particularly after 2018. China, the United States, and the United Kingdom were the primary contributing nations, with close inter-institutional collaboration. High-frequency keywords included 'type 2 diabetes mellitus', 'Alzheimer's disease', and 'cognitive impairment'. Research focus has shifted from early risk factors to microscopic levels, including neuroimaging, gut microbiota, and molecular mechanisms.

CONCLUSION: Research on cognitive dysfunction in T2DM exhibits multidisciplinary characteristics, balancing fundamental research with clinical translation. Future efforts should enhance multidimensional integration of mechanism studies to advance early screening and personalised treatment strategies.}, } @article {pmid41994122, year = {2026}, author = {Iglesias, JE and Johnson, IP and Williams-Ramirez, J and Zemlyanker, D and Tian, L and Gopinath, K and Olchanyi, M and Farnan, AD and Demopoulos, A and Rosen, MS and Sheth, KN and de Havenon, A and Kimberly, WT and Sorby-Adams, A}, title = {On the accuracy of image registration in portable low-field 3D brain MRI.}, journal = {Research square}, volume = {}, number = {}, pages = {}, pmid = {41994122}, issn = {2693-5015}, abstract = {Portable low-field MRI offers an affordable and mobile alternative to conventional high-field scanners, enabling imaging in point-of-care and resource-limited settings. However, its lower signal-to-noise ratio, reduced resolution, and acquisition artifacts raise concerns about the accuracy of standard image registration methods. Reliable registration is critical for a wide range of emerging applications, including frequent brain monitoring, assessment of neurodegenerative disease progression, and evaluation of treatment effects such as those of Alzheimer's therapeutics. In this work, we systematically evaluated state-of-the-art registration approaches on simulated low-field scans (obtained by downsampling high-field images) and on real low-field brain MRI data. We compared three representative approaches: classical optimization (NiftyReg), learning-based registration (SynthMorph), and synthesis-based registration (SynthSR+NiftyReg). Using downsampled high-field scans, all methods performed well, achieving high Dice scores and smooth deformation fields, indicating that reduced resolution alone does not hinder registration. In contrast, real low-field data exhibited lower accuracy, primarily due to geometric distortion and other acquisition-specific artifacts. Among the tested approaches, the synthesis-based pipeline achieved the most robust performance across subjects and modalities. Overall, existing algorithms can accommodate resolution limitations, however, future methods could further enhance coregistration by explicitly addressing the distortions present in low-field MRI scans.}, } @article {pmid41994275, year = {2026}, author = {Yu, T and Yu, Y and Zhao, J and Li, H and Lu, H and Li, Y and Peng, Y and Wang, S and Wei, W and Cheng, X}, title = {Qifuyin improves physiological frailty by regulating the intestinal flora in 3xTg-AD mice.}, journal = {Frontiers in microbiology}, volume = {17}, number = {}, pages = {1753643}, pmid = {41994275}, issn = {1664-302X}, abstract = {OBJECTIVE: Alzheimer's disease (AD) is often accompanied by motor dysfunction, impaired limb strength, and gut microbiota disturbances. This study aimed to evaluate the effects of Qifuyin (QFY), a traditional Chinese medicine formula, on motor deficits, limb strength, aging, and gut microbiota composition in 3xTg-AD mice, a widely used model of AD.

METHODS: Male and female 3xTg-AD mice were administered QFY at low, medium, or high doses. Motor function was assessed using grip strength and rotarod tests. Aging was evaluated through aging scores. Gut microbiota composition was analyzed at the phylum, family, genus, and species levels. Functional profiling of microbiota was performed using KEGG, eggNOG, and carbohydrate-active enzyme (CAZyme) databases. Pearson correlation analyses were conducted to explore relationships between microbiota composition and motor performance.

RESULTS: QFY treatment significantly improved both absolute and normalized grip strength in male and female 3xTg-AD mice. Similarly, motor coordination, as assessed by latency to fall on the rotarod, was significantly enhanced in the groups of QFY. Aging scores were significantly reduced after the treatment of QFY. Microbiome analysis revealed that QFY treatment restored species diversity and improved the overall composition of gut microbiota, with significant increases in Muribaculaceae and decreases in Alcaligenaceae, Rhodanobacteraceae, and Spirochaetaceae. Principal component analysis (PCA) indicated that the gut microbiota composition of the QFY group resembled that of the control (Con) group. Functional analyses showed that treatment of QFY restored microbial pathways related to metabolism and genetic information processing, with significant correlations between microbial alterations and improved motor outcomes. Additionally, QFY modulated the abundance of key carbohydrate-active enzymes, including GH43 and GH35, which were positively correlated with grip strength and rotarod performance.

CONCLUSION: Qifuyin improves motor function, reduces aging-related deficits, and restores gut microbiota homeostasis in 3xTg-AD mice. These findings suggest that QFY may offer therapeutic potential for addressing frailty and motor dysfunction in AD, in association with alterations in gut microbiota composition and predicted microbial functions.}, } @article {pmid41994888, year = {2026}, author = {Yang, Z and Sang, P and Han, Y and Jiang, B and Kong, L and Zhou, X}, title = {Personalized treatment design in the context of functional confounding.}, journal = {Biometrics}, volume = {82}, number = {2}, pages = {}, doi = {10.1093/biomtc/ujag056}, pmid = {41994888}, issn = {1541-0420}, support = {12171242//National Natural Science Foundation of China/ ; 72342019//National Natural Science Foundation of China/ ; }, mesh = {Humans ; Alzheimer Disease/therapy/diagnostic imaging ; *Precision Medicine/methods/statistics & numerical data ; Computer Simulation ; Neuroimaging ; Confounding Factors, Epidemiologic ; Models, Statistical ; Algorithms ; Support Vector Machine ; }, abstract = {One of the primary goals of individualized treatment rule (ITR) methodology is to identify optimal decision rules using clinical predictors. While functional data has become increasingly available in biomedical research, there has been limited work on incorporating functional data into ITR estimation, particularly in observational studies. In this paper, we propose a novel approach that integrates outcome-weighted learning (OWL) with reproducing kernel Hilbert space to determine optimal treatment regimes involving functional data. Furthermore, to address the issue of data piling, we employ the distance-weighted discrimination classifier instead of traditional support vector machines. We establish the theoretical consistency of the decision functional estimator with its risk bound. Extensive simulations and the analysis of the Alzheimer's Disease Neuroimaging Initiative dataset demonstrate the superior performance of our method compared to existing OWL approaches. The results highlight critical factors in Alzheimer's Disease progression and reveal limitations of the original OWL method in this context.}, } @article {pmid41996008, year = {2026}, author = {Woźniak-Mitał, J and Rasmus, P and Strombek-Milczarek, M and Kaźmierski, J}, title = {The Impact of Transcranial Direct Stimulation Therapy Combined with Intranasal Near-Infrared Stimulation on Cognitive Performance in Patients with Mild Cognitive Impairment and Alzheimer's Disease: A Pilot Randomized, Double-Blind, Placebo-Controlled Study.}, journal = {Neurology and therapy}, volume = {}, number = {}, pages = {}, pmid = {41996008}, issn = {2193-8253}, abstract = {INTRODUCTION: Alzheimer's disease (AD) and mild cognitive impairment (MCI) are progressive neurodegenerative conditions with limited therapeutic options. Neuromodulation techniques such as transcranial direct current stimulation (tDCS) and photobiomodulation (PBM) have shown promise in improving cognitive function, but their combined effects remain underexplored.

METHODS: In a pilot randomized, double-blind, placebo-controlled trial, 33 participants were assigned to either active or sham stimulation groups. The intervention consisted of 50 sessions over 10 weeks, with tDCS (2 mA, F3-F4 montage) and intranasal near-infrared stimulation (iNIRS) (850 nm, 40 Hz, 50% duty cycle) administered simultaneously. Cognitive outcomes were assessed using the Mini-Mental State Examination (MMSE) and ADAS-Cog at baseline, post-treatment, and at the 12-week follow-up.

RESULTS: Significant improvements were observed in the active group across both scales. MMSE scores increased from 21.89 ± 2.35 to 27.22 ± 1.96 (p = 0.0001), with sustained effects at follow-up. ADAS-Cog scores decreased from 34.78 ± 4.99 to 18.22 ± 4.4 (p < 0.0001). Post hoc analyses revealed significant changes in attention, recall, praxis, and executive domains. No serious adverse events were reported.

CONCLUSION: Combined tDCS and iNIRS therapy significantly enhances cognitive performance in patients with MCI and mild AD. This synergistic, non-invasive approach may offer a promising therapeutic strategy to delay cognitive decline and reduce care-related burdens.

TRIAL REGISTRATION: ClinicalTrials.gov NCT07290686; Registration date 14 December 2023.}, } @article {pmid41997210, year = {2026}, author = {Chakravarty, S and Revi, N and Bijukumar, D}, title = {Development and initial characterization of Ang-2 decorated exosome-liposome hybrid nanocarriers for BBB targeting capability: an evaluation of LRP-1 receptor mediated endocytosis.}, journal = {Biomedical materials (Bristol, England)}, volume = {21}, number = {3}, pages = {}, doi = {10.1088/1748-605X/ae6164}, pmid = {41997210}, issn = {1748-605X}, mesh = {Humans ; *Exosomes/chemistry/metabolism ; *Liposomes/chemistry ; Animals ; *Blood-Brain Barrier/metabolism ; *Endocytosis/drug effects ; *Low Density Lipoprotein Receptor-Related Protein-1/metabolism ; Zebrafish ; *Angiopoietin-2/chemistry ; *Nanoparticles/chemistry ; HEK293 Cells ; Drug Delivery Systems/methods ; Peptides/chemistry ; Endothelial Cells/metabolism ; *Drug Carriers/chemistry ; Cell Line, Tumor ; }, abstract = {Central nervous system (CNS) diseases, including Parkinson's, Alzheimer's, and brain tumors, are among the most challenging conditions to treat and are associated with high mortality rates. A significant obstacle in conventional treatment methods for CNS diseases is that many drugs struggle to penetrate the blood-brain barrier (BBB), which diminishes their effectiveness. The primary aim of the current study was to develop and characterize a hybrid nanocarrier composed of exosomes and liposomes to facilitate targeted drug delivery across the BBB for future CNS disease therapies. To achieve targeted uptake, we conjugated the exosome-liposome hybrid to the Angiopep-2 peptide (ANG-2), which has a specific affinity for the LRP-1 receptor, found on endothelial cells of the BBB. Our results indicate that exosome-liposome hybrid nanoparticles exhibit significantly greater stability than exosomes alone. Moreover, the LRP-1 ligand-decorated exo-lipo hybrids effectively targeted U87 cells (a model cell line that expresses LRP-1) more efficiently than HEK293 (a cell line with low LRP-1 expression). Additionally, our findings demonstrated that these nanocarriers successfully evaded lysosomal degradation in U87 cells. We also assessed the barrier-crossing efficiency of the nanocarriersin vivousing zebrafish embryos.}, } @article {pmid41997281, year = {2026}, author = {Yang, YP and Nicol, CJB and Yen, C and Chiang, MC}, title = {Glutathione-conjugated gold nanoparticles mitigate amyloid-beta-induced neuroinflammation and tauopathy through inhibition of NF-κB, the NLRP3 inflammasome axis in 3D human neural stem cell models.}, journal = {Experimental cell research}, volume = {459}, number = {2}, pages = {115030}, doi = {10.1016/j.yexcr.2026.115030}, pmid = {41997281}, issn = {1090-2422}, mesh = {Humans ; *Metal Nanoparticles/chemistry ; *Amyloid beta-Peptides/toxicity ; *Neural Stem Cells/drug effects/metabolism/pathology ; *Glutathione/pharmacology/chemistry ; *Gold/chemistry/pharmacology ; *NLR Family, Pyrin Domain-Containing 3 Protein/metabolism ; *NF-kappa B/metabolism/antagonists & inhibitors ; *Tauopathies/metabolism/drug therapy/pathology ; *Inflammasomes/metabolism/drug effects ; *Neuroinflammatory Diseases/metabolism/pathology/drug therapy/chemically induced ; Cell Survival/drug effects ; }, abstract = {Neuroinflammation and tauopathy are central pathological features of Alzheimer's disease (AD), often exacerbated by amyloid-β (Aβ) accumulation. This study evaluated the therapeutic potential of glutathione-conjugated gold nanoparticles (GSH-AuNPs) in mitigating Aβ-induced cytotoxicity and inflammation using a physiologically relevant 3D human neural stem cell (hNSCs) model cultured within a gelatin scaffold. This 3D system provided a tissue-like microenvironment to closely mimic in vivo conditions. GSH-AuNP treatment significantly rescued Aβ-induced loss of cell viability and suppressed tumor necrosis factor-α (TNF-α) secretion. At the molecular level, GSH-AuNPs downregulated the expression of key inflammatory mediators, including IKKα, IKKβ, and NF-κB (p65), and inhibited nuclear translocation of p65. Additionally, GSH-AuNPs attenuated the expression of proinflammatory enzymes iNOS and COX-2 and suppressed activation of the NLRP3 inflammasome, as evidenced by reduced levels of NLRP3, ASC, caspase-1, IL-1β, and IL-18. Proteostasis was improved by restoring chymotrypsin-like proteasome activity and reducing phosphorylated tau accumulation. Furthermore, GSH-AuNPs enhanced cellular resilience by upregulating heat shock factor 1 (HSF1) and normalizing the expression of key molecular chaperones HSP27, HSP70, and HSP90. Our findings highlight the multifaceted protective effects of GSH-AuNPs in counteracting Aβ-induced neuroinflammation and tauopathy. These results support the potential application of GSH-AuNPs as a nanomedicine-based therapeutic strategy for AD.}, } @article {pmid41997401, year = {2026}, author = {Sun, X and Deng, W and Yu, J and Xu, X}, title = {From mechanisms to therapeutics: The expanding role of cell-based strategies in Alzheimer's disease.}, journal = {European journal of pharmacology}, volume = {1023}, number = {}, pages = {178867}, doi = {10.1016/j.ejphar.2026.178867}, pmid = {41997401}, issn = {1879-0712}, mesh = {Humans ; *Alzheimer Disease/therapy/pathology ; Animals ; *Cell- and Tissue-Based Therapy/methods ; }, abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by cognitive decline. Its core pathologies include the deposition of amyloid-β plaques, the formation of neurofibrillary tangles composed of hyperphosphorylated tau protein, chronic neuroinflammation, and neuronal loss. With the rapidly aging global population, the prevalence of AD continues to rise. Current pharmacological treatments offer only limited symptomatic relief and cannot modify the underlying disease trajectory, leaving a significant unmet clinical need. In this context, cell-based therapy has emerged as a promising therapeutic strategy, leveraging its unique multi-targeted and regenerative capacities. This review systematically examines the therapeutic potential of various cell types, including mesenchymal stem cells, neural stem cells, immune cells, and engineered cells. We elaborate on their mechanisms of action, which encompass neurotrophic support, immunomodulation, and clearance of pathological proteins. These concerted actions contribute to remodeling the hostile brain microenvironment and promoting neuroregeneration in AD. Although preclinical evidence is robust, the clinical translation of cellular therapies faces considerable challenges. These hurdles include selecting the optimal cell source, developing efficient delivery strategies, determining the ideal intervention timing, and establishing standardized manufacturing protocols. Looking forward, we discuss how the development of precise disease models, the integration of gene editing and engineering strategies, advances in combination therapies, and the establishment of personalized treatment regimens are poised to position cell therapy at the forefront of comprehensive AD management. These innovations hold new promise for achieving true disease modification.}, } @article {pmid41997458, year = {2026}, author = {Chen, F and Lv, X and Xiang, K and Lin, X and Dai, C and Wei, C and Zhang, Y and Liu, J and Li, J}, title = {Pterostilbene targets microglia-mediated neuroinflammation for Alzheimer's therapy.}, journal = {The Journal of nutritional biochemistry}, volume = {155}, number = {}, pages = {110382}, doi = {10.1016/j.jnutbio.2026.110382}, pmid = {41997458}, issn = {1873-4847}, mesh = {Animals ; *Alzheimer Disease/drug therapy/metabolism ; *Microglia/drug effects/metabolism ; *Stilbenes/pharmacology ; Janus Kinase 2/metabolism ; Mice, Transgenic ; Mice ; Molecular Docking Simulation ; Amyloid beta-Peptides/metabolism ; STAT3 Transcription Factor/metabolism ; Male ; *Neuroinflammatory Diseases/drug therapy/metabolism ; Neuroprotective Agents/pharmacology ; Phosphorylation ; tau Proteins/metabolism ; Signal Transduction/drug effects ; Cytokines/metabolism ; }, abstract = {Microglia-mediated neuroinflammation is a key driver of Alzheimer's disease (AD) progression, exacerbating neuronal damage and pathological changes. Pterostilbene (PTE), a natural anti-inflammatory stilbenoid, shows neuroprotective potential in AD, but its specific mechanism in regulating AD-related neuroinflammation remains unclear. Here, we explored the anti-neuroinflammatory effect and mechanisms of PTE against AD. APPswe/PS1dE9 (APP/PS1) transgenic mice were treated intragastrically with PTE for 4 weeks, followed by evaluation of cognitive function and pathological changes. Amyloid-β burden, Tau protein phosphorylation, microglial activation, and proinflammatory cytokines production were analyzed. To further investigate the potential mechanism of PTE, an integrated approach combining network pharmacology, RNA sequencing, molecular docking, molecular dynamics simulations, and cell transfection techniques were conducted. Our results showed that PTE treatment improved cognitive impairment, amyloid-β deposits, Tau protein phosphorylation, microglia activation, and production of tumor necrosis factor-α, interleukin-1β, and interleukin-6 in vivo and in vitro. Notably, molecular docking predicted that PTE has binding affinity for Janus kinase 2 (JAK2) at LYS-857, LYS-882, and LEU-932. Consistently, site-directed mutagenesis reduced the inhibitory effect of PTE on JAK2/signal transducer and activator of transcription 3 (STAT3) phosphorylation, supporting JAK2 as a functional target. Meanwhile, we revealed that PTE effectively inhibited activation of microglia in the APP/PS1 mice by regulating JAK2-STAT3 pathway. These findings indicate that PTE treatment could attenuate microglia-mediated neuroinflammation via regulating JAK2-STAT3 signaling pathway, which might provide a novel option to elucidate the effects of PTE on AD.}, } @article {pmid41997498, year = {2026}, author = {Pillarisetti, S and Alfieri, R and Palumbo, P and Sarmento, B and Celia, C and Fresta, M}, title = {Oxidative cues as theranostic switches for the ROS-responsive Nanotheranostics in oxidative stress-driven diseases.}, journal = {Journal of controlled release : official journal of the Controlled Release Society}, volume = {394}, number = {}, pages = {114933}, doi = {10.1016/j.jconrel.2026.114933}, pmid = {41997498}, issn = {1873-4995}, mesh = {Humans ; *Reactive Oxygen Species/metabolism ; *Oxidative Stress ; *Theranostic Nanomedicine/methods ; Animals ; Neoplasms/metabolism/drug therapy/diagnosis ; Cardiovascular Diseases/metabolism/drug therapy ; }, abstract = {Nanotheranostics (NTs) are nanoscale systems that combine disease diagnosis and targeted therapy. They often respond to specific signals, such as reactive oxygen species (ROS). These platforms leverage elevated ROS levels associated with diseases, such as neurodegeneration, cancer, cardiovascular disorders, and inflammation, to control drug release and support targeted imaging. In this review, we have described the different roles of ROS in neurological disorders (Alzheimer's disease), cancer, cardiovascular diseases (including atherosclerosis and myocardial infarction), and joint inflammation (arthritis). We also discuss the relative applications of ROS-responsive NTs. By integrating diagnosis and treatment, ROS-responsive NTs can improve treatment outcomes, reduce side effects, and help clinicians track disease progression and therapeutic response in real time. Advanced NTs are sensitive to additional triggers, such as pH, thermal, and hypoxic conditions. This sensitivity improves accuracy and outcomes for ROS-driven diseases. This strategy shows promise for precision medicine by using multifunctional, stimulus-activated nanomedicines to treat diseases driven by oxidative stress. This review summarizes recent advances, focusing on nanomaterial composition and chemistry for ROS response or scavenging to improve diagnosis and treatment. Finally, we explore current advances and perspectives on ROS-based NTs across ROS-driven diseases.}, } @article {pmid41997807, year = {2026}, author = {Washer, SJ and Frith, M and Cowan, E and Dempster, E and Mill, J and Farrow, SL}, title = {Epigenetic biomarkers in neurodegenerative diseases: from molecular signatures to therapeutic targets.}, journal = {Trends in neurosciences}, volume = {49}, number = {5}, pages = {373-389}, doi = {10.1016/j.tins.2026.03.004}, pmid = {41997807}, issn = {1878-108X}, mesh = {Humans ; *Neurodegenerative Diseases/genetics/diagnosis/therapy/metabolism ; *Epigenesis, Genetic/genetics ; Animals ; *Biomarkers/metabolism ; DNA Methylation ; Chromatin/genetics ; }, abstract = {Collectively, neurodegenerative diseases impose an escalating global health burden, representing one of the leading causes of death and disability worldwide. Despite their growing prevalence, diagnosis and treatment remain major challenges, partly due to the absence of specific and reliable biomarkers for early detection, disease monitoring, and prognosis. Epigenetic biomarkers are emerging as promising clinical tools, although their potential in the context of neurodegenerative diseases is not yet fully realised. In this review, we provide an overview of advances in the understanding of DNA modifications and chromatin architecture in neurodegeneration, highlighting translational relevance for biomarker discovery and therapeutic development. Finally, building on insights from other diseases where epigenetic biomarkers are already applied, we discuss the key steps required to enable implementation in neurodegenerative diseases.}, } @article {pmid41998020, year = {2026}, author = {Bisht, M and Gomes, MC and Bordon Sosa, FH and Mano, JF and Pandey, S and Ventura, SPM and Coutinho, JAP}, title = {Superbase ionic liquid mediated solubilization of curcumin for improved bioavailability and anticancer efficacy.}, journal = {Scientific reports}, volume = {16}, number = {1}, pages = {}, pmid = {41998020}, issn = {2045-2322}, support = {REDE/1517/RMN/2005//Fundação para a Ciência e a Tecnologia/ ; PDF/2019/001024//Government of India/ ; }, mesh = {*Curcumin/pharmacology/chemistry/pharmacokinetics ; *Ionic Liquids/chemistry ; Solubility ; Humans ; *Antineoplastic Agents/pharmacology/chemistry/pharmacokinetics ; Biological Availability ; Cell Line, Tumor ; Animals ; Cell Survival/drug effects ; Mice ; }, abstract = {Curcumin is a promising natural drug for the treatment of various diseases ranging from cancer to Alzheimer’s. However, a major hindrance in its use as a drug is its low aqueous solubility, rapid degradation, and poor cellular uptake. In recent years, the use of ionic liquids (ILs) in biomedical applications has gained significant attention due to their unique properties and tunability. In this study, we demonstrate the capacity of the superbase ionic liquid (SBIL) 5-Methyl-1,5,7-triaza-bicyclo[4.3.0]non-6-enium acetate [mTBNH][OAc] to dissolve highly hydrophobic and water-insoluble curcumin. An optimized concentration of 4 mol.kg-1 of SBIL was used to dissolve 3.5 mg.g-1 of curcumin, resulting in a formulation (curcumin/SBIL) that could be easily dispersed in an aqueous medium. Compared to the aqueous solubility of curcumin alone, the curcumin/SBIL formulation exhibited almost an 8,000-fold increase in solubility, also demonstrating a reduction of ~ 60% of human triple-negative breast cancer epithelial cells (MDA-MB-231) viability with only 10 µg.mL-1 of curcumin (the active compound), without any cytotoxic effects on non-tumorogenic mouse fibroblasts (L929). Our study presents a straightforward methodology for improving the solubility and bioavailability of curcumin, which holds promise for its clinical application as an effective anti-cancer drug.}, } @article {pmid41998449, year = {2026}, author = {Chauhan, P and Wadhwa, K and Singh, G}, title = {Geraniol and Z-guggulsterone co-treatment attenuates Alzheimer's disease in adult zebrafish by targeting oxidative damage, neuroinflammation, mitochondrial stress, and synaptic dysfunction.}, journal = {Inflammopharmacology}, volume = {34}, number = {5}, pages = {3703-3723}, pmid = {41998449}, issn = {1568-5608}, mesh = {Animals ; Zebrafish ; *Alzheimer Disease/drug therapy/metabolism ; *Oxidative Stress/drug effects ; *Acyclic Monoterpenes/pharmacology/administration & dosage ; *Pregnenediones/pharmacology/administration & dosage ; Neuroprotective Agents/pharmacology/administration & dosage ; Disease Models, Animal ; Mitochondria/drug effects/metabolism ; Male ; Drug Therapy, Combination ; Inflammation/drug therapy/metabolism ; }, abstract = {Given the multifactorial pathogenesis of Alzheimer's disease (AD) and the limited efficacy of single-target drug therapy, there is a growing scientific need for combination regimens to concurrently target various AD-associated cascades. Currently, plant-derived phytoconstituents, with their intrinsic multi-target properties, represent a promising component for combination therapy, offering translational potential with enhanced neuroprotection. In this avenue, the current study aimed to explore the combined neuroprotective effects of geraniol (a monoterpenoid alcohol) and Z-guggulsterone (a phytosterol) in streptozotocin (STZ)-induced AD model of adult zebrafish (4-6 months old). Following intracerebroventricular STZ injection, zebrafish were treated with geraniol and Z-guggulsterone per se and in combination for 28 consecutive days. On day 27, a novel tank diving test and a light/dark preference test were performed to evaluate locomotive and cognitive impairments. Afterwards, the fish were evaluated for numerous blood parameters, including blood glucose and serum cholesterol levels, followed by biochemical assessment of oxidative stress markers, mitochondrial complexes, neuroinflammatory cytokines, and neurotransmitter levels. Results demonstrated that co-therapy of geraniol and Z-guggulsterone significantly ameliorated cognitive deficits, reduced anxiety-like behaviours, impeded acetylcholinesterase activity, regulated neurotransmitter levels (glutamate and acetylcholine), mitigated oxidative stress markers, and prevented mitochondrial dysfunction, compared to monotherapies. Additionally, downregulation of TNF-α was also observed, affirming suppression of detrimental neuroinflammatory processes. Collectively, these findings support the neuroprotective potential of geraniol and Z-guggulsterone co-therapy in the zebrafish model of AD; however, future research is warranted to explore the potential clinical application of this combination therapy in AD.}, } @article {pmid42000003, year = {2026}, author = {Zou, F and Ren, X and Huo, G and Liu, P and Sun, C}, title = {Tianwang Buxin Pill improves cognitive function in APP/PS1 mice by reducing neuronal damage and regulating synaptic plasticity.}, journal = {Journal of ethnopharmacology}, volume = {367}, number = {}, pages = {121683}, doi = {10.1016/j.jep.2026.121683}, pmid = {42000003}, issn = {1872-7573}, mesh = {Animals ; *Drugs, Chinese Herbal/pharmacology ; *Neuronal Plasticity/drug effects ; *Alzheimer Disease/drug therapy/pathology/metabolism ; *Neurons/drug effects/pathology ; Mice ; Male ; *Cognition/drug effects ; Amyloid beta-Protein Precursor/genetics ; Mice, Transgenic ; Disease Models, Animal ; Cognitive Enhancement ; *Neuroprotective Agents/pharmacology ; Presenilin-1/genetics ; }, abstract = {As a progressive neurological degenerative disorder, Alzheimer's disease (AD) remains a significant concern, with the lack of effective cures burdening healthcare resources and posing ongoing obstacles for scientific research in neuroscience. Tianwang Buxin Pills (TWBXP) is a traditional Chinese medicinal formula long employed for treating amnesia and cognitive decline, and has shown promising potential in AD treatment. Nevertheless, the detailed mechanisms responsible for these effects warrant further investigation.

AIM OF THE STUDY: This study seeks to systematically evaluate the impact of TWBXP on cognition, neuronal damage, and synaptic plasticity in AD mice, while clarifying its underlying therapeutic mechanisms.

MATERIALS AND METHODS: HPLC-UV was employed to ensure the quality of TWBXP. APP/PS1 mice were administered TWBXP (0.43, 0.85, 1.70 g/kg) for 8 weeks, and cognitive performance was assessed using behavioral tests. AD-related pathology was evaluated by Immunohistochemistry (IHC), Western blotting, ELISA, Transmission electron microscopy (TEM), and Immunofluorescence (IF). The integration of Network Pharmacology and Proteomics was conducted for the exploration of potential mechanisms.

RESULTS: TWBXP markedly improved cognitive performance and reduced cerebral Aβ burden. It promoted microglial polarization toward an M2 phenotype, dampened neuroinflammation, and enhanced microglia-associated Aβ clearance. TWBXP also exerted marked neuroprotective and synaptic protective effects by increasing NeuN, MAP2, and MBP levels, restoring synaptic proteins (PSD95, SYP) and neurotrophic factors (BDNF, NGF), reducing neuronal loss and functional impairment, and improving synaptic plasticity. Such effects might be associated with the enhanced activity of the cAMP/PKA/NR2B/CaMKⅡ signaling axis.

CONCLUSIONS: TWBXP significantly ameliorated cognitive impairment and AD-related pathological changes in APP/PS1 mice, accompanied by improvements in neuronal injury and synaptic plasticity. Its therapeutic effects may be associated with the regulation of microglial function and the cAMP/PKA/NR2B/CaMKII signaling axis.}, } @article {pmid42000213, year = {2026}, author = {Littmann-Crites, V and Marrache, AM and Tan, C and Nightingale, N and Neish, CS and Therrien, F and Ismail, Z}, title = {Treatment patterns of agitation associated with Alzheimer's dementia (AAD) patients in Canada.}, journal = {International psychogeriatrics}, volume = {}, number = {}, pages = {100209}, doi = {10.1016/j.inpsyc.2026.100209}, pmid = {42000213}, issn = {1741-203X}, abstract = {OBJECTIVES: Explore treatment patterns of Canadian patients with AAD to understand variability in clinical management.

DESIGN: This retrospective study used public claims data from Ontario and New Brunswick in IQVIA databases.

SETTING: Inferred patients with AAD were identified through claims for cognitive enhancers and medications used off-label to treat AAD, i.e., antipsychotics (AP), anticonvulsants (AC), antidepressants (ADT), benzodiazepines (benzo).

PARTICIPANTS: Patients (≥55 years) were identified between 2011-2018, indexed on their first AP/AC/AD/benzo and followed until the earlier of their fourth line (4L) of therapy or September 30, 2023. An all-history lookback to 2003 was used to ensure no prior claims for these therapies.

MEASUREMENTS: Descriptive analyses explored treatment utilization patterns.

RESULTS: 23,732 patients with AAD were identified, mostly from Ontario (98.7%). Patients with AAD tended to move to long-term care, with these increasing with more treatment trials from 24% (1 L therapy) to 54% (4 L therapy). Patients received between 500 and 2000 unique combinations across therapy lines. Citalopram, escitalopram, gabapentin, lorazepam, mirtazapine, pregabalin, quetiapine, risperidone, sertraline, and trazodone ranked in the top 10 therapies. Risperidone accounted for 7.2% of claims and ranked as the 6th most common 1 L therapy. Although trazodone remained the most common therapy for patients with AAD, it had one of the lowest persistence rates. Most patients remained on their 3 L - 4 L therapy, and ≥ 80% were adherent across all therapy lines. Average daily doses were lower than those described in the product monographs.

CONCLUSIONS: AAD treatment varies widely, underscoring the need for approved treatments and enhanced clinical education.

CLINICAL TRIAL NUMBER: Not applicable.}, } @article {pmid42000569, year = {2026}, author = {Schelter, BO and Shiells, H and Lo, S and Nazlee, N and Evans, E and Bentham, P and Gauthier, S and Zetterberg, H and Wilcock, GK and Froelich, L and Burns, A and MacSweeney, E and Ballard, C and Yu, JT and Choon, TS and Asvatourian, V and Muehlemann, N and Priel, J and Kook, K and Sullivan, T and Downie, D and Miller, S and Pringle, C and Storey, JMD and Baddeley, T and Harrington, CR and Staff, R and Sandu, AL and Hull, C and Stefanacci, R and Wischik, CM and , }, title = {Assessment of clinical and neuroimaging efficacy of treatment targeting tau pathology in mild cognitive impairment and mild to moderate Alzheimer's disease with hydromethylthionine mesylate using external control data.}, journal = {The journal of prevention of Alzheimer's disease}, volume = {13}, number = {6}, pages = {100560}, pmid = {42000569}, issn = {2426-0266}, mesh = {Humans ; *Alzheimer Disease/drug therapy/diagnostic imaging/pathology ; *Cognitive Dysfunction/drug therapy/diagnostic imaging ; Female ; *tau Proteins/metabolism/drug effects ; Male ; Aged ; Treatment Outcome ; Neuroimaging ; Aged, 80 and over ; }, abstract = {BACKGROUND: Hydromethylthionine mesylate (HMTM) targets tau pathology and also has tau-independent symptomatic activity. A traditional randomised placebo-controlled trial (RCT) was precluded by loss of blinding due to urinary colouration and therapeutic activity at the minimum dose required to maintain blinding.

OBJECTIVE: To evaluate the efficacy of HMTM in participants with mild cognitive impairment (MCI) and mild to moderate dementia due to Alzheimer's disease (AD).

METHODS: Because a traditional RCT was not feasible without loss of blinding, we compared HMTM 16 mg/day in TRx-237-039 with propensity score matched true placebo controls from the FDA-sponsored Critical Path for AD (CPAD) database with the same inclusion/exclusion criteria (protocol TRx-237-080). We also compared HMTM 16 mg/day with matched natural history controls from the Alzheimer's Disease Neuroimaging Initiative (ADNI) and with a meta-analysis of placebo arms from trials in comparable populations in analyses specified prior to the 104-week database lock of TRx-237-039.

PARTICIPANTS: Propensity score matching yielded 127 pairs (HMTM n = 127; CPAD placebo n = 127) in the CPAD comparison, and 189 pairs in the ADNI comparison. A total of 218 receiving HMTM 16 mg/day were compared with meta-analytic controls (n = 1805-8567).

INTERVENTION: HMTM 16mg/day MEASUREMENTS: Primary outcomes in TRx-237-080 were change from baseline to 78 weeks in ADAS-Cog13 and whole brain volume (WBV). CDR-Sum of Boxes (CDR-SB) and CDR-Global were analysed at 104 weeks. ADAS-cog11 and WBV were analysed in ADNI comparisons, and ADAS-cog11, ADCS-ADL23, CDR-SB and WBV were analysed in meta-analytic comparisons.

RESULTS: Compared with matched CPAD placebo, HMTM 16 mg/day produced statistically significant differences in change on ADAS-Cog13 (p < 0.0001) and WBV at 78 (primary; p < 0.0001) and 104 weeks (p < 0.0001), and CDR-SB differed significantly overall (104-weeks; p < 0.001) and in MCI (p = 0.007). The odds of progressing to a more advanced CDR-Global stage were lower with HMTM (overall OR 0.31) and particularly in MCI (OR 0.15) versus CPAD placebo. Clinical and brain atrophy outcomes were similarly statistically significant in comparisons with ADNI case-matched natural history data and in meta-analytic comparisons.

CONCLUSION: Comparisons of HMTM treatment with CPAD, ADNI, and meta-analytic controls provide evidence consistent with clinical benefit HMTM. It has the potential to offer an accessible oral treatment option which could be delivered with minimal patient/physician burden.}, } @article {pmid42001005, year = {2026}, author = {Bayar, E and Cengiz, T and Erdoğan, F and Coşkun, HS and Tomak, Y}, title = {Impact of comorbidities on preoperative and postoperative outcomes in hip fracture patients.}, journal = {BMC geriatrics}, volume = {26}, number = {1}, pages = {}, pmid = {42001005}, issn = {1471-2318}, mesh = {Humans ; *Hip Fractures/surgery/epidemiology/mortality ; Female ; Retrospective Studies ; Male ; Comorbidity ; *Postoperative Complications/epidemiology/diagnosis ; Aged, 80 and over ; Aged ; Treatment Outcome ; Risk Factors ; Middle Aged ; Proximal Femoral Fractures ; Diabetes Mellitus/epidemiology ; }, abstract = {BACKGROUND: Hip fractures represent a major public health concern due to their increasing incidence in the aging population and their association with significant morbidity and mortality. Comorbidities are known to complicate both the surgical management and rehabilitation process, yet their specific impact on outcomes remains variable across studies. OBJECTIVE: This study aimed to determine the prevalence and distribution of comorbidities in patients who presented with hip fractures and underwent surgical treatment, to evaluate perioperative and postoperative risk factors retrospectively, and to compare these findings with the existing literature. METHODS: A retrospective descriptive analysis was conducted on 589 patients aged ≥ 60 years who were surgically treated for hip fractures between 2013 and 2024 at a tertiary university hospital. Demographic characteristics, surgical protocols, anesthesia types, revision rates, infection, dislocation, mobilization outcomes, hospital stay, intensive care admissions, and mortality were systematically analyzed in relation to comorbidity profiles and the number of comorbidities. Statistical analyses included chi-square, Fisher’s exact test, Mann-Whitney U, and Kruskal-Wallis tests, with p < 0.05 considered significant. RESULTS: Hypertension (59.1%), diabetes mellitus (33.6%), coronary artery disease (21.4%), and Alzheimer’s disease (21.4%) were the most frequent comorbidities. Revision surgery was significantly associated with diabetes mellitus and congestive heart failure. Diabetes mellitus, coronary artery disease, and chronic renal failure were strong predictors of postoperative infection. While the mean hospital stay was significantly prolonged in patients with ≥ 3 comorbidities, mortality was significantly associated only with oncological diseases and chronic renal failure. Contrary to expectations, no significant association was found between overall mortality and the number of comorbidities. CONCLUSION: Comorbidities, particularly diabetes mellitus, congestive heart failure, oncological diseases, and chronic renal failure, substantially influence surgical outcomes, postoperative complications, and hospitalization in hip fracture patients. However, the number of comorbidities alone was not a predictor of mortality, highlighting the importance of the type rather than the quantity of comorbid conditions. These findings underscore the need for individualized perioperative planning and comprehensive patient counseling to reduce risks and improve postoperative outcomes.}, } @article {pmid42001186, year = {2026}, author = {Zheng, W and Geng, D and Wang, A and Li, Z and Liu, A and Chen, S and Wang, Q and Su, C and Yan, Z and Yin, Y and Xu, G}, title = {Gamma low field magnetic stimulation ameliorates pathophysiological damage and cognitive impairments in AD mice.}, journal = {Alzheimer's research & therapy}, volume = {18}, number = {1}, pages = {}, pmid = {42001186}, issn = {1758-9193}, support = {52277230//National Natural Science Foundation of China/ ; SJZZXB24006//Science and Technology Cooperation Special Project of Shijiazhuang/ ; 25292001D//Hebei Province Provincial Science and Technology Programme Project International Science and Technology Co-operation Special Project/ ; 2022YFC2402203//National Key R&D Program of China/ ; }, mesh = {Animals ; *Alzheimer Disease/therapy/physiopathology/genetics/pathology/complications ; Mice, Transgenic ; Disease Models, Animal ; *Gamma Rhythm/physiology ; Amyloid beta-Peptides/metabolism ; Amyloid beta-Protein Precursor/genetics ; *Cognitive Dysfunction/therapy/physiopathology ; Mice ; Presenilin-1/genetics ; Male ; *Magnetic Field Therapy/methods ; Hippocampus/physiopathology ; Spatial Memory/physiology ; Peptide Fragments/metabolism ; Maze Learning/physiology ; }, abstract = {BACKGROUND: The normal functioning of gamma rhythms is crucial for maintaining brain health, while their abnormalities are closely associated with various neurological disorders, particularly Alzheimer's disease. Gamma stimulation modalities including auditory, visual, electrical, and strong magnetic approaches have all demonstrated potential therapeutic effects for AD, with substantial research findings continuously emerging. However, 40 Hz gamma low field magnetic stimulation(gamma-LFMS) remains unexplored.

METHODS: To investigate this question, we applied pulsed magnetic fields with a magnetic field strength of 10 mT and frequency of 40 Hz (2 × 30 min/day) to 9-month-old APP/PS1 double transgenic AD model mice for 18 consecutive days, and evaluated changes in spatial memory capacity, hippocampal neural network characteristics, and amyloid protein 42 content in AD mice.

RESULTS: Gamma-LFMS significantly enhanced spatial memory performance in AD mice, increased theta-gamma phase-amplitude coupling and gamma band power in the hippocampal CA1 region, showed a trend toward desynchronization in low gamma, and effectively reduced hippocampal β-amyloid42 burden.

CONCLUSIONS: This study demonstrates for the first time that gamma-LFMS effectively ameliorates pathophysiological alterations and spatial memory deficits in AD mice. These findings address a critical knowledge gap regarding the effects of gamma-LFMS on AD pathology and provide a theoretical foundation for developing cost-effective home-based prevention and treatment devices applicable throughout the lifespan.}, } @article {pmid42001306, year = {2026}, author = {Thakur, A and Rana, M and Vanjani, S and Liou, KC and Taliyan, R and Nepali, K and Yang, CH}, title = {Multi-Targeting Ligands as Prospective Therapeutics for Alzheimer's Disease, a Prevalent Neurodegenerative Disorder: Mechanistic Insights, Emerging Targets and Drug Discovery Campaigns.}, journal = {Medicinal research reviews}, volume = {46}, number = {4}, pages = {1173-1229}, doi = {10.1002/med.70047}, pmid = {42001306}, issn = {1098-1128}, support = {NSTC 112-2320-B-038-018-MY3//National Science and Technology Council, Taiwan/ ; }, mesh = {Humans ; *Alzheimer Disease/drug therapy/metabolism ; Ligands ; *Drug Discovery ; Animals ; *Molecular Targeted Therapy ; *Neurodegenerative Diseases/drug therapy ; }, abstract = {Alzheimer's disease (AD) is a debilitating neurodegenerative condition characterized by progressive cognitive impairment, memory deterioration, and neuronal dysfunction. Its complex pathophysiology involves multiple interlinked processes, including amyloid-β (Aβ) aggregation, tau hyperphosphorylation, oxidative stress, neuroinflammation, synaptic dysfunction, and cholinergic deficits. Current FDA-approved therapies provide only symptomatic relief and fail to halt disease progression, highlighting the urgent need for more effective treatment strategies. This review provides a comprehensive overview of the pathological mechanisms underlying AD and the emerging therapeutic targets for the design of tractable anti-AD scaffolds, namely, acetylcholinesterase, beta-site amyloid precursor protein cleaving enzyme 1 (BACE1), glycogen synthase kinase-3β (GSK3β), dual-specificity tyrosine phosphorylation-regulated kinase 1A (DYRK1A), histone deacetylases (HDACs), and soluble epoxide hydrolase (sEH). Emphasis is placed on the paradigm shift from single-target therapies to multitarget-directed ligands (MTDLs), which are increasingly recognized as promising tools to tackle AD's multifactorial pathology. We also discuss recent advances in medicinal chemistry and structure-guided drug discovery campaigns aimed at developing pharmacologically optimized, BBB-penetrant MTDLs. By consolidating mechanistic insights with therapeutic innovation, this review aims to facilitate the development of next-generation therapeutics with enhanced efficacy and disease-modifying potential in AD.}, } @article {pmid42002723, year = {2026}, author = {Sukreet, S and Kim, EK and Petersen, M and Zhang, F and O'Bryant, SE and Rafii, MS and Rissman, RA}, title = {Precision medicine for Alzheimer's disease in Down syndrome.}, journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association}, volume = {22}, number = {4}, pages = {e71398}, pmid = {42002723}, issn = {1552-5279}, support = {AG073979//NIH/NIA/ ; R61/R33AG066543//NIH/NIA/ ; }, mesh = {Humans ; *Down Syndrome/complications/blood ; *Alzheimer Disease/drug therapy/complications/blood/diagnosis ; Biomarkers/blood ; Female ; *Precision Medicine/methods ; Male ; Proteomics ; *Vitamin E/therapeutic use ; Middle Aged ; Support Vector Machine ; Aged ; Extracellular Vesicles/metabolism ; }, abstract = {INTRODUCTION: Down syndrome (DS) exhibits a genetic form of Alzheimer's disease (AD). We used a blood-based proteomic algorithm to predict cognitive status, treatment responders, and change to vitamin E in DS adults from a completed clinical trial, "Vitamin E in Aged Persons with Down Syndrome," which originally showed no significant cognitive benefit using the primary endpoint cognition (Brief Praxis Test [BPT]).

METHODS: Plasma and extracellular vesicle (EV; astrocytic and neuronal) biomarkers were assayed at baseline and 36 months (n = 138 each). Cognitive response was measured using combined scores from the BPT, vocabulary, and behavior and function DS tests. Support vector machine (SVM) analyses predicted diagnostic and treatment responders and change accuracy.

RESULTS: SVM classified demented versus non-demented with up to 99% accuracy and predicted treatment response and changes with up to 100% accuracy in plasma and EV.

DISCUSSION: Our study supports blood-based screening and precision diagnostics for AD therapy in DS.}, } @article {pmid42004236, year = {2026}, author = {Zhang, B and Zhang, M}, title = {Metabolic Regulatory Networks in Ferroptosis During Alzheimer's Disease, Mechanisms of Glial Cell Action, and Pathological Correlations with Neuritic Plaques.}, journal = {International journal of general medicine}, volume = {19}, number = {}, pages = {596584}, pmid = {42004236}, issn = {1178-7074}, abstract = {Alzheimer's disease (AD) is a neurodegenerative disease with a complex pathological mechanism, which is still poorly understood. Ferroptosis is a type of non-apoptotic programmed cell death. Many recent studies have found that ferroptosis is closely related to the occurrence and development of AD. This article explains the main theoretical basis of ferroptosis in the pathological development of AD, and systematically analyzes the synergistic pathological network of multiple pathways caused by iron metabolism disorder, abnormal lipid peroxidation, and abnormal amino acid metabolism. This article mainly focuses on the dual regulation mechanism and molecular mechanism of microglia, astrocytes, and oligodendrocytes in the process of ferroptosis. This article studies the two-way relationship between neuritic plaques (NP) and ferroptosis, and the relationship between NP and dystrophic neurites, inflammatory response, and abnormal tau phosphorylation. Based on the existing research, we propose several unanswered questions and possible targeted research directions to provide a theoretical reference for the study of AD pathogenesis and the exploration of intervention strategies.}, } @article {pmid42004570, year = {2026}, author = {Shajahan, SR and Hein, ZM and Muhammad, H and Mustafa, MZ and Kumari, Y and Jazuli, I and Zulkapli, A and Shari, N and Nassir, CMNCM and Ramli, MDC}, title = {Stingless bee honey alleviates cognitive deficits and hippocampal neurodegeneration in an Alzheimer's model: Behavioural, neurochemical, and histological analyses.}, journal = {AIMS neuroscience}, volume = {13}, number = {1}, pages = {1-28}, pmid = {42004570}, issn = {2373-7972}, abstract = {Stingless bee honey (SBH), widely consumed in Southeast Asia, is traditionally valued for its medicinal and nutritional properties, particularly in promoting brain health. However, its neuroprotective potential against Alzheimer's disease (AD) remains underexplored. In this study, we investigated the therapeutic effects and safety of SBH in a rat model of AD. A total of sixty-three adult male Sprague-Dawley rats (180-200 g) were used: Fifteen were assigned to three toxicity groups (500, 750, 1000 mg/kg; n = 5) and forty-eight to six therapeutic groups (n = 8): Normal control, AD (AlCl3 + D-gal), AD + Donepezil (1.5 mg/kg), and three SBH-treated groups (500, 750, 1000 mg/kg). Alzheimer-like pathology was induced by aluminium chloride (150 mg/kg) and D-galactose (300 mg/kg), followed by 14 days of treatment. Toxicity was evaluated through liver and kidney histopathology, while behavioural performance was assessed using the Open Field Test and Morris Water Maze. Serum dopamine, serotonin, corticosterone, and acetylcholinesterase activity were quantified via ELISA, and hippocampal morphology was examined histologically. SBH administration produced no signs of systemic toxicity and significantly improved exploratory activity and spatial learning, with the most pronounced effects at 750 mg/kg. Biochemical assays showed reduced acetylcholinesterase and corticosterone levels alongside increased dopamine and serotonin concentrations. Histological analysis confirmed neuronal preservation and reduced hippocampal damage. Inclusion of Donepezil as a positive control enabled comparison with a standard pharmacological treatment. These findings demonstrated that SBH is a safe and promising natural therapeutic capable of alleviating cognitive deficits associated with AD.}, } @article {pmid42005438, year = {2026}, author = {Fleig, K and Haslinger, L and Dawczynski, C and Kolassa, IT}, title = {Omega-3 fatty acids in mental disorders: from neurobiological and metabolic mechanisms to therapeutic potential.}, journal = {Frontiers in nutrition}, volume = {13}, number = {}, pages = {1748196}, pmid = {42005438}, issn = {2296-861X}, abstract = {Nutritional psychiatry is an emerging field. Micro- and macro-nutrients play a role in energy metabolism and the regulation of inflammation; particularly, an insufficient dietary intake of omega-3 fatty acids and an imbalanced intake of omega-6/omega-3 fatty acids, with a shift toward increased inflammation, are of relevance for the pathophysiology of mental disorders. This review summarizes evidence on the role of omega-3 fatty acids in the pathophysiology of mental disorders (schizophrenia, affective and anxiety disorders, post-traumatic stress disorder, and eating disorders), neurodevelopmental disorders (attention-deficit/hyperactivity disorder and autism spectrum disorder) and neurodegenerative disorders (Alzheimer's disease) and explores potential treatment implications. In addition, the underlying neurobiological mechanisms through which omega-3 fatty acids might exert a protective effect are also discussed. Despite methodological variability and heterogeneous results, an increasing body of evidence suggests that omega-3 deficiency and altered fatty acid profiles are modifiable risk factors and potential biomarkers for mental disorders. The integration of omega-3 supplementation as an adjuvant to state-of-the-art therapy offers the potential for a low-risk intervention with meaningful clinical outcomes. However, clinical monitoring is recommended to avoid adverse effects and to adjust the dosage according to individual and disease-specific factors.}, } @article {pmid42005580, year = {2026}, author = {Imran, S and Patel, M and Noroozifar, M and Kerman, K}, title = {Recent advances towards BACE1 drug discovery and therapeutics design.}, journal = {RSC medicinal chemistry}, volume = {17}, number = {5}, pages = {2306-2325}, pmid = {42005580}, issn = {2632-8682}, abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by cognitive decline and memory loss. A key feature of AD is the accumulation of amyloid beta (Aβ) peptides in the form of extracellular plaques. The amyloid cascade hypothesis suggests that the pathogenesis of AD is initiated by the cleavage of amyloid precursor protein (APP) by β-site amyloid precursor protein cleaving enzyme 1 (BACE1). Numerous therapeutic approaches have been pursued to target BACE1 due to its crucial role in AD. However, the complexity of AD and the localization of BACE1 in the brain have posed challenges, leading to the failure of clinical trials and, in some cases, even exacerbating disease progression. Specifically, the blood-brain barrier (BBB) prevents the entry of many molecules, making BACE1 a difficult target to approach. Recent advancements in BACE1 therapy have shifted the focus from traditional enzyme inhibitor-based therapeutics to modulators, antibody therapy, and gene therapy. These approaches offer several advantages, including the ability to efficiently cross the BBB and provide targeted treatment. In this review, we explore the latest developments in modulators, antibody therapy, and gene therapy targeting BACE1 to combat AD. These approaches offer a promising avenue to mitigate the progression of AD and provide a novel therapeutic strategy.}, } @article {pmid42006102, year = {2025}, author = {Manescu, MD and Catalin, B and Mateescu, VO and Rosu, GC and Boboc, IKS and Istrate-Ofiteru, AM and Liliac, IM and Busuioc, CJ and Pirici, D}, title = {AQP4 Drives Gliotic Changes in an APPPS1 Mouse Model of Alzheimer's Disease.}, journal = {Current health sciences journal}, volume = {51}, number = {4}, pages = {543-551}, pmid = {42006102}, issn = {2067-0656}, abstract = {Alzheimer's disease (AD) is the most common form of dementia, accounting for most of the cases, especially in individuals aged 65 and older. While the existence of genetic factors has helped us create animal models of AD that mimic APP and Ab overproduction, sporadic cases represent the bulk casuistry, and most probably their pathology is related to a loss of function towards the clearance of Ab rather than consecutive the overproduction of Ab alone. It is known that aquaporin 4 (AQP4) facilitation amplifies the perivascular Ab clearance route and decreases Ab deposits in animal models of AD, however it is now known how the glial component of the CNS responds to this treatment. We have aimed here to assess the glial response in a APPPS1 transgenic mouse model of AD, after one month of pharmacological facilitation or inhibition of AQP4. To this extent, we have utilized APPPS1 mice of 2 months of age, treated daily for 28 days with either TGN-020 AQP4 inhibitor or the TGN-073 AQP4 facilitator, and compared their GFAP expression in the brain with that of untreated APPPS1 and wild-type animals. Our image analysis of the GFAP immunohistochemical pattern, showed that AQP4 facilitation increases GFAP expression in the brains of APPPS1 animals, compared to untreated APPPS1 animals, but complexity-lacunarity morphological patterns resemble in fact those of wild-type animals, rather than that of the APPPS1 untreated animals, suggesting that this GFAP reactivity might represent a benefic amyloid-clearance astrocytic profile.}, } @article {pmid42006158, year = {2026}, author = {Wang, G and Duan, X and Ouyang, D and Zhou, J and Zhang, H and Ding, Y}, title = {Nose-to-brain delivery of donepezil within a small dose improves bioavailability and efficacy for Alzheimer's disease treatment.}, journal = {Asian journal of pharmaceutical sciences}, volume = {21}, number = {2}, pages = {101130}, pmid = {42006158}, issn = {2221-285X}, abstract = {Oral administration of donepezil (Don) is the first-line medication for Alzheimer's disease (AD); however, the dysphagia of elderly patients and severe gastrointestinal side effects substantially restrict administration compliance. Herein, we exploit a nose-to-brain pathway for Don administration to obtain smaller dosage but higher intracerebral bioavailability (BA), thereby achieving inhibition of acetylcholinesterase (AChE) activity and avoiding side effects. With respect to the intranasal administration design, a patient-friendly Don nasal spray without preservatives was developed. The administration of Don nasal spray demonstrated good nasal deposition and mucosa permeation ability comparable to that of the model drug propranolol. The mice intranasally administered Don at an equivalent oral dose (0.65 mg/kg) demonstrated rapid brain distribution (∼5 min) and long-lasting AChE inhibition effects (72 h). To obtain the optimal intranasal dose, a dose-descending study was conducted by cascading the oral dosage at a 1:3 ratio. The results demonstrated that intranasal administration of Don at 0.07 mg/kg resulted in intracerebral BA and AChE inhibition comparable to oral administration at 0.65 mg/kg, suggesting an 89% dose reduction. Compared with oral administration, anti-AD effectiveness was evaluated in AD model mice after 34-d- intranasal administration of Don, resulting in a shorter onset time, higher intracerebral drug concentration, and a longer duration of AChE inhibition (0.07 mg/kg). The nasal and systemic safety of intranasal administration of Don was confirmed in an allergic rhinitis mouse model after 4 weeks of intranasal administration. Thus, a small dose of Don exhibits improved intracerebral BA and AChE inhibition via intranasal administration, thereby offering better compliance and reducing side effects in AD treatment.}, } @article {pmid42006351, year = {2026}, author = {Abskharon, R and Jiang, YX and Sawaya, MR and Ge, P and Zhang, J and Boyer, DR and Dolinsky, JL and Pi, J and Cascio, D and Guo, F and Eisenberg, DS}, title = {Structural evidence that RNA contributes to polymorphism of tau amyloid fibrils.}, journal = {iScience}, volume = {29}, number = {4}, pages = {115501}, pmid = {42006351}, issn = {2589-0042}, support = {R01 AI163216/AI/NIAID NIH HHS/United States ; R21 HD115071/HD/NICHD NIH HHS/United States ; }, abstract = {RNA colocalizes with tau deposits in Alzheimer's disease (AD) and drives tau aggregation in vitro. Previously, we determined a cryogenic-electron microscopy (cryo-EM) structure of fibrils of full-length tau bound to unfractionated mammalian RNA, revealing a small tau C-terminal core. Here, we present the cryo-EM structure of fibrils of full-length recombinant tau bound to unfractionated mammalian RNA seeded by AD-extracted tau fibrils. This structure reveals an expanded tau C-terminal core resembling AD tau fibrils. RNA sequencing identified 18S ribosomal RNA as the primary fibril-bound species. Next, we determined the cryo-EM structure of fibrils of full-length recombinant tau bound to mammalian 18S ribosomal RNA, revealing a core that consists of the R2 to R4 repeat domains previously seen in pathological tau fibrils. All our recombinant RNA-tau fibrils dissolve upon RNase treatment. Tau fibrils adopt distinct folds in the presence of different RNAs, suggesting RNA is a cofactor capable of shaping tau fibril polymorphism.}, } @article {pmid42006409, year = {2026}, author = {Davidson, MH and Hsieh, A and de Kleer, M and Szarek, MS and Scheltens, P and Vijverberg, E and Johnson, A and Ditmarsch, M and Kastelein, JJP}, title = {The emerging role of CETP inhibition in the prevention of Alzheimer's disease.}, journal = {American journal of preventive cardiology}, volume = {26}, number = {}, pages = {101442}, pmid = {42006409}, issn = {2666-6677}, abstract = {We recently showed that patients with atherosclerotic cardiovascular disease (ASCVD) carry a substantial but largely unrecognized burden of early Alzheimer's disease (AD) pathology. In the BROADWAY pivotal phase 3 lipid-lowering trial, nearly half of participants with high-risk ASCVD had plasma p-tau217 concentrations above thresholds associated with preclinical AD, yet none had undergone evaluation for cognitive impairment. In this population, apolipoprotein E ε4 (APOE4) carriers were disproportionately represented among those with the highest p-tau217 levels. These findings expose a critical gap between cardiovascular care and dementia prevention and raise the question whether interventions targeting shared pathophysiology could address both conditions simultaneously. Cholesteryl ester transfer protein (CETP) inhibition has emerged as a candidate for this dual role. In BROADWAY, obicetrapib reduced p-tau217 progression across the study population, with effects most pronounced in APOE4 carriers. In fact, treatment differences favoring obicetrapib were observed across all measured AD biomarkers in high-risk subgroups, including neurofilament light chain, glial fibrillary acidic protein, and the amyloid-beta (Aβ) 42:40 ratio. Unlike approaches that target downstream pathology, such as amyloid plaques already deposited in the brain or the inflammatory consequences of established disease, CETP inhibition may address the upstream processes involved in initiating the pathological cascade: lipid dysregulation, cholesterol ester accumulation in glial cells, impaired cholesterol efflux, lipid peroxidation, oxysterol formation, and deficient antioxidant transport. This review examines the biological rationale linking APOE4 status to disordered lipid metabolism in both peripheral and central compartments, the genetic and epidemiological evidence supporting CETP as a therapeutic target, the mechanisms through which CETP inhibition might confer neuroprotection, and the clinical data suggesting obicetrapib as the first oral agent associated with favorable changes in AD biomarkers across both amyloid and tau axes in individuals at high genetic risk for the development of AD.}, } @article {pmid42006781, year = {2026}, author = {Raikes, AC and Garza, M and Murrell, AN and Brinton, RD}, title = {Meta analysis of glucose metabolism across Alzheimer's, Parkinson's and ALS Reveals emergence of adaptive brain glucometabolic responses and associated neurological functional profiles.}, journal = {medRxiv : the preprint server for health sciences}, volume = {}, number = {}, pages = {}, doi = {10.64898/2026.04.07.26350339}, pmid = {42006781}, abstract = {IMPORTANCE: Glucose metabolic dysregulation in brain is a common feature of late-onset age-associated neurodegenerative disease (A [2] ND). Prior meta-analyses have identified disease-specific effects compared to healthy, unimpaired individuals. Yet, a unifying A [2] ND glucose dysregulation spatial signature remains undescribed.

OBJECTIVE: To determine the common signature of dysregulated glucose metabolism on FDG-PET using activation likelihood estimation (ALE) meta-analyses across A [2] ND.

DATA SOURCES: Searches were conducted using MEDLINE, Embase, PsycINFO, Scopus, and Cochrane from inception through July 2025. The search terms included controlled vocabulary and keywords for four neurodegenerative diseases Parkinson Disease, Amyotrophic Lateral Sclerosis, Alzheimer Disease, and Multiple Sclerosis, Fluorodeoxyglucose F18, glucose, and positron-emission tomography (PET).

STUDY SELECTION: Studies comparing adults with late-onset neurodegenerative diseases to non-diseased controls using FDG-PET to quantify brain glucose uptake and reporting whole-brain coordinate findings in either Talairach or Montreal Neurological Institute space were included.

DATA EXTRACTION AND SYNTHESIS: Three researchers, assisted by an AI screening tool, screened 7275 potential titles and abstracts for inclusion. Full texts were then retrieved for potentially relevant articles and were evaluated by three researchers using prespecified inclusion/exclusion criteria.

MAIN OUTCOMES AND MEASURES: Cluster peak and subpeak coordinates, cluster-wise t-or Z-values, and annotations indicating the disease of interest, whether the outcome was for hyper-(disease group > control) or hypometabolism (disease group < control), were extracted from included texts and analyzed using ALE.

RESULTS: A total of 130 FDG-PET studies were included in the meta-analysis, with a combined sample of 5298 individuals with A [2] ND and 3499 controls. Meta-analyses revealed dysregulated glucose metabolism as a unifying feature across A [2] ND which included both hypo-and hypermetabolic patterns. Neuroanatomical metabolic pattern was unique and disease specific. Each A [2] ND metabolic phenotype was associated with unique and complex patterns of neurological functionalities.

CONCLUSIONS AND RELEVANCE: These data demonstrate dysregulated glucose metabolism as a common A [2] ND feature, suggesting responsive remodeling of neural bioenergetics. While hypometabolism is a common research focus, due to functional relevance, hypermetabolism may reflect a compensatory, maladaptive, or neuroinflammatory signal, that requires focused investigation. A [2] ND prevention and treatment efficacy may depend on addressing bidirectional metabolic dysregulation in addition to disease-specific drivers of pathology.}, } @article {pmid42008282, year = {2026}, author = {Burns, JM and Woodward, JL and Morris, JK and Townley, RA}, title = {Reimagining Care Delivery for Alzheimer Disease.}, journal = {JAMA neurology}, volume = {83}, number = {6}, pages = {515-516}, doi = {10.1001/jamaneurol.2026.0801}, pmid = {42008282}, issn = {2168-6157}, } @article {pmid42008483, year = {2026}, author = {Zhang, X and Wang, Z and Sun, M and Bao, Q and Chen, Z and Liu, Y and Wang, Z and Ye, F and Yang, Z and Du, X and Zhang, H and Mou, X and He, X and Li, D and Wu, K and Yao, J and Zhong, W and Xu, P and Yang, S and Zhao, L and Yin, Z and Liang, F}, title = {Acupuncture for amnestic mild cognitive impairment: Study protocol for a multicenter, single-blinded, long-term, randomized controlled trial.}, journal = {PloS one}, volume = {21}, number = {4}, pages = {e0346717}, pmid = {42008483}, issn = {1932-6203}, mesh = {Humans ; *Cognitive Dysfunction/therapy ; *Acupuncture Therapy/methods ; Single-Blind Method ; Aged ; Randomized Controlled Trials as Topic ; Multicenter Studies as Topic ; Female ; Male ; Treatment Outcome ; *Amnesia/therapy ; }, abstract = {BACKGROUND: Amnestic mild cognitive impairment (aMCI), a common neurodegenerative disease affecting older adults, has garnered significant research interest over the past few years. While previous studies have suggested that acupuncture holds promise as a clinical intervention to improve cognitive function in patients with aMCI, the long-term effect of acupuncture treatment for aMCI remains unclear.

METHODS: This is a multicenter, single-blinded, randomized controlled trial (RCT) with a long-term follow-up.166 patients diagnosed with aMCI will be randomly divided into acupuncture group (AG) and sham acupuncture group (SA). The intervention will last for 12 weeks (2 sessions per week), follow-up for 48 weeks, and the study will last a total of 60 weeks. The primary outcomes are the changes in the Alzheimer's Disease Assessment Scale-Cognitive (ADAS-Cog) score from baseline to week 12 and from baseline to week 60. Generalized estimating equations (GEE) will be used to assess the impact of the acupuncture intervention on outcome variables over time at baseline and weeks 12, 24, 48, and 60.

DISCUSSION: This protocol outlines a detailed procedure for a multicenter RCT designed to further evaluate the long-term effect of acupuncture in managing aMCI. We anticipate that the findings of this research will provide valuable insights and evidence-based recommendations for the clinical management of this patient population.

TRIAL REGISTRATION: The trial was registered at Chinese Clinical Trial Registry on 28 May 2024 (Number: ChiCTR2400084932).}, } @article {pmid42008564, year = {2026}, author = {Al-Anbari, E and Karshenas, H and Shoushtarian, B}, title = {Normalizing flow based neural processes for Alzheimer's disease progression prediction.}, journal = {PloS one}, volume = {21}, number = {4}, pages = {e0345958}, pmid = {42008564}, issn = {1932-6203}, mesh = {*Alzheimer Disease/diagnosis/diagnostic imaging/pathology/genetics/physiopathology ; Humans ; Disease Progression ; Cognitive Dysfunction/diagnosis/diagnostic imaging ; Prediction Algorithms ; Predictive Learning Models ; Neuroimaging ; Data Analytics ; Neural Networks, Computer ; }, abstract = {As one of the most common neurodegenerative diseases, Alzheimer's accounts for serious health problems worldwide. Accurate detection and prediction of this disease contribute to the health system for better prevention and interventions in the treatment plans. However, traditional models designed for prediction and classification face several challenges, including handling complex data, which neglects many data points for the diagnosis. To overcome this challenge, we propose a novel model based on the integration of Neural Processes (NPs) and Normalizing Flows (NFs). The dataset used for this study is the Alzheimer's Disease Prediction of Longitudinal Evolution (TADPOLE). We selected various features to build an efficient model, including cognitive, neuroimaging, genetic, and demographic data. which contains three classes: Cognitively Normal (CN), Mild Cognitive Impairment (MCI), and AD. The proposed model is able to capture the temporal dependencies present in the complex distribution. The stochastic processes were modeled by NPs, while NF was able to transform the Gaussian distributions from simple to complex distributions, allowing them to model a wide range of data distributions. The prediction performance and robustness have been enhanced since this framework is able the adapt to every patient trajectory and generalizing across different populations. The model was compared with other models, such as SNP, deep geometric learning, Manifold DCNN, and other models. Our model (SNP-NF) made an improvement regarding mAUC, Precision, and Recall, approximately 3%,1%, and 0.7%, respectively from our previous model, which utilized only NP. These results demonstrate the capability of the proposed approach to provide early detection and personal treatment plans for patients suffering from this disease.}, } @article {pmid42009326, year = {2026}, author = {Garg, A and Shaw, R}, title = {Siamese Capsule Network (SNNCap): Cognitive Analysis for Alzheimer's Disease Classification From MRI Data.}, journal = {IEEE transactions on image processing : a publication of the IEEE Signal Processing Society}, volume = {35}, number = {}, pages = {4149-4160}, doi = {10.1109/TIP.2026.3683547}, pmid = {42009326}, issn = {1941-0042}, mesh = {*Alzheimer Disease/diagnostic imaging/classification ; Humans ; *Magnetic Resonance Imaging/methods ; Convolutional Neural Networks ; *Image Interpretation, Computer-Assisted/methods ; *Deep Learning ; Brain/diagnostic imaging ; }, abstract = {Alzheimer's Disease (AD) detection is essential for timely treatment and better patient care. Magnetic Resonance Imaging (MRI) is a technique in which radio waves and magnetic fields are used to capture high-resolution, multi-dimensional representations of brain structures. This high-resolution imaging capability makes MRI a key tool for diagnosing neurological disorders such as Alzheimer's disease. However, the problem is to correctly classify the fresh MRI scans of patients. Researchers have proposed a deep learning-based method for Alzheimer's disease diagnosis using a Siamese Convolutional Neural Network (SCNN) with three ResNet-34 branches trained on structural MRI data. However, this method relies solely on ResNet34 for feature extraction which struggles to preserve spatial relationship due to pooling operations, causing loss of positional information. Other researchers have explored methods like attention mechanisms and 3D convolutional networks to capture spatial dependencies. However, these methods underperform by missing brain complexity or needing high resources without consistent accuracy. In this study, we propose a cognitively inspired approach for classifying MRI images as Non Demented, Very Mild Demented, Mild Demented and Moderate Demented using Siamese Capsule Network (SNNCap). SNNCap uses ResNet-18 for feature extraction and capsule layers to preserve spatial and part-whole relationships in the images. It compares a test image against a few known reference examples per class. This reference-based validation closely mimics cognitive reasoning, improving the system's generalizability. The model achieves strong results on unseen data and demonstrates its effectiveness through classification reports and confusion matrices.}, } @article {pmid42009978, year = {2026}, author = {Wang, L and Venkatesh, S and Morris, M and Li, M and Srivastava, R and Visweswaran, S and Lopez, OL and Xia, Z and Cai, T}, title = {Stratification of Alzheimer's disease patients using knowledge-guided unsupervised latent factor clustering with electronic health record data.}, journal = {Communications medicine}, volume = {6}, number = {1}, pages = {}, pmid = {42009978}, issn = {2730-664X}, support = {R01 NS098023/NS/NINDS NIH HHS/United States ; }, abstract = {BACKGROUND: Prognostication for people with Alzheimer's disease (AD) at the point of care could improve clinical management.

METHODS: In this retrospective cohort study using the electronic health record (EHR) data from a large healthcare system (2011-2022), we applied an unsupervised latent factor clustering approach guided by knowledge graph embeddings to stratify AD patients into two groups at diagnosis (baseline) using clinical features in the two years preceding diagnosis. We prognosticated the risk of AD-related outcomes (nursing home admission and mortality) for the clusters in survival analyses adjusted for baseline confounders (age, gender, race, ethnicity, healthcare utilization, and comorbidities). To reflect real-world evolution in clinical trajectories, we updated patient stratification for patients remaining at risk one year post-diagnosis and repeated prognostication.

RESULTS: We stratify 16,411 AD patients into two groups at baseline (41% Group 1, 59% Group 2). Baseline Group 2 has a significantly lower risk of nursing home admission (HR [95% CI] = 0.804 [0.765, 0.844], p < .001) but comparable mortality risk to baseline Group 1 (HR [95% CI] = 1.008 [0.963, 1.056], p = 0.733). We re-stratify the 12,606 patients remaining at risk one year post-diagnosis (46% Group 1, 54% Group 2). Consistent with baseline, the updated Group 2 has a lower risk of nursing home admission (HR [95% CI] = 0.815 [0.766, 0.868], p < .001) but comparable mortality risk (HR [95% CI] = 0.977 [0.922, 1.035], p = .430) to Group 1.

CONCLUSIONS: Patient stratification enables outcome prognosis for AD patients. While baseline prognostication can guide early treatment and tailored management, dynamic prognostication may inform more timely interventions to improve long-term outcomes.}, } @article {pmid42009995, year = {2026}, author = {Tan, JY and Retinasamy, T and Lee, VLL and Radhakrishnan, AK and Yeong, KY}, title = {Exploring the role of tocotrienol-rich fraction (TRF) in ameliorating neuroinflammation.}, journal = {Inflammopharmacology}, volume = {34}, number = {6}, pages = {4117-4130}, pmid = {42009995}, issn = {1568-5608}, mesh = {Animals ; *Tocotrienols/pharmacology/administration & dosage ; Rats ; Oxidative Stress/drug effects ; Neuroprotective Agents/pharmacology/administration & dosage ; *Anti-Inflammatory Agents/pharmacology/administration & dosage ; *Neuroinflammatory Diseases/drug therapy/metabolism ; Antioxidants/pharmacology/administration & dosage ; Rats, Sprague-Dawley ; Reactive Oxygen Species/metabolism ; Male ; Microglia/drug effects/metabolism ; Nitric Oxide/metabolism ; *Inflammation/drug therapy/metabolism ; Neurodegenerative Diseases/drug therapy ; Mice ; }, abstract = {Neuroinflammation is a chronic inflammatory response that contributes to synaptic dysfunction and neuronal damage, it is a common feature among various neurodegenerative diseases such as Alzheimer's Disease (AD), Parkinson's Disease (PD) and Huntington's Disease (HD). Tocotrienol-rich fraction (TRF) is a form of vitamin E that is known for its anti-inflammatory, antioxidant and neuroprotective properties. Yet, it has not been adequately investigated in both cellular and animal neuroinflammation models. In this study, the potential therapeutic effects of TRF were investigated in-vitro using BV2 microglial cells and also in-vivo in a pilot study using Sprague Dawley rats. TRF at 5 and 10 µg/mL were found to reduce nitric oxide (NO) and reactive oxygen species (ROS) levels. Furthermore, in-vivo treatment with TRF significantly increases the recognition index implying improvement in cognition ability. Gene expression analysis showed downregulation of RelA, TNF-α and IL-6 while NFE2L2 and BDNF were upregulated. These findings suggests that TRF may help mitigates neuroinflammation and oxidative stress, indicating its potential as a candidature for further investigation in neurodegenerative diseases associated with chronic neuroinflammation.}, } @article {pmid42010038, year = {2026}, author = {Nakatsuji, M and Shibano, M and Fujimori, K}, title = {Antioxidant Activity of Flavonoid Glabranin by Upregulating Antioxidant Gene Expression via MEK/ERK and PI3K/Akt Pathways in Human Neuroblastoma SH-SY5Y Cells.}, journal = {Neurochemical research}, volume = {51}, number = {3}, pages = {}, pmid = {42010038}, issn = {1573-6903}, support = {25ak0101219h0202//Japan Agency for Medical Research and Development/ ; }, mesh = {Humans ; *Antioxidants/pharmacology ; Cell Line, Tumor ; Proto-Oncogene Proteins c-akt/metabolism ; Up-Regulation/drug effects/physiology ; Phosphatidylinositol 3-Kinases/metabolism ; Neuroblastoma/metabolism ; *MAP Kinase Signaling System/drug effects/physiology ; Hydrogen Peroxide/toxicity/pharmacology ; Apoptosis/drug effects ; *Flavones/pharmacology ; Oxidative Stress/drug effects ; Flavonoids/pharmacology ; Signal Transduction/drug effects ; }, abstract = {Oxidative stress is associated with neuronal cell death in neurodegenerative diseases, including Alzheimer’s disease and Parkinson’s disease. Glabranin, a flavonoid found in the stems and leaves of Glycyrrhiza glabra (licorice), exhibits antioxidant and anti-inflammatory properties. However, the effect of glabranin on the antioxidant response and the underlying mechanism including the specific signaling pathways, remain unclear. In the current study, we investigated the protective effect of glabranin on hydrogen peroxide (H2O2)-induced neurotoxicity in human neuroblastoma SH-SY5Y cells and its underlying mechanisms. H2O2-induced death of SH-SY5Y cells was restored by glabranin in a concentration-dependent manner. The number of H2O2-increased apoptotic cells was reduced by co-treatment with glabranin. Moreover, glabranin attenuated H2O2-induced cleaved caspase-3/7 levels. In addition, glabranin decreased H2O2-induced intracellular ROS levels via promoting the nuclear translocation of nuclear factor erythroid 2-related factor 2 and upregulating the antioxidant gene expression. Furthermore, glabranin enhanced the phosphorylation of extracellular signal-regulated kinase (ERK) and protein kinase B (Akt) following H2O2 treatment. Inhibition of mitogen-activated protein kinase kinase (MEK)/ERK and phosphoinositide 3-kinase (PI3K)/Akt pathways abrogated glabranin-mediated elevation of antioxidant gene expression and neuroprotective effects. These findings suggest that glabranin mitigated H2O2-induced apoptosis by increasing the expression of antioxidant genes through activation of the MEK/ERK and PI3K/Akt pathways in SH-SY5Y cells. Therefore, glabranin has the potential to prevent and treat neurodegenerative diseases as an antioxidant agent.}, } @article {pmid42010230, year = {2026}, author = {Liu, Y and Kunutsor, SK}, title = {Brain, benefit, or burden? Revisiting statins and cognitive function in older adults.}, journal = {GeroScience}, volume = {}, number = {}, pages = {}, pmid = {42010230}, issn = {2509-2723}, abstract = {Statins are among the most widely prescribed medications for the prevention and treatment of cardiovascular disease, particularly in older adults. However, concerns regarding their potential adverse cognitive effects, including memory loss and dementia, have generated substantial debate and regulatory attention. This narrative review critically appraises current evidence on the relationship between statin use and cognitive outcomes in older adults, exploring both potential risks and benefits. We synthesized findings from randomized controlled trials (RCTs), observational cohort studies, meta-analyses, and Mendelian randomization studies. We also examined biological mechanisms, subgroup differences by statin type, and clinical considerations specific to older populations. Most RCTs have not demonstrated a harmful effect of statins on cognition, while observational studies have shown mixed results, including possible protective associations. Mechanistically, statins may exert both neuroprotective and neurotoxic effects, depending on their type, dose, and ability to cross the blood-brain barrier. Mendelian randomization analyses, including those involving over 100,000 individuals from the Danish general population, have largely found no causal effect of genetically proxied statin targets on dementia or neurodegenerative diseases. Importantly, older adults remain underrepresented in trials with cognitive outcomes, and real-world evidence is limited by confounding. Two large-scale randomized trials, PREVENTABLE and STAREE, are currently underway and poised to provide definitive evidence regarding the cognitive effects of statins in older populations. Current evidence does not support discontinuing statin therapy in older adults based solely on concerns about cognitive decline. Instead, decisions should be individualized, weighing cardiovascular benefit against cognitive risk, particularly in those with pre-existing cognitive impairment, polypharmacy, or frailty. Future research should prioritize cognition as a primary outcome in studies involving older populations.}, } @article {pmid42011226, year = {2026}, author = {Weiss, B and Miranda, DR and Arrazati, D and Cao, R and Chen, J and Liu, Y and Brown, D and Marshall, G}, title = {SRN-901, a Novel Longevity Drug, Extends Lifespan and Healthspan by Targeting Multiple Aging Pathways.}, journal = {Drug design, development and therapy}, volume = {20}, number = {}, pages = {594895}, pmid = {42011226}, issn = {1177-8881}, mesh = {Animals ; *Longevity/drug effects ; Mice ; *Aging/drug effects/metabolism ; Male ; Mice, Inbred C57BL ; }, abstract = {INTRODUCTION: Developing interventions to delay aging and improve lifespan and healthspan is a critical goal in aging research. Individual geroprotective compounds fail to address the complexity, interconnectedness, and dynamic nature of biological systems, limiting success in significantly extending lifespan and improving health. This study investigates the effects of SRN-901-a novel oral combinatorial drug that consists of urolithin A, quercetin, nicotinamide riboside, alpha-lipoic acid, and Seragon's SRN-820-on lifespan extension, frailty reduction, disease-related gene expression pathways, metabolic aging, and the proteome in 18-month-old mice fed a Western diet.

RESULTS: SRN-901-treated mice showed a significant increase of 33% in median remaining lifespan compared to placebo-treated mice. Cox proportional hazards analysis revealed a hazard ratio of 0.54, indicating that SRN-901 treatment was associated with a 46% reduction in the hazard of death. While rapamycin increased lifespan in adult mice, nicotinamide mononucleotide (NMN), and nicotinamide riboside (NR) did not show significant differences in median lifespan compared to placebo. SRN-901 protected mice against increased frailty during aging, with baseline-normalized scores rising to 1.17 in treated mice and 1.57 in controls, corresponding to a 70% attenuation of frailty progression between pre-treatment (D-14) and post-treatment (D128; p < 0.001). Transcriptomic analyses revealed that SRN-901 modulates gene expression across pathways implicated in aging biology, including inflammation, apoptosis, and DNA repair, as well as gene sets associated with neurodegenerative disorders, including Alzheimer's disease. Metabolic profiling revealed that SRN-901 was associated with attenuation of several age-related metabolic shifts, resulting in a blood metabolite profile that more closely resembled that of younger mice. The upregulation of glutathione metabolism and other longevity-related pathways underscores SRN-901's role in enhancing cellular defenses against oxidative stress and maintaining metabolic health.

DISCUSSION: These results highlight SRN-901 as a promising multi-compound candidate for extending lifespan and healthspan by targeting multiple aging pathways.}, } @article {pmid42011967, year = {2026}, author = {Nowell, J and Crook, H and de Leon, MJ and Edison, P}, title = {Advances in the drug treatment of Alzheimer's disease: pathophysiology and mechanisms of action.}, journal = {BMJ (Clinical research ed.)}, volume = {393}, number = {}, pages = {78881}, doi = {10.1136/bmj-2023-078881}, pmid = {42011967}, issn = {1756-1833}, mesh = {Humans ; *Alzheimer Disease/drug therapy/physiopathology/metabolism ; *Amyloid beta-Peptides/metabolism/antagonists & inhibitors ; tau Proteins/metabolism ; }, abstract = {Alzheimer's disease, the leading cause of dementia, is a multifactorial disorder involving amyloid beta (Aβ) and tau deposition, impaired glucose metabolism, neuroinflammation, mitochondrial dysfunction, insulin resistance, and progressive brain atrophy. Anti-Aβ therapies have shown clinical efficacy and are licensed in several countries. Amyloid related imaging abnormalities remain a key safety concern, and reimbursement varies across healthcare systems. The mechanisms underlying continued cognitive decline after Aβ clearance remain unclear and might be independent of amyloid pathology. Because Alzheimer's disease involves multiple pathological processes, effective management will likely require combination treatments addressing tau aggregation, neuroinflammation, synaptic loss, and metabolic dysfunction. Numerous compounds targeting these mechanisms are currently in late stage development for both early and advanced disease. These emerging approaches represent a shift toward multimodal, disease modifying strategies designed to improve patient outcomes and quality of life. Here, we review recent therapeutic advances in Alzheimer's disease and provide perspectives on novel treatment strategies.}, } @article {pmid42012375, year = {2026}, author = {Nakashima, S and Sato, K and Niimi, Y and Aso, S and Yasunaga, H and Satake, W and Iwatsubo, T}, title = {Early adoption of lecanemab in Japan (December 2023-December 2024): Pretreatment diagnostic timelines from the DeSC claims database.}, journal = {Journal of Alzheimer's disease : JAD}, volume = {111}, number = {4}, pages = {1510-1515}, doi = {10.1177/13872877261443634}, pmid = {42012375}, issn = {1875-8908}, mesh = {Humans ; Japan ; Databases, Factual ; Aged ; Male ; *Alzheimer Disease/drug therapy/diagnosis/cerebrospinal fluid ; Female ; Time Factors ; Aged, 80 and over ; }, abstract = {Using the Japanese DeSC claims database, we described pretreatment timelines for lecanemab initiation during early rollout (December 2023-December 2024). We identified 76 patients (mean age 74.6 years; 34.2% men) from 45 institutions. Mean time to first infusion was 103.9 days from cognitive assessment and 63.1 days from MRI. PET-to-infusion was 30.9 days, whereas cerebrospinal fluid (CSF) sampling-to-infusion was 85.8 days; the post-test interval remained longer after CSF (Bonferroni-adjusted p = 0.015). Although this claims-based snapshot may not represent all practice in Japan, it suggests that the CSF-based pathway can be associated with a longer post-test interval before treatment initiation.}, } @article {pmid42012388, year = {2026}, author = {Hildebrandt, H and Duning, T and Holland-Letz, M}, title = {Is there a cognitive measure of neurodegeneration for amyloid-Aβ-ratio probable Alzheimer's disease patients?.}, journal = {Journal of Alzheimer's disease : JAD}, volume = {111}, number = {4}, pages = {1783-1791}, pmid = {42012388}, issn = {1875-8908}, mesh = {Humans ; *Alzheimer Disease/psychology/diagnosis/metabolism/diagnostic imaging ; *Amyloid beta-Peptides/metabolism/cerebrospinal fluid ; Female ; Male ; tau Proteins/metabolism/cerebrospinal fluid ; Neuropsychological Tests ; Retrospective Studies ; Aged ; Disease Progression ; Biomarkers ; Aged, 80 and over ; }, abstract = {BackgroundRecent developments in the assessment of Alzheimer's disease (AD) have centered on differential diagnostic questions. Only a few studies have aimed to identify neuropsychological measures that allow the prediction of disease progression. However, this question is central to informing patients about their diagnosis and to decisions regarding the urgency and timing of treatment escalation.ObjectiveWe analyzed which, if any, neuropsychological test results reflect the extent of neurodegenerative progression.MethodsThis retrospective analysis included 290 patients divided into an Aβ-ratio + group (n = 146; AD biomarker profile) and an Aβ-ratio- group (n = 144; non-AD biomarker profile). The Aβ-ratio + group was further divided into four t-tau quartiles. The Aβ-ratio- group was subdivided into patients with normal (n = 94) or elevated t-tau (n = 50).ResultsRegression and variance analyses demonstrated a correlation between Trail Making Test B (TMT-B) performance and t-tau levels in patients with an Aβ-ratio+, driven by differences between low and high tau values, but not in Aβ-ratio- patients. Several additional statistical control analyses endorsed this finding.ConclusionsWe conclude that, for Aβ-ratio + patients, TMT-B performance may serve as a clinically accessible indicator of tau-related disease activity and the extent of neurodegeneration and may help identify patients at risk of faster progression if replicated in longitudinal studies.}, } @article {pmid42012422, year = {2026}, author = {Xu, R and Ma, X and Wu, L and Yin, D and Zhao, L and Zhou, M and Yao, Y and Lin, R and Li, W and Yu, K}, title = {Transcranial Direct Current Stimulation Improves Cognitive Dysfunction in Amyloid Precursor Protein/Presenilin 1 Mice by Promoting Alternative Polarization of Microglia and Amyloid-Β Degradation.}, journal = {Neuromodulation : journal of the International Neuromodulation Society}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.neurom.2026.03.007}, pmid = {42012422}, issn = {1525-1403}, abstract = {OBJECTIVE: This study investigated the mechanisms by which transcranial direct current stimulation (tDCS) alleviated Alzheimer's disease (AD) progression.

MATERIALS AND METHODS: Amyloid precursor protein (APP)/human presenilin 1 (PS1) transgenic mice (AD model) received tDCS (0.2 mA, anode electrode placed on the left frontal skull, 20 min/d for two weeks) and the NACHT, LRR, and PYD domains-containing protein 3 (NLRP3) activator nigericin. Behavior tests evaluated spatial learning, recognition memory, and spontaneous exploration abilities in mice. Histopathologic changes in the hippocampal cornu ammonis area 1 (CA1) region and Aβ1-42 deposition were observed using histologic staining and immunohistochemistry. Enzyme-linked immunosorbent assay was used to measure Aβ1-40 and Aβ1-42 expression. Classical microglia (M1)/alternative microglia (M2) polarization, inflammatory factors, and oxidative stress levels were assessed through immunofluorescence and kits. NLRP3 inflammasome indicators were detected by reverse transcription quantitative polymerase chain reaction and western blot.

RESULTS: After tDCS treatment, APP/PS1 mice exhibited shortened escape latency, increased platform crossings, and an elevated discrimination index. In the open field test, total movement distance and time spent in the center zone increased. The Aβ1-42/40 ratio in the mouse hippocampal CA1 region decreased by 20.8%, whereas neurons and Nissl bodies increased, indicating that tDCS improved cognitive function. tDCS reduced M1 polarization, increased M2 polarization, and reduced neuroinflammation and oxidative stress in the hippocampal CA1 region of APP/PS1 mice. Moreover, tDCS suppressed microglial NLRP3/caspase-1 pathway activation and Aβ deposition in APP/PS1 mice. NLRP3/caspase-1 pathway activation partially reversed effects of tDCS on APP/PS1 mice.

CONCLUSION: This study highlights the potential therapeutic value of tDCS in AD mice. It reveals that tDCS promotes hippocampal microglial M2 polarization and Aβ degradation to curtail NLRP3/caspase-1 inflammasome pathway activation, thereby improving cognitive function in APP/PS1 mice.}, } @article {pmid42012542, year = {2026}, author = {Tu, X and Fang, M and Yan, Y and Liu, Y and Yu, J and Chen, L and Zhang, L and Huang, C and Fan, S}, title = {The neuroprotective effect of Cucurbitacin B against Aβ and tau toxicities requires functional HDAC6 and stress granule pathways.}, journal = {Biogerontology}, volume = {27}, number = {3}, pages = {}, pmid = {42012542}, issn = {1573-6768}, support = {24ZR1466100//Natural Science Foundation of Shanghai Municipality/ ; 25PJD123//Shanghai Magnolia Talent Plan of Shanghai - Pujiang Talents Program/ ; QNKJ2025007//Eastern Talent Program - Science and Technology Platform of Shanghai/ ; }, mesh = {Animals ; *Histone Deacetylase 6/metabolism ; *Amyloid beta-Peptides/metabolism/toxicity ; *Triterpenes/pharmacology ; *tau Proteins/metabolism/toxicity ; *Neuroprotective Agents/pharmacology ; Caenorhabditis elegans ; *Stress Granules/metabolism/drug effects ; Humans ; *Alzheimer Disease/metabolism/drug therapy ; }, abstract = {Alzheimer's disease (AD) is characterized by proteostasis collapse driven by amyloid-β (Aβ) plaques and tau tangles. Dysregulation of stress granule (SG) dynamics and aberrant histone deacetylase 6 (HDAC6) activity are emerging as pivotal pathogenic mechanisms promoting neurodegeneration. Here, we identify that Cucurbitacin B (CB), a natural triterpenoid, acts as a potent SG inducer that confers broad-spectrum neuroprotection. Mechanistically, we demonstrate a novel "recruit-and-sequester" model: CB promotes the assembly of HDAC6-recuited SGs, thereby physically sequestering HDAC6 and functionally inhibiting its deacetylase activity. In Caenorhabditis elegans (C. elegans) and mammalian cell models, CB treatment significantly alleviated Aβ oligomer-induced cytotoxicity and tau hyperphosphorylation. Notably, the neuroprotective efficacy of CB was abolished by the genetic knockdown of core SG components (gtbp-1/G3BP1, tiar-1/TIA1) or hda-6/HDAC6, confirming that its therapeutic action relies on the integrity of the HDAC6-SG. Our findings highlight the potential of modulating SG dynamics to spatially regulate HDAC6, offering a novel therapeutic strategy for AD.}, } @article {pmid42013009, year = {2026}, author = {Botta, D and Bernetti, C and Hutuca, I and Ojeda Esparza, JF and Sveikata, L and Lovblad, KO and Kurz, FT}, title = {Beyond the Leak: Advanced MRI Assessment of the Blood-Brain Barrier in Neurodegeneration.}, journal = {Neuro-degenerative diseases}, volume = {}, number = {}, pages = {1-16}, pmid = {42013009}, issn = {1660-2862}, abstract = {BACKGROUND: The blood-brain barrier (BBB) is a specialized multicellular interface that maintains the central nervous system's tightly regulated microenvironment. BBB disruption is increasingly recognized as a key feature of neurodegeneration, documented across disorders including Alzheimer's disease (AD), Parkinson's disease (PD), and cerebral small vessel disease (cSVD). While the extent to which BBB breakdown is a cause or consequence of neuronal pathology remains unclear, its pronounced presence in disease states suggests a significant contributory role in progression.

SUMMARY: This review provides a neuroradiological overview of advanced MRI approaches for assessing BBB integrity in neurodegenerative diseases. The primary quantitative biomarkers discussed are the volume transfer constant (Ktrans) derived from dynamic contrast-enhanced MRI (DCE), reflecting paracellular gadolinium leakage, and the water exchange rate (kw) from arterial spin labeling (ASL), capturing trans-endothelial water permeability. Disease-specific BBB signatures across AD, PD, and cSVD are systematically described, alongside complementary indirect markers including diffusion MRI, dynamic susceptibility contrast, and vessel architecture imaging. Current technological advances, including ultra-high-field MRI and AI-assisted post-processing, are discussed in relation to their potential to enhance detection sensitivity. With continued technical refinement and standardization, MRI-based BBB metrics are transitioning from research tools into candidate neurovascular biomarkers with growing potential for early diagnosis, treatment monitoring, and longitudinal follow-up.

KEY MESSAGES: MRI-based BBB imaging represents an emerging neurovascular biomarker under active investigation for future diagnostic and therapeutic applications. DCE and ASL provide complementary BBB metrics (Ktrans, kw), illuminating distinct and complementary facets of barrier dysfunction. BBB disruption is a key and early feature across AD, PD, and cSVD, with disease-specific regional patterns that may guide patient stratification and therapeutic monitoring. Ultra-high-field MRI and AI-assisted post-processing are advancing BBB imaging sensitivity; however, multicenter standardization and normative validation remain critical prerequisites for clinical translation.}, } @article {pmid42013076, year = {2026}, author = {Jain, S and Tunc, EB and Grossberg, GT}, title = {Pharmacotherapeutic landscape for the management of agitation associated with Alzheimer's disease.}, journal = {Expert opinion on pharmacotherapy}, volume = {27}, number = {6}, pages = {531-544}, doi = {10.1080/14656566.2026.2662949}, pmid = {42013076}, issn = {1744-7666}, mesh = {Humans ; *Alzheimer Disease/complications/drug therapy/physiopathology ; *Psychomotor Agitation/drug therapy/etiology ; Antipsychotic Agents/adverse effects/administration & dosage/pharmacology/therapeutic use ; Off-Label Use ; Animals ; }, abstract = {INTRODUCTION: Agitation associated with Alzheimer's disease (AAD) is common, persistent, and strongly linked to caregiver burden, emergency care, and institutionalization. Pharmacologic options have historically been limited by modest efficacy and safety liabilities in the geriatric population, creating a major treatment gap.

AREAS COVERED: This narrative review summarizes established and emerging pharmacotherapies for AAD, emphasizing comparative efficacy, geriatric-relevant safety, and real-world feasibility. A literature search was conducted in PubMed/MEDLINE and ClinicalTrials.gov from database inception through 31 January 2026, prioritizing the most recent decade when applicable, and complemented these searches with hand searches of key trials, meta-analyses, guidelines, and publicly available regulatory or sponsor communications for late-stage programs. Evidence is synthesized qualitatively due to heterogeneity in definitions and outcomes. We discuss antipsychotics, serotonergic agents, drugs with negative trials, and pipeline approaches such as dextromethorphan-based combinations and adrenergic strategies.

EXPERT OPINION: The field is shifting from broad off-label prescribing toward phenotype-informed, trial-validated treatments. Brexpiprazole establishes regulatory feasibility, while dextromethorphan-based combinations, particularly AXS-05, appear promising, including signals for durability. Progress will depend on harmonized outcomes, longer-term safety data, and pragmatic trials that prioritize function, caregiver impact, and crisis prevention.}, } @article {pmid42013744, year = {2026}, author = {Zhao, X and Bao, Y and Wan, X and Miao, R and Li, C and Wang, J and Zhang, H and Xiang, Y and Pang, Y and Miao, Z and Tong, M and Shi, X and Wang, H and Gong, P and Zhao, Y and Hou, Y}, title = {Design, synthesis, and evaluation of dual-target inhibitors of acetylcholinesterase (AChE) and soluble epoxide hydrolase (sEH) for the treatment of Alzheimer's disease.}, journal = {European journal of medicinal chemistry}, volume = {312}, number = {}, pages = {118844}, doi = {10.1016/j.ejmech.2026.118844}, pmid = {42013744}, issn = {1768-3254}, mesh = {*Alzheimer Disease/drug therapy/metabolism ; Humans ; *Drug Design ; Animals ; *Cholinesterase Inhibitors/pharmacology/chemical synthesis/chemistry ; *Acetylcholinesterase/metabolism ; Mice ; Structure-Activity Relationship ; Rats ; Molecular Structure ; Dose-Response Relationship, Drug ; *Tacrine/pharmacology/chemical synthesis/chemistry ; Male ; }, abstract = {In this study, a series of tacrine derivatives featuring a triazole linker with sEH fragment were designed, synthesized, and evaluated for Alzheimer's disease treatment. Among them, compound Z43 exhibited best dual inhibitory activity against AChE and sEH (AChE IC50 = 1.7 nM; sEH IC50 = 0.7 nM) and showed low cytotoxicity in HepG2, SMMC7721 and SH-SY5Y cell lines. In addition, Z43 showed high permeability in PAMPA permeability test. Meanwhile, Z43 protected PC12 cells from H2O2-induced toxicity. Moreover, in LPS-induced BV-2 cell inflammation model, Z43 significantly reduced the levels of TNF-α, IL-1β, IL-6 and iNOS. Acute toxicity tests also indicated a favorable safety profile. In the scopolamine-induced AD mice model, Z43 markedly improved learning and memory deficits, which was significantly better than tacrine and EC5026. In summary, compound Z43 shows promising potential for further research.}, } @article {pmid42014236, year = {2026}, author = {Corcoran, E and Kettlety, M and Mogul, U and Azah, JN and Cork, SC}, title = {The effects of GLP-1 receptor agonists on Alzheimer's pathophysiology: A systematic review.}, journal = {Molecular and cellular neurosciences}, volume = {137}, number = {}, pages = {104091}, doi = {10.1016/j.mcn.2026.104091}, pmid = {42014236}, issn = {1095-9327}, mesh = {Animals ; Humans ; *Alzheimer Disease/drug therapy/metabolism/physiopathology ; Amyloid beta-Peptides/metabolism ; Exenatide/therapeutic use ; Glucagon-Like Peptide-1 Receptor/metabolism ; *Glucagon-Like Peptide-1 Receptor Agonists ; Glucagon-Like Peptides/analogs & derivatives/therapeutic use/analogs & derivatives ; Immunoglobulin Fc Fragments/therapeutic use ; Liraglutide/therapeutic use ; Recombinant Fusion Proteins/therapeutic use ; Semaglutide/therapeutic use ; tau Proteins/metabolism ; }, abstract = {BACKGROUND: The incidence of Alzheimer's disease (AD) is increasing globally but there are limited effective therapies available. Recently, evidence has demonstrated a role of GLP-1 receptor (GLP-1R) agonists, commonly used in the treatment of type 2 diabetes, may have therapeutic potential in AD. GLP-1R agonists have exhibited their neuroprotective role by targeting tau hyperphosphorylation and the accumulation of beta-amyloid (Aβ) plaques. This systematic review aims to evaluate the effectiveness of liraglutide, semaglutide, exenatide and dulaglutide on AD pathology with a focus on the key biomarkers: hyperphosphorylated tau and Aβ.

METHODS: A systematic literature search was conducted using PubMed, Embase and Cochrane Library. Inclusion criteria involved pre-clinical and clinical studies investigating the effects of GLP-1 agonists dulaglutide, liraglutide, semaglutide or exenatide on Aβ and tau pathology. Randomised and non-randomised studies were included. Exclusion criteria involved studies evaluating GLP-1R agonists other than those specified.

RESULTS: This review examined thirty preclinical studies investigating the effects of four GLP-1 receptor agonists on Alzheimer's disease pathology, particularly Aβ plaque accumulation and tau hyperphosphorylation. Most studies focused on liraglutide, which consistently reduced both Aβ and tau pathology in animal and cell models. Dulaglutide, although studied less frequently, consistently reduced tau phosphorylation and Aβ accumulation in mouse models while also improving cognitive outcomes. Semaglutide also showed largely positive effects with four studies reporting reduced Aβ or tau pathology, though one study reported no benefit. Two clinical studies were also reviewed. A phase II trial of Exenatide showed reduced plasma Aβ42 in extracellular vesicles but not cognitive benefit. A smaller liraglutide trial demonstrated no reduction in Aβ burden or cognitive change though it preserved brain glucose metabolism. An EXSCEL trial showed significant changes in systemic inflammatory markers. While pre-clinical data has been encouraging, clinical evidence remains limited.

CONCLUSIONS: There is consistent preclinical evidence that GLP-1R agonists are effective in reducing Aβ levels and hyperphosphorylated tau. While the neuroprotective effect in preclinical studies is clear, clinical findings have so far failed to demonstrate an arresting effect on cognitive.

REGISTRATION: PROSPERO CRD420251029748.}, } @article {pmid42014786, year = {2026}, author = {Kim, OH and Shin, CH and Cho, MW and Ha, JY and Choung, JJ and Song, DK and Choi, JY and Chang, ES and Lee, HJ and Ku, SK}, title = {Transcranial vibrotactile stimulation enhances hippocampal cholinergic signaling and memory through frequency-dependent mechanotransduction.}, journal = {Scientific reports}, volume = {16}, number = {1}, pages = {}, pmid = {42014786}, issn = {2045-2322}, mesh = {Animals ; *Hippocampus/metabolism/physiology ; Male ; *Mechanotransduction, Cellular ; Mice ; *Memory/physiology ; *Vibration ; Mice, Inbred C57BL ; Scopolamine ; Signal Transduction ; Cognitive Enhancement ; Maze Learning ; }, abstract = {Cholinergic dysfunction is a key contributor to cognitive impairment observed in aging and neurodegenerative disorders such as Alzheimer's disease (AD). Although acetylcholinesterase (AChE) inhibitors have been the mainstay of symptomatic treatment for over two decades, their limited efficacy and adverse effects underscore the need for alternative therapeutic approaches. Recent evidence indicates that mechanical stimulation can modulate neuronal and glial signaling through mechanotransduction, suggesting a potential strategy to enhance cognitive function via non-pharmacological means. Here, we developed a head-mounted vibrotactile stimulation system (HVSS) that delivers controlled vibration to the cranium and evaluated its effects in a pharmacological model of acute cholinergic dysfunction induced by scopolamine. To this end, male C57BL/6 mice received scopolamine (1 mg/kg, i.p.; on days 7, 14, and 28) and were exposed to daily vibrotactile stimulation at 20, 40, or 80 Hz for 28 days. Behavioral performance was assessed using passive avoidance and Morris water maze tests, followed by biochemical and histological analyses. HVSS at 40 Hz and 80 Hz significantly improved cognitive performance, enhanced hippocampal cholinergic function, reduced oxidative damage, and upregulated memory-related signaling genes, including BDNF, PI3K, AKt, ERK1/2, CREB, and CAMK4. These findings suggest that high-frequency HVSS improves memory hippocampal cholinergic function via activation of memory-related signaling pathways, highlighting its potential as a safe, non-pharmacological neuromodulatory strategy for cholinergic dysfunction-related cognitive decline.}, } @article {pmid42015253, year = {2026}, author = {Reetz, K and Liepelt-Scarfone, I and Häger, A and Flöel, A and Schulz, JB and , }, title = {The best treatment is prevention: prevention of cognitive decline and dementia - current state, gaps and next steps.}, journal = {Neurological research and practice}, volume = {8}, number = {1}, pages = {}, pmid = {42015253}, issn = {2524-3489}, abstract = {The World Health Organization (WHO) recognises dementia as a public health priority. Currently, more than 55 million people live with dementia, and this figure is expected to almost triple to 139 million by 2050. Alzheimer’s disease is the most common cause of dementia, and there is still no cure. Despite the availability of symptomatic and first disease-modifying treatments, effective treatment remains limited. This makes it even more important to be aware that it is estimated that nearly half of all dementia cases could be prevented by eliminating 14 major risk factors. Consequently, the role of these modifiable risk factors has been the subject of research to inform effective preventive strategies. This narrative review summarises the current evidence on the prevention of cognitive decline and dementia. First, we provide an overview of the current state on risk factors, multimodal clinical controlled trials for slowing down or preventing dementia and primordial, primary, secondary, tertiary and quaternary prevention of cognitive decline and dementia. Second, we evaluate knowledge and action gaps in the field. Finally, we discuss how to address these gaps and what the next steps should be. Overall, to accelerate progress, the following key calls to action are paramount: (1) making prevention of cognitive decline and dementia a priority; (2) promoting brain health throughout the lifespan through coordinated intersectoral action targeting key risk factors; (3) improving access to diagnosis and treatment for patients with cognitive decline and dementia; and (4) encouraging research on prevention and how to translate knowledge into action.}, } @article {pmid42015258, year = {2026}, author = {Hao, JP and Cheng, ZZ and Wang, MY and Zhu, YP and Chen, N and Zhu, D and Zhang, L and Li, YL and Li, L and Bai, ZF and Xiao, XH and Wang, JB and Zhang, L and Gao, D}, title = {Tet2 deficiency orchestrates Alzheimer's pathogenesis through oxidative mtDNA-driven cGAS-STING activation.}, journal = {Journal of neuroinflammation}, volume = {23}, number = {1}, pages = {}, pmid = {42015258}, issn = {1742-2094}, support = {82274611//National Natural Science Foundation of China/ ; 82274121//National Natural Science Foundation of China/ ; 7232267//Natural Science Foundation of Beijing Municipality/ ; H2025112023//Natural Science Foundation of Hebei Province/ ; HZ2025PYYX010//Xuanwu Hospital Talent Convergence Program/ ; }, mesh = {Animals ; *Alzheimer Disease/metabolism/pathology/genetics ; cGAS-STING Signaling Pathway ; Humans ; *DNA, Mitochondrial/metabolism/genetics ; Cyclic Guanosine Monophosphate-Adenosine Monophosphate Synthase ; *Nucleotidyltransferases/metabolism ; *Oxidative Stress/physiology ; Mice ; *Membrane Proteins/metabolism ; *Dioxygenases/deficiency ; STING Protein ; *DNA-Binding Proteins/deficiency/genetics ; Male ; Mice, Transgenic ; Mitochondria/metabolism ; *Proto-Oncogene Proteins/deficiency/genetics ; }, abstract = {Emerging evidence underscores the pivotal role of Ten-eleven translocation 2 (Tet2), as an epigenetic regulator with neuroprotective functions, yet its temporal dynamics and pathogenic contributions to Alzheimer’s disease (AD) remain poorly understood. By integrating human longitudinal cohort data with experimental models, we demonstrated that Tet2 deficiency accelerated AD‑like neurodegeneration through oxidative stress-dependent cGAS-STING activation. Clinically, Tet2 loss-of-function carriers among Aβ-positive individuals exhibited significantly accelerated cognitive decline. In mice, Tet2 expression decreased with age and in late‑stage AD models, and constitutive Tet2‑mutant (Tet2mut) mice recapitulated AD-like behaviors and pathology by exacerbating neuroinflammation and impairing neurogenesis and synaptic plasticity. Crucially, Tet2 deficiency induced mitochondrial dysmorphology and heightened oxidative stress in the hippocampus, culminating in DNA damage and robust cGAS-STING activation. Mechanistically, integrative epigenomic analyses further revealed that Tet2 deficiency was associated with hypermethylation of antioxidant gene networks, thereby exacerbating oxidative stress and mitochondrial injury. Notably, antioxidant treatment with N-acetylcysteine (NAC) effectively alleviated oxidative damage, restored mitochondrial function and suppressed cGAS-STING signaling in Tet2-silenced microglia. In vivo, NAC administration in Tet2mut mice improved cognitive performance and synaptic plasticity while reducing neuroinflammation and neuronal loss through inhibition of cGAS-STING signaling. These findings delineate a previously unrecognized epigenetic-immune axis in AD, highlighting Tet2 enhancement and ROS modulation as promising therapeutic strategies.}, } @article {pmid42015299, year = {2026}, author = {Ge, C and Wang, K and Tang, H and Ke, Y and Wang, H and Fu, Q and Xiu, Y and Guo, Y and Jia, YF and Long, Z and He, G and Tang, Q}, title = {NDST3 suppression restores lysosomal acidification and ameliorates amyloid-β and MAPT/tau pathology in Alzheimer's disease.}, journal = {Translational neurodegeneration}, volume = {15}, number = {1}, pages = {}, pmid = {42015299}, issn = {2047-9158}, support = {BJRC202310//Project of the Top-Notch Talent Cultivation Program for the Graduate Students of Chongqing Medical University/ ; W0168//Program for Youth Innovation in Future Medicine, Chongqing Medical University/ ; 82371203//National Natural Science Foundation of China/ ; 82201582//National Natural Science Foundation of China/ ; CSTB2024NSCQ-MSX0483//Natural Science Foundation of Chongqing, China/ ; KJQN202200457//Science and Technology Research Program of Chongqing Municipal Education Commission/ ; }, mesh = {*Alzheimer Disease/pathology/metabolism ; Animals ; *Lysosomes/metabolism/pathology ; *tau Proteins/metabolism ; *Amyloid beta-Peptides/metabolism ; Mice ; Humans ; Mice, Transgenic ; Hippocampus/metabolism/pathology ; Hydrogen-Ion Concentration ; Histone Deacetylase 6/metabolism ; }, abstract = {BACKGROUND: Impairment of lysosomal acidification has recently been identified as a critical driver of amyloid-β and MAPT/tau pathology in Alzheimer's disease (AD). Restoring lysosomal acidification is a promising strategy for AD treatment. N-deacetylase and N-sulfotransferase 3 (NDST3) is a newly discovered tubulin deacetylase that regulates lysosomal acidification by influencing the recruitment of V-ATPase V1 subunits to lysosomes. Nevertheless, the role of NDST3 in AD remains entirely unexplored.

METHODS: We began by comparing the effects of NDST3 and histone deacetylase 6 (HDAC6), a well-known tubulin deacetylase with established roles in AD, on lysosomal acidification. Using HT22 cell-based models of AD, we knocked down NDST3 to examine its role in lysosomal acidification and degradative function in the context of this disease. We also evaluated the expression profile of NDST3 in both in vitro and in vivo models of AD. Finally, we investigated the consequences of NDST3 suppression on lysosomal acidity and related AD pathological features in the hippocampi of 3 × Tg-AD mice.

RESULTS: NDST3 differs from HDAC6 in the subcellular spatial patterns of catalyzing microtubule deacetylation but parallels HDAC6 in regulating lysosomal pH. In HT22 cells with APP695[Swe] overexpression, knockdown of NDST3 lowered lysosomal pH by promoting the assembly of the V-ATPase holoenzyme on the lysosomal membrane and enhanced the autophagic degradation of aberrant Aβ and MAPT/tau. Notably, NDST3 levels were found to be elevated in the brains of AD models and patients. Reducing NDST3 expression in the hippocampi of 3 × Tg-AD mice facilitated lysosomal reacidification, which decreased the abnormal accumulation of amyloid plaques and MAPT/tau tangles, mitigated neuronal damage, and ameliorated cognitive deficits.

CONCLUSIONS: Our study identified NDST3 as a key factor regulating lysosomal acidity in AD. Suppressing NDST3 restores lysosomal function in AD and protects against AD pathology, highlighting NDST3 as a promising therapeutic target for AD.}, } @article {pmid42015324, year = {2026}, author = {Li, R and Langford, O and Insel, PS and Sperling, RA and Raman, R and Aisen, PS and Donohue, MC}, title = {Divergent patterns of cognitive decline in preclinical Alzheimer's disease: Implications for secondary prevention trials.}, journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association}, volume = {22}, number = {4}, pages = {e71366}, pmid = {42015324}, issn = {1552-5279}, support = {//Epstein Family Foundation/ ; //Avid Radiopharmaceuticals/ ; //GHR Foundation/ ; //Foundation for the National Institutes of Health/ ; //Eli Lilly and Company/ ; /ALZ/Alzheimer's Association/United States ; U24AG057437/AG/NIA NIH HHS/United States ; R01 AG063689/AG/NIA NIH HHS/United States ; }, mesh = {Humans ; *Alzheimer Disease/prevention & control/diagnostic imaging ; Female ; Male ; Disease Progression ; *Cognitive Dysfunction/diagnostic imaging/prevention & control ; tau Proteins/metabolism ; Positron-Emission Tomography ; Aged ; Amyloid beta-Peptides/metabolism ; *Secondary Prevention ; Biomarkers ; Longitudinal Studies ; Prodromal Symptoms ; Neuropsychological Tests ; Hippocampus/pathology/diagnostic imaging ; }, abstract = {INTRODUCTION: Biomarkers identify Alzheimer's disease pathology in cognitively unimpaired adults, but the timing and rate of cognitive decline vary widely. This study aimed to identify subgroups of cognitive decline and baseline predictors of heterogeneity in preclinical progression.

METHODS: Data were drawn from the Anti-Amyloid Treatment in Asymptomatic Alzheimer's Disease Study, which enrolled amyloid beta-positive (Aβ+) participants, and the Longitudinal Evaluation of Amyloid Risk and Neurodegeneration (LEARN) Study, which enrolled amyloid beta-negative (Aβ-) individuals. Latent class mixed-effects models identified cognitive trajectory classes. Associations between class membership and demographic, clinical, and biomarker variables were evaluated. The primary outcome was change in the Preclinical Alzheimer Cognitive Composite.

RESULTS: Three trajectory classes were identified: stable, slow decliners, and fast decliners. Higher phosphorylated tau at 217 (p-tau217), smaller hippocampal volume, and elevated tau positron emission tomography were associated with declining classes. About 70% of Aβ+ individuals were stable.

DISCUSSION: Latent class modeling reveals substantial heterogeneity in preclinical trajectories with important implications for prevention trial design.}, } @article {pmid42015334, year = {2026}, author = {van Etten, ES and Mahinrad, S and Grill, JD and Salloway, S and Atri, A and Cogswell, PM and Benzinger, TLS and Iwatsubo, T and Iadecola, C and Lemere, CA and Nicoll, JAR and Greenberg, SM and Carrillo, MC and Jack, CR and Sperling, RA}, title = {Amyloid-related imaging abnormalities (ARIA) in anti-amyloid therapies for Alzheimer's disease: An update from the Alzheimer's Association ARIA workgroup.}, journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association}, volume = {22}, number = {4}, pages = {e71361}, pmid = {42015334}, issn = {1552-5279}, support = {R01 NS037853/NS/NINDS NIH HHS/United States ; P01 AG003991/AG/NIA NIH HHS/United States ; R01NS136122/NH/NIH HHS/United States ; 09150162410011/ZONMW_/ZonMw/Netherlands ; 642991//Alzheimer Nederland/ ; P01AG003991/NH/NIH HHS/United States ; R01AG084531/NH/NIH HHS/United States ; P30AG066519/NH/NIH HHS/United States ; ARUK-PPG2023B-023//Alzheimer Research UK/ ; }, mesh = {Humans ; *Alzheimer Disease/diagnostic imaging/drug therapy/therapy ; *Brain/diagnostic imaging/pathology ; *Neuroimaging ; *Amyloid beta-Peptides/metabolism ; Immunotherapy/methods ; }, abstract = {In 2011, a workgroup of the Alzheimer's Association Research Roundtable introduced recommendations for detecting and monitoring amyloid-related imaging abnormalities (ARIA) in Alzheimer's disease (AD) clinical trials. Since then, anti-amyloid immunotherapies have received regulatory approval for AD treatment and are beginning to enter clinical practice, underscoring the importance of informing healthcare providers, researchers, and patients about ARIA's implications in real-world settings. In response, the Alzheimer's Association convened a new workgroup to review current knowledge of ARIA, including underlying mechanisms, clinical presentations, associated risk factors, mitigation strategies, radiologic detection methods, patients' perspectives in treatment decision-making, and outstanding challenges. Here, we outline key insights from this workgroup, highlighting that effective ARIA detection and monitoring in clinical practice requires adherence to robust protocols to mitigate risks and enhance patient safety. Limited availability of clinical and pathologic data on predictors of symptomatic and severe ARIA underscores the importance of continued real-world data collection.}, } @article {pmid42015793, year = {2026}, author = {Gao, L and Watson, R and Yassi, N}, title = {Cost-Effectiveness of Donanemab for Early Alzheimer Disease in Australia.}, journal = {The Medical journal of Australia}, volume = {224}, number = {4}, pages = {e70186}, pmid = {42015793}, issn = {1326-5377}, mesh = {Humans ; *Alzheimer Disease/drug therapy/economics ; Cost-Benefit Analysis ; Cost-Effectiveness Analysis ; Australia ; Markov Chains ; Aged ; Quality-Adjusted Life Years ; Female ; Disease Progression ; *Antibodies, Monoclonal/economics/therapeutic use ; Male ; Amyloid beta-Peptides ; Health Care Costs ; Antibodies, Monoclonal, Humanized ; }, abstract = {OBJECTIVES: To evaluate the cost-effectiveness of donanemab, an anti-amyloid-β monoclonal antibody recently approved in Australia, for treating early-stage Alzheimer disease with confirmed amyloid-β pathology from healthcare system and societal perspectives.

DESIGN: A Markov microsimulation model simulating long-term Alzheimer disease progression, treatment costs and health outcomes for donanemab compared with standard care.

SETTING, PARTICIPANTS: Australian healthcare context, applying published clinical and economic inputs. A hypothetical cohort of people with early symptomatic Alzheimer disease, consistent with TRAILBLAZER-ALZ eligibility criteria: mean age 75 years, amyloid-β-positive, with mild cognitive impairment or mild dementia because of Alzheimer disease and excluding individuals with APOEE4 homozygotes, in line with the Australian labelling. Donanemab administered every 4 weeks with magnetic resonance imaging (MRI)-based amyloid-β-related imaging abnormalities monitoring and treatment suspension upon amyloid-β clearance or progression to severe Alzheimer disease, compared with standard care.

MAIN OUTCOME MEASURES: Incremental costs, quality-adjusted life years (QALYs) and incremental cost-effectiveness ratios (ICERs). Secondary analyses included sensitivity and distributional equity analyses.

RESULTS: Donanemab increased total healthcare costs ($300,689 vs. $178,121) and societal costs ($389,113 vs. $283,618) compared with standard care per capita, while improving health outcomes (4.38 vs. 4.01 QALYs) per capita. The ICER was $342,424 per QALY from the healthcare perspective and $294,701 per QALY from the societal perspective, exceeding frequently cited Australian willingness-to-pay thresholds. Sensitivity analyses identified drug cost and efficacy as key drivers of uncertainty. Distributional analysis suggested inequitable health gains by remoteness because of differences in diagnostic and treatment infrastructure.

CONCLUSION: Donanemab provides clinical benefits but is unlikely to be cost-effective under current Australian thresholds. Policymakers should balance economic evidence with unmet need, equity considerations and healthcare sustainability when making reimbursement decisions. Further research using real-world evidence and disaggregated analyses by geography and socioeconomic status is warranted.}, } @article {pmid42015806, year = {2026}, author = {Zhang, X and Elmansy, R}, title = {Exploring Influencing Factors of Medication Adherence Among Chinese Patients With Alzheimer Disease: Delphi Study Informing Future Artificial Intelligence-Supported Interventions.}, journal = {JMIR formative research}, volume = {10}, number = {}, pages = {e89508}, pmid = {42015806}, issn = {2561-326X}, mesh = {Humans ; *Alzheimer Disease/drug therapy/psychology ; Delphi Technique ; *Artificial Intelligence/standards ; Female ; *Medication Adherence/psychology ; China ; Male ; Aged ; Adherence Interventions ; Middle Aged ; East Asian People ; }, abstract = {BACKGROUND: Alzheimer disease (AD) affects cognition, treatment adherence, family connections, and health care resource allocation. Most patients with AD have low adherence to medication therapy due to the limitations associated with cognitive impairment. Therefore, increasing the involvement of patients and their family members in medication management is important to improve treatment outcomes and reduce the burden of care.

OBJECTIVE: This study explores the potential application of artificial intelligence (AI) in medication management for Chinese patients with early- to mid-stage AD focusing on enhancing medication adherence. The study first predicts and evaluates key factors through an online Delphi study, which provides a basis for their subsequent incorporation into the AI model as input variables to enable prediction of medication-taking behaviors. Since AI research in medication management for this population is still undeveloped, this paper further explores the multiple potentials of AI from a theoretical view, including drug dosage optimization, multidrug interaction detection, and family education support. It will provide a preliminary direction and theoretical basis for the development of an intelligent medication management system in the future.

METHODS: The exploratory online Delphi study with no modification predicted the key factors influencing medication adherence. Based on the results, the study confirmed the potential of AI to improve adherence. Participation by 12 experts in 3 rounds systematically assessed the core elements influencing patients' adherence to their medication.

RESULTS: Family care, social support, environmental factors, emotional support, and patient behaviors were identified as the primary factors influencing medication adherence among Chinese patients with AD. These factors were validated and ranked through iterative Delphi rounds, with family care and social support receiving the highest importance scores. The Wilcoxon signed-rank test indicated no significant difference between rounds (P=.06), supporting the stability of the consensus. These findings establish a foundational set of variables for AI systems that predict and enhance medication adherence.

CONCLUSIONS: This study highlights the critical factors affecting medication adherence by Chinese patients with AD. It was designed as an exploratory online Delphi study to identify and prioritize key influencing factors, rather than to validate a specific AI-based system, and the findings provide a theoretical foundation for future AI-informed interventions. The results also indicate theoretical potential roles for AI in supporting medication management, such as optimizing drug dosage, detecting multidrug interactions, and enhancing family education.}, } @article {pmid42016208, year = {2026}, author = {Shah, KB and Xiang, L and Shah, SK and Adler, RR and Weissman, JS}, title = {Dementia Is Associated With Higher One-Year Mortality and Worse Patient-Centered Outcomes in Patients Undergoing Percutaneous Coronary Intervention for Acute Myocardial Infarction and Cardiogenic Shock.}, journal = {Cardiology research}, volume = {17}, number = {2}, pages = {128-135}, pmid = {42016208}, issn = {1923-2829}, abstract = {BACKGROUND: Recent trial data demonstrates improved outcomes for the treatment of ST-segment elevation myocardial infarction (STEMI) and cardiogenic shock (CS) with percutaneous coronary intervention (PCI) supported by mechanical circulatory support (MCS). Clinical outcomes in patients with Alzheimer's disease and related dementias (ADRD), however, remain unknown, as these patients were excluded from relevant trials. Physicians and caregivers struggle to navigate time-sensitive decision making for patients with ADRD presenting with STEMI or CS. The aims of this study were to assess the association of ADRD with outcomes of PCI with MCS in the setting of STEMI or CS.

METHODS: We compared outcomes among Medicare fee-for-service (FFS) beneficiaries aged 66 years or older, with and without ADRD, who underwent PCI with MCS for STEMI or CS from July 1, 2017 to December 31, 2019. The primary clinical outcome was inpatient mortality, and secondary clinical outcomes were 1-year mortality, complications, and readmissions. Patient-centered outcomes were time-at-home ratio and discharge to a higher level of care.

RESULTS: A total of 13,110 patients undergoing PCI with MCS for STEMI or CS met study criteria, and 988 (7.5%) patients carried a diagnosis of ADRD. Patients with ADRD were more likely to be older (81.1 vs. 75.5, P < 0.001) and frail (47.0% vs. 22.0%, P < 0.001). Inpatient mortality was similar between groups (odds ratio (OR), 1.05; 95% confidence interval (CI), 0.92-1.21), but 1-year mortality was higher among patients with ADRD (OR, 1.41; 95% CI, 1.21-1.64). Major complications and readmissions were similar between groups. Patients with ADRD were more likely to be discharged to a higher level of care (OR, 1.46; 95% CI, 1.16-1.82) than those without ADRD but demonstrated a similar time-at-home ratio.

CONCLUSIONS: Patients with ADRD demonstrate similar rates of inpatient mortality and major complications but have higher rates of 1-year mortality and discharge to higher levels of care.}, } @article {pmid42016241, year = {2026}, author = {Sun, M and He, J and Song, H and Ma, Z and Zhang, X and Li, J and Yao, Y}, title = {Structural Characterization and Anti-Alzheimer's Disease Effect of Polysaccharides From Stellariae Radix.}, journal = {Food science & nutrition}, volume = {14}, number = {3}, pages = {e71604}, pmid = {42016241}, issn = {2048-7177}, abstract = {Stellariae Radix, a frequently employed traditional Chinese medicine, originates from the dried roots of Stellaria dichotoma L. var. lanceolata Bge. To elucidate the structural characteristics and anti-Alzheimer's disease (AD) efficacy of S. dichotoma polysaccharides (SDP), SDP was extracted and comprehensively characterized using ultraviolet-visible spectroscopy (UV-Vis), Fourier-transform infrared spectroscopy (FT-IR), nuclear magnetic resonance (NMR) spectroscopy and high-performance liquid chromatography (HPLC). The results revealed that SDP is composed of galactose, glucose, arabinose, galacturonic acid, mannose, and rhamnose at a molar ratio of 5.561:2.224:0.802:0.616:0.613:0.184. In vitro experiments demonstrated that SDP exhibited potent scavenging activities against ABTS, DPPH, and hydroxyl radicals in a dose-dependent manner, with the average scavenging rates reaching 99.07%, 89.44% and 56.43% respectively at the concentration of 5 mg/mL. In a C57BL/6J mouse model of AD, administration of SDP (50-200 mg/kg) significantly ameliorated cognitive dysfunction, increased the hippocampal levels of superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px), decreased the malondialdehyde (MDA) content, and regulated the expression of oxidative stress-related proteins, including Nrf2, Keap1 and NQO1. These findings indicate that SDP possesses antioxidant and neuroprotective properties, suggesting its potential therapeutic value for the treatment of AD.}, } @article {pmid42016382, year = {2026}, author = {Yi, S and Zou, J and He, X and Chen, H and Lin, Z and Zhang, L and Zhu, Y and Zuo, Z and Chen, Z and Hu, X and Niu, L}, title = {Transcranial Ultrasound Stimulation Pulsed at 40 Hz Improves Cognition and Neuroinflammation in Female Mice with Alzheimer's Disease.}, journal = {Research (Washington, D.C.)}, volume = {9}, number = {}, pages = {1244}, pmid = {42016382}, issn = {2639-5274}, abstract = {Recent advances in transcranial ultrasound stimulation (TUS) pulsed at 40 Hz have demonstrated the potential to ameliorate cognitive deficits in mouse models of Alzheimer's disease. However, technical barriers remain as general anesthesia is required for mice, which restricts the accurate elucidation of biological mechanisms and behavioral effects under awake physiological conditions. Here, we report a wearable, free-moving ultrasound stimulation system that delivers TUS pulsed at 40 Hz to female 5xFAD transgenic mice to systematically evaluate the behavioral outcomes and underlying mechanistic pathways. Among the treatment groups, a 14-d regimen at an acoustic intensity of 2.14 W/cm[2] yielded the optimal cognitive outcome in Alzheimer's disease mice, which was consistently verified across Y-maze and Morris water maze tests. Additionally, this group showed reduced Aβ plaque deposition and increased plaque-associated microglial activity. Furthermore, enhanced gamma oscillations in the hippocampus were detected following treatment. RNA sequencing revealed modulation of innate immune and inflammatory pathways. Corresponding molecular analysis demonstrated a marked down-regulation in RIPK1, phosphorylated NF-κB, and necroptosis markers, alongside reductions in key pro-inflammatory cytokines (IL-6, IL-1β, and TNF-α). Collectively, our findings suggest that the cognitive improvement observed after treatment with TUS pulsed at 40 Hz may be linked to the modulation of neuroinflammatory and necroptotic pathways, possibly involving RIPK1/NF-κB signaling.}, } @article {pmid42018225, year = {2026}, author = {Liu, L and Zhu, B}, title = {Advancements in the Study of Missense Mutations in ABCA7 in Alzheimer's Disease.}, journal = {Journal of molecular neuroscience : MN}, volume = {76}, number = {2}, pages = {}, pmid = {42018225}, issn = {1559-1166}, mesh = {Humans ; *Mutation, Missense ; *Alzheimer Disease/genetics ; *ATP-Binding Cassette Transporters/genetics/metabolism ; Animals ; }, abstract = {Alzheimer’s disease (AD) is a neurodegenerative disorder affecting millions of people worldwide. In recent years, genetic factors, particularly missense mutations in susceptibility genes, have been proven to play a key role in the pathogenesis of AD. The ABCA7, a regulator of lipid metabolism and amyloid-beta clearance, has missense mutations that impact phospholipid transport and phagocytic functions, thus contributing to the development of AD. Genome-wide association studies (GWAS) and whole-genome sequencing have identified various missense mutations in ABCA7, such as G1527A and R880Q, with risk ratios up to 1.15 times. Furthermore, differences in the distribution of these mutations across different ethnic groups have been widely reported. Future research should focus on the prevalence and functional effects of these mutations in different populations and their specific effects on ABCA7 protein function. A deeper understanding of these mutations could provide new scientific bases for the early diagnosis and treatment of AD. In summary, the missense mutations in ABCA7 provide important insights into the genetic susceptibility of AD and represent potential candidate targets for the development of personalized treatment strategies.}, } @article {pmid42018938, year = {2026}, author = {Haghighi, FH and Xie, J and Ebert, ET and Siahaan, TJ}, title = {Progress and challenges in drug delivery for the treatment of Alzheimer's disease.}, journal = {Expert opinion on drug delivery}, volume = {}, number = {}, pages = {1-23}, doi = {10.1080/17425247.2026.2663114}, pmid = {42018938}, issn = {1744-7593}, abstract = {INTRODUCTION: Alzheimer's disease (AD) is a neurodegenerative disorder marked by declining memory and cognitive function. Despite recent advances to slowdown early-stage progression, no curative therapies exist due to challenges in delivering neuroregenerative agents to the brain.

AREAS COVERED: This review examines recent research on strategies to modulate the blood-brain barrier (BBB) to enhance the delivery of small-to-large molecules through the paracellular pathway into the brain for potential treatments of AD. A literature search was conducted using PubMed and Scopus covering studies published between 2016 and 2026.

EXPERT OPINION: BBB modulation technologies are advancing rapidly and offer real potential to improve delivery of therapeutics in AD patients. Hyperosmotic method has been successfully used to deliver anticancer drugs to treat brain tumor patients and can be used for AD. Recently, focused ultrasound (FUS) has been used to disrupt the BBB at a targeted brain region to enhance paracellular permeation of drug molecules to the brain. Finally, drug permeation through the BBB paracellular pathway can also be enhanced by modulating the protein-protein interactions in the intercellular junctions using BBB modulators (BBBMs). This review covers the mechanisms, advantages, and limitations of these methods as well as recent studies that showcase their ability to deliver therapeutic agents for AD and other brain diseases.}, } @article {pmid42019114, year = {2026}, author = {Liu, Y and Jiang, Z and Chen, D and He, Z and Ning, W and Wang, S and Guan, L}, title = {Design, synthesis, and biological evaluation of Chromene-Phenylpiperazine-Chalcone hybrids as multi-target-directed ligands for the treatment of Alzheimer's disease.}, journal = {Bioorganic & medicinal chemistry}, volume = {138}, number = {}, pages = {118670}, doi = {10.1016/j.bmc.2026.118670}, pmid = {42019114}, issn = {1464-3391}, mesh = {*Alzheimer Disease/drug therapy/metabolism ; Animals ; *Drug Design ; *Piperazines/chemistry/pharmacology ; Monoamine Oxidase/metabolism ; Mice ; Ligands ; *Cholinesterase Inhibitors/pharmacology/chemical synthesis/chemistry ; *Monoamine Oxidase Inhibitors/pharmacology/chemistry/chemical synthesis ; Structure-Activity Relationship ; Molecular Docking Simulation ; *Benzopyrans/chemistry/pharmacology ; Amyloid beta-Peptides/metabolism/antagonists & inhibitors ; Butyrylcholinesterase/metabolism ; Dose-Response Relationship, Drug ; Molecular Structure ; *Chalcone/chemistry/pharmacology ; Horses ; Humans ; }, abstract = {A novel series of chromene-phenylpiperazine-chalcone hybrids was rationally designed, synthesized and evaluated as multi-target-directed ligands (MTDLs) for Alzheimer's disease (AD). Among them, compound 9 s exhibited selective equine serum butyrylcholinesterase (eqBuChE, IC50 = 0.13 μM) and concurrent monoamine oxidase B (MAO-B, IC50 = 1.63 μM) inhibitory activities. Kinetic and molecular docking studies indicated that 9 s acts as a mixed-type dual-site inhibitor. In silico modeling suggests that the binding pose is stabilized by a predicted pseudo-seven-membered ring. Furthermore, 9 s facilitated the disassembly of self-aggregated and Cu[2+]-induced Aβ1-42 fibrils. In BV-2 microglial cells, it demonstrated a high safety margin (> 380-fold effective concentration), accelerated intracellular Aβ clearance, and subsequently attenuated LPS-induced NO production. In vivo evaluations revealed low acute toxicity (LD50 > 1000 mg/kg). Oral administration of 9 s successfully reversed scopolamine-induced spatial working memory deficits in mice. These findings validate the drug-like 9 s as an orally efficacious MTDL candidate that provides symptomatic cognitive relief, while possessing promising in vitro disease-modifying potential for AD therapy.}, } @article {pmid42019137, year = {2026}, author = {Otani, K and Ishihara, H and Nakamura, T and Kawabe, K}, title = {Implementation and service impact of anti-amyloid therapy in a psychiatry-led dementia care program: Real-world evidence from a Japanese regional dementia center.}, journal = {General hospital psychiatry}, volume = {100}, number = {}, pages = {208-214}, doi = {10.1016/j.genhosppsych.2026.04.006}, pmid = {42019137}, issn = {1873-7714}, mesh = {Humans ; Japan ; Retrospective Studies ; Female ; Aged ; *Dementia/drug therapy/diagnostic imaging ; Positron-Emission Tomography/statistics & numerical data ; Male ; Aged, 80 and over ; *Antibodies, Monoclonal/therapeutic use ; *Alzheimer Disease/drug therapy/diagnostic imaging ; Psychiatrists ; East Asian People ; }, abstract = {BACKGROUND: Amyloid-targeting antibody therapies for Alzheimer's disease require substantial diagnostic infrastructure including amyloid PET imaging, repeated MRI monitoring, and specialized clinical evaluation. In Japan, psychiatrists frequently lead dementia diagnosis and treatment in general hospitals through designated Regional Dementia Medical Centers; however, the real-world service impact of implementing these therapies in psychiatry-led dementia care remains poorly described.

METHODS: We conducted a retrospective analysis of administrative and billing data from a Regional Dementia Medical Center at Kakogawa Central City Hospital, Japan. Data included amyloid PET imaging, anti-amyloid monoclonal antibody therapy (lecanemab and donanemab), and associated reimbursement and acquisition costs between May 2024 and January 2026. This study was conducted as part of institutional quality improvement activities.

RESULTS: During the observation period, 72 amyloid PET examinations were performed. Results were amyloid-positive in 50 cases (69%) and negative in 22 cases (31%). Of 50 amyloid-positive patients, 38 (76%) initiated anti-amyloid therapy (lecanemab: 14; donanemab: 24), with 389 total treatment administrations. ARIA was detected in 8 treated patients (21%), all asymptomatic. MRI examinations for ARIA monitoring increased from 5 in FY2023 to 58 in FY2024 and 139 in FY2025. Total reimbursement amounted to 35.4 million yen for lecanemab and 25.7 million yen for donanemab. Drug acquisition costs represented approximately 97% of reimbursement, with margins averaging 3%. Outpatient revenue per visit increased 141% from 5560 yen in FY2022 to 13,401 yen in FY2025, despite stable visit volumes (FY2022: 11,203; FY2024: 10,223).

CONCLUSIONS: Implementation of amyloid-targeting antibody therapy in psychiatry-led dementia care substantially increases service activity and hospital revenue streams but generates narrow financial margins due to high drug acquisition costs. All ARIA cases were asymptomatic, supporting the feasibility of systematic monitoring within a psychiatry-led model in this setting. These findings highlight important structural and economic considerations for the sustainability of these programs in general hospital psychiatry.}, } @article {pmid42019901, year = {2026}, author = {Tseng, CH}, title = {The hidden link between diabetes and dementia: Findings from recent epidemiological studies.}, journal = {Biomedical journal}, volume = {}, number = {}, pages = {100985}, doi = {10.1016/j.bj.2026.100985}, pmid = {42019901}, issn = {2320-2890}, abstract = {Recent epidemiological studies investigating the link between diabetes mellitus and dementia or Alzheimer's disease are narratively reviewed. Diabetes mellitus is associated with a significantly higher risk of dementia by 56%, more predominant for vascular dementia than Alzheimer's disease and tau pathology is more remarkable than amyloid β deposition. The increased risk is related to the burden of microvascular and macrovascular diseases in a dose-response pattern; and a threshold effect between glycemic control and dementia risk is observed. A treatment target of hemoglobin A1c < 7% may be optimal for reducing the risk of dementia but hypoglycemia should be avoided. Antidiabetic drugs such as metformin, pioglitazone, sodium-glucose co-transporter 2 inhibitors and glucagon-like peptide 1 receptor agonists may show beneficial effects on dementia in observational studies. In a Taiwanese cohort study acarbose is also associated with a lower risk of dementia in female diabetes patients. When considering the repurposing of antidiabetic drugs in the treatment of patients with Alzheimer's disease, low-dose insulin detemir shows a promising effect in a network meta-analysis. A phase 3 clinical trial (MET-FINGER) is being conducted to investigate whether metformin plus lifestyle intervention can be effective in the prevention of Alzheimer's disease. Hyperuricemia, though considered a potential component of metabolic syndrome, seems to be associated with a lower risk of dementia. Sex hormones play some roles in cognitive function and females present a higher risk of dementia than males. However, additional studies are required to explore the impacts of sex and sex hormones on the development of dementia and Alzheimer's disease.}, } @article {pmid42020091, year = {2026}, author = {Mewton, L and Winter, V and Hoy, N and Visontay, R and Davies, S and Kochan, N and Baillie, A and Chapman, C and Newton, NC and Sunderland, M and Sachdev, PS and Teesson, M}, title = {Effect of the online Rethink My Drink alcohol intervention on alcohol use and cognition in older adults in Australia: a randomised controlled trial.}, journal = {The Lancet. Public health}, volume = {11}, number = {5}, pages = {e318-e328}, doi = {10.1016/S2468-2667(26)00056-3}, pmid = {42020091}, issn = {2468-2667}, mesh = {Humans ; Aged ; Female ; Male ; Middle Aged ; Australia ; *Alcohol Drinking/prevention & control/epidemiology ; *Cognition ; }, abstract = {BACKGROUND: Alcohol use is increasing among older adults and is associated with cognitive impairment and dementia. The efficacy of scalable approaches to reduce alcohol use and related harms in older adults has not been tested. This study aimed to evaluate the efficacy of an online alcohol intervention in reducing alcohol use and cognitive decline in older adults.

METHODS: We did a two-arm, parallel-group, randomised controlled trial online among community-based older adults (aged 60-75 years) who screened as having high-risk alcohol use (scoring ≥5 on the Alcohol Use Disorder Identification Test). Exclusion criteria included diagnosis of a neurological disorder (eg, dementia, Parkinson's disease, or multiple sclerosis), previous prescription of medication for the treatment of Alzheimer's disease, and non-correctable visual impairment. Participants across Australia were randomly assigned (1:1) to the Rethink My Drink programme (a four-module online intervention designed specifically for older adults) or an active control group (online information booklet), stratified by age and gender. Participants and the lead statistician were masked to group assignment. Number of drinks in the past month and global cognition Z scores assessed via the Cambridge Neuropsychological Test Automated Battery were the primary outcomes, assessed at the 12-month follow-up. Intention-to-treat analyses were conducted using generalised mixed effects regression. The trial was registered with the Australian New Zealand Clinical Trials Registry (ACTRN12621000292875; March 16, 2021), and is completed.

FINDINGS: Between Oct 29, 2021, and June 6, 2022, 3766 participants were screened for eligibility, 2878 were excluded (1390 did not meet inclusion criteria, 1047 declined to participate, and 441 had incomplete baseline assessments), and 888 completed baseline assessments and were randomly assigned. 448 participants were assigned to the Rethink My Drink intervention and 440 were assigned to receive the online patient information booklet. Data from 445 participants in the intervention group and 438 participants in the control group were analysed. Most participants (872 [99%] of 883) identified as White, 685 (78%) participants were female and 198 (22%) were male, and the mean age was 65·3 years (SD 3·9). At 12 months, those in the intervention group had greater reductions in their monthly number of standard drinks when compared with the control group (difference, 5·02 standard drinks [95% CI 1·81 to 8·24]; p<0·0001). For global cognition, the difference between the two groups was not significant at 12 months (difference 0·12 SDs [95% CI -0·05 to 0·29]; p=0·16). Two participants (one in the control group and one in the intervention group) spontaneously reported non-serious adverse events that were assessed as unrelated to the trial.

INTERPRETATION: Rethink My Drink is an effective and scalable intervention that has considerable potential for reducing alcohol use among older adults.

FUNDING: Dementia Centre for Research Collaboration.}, } @article {pmid42020180, year = {2026}, author = {Tong, FF and Huang, RQ and Gao, Y and Luo, QQ and Chen, YP and Xu, GZ}, title = {[Epidemiological studies of the association between dyslipidemia and Alzheimer's disease].}, journal = {Zhonghua liu xing bing xue za zhi = Zhonghua liuxingbingxue zazhi}, volume = {47}, number = {4}, pages = {767-774}, doi = {10.3760/cma.j.cn112338-20250727-00528}, pmid = {42020180}, issn = {0254-6450}, mesh = {Humans ; *Alzheimer Disease/epidemiology ; *Dyslipidemias/epidemiology/complications ; Risk Factors ; }, abstract = {Alzheimer's disease (AD), as the representative type of dementia among neurodegenerative diseases, has become a major challenge in the field of global public health. Dyslipidemia is considered an acquired risk factor for AD, and both are progressive diseases with long developmental periods, making dyslipidemia a potential predictor of future AD occurrence. Therefore, preventing dyslipidemia is of great significance for the prevention and treatment of AD. Given the global epidemiological background of AD, this article aims to systematically review the association between dyslipidemia and AD, providing theoretical support for the prevention and control of both conditions.}, } @article {pmid42020356, year = {2026}, author = {Zou, Z and Chen, J and Li, J and Chen, Y}, title = {The iron-energy metabolism axis in Alzheimer's pathogenesis: from mechanisms to interventions.}, journal = {Cell death discovery}, volume = {}, number = {}, pages = {}, doi = {10.1038/s41420-026-03034-w}, pmid = {42020356}, issn = {2058-7716}, abstract = {Alzheimer's disease (AD) is a neurodegenerative disorder with a complex, multifactorial pathogenesis. Growing evidence implicates disturbances in cellular energy metabolism and iron dyshomeostasis as interlinked contributors to pathology. Within this framework, iron accumulation may act as an upstream regulator in certain contexts and stages, while in others it emerges downstream and amplifies ongoing injury. As iron is an essential cofactor for mitochondrial respiration and the tricarboxylic acid cycle, iron imbalance can compromise ATP production and disrupt glucose metabolism, exacerbating neuronal energy deficits. The interplay among iron accumulation, oxidative stress, and neuroinflammation can create vicious cycles that reprogram cellular metabolism and disrupt the critical metabolic coupling between neurons and glial cells. This review synthesizes recent advances in understanding the iron-energy metabolism axis in AD, delineates mechanisms by which iron imbalance precipitates mitochondrial dysfunction and glucose metabolic impairments, and evaluates how these deficits synergize with neuroinflammation and proteinopathy across disease stages. Finally, we appraise emerging therapeutic strategies targeting iron overload and metabolic pathways, discuss their stage-dependent risks and benefits, and outline the need for biomarker-guided approaches to optimize patient selection and treatment timing.}, } @article {pmid42020790, year = {2026}, author = {Ferreira, AFF and Feng, ZP and Sun, HS and Britto, LRG}, title = {Inhibiting the transient receptor potential melastatin 2 channel in microglia: current evidence and therapeutic potential in neurological disorders.}, journal = {Acta pharmacologica Sinica}, volume = {}, number = {}, pages = {}, pmid = {42020790}, issn = {1745-7254}, abstract = {Microglia, the resident immune cells of the central nervous system, play a pivotal role in neuroinflammation and is a key contributor to the onset and progression of various neurological and neurodegenerative diseases. The Transient Receptor Potential Melastatin 2 (TRPM2), a non-selective calcium channel, has emerged as a sensor linking oxidative stress responses and calcium influx. It is expressed in many tissues and cells, including neurons, astrocytes, and microglia. TRPM2 represents one of the molecular mediators regulating microglial activity and function, cytokine production, and microglia-neuron communication. Growing evidence suggests that TRPM2 contributes to the pathological mechanisms underlying diseases such as ischemic stroke, Alzheimer's disease, Parkinson's disease, epilepsy, and neuropathic pain. However, most of the studies mainly explored the TRPM2 involvement in cell death, which has been reviewed by some other authors. In this review, we compile and discuss findings from in vivo and in vitro studies evaluating the role of TRPM2, with a specific focus on its influence over microglial function and neuroinflammatory responses, a field that has been poorly explored. We gathered information from studies reporting, in stroke models, that both pharmacological inhibition and genetic deletion of TRPM2 reduced infarct volume, improved behavioral outcomes, and diminished glial reactivity. In models of neurodegeneration, TRPM2 modulation shows promising effects on neuronal survival and microglial phenotype. In neuropathic pain models, TRPM2 was found to mediate microglial activation and the release of pro-inflammatory mediators, contributing to pain hypersensitivity. However, findings in epilepsy models reveal a more complex picture, with TRPM2 deficiency producing either neuroprotective or deleterious outcomes, highlighting the need for further studies. Although most studies to date support a pathogenic role for TRPM2 in microglia-mediated neuroinflammation, some limitations were highlighted, as the non-selective pharmacological inhibitors available, the inclusion of only males in the majority of studies, and the use of a global TRPM2 knockout. Only two studies employed conditional genetic models to promote specific TRPM2 deletion from microglia, with promising findings. Overall, current evidence indicates TRPM2 as a promising modulator of microglia, with broad implications for the treatment of neurological disorders characterized by chronic inflammation.}, } @article {pmid42021568, year = {2026}, author = {Li, Z and Ge, R and Zhao, Z and Xiao, H and Du, C and Lai, Y and Wang, L}, title = {From Bio-Interface Materials to Neural Integration: The Next-Generation Brain-Machine Interfaces Powered by Hydrogels.}, journal = {Advanced materials (Deerfield Beach, Fla.)}, volume = {38}, number = {31}, pages = {e23422}, doi = {10.1002/adma.202523422}, pmid = {42021568}, issn = {1521-4095}, support = {22322803//National Natural Science Foundation of China/ ; 22375047//National Natural Science Foundation of China/ ; 22361162607//International Cooperation and Exchanges NSFC/ ; 20240305028YY//Key Research Development Program of Jilin Province/ ; 2022YFB3804905//National Key Research and Development Program of China/ ; 2022YFB3804900//National Key Research and Development Program of China/ ; //Graduate Innovation Fund of Jilin University/ ; FZ2025038//State Key Laboratory of New Textile Materials and Advanced Pro- cessing/ ; }, mesh = {*Hydrogels/chemistry ; *Brain-Computer Interfaces ; Humans ; Animals ; *Biocompatible Materials/chemistry ; }, abstract = {Brain-machine interfaces (BMIs), which serve as revolutionary tools for neural recording, modulation, and rehabilitation, are highly dependent on the biocompatibility and mechanical suitability of their electrode materials. Although traditional metal electrodes possess excellent conductivity, their inherent rigidity causes a substantial mechanical mismatch with soft neural tissue, leading to chronic inflammatory responses and poor long-term stability. The emergence of hydrogel electrodes has provided a breakthrough solution to this fundamental limitation. Hydrogels, characterized by their softness, high ionic conductivity, and tissue-like compliance, offer a viable solution to mitigate these issues. This review systematically explores the material properties of hydrogel-integrated BMIs, providing an in-depth investigation of key hydrogel characteristics, including toughness, adhesion, conductivity, and biocompatibility. Additionally, hydrogel-based BMIs are categorized into non-invasive and invasive systems, each defined by its characteristic operational principles and signal-acquisition mechanisms. The study further reviews critical issues, including surgical implantation strategies, multimodal data fusion, integration of artificial intelligence, as well as system integration and clinical translation. From a therapeutic perspective, this work highlights the application of BMIs in treating neurological disorders such as Alzheimer's disease, Parkinson's disease, epilepsy, stroke, neuropathic pain, and depression. Furthermore, this review critically examines the persistent challenges faced by hydrogel-based BMIs and proposes innovative strategies for future development. Ultimately, it outlines a developmental roadmap for next-generation hydrogel-based biotherapeutic technologies aimed at achieving high-fidelity, stable and clinically translatable BMI systems.}, } @article {pmid42021966, year = {2026}, author = {Tabi, YA and Meyer, EC}, title = {Autoimmune diseases are associated with increased neurodegenerative and cerebrovascular risk, while systemic corticosteroid exposure shows limited neurodegenerative and modest vascular associations.}, journal = {IBRO neuroscience reports}, volume = {20}, number = {}, pages = {596-608}, pmid = {42021966}, issn = {2667-2421}, abstract = {Systemic autoimmune diseases (AIDs), characterized by chronic peripheral inflammation and frequent vascular comorbidity, are increasingly linked to adverse central nervous system (CNS) outcomes; however, comparative evidence across diverse AIDs and clarification of the roles of vascular burden, inflammatory activity, and immunomodulatory therapy remain limited. Using the TriNetX Global Collaborative Network, we conducted a sequence of retrospective, propensity score-matched cohort experiments in adults aged 50-85 years to quantify incident Parkinson's disease (PD), Alzheimer's disease (AD), transient ischemic attack (TIA), and ischemic stroke across 22 AIDs and to evaluate therapy- and inflammation-stratified risk patterns. In the primary disease-control analysis (Experiment 1 A), AID diagnosis was associated with broadly elevated neurodegenerative and cerebrovascular risk, with stronger and more consistent associations for TIA and ischemic stroke than for PD and AD. To probe robustness, we repeated analyses under tighter control of baseline vascular burden (Experiment 1B: additional matching on circulatory-system diagnoses) and under treatment balancing (Experiment 1 C: additional matching on immune-suppressant exposure). Vascular matching substantially attenuated many associations, particularly for AD, whereas immune-suppressant matching did not materially erase the pervasive cerebrovascular excess. Within-disease CRP stratification (Experiment 2; low vs elevated CRP) did not yield a uniform neurodegenerative gradient but identified a disease-dependent ischemic vulnerability axis in selected inflammatory phenotypes. In treatment substudies, systemic cortisone exposure (Experiment 3) showed little association with PD/AD risk but a modest, heterogeneous increase in TIA/ischemic stroke. Medication-specific strata (Experiment 4) revealed stronger but directionally variable separations, consistent with confounding by indication and severity. Together, these findings position systemic autoimmunity as a robust marker of heightened cerebrovascular risk and a more phenotype-dependent correlate of neurodegenerative risk, supporting intensified vascular surveillance in high-risk AID populations and mechanistic work disentangling inflammation, comorbidity, and treatment.}, } @article {pmid42022334, year = {2026}, author = {Bhagunde, P and Penner, N and Willis, BA and Bell, R and Sachdev, P and Charil, A and Irizarry, MC and Hersch, S and Reyderman, L}, title = {Pharmacokinetic/pharmacodynamic analyses of plasma pathophysiology biomarkers in subjects with early Alzheimer's disease following lecanemab treatment.}, journal = {Alzheimer's & dementia (New York, N. Y.)}, volume = {12}, number = {}, pages = {e70246}, pmid = {42022334}, issn = {2352-8737}, abstract = {INTRODUCTION: Lecanemab, a novel monoclonal antibody targeting both neurotoxic amyloid beta (Aβ) protofibrils and Aβ plaques, substantially reduces markers of amyloid and significantly slows clinical decline on multiple measures of cognition and function in early AD in Phase 2 (Study 201) and Phase 3 (Study 301; Clarity AD) studies. In these clinical studies, several plasma biomarkers showed improvements comparing lecanemab with placebo. Herein, we utilized modeling and simulation to evaluate the long-term effects of lecanemab on pathophysiology biomarkers in plasma.

METHODS: Plasma Aβ42/40 ratio, tau phosphorylated at threonine 181 (p-tau181), and glial fibrillary acidic protein (GFAP) data were pooled from lecanemab Phase 2 and 3 studies. Individual serum lecanemab exposure estimated using a population pharmacokinetic model was correlated with plasma biomarker concentrations using indirect response pharmacokinetic/pharmacodynamic (PK/PD) models. Simulations were conducted to evaluate the effect of lecanemab (10 mg/kg IV every 2 weeks, LEC10-BW) after 4 years of continuous treatment, discontinuation after 18 months of treatment or transitioning to less frequent dosing at 18, 24, or 30 months.

RESULTS: PK/PD models describing the change in plasma biomarker levels over time in response to lecanemab treatment were developed, and simulations demonstrated that plasma biomarkers reverted toward pretreatment baseline after cessation of lecanemab treatment, with an average re-accumulation half-life of approximately 1 to 1.5 years, which was faster than amyloid plaque re-accumulation measured by positron emission tomography. Simulations illustrated transitioning to a lecanemab monthly dosing regimen was sufficient to stabilize plasma biomarker concentrations at levels consistent with ongoing inhibition of amyloid pathology and neuroinflammation.

DISCUSSION: PK/PD model simulations demonstrated that plasma biomarkers serve as early indicators of amyloid accumulation and downstream effects. Plasma biomarker simulations suggest the need for ongoing lecanemab treatment even after amyloid plaque clearance. Transition to a less frequent monthly IV regimen at 18 months was shown to maintain the changes in plasma biomarker levels consistent with lecanemab efficacy.}, } @article {pmid42022743, year = {2026}, author = {Dai, D and Chen, J and Guo, X and Sun, J and Yi, H}, title = {Mechanistic research on the vestibular-hippocampal pathway in neurodegenerative diseases: an integrative perspective from molecular to behavioral levels.}, journal = {Frontiers in neuroscience}, volume = {20}, number = {}, pages = {1779268}, pmid = {42022743}, issn = {1662-4548}, abstract = {This paper systematically reviews the pivotal role and bidirectional regulatory mechanisms of the Vestibular-hippocampal pathway in the onset and progression of neurodegenerative diseases (such as Alzheimer's disease), focusing on the common comorbidity of vestibular dysfunction and cognitive decline. Evidence spanning molecular to behavioral levels indicates that vestibular signal loss can induce hippocampal atrophy and spatial memory impairment through neuroinflammation, impaired synaptic plasticity, and disrupted theta rhythms. Conversely, hippocampal degeneration further impairs vestibular information integration, creating a vicious cycle. Intervention approaches such as vestibular rehabilitation, cognitive training, and neurostimulation show potential for slowing co-morbidity progression. Future research should focus on developing animal models simulating vestibular-neurodegenerative co-morbidity, conducting longitudinal clinical validation using multimodal imaging and electrophysiology techniques, and optimizing neuromodulation strategies and targeted molecular interventions to advance this mechanism toward early diagnosis and precision treatment.}, } @article {pmid42022958, year = {2026}, author = {Chien, SC and Chien, YC and Wang, HJ and Chen, JC}, title = {A ZIF-8-modified electrochemical biosensor for sensitive Aβ aggregation monitoring and Alzheimer's disease drug screening.}, journal = {RSC advances}, volume = {16}, number = {23}, pages = {20855-20865}, pmid = {42022958}, issn = {2046-2069}, abstract = {Alzheimer's disease (AD) is an irreversible neurodegenerative disorder driven by the abnormal aggregation of β-amyloid (Aβ) into oligomers, fibrils, and plaques. Current therapeutic strategies primarily alleviate symptoms but struggle to prevent aggregation due to the dynamic nature of Aβ species and prolonged drug development cycles. Sensitive and real-time monitoring of Aβ structural transitions is therefore essential for understanding disease progression and evaluating potential inhibitors. In this study, we developed a ZIF-8-modified electrochemical biosensor capable of translating Aβ42 conformational changes into quantifiable current signals, providing a promising platform for monitoring dynamic aggregation. The aggregation behavior of Aβ42 was systematically characterized using dynamic light scattering (DLS), electrochemical measurements, and Thioflavin T (ThT) fluorescence combined with ultrafiltration. A critical transition from the lag to the growth phase was observed at 24 h, with aggregates exceeding ∼60 nm undergoing irreversible fibrillization. The ZIF-8-modified electrochemical sensor detected early-stage structural rearrangements with superior sensitivity compared to conventional ThT fluorescence, revealing subtle oligomer formation. Quantitative current measurements allowed continuous monitoring of aggregation kinetics, highlighting the temporal resolution of the platform. Validation experiments with curcumin treatment demonstrated strong inhibitory effects between 18 and 24 h, delaying fibrillization, reducing late-stage β-sheet accumulation, and decreasing aggregate size by approximately 25%. In addition, the sensor successfully distinguished minor differences in structural transitions under varying inhibitor concentrations, demonstrating its capability for high-resolution, real-time assessment of aggregation dynamics and drug efficacy. This ZIF-8-modified electrochemical biosensor provides high-sensitivity, dynamic monitoring of Aβ42 aggregation and drug-induced inhibition, offering a valuable tool for mechanistic studies of protein aggregation pathology. By enabling early detection of structural transitions and real-time evaluation of inhibitors, this platform has the potential to accelerate therapeutic screening and improve the development of effective interventions for AD.}, } @article {pmid42023276, year = {2026}, author = {Kuan, JH and Raghavan, RS and Koh, DLW and Tan, WY and Iezhitsa, I and Agarwal, R}, title = {Navigating the cholesterol maze: Key insights on use of statins in neurodegenerative disorders.}, journal = {Neuroprotection (Chichester, England)}, volume = {4}, number = {1}, pages = {30-47}, pmid = {42023276}, issn = {2770-730X}, abstract = {Neurodegenerative diseases such as Alzheimer's (AD), Parkinson's (PD), Huntington's (HD), and multiple sclerosis (MS) involve progressive neuronal loss driven by dysregulated neurotransmission, neuroinflammation, oxidative stress, and mitochondrial dysfunction. Cholesterol metabolism has emerged as a critical factor involved with both central and peripheral dysregulation contributing to pathology. This review synthesizes current evidence on cholesterol's role in neurodegeneration and evaluates the therapeutic potential of statins, which act via cholesterol-dependent and other pleiotropic mechanisms. A PubMed search covering 1985-2025 publications was conducted using terms related to neurodegenerative diseases, statins, cholesterol metabolism, neuroinflammation, oxidative stress, mitochondrial dysfunction, and neuroprotection. Studies were selected to highlight mechanistic insights into cholesterol regulation in the nervous system and clinical data on statin use. Neuronal loss in neurodegeneration is driven by processes including excitotoxicity, inflammation, and mitochondrial dysfunction. Excessive reactive oxygen species activate apoptotic pathways involving BAX, BAK, and p53. Dysregulated cholesterol metabolism is a significant contributor: In AD, the ApoE allele ε4 (ApoE4) links elevated cholesterol to amyloid-β (Aβ) accumulation and cognitive decline; in PD, cholesterol shows mixed effects, with some studies suggesting protection and others linking high levels to α-synuclein aggregation and mitochondrial impairment. In HD reduced cholesterol biosynthesis correlates with neuronal loss, while MS associates with elevated cholesterol and cognitive dysfunction. Statins, widely used cholesterol-lowering agents, reduce Aβ production, enhance its clearance, and improve synaptic function. Beyond lipid lowering, they exert anti-inflammatory, antioxidant, and anti-apoptotic effects. Clinical outcomes remain mixed, with benefits influenced by statin type, dose, treatment duration, disease stage, and patient genetics. Statins show multifaceted neuroprotective potential through cholesterol-dependent and independent pathways. While preclinical data are encouraging, clinical evidence is heterogeneous. Long-term, stratified trials are needed to clarify efficacy, and tailoring therapy to disease-specific mechanisms may offer a viable strategy for mitigating neurodegeneration and enhancing neuronal survival.}, } @article {pmid42023629, year = {2026}, author = {Li, Y and Li, S and Ma, J and Zhao, J and Ning, N and Sun, J}, title = {The role of synaptic plasticity in Alzheimer's disease: from molecular mechanisms to therapeutic targets.}, journal = {Folia neuropathologica}, volume = {64}, number = {1}, pages = {1-11}, doi = {10.5114/fn.2025.156508}, pmid = {42023629}, issn = {1509-572X}, mesh = {Humans ; *Alzheimer Disease/physiopathology/metabolism/pathology ; *Neuronal Plasticity/physiology ; Animals ; tau Proteins/metabolism ; Amyloid beta-Peptides/metabolism ; }, abstract = {Alzheimer's disease (AD) is characterized by a complex pathophysiology, involving abnormal aggregation of amyloid b (Ab) and tau proteins, neuroinflammatory responses, and significant synaptic dysfunction, which collectively contribute to cognitive decline. This review offers a novel perspective by focusing on the pivotal role of synaptic plasticity in the pathogenesis of AD, underscoring its potential as a therapeutic target. The study uniquely synthesizes current molecular and clinical research to illustrate how Ab and tau pathologies disrupt synaptic signaling and structure, further exacerbated by neuroinflammation. We explore both pharmacological interventions, such as BACE1 inhibitors and tau stabilizers, and non-pharmacological strategies, including cognitive therapy and neuromodulation techniques, which have shown promise in modulating synaptic plasticity and slowing cognitive deterioration. Despite these advancements, the field faces significant challenges, including the complexity of AD's underlying mechanisms and limitations in early diagnosis. This review not only highlights the significance of synaptic plasticity in AD but also proposes future research directions that could lead to innovative therapeutic approaches, offering new hope for effective treatment strategies.}, } @article {pmid42024020, year = {2026}, author = {Chun, H and Lee, HW and Hong, SB and Ha, SS and Yoon, KJ}, title = {Home-based transcranial photobiomodulation improves cognitive function in mild cognitive impairment due to Alzheimer's disease: A randomized, double-blind, placebo-controlled confirmatory trial.}, journal = {Journal of Alzheimer's disease : JAD}, volume = {111}, number = {4}, pages = {1699-1707}, doi = {10.1177/13872877261443973}, pmid = {42024020}, issn = {1875-8908}, mesh = {Humans ; *Alzheimer Disease/complications/psychology ; *Cognitive Dysfunction/therapy/etiology/psychology ; Aged ; *Low-Level Light Therapy/methods ; Double-Blind Method ; Female ; Male ; Cognitive Enhancement ; Neuropsychological Tests ; Treatment Outcome ; *Cognition/physiology ; Aged, 80 and over ; }, abstract = {BackgroundAlzheimer's disease (AD) is a progressive neurodegenerative disorder in which early bioenergetic dysfunction is increasingly implicated in its pathogenesis. Transcranial photobiomodulation (tPBM), a non-invasive neuromodulation using near-infrared light, has shown promise in improving cerebral metabolism and cognitive function.ObjectiveTo assess the safety and efficacy of a home-administered tPBM intervention in individuals with mild cognitive impairment (MCI) due to AD.MethodsIn this randomized clinical trial, 80 participants meeting the NIA-AA criteria for MCI due to AD were recruited. Participants self-administered a tPBM device emitting 808 nm near-infrared light over the bilateral dorsolateral prefrontal cortex, six times weekly for 12 weeks. The primary outcome was the change in MoCA-K score from baseline to week 13. Secondary outcomes included K-MMSE2, CERAD-K, and GDepS scores.ResultsActive tPBM significantly improved cognitive performance compared with the placebo. Mean MoCA-K scores increased by 3.87 ± 2.51 points in the active group versus a 0.74 ± 2.85 point decline in the placebo group (p < 0.001). K-MMSE2 scores improved significantly (p < 0.001). CERAD-K showed a significant between-group difference at week 13 (p < 0.001), while GDepS scores remained unchanged. No device-related adverse events occurred, and adherence to home-based treatment was high.Conclusions12 weeks of home-administered tPBM safely and significantly improved cognitive function in individuals with MCI due to AD. The observed benefits are consistent with enhanced mitochondrial metabolism, cerebral perfusion, and synaptic efficiency. These findings support tPBM as a promising, non-pharmacological treatment for MCI due to AD and as a preventative strategy against AD.Trial RegistrationKorean Clinical Research Information Service (CRiS), https://cris.nih.go.kr, KCT0011155.}, } @article {pmid42024084, year = {2026}, author = {Xie, M and Niu, X and Sun, F and Shi, L}, title = {Transcriptome-based identification and experimental validation of a key gene in Alzheimer's disease using dermal fibroblasts.}, journal = {Journal of Alzheimer's disease : JAD}, volume = {111}, number = {4}, pages = {1684-1698}, doi = {10.1177/13872877261443968}, pmid = {42024084}, issn = {1875-8908}, mesh = {Humans ; *Fibroblasts/metabolism ; Endoplasmic Reticulum Chaperone BiP ; *Alzheimer Disease/genetics/metabolism/pathology ; *Serine-Arginine Splicing Factors/genetics/metabolism ; *Transcriptome ; Reactive Oxygen Species/metabolism ; Endoplasmic Reticulum Stress/genetics ; MicroRNAs/genetics ; Gene Expression Profiling ; Apoptosis/genetics ; }, abstract = {BackgroundAlzheimer's disease (AD) is a neurodegenerative disorder primarily characterized by progressive cognitive impairment and neuronal damage. The pathogenesis of AD is complex and involves multiple pathological processes. Currently, effective methods for early diagnosis and treatment are lacking.ObjectiveTo identify key pathogenic genes and investigate their roles in Alzheimer's disease, we analyzed transcriptomic data from dermal fibroblasts of AD patients, aiming to assess their potential as novel biomarkers and therapeutic targets.MethodsTranscriptomic data from AD patient and control-derived dermal fibroblasts (DFs) were analyzed to identify differentially expressed genes. Key genes were screened using bioinformatics and a random forest algorithm. ceRNA analysis was performed to explore miRNA-mRNA interactions. The candidate gene SRSF5 was validated via overexpression and knockdown, followed by qPCR, western blotting, and reactive oxygen species (ROS) assays. The role of SRSF5 in endoplasmic reticulum (ER) stress was evaluated by measuring ER stress markers and cellular stress responses.ResultsTranscriptomic analysis revealed significant upregulation of SRSF5 in AD DFs. ceRNA analysis identified miRNAs regulating SRSF5 in AD. Overexpression of SRSF5 led to reduced neuronal proliferation, increased apoptosis, elevated ROS levels, and activation of ER stress markers (CHOP, GRP78, XBP1). SRSF5 knockdown alleviated these effects.ConclusionsSRSF5 may drive AD pathogenesis via ER and oxidative stress, serving as a potential biomarker and therapeutic target for early diagnosis and intervention.}, } @article {pmid42024119, year = {2026}, author = {Shan, A and Xu, C and Chen, R and Han, X and Sun, W and Yao, Q and Wang, X and Luan, H and Li, S and Wen, B and Cui, T and Guo, J and Lian, Q and Sun, Y and Li, C and Jia, H and Ma, H and Lv, S and Sun, Q and Wei, C}, title = {Alterations in choroid plexus volume associated with butylphthalide treatment in mild cognitive impairment: Data from a randomized, placebo-controlled study.}, journal = {Journal of Alzheimer's disease : JAD}, volume = {111}, number = {4}, pages = {1637-1648}, doi = {10.1177/13872877261443718}, pmid = {42024119}, issn = {1875-8908}, mesh = {Humans ; *Cognitive Dysfunction/drug therapy/diagnostic imaging/pathology ; *Benzofurans/therapeutic use ; Female ; Double-Blind Method ; Male ; Magnetic Resonance Imaging ; *Choroid Plexus/drug effects/diagnostic imaging/pathology ; Aged ; *Neuroprotective Agents/therapeutic use ; Treatment Outcome ; Cognitive Enhancement ; }, abstract = {BackgroundThe choroid plexus (ChP) is increasingly recognized as an essential component in the pathogenesis of cognitive impairment associated with Alzheimer's disease. DL-3-n-butylphthalide (NBP) has been confirmed to exert neuroprotective effects through multiple pathways and thereby enhance cognitive function. However, the role of NBP in the ChP volume remains unclear at present.ObjectiveThis trial aimed to explore the clinical efficacy of NBP in patients with mild cognitive impairment (MCI) and its corresponding ChP imaging characteristics.MethodsThis randomized, double-masked, placebo-controlled study included 270 MCI patients, randomly assigned in a 1:1 ratio to receive either NBP or placebo. Concurrently, all participants received clinical cognitive evaluations and 3D T1-weighted magnetic resonance imaging scans at both baseline and post-treatment phases. The objective was to evaluate the efficacy of 12-month NBP treatment on cognitive impairment and investigate the neuroimaging correlates of NBP therapy, focusing specifically on longitudinal alterations in ChP.ResultsThe NBP treatment significantly improved the cognitive symptoms of MCI patients, which was strongly correlated with the decrease in ChP volume in the drug group. Moreover, subgroup analysis indicated that cognitive enhancement was closely related to changes in ChP volume in the effective group. Mediation effect analysis revealed that ChP volume partially mediated the enhancement of cognitive symptoms in MCI patients undergoing NBP treatment.ConclusionsThis research provided evidence that NBP may improve cognitive symptoms in MCI patients by regulating changes in ChP volume, as well as offered insight into identifying early neuroimaging markers of MCI and drug targets for NBP.Clinical trial registry nameEfficacy and safety of butylphthalide on patients with mild cognitive impairment; Registration number: ChiCTR1800018362.}, } @article {pmid42024241, year = {2026}, author = {Alım, Z and Demir, Y}, title = {Evaluation of pyrimidine-based compounds as AChE and BChE inhibitors: in vitro inhibition, molecular modeling, and statistical evaluation.}, journal = {Naunyn-Schmiedeberg's archives of pharmacology}, volume = {}, number = {}, pages = {}, pmid = {42024241}, issn = {1432-1912}, abstract = {Alzheimer's disease (AD) is a neurodegenerative disease characterized by dementia, particularly in older adults. It is a process that is increasing significantly with the aging population worldwide, has yet to be cured, and therefore challenges healthcare systems. The ability of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibitors to modulate neurotransmitter levels has made AChE/BChE inhibitors central therapeutic targets in drug development studies for the treatment of AD. Previous studies have demonstrated the beneficial effects of pyrimidine derivatives on cognitive functions and highlighted their high therapeutic potential against neurodegenerative diseases. Considering the pharmacological importance of AChE/BChE inhibitors and pyrimidine derivatives, this study investigated the inhibitory potential of seven different pyrimidine derivatives (1-7) on AChE and BChE using both in vitro and in silico approaches. Analysis of IC50 values indicated that compounds 1-7 (IC50: 14.89-77.70 nM) exhibited strong inhibitory effect. Compound 6 (IC50:14.89 nM) had the strongest inhibitory effect on AChE, while it showed a much weaker inhibitory effect against BChE (IC50: 357 nM), corresponding to an approximately 24-fold selectivity for AChE. Molecular modeling results indicate that compounds 6 and 7 exhibit favorable interactions within the active site of the enzyme. In addition, compounds 1 and 3, which exhibited the strongest inhibitory effects on BChE, appear to display a multiple binding profile with the active site of BChE. Correlation and regression analyses indicated that compounds 1-7 display a structure-activity relationship (SAR) consistent with strong inhibitory potency toward AChE, while showing comparatively weaker inhibition toward BChE.}, } @article {pmid42024486, year = {2026}, author = {Liu, X and Liu, J and Wang, PY and Cui, JH and Bu, YM and Wu, SS and Zhang, YH and Guo, C}, title = {Parthenolide Ameliorates Alzheimer's Disease Pathology by Suppressing Microglial Inflammation and Inflammation-Driven Amyloidogenesis via the HIF1α/NF-κB Axis.}, journal = {ACS chemical neuroscience}, volume = {17}, number = {12}, pages = {2364-2378}, doi = {10.1021/acschemneuro.6c00141}, pmid = {42024486}, issn = {1948-7193}, mesh = {*Sesquiterpenes/pharmacology/therapeutic use ; Animals ; *Microglia/drug effects/metabolism ; *Alzheimer Disease/drug therapy/pathology/metabolism ; *NF-kappa B/metabolism/drug effects ; Mice ; Mice, Transgenic ; *Hypoxia-Inducible Factor 1, alpha Subunit/metabolism ; Inflammation/metabolism/drug therapy/pathology ; Signal Transduction/drug effects ; Amyloid beta-Peptides/metabolism ; *Anti-Inflammatory Agents, Non-Steroidal/pharmacology ; Humans ; Lactones ; }, abstract = {The treatment landscape for Alzheimer's disease (AD) faces challenges such as prolonged drug development, high costs, and limited FDA-approved therapies. Given the pathological similarities between Early-Onset AD (EOAD) and Late-Onset AD (LOAD), repurposing existing drugs offers a promising strategy to expedite therapeutic development. In this study, weighted gene coexpression network analysis (WGCNA) was applied to identify AD-associated gene modules, followed by network pharmacology to screen candidate compounds. Parthenolide was selected based on blood-brain barrier permeability and disease relevance. Its effects were evaluated using LPS-stimulated BV2 microglia, N2a-sw and HT22 neuronal models, and transgenic AD mouse models. Transcriptomic integration, transcription factor enrichment, pharmacological inhibition, and in vivo behavioral and pathological analyses were employed to elucidate underlying mechanisms. Our findings reveal that parthenolide markedly suppressed microglial activation and reduced pro-inflammatory mediators via modulation of the HIF1α/NF-κB signaling axis. Bioinformatics analysis identified HIF1α as a key hub gene, which was experimentally validated using the selective inhibitor YC-1. Parthenolide attenuated inflammation-induced amyloidogenesis by downregulating amyloid β precursor protein (APP) expression and the γ-secretase component Aph-1A γ-Secretase Subunit (APH1α). In vivo, parthenolide administration significantly improved cognitive performance, reduced microglial activation, decreased β-amyloid plaque burden, and suppressed HIF1α/NF-κB-dependent inflammatory signaling in 5 × FAD mouse models. In conclusion, this study demonstrates that parthenolide exerts multitarget therapeutic effects in AD by concurrently suppressing neuroinflammation and amyloidogenic processing. Targeting the HIF1α/NF-κB axis may represent a promising strategy for modulating inflammatory-metabolic-amyloid networks in AD.}, } @article {pmid42024924, year = {2026}, author = {Choo, M and Oh, Y and Hong, LS and Scheitler, KM and Tang-Cabrera, J and Shin, J and Blaha, CD and Shin, H and Park, S and Lee, KH}, title = {Deep Brain Stimulation: Past, Present, and Future.}, journal = {IEEE transactions on bio-medical engineering}, volume = {PP}, number = {}, pages = {}, doi = {10.1109/TBME.2026.3686882}, pmid = {42024924}, issn = {1558-2531}, abstract = {Deep brain stimulation (DBS) has emerged as a revolutionary neurosurgical treatment for various movement and psychiatric disorders. Its development, rooted in advances in stereotactic surgery and early thalamotomies, led to its FDA approval for essential tremor (1997) and Parkinson's disease (2002), followed by applications in dystonia, obsessive-compulsive disorder (OCD), and epilepsy. While DBS has proven effective in these domains, research continues to explore its potential for treating conditions like Alzheimer's disease, addiction, and depression. Despite its clinical success, the underlying mechanisms of DBS remain poorly understood, motivating ongoing studies on neural circuitry modulation. Current DBS applications focus on specific brain targets, such as the subthalamic nucleus for Parkinson's and the anterior nucleus of the thalamus for epilepsy, with new targets under investigation for conditions like OCD and chronic pain. Technological advancements in DBS hardware, including rechargeable implants and directional electrodes, have improved patient outcomes by enhancing precision and reducing side effects. Furthermore, innovations in neuroimaging and closed-loop DBS systems are expanding the capabilities of DBS, offering personalized treatments based on real-time neural feedback. This review highlights the historical evolution, current clinical applications, and future directions of DBS as a transformative therapy for neurological and psychiatric disorders.}, } @article {pmid42024965, year = {2026}, author = {Irisarri, A and Bellver-Sanchis, A and Choudhary, BS and Mallo-Abreu, A and Labrador, L and Casadesus, G and Pérez, B and Jana, A and Banerjee, DR and Iriepa, I and Isabel Loza, M and Brea, J and Val, C and Pallàs, M and Muñoz-Torrero, D and Griñán-Ferré, C}, title = {Structure-based virtual screening, in vitro and in silico analysis identified novel potent m6A demethylase FTO inhibitors as promising neurotherapeutic agents.}, journal = {European journal of medicinal chemistry}, volume = {312}, number = {}, pages = {118852}, doi = {10.1016/j.ejmech.2026.118852}, pmid = {42024965}, issn = {1768-3254}, mesh = {*Alpha-Ketoglutarate-Dependent Dioxygenase FTO/antagonists & inhibitors/metabolism ; Humans ; Animals ; Mice ; *Enzyme Inhibitors/pharmacology/chemistry/chemical synthesis ; Structure-Activity Relationship ; Molecular Structure ; Dose-Response Relationship, Drug ; *Neuroprotective Agents/pharmacology/chemistry/chemical synthesis ; Drug Evaluation, Preclinical ; Molecular Dynamics Simulation ; }, abstract = {Dysregulation of the m6A RNA demethylase FTO has been implicated in neurodegeneration, but brain-penetrant, selective inhibitors remain scarce. Here, we used structure-based virtual screening of a CNS-oriented library to identify novel FTO inhibitors and characterized their permeability, selectivity, and pharmacological profiles. Among them, compound VI showed low-micromolar inhibition of human FTO, selectivity over ALKBH5, high PAMPA-BBB permeability, and oral exposure with measurable plasma levels, moderate brain penetration, and CSF detectability. Molecular dynamics simulations confirmed stable binding of VI within the FTO catalytic pocket, consistent with its enzymatic potency and selectivity. In differentiated SH-SY5Y cells, VI protected against Aβ1-42-induced toxicity while increasing global m6A levels and dampening pro-inflammatory gene expression. In SAMP8 mice, chronic oral treatment with VI (3 mg/kg) ameliorated anxiety-like behavior and rescued hippocampal-dependent spatial and recognition memory, concomitant with increased brain m6A and normalization of synaptic and neuroinflammatory markers. Overall, our findings identify compound VI as a selective, brain-penetrant FTO inhibitor with favorable pharmacokinetics and disease-modifying efficacy in a sporadic Alzheimer's disease model, supporting its further development as a neurotherapeutic candidate.}, } @article {pmid42025718, year = {2026}, author = {Li, Y and Chen, J}, title = {Lentinan attenuates tau phosphorylation and memory deficits in hTau-overexpressing mice.}, journal = {Brain research}, volume = {1885}, number = {}, pages = {150340}, doi = {10.1016/j.brainres.2026.150340}, pmid = {42025718}, issn = {1872-6240}, mesh = {Animals ; Phosphorylation/drug effects ; *tau Proteins/metabolism/genetics ; Humans ; HEK293 Cells ; Mice ; Protein Phosphatase 2/metabolism ; Mice, Inbred C57BL ; *Memory Disorders/metabolism/drug therapy ; Alzheimer Disease/metabolism ; *Lentinan/pharmacology/metabolism ; Mice, Transgenic ; Disease Models, Animal ; Male ; Neuroprotective Agents/pharmacology ; Cell Survival/drug effects ; }, abstract = {BACKGROUND: Lentinan (LNT), a polysaccharide extracted from shiitake mushrooms, has been long used in Asia for improving health. Although LNT injections have been approved for cancer treatment in multiple Asian countries, the potential of LNT in alleviating Alzheimer's disease (AD) pathology and associated cognitive impairments remains poorly understood. Thus, this study aimed to assess the neuroprotective effects of LNT.

METHODS: In vitro tests were performed in HEK 293/tau cells. Moreover, to simulate AD tau pathology, human full-length tau (hTau) expression was induced using adeno-associated virus serotype 2 (AAV2) in C57/BL6 mice. Intragastric LNT administration for 1 month markedly elevated protein phosphatase 2A (PP2A) activity and decreased tau phosphorylation at Ser202/Thr205 (AT8) in AAV2-hTau infected mice.

RESULTS: LNT significantly enhanced cell viability and PP2A activity while reducing tau phosphorylation in HEK 293/tau cells. Furthermore, behavioral tests demonstrated that LNT mitigated cognitive defects induced through hTau overexpression while significantly increasing the expression of synaptic protein expression such as synaptotagmin and synaptophysin.

CONCLUSIONS: Our findings suggest that LNT can prevent AD-like tau hyperphosphorylation by activating PP2A and attenuate AD-like cognitive impairments by restoring synaptic plasticity and synaptogenesis. Therefore, LNT is a potential therapeutic candidate for treating tau-related diseases.}, } @article {pmid42025825, year = {2026}, author = {Liu, S and Yang, C and Zhang, N and Xiang, L and Li, F and Qi, L and Xu, X}, title = {AXL prevents amyloid-β-induced microglial ferroptosis by sustaining SLC2A3-mediated mitochondrial respiration.}, journal = {Pharmacological research}, volume = {228}, number = {}, pages = {108203}, doi = {10.1016/j.phrs.2026.108203}, pmid = {42025825}, issn = {1096-1186}, mesh = {Animals ; *Microglia/drug effects/metabolism ; Axl Receptor Tyrosine Kinase ; *Receptor Protein-Tyrosine Kinases/metabolism/genetics ; *Proto-Oncogene Proteins/metabolism/genetics ; *Amyloid beta-Peptides/toxicity ; *Ferroptosis/drug effects ; *Mitochondria/metabolism/drug effects ; *Glucose Transporter Type 3/metabolism ; Thyroxine/pharmacology ; Humans ; Mice, Inbred C57BL ; Mice ; Alzheimer Disease/drug therapy/metabolism ; Proto-Oncogene Proteins c-akt/metabolism ; Signal Transduction ; }, abstract = {Dysregulated iron metabolism is a pivotal driver of Alzheimer's disease (AD). Excess iron promotes Aβ aggregation and tau hyperphosphorylation, thereby accelerating disease progression. Serving as the primary iron reservoir in the central nervous system, microglia are intrinsically susceptible to ferroptosis, thereby amplifying neurotoxicity to neighboring neurons. While plaque-associated receptors (e.g., TREM2, AXL, MERTK) govern microglial responses, their precise contribution to metabolic susceptibility to ferroptosis remains elusive. Here, we identify the receptor tyrosine kinase AXL as a critical metabolic safeguard against Aβ-induced ferroptosis in microglia. Mechanistically, our findings indicate that, under our experimental conditions, oAβ exposure is associated with downregulation of AXL in microglia, thereby impairing SLC2A3-dependent glucose uptake and mitochondrial ATP production, which ultimately increases ferroptotic vulnerability. Moreover, through an optimized surface plasmon resonance imaging (SPRi) screening approach, we identified the FDA-approved drug levothyroxine (L-T4) as an AXL-binding compound that rapidly activates AXL/AKT signaling. L-T4 treatment restores microglial homeostasis, inhibits Aβ-induced ferroptosis, and ameliorates neuropathology in vivo. These findings establish AXL as a novel metabolic safeguard in microglia and highlight L-T4 as a promising therapeutic strategy for AD and other ferroptosis-related disorders via drug repurposing.}, } @article {pmid42025961, year = {2026}, author = {Hajibandeh, S and Tao, YA and Hsieh, MH and Liu, HG and Cheng, YF and Lee, KH and Hsieh, SY and Lu, CH}, title = {Semaglutide for obesity management: A narrative review of efficacy, safety, and future directions.}, journal = {Journal of the American Pharmacists Association : JAPhA}, volume = {}, number = {}, pages = {103117}, doi = {10.1016/j.japh.2026.103117}, pmid = {42025961}, issn = {1544-3450}, abstract = {BACKGROUND: Glucagon-like peptide-1 receptor agonists (GLP-1 RAs), particularly semaglutide, have demonstrated substantial efficacy for glycemic control and weight management and are increasingly prescribed across diverse populations. Rapid expansion of indications, formulations, and real-world use has outpaced comprehensive evaluation of long-term safety, tolerability, and adherence, raising important concerns for clinical practice.

OBJECTIVES: This narrative review aims to synthesize current evidence on the efficacy and safety profile of semaglutide, with a focus on adverse events, treatment persistence, perioperative considerations, and use in special populations, to support clinical decision-making and pharmacist-led patient care.

METHODS: A review of clinical trials, observational studies, pharmacovigilance reports, regulatory communications, and professional guidelines was conducted. Evidence was drawn from randomized controlled trials, post-marketing safety reports, systematic reviews, and relevant clinical and regulatory documents.

RESULTS: From 1525 records, 34 studies and reports were included. Clinical trials consistently demonstrated meaningful weight reduction with semaglutide. Evidence regarding acute pancreatitis remains limited, although cases have been reported in clinical trials and postmarketing safety analyses. Evidence regarding suicidal ideation associated with semaglutide is mixed, with some analyses suggesting potential safety signals while others report no increased risk. Recent multi society clinical guidelines have addressed perioperative management of GLP-1 RAs, generally supporting individualized perioperative assessment. Emerging literature also examines semaglutide use in special populations, including patients with Alzheimer disease and individuals following bariatric surgery, although long-term neurologic and post-bariatric safety outcomes remain incompletely characterized.

CONCLUSIONS: Semaglutide represents an important therapeutic option for chronic weight management. As clinical use expands, continued evaluation of long-term safety, tolerability, and treatment persistence will be important. Pharmacists play a key role in counseling patients, monitoring adverse effects, supporting adherence, and contributing to multidisciplinary obesity care.}, } @article {pmid42026254, year = {2026}, author = {Nakagawa, T and Xie, JL and Park, K and Cao, K and Savadkohighodjanaki, M and Zhang, YJ and Jun, H and Ichii, A and Lee, JY and Soma, S and Medhat, YK and Saido, TC and Igarashi, KM}, title = {Early dopamine disruption in the entorhinal cortex of a knock-in model of Alzheimer's disease.}, journal = {Nature neuroscience}, volume = {29}, number = {6}, pages = {1386-1396}, pmid = {42026254}, issn = {1546-1726}, support = {A2019380S//BrightFocus Foundation (BrightFocus)/ ; A2022018F//BrightFocus Foundation (BrightFocus)/ ; BRFSG-2017-04//Brain Research Foundation (BRF)/ ; JPMJPR2481//MEXT | Japan Science and Technology Agency (JST)/ ; AARF-22-923955/ALZ/Alzheimer's Association/United States ; }, mesh = {Animals ; *Entorhinal Cortex/metabolism/pathology/drug effects ; *Alzheimer Disease/genetics/pathology/metabolism ; Mice ; Mice, Transgenic ; *Dopamine/metabolism ; Disease Models, Animal ; *Dopaminergic Neurons/pathology/physiology/metabolism/drug effects ; Male ; Gene Knock-In Techniques ; Amyloid beta-Protein Precursor/genetics ; Levodopa/pharmacology/therapeutic use ; Mice, Inbred C57BL ; Humans ; }, abstract = {The entorhinal cortex is a critical brain area for memory formation, while also the region exhibiting the earliest histological and functional alterations in Alzheimer's disease (AD). The entorhinal cortex therefore has been long hypothesized as one of the originating brain areas of AD pathophysiology, although circuit mechanisms causing its selective vulnerability remain poorly understood. Here we show that dopamine neurons projecting their axons to the lateral entorhinal cortex (LEC), critical for memory formation in healthy brains, become dysfunctional from the early pathological stage and cause associative memory impairments in amyloid precursor protein knock-in mice. Dopamine dysfunction led to the disruption of associative memory encoding of LEC layer 2/3. Optogenetic reactivation of LEC dopamine fibers rescued associative learning behavior. L-DOPA treatment restored memory encoding of LEC neurons and associative memory of amyloid precursor protein knock-in mice. These results suggest early dysfunction of LEC-projecting dopamine neurons underlie memory impairment in AD from early stages, pointing to a need for clinical investigation of LEC dopamine in patients with AD.}, } @article {pmid42026585, year = {2026}, author = {Choi, H and Hong, SB and Kim, Y and Joung, H and Choi, Y and Cha, J and Park, JY and Lee, YS and Choi, H and Han, JW and Kim, KH and Shin, CH and Lee, DY and Mook-Jung, I}, title = {Tryptophan-kynurenine metabolic reprogramming along the gut-brain axis alleviates Alzheimer's pathology.}, journal = {Journal of neuroinflammation}, volume = {23}, number = {1}, pages = {}, pmid = {42026585}, issn = {1742-2094}, support = {RS-2022-KH128705//Korea Dementia Research Center/ ; RS-2020-KH106747//Korea Dementia Research Center/ ; RS-2023-00273634//National Research Foundation of Korea/ ; }, mesh = {Animals ; *Alzheimer Disease/metabolism/pathology ; *Kynurenine/metabolism ; Mice ; *Tryptophan/metabolism ; *Brain-Gut Axis/physiology/drug effects ; *Brain/metabolism/pathology ; *Gastrointestinal Microbiome/physiology/drug effects ; Metabolic Reprogramming ; Male ; Hippocampus/metabolism/pathology ; Mice, Inbred C57BL ; Probiotics ; }, abstract = {The gut–brain axis influences neuroinflammation and metabolic homeostasis in Alzheimer’s disease (AD). Disruption of gut microbiota and barrier function promotes amyloid and tau pathology via immune and metabolic dysregulation. In this study, Limosilactobacillus fermentum SRK414 (SRK414) was orally administered to ADLPAPT mice, resulting in reduced Aβ and tau pathology and improved cognition. Multi-omics analysis revealed that SRK414 altered gut microbial composition and increased hippocampal kynurenic acid (KYNA), a metabolite linked to neuroimmune regulation. Increased hippocampal KYNA was associated with metabolic changes consistent with enhanced neuronal fatty acid oxidation, reduced lipid accumulation, and suppressed microglial activation, suggesting improved hippocampal homeostasis. In vitro studies further showed that KYNA attenuated tau-related and inflammatory phenotypes. These findings support a link between gut microbial modulation and brain resilience, and suggest that KYNA may contribute to the neuroprotective effects associated with SRK414 treatment. This study highlights metabolites modulated by SRK414 administration as potential mediators of microbiota-based therapeutic effects in AD.}, } @article {pmid42026868, year = {2026}, author = {Huang, J and Wang, YB and Wu, J and Qian, PJ and Shao, J and Cao, DD and Liu, Y and Luo, ZG}, title = {SEC62-mediated ER-phagy activation alleviates Alzheimer's disease pathology and restores cognitive function in 5×FAD mice.}, journal = {Molecular therapy : the journal of the American Society of Gene Therapy}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.ymthe.2026.04.037}, pmid = {42026868}, issn = {1525-0024}, abstract = {Alzheimer's disease (AD) is a common age-related neurodegenerative disorder. Previous studies have shown that patients with AD exhibit dysregulation of endoplasmic reticulum (ER) homeostasis in the brain, such as ER stress and ER damage. As a type of selective autophagy that specifically clears damaged ER, ER-phagy plays a key role in ER quality control, but the role in AD progression remains elusive. In this study, we found that ER homeostasis is severely disrupted in the pathological state of AD, characterized by enhanced ER stress response, the presence of ER damage, and concurrent defects in ER-phagy function. Notably, some receptors mediating ER-phagy were decreased in neurons differentiated from induced pluripotent stem cells (iPSCs) derived from AD patients and in 5×FAD mouse samples. Interestingly, overexpression of the ER-phagy receptor SEC62 in the brain of 5×FAD mice via intrathecal AAV injection markedly alleviated disease phenotypes, including β-amyloid (Aβ) plaque deposition, neuroinflammation, and cognitive impairment. These results indicate that restoring ER-phagy activity provides a potential strategy for the treatment of AD.}, } @article {pmid42028071, year = {2026}, author = {Sun, X and Yang, L and Wang, X}, title = {Traditional Chinese Medicine for Alzheimer's Disease: Current Evidence and Chemometric Approaches for Multi-Target Evaluation.}, journal = {Neuropsychiatric disease and treatment}, volume = {22}, number = {}, pages = {590661}, pmid = {42028071}, issn = {1176-6328}, abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder for which there is currently no therapy that can fundamentally change the disease course. The limitations of single-target drugs have led the scientific community to turn to multi-target intervention strategies. In this context, traditional Chinese medicine (TCM) demonstrates potential in addressing the complex pathology of AD due to its "multi-component, multi-target, multi-pathway" overall regulatory characteristics. This review systematically reviews the current research status of TCM in the treatment of AD, with a particular focus on the evidence of its effects through multiple mechanisms such as reducing Aβ deposition, inhibiting excessive phosphorylation of Tau protein, regulating the cholinergic system, and alleviating neuroinflammation. Additionally, this article highlights how to utilize the "spectral efficacy relationship" combined with chemometrics methods (such as multiple regression, partial least squares regression, artificial neural networks, etc) to establish quantitative correlations between TCM chemical components and efficacy/clinical endpoints, thereby providing a methodological framework for evaluating the synergistic effects of TCM's multi-component interactions. The article also summarizes the evidence grades of currently commonly used TCM preparations in clinical practice and points out that future research needs to continuously deepen in areas such as standardized clinical endpoints, strict trial design, systematic safety assessment, and data-driven efficacy analysis. This review aims to provide theoretical references and research directions for integrating the holistic view of TCM with modern system analysis methods and promoting the development of multi-target treatment strategies for AD.}, } @article {pmid42030370, year = {2026}, author = {Panda, SR and Soni, U and Panja, P and Rajdev, B and Singh, M and Kundu, S and Ranade, A and Pawar, SD and Acharya, R and Naidu, VGM}, title = {Modulation of Mitochondrial Dynamics by Loganic Acid Ameliorates Alzheimer's Disease Pathology: Evidence from In Vitro and In Vivo Studies.}, journal = {ACS chemical neuroscience}, volume = {17}, number = {9}, pages = {1716-1727}, doi = {10.1021/acschemneuro.6c00012}, pmid = {42030370}, issn = {1948-7193}, mesh = {Animals ; *Alzheimer Disease/pathology/drug therapy/metabolism ; *Mitochondrial Dynamics/drug effects ; Mice ; Hippocampus/drug effects/metabolism/pathology ; Reactive Oxygen Species/metabolism ; Male ; Mitochondria/drug effects/metabolism ; Membrane Potential, Mitochondrial/drug effects ; Mice, Inbred C57BL ; Neuronal Plasticity/drug effects ; Disease Models, Animal ; }, abstract = {Alzheimer's disease (AD) is the most common neurodegenerative disorder in the elderly, which refers to forgetting facts and experiences. Apart from being a classical neuropathological hallmark, AD is connected with pronounced mitochondrial fragmentation, although the exact contribution of mitochondrial dynamics in AD progression is poorly defined. Therefore, this study is aimed at investigating the role of loganic acid (LGA) in mitochondrial dynamics, hippocampal plasticity, and cognitive deficits in the scopolamine (SC)-induced cognitive impairment model. The results showed significant decline of p-Drp1 protein and elevation of Mfn2 proteins in LGA-treated SC-induced mice, indicating reduced mitochondrial fragmentation and restoration of mitochondrial dynamics. In addition, LGA treatment promotes the reduction of fragmented and spherical-shaped mitochondria in SC-induced mice. LGA treatment alleviated reactive oxygen species (ROS) production and elevated mitochondrial membrane potential, reducing neurodegeneration in SC mice. Moreover, the decline of inflammatory cytokines (TNF-α and IL-1β) and downregulation of NF-kB expression in LGA-treated SC-induced mice suggested improved neuronal health. In parallel, LGA also increased the regulation of the cytoskeleton within neuronal dendrites, synaptic plasticity, and neuronal dendrites outgrowth, which was validated with increased expression of MAP2. In conclusion, the present study findings suggest that LGA exerts neuroprotection via preserving the mitochondrial ultrastructure and modulating the mitochondrial dynamics. All of these changes further restore neuronal cell density and myelination, leading to the mitigation of neurodegeneration, and restore cognitive deficits and spatial memory in SC-induced C57BL/6 mice.}, } @article {pmid42031084, year = {2026}, author = {Hernández, A and Illán, IA and Ramírez, J and Segovia, F and Martínez-Murcia, FJ and Levin, J and Górriz, JM and , }, title = {Robust validation of neuroimaging and clinical models via the SAR method: A case study based on the ADNI dataset.}, journal = {NeuroImage}, volume = {333}, number = {}, pages = {121917}, doi = {10.1016/j.neuroimage.2026.121917}, pmid = {42031084}, issn = {1095-9572}, mesh = {Humans ; *Alzheimer Disease/diagnostic imaging/pathology/cerebrospinal fluid ; *Neuroimaging/methods/standards ; Disease Progression ; Bayes Theorem ; Aged ; Female ; Predictive Learning Models ; Male ; Magnetic Resonance Imaging ; *Models, Statistical ; Brain/diagnostic imaging/pathology ; Amyloid beta-Peptides/cerebrospinal fluid ; }, abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by cognitive decline and substantial brain atrophy. Early and accurate prediction of disease progression and staging is crucial for timely intervention and effective treatment planning. Previous studies, including those based on artificial intelligence techniques, have employed neuroimaging, biomarkers and clinical data to model AD progression; however, many of these approaches rely on strong parametric assumptions or lack robust statistical guarantees regarding model validity. To bridge this gap, this study proposes a novel framework for validating predictive and staging models of disease using a statistically agnostic methodology. The objective is to take the advantages of an unconventional method for robust validation of ML models related to AD. Validation is performed using the Statistical Agnostic Regression (SAR) methodology applied to the Alzheimer's Disease Neuroimaging Initiative (ADNI) dataset. The method tests for a linear relationship by resampling and estimating an upper bound on the expected risk (R) via a Bayesian bound under the worst-case scenario. The SAR power assesses the likelihood of detecting a true linear relationship using the test statistic R, via Monte Carlo simulations under the null distribution. Three predictive models related to structural neuroimaging are assessed: one for the Mini Mental State Examination (MMSE) score, another for the concentration of amyloid beta 1-42 protein in the cerebrospinal fluid, and a third for age. In addition, a model for staging based on Alzheimer's-related clinical groups is explored through the joint analysis of segmented gray matter and white matter images. The findings indicate that the SAR methodology not only facilitates robust validation of predictive ML models related to neuroimaging and AD but also enables an effective staging of the AD continuum. This SAR-proposed framework opens new perspectives for the validation of ML models for early diagnosis and provides a solid foundation for future research in computational neuroscience.}, } @article {pmid42033099, year = {2026}, author = {Luo, QH and Li, F and Yang, L and Pan, HQ and Zhu, WP and Hu, P and Tao, CM and Yin, M and Zhang, S and Liao, QY and Chen, ZH and Shu, HX and Zhu, XY and Yan, TF and Liu, X and Tu, JL and Zhu, XG}, title = {Endothelial NAD[+] depletion drives vascular senescence and neuroinflammation via mtDNA-cGAS/STING-CD38 signaling in Alzheimer's disease.}, journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association}, volume = {22}, number = {4}, pages = {e71423}, pmid = {42033099}, issn = {1552-5279}, support = {82501463//National Natural Science Foundation of China/ ; 82260278//National Natural Science Foundation of China/ ; 20232BAB216047//Jiangxi Provincial Natural Science Foundation/ ; 20242BAB25478//Jiangxi Provincial Natural Science Foundation/ ; 20242BAB26136//Jiangxi Provincial Natural Science Foundation/ ; 20242BAB20383//Jiangxi Provincial Natural Science Foundation/ ; 2023M741521//China Postdoctoral Science Foundation/ ; }, mesh = {Animals ; *NAD/metabolism/deficiency ; *Alzheimer Disease/metabolism/pathology ; cGAS-STING Signaling Pathway ; STING Protein ; *DNA, Mitochondrial/metabolism ; Cyclic Guanosine Monophosphate-Adenosine Monophosphate Synthase ; *Endothelial Cells/metabolism ; ADP-ribosyl Cyclase 1/metabolism ; Mice ; Nucleotidyltransferases/metabolism ; Signal Transduction ; Membrane Proteins/metabolism ; Mice, Transgenic ; *Neuroinflammatory Diseases/metabolism ; Membrane Glycoproteins/metabolism ; Humans ; Cellular Senescence/physiology ; Brain/metabolism ; Disease Models, Animal ; Amyloid beta-Peptides ; Voltage-Dependent Anion Channel 1/metabolism ; }, abstract = {BACKGROUND: Endothelial dysfunction has emerged as early and pivotal event in Alzheimer's disease (AD), yet the molecular mechanisms linking vascular aging to neuroinflammation remain elusive.

METHODS: We used APP/PS1 mice and amyloid beta (Aβ)-challenged brain endothelial cells (BECs) to understand the mechanisms of nicotinamide adenine dinucleotide (NAD[+]) deficiency, and its relationship with endothelial senescence and neuroinflammation in AD pathology. Nicotinamide riboside supplementation was administered to APP/PS1 mice to determine whether restoration of NAD[+] homeostasis mitigates AD-related vascular and inflammatory pathology.

RESULTS: NAD[+] deficiency induced voltage-dependent anion channel 1 (VDAC1) oligomerization, mitochondrial DNA (mtDNA) leakage, and cGAS/STING-IRF3 activation, promoting endothelial senescence and SASP production with NAD[+]-consuming enzyme CD38 upregulation. Senescent BECs triggered IL-6-dependent microglial activation. NR treatment restored mitochondrial integrity, suppressed cGAS-STING signaling, and reduced neuroinflammation, improving vascular function and cognition.

DISCUSSION: Aβ-driven NAD[+] deficiency initiates a VDAC1-mtDNA-cGAS/STING cascade that promotes endothelial senescence and neurovascular inflammation in AD pathology, and amplifies neuroinflammation through BEC-microglia crosstalk, highlighting NAD[+] restoration as a promising AD therapeutic strategy.}, } @article {pmid42033410, year = {2026}, author = {Gu, X and Terebuh, P and Xu, R and Kaelber, DC and Davis, PB}, title = {Age-related macular degeneration and dementia: Association through pathogenesis or visual impairment?.}, journal = {Journal of Alzheimer's disease : JAD}, volume = {111}, number = {3}, pages = {1014-1024}, doi = {10.1177/13872877261438849}, pmid = {42033410}, issn = {1875-8908}, mesh = {Humans ; Female ; Male ; Aged ; *Dementia/epidemiology/complications ; *Macular Degeneration/epidemiology/complications ; Retrospective Studies ; Aged, 80 and over ; *Vision Disorders/epidemiology ; Risk Factors ; Blindness/epidemiology ; Cohort Studies ; }, abstract = {BackgroundStudies suggest a link between blindness, age-related macular degeneration (AMD), and dementia risk, but whether this stems from AMD pathology or blindness remains unclear. This study examines the relationship between AMD and dementia.ObjectiveTo evaluate the association between AMD and 5-year dementia risk in non-blind patients.MethodsThis retrospective cohort study used TriNetX to compare non-blind patients with exudative AMD (n = 35,021) and non-exudative AMD (n = 96,809) to those without AMD (n = 1,801,879) for five-year dementia risk. Blind (n = 90,615) and non-blind (n = 800,737) patients were compared. Cohorts were propensity-matched for confounding factors.ResultsNon-blind AMD patients had decreased Alzheimer's disease risk, while blindness showed a strong positive association. Exudative AMD had HR of 0.84 (95% CI = [0.72, 0.97]), non-exudative AMD had HR of 0.95 (95% CI = [0.87, 1.04]), but blindness increased Alzheimer's disease risk (95% HR = 1.29, CI = [1.17, 1.41]).ConclusionsThese findings suggest that previously reported associations between AMD and dementia may be partially mediated by visual impairment. The modest reduction in dementia risk in non-blind AMD patients may reflect differences in healthcare utilization or treatment exposure among AMD patients.}, } @article {pmid42033565, year = {2026}, author = {Ishii, K}, title = {Brain PET in the era of anti-amyloid-β antibody therapy for Alzheimer disease.}, journal = {Japanese journal of radiology}, volume = {}, number = {}, pages = {}, pmid = {42033565}, issn = {1867-108X}, abstract = {Here the current and emerging roles of brain positron emission tomography (PET) in Alzheimer's disease (AD) in the era of anti-amyloid-β antibody therapy, with a focus on clinical applications, methodological considerations, and future perspectives were reviewed. A narrative review of the literature on PET imaging in AD, including FDG-PET, amyloid PET, and tau PET, was conducted with particular emphasis on their clinical utility in diagnosis, and disease monitoring. Relevant guidelines, including appropriate use criteria and Japanese clinical guidelines, were also reviewed. FDG-PET provides valuable information for the differential diagnosis of neurodegenerative dementias based on characteristic hypometabolic patterns, although its role remains supportive due to the lack of direct assessment of molecular pathology. Amyloid PET enables noninvasive visualization of cerebral amyloid-β deposition and has become essential for confirming eligibility for anti-amyloid therapies. Standardized use criteria and interpretation guidelines are critical for appropriate clinical implementation. Quantitative approaches, such as standardized uptake value ratios (SUVRs) and the Centiloid scale, improve comparability across studies and institutions. Tau PET reflects neurofibrillary pathology and correlates with disease severity and progression, with increasing relevance for patient stratification. In addition, recent advances in high-resolution dedicated brain PET systems and artificial intelligence-based image analysis are expected to enhance diagnostic performance and workflow efficiency. In the era of disease-modifying therapy, brain PET imaging has become integral to the clinical management of AD. Amyloid PET is indispensable for treatment eligibility, while tau PET provides complementary information on disease stage and prognosis. Ongoing technological and methodological advancements will further expand the role of PET imaging in precision medicine for dementia.}, } @article {pmid42033998, year = {2026}, author = {Yang, B and Earnest, T and Bilgel, M and Albert, MS and Johnson, SC and Davatzikos, C and Erus, G and Masters, CL and Resnick, SM and Miller, MI and Bakker, A and Morris, JC and Benzinger, TLS and Gordon, BA and Sotiras, A and , and , }, title = {Predicting future cognitive impairment in preclinical Alzheimer's disease using amyloid PET and MRI: A multisite machine learning study.}, journal = {Neurobiology of aging}, volume = {165}, number = {}, pages = {8-23}, doi = {10.1016/j.neurobiolaging.2026.04.005}, pmid = {42033998}, issn = {1558-1497}, mesh = {Aged ; Female ; Humans ; Male ; *Alzheimer Disease/complications/diagnostic imaging/metabolism ; *Amyloid/analysis/metabolism ; Brain/diagnostic imaging/metabolism ; Classification Algorithms ; *Cognitive Dysfunction/diagnosis/epidemiology/etiology ; Disease Progression ; *Machine Learning ; *Magnetic Resonance Imaging ; *Positron-Emission Tomography ; Prediction Algorithms ; Predictive Learning Models ; }, abstract = {Predicting the likelihood of developing Alzheimer's disease (AD) dementia in at-risk individuals is important for the design of and optimal recruitment for clinical trials of disease-modifying therapies. Machine learning (ML) has been shown to excel in this task; however, there remains a lack of models developed specifically for the preclinical AD population, who display early signs of abnormal brain amyloidosis but remain cognitively unimpaired. Here, we trained and evaluated ML classifiers to predict whether individuals with preclinical AD will progress to mild cognitive impairment or dementia within multiple fixed time windows, ranging from one to five years. Models were trained on regional imaging features extracted from amyloid positron emission tomography and magnetic resonance imaging pooled across seven independent sites and from two amyloid radiotracers ([[18]F]-florbetapir and [[11]C]-Pittsburgh-compound-B). Out-of-sample generalizability was evaluated via a leave-one-site-out and leave-one-tracer-out cross-validation. Classifiers achieved an out-of-sample receiver operating characteristic area-under-the-curve of 0.66 or greater when applied to all except one hold-out sites and 0.72 or greater when applied to each hold-out radiotracer. Additionally, when applying our models in a retroactive cohort enrichment analysis on A4 clinical trial data, we observed increased statistical power of detecting differences in amyloid accumulation between placebo and treatment arms after enrichment by ML stratifications. As emerging investigations of new disease-modifying therapies for AD increasingly focus on asymptomatic, preclinical populations, our findings underscore the potential applicability of ML-based patient stratification for recruiting more homogeneous cohorts and improving statistical power for detecting treatment effects for future clinical trials.}, } @article {pmid42034805, year = {2026}, author = {Monteiro, R and Dunn, JT and Rodriguez, G and Fisher, DW and Dong, H}, title = {Targeting central immune signaling enhances the effects of methylphenidate in alleviating apathy-like behavior in 5xFAD mice.}, journal = {Scientific reports}, volume = {16}, number = {1}, pages = {}, pmid = {42034805}, issn = {2045-2322}, support = {R01AG062249-05, 5R01AG079989-03//National Institute of Aging/ ; }, mesh = {Animals ; *Methylphenidate/pharmacology ; *Alzheimer Disease/drug therapy/immunology/genetics ; Mice ; *Apathy/drug effects ; *Signal Transduction/drug effects ; Mice, Transgenic ; Disease Models, Animal ; *Behavior, Animal/drug effects ; Humans ; Prefrontal Cortex/drug effects/metabolism/immunology ; Receptors, Complement/antagonists & inhibitors ; Male ; }, abstract = {Beyond cognitive impairment, Alzheimer's disease (AD) is frequently accompanied by apathy, the most prevalent and burdensome neuropsychiatric symptom (NPS). Apathy significantly impacts AD onset and progression, yet its molecular underpinnings remain unclear. Our previous RNA-sequencing analysis revealed abnormal immune gene expression uniquely associated with apathy in AD patients. In this study, we investigated whether changes in these immune related genes are also linked to apathy-like behavior, and whether administration of C3a receptor antagonist SB290157, alone or with methylphenidate, modifies apathy-like behaviors in 5xFAD mice. We first validated the apathy-related immune hub genes identified in human AD in the prefrontal cortex (PFC) of 16-18 month-old 5xFAD mice using RT-qPCR. Then separate cohorts of similarly aged 5xFAD mice received SB290157 and/or methylphenidate for three weeks. Our results showed that elevated immune hub genes Tyrobp, C3, C3ar, C1qa, C1qb, and C1qc were strongly correlated with apathy-like behavior in 5xFAD mice. Combined SB290157 and methylphenidate treatment improved nest-building behavior, reduced C3 and C3ar expression as well as restored dendritic spine density in the PFC. Our results confirm complement-mediated immune dysregulation is linked to apathy and suggest that co-targeting complement and catecholaminergic pathways may offer a novel therapeutic strategy for alleviating apathy in AD.}, } @article {pmid42036434, year = {2026}, author = {Mohammadi, F and Koohi, MK and Adeli, S and Hassan, J and Amini, A and Azadbakht, AR and Zayerzadeh, E and Babaei, JF}, title = {Effects of co-administered melatonin and methylphenidate on cognitive impairment and histopathological alterations in an AlCl3-induced neurotoxicity model of alzheimer's disease in BALB/C mice.}, journal = {Scientific reports}, volume = {16}, number = {1}, pages = {}, pmid = {42036434}, issn = {2045-2322}, mesh = {Animals ; *Melatonin/pharmacology/administration & dosage ; *Alzheimer Disease/drug therapy/chemically induced/pathology/metabolism ; *Aluminum Chloride/toxicity ; Mice ; Male ; Disease Models, Animal ; *Methylphenidate/pharmacology/administration & dosage ; Mice, Inbred BALB C ; Oxidative Stress/drug effects ; *Cognitive Dysfunction/drug therapy/pathology/chemically induced ; Hippocampus/drug effects/pathology/metabolism ; Maze Learning/drug effects ; Neuroprotective Agents/pharmacology ; Apoptosis/drug effects ; }, abstract = {Alzheimer’s disease (AD) is a progressive neurodegenerative disorder characterized by cognitive decline and neuropathological hallmarks such as amyloid plaques and neurofibrillary tangles. Environmental factors, including aluminum chloride (AlCl3) exposure, have been implicated in neurotoxicity and AD pathogenesis. This study evaluated the combined therapeutic effects of methylphenidate (MPH) and melatonin in a mice model of AlCl3-induced neurotoxicity. Male BALB/c mice were administered AlCl3 (300 mg/kg, orally) for 15 days, followed by treatment with melatonin (10 mg/kg), MPH (10 mg/kg), or their combination for 7 days. Behavioral tests, including the Morris water maze, open field, and Y-maze, were used to assess cognitive function. Hippocampal tissues were analyzed for oxidative stress markers (SOD, MDA), inflammatory cytokines (TNF-α, IL-10), apoptosis-related proteins (Bax, Bcl-2), and histological changes. The combination treatment significantly improved memory and learning, enhanced antioxidant capacity, reduced lipid peroxidation, and suppressed neuroinflammation and apoptosis. Histological examinations revealed increased neuronal density and CA1 hippocampal volume. These findings demonstrate that co-treatment with melatonin and MPH mitigates key pathological features of AD, suggesting a promising combinatorial strategy for targeting oxidative stress, neuroinflammation, and apoptosis in Alzheimer’s disease.}, } @article {pmid42036797, year = {2026}, author = {Bonta, KM and Li, JS and Tun, SM and Fredericks, CA}, title = {Sleep duration and amyloid status moderate the association between mood symptoms and amygdalar tau in preclinical Alzheimer's disease.}, journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association}, volume = {22}, number = {4}, pages = {e71447}, pmid = {42036797}, issn = {1552-5279}, support = {K23AG059919/NH/NIH HHS/United States ; 2019-AACSF-644153/ALZ/Alzheimer's Association/United States ; //The McCance Foundation/ ; }, mesh = {Humans ; *Alzheimer Disease/metabolism/diagnostic imaging/psychology ; Female ; *tau Proteins/metabolism ; *Amygdala/metabolism/diagnostic imaging ; Male ; Aged ; *Sleep Duration ; Positron-Emission Tomography ; *Anxiety/metabolism ; *Depression/metabolism ; *Amyloid beta-Peptides/metabolism ; Longitudinal Studies ; Aged, 80 and over ; }, abstract = {INTRODUCTION: Anxiety and depressive symptoms are common in Alzheimer's disease (AD), yet their relationships with amyloid, tau, and sleep remain unclear. We examined whether amyloid status and sleep duration moderate the relationships between anxiety and depressive symptoms and amygdalar tau burden in cognitively unimpaired older adults at risk for AD.

METHODS: Participants (n = 393) from the Anti-Amyloid Treatment in Asymptomatic Alzheimer's Disease (A4) and the Longitudinal Evaluation of Amyloid Risk and Neurodegeneration (LEARN) studies underwent tau and amyloid positron emission tomography imaging. Anxiety and depressive symptoms were evaluated using the State-Trait Anxiety Inventory and Geriatric Depression Scale. Sleep duration was self-reported.

RESULTS: Positive amyloid status moderated the relationship between depressive symptoms and amygdalar tau. Sleep duration moderated the relationship between anxiety and amygdalar tau, such that greater anxiety symptoms were associated with higher tau levels at shorter sleep durations.

DISCUSSION: Findings suggest biological and behavioral factors jointly influence neuropsychiatric symptom-tau relationships in preclinical AD, supporting an interactive model of early disease vulnerability.}, } @article {pmid42037680, year = {2026}, author = {Sirajo, MU and Obie, R and Mukhtar, AI and Abdullahi, NM and Taniyohwo, EM and Oyem, JC and Badamasi, IM}, title = {Targeting VDR-RXR heterodimerization in neurodegenerative diseases: a hypothetical framework for combined vitamin D3 and vitamin A therapy.}, journal = {Frontiers in neurology}, volume = {17}, number = {}, pages = {1754364}, pmid = {42037680}, issn = {1664-2295}, abstract = {Neurodegenerative diseases such as Alzheimer's and Parkinson's disease are characterized by progressive neuronal loss, oxidative stress, and limited treatment options. While vitamin D3 has demonstrated neuroprotective potential, we hypothesize that its co-administration with vitamin A may enhance therapeutic effects via synergistic interactions between their nuclear receptors (the vitamin D Receptor (VDR) and Retinoid X Receptor (RXR)). The interaction leads to the formation of a heterodimer, which regulates genes involved in neuronal survival, inflammation, and oxidative balance. A comprehensive literature review was conducted to evaluate the mechanisms underlying Vitamin D3's neuroprotection and Vitamin A's modulatory role through RXR activation, focusing on studies exploring the VDR-RXR heterodimer in Alzheimer's and Parkinson's disease models. Evidence indicates that vitamin D3 mitigates neurodegeneration by upregulating neuroprotective genes, reducing oxidative stress, and modulating calcium homeostasis, with these effects amplified by RXR activation. The VDR-RXR heterodimer interaction appears critical for enhancing transcriptional activity, promoting neuronal resilience, while potentially slowing neurodegeneration progression. We propose that combined vitamin D3 and vitamin A supplementation could offer a promising therapeutic strategy by synergistically optimizing VDR-RXR signaling, thereby improving neuroprotection. This hypothesis requires validation through an integrated approach that includes molecular, cellular, behavioral, and translational neuroimaging methods to investigate neuroprotective effects associated with VDR-RXR co-activation.}, } @article {pmid42038088, year = {2026}, author = {Permoda-Pachuta, A and Obszanski, P and Grad, Z and Futyma-Jędrzejewska, M and Ziemecki, P and Dominiak, M}, title = {Depression as an early symptom and risk factor of dementia - a narrative review.}, journal = {Frontiers in psychiatry}, volume = {17}, number = {}, pages = {1786179}, pmid = {42038088}, issn = {1664-0640}, abstract = {Depression is a common psychiatric disorder, while dementia represents a growing global health challenge, particularly in aging populations. Although substantial progress has been made in pharmacotherapy, neurodegenerative processes can only be partially slowed, and disease progression cannot be completely halted. Neurodegenerative diseases therefore remain largely incurable, underscoring the importance of early recognition and intervention. This raises an important clinical and conceptual question: does depression represent an early manifestation of dementia, act as a risk factor for its development or both? Understanding these relationships is essential for accurate diagnosis, appropriate treatment, and timely implementation of preventive strategies. This article presents a narrative review of the literature examining the complex relationship between depression and dementia, with a focus on clinical presentation, diagnostic challenges, and neurobiological mechanisms. Neuroimaging techniques such as MRI and PET, and in selected contexts SPECT, support the differential diagnosis of depression and dementia, although limitations in sensitivity and specificity persist. Inflammation has been extensively investigated as a shared pathological mechanism underlying both conditions. Emerging evidence also suggests that anti-amyloid therapies may be associated with improvements in depressive symptoms in selected patient populations, further highlighting overlapping pathophysiological pathways between depression and dementia. Improved understanding of the interplay between depression and dementia may facilitate earlier diagnosis, reduce diagnostic uncertainty, and support the development of more effective preventive and therapeutic strategies.}, } @article {pmid42038337, year = {2026}, author = {Hong, R and Han, J and Dong, F and Kalsoom, UE and Cao, C and Zhou, A and Wu, Q and Qu, X}, title = {Cynanchum bungei Decne-derived extracellular vesicles alleviate cognitive impairment and pathological damage in Alzheimer's disease.}, journal = {Frontiers in cellular neuroscience}, volume = {20}, number = {}, pages = {1798965}, pmid = {42038337}, issn = {1662-5102}, abstract = {INTRODUCTION: Cynanchum bungei Decne (CB) is known for its therapeutic benefits for neurodegenerative conditions as anti-inflammatory, antioxidant, and barrier significantly limits their potential advantages. Given the ability of crossing the barrier with minimal toxicity, extracellular vesicles derived from CB (CB-EVs) were utilized as an innovative approach to mitigate Alzheimer's disease (AD).

METHODS: CB-EVs were isolated using gradient ultracentrifugation and identified via TEM imaging, nanoparticle tracking analysis, marker identification, and in vivo imaging system. Ten-month-old triple transgenic AD (3xTg-AD) mice received intravenous administration of CB-EVs at doses of 10 or 20 mg/kg every 3 days for the cognitive and pathological assessments. The human APP Swedish mutation transgenic SH-SY5Y cells were constructed as Aβ-induced neural damage model, and different concentrations of CB-EVs were added into medium to analyze its roles on cell viability, transcriptome changes, oxidative stress, and mitochondrial damage.

RESULTS: CB-EVs exhibited standard morphological and molecular traits, accumulating in the cerebral cortex and hippocampus. Two months of CB-EVs treatment alleviated cognitive impairments, diminished Aβ plaque, reduced Tau protein hyperphosphorylation, and lessened neuronal loss in 3xTg-AD mice. In transgenic SH-SY5Y cells, CB-EVs improved cell viability, enhanced superoxide dismutase activity, downregulated oxidative stress related NUPR1 and CHOP expression, decreased reactive oxygen species, lipid peroxidation, and malondialdehyde levels, reduced mitochondrial damage.

CONCLUSION: These results demonstrated that CB-EVs could protect neurons from oxidative stress, attenuate cognitive impairment and pathological damage in AD.}, } @article {pmid42038539, year = {2026}, author = {K, V and Jaisankar, N}, title = {Design of a deep learning prediction model for Alzheimer's and Parkinson's Disease using MRI images.}, journal = {Frontiers in artificial intelligence}, volume = {9}, number = {}, pages = {1777236}, pmid = {42038539}, issn = {2624-8212}, abstract = {INTRODUCTION: Alzheimer's disease (AD) and Parkinson's disease (PD) are types of neurodegenerative diseases that affect the body and get worse over time. The cause of AD mainly involves the buildup of protein which are abnormal, issues with the immune reaction, death of neurons. Different from this, the death of the neurons that make dopamine leads to PD and causes both motor and non-motor problems. MRI images are used to provide an early and correct diagnosis to enable timely treatment planning and management of the disease.

METHODS: In this paper, a design of an AI-based deep learning framework is proposed for the classification of neurodegenerative disease based on the brain MRI data. The pipeline that we propose begins with data preparation including data augmentation using InceptionGAN for augmentation of the dataset and fixing of class imbalance issues. A composite method of feature extraction using ConvNeXt and MaxViT along with the Cross-Fusion Attention model, worked well to capture local and global spatial features. Bayesian Optimization and Genetic Algorithm are used to optimize hyperparameters for improving the performance of the model.

RESULTS: The Hybrid Deep Neural Network (HDNN) is the last classifier with an accuracy of 97.4%. Based on performance accuracy, F1-score, the model is strong and reliable. We used Gradient-weighted Class Activation Mapping++ to explain how regions of interest in the brain influence our model's decisions.

DISCUSSION: This study offers an interpretable and high-performing deep learning framework for the early and precise prediction of neurodegenerative disorders utilizing MRI imaging, thereby enhancing clinical decision-making and patient care.}, } @article {pmid42038695, year = {2026}, author = {Wang, X and Tian, L}, title = {The therapeutic efficacy of transcranial direct current stimulation in managing Alzheimer's disease: a systematic review and meta-analysis.}, journal = {Frontiers in aging neuroscience}, volume = {18}, number = {}, pages = {1726469}, pmid = {42038695}, issn = {1663-4365}, abstract = {OBJECTIVE: The present study aimed to investigate the therapeutic efficacy of transcranial direct current stimulation (tDCS) for Alzheimer's disease (AD) and identify potential influential factors.

METHODS: A comprehensive literature search was conducted in PubMed, Embase, Web of Science, and the Cochrane Library up to April 2025. Eligible studies were randomized controlled trials (RCTs) in which tDCS was the sole differential intervention between study arms. The pooled effects of tDCS on patients' global cognition, language, memory, executive function, and emotion were evaluated. Subgroup analyses were also performed to identify potential influential factors.

RESULTS: A total of 23 studies involving 24 trials and 823 mild to moderate AD patients were included. Our meta-analysis showed that tDCS significantly improved global cognition in AD patients (standardized mean difference [SMD] = 0.66; 95% confidence interval [CI], 0.38-0.95; p < 0.01), but had no significant effects on language or emotion. Subgroup analyses further revealed that significant memory improvement was observed in patients who received ≤ 10 sessions of tDCS and those with >6 years of education. Additionally, executive function was improved in patients who received stimulation on the left dorsolateral prefrontal cortex and in tDCS groups with ≤ 10 sessions. Moreover, improved executive function was observed in patients with 6-10 years of education, but not in other subgroups.

CONCLUSION: tDCS treatment leads to improvements in global cognition, memory, and executive function in AD patients, but not in language or psychomotor symptoms. However, due to the relatively high heterogeneity of the included data, further well-designed studies are warranted before tDCS can be established as a standard therapeutic approach for AD.}, } @article {pmid42038702, year = {2026}, author = {Zhao, S and Shi, H and Guan, C and Zeng, Q and Zhang, C and Wan, Y}, title = {Research on Alzheimer's disease MRI image classification based on spatial attention mechanism.}, journal = {Frontiers in aging neuroscience}, volume = {18}, number = {}, pages = {1657578}, pmid = {42038702}, issn = {1663-4365}, abstract = {INTRODUCTION: Early diagnosis of Alzheimer's Disease (AD) is crucial for improving patient quality of life and treatment outcomes. However, accurately classifying MRI scans of AD remains challenging due to the subtle and spatially complex nature of lesion regions. This study proposes a novel bidirectional spatial attention mechanism to enhance the focus on key pathological features in AD MRI images, aiming to improve classification accuracy and support earlier intervention.

METHODS: To enhance model performance, we introduced a customized bidirectional spatial attention module (ATT) integrated into a Swin-Tiny Transformer backbone. Unlike conventional attention methods, the ATT module generates spatial attention maps by adaptively pooling features along both vertical and horizontal orientations, allowing refined adjustment of attention weights across different image regions. Furthermore, to address issues of limited sample size and class imbalance, we employed data augmentation and expansion strategies, enriching the diversity of training data. The model was trained and evaluated on the augmented OASIS1 dataset.

RESULTS: The improved Swin-Tiny+ATT model demonstrated significant performance gains across all key metrics on the augmented dataset. Compared to the baseline Swin Transformer, accuracy improved from 84.83% to 87.96%, recall from 89.82% to 91.92%, precision from 85.27% to 91.98%, and the F1 score from 87.26% to 91.89%. These results confirm that the ATT module effectively enhances the model's ability to capture complex spatial features and identify critical lesion regions.

DISCUSSION: The proposed Swin-Tiny+ATT model exhibits strong potential for improving MRI-based classification of Alzheimer's Disease. The bidirectional spatial attention mechanism successfully directs the model's focus to relevant anatomical regions, contributing to higher precision and recall. Combined with data augmentation strategies, the approach mitigates class imbalance and enhances generalization. This work provides a promising deep learning framework to support early and accurate diagnosis of AD, with implications for clinical decision-making and personalized treatment planning.}, } @article {pmid42039150, year = {2026}, author = {Ouro, A and Ben-Dor, GA and Debasa-Mouce, M and Gulkarov, S and De Leon, J and Castro-Mosquera, M and Sobrino, T and Bougea, A and Reiss, AB}, title = {Monoclonal antibodies and small molecules: on the cutting edge of Alzheimer's disease therapy.}, journal = {Frontiers in cell and developmental biology}, volume = {14}, number = {}, pages = {1766762}, pmid = {42039150}, issn = {2296-634X}, abstract = {Alzheimer's disease (AD) remains a major global health challenge, with prevalence projected to increase dramatically in the coming decades and no effective treatments available. Current therapies offer only symptomatic relief, reinforcing the need for disease-modifying strategies targeting underlying pathogenic mechanisms. Advances in understanding amyloid-β (Aβ) and tau pathology have propelled the development of targeted interventions, particularly monoclonal antibodies (mAbs) and small-molecule therapeutics. Recent anti-Aβ antibodies, such as aducanumab, lecanemab, and donanemab, have demonstrated significant biological activity and reductions in amyloid burden, leading to regulatory approvals that represent important proof-of-concept milestones. However, these therapies face ongoing controversies related to modest clinical efficacy, accessibility, cost, and safety concerns. In parallel, small-molecule development has expanded beyond failed secretase inhibitors toward more refined mechanisms, including tau aggregation inhibition, kinase modulation, mitochondrial stabilization, and anti-inflammatory pathways. These compounds offer advantages in oral administration, blood-brain barrier penetration, and multi-target engagement. Together, mAbs and small molecules represent complementary therapeutic strategies addressing different aspects of AD pathophysiology. Their integration with emerging biomarkers, genetic profiling, and early diagnostic frameworks is driving a transition toward personalized and stage-specific treatment approaches. This review synthesizes current mechanistic insights, clinical evidence, and translational challenges of both modalities, highlighting how their convergence may shape the next-generation of AD therapeutics.}, } @article {pmid42039285, year = {2026}, author = {Chen, Y and Sun, X and Xi, Y and Luo, Z and Lai, H and Zhu, D and Zhang, Y and Xu, F and Li, J and Zhou, J and Ding, Y and Zhang, H}, title = {Pathology-directed drug delivery strategies: How to overcome blood-brain barrier for the treatment of brain diseases.}, journal = {Acta pharmaceutica Sinica. B}, volume = {16}, number = {4}, pages = {2250-2281}, pmid = {42039285}, issn = {2211-3835}, abstract = {Despite the different degrees of blood-brain barrier (BBB) damage in diverse brain diseases, it remains a formidable barrier that restricts most drugs from penetrating the brain. A comprehensive understanding and elucidation of the disease-specific changes of BBB in various brain pathologies are essential for directing the customized brain-targeted drug delivery systems, potentially improving cerebral delivery efficiency and therapeutic efficacy. Hence, this review compared anatomical and physiological changes of BBB under healthy and pathological states and discussed the effects of these changes on cerebral delivery efficiency. Thereafter, a particular emphasis was placed on the pathology-directed drug delivery strategies tailored to different brain diseases, including Alzheimer's disease, Parkinson's disease, multiple sclerosis, stroke, and brain tumors. By combining insights from cutting-edge studies and emerging technologies, we proposed forward-looking suggestions on future directions to brain-targeted drug delivery, thereby improving the therapeutic efficacy and accelerating the translation from preclinical attempts into clinical practice.}, } @article {pmid42039533, year = {2026}, author = {Lucciola, R and Herdy, JR and Vajaphattana, Y and Karbacher, L and Sabedot, TS and Cuoco, MS and Traxler, L and Kang, A and Reynolds, M and Jones, JR and Schafer, ST and Mertens, J and Gage, FH}, title = {RUNX1 and YY1 modulate neuronal fate and energy metabolism in Alzheimer's disease.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, doi = {10.64898/2026.04.13.716801}, pmid = {42039533}, issn = {2692-8205}, abstract = {Loss of neuronal identity and metabolic dysfunction are features of Alzheimer's disease (AD), yet the upstream-acting molecular drivers remain incompletely understood. By integrating multi-omics data from patient-derived induced neurons (iNs) and AD post-mortem human brains, we discovered that AD neurons express two master transcription factors (TFs), RUNX1 and YY1. While these TFs are primarily expressed during development where they play fundamental roles in cell fate determination and cellular bioenergetics, respectively, they can be reactivated in adult neurons in response to stress. To understand their functional role in AD neurons, we overexpressed RUNX1 or YY1 in aged iNs and found that the expression of each TF was sufficient to recapitulate two AD-associated features. Specifically, RUNX1 overexpression caused loss of neuronal fate, whereas YY1 overexpression regulated gene regulatory programs associated with metabolic dysfunction. Conversely, downregulation of either TF, in AD iNs, reinstated gene regulatory programs associated with a healthy mature neuronal phenotype. Together, these findings identify two transcriptional master regulators of the AD neuronal phenotype and establish a mechanistic foundation for further studying their role in the pathogenesis of AD and as putative therapeutical targets for the treatment of AD and age-associated neurodegeneration.}, } @article {pmid42039828, year = {2026}, author = {Li, Z and Xie, C and Pan, C}, title = {The oral-gut-brain axis: how periodontitis influence depression.}, journal = {Frontiers in microbiology}, volume = {17}, number = {}, pages = {1778744}, pmid = {42039828}, issn = {1664-302X}, abstract = {Depression has a high global prevalence and is a common mental-emotional disorder that severely jeopardizes human health. However, current treatment options remain limited, necessitating the exploration of novel pathological mechanisms and intervention targets. Recent studies indicate that periodontitis, as a prevalent chronic oral infectious disease, not only causes local microbial dysbiosis and inflammatory responses but may also influence central nervous system function through the "oral-gut-brain axis," thereby contributing to the pathogenesis and progression of neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, and multiple sclerosis, as well as neuropsychiatric disorders like depression. This review systematically examines the impact of periodontitis on oral microbiota and its subsequent translocation and colonization in the gut microbiota through pathways including swallowing and bloodstream circulation, ultimately leading to structural and functional dysregulation of the gut microbiota. The interaction between oral and gut microbiota can influence the brain through the "gut-brain axis," including disturbances in neurotransmitter metabolism, activation of systemic immune responses, and direct or indirect effects of bacterial metabolites (such as short-chain fatty acids, lipopolysaccharides, etc.) on the blood-brain barrier and neural function. This suggests that periodontal health management may serve as a novel strategy for the prevention and treatment of depression. This article further summarizes the potential of oral interventions for periodontitis (such as mechanical debridement and local/systemic antimicrobial therapy), microbiota modulation methods (such as probiotics, prebiotics, and fecal microbiota transplantation), and multidisciplinary collaborative comprehensive treatment strategies in improving microbial homeostasis and alleviating depressive symptoms. Finally, this paper points out the current research limitations in mechanistic details, causal relationships, and clinical translation, while envisioning the feasibility and prospects of developing personalized treatment strategies by targeting the "oral-gut-brain axis" in the future.}, } @article {pmid42039925, year = {2026}, author = {Lennon, MJ and Xu, Y and Thalamuthu, A and Mather, K and Sachdev, PS}, title = {Druggable genome-wide Mendelian randomization analysis identifies potential treatment targets in vascular dementia.}, journal = {Alzheimer's & dementia (New York, N. Y.)}, volume = {12}, number = {}, pages = {e70258}, pmid = {42039925}, issn = {2352-8737}, abstract = {BACKGROUND: There are currently no US Food and Drug Administration-approved treatments for vascular dementia (VaD). Genome-wide approaches have successfully identified druggable targets and treatments for various disorders. In this study, we performed druggable genome-wide two-sample Mendelian randomization (2SMR) analysis to identify possible treatment targets for VaD.

METHODS: 2SMR analyses were used to estimate the causal effects of druggable gene expression on VaD risk. The exposure variables were significant cis-expression quantitative trait loci (eQTLs) and cis-protein quantitative trait loci (pQTLs) in the cerebrospinal fluid (CSF), brain, and plasma. The main outcome variable was genetic VaD risk, based on the Mega Vascular Cognitive Impairment and Dementia Consortium genome-wide association study. 2SMR analysis examined the causal relationship between eQTLs/pQTLs and imaging markers of VaD. A phenome-wide 2SMR analysis explored the relationships between significant druggable genes and phenotype summary statistics derived from the UK Biobank. False discovery rate (FDR) P value corrections were applied to all analyses.

RESULTS: A total of 12,224 druggable genes were identified from the Drug-Gene Interaction Database (DGIdb) and associated papers. Of these, the 2SMR analysis identified four FDR-significant genes in the pQTL analysis, with none identified among the eQTLs. In the CSF, TOMM40 had a significant (P = 3.67E-36) effect on VaD outcomes as well as cerebral small vessel disease (cSVD), white matter hyperintensities (WMH; P = 0.0001) and fractional anisotropy (FA; P = 0.0028). In the brain, apolipoprotein E (APOE; P = 1.90E-54) was associated with VaD and three cSVD markers: WMH (P = 1.61E-06), FA (P = 0.0018), and mean diffusivity (P = 0.0244). ERAP1 (P = 0.0163), and SAA1-4 (P = 0.0163) showed weaker associations with VaD, did not show colocalization, and were not associated with cSVD imaging markers.

DISCUSSION: This study identified four potential drug targets for VaD, using a 2SMR analysis approach. Two genes, APOE and TOMM40, are well understood to be associated with both Alzheimer's disease and VaD, whereas the other two, ERAP1 and SAA1-4, are novel targets involved in immune system regulation and inflammation.}, } @article {pmid42040886, year = {2026}, author = {Fawad, A and van der Landen, SM and Tideman, P and van der Putten-Toorenburg, A and Butterbrod, E and Smith, R and van Westen, D and Calling, S and Midlöv, P and Mattsson-Carlgren, N and Borgström Bolmsjö, B and Stomrud, E and Nilsson, MH and Hansson, O and Sikkes, SAM and Palmqvist, S}, title = {Clinical staging in Swedish primary care using the Amsterdam Instrumental Activities of Daily Living Questionnaire.}, journal = {Alzheimer's & dementia (Amsterdam, Netherlands)}, volume = {18}, number = {}, pages = {e70344}, pmid = {42040886}, issn = {2352-8729}, abstract = {INTRODUCTION: We assessed the accuracy of the Amsterdam Instrumental Activities of Daily Living Questionnaire (A-IADL-Q) for clinical staging in Swedish primary care.

METHODS: Participants from the Swedish BioFINDER Primary Care study were included. Discriminative performance of the A-IADL-Q was evaluated using receiver operating curves. Multinomial and linear regression models assessed associations among A-IADL-Q scores, clinical stage, demographics, cognition, and comorbidities.

RESULTS: Among 623 patients, 148 (23.8%) had subjective cognitive decline (SCD), 274 (43.9%) mild cognitive impairment (MCI), and 201 (32.3%) dementia with a mean (standard deviation) age of 76.7 (7.3). The area under the curve (95% confidence interval) for discriminating between SCD versus MCI/dementia was 0.89 (0.86-0.91) and for SCD/MCI versus dementia 0.89 (0.87-0.92). Age (β = -0.25), Mini-Mental State Examination (β = 0.91) and Montreal Cognitive Assessment (β = 0.57), but no other demographics and comorbidities, were associated with the A-IADL-Q.

DISCUSSION: The A-IADL-Q may help primary care physicians determine clinical stage and shows promise for use to adequately refer patients to secondary or tertiary care.}, } @article {pmid42041219, year = {2024}, author = {Xie, P and Sun, C and Li, Y and Deng, Y and Xie, C}, title = {Clinical Study on Mesenchymal Stem Cell Factors Therapy for Alzheimer's Disease.}, journal = {Nigerian journal of clinical practice}, volume = {27}, number = {10}, pages = {1216-1220}, doi = {10.4103/njcp.njcp_561_24}, pmid = {42041219}, issn = {1119-3077}, abstract = {BACKGROUND: Alzheimer's disease (AD), characterized by cognitive decline, lacked effective cures. Mesenchymal stem cell (MSC) factors (MSCFs) offered a new approach by promoting brain tissue repair and modulating immune responses, presenting a promising alternative to AD treatment with minimal risks.

AIM: This study aimed to investigate the effects of MSCF on AD and to compare the effects with traditional MSC treatments.

METHODS: Sixty patients were divided into control and observation groups, with 30 cases in each group. The control group were injected intravenously with 10 mL of MSCs (5.0 × 10 9 L -1) plus 100 mL normal saline (once every 5 days for six consecutive treatments). The observation group received intramuscular injections of 0.5 mL (1 mL for the first dose) of MSCF (every other day for 15 consecutive treatments). Amyloid-β 42 (Aβ42) and Tau protein concentrations in cerebrospinal fluid were determined by ELISA pretreatment and at 1, 3, and 6 months' post-treatment. The Clinical Dementia Rating of AD patients was recorded at these intervals to evaluate treatment efficacy.

RESULTS: Aβ42 levels increased, and Tau protein levels decreased in both groups. The CDR score dropped post treatment. The total effective rate and clinical cure rate were 86.67% and 6.70% in the control group and 100% and 40% in the observation group, respectively. MSCF and MSCs uniquely impact AD.

CONCLUSION: MSCs contributed to damaged nerve cell repair, new nerve cell differentiation, and the participation of some dormant nerve cells in physiological activity. MSCF offered a small-dose, rapid, and safe treatment with simple operation.}, } @article {pmid42041396, year = {2026}, author = {Sumbria, RK and Boado, RJ}, title = {Brain Delivery of Antibody-Derived Biologicals for Alzheimer's Disease: An Updated Narrative Review.}, journal = {Antibodies (Basel, Switzerland)}, volume = {15}, number = {2}, pages = {}, pmid = {42041396}, issn = {2073-4468}, abstract = {Antibodies directed against β-amyloid (Aβ) have been developed for the treatment of Alzheimer's disease (AD). However, the in vivo central efficacy is reduced by the poor penetration of antibodies across the blood-brain barrier (BBB). In addition, these antibodies have been associated with adverse effects like amyloid-related imaging abnormalities. Thus, the development of new antibody-based therapies for AD with improved transport across the BBB may improve efficacy and reduce adverse effects. Antibodies targeting the BBB transferrin receptor (TfR) are able to cross the BBB through receptor-mediated transcytosis, producing a global distribution throughout the brain. Along the same line, bispecific antibodies directed to both the BBB TfR and Aβ showed enhanced brain uptake and pharmacological effects with diminished adverse side effects in experimental animal models of AD and in clinical trials. A generation of brain-penetrating fusion proteins targeting the BBB-TfR has been shown to represent novel treatments for AD, and this includes erythropoietin, tumor necrosis factor alpha inhibitors, neprilysin, somatostatin, oligonucleotides, and an antibody activating TREM2. The aim of this article is to review the progress made in the delivery of antibody-derived biologicals to the brain for AD, targeting the BBB-TfR.}, } @article {pmid42041587, year = {2026}, author = {Elias, A and Stern, S}, title = {Gene Editing Strategies for Neurological and Mental Disorders: Advances in Delivery, Methodology, and Clinical Translation.}, journal = {Cells}, volume = {15}, number = {8}, pages = {}, pmid = {42041587}, issn = {2073-4409}, mesh = {Humans ; *Gene Editing/methods ; *Nervous System Diseases/genetics/therapy ; *Mental Disorders/genetics/therapy ; Animals ; *Genetic Therapy/methods ; *Translational Research, Biomedical ; *Gene Transfer Techniques ; CRISPR-Cas Systems/genetics ; Blood-Brain Barrier/metabolism ; }, abstract = {Neurological and mental disorders are among the main causes of disability worldwide, affecting over three billion people and increasing the socioeconomic burden. Advances in molecular genetics and genome engineering have led to gene-targeted therapies that address root causes rather than just symptoms. This review covers current genome-editing tools, including CRISPR/Cas, base editing, and prime editing. The focus is on the benefits of gene editing in the central nervous system, where post-mitotic neurons allow lasting effects after a single treatment. It also discusses emerging delivery platforms such as viral vectors, nanoparticles, and exosome systems, as well as methods to bypass the blood-brain barrier. Recent clinical progress in spinal muscular atrophy, Parkinson's disease, Huntington's disease, and Alzheimer's disease is highlighted, with promising preclinical results for autism, bipolar disorder, epilepsy, and other neurogenetic conditions. The review concludes with regulatory issues, market trends, and ongoing clinical trials, underscoring the potential of gene therapies to transform disease management and provide long-term solutions.}, } @article {pmid42042055, year = {2026}, author = {Jakobović, N and Kalinovčić, P and Borovec, J and Primožič, I and Hrenar, T}, title = {Quantum-Chemical Multiligand Simultaneous Docking of Three-Membered Rings in the Active Site of Butyrylcholinesterase.}, journal = {Current issues in molecular biology}, volume = {48}, number = {4}, pages = {}, pmid = {42042055}, issn = {1467-3045}, support = {HRZZ-IP-2022-10-9525//Croatian science foundation/ ; }, abstract = {Alzheimer's disease is a progressive neurodegenerative disorder marked by declining cognitive function. While early-stage treatment focuses on acetylcholinesterase (AChE) inhibition, butyrylcholinesterase (BChE) activity increases as the disease progresses, contributing to cholinergic deficits and neuroinflammation. This shift in enzyme dominance presents a compelling rationale for developing BChE-specific inhibitors as a potential therapeutic avenue. This study explores small, three-membered rings, scaffolds offering potential for interaction with the enzyme's active site, as building blocks for novel BChE inhibitors. Employing a computational approach based on quantum-chemical multiligand simultaneous molecular docking, we virtually fitted these compounds into the BChE active site to predict binding affinity and key interactions. Our calculations extend beyond simple shape matching by incorporating accurate electronic properties, leading to more reliable predictions of binding strength and stability. The goal was not immediate identification of potent inhibitors, but a systematic assessment of how these rings interact with BChE. This foundational knowledge will inform the design and synthesis of larger, more complex molecules with enhanced binding affinity and selectivity, ultimately aiming to develop compounds to inhibit BChE activity and potentially slow Alzheimer's progression.}, } @article {pmid42042094, year = {2026}, author = {Allegra, P and Lodico, M and Migliazzo, C and Tarantino, D and Piccoli, T and Vanacore, N and Salemi, G and Maniscalco, L and Matranga, D}, title = {The Need for Standardized Data Collection to Improve Harmonization and Pooling of Information About Modifiable Risk Factors for Alzheimer's Diseases in Italian Clinical Studies: A Systematic Review.}, journal = {Geriatrics (Basel, Switzerland)}, volume = {11}, number = {2}, pages = {}, pmid = {42042094}, issn = {2308-3417}, support = {"PNRR M6C2- Investimento 2.1 Valorizzazione e potenziamento della ricerca biomedica del SSN", grant number PNRRMAD-2022-12375822, CUP derivato: I75E22000550006-CUP Master ISS I55E22000560006//European Union-Next Generation EU/ ; }, abstract = {BACKGROUND/OBJECTIVES: At the international level, harmonized networks of dementia clinical studies are available, but Italian participation remains limited. This systematic review aims to define harmonization rules to facilitate the inclusion of Italian clinical studies in existing networks and to propose standardized data collection methods to enable comparison of the study results.

METHODS: A systematic review was conducted (January 2019-December 2024) to identify Italian clinical studies evaluating Alzheimer's disease and other dementias as outcomes. Eight modifiable risk factors were extracted: BMI, arterial hypertension, diabetes, dietary patterns, alcohol consumption, smoking habits, depressive symptomatology, and physical activity. WHO definitions and internationally accepted criteria were used as reference standards. Variable harmonization potential was assessed using the DataSHaPER methodology and classified as complete, partial, or impossible, considering information loss across studies.

RESULTS: Of 365 records identified, 18 studies met the inclusion criteria. Obesity assessed via BMI showed the highest harmonization potential (44% complete, 33% partial), along with dietary habits measured by food frequency questionnaires (44% complete). Diabetes and physical inactivity followed (33% complete), assessed through fasting glucose or pharmacological treatment and the IPAQ, respectively. Smoking habits classified as current, former, or never smokers were reported in 28% of studies. Depression (assessed by GDS or CES-D) and hypertension (blood pressure measurement or antihypertensive treatment) showed complete harmonization in only 22% of studies.

CONCLUSIONS: Italian studies show substantial limitations in the harmonization of modifiable risk factor data for Alzheimer's disease, mainly due to heterogeneous and non-standardized data collection methods, highlighting the need for uniform research protocols.}, } @article {pmid42042095, year = {2026}, author = {Durrani, S and Mussawar, M and Alaverdashvili, M}, title = {Impact of Comprehensive Geriatric Assessments on Dementia Care.}, journal = {Geriatrics (Basel, Switzerland)}, volume = {11}, number = {2}, pages = {}, pmid = {42042095}, issn = {2308-3417}, abstract = {Introduction: According to the Alzheimer Society of Canada, over 770,000 people in Canada are living with dementia. This number is expected to rise to nearly 1 million people by 2030. Although the provision of team-based interprofessional assessment in gerontological care is critical for the early detection and prevention of dementia, its planning and delivery can be a challenge. In Saskatchewan, previous assessments have identified significant gaps between actual and best practices in dealing with this medical condition. The emergence of Geriatric Services Resource Teams (GSRTs), which apply an innovative, team-based model to improve the diagnosis and care of older adults with complex health practices, can be proven beneficial in this regard. The purpose of this study is to compare the efficacy of the care provision process between a GSRT and a traditional medical care channel (i.e., primary health) with respect to dementia patients. Methods: A retrospective patient chart review was conducted by collecting data from a large Primary Care practice (n = 90) and the GSRT in Regina (n = 75). Collected data included information on patient demographics and treatment, and the diagnosis process itself. Results: While demographic characteristics between patient groups were similar, significant differences (p < 0.05) were found in the involvement of pharmacy and other healthcare professionals, prescriptions for memory loss, and in who made the diagnosis. Moreover, although the dementia diagnosis was usually made first in Primary Care, further clarification of the type of dementia, counseling of diagnosis, review of medication, and assessment of functions and social supports were better managed in the GSRT group. Discussion: The use of Geriatric Services Resource Teams is a relatively new concept in Saskatchewan. As these teams are established, initial results show that their role in complex care management has beneficial outcomes for dementia patients.}, } @article {pmid42042200, year = {2026}, author = {Xu, ZH and Zou, ZB and Wang, CX and Li, C and Yang, XW and Wang, JS}, title = {Anti-Neuroinflammatory Naphtho-γ-Pyrones from a Deep-Sea-Derived Fungus Aspergillus niger 3A00562.}, journal = {Marine drugs}, volume = {24}, number = {4}, pages = {}, pmid = {42042200}, issn = {1660-3397}, support = {22177143//National Natural Science Foundation of China/ ; }, mesh = {Animals ; Zebrafish ; *Aspergillus niger/chemistry ; *Anti-Inflammatory Agents/pharmacology/chemistry/isolation & purification ; Nitric Oxide Synthase Type II/metabolism ; Oxidative Stress/drug effects ; Molecular Docking Simulation ; *Pyrones/pharmacology/chemistry/isolation & purification ; Microglia/drug effects/metabolism ; Mice ; Alzheimer Disease/drug therapy ; Cell Line ; Reactive Oxygen Species/metabolism ; Lipopolysaccharides ; *Neuroprotective Agents/pharmacology/chemistry ; Inflammation/drug therapy ; }, abstract = {Inhibition of inflammation and oxidative stress is increasingly recognized as a promising therapeutic strategy for neurodegenerative diseases. In this study, we isolated two new dimeric naphtho-γ-pyrone (aS)-fonsecinones B and D (1 and 2) and 14 known compounds (3-16) from the deep-sea-derived fungus Aspergillus niger 3A00562. Their structures were unambiguously determined through integrated physicochemical and spectroscopic analyses. Screening for neuroinflammatory inhibitors using a BV2 microglial cell model identified TMC 256 A1 (10) as the most potent candidate. Compound 10 significantly suppressed LPS-induced inflammation in BV2 cells without cytotoxicity. It concurrently inhibited LPS-triggered ROS overproduction and neutrophilic infiltration in zebrafish. Subsequent proteomics revealed that 10 targets NOS2 to modulate Alzheimer's disease (AD)-associated pathways and the KEAP1-NRF2 axis. Molecular docking and dynamics simulations demonstrated that 10 occupies the NOS2 heme-binding pocket, thereby preventing dimerization and inhibiting enzymatic activity. Finally, 10 ameliorated locomotor deficits in an AD zebrafish model. Collectively, these findings highlight compound 10 as a candidate compound for preventing inflammatory and oxidative stress damage during treatment of neurodegenerative diseases, particularly AD.}, } @article {pmid42042246, year = {2026}, author = {Abdullah, and Fatima, Z and Ruiz, MJT and Espinosa-Sosa, O and Sánchez-Mejorada, CG and Téllez, RQ and Rodríguez, JLO and Sidorov, G}, title = {Explainable Patient-Level Cognitive Impairment Screening via Temporal, Semantic, and Psycholinguistic Multimodal AI.}, journal = {Journal of Intelligence}, volume = {14}, number = {4}, pages = {}, pmid = {42042246}, issn = {2079-3200}, abstract = {Early diagnosis of cognitive decline is vital for timely treatment of mild cognitive impairment (MCI) and Alzheimer's disease (AD), yet standard clinical assessments often miss subtle longitudinal language changes. We propose a hierarchical hybrid intelligence framework integrating long-context language modeling, temporal progression, semantic graph reasoning, psycholinguistic biomarkers, and contrastive progression learning to classify patient states (Normal, MCI, AD) from longitudinal electronic health record (EHR) notes. The model was trained on 4500 patients and 68,000 clinical notes from Medical Information Mart for Intensive Care III (MIMIC-III) and externally validated on the Medical Information Mart for Intensive Care IV (MIMIC-IV) clinical notes dataset (5200 patients, 72,000 notes). Inputs combined Biomedical and Clinical Bidirectional Encoder Representations from Transformers (BioClinicalBERT) embeddings, Bidirectional Long Short-Term Memory (Bi-LSTM) temporal encodings, Graph Sample and Aggregate (GraphSAGE)-based Unified Medical Language System (UMLS) concept graphs, and psycholinguistic vectors (lexical diversity, grammatical complexity, discourse coherence). On the MIMIC-III hold-out set, the model achieved 99.999% accuracy, a macro F1-score of 0.999, a Receiver Operating Characteristic Area Under the Curve (ROC AUC) of 0.999, and a temporal stability variance of 0.0008. Monte Carlo cross-validation (10,000 folds) yielded 99.997±0.003% accuracy and 0.999±0.001 macro F1. Feature ablation confirmed distinct gains from temporal, semantic, and psycholinguistic modules, improving performance by 1.1% over text-only baselines. Cross-cohort zero-shot testing on MIMIC-IV showed strong generalization with minimal decline in macro F1 and balanced accuracy. Explainability analyses, such as SHapley Additive exPlanations (SHAP) token/concept attribution, attention maps, counterfactual perturbations, and psycholinguistic importance, revealed clinically interpretable markers, such as pronoun overuse, reduced lexical diversity, and syntactic simplification, as predictors of decline. Our framework supports scalable, non-invasive early screening in a variety of healthcare settings by providing longitudinally stable predictions.}, } @article {pmid42043712, year = {2026}, author = {Khozani, MS and Palizvan, M and Mosayebi, G and Ganji, A and Ghazavi, A}, title = {Chitosan-curcumin nanoparticles: a potential nano-therapeutic for cognitive restoration in a streptozotocin-induced rat model of Alzheimer's disease.}, journal = {Inflammopharmacology}, volume = {34}, number = {5}, pages = {3527-3541}, pmid = {42043712}, issn = {1568-5608}, mesh = {Animals ; *Curcumin/administration & dosage/pharmacology ; *Chitosan/chemistry/administration & dosage ; *Alzheimer Disease/drug therapy/chemically induced/metabolism ; Male ; Rats, Wistar ; Streptozocin/pharmacology ; Rats ; *Nanoparticles/administration & dosage ; Disease Models, Animal ; Neuroprotective Agents/pharmacology/administration & dosage ; Oxidative Stress/drug effects ; Hippocampus/drug effects/metabolism ; *Cognition/drug effects ; Maze Learning/drug effects ; Cognitive Enhancement ; }, abstract = {BACKGROUND: Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by cognitive decline and memory impairment, with no definitive cure currently available. Neuroinflammation, oxidative stress, and amyloid-beta accumulation play central roles in disease progression. While curcumin shows therapeutic promise, its clinical efficacy is limited due to poor bioavailability. This study investigates the neuroprotective effects of chitosan-curcumin nanoparticles in a streptozotocin (STZ)-induced rat model of AD, focusing on cognitive performance, hippocampal integrity, and molecular markers of neurodegeneration.

METHODS: Sixty male Wistar rats were randomly divided into five groups: control, AD, AD + chitosan, AD + curcumin, and AD + chitosan-curcumin. AD was induced via intraventricular injection of STZ (3 mg/kg). Two weeks' post-induction, cognitive function was assessed using the Morris water maze (MWM). At the end of the treatment period, oxidative stress parameters, inflammatory cytokines, and gene expression levels (IL-1β, IL-6, IL-10, NRF2, PPARγ, BDNF) were measured via real-time PCR. Data were analyzed using one-way ANOVA with Tukey's post hoc test (p < 0.05).

RESULTS: Rats treated with chitosan-curcumin nanoparticles exhibited significantly improved memory and learning compared to all other groups (p < 0.001). There was a marked downregulation of IL-1β and IL-6, along with increased expression of NRF2, PPARγ, and BDNF (p < 0.05). Histological analysis confirmed reduced neuronal damage and increased neuronal density. Chitosan-curcumin nanoparticles demonstrated potent neuroprotective effects, enhancing cognitive performance, reducing inflammation and oxidative stress, and preserving neuronal structure.

CONCLUSION: These multifaceted effects highlight the therapeutic potential of CS-CUR nanoparticles in targeting the core pathological mechanisms of AD. Future studies should focus on long-term safety and efficacy assessments, dose-response optimization, and mechanistic pathway analyses to further elucidate the neuroprotective actions of CS-CUR nanoparticles. Additionally, translational and clinical investigations are warranted to validate the therapeutic potential of this nanocarrier system for Alzheimer's disease management.}, } @article {pmid42043831, year = {2026}, author = {Farrell, C and Saini, F and Beidas, MM and Ryan, NS and Strydom, A and Wiseman, FK}, title = {Use of anti-amyloid-β monoclonal antibodies in persons with Down syndrome Alzheimer's disease.}, journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association}, volume = {22}, number = {4}, pages = {e71404}, pmid = {42043831}, issn = {1552-5279}, support = {UKDRI-1211//UK Dementia Research Institute through UK DRI Ltd, principally funded by the UK Medical Research Council/ ; UKDRI-1010//UK Dementia Research Institute through UK DRI Ltd, principally funded by the UK Medical Research Council/ ; UKDRI-TAP23∖12//UK Dementia Research Institute through UK DRI Ltd, principally funded by the UK Medical Research Council/ ; AS-PhD-19a-007/ALZS_/Alzheimer's Society/United Kingdom ; MB2020∖100003//Rosetrees Trust/ ; 2021B#2083//the Jérôme Lejeune Foundation/ ; MR/S011277/1/MRC_/Medical Research Council/United Kingdom ; MR/S005145/1/MRC_/Medical Research Council/United Kingdom ; MR/R024901/1/MRC_/Medical Research Council/United Kingdom ; //National Institute for Health and Care Research/ ; //NIHR University College London Hospitals Biomedical Research Centre (BRC), NIHR Maudsley BRC/ ; //UCL Neurogenetic Therapies Programme/ ; //funded by the Sigrid Rausing Trust/ ; NC/S001298/1/NC3RS_/National Centre for the Replacement, Refinement and Reduction of Animals in Research/United Kingdom ; ARUK-SRF2018A-001//Alzheimer's Research UK/ ; ARUK-SRFEXT2022-001//Alzheimer's Research UK/ ; }, mesh = {Humans ; *Down Syndrome/complications/drug therapy ; *Alzheimer Disease/drug therapy/complications ; *Antibodies, Monoclonal/therapeutic use/adverse effects ; *Amyloid beta-Peptides/immunology ; }, abstract = {INTRODUCTION: The recent development and licensing of anti-amyloid-β monoclonal antibodies for the treatment of early-stage Alzheimer's disease have significantly shifted the clinical landscape. However, current use recommendations preclude the administration of these new drugs to persons who have Down syndrome.

METHODS: This narrative review considers the ethical and biological factors relating to the administration of anti-amyloid-β monoclonal antibody therapies to persons who have Down syndrome. Literature was selected based on relevance.

RESULTS: Here, we discuss the current understanding of Down syndrome Alzheimer's disease, and how this informs potential benefits and risks of treatment with anti-amyloid-β monoclonal antibodies.

DISCUSSION: The blood-brain barrier and immune system differ in persons with Down syndrome, and cerebral amyloid angiopathy is elevated compared to late-onset Alzheimer's disease. Thus, side-effect risks from anti-amyloid-β monoclonal antibodies are likely to be elevated. Further research is needed to facilitate the treatment of persons with Down syndrome with these new therapies.}, } @article {pmid42043884, year = {2026}, author = {Bonpandi, E and John, C and Arumugam, P}, title = {Synthesis, structural elucidation, DNA binding, cleavage, cholinesterase inhibitory activity of metal complexes of novel 2,2'-bipyridyl derivative.}, journal = {Nucleosides, nucleotides & nucleic acids}, volume = {}, number = {}, pages = {1-34}, doi = {10.1080/15257770.2026.2659226}, pmid = {42043884}, issn = {1532-2335}, abstract = {To achieve efficient cholinesterase inhibitory activity of metal(II) complexes of Cu(II), Ni(II), Co(II), and Zn(II) with 2,2'-bipyridyl framework [M-L] (L = 2,2'-bipyridyl derivative containing an aromatic center and an e[-]-withdrawing -NO2 group) was developed. The structural characteristics were identified through spectroscopic and analytical studies. The antibacterial activity of the produced ligand and metal(II) complexes against bacteria and fungi was evaluated. The synthesized metal(II) complexes ability to fragment DNA has been studied on pUC 18 DNA using agarose gel electrophoresis. The copper(II) complex (Kb=4.11 × 10[5] M[-1]) is stronger binding affinity for DNA than ethidium bromide (EB) (Kb=3.3 × 10[5] M[-1]) and metal(II) complexes. The chemically produced 2,2'-bipyridyl derivative had the strongest inhibitory effects against acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) with IC50 values that were less than the standard compounds (0.34 and 3.42 µM, respectively). Our research results could aid in the creation of novel drug molecules, especially for the treatment of neurological conditions like Alzheimer's disease and neurological disorders occurring through diabetes.}, } @article {pmid42043894, year = {2026}, author = {Dendooven, A and Vandendriessche, A and Koshy, PJ and Timmermans, F and Speeckaert, M and Kint, N and Van Aelst, L and Vekemans, MC and Meuleman, N and Pouleur, AC and Bondue, A and Droogmans, S and Debonnaire, P and De Bleecker, J and Van Craenenbroeck, A and Gallardo, R and Schymkowitz, J and Rousseau, F and Impens, F and Devos, S and Delforge, M}, title = {Belgian recommendations for tissue diagnosis of amyloidosis.}, journal = {Acta clinica Belgica}, volume = {}, number = {}, pages = {1-14}, doi = {10.1080/17843286.2026.2660739}, pmid = {42043894}, issn = {2295-3337}, abstract = {BACKGROUND: Amyloidosis is a disorder caused by the extracellular deposition of misfolded protein fibrils, leading to organ dysfunction. Diagnosis remains challenging due to non-specific clinical presentations and the diversity of amyloid subtypes. Accurate identification of the amyloid precursor protein is key for prognostication and treatment strategy.

OBJECTIVES: This document aims to provide practical recommendations for the tissue diagnosis of amyloidosis within the Belgian healthcare context. It targets clinicians managing amyloidosis patients and pathologists evaluating biopsies with suspected amyloid deposits.

METHODS: A structured PubMed search ('amyloidosis AND biopsy AND stain*'; 'amyloidosis AND mass spectro*') was conducted in August 2025. After exclusion of case reports, preclinical studies, and Alzheimer-related articles, 298 publications were reviewed. Recommendations were formulated based on available evidence and discussed among Belgian clinical and pathology experts.

RESULTS: Key recommendations emphasize that tissue biopsies remain essential for amyloidosis diagnosis and typing. Congo red staining with birefringence and fluorescence confirmation is required. Immunohistochemistry and immunofluorescence are first-line subtyping tools, while mass spectrometry serves as a reference method when results remain inconclusive. Centralization of complex analyses in experienced centres is encouraged.

CONCLUSIONS: These recommendations promote standardized, early and accurate tissue diagnosis of amyloidosis in Belgium, supporting optimal patient management and harmonization of diagnostic practices across institutions.}, } @article {pmid42044556, year = {2026}, author = {Braak, S and Mennes, M and Su, T and Pijnenburg, Y and Bakker, G and Arango, C and van der Wee, N and Bauduin, S and Ortiz-Tallo Moya, A and Lopez-Morinigo, JD and Dawson, GR and Abrahams, AB and Beckenstrom, AC and Beckmann, CF and Marston, HM and Penninx, BWJH and Kas, MJH}, title = {Social dysfunction and default mode network functional integrity in neuropsychiatric disorders: A cross-disorder replication and generalization study.}, journal = {European neuropsychopharmacology : the journal of the European College of Neuropsychopharmacology}, volume = {110}, number = {}, pages = {112847}, doi = {10.1016/j.euroneuro.2026.112847}, pmid = {42044556}, issn = {1873-7862}, abstract = {Cross-disorder research and replication of neuroimaging findings remains scarce. Social dysfunction is an early manifestation across diverse neuropsychiatric disorders that may relate to altered default mode network (DMN) integrity. This study aimed to replicate previous findings linking social dysfunction with diminished resting-state DMN functional connectivity and altered task-based DMN functional activation in response to emotional faces across schizophrenia (SZ), Alzheimer's disease (AD), and healthy controls (HC), and to extend these findings to major depressive disorder (MDD). Resting-state fMRI and task-based fMRI data on implicit facial emotional processing were acquired in an overlapping cohort (resting-state fMRI: N=167; SZ=32, MDD=44, AD=29, HC=62. Task-based fMRI: N=152; SZ=30, MDD=42, AD=26, HC=54). Additionally, mega-analyses (N=317 for resting-state fMRI; N=291 for task-based fMRI) of the current and a prior independent sample were conducted. Social dysfunction was indexed with the Social Functioning Scale (SFS) and the De Jong-Gierveld Loneliness (LON) scale. The association between higher mean SFS+LON social dysfunction scores and diminished DMN connectivity within the dorsomedial prefrontal cortex across SZ/AD/HC participants was replicated, and extended to MDD patients. Similar observations within the dorsomedial and rostromedial prefrontal cortex were found in the mega-analysis. Associations between social dysfunction and DMN activation in response to sad and happy faces were not replicated or found in the mega-analysis. To conclude, diminished dorsomedial prefrontal cortex DMN connectivity emerged as a transdiagnostic neurobiological marker for social dysfunction, suggesting a potential treatment target for precision medicine approaches. DMN functional responses to emotional faces may not be a sensitive biomarker for social dysfunction.}, } @article {pmid42045164, year = {2026}, author = {Pozzi-Ruiz, V and Giner de Gracia, A and Glauser, L and Romani, M and Gunter-Rahman, F and González-Ramón, A and Haj-Yahya, M and Kolla, R and Burns, AM and Lashuel, HA and Auwerx, J and Gräff, J and Sanchez-Mut, JV}, title = {The PM20D1-OLE pathway induces microglia rewiring to ameliorate Alzheimer disease.}, journal = {Cell death & disease}, volume = {17}, number = {1}, pages = {}, pmid = {42045164}, issn = {2041-4889}, support = {PID2022-143263OB-I00//Ministry of Economy and Competitiveness | Agencia Estatal de Investigación (Spanish Agencia Estatal de Investigación)/ ; PRE2020-093825//Ministry of Economy and Competitiveness | Agencia Estatal de Investigación (Spanish Agencia Estatal de Investigación)/ ; PRE2020-093389//Ministry of Economy and Competitiveness | Agencia Estatal de Investigación (Spanish Agencia Estatal de Investigación)/ ; ERC-AdG-787702//EC | EU Framework Programme for Research and Innovation H2020 | H2020 Priority Excellent Science | H2020 European Research Council (H2020 Excellent Science - European Research Council)/ ; SNSF 31003A_179435//Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung (Swiss National Science Foundation)/ ; }, mesh = {*Microglia/metabolism/drug effects/pathology ; *Alzheimer Disease/pathology/metabolism/drug therapy/genetics ; Animals ; Humans ; Amyloid beta-Peptides/metabolism ; *Leucine/analogs & derivatives/pharmacology/metabolism ; Plaque, Amyloid/pathology/metabolism ; Mice ; Neurons/metabolism/drug effects/pathology ; Disease Models, Animal ; Signal Transduction ; }, abstract = {There is increasing evidence of microglia participation in Alzheimer's disease (AD), which incentives their modulation to intercept the disease. Here, we describe a new mechanism by which the recently AD-associated Peptidase M20 Domain Containing 1 (PM20D1) instructs microglia to tackle AD. We show that the PM20D1-derived N-oleoyl-Leucine (OLE) improves AD pathologies in two animal models of AD. OLE induces microglia association with amyloid beta (Aβ) plaques, reduce their size, number and toxicity, and leads to enhanced neuroprotection and cognition. Furthermore, OLE also increases Aβ chemotaxis and clearance in microglia cultures and enhances cell viability in neurons subjected to AD-related stressors. Finally, we also find evidence for a PM20D1- and OLE-mediated microglia association with amyloid plaques and neuroprotection in human AD brains. In sum, our results provide further insight into the protective role of PM20D1 in AD and support the use of OLE as a microglia-modifying treatment for AD.}, } @article {pmid42046101, year = {2026}, author = {Andrews, D and Golchi, S and Collins, DL and , }, title = {A digital twin methodology using retrospective patient data for sample size reduction in Alzheimer's disease clinical trials.}, journal = {Alzheimer's research & therapy}, volume = {18}, number = {1}, pages = {}, pmid = {42046101}, issn = {1758-9193}, support = {FRN 165921/CAPMC/CIHR/Canada ; RGPIN-2015-03633//Natural Sciences and Engineering Research Council of Canada/ ; }, mesh = {Humans ; *Alzheimer Disease/diagnostic imaging ; Retrospective Studies ; Sample Size ; Female ; *Randomized Controlled Trials as Topic/methods ; Male ; Patient Selection ; Aged ; }, abstract = {BACKGROUND: Recruitment for Alzheimer’s disease randomized controlled trials (RCTs) is difficult and expensive. To reduce RCT sample sizes while maintaining high statistical power, our Digital Twin Trial (DTT) methodology combines an interpretable cognitive decline prediction model with prediction-powered inference. Unlike RCT sample size reduction techniques that maintain power by recruiting only patients likely to decline, prediction-powered inference is used within the data analysis stage of the trial and does not impose additional restrictions on participant eligibility. METHODS: For DTT participants, our model identifies similar individuals (“Digital Twins”) from a retrospective trial-matched database and uses their cognitive scores to predict decline. Predictions adjust observed scores, reducing variance within treatment groups. We simulated 18-month DTTs and standard RCTs using mixed effects models of decline in Alzheimer’s Disease Neuroimaging Initiative subjects meeting lecanemab’s Phase 3 inclusion criteria. RESULTS: Predicted and observed change in Clinical Dementia Rating Sum-of-Boxes correlated at r = 0.437. DTTs required 9.5–19.0% fewer subjects than standard RCTs to detect a simulated 25% decline-slowing drug effect at 0.9 power. DTT Type 1 error was consistent with 0.05. CONCLUSIONS: DTTs could reduce clinical trial recruitment and cost burdens without imposing additional inclusion criteria, enabling efficient testing of new treatments in all populations who might benefit. Model interpretability will foster clinician and regulator trust in individualized prognoses. This transparency could help smooth the model’s translation to real trials and eventually the clinic, where it could help make prognoses and better evaluate treatment effects in individual patients.}, } @article {pmid42047299, year = {2026}, author = {Phares, S and Kremer, I and Wall, JK and Wood, J and Baumgart, M and Dickson, S and Fickie, M and Hubbard, T and Jannati, A and Monane, M and Rivet, C and Hirsch, G}, title = {System changes to empower primary care in Alzheimer's disease detection and care.}, journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association}, volume = {22}, number = {4}, pages = {e71276}, pmid = {42047299}, issn = {1552-5279}, mesh = {*Alzheimer Disease/diagnosis/therapy ; Humans ; *Primary Health Care ; United States ; Access to Primary Care ; Health Services Accessibility ; }, abstract = {Despite advances in disease-modifying treatments, significant barriers in the evaluation and clinical management of people with early Alzheimer's disease (AD) remain. These barriers have been documented in scientific literature and increasingly call for primary care to play a larger role in the detection, diagnosis, treatment, and monitoring of AD. Drawing upon the work of a multistakeholder consortium, this article identifies systemic and structural barriers that hinder primary care professionals in the United States from playing a larger role. We propose solutions to these barriers and call for evolution of the U.S. healthcare system to ensure it is prepared to adapt to the rapidly progressing scientific and societal landscape and meet the growing needs of people affected by the early stages of AD.}, } @article {pmid42047940, year = {2026}, author = {He, DL and Wu, Z and Jia, RJ and Wu, TY and Qiu, YM and Fan, YG}, title = {AS1842856 Reduces β-Amyloid Burden via Inhibiting PLA2G4A-Mediated Lysosomal Dysfunction in APP/PS1 Mice.}, journal = {CNS neuroscience & therapeutics}, volume = {32}, number = {4}, pages = {e70910}, pmid = {42047940}, issn = {1755-5949}, support = {82301626//National Natural Science Foundation of China/ ; }, mesh = {Animals ; *Lysosomes/drug effects/metabolism/pathology ; Amyloid beta-Protein Precursor/genetics ; *Group IV Phospholipases A2/metabolism/antagonists & inhibitors ; Mice, Transgenic ; *Amyloid beta-Peptides/metabolism ; Mice ; Presenilin-1/genetics ; *Alzheimer Disease/drug therapy/metabolism/pathology/genetics ; Glycogen Synthase Kinase 3 beta/metabolism ; Disease Models, Animal ; Male ; Cell Line, Tumor ; }, abstract = {AIMS: Both cytosolic phospholipase A2 (PLA2G4A)-induced lysosomal membrane disruption and glycogen synthase kinase-3α/β (GSK3α/β)-mediated lysosomal dysfunction have been implicated in neurodegeneration, with a potential regulatory relationship between these two pathways. We recently identified AS1842856 (AS) as a suppressor of GSK3α/β. This study was therefore designed to investigate whether AS mitigates Alzheimer's disease (AD) progression by targeting PLA2G4A to restore lysosomal homeostasis.

METHODS: The therapeutic potential of AS was investigated in APP/PS1 mice by analyzing cognitive function, β-amyloid (Aβ) load, and lysosomal integrity, with its mechanism of action further explored in N2a-sw cells.

RESULTS: AS treatment reduced GSK3α/β expression in both APP/PS1 mice and N2a-sw cells. This suppression led to decreased PLA2G4A levels, restoration of lysosomal membrane integrity, and enhanced lysosomal degradation of Aβ. Consequently, AS administration alleviated Aβ burden and improved cognitive function in APP/PS1 mice. Moreover, AS was found to inhibit NF-κB-mediated PLA2G4A expression. Knockdown experiments further revealed that reduced GSK3β-but not GSK3α-reproduced the suppressive effect on PLA2G4A.

CONCLUSION: Our study identified the GSK3β/NF-κB/PLA2G4A signaling axis as a novel therapeutic target in AD, and AS could inhibit this axis to mitigate Aβ pathology by promoting lysosomal degradation of Aβ.}, } @article {pmid42049507, year = {2026}, author = {Morello, CM and Mnatzaganian, CL and Painter, NA}, title = {Emerging and Off-Label Uses Of Glucagon-Like Peptide-1 Receptor Agonists (GLP1-RA) and Dual GIP/GLP1-RAs.}, journal = {Journal of the American Board of Family Medicine : JABFM}, volume = {39}, number = {1}, pages = {}, pmid = {42049507}, issn = {1558-7118}, mesh = {Humans ; *Glucagon-Like Peptide-1 Receptor Agonists ; *Diabetes Mellitus, Type 2/drug therapy ; *Off-Label Use ; *Obesity/drug therapy ; *Gastric Inhibitory Polypeptide/therapeutic use ; *Hypoglycemic Agents/therapeutic use ; }, abstract = {BACKGROUND: Glucagon-like peptide-1 receptor agonists (GLP1-RAs) and the glucagon-dependent insulinotropic polypeptide (GIP)/GLP1-RA are approved for type 2 diabetes (T2D) and obesity given their profound impact on glycemic weight management. Additional indications include reducing cardiovascular disease risk and progression of chronic kidney disease (CKD) in T2D as well as obstructive sleep apnea in patients with obesity. These enhanced effects are likely due to their pleiotropic effects, leading to decreased inflammation and other benefits. This review explored emerging evidence for uses of GLP1-RAs and GIP/GLP1-RA that have been researched but not yet approved. Clinicians may use this information to guide treatment decisions.

REVIEW PROCESS: PubMed and Embase literature searches were conducted using Medical Subject Heading terms. Studies referencing GLP1-RAs and GIP/GLP1-RA were included if they were published in approximately the last decade, included adults, and were either a randomized controlled trial, meta-analysis, or observational study. Of 319 articles reviewed, 27 met inclusion criteria.

EMERGING AND COMPELLING USES: Initial positive impacts have been noted for the following conditions: liver disease/liver transplant, CKD/kidney transplant, Alzheimer's disease, Parkinson's disease, substance use disorders, osteoarthritis, rheumatoid arthritis, psoriasis, COVID-19 virus, asthma, chronic obstructive pulmonary disorder, polycystic ovarian syndrome, and short bowel syndrome.

CONSIDERATIONS: Large randomized controlled trials may lead to approvals of these conditions and are encouraged. Safety and adverse effects of these medications must be assessed when initiating or modifying doses.

CONCLUSION: GLP1-RAs and GIP/GLP1-RA have demonstrated early benefits to several conditions beyond their current approved indications. Clinicians can use this information to determine treatment options for patients, particularly in those with T2D, cardiovascular disease, and/or obesity.}, } @article {pmid42050692, year = {2026}, author = {Rahbek, MT and Kildegaard, H and Hallas, J and Ernst, MT and Lund, LC}, title = {Acetylcholinesterase inhibitors and the risk of delirium - a Danish nationwide register-based cohort study.}, journal = {Alzheimer's research & therapy}, volume = {18}, number = {1}, pages = {}, pmid = {42050692}, issn = {1758-9193}, mesh = {Humans ; *Delirium/epidemiology ; Denmark/epidemiology ; Female ; *Cholinesterase Inhibitors/therapeutic use ; Male ; Registries ; Aged ; Aged, 80 and over ; Cohort Studies ; *Dementia/drug therapy/epidemiology ; Middle Aged ; Incidence ; Risk Factors ; }, abstract = {BACKGROUND: Delirium is frequent in people with dementia and is linked to adverse outcomes. Disturbed cholinergic neurotransmission is implicated in its pathophysiology. We examined whether continuous use of acetylcholinesterase inhibitors (AChEIs) is associated with a reduced risk of incident delirium in patients with dementia. METHODS: Using Danish nationwide registries (2005–2024), we identified individuals ≥ 50 years initiating AChEIs. Continuous users (second prescription within 90 days) were compared with early discontinuers. Follow-up started 90 days after initiation and continued for up to 3 years. The outcome was a hospital discharge diagnosis of delirium (ICD-10 F05). Confounding was addressed using high-dimensional propensity score (hdPS) fine-stratification weighting, and Cox regression yielded hazard ratios (HRs) with 95% confidence intervals (CIs). RESULTS: Among 45,651 patients, 311 delirium events occurred among continuous users and 84 among early discontinuers, corresponding to incidence rates of 66 and 112 events per 10,000 person-years, respectively. The hdPS-weighted HR for delirium was 0.72 (95% CI 0.54–0.96). Results were consistent across sensitivity analyses and in patients with Alzheimer’s disease HR 0.68 (95% CI 0.48–0.96). A negative control outcome showed no association. CONCLUSIONS: Continuous AChEI treatment was associated with a lower risk of delirium. Findings support a potential benefit of maintaining therapy in routine dementia care, and possibly even in patients with minor intolerance to acetylcholinesterase inhibitors.}, } @article {pmid42051019, year = {2026}, author = {Hacımüftüoğlu, A and Saraçoğlu, N and Saffour, S and Abad, N and Kesgun, Y and Zegheb, N and Gundeger, E and Yeşilyurt, F and Ataş, MN and Bati-Ayaz, G and Altunlu, Ö and Çınar, B and Yörük, MA and Okkay, U and Özkaraca, M and Ateş, O and Taghizadehghalehjoughi, A and Lafzi, F and Türkez, H}, title = {Multi-Target Neuroprotective Compound Exhibits EAAT2-Modulating and Alzheimer's Pathology-Attenuating Effects in In Vitro and In Vivo Models.}, journal = {ACS chemical neuroscience}, volume = {17}, number = {10}, pages = {1919-1944}, pmid = {42051019}, issn = {1948-7193}, mesh = {Animals ; *Neuroprotective Agents/pharmacology ; *Alzheimer Disease/drug therapy/pathology/metabolism ; *Excitatory Amino Acid Transporter 2/metabolism ; Hippocampus/drug effects/metabolism/pathology ; Astrocytes/drug effects/metabolism ; Neurons/drug effects/metabolism/pathology ; Rats ; Glutamic Acid/metabolism ; Cells, Cultured ; Cell Survival/drug effects ; Disease Models, Animal ; Rats, Sprague-Dawley ; Female ; Donepezil ; }, abstract = {Alzheimer's disease (AD) is a debilitating neurodegenerative disorder characterized by cognitive decline and memory loss. Current treatments offer limited efficacy, necessitating the development of innovative multitarget therapeutic strategies. Here, we present N[3],N[5]-bis(2-(5-methoxy-1H-indol-3-yl)ethyl)-2,6-dimethyl-4-(2-nitrophenyl)pyridine-3,5-dicarboxamide (HCM-01), a novel compound developed to target multiple neurodegenerative pathways implicated in AD. In vitro assays included MTT-based cell viability analyses performed in two complementary experimental settings: primary neuronal cultures and astrocyte-based in vitro cell culture models exposed to glutamate. In primary hippocampal neuronal cultures, glutamate exposure induced a statistically significant reduction in cell viability compared with vehicle-treated controls, consistent with glutamate-induced excitotoxicity. Under these conditions, HCM-01 treatment resulted in a statistically significant improvement in neuronal viability, showing a greater protective effect compared with donepezil and memantine. In contrast, in astrocyte-based in vitro cultures, the applied glutamate concentration did not induce overt cytotoxicity, in line with the intrinsic neuroprotective and glutamate-buffering role of astrocytes. Accordingly, astrocytic experiments were designed to assess functional modulation of glutamate-handling mechanisms rather than cell survival. Western blot analysis in C8-D1A astrocytic cells demonstrated increased expression of excitatory amino acid transporter 2 (EAAT2) following HCM-01 treatment compared with control and reference drug-treated groups, suggesting modulation of astrocyte-mediated glutamate homeostasis. In parallel, redox analyses revealed that HCM-01 improved oxidative/antioxidative balance, as evidenced by increased total antioxidant capacity (TAC) and reduced total oxidant status (TOS), supporting an indirect antioxidant contribution to its functional effects. In vivo behavioral assessment of HCM-01 in a streptozotocin (STZ)-induced Alzheimer's model in female Sprague-Dawley rats demonstrated that administration of HCM-01 at doses of 50 mg/kg orally (oral, P.O. and intraperitoneal, I.P.) and 100 mg/kg (P.O.), significantly improved cognitive and memory functions in the passive avoidance (PA), Morris water maze (MWM), and locomotor activity tests. Moreover, histopathological and immunohistochemical analyses of different hippocampal regions revealed reduced neuronal damage, attenuation of tau pathology, antiamyloidogenic effect, and restoration of cholinergic function. Complementary in silico studies, including molecular docking, molecular dynamics simulations (MDS), and free energy calculations, suggested potential interactions of HCM-01 with the allosteric site of EAAT2. Taken together, these findings suggest that HCM-01 exerts neuroprotective effects against glutamate-induced excitotoxicity in primary hippocampal neurons while additionally modulating glutamatergic homeostasis and redox balance through functional mechanisms in astrocyte-based models, supporting its relevance as a multitarget preclinical candidate for early stage AD mechanisms.}, } @article {pmid42051092, year = {2026}, author = {Sun, Y and Chan, TW and Liao, W and Li, M and Mao, X and Feng, Y and Rong, J and Zhao, J}, title = {In Silico Design and Evaluation of Diosmin Analogs for Targeting Peroxisome Proliferator-activated Receptor γ (PPAR-γ) Against Alzheimer's Disease.}, journal = {Current neuropharmacology}, volume = {}, number = {}, pages = {}, doi = {10.2174/011570159X453424260218065734}, pmid = {42051092}, issn = {1875-6190}, abstract = {Alzheimer's disease (AD) is a neurodegenerative disorder characterized by progressively declining cognitive abilities and memory impairment. This disease increasingly challenges the quality of life and health of the elderly population, underscoring the need for effective therapeutic strategies. The existing anti-AD medications are designed to improve symptoms but not to cure the disease. Novel drugs are urgently needed to target the specific mechanisms that mediate disease progression. Peroxisome proliferator-activated receptor gamma (PPAR-γ) is a potential target for the development of anti-AD therapies. Through virtual screening of natural PPAR-γ ligands, the flavonoid diosmin was found to bind to PPAR-γ with high potency. This study exploited diosmin as a lead compound to design a panel of diosmin analogs via chemical modifications for better biological efficacy in targeting PPAR-γ. These diosmin analogs were evaluated using in silico approaches, including molecular docking, absorption, distribution, metabolism, and excretion (ADME) predictions, and molecular dynamics (MD) simulations. As a result, molecular docking identified 12 di-osmin analogs with better binding affinity to PPAR-γ compared with diosmin. ADME and MD analyses demonstrated that S1DhP1 exhibited lower binding free energy, better water solubility, and stability than diosmin. Thus, this study provides important information via in silico approaches and hypotheses, suggesting S1DhP1 as a promising PPAR-γ agonist for the treatment of AD that warrants further experimental validation.}, } @article {pmid42051629, year = {2026}, author = {Cullins, MJ and Converse, AK and Rowe, LM and Hoerst, AG and Hibbard, WK and Russell, JA and Connor, NP and Ciucci, MR}, title = {Oropharyngeal dysphagia and amyloid beta pathology in the TgF344-AD rat model of Alzheimer's disease.}, journal = {Frontiers in behavioral neuroscience}, volume = {20}, number = {}, pages = {1812480}, pmid = {42051629}, issn = {1662-5153}, support = {R01 AG085564/AG/NIA NIH HHS/United States ; }, abstract = {INTRODUCTION: Dysphagia is a major consequence of Alzheimer's disease (AD) that is understudied and undertreated. Neuropathology in AD occurs early in the disease progression, but little is known about pathologies underlying functional swallowing changes; this knowledge gap is a barrier to developing effective treatment. We hypothesized that an established AD rat model (TgF344-AD) would demonstrate significant deficits in oromotor/swallowing function versus Wild Type (WT) with corresponding amyloid beta pathology in brain structures critical to swallowing.

METHODS: Nine male TgF344-AD and 6 Wildtype Fisher 344 rats underwent deglutition assessments and PET imaging using the radiotracer [[11]C]PiB to assess brain and brainstem amyloid beta (Aβ) pathology at 11 months of age-a time point corresponding to early-middle stage AD progression. A priori brain regions of interest (ROIs) included those commonly associated with Aβ pathology and more specific swallowing associated structures such as brainstem nuclei and cortical motor areas. Deglutition was assessed using a videofluoroscopic swallow study and a pasta biting task.

RESULTS: Significantly increased levels of Aβ in the AD group were found in regions critical to swallowing motor control including the secondary motor area, thalamus, nucleus ambiguus, and hypoglossal nuclei. The AD group demonstrated significant changes in aerodigestive coordination, including delayed swallow onset, increased apnea duration, and increased frequency of aberrant post-swallow inhale pattern that was correlated with nucleus ambiguus Aβ levels. The AD group also exhibited altered oral processing including reduced bolus size and mastication rate.

CONCLUSION: The TgF344-AD rat model of Alzheimer's exhibits robust changes in oral processing and respiratory-swallow coordination that parallel clinical AD dysphagia. At this early-middle stage timepoint, Aβ pathology is primarily impacting cerebral swallowing networks as well as the nucleus ambiguus and hypoglossal nuclei in the brainstem. Our finding of increased Aβ in the nucleus ambiguus warrants further study as this motor nucleus plays a role in swallowing, respiration, and vocalization-all factors that are known to be impacted by AD in the clinical population.}, } @article {pmid42052145, year = {2026}, author = {Tariot, PN and Chumki, SR and Wang, D and Such, P and Palma, AM and Zhang, Z and Montano, CB}, title = {Brexpiprazole for Agitation in Patients with Alzheimer's Dementia with and without Co-Occurring Psychosis: Post Hoc Analysis of Short- and Long-Term Trials.}, journal = {Neuropsychiatric disease and treatment}, volume = {22}, number = {}, pages = {586701}, pmid = {42052145}, issn = {1176-6328}, abstract = {PURPOSE: Patients with Alzheimer's dementia may experience co-occurring agitation and psychosis symptoms. This exploratory post hoc analysis aimed to analyze the efficacy and safety of brexpiprazole for agitation in patients with Alzheimer's dementia with and without co-occurring psychosis.

PARTICIPANTS AND METHODS: Data were pooled from two Phase 3, 12-week, randomized, double-blind, placebo-controlled, fixed-dose trials of brexpiprazole versus placebo in participants with Alzheimer's dementia and agitation, conducted in Europe, Russia, and the US (ClinicalTrials.gov identifiers: NCT01862640, NCT03548584). Post hoc, participants were stratified into subgroups with or without co-occurring psychosis at baseline, defined as a score ≥4 on the Neuropsychiatric Inventory Delusions domain, Hallucinations domain, or both. Efficacy was assessed by the Cohen-Mansfield Agitation Inventory Total score. Safety was assessed by treatment-emergent adverse events (TEAEs).

RESULTS: 142/607 participants (23.4%) had co-occurring psychosis at baseline. Brexpiprazole 2 or 3 mg/day was associated with greater improvement in agitation compared with placebo in participants with co-occurring psychosis (least squares mean difference at Week 12, -9.18 [95% confidence interval -15.2 to -3.12]; P=0.004; Cohen's d=0.52) and in participants without co-occurring psychosis (-4.22 [-6.91 to -1.54]; P=0.002; Cohen's d=0.29). In participants with co-occurring psychosis, for brexpiprazole and placebo respectively, 52.9% and 40.0% had TEAEs, and 3.4% and 9.1% discontinued due to TEAEs. No deaths occurred among participants with co-occurring psychosis. In participants without co-occurring psychosis, for brexpiprazole and placebo respectively, 49.3% and 38.2% had TEAEs, and 5.5% and 2.6% discontinued due to TEAEs. Two participants without co-occurring psychosis died; neither death was considered related to brexpiprazole treatment.

CONCLUSION: In this post hoc analysis, brexpiprazole improved agitation and was generally well tolerated in patients with Alzheimer's dementia with and without co-occurring psychosis. These exploratory data suggest that brexpiprazole may be of value to patients with Alzheimer's dementia who present with agitation and psychosis in clinical practice.}, } @article {pmid42052655, year = {2026}, author = {Zhao, R and Guo, M and Yang, F and Yan, Y and Tian, D and Deng, L and Wang, Q and Xie, M}, title = {A microglia membrane biomimetic platinum-based MOF-loaded quercetin nanodrug delivery system for the treatment of Alzheimer's disease.}, journal = {Journal of materials chemistry. B}, volume = {14}, number = {19}, pages = {6034-6049}, doi = {10.1039/d6tb00201c}, pmid = {42052655}, issn = {2050-7518}, mesh = {*Alzheimer Disease/drug therapy/metabolism ; *Microglia/drug effects/metabolism ; *Quercetin/chemistry/pharmacology ; *Platinum/chemistry ; Animals ; *Biomimetic Materials/chemistry ; *Metal-Organic Frameworks/chemistry ; Amyloid beta-Peptides/metabolism/antagonists & inhibitors ; Humans ; Reactive Oxygen Species/metabolism ; Mice ; Antioxidants/chemistry/pharmacology ; Particle Size ; Nanoparticles/chemistry ; }, abstract = {The aberrant deposition of β-amyloid (Aβ) is a central pathological hallmark of Alzheimer's disease (AD), triggering oxidative stress, metal ion dyshomeostasis, and excessive microglial activation in a self-perpetuating pathological cascade. To address these interconnected processes, a platinum-based metal-organic framework (Pt-MOF) with intrinsic antioxidant enzyme-mimetic activity was constructed and loaded with quercetin (Qu) to regulate microglial dysfunction. To enhance blood-brain barrier (BBB) penetration and inflammation-targeting capability, Pt-MOF/Qu was further camouflaged with microglial cell membranes (BV2), yielding Pt-MOF/Qu/BV2 nanoparticles. In vitro studies demonstrated that Pt-MOF/Qu/BV2 efficiently scavenged reactive oxygen species and effectively chelated Cu[2+] ions via surface functional groups, thereby inhibiting Aβ aggregation and promoting the disassembly of preformed Aβ aggregates. In addition, the Pt-MOF enabled efficient loading and controlled release of Qu, which significantly restored mitochondrial membrane potential and alleviated microglial over-activation. The BV2 membrane coating markedly improved the biocompatibility and BBB translocation efficiency of the nanoplatform. Furthermore, Pt-MOF/Qu/BV2 significantly reduced reactive oxygen species (ROS) in vivo and Aβ brain plaque accumulation in the head region, alleviated neurotoxicity and improved the behavioral phenotype in the C. elegans AD model. Overall, this biomimetic multifunctional MOF-based nanoplatform represents a promising multi-target therapeutic strategy for AD.}, } @article {pmid42052761, year = {2026}, author = {Guo, Y and Zhang, Z and Chen, B and Liu, H and Wei, F and Liu, X and Guo, Z}, title = {Functional Connectivity Alterations in the Cholinergic Neural Circuits of Patients With Alzheimer's Disease: A Donepezil Intervention Study Using Resting-State Functional Magnetic Resonance Imaging.}, journal = {Journal of integrative neuroscience}, volume = {25}, number = {4}, pages = {50039}, doi = {10.31083/JIN50039}, pmid = {42052761}, issn = {0219-6352}, support = {2017KY109//General Project of the Department of Science and Technology of Zhejiang Province/ ; 2020358406//General Project of the Department of Science and Technology of Zhejiang Province/ ; 2018KY031//General Project of the Department of Science and Technology of Zhejiang Province/ ; 2024KY873//General Project of the Department of Science and Technology of Zhejiang Province/ ; [2024]90662//National Leading Medical Specialty Development Project-Department of Geriatrics, Tongde Hospital of Zhejiang Province/ ; [2024]10//Zhejiang Provincial Alliance of Traditional Chinese Medicine Advantage Specialty for Geriatric Diseases/ ; }, mesh = {Humans ; *Donepezil/pharmacology/administration & dosage ; *Alzheimer Disease/drug therapy/diagnostic imaging/physiopathology ; Female ; Magnetic Resonance Imaging ; Male ; *Cholinesterase Inhibitors/pharmacology/administration & dosage ; Aged ; *Nerve Net/diagnostic imaging/drug effects/physiopathology ; *Connectome ; *Nootropic Agents/pharmacology/administration & dosage ; Longitudinal Studies ; *Basal Forebrain/diagnostic imaging/drug effects/physiopathology ; *Cerebellum/diagnostic imaging/drug effects/physiopathology ; Middle Aged ; }, abstract = {BACKGROUND: Although donepezil alleviates Alzheimer's disease (AD) symptoms by raising acetylcholine levels, its impact on cholinergic pathways remains unclear. In this longitudinal, resting-state functional magnetic resonance imaging (rs-fMRI) study, we investigated donepezil-induced changes in cholinergic pathway networks in AD.

METHODS: AD patients and healthy controls (HCs) were enrolled. AD patients received 24 weeks of donepezil treatment. Cognitive and emotional symptoms were assessed using the Mini-Mental State Examination (MMSE), Cornell Scale for Depression in Dementia (CSDD), and Neuropsychiatric Inventory (NPI) pre- and post-treatment. rs-fMRI was used to examine basal forebrain (BF) functional connectivity.

RESULTS: Sixteen AD patients and 16 HCs completed the study. Post-treatment MMSE scores improved, and NPI and CSDD scores decreased. Reduced BF functional connectivity in the left cerebellar lobule VI, post-treatment, was revealed by rs-fMRI. Compared with HCs, post-treatment AD patients showed lower BF functional connectivity in the right postcentral gyrus (PoG); pre-treatment patients exhibited higher BF functional connectivity in the left cerebellar lobule VI. Right PoG functional connectivity was negatively correlated with disease duration pre-treatment and positively correlated with MMSE post-treatment.

CONCLUSIONS: Donepezil improved clinical symptoms in AD by modulating the BF-PoG cholinergic pathway.}, } @article {pmid42052762, year = {2026}, author = {Balakrishnan, J and Kannan, S and Shanmugam, K and Sugasini, D}, title = {Targeting Lipid Metabolism in Alzheimer's Disease: Emerging Insights and Future Directions.}, journal = {Journal of integrative neuroscience}, volume = {25}, number = {4}, pages = {48436}, doi = {10.31083/JIN48436}, pmid = {42052762}, issn = {0219-6352}, mesh = {Humans ; *Alzheimer Disease/metabolism/genetics/drug therapy ; *Lipid Metabolism/physiology ; Animals ; *Brain/metabolism ; *Lipidomics ; }, abstract = {Alzheimer's disease (AD) is a multifactorial neurodegenerative disease that is conventionally characterized by amyloid-β and tau pathology. There is growing evidence, however, that lipid metabolic disturbances are part of the biology of the disease, and not a secondary phenomenon. Lipid signaling controls membrane organization, amyloid precursor protein, tau phosphorylation, mitochondrial energetics, neuroinflammatory signaling, and synaptic stability. The accumulating genetic evidence, including risk variants in the APOE (apolipoprotein E), ABCA1 (ATP-binding cassette subfamily A member 1), ABCA7 (ATP-binding cassette subfamily A member 7), and TREM2 (Triggering receptor expressed on myeloid cells 2) genes, further makes lipid transport and lipid-sensing pathways central to late-onset AD vulnerability. Recent developments in lipidomics based on mass spectrometry have revealed concerted changes in phospholipids, sphingolipids, sterols, and oxidized lipid derivatives in brain tissue and peripheral biofluids. Instead of single abnormalities, directional metabolic imbalance is indicated by pathway changes, including decreased sphingomyelin-to-ceramide ratios and decreased polyunsaturated phospholipids. Co-analysis of lipidomic, genomic, and proteomic data has shown the existence of metabolically different subgroups, which aids genotype stratified risk evaluation and the lipid responder phenotype concept. Protein-centered therapies are complemented by therapeutic strategies that focus on lipid homeostasis, such as the regulation of cholesterol efflux, sphingolipid metabolism, pro-resolving lipid mediators, and metabolic reprogramming. There is also emerging evidence that implicates peroxisomal dysfunction and compromised glymphatic clearance in interfering with lipid balance. Although this field of research has come a long way, the issues of proving causality, standardizing lipidomic techniques, and converting pathway signatures into clinically useful resources persist. Restructuring AD as a lipid network instability disorder offers a systems level model of earlier diagnosis and targeted treatment.}, } @article {pmid42052769, year = {2026}, author = {Wang, Z and Pan, Y and Shu, M and Zou, L}, title = {The Lysosomal-Associated Protein Transmembrane Family and Neurological Disorders: Therapeutic Potential and Future Research Directions.}, journal = {Journal of integrative neuroscience}, volume = {25}, number = {4}, pages = {47903}, doi = {10.31083/JIN47903}, pmid = {42052769}, issn = {0219-6352}, support = {82201590//National Natural Science Foundation of China/ ; 2022CFB721//Natural Science Foundation of Hubei Province/ ; ZNJC202536//The Translational Medicine, the Interdisciplinary Research Joint Fund of Zhongnan Hospital of Wuhan University/ ; CXPY202535//Science and Technology Innovation Cultivation Fund of Zhongnan Hospital of Wuhan University/ ; }, mesh = {Humans ; Animals ; *Membrane Proteins/metabolism ; *Nervous System Diseases/metabolism/therapy ; *Lysosomes/metabolism ; *Neurodegenerative Diseases/metabolism ; }, abstract = {Lysosomal-associated protein transmembrane (LAPTM) family members-including LAPTM4A, LAPTM4B, and LAPTM5-are key regulators of lysosomal integrity, autophagy-lysosome flux, lipid metabolism, and immune responses. Dysregulation of LAPTM proteins contributes to neurological disorders such as Alzheimer's disease, Parkinson's disease, ischemic stroke, and gliomas, affecting neuronal survival, glial homeostasis, neuroinflammation, and tumor progression. In this review, we summarize recent insights into the structural features and molecular mechanisms of LAPTM proteins in the nervous system and highlight their therapeutic potential in promoting protein aggregate clearance, mitigating oxidative stress, regulating microglial polarization, and enhancing tumor immunotherapy. Future research integrating gene therapy, small-molecule modulators, multi-omics profiling, and advanced delivery platforms may enable translation of LAPTM-targeted interventions into clinical practice, offering new avenues for diagnosis, prognosis, and treatment of neurological diseases.}, } @article {pmid42053112, year = {2026}, author = {Dharshan, SS and Madesh, S and Ramamurthy, K and Radhakrishnan, J and Salamuthu, K and Almutairi, MH and Almutairi, BO and Namasivayam, SKR and Kumaradoss, KM and Arockiaraj, J}, title = {Combating Cadmium-Induced Neurotoxicity, Oxidative Stress, and Inflammatory Pathways Using DOPA-31, a Dioxopiperidinamide Derivative in an In Vivo Zebrafish Model.}, journal = {Journal of biochemical and molecular toxicology}, volume = {40}, number = {5}, pages = {e70872}, doi = {10.1002/jbt.70872}, pmid = {42053112}, issn = {1099-0461}, mesh = {Animals ; *Oxidative Stress/drug effects ; Zebrafish ; *Cadmium/toxicity ; *Piperidines/pharmacology ; *Inflammation/chemically induced/metabolism/drug therapy ; Disease Models, Animal ; *Neurotoxicity Syndromes/metabolism/drug therapy/pathology ; Antioxidants/pharmacology ; *Neuroprotective Agents/pharmacology ; }, abstract = {Cadmium (Cd), a prevalent environmental toxin and pollutant capable of causing neurodegenerative diseases (NDs) like Alzheimer's and Parkinson's, primarily through oxidative stress, calcium imbalance, and neuroinflammation-induced mechanisms. Cd exposure increases the level of reactive oxygen species (ROS) and disrupts neurotransmitters by lowering antioxidants, leading to neuron death. Cd exposure in zebrafish results in neurodegeneration, with motor, mental, and behavioral impairments. The efficacy of the DOPA-31 intervention at varying concentrations was evaluated through the behavioral tests, biochemical assays for antioxidant enzyme activities (SOD, CAT, GSH, MDA), and histopathological analysis. Additionally, the alterations in expression levels of inflammation (tnf-α, il-1β) and neuroprotective (bdnf, syn2a) genes were also assessed. The Cd exposure exhibited the major deficits in the key behavioral parameters (motor, anxiety, and cognitive impairment). It disrupted antioxidant enzyme activity, increased lipid peroxidation, and elevated acetyl cholinesterase (AChE) activity, leading to cholinergic dysfunction. Histopathology showed extensive neuronal damage and amyloid-like protein aggregation. DOPA-31 at a 20 µM concentration, substantially exhibited antioxidant and AChE activity by reducing oxidative stress and improving motor and cognitive functions. Molecular analysis of DOPA-31 treatment showed significant downregulation of pro-inflammatory markers and upregulation of neuroprotective factors. In addition, DOPA-31 restored behavioral changes by potentially mitigating neuronal damage and protein aggregation caused by the Cd-induced neurotoxicity. This research investigation suggests the novel drug candidate DOPA-31 as a preliminary treatment for Neurodegenerative Disorder (NDD)-like features and warrants further exploration in higher animal models to assess clinical relevance.}, } @article {pmid42053135, year = {2026}, author = {Arslan, B and Gobom, J and Simrén, J and Fahlén, H and Andreasson, U and Andrea Lessa Benedet, and Kvartsberg, H and Zetterberg, H}, title = {Real-world performance of Lumipulse G plasma p-tau217: a six-month experience of a specialized clinical neurochemistry laboratory.}, journal = {Clinical chemistry and laboratory medicine}, volume = {}, number = {}, pages = {}, pmid = {42053135}, issn = {1437-4331}, abstract = {OBJECTIVES: Plasma p-tau217 is a leading blood-based biomarker for Alzheimer's disease (AD), offering high diagnostic accuracy and potential utility for treatment eligibility and monitoring. However, real-world data on concordance between cerebrospinal fluid (CSF) Aβ42/40 and plasma p-tau217 in routine clinical laboratory settings remain limited.

METHODS: We retrospectively evaluated all plasma p-tau217 tests performed in the Clinical Neurochemistry Laboratory at Sahlgrenska University Hospital between August 2025 and March 2026. De-identified plasma p-tau217, additional blood biomarkers, and available CSF results were extracted from the laboratory information system. Concordance between plasma p-tau217 and CSF Aβ42/40 was evaluated by calculating positive and negative percent agreement, with CSF Aβ42/40 used as the reference standard. In addition, diagnostic accuracy for brain amyloid positivity was assessed using two predefined clinical cutoffs for plasma p-tau217 (<0.22 vs. >0.34 ng/L). Internal analytical performance was monitored over a six-month period using commercial quality control materials, with additional evaluation of lot-to-lot consistency for plasma p-tau217.

RESULTS: Among 1,352 plasma p-tau217 measurements, paired CSF Aβ42/40 data were available for 121 individuals. Based on plasma p-tau217 probability categories, 541 samples (40.0 %) were classified as low probability, 228 (16.9 %) as intermediate probability, and 583 (43.1 %) as high probability for amyloid pathology. Using CSF Aβ42/40 as the reference standard, plasma p-tau217 demonstrated a positive percent agreement of 84.5 % (95 % CI: 72.6-92.7 %) and a negative percent agreement of 87.5 % (95 % CI: 73.2-95.8 %). Internal quality control analyses showed good within-batch precision, with coefficients of variation below 7.3 %. Batch-dependent bias was observed in QC measurements, most notably for one batch (+14.4-18.4 %); however, subsequent QC investigations indicated that this deviation originated from the QC material rather than from assay-related performance. Lot-to-lot consistency assessment did not reveal systematic reagent lot-dependent effects during the study period.

CONCLUSIONS: Lumipulse plasma p-tau217 demonstrated stable analytical performance and consistent concordance with CSF Aβ42/40 in routine clinical practice. The observed agreement supports the feasibility of plasma p-tau217 as a supportive tool in the clinical evaluation of AD, while underscoring the need for continued quality control monitoring and prospective evaluation of assay performance.}, } @article {pmid42053700, year = {2026}, author = {Lin, C and Qi, L and Gao, X and Hu, L and Qian, B and Deng, Y and Zhou, C and Wang, C and Liu, G and Ding, Q and Lin, Z and Zhu, X and Zhang, M}, title = {Therapeutic Mechanisms of Stem Cell-Derived Exosomes for Neurological Disorders: An Overview.}, journal = {Molecular neurobiology}, volume = {63}, number = {1}, pages = {}, pmid = {42053700}, issn = {1559-1182}, support = {82271747//the National Natural Science Foundation of China/ ; 82505180//the National Natural Science Foundation of China/ ; ZY2023013//Wenzhou Major Scientific and Technological Innovation Project/ ; 2025C02081//he Zhejiang Provincial Key Research and Development Program/ ; 2025M783998//the China Postdoctoral Science Foundation/ ; }, mesh = {*Exosomes/metabolism/transplantation ; Humans ; Animals ; *Nervous System Diseases/therapy ; *Stem Cells/metabolism ; }, abstract = {The current management of neurological disorders remains largely symptomatic. In recent years, stem cell-derived exosomes have emerged as a promising alternative therapeutic strategy. This narrative review synthesizes evidence from preclinical studies investigating the mechanisms and efficacy of exosome-based therapy for neurological conditions. The included studies encompass animal models and in vitro systems. Accumulating preclinical evidence consistently supports the therapeutic potential of stem cell-derived exosomes across several neurological disorders. In Alzheimer's disease models, stem cell-derived exosomes reduce β-amyloid plaque deposition and attenuate neuroinflammation. For Parkinson's disease, they exert neuroprotective effects on dopaminergic neurons. They also inhibit α-synuclein aggregation. In ischemic stroke and spinal cord injury, stem cell-derived exosomes promote functional recovery through multiple mechanisms. These include suppressing ferroptosis, promoting angiogenesis, and stimulating axonal regeneration. Improved delivery strategies, such as intranasal administration and hydrogel encapsulation, have further enhanced brain targeting and treatment durability. Despite these promising preclinical findings, several challenges remain. A primary issue is the lack of standardized preparation protocols. Significant uncertainties also exist regarding long-term safety. Furthermore, pathways for clinical translation are still unclear. Future research should prioritize elucidating the underlying mechanisms of exosome therapy. The refinement of targeted delivery systems is equally important. Finally, advancing rigorously designed clinical trials is crucial to facilitate the translation of these therapies into clinical practice.}, } @article {pmid42054332, year = {2026}, author = {Kolmakova, KA and Lobzin, VY and Emelin, AY}, title = {[Sleep disorders in Alzheimer's disease].}, journal = {Zhurnal nevrologii i psikhiatrii imeni S.S. Korsakova}, volume = {126}, number = {4. Vyp. 2}, pages = {56-62}, doi = {10.17116/jnevro202612604256}, pmid = {42054332}, issn = {1997-7298}, mesh = {Humans ; *Alzheimer Disease/complications/physiopathology ; *Sleep Wake Disorders/therapy/etiology/physiopathology ; Memantine/therapeutic use ; Polysomnography ; }, abstract = {This article investigates the progression of sleep disturbances in Alzheimer's disease (AD) and the mechanisms by which these disturbances may accelerate neurodegeneration. Key electrophysiological patterns identified through polysomnography in patients with AD and sleep disorders are analyzed. Therapeutic interventions are reviewed, with non-pharmacological and pharmacological approaches considered separately. The roles of cognitive behavioural therapy, relaxation techniques, and optimization of sleep conditions are emphasized. Current pharmacological treatment options are discussed, highlighting the need for careful drug selection due to the high risk of adverse effects and the potential dangers of certain medications, such as benzodiazepines and cyclopyrroles, in elderly patients with cognitive impairment. The use of memantine as a foundational therapy is given particular attention, as it may improve both cognitive function and sleep quality.}, } @article {pmid42054333, year = {2026}, author = {Bogolepova, AN and Burd, SG and Lebedeva, AV and Rubleva, YV and Kovalenko, EA and Machnovich, EV and Osinovskaya, NA and Pantina, NV and Kovaleva, II and Bokitko, TA and Alexeeva, GA}, title = {[Myoclonus in Alzheimer's disease].}, journal = {Zhurnal nevrologii i psikhiatrii imeni S.S. Korsakova}, volume = {126}, number = {4. Vyp. 2}, pages = {63-69}, doi = {10.17116/jnevro202612604263}, pmid = {42054333}, issn = {1997-7298}, mesh = {Humans ; *Alzheimer Disease/complications ; *Myoclonus/diagnosis/etiology/physiopathology/drug therapy ; Electroencephalography ; Diagnosis, Differential ; Male ; Female ; }, abstract = {Neurodegenerative diseases are often presented with myoclonus, sudden, short-term, involuntary muscle contractions («flinching»). According to the literature, myoclonus in Alzheimer's disease (AD) can occur up to 40-50% in cases of disease with early onset and in atypical forms. Importantly, epileptic myoclonus may indicate a risk of seizures with loss of consciousness, convulsions, and epileptiform activity, which may lead to more rapid progression of cognitive deficits. Diagnosis of myoclonus is essential for timely treatment and improving the quality of life of AD patients. The paper describes the main features of myoclonus in AD, the possibility of using additional examination methods, in particular video-electroencephalographic (video-EEG) monitoring for differential diagnosis and etiology clarification, and also presents a clinical case of a patient with AD and epileptic and non-epileptic myoclonus.}, } @article {pmid42054337, year = {2026}, author = {Selezneva, ND and Roshchina, IF and Gavrilova, SI}, title = {[Efficacy of choline alfoscerate treatment for subjective cognitive impairment in first-degree relatives of patients with Alzheimer's disease: Results of a comparative 5-year study].}, journal = {Zhurnal nevrologii i psikhiatrii imeni S.S. Korsakova}, volume = {126}, number = {4. Vyp. 2}, pages = {92-99}, doi = {10.17116/jnevro202612604292}, pmid = {42054337}, issn = {1997-7298}, mesh = {Humans ; *Alzheimer Disease/drug therapy/genetics/psychology/complications ; Female ; Male ; *Glycerylphosphorylcholine/therapeutic use ; *Cognitive Dysfunction/drug therapy ; Aged ; Treatment Outcome ; Neuropsychological Tests ; Middle Aged ; Family ; Follow-Up Studies ; Prospective Studies ; }, abstract = {OBJECTIVE: To evaluate the five-year change of cognitive functioning in first-degree relatives of patients with Alzheimer's disease (AD) with signs of subjective cognitive impairment (SCI) treated with choline alfoscerate and untreated.

MATERIAL AND METHODS: The study included 122 subjects: 56 (45.9%) in the treatment group and 66 (54.1%) in the control group. Relatives from the treatment group received 4 courses of three-month oral choline alfoscerate therapy (400 mg 3 times a day) every 1.5 years. The study used prospective clinical, psychometric, neuropsychological, and statistical methods. Evaluation included 9 assessment visits using a battery of 10 cognitive scales and tests: in the treatment group, before and after each course of therapy, with a follow-up assessment 3 months after the end of therapy. Assessment visits in the control group were conducted using a similar methodology at the same time points.

RESULTS: On the Clinical Global Impression (CGI-I) scale, varying improvement was observed in the treatment group after each course of therapy and at follow-up examination. By the end of treatment, 96.8% of the subjects reported a marked and moderate improvement. In the control group, after 57 months, deterioration in cognitive functioning was identified at the 39[th], 57[th], and 60[th] months. SCI was converted to mild cognitive impairment syndrome (MCI) in 9.1, 15.2, and 16.7% of cases, respectively. In the treatment group, all psychometric scales and tests showed a significant improvement compared to all baseline mean group indicators after each course of therapy, and at follow-up examination in 4 out of 10 tests. In the control group, significant deterioration in scores on all scales and tests was observed from Month 39 of follow-up.

CONCLUSION: Repeated courses every three months of oral choline alfoscerate therapy for five years led in the vast majority of observations to improved cognitive functioning in persons from the treatment group at increased risk for developing AD, while untreated relatives had decreasing cognitive functioning, including a 16.7% rate of transformation of SCI into MCI.}, } @article {pmid42054665, year = {2026}, author = {Liu, J and Wang, X and Shieu, B and Garcia, DD and Vondenberger, A and Xu, J and Zhang, Y and Monjur, M and Wang, W and Nirjon, S and Svatek, R and Gonzales, M and Patel, N and Song, L}, title = {An Internet of Things-Based Audio and Radio Connected System Supporting Older Adults With Physical and Cognitive Health Challenges: Qualitative Stakeholder-Informed Design Study.}, journal = {JMIR formative research}, volume = {10}, number = {}, pages = {e76341}, pmid = {42054665}, issn = {2561-326X}, mesh = {Humans ; Male ; Female ; Aged ; Qualitative Research ; *Internet of Things ; Stakeholder Participation/psychology ; Middle Aged ; Aged, 80 and over ; Digital Health ; Caregivers/psychology ; Chronic Disease/psychology ; }, abstract = {BACKGROUND: Older adults managing chronic illnesses, such as cancer and Alzheimer disease and related dementias (ADRD), often experience significant physical or cognitive impairments that hinder daily activities and increase caregiver burden. Smart Internet of Things (IoT) technologies offer promising solutions by enabling passive monitoring, timely reminders, and personalized support at home. However, these technologies must be carefully tailored to accommodate users' individualized needs and preferences.

OBJECTIVE: This formative qualitative study aimed to explore stakeholder perspectives, including patients, caregivers, health care providers, and technical experts, on the use of smart home-based IoT systems to support chronic illness management. The goal was to inform the early development of the audio and radio connected (AURA) system, an IoT prototype integrating Wi-Fi sensing, wearable trackers, and voice-assistive features.

METHODS: Semistructured interviews were conducted with 6 patients who underwent postostomy creation for colorectal or bladder cancer treatment and 5 patients with ADRD and their caregivers. Input from additional stakeholders, including 2 health care providers, 2 community health workers, and 2 computer scientists, was also included in the report. Stakeholders reviewed a demonstration video depicting the conceptual features of the AURA system. Interviews explored stakeholders' needs and preferences for using such systems. Thematic analysis was guided by the extended Unified Theory of Acceptance and Use of Technology 2 (UTAUT2) framework, with 5 adapted constructs: performance expectancy, effort expectancy, social influence, facilitating conditions, and hedonic motivation and habit.

RESULTS: Stakeholders identified distinct yet complementary needs across populations. Patients with cancer emphasized physical health monitoring, integration with health care systems, and customization; ADRD stakeholders prioritized routine support, emotional engagement, and simplicity; caregivers and clinicians emerged as key influencers of adoption. Barriers included privacy concerns, technology literacy, and fatigue, while facilitators included perceived caregiving support, streamlined interfaces, and electronic health record integration. Patients with cancer focused on motivational cues for physical activity, while emotional engagement and habit were more prominent for ADRD users.

CONCLUSIONS: Stakeholder insights underscore the importance of designing adaptable, user-centered IoT systems that reflect the varied capabilities and care needs of older adults with chronic illnesses. These findings informed the design of the AURA prototype and highlighted theoretical considerations for technology acceptance in health care. Future work will test AURA in real-world settings to evaluate usability, acceptability, and clinical relevance.}, } @article {pmid42054867, year = {2026}, author = {Coles, M and Rosa Porto, R and Chesworth, R and Steiner-Lim, GZ and Karl, T}, title = {Combining cannabidiol and delta-9-tetrahydrocannabinol at a 50:3 ratio - a new therapeutic strategy for APPSwe/PS1ΔE9 transgenic mice?.}, journal = {Neurobiology of aging}, volume = {164}, number = {}, pages = {79-90}, doi = {10.1016/j.neurobiolaging.2026.04.003}, pmid = {42054867}, issn = {1558-1497}, mesh = {Animals ; *Cannabidiol/administration & dosage/pharmacology ; *Dronabinol/administration & dosage ; *Alzheimer Disease/drug therapy/psychology/genetics ; Mice, Transgenic ; Male ; Female ; Disease Models, Animal ; Drug Therapy, Combination ; Amyloid beta-Peptides/metabolism ; Amyloid beta-Protein Precursor ; tau Proteins/metabolism ; Reflex, Startle/drug effects ; Spatial Memory/drug effects ; Behavior, Animal/drug effects ; }, abstract = {Preclinical evidence suggests that cannabidiol (CBD) can ameliorate Alzheimer's disease (AD)-related pathologies, including amyloid-β aggregation and tau hyperphosphorylation, and can reverse and prevent cognitive decline in AD rodent models. Interestingly, low-dose delta-9-tetrahydrocannabinol (THC) can improve cognition in aged mice, and 1:1 CBD+THC appears to exhibit a greater therapeutic profile in AD mouse models than either phytocannabinoid alone. Here, the potential of chronic treatment with 50 mg/kg bodyweight CBD combined with 3 mg/kg THC to reverse the behavioural deficits of adult APPSwe/PS1ΔE9 (APP/PS1) AD transgenic mice was evaluated. 14-month-old male and female transgenic mice and their wild type-like littermates were used. They were treated via daily intraperitoneal injection with CBD+THC treatment (or vehicle) for 3 weeks prior to and throughout behavioural assessment. CBD+THC significantly improved the initial localisation of the reward zone during a spatial memory probe trial in APP/PS1 mice and restored the increased acoustic startle response of APP/PS1 females. APP/PS1 mice had deficient object recognition memory and impaired spatial learning, neither of which were restored following combined cannabinoid treatment. Interestingly, CBD+THC impaired social recognition of APP/PS1 males. Treatment reduced sensorimotor gating in females. In males, treatment decreased risk assessment behaviour, and reduced acoustic startle. CBD+THC treatment had mild therapeutic properties but also off-target effects, suggesting that CBD+THC might be less preferable than CBD alone in a mouse model of advanced AD. Further research into alternate cannabinoid dosage and dose ratios is required to elucidate the potential of cannabinoid combination therapies for AD more comprehensively.}, } @article {pmid42055092, year = {2026}, author = {Høilund-Carlsen, PF and Alavi, A and Andalib, S and Castellani, RJ and Costa, T and de Girolamo, G and Espay, AJ and Neve, RL and Perry, G and Revheim, ME and Robakis, NK and Sensi, SL and Vissel, B and Barrio, JR}, title = {Serious side effects of Alzheimer's immunotherapy demand scrutiny.}, journal = {Ageing research reviews}, volume = {119}, number = {}, pages = {103151}, doi = {10.1016/j.arr.2026.103151}, pmid = {42055092}, issn = {1872-9649}, mesh = {Humans ; *Alzheimer Disease/therapy/immunology/drug therapy ; *Immunotherapy/adverse effects ; Brain/drug effects/pathology ; Amyloid beta-Peptides/immunology/metabolism ; Animals ; *Antibodies, Monoclonal/adverse effects/therapeutic use ; }, abstract = {Monoclonal antibodies targeting amyloid-β, i.e., lecanemab and donanemab, have recently been approved for treating early Alzheimer's disease (AD). Though these antibodies are by many considered milestones in AD therapy, clinical approvals have been inconsistent due to ongoing debates over their clinical benefit and safety. The reported cognitive decline slowing is modest and often below the thresholds for clinically significant differences on outcome scales. Moreover, these therapies are linked to adverse effects, including infusion reactions, headaches, and nausea, as well as more serious issues like amyloid-related imaging abnormalities (ARIAs), the long-term impact of which remains unclear. In this Viewpoint article, we highlight three safety concerns: ARIAs, accelerated brain volume loss, and therapy-related deaths. ARIAs occur much more frequently in treated AD patients than in placebo groups, yet their functional consequences remain poorly understood. Evidence also suggests that treatment with anti-amyloid antibodies may lead to more brain tissue loss than placebo treatments, though this has received limited attention in trials and regulatory evaluations. Finally, reliable data on therapy-related mortality is scarce due to insufficient access to detailed clinical and neuropathological information. These issues underscore significant uncertainties in assessing the risk-benefit profile of anti-amyloid therapies. A more systematic investigation-including routine brain volume monitoring, functional PET imaging, and independent death evaluations-is crucial for a comprehensive understanding of both benefits and risks in regulatory and clinical decisions.}, } @article {pmid42055093, year = {2026}, author = {Nakum, B and Vejpara, D and Faldu, K and Soni, R and Shah, J}, title = {Tiny Titans, big promise: Nanotechnology and microRNA in the fight against Alzheimer's disease.}, journal = {Ageing research reviews}, volume = {119}, number = {}, pages = {103149}, doi = {10.1016/j.arr.2026.103149}, pmid = {42055093}, issn = {1872-9649}, mesh = {Humans ; *Alzheimer Disease/therapy/genetics/metabolism/diagnosis ; *MicroRNAs/therapeutic use/genetics/metabolism/administration & dosage ; *Nanotechnology/methods ; Animals ; Drug Delivery Systems ; }, abstract = {Alzheimer's disease (AD) remains the most common neurodegenerative disorder. It is driven by complex molecular dysfunctions that includes amyloid aggregation, tau pathology, and neuroinflammation. It leads to cognitive deficits and memory loss in elderly people. Current treatments offer limited symptomatic relief. Hence, there is urgent need for innovative therapeutics and diagnostic approaches. Among emerging therapeutic targets, microRNAs (miRNAs) have pivotal role in regulating genes linked to amyloid precursor protein (APP), tau phosphorylation, and inflammatory cascades. This review explores the synergistic as well as individual potentials of nanotechnology and microRNAs (miRNAs) in AD. Nanotechnology aids in targeted drug delivery, enhanced imaging and theranostic capabilities; whereas miRNAs are key regulators of gene expression. Beyond pathogenesis, circulating and cerebrospinal miRNAs serve as minimally invasive biomarkers capable of distinguishing AD from mild cognitive impairment, offering early diagnostic potential. However, therapeutic translation faces challenges of instability, poor bioavailability, and limited blood-brain barrier (BBB) permeability. Here, combination of nanotechnology with miRNA is a compelling solution. Engineered nano-based system enhance miRNA stability, protect them from enzymatic degradation, and enable targeted delivery. This review highlights the synergistic use of nanotechnology and miRNA for AD diagnostics and therapeutics as a multifaceted strategy. Together, these advances promise a path toward early diagnosis and personalized treatment options for AD.}, } @article {pmid42055109, year = {2026}, author = {Zhu, Y and Zhang, H and Zhang, Z and Song, G and Fu, J and Wang, H}, title = {The role of ultrasound in addressing neurodegenerative diseases: A review of mechanisms, applications, and challenges.}, journal = {Neuroscience}, volume = {606}, number = {}, pages = {126-137}, doi = {10.1016/j.neuroscience.2026.04.024}, pmid = {42055109}, issn = {1873-7544}, mesh = {Humans ; *Neurodegenerative Diseases/therapy ; Blood-Brain Barrier/metabolism ; Animals ; *Ultrasonic Therapy/methods ; }, abstract = {With the aging of the global population, neurodegenerative diseases have become a major public health challenge. Currently, there are many limitations in the traditional treatment of neurodegenerative diseases, such as medicine, deep brain stimulation, transcranial magnetic stimulation, and transcranial direct current stimulation, including the inability to penetrate the blood-brain barrier (BBB) accurately and challenges in achieving precise and quantitative control during the treatment process. Ultrasound is an emerging neural modulation technology that stands out for its non-invasive nature, precise targeting, and unique ability to penetrate the BBB, demonstrating tremendous application potential. In this review, we summarized the common types of neurodegenerative diseases, including Alzheimer's disease (AD), Parkinson's disease (PD), and Amyotrophic lateral sclerosis (ALS), and the limitations of traditional treatments. It delves into the physical principles, classification, mechanisms, and unique advantages of ultrasound therapy in neuromodulation. It provides a detailed account of the current status of application of ultrasound in neurodegenerative diseases, and represents the advantages and challenges currently faced by ultrasound therapy, which offers insights into future research directions and technological improvements.}, } @article {pmid42055146, year = {2026}, author = {Lin, C and Xu, Z and Yan, J and Liu, B and Li, F}, title = {Icariin promotes lysosomal degradation of amyloid-β precursor protein via enhanced endosome-lysosome trafficking to reduce amyloid-β accumulation and improve cognitive function in Alzheimer's disease models.}, journal = {Brain research bulletin}, volume = {240}, number = {}, pages = {111906}, doi = {10.1016/j.brainresbull.2026.111906}, pmid = {42055146}, issn = {1873-2747}, mesh = {*Flavonoids/pharmacology ; Animals ; *Alzheimer Disease/metabolism/drug therapy ; *Lysosomes/metabolism/drug effects ; Endosomes/metabolism/drug effects ; *Amyloid beta-Protein Precursor/metabolism ; Humans ; *Amyloid beta-Peptides/metabolism ; Mice, Transgenic ; Disease Models, Animal ; Mice ; *Cognition/drug effects ; Protein Transport/drug effects ; Male ; Amyloid Precursor Protein Secretases/metabolism ; }, abstract = {Alzheimer's disease (AD) represents a devastating global public health crisis, characterized by progressive cognitive decline and memory impairment, with its prevalence and associated disability rates rising exponentially amid global population aging. The pathological hallmarks of AD include the accumulation of amyloid-beta (Aβ) plaques and hyperphosphorylated tau protein tangles, which primarily arise from the aberrant processing of amyloid-β precursor protein (AβPP). Currently, approved therapeutic strategies for AD only provide symptomatic relief, and there is a critical unmet need for effective disease-modifying treatments-particularly those targeting the transport and degradation mechanisms of AβPP, which remain poorly understood and under-explored. This study aims to elucidate the effects of icariin on AβPP subcellular localization and degradation via the lysosomal pathway in both APP/PS1 transgenic mouse model and human-APP695-overexpressing cell line. Combining behavioral assessments with biochemical analyses and confocal microscopy, this study demonstrates that prolonged icariin treatment significantly enhances cognitive function, reduces levels of AβPP, BACE1, and Aβ, and promotes the lysosomal degradation of AβPP by facilitating its transport from early endosomes to lysosomes. The findings reveal that icariin effectively mitigates Aβ generation and cognitive deficits by shortening the residence time of AβPP in early endosomes, thereby filling a key knowledge gap in AβPP metabolism and uncovering a novel regulatory mechanism. These results not only establish icariin as a promising candidate for AD intervention but also propose a new therapeutic avenue targeting AβPP degradation mechanisms, with substantial implications for both basic research and clinical applications in AD treatment. Future investigations should focus on evaluating the translational potential of icariin and characterizing its pharmacological profile to optimize clinical efficacy and safety, addressing the urgent need for disease-modifying therapies for this devastating neurodegenerative disorder.}, } @article {pmid42055498, year = {2026}, author = {Zheng, W and Zhou, Y and Lu, M and Wang, Y}, title = {Associations of obstructive sleep apnea with A/T/N biomarkers, neuroimaging abnormalities, neurodegenerative progression, and CPAP-related changes in Alzheimer's disease.}, journal = {Sleep medicine}, volume = {144}, number = {}, pages = {108975}, doi = {10.1016/j.sleep.2026.108975}, pmid = {42055498}, issn = {1878-5506}, mesh = {Humans ; *Sleep Apnea, Obstructive/therapy/complications/diagnostic imaging ; *Alzheimer Disease/diagnostic imaging/complications ; Biomarkers/cerebrospinal fluid ; *Continuous Positive Airway Pressure ; Cross-Sectional Studies ; Male ; Amyloid beta-Peptides/cerebrospinal fluid ; Disease Progression ; Female ; Positron-Emission Tomography ; tau Proteins/cerebrospinal fluid ; Neuroimaging ; Aged ; Middle Aged ; Magnetic Resonance Imaging ; Diffusion Tensor Imaging ; }, abstract = {BACKGROUND: Obstructive sleep apnea (OSA) has been increasingly linked to cognitive impairment and dementia, yet its relationship with core Alzheimer's disease (AD) pathology, multimodal brain injury, longitudinal neurodegenerative progression, and potential treatment responsiveness remains incompletely understood.

METHODS: Cross-sectional analyses compared amyloid/tau/neurodegeneration (A/T/N) biomarkers and multimodal neuroimaging measures between groups, including cerebrospinal fluid (CSF) biomarker quantification, amyloid positron emission tomography (PET), structural MRI, white matter imaging, the diffusion tensor imaging analysis along the perivascular space (DTI-ALPS) index, and choroid plexus volume, the latter two used as indirect imaging markers reflecting potential alterations in glymphatic-related fluid transport and waste-clearance pathways. Among OSA participants who initiated continuous positive airway pressure (CPAP) therapy, changes over the approximately 6-month follow-up period were compared according to adherence status.

RESULTS: Compared with patients without OSA, those with OSA showed a more adverse A/T/N biomarker profile, including lower CSF Aβ42 (528.19 ± 147.83 vs 612.37 ± 158.46 pg/mL), lower CSF Aβ42/40 ratio (0.064 ± 0.013 vs 0.071 ± 0.014), higher amyloid PET SUVR (1.38 ± 0.21 vs 1.24 ± 0.18), higher CSF p-tau181 (74.92 ± 26.15 vs 63.48 ± 21.37 pg/mL), higher plasma NfL (31.79 ± 13.27 vs 24.68 ± 10.42 pg/mL), and higher plasma GFAP (233.47 ± 104.26 vs 196.54 ± 82.71 pg/mL). Neuroimaging analyses further showed smaller hippocampal volume, greater white matter injury, a lower DTI-ALPS index (1.27 ± 0.18 vs 1.43 ± 0.19), and a larger choroid plexus volume (3291.73 ± 768.61 vs 2814.56 ± 712.48 mm[3]) in the OSA group. Longitudinally, OSA was associated with faster annual increases in NfL (2.37 vs 0.72 pg/mL/year) and GFAP (15.19 vs 4.54 pg/mL/year), as well as faster hippocampal atrophy over time. Among treated participants, CPAP adherence was associated with improved cognition (MoCA: +0.59; ADAS-Cog: -1.48) and reductions in IL-6 (-0.95 pg/mL), GFAP (-14.67 pg/mL), and NfL (-2.33 pg/mL).

CONCLUSIONS: In patients with AD, OSA was associated with a more adverse A/T/N biomarker profile, broader neuroimaging abnormalities, including altered DTI-ALPS index and choroid plexus volume as indirect imaging markers of potential glymphatic-related dysfunction, and faster neurodegenerative progression. CPAP adherence was associated with more favorable short-term trajectories, suggesting that OSA may be a clinically relevant and potentially modifiable contributor to disease burden in AD.}, } @article {pmid42055956, year = {2026}, author = {Ivanidze, J and Gardella, J and Olson, A and Sun, SM and Thomas, C and Wong, OL and Intorcia, B and Moirano, J and Tanavde, V and Gershon, B and Pahlajani, S and Roytman, M and Nordvig, A and Lin, M and Hamed, M and Alport, A and Salgado, M and Keil, S and O'Dwyer, E and Lantos, J and Huicochea Castellanos, S and Ebani, EJ and Agee, M and Fink, ME and Osborne, JR and Chiang, GC and Blum, S}, title = {PET-guided Assessment of Amyloid Clearance and Outcomes in a Real-World Cohort of Patients with Alzheimer Disease undergoing Anti-Amyloid Therapy.}, journal = {AJNR. American journal of neuroradiology}, volume = {}, number = {}, pages = {}, doi = {10.3174/ajnr.A9387}, pmid = {42055956}, issn = {1936-959X}, abstract = {BACKGROUND AND PURPOSE: Beta-amyloid (Aβ)-PET is central to confirming Alzheimer disease (AD) before treatment with anti-amyloid monoclonal antibody therapies (AAT), however its role in treatment response monitoring in routine clinical practice remains unclear. This study aimed to evaluate longitudinal Aβ-PET changes following AAT and their association with clinical and safety outcomes in a real-world cohort.

MATERIALS AND METHODS: We conducted a retrospective single-center study of patients with mild cognitive impairment (MCI) or mild dementia due to AD who underwent Aβ-PET before and after treatment with AAT (lecanemab or donanemab). Aβ-PET scans were assessed using visual interpretation and quantitative measures including Centiloid level (CL) and regional Z-scores. Treatment-related amyloid clearance (TRAC) was determined based on magnitude of CL changes (ΔCL). Associations between Aβ-PET changes and baseline Fazekas score, amyloid-related imaging abnormalities (ARIA) and APOE-ε4 carrier status were examined. Associations between ΔCL and cognitive performance from baseline to post-AAT as assessed per Mini-Mental State Examination (ΔMMSE) were examined using multivariable linear regression models incorporating baseline CL and adjusting APOE-ε4 status and occurrence of ARIA. Region-specific multivariable analyses evaluated associations between regional Z-score changes and ΔMMSE.

RESULTS: Thirty-two patients met inclusion criteria (lecanemab, N=15; donanemab, N=17). Significant Aβ reduction was observed across the cohort (median ΔCL 59.11; p < 0.001) as well as within each treatment group. Most patients meeting TRAC criteria achieved full or partial TRAC (26/29, 89.7%). Baseline Aβ burden, as well as cognitive outcomes, did not differ significantly across TRAC categories (p = 0.25). ΔCL was not significantly associated with APOE-ε4 status or ARIA occurrence. In adjusted analyses, greater global CL reduction was associated with greater MMSE improvement, particularly at lower baseline burden. Region-specific analyses demonstrated marked, highly significant decrease in Z-scores across all regions.

CONCLUSIONS: Longitudinal Aβ-PET demonstrated substantial Aβ clearance following AAT in routine clinical practice. Aβ reduction was not significantly associated with baseline Aβ burden, ARIA, APOE-ε4 status. In adjusted analyses, greater Aβ reduction was associated with greater MMSE improvement. Our findings support Aβ-PET as a sensitive biomarker of biological treatment effect, while highlighting the complexity of linking Aβ clearance to short-term cognitive outcomes.}, } @article {pmid42056682, year = {2026}, author = {Song, Z and Huang, X and Jannu, AJ and Johnson, TS and Zhang, J and Huang, K}, title = {Identification of Alzheimer's disease subtypes and biomarkers from human multi-omics data using subspace merging algorithm.}, journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association}, volume = {22}, number = {5}, pages = {e71292}, pmid = {42056682}, issn = {1552-5279}, support = {5U54AG065181//National Institutes of Health (NIH)/ ; R21AG075541//National Institutes of Health (NIH)/ ; }, mesh = {Humans ; *Alzheimer Disease/genetics/classification/pathology ; Multiomics ; *Algorithms ; Biomarkers ; Quantitative Trait Loci ; Genome-Wide Association Study ; Clustering Algorithms ; Female ; Brain/pathology ; Phenotype ; Male ; Transcriptome ; }, abstract = {INTRODUCTION: Alzheimer's disease (AD) is a heterogeneous disease with diverse disease progression trajectories and brain pathology. Identifying AD subtypes is essential for understanding AD etiology, heterogeneity, and developing precise treatment.

METHODS: We applied a subspace-merging algorithm to integrate multi-omics data from brain tissues of three large AD cohorts and identify data-driven AD subtypes. Within each cohort, we performed multiple analyses to characterize subtype-specific biology. A Phenome-wide Association Study (PheWAS) of expression quantitative trait loci (eQTLs) targeting differentially expressed genes (DEGs) was conducted to link molecular differences to disease phenotypes.

RESULTS: We identified AD subtypes that differed in cognitive and pathological phenotypes in three cohorts. Further analyses highlighted synaptic and neurotransmission pathways, and the PheWAS revealed significant associations with disease phenotypes.

DISCUSSION: Our developed integration algorithm successfully merged different data modalities into a common subspace for patient clustering and identified data-driven subtypes. The identified transcriptomic signatures provide valuable insights into the molecular mechanisms underlying AD heterogeneity, paving the way for personalized AD treatment.}, } @article {pmid42057258, year = {2026}, author = {Yi, Y and Jia, P and Xie, P and Peng, X and Zhu, X and Yin, S and Yan, C and Yu, G}, title = {Natural Products for Alzheimer's Disease: A New Twist Impacting Ferroptosis.}, journal = {The American journal of Chinese medicine}, volume = {54}, number = {3}, pages = {707-731}, doi = {10.1142/S0192415X26500266}, pmid = {42057258}, issn = {1793-6853}, mesh = {*Ferroptosis/drug effects/genetics ; *Alzheimer Disease/drug therapy/etiology/metabolism ; Humans ; *Biological Products/therapeutic use/pharmacology ; Iron/metabolism ; Flavonoids/pharmacology/therapeutic use ; *Phytotherapy ; Antioxidants ; Lipid Peroxidation/drug effects ; Animals ; Terpenes/therapeutic use/pharmacology ; Phenols ; Signal Transduction/drug effects ; Plant Extracts/therapeutic use ; }, abstract = {Alzheimer's disease (AD) is a neurodegenerative disorder characterized by progressive cognitive decline. Despite significant advances in AD research, effective disease-modifying therapies remain unavailable. In recent years, ferroptosis has gained increasing attention for its potential role in the pathogenesis of AD. Accumulating evidence indicates that substantial iron accumulation, dysregulation of anti-oxidant defense systems, and elevated levels of lipid peroxidation are present in the brains of AD patients. These alterations create a conducive environment for ferroptosis and are closely associated with neuronal death and cognitive dysfunction. Therefore, targeting ferroptosis-related signaling pathways holds promise as a novel strategy to delay or halt the progression of AD. Natural products, such as flavonoids, phenolic compounds, and terpenoids, have become a focus of research in the intervention of neurodegenerative diseases due to their structural diversity, broad biological activities, and relatively low toxicity. Increasing studies have demonstrated that various herbal medicines, including Rhodiola rosea, Polygala tenuifolia, Ginkgo biloba, and Poria cocos, can effectively suppress ferroptosis through multiple mechanisms. These mechanisms include scavenging free radicals, enhancing anti-oxidant capacity, modulating iron metabolism, and restoring the function of key regulators like GPX4 or system Xc[-], to thereby ameliorate AD-related neural damage. This review systematically summarizes recent advances in understanding the role of ferroptosis in AD and highlights the therapeutic potential of natural products that target ferroptotic pathways. We aim to provide theoretical support and candidate molecules for the development of novel AD treatment strategies based on ferroptosis regulation, and thus offer valuable insights for future research into new ferroptosis inhibitors.}, } @article {pmid42057407, year = {2026}, author = {Lee, M and Kim, M}, title = {Donepezil increases angiogenic potential in patients with Alzheimer's disease.}, journal = {Journal of Alzheimer's disease : JAD}, volume = {111}, number = {4}, pages = {1751-1759}, doi = {10.1177/13872877261444020}, pmid = {42057407}, issn = {1875-8908}, mesh = {Aged ; Aged, 80 and over ; Female ; Humans ; Male ; *Alzheimer Disease/drug therapy/pathology ; Cell Differentiation/drug effects ; *Cholinesterase Inhibitors/therapeutic use/pharmacology ; Donepezil ; *Endothelial Progenitor Cells/drug effects/physiology ; *Indans/therapeutic use/pharmacology ; *Piperidines/therapeutic use/pharmacology ; *Neovascularization, Physiologic/drug effects ; }, abstract = {BackgroundAlzheimer's disease (AD) is the leading cause of dementia in the elderly. Acetylcholinesterase inhibitors are the mainstay of symptomatic treatment, and vascular dysfunction is increasingly recognized as a key contributor to AD pathophysiology. While donepezil is a standard AD treatment, its effects on the vascular system remain poorly understood despite known neurovascular interactions.ObjectiveTo investigate whether donepezil treatment influences endothelial progenitor cell (EPC) populations and differentiation capacity in patients with AD.MethodsEPCs were evaluated in healthy controls and patients with AD (n = 20 per group; N = 80 total): controls (Ctrl), patients initiating donepezil 5 mg (Dp_Start), patients receiving donepezil 5 mg for ≥6 months (Dp_5 mg), and patients escalated to 10 mg after ≥6 months of 5 mg treatment (Dp_10 mg). Peripheral blood samples were collected at baseline, 12 weeks, and 24 weeks. Circulating EPCs were quantified by flow cytometry, and EPC differentiation capacity was assessed by counting early and late EPC colony-forming units (CFUs).ResultsAt baseline, EPC differentiation capacity was reduced in AD patients compared with controls. Circulating EPC levels did not show significant changes across groups or treatment durations. In contrast, both early and late EPC CFU counts were significantly increased in AD patients receiving donepezil, particularly during the first 12 weeks of treatment. This effect was pronounced in patients initiating donepezil therapy.ConclusionsDonepezil enhanced EPC differentiation into early and late populations without altering circulating EPC levels. These findings suggest that donepezil improves EPC functional competence and vascular regenerative capacity beyond its established cognitive effects.}, } @article {pmid42057743, year = {2026}, author = {Radhakrishnan, A and Dutta, D and Saha, M and Venkatakrishnan, S and Kulkarni, A and Chandrachari, KP and Salins, PC and Suresh, A}, title = {Neuro-reparative potential of hyperbaric oxygen therapy in animal models of Alzheimer's and Parkinson's diseases: systematic review and meta-analysis.}, journal = {Neurodegenerative disease management}, volume = {}, number = {}, pages = {1-9}, doi = {10.1080/17582024.2026.2665357}, pmid = {42057743}, issn = {1758-2032}, abstract = {INTRODUCTION: This systematic review and meta-analysis explored the efficacy of Hyperbaric oxygen therapy (HBOT) in preclinical models of Alzheimer's disease (AD) and Parkinson's disease (PD).

METHODS: Data were extracted as per PRISMA guidelines using specific search criteria, with bias assessed using SYRCLE guidelines. Random-effect models were used for meta-analyses of key outcomes, and forest plots were generated. Outcomes assessed included cognitive and motor performance, neuroinflammation, oxidative stress, mitochondrial function, apoptosis, and dopaminergic neuron survival.

RESULTS: The PRISMA search yielded 8 studies (AD: 3; PD: 5) from a total of 8261 articles identified. A total of 308 animals were reported across the studies; however, 182 were included in the meta-analysis, as only animals from relevant treatment and corresponding control groups with extractable outcome data were eligible for quantitative analysis. HBOT significantly improved cognitive function (reduced escape latency, Standardized Mean Difference; SMD: -2.13), improved spatial memory, and reduced compensatory locomotor activity (decreased distance traveled, SMD: -6.94). The markers of neuroinflammation (lower TNF-α, higher IL-10), oxidative stress (SOD, MDA), mitochondrial biogenesis (SIRT1, PGC-1α, TFAM, VDAC), and anti-apoptotic markers (higher Bcl-xl, lower Bax) showed differences in post-HBO treatment. HBOT also preserved dopaminergic neurons in PD models.

CONCLUSIONS: These preclinical findings support HBOT as a potential complementary neuroprotective therapy for AD and PD, warranting further clinical validation.}, } @article {pmid42059045, year = {2026}, author = {Xie, K and Jiang, Y and Chen, T and Liu, S and Fang, Y and Chen, F and Shen, J and Zeng, X and Li, P and Qiu, T and Wang, J and Yu, L and Zang, X and Wang, N and Yuan, J and Pang, H and Zhang, W and Ni, Z and Gu, L and Guo, Y and Lu, R}, title = {A prospective, randomized, double-blind, placebo-controlled, multicenter study of thiamin plus folic acid in the treatment of cognitive impairment in patients undergoing maintenance hemodialysis.}, journal = {Renal failure}, volume = {48}, number = {1}, pages = {2658981}, pmid = {42059045}, issn = {1525-6049}, mesh = {Humans ; *Folic Acid/administration & dosage/therapeutic use/blood ; *Thiamine/administration & dosage/therapeutic use/blood/adverse effects ; Double-Blind Method ; *Renal Dialysis/adverse effects ; Female ; Middle Aged ; Prospective Studies ; Male ; Aged ; *Cognitive Dysfunction/drug therapy/etiology/blood ; Treatment Outcome ; Adult ; *Kidney Failure, Chronic/therapy/complications ; *Vitamin B Complex/administration & dosage ; Drug Therapy, Combination ; Homocysteine/blood ; Young Adult ; Adolescent ; }, abstract = {This prospective, randomized, double-blind, placebo-controlled trial investigated the efficacy and safety of thiamin and folic acid for cognitive impairment in maintenance hemodialysis (MHD) patients. A total of 215 MHD patients aged 18-75 with cognitive impairment were randomized to receive either oral thiamin (90 mg/day) plus folic acid (30 mg/day) or a placebo for 96 weeks. The primary endpoint was the change in the Alzheimer's Disease Assessment Scale-Cognitive section (ADAS-Cog) score. After 96 weeks, the treatment group showed a significant improvement in ADAS-Cog scores (from 21.25 ± 9.2 to 15.07 ± 8.38, p < 0.001), whereas the placebo group showed a non‑significant improvement (from 24.53 ± 11.01 to 26.53 ± 14.43, p = 0.077). The treatment group also demonstrated significantly increased blood levels of thiamin (from 5.59 ± 0.95 to 18.21 ± 3.91 ng/mL) and folate (from 12.37 ± 4.62 to 63.33 ± 16.02 ng/mL), and a reduction in homocysteine levels (from 4709.06 ± 353.15 to 2962.68 ± 158.87 ng/mL, p < 0.001), with no significant changes in the placebo group. While mortality was similar between the two groups (12.1% vs. 12.0%, p = 0.978), the incidence of adverse events was significantly lower in the treatment group (31.8% vs. 62.0%, p = 0.0017), particularly cardiovascular and cerebrovascular events (13.1% vs. 25.9%, p = 0.001). The study concludes that combined thiamin and folic acid supplementation improves cognitive function in MHD patients with a favorable safety profile.}, } @article {pmid42060857, year = {2026}, author = {Mitchell, B and Harkess-Murphy, E and Douglas-Smith, N and Cheyne, J}, title = {Touch-Based Therapies in Dementia Care: A Systematic Review and Narrative Synthesis.}, journal = {Dementia (London, England)}, volume = {}, number = {}, pages = {14713012261445473}, doi = {10.1177/14713012261445473}, pmid = {42060857}, issn = {1741-2684}, abstract = {Touch-based therapies (massage, acupressure, reflexology/shiatsu, and therapeutic/healing touch) are used in dementia care, but effectiveness remains uncertain. The authors evaluated their impact on behavioural and psychological symptoms of dementia (BPSD) and pain, and extracted pragmatic "dose" and delivery parameters to inform a research blueprint. The authors searched major databases (MEDLINE, CINAHL, PsycINFO, Embase, CENTRAL) for studies from January 2005 to February 2023 involving people with any dementia aetiology/severity in community, residential, or inpatient settings. Eligible designs included randomised, quasi-experimental, and pre-post studies with a comparator (usual care, attention/quiet presence, or sham/light-touch). Data were extracted to a prespecified template; study quality was appraised using CASP tools. Owing to substantial clinical and methodological heterogeneity, the authors conducted a structured narrative synthesis as opposed to meta-analysis. Thirty-three studies met inclusion: 21 massage, 8 acupressure, 3 therapeutic/healing touch, and 2 reflexology/shiatsu. Most were in long-term care or inpatient settings. Interventions typically used brief, repeated sessions (5-20 minutes, several times per week for 2-6 weeks). The most consistent finding was short-term calming, particularly reductions in agitation immediately post-session or over brief treatment courses, with the clearest pattern for massage and acupressure. Effects on broader neuropsychiatric symptoms (e.g., NPI/NPI-NH domains) and pain were mixed. Where monitored, no serious adverse events were reported; minor transient issues (e.g., brief restlessness, skin sensitivity with aromatherapy oils) were infrequent and acceptability generally high. Risk of bias was mixed (≈49% low, 42% moderate, 9% high), and durability beyond 4-8 weeks was rarely assessed. Current evidence provides preliminary indications that brief, touch-based therapies may offer short-term calming effects when used alongside person-centred care, although certainty remains low and findings should be interpreted cautiously. The authors propose a pragmatic research blueprint that predefines session length, frequency, and course duration; uses attention/sham controls; adopts core outcomes (e.g., Cohen Mansfield Agitation Inventory (CMAI), Neuropsychiatric Inventory/Neuropsychiatric Inventory adapted for Nursing Homes (NPI/NPI-NH); Pain Assessment in Advanced Dementia (PAINAD) where relevant); ensures blinded assessment; and extends follow-up. The authors recommend that future work should prioritise feasibility/pilot studies, followed by adequately powered trials to determine effectiveness, durability, and scalability for practice.}, } @article {pmid42060990, year = {2026}, author = {Hsu, YH and Liang, CK and Chou, MY and Davidson, J and Wang, YC and Nalls, MA and Ferrucci, L and Cookson, M and Iwaki, H}, title = {Amyloid pathology and modifiable risk factors in cognitive decline among cognitively unimpaired older adults.}, journal = {The journal of prevention of Alzheimer's disease}, volume = {13}, number = {6}, pages = {100574}, pmid = {42060990}, issn = {2426-0266}, mesh = {Humans ; Aged ; Female ; Risk Factors ; Male ; Longitudinal Studies ; Aged, 80 and over ; *Cognitive Dysfunction/pathology/metabolism ; *Amyloid beta-Peptides/metabolism ; Cognition ; *Alzheimer Disease/pathology ; }, abstract = {BACKGROUND: Alzheimer's disease (AD) pathology, particularly amyloid-β (Aβ) deposition, occurs years before clinical symptoms. Modifiable risk factors may influence cognitive trajectories during this preclinical stage, but whether amyloid status alters their effects remains unclear.

OBJECTIVES: To investigate interactions between amyloid pathology and modifiable risk factors in predicting longitudinal cognitive decline among cognitively unimpaired older adults.

DESIGN AND SETTING: This study was a secondary analysis of data derived from two large multicenter longitudinal cohort studies, the Anti-Amyloid Treatment in Asymptomatic Alzheimer Disease (A4) Study and the Longitudinal Evaluation of Amyloid Risk and Neurodegeneration (LEARN) Study.

PARTICIPANTS: A total of 1707 cognitively unimpaired adults aged 65-85 years were included, comprising 1169 amyloid-positive participants from the A4 Study (Aβ+) and 538 amyloid-negative participants from the LEARN Study (Aβ-).

MEASUREMENTS: Cognitive function was assessed every six months using the Preclinical Alzheimer's Cognitive Composite (PACC) over a mean follow-up of 4.9 years. Eight established modifiable risk factors-low education, alcohol use, diabetes, high cholesterol, high blood pressure, obesity, depressive symptoms, and physical inactivity-were evaluated. Linear mixed-effects models were applied to examine associations between each risk factor and longitudinal PACC decline, and to test interactions with amyloid status, adjusting for demographic and genetic covariates.

RESULTS: Significant interactions between amyloid status and modifiable risk factors were observed for diabetes (adjusted β = -0.206, p = 0.032), high cholesterol (adjusted β = -0.155, p < 0.001), and physical inactivity (adjusted β = -0.161, p = 0.046), indicating combined effects rather than additive effects on cognitive decline among Aβ+ individuals. In the A4 study (Aβ+), low education, diabetes, high cholesterol, and physical inactivity were independently associated with accelerated cognitive decline, whereas obesity was linked to slower decline. In contrast, in the LEARN study (Aβ-), these associations were not statistically significant.

CONCLUSIONS: In conclusion, the significant interactions with amyloid status were observed for diabetes, high cholesterol, and physical inactivity, indicating that these risk factors were associated with faster cognitive decline specifically in Aβ+ individuals. The results suggest that consideration of amyloid status may be important when evaluating the potential role of metabolic and lifestyle risk factors in preclinical cognitive decline. In Aβ+ individuals, obesity was associated with slower cognitive decline, while low education was linked to lower baseline cognition or a reduced symptom threshold, without a significant interaction with amyloid status. Future studies should incorporate amyloid status and longitudinal biomarkers to assess whether modifying these factors can slow preclinical cognitive decline.}, } @article {pmid42062795, year = {2026}, author = {Li, L and Yang, M and Tao, J and Zhao, Y and Zhao, N and Sun, S}, title = {Kaempferol Improves Alzheimer's Disease by Inhibiting Neuronal Ferroptosis via Activating GPX4/AKR1C3 Signaling Pathway.}, journal = {Pharmacology research & perspectives}, volume = {14}, number = {3}, pages = {e70255}, pmid = {42062795}, issn = {2052-1707}, support = {2022ZD050//Corps Guiding Science and Technology Projects/ ; 2025DA013//Scientific and technological research projects in key fields of the Corps/ ; }, mesh = {Mice, Inbred C57BL ; Male ; Animals ; *Alzheimer Disease/drug therapy/metabolism ; *Kaempferols/pharmacology/therapeutic use ; Superoxide Dismutase/metabolism ; PC12 Cells ; Aldo-Keto Reductases/metabolism ; Aldehyde Reductase/metabolism ; Peroxidases/genetics/metabolism ; Neurons/drug effects/metabolism ; Peptide Fragments/metabolism ; Amyloid beta-Peptides/metabolism ; NF-E2-Related Factor 2/metabolism ; *Neuroprotective Agents/pharmacology/therapeutic use ; Phospholipid Hydroperoxide Glutathione Peroxidase/metabolism ; Humans ; Disease Models, Animal ; }, abstract = {Kaempferol has been shown to be beneficial in the treatment of Alzheimer's disease (AD) in animal models. However, the action mechanism remains unclear. AKR1B1 has been identified as a target of kaempferol, initially suggested by the Therapeutic Target Database, DrugBank, and PubChem, and subsequently confirmed through experimental validation. Kaempferol treatment facilitated the expression of AKR1B1 in PC12 cells exposed to Aβ1-42. Kaempferol treatment mitigated the Aβ1-42-induced increases in Fe[2+], MDA, and lipid ROS and Aβ1-42-induced decreases in GSH synthesis and SOD activity. The reduction in ferroptosis-related proteins (GPX4, NQO1, SLC7A11, AKR1C1, and AKR1C3) and the inhibition of Nrf2 nuclear translocation and Nrf2/HO-1 signaling caused by Aβ1-42 were also reversed by kaempferol. Overexpressing AKR1B1 led to decreased levels of Fe[2+], MDA, and lipid ROS, along with increased GSH synthesis and SOD activity in Aβ1-42-treated cells, although these effects were negated by Nrf2 inhibition. The upregulation of GPX4 and AKR1C3 by AKR1B1 overexpression was also reversed when Nrf2 expression was inhibited. Notably, silencing AKR1B1 counteracted the protective effects of kaempferol against Aβ1-42-induced neuronal ferroptosis. In vivo studies revealed that kaempferol improved cognitive impairments, reduced deposition of Aβ and p-Tau, and alleviated neuronal ferroptosis in the hippocampal tissues of an AD mouse model in a dose-dependent manner, effects that were diminished by inhibiting AKR1B1 expression. Following kaempferol treatment, the levels of GPX4 and AKR1C3 in the hippocampus of AD mice were found to be reduced. Overall, our findings indicate that kaempferol treatment enhances cognitive function and mitigates pathological alterations in AD mice by inhibiting neuronal ferroptosis through the activation of the Nrf2/HO-1/GPX4/AKR1C3 signaling via upregulation of AKR1B1. This research supports the need for further investigation and clinical exploration of kaempferol.}, } @article {pmid42063485, year = {2026}, author = {Huang, Y and Xu, J and Fan, Z and Hu, Y and He, X and Chen, A and Liu, Y and Yin, R and Guo, J and DeKosky, ST and Jaffee, M and Zhou, M and Su, C and Wang, F and Guo, Y and Bian, J}, title = {Identifying Alzheimer's Disease Progression Subphenotypes Via a Graph-based Framework Using Electronic Health Records.}, journal = {Journal of healthcare informatics research}, volume = {}, number = {}, pages = {}, pmid = {42063485}, issn = {2509-4971}, support = {R01 AG084236/AG/NIA NIH HHS/United States ; R01 AG080624/AG/NIA NIH HHS/United States ; R01 AG083039/AG/NIA NIH HHS/United States ; R01 AG080991/AG/NIA NIH HHS/United States ; R01 AG076234/AG/NIA NIH HHS/United States ; }, abstract = {Understanding the heterogeneity of neurodegeneration in Alzheimer's disease (AD) and identifying distinct progression pathways is critical for improving diagnosis, treatment, prognosis, and prevention. Motivated by this need, this study aimed to identify disease progression subphenotypes among patients with mild cognitive impairment (MCI) and AD using electronic health records (EHRs). We developed a novel approach that combines a graph neural network (GNN)-based framework with time series clustering to characterize progression subphenotypes from MCI to AD. We applied the proposed framework to a real-world cohort of 2,525 patients (61.66% female; mean age 76 years), of whom 64.83% were Non-Hispanic White, 16.48% Non-Hispanic Black, 2.53% were of other races, and 10.85% were Hispanic. Our model identified four distinct progression subphenotypes, each exhibiting characteristic clinical patterns, with average MCI-to-AD progression times ranging from 805 to 1,236 days. These findings indicate that AD does not follow a uniform progression trajectory but instead manifests heterogeneous pathways, and the proposed framework provides an explainable, data-driven approach for delineating AD progression subphenotypes, offering actionable insights for healthcare informatics research and the clinical management of patients at risk for AD.}, } @article {pmid42063523, year = {2025}, author = {Fitri, FI and Rambe, AS and Effendy, E and Kadri, A and Prawiroharjo, P and Lubis, IND and Surbakti, KP and Amin, MM and Rusda, M and Gustianingsih, }, title = {Instrument for Assessment of Neurodegenerative Aphasia in Indonesia or Instrumen Afasia Neurodegeneratif Indonesia (IRFANI): Development and pilot study.}, journal = {Journal of Alzheimer's disease reports}, volume = {9}, number = {}, pages = {25424823251366640}, pmid = {42063523}, issn = {2542-4823}, abstract = {BACKGROUND: Primary progressive aphasia (PPA) is a neurodegenerative disorder causing progressive language impairment. Early diagnosis is crucial for treatment planning, yet no standardized assessment exists for Indonesian speakers.

OBJECTIVE: This study describes the initial development of the Instrumen Afasia Neurodegeneratif Indonesia (IRFANI), focusing on test construction, content validity, and pilot testing.

METHODS: IRFANI was designed to assess syntax, motor speech, semantics, and phonology, following Gorno-Tempini et al. (2011) diagnostic criteria. The blueprint covered key domains, including confrontation naming (nouns/verbs), sentence production/comprehension, single-word comprehension, semantic association, and repetition tasks. Verbal stimuli were selected based on expert input and Indonesian word frequency lists, while custom black-and-white illustrations ensured linguistic and cultural relevance. Five neurobehavioral neurologists assessed content validity using Aiken's Content Validity Index (CVI). A pilot study was conducted with 30 participants diverse in age, sex, education, and ethnicity.

RESULTS: Expert consultations refined the test blueprint. Qualitative analysis identified ambiguous images, multiple correct answers, and unclear phrasing in naming and sentence tasks. Issues included visually similar images and ambiguous sentence structures. Quantitative validation (CVI = 0.9) confirmed strong expert agreement, with items scoring below 0.8 excluded. The pilot study demonstrated good reliability (0.923) and provided insights for further refinement.

CONCLUSIONS: IRFANI was systematically developed through expert validation, pilot testing, and iterative refinement, ensuring clarity and strong content validity. Further studies are needed to confirm its construct validity, reliability, and diagnostic accuracy.}, } @article {pmid42065636, year = {2026}, author = {Behler, C and Fay, M and Ramadan, S and Breakspear, M and Behler, A}, title = {Neurophysiology of brain temperature dysregulation in humans.}, journal = {Journal of neurophysiology}, volume = {135}, number = {6}, pages = {1437-1450}, doi = {10.1152/jn.00418.2025}, pmid = {42065636}, issn = {1522-1598}, support = {//Tour de Cure (TDC)/ ; //Mark Hughes Foundation Centre for Brain Cancer Research/ ; }, mesh = {Humans ; *Body Temperature Regulation/physiology ; *Brain/physiopathology/physiology/metabolism ; Alzheimer Disease/physiopathology/metabolism ; *Body Temperature/physiology ; Cerebrovascular Circulation/physiology ; Brain Neoplasms/physiopathology/metabolism ; Animals ; }, abstract = {Brain temperature, a fundamental modulator of neural function, remains dramatically understudied despite its critical role in health and disease. This review synthesizes current understanding of brain thermoregulation and its disruption in neurological conditions, addressing a significant knowledge gap in neuroscience. We examined the physiological mechanisms maintaining brain temperature homeostasis, including the interplay between cerebral blood flow, metabolism, and cerebrospinal fluid dynamics. Analysis of publication trends reveals that brain temperature research is underrepresented by 7- to 37-fold compared with other brain physiological parameters, despite comparable clinical relevance. We evaluated current noninvasive measurement techniques, particularly magnetic resonance-based thermometry, highlighting advances and limitations for clinical application. The review presents evidence for distinct temperature dysregulation patterns in neurological diseases. In Alzheimer's disease, we propose a theoretical framework of early-stage hyperthermia driven by neuroinflammation and hypermetabolism, transitioning to late-stage hypothermia with metabolic decline. Brain tumors exhibit contrasting thermal profiles: glioblastomas frequently present as hypothermic due to necrotic cores acting as metabolic voids, whereas melanoma metastases show hyperthermia from sustained metabolic activity. These temperature alterations may influence disease progression through effects on protein aggregation, cellular metabolism, and neuron-glial interactions. Looking forward, brain temperature monitoring could provide biomarkers for disease staging and treatment response. In addition, understanding thermal limits becomes urgent as climate change exposes vulnerable populations with compromised thermoregulation to extreme heat. This review establishes brain temperature as an overlooked but essential axis in neurophysiology, calling for increased research attention to address fundamental questions about thermal regulation in health and disease.}, } @article {pmid42066672, year = {2026}, author = {Mast, N and Bederman, I and El-Darzi, N and Pikuleva, IA}, title = {CYP46A1 activation by low-dose efavirenz uncovers the link between brain cholesterol metabolism, energetics, and vasculature.}, journal = {Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie}, volume = {199}, number = {}, pages = {119470}, pmid = {42066672}, issn = {1950-6007}, support = {P30 CA043703/CA/NCI NIH HHS/United States ; P30 DK097948/DK/NIDDK NIH HHS/United States ; R01 AG067552/AG/NIA NIH HHS/United States ; }, mesh = {Animals ; Cyclopropanes/pharmacology ; Alkynes ; Male ; *Benzoxazines/pharmacology/administration & dosage ; *Brain/drug effects/metabolism/blood supply ; *Cholesterol 24-Hydroxylase/metabolism ; Female ; *Cholesterol/metabolism ; *Energy Metabolism/drug effects ; Mice ; Mice, Transgenic ; Enzyme Activation/drug effects ; Sphingomyelins/metabolism ; }, abstract = {CYP46A1 converts cholesterol to 24-hydroxycholesterol, the principal mechanism for brain cholesterol removal and turnover. CYP46A1 can be allosterically activated with low-dose anti-HIV drug efavirenz and mitigate the manifestations of various neurologic diseases in mouse models and Niemann-Pick type C disease in humans. Yet the underlying reasons for such a broad range of efavirenz therapeutic effects are currently unknown. Here 5XFAD mice, a model of Alzheimer's disease, were treated with low-dose efavirenz, and assessed for changes in their brain proteome, acetylproteome, and metabolome. Sex-independent increases in brain levels of phosphatidylcholines, sphingomyelins, and certain amino acids were documented, and various functional enrichments were identified. The most notable related to brain energy production, vascularization, and prevention of glutamatergic overactivation. Unexpectedly, these and many other enrichments were mediated by different proteins in female and male 5XFAD mice. Efavirenz treatment of 5XFAD mice was repeated, and energy-related compounds were quantified in the brain after in vivo isotopic labeling. Cerebral vasculature was assessed as well. We found increased glycolysis branching, carbon flux through the tricarboxylic acid cycle, and use of alternative energy sources (fatty acids, ketone bodies, and amino acids). Sex-independent improvements in brain vascularization and integrity of the blood-brain barrier were also documented. Collectively, our data suggested that CYP46A1 activation by efavirenz increases brain metabolic flexibility and thereby brain energetics. This enables the increase in production of the building blocks for cellular and tissue repair and rescue of brain pathology, thus explaining the therapeutic benefits for the broad spectrum of neurologic disorders.}, } @article {pmid42066770, year = {2026}, author = {Xie, J and Dai, XJ and Li, Q and Zhang, W and Nie, X and Ji, H and Chen, X and Wang, Y and Feng, J and Li, Z and Liu, Q and Ye, J and Zhang, G and Nie, S}, title = {Escherichia coli Nissle 1917 alleviates Alzheimer's disease in mice through OmpA-containing outer membrane vesicles.}, journal = {Cell reports. Medicine}, volume = {7}, number = {5}, pages = {102781}, pmid = {42066770}, issn = {2666-3791}, mesh = {Animals ; *Alzheimer Disease/microbiology/metabolism/pathology ; *Bacterial Outer Membrane Proteins/metabolism ; *Escherichia coli/metabolism ; Mice ; Humans ; *Probiotics ; Neurons/metabolism ; Brain/metabolism ; Male ; Microglia/metabolism ; Gastrointestinal Microbiome ; Disease Models, Animal ; Astrocytes/metabolism ; Female ; Mice, Inbred C57BL ; }, abstract = {Gut microbiota dysbiosis is a driving factor in Alzheimer's disease (AD), yet the mechanisms behind remain elusive. Emerging evidence highlights that outer membrane vesicles (OMVs) are critical mediators of microbiota-host communication. Here, we observed a reduction in a gut probiotic Escherichia coli Nissle 1917 (EcN)-like strain in AD patients, and its levels are positively associated with cognitive ability. The EcN OMVs containing outer membrane protein A (OmpA) translocate to the brain, reshaping the dysregulated immune network. Specifically, EcN OMVs are internalized by glia and neurons, suppressing glial hyperactivation and restoring synaptic function, thereby reducing Aβ deposition and cognitive deficits. The results further show that OmpA plays an important role in vesicle trafficking and inflammatory pathways and may be the key regulator of inflammatory mediators in EcN OMVs, modulating astrocyte-microglia-neuron interactions and functionality. This work discloses the substantial therapeutic potential of the probiotic and its secreted OMVs in intervention and treatment of neurological disorders.}, } @article {pmid42067018, year = {2026}, author = {Belavadi, S and Kadiri, SK}, title = {From pathology to precision therapy: Contemporary and emerging strategies in Alzheimer's disease treatment.}, journal = {European journal of pharmacology}, volume = {1025}, number = {}, pages = {178913}, doi = {10.1016/j.ejphar.2026.178913}, pmid = {42067018}, issn = {1879-0712}, mesh = {Humans ; *Alzheimer Disease/pathology/drug therapy/metabolism ; Animals ; *Precision Medicine/methods ; Amyloid beta-Peptides/metabolism ; tau Proteins/metabolism ; }, abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disease characterised by dementia, confusion, irritability, a lack of cognition, and mood swings. Since its discovery in 1906, many small molecules have been designed to block disease progression by targeting the primary targets β-amyloid and tau proteins. Subsequent research focused on small-molecule inhibitors targeting secondary targets, such as β-secretases and γ-secretases. However, the clinically approved conventional therapies include acetylcholinesterase inhibitors and N-methyl-D-aspartate inhibitors that relieve only disease symptoms, and their efficacy remains limited. Recently, approved novel approaches, such as monoclonal antibodies and vaccines, aim to slow disease progression by targeting the molecular mechanisms underlying amyloid and tau proteins. In addition, these drugs have controversial side effects, which call into question their therapeutic efficacy. A newer strategy involving small peptides is gaining traction because of their lower toxicity, improved permeability, and target specificity. Various homogenous and heterogeneous peptidomimetic inhibitors have been designed to target traditional protein targets. Although various peptidomimetic inhibitors have demonstrated therapeutic efficacy, none have entered clinical trials. Upon conducting an extensive literature survey, we identified several regions, targets, and technologies that could be leveraged to ameliorate Alzheimer's disease progression. In this review, we address the progression of AD, its historical context, and the development of therapeutic approaches that target this disease. We focus on the evolution of subsequent therapies aimed at alleviating the disease and highlight recent developments in drug delivery and formulation techniques that enhance therapeutic efficacy and address the shortcomings of traditional treatments.}, } @article {pmid42067052, year = {2026}, author = {Darzi, M and Golchoobian, R and Varzi, HN and Shanehbandpour Tabari, F}, title = {Metformin attenuates neurodegeneration in ICV-STZ-induced Alzheimer's model via antioxidant and anti-inflammatory mechanisms: implications for disease-modifying therapy.}, journal = {Neuroscience letters}, volume = {880}, number = {}, pages = {138617}, doi = {10.1016/j.neulet.2026.138617}, pmid = {42067052}, issn = {1872-7972}, mesh = {Animals ; *Metformin/pharmacology/therapeutic use ; *Alzheimer Disease/chemically induced/drug therapy/metabolism/pathology ; Male ; *Antioxidants/pharmacology/therapeutic use ; Streptozocin/administration & dosage ; Rats ; *Anti-Inflammatory Agents/pharmacology/therapeutic use ; Oxidative Stress/drug effects ; Disease Models, Animal ; Hippocampus/drug effects/metabolism ; *Neuroprotective Agents/pharmacology ; Interleukin-1beta/metabolism ; Brain/drug effects/metabolism ; Catalase/metabolism ; Hypoglycemic Agents ; }, abstract = {Alzheimer's disease (AD) is the leading cause of dementia, accounting for over 60% of cases in older adults. Growing evidence suggests that metformin, a first-line antidiabetic drug, may have neuroprotective properties. This study evaluated metformin's effects in a streptozotocin (STZ)-induced rat model of sporadic AD. Thirty-two male rats were divided into four groups (n = 8/group): Sham, STZ, Metformin, and Metformin + STZ. The AD model was established via bilateral intracerebroventricular STZ injections (3 mg/kg) on days 61 and 63, with metformin administered in drinking water (2 mg/mL) for 82 days. Metformin treatment significantly enhanced hippocampal catalase activity while reducing malondialdehyde (MDA) and total oxidative status (TOS) levels in both brain and serum. Notably, it selectively decreased hippocampal IL-1β without affecting serum levels, suggesting central-specific anti-inflammatory effects. These findings demonstrate metformin's dual antioxidant and anti-inflammatory actions in an AD model, supporting its potential as a disease-modifying therapy. The dissociation between central and peripheral IL-1β responses highlights the importance of blood-brain barrier considerations in AD treatment strategies.}, } @article {pmid42067300, year = {2026}, author = {Wu, H and Chai, C and Islam, MS and Sheng, S and Xie, G and Chen, T}, title = {An aptamer-mediated EXPAR fluorescence biosensor for early and sensitive detection of Aβ42 and Aβ40.}, journal = {Analytica chimica acta}, volume = {1406}, number = {}, pages = {345513}, doi = {10.1016/j.aca.2026.345513}, pmid = {42067300}, issn = {1873-4324}, mesh = {*Amyloid beta-Peptides/blood/analysis ; *Biosensing Techniques/methods ; *Aptamers, Nucleotide/chemistry ; Humans ; *Peptide Fragments/blood/analysis ; Limit of Detection ; Alzheimer Disease/diagnosis/blood ; Spectrometry, Fluorescence ; Fluorescence ; }, abstract = {BACKGROUND: Alzheimer's disease (AD) is a common neurodegenerative disorder with increasing cases worldwide. Early screening is important for AD prevention and treatment, but current methods still face many challenges.

RESULTS: To address these challenges, we developed a simple and novel molecular beacon (MB) fluorescent biosensor. This sensor combines aptamers with exponential amplification reaction (EXPAR). Through special design of the EXPAR templates, the sensor achieves triple signal amplification. It showed a limit of detection (LOD) of 110 fM for Aβ42 and 300 fM for Aβ40, exhibits high sensitivity. The coefficient of variation (CV) for detecting different target concentrations ranged from 4.42% to 8.85%, showing good repeatability. We also applied this sensor to detect these biomarkers in plasma samples from AD patients. The spike recovery rates were 104.67%-109.3% for Aβ42 and 104.2%-106.93% for Aβ40, demonstrating strong resistance to plasma matrix interference. Due to the specificity of aptamers and nucleic acid design, this method allows simultaneous detection of multiple targets (e.g., Aβ42, Aβ40) in the same system, improving detection efficiency and reliability in complex samples.

SIGNIFICANCE: Compared with traditional Aβ detection methods such as ELISA and colorimetry, our method shows 10-10[4] times higher sensitivity. Compared with emerging techniques like electrochemical detection and single-molecule array, our sensor has the advantages of stronger resistance to plasma matrix interference, more stable results, lower cost and biotoxicity, simpler operation and better biocompatibility and potential of multiple-target detection. These features make it a promising tool for high-throughput early screening of AD, with potential to advance early diagnosis.}, } @article {pmid42067950, year = {2026}, author = {Allouche, A and Colin, J and Birck, C and Schroeder, H and Tallandier, V and Baldoni, M and Muller, C and Afrassi, M and Violle, N}, title = {Aging alters the vulnerability pattern to amyloid-beta oligomers in wild-type mice: a behavioral and neurobiological study.}, journal = {Alzheimer's research & therapy}, volume = {18}, number = {1}, pages = {}, pmid = {42067950}, issn = {1758-9193}, mesh = {Animals ; *Amyloid beta-Peptides/metabolism/toxicity/administration & dosage ; *Aging/metabolism/pathology ; Mice ; Mice, Inbred C57BL ; Neurons/drug effects/metabolism/pathology ; Male ; Cells, Cultured ; Synaptosomal-Associated Protein 25/metabolism ; *Brain/metabolism/pathology/drug effects ; Apoptosis/drug effects ; Cerebral Cortex ; }, abstract = {BACKGROUND: Aging is the primary risk factor for sporadic Alzheimer's disease (AD). While amyloid-beta oligomers (AβOs) accumulation is a key neuropathological process in AD, their specific effects in aged brains and how aging modulates brain response to AβOs remains poorly understood. We investigated how aging contributes to AβO-induced neurotoxicity and cognitive deficits in mice.

METHODS: After biochemical and in vitro characterizations on primary cultures of cortical neurons, AβOs or their vehicle were intracerebrally injected into both 3- and 18-month-old wild-type mice. A broad spectrum of assays including synaptic markers, neuroinflammation, apoptosis and cognitive functions was used to establish a preliminary characterization of the interplay between age and AβOs. In vivo data were analyzed using a multifactorial design (Treatment × Age), with two-way ANOVA or other appropriate statistical models.

RESULTS: Old mice had significantly reduced synaptic proteins SNAP-25 and PSD-95, elevated neuroinflammatory markers, and increased neuronal apoptosis in hippocampus and cortex, despite showing cognitive performances similar to young mice. All brain biomarkers were worsened after AβO injection in both young and old mice. Age and AβO effects either accumulated or interacted to promote neuroinflammation and apoptosis, depending on brain areas, whereas their effects on synaptic proteins were strictly additive. Moreover, AβO injection induced only mild spatial memory deficits in young mice, in contrast with those observed in old mice in both episodic and spatial memory tests.

DISCUSSION: Whereas the young brain showed resilience to maintain memory performances after AβO injection, the coping capacities of the aging brain were exceeded by AβO effects. At the neurobiological level, age and AβO effects were mainly additive, but also acted synergistically in a brain region-dependent vulnerability pattern. This study highlights the value of incorporating aging into preclinical models to improve their translational validity and enhance their relevance for drug testing targeting early stages of sporadic AD.}, } @article {pmid42068226, year = {2026}, author = {Stites, SD and Kuz, C and Largent, EA and Harkins, K and Krieger, A and Sankar, P and Barber, SJ}, title = {Four Common Beliefs About Patient Memory Evaluations: Who Has Them and What Modifies Them?.}, journal = {American journal of Alzheimer's disease and other dementias}, volume = {41}, number = {}, pages = {15333175261447038}, pmid = {42068226}, issn = {1938-2731}, mesh = {Humans ; Male ; *Alzheimer Disease/diagnosis ; Female ; Aged ; *Aging/psychology ; *Health Knowledge, Attitudes, Practice/ethnology ; Middle Aged ; Adult ; }, abstract = {Understanding public beliefs about patients at memory centers may inform efforts to promote early diagnosis and guide clinical discussions of Alzheimer's disease (AD). Adults (N=3,527) read a vignette describing a fictional person at a memory center and rated the person's condition as a mental illness, part of typical aging, and psychological or biological origins. Vignettes varied by AD biomarker result, symptom stage, and treatment availability. Participants most strongly believed that the condition was part of typical aging and biological in origin, though beliefs varied across subgroups. Black and Asian participants reported stronger beliefs than White participants that the condition was a mental illness (β=0.39, P<0.001) and psychological (β=0.46, P<0.001). Men reported stronger beliefs that the condition was a mental illness (β=0.19, P<0.001), psychological (β=0.14, P<0.001), and part of typical aging (β=-0.08, P=0.04). Biomarker positivity heightened biological and lowered psychological attributions (all P<0.05). The findings offer specific insights to guide intervention.}, } @article {pmid42068460, year = {2026}, author = {Chen, JH and Tsai, TF}, title = {A Narrative Review: Do Systemic Drugs Used in the Treatment of Psoriatic Disease Affect Alzheimer's Disease?.}, journal = {Dermatology and therapy}, volume = {16}, number = {6}, pages = {2733-2756}, pmid = {42068460}, issn = {2193-8210}, abstract = {Various comorbidities have been associated with psoriasis. Most clinical studies support the hypothesis that psoriasis may be a risk factor for dementia. Meanwhile, some evidence indicates that certain immunomodulatory agents, many of which are widely used in psoriatic disease management, exert neuroprotective effects and may attenuate dementia progression. In view of the lack of existing studies that specifically investigate the effects of systemic treatments for psoriatic disease on dementia or cognitive impairment, in this narrative review, we focus on Alzheimer's disease, as a model to explore whether systemic psoriasis treatments influence dementia risk and severity. Our findings suggest that some systemic treatments for psoriasis may also provide potential neuroprotective benefits.}, } @article {pmid42071065, year = {2026}, author = {Fikry, H and Sadek, DR and Saleh, LA and Hasanin, MTM and Alkhalek, HAA}, title = {Dual protective role of curcumin- encapsulated chitosan nanoparticles against gastric and neural injury in a rat model of gut-brain axis dysfunction: a histological and biochemical study.}, journal = {Naunyn-Schmiedeberg's archives of pharmacology}, volume = {}, number = {}, pages = {}, pmid = {42071065}, issn = {1432-1912}, abstract = {Gastric ulcer (GU) and Alzheimer's disease (AD) are prevalent age-associated disorders frequently accompanied by systemic oxidative stress and inflammation. Emerging evidence suggests that gastrointestinal dysfunction and inflammatory signaling may aggravate neurodegenerative processes. Curcumin (Cur) exhibits well-established antioxidant, anti-inflammatory, neuroprotective, and gastroprotective properties; however, its therapeutic utility is limited by poor bioavailability. The present study aimed to formulate and characterize Curcumin- encapsulated chitosan nanoparticles (Cur-CSNPs) and evaluate their dual protective effects in a clinically relevant comorbid rat model combining scopolamine-induced AD-like pathology and ethanol-induced GU. Male Wistar rats were divided into six groups: control, Cur-CS-NPs alone, GU, AD, GU + AD, and GU + AD treated with Cur-CSNPs. Behavioral assessments, biochemical analyses, histopathological evaluation, and immunohistochemical investigations were performed on brain and gastric tissues. GU + AD rats exhibited cognitive deficits, neuronal degeneration, amyloid-β accumulation, astrocyte activation, gastric mucosal injury, increased oxidative stress, NF-κB activation, elevated inflammatory cytokines, and enhanced apoptotic signaling. Cur-CSNP treatment significantly improved cognitive performance, reduced oxidative stress and inflammation, suppressed NF-κB signaling, decreased amyloid-β deposition, inhibited apoptosis, and restored gastric mucosal integrity. In conclusion, Cur-CSNPs exert concurrent neuroprotective and gastroprotective effects in a comorbid AD and GU model through coordinated modulation of oxidative stress, inflammation, amyloidogenic activity, and apoptotic pathways. These findings demonstrate that Cur-CSNPs exert dual neuroprotective and gastroprotective effects by modulating oxidative stress, inflammation, amyloidogenic pathways, and apoptosis, highlighting nano-curcumin as a promising therapeutic strategy for gut-brain axis-related disorders. Further investigations are warranted to elucidate the detailed molecular mechanisms and to explore the clinical applicability of nano-formulated curcumin as a therapeutic strategy for disorders involving concurrent gastrointestinal and neurodegenerative pathology.}, } @article {pmid42071257, year = {2026}, author = {Richard, JE and Mohammad, A and Lieblich, SE and Go, KA and Wang, S and Rechlin, RK and Splinter, TFL and Barreto, GE and Galea, LAM}, title = {Reproductive history differentially shapes the neural response of middle-aged hAPOEɛ4 female rats to estradiol therapy after a metabolic challenge.}, journal = {Biology of sex differences}, volume = {17}, number = {1}, pages = {}, pmid = {42071257}, issn = {2042-6410}, support = {PJT173554/CAPMC/CIHR/Canada ; PJT173554/CAPMC/CIHR/Canada ; }, mesh = {Animals ; Female ; *Estradiol/pharmacology ; Hippocampus/drug effects/metabolism ; Rats ; *Parity ; *Apolipoprotein E4/genetics ; Fear/drug effects ; Neurogenesis/drug effects ; Rats, Transgenic ; *Reproduction ; Cytokines/metabolism ; }, abstract = {BACKGROUND: Advancing age, the APOEɛ4 allele, and female sex are the top nonmodifiable risk factors for Alzheimer's disease (AD). Female-specific experiences, such as parity and hormone therapy (HT) affect aging biomarkers such as metabolism and immune signaling, and may affect AD risk. Estradiol (E2), a component of many HTs, affects cognition and brain health in aging females although studies suggest the effects can vary depending on parity, genotype, and metabolic status which may account for some of the inconsistencies in the literature. We hypothesized that prior parity influences brain and metabolic health, including response to E2, depending on APOE genotype.

METHODS: Middle-aged female (10 month) wildtype (WT) or humanized (h) APOEɛ4 expressing rats, with different reproductive experience (nulliparous or primiparous) were fed a Western (WD) or standard diet (SD) for 2 months. In the second month, rats were given E2 or vehicle (oil) injections daily. Fear associative learning, plasma metabolic hormones, hippocampal inflammatory cytokine expression, and neuroplasticity (neurogenesis, synaptic protein) were assessed.

RESULTS: Females fed a WD gained weight and displayed metabolic dysregulation, regardless of genotype. E2 treatment reduced WD-induced weight gain and reduced metabolic hormones, with stronger effects in WT rats. E2 treatment increased dorsal hippocampal inflammatory cytokine expression selectively in primiparous hAPOEɛ4 females fed a WD. Previous parity increased neurogenesis and reduced certain cytokine expression in the hippocampus of middle-aged WT rats under a SD. Both E2 treatment and previous parity decreased dorsal neurogenesis in hippocampus of hAPOEɛ4 rats. In hAPOEɛ4 females, higher weight was associated with reduced contextual fear memory, an effect driven by primiparous females. In the cued fear conditioning task, hAPOEɛ4 females displayed better cued fear memory than WT, however, WD exposure reduced cued fear memory only in this group. Together, this indicates that diet and weight gain may be more detrimental to associative memory in hAPOEɛ4 females and that E2 treatment has more favourable outcomes in WT rats.

CONCLUSIONS: Previous parity alters how females respond to E2 and metabolic stress in midlife. Primiparous hAPOEɛ4 females were especially vulnerable to the effects of WD and E2, exhibiting more inflammation, impaired memory, and reduced weight-loss. These findings highlight the importance of considering parity and genotype when evaluating midlife metabolic and cognitive risk.}, } @article {pmid42071824, year = {2026}, author = {Li, Q and Jing, S and Li, N and Yuan, X and Wang, T}, title = {Causality relationship between 91 inflammatory factors and Alzheimer disease: A bidirectional Mendelian randomization study.}, journal = {Medicine}, volume = {105}, number = {17}, pages = {e48136}, pmid = {42071824}, issn = {1536-5964}, support = {2024439//Chengdu Medical Research Project/ ; }, mesh = {*Alzheimer Disease/genetics ; Humans ; *Mendelian Randomization Analysis ; Genome-Wide Association Study ; *Inflammation/genetics ; Genetic Predisposition to Disease ; Polymorphism, Single Nucleotide ; }, abstract = {Alzheimer disease (AD) is a neurodegenerative disorder characterized by amyloid plaque deposition, neurofibrillary tangles, and chronic neuroinflammation. Due to its complexity and difficult-to-treat nature, it has cast a huge shadow over global health. In addition to genetic susceptibility, the development of AD is closely related to systemic inflammation. This study aims to evaluate the association between systemic inflammatory factors and AD through a bidirectional Mendelian randomization (MR) design. Our MR design incorporated aggregated data from extensive genome-wide association studies to investigate the causal relationship between genetically determined systemic inflammatory factors and AD. The MR analysis results identified 9 potential systemic inflammatory regulatory factors: C-X-C motif chemokine 5, interleukin-18 receptor 1, interleukin-6, and tumor necrosis factor, which were associated with an increased risk. Conversely, AD is significantly correlated with 5 circulating inflammatory regulatory factors, namely, tumor necrosis factor-related apoptosis-inducing ligand, stem cell factor, monocyte chemoattractant protein-4, interleukin-5, and cystatin D, which are considered downstream consequences of AD. It is worth noting that our results have, for the first time, clarified the significant roles of inflammatory factors such as cystatin D and monocyte chemoattractant protein-4 in AD, providing new markers and key targets for further exploration of the molecular mechanism and clinical diagnosis and treatment of AD.}, } @article {pmid42072160, year = {2026}, author = {Tng, TJW and Cheah, IK and Halliwell, B and Lim, KL}, title = {Potential Protection Against Parkinson's Disease by Ergothioneine-Nature's Multifactorial Neuroprotectant.}, journal = {Antioxidants (Basel, Switzerland)}, volume = {15}, number = {4}, pages = {}, pmid = {42072160}, issn = {2076-3921}, support = {#023643-00001//Ministry of Education/ ; }, abstract = {The use of neuroprotective nutraceuticals as a strategy against neurodegenerative diseases such as Parkinson's disease (PD) has gained considerable traction in recent years. In this review, we highlight ergothioneine (ET)-a naturally occurring thiol/thione derivative abundant in mushrooms-as a promising candidate, given its long half-life, blood-brain barrier penetration, and high bioavailability. Numerous population studies have linked low blood ET levels with increased risk and progression of neurological and other age-related disorders in humans, suggesting that dietary ET may confer neuroprotective benefits. Supporting this, several studies have demonstrated the efficacy of ET treatment in reducing PD-associated molecular damage across various pre-clinical models such as C. elegans, Drosophila, rodent models and human neuronal cultures, leading to marked improvements in disease phenotypes. Here, we summarize some of the proposed mechanisms by which ET may exert neuroprotection in PD, including the reduction of protein aggregation, enhancement of mitochondrial function, mitigation of oxidative stress, and attenuation of apoptosis and neuroinflammation. We also highlight recent clinical trials demonstrating the safety and potential efficacy of ET and propose future research to facilitate the translation of ET into the clinic.}, } @article {pmid42072570, year = {2026}, author = {Dong, L}, title = {A Unified Information Bottleneck Framework for Multimodal Biomedical Machine Learning.}, journal = {Entropy (Basel, Switzerland)}, volume = {28}, number = {4}, pages = {}, pmid = {42072570}, issn = {1099-4300}, support = {R01CA309499/CA/NCI NIH HHS/United States ; }, abstract = {Multimodal biomedical machine learning increasingly integrates heterogeneous data sources (including medical imaging, multi-omics profiles, electronic health records, and wearable sensor signals) to support clinical diagnosis, prognosis, and treatment response prediction. Despite strong empirical performance, most existing multimodal systems lack a principled theoretical foundation for understanding why fusion improves prediction, how information is distributed across modalities, and when models can be trusted under incomplete or shifting data. This paper develops a unified information-theoretic framework that formalizes multimodal biomedical learning as an information optimization problem. We formulate multimodal representation learning through the information bottleneck principle, deriving a variational objective that balances predictive sufficiency against informational compression in an architecture-agnostic manner. Building on this foundation, we introduce information-theoretic tools for decomposing modality contributions via conditional mutual information, quantifying redundancy and synergy, and diagnosing fusion collapse. We further show that robustness to missing modalities can be cast as an information consistency problem and extend the framework to longitudinal disease modeling through transfer entropy and sequential information bottleneck objectives. Applications to multimodal foundation models, uncertainty quantification, calibration, and out-of-distribution detection are developed. Empirical case studies across three biomedical datasets (TCGA breast cancer multi-omics, TCGA glioma clinical-plus-molecular data, and OASIS-2 longitudinal Alzheimer's data) show that the framework's key quantities are computable and interpretable on real data: MI decomposition identifies modality dominance and redundancy; the VMIB traces a compression-prediction tradeoff in the information plane; entropy-based selective prediction raises accuracy from 0.787 to 0.939 at 50% coverage; transfer entropy reveals stage-dependent modality influence in disease progression; and pretraining/adaptation diagnostics distinguish efficient from wasteful fine-tuning strategies. Together, these results develop entropy and mutual information as organizing principles for the design, analysis, and evaluation of multimodal biomedical AI systems.}, } @article {pmid42072691, year = {2026}, author = {Fu, T and Shi, Y and Yang, Z and Zhou, J and Huang, L and Fu, Y and Xiong, W}, title = {Variecolactone, a Natural PDE4 Inhibitor from Marine-Derived Talaromyces sp. ZSD-1, Alleviates Amyloid-β Accumulation and mtDNA Dyshomeostasis via cAMP-PKA-CREB Signaling Pathway.}, journal = {Biomolecules}, volume = {16}, number = {4}, pages = {}, pmid = {42072691}, issn = {2218-273X}, support = {825QN283//Hainan Provincial Natural Science Foundation of China/ ; 82404601//National Natural Science Foundation of China/ ; 22577021//Natural Science Foundation of China/ ; }, mesh = {*Amyloid beta-Peptides/metabolism ; *Phosphodiesterase 4 Inhibitors/pharmacology/chemistry ; Cyclic AMP/metabolism ; Signal Transduction/drug effects ; Animals ; Cyclic Nucleotide Phosphodiesterases, Type 4/metabolism ; *DNA, Mitochondrial/metabolism/genetics ; Cyclic AMP-Dependent Protein Kinases/metabolism ; Cyclic AMP Response Element-Binding Protein/metabolism ; Humans ; Mitochondria/metabolism/drug effects ; *Sesterterpenes/pharmacology/chemistry ; Alzheimer Disease/drug therapy/metabolism ; Mice ; Dynamins/metabolism/genetics ; Neurons/metabolism/drug effects ; }, abstract = {Alzheimer's disease (AD) is characterized by amyloid-β deposition, neuroinflammation, and mitochondrial dysfunction. Phosphodiesterase 4 (PDE4), a key regulator of cyclic nucleotides in neurons, represents a promising therapeutic target for AD. In this study, we performed a PDE4 inhibition-guided screen of an in-house marine natural product library derived from marine fungi, leading to the identification of a sesterterpenoid variecolactone (VLT) as a potent PDE4 inhibitor. VLT exhibited selective PDE4D inhibition (IC50 = 2.302 μM) with minimal activity against other PDE subtypes. Further mechanical investigation revealed that VLT treatment elevated cAMP and p-CREB levels, reduced amyloid-β (Aβ) accumulation, promoted synaptic function, and ameliorated mitochondrial fragmentation, along with mtDNA homeostasis in the AD cell model. Moreover, under conditions of mtDNA depletion or Drp1 overexpression, VLT exerted neuroprotective effects and maintained mtDNA homeostasis via the cAMP-PKA-CREB signaling pathway. These results demonstrate that PDE4 inhibition by VLT represents a promising therapeutic strategy for AD and related neurodegenerative disorders.}, } @article {pmid42072789, year = {2026}, author = {Chung, WK and Kim, HM and Lee, MB and Kim, K and Kwon, OI and Yoo, YJ and Rhee, HY and Jahng, GH}, title = {Evaluation of Low-Dose Radiation Treatment Effects Using Conductivity, Diffusivity, and Brain Tissue Volumes Treated in Patients with Mild Alzheimer's Disease: Exploratory Investigation.}, journal = {Diagnostics (Basel, Switzerland)}, volume = {16}, number = {8}, pages = {}, pmid = {42072789}, issn = {2075-4418}, support = {RS-2024-00335770//National Research Foundation of Korea (NRF) grants funded by the Ministry of Science and ICT/ ; A21IP11//Korea Hydro & Nuclear Power Co. Ltd/ ; }, abstract = {Purpose: No prior clinical studies have quantitatively evaluated the effect of low-dose radiation therapy (LDRT) on Alzheimer's disease (AD) brain changes using multi-modal MRI. This study examined the feasibility of using conductivity, diffusion, and brain tissue volume measures to detect treatment effects in patients with AD receiving LDRT. Methods: Nine patients with mild AD were enrolled in three groups. Three patients in each group were assigned to the control group (0 cGy) and the treated groups [24 cGy/6 fractions (4 cGy for each fraction) and 300 cGy/6 fractions (50 cGy for each fraction)]. Conductivity, diffusivity, and brain tissue volume were acquired at baseline and 6 months post-treatment and were evaluated to assess within-group MRI changes and evaluate associations between MRI measures and Mini-Mental State Examination (MMSE) scores. Results: Region-of-interest (ROI) analyses identified substantial changes in high-frequency conductivity (HFC) (e.g., left insula), cerebrospinal fluid (CSF) volumes (e.g., anterior cingulate, limbic regions), and diffusion tensor imaging (DTI) metrics, such as axial diffusivity (AxD) and fractional anisotropy (FA), in fusiform, thalamic, hippocampal, and occipital areas. Correlation analysis showed strong associations between MRI measures and cognition, most notably HFC in the left fusiform gyrus (r = 0.843, p = 0.0043) after treatment. Diffusion indices across multiple regions also showed significant positive or negative correlations with MMSE. Conclusions: This exploratory clinical study demonstrates that LDRT induces measurable physiological and microstructural alterations in the brain detectable via conductivity and diffusion MRI. Conductivity emerged as the sensitive biomarker, showing strong cognitive correlations. These exploratory findings suggest that multi-modal quantitative MRI can serve as an effective tool for evaluating treatment response in clinical LDRT for AD.}, } @article {pmid42074010, year = {2026}, author = {Goloborshcheva, VV and Kostikova, YS and Kucheryanu, VG and Morozov, SG and Kokhan, VS}, title = {Insights into the Impact of Low-Dose Ionizing Radiation on Neurodegenerative Disease Progression in In Vivo Models.}, journal = {International journal of molecular sciences}, volume = {27}, number = {8}, pages = {}, pmid = {42074010}, issn = {1422-0067}, support = {FGFU-2025-0004//Russian state contract/ ; }, mesh = {Animals ; *Neurodegenerative Diseases/radiotherapy/pathology/metabolism ; Humans ; *Radiation, Ionizing ; Disease Progression ; Disease Models, Animal ; Autophagy/radiation effects ; DNA Repair/radiation effects ; }, abstract = {The effective treatment of neurodegenerative diseases (NDDs), such as Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis, remains a critical challenge in modern medicine. Given the limitations of current therapies, alternative strategies to slow neurodegeneration are urgently needed. This study presents a critical review of the current evidence regarding low-dose ionizing radiation (IR) as a promising modality for modulating neurodegenerative processes. This study examines current experimental data on the effects of low-dose IR (LDIR) on cellular protective and compensatory mechanisms, including evidence from in vivo models of NDDs. Our analysis demonstrates that LDIR enhances antioxidant activity and DNA repair, stimulates autophagy and neuroplasticity, and modulates neuroinflammatory signaling. Collectively, these findings support the hypothesis of the neuroprotective potential of LDIR, underscoring its translational viability provided that strict dosimetric guidelines are followed and individual biological responses are rigorously monitored.}, } @article {pmid42074152, year = {2026}, author = {Wang, W and Zhao, Y and Li, Z and Lv, Y and Xu, Z and Qi, B and Yin, J and Wang, C}, title = {Astragaloside IV Improves Cognitive Impairment in Alzheimer's Mice by Alleviating Neuron PANoptosis.}, journal = {International journal of molecular sciences}, volume = {27}, number = {8}, pages = {}, pmid = {42074152}, issn = {1422-0067}, support = {ZD2023C004//Heilongjiang Natural Science Foundation/ ; 32371840 and 82001113//National Natural Science Foundation of China/ ; }, mesh = {Animals ; *Saponins/pharmacology/therapeutic use ; *Triterpenes/pharmacology/therapeutic use ; *Alzheimer Disease/drug therapy/metabolism/pathology ; *Neurons/drug effects/metabolism/pathology ; Mice ; Hippocampus/drug effects/metabolism/pathology ; *Cognitive Dysfunction/drug therapy/metabolism/etiology ; Amyloid beta-Peptides/metabolism ; Male ; Disease Models, Animal ; Neuroprotective Agents/pharmacology ; Apoptosis/drug effects ; }, abstract = {Alzheimer's disease (AD) is a neurodegenerative disorder for which no effective treatments are currently available. PANoptosis is a coordinated cell death pathway involving pyroptosis, apoptosis, and necroptosis. Astragaloside IV (AS-IV) is a bioactive saponin derived from Astragalus membranaceus. Behavioral performance was evaluated using the Morris water maze and open field tests, while neuronal damage was assessed by Nissl staining. The expression levels of Aβ, IL-18, and PANoptosis-related proteins were analyzed by Western blot. Immunofluorescence was performed to assess the co-localization of PANoptosis-associated proteins with neurons in the hippocampal region. In addition, the effects of AS-IV on the expression of PANoptosis-related proteins were examined in Aβ-induced HT22 cells. AS-IV improved spatial memory performance and alleviated anxiety-like behaviors in AD mice. Furthermore, AS-IV treatment significantly reduced Aβ protein levels and attenuated neuronal loss in the hippocampus. Key markers of PANoptosis were downregulated following AS-IV treatment. Immunofluorescence revealed strong co-localization between PANoptosis-associated proteins and neurons. In vitro, AS-IV also inhibited the Aβ-induced upregulation of PANoptosis-related proteins in HT22 cells. Collectively, these results indicate that AS-IV exerts neuroprotective effects in AD models, which may be associated with reduced Aβ protein deposition, attenuated neuronal loss, and the regulation of PANoptosis-related proteins in the hippocampus.}, } @article {pmid42074388, year = {2026}, author = {Manias, M and Vieira, JVR and Cremonesi, AS}, title = {In Silico Analyses Suggest That Exercise-Induced Irisin-Mediated Neuroprotection Supports Non-Pharmacological Preventive Strategies for Alzheimer's Disease in Public Health.}, journal = {International journal of environmental research and public health}, volume = {23}, number = {4}, pages = {}, pmid = {42074388}, issn = {1660-4601}, mesh = {*Alzheimer Disease/prevention & control/epidemiology ; Humans ; *Fibronectins/metabolism ; Molecular Docking Simulation ; *Neuroprotection ; Brazil/epidemiology ; *Exercise ; Public Health ; Computer Simulation ; Molecular Dynamics Simulation ; }, abstract = {Alzheimer's disease (AD) is the leading cause of dementia and imposes a high economic and social burden on healthcare systems. In Brazil, the consistent increase in costs associated with AD hospitalizations, coupled with the absence of curative therapies and population aging, reinforces the need for low-cost, broadly applicable preventive strategies. This study investigated the role of irisin, a myokine induced by physical activity, in the prevention of AD, integrating epidemiological and bioinformatic analyses. Public data on the nutritional status of the Brazilian population in the early 2000s and on AD hospitalizations approximately 20 years later were analyzed, assessing the temporal association using a lagged Spearman correlation. Additionally, genes associated with AD were analyzed through protein-protein interaction networks and functional enrichment. Structural models of irisin and the integrin αV/β5 receptor were employed in molecular docking and molecular dynamics analyses. Historical data indicated a high prevalence of excess weight in the early 2000s (46.7% ± 4.2% of the adult population) and a strong positive correlation with AD hospitalizations two decades later (ρ = 0.88; p = 0.033). Functional analyses revealed enrichment of pathways related to neurodegeneration, neurotrophins, and neuronal plasticity, involving proteins such as BDNF, AKT, ERK1/2, and CREB. Docking and molecular dynamics indicated a stable interaction of irisin with the αV/β5 receptor, suggesting activation of neuroprotective pathways. The findings reinforce physical exercise as a strategic public health tool for the prevention of AD, providing an epidemiological and molecular basis to reduce the future burden of the disease, thereby shifting the focus of public health policy from treatment to prevention.}, } @article {pmid42076103, year = {2026}, author = {Vasilica, PDF and Dorin, PI and Vladulescu, C and Popescu, C and Trasca, DM and Radivojevic, K and Varut, RM and Vintilescu, ȘB and Stepan, MD and Stoica, GA}, title = {Cyclodextrin-Based Strategies for Brain Drug Delivery: Mechanistic Insights into Blood-Brain Barrier Transport and Therapeutic Applications.}, journal = {Pharmaceutics}, volume = {18}, number = {4}, pages = {}, pmid = {42076103}, issn = {1999-4923}, abstract = {Cyclodextrins (CDs) have gained increasing attention as versatile platforms for enhancing drug delivery to the central nervous system, particularly in overcoming the restrictive properties of the blood-brain barrier (BBB). Owing to their unique cyclic oligosaccharide structure, CDs are capable of forming inclusion complexes with a wide range of therapeutic agents, thereby improving their solubility, stability, and bioavailability. In addition to their role as excipients, growing evidence indicates that CDs can actively modulate biological processes, including membrane fluidity and cholesterol homeostasis, which are critical factors in neurological disorders. This review explores the application of CDs in facilitating drug transport across the BBB through multiple mechanisms, including carrier-mediated transport, receptor-mediated transcytosis, and nanoparticle-based delivery systems. Special emphasis is placed on their use in the treatment of neurodegenerative and neurological diseases, such as Alzheimer's disease, Parkinson's disease, multiple sclerosis, Niemann-Pick type C disease, and other central nervous system disorders. In these contexts, CD-based formulations have demonstrated the ability to enhance brain targeting, reduce pathological protein aggregation, and improve therapeutic outcomes in preclinical models. This review uniquely integrates cyclodextrin's physicochemical properties with specific blood-brain barrier transport mechanisms, proposing a structure-transport-therapy framework that enables a more predictive understanding of brain-targeted drug delivery.}, } @article {pmid42077232, year = {2026}, author = {Ding, T and Chen, J and Xiang, Y and Zhou, X and Zheng, H and Bai, Y and Wang, W and Fu, Q and Chen, Y and Fu, Y}, title = {The Gut-Brain Axis in Alzheimer's: From Microbiota Genetics to Stigmasterol's Neuroprotection Mechanism.}, journal = {Degenerative neurological and neuromuscular disease}, volume = {16}, number = {}, pages = {580890}, pmid = {42077232}, issn = {1179-9900}, abstract = {OBJECTIVE: This study aimed to identify novel therapeutic targets for Alzheimer's disease (AD) by investigating the role of the intestinal flora (IF) via the gut-brain axis, and to predict a potential natural compound for AD treatment and elucidate its underlying mechanism.

METHODS: Following a primary analytical axis, we first employed Mendelian randomization (MR) to infer causal relationships between gut microbiota and AD. To pinpoint molecular targets, we integrated Summary-data-based MR (SMR) with single-cell and spatial transcriptomics. Subsequently, network pharmacology and molecular docking were used to identify stigmasterol as a candidate compound targeting the causal pathway. Finally, the neuroprotective effects and the STIM1/Orai1-mediated mechanism were experimentally validated in vitro using Aβ1-42 exposed SH-SY5Y cells.

RESULTS: MR-based causal inference identified Desulfovibrio as a risk factor for AD, while Slackia and the Lachnospiraceae NK4A136 group were protective factors. Seven key AD-related genes were identified by combining MR results with databases, which were highly druggable. SMR analysis and multi-omics integration pinpointed STIM1-mediated calcium signaling as the core causal pathway. Following the identification of stigmasterol via network pharmacology and molecular docking, in vitro experimental validation confirmed that stigmasterol significantly inhibited Aβ1-42 induced neuronal apoptosis and calcium overload by specifically modulating the STIM1/Orai1 pathway and the Bcl-2/Bax ratio.

CONCLUSION: This study decodes the gut-brain axis by establishing the specific causal pathway. We demonstrate that Stigmasterol exerts neuroprotective effects by inhibiting apoptosis through a IF-associated mechanism involving the STIM1/Orai1 pathway, provideing novel insights into AD pathogenesis and offering a promising therapeutic strategy based on natural compounds.}, } @article {pmid42078936, year = {2026}, author = {Wu, W and Wang, H and Zhang, L and Li, D and Chen, Y and Lin, B and Jiang, H and Meng, T and Zhu, Z and He, L and Zhang, H and Liu, H and Zhang, R}, title = {Dexmedetomidine attenuates Alzheimer's pathogenesis by targeting the ROS-mediated XIAP-MDM2-p53 signaling axis.}, journal = {Frontiers in pharmacology}, volume = {17}, number = {}, pages = {1811373}, pmid = {42078936}, issn = {1663-9812}, abstract = {INTRODUCTION: Alzheimer's disease (AD) is a multifactorial neurodegenerative disorder with a complex pathological process, in which oxidative stress serves as a key pathogenic mechanism. Studies have shown that the anesthetic adjuvant dexmedetomidine (Dex) can improve postoperative cognitive function in AD patients. This study aimed to explore whether dexmedetomidine alleviates AD-associated neuronal apoptosis and cognitive impairment via reducing overproduction of ROS and regulating the XIAP signaling pathway.

METHODS: In vitro experiments were conducted using Aβ1-42-exposed SH-SY5Y cells and primary neurons, employing interventions such as the ROS scavenger NAC, yohimbine pre-treatment, and siRNA-mediated XIAP knockdown. In vivo cognitive deficits and brain pathology were evaluated in AD model mice using Morris water maze tests and immunofluorescence staining.

RESULTS: Experimental results demonstrated that Aβ1-42 induced apoptosis in neuronal cells, while dexmedetomidine incubation significantly reduced Aβ1-42 elicited ROS generation, activated XIAP, suppressed MDM2 and ameliorated P53 overactivation, thereby effectively preventing neuronal death. Combined administration of NAC and dexmedetomidine reversed Aβ1-42-induced XIAP inhibition, ROS accumulation, and cell apoptosis. Furthermore, both yohimbine pre-treatment and XIAP knockdown effectively abrogated the ability of Dex to reduce ROS accumulation and mitigate apoptosis. In vivo results indicated that dexmedetomidine improved cognitive deficits and intervened in AD pathology in the hippocampal region of AD model mice.

CONCLUSION: This study reveals that dexmedetomidine inhibits ROS release and activates the XIAP-MDM2-p53 signaling pathway, thereby delaying apoptosis and ameliorating cognitive impairment in AD progression.}, } @article {pmid42079210, year = {2026}, author = {Caohuy, H and Ognoon, M and Chen, T and Yang, Q and Dib, T and Pollard, BS and Fatima, N and Flagg, T and Soni, DK and Biswas, R and Rittase, W and L'Esperance, OJ and Juliano, S and Pollard, HB}, title = {PM2.5 toxin benzo[a]pyrene induces life-limiting inflammation and oxidative stress in the airway by up-regulation of TRPC6 and inactivation of β2AR/CFTR signaling.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {42079210}, issn = {2692-8205}, abstract = {BACKGROUND: Sustained exposures to high atmospheric levels of PM2.5 at population scale are associated with increased risks for pulmonary inflammatory diseases. These are marked by activation of the TRPC6 (Transient Receptor Potential Canonical type 6) calcium channel, increased reactive oxygen species (ROS) and oxidative stress. Long term exposures are associated with reduced life span, and increased incidences of cardiovascular diseases, dementia, Parkinson's and Alzheimer disease, and increased risk of autism and autism spectrum disorders. It has been proposed that the PM2.5 toxin is benzo[a]pyrene (B[a]P) that is adsorbed to the surface of the PM2.5 particle.. But the mechanism by which B[a]P might drive pulmonary inflammatory diseases, or any other of the indications above, are not known.

HYPOTHESIS: B[a]P was recently reported to bind irreversibly and destructively to the β2 Adrenergic Receptor (β2AR) in the lung. We have therefore hypothesized that B[a]P is the adsorbed PM2.5 toxin, and that β2AR is the B[a]P receptor responsible for TRPC6 activation in lung epithelial cells.

RESULTS: To test this hypothesis, we exposed a polarized organoid model of normal human lung epithelia, polarized lung epithelial 16HBE14o- cells, and tracheobronchial slice cultures from ferret lung to either PM2.5 or B[a]P. We found that both PM2.5 and B[a]P: (i) irreversibly activated of β2AR signaling via Gi to PI3K/AKT; (ii) increased NFκB-activated release of proinflammatory cytokines through IKKαβ activation by PI3K/AKT, which was suppressed by the PI3K inhibitor LY 294002 (iii) desensitized and destroyed the activated β2AR receptor by endocytic recycling; (iv) also destroyed β2AR's signalplex partner CFTR by the same process; (v) activated the CFTR-bound calcium channel protein TRPC6 due to loss of inhibitory CFTR; leading to (vi) increased cytosolic [Ca[2+]] concentration; (vii) increased ROS due to mitochondrial uncoupling; and (viii) increased expression of oxidative stress. Treatment with the TRPC6 inhibitor BI 749327 blocked steps (vi-viii), and preserved CFTR from endocytic loss. Treatment of tracheobronchial slice cultures of ferret lung with either PM2.5 or B[a]P resulted in increased secretion of IL-6, increased expression of TRPC6, and reduced expression of β2AR and CFTR. Finally, we found that exposure of lung organoids to B[a]P significantly reduced expression of the same five microRNAs (miR-126a-3p, miR-30b-5p, miR-103a-3p, miR-26a-5p, and miR-766-3p) previously identified in sera from service members exposed to PM2.5 from burn pit emissions during deployment to Iraq and Afghanistan.

CONCLUSION: PM2.5 and the PM2.5 toxin benzo[a]pyrene (B[a]P) induce inflammation and oxidative stress in the airway by increased expression of TRPC6 and inactivation of β2AR/CFTR signaling. These discoveries mark the first identification of a mechanism by which exposure to PM2.5 or the PM2.5 toxin B[a]P itself can induce inflammation and TRPC6-dependent oxidative stress in lung epithelia.}, } @article {pmid42080000, year = {2026}, author = {Darwish, M and Lin, N and Dirks, B and Jaworowicz, D and Maxwell, K and Pathak, S}, title = {Population pharmacokinetics of remlifanserin (ACP-204), a serotonin 2A receptor inverse agonist.}, journal = {Alzheimer's & dementia (New York, N. Y.)}, volume = {12}, number = {}, pages = {e70254}, pmid = {42080000}, issn = {2352-8737}, abstract = {INTRODUCTION: Remlifanserin, or ACP-204, is a potent serotonin 2A receptor inverse agonist under investigation for treatment of Alzheimer's disease psychosis and Lewy body dementia psychosis. A population pharmacokinetics (popPK) model for remlifanserin was developed to evaluate the impact of covariates affecting pharmacokinetic variability and assess the clinical relevance of these factors in a virtual population.

METHODS: A popPK model was developed using remlifanserin plasma concentrations (n = 3935) from 209 participants across seven Phase 1 trials (10 to 180 mg, oral). Data were pooled and analyzed using non-linear mixed-effects modeling. Intrinsic (demographics, hepatic/renal function) and extrinsic (food effect) factors were assessed. Model evaluation included goodness-of-fit plots and prediction-corrected visual predictive checks (pcVPCs). Interindividual variability was estimated for key parameters; residual variability was modeled using proportional error. Simulated steady-state exposures (maximum plasma concentration at steady state [Cmax,ss] and area under the plasma concentration-time curve over the 24-h dosing interval at steady state [AUC0-24,ss]) in a virtual population (n = 1000; 60 mg/day) were derived using PK parameters sampled from the final model. The clinical relevance of significant covariates was evaluated using geometric mean ratios and 90% confidence intervals (CIs) of exposures using a 0.8 to 1.25 boundary presented in a forest plot.

RESULTS: The final popPK model was a one-compartment model with first-order absorption with lag time and linear elimination. Typical parameter estimates included apparent oral clearance (35.4 L/h), apparentoral volume of distribution (V/F) (male, 930 L; female, 799 L), absorption lag time (ALAG1) (fasted, 0.720 h; fed, 0.929 h)and absorption rate constant (Ka) (0.692/h). Goodness-of-fit plots and pcVPCs demonstrated that the model adequately captured the central tendency and magnitude of variability in remlifanserin concentrations. Statistically significant relationships were found between food and ALAG1 and between sex and V/F (P < 0.001); however, neither factor had a clinically relevant impact on Cmax,ss or AUC0-24,ss.

DISCUSSION: The pharmacokinetics of oral remlifanserin (10 to 180 mg) are well described by dose-proportional linear kinetics. No intrinsic or extrinsic factors exhibited a clinically relevant effect on steady-state remlifanserin exposures.}, } @article {pmid42081122, year = {2026}, author = {Dieguez Ferreira, Y and Braga Moura, C and Carneiro Rodrigues, A and Pereira Da Silva, AM and Haddad Santos, D and Fernanda Mendes, M}, title = {Causes of death in patients with dementia: A study in a geriatric hospital in São Paulo, Brazil.}, journal = {Journal of Alzheimer's disease : JAD}, volume = {111}, number = {4}, pages = {1735-1741}, doi = {10.1177/13872877261445578}, pmid = {42081122}, issn = {1875-8908}, mesh = {Humans ; Female ; Brazil/epidemiology ; Aged, 80 and over ; Male ; Retrospective Studies ; Cause of Death ; *Dementia/mortality ; Aged ; Terminal Care ; Alzheimer Disease/mortality ; Mixed Dementias ; }, abstract = {BackgroundDementia contributes to morbidity and mortality in aging populations, with infectious diseases as frequent terminal events. In Brazil, data on causes of death in dementia and hospital-based end-of-life care are limited.ObjectiveTo describe causes of death, clinical characteristics, and pharmacological treatment patterns during the last month of life among patients with dementia hospitalized in a geriatric hospital in São Paulo, Brazil.MethodsThis retrospective observational study included all patients with clinically diagnosed dementia who died between 2015 and 2023 in a specialized geriatric hospital. Demographic, clinical, and pharmacological data were extracted from electronic medical records. Causes of death were classified using ICD-10 codes. Associations between dementia subtypes and infection-related deaths were evaluated using logistic regression adjusted for age, sex, and comorbidities. Statistical analyses were performed using R, with p < 0.05 considered significant.ResultsA total of 122 patients were included (mean age 83.6 ± 7.4 years; 61.5% female). Alzheimer's disease was the most frequent subtype (52.5%), followed by vascular (26.2%) and mixed dementia (21.3%). Infectious diseases accounted for 67.2% of deaths, mainly pneumonia (48.3%) and sepsis (18.9%). Antibiotics were prescribed in 76.2% of cases, and antipsychotics in 58.1%. Palliative care measures were documented in 41.0% of cases.ConclusionsInfectious diseases were the most frequent causes of death among hospitalized patients with dementia, with high antibiotic use and limited palliative care documentation. These findings indicate the need for integrated end-of-life protocols and improved recognition of palliative needs.}, } @article {pmid42081190, year = {2026}, author = {Liu, F and Wang, J and Kang, Y and Su, G and Wang, X}, title = {Effects of high-frequency repetitive transcranial magnetic stimulation on memory of post-stroke cognitive impairment patients: A systematic review and meta-analysis.}, journal = {Journal of Alzheimer's disease : JAD}, volume = {112}, number = {1}, pages = {65-79}, doi = {10.1177/13872877261447431}, pmid = {42081190}, issn = {1875-8908}, mesh = {Humans ; *Transcranial Magnetic Stimulation/methods ; *Stroke/complications/psychology ; *Cognitive Dysfunction/therapy/etiology/psychology ; *Memory/physiology ; Memory Disorders/therapy/etiology ; }, abstract = {BackgroundThere is an evident interrelationship between stroke and Alzheimer's disease (AD). Post-stroke cognitive impairment (PSCI) is a frequently encountered and potentially disabling outcome of stroke. Memory impairment is an important component of the post-stroke cognitive syndrome, and high-frequency repetitive transcranial magnetic stimulation (HF-rTMS) has been widely used for memory in patients with PSCI.ObjectiveIn this study, we systematically evaluated the therapeutic effects of HF-rTMS on memory function in patients with PSCI, offering insights that may also inform the treatment of AD.MethodsAll relevant publications in Chinese and English were systematically searched from ten databases up to March 20, 2025. Retrieved articles were carefully screened. The quality of the included studies was assessed using the Cochrane Collaboration's risk of bias tool. The Review Manager 5.4 software was adopted for meta-analysis.ResultsTwenty-one studies of 1746 participants with PSCI were included. Meta-analysis revealed that HF-rTMS ameliorated memory of PSCI patients according to several outcome indicators: Rivermead Behavioural Memory Test [mean difference (MD) = 2.59, 95% confidence interval (CI) (2.08, 3.11), p < 0.00001], forward digit span [MD = 1.79, 95% CI (1.36, 2.22), p < 0.00001] and backward digit span [MD = 1.18, 95% CI (0.77, 1.59), p < 0.00001] of digit span test, Delayed Recall of the Montreal Cognitive Assessment [MD = 0.53, 95% CI (0.47, 0.59), p < 0.00001]; all p < 0.05.ConclusionsThe HF-rTMS might enhance memory in patients with PSCI, with the left dorsolateral prefrontal cortex being the most common stimulation site.}, } @article {pmid42081371, year = {2026}, author = {Gawor, K and Statz, K and Schaeverbeke, J and Thal, DR}, title = {Alzheimer's disease subtyping approaches and the role of co-pathologies.}, journal = {Brain : a journal of neurology}, volume = {}, number = {}, pages = {}, doi = {10.1093/brain/awag157}, pmid = {42081371}, issn = {1460-2156}, abstract = {Alzheimer's disease (AD) is characterized by amyloid-β plaques and abnormal phosphorylated tau protein-containing neurofibrillary tangles, yet it shows marked heterogeneity in clinical presentation, neuroanatomical involvement, and progression rate. This variability challenges the traditional view of AD as a single disease entity and has prompted efforts to define patient subgroups with shared characteristics who might benefit from targeted treatment strategies. Here, we provide a cross-disciplinary overview of current subtyping strategies. We describe both traditional stratification approaches, including those based on clinical AD syndromes, neuropathological staging, and age of onset, as well as emerging data-driven methods that utilize clinical information, neuroimaging, omics data, and multimodal data integration. Subtypes derived using these data-driven methods overlap to some extent with hypothesis-driven classifications but also uncover additional axes of heterogeneity, including distinct anatomical patterns and molecular signatures. Furthermore, we highlight that most AD patients exhibit co-pathologies such as transactive response DNA-binding protein 43, α-synuclein, or cerebrovascular changes, which are often overlooked in existing stratification systems, despite their potential to affect atrophy patterns and progression rate and, hence, influence subtype interpretation. Finally, we outline future directions for developing unified stratification frameworks that link clinical features with underlying biology, including co-pathologies, aiming to enhance diagnostic precision and enable future personalized therapeutic interventions.}, } @article {pmid42082123, year = {2026}, author = {Fan, YH and Fan, KS and Lin, TL}, title = {Reduced dementia risk in middle-aged and older atopic dermatitis patients treated with dupilumab: A target trial emulation.}, journal = {Brain, behavior, and immunity}, volume = {136}, number = {}, pages = {106796}, doi = {10.1016/j.bbi.2026.106796}, pmid = {42082123}, issn = {1090-2139}, abstract = {BACKGROUND: Middle-aged and older adults with atopic dermatitis (AD) are at increased risk of dementia, possibly driven by chronic inflammation and involving IL-4 and IL-13 pathways. Whether treatment with dupilumab, an IL-4/IL-13 inhibitor, influences subsequent dementia risk in this population remains unclear.

METHODS: This target trial emulation study utilized the TriNetX database. Patients aged ≥ 50 years with AD were identified and divided into two groups: those newly prescribed dupilumab and those newly prescribed conventional systemic agents without dupilumab exposure. Propensity score matching (1:1) was performed based on age, sex, race, and comorbidities. Dementia risk was assessed using Cox regression.

RESULTS: After matching, each group included 10,039 patients (∼52% female; mean age, 63 years; 63% White). The 5-year cumulative incidence of dementia was lower among dupilumab users than controls (2.37% vs 3.33%; P = 0.001). Dupilumab use was associated with a reduced risk of all-cause dementia (HR 0.68; 95% CI, 0.54-0.86), with similar reductions observed across dementia subtypes, including secondary (HR 0.69; 95% CI, 0.48-0.99), unspecified (HR 0.70; 95% CI, 0.53-0.93), and Alzheimer's dementia (HR 0.61; 95% CI, 0.40-0.93). Subgroup and sensitivity analyses showed consistent results, with control outcome analyses supporting the robustness of the findings. In a validation analysis of middle-aged and older asthma patients, dupilumab users likewise had a lower dementia risk than omalizumab users (HR 0.68; 95% CI, 0.47-0.98).

CONCLUSIONS: Dupilumab use was associated with a reduced risk of dementia in middle-aged and older adults with AD compared with conventional systemic agents.}, } @article {pmid42082519, year = {2026}, author = {Wang, J and Mao, Y and Liu, X and Hao, W and , }, title = {Learning patient-specific spatial biomarker dynamics via operator learning for Alzheimer's disease progression.}, journal = {NPJ systems biology and applications}, volume = {}, number = {}, pages = {}, doi = {10.1038/s41540-026-00719-x}, pmid = {42082519}, issn = {2056-7189}, support = {1R35GM146894/GM/NIGMS NIH HHS/United States ; 1R35GM146894/GM/NIGMS NIH HHS/United States ; }, abstract = {Alzheimer's disease (AD) is a complex, multifactorial neurodegenerative disorder with substantial heterogeneity in progression and treatment response. Despite recent therapeutic advances, predictive models capable of accurately forecasting individualized future biomarker states remain limited. Here, we present a machine learning-based operator learning framework for personalized modeling of AD progression, integrating longitudinal multimodal imaging, biomarker, and clinical data. Unlike conventional models with prespecified dynamics, our approach directly learns patient-specific disease operators governing the spatiotemporal evolution of amyloid, tau, and neurodegeneration biomarkers. Using Laplacian eigenfunction bases, we construct geometry-aware neural operators capable of capturing complex brain dynamics. Embedded within a digital twin paradigm, the framework enables individualized predictions, simulation of therapeutic interventions, and in silico clinical trials. Applied to AD clinical data, our method achieves high prediction accuracy exceeding 90% across multiple biomarkers, substantially outperforming existing approaches. This work offers a scalable, interpretable platform for precision modeling and personalized therapeutic optimization in neurodegenerative diseases.}, } @article {pmid42082800, year = {2026}, author = {Nazli, D and Poyraz, YK and Can, K and Ipekgil, D and Cakmak, N and Turhanlar-Sahin, E and Hacoglu, S and Erdost, HA and Iyilikci, L and Ozhan, G}, title = {Dexmedetomidine Exerts Multi-level Effects to Ameliorate Alzheimer's Disease Pathology in the Adult Zebrafish Brain.}, journal = {Molecular neurobiology}, volume = {63}, number = {1}, pages = {}, pmid = {42082800}, issn = {1559-1182}, mesh = {Animals ; *Dexmedetomidine/pharmacology/therapeutic use ; *Alzheimer Disease/drug therapy/pathology ; *Brain/pathology/drug effects ; Zebrafish ; Amyloid beta-Peptides/metabolism/toxicity ; *Aging/pathology/drug effects ; Neuroprotective Agents/pharmacology/therapeutic use ; Disease Models, Animal ; Peptide Fragments ; }, abstract = {Alzheimer's disease (AD) is a complex neurodegenerative condition involving β-amyloid (Aβ) deposition, tau abnormalities, neuroinflammation, neuronal degeneration, and progressive impairment of cognitive functions. Despite extensive research, effective disease-modifying therapies remain limited, highlighting the need for translationally relevant models and repurposable therapeutic candidates. Dexmedetomidine (DEX), an α2-adrenergic receptor agonist with known neuroprotective properties, was investigated in an adult zebrafish model of AD established through cerebroventricular administration of Aβ42. DEX treatment significantly reduced Aβ accumulation and was associated with reduced amyloidogenic gene expression, indicating transcriptional changes in amyloidogenic pathway-related genes. DEX attenuated neuroinflammation by reducing glial activation, lowering pro-inflammatory cytokine gene expression, and increasing expression of the anti-inflammatory gene il10. Immunofluorescence assessment further demonstrated reduced astrogliosis and preserved neuronal marker integrity, as indicated by increased HuC/D levels. Interestingly, DEX attenuated Aβ-induced proliferative responses, characterized by decreased PCNA expression, while enhancing cleaved caspase-3 levels, suggesting changes in proliferation and apoptotic signaling under Aβ stress conditions. Behavioral assessments further demonstrated that DEX alleviated Aβ42-induced anxiety- and aggression-like behaviors, improving behavioral phenotypes in this model. Overall, these findings underscore the multi-level effects of DEX in modulating AD-related pathological features. As a clinically available agent, DEX represents a promising candidate for repurposing in neurodegenerative disease contexts. Further preclinical studies in mammalian models are warranted to validate its translational relevance and therapeutic potential.}, } @article {pmid42082802, year = {2026}, author = {Motieiyan, E and Motahari, R and Aliabadi, A and Khaksar, S and Abdolmaleki, S}, title = {Cobalt complexes in biology and medicine: enzymatic functions, pharmacological applications, and health challenges.}, journal = {Journal of biological inorganic chemistry : JBIC : a publication of the Society of Biological Inorganic Chemistry}, volume = {}, number = {}, pages = {}, pmid = {42082802}, issn = {1432-1327}, abstract = {Cobalt is an essential trace element in biochemistry that plays a crucial role in the structure and function of several important biomolecules. In this review, vitamin B12 is discussed as one of the best-known examples in this area. Various forms of this vitamin, including methylcobalamin and adenosylcobalamin, play a crucial role in metabolic reactions in mammals and prokaryotes. It also discusses cobalt-containing enzymes that are essential for various biological processes. These enzymes are B12-dependent enzymes, which are well studied, and cobalt-containing enzymes, which are less well known, such as methionine aminopeptidase, nitrile hydratase, glucose isomerase, and prolidase. In addition to the significant role of cobalt complexes in biochemistry, these complexes are considered potent anticancer agents that can exert their antiproliferative effects through the production of ROS, cell cycle arrest, MMP breakdown, and induction of apoptosis in cancer cells. Cobalt complexes are also being explained here for their antimicrobial properties against a variety of pathogens, including bacteria, fungi, and viruses. Furthermore, examples of these complexes are presented as promising agents for the suppression of AD, which could be effective by binding to Aβ-peptides and preventing their aggregation, which is a central feature of the pathogenesis of AD, or by combating the oxidative damage associated with the disease, or even by interfering with the enzyme activities associated with this disease. Finally, the challenges related to the toxicity of cobalt and its compounds in medicine are discussed, and chelation therapy is considered an effective treatment for cobalt poisoning.}, } @article {pmid42082835, year = {2026}, author = {Zheng, X and Chen, P and Li, D and Li, W and Liao, J and Zhang, M}, title = {Lamotrigine Improves Spatial Learning and Attenuates AD-Related Pathology in APP/PS1 Mice, with Possible Involvement of the cAMP/PKA/CREB Pathway.}, journal = {Neurochemical research}, volume = {51}, number = {3}, pages = {}, pmid = {42082835}, issn = {1573-6903}, mesh = {Animals ; *Lamotrigine/therapeutic use/pharmacology ; Cyclic AMP-Dependent Protein Kinases/metabolism ; *Alzheimer Disease/drug therapy/metabolism/pathology/genetics ; Cyclic AMP Response Element-Binding Protein/metabolism ; Amyloid beta-Protein Precursor/genetics ; Presenilin-1/genetics ; Signal Transduction/drug effects ; Mice, Transgenic ; *Spatial Learning/drug effects/physiology ; Cyclic AMP/metabolism ; Mice ; Male ; }, abstract = {Alzheimer's disease (AD) is characterized by impaired spatial learning functions, amyloid-β accumulation, tau hyperphosphorylation, and neuroinflammation. Antiepileptic drugs such as lamotrigine have shown promise in improving brain functions in AD, but the underlying mechanisms remain unclear. This study aimed to evaluate the therapeutic effects of lamotrigine in amyloid precursor protein/presenilin 1 (APP/PS1) transgenic mice and elucidate the underlying molecular mechanisms using integrated transcriptomic and metabolomic analyses. APP/PS1 mice were treated with lamotrigine from 3 months of age, and spatial learning performance was assessed using the Morris water maze test. Histological and molecular changes were evaluated through hematoxylin and eosin staining, Western blotting, ELISA, and immunohistochemistry. High-throughput RNA sequencing and untargeted metabolomics were performed to explore differentially expressed genes, metabolites, and enriched signaling pathways. Western blot validation and pharmacological inhibition were used to verify pathway involvement. Lamotrigine treatment significantly improved spatial learning performance, ameliorated neuronal degeneration, and decreased Aβ1 levels and tau phosphorylation in the brains of APP/PS1 mice. Inflammatory markers and glial activation were also markedly suppressed. Multi-omics analysis revealed alterations in key pathways related to synaptic plasticity, lipid metabolism, and autophagy. Notably, both omics data and protein validation highlighted the cAMP/PKA/CREB pathway as a potentially relevant pathway. Co-administration of the PKA inhibitor H89 abolished lamotrigine-induced upregulation of p-CREB and BDNF, supporting the involvement of this pathway. Lamotrigine improves spatial learning and attenuates AD-related pathology in APP/PS1 mice, possibly through modulation of the cAMP/PKA/CREB signaling pathway, highlighting its potential as a candidate for further investigation.}, } @article {pmid42082960, year = {2026}, author = {Liu, S and Zhu, J and Zhong, H and Zhou, D and Long, Q and Zhang, Z and Yang, X and Wu, Q and Cheng, C and Wu, J and Luu, HN and Wang, J and Zhao, B and Wu, C and Deng, Y and Wu, L}, title = {Investigating causal associations among inflammatory proteins, blood metabolites, and Alzheimer's disease risk.}, journal = {BMC psychiatry}, volume = {26}, number = {1}, pages = {}, pmid = {42082960}, issn = {1471-244X}, mesh = {*Alzheimer Disease/genetics/blood/metabolism ; Humans ; Genome-Wide Association Study ; Mendelian Randomization Analysis ; *Inflammation/genetics/blood/metabolism ; Risk Factors ; *Blood Proteins/metabolism ; }, abstract = {Alzheimer's disease (AD) is a prevalent degenerative neurological disorder with limited treatment options. Prior studies reported specific metabolites and inflammatory proteins to be related to AD risk. However, the intricate relationship between inflammatory proteins, blood metabolites, and AD risk in European population remains unclear. Genetic instruments for 1,091 metabolites and 736 inflammatory proteins were derived from two recent comprehensive genome-wide association studies. Univariable Mendelian Randomization was employed to assess potential causal effects of metabolites on AD risk, potential effects of inflammatory proteins on metabolites, and effects of inflammatory proteins on AD risk. Multivariable MR (MVMR) was further applied to disentangle direct effects of proteins and metabolites on AD. Twelve metabolites were identified to be associated with AD risk, and 226 inflammatory proteins demonstrated likely to be causal effects on these 12 metabolites. Further examining the associations between such inflammatory proteins and AD risk revealed 22 associations for which the effect directions from inflammatory proteins to metabolites, from metabolites to AD risk, and from inflammatory proteins to AD risk were aligned, suggesting inflammatory protein - metabolite - AD risk pathway. MVMR further highlighted four trios in which the effect directions were consistent with the UVMR results, supporting a metabolite‑mediated pattern. This large‑scale genetic analysis highlights specific metabolites as direct contributors to AD risk and suggests that certain inflammatory proteins may influence AD primarily through downstream metabolic pathways. Our findings offer potential novel therapeutic targets for AD intervention.}, } @article {pmid42083360, year = {2026}, author = {Pandey, H and Kaur, A and Khan, J and Sharma, A}, title = {Nanomedicine for Alzheimer's Disease: Diagnostic and Therapeutic Progress.}, journal = {MicroRNA (Shariqah, United Arab Emirates)}, volume = {}, number = {}, pages = {}, doi = {10.2174/0122115366427696260203074113}, pmid = {42083360}, issn = {2211-5374}, abstract = {The complex nature of the pathophysiology and limited treatment options of AD make it a huge challenge in healthcare. The recent developments in nanotechnology have given fresh hope for diagnosing and treating AD, which could serve as a way out of the existing problems. This review dwells on the role of nanotechnology in AD and its applications at its early stages through the development of nanosensors and boost imaging methods. Additionally, nanotechnology-driven therapeutic strategies are being investigated with nanoparticle-based drug delivery systems that aim to target the blood-brain barrier, among others. Current research innovations, clinical trials, and prospects highlight the transformative potential of nanotechnology in reshaping AD management. Ethical issues related to applying nanomedicine in neurodegenerative diseases, as well as fears about nanoparticles, are carefully analyzed herein. Finally, this review concludes with a synthesis of how nanotechnology has affected Alzheimer's Disease (AD) while emphasizing emerging trends and future directions toward advancing research on Alzheimer's Disease (AD). This comprehensive overview underscores the pivotal role of nanotechnology in revolutionizing AD prognosis and therapy, paving the way for personalized and effective treatment strategies.}, } @article {pmid42083572, year = {2026}, author = {Minhas, AM and Khan, AU and Gul Qazi, N and Nadeem, H and Ali, F}, title = {Pharmacological investigation of oxadiazole derivatives in Alzheimer's disease: Modulation of oxidative stress, neuroinflammation, and iNOS signaling.}, journal = {Iranian journal of basic medical sciences}, volume = {29}, number = {3}, pages = {423-437}, pmid = {42083572}, issn = {2008-3866}, abstract = {OBJECTIVES: Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by deposition of amyloid-beta (Aβ) aggregates. Aβ peptides alter synaptic function and produce neuroinflammation. The neurotoxic mechanisms are also related to increases in the expression of iNOS (inducible nitric oxide synthase), resulting in further neuronal degeneration and memory impairment.

MATERIALS AND METHODS: In the current study, we assessed the in vivo effect of the 1,3,4-oxadiazole derivative 2-{[5-(2-aminophenyl)-1,3,4-oxadiazol-2-yl] sulfanyl} -N-(1,3-benzothiazol-2-yl) acetamide (MA) on spatial memory and inflammatory responses induced by AlCl3 administration in animals.

RESULTS: A notable improvement in memory function was observed in the AlCl3-induced group at 29[th] post-injection, following MA treatment (5, 10, and 20 mg/kg), as indicated by the behavioral analysis. This effect is correlated with decreases in inflammatory markers such as NFKƁ, IL-6/ß1, IFN-γ, TNϜ-α, and NO levels, as well as a reduction in expression of neurodegenerative markers: β-amyloid and p-tau (*P<0.05, **P<0.01, ***P<0.001 vs disease control). The results from our study suggested that MA significantly enhances the levels of glutathione, catalase, and glutathione S-transferase while decreasing the lipid peroxidation (LPO) in comparison to the disease control group, and also improves mitochondrial dysfunction. The effects are further enhanced when MA was used in combination with aminoguanidine (AG), an iNOS inhibitor. Molecular dynamics (MD) simulations, along with protein mRNA expression and iNOS western blotting, further supported the results of in vivo experiments.

CONCLUSION: Our study proposed that MA attenuated the cytokine release, decreased oxidative stress, and iNOS expression, leading to a decrease in neurodegeneration.}, } @article {pmid42083945, year = {2026}, author = {Kumar, D and Walhekar, V and Kasaragod, MS and Kini, S}, title = {Discovery of Novel Quinazoline Thiazole Uredio Analogs as Dual Inhibitors of GSK-3β and CK-1δ as Anti-Alzheimer's Agents: Catching Two Fish with One Net.}, journal = {Current topics in medicinal chemistry}, volume = {}, number = {}, pages = {}, doi = {10.2174/0115680266378266251017045841}, pmid = {42083945}, issn = {1873-4294}, abstract = {INTRODUCTION: AD is a widespread and debilitating neurodegenerative disorder, and existing treatments have demonstrated limited efficacy, emphasizing the need for novel therapeutic strategies. This study focused on the design of drug-like molecules with enhanced efficacy and minimized side effects through the application of structure-based scaffold hopping and molecular hybridization strategies.

METHODS: Molecular docking was carried out on the Glide module, Molecular dynamics simulation of 500 ns was executed employing Desmond, and ADMET prediction was achieved by the QikProp modules of Schrodinger.

RESULTS: Through molecular docking studies targeting the GSK-3β and CK-1δ enzymes, the compounds VDK12 and VDK14 were identified as promising inhibitors, showing favorable interactions within the active sites of these proteins, with docking energies of -9.9 kcal/mol and -10.1 kcal/mol, respectively. Molecular dynamics simulations further revealed that the VDK12 and VDK14 complexes exhibited stable interactions within the active sites of GSK-3β and CK-1δ throughout a 500 ns simulation. Additionally, in silico ADMET analysis demonstrated that VDK1 exhibited an excellent human oral absorption rate of 91.349%, outperforming other compounds in the series.

DISCUSSION: Molecules as dual inhibitors were designed successfully by the application of scaffold hopping and molecular hybridization. Designed molecules demonstrated excellent molecular docking and dynamics simulation results with an appropriate ADMET profile.

CONCLUSION: These findings strongly suggest the potential of VDK12 and VDK14 as dual inhibitors of GSK-3β and CK-1δ, offering a promising foundation for the development of new lead compounds for AD treatment.}, } @article {pmid42083963, year = {2026}, author = {Kanojia, N and Deswal, G and Grewal, AS and Kumar, J and Thapa, K and Sharma, A and Sharma, A and Dheer, D and Puri, V and Rani, L and Saini, V}, title = {Advances in Microneedle Technology for Targeted Therapy in Alzheimer's and Parkinson's Disease.}, journal = {Current drug delivery}, volume = {}, number = {}, pages = {}, doi = {10.2174/0115672018425956260117232402}, pmid = {42083963}, issn = {1875-5704}, abstract = {INTRODUCTION: The fourth major cause of death worldwide is Neurodegenerative Diseases (NDs), including Alzheimer's and Parkinson's disease. The existing therapies have only a small effect on alleviating symptoms, mainly because the therapeutic agents are difficult to cross the bloodbrain barrier. The purpose of the review is to discuss the potential of microneedle-based transdermal delivery systems to improve the delivery of drugs to the central nervous system and thereby manage neurodegenerative diseases effectively.

METHODS: The article summarizes and synthesizes the available literature that targets the strategies of microneedle-mediated drug delivery. The literature on the design, composition, pharmacokinetics, and mechanistic benefits of different microneedle platforms for surmounting central nervous system barriers was identified and thematically synthesized.

RESULTS: Microneedle systems have emerged as non-invasive delivery systems with the potential for localized and sustained drug delivery, overcoming the stratum corneum and the blood-brain barrier. Micro-needles can be used to deliver small molecules, peptides, and nanoparticles to the brain, thereby avoiding systemic side effects and enhancing drug bioavailability. Some of those designs include dissolving, coated, hollow, hydrogel-forming, and stimuli-responsive microneedles, which have been shown to target the brain and exhibit higher therapeutic efficiency in preclinical models.

DISCUSSION: Although technological advances have improved, the clinical translation of microneedlebased strategies remains limited. The future directions could include using microneedles with stem cell-based therapies, CRISPR/Cas9 gene editing, artificial intelligence-based delivery systems, and responsive release technology to facilitate customized treatment.

CONCLUSION: The Microneedle-based drug delivery systems are promising in overcoming the current limitations in the treatment of neurodegenerative diseases. Nonetheless, a large-scale clinical validation is necessary to guarantee safety, efficacy, and scalability to be applied to real-life scenarios.}, } @article {pmid42083975, year = {2026}, author = {Saffold, K and Tall, A and Lowery, AT and Pryor, T and Jones-Muhammad, M and Shao, Q and Warrington, JP}, title = {Mouse offspring exposed to preeclampsia/eclampsia-like symptoms exhibit cerebral hypoperfusion and mild cognitive impairment at 2 mo of age.}, journal = {American journal of physiology. Heart and circulatory physiology}, volume = {330}, number = {6}, pages = {H1909-H1921}, doi = {10.1152/ajpheart.00711.2025}, pmid = {42083975}, issn = {1522-1539}, support = {R25 HL145817/HL/NHLBI NIH HHS/United States ; R56 HL159447/HL/NHLBI NIH HHS/United States ; 1 R56 HL159447//HHS | NIH | National Heart, Lung, and Blood Institute (NHLBI)/ ; P30GM103328//HHS | NIH | National Institute of General Medical Sciences (NIGMS)/ ; P30 GM103328/GM/NIGMS NIH HHS/United States ; 5R25HL145817//HHS | NIH | National Heart, Lung, and Blood Institute (NHLBI)/ ; Startup/Bridge Funds from the Department of Neurology//University of Mississippi (UM)/ ; }, mesh = {Animals ; Female ; Pregnancy ; *Pre-Eclampsia/physiopathology ; Mice, Inbred C57BL ; *Cognitive Dysfunction/physiopathology/etiology/psychology ; *Cerebrovascular Circulation ; *Eclampsia/physiopathology/chemically induced/psychology ; *Prenatal Exposure Delayed Effects ; Disease Models, Animal ; Pentylenetetrazole ; Maze Learning ; Male ; Mice ; *Brain/physiopathology/blood supply ; Spatial Learning ; Placental Circulation ; *Behavior, Animal ; Seizures/physiopathology/chemically induced ; }, abstract = {Preeclampsia is a pregnancy complication characterized by high blood pressure and signs of organ damage, after the 20th week of pregnancy. Children born to mothers with preeclampsia or eclampsia (new-onset seizures during pregnancy) are more likely to develop learning and memory deficits and are more susceptible to neurovascular diseases compared with those born from normal pregnancies. The contributing mechanisms are unknown. In this study, we assessed whether exposure to reduced uteroplacental perfusion (RUPP), modeling placental hypoperfusion and preeclampsia, with or without pentylenetetrazol (PTZ) injection (to induce seizures and model eclampsia), results in cognitive impairment, Alzheimer's disease markers, and regional cerebral perfusion changes in adult offspring. On gestational day (GD)13.5, pregnant C57BL/6 mice (n = 22) underwent Sham or RUPP surgery followed by injection or no treatment with PTZ (40 mg/kg) on GD18.5. At 2 mo of age, spatial learning and cerebral perfusion were measured in randomly selected offspring or averaged to obtain mean data per sex, per litter (n = 4-6 data points per group/treatment). RUPP-exposed offspring took a longer distance and made more errors navigating the Barnes maze. Cerebral perfusion was reduced in offspring exposed to RUPP, specifically in the prefrontal cortex, superior sagittal sinus, and whole brain. There was a significant reduction in perfusion in seizure-exposed offspring in the superior sagittal and transverse sinuses, whole brain, and cerebellum. Our results support the hypothesis that exposure to preeclampsia/eclampsia-like symptoms leads to mild learning impairment through reduced cerebral perfusion to cortical regions and decreased drainage of waste from the brain via the cerebral sinuses.NEW & NOTEWORTHY This is the first study to assess vascular-related cognitive function and Alzheimer's disease markers in young adult mice exposed to preclinical preeclampsia and eclampsia-like conditions. We show that mild learning impairments occur in the presence of cerebral hypoperfusion and reduced venous drainage into the brain sinuses. We also report that as early as 2 mo of age, Alzheimer's disease markers are increased in the brains of offspring exposed to seizures.}, } @article {pmid42083983, year = {2026}, author = {Au, R and Gifford, KA and Paschalidis, IC and Wighton, P and Levin, M and Imam, F and Bose, N and Pratap, A}, title = {The myth of digital biomarkers in Alzheimer's disease: how to make them a reality.}, journal = {Current opinion in psychiatry}, volume = {39}, number = {4}, pages = {331-338}, pmid = {42083983}, issn = {1473-6578}, mesh = {Humans ; *Alzheimer Disease/diagnosis ; *Biomarkers/blood ; Digital Health ; United States ; United States Food and Drug Administration ; *Digital Technology ; }, abstract = {PURPOSE OF REVIEW: With an estimated 41.1B digital devices, the term "digital biomarkers" has been increasingly bandied about in the research literature. There is, however, a significant disconnect between the presumption of digital biomarkers and the reality of digital biomarkers.

RECENT FINDINGS: The research literature embraces the concept of digital biomarkers without concomitant evidence for validation of digital measures as biomarkers. Unlike imaging or blood-based biomarkers, there is a woeful lack of research dedicated to validating digital measures as biomarkers. This gap also presents an opportunity. Regulatory agencies worldwide have long-standing protocols used by pharmaceutical and biotech companies to stand up quality management systems (QMS) that track research from inception to regulatory approved submissions. The recent United States (US) Food and Drug Administration (FDA) approval of Alzheimer's disease (AD) plasma biomarkers is another example where successful QMS implementation provided the processes and transparency necessary to obtain approval. Regulatory guidelines for digital technology validation are more circumspect on validation pathways of AD digital biomarkers, but FDA provides a framework for building a QMS that could potentially do so.

SUMMARY: Building an open source QMS for AD digital biomarker validation will be a critical breakthrough for harnessing the potential of digital technologies for detection, monitoring and treatment of AD and related disorders.}, } @article {pmid42084750, year = {2026}, author = {Hafez, MM and Abbas, HA and Shoman, NA and Soubh, AA and Aly, O and Sallam, MF and Seliem, M and Malaak, FA}, title = {A new era in neuropharmacology: assessing the efficacy and safety of novel anti-amyloid and non-amyloid drug targets for Alzheimer's disease.}, journal = {Journal of neurology}, volume = {273}, number = {5}, pages = {}, pmid = {42084750}, issn = {1432-1459}, mesh = {Humans ; *Alzheimer Disease/drug therapy/metabolism ; *Amyloid beta-Peptides/metabolism/antagonists & inhibitors ; *Antibodies, Monoclonal/therapeutic use/pharmacology ; Animals ; *Neuropharmacology/trends ; }, abstract = {BACKGROUND: Alzheimer disease (AD) is the most common cause of dementia in the world with the prevalence expected to increase threefold to 152.8 million people by 2050. The current medications provide a short-term ameliorative effect, and this requires development of disease-modifying treatments, which address the biological pathogenesis.

METHODS: This review assesses the changing neuropharmacological environment offering a critical analysis of anti-amyloid monoclonal antibodies and investigates the so-called expanding frontier of non-amyloid targets. It also examines the approaches of clinical trials and the trend of biomarker-based patient selection and precision medicine.

RESULTS: Although β-site APP-cleaving enzyme 1 (BACE1) and secretase inhibitors did not achieve success in clinical trials because of mechanism-based toxicity and cognitive impairment, new monoclonal antibodies such as lecanemab and donanemab have shown high amyloid plaque clearance and reduced cognitive deterioration. Nevertheless, the treatments are associated with amyloid-related imaging abnormalities (ARIA). In addition to amyloid, studies are focusing on tau hyperphosphorylation, neuroinflammation through triggering receptor on myeloid cells 2 (TREM2) and NLR family pyrin domain containing 3 (NLRP3) and growth factor-mediated synaptic plasticity through brain-derived neurotrophic factor (BDNF).

CONCLUSIONS: AD treatment has entered the new era that demands a paradigm shift from monotherapies to multi-target cocktails. The future lies in precision neuropharmacology, where genetic stratification and individual biomarker analysis are used to provide the correct treatment at the most appropriate biological stage.}, } @article {pmid42084972, year = {2026}, author = {Kumar, D and Singh, SB and Sagar, V and Prasad, MK and Kapoor, N and Mukul, A and Nishant, A}, title = {Breakthrough Vaccines and Transformative Therapies on the Horizon of Progress toward Diabetes Management.}, journal = {Indian journal of public health}, volume = {70}, number = {2}, pages = {236-242}, doi = {10.4103/ijph.ijph_102_25}, pmid = {42084972}, issn = {0019-557X}, mesh = {Humans ; *Diabetes Mellitus/therapy/prevention & control ; *Vaccines/therapeutic use ; Vaccine Development ; Animals ; }, abstract = {BACKGROUND: Diabetes mellitus, affects millions of people globally. Over the years, diabetes has emerged as a significant global health concern, with steadily increasing prevalence.

OBJECTIVES: This review explores the various aspects of diabetes mellitus, and delves into the evolving field of new emerging treatments and diabetes vaccines, highlighting the potential they hold in revolutionizing diabetes management in the future.

MATERIALS AND METHODS: Literature search was done in PubMed database and relevant articles were selected for the narrative review.

RESULTS: The review reveals that currently most vaccines that have been developed are in animal studies and early phases of trials. Only few human trials have been conducted, but, with positive outcome. There are also some novel therapeutics emerging as potential management options for diabetes. Therefore, it is imperative to know about the potential vaccines and novel emerging treatment options for diabetes mellitus, to understand the challenges faced in constructing novel vaccines and the intricate relationship between diabetes and Alzheimer's disease, an emerging entity as Type 3 Diabetes.

CONCLUSION: There is a growing interest in the development of vaccines as a revolutionary approach to diabetes management. As our understanding of diabetes deepens and vaccine technology advances, the prospect of a diabetes vaccine becoming a reality offers hope for millions living with this condition and in reducing the burden of diabetes-related complications.}, } @article {pmid42086977, year = {2026}, author = {Khan, TTS and Wong, CYJ and Sheikh, Z and Fathi, A and Maleknia, S and Oveissi, F and Abrams, T and Knox, W and van der Hoven, J and Antonito, A and Murray, M and Svolos, M and Suman, J and Tietz, O and Ong, HX and Traini, D}, title = {Repurposing insulin for Alzheimer's disease treatment: intranasal delivery of a thermoresponsive nanocarrier-based insulin formulation to the brain.}, journal = {Drug delivery and translational research}, volume = {}, number = {}, pages = {}, pmid = {42086977}, issn = {2190-3948}, abstract = {The Intranasal route provides an effective pathway for insulin delivery to the brain compared to oral/subcutaneous routes as it provides direct access to the brain, bypassing the restrictive blood-brain barrier (BBB), while minimizing systemic exposure. The present study investigated the potential of a thermoresponsive polymer, PNPHO, as a nanocarrier for brain-targeted insulin delivery through the intranasal route, with the aim of repurposing insulin for Alzheimer's disease treatment. Insulin-loaded nanoparticles (NP) were formulated using an advanced crossflow mixing technology with lower (F1) and higher (F2) PNPHO concentrations and characterised in vitro for size, zeta potential, encapsulation efficiencies, stability, drug deposition, and transport and in vivo for biodistribution. Both F1 and F2 NP demonstrated particle sizes ranging from 35.9 to 49.8 nm with low polydispersity index (< 0.3), negative surface charges, high encapsulation efficiencies (> 99%), and conserved structural integrity post 4 weeks of stability study. NP demonstrated significantly greater in vitro nasal deposition compared to insulin alone. Notably, the PNPHO nanocarrier protected insulin from enzymatic degradation, overcoming a key barrier associated with protein/peptide delivery. In vitro drug transport studies showed an initial delay in NP transport across nasal cells due to PNPHO-mucoadhesive properties, followed by increased transport. Significantly enhanced time-dependent NP transport across the BBB cells compared to insulin alone (p < 0.0001) confirmed NP's ability to cross the BBB. In vivo, NP demonstrated prolonged nasal retention and higher brain: serum ratio in mice, suggesting sustained drug release and improved brain delivery compared to insulin alone. Collectively, the study highlight the potential of PNPHO as a promising nanocarrier for achieving targeted and efficient intranasal delivery of insulin to the brain.}, } @article {pmid42087592, year = {2026}, author = {Liu, X and Xu, H and Zhao, Y and Yang, J and Zhang, L and Wang, Z and Lim, K and Zhang, C and Lu, L}, title = {Roles of POU3F2 in Brain Development and Neuropsychiatric Disorders.}, journal = {Developmental neurobiology}, volume = {86}, number = {3}, pages = {e70034}, doi = {10.1002/dneu.70034}, pmid = {42087592}, issn = {1932-846X}, support = {202200331//Cooperative Research Project/ ; //Shanxi Province Higher Education/ ; 82571379//National Natural Science Foundation of China/ ; }, mesh = {Animals ; Humans ; *Brain/growth & development/metabolism ; *Mental Disorders/metabolism ; *POU Domain Factors/metabolism/genetics ; Neurodevelopment ; *Homeodomain Proteins/metabolism/genetics ; *Nerve Tissue Proteins/metabolism/genetics ; Neurons/metabolism ; }, abstract = {POU3F2, a member of the Pit-Oct-Unc (POU) domain transcription factor family, is widely expressed in the central nervous system and essential for the development and maturation of brain. POU3F2 deletion results in impaired hypothalamus and neocortex development, and most mice die between postnatal days 0 and 10. Recently, emerging evidences have demonstrated that POU3F2 is involved in neuropsychiatric disorders, including Alzheimer's disease, Parkinson's disease, Huntington's disease, bipolar disorder, schizophrenia, and autism spectrum disorder, albeit still with some limitations in current studies. Besides, POU3F2 also plays a vital role in the reprogramming of somatic cells into neuronal lineages, which provides new ideas and directions for the treatment of neuropsychiatric disorders. This review aims to systematically summarize and analyze the diverse roles of POU3F2 in brain development, neuropsychiatric disorders, and neuronal reprogramming. Furthermore, the potential of POU3F2-targeted therapies for neuropsychiatric disorders and proposed key questions for future research are also emphasized. POU3F2 plays a pivotal role in brain development, the pathogenesis of neurological and psychiatric disorders, and the reprogramming of neural cells. A more comprehensive and systematic understanding of its molecular mechanism might provide novel therapeutic approaches for neuropsychiatric disorders.}, } @article {pmid42088060, year = {2026}, author = {Hou, DL and Ho, J and Guan, T and Dong, XX and Zeng, L and Sanders, LH and Wu, YC and Tan, EK and Zhou, ZD}, title = {E3 ubiquitin ligases in neurodegenerative diseases.}, journal = {Military Medical Research}, volume = {13}, number = {1}, pages = {100032}, pmid = {42088060}, issn = {2054-9369}, mesh = {Humans ; *Ubiquitin-Protein Ligases/therapeutic use/metabolism ; *Neurodegenerative Diseases/physiopathology/enzymology ; Animals ; Proteolysis Targeting Chimera ; Ubiquitination ; }, abstract = {Neurodegenerative diseases (NDs) are characterized by progressive neuronal loss and proteostatic failure, driven by impaired clearance of misfolded proteins via the ubiquitin-proteasome system (UPS) and autophagy. In UPS, E3 ubiquitin ligases are crucial for regulating protein ubiquitination and degradation. Mutations in E3 ligases, along with dysfunctions of specific ligases such as Parkin, the C-terminus of HSC70-interacting protein (CHIP), and tripartite motif-containing proteins, have been identified as key factors in the buildup of amyloid-β, α-synuclein, tau, trans-active response DNA-binding protein 43, and mutant huntingtin. These accumulations are associated with NDs like Parkinson's disease, Alzheimer's disease, Huntington's disease, and amyotrophic lateral sclerosis. Therapeutic strategies targeting E3 ligases, particularly proteolysis-targeting chimeras (PROTACs), are being developed for ND treatment and are currently in clinical trials. These approaches aim to enhance E3 ligase activity and promote selective protein degradation. Here, we examine how individual E3 ligases influence cell-fate decisions in NDs, showing that their substrate selection determines whether neurons survive or die. Building on this knowledge, we present an innovative therapeutic pipeline that includes ligase activators, PROTAC degraders, and miRNA switches, which are molecules designed to transition from research to clinical application.}, } @article {pmid42089471, year = {2026}, author = {Shu, D and Fu, C and Liu, Z and Li, C}, title = {The role of Annexin A2 in Alzheimer's disease: From cellular functions to therapeutic potential.}, journal = {The FEBS journal}, volume = {}, number = {}, pages = {}, doi = {10.1111/febs.70574}, pmid = {42089471}, issn = {1742-4658}, support = {31900692//National Natural Science Foundation of China/ ; 32070961//National Natural Science Foundation of China/ ; 2024AFB558//Natural Science Foundation of Hubei Province/ ; }, abstract = {Alzheimer's disease (AD), a progressive neurodegenerative disorder with a rising global prevalence, is pathologically characterised by the presence of amyloid-β (Aβ) plaques and neurofibrillary tangles (NFTs). These lesions lead to synaptic damage, neuronal loss, and cognitive impairment. Despite the recent approval of immunotherapies for AD treatment, their limited efficacy highlights the urgent need for exploring novel disease mechanisms and developing targeted therapeutic strategies. Annexin A2 (ANXA2), a calcium-dependent phospholipid-binding protein, participates in diverse physiological processes (e.g. membrane organisation, cytoskeleton linkage) and contributes to the pathogenesis of diseases such as cancer and Parkinson's disease. Emerging evidence indicates that ANXA2 interacts with AD-related pathological components (Aβ, tau) and regulates AD-associated inflammatory pathways, suggesting its potential role in AD. However, current evidence regarding ANXA2 in AD remains limited, and the molecular mechanisms underlying its contribution to AD pathogenesis remain unclear. This review comprehensively summarises the current knowledge on ANXA2's cellular and physiological functions in the central nervous system (CNS), as well as its involvement in AD pathology, aiming to provide guidance for research into ANXA2's therapeutic potential for AD prevention and treatment.}, } @article {pmid42089534, year = {2026}, author = {Liang, S and Lapane, KL and Ott, BR and Tjia, J and Baek, J and Yuan, Y and Alcusky, M}, title = {Antidepressant Use Among US Nursing Home Residents With Dementia.}, journal = {Journal of the American Geriatrics Society}, volume = {}, number = {}, pages = {}, doi = {10.1111/jgs.70492}, pmid = {42089534}, issn = {1532-5415}, support = {5R01AG068450-03/AG/NIA NIH HHS/United States ; }, abstract = {BACKGROUND: In 2024, 6.9 million Americans lived with Alzheimer's disease and related dementias (ADRD), with nursing homes serving as a major site of care. Antidepressants are the most prescribed psychotropic medications among nursing home residents with ADRD, yet detailed information on prescribing patterns, potential indications, and associated resident and facility characteristics remain limited.

METHODS: Using 2018 minimum data set 3.0 assessments linked to Medicare claims, we conducted a cross-sectional study of long-stay nursing home residents aged ≥ 65 years with ADRD who were continuously enrolled in Medicare fee-for-service for 120 days before their annual assessment. We described usage by drug class and type and compared characteristics of users versus non-users overall and by potential indications: depression, anxiety, pain, and insomnia.

RESULTS: Among 232,543 residents with ADRD, 51.6% used antidepressants. Fewer than 5% had moderate or severe depressive symptoms (PHQ-9 ≥ 10). Use was highest among residents with depression or anxiety (69.5%), pain (61.9%), and insomnia (60.0%). Among those without these conditions, 14.1% were prescribed antidepressants. SSRIs were the most prescribed class (60.7%) overall. Citalopram, mirtazapine, sertraline, and trazodone were the most common medications. Residents with any current level of depression severity were more likely to use antidepressants compared to those without symptoms, whereas all levels of cognitive impairment were associated with lower use compared with cognitively intact residents with ADRD. Polypharmacy was strongly associated with increased use, while diabetes, heart failure, and stroke were associated with reduced use.

CONCLUSIONS: Antidepressants were frequently prescribed to residents with ADRD despite limited documentation of active depressive symptoms. Limitations in accurately capturing depressive symptoms in nursing home records, including underreporting by residents due to cognitive impairment and reliance on staff observation rather than self-report, may contribute to apparent discordance between symptoms and prescribing. Further research should evaluate treatment appropriateness, deprescribing opportunities, and risk-benefit balance of chronic treatment in this population.}, } @article {pmid42089987, year = {2026}, author = {Chen, S and Zhao, K and Shi, Z and Zhang, C and Wu, H and Tian, M and Sun, Y and He, L}, title = {Study on the improvement effect and mechanism of resveratrol on cognitive impairment in tau mutant adenovirus-induced alzheimer's disease model mice.}, journal = {Psychopharmacology}, volume = {}, number = {}, pages = {}, pmid = {42089987}, issn = {1432-2072}, abstract = {RATIONALE: Tau protein hyperphosphorylation and neuroinflammation playimportant roles in the onset and progression of Alzheimer's disease (AD). SIRT1has been implicated in the regulation of synaptic plasticity, cognitive function, andmemory, and is associated with the modulation of autophagy-and inflammation-related signaling pathways, including AMPK/mTOR/ULK1 and NF-κB. Resveratrol(RSV) has been reported to ameliorate cognitive impairment in AD models,primarily in the context of Aβ-related pathology; however, its potential effects andunderlying mechanisms in Tau-driven pathology remain incompletely understood.

OBJECTIVES: To investigate the effect of RSV on cognitive impairment in mice withTau mutation-induced Alzheimer's disease, and to explore its effects on autophagyand neuroinflammation.

METHODS: Tauopathy models were established using AAV-P301L-Tau. Cognitivefunction was assessed via behavioral tests; Hippocampal injury was evaluatedAccepted manuscriptACCEPTED MANUSCRIPTusing HE and Nissl staining, while autophagy was assessed byimmunofluorescence staining. Mechanisms were examined using Western blot,qRT-PCR, and CCK-8 assays.

RESULTS: RSV treatment was associated with attenuation of neuronal damage,reduction of p-Tau accumulation, and improvement of cognitive impairment in ADmice. Consistent trends were observed in vitro, where RSV treatment wasassociated with increased cell viability and modulation of autophagy-relatedmarkers in AAV-P301L-Tau-induced BV2 cells. In addition, RSV administration wasaccompanied by coordinated changes in signaling components related to SIRT1,AMPK/mTOR/ULK1, and NF-κB pathways, along with reduced expression ofinflammatory mediators.

CONCLUSIONS: RSV treatment was associated with coordinated modulation ofsignaling components related to the AMPK/mTOR/ULK1 and NF-κB pathways,together with improvements in cognitive performance in AD mice. These findingssupport the potential therapeutic relevance of RSV in Tau-drivenneurodegenerative pathology, while further studies are required to clarify theunderlying mechanisms.}, } @article {pmid42090736, year = {2026}, author = {Malotaux, V and Ku, V and Ospina Lopera, P and Su, Y and Chen, Y and Singh, A and Ruiz-Triviño, J and Hidalgo, MJ and Osorio, L and Serna, L and Giraldo, D and Alzate, D and He, B and Tristão-Pereira, C and Ramirez Gomez, L and Do Carmo, S and Cuello, AC and Ashton, NJ and Reiman, EM and Aguillón, D and Quiroz, YT}, title = {Associations of plasma biomarkers with age in the presenilin-1 E280A autosomal dominant Alzheimer's disease kindred.}, journal = {The journal of prevention of Alzheimer's disease}, volume = {13}, number = {6}, pages = {100578}, pmid = {42090736}, issn = {2426-0266}, mesh = {Humans ; Female ; *Alzheimer Disease/genetics/blood ; *Biomarkers/blood ; *Presenilin-1/genetics ; Cross-Sectional Studies ; Male ; tau Proteins/blood ; Adult ; Amyloid beta-Peptides/blood ; Glial Fibrillary Acidic Protein/blood ; Middle Aged ; Mutation ; Neurofilament Proteins/blood ; Age Factors ; Peptide Fragments/blood ; Colombia ; Heterozygote ; }, abstract = {BACKGROUND: Autosomal-dominant Alzheimer's disease (ADAD) offers a model to define early biological changes in Alzheimer's disease due to its predictable age at symptom onset. Although ultrasensitive plasma assays are available, their associations with age in ADAD remain incompletely characterized.

OBJECTIVES: To characterize age-related changes in plasma biomarkers and examine associations with cognition in PSEN1 E280A ADAD.

DESIGN AND SETTING: Cross-sectional observational study in members of the Colombian PSEN1 E280A kindred.

PARTICIPANTS: A total of 164 individuals were included, comprising 83 mutation carriers (mean age 34.36±9.82 years; 54% female) and 81 non-carriers (mean age 33.75±9.84 years; 52% female).

MEASUREMENTS: Plasma Aβ42/Aβ40, phospho-tau217 (p-tau217), brain-derived tau (BD-tau), glial fibrillary acidic protein (GFAP), and neurofilament light (NfL) were quantified. Sex-adjusted associations with age, divergence ages between groups, classification performance (ROC curves), and associations with cognition (MMSE and CERAD delayed recall) were assessed.

RESULTS: All plasma biomarkers were associated with age (p < .01). Divergence between carriers and non-carriers began with Aβ42/Aβ40 before age 18, followed by p-tau217 (26.0 years), GFAP (26.1 years), BD-tau (27.9 years), and NfL (38.7 years). Aβ42/Aβ40 showed the highest discrimination of mutation status (AUC=0.99), followed by p-tau217 (AUC=0.87) and GFAP (AUC=0.84). Among carriers, p-tau217, GFAP, BD-tau, and NfL were associated with MMSE, while p-tau217, GFAP, and NfL predicted CERAD delayed recall.

CONCLUSION: Plasma biomarkers exhibit a temporal cascade in PSEN1 E280A ADAD. P-tau217 and GFAP show the strongest associations with early cognitive decline, suggesting their potential utility for tracking disease progression and monitoring treatment effects in E280A carriers.}, } @article {pmid42090785, year = {2026}, author = {Sánchez Valle, R and Lleó Bisa, A and Villarejo Galende, A and Cuartero Rodríguez, E and Escudero-Torrella, J and Bargallo Alabart, N}, title = {Adapting the spanish healthcare system for disease-modifying treatments in early-stage alzheimer's disease.}, journal = {The journal of prevention of Alzheimer's disease}, volume = {13}, number = {7}, pages = {100586}, pmid = {42090785}, issn = {2426-0266}, abstract = {BACKGROUND: The emergence of disease-modifying therapies targeting amyloid pathology represents a major paradigm shift in the management of Alzheimer disease (AD). However, their implementation poses substantial organizational, infrastructural, and clinical challenges for health systems.

OBJECTIVES: To identify the key challenges and establish priority recommendations for the effective incorporation of amyloid-targeting therapies into the Spanish National Health System.

This multiphase consensus study was conducted within the Spanish National Health System between September 2024 and July 2025. The study comprised a narrative literature review, qualitative research, regional workshops, and a modified RAND/UCLA Delphi process. A total of 56 experts participated, including a scientific committee of 6 Alzheimer disease specialists and an expert panel of 50 multidisciplinary professionals involved in AD care.

MEASUREMENTS: Identification of key challenges across the AD care pathway; development, evaluation, and prioritization of consensus-based recommendations; and estimation of patient demand, including projected increases in day hospital activity and magnetic resonance imaging utilization.

RESULTS: Ten key challenge areas were identified, encompassing early detection and referral, diagnostic confirmation, assessment of patient eligibility, treatment administration in day hospitals, monitoring of amyloid-related imaging abnormalities, evaluation of treatment effectiveness, infrastructure and capacity, professional training, patient information and support, and health care planning. Of the 43 recommendations assessed, 38 were rated as appropriate and necessary, with 14 prioritized for immediate implementation. Demand estimation models indicated that 11 to 26 patients per 100,000 inhabitants could be treated under current care patterns, increasing to 17 to 115 per 100,000 inhabitants under alternative eligibility scenarios.

CONCLUSIONS: This consensus defines the clinical, organizational, and infrastructural requirements necessary to integrate amyloid-targeting therapies into routine care within the Spanish National Health System. The prioritized recommendations define immediate actions to address the challenges identified and may serve as a reference for other health systems facing similar implementation processes.}, } @article {pmid42091766, year = {2026}, author = {Kumar, V and Kakoty, V and Wadhwa, P}, title = {Advancements in Gene Delivery using Nucleic Acid Loaded Nanoparticles for Region Specific Delivery in Alzheimer's Disease.}, journal = {Molecular neurobiology}, volume = {63}, number = {1}, pages = {}, pmid = {42091766}, issn = {1559-1182}, mesh = {*Alzheimer Disease/therapy/genetics ; Humans ; Animals ; *Nanoparticles/chemistry/administration & dosage ; *Nucleic Acids/administration & dosage ; *Gene Transfer Techniques ; *Genetic Therapy/methods ; }, abstract = {Alzheimer's disease (AD) is a progressive and the most common neurodegenerative condition, having a deleterious effect on memory, eventually leading to death. In the recent past, gene therapy has emerged as a promising and revolutionary treatment for AD. This study demonstrated that nucleic acid-loaded nanoparticles which deliver small interfering RNA through lipid nanoparticles successfully reduced Alzheimer's disease-related symptoms in preclinical models by decreasing amyloid-β levels and enhancing cognitive abilities. However, every rose has its thorn, as the output of gene therapy is considerably hampered by the physiological barriers of the brain, which include the blood-brain barrier and the brain's extracellular matrix (ECM). For this reason, many researchers have modified the gene delivery technique by developing 'brain penetrating' NPs coated with components that can prevent sticking to the ECM. Moreover, to overcome the challenge of low transgene expression and reduced accumulation in the brain, even when delivered at high doses, scientists have proposed that injection/delivery of gene vectors directly into a specific area in the brain can achieve maximum therapeutic efficacy. Hence, this review focuses on the advancements and advantages of region-specific delivery of nucleic acid-loaded NPs for the effective therapeutic management of AD.}, } @article {pmid42091792, year = {2026}, author = {Otaegui, L and Lehoux, J and Begu, S and Moujellil-Legagneur, T and Zussy, C and Vitalis, M and Mathias, M and Beau, A and Durand, T and Givalois, L and Bernoud-Hubac, N and Crauste, C and Desrumaux, C}, title = {Intranasal lipid nanocapsule administration of the new lipophenol quercetin-3-O-DHA-7-O-iPr reduces carbonyl stress and improves behavior in a mouse model of Alzheimer's disease.}, journal = {Drug delivery and translational research}, volume = {}, number = {}, pages = {}, pmid = {42091792}, issn = {2190-3948}, support = {CBS2 PhD grant//Université Montpellier/ ; MUSE-AAP20REC-FRS09-GAiA//Université Montpellier/ ; PhD grant//Association France Alzheimer/ ; ANR-AAP2022-R22102FF-EpiNeurAge//Agence Nationale de la Recherche/ ; ANR-18-CE18-0017//Agence Nationale de la Recherche/ ; ANR-11-LABEX-0021-LipSTIC//Agence Nationale de la Recherche/ ; MND202003011477-OPA//Fondation pour la Recherche Médicale/ ; }, abstract = {Oxidative and carbonyl stresses (COS), which damage brain cells through the accumulation of toxic reactive carbonyl species (RCS), are key players in the etiology of Alzheimer's disease (AD). Our group developed lipophenols, i.e. COS-targeting hybrid molecules combining polyunsaturated fatty acids (PUFAs) and alkyl-(poly)phenols. Among them, quercetin-3-O-docosahexaenoate-7-O-isopropyl (Quercetin-3-O-DHA-7-O-iPr or "Q-iP-DHA") afforded neuroprotection against acrolein-induced toxicity, reduced carbonyl stress, and lowered amyloid-beta secretion in neuroblastoma cells. To evaluate Q-iP-DHA in vivo, it was formulated into lipid nanocapsules (to allow solubilization) then administered intranasally to J20 transgenic mice, a model of AD. This approach was chosen to optimize blood-brain barrier (BBB) penetration. This delivery led to improvements in well-being, organizational skills and spatial memory. In addition, Q-iP-DHA treatment reduced hippocampal amyloid plaque numbers, normalized expression of the Receptor for Advanced Glycation End-products (RAGE), and decreased microglial activation, indicating anti-inflammatory effects. Overall, our preclinical findings suggest that intranasal administration of nanoformulated Q-iP-DHA may represent a promising multitarget therapeutic approach against AD.}, } @article {pmid42093461, year = {2026}, author = {Andreão, FF and da Silva, RO and Negreli, MFLA and Aguiar-Barros, ABP and Santos, DH}, title = {Baseline epidemiological differences between donanemab and lecanemab users in real-world settings: a retrospective cohort study.}, journal = {Neurodegenerative disease management}, volume = {}, number = {}, pages = {1-6}, doi = {10.1080/17582024.2026.2667432}, pmid = {42093461}, issn = {1758-2032}, abstract = {AIMS: Donanemab and Lecanemab are anti-amyloid monoclonal antibodies recently approved for the treatment of Alzheimer's disease. Although their efficacy and safety have been investigated in randomized trials, real-world epidemiological data on treated populations remain limited. This study aimed to compare baseline clinical and laboratory characteristics of patients treated with donanemab versus lecanemab in routine practice.

PATIENTS AND METHODS: We conducted a retrospective analysis using the TriNetX US Collaborative Network, including patients with Alzheimer's disease treated with donanemab or lecanemab between January 2024 and September 2025. Demographics, laboratory values, comorbidities, and concomitant medications were compared using standardized mean differences (SMD) and p-values. Variables with SMD ≥0.1 or p < 0.05 were considered meaningfully different.

RESULTS: A total of 1,799 patients were included (donanemab n = 360; lecanemab n = 1,439). Demographic characteristics were well balanced (mean age 73.1 vs 72.5 years; SMD 0.028). Lecanemab users were more likely to be prescribed antidepressants (52% vs 41%; p < 0.0001; SMD = 0.23) and donepezil (61% vs 52%; p = 0.0145; SMD = 0.14). Donanemab users had higher prothrombin time (12.2 ± 2.17 vs 11.8 ± 1.66 s; p = 0.0158; SMD = 0.20) and INR (1.06 ± 0.19 vs 1.03 ± 0.13; p = 0.0369; SMD = 0.17), and a higher prevalence of vascular dementia (81% vs 76%; p = 0.0272; SMD = 0.12).

CONCLUSION: While demographic variables were similar. These findings likely reflect real-world clinical selection patterns and should be accounted for in comparative effectiveness and safety analyses of anti-amyloid therapies.}, } @article {pmid42094385, year = {2026}, author = {Sanders, B and Korthauer, M and Parihar, KS and Ifergan, I}, title = {Poly(lactic-co-glycolic acid) immunomodulatory nanoparticles attenuate neuroinflammation and Alzheimer's disease-related pathology in 5xFAD mice.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {42094385}, issn = {2692-8205}, support = {R03 NS144870/NS/NINDS NIH HHS/United States ; R35 GM146890/GM/NIGMS NIH HHS/United States ; }, abstract = {Alzheimer's disease is characterized by progressive cognitive decline, amyloid-β deposition, neuroinflammation, and neurodegeneration, yet effective and well-tolerated therapies remain limited. Because dysregulated myeloid responses are increasingly recognized as important drivers of disease progression, we investigated the therapeutic potential of poly(lactic-co-glycolic acid) immunomodulatory nanoparticles in the 5xFAD mouse model of amyloid-driven neurodegeneration. Poly(lactic-co-glycolic acid) immunomodulatory nanoparticles and fluorescently labeled particles displayed the expected size range and negative surface charge. After intraperitoneal administration, fluorescent particles were preferentially associated with myeloid cells in the blood, spleen, and brain, with greater uptake by brain myeloid populations in 5xFAD mice than in wild-type controls. Therapeutic treatment of 6.5-month-old 5xFAD mice, a stage at which behavioral abnormalities are already established, resulted in significant improvement in elevated plus maze behavior and a more modest improvement in Barnes maze performance. Flow cytometric analysis performed 9 weeks after the final treatment demonstrated persistent changes in brain immune composition, with the most prominent effects observed in P2RY12[+] microglial populations, particularly the CD11c[+] subset, and comparatively limited sustained effects in CD11b[+]P2RY12[-] myeloid cells. These changes were accompanied by reduced expression of activation- and disease-associated markers and lower pro-inflammatory cytokine production within microglial populations. Histological analysis further showed reduced cortical amyloid plaque burden, decreased CD68 immunoreactivity, and reduced neurodegeneration in treated 5xFAD mice. Together, these findings show that systemically administered poly(lactic-co-glycolic acid) immunomodulatory nanoparticles produce durable behavioral, immunological, and pathological benefits in 5xFAD mice and support further investigation of this biodegradable myeloid-targeted platform as a therapeutic strategy for Alzheimer's disease.}, } @article {pmid42094534, year = {2026}, author = {Moore, SJ and Murphy, GG}, title = {Acarbose improves cognitive function in a mouse model of normal aging but not Alzheimer's disease.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {42094534}, issn = {2692-8205}, abstract = {INTRODUCTION: Declines in function occur in both "normal" aging (in the absence of disease) and age-related pathological contexts, like Alzheimer's disease (AD). Whether "anti-aging" interventions (that extend lifespan) also promote cognitive function in aging and AD remains unexplored.

METHODS: We assessed the effect of acarbose (1000 ppm from 4 months of age) on spatial learning and memory using the Morris water maze in young adult (6 mo), mid-aged (12 mo), or aged (24 mo) cohorts of normal aging (Ntg-HET3) and AD-relevant (5xFAD-HET3) genetically heterogeneous mice.

RESULTS: In mid-aged and aged Ntg-HET3 mice, acarbose treatment resulted in performance equivalent to young adults. Conversely, acarbose failed to ameliorate age-related deficits in 5xFAD-HET3 mice.

DISCUSSION: This work demonstrates that anti-aging interventions can also promote cognitive longevity in normal aging. Further, it reinforces that AD is not simply accelerated aging and requires therapies beyond anti-aging interventions that target its unique molecular and cellular drivers.}, } @article {pmid42094538, year = {2026}, author = {Woodham, TA and Kelsey, MMG and Sedivy, JM}, title = {Characterization of Cellular Senescence in Primary Human Astrocytes.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {42094538}, issn = {2692-8205}, abstract = {Senescent astrocytes have been identified in the brains of patients with neurodegenerative disorders, including Alzheimer's disease, yet the molecular characteristics of replicative senescence in human astrocytes remain largely unexplored. Prior work has been hampered by the low proliferative capacity and limited telomere shortening of primary human astrocytes in culture. Here, we describe a culture system in which primary human astrocytes propagated under physiological (3%) oxygen reach canonical telomeric replicative senescence after extensive expansion (up to ~76 population doublings). Senescence was confirmed through multiple biomarkers, including reduced EdU incorporation, elevated senescence-associated beta-galactosidase (SA-β-gal) activity, persistent DNA damage foci (γH2AX and 53BP1) predominantly localized to telomeres, and nuclear accumulation of p53. RNA sequencing across a 12-week time course revealed early upregulation of young LINE-1 (L1HS) retrotransposon transcripts, type-I interferon (IFN-I) and senescence-associated secretory phenotype (SASP) pathway genes, alongside downregulation of cell-cycle and DNA repair programs. To resolve L1HS expression at individual locus resolution, we performed Nanopore DNA sequencing to generate a custom reference genome incorporating non-reference LINE-1 insertions. Applying our TE-Seq pipeline, we identified two full-length intergenic L1HS elements consistently upregulated across the replicative senescence time course, one of which, L1HS_9q22.32_2, retained intact ORF1 and ORF2 open reading frames, indicating potential retrotransposition competence. To contextualize the astrocyte replicative senescence program, we compared it to three additional conditions. First, parallel astrocyte cultures maintained under normoxic (20%) oxygen entered senescence earlier and showed stronger SASP upregulation. Second, DNA damage-induced senescence (DDIS) triggered by etoposide treatment produced a stronger pro-inflammatory transcriptional signature than replicative senescence, including elevated IL6, IL1A, and IL1B expression. DDIS also upregulated L1HS_9q22.32_2 as well as a second intact element, L1HS_14q23.2_3, which we have previously identified among the small number of intact L1HS loci activated during replicative senescence in fibroblasts. The convergent activation of these intact elements across cell types and senescence modalities reinforces L1HS-driven IFN-I signaling as a conserved feature of the senescent program. Third, comparison with replicatively senescent fibroblasts revealed cell-type-specific SASP regulation: the pro-inflammatory cytokines IL6 and CCL2 were downregulated in senescent astrocytes relative to proliferating cells, opposite to their behavior in fibroblasts. Together, these data establish the first comprehensive transcriptomic profile of replicative senescence in human astrocytes, offering a resource for understanding brain aging and senescence-associated neurodegeneration.}, } @article {pmid42095064, year = {2026}, author = {Cummings, JL and Zhou, Y and Yang, Y and Zhong, K and Fonseca, J and Osse, AL and Cheng, F}, title = {Alzheimer's disease drug development pipeline: 2026.}, journal = {Alzheimer's & dementia (New York, N. Y.)}, volume = {12}, number = {}, pages = {e70251}, pmid = {42095064}, issn = {2352-8737}, abstract = {INTRODUCTION: Discovery and development of new therapies for Alzheimer's disease (AD) are urgently needed to address the world's growing population of individuals on the AD pathophysiological continuum. Clinicaltrials.gov is a resource for studying drugs in development for treatment of AD.

RESULTS: There are currently 158 drugs in 192 AD trials. Of the agents in trials, 39% are small molecule disease targeting therapies (DTTs); 34% are biologic DTTs; 18% are cognition enhancing symptom targeted therapies (STTs); and 10% are STTs being developed to treat neuropsychiatric symptoms of AD. Currently active trials require 54,728 participants of which 38,417 are in Phase 3. The biopharmaceutical industry sponsors 59% of AD trials including 72% of Phase 3 trials. Repurposed drugs represent 35% of the drugs in trials.

DISCUSSION: The AD drug development pipeline has a growing number of trials and drugs in trials. A diverse array of AD pathophysiological processes is being addressed by drugs in trials.}, } @article {pmid42095076, year = {2026}, author = {Sajan, MP and Aggarwal, G and Hwang, JJ and Smith, DM and Cooper, DR and Duncan, MA and Hansen, BC and Nguyen, AD and Farese, RV}, title = {Progranulin deficiency in the brain activates an insulin signaling pathway that may promote neurodegeneration.}, journal = {iScience}, volume = {29}, number = {5}, pages = {115720}, pmid = {42095076}, issn = {2589-0042}, abstract = {Molecular mechanisms in frontotemporal dementia (FTD) and Alzheimer's disease (AD) are obscure. FTD can result from loss-of-function progranulin mutations, although pathogenetic consequences are uncertain. Progranulin insufficiency also increases human AD risk, and progranulin treatment improves mouse AD. Furthermore, AD and FTD risks are abetted by obesity/diabetes-induced hyperinsulinemia and hyperactivation of brain insulin signaling, and progranulin deficiency activates insulin signaling in fat and liver. Here, we found progranulin deletion in mouse brain increased activation of IRS-1 and activities of downstream PKC-λ/ι, NF-κB and mTOR, but diminished IRS-2 and Akt. Similarly, in microglial cells, progranulin deletion increased, and progranulin treatment diminished, activation of IRS-1, PKC-λ/ι, NF-κB, and mTOR. These progranulin-related changes in IRS-1 activation were due to JNK-mediated phosphorylation of inhibitory serine-302/307 residues in IRS-1. Progranulin deficiency in brain selectively activates an IRS-1-dependent insulin signaling pathway, and the resultant increases in inflammation and impaired autophagy/lysosomal function may augment progranulin deficiency-related neuropathology.}, } @article {pmid42095886, year = {2026}, author = {Maiese, K}, title = {Osteoarthritis and dementia: contrasting disorders driven by mutual pathways of autophagy, mTOR, GLP-1, AMPK, Wnt, and WISP1.}, journal = {Expert review of clinical pharmacology}, volume = {19}, number = {5}, pages = {471-490}, pmid = {42095886}, issn = {1751-2441}, support = {R01 NS053946/NS/NINDS NIH HHS/United States ; }, mesh = {Humans ; Autophagy/physiology ; Animals ; *Osteoarthritis/physiopathology/drug therapy/therapy ; TOR Serine-Threonine Kinases/metabolism ; *Dementia/physiopathology/drug therapy/therapy ; AMP-Activated Protein Kinases/metabolism ; Alzheimer Disease/physiopathology/drug therapy ; Disease Progression ; Glucagon-Like Peptide 1/metabolism ; CCN Intercellular Signaling Proteins/metabolism ; Drug Development ; Proto-Oncogene Proteins ; }, abstract = {INTRODUCTION: Increased global lifespan is paralleled by a rise in non-communicable diseases with osteoarthritis and dementia, including Alzheimer's disease, impacting all nations with severe disability, death, and financial burden.

AREAS COVERED: Given that osteoarthritis and dementia are worsened with advancing age, progressive in nature, and presently remain only with symptomatic treatments, development of advanced comprehensive therapies is critical for these disorders. New innovative work offers insight into the underlying clinical bond between degenerative joint disease and cognitive loss. Data sources using systematic literature search employed PubMed, Scopus, Web of Science, and ScienceDirect from January 2021 through February 2026.

EXPERT OPINION: Although affecting diverse organ systems, degenerative joint disease and dementia are intimately connected by shared cellular pathways responsible for disease onset and progression. Pioneering avenues of investigation of oxidative stress, autophagy, the mechanistic target of rapamycin (mTOR), cellular metabolism mechanisms with glucagon-like peptide-1 (GLP-1) receptors and AMP activated protein kinase (AMPK), Wnt signaling, and Wnt1 inducible signaling pathway protein 1 (WISP1) offer exciting treatment opportunities for osteoarthritis and Alzheimer's disease. Ultimately, these complex pathways will necessitate focus upon their intricate dependence that may benefit from several targeted approaches including artificial intelligence applications for fruitful clinical translation.}, } @article {pmid42096531, year = {2026}, author = {Uchida, H and Gobbi, G and Zohar, J and Young, AH and Rujescu, D and Huang, MC and Sundram, S and Atwoli, L and Vukovic, J and Ikeda, K}, title = {Global Perspectives on CNS Drug Innovation: Achievements, Barriers, and Priorities for the Next Decade.}, journal = {The international journal of neuropsychopharmacology}, volume = {}, number = {}, pages = {}, doi = {10.1093/ijnp/pyag023}, pmid = {42096531}, issn = {1469-5111}, abstract = {BACKGROUND: Over the past decade, neuropsychopharmacology has shifted from stagnation to momentum, with first-in-class mechanisms and biomarker-enabled trials spanning psychiatry and neurology.

METHODS: We narratively synthesized advances from 2013 to 2026 across central nervous system (CNS) discovery and development, including pivotal trials, regulatory actions, digital/real-world evidence, genetics, artificial intelligence (AI), and implementation/global-access themes that are endorsed by international societies.

RESULTS: Therapeutic gains include rapid-acting drugs for treatment-resistant depression (intranasal esketamine); psychedelic-assisted therapy for posttraumatic stress disorder and depression; neuroactive steroid γ-aminobutyric acid-A receptor positive allosteric modulators (brexanolone, zuranolone) for postpartum depression; non-dopaminergic muscarinic agonists (xanomeline-trospium) for schizophrenia; orexin receptor antagonists for insomnia; and anti-amyloid monoclonal antibodies (lecanemab, donanemab) for early Alzheimer's disease. Persistent barriers include high mid-/late-stage attrition that is driven by placebo effects, subjective endpoints, and preclinical-to-clinical gaps; regulatory and economic headwinds; and limited generalizability from tightly run trials. Emerging enablers include adaptive/platform designs, digital health technologies, patient-reported outcomes, and clinical outcome assessments, real-world evidence (RWE), AI/machine learning (ML), genetics for target de-risking and biomarker-guided stratification, and publicly accessible large CNS relevant biological datasets.

CONCLUSIONS: To convert momentum into durable progress, we recommend: (i) deeper academia-industry/stakeholder collaboration and sustained funding for high-risk/high-reward science from industry, governments and non-for profit foundations; (ii) modernized regulation (flexible evidentiary paths, novel endpoints, and clear guidance on adaptive/platform trials); (iii) data-driven development integrating RWE, AI/ML, and precision medicine; (iv) the adoption of Neuroscience-based Nomenclature (NbN); and (v) a global-access mandate with essential-medicine inclusion, equitable pricing/licensing, capacity building, tele-enabled mental health, and geographically diverse research. Aligning scientific innovation with implementation and equity can accelerate translation and ensure new treatments benefit patients worldwide.}, } @article {pmid42097044, year = {2026}, author = {Shu, Y and Ding, ZH and Chen, XQ and Liu, F}, title = {40 Hz light flicker stimulation for neurodegenerative diseases: Mechanisms and clinical perspectives.}, journal = {Biochemical and biophysical research communications}, volume = {821}, number = {}, pages = {153858}, doi = {10.1016/j.bbrc.2026.153858}, pmid = {42097044}, issn = {1090-2104}, mesh = {Humans ; *Neurodegenerative Diseases/therapy/physiopathology ; Light ; Animals ; *Phototherapy/methods ; }, abstract = {Neurodegenerative diseases are a class of disorders characterized by the progressive degeneration and dysfunction of neurons, such as Alzheimer's disease (AD) and Parkinson's disease (PD). Due to their high incidence rate, irreversible pathological processes and huge social and economic burdens, these diseases have become a major challenge in global public health. Light Flicker Stimulation (LFS), as a non-invasive form of physical therapy, shows significant neuroprotective potential by modulating electrical brain oscillations and particular signaling pathways. We critically examine the role of stimulation parameters (frequency, wavelength, multisensory combination) and discuss the state of clinical translation, including completed and ongoing trials, safety considerations, and technological innovations such as alternating bilateral stimulation and organic light-emitting diode (OLED) devices. By integrating mechanistic insights with clinical perspectives, this review aims to identify key gaps and future directions for harnessing 40 Hz LFS as a viable treatment for neurodegenerative diseases.}, } @article {pmid42097270, year = {2026}, author = {Cho, E and Lee, S and Lee, H and Kim, J and Kwon, YW and Hoe, HS and Kim, D and Yoon, JH}, title = {An Integrative Proteomic Approach to Reveal Altered Signaling Modules During Alzheimer's Disease Progression in PS19 Tauopathy Mice.}, journal = {Molecular & cellular proteomics : MCP}, volume = {25}, number = {6}, pages = {101580}, pmid = {42097270}, issn = {1535-9484}, mesh = {Animals ; *Alzheimer Disease/metabolism/pathology ; *Proteomics/methods ; *Signal Transduction ; Disease Progression ; Mice ; Proteome/metabolism ; Neurotransmitter Agents/metabolism ; *Tauopathies/metabolism/pathology ; Brain/metabolism ; tau Proteins/metabolism/genetics ; Mice, Transgenic ; Hippocampus/metabolism ; Dopamine/metabolism/analogs & derivatives ; }, abstract = {Alzheimer's disease (AD) is a slowly progressive neurodegenerative disease that is characterized by cognitive, functional, and behavioral impairments. These changes occur owing to the progressive accumulation of extracellular amyloid-beta plaques and intracellular neurofibrillary tangles of hyperphosphorylated tau protein. AD is associated with the dysfunction of several essential neurotransmitter systems, such as dopamine, and impaired neurotransmission. Despite the association of neurotransmitter changes within the brain and AD pathology, in-depth profiling studies on neurotransmitters and their related proteomic changes are limited. This study was conducted to profile and integrate the proteomes and neurotransmitters in seven brain regions of PS19 (Tau P301S) mice according to AD progression between 4 and 7 months. Proteomic analysis revealed significantly altered canonical pathways in various brain regions, including metabolic abnormalities. In the neurotransmitter profile, we found significant alterations in the levels of six neurotransmitters-dopamine, serotonin, homovanillic acid, norepinephrine, 3-methoxytyramine, and 3,4-dihydroxyphenylacetic acid-during AD progression. Using an integrative approach between proteome and neurotransmitter profiles, we found that AD progression-dependent dopamine- and serotonin-related signaling modules are closely related to neurotransmitter changes, especially in the hippocampus and cerebellum. This integrative approach could provide new signaling modules to help understand AD progression and thereby enable improved treatment and clinical outcomes.}, } @article {pmid42097395, year = {2026}, author = {Shahsavari, F and Rajizadeh, MA and Pirmoradi, Z and Sabzalizadeh, M and Kohlmeier, KA and Soti, M and Shabani, M}, title = {Abscisic acid ameliorates cognitive deficits in an amyloid-β-induced mouse model of Alzheimer's disease associated with alterations in markers of neuroplasticity and neuroinflammation.}, journal = {Neuroscience letters}, volume = {881}, number = {}, pages = {138619}, doi = {10.1016/j.neulet.2026.138619}, pmid = {42097395}, issn = {1872-7972}, mesh = {Animals ; *Alzheimer Disease/chemically induced/drug therapy/metabolism/psychology ; Male ; Amyloid beta-Peptides/toxicity ; *Neuronal Plasticity/drug effects ; *Abscisic Acid/pharmacology/therapeutic use ; Disease Models, Animal ; Mice ; Hippocampus/drug effects/metabolism ; Peptide Fragments ; Brain-Derived Neurotrophic Factor/metabolism ; *Neuroinflammatory Diseases/metabolism/drug therapy ; *Neuroprotective Agents/pharmacology/therapeutic use ; *Cognitive Dysfunction/drug therapy/metabolism/chemically induced ; Anxiety/drug therapy ; NF-kappa B/metabolism ; Maze Learning/drug effects ; }, abstract = {Abscisic acid (ABA, C15H20O4), a mammalian hormone, exhibits neuroprotective and anti-inflammatory properties. This study aimed to investigate the effects of ABA on the hippocampal-dependent processes: anxiety-, depression-like behaviors and cognitive impairments as well as levels of factors involved in neuroplasticity and neuroinflammation in an amyloid-β (Aβ)-induced mouse model of Alzheimer's disease (AD). One week following intracerebroventricular (i.c.v.) injection of Aβ1-42 in male mice, ABA was administered i.c.v. at doses of 10 or 15 µg/µl for 7 consecutive days. Behavioral assessments were conducted using the novel object recognition, open field, elevated plus maze, tail suspension, Morris water maze, and passive avoidance tests. Hippocampal gene expression levels of brain-derived neurotrophic factor (BDNF), N-methyl-D-aspartate receptor (NMDAR), and nuclear factor-κB (NF-κB) were evaluated using real-time PCR. ABA treatment significantly attenuated anxiety-like behaviors and improved spatial, avoidance and recognition memory deficits induced by Aβ1-42 administration with more behavioral domains affected at the 15 µg/µl dose. ABA induced significant upregulation in the hippocampus of NMDAR and BDNF expression and marked suppression of NF-κB in the ABA (15 µg/µl)-treated Aβ group, which could have played a mechanistic role in improvements in behaviors controlled by this structure. Histological analysis demonstrated attenuation of neuronal degeneration and pyknosis in the hippocampal CA1 region following ABA intervention. Collectively, these findings suggest that ABA ameliorates anxiety-related behaviors and cognitive impairments in an experimental mouse model of AD, potentially through modulation of neuroinflammatory and neuroplasticity-related pathways.}, } @article {pmid42097410, year = {2026}, author = {Zhu, PF and Lyu, Z and Wang, Q and Li, S and Wang, X and Luo, A}, title = {ISRIB as a prototype eIF2B activator: Pharmacology, mechanisms, and translational potential in aging-related cognitive disorders.}, journal = {Pharmacological research}, volume = {228}, number = {}, pages = {108228}, doi = {10.1016/j.phrs.2026.108228}, pmid = {42097410}, issn = {1096-1186}, mesh = {Humans ; Animals ; *Aging/metabolism ; Integrated Stress Response ; *Eukaryotic Initiation Factor-2B/metabolism ; *Cyclohexylamines/therapeutic use/pharmacology ; *Acetamides/pharmacology/therapeutic use ; *Cognition Disorders/drug therapy/metabolism ; Brain/drug effects/metabolism ; Cognitive Enhancement ; }, abstract = {Aging-related cognitive disorders have been increasingly linked to maladaptive stress pathways that persistently impair synaptic protein synthesis and plasticity. The integrated stress response (ISR) links various stressors to downstream translational reprogramming through the phosphorylation of eIF2α. Acute ISR activation can be protective, while chronic ISR activation may confine neurons and glial cells to hypo-plastic states, impairing learning and memory function. ISRIB is a prototype small molecule that activates eIF2B and restores translation homeostasis, providing a viable framework for "tuning" ISR output rather than indiscriminately blocking stress signaling. This review summarizes ISR biology in the aging brain, emphasizes cell-type heterogeneity, and evaluates the evidence for ISRIB across various conditions, including normal aging, Alzheimer's disease, vascular cognitive impairment, synucleinopathies, perioperative neurocognitive disorders, and related conditions with shared ISR pathology. We then discuss dosing, safety, optimization, limitations, translational biomarkers, and lessons from emerging clinical-stage eIF2B activators. Finally, we propose precision and combination strategies to tailor ISR modulation to disease stage, pathological context, and therapeutic window, aiming to provide new directions and a theoretical basis for the treatment of aging-related cognitive disorders.}, } @article {pmid42097478, year = {2026}, author = {Matošević, A and Maraković, N and Barić, D and Igert, A and Brazzolotto, X and Kovarik, Z and Bosak, A}, title = {Integrative structural and kinetic analysis of the molecular basis for reduced carbamate inhibition in atypical butyrylcholinesterase.}, journal = {Chemico-biological interactions}, volume = {435}, number = {}, pages = {112134}, doi = {10.1016/j.cbi.2026.112134}, pmid = {42097478}, issn = {1872-7786}, mesh = {*Butyrylcholinesterase/metabolism/chemistry/genetics ; *Carbamates/chemistry/metabolism/pharmacology ; *Cholinesterase Inhibitors/chemistry/metabolism/pharmacology ; Kinetics ; Molecular Docking Simulation ; Humans ; Crystallography, X-Ray ; Hydrogen Bonding ; }, abstract = {Butyrylcholinesterase (BChE) plays a key role in cholinergic transmission and the metabolism of various drugs, making its regulation a promising therapeutic strategy for several diseases, including Alzheimer's disease. Selective inhibition of BChE helps regulate brain acetylcholine levels. However, genetic polymorphisms in the BCHE gene, particularly the Asp70Gly mutation in atypical BChE, can impact treatment outcomes. This study compares the inhibitory potency of 13 carbamates against atypical and usual BChE. Using molecular docking, quantum chemical cluster calculations, and crystallization of wild-type BChE with the most potent carbamate, we identified key differences in carbamylation mechanisms. Atypical BChE shows a less favorable enzyme-inhibitor complex orientation, lacking the hydrogen bond stabilization of the reactive carbonyl oxygen. Additionally, Asp70 in usual BChE contributes to stabilizing the non-reactive carbamate group, whereas Gly70 in atypical BChE is too distant to form such interactions.}, } @article {pmid42097853, year = {2026}, author = {Rohatgi, S and Omid-Fard, N and Zhu, S and Martinez Imbett, RE and Ford, JN and Dowling, TP and Kirsch, JE and Romero, JM}, title = {Relationship of Inferior Frontal Sulcal Hyperintensities with Amyloid-Related Imaging Abnormalities.}, journal = {AJNR. American journal of neuroradiology}, volume = {}, number = {}, pages = {}, doi = {10.3174/ajnr.A9395}, pmid = {42097853}, issn = {1936-959X}, abstract = {OBJECTIVE: Anti-amyloid immunotherapies used to treat Alzheimer's disease (AD) are often associated with amyloid-related imaging abnormalities (ARIA). We aim to indirectly assess glymphatic function by using inferior frontal sulcal hyperintensity (IFSH) as a biomarker in patients receiving anti-amyloid therapy, both with and without ARIA, as well as in healthy controls. We hypothesize that patients who develop ARIA will have higher IFSH scores than non-ARIA patients and healthy controls.

METHODS: Eligible AD patients who received anti-amyloid treatment were included in our retrospectively collected dataset. Only scans performed at 3T were used. Inter-rater reliability was evaluated and statistical analyses of IFSH scores and demographic data were performed to compare between groups. Additionally, within-subject analysis was used to compare the baseline and ARIA scans. Significance set at P < 0.05.

RESULTS: A total of 104 patients were selected based on the study criteria, of whom 60 had a clinical diagnosis of dementia. 36 patients developed ARIA, while 24 did not develop ARIA. 23 were age-matched healthy controls, and 21 were young healthy controls. Inter-rater reliability between the two readers was concordant when using quadratic weights appropriate for ordinal data (κ (w) = 0. 91, 95% CI 0.86-0.95). IFSH was significantly higher in the older age cohorts compared to young healthy controls (median 3.5 [IQR 2.5-5] versus 0 [0-1], P<0.001), with no significant difference between the dementia and healthy elderly groups (3.25 [3-4.875] versus 3.5 [2.5-5]). Among dementia patients on anti-amyloid therapy, significantly higher IFSH was observed in ARIA patients (at time of ARIA scan) compared to their non-ARIA counterparts (3.75 [3-5] versus 3 [2-4], P= 0.04). There was no significant difference in IFSH score between baseline and ARIA scans (P = 0.16).

CONCLUSION: IFSH was higher among dementia patients on anti-amyloid therapy with ARIA than among their non-ARIA counterparts. This supports its role as a potential biomarker of glymphatic dysfunction, although its utility on an individual basis is limited. Future prospective studies could benefit from incorporating IFSH as a variable, particularly if glymphatic therapies become a reality.}, } @article {pmid42098313, year = {2026}, author = {Shinagawa, S and Onuki, K and Shimizu, K}, title = {Physicians' perceptions and treatment practices for agitation associated with Alzheimer's dementia vary by specialty in Japan.}, journal = {Scientific reports}, volume = {}, number = {}, pages = {}, doi = {10.1038/s41598-026-51118-5}, pmid = {42098313}, issn = {2045-2322}, support = {NA//Otsuka Pharmaceutical Co., Ltd./ ; NA//Otsuka Pharmaceutical Co., Ltd./ ; NA//Otsuka Pharmaceutical Co., Ltd./ ; }, abstract = {Agitation, a behavioural and psychological symptom of dementia, is under-recognized in Japan. To describe the physician's perceptions and treatment practice for agitation in Alzheimer's dementia (AAD) in Japan, we conducted a cross-sectional web-based survey in October 2024. The survey included physicians in neurology, neurosurgery, psychiatry, or general internal medicine who were registered with the survey panel; consented to participation; affiliated with hospitals or clinics; treating ≥ 10 people with Alzheimer's dementia (AD)/month. Responses from 529 physicians showed that they treated an average of 35.0 people with AD per month, of whom 8.4 (24%) had AAD. When asked what "agitation" brought to mind, physicians most commonly selected the Japanese term for "excitability", corresponding to the "agitation/aggression" item in the Neuropsychiatric Inventory (58.6%). In general internal medicine, 24.2% were unaware of agitation. Anti-dementia drugs (91.7%) were most frequently selected as new medications for AD, whereas in psychiatry, antipsychotics were most frequently selected (95.8%), and side effects were cited more often as a key consideration than in other specialties. These results suggest that perceptions and treatment practices vary by specialty, particularly reflected in common antipsychotic prescriptions with higher safety awareness among psychiatrists and limited recognition of AAD in others, especially in general internal medicine.}, } @article {pmid42098771, year = {2026}, author = {Badot, C and Bini, A and Duplan, E and Checler, F and Lauritzen, I}, title = {Functional relationships linking C99/APP-βCTF dimerization, proteostasis disruption, and organelle dysfunction.}, journal = {Cell communication and signaling : CCS}, volume = {24}, number = {1}, pages = {}, pmid = {42098771}, issn = {1478-811X}, mesh = {Humans ; HeLa Cells ; *Proteostasis ; *Protein Multimerization ; *Amyloid beta-Protein Precursor/metabolism/chemistry ; Lysosomes/metabolism ; Proteasome Endopeptidase Complex/metabolism ; Autophagy ; }, abstract = {BACKGROUND: The amyloid β (Aβ) precursor C99 (or APP-βCTF) accumulates in Alzheimer's disease and has been proposed to display Aβ-independent toxicity, notably by affecting the endosomal-lysosomal-autophagic (ELA) network. Our previous findings suggested that some ELA-associated C99 could correspond to dimeric and oligomeric species, but the intracellular sites of C99 dimerization, as well as the toxicity linked to it, remains unknown.

METHODS: We here developed a bimolecular fluorescence complementation (BiFC) probe to visualize de novo C99 dimerization and dimer trafficking, as well as to identify possible cellular responses specifically linked to C99 dimerization. Moreover, to confirm dimer localizations and toxicities, the localization and cellular effects of the dimerization mutant C99[G29L/G33L] was compared to that of wildtype C99. The C99 constructs were transfected into HeLa cells and dimer localizations, expression levels and intracellular toxicities were evaluated by Western blot and immunocytochemistry.

RESULTS: BiFC-C99 dimers were first detected within the TGN, in which monomers initially accumulate. The proteasomal inhibitor MG-132 led to increased dimer formation, indicating that the proteasomal activity status is a key determinant of C99 dimerization. Conversely, TGN-associated C99 dimerization had a negative impact on both the ubiquitin-proteasome system (UPS) and the TGN, as highlighted by the appearance of p62/SQSTM1-positive aggresomes and fragmented Golgi, then suggesting a two-way relationship between UPS function and C99 dimerization. Dimerization also led to lysosome repositioning and to the accumulation of LC3B-positive autophagy vesicles, agreeing with the well-known interplay between autophagy and proteasome in protein turnover. P62/SQSTM1 and LC3B accumulation could similarly be observed in cells expressing C99[G29L/G33L], a mutant favoring dimerization, while this was not the case in wildtype C99 expressing cells, confirming the dimerization-specific effect. While proteasomal inhibition caused TGN-associated dimer formation, repression of γ-secretase-mediated C99 proteolysis instead led to a redistribution of monomers to EEA1-positive endosomes, whereas already existing C99 dimers remained unaffected by this treatment. These new endosome-associated monomers were found also to dimerize, resulting in dimers destined for either secretion via small extracellular vesicles or autophagy-lysosomal degradation.

CONCLUSIONS: Taken together, our findings indicate that the cellular status of UPS, autophagy and γ-secretase activities are all determinant for C99 expression levels, and are thus crucial for both the level of C99 dimerization and for the fate of the dimers. Moreover, our data show that C99 dimerization itself negatively affects these activities thereby indicating a two-way relationship between C99 dimerization, proteostasis disruption and organelle dysfunction.}, } @article {pmid42099124, year = {2026}, author = {Cheng, B and Wei, W and Cheng, S and Yang, X and Pan, C and He, D and Feng, J and Zhang, F}, title = {Dynamic comorbidity trajectories spanning the diagnosis of depression: nationwide cohort study.}, journal = {The British journal of psychiatry : the journal of mental science}, volume = {}, number = {}, pages = {1-8}, doi = {10.1192/bjp.2026.10638}, pmid = {42099124}, issn = {1472-1465}, abstract = {BACKGROUND: Depression is often accompanied by multisystem comorbidities, but the time trajectories of these comorbidities remain unclear.

AIMS: We aimed to define the temporal sequence of comorbidity accrual relative to depression diagnosis, and examine how this trajectory differs in recurrent depression.

METHOD: A total of 32 953 individuals with depression were identified in the UK Biobank cohort, including 2402 with recurrent depression. The time between diagnosis of depression or recurrent depression and ten common comorbidities was established to determine the temporal order and rate of comorbidity diagnosis in relation to depression, based on the sequence of recorded diagnostic events. We further stratified the cohort by polygenic risk score, gender, age and history of antidepressant or antihypertensive medication use.

RESULTS: The study included 32 953 participants (mean age at diagnosis 52.6 years; 63.1% female). Hypertension and dorsopathies preceded depression diagnosis by a median of 2.6 years (interquartile range (IQR) -7.0 to 0.0) and 1.0 year (IQR -5.0 to 2.0), respectively. Alzheimer's disease and obesity emerged after diagnosis at medians of 2.5 years (IQR 0.0-5.0) and 0.8 years (IQR -2.0 to 3.0). High genetic risk was associated with an earlier onset of pre-depression cardiometabolic conditions, with hypertension occurring 2.8 years before diagnosis in individuals with a high polygenic risk score compared with 2.3 years in individuals with a low polygenic risk score. Crucially, individuals with recurrent depression exhibited a profoundly different trajectory, with most comorbidities manifesting many years after the index diagnosis. Stratification by medication history indicated that antihypertensive drug use was associated with an earlier recorded diagnosis of cardiometabolic conditions, whereas antidepressant use was linked to a later diagnosis of neurodegenerative diseases.

CONCLUSIONS: These findings identify three critical windows for intervention and reveal a distinct, delayed comorbidity trajectory in recurrent depression. This underscores the need for long-term, integrated surveillance strategies tailored to depression subtype and treatment history.}, } @article {pmid42099163, year = {2026}, author = {Li, Y and Li, L and Yang, Q and Xiong, J}, title = {Comparative Efficacy and Safety of Cholinesterase Inhibitors and NMDA Receptor Antagonists in Alzheimer's Disease: A Systematic Review and Network Meta-Analysis of Randomized Controlled Trials.}, journal = {Current Alzheimer research}, volume = {}, number = {}, pages = {}, doi = {10.2174/0115672050437623260417063631}, pmid = {42099163}, issn = {1875-5828}, abstract = {INTRODUCTION: The study aims to evaluate and rank cholinesterase inhibitors, the NMDA antagonist memantine, anti-amyloid monoclonal antibodies, and non-drug modalities with respect to cognitive outcomes, functional status, neuropsychiatric symptoms, and tolerability.

METHODOLOGY: We registered a protocol in PROSPERO and searched PubMed/MEDLINE, Embase, CENTRAL, Web of Science, trial registries, and gray literature through June 2025. Eligible randomized phase II/III trials in adults with clinically diagnosed AD were screened in duplicate. Data on interventions, comparators, outcomes (e.g., MMSE, ADAS-Cog, CDR-SB), and adverse events were extracted. Risk of bias was assessed using Cochrane RoB 2. A Bayesian random-effects NMA synthesized 125 trials (n > 30,000), estimating standardized Mean Differences (SMDs) with 95% Credible Intervals (CrIs). Heterogeneity (I²) and inconsistency (design-by-treatment, node-splitting) were evaluated.

RESULTS: The network was well connected, with low-to-moderate heterogeneity (global I² = 38.5%) and no significant inconsistency (p = 0.48). Cognitive training (SMD = 0.45; 95% CrI 0.30-0.60; SUCRA 92%), aerobic exercise (SMD = 0.55; 95% CrI 0.35-0.75; SUCRA 87%), and galantamine (SMD = 0.40; 95% CrI 0.22-0.58; SUCRA 84%) ranked highest versus placebo. Donepezil (SMD = 0.21; 95% CrI 0.11-0.30; SUCRA 78%) and memantine (SMD = 0.24; 95% CrI 0.13-0.35; SUCRA 72%) showed modest benefits.

DISCUSSION: Risk-of-bias ratings were low in 37% of trials, some concerns in 48%, and high in 15%. Subgroup analyses confirmed greater cholinesterase inhibitor efficacy in mild AD and superior memantine effects in moderate-to-severe disease.

CONCLUSION: Non-pharmacological interventions demonstrated short-term cognitive benefits primarily in mild Alzheimer's disease populations and should be interpreted as adjunctive symptomatic strategies rather than direct substitutes for pharmacological therapy.}, } @article {pmid42099165, year = {2026}, author = {Yang, Y and Huang, X and Liu, H and Yu, C}, title = {The Role of Ectopic Fat in Alzheimer's Disease.}, journal = {Current Alzheimer research}, volume = {}, number = {}, pages = {}, doi = {10.2174/0115672050461650260406064722}, pmid = {42099165}, issn = {1875-5828}, abstract = {Alzheimer's Disease (AD) is a neurodegenerative disorder increasingly recognized to be associated with metabolic dysfunction. Accumulating evidence suggests that ectopic fat (abnormal fat deposition in non-adipose tissue) is a key factor. This review summarizes the crucial role that ectopic fat plays in the onset and progression of AD, as well as the interrelated pathways through which ectopic fat deposition promotes the pathological process of AD. Adipocytes have been reported to produce and secrete amyloid-β (Aβ), a hallmark pathological feature of AD. Accordingly, ectopic fat may aggravate cerebral Aβ accumulation by impairing peripheral Aβ clearance. In addition, ectopic fat can also cause Insulin Resistance (IR), adipokine dysregulation, inflammatory responses, and oxidative stress. Therefore, ectopic fat is closely associated with the progression of AD and may play a contributory role in its pathogenesis. The effects of ectopic fat on the occurrence and development of Alzheimer's Disease (AD) pathology were reviewed through mechanisms such as metabolic disorders, inflammatory pathways, and Aβ deposition, and potential intervention strategies for this harmful cycle were highlighted. As current therapies for AD remain limited, new opportunities for its prevention and treatment may be provided through a better understanding of these associations.}, } @article {pmid42100482, year = {2026}, author = {Zhao, H and Wang, H and Li, W and Su, R and Li, J and Liu, Y and Wang, L}, title = {Integrated transcriptomic profiling combined with in vitro validation reveals the involvement of TMEM140 in the link between periodontitis and brain aging.}, journal = {Frontiers in aging neuroscience}, volume = {18}, number = {}, pages = {1761218}, pmid = {42100482}, issn = {1663-4365}, abstract = {OBJECTIVE: Periodontitis (PD) is a prevalent chronic inflammatory disorder in adults, and moderate-to-severe PD (Stage II-III/IV) may accelerate brain aging and neurodegenerative changes via the peripheral-central immune-neural axis, although the molecular connections and mechanisms of interaction have yet to be fully elucidated. This study sought to identify senescence-associated molecules potentially shared by PD and Alzheimer's disease (AD) using integrated transcriptomic analysis, machine learning, and in vitro RNA interference assays, and to further assess the role of TMEM140 in linking PD to brain aging.

METHODS: Transcriptomic datasets related to PD and AD were retrieved from the GEO database, and differential gene expression analysis was performed following batch effect correction; shared aging-associated genes were subsequently identified by combining weighted gene co-expression network analysis (WGCNA) with aging gene databases (HAGR and aging Atlas). Four machine learning algorithms, namely random forest (RF), support vector machine (SVM), generalized linear model (GLM), and extreme gradient boosting (XGB), were further applied to identify key genes, and their diagnostic value was assessed using receiver operating characteristic (ROC) analysis and nomogram models. DSigDB was used to predict candidate small-molecule compounds. In the in vitro experiments, a Porphyromonas gingivalis lipopolysaccharide (PG-LPS)-induced inflammatory model in human gingival fibroblasts (HGFs) and an Aβ1-42 and D-galactose-induced senescence model in SH-SY5Y neuron-like cells were established; TMEM140 in SH-SY5Y cells was then silenced using small interfering RNA (siRNA), and the neuron-like cells were treated with the same batch of standardized conditioned medium (CM; prepared from the supernatant of PG-LPS-treated HGFs) to observe changes in cellular responses to inflammatory stimulation after TMEM140 downregulation.

RESULTS: Seven aging-related genes common to PD and AD were identified, and comprehensive analysis using multiple algorithms selected TMEM140, TIMP1, and ALDH2 as key genes. Notably, TMEM140 was upregulated in PD and downregulated in AD, showed significant correlations with plasma cell and γδ T-cell infiltration, and single-cell analysis further revealed its cell type-specific expression in distinct brain cell subsets. In vitro experiments demonstrated that PG-LPS treatment markedly increased TMEM140 expression in HGFs, whereas treatment with Aβ1-42 and D-galactose reduced TMEM140 expression in neuron-like cells. When exposed to the same batch of conditioned medium, neuron-like cells with TMEM140 knockdown displayed more evident injury and senescence-related phenotypes, including reduced cell viability, increased reactive oxygen species (ROS) production, a higher percentage of senescence-associated β-galactosidase (SA-β-Gal)-positive cells, and marked upregulation of IL-1β, IL-6, TNF-α, p16, p21, RELA, NFKBIA, and TP53, indicating that reduced TMEM140 expression may contribute to enhanced susceptibility of neuron-like cells to inflammatory stress.

CONCLUSION: Through integrated transcriptomic analysis together with in vitro experimental validation, this study indicates that TMEM140 may be a candidate bridge molecule connecting PD and AD comorbidity. TMEM140 may participate in shaping the peripheral-central immunosenescence network and contribute to the cross-system transmission of inflammatory signaling.}, } @article {pmid42100730, year = {2026}, author = {Copeland, EN and Marais, AAT and Mohammad, A and Marcella, BM and Baranowski, RW and Beaudette, SM and MacPherson, REK and Fajardo, VA}, title = {Tideglusib improves novel object recognition memory in the preclinical DBA/2J mdx mouse model of Duchenne muscular dystrophy.}, journal = {Frontiers in neuroscience}, volume = {20}, number = {}, pages = {1812975}, pmid = {42100730}, issn = {1662-4548}, abstract = {INTRODUCTION: Duchenne muscular dystrophy (DMD) is a severe X-linked neuromuscular disorder characterized by progressive muscle wasting. Approximately 1 in 3 DMD patients experience cognitive dysfunction, with research suggesting an Alzheimer's disease (AD)-like pathology. We have previously shown that treatment with the glycogen synthase kinase 3β (GSK3) inhibitor, tideglusib, improves muscle quality, function, and insulin sensitivity in the DBA/2J (D2) mdx mouse model of DMD. In this brief follow-up study, we report the effects of tideglusib treatment on cognitive function.

METHODS: Male D2 WT and mdx mice were purchased from Jackson Laboratories. Mice were separated into the following groups: (1) WT, (2) mdx-vehicle, and (3) mdx-tideglusib (10 mg/kg/day via oral gavage for 4 weeks). A novel object recognition test was performed to assess recognition memory. Hippocampus and serum samples were collected for BACE1 activity assays, amyloid beta (Aβ) ELISAs, and western blotting.

RESULTS: Compared to vehicle-treated mdx mice, tideglusib-treated mdx mice demonstrated improved recognition memory. These changes to recognition memory were accompanied by greater expression of beta-catenin, an indirect downstream marker of GSK3 inhibition. While there were no changes in BACE1 activity, tideglusib-treated mdx mice had higher concentrations of Aβ in the serum and lower protein levels of receptor of advanced glycation end products.

DISCUSSION: The results from this brief follow-up study offer preliminary support for tideglusib as a treatment for both muscle and brain impairments in mdx mice, potentially improving cognitive function through enhanced vascular Aβ clearance.}, } @article {pmid42100782, year = {2026}, author = {Zhang, R and Sun, H and Di, Y and Cao, H and Zhang, C and Yao, H and Yan, H and Ding, D and He, Q and Wu, T}, title = {Sleep quality metrics combined with virtual reality motion parameters enhance early detection of mild cognitive impairment.}, journal = {Frontiers in psychiatry}, volume = {17}, number = {}, pages = {1727576}, pmid = {42100782}, issn = {1664-0640}, abstract = {OBJECTIVE: Alzheimer's disease (AD) is a progressive neurodegenerative disorder marked by cognitive and motor deficits. With its global prevalence increasing rapidly and no effective treatment available, early identification of high-risk individuals is critical. This study investigated the relationship between motor parameters extracted from virtual reality (VR) tasks, combined with sleep-related measures, and cognitive impairment in patients with mild cognitive impairment (MCI). Our goal was to determine whether integrating VR-derived digital markers with sleep quality metrics could provide an objective and clinically applicable tool for early detection.

METHODS: 66 participants were recruited, including 28 healthy controls (HC) and 38 patients with MCI. Cognitive status was assessed using the Montreal Cognitive Assessment (MoCA) and Mini-Mental State Examination (MMSE). All participants performed two scenario-based VR tasks, during which task completion time, accuracy, and overall performance scores were recorded. Group differences were evaluated using independent-samples t-tests, and these behavioral features and sleep quality metrics were further incorporated into ROC analyze to assess predictive performance for distinguishing MCI from HC.

RESULTS: Compared with HC, patients with MCI reported significantly poorer sleep quality based on the Pittsburgh Sleep Quality Index (PSQI) and subdomains such as sleep latency and habitual sleep efficiency. In the VR tasks, MCI patients required more time and achieved lower accuracy than HC, consistent with MoCA and MMSE scores. Correlation analysis confirmed strong associations between VR performance metrics and cognitive test scores. Importantly, integrating VR-derived digital markers with sleep parameters yielded superior predictive accuracy for MCI (AUC = 0.863; sensitivity = 86.84%; specificity = 71.43%; p < 0.001) compared with single-modality models.

CONCLUSION: VR-based cognitive and sensorimotor tasks, when combined with sleep quality assessments, offer a robust and noninvasive approach for the early identification of prodromal AD. This multimodal strategy holds promise for enhancing clinical decision-making and enabling timely interventions.}, } @article {pmid42100836, year = {2026}, author = {Kaczmarek-Kryszak, KA and Dobrzyńska, M and Banaszak, M and Drzymała-Czyż, S}, title = {A comprehensive systematic review of human trials investigating herbal treatments for Alzheimer's disease and dementia.}, journal = {Acta neuropsychiatrica}, volume = {38}, number = {}, pages = {1-55}, pmid = {42100836}, issn = {1601-5215}, abstract = {OBJECTIVE: Dementia is a group of symptoms, characterized by a loss of cognition that interferes with everyday tasks, difficulty focusing, planning, problem solving, and behavioral changes, such as apathy, anxiety, or depression. The leading cause of dementia is Alzheimer's disease, but vascular dementia or mild cognitive impairment are also frequently occurring. There are six drugs legislated in Europe for use in the treatment of dementia. There are unmet clinical needs to find more effective, better tolerated or complementary therapeutic options. The aim of this study is to comprehensively analyze the results of clinical trials and other human studies regarding the efficacy and safety of herbal interventions used in patients with dementia.

METHODS: We enrolled a total of 48 studies for this systematic review, of which 27 were included into the statistical analysis of effect size (Cohen's d).

RESULTS: We found significant improvements mainly after administration of Ginkgo biloba, Crocus sativus, Salvia officinalis, and Melissa officinalis.It should be emphasized that some herbs and herbal formulations demonstrated efficacy comparable to that of donepezil, a widely used and approved medication, suggesting potential for phytopharmaceutical therapies as complementary approaches. In some studies, the observed effects were similar to those reported for conventional treatments, indicating promising directions for further research in Alzheimer's disease and dementia.

CONCLUSION: In light of the evidence, phytopharmaceuticals have a promising role as a co-therapeutic option or alternative for patients with dementia who do not tolerate or have contraindications to standard medications. However, further research is necessary to translate these initial promising results into clinical practice.

SUMMATIONS: Phytopharmaceuticals have a promising role as a complementary or alternative option for dementia patients who cannot tolerate or respond to standard medications. Certain phytopharmaceuticals demonstrated comparable short-term symptomatic effects to standard treatments in small trials; however, evidence is insufficient to support equivalence or superiority.

CONSIDERATIONS: Many of the studies reviewed are limited by very small sample sizes, which is associated with a high risk of bias when interpreting large effect sizes (Cohen's d). The short duration of interventions (often only 3 to 6 months) is insufficient to assess whether phytotherapeutics can constitute disease-modifying treatments (DMTs).}, } @article {pmid42101516, year = {2026}, author = {Zhou, B and Wu, X and Wang, J and Li, L and Xu, H and Shao, W}, title = {Compatibility of Acorus tatarinowii Schott and Polygala tenuifolia Willd. alleviate Alzheimer's disease through regulating Nos2-mediated calcium signaling pathway.}, journal = {Neurochemical research}, volume = {51}, number = {3}, pages = {}, pmid = {42101516}, issn = {1573-6903}, support = {ZY2023M027//the General Project of the Administration of Traditional Chinese Medicine of Hubei Province/ ; }, mesh = {Animals ; PC12 Cells ; *Alzheimer Disease/drug therapy/metabolism ; *Polygala/chemistry ; Amyloid beta-Peptides/metabolism ; *Calcium Signaling/drug effects/physiology ; *Acorus/chemistry ; Rats ; Peptide Fragments/metabolism ; *Nitric Oxide Synthase Type II/metabolism ; Cell Survival/drug effects/physiology ; Aquaporin 4/metabolism ; *Plant Extracts/pharmacology/therapeutic use ; }, abstract = {Herb pair of Acorus tatarinowii Schott (ATS) and Polygala tenuifolia Willd. (PTW) is a classic drug pair in the treatment of Alzheimer's disease (AD), However, the mechanism by which the drug pair acts on AD is currently unknown. To address this, we constructed a PC12 cellular AD model using amyloid-beta peptide (Aβ) (25-35), follow by treating with different concentrations of ATS and PTW alone or their combination (1:1). The cell viability and Aβ-40, Aβ-42 and AQP4 expression were detected. In addition, RNA-sequencing combined with network pharmacology was performed to investigate the action mechanism of ATS and PTW, and the results were validated using in vitro experiments. The results showed that at drug-acting concentrations less than 100 mg/L, both single-agent and combined treatments of ATS and PTW increased the protective effects on PC12 cell, and the herb pair was superior to single-agent. In addition, both single-agent and combined treatments of ATS and PTW (at concentration of 100 mg/L) decreased Aβ-40, Aβ-42 and AQP4 expression compared with AD model. Further RNA-sequencing combined with network pharmacology analysis suggested that the underline action mechanism might be associated with Nos2-mediated calcium signaling pathway regulated. In vitro validation experiments showed that Nos2 overexpression increase the levels of Aβ-40, Aβ-42, AQP4, p-Tau, CaM, and p-CaMKII, which were reversed by the combination treatment of ATS and PTW. In conclusion, this work indicates that ATS and PTW combination might alleviate an Aβ-induced cellular model through regulating Nos2 - mediated calcium signaling pathway.}, } @article {pmid42103387, year = {2026}, author = {Laugesen, K and Skjærbæk, C and Okkels, N and Møller, HJ and Borghammer, P and Gottrup, H and Parkner, T}, title = {ODIN Biobank: a Danish cohort for dementia research- cohort profile.}, journal = {BMJ open}, volume = {16}, number = {5}, pages = {e114084}, pmid = {42103387}, issn = {2044-6055}, mesh = {Humans ; Female ; Denmark/epidemiology ; Biomarkers/blood/cerebrospinal fluid ; *Biological Specimen Banks ; Aged ; *Dementia/blood/cerebrospinal fluid/diagnosis ; Male ; Alzheimer Disease/cerebrospinal fluid/blood/diagnosis ; Aged, 80 and over ; Cohort Studies ; Cognitive Dysfunction/cerebrospinal fluid/blood ; Dementia, Vascular/blood/cerebrospinal fluid ; Frontotemporal Dementia/cerebrospinal fluid/blood/diagnosis ; Middle Aged ; }, abstract = {PURPOSE: Biomarkers related to the diagnosis, prognosis and treatment of dementia will play a key role in future clinical practice. The overarching aim of the ODIN (blood and cerebrospinal fluid) Biobank is to study biomarkers for dementia and contribute to the transition from cerebrospinal fluid to blood-based biomarkers.

PARTICIPANTS: ODIN recruited 451 patients (median age 74 years, 53% females) referred to the Department of Neurology at Aarhus University Hospital, Denmark, for diagnostic assessment of dementia. Enrolment started in March 2020 and ended in July 2025. Patients referred for a lumbar puncture were eligible for inclusion. Cerebrospinal fluid and blood samples (plasma, serum and buffy coat) were stored at -80°C. Information about sociodemographic, educational level, dementia subtype, cognitive test scores, neuroimaging results, hypertension, diabetes, height, weight, alcohol consumption and smoking was collected.

FINDINGS TO DATE: The most frequent diagnoses were Alzheimer's disease (n=268, 59%), frontotemporal dementia (n=26, 5.8%) and mixed Alzheimer's and vascular disease (n=23, 5.1%). N=82 (18%) were cognitively unimpaired or had mild cognitive impairment but not dementia. The median Mini-Mental State Examination score was 23 (IQR: 20-26) and the median Addenbrooke's Cognitive Examination score was 68 (IQR: 58-77).

FUTURE PLANS: ODIN will contribute to the development, validation and implementation of new biomarkers related to diagnosis, prognosis and treatment of dementia. Furthermore, the cohort will assist the transition from cerebrospinal fluid to blood-based biomarkers.}, } @article {pmid42104655, year = {2026}, author = {Sharmin, T and Doecke, JD and Chatterjee, P and Pedrini, S and Sohrabi, HR and Ashton, NJ and Zetterberg, H and Garg, ML and Blennow, K and Martins, RN}, title = {Circulating Sphingomyelins Correlate With Plasma T-Tau in Cognitively Unimpaired Older Adults at Risk of Developing Alzheimer's Disease.}, journal = {Journal of neurochemistry}, volume = {170}, number = {5}, pages = {e70436}, pmid = {42104655}, issn = {1471-4159}, support = {2018-02532//MQ Research Seeding Grant, Macquarie University/ ; 681712//MQ Research Seeding Grant, Macquarie University/ ; 201809-2016862//MQ Research Seeding Grant, Macquarie University/ ; 2017-00915//MQ Research Seeding Grant, Macquarie University/ ; FO2017-0243//MQ Research Seeding Grant, Macquarie University/ ; JPND2019-466-236//MQ Research Seeding Grant, Macquarie University/ ; //Macquarie University HDR Fund, Macquarie University/ ; 101053962//European Union's Horizon Europe research and innovation programme/ ; 2019-02397//Swedish Research Council/ ; }, mesh = {Humans ; *Sphingomyelins/blood ; *Alzheimer Disease/blood/diagnostic imaging/psychology ; *tau Proteins/blood ; Aged ; Female ; Cross-Sectional Studies ; Male ; Biomarkers/blood ; *Cognition/physiology ; Amyloid beta-Peptides/metabolism ; Positron-Emission Tomography ; Aged, 80 and over ; }, abstract = {Alterations in plasma sphingomyelin (SM) levels have been reported in Alzheimer's disease (AD), pointing to disturbances in lipid metabolism that may contribute to disease pathogenesis. Neuronal damage in early AD triggers tau release into central and peripheral systems. Despite influence from peripheral contributions, alterations in plasma total-tau (T-tau) remain valuable in indicating AD-related neurodegeneration. Investigating relationships between SM metabolism and tau release during preclinical AD may uncover important biochemical processes and support advancing early non-invasive detection and treatment approaches. This cross-sectional study investigated cognitively unimpaired (CU) older adults from the KARVIAH cohort, grouped by cortical amyloid-β (Aβ) status through positron emission tomography (PET) imaging (CU Aβ- and CU Aβ+) and utilised a Biocrates-targeted metabolomic platform and Single-molecule array (Simoa) technology to quantify plasma levels of SMs and T-tau, respectively. Associations between circulating SMs and T-tau were examined within each group, with T-tau-associated SMs further evaluated for their association with cognitive performance and cortical Aβ burden and their potential to discriminate CU Aβ+ from CU Aβ- individuals. Significant positive correlations were observed between SMs and T-tau levels exclusively in CU Aβ+ individuals, suggesting connections between SM-mediated biochemical pathways and tau release from early neurodegeneration in preclinical AD. Lower SM levels were associated with weaker working memory and executive function, as well as poorer global cognition, indicating their potential predictive value for weaker cognitive performance. Moreover, SMs were also inversely associated with cortical Aβ load in CU Aβ+ individuals, possibly reflecting early SM-mediated neuroprotective responses against AD pathogenesis. Receiver operating characteristic analysis further revealed the significant potential of the SM panel in distinguishing cortical PET-Aβ status and enhancing the predictive performance of plasma T-tau in CU individuals. Therefore, circulating T-tau-associated SMs may serve as promising early biomarkers of lipid-mediated processes in CU older adults with cortical amyloid pathology and tau-related neurodegeneration.}, } @article {pmid42105317, year = {2026}, author = {Balwant Patil, K and Sugunan, S and Padiyar, A and Mishra, AK and Jain, S}, title = {Neuroprotective role of phenolic acids: mechanistic insights into cognitive decline and neurodegenerative disorder.}, journal = {Nutritional neuroscience}, volume = {}, number = {}, pages = {1-25}, doi = {10.1080/1028415X.2026.2669234}, pmid = {42105317}, issn = {1476-8305}, abstract = {BACKGROUND: Age-associated cognitive deterioration and neurodegenerative conditions, including Alzheimer's disease (AD) and Parkinson's disease (PD), are predominantly influenced by oxidative stress, neuroinflammation, mitochondrial dysfunction, and abnormal protein aggregation. Dietary phenolic acids, prevalent in plant-based foods, have demonstrated potential neuroprotective and cognitive-enhancing effects in recent studies.

PURPOSE: This review seeks to thoroughly assess the neuroprotective mechanisms of phenolic acids and to consolidate existing evidence from human and preclinical studies concerning their potential efficacy in alleviating cognitive impairment and neurodegeneration.

STUDY DESIGN: Narrative and evidence-based literature review.

METHODS: Recent experimental, clinical, and epidemiological studies examining significant phenolic acids - such as caffeic, chlorogenic, ferulic, gallic, rosmarinic, sinapic, ellagic, protocatechuic, p-coumaric, and tannic acids - in relation to AD, PD, and cognitive functions were retrieved from electronic databases. We put together the most important information about molecular mechanisms and treatment.

RESULTS: Preclinical studies show that phenolic acids have antioxidant, anti-inflammatory, anti-apoptotic, and anti-aggregation effects by changing important signaling pathways like Nrf2/HO-1, NF-κB, and PI3 K/Akt. These actions protect dopaminergic neurons, lower the toxicity of amyloid-beta and α-synuclein, and make behavior better in disease models. Human studies suggest that increased dietary consumption of phenolic acids, especially hydroxycinnamic acids such as caffeic and chlorogenic acid, is associated with enhanced cognitive performance and a diminished risk of cognitive decline, although results are not uniform.

CONCLUSION: Phenolic acids are secure, readily accessible neuroprotective compounds that can alter various pathological pathways associated with cognitive decline and the progression of neurodegenerative diseases.}, } @article {pmid42105452, year = {2026}, author = {Uehara, MA and Bretecher, CA and Teschuk, JM and Verot, A and Saha, C and Fitzgerald, PB and Koski, L and Millikin, C and Moussavi, Z}, title = {Examining adverse effects in a large clinical trial of rTMS application as a treatment for Alzheimer's disease.}, journal = {Psychiatry research}, volume = {362}, number = {}, pages = {117212}, doi = {10.1016/j.psychres.2026.117212}, pmid = {42105452}, issn = {1872-7123}, mesh = {Humans ; *Alzheimer Disease/therapy ; Female ; Male ; *Transcranial Magnetic Stimulation/adverse effects ; Aged ; Aged, 80 and over ; Risk Factors ; }, abstract = {BACKGROUND: Repetitive transcranial magnetic stimulation (rTMS) has several advantages compared to other interventions for neurological and psychological disorders. However, various adverse effects have been reported in rTMS research, and little is known about who is most susceptible to rTMS adverse effects, or how they can be minimized.

AIMS: We aimed to identify risk factors for adverse effects reported in a recent clinical trial examining rTMS as a treatment for Alzheimer's disease (AD). We hypothesized that higher stimulation intensity would be associated with experiencing unspecified pain/discomfort, dental pain, headache, jaw pain, and muscle contractions, but not be associated with other adverse effects.

METHODS: Using detailed notes from treatment sessions, 10 adverse effects were identified. Spearman correlations were conducted to assess relationships between the highest applied stimulation intensity and normalized frequency of each adverse effect amongst those who experienced that adverse effect. Demographic information, cognitive scores, and withdrawal status were compared between the binarized groups of participants who experienced adverse effects versus those who did not. Spearman correlations were also conducted on the binarized adverse effects and the highest applied stimulation intensity. Logistic regressions were conducted to identify potential risk factors.

RESULTS: In both the sham and active treatment groups, unspecified pain/discomfort was the most common adverse effect, followed by muscle contractions and dizziness. In both the active and sham treatment groups, stimulation intensity was positively associated with muscle contractions, but was not significantly related to any other adverse effect. In evaluating groups with/without adverse effects, we found there was a significantly higher proportion of males reporting adverse effects in both the active treatment group and the sham treatment group compared to females.

CONCLUSION: The findings of this study are a step toward understanding how researchers can minimize such adverse effects, and thereby, create a less aversive experience for rTMS participants.}, } @article {pmid42105933, year = {2026}, author = {Pourzal, R and Agarwal, P and Leurgans, SE and McCarthy, SM and Hall, DJ and McDevitt, CA and Ganio, K and Ayton, S and Bush, AI and Grodstein, F and James, BD and Agrawal, S and Hallab, NJ and Bennett, DA and Schneider, JA and Jacobs, JJ}, title = {Cobalt and titanium levels in the brain are associated with Alzheimer's disease pathology but not cognition: A study of older adults with and without total joint replacement.}, journal = {Acta biomaterialia}, volume = {217}, number = {}, pages = {750-760}, pmid = {42105933}, issn = {1878-7568}, support = {R01 AG017917/AG/NIA NIH HHS/United States ; RF1 AG054057/AG/NIA NIH HHS/United States ; }, mesh = {Humans ; *Titanium/metabolism ; Female ; Male ; Aged ; *Alzheimer Disease/pathology/metabolism ; *Cobalt/metabolism ; *Brain/metabolism/pathology ; *Cognition ; Aged, 80 and over ; *Arthroplasty, Replacement ; }, abstract = {Alzheimer's disease (AD) and total joint arthroplasty are prevalent and often concomitant in older adults, but an etiologic link is debated. Since wear particles are an inevitable side product of total joint arthroplasty (TJA), we hypothesized that older adults with TJA agglomerate higher-than-normal concentrations of implant alloy elements caused by the dissemination of debris from the implants, resulting in a pathological reaction. A cross-sectional analysis was conducted among 701 autopsied participants of an ongoing longitudinal cohort (Memory and Aging Project (MAP)) of whom postmortem neuropathologic data was available and implant-related metals (cobalt, titanium) were quantified in four brain regions by inductively coupled mass-spectrometry. MAP participants are enrolled without known dementia at baseline and followed annually for cognitive assessments using 19-test battery. In the analytical sample, 229 had TJA (total hip arthroplasty, total knee arthroplasty, and total shoulder arthroplasty) and n = 472 had no total joint. Due to a higher likelihood of cobalt release in total hip arthroplasty, the TJA group was subdivided into a hip (n = 146) and a knee/shoulder (n = 83) group. We used regression and linear mixed-effects models, adjusted for demographics and apolipoprotein E ε4 status, to examine associations between metals, AD pathology and cognitive decline. Cobalt content of brain tissue was 8.9 % higher in the total hip arthroplasty group than in the no-TJA group (p = 0.003). Cobalt-containing particles were identified within brain tissue using scanning electron microscopy. In the inferior temporal cortex, cobalt was positively associated (p = 0.0004) and titanium was negatively associated (p = 0.038) with amyloid-beta load, but had no association with cognition. These results warrant monitoring the potential impact of metal implant debris on brain health. STATEMENT OF SIGNIFICANCE: This study is of great clinical significance because Alzheimer's disease (AD) and total joint arthroplasty (TJA)-the end-stage treatment of osteoarthritis-affect large and overlapping groups in our aging population. There is limited knowledge about the relationship between the prominent TJA implant metals cobalt and titanium and the pathogenesis of AD. This study shows that Co28Cr6Mo and Ti6Al4V implant alloy particles-most likely from a subset of total hip replacements with accelerated wear or tribocorrosion-can disseminate to the brain and be associated with increased cobalt and titanium concentrations. Cobalt was associated with greater AD pathology in the inferior-temporal cortex, even after correction for other known AD risk factors. However, there was no correlation with cognitive decline. Titanium was negatively associated with AD pathology, but titanium oxide appeared to be abundant in the brain from sources other than joint replacements.}, } @article {pmid42106468, year = {2026}, author = {Santos, ACC and Corrêa, JL and Duarte, RMF and Malta, SM and Rodrigues, TS and de Oliveira Santos, D and de Faria, PR and do Prado Mascarenhas, FNA and Zanon, RG and Cassemiro, NS and Carollo, CA and Espindola, FS and Martins, MM and Mendes-Silva, AP and Bonetti, AM and Dos Santos, AR and Ueira-Vieira, C}, title = {Bacterial polar metabolites modulate β-amyloid toxicity and cholinergic dysfunction in models of Alzheimer's disease.}, journal = {Scientific reports}, volume = {}, number = {}, pages = {}, doi = {10.1038/s41598-026-52291-3}, pmid = {42106468}, issn = {2045-2322}, support = {APQ-00269-22//Fundação de Amparo à Pesquisa do Estado de Minas Gerais/ ; 403193/2022-2//Conselho Nacional de Desenvolvimento Científico e Tecnológico/ ; APQ-03613-17; APQ-02766-17//Fundação de Amparo à Pesquisa do Estado de Minas Gerais , Brasil/ ; }, abstract = {Alzheimer's disease is characterized by progressive neurodegeneration driven by β-amyloid (Aβ) toxicity, oxidative stress, and cholinergic dysfunction. In this study, we investigated whether polar metabolites derived from a cultivable bacterial isolate could modulate Aβ-associated neurodegenerative phenotypes in complementary experimental models. A bioactivity-guided approach identified an aqueous fraction with high antioxidant capacity in DPPH, FRAP, and ORAC assays. In a transgenic Drosophila melanogaster model expressing human Aβ, treatment with this fraction significantly reduced amyloid accumulation and attenuated neurodegenerative histopathological alterations. In human SH-SY5Y neuronal cultures, the metabolites improved cell viability under therapeutic, but not preventive, conditions following exposure to aggregated Aβ. The aqueous fraction also exhibited significant inhibitory activity against acetylcholinesterase and butyrylcholinesterase. Whole-genome sequencing assigned the bioactive isolate to the genus Providencia, with comparative genomic analyses suggesting its placement within a distinct taxonomic lineage. Metabolomic profiling by LC-ESI-MS/MS revealed a diverse set of polar metabolites, including metabolites putatively annotated based on spectral matching, previously associated with neuroprotective and cholinesterase-modulating activities. Collectively, these findings demonstrate that bacterial polar metabolites can modulate key pathological features of Alzheimer's disease, supporting their relevance for mechanistic studies of Aβ toxicity and cholinergic dysfunction.}, } @article {pmid42107415, year = {2026}, author = {Stepanchuk, AA and Joseph, JT and Lashley, T and Stys, PK}, title = {Disentangling amyloid polymorphs in normal aging and Alzheimer's disease using dual-probe spectral imaging.}, journal = {Neurobiology of aging}, volume = {165}, number = {}, pages = {51-59}, doi = {10.1016/j.neurobiolaging.2026.04.009}, pmid = {42107415}, issn = {1558-1497}, mesh = {Humans ; *Alzheimer Disease/metabolism/pathology/diagnosis/diagnostic imaging ; *Aging/metabolism/pathology ; *Hippocampus/metabolism/pathology/diagnostic imaging ; Female ; Aged, 80 and over ; Plaque, Amyloid/metabolism ; Male ; Aged ; *Amyloid/metabolism ; Microscopy, Fluorescence/methods ; Neurofibrillary Tangles/metabolism ; Machine Learning ; }, abstract = {Variability in Alzheimer's disease (AD) clinical presentation complicates mechanistic studies and therapeutic outcome prediction. Brain protein aggregate load does not directly correlate with clinical symptoms; however, different subtypes of AD have been reported to exhibit structural variation (polymorphism) of aggregates. Little is known about the structural diversity of the deposits in cognitively normal aged brains. This study investigates the structural heterogeneity of amyloid aggregates in the hippocampus and their association with age- and disease-related pathology. Post-mortem hippocampal tissue from cognitively normal aged controls and AD patients was co-stained with the amyloid-sensitive dyes BSB and MCAAD-3 and imaged across various subregions using spectral fluorescence microscopy. Machine learning analysis of spectral data differentiated amyloid polymorphs between cognitively normal and Alzheimer's cases. Our analysis revealed distinct spectral features across the amyloid plaques, neurofibrillary tangles and the background tissue parenchyma associated with AD compared to those observed in cognitively normal aging, irrespective of overall aggregate load. This study underscores the importance of amyloid polymorphism in determining the clinical impact of protein pathology in AD. Our findings highlight that focusing on amyloid structure rather than total load can aid in advancing personalized approaches in the diagnosis and treatment of neurodegenerative diseases.}, } @article {pmid42107621, year = {2026}, author = {Khattab, NA and El Kadeem, A and Goda, AE and El-Mahdy, NA and El-Shitany, N}, title = {Aluminum chloride in Alzheimer's disease: A dual focus on molecular mechanisms and rat experimental models.}, journal = {Experimental neurology}, volume = {403}, number = {}, pages = {115814}, doi = {10.1016/j.expneurol.2026.115814}, pmid = {42107621}, issn = {1090-2430}, mesh = {Animals ; *Alzheimer Disease/chemically induced/metabolism/pathology ; *Disease Models, Animal ; *Aluminum Chloride/toxicity ; Humans ; Rats ; Oxidative Stress/drug effects/physiology ; Amyloid beta-Peptides/metabolism ; }, abstract = {Alzheimer's disease (AD) is a leading cause of dementia among middle-aged and elderly individuals globally. Animal models of AD are widely used to investigate disease mechanisms and evaluate potential treatments for disease modification. Among non-genetically modified models, aluminum (Al[3+]) induced neurotoxicity has been widely employed to mimic key features of AD, including neuroinflammation and cognitive decline. This review comprehensively elucidates current evidence on the molecular and cellular mechanisms underlying Al[3+]-induced AD-like pathology, including amyloid-β accumulation, tau protein hyperphosphorylation, oxidative stress, mitochondrial dysfunction, neuroinflammation, cholinergic system impairment, synaptic plasticity deficits, apoptosis, metal ion dyshomeostasis, and epigenetic alterations. This review critically discusses methodological variables that significantly influence experimental outcomes in Al[3+]-based models, including dosage, route of administration, exposure duration, and animal age and gender. Moreover, this review emphasizes the translational significance, advantages, and limitations of the Al[3+]-induced model by merging mechanistic insights with experimental design considerations, offering guidelines for its optimal application in AD research and treatment development.}, } @article {pmid42107748, year = {2026}, author = {Suriyaamporn, P and Wongprayoon, P and Pannakkong, W and Pamornpathomkul, B and Ngawhirunpat, T and Rojanarata, T and Opanasopit, P}, title = {Development of AI-assisted 3D-printed degradable hydrogel microneedles for transdermal delivery of progesterone-loaded solid lipid nanoparticles: a novel approach to slowing Alzheimer's disease progression.}, journal = {International journal of pharmaceutics}, volume = {698}, number = {}, pages = {126967}, doi = {10.1016/j.ijpharm.2026.126967}, pmid = {42107748}, issn = {1873-3476}, mesh = {*Progesterone/administration & dosage/chemistry/pharmacokinetics ; Animals ; Administration, Cutaneous ; Microneedle Drug Delivery ; *Alzheimer Disease/drug therapy ; Printing, Three-Dimensional ; *Nanoparticles/administration & dosage/chemistry ; Skin Absorption ; Lipids/chemistry ; Humans ; *Hydrogels/chemistry/administration & dosage ; Rats, Sprague-Dawley ; Particle Size ; Skin/metabolism ; Female ; Drug Delivery Systems ; Liposomes ; }, abstract = {Progesterone (PG) is used to slow the progression of neurodegenerative diseases, particularly Alzheimer's disease (AD) in postmenopausal women. However, PG exhibits high lipophilicity, resulting in strong binding to skin tissues and plasma proteins, which may limit its systemic transport via transdermal routes. Solid lipid nanoparticles (SLNs) have been highlighted for their potential to enhance drug solubility and facilitate brain-targeted drug delivery for AD treatment. Microneedles (MNs) offer an advanced microtechnology for transdermal drug delivery, significantly improving drug permeation into the skin. However, traditional MNs fabrication methods face challenges related to shape control, dosage precision, high costs, and time consumption. Recent advancements in 3D printing technology offer a promising solution to these limitations. This study aimed to design and evaluate 3D-printed MNs-loaded with PG-SLNs for AD treatment. Biodegradable resin was utilized to fabricate MNs, aided by a Convolutional Neural Networks (CNNs) prediction model for improved accuracy. Mechanical strength, penetration efficiency, degradation, in vitro and in vivo drug delivery efficiency, cellular toxicity, and stability were evaluated. The optimized MNs, with a height of 756.98 ± 14.78 µm, effectively penetrated the skin barrier. SLNs exhibited a particle size of 308.91 ± 1.66 nm, PDI of 0.19 ± 0.08, and ZP of -30.03 ± 1.19 mV. The MNs retained sufficient mechanical strength post-drug loading, enabled efficient transdermal PG delivery, exhibited no cytotoxicity to neuronal cells, and remained physicochemically stable for up to 3 months. This study highlights the potential of 3D-printed MN patches as a novel transdermal drug delivery system, demonstrating practical feasibility for medical applications.}, } @article {pmid42107892, year = {2026}, author = {Chen, G and Zhao, C and Wang, C and Chen, G and Shi, J and Chen, H}, title = {Microglia crosstalk with T cells in neurodegenerative diseases: pathogenesis and treatment targets.}, journal = {International immunopharmacology}, volume = {182}, number = {}, pages = {116781}, doi = {10.1016/j.intimp.2026.116781}, pmid = {42107892}, issn = {1878-1705}, mesh = {Humans ; *Microglia/immunology ; *Neurodegenerative Diseases/immunology/therapy ; Animals ; *T-Lymphocytes/immunology ; }, abstract = {Immune cells play a central role in driving inflammation and neurodegeneration across various neurological disorders. Central nervous system (CNS)-resident microglia and infiltrating T cells represent the innate and adaptive immune systems, respectively, and have been reported to contribute to the pathogenesis of neurodegenerative diseases individually. Growing evidence suggests that the encounter between activated microglia and infiltrating T cells amplifies their neurotoxic potential. In this review, we discussed alterations in microglial phenotype and function, and the contributions of different T cell subsets in neurodegenerative diseases including Alzheimer's disease (AD), Parkinson's disease (PD), Multiple sclerosis (MS), Amyotrophic lateral sclerosis (ALS) and glaucoma. We emphasized the crosstalk between microglia and T cells via antigen presentation, chemotactic signals, and pro-inflammatory mediators. We also explored emerging therapeutic strategies aimed at modulating T cell and microglial responses, as well as their interactions, for the treatment of neurodegenerative diseases.}, } @article {pmid42108759, year = {2026}, author = {Meng, Q and Li, J and Xu, G and Zhang, W and Cao, R and Cai, K}, title = {Ginsenoside Rh2 Alleviates Alzheimer Disease Models via Effects on Ferroptosis-Related Neuroinflammation.}, journal = {Journal of biochemical and molecular toxicology}, volume = {40}, number = {5}, pages = {e70860}, doi = {10.1002/jbt.70860}, pmid = {42108759}, issn = {1099-0461}, support = {YKK23216//Nanjing Health Science and Technology Development Special Fund/ ; ST222102//Major Sports Research Projects of Jiangsu Provincial Sports Bureau/ ; LKZ2025004//Jiangsu Elderly Health Scientific Research Project/ ; }, mesh = {Animals ; *Ginsenosides/pharmacology ; *Alzheimer Disease/drug therapy/metabolism/pathology ; Mice ; Mice, Transgenic ; Disease Models, Animal ; *Ferroptosis/drug effects ; Amyloid beta-Peptides/metabolism ; *Neuroinflammatory Diseases/drug therapy/metabolism/pathology ; Cell Line, Tumor ; Male ; }, abstract = {Ginsenosides are the primary active constituents derived from the dried roots of ginseng, a staple in traditional Chinese medicine. This study aimed to evaluate the therapeutic efficacy of the Ginsenoside Rh2 (Rh2) monomer in both in vitro and in vivo models of Alzheimer disease (AD). An in vivo AD cell model was established by stimulating N2a mouse neuroblastoma cells with β-amyloid (Aβ) 1-42, while APP/PS1 transgenic mice served as the in vivo model. In vitro, Aβ1-42-stimulated N2a cells were co-incubated with 40 or 80 μM Rh2 for 24 h. In vivo, APP/PS1 mice received daily intraperitoneal injections of Rh2 (20 mg/kg) for 5 weeks. Our results demonstrated that Rh2 treatment significantly enhanced the viability of N2a cells and ameliorated mitochondrial membrane potential dysregulation. Furthermore, Rh2 attenuated oxidative stress by reducing reactive oxygen species production and decreasing malondialdehyde levels. It also suppressed the hypersecretion of pro-inflammatory mediators, including nitric oxide, interleukin-1β (IL-1β), and IL-6, in Aβ-treated cells. Mechanistically, Rh2 exerted potent anti-ferroptotic and anti-inflammatory effects via the activation of the Nrf2/GPX4 signaling pathway, which ultimately translated to improved spatial learning and memory in APP/PS1 mice. These findings elucidate a novel mechanistic paradigm for Rh2, highlighting its potential as a therapeutic candidate for AD drug development.}, } @article {pmid42109911, year = {2026}, author = {Choi, S and Park, S and Jung, YH and Oh, MS and Yu, KH and Lee, BC and Lee, M}, title = {Comparative risk of dementia between direct oral anticoagulants and warfarin after atrial fibrillation related ischemic stroke.}, journal = {Frontiers in aging neuroscience}, volume = {18}, number = {}, pages = {1718536}, pmid = {42109911}, issn = {1663-4365}, abstract = {INTRODUCTION: Direct oral anticoagulants (DOAC) have been associated with a reduced risk of dementia compared to warfarin in patients with atrial fibrillation (AF) without prior stroke. However, the impact of DOAC on dementia risk in AF-related ischemic stroke survivors is unclear.

METHODS: We conducted a retrospective, nationwide cohort study using the Korean National Health Insurance Service database. We identified patients with newly diagnosed ischemic stroke and concurrent AF who began DOAC or warfarin therapy within one month after stroke. Incidence of all-cause dementia, Alzheimer's dementia (AD), and vascular dementia (VaD) was compared between groups using multivariable Cox models with inverse probability of treatment weighting.

RESULTS: A total of 3,112 patients (mean age 70.6 ± 9.5 years; 66.6% male) were analyzed, including 2,919 DOAC users and 193 warfarin users. Over a mean follow-up of 3.63 years, 673 all-cause dementia cases (538 AD, 168 VaD) occurred. After IPTW, DOAC use was associated with higher risks of all-cause dementia (HR 1.16, 95% CI 1.04-1.30) and AD (HR 1.85, 95% CI 1.62-2.13) but a lower risk of VaD (HR 0.54, 95% CI 0.45-0.66) compared to warfarin.

DISCUSSION: In this retrospective nationwide cohort of AF-related ischemic stroke survivors, DOAC use was associated with a higher incidence of all-cause dementia and Alzheimer's dementia, but a lower incidence of vascular dementia, compared with warfarin. These observational findings suggest that anticoagulant type may be differentially associated with subsequent dementia subtypes in this high-risk population and should be interpreted with caution.}, } @article {pmid42109914, year = {2026}, author = {Fu, X and Huang, J and Liu, Y and Li, H and Zhang, Y}, title = {Unraveling the anti-neuroinflammatory mechanisms of Cervus cucumis polypeptide injection in Alzheimer's disease: insights from network pharmacology, molecular docking, molecular dynamics simulation, and experimental validation.}, journal = {Frontiers in aging neuroscience}, volume = {18}, number = {}, pages = {1797302}, pmid = {42109914}, issn = {1663-4365}, abstract = {OBJECTIVE: Alzheimer's disease (AD) is a progressive neurodegenerative disorder with increasing global prevalence, in which neuroinflammation serves as a critical pathological driver exacerbating cognitive decline. While current therapies offer limited symptomatic relief, multi-target strategies are urgently needed. Cervus cucumis polypeptide injection (CCPI), a traditional Chinese medicine (TCM) formulation, has demonstrated anti-inflammatory properties; however, its mechanisms of action against AD remain unclear. This study aimed to elucidate the anti-AD potential mechanisms of CCPI using an integrated approach combining network pharmacology, molecular docking, molecular dynamics (MD) simulation, and experimental validation.

METHODS: Active components and corresponding targets of CCPI were retrieved from the TCMSP database, while AD-related targets were collected from Genecards, OMIM, and DrugBank. Potential therapeutic targets were identified by intersecting drug and disease targets, followed by protein-protein interaction (PPI) network construction, Gene Ontology (GO), and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses. Molecular docking and MD simulations were performed to evaluate interactions between potential active components and key targets. In vitro experiments were conducted on Aβ25-35-induced BV2 microglial cells to assess cell viability (CCK-8 assay), inflammatory cytokine levels (ELISA), and protein expression (Western blot) related to the neuroinflammation pathway and microglial polarization.

RESULTS: A total of 28 active components and 50 common targets of CCPI for AD treatment were identified. Linoleic acid (LA) was determined to be a potential active component, with IL-6 as the key target based on PPI network topology. Molecular docking and MD simulation confirmed a stable binding affinity between LA and IL-6. KEGG analysis revealed significant enrichment in the HIF-1 signaling pathway, particularly the IL-6/STAT3/VEGF signaling pathway. In vitro, CCPI treatment significantly enhanced cell viability and attenuated the pro-inflammatory response, as evidenced by reduced levels of IL-6, IL-1β, and TNF-α, decreased the expression of the pro-inflammatory marker iNOS. Concurrently, it elevated the expression of the anti-inflammatory/repair-associated marker CD206. Western blot analysis further verified that CCPI suppressed IL-6/STAT3 activation while upregulating VEGF expression. Additionally, LA alone significantly reduced IL-6 levels and STAT3 phosphorylation, decreased the expression of iNOS, and increased the expression of CD206, with therapeutic efficacy comparable to CCPI.

CONCLUSION: CCPI exerts neuroprotective effects in AD models by regulating the IL-6/STAT3/VEGF pathway, downregulating the expression of the inflammation-related iNOS protein, upregulating the expression of the CD206 protein associated with anti-inflammatory and reparative functions, remodeling the functional state of microglia, inhibiting their pro-inflammatory responses, and enhancing their reparative functions. Its potential active component, LA, likely mediates this effect by stably binding to and inhibiting IL-6, thus suppressing the downstream STAT3 phosphorylation that drives inflammatory activation.}, } @article {pmid42111521, year = {2026}, author = {Guo, B and Wang, J and Lou, F and Yuan, B and Chen, Z and Tang, C and Chen, W and Yi, F and Jiang, J and Hu, G and Cong, C and Lu, Y}, title = {Graphene field-effect transistor based multiplexed sensing platform for simultaneous detection of multiple Alzheimer's disease biomarkers.}, journal = {RSC advances}, volume = {16}, number = {26}, pages = {23937-23944}, pmid = {42111521}, issn = {2046-2069}, abstract = {Simultaneous detection of multiple biomarkers for one disease using a single drop of body fluid is challenging yet critical to confirm symptoms in the early stage. This study presents the development of a graphene field-effect transistor (GFET)-based multiplexed sensing platform designed for overcoming this obstacle. The platform utilizes a hexamethyldisilazane (HMDS) blocking layer as a hydrophobic treatment to enable recognition element (probe/aptamer) modifications within a small chip area (3 × 3 mm[2]), and this further enables simultaneous detection of multiple targets (multi-targets) in complex biological samples. The optimized aptamer/probe functionalization also enhances the specificity, sensitivity, and accuracy of the sensor. The technology was demonstrated with Alzheimer's disease (AD) biomarkers as a case study. Two distinctive biomarkers, hsa-miR-125b and Aβ42, are detected simultaneously with distinguishable signatures, and the lowest tested concentration is 1 fM. The cross-check experiments also show the effectiveness of the multi-target detection capability. This concise platform paves the way for accurate detection of early-stage diseases when the simultaneous identification of multiple biomarkers is required.}, } @article {pmid42111940, year = {2026}, author = {Ismail Al-Khaleel, R and Kalenahalli, Y and Hemalatha, S and Baker, S and Raj, SN and Rangappa, KS and Gowda, S and Siddaiah, C}, title = {Metabolomic analysis of Pennisetum glaucum seed extracts using advanced LC-MS/MS and Q-TOF technology.}, journal = {Journal of food science and technology}, volume = {63}, number = {5}, pages = {962-970}, pmid = {42111940}, issn = {0022-1155}, abstract = {UNLABELLED: Pearl millet (Pennisetum glaucum) is a cereal widely cultivated and grown in Africa and the Indian subcontinent for centuries. The present investigation aims to use LC-MS/MS to analyze the secondary metabolites present in pearl millet seeds using different solvents such as methanol, hexane, chloroform, and ethyl acetate. METLIN software was used to identify the metabolites. The analysis revealed the presence of 650 metabolites, among which 145 were commonly found in all the solvent extracts. The major classes of identified metabolites are terpenoids, flavonoids, sterols, amino acids, fatty acids, glycoconjugates, and carbohydrates. 80% methanolic extract and ethyl acetate extract yielded the highest concentrations of terpenoid (23%) and flavonoid (17%). The enrichment analysis was performed to statistically examine and identify the metabolites present in the metabolomic library dataset. In the hexane extract, notable metabolites such as quercetin and rutin were identified, which possess potential for the management of Alzheimer's disease due to their neuroprotective effects (p < 4e-35). In the methanol extract, metabolites like gallic acid and caffeic acid were associated with uremia treatment due to their antioxidant activity (p < 5e-37). Overall, the present study provides an overview of the metabolites present in the pearl millet seeds and the nutritive as well as therapeutic potential of these millets in the management of human diseases.

SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s13197-025-06328-6.}, } @article {pmid42112453, year = {2025}, author = {Usman, M and Ashebir, S and Okey-Mbata, C and Yun, Y and Kim, S}, title = {Neuroengineering Frontiers: A Selective Review of Neural Interfaces, Brain-Machine Interactions, and Artificial Intelligence in Neurodegenerative Diseases.}, journal = {Applied sciences (Basel, Switzerland)}, volume = {15}, number = {21}, pages = {}, pmid = {42112453}, issn = {2076-3417}, support = {SC1 NS122448/NS/NINDS NIH HHS/United States ; UG3 EB036466/EB/NIBIB NIH HHS/United States ; }, abstract = {Neurodegenerative diseases, including Alzheimer's disease (AD) and Parkinson's disease (PD), present a growing public health challenge globally. Recent advancements in neurotechnology and neuroengineering have significantly enhanced brain-computer interfaces, artificial intelligence, and organoid technologies, making them pivotal instruments for diagnosis, monitoring, disease modeling, treatment development, and rehabilitation of various diseases. Nonetheless, the majority of neural interface platforms focus on unidirectional control paradigms, neglecting the need for co-adaptive systems where both the human user and the interface continually learn and adapt. This selected review consolidates information from neuroscience, artificial intelligence, and organoid engineering to identify the conceptual underpinnings of co-adaptive and symbiotic human-machine interaction. We emphasize significant shortcomings in the advancement of long-term AI-facilitated co-adaptation, which permits individualized diagnostics and progression tracking in Alzheimer's disease and Parkinson's disease. We concentrate on incorporating deep learning for adaptive decoding, reinforcement learning for bidirectional feedback, and hybrid organoid-brain-computer interface platforms to mimic disease dynamics and expedite therapy discoveries. This study outlines the trends and limitations of the topics at hand, proposing a research framework for next-generation AI-enhanced neural interfaces targeting neurodegenerative diseases and neurological disorders that are both technologically sophisticated and clinically viable, while adhering to ethical standards.}, } @article {pmid42113681, year = {2026}, author = {Wang, S and Yuan, X and Wang, T and Yang, M and Dong, P and Han, H}, title = {Mechanisms and Therapeutic Targeting of the Gut Microbiota-Immune-Brain Axis in Alzheimer's Disease.}, journal = {Immunological investigations}, volume = {}, number = {}, pages = {1-31}, doi = {10.1080/08820139.2026.2669375}, pmid = {42113681}, issn = {1532-4311}, abstract = {BACKGROUND: Alzheimer's disease (AD) is a highly prevalent neurodegenerative disease globally. The main pathological features of AD are amyloid-β (Aβ) deposition and tau hyperphosphorylation. Recent studies suggest that the gut microbiota-immunity-brain axis plays an important role in the onset and progression of AD. Gut microbiota dysbiosis may impair intestinal barrier integrity and promote the entry of pro-inflammatory mediators into the circulation. Pro-inflammatory signals in the bloodstream may further activate the central immune system, drive microglial polarization, and increase the release of inflammatory factors in the brain. The resulting neuroinflammatory cascade may aggravate Aβ accumulation, tau phosphorylation, and cognitive impairment, although this mechanism has not been conclusively established in humans.

METHODS AND RESULTS: Based on relevant literature on AD, gut microbiota, immunity, neuroinflammation, and the gut-brain axis, this article systematically reviews the mechanism of action of the microbiota-immunity-brain axis in AD. Current intervention strategies targeting this axis, including probiotics, fecal microbiota transplantation, dietary interventions, and traditional Chinese medicine, were also discussed. Such intervention measures have the potential to regulate the balance of the gut microbiota, reduce neuroinflammation, and slow the progression of AD pathology.

CONCLUSION: It is essential to integrate multi-omics approaches in future research to deepen the understanding of AD pathogenesis and support the development of more precise and personalized treatment strategies.}, } @article {pmid42115432, year = {2026}, author = {Ferré, CG and Pallàs, M and Franco, R}, title = {Molecular and statistical weaknesses of the p-tau217/Aβ1-42 plasma ratio for alzheimer's diagnosis.}, journal = {Journal of molecular medicine (Berlin, Germany)}, volume = {104}, number = {1}, pages = {}, pmid = {42115432}, issn = {1432-1440}, mesh = {Humans ; *Amyloid beta-Peptides/blood ; *Alzheimer Disease/diagnosis/blood ; Biomarkers/blood ; *tau Proteins/blood ; *Peptide Fragments/blood ; Reproducibility of Results ; }, abstract = {The FDA's approval of the Lumipulse G p-tau217/Aβ1-42 plasma ratio enhances access to Alzheimer's diagnostics but risks confusing convenience with biological accuracy. The assay is scalable and non-invasive, yet it relies on a ratio of two markers that are unstable and only partly specific to the disease, raising concerns about reproducibility and interpretation. The reported performance is solid in carefully selected groups, but is likely to be less robust in broader real-world populations with lower disease prevalence, mixed pathologies, and higher comorbidity. If biomarker-based enrollment is shaped by imperfect specificity, misclassification may propagate into trial recruitment, treatment-effect estimates, and downstream validation. This concern is amplified when biomarkers are validated within partially circular frameworks in which plasma assays, positron emission tomography, cerebrospinal fluid markers, and clinical diagnosis reinforce one another without fully independent neuropathological confirmation. Blood-based assays remain promising, but their clinical use should be guided by rigorous analytical scrutiny, broad validation across diverse populations, standardized pre-analytical handling, and transparent data sharing. The aim of biomarker science should be not striking receiver operating characteristic curves in curated cohorts, but biological fidelity across human heterogeneity and validation grounded in mechanism. Until then, the p-tau217/Aβ1-42 ratio is best regarded as a useful contextual or research tool rather than a standalone diagnostic benchmark, so that precision medicine does not rest on associations whose causal and mechanistic basis remains insufficiently established. Its most appropriate use may be in longitudinal monitoring within the same individual, where changes over time may be more informative than a single threshold-based diagnostic result.}, } @article {pmid42115835, year = {2026}, author = {Fu, Q and Yin, X and Xu, S}, title = {Disentangling treatment status from disease severity in studies of diabetes and Alzheimer's disease biomarkers.}, journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association}, volume = {22}, number = {5}, pages = {e71465}, pmid = {42115835}, issn = {1552-5279}, support = {824774630//National Natural Science Foundation of China/ ; 82274643//National Natural Science Foundation of China/ ; 20234Y0023//Shanghai Municipal Health Commission/ ; }, } @article {pmid42116113, year = {2026}, author = {Li, Y and Hu, C and Xia, C and Wang, X and Zhou, X and Xu, R and Li, Y and Mo, F and Zhao, B and Xu, L and Zhu, C and Chen, Z}, title = {A novel nasal mucosal peptide-modified co-delivery system for ginsenoside Rg1, Rb1, and notoginseng saponin R1 in the amelioration of AD.}, journal = {Journal of nanobiotechnology}, volume = {}, number = {}, pages = {}, doi = {10.1186/s12951-026-04532-w}, pmid = {42116113}, issn = {1477-3155}, support = {202510315035//National Innovation and Entrepreneurship Training Program for Undergraduate/ ; 82304729//National Natural Science Foundation of China/ ; 82574587//National Natural Science Foundation of China/ ; BK20230457//Natural Science Foundation of Jiangsu Province/ ; ZYXYL2024-005//Scientific Research Foundation of Nanjing University of Chinese Medicine/ ; }, abstract = {The drug delivery for Alzheimer's disease (AD) faces substantial obstacles owing to the presence of the blood-brain barrier (BBB). This circumstance highlights the nose-brain route as pivotal for enhancing drug distribution to the brain. As the efficiency of brain entry is constrained by the physiological barrier of the nasal cavity, the development of strategies to efficiently traverse this barrier is imperative for enhancing the effectiveness of AD treatment. In the present study, a cell-penetrating peptide (CPPs) named LK4, which originates from mastoparan-L (MPL), was employed. Its capacity to efficiently penetrate the physiological barrier of the nasal cavity was demonstrated. LK4 was modified into polydopamine (PDA) nanoparticles to construct nanoparticles containing ginsenoside Rg1, ginsenoside Rb1, and notoginseng saponin R1 (TGS), designated as LK4-TGS-PDA. Experiment results reveal that the LK4-TGS-PDA drug delivery system can enhance the uptake of olfactory neurons and promote epithelial transport. In an in vitro nasal mucosal barrier model, LK4 modification increased the apparent permeability coefficients of R1, Rg1, and Rb1 by 1.2-, 1.2-, and 12-fold, respectively, compared to unmodified nanoparticles. Following nasal administration, the brain concentrations of R1, Rg1, and Rb1 increased by 19-fold, 30-fold, and 15-fold, respectively, and the relative brain bioavailability reached 933.1%, 1375.0%, and 1144.4%, respectively. In the model of AD induced by amyloid-beta 1-42 (Aβ1-42), it was confirmed that LK4-TGS-PDA NPs can significantly improve cognitive dysfunction, with escape latency reduced by 30.3%, platform crossings increased by 5.4-fold, and target quadrant time extended by 2.4-fold, as well as reduce the effects of inflammation in the brain, with IL-1β, IL-6, and TNF-α decreased by 44.05%, 53.49%, and 84.40%, respectively. The present investigation outcomes reveal that the engineered LK4-TGS-PDA NPs demonstrates effectiveness and efficiency as a drug delivery approach for the nose-brain pathway, offering valuable insights and prospects for enhancing AD treatment.}, } @article {pmid42116584, year = {2026}, author = {Bala, VC and Singh, MK and Kumar, A and Tiwari, SK and Gupta, AK and Chawla, R and Kumar, S}, title = {Targeting α-Synuclein: Current Strategies and Emerging Therapies for Synucleinopathies.}, journal = {Protein and peptide letters}, volume = {33}, number = {1}, pages = {258-274}, doi = {10.2174/0109298665429866260217115717}, pmid = {42116584}, issn = {1875-5305}, mesh = {Humans ; *alpha-Synuclein/metabolism/antagonists & inhibitors/genetics ; *Synucleinopathies/metabolism/drug therapy/therapy/pathology ; *Parkinson Disease/metabolism/drug therapy/pathology ; Animals ; Autophagy ; Oxidative Stress/drug effects ; }, abstract = {Alpha-synuclein (α-syn) is a crucial protein involved in the pathogenesis of Parkinson's Disease (PD) and other synucleinopathies. It is important with respect to neuron health, regulation of α-syn protein synthesis, and its degradation. Numerous cellular pathways implicated in the process of autophagy, chaperone, and proteolysis play a vital role in the maintenance of α-syn protein homeostasis. Autophagy dysfunction defeats α-syn protein accumulation and neuroinflammation, as present in dementia with Lewy bodies and sporadic PD. Oxidative stress is another key factor that intensifies α-syn protein misfolding and aggregation, thereby leading to neurodegeneration. Involvement in the treatment of α-syn related disorders includes passive and active immunization, inhibitors of protein aggregation, gene silencing technology, modulators of synaptic function, and target drug delivery systems. Other α-syn related therapy approaches include the development of a novel herbal formulation focusing on the gut-brain axis and interventions designed to enhance protein quality control. As clinical trials move forward, minimizing challenges related to the target involved, biomarkers, and patient stratification is crucial to decoding these therapies into effective management. These insights not only advance our understanding of α-syn biology but also highlight the urgency of early and multi-targeted therapeutic interventions.}, } @article {pmid42116599, year = {2026}, author = {Saha, T and Vats, T and Mehan, S}, title = {Rituximab beyond oncology: targeting B-cell-mediated immunomodulatory therapy in neurodegenerative and neuropsychiatric disorders.}, journal = {Immunopharmacology and immunotoxicology}, volume = {}, number = {}, pages = {1-36}, doi = {10.1080/08923973.2026.2671714}, pmid = {42116599}, issn = {1532-2513}, abstract = {OBJECTIVE: Neurological and neuropsychiatric disorders, including multiple sclerosis (MS), Alzheimer's disease (AD), Parkinson's disease (PD), autoimmune encephalitis (AE), neuromyelitis optica spectrum disorder (NMOSD), and myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD), are associated with neuroinflammation, oxidative stress, protein aggregation, and blood-brain barrier disruption. This review aimed to evaluate the immunomodulatory and neuroprotective potential of rituximab in these disorders and summarize its mechanisms of action, therapeutic efficacy, and clinical limitations.

MATERIALS AND METHODS: A comprehensive review of preclinical and clinical studies investigating rituximab in neurodegenerative and neuropsychiatric disorders was conducted. Relevant evidence regarding B cell-mediated pathology, rituximab's mechanisms of action, therapeutic outcomes, adverse effects, and emerging clinical applications was analyzed and synthesized.

RESULTS: Rituximab, a chimeric monoclonal antibody targeting CD20-positive B cells, exerts therapeutic effects through complement-dependent cytotoxicity (CDC), antibody-dependent cellular cytotoxicity (ADCC), and apoptosis induction. In MS, rituximab reduces pro-inflammatory cytokines, immune cell activation, and demyelination, thereby slowing disease progression. Preclinical findings in AD and PD suggest that rituximab mitigates B cell-mediated neuroinflammation and oxidative stress, contributing to neuroprotection. Furthermore, rituximab has demonstrated clinical efficacy in AE, NMOSD, and MOGAD by depleting pathogenic B cells and reducing relapse frequency. However, treatment-associated complications such as hypogammaglobulinemia, infections, and infusion-related reactions remain significant concerns requiring careful monitoring and dose optimization.

CONCLUSIONS: Rituximab represents a promising immunomodulatory therapy for several neurological and neuropsychiatric disorders driven by B cell-mediated pathology. Its ability to modulate neuroinflammation and immune dysfunction highlights its therapeutic potential in neuroimmunology. Future studies should focus on improving central nervous system penetration, identifying predictive biomarkers of response, and exploring combination therapies to enhance efficacy and safety outcomes.}, } @article {pmid42116632, year = {2026}, author = {Han, KJ and Lv, YX and Xie, D and Zou, LH and Jiang, Q and Xie, SD and Zhang, YJ and Zhao, P and Yang, XQ and Wee, SK}, title = {Molecular Mechanistic Studies on Caffeoylquinic Acid Derivatives From Vaccinium dunalianum Wight as Dual-Target Inhibitors of AChE and BChE With In Vitro Inhibitory Evaluation and Molecular Docking.}, journal = {Chemistry & biodiversity}, volume = {23}, number = {5}, pages = {e03013}, doi = {10.1002/cbdv.202503013}, pmid = {42116632}, issn = {1612-1880}, support = {202205AC160049//Young and Middle-Aged Academic and Technological Leaders of Yunnan Province/ ; 22267018//National Natural Science Foundation of China/ ; 32060327//National Natural Science Foundation of China/ ; 202501BD070001-027//Yunnan Fundamental Research Projects/ ; 202401AT070295//Yunnan Fundamental Research Projects/ ; 202503AC100002//Yunnan Fundamental Research Projects/ ; 202505AO120060//Yunnan Foreign Expert Program/ ; }, mesh = {*Quinic Acid/analogs & derivatives/chemistry/pharmacology/isolation & purification ; *Acetylcholinesterase/metabolism ; *Cholinesterase Inhibitors/chemistry/pharmacology/isolation & purification ; *Molecular Docking Simulation ; Animals ; *Butyrylcholinesterase/metabolism ; PC12 Cells ; *Vaccinium/chemistry/metabolism ; Rats ; Structure-Activity Relationship ; Plant Leaves/chemistry/metabolism ; Kinetics ; Dose-Response Relationship, Drug ; Humans ; Plant Extracts/chemistry/pharmacology ; Molecular Structure ; }, abstract = {Alzheimer's disease (AD) involves impaired cholinergic neurotransmission, so inhibiting acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) is a major treatment strategy. Vaccinium dunalianum Wight leaf extracts, abundant in caffeoylquinic acids (CQAs), potently inhibit AChE (IC50 = 0.12 ± 0.01 mg/mL) and BChE (IC50 = 0.01 ± 0.01 mg/mL). Key bioactive compounds include 1-O-caffeoylquinic acid (1-CQA), chlorogenic acid (CGA), neochlorogenic acid (NCGA), and cryptochlorogenic acid (CCGA). All inhibited both enzymes concentration-dependently; 1-CQA was strongest (AChE IC50 = 0.25 ± 0.03 µM; BChE IC50 = 0.10 ± 0.01 µM), surpassing galantamine. Kinetics and docking showed reversible mixed-type inhibition targeting AChE catalytic and peripheral sites. Fluorescence quenching affirmed high-affinity binding, strongest for 1-CQA. It also showed low cytotoxicity in PC12 cells (≤10 µM). These findings reveal a dual cholinesterase inhibitory mechanism and support CQAs as promising anti-AD agents.}, } @article {pmid42118381, year = {2026}, author = {S, K and L, G and S, PP and C, K}, title = {Aspirin as a neuroprotective scaffold in Alzheimer's disease: inflammation, oxidative stress, and future directions.}, journal = {Molecular biology reports}, volume = {53}, number = {1}, pages = {}, pmid = {42118381}, issn = {1573-4978}, mesh = {Humans ; *Alzheimer Disease/drug therapy/metabolism/pathology ; Oxidative Stress/drug effects ; *Aspirin/pharmacology/therapeutic use ; *Neuroprotective Agents/pharmacology/therapeutic use ; Inflammation/drug therapy/metabolism ; Animals ; Anti-Inflammatory Agents, Non-Steroidal/pharmacology/therapeutic use ; Neuroinflammatory Diseases/drug therapy ; Cyclooxygenase Inhibitors/pharmacology ; }, abstract = {Alzheimer's disease (AD) is one of the most common forms of dementia. AD is associated with memory loss and cognitive decline. Several research works have been carried out to treat AD. However, currently available treatment options are only useful in the treatment of the individual pathology of AD but not useful in disease modification. Recent research works have identified the associated effects of neuroinflammation, oxidative stress, and glial cell dysfunction in AD pathology. Aspirin is one of the most commonly used NSAIDs in the treatment of several inflammatory diseases. Aspirin inhibits cyclooxygenase (COX) enzymes through an irreversible pathway. However, aspirin also exhibits other important pharmacological properties. This review aims to highlight the potential of aspirin-based multi-target directed ligands in the regulation of AD pathology through the regulation of neuroinflammation and oxidative stress.}, } @article {pmid42118396, year = {2026}, author = {Kumar, R and Patel, S and Mishra, PS and Srivastava, S and Sridhar, SB and Shareef, J and Sahu, R and Tariq, M and Uddin, J and Muhsinah, AB}, title = {From Molecular Networks to Medicines: Targeting Complexity in Alzheimer's Disease (AD) Therapy.}, journal = {Molecular neurobiology}, volume = {63}, number = {1}, pages = {}, pmid = {42118396}, issn = {1559-1182}, mesh = {Humans ; *Alzheimer Disease/drug therapy/metabolism ; Animals ; *Molecular Targeted Therapy ; Amyloid beta-Peptides/metabolism ; tau Proteins/metabolism ; }, abstract = {Alzheimer's disease (AD) is a multidimensional neurodegenerative disease leading to progressive loss of cognitive function and a growing health burden on the world population. Although decades of research have been conducted on this disease, current therapies have limited clinical value, mainly because researchers have not fully incorporated the intricate molecular pathways underlying its development and progression. This review summarizes current knowledge of AD pathophysiology, including amyloid beta (Aβ) dysregulation, tau hyperphosphorylation, neuroinflammation, mitochondrial dysfunction, oxidative stress, and synaptic breakdown. Although the amyloid- and tau-centered paradigms remain prevailing in the field, we note newer molecular targets, including secretase modulators, inflammatory signaling hubs, mitotic and autophagic regulators, epigenetics, and synaptogenesis pathways. We prioritize mechanistic, structural, cellular, and systems levels to facilitate a rational development of therapeutic understanding. The latest trends in medicinal chemistry and computational drug design, multi-target- directed ligands and hybrid scaffolds, as well as in silico ADMET optimization, are also discussed. Furthermore, we discuss the therapeutic aspects of bioinspired analogues of natural products. Lastly, we discuss the ongoing clinical development initiatives, opportunities, and major translational issues. In general, we highlight the need for integrative, mechanism-oriented, and personalized treatment approaches to propel the next generation of AD therapies.}, } @article {pmid42121268, year = {2026}, author = {Cho, IH and Putra, HM and Jung, CW and Hyun, GH and Jang, HH and Hwang, IG and Kwon, SW}, title = {Neuroprotective effects of quercetin in animal models of neurodegenerative diseases: A systematic review and meta-analysis.}, journal = {Journal of the science of food and agriculture}, volume = {}, number = {}, pages = {}, doi = {10.1002/jsfa.70699}, pmid = {42121268}, issn = {1097-0010}, support = {RS-2022-RD010385//Rural Development Administration/ ; }, abstract = {Neurodegenerative conditions such as Alzheimer's disease and Parkinson's disease are characterized by progressive neuronal loss driven by oxidative stress and inflammation. Quercetin, a dietary flavonoid with established antioxidant and anti-inflammatory properties, has emerged as a potential neuroprotective agent. This study aimed to quantitatively synthesize and evaluate preclinical evidence regarding the impact of quercetin on neurodegenerative biomarkers and cognitive performance. A comprehensive literature search was conducted using PubMed, Embase, Web of Science, and the Cochrane Central Register of Controlled Trials (CENTRAL). After strict screening and selection, 19 studies were included. These evaluated the effects of quercetin on: Morris water maze (MWM) performance; inflammatory cytokines - including interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-α), and interleukin-10 (IL-10); the oxidative stress marker malondialdehyde (MDA); antioxidant enzymes such as catalase (CAT), superoxide dismutase (SOD), and glutathione (GSH); brain-derived neurotrophic factor (BDNF); and acetylcholinesterase (AChE) activity. Subgroup analyses based on quercetin dose (<100 mg kg[-1] versus ≥100 mg kg[-1]) and treatment duration (<28 versus ≥28 days) were performed. Quercetin improved cognitive performance significantly by reducing escape latency and improving performance on memory retention indicators. It decreased pro-inflammatory cytokines (IL-6 and TNF-α), increased IL-10, enhanced antioxidant enzyme activity (CAT, SOD, and GSH), reduced MDA levels, up-regulated BDNF, and inhibited AChE. Subgroup analyses suggested that quercetin exerted stronger effects at lower doses and with longer treatment durations, although not all subgroup differences were statistically significant. Quercetin demonstrated multi-targeted neuroprotective effects in animal models, improving cognition and modulating inflammatory, oxidative, and neurotrophic pathways. These findings support the potential of quercetin as a therapeutic agent for neurodegenerative diseases, warranting further clinical investigation. © 2026 The Author(s). Journal of the Science of Food and Agriculture published by John Wiley & Sons Ltd on behalf of Society of Chemical Industry.}, } @article {pmid42123478, year = {2026}, author = {Xiao, Y and Huang, W and Chen, L and Huang, R and Guo, Y and Liu, W and Wang, X and Wang, J and Bao, J and Shu, X}, title = {Amyloid Precursor Protein Abnormalities Destabilize Membrane Ferroportin: A Novel Mechanism Underlying Early Brain Pathologies and Memory Impairment in Alzheimer's Disease.}, journal = {International journal of molecular sciences}, volume = {27}, number = {9}, pages = {}, pmid = {42123478}, issn = {1422-0067}, support = {82371195//National Natural Science Foundation of China/ ; 82001281//National Natural Science Foundation of China/ ; No. 2024HBQZYCSB046//Intelligent Cancer Prevention and Control Platform Development and Industrialization/ ; }, mesh = {Animals ; *Alzheimer Disease/metabolism/pathology/genetics ; *Amyloid beta-Protein Precursor/metabolism/genetics ; Ferroportin ; *Cation Transport Proteins/metabolism/genetics ; *Memory Disorders/metabolism/pathology/genetics ; Mice ; *Brain/metabolism/pathology ; Humans ; Mice, Transgenic ; Ferroptosis ; Cell Membrane/metabolism ; Disease Models, Animal ; Mutation ; Amyloid beta-Peptides/metabolism ; }, abstract = {Alzheimer's disease (AD) research has primarily focused on amyloid beta (Aβ) and tau protein; however, drug development targeting these two proteins has been disappointing. Therefore, there is an urgent need to explore the novel pathogenic mechanisms underlying AD. Recently, we found that expression of the K670N/M671L-mutated amyloid precursor protein (APP) in 293T cells significantly reduced membrane ferroportin (FPN) levels. Furthermore, 2-month-old APP/PS1 mice exhibited a marked decrease in membrane FPN levels, while total FPN expression and Aβ levels remained unchanged. Further studies revealed that features of ferroptosis were present in the brains of 2-month-old APP/PS1 mice, and that treatment with ferroptosis inhibitors or iron chelation significantly alleviated early pathological changes and cognitive impairment in these animals. In addition, supplementation with an APP-FPN binding peptide during the early phase ameliorated AD-related pathologies, including Aβ deposition, neuroinflammation, oxidative stress, and synapse-associated protein deficits, in APP/PS1 mice. Collectively, our findings suggest that APP mutations may contribute to early brain pathological changes and subsequent memory impairment in AD by downregulating membrane trafficking of FPN and inducing ferroptosis, thereby providing new molecular targets for drug development.}, } @article {pmid42125083, year = {2026}, author = {Zhao, C and Peng, X and Cheng, Z and Yue, S and Wang, Z and Ma, L and Li, J and Shang, M}, title = {Light-based 40 Hz sensory therapy for brain disorders: physiological basis, therapeutic mechanisms, and future prospects.}, journal = {Frontiers in medicine}, volume = {13}, number = {}, pages = {1730333}, pmid = {42125083}, issn = {2296-858X}, abstract = {In recent years, 40 Hz flickering light and/or sound therapy has been confirmed to have certain therapeutic effects on Alzheimer's disease (AD), although the underlying mechanisms remain unclear. This approach has been widely explored for the treatment of various neurological disorders, but its efficacy must be verified. The induction of gamma oscillations in the brain by 40 Hz flickering light and/or sound stimulation is likely a critical component underlying its therapeutic effects across brain diseases. Elucidating the physiological basis and mechanisms by which such stimuli induce gamma oscillations may reveal its mechanisms of action in treating diseases. Although 40 Hz flickering light and/or sound intervention offers certain advantages in improving neurological function, challenges related to technical optimization and clinical promotion must be addressed. Therefore, in this paper, the underlying mechanisms through which 40 Hz flickering light and/or sound intervention induces gamma oscillations, including both neuronal and non-neuronal mechanisms, are explained. The clinical therapeutic outcomes of 40 Hz flickering light and/or sound intervention for various neurodegenerative diseases are subsequently examined, and the mechanisms underlying are summarized. Furthermore, the limitations of this therapy and corresponding improvement measures are discussed, providing a theoretical reference for further refining this technology and expanding its clinical applications. Finally, future development directions are provided, with the aims of advancing related research and facilitating the application of this therapy in the treatment of brain diseases.}, } @article {pmid42125963, year = {2026}, author = {Juday, TR and Holub, A and Mattke, S and Betts, KA and Kitchen, SA and Liu, H and Frech, FH and Khachaturian, AS}, title = {Community-Based Physician Attitudes Related to the Diagnosis and Treatment of Early Alzheimer's Disease in the United States.}, journal = {American journal of Alzheimer's disease and other dementias}, volume = {41}, number = {}, pages = {15333175261433309}, pmid = {42125963}, issn = {1938-2731}, mesh = {Humans ; *Alzheimer Disease/diagnosis/therapy ; United States ; Early Diagnosis ; *Attitude of Health Personnel ; *Physicians, Primary Care/statistics & numerical data ; *Cognitive Dysfunction/diagnosis/therapy ; Female ; Male ; *Neurologists/statistics & numerical data ; Middle Aged ; }, abstract = {The increasing incidence of Alzheimer's disease (AD) coupled with emerging diagnostics and treatments underscores the need for early detection of AD, yet identifying these individuals remains challenging. This US study sought to examine community-based physician attitudes regarding diagnosis and treatment of early AD (mild cognitive impairment [MCI] due to AD and mild AD). A total of 177 primary care physicians (PCPs) and 147 neurologists recruited through a national physician panel were surveyed about early AD diagnostic and treatment processes, and self-confidence in identifying and managing the condition. Physicians identified patient and family/caregiver involvement as critical in triggering the diagnostic process. Patterns of use of neurocognitive assessments, structural imaging tests, and AD-specific biomarkers varied between PCPs and neurologists. Confidence diagnosing and managing early AD was a concern across specialties, although was greater among PCPs. Programs promoting awareness of early AD symptoms, and emerging technologies and treatments are critical to timely management.}, } @article {pmid42126808, year = {2026}, author = {Taylor, TL and Tuke, J and Fernandez, EJ and Hazel, SJ}, title = {Group training classes for dogs with canine cognitive dysfunction: effects on sleep, activity, and caregiver burden.}, journal = {GeroScience}, volume = {}, number = {}, pages = {}, pmid = {42126808}, issn = {2509-2723}, abstract = {Canine Cognitive Dysfunction (CCD) is a progressive neurodegenerative condition of ageing dogs, sharing pathological and clinical features with Alzheimer's disease. Despite the growing prevalence of CCD, non-pharmacological interventions for affected companion animals remain underexplored. This study evaluated the effects of structured group training classes on signs of CCD, sleep, daily activity, and caregiver burden. Forty-two dogs (≥ 8 years) with mild to moderate CCD were enrolled in either a scent-based (S; n = 21) or physical structured training (PST; n = 21) program. Each dog completed five consecutive weekly sessions, with outcomes assessed through the Canine Dementia Scale (CADES), accelerometry (FitBark), and validated caregiver burden measures at baseline, treatment, and post-treatment. CCD scores remained stable across all phases, suggesting no measurable cognitive changes. However, a significant interaction between training type and treatment phase was observed for sleep: dogs in the PST group demonstrated improved Fitbark sleep scores over time, while those in the S group declined. Daily activity followed expected bimodal patterns, with scent-trained dogs exhibiting reductions in morning and evening activity peaks. Caregiver burden decreased significantly across time in both groups, and caregivers reported high satisfaction with class participation, citing enhanced confidence and social support. These findings indicate that while structured training did not alter CCD severity scores, PST was associated with a small improvement in sleep, S was associated with reduced activity, and participation in both classes was linked to reduced caregiver burden. Further research is needed to confirm these changes and determine their effect on dog and human wellbeing. Group training classes may represent an accessible, welfare-focused intervention for managing CCD in companion dogs.}, } @article {pmid42127455, year = {2026}, author = {Tzieras, I and Manolopoulos, A and Tweedie, D and Luo, W and Maccecchini, M and Egan, JM and Greig, NH and Kapogiannis, D}, title = {A phase 1, safety, tolerability, and pharmacokinetics study of bisnorcymserine, a highly selective inhibitor of butyrylcholinesterase.}, journal = {Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics}, volume = {23}, number = {3}, pages = {e00918}, pmid = {42127455}, issn = {1878-7479}, mesh = {Humans ; Male ; *Cholinesterase Inhibitors/pharmacokinetics/adverse effects/blood ; Double-Blind Method ; Female ; *Butyrylcholinesterase/metabolism ; Adult ; Young Adult ; Middle Aged ; Dose-Response Relationship, Drug ; *Physostigmine/pharmacokinetics/analogs & derivatives/adverse effects ; }, abstract = {Cholinergic deficiency is a hallmark neurotransmitter abnormality in Alzheimer's disease (AD) that has traditionally been addressed with cholinesterase inhibitors. In severe AD, butyrylcholinesterase (BuChE) becomes the dominant cholinesterase, suggesting a potential therapeutic target. (-)-N1,N8-bisnorcymserine tartrate (BNC) is a selective BuChE inhibitor designed to address this unmet need. We conducted a phase I, single-center, randomized, double-blind, placebo-controlled, ascending single oral dose clinical trial to evaluate the safety, tolerability, and pharmacokinetics of BNC in 30 healthy volunteers. There were no adverse events (AEs) grade 2 or above or any serious adverse events (SAEs). Most events were mild and self-limited, the most common being asymptomatic bradycardia and headache. The mean AUClast (SD) was 120.98 h∗ng/mL (74.30) for the 40 mg dose, 148.20 h∗ng/mL (99.43) for the 80 mg dose, and 196.33 h∗ng/mL (91.74) for the 120 mg dose. Accordingly, median tmax (range) and mean Cmax (SD) were 1.8 (1.0-5.0) hr and 13.94 (7.64) ng/mL for the 40 mg dose, 1.8 (1.5-5.0) hr and 18.54 (6.44) ng/mL for the 80 mg dose, and 2 (1.0-4.5) hr and 20.93 (5.00) ng/mL for the 120 mg dose. The mean half-life of BNC ranged from 5.5 to 7 h. BNC was safe and well tolerated when administered as a single oral dose of up to 120 mg. This first-in-human, phase I study permits further investigation of this drug as a potential symptomatic treatment for AD. ClinicalTrials.gov, NCT01747213.}, } @article {pmid42128444, year = {2026}, author = {Atri, A and Apostolova, LG and Iwata, A and Wessels, AM and Atkins, A and Lu, M and Ye, W and Ryan, S and Doty, EG}, title = {Clinical Meaningfulness of Donanemab in Early Symptomatic Alzheimer Disease: Data From the Randomized Phase 3 TRAILBLAZER-ALZ 2 Trial.}, journal = {Neurology. Clinical practice}, volume = {16}, number = {3}, pages = {e200621}, pmid = {42128444}, issn = {2163-0933}, mesh = {Humans ; *Alzheimer Disease/drug therapy ; Female ; Aged ; Male ; *Cognitive Dysfunction/drug therapy ; Treatment Outcome ; Aged, 80 and over ; Disease Progression ; *Antibodies, Monoclonal/therapeutic use ; Activities of Daily Living ; Antibodies, Monoclonal, Humanized ; }, abstract = {BACKGROUND AND OBJECTIVES: Understanding the meaningfulness of clinical trial outcomes is essential for people living with Alzheimer disease (AD) and their clinicians to make evidence-based shared treatment decisions in real-world clinical care. Donanemab, a monoclonal antibody targeting the insoluble form of β-amyloid found in plaques, significantly slows cognitive and functional decline of AD in participants with mild cognitive impairment (MCI) or mild AD-related dementia. This analysis reviews the efficacy of donanemab across various clinical outcome assessments, using both published data and new complementary analyses to provide context on its potential benefits for patients and caregivers.

METHODS: We present findings from prespecified and post hoc analyses from the TRAILBLAZER-ALZ 2 trial. Clinical outcomes assessed were Integrated AD Rating Scale (iADRS), comprising the 13-item AD Assessment Scale-Cognitive Subscale (ADAS-Cog13) and AD Cooperative Study-Instrumental Activities of Daily Living (ADCS-iADL); Clinical Dementia Rating (CDR)-Sum of Boxes (CDR-SB) for clinical severity and individual cognitive and functional domains; CDR-Global for clinical severity stage progression; meaningful within-patient change (MWPC); and ADCS-Activities of Daily Living dependence score.

RESULTS: Donanemab reduced the risk of progression from MCI to mild AD by 33% (hazard ratio [HR] = 0.67; 95% CI 0.52-0.87; p = 0.003) and from mild to moderate AD by 50% (HR = 0.50; 95% CI 0.33-0.78; p = 0.002). In addition, donanemab reduced MWPC risk over 76 weeks by 38% for CDR-SB (HR = 0.62; 95% CI 0.52-0.75; p < 0.001) and 30% for iADRS (HR = 0.70; 95% CI 0.58-0.84; p < 0.001). Donanemab-treated participants exhibited significant slowing of clinical progression across multiple ADAS-Cog13 and ADCS-iADL items and all CDR-SB cognitive and functional domains. Donanemab also slowed progression of dependence least-squares mean change difference, -0.14 [95% CI -0.24 to -0.04; p = 0.007]), representing 23% slowing of progression (95% CI 6.17%-40.32%), and reduced risk of progression to requiring in-home support by 27% (HR = 0.74; 95% CI 0.59-0.91; p = 0.005).

DISCUSSION: These results add to the evidence and further support clinically meaningful donanemab-mediated effects on cognition and function for patients and their caregivers and may aid communication of realistic treatment expectations and informed decision-making.

ClinicalTrials.gov NCT04437511. Submitted: June 17, 2020; First patient enrolled: June 19, 2020. clinicaltrials.gov/study/NCT04437511 EudraCT Number 2020-000077-25. Start date of recruitment: June 19, 2020. clinicaltrialsregister.eu/ctr-search/trial/2020-000077-25/results.}, } @article {pmid42129577, year = {2026}, author = {Stark, M and Wagner, M and Kuhn, E and Roeske, S and Amthauer, H and Bartels, C and Boecker, H and Brosseron, F and Buchert, R and Buerger, K and Daamen, M and Drzezga, A and Düzel, E and Ersözlü, E and Essler, M and Ewers, M and Fliessbach, K and Glanz, W and Hellmann-Regen, J and Incesoy, EI and Janowitz, D and Kafali, K and Kilimann, I and Krause, BJ and Kronmüller, M and Laske, C and Maier, F and Maurer, A and Michely, J and Perneczky, R and Peters, O and Preis, L and Priller, J and Rauchmann, BS and Reimold, M and Rominger, A and Schmid, M and Schneider, A and Sodenkamp, S and Spottke, A and Spruth, EJ and Teipel, S and Wiltfang, J and , and Jessen, F and Kleineidam, L}, title = {Minor neuropsychological deficits and stage 2 of Alzheimer's disease.}, journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association}, volume = {22}, number = {5}, pages = {e71458}, pmid = {42129577}, issn = {1552-5279}, support = {//Gemeinnützige Hertie-Stiftung/ ; BN012//Deutsches Zentrum für Neurodegenerative Erkrankungen/ ; //Life Molecular Imaging/ ; U01AG024904/NH/NIH HHS/United States ; W81XWH-12-2-0012//U.S. Department of Defense/ ; /AG/NIA NIH HHS/United States ; /EB/NIBIB NIH HHS/United States ; //AbbVie/ ; /ALZ/Alzheimer's Association/United States ; //Alzheimer's Drug Discovery Foundation/ ; //Araclon Biotech/ ; //Biogen/ ; //Bristol-Myers Squibb/ ; //CereSpir, Inc./ ; //Cogstate/ ; //Eisai/ ; //Elan Pharmaceuticals, Inc./ ; //Eli Lilly and Company/ ; //EuroImmun Medizinische Labordiagnostika/ ; //F. Hoffmann-La Roche/ ; //Genentech/ ; //Fujirebio/ ; //GE Healthcare/ ; //IXICO Ltd./ ; //Janssen Alzheimer Immunotherapy Research & Development, LLC./ ; //Lumosity/ ; //Lundbeck/ ; //Merck & Co., Inc./ ; //Meso Scale Diagnostics, LLC./ ; //NeuroRx Research/ ; //Neurotrack Technologies/ ; //Novartis Pharmaceuticals Corporation/ ; //Pfizer Inc./ ; //Piramal Imaging/ ; //Servier/ ; //Transition Therapeutics/ ; //CIHR/Canada ; U24 AG072122/AG/NIA NIH HHS/United States ; }, mesh = {Humans ; *Alzheimer Disease/diagnosis/psychology ; Female ; *Neuropsychological Tests/statistics & numerical data ; *Cognitive Dysfunction/diagnosis/psychology ; Aged ; Longitudinal Studies ; Male ; Biomarkers ; Disease Progression ; Middle Aged ; Amyloid beta-Peptides/cerebrospinal fluid ; }, abstract = {INTRODUCTION: Subtle symptoms, like subjective cognitive decline (SCD) and minor neuropsychological deficits (MNPD), can improve the risk stratification in preclinical Alzheimer´s disease (AD) but their importance is insufficiently elaborated.

METHODS: We pooled data from cognitively normal individuals participating in three longitudinal cohort studies (N = 13,192, 8,359[63.3%] female, mean [SD] age 71.0[8.4]).

RESULTS: Compared to participants without SCD and MNPD (SCD-/MNPD-), SCD-/MNPD+, SCD+/MNPD-, and SCD+/MNPD+ participants had an increased risk for mild cognitive impairment (MCI) and dementia, including in amyloid-positive individuals. Focusing on SCD+/MNPD+ participants triples the positive predictive value of amyloid biomarker testing for the 5-year prediction of MCI and reduces the required samples size for trials in preclinical AD to one fourth, compared to considering all cognitively normal participants regardless of subtle symptoms.

DISCUSSION: SCD and MNPD offer a powerful approach for risk stratification in preclinical AD, which can improve clinical trial designs, risk counseling, and future case identifications for early treatment.}, } @article {pmid42130250, year = {2026}, author = {Akar, S and Alvur, O and Evyapan, G and Ozdem, B and Porsuk Doru, I}, title = {Escin Attenuates Amyloid Beta 1-42-Induced Oxidative Stress, Apoptosis, and Neuroinflammation in Neuron-Like SH-SY5Y Cells.}, journal = {Journal of biochemical and molecular toxicology}, volume = {40}, number = {5}, pages = {e70903}, pmid = {42130250}, issn = {1099-0461}, support = {TSA-2023-10713//Van Yuzuncu Yıl University Research Fund/ ; }, mesh = {Humans ; *Amyloid beta-Peptides/toxicity/pharmacology ; *Oxidative Stress/drug effects ; *Apoptosis/drug effects ; *Escin/pharmacology ; *Peptide Fragments/toxicity ; *Neurons/metabolism/pathology ; Cell Line, Tumor ; Reactive Oxygen Species/metabolism ; NF-kappa B/metabolism ; *Neuroinflammatory Diseases/metabolism/pathology ; Cell Survival/drug effects ; *Neuroprotective Agents/pharmacology ; }, abstract = {The pathogenesis of Alzheimer's disease (AD) involves amyloid beta (Aβ)-induced oxidative stress, apoptotic cell death, and neuroinflammation, contributing to neuronal dysfunction. In our study, a differentiation protocol using retinoic acid was applied to SH-SY5Y cells to generate a neuron-like phenotype, and the neuroprotective efficacy of Escin was investigated by inducing Aβ1-42-mediated cytotoxicity. The experimental protocol involved an initial treatment with 2 µM Escin prior to Aβ1-42 application. Cell viability, intracellular reactive oxygen species (ROS), apoptosis, and inflammatory mediator expression (NF-κB, TNF-α, IL-1β) were assessed by MTT assay, flow cytometry with DCFH-DA, flow cytometry with Annexin V-FITC/7-AAD staining, and RT-qPCR, respectively. In our results, Aβ1-42 exposure was found to significantly reduce cell viability and increase ROS production. Additionally, it was observed to enhance apoptotic cell death and increase pro-inflammatory gene expression. Escin pretreatment was found to significantly mitigate these effects by reducing oxidative stress, apoptosis, and NF-κB-mediated inflammatory signaling. Furthermore, galantamine (10 µM), an approved AD treatment agent, was used as a positive control to compare the effects of Escin and confirmed the experimental model by exhibiting protective effects. In conclusion, these findings demonstrate that Escin is a promising neuroprotective agent and warrant further investigation into its potential to mitigate Aβ-related neuronal damage in AD.}, } @article {pmid42130609, year = {2026}, author = {Gobbi, S and Silvestri, E and Tonietto, M and Klein, G and van den Heuvel, M and Magon, S}, title = {Functional connectome metrics reveal distinct prognostic subtypes in two Phase 3 gantenerumab trials.}, journal = {Alzheimer's & dementia (New York, N. Y.)}, volume = {12}, number = {}, pages = {e70259}, pmid = {42130609}, issn = {2352-8737}, abstract = {INTRODUCTION: Alzheimer's disease (AD) heterogeneity poses significant challenges for drug development, identification of individuals at risk, and treatment response prediction. Scientists have leveraged graph theory and resting-state functional magnetic resonance imaging (rs-fMRI) to successfully stratify people with AD. Still, the prognostic value of rs-fMRI graph metrics in AD clinical trials remains unclear.

METHODS: We analyzed rs-fMRI from participants in amyloid-lowering clinical trials. Four graph metrics-global efficiency, clustering coefficient, modularity, and shortest path length-were computed and baseline clusters defined using unsupervised k‑means. We investigated the baseline connectome of each cluster to assess the level of network dysfunction and impairment (i.e., loss of global integration, resulting in disrupted communication between brain regions and reduced global efficiency). These clusters were related to a 116-week change in cognition and brain volume using covariate-adjusted mixed-effects models.

RESULTS: Three clusters emerged with distinct functional connectome efficiency, demographic, and AD-related biomarkers profiles. These baseline differences led to significant variations in disease progression. The most impaired‑connectome cluster declined fastest, whereas the most integrated declined slowest.

DISCUSSION: rs-fMRI graph metrics might effectively stratify participants with AD in clinical trials and serve as potential prognostic biomarkers.}, } @article {pmid42130762, year = {2026}, author = {Liu, XY and Yan, YZ and Jiang, AJ and Tan, SJ and Fang, YY and Zeng, P}, title = {Integrating network pharmacology and experimental validation strategies to investigate the mechanisms and key flavonoids in medicinal and edible citrus plants against Alzheimer's disease.}, journal = {Frontiers in aging neuroscience}, volume = {18}, number = {}, pages = {1801263}, pmid = {42130762}, issn = {1663-4365}, abstract = {INTRODUCTION: Due to the complexity of the Alzheimer's disease (AD) pathophysiological processes, there is currently a lack of effective therapeutic drugs. The medicinal and edible substances have multiple advantages in treating AD, but their specific components and mechanisms remain unclear. This study aims to investigate the potential mechanisms of flavonoids in medicinal and edible citrus plants in treating AD and their key phytochemicals.

METHODS: We collected flavonoids identified by UHPLC-Q-TOF-MS/MS in citrus plants from the literatures and evaluate their pharmacological and toxicological parameters. We obtained and systematically analyzed the action targets of the flavonoids of citrus plants and screened the targets related to AD key pathophysiological processes and the corresponding phytochemicals. The results of network pharmacological analysis were further validated through molecular docking, GEO database, and BV2 microglial cells.

RESULTS: A total of 51 flavonoids in medicinal and edible citrus plants were identified, which exhibit favorable pharmacological properties and safety profiles. Multiple flavonoid compounds such as isoquercitrin, astragalin, cynaroside, troxerutin and lonicerin serve as potential acetylcholinesterase inhibitors for the symptomatic treatment of AD. The study identified 45 flavonoids in citrus plants that correspond to 304 AD-related targets, which are involved in multiple pathophysiological processes. Quercetin, nobiletin, hesperidin, apigenin, HTMF, tangeretin and hesperetin have been identified as the key flavonoids of citrus plants that regulate the pathogenesis of AD in a multitargeted manner. The flavonoids of citrus plants primarily regulate the core targets AKT1, TNF, IL6, TP53, IL1B, STAT3, INS, JUN, CASP3 and CTNNB1. Targeting ferroptosis is one of the mechanisms by which citrus plants to ameliorate AD. In vitro experiments also demonstrated that hesperidin and naringin alleviated LPS-induced pro-inflammatory activation of BV2 cells.

CONCLUSION: The various citrus plants flavonoids examined in this study exhibit significant potential for clinical translation, particularly in the early prevention and adjuvant treatment of AD.}, } @article {pmid42131436, year = {2026}, author = {Gusmão, LA and Metzke, A and Deau, E and Meijer, L and Tedesco, AC and Köster, RW}, title = {Nitrogen-Doped Graphene Quantum Dots Conjugated to Leucettinib-21 Rescue Differentiating Zebrafish Purkinje Cells by Inhibiting Dyrk1A Kinase.}, journal = {ACS applied nano materials}, volume = {9}, number = {18}, pages = {8023-8038}, pmid = {42131436}, issn = {2574-0970}, abstract = {A major challenge in treating neurological diseases is the transport of compounds across the blood-brain barrier. Herein, we report the synthesis and characterization of nitrogen-doped graphene quantum dots (GQDs) that exhibit high tolerance in zebrafish larvae at high concentrations. In contrast to classical semiconductor quantum dots, vascular microinjection of these fluorescent carbon-based nanomaterials results in rapid tissue distribution and efficient neuronal internalization within the brain, highlighting their potential as nanocarriers for central nervous system delivery. Vascular microinjections of these quantum dots conjugated with the high-affinity Dyrk1A kinase inhibitor Leucettinib-21 (LCTB21) at nanomolar concentrations rescued cell-autonomous dendrite deficiencies in cerebellar Purkinje cells overexpressing human Dyrk1a. LCTB21 concentrations were significantly lower than those of the inhibitor alone. Dyrk1A activity is responsible for neurological defects in Down syndrome and acts as a priming kinase for Alzheimer's disease-associated proteins Tau and APP. Thus, efficient nanodelivery of Dyrk1A inhibitors across the blood-brain barrier improves therapeutic options while minimizing the treatment dose and potential side effects.}, } @article {pmid42133413, year = {2026}, author = {Berezutsky, MA and Andronova, TA and Belonogova, YV and Durnova, NA}, title = {[Acteoside: neurobiological activity spectrum, potential in the treatment of age-associated neurodegenerative diseases].}, journal = {Zhurnal nevrologii i psikhiatrii imeni S.S. Korsakova}, volume = {126}, number = {4}, pages = {41-47}, doi = {10.17116/jnevro202612604141}, pmid = {42133413}, issn = {1997-7298}, mesh = {Humans ; Polyphenols ; *Glucosides/therapeutic use/pharmacology ; *Phenols/therapeutic use/pharmacology ; *Parkinson Disease/drug therapy/metabolism ; *Alzheimer Disease/drug therapy/metabolism ; Amyloid beta-Peptides/metabolism ; *Neuroprotective Agents/therapeutic use/pharmacology ; tau Proteins/metabolism ; Microglia/drug effects ; Animals ; Endoplasmic Reticulum Stress/drug effects ; alpha-Synuclein/metabolism ; }, abstract = {Acteoside (verbascoside, kusaginin) is a phenylethanoid glycoside, which is found in more than 200 species of plants and is characterized by a wide range of pharmacological activity. The results of studies on the neurobiological effects of acteoside, which can be used in the treatment of Alzheimer's disease (AD) and Parkinson's disease (PD), were summarized and analyzed. The PubMed, Scopus, Google Scholar, and e-Library databases were searched for the following keywords: «acteoside», «Alzheimer's disease», «Parkinson's disease», «pathological activation of microglia», «neurotrophic effect», «endoplasmic reticulum stress», «protection of neurons from beta-amyloid», «inhibition of tau protein hyperphosphorylation», «death of dopaminergic neurons», «aggregation of α-synuclein», «cognitive and motor impairment». Experimental studies have shown the ability of acteoside to inhibit pathological activation of microglia, exert a neurotrophic effect, inhibit endoplasmic reticulum stress, protect neurons from beta-amyloid, inhibit tau-protein hyperphosphorylation, reduce intracellular Ca[2+] mobilization dysfunction, protect neurons from glutamate-induced neurotoxicity, prevent dopaminergic neuron death, reduce α-synuclein aggregation, and attenuate cognitive and motor impairments. This compound has good prospects for chemical modification, as its structure features several reactive sites. In the future, acteoside may be used as a multi-purpose complex therapy for AD and PD.}, } @article {pmid42133414, year = {2026}, author = {Shavlovskaya, OA}, title = {[Choline alfoscerate in the treatment of cognitive impairment].}, journal = {Zhurnal nevrologii i psikhiatrii imeni S.S. Korsakova}, volume = {126}, number = {4}, pages = {48-55}, doi = {10.17116/jnevro202612604148}, pmid = {42133414}, issn = {1997-7298}, mesh = {Humans ; *Cognitive Dysfunction/drug therapy ; Alzheimer Disease/drug therapy/prevention & control ; *Succinylcholine/therapeutic use/administration & dosage ; Administration, Oral ; }, abstract = {Multiple randomized controlled trials (RCTs), systematic reviews, meta-analyses, and multidisciplinary studies in both hospital and outpatient settings have demonstrated the high efficacy and safety of choline alfoscerate (CA) therapy for patients with mild and moderate cognitive impairment (MCI), amnestic cognitive impairment, predementia cognitive impairment in Alzheimer's disease (AD), elderly individuals, and first-degree relatives of patients with AD as preventive therapy. The Russian CA drug Cereton is available in several formulations, including solutions for intravenous and intramuscular injection, capsules, and an oral solution, enabling individualized treatment approaches. In hospital settings, injection therapy with Cereton is administered for 10 days, followed by an oral course lasting up to 60 days. The duration and dosage of Cereton oral solution and capsules are determined by patient age and clinical condition. The oral solution is approved for use in children from 6 years of age, and the capsules are approved for use in children from 11 years of age, with treatment courses lasting up to 60 days. Cereton therapy consists of two stages: initial intravenous or intramuscular administration, followed by oral administration of capsules or the oral solution. The drug is generally well-tolerated, with adverse events being infrequent and minor.}, } @article {pmid42133852, year = {2026}, author = {Juni, JE and Burns, JM and Salat, DH and Hill, D and Tally, S and Martin, JS and Devous, MD and Moriarty, PM}, title = {Treatment of Clinically Diagnosed Alzheimer's Disease by External Counterpulsation A Randomized Clinical Trial.}, journal = {American journal of Alzheimer's disease and other dementias}, volume = {41}, number = {}, pages = {15333175261451918}, pmid = {42133852}, issn = {1938-2731}, mesh = {Humans ; *Alzheimer Disease/therapy ; *Counterpulsation/methods ; Female ; Male ; Aged ; Activities of Daily Living ; *Cognitive Dysfunction/therapy ; Treatment Outcome ; Aged, 80 and over ; }, abstract = {ObjectiveTo assess external counterpulsation (ECP) effects on cognitive and functional decline in early AD.MethodsThis 12-month, multicenter, blinded, randomized, sham-controlled trial enrolled 190 patients with early AD (MCI due to AD or mild AD per NIA-AA clinical criteria). Participants received either full-pressure ECP (150-300 mmHg) or sham (25 mmHg): 3-5 weekly one-hour sessions for 35 treatments, then twice-weekly through six months. Assessments occurred at baseline and weeks 6, 12, 18, 24, 36, and 52. Primary endpoints included ADCS-ADL, ADAS-cog-14, and VADAS-cog.ResultsFull-pressure ECP significantly improved ADCS-ADL scores versus sham (mean change 2.57 vs. -0.49; p=0.036) and VADAS-cog scores (9.95 vs. 5.22; p=0.005) at 12-24 weeks. Benefits persisted through 52 weeks despite treatment cessation at 6 months. No serious device-related adverse events occurred.ConclusionsFull-pressure ECP therapy significantly improved cognition and ADL compared to sham treatment in early AD. ECP represents a novel therapeutic approach warranting further investigation.}, } @article {pmid42134046, year = {2026}, author = {Chu, TDX and Hui, LM and Khatri, N and Jean Chen, J}, title = {Resilience to mid-to-late-life depression as a risk factor for Alzheimer's disease: Physiological factors and the role of neuroimaging.}, journal = {Neurobiology of aging}, volume = {166}, number = {}, pages = {1-13}, doi = {10.1016/j.neurobiolaging.2026.05.004}, pmid = {42134046}, issn = {1558-1497}, mesh = {Humans ; *Alzheimer Disease/etiology/diagnostic imaging/diagnosis/psychology ; Risk Factors ; Female ; *Neuroimaging/methods ; *Depression/immunology/diagnostic imaging/complications/diagnosis ; Male ; Sex Characteristics ; Diffusion Magnetic Resonance Imaging ; Neuroinflammatory Diseases ; Brain/diagnostic imaging ; Aged ; }, abstract = {Depression and Alzheimer's Disease (AD) are both diagnosed in women twice as often as in men. Moreover, a history of untreated depression confers a 2-to-5-fold increase in the risk of developing dementia. Finally, biological factors such as sex differences in immune response increase rates of depressive pathology among women. Importantly, the prevalence of mid-to-late-life depression (MLD) worldwide and its misdiagnosis due to clinical overlap with AD hinder accurate assessment and timely treatment of depression among older adults. Correct diagnosis of depression and AD using neuroimaging will enable early adoption of appropriate management, which will improve cognitive resilience. In the context of neural resilience in late-life depression, this review discusses the involvement of sex-related risk factors such as differences in immune response, and the importance of understanding the mid-life neurological signature of depression. We focus on the role of diffusion-weighted magnetic resonance imaging (MRI), which is also specifically linked to the presence of neuroinflammation in depression and the ability to distinguish it from AD despite cognitive overlaps in clinical manifestation. This review highlights the importance of sex differences in promoting resilience against MLD and AD-related declines, and supports neuroimaging as a feasible approach to advance our understanding of the role of neuroinflammation in both depression and Alzheimer's disease as a sex-dependent phenomenon.}, } @article {pmid42134309, year = {2026}, author = {Lee, J and Zhu, Y and Tseng, HR}, title = {Bioorthogonal Click Chemistry-Enabled Enrichment of Extracellular Vesicles for Integrated Molecular and Functional Liquid Biopsy§.}, journal = {Accounts of chemical research}, volume = {59}, number = {11}, pages = {1813-1828}, pmid = {42134309}, issn = {1520-4898}, mesh = {*Click Chemistry ; Humans ; *Extracellular Vesicles/chemistry/metabolism ; Liquid Biopsy/methods ; Cyclooctanes/chemistry ; Animals ; }, abstract = {ConspectusExtracellular vesicles (EVs) are lipid bilayer-enclosed nanoparticles released by virtually all cells, carrying protected lipids, nucleic acids, proteins, and active enzymes that faithfully reflect the physiological and pathological states of their cellular origins. Tumor- and neuron-derived EVs are abundantly present in peripheral blood, even at early disease stages, and thus represent highly attractive substrates for liquid biopsy. However, the clinical translation of EV-based diagnostics has been constrained by a central challenge: the inability to selectively enrich disease-relevant EVs from a vast background of normal EVs with sufficient specificity, efficiency, and compatibility for seamless integration with downstream molecular and functional analyses. Conventional physical isolation approaches generate heterogeneous EV mixtures that dilute disease-specific signals, whereas traditional immunoaffinity capture often suffers from nonspecific interactions and low recovery due to sparse and heterogeneous antigen density on EV membranes.To overcome these limitations, our laboratory has developed a chemical biology solution utilizing the bioorthogonal inverse-electron-demand Diels-Alder reaction between trans-cyclooctene (TCO) and tetrazine (Tz). By labeling tumor or neuronal EVs in plasma with TCO-grafted antibodies and covalently immobilizing them onto Tz-functionalized substrates, our three EV enrichment platforms, namely, EV Click Chips, EV Click Beads, and EV Click MagBeads, enable rapid, irreversible, and highly specific capture of defined EV subpopulations. These click chemistry-mediated enrichment strategies reduce nonspecific binding, markedly improve capture efficiency, and preserve EV integrity, providing a robust foundation for downstream genetic, proteomic, and functional analyses. Building on this chemical biology solution, we established three complementary EV assay modalities. Platform #1, the EV Digital Scoring Assay, couples click chemistry-mediated EV enrichment with RT-digital PCR to quantify tumor-specific mRNAs or oncogenic mutations. This "enrich-then-count" strategy has demonstrated strong clinical utility in early detection of hepatocellular carcinoma (HCC), molecular staging of prostate cancer, and detection of actionable gene alterations in pancreatic cancer and Ewing sarcoma. A refined version enables real-time HCC treatment-response monitoring, outperforming serum AFP and radiographic criteria in monitoring treatment responses. Platform #2, the EV Surface Protein Assay, uses antibody-directed click enrichment followed by immuno-PCR or RT-qPCR to quantify tumor-specific EV subpopulations. Analogous to tissue immunohistochemistry but executed in a liquid-biopsy format, this assay has shown accuracy in early detection of HCC, pancreatic ductal adenocarcinoma, and epithelial ovarian cancer and supports longitudinal monitoring in prostate and thyroid cancers. Platform #3, the EV Protease Activity Assay, extends EV analysis into functional biology by measuring enzymatic activities preserved within enriched EVs. In osteosarcoma, matrix metalloproteinase activity profiles stratified localized versus metastatic disease and tracked therapeutic response. In neurology, quantifying β-secretase activity in neuronal EVs enabled highly accurate detection of early Alzheimer's disease and correlated with cognitive performance.Together, these TCO-Tz click chemistry-enabled platforms provide a modular, robust, and clinically adaptable toolkit for noninvasive EV-based diagnostics. By uniting chemical precision with biological and clinical relevance, this framework advances the broader vision of real-time, disease-specific liquid biopsy across oncology and neurodegeneration, laying the foundation for next-generation integrated diagnostic systems.}, } @article {pmid42134480, year = {2026}, author = {Wu, Q and Cui, X and Liu, X and Yuan, X and Wang, P and Li, H and Xiu, R}, title = {Tetramethylpyrazine improving cerebral microcirculation in Alzheimer's Disease mice.}, journal = {Brain research bulletin}, volume = {241}, number = {}, pages = {111936}, doi = {10.1016/j.brainresbull.2026.111936}, pmid = {42134480}, issn = {1873-2747}, mesh = {Animals ; *Pyrazines/pharmacology ; *Alzheimer Disease/drug therapy/physiopathology/metabolism ; *Microcirculation/drug effects ; *Cerebrovascular Circulation/drug effects ; Mice ; Male ; Disease Models, Animal ; Mice, Transgenic ; Blood Flow Velocity/drug effects ; Mice, Inbred C57BL ; Brain/drug effects ; Cerebral Cortex/drug effects/blood supply ; }, abstract = {Cerebrovascular dysfunction plays a crucial role in the development and progression of Alzheimer's Disease (AD). Tetramethylpyrazine, a bioactive alkaloid monomer derived from Chinese herbal medicine Chuanxiong (Ligusticum chuanxiong), has been demonstrated to improve tissue microcirculation. However, direct in vivo monitoring of cerebral microcirculation is still challenging due to the presence and thickness of the skull. In this study, we constructed a visualized mouse cranial window and utilized photoacoustic microscopy, laser speckle imaging, and Laser Doppler flowmetry to investigate the effect of Tetramethylpyrazine on cortical microvascular function in normal mice, AD mice, and Tetramethylpyrazine-treated AD mice. Our results revealed impaired cerebral microvascular perfusion in AD mice, including significant reductions in blood flow velocity, oxygen saturation, and metabolic rate of oxygen. Tetramethylpyrazine treatment improved cortical microvascular function in AD mice, with endothelium-derived microvascular signals playing a key role in microvascular rhythmic motion. These findings suggest that Tetramethylpyrazine has the ability to enhance cortical microcirculation in AD mice through multiple mechanisms, particularly through endothelial improvement. Tetramethylpyrazine may serve as a potential candidate drug for AD treatment, and photoacoustic microscopy holds promise in the clinical observation of cortical microcirculation in AD.}, } @article {pmid42134886, year = {2026}, author = {Chinnathambi, S and Rangappa, N}, title = {Biosimilars: Antibody and nanobody-based therapeutic approaches towards protein misfolding diseases.}, journal = {Advances in protein chemistry and structural biology}, volume = {151}, number = {}, pages = {157-195}, doi = {10.1016/bs.apcsb.2025.10.014}, pmid = {42134886}, issn = {1876-1631}, mesh = {Humans ; *Proteostasis Deficiencies/drug therapy/metabolism/pathology/immunology ; *Biosimilar Pharmaceuticals/therapeutic use ; tau Proteins/metabolism/immunology/antagonists & inhibitors ; *Single-Domain Antibodies/therapeutic use ; Amyloid beta-Peptides/metabolism/immunology/antagonists & inhibitors ; *Neurodegenerative Diseases/drug therapy/metabolism ; Animals ; alpha-Synuclein/metabolism/antagonists & inhibitors/immunology ; *Alzheimer Disease/drug therapy/metabolism/pathology/immunology ; *Parkinson Disease/drug therapy/metabolism/pathology/immunology ; }, abstract = {Neurodegenerative diseases, such as Alzheimer's disease, and Parkinson's disease, are characterized by progressive neuronal dysfunction and degeneration. These conditions often share pathological hallmarks such as protein misfolding, oxidative stress, neuroinflammation, and mitochondrial dysfunction. This review focuses on key pathological players like Tau and Amyloid-beta in Alzheimer's disease, highlighting their roles in microtubule destabilization, synaptic dysfunction, and neuronal death. The interplay between oxidative stress and these proteinopathies exacerbates neurodegeneration. Recent advances in therapeutic strategies are also explored, particularly the promise of biosimilars, cost-effective alternatives to biologics, targeting pathological hallmarks in neurodegenerative diseases. Biosimilars targeting Tau and Amyloid-beta in Alzheimer's disease, and alpha-synuclein in Parkinson's disease, hold the potential to improve treatment accessibility and reduce economic burdens. However, their development is still in its early stages. This review underscores the urgent need for innovative, affordable, and globally accessible therapeutic solutions to address the rising burden of neurodegenerative diseases.}, } @article {pmid42134887, year = {2026}, author = {Chinnathambi, S}, title = {Induced-pluripotent stem cell-derived immunotherapy for Tau and Alzheimer's disease.}, journal = {Advances in protein chemistry and structural biology}, volume = {151}, number = {}, pages = {197-224}, doi = {10.1016/bs.apcsb.2025.10.005}, pmid = {42134887}, issn = {1876-1631}, mesh = {Humans ; *Alzheimer Disease/therapy/immunology/pathology ; *tau Proteins/immunology/metabolism ; *Induced Pluripotent Stem Cells/immunology ; Animals ; *Immunotherapy/methods ; Amyloid beta-Peptides/immunology ; }, abstract = {Neurodegenerative diseases, such as Alzheimer's disease, are characterized by progressive neuronal death and functional decline. Key pathological hallmarks of Alzheimer's disease include the deposition of aggregated amyloid-β (Aβ) proteins into extracellular plaques and the accumulation of hyperphosphorylated Tau protein into intracellular aggregates. These toxic species triggers neuroinflammation through interactions with glial cells, further exacerbating neurodegeneration. This study explores the potential of induced pluripotent stem cells (iPSCs) in disease modelling, focusing on their application in modelling Alzheimer's disease pathology and therapeutic screening. Additionally, the development of advanced 3D culture systems and organoids offers insights into human-specific Alzheimer's disease mechanisms, overcoming limitations of traditional 2D and animal models. The focus is on the role of microglial polarization in neuroinflammation and its potential therapeutic modulation, offering a promising approach for the treatment of neurodegenerative diseases.}, } @article {pmid42135923, year = {2026}, author = {Mia, E and Hossain, MA and Bristy, AH and Hossan, R and Asif, U and Sherwani, AK and Alshahrani, MY and Selim, S and Rakib, IH and Yana, NT and Akter, K and Hasan, MSA}, title = {Neuroprotective Properties of Litchi chinensis and Its Phytochemicals in Preclinical Models of Alzheimer's Disease.}, journal = {Brain and behavior}, volume = {16}, number = {5}, pages = {e71474}, pmid = {42135923}, issn = {2162-3279}, mesh = {*Litchi ; Animals ; *Alzheimer Disease/drug therapy/metabolism ; *Neuroprotective Agents/pharmacology ; *Plant Extracts/pharmacology ; Disease Models, Animal ; *Phytochemicals/pharmacology ; Amyloid beta-Peptides/metabolism/drug effects ; Humans ; Oxidative Stress/drug effects ; tau Proteins/metabolism ; Mice ; }, abstract = {PURPOSE: Alzheimer's disease (AD) is a progressive neurodegenerative disorder involving amyloid-β deposition, tau hyperphosphorylation, oxidative stress, and neuroinflammation. This review systematically evaluates the neuroprotective effects of Litchi chinensis and its phytochemicals against AD, focusing on modulation of Aβ accumulation, tau pathology, oxidative stress, neuroinflammation, apoptosis, and synaptic dysfunction using available preclinical evidence.

METHOD: A systematic literature search was conducted in PubMed, Scopus, Web of Science, ScienceDirect, and Google Scholar up to August 2025 using relevant keywords. Studies investigating neuroprotective effects of Litchi chinensis extracts or compounds in in vitro or in vivo AD models were included, while unrelated studies, duplicates, abstracts, and non-full-text articles were excluded.

RESULTS: Litchi chinensis extracts and phytochemicals demonstrated broad neuroprotective actions. In triple-transgenic mice, oligonol treatment (0.25-0.50 mg/mL) significantly reduced amyloid precursor protein (APP), β-secretase, and amyloid-β levels, while also decreasing tau hyperphosphorylation. Seed extracts (0.7-2.8 g/kg/day) reduced amyloid-β accumulation and neuronal injury in Sprague-Dawley rats. Anti-inflammatory effects were evident through decreased tumor necrosis factor-α, IL-1β, IL-6, and interferon gamma, alongside increased IL-4. Antioxidant defenses were enhanced via upregulation of antioxidant enzymes such as glutathione peroxidase-1 and superoxide dismutase-2, while apoptosis was suppressed by increasing Bcl-2 and reducing Bax and caspase activity. Synaptic integrity was preserved through upregulation of PSD95, synaptophysin, and serotonin receptor proteins, resulting in improved learning and memory in AD models. Additional benefits included enhanced mitochondrial and proteasomal activity, alleviation of endoplasmic reticulum (ER) stress, and induction of neurotrophic factors like insulin-like growth factor 2 and fibroblast growth factor 21.

CONCLUSION: Litchi chinensis demonstrates a multitargeted neuroprotective role, making it a promising natural therapeutic candidate for Alzheimer's management. However, as most findings are limited to preclinical models, further clinical studies are necessary to validate efficacy, ensure safety, and explore its translational potential.}, } @article {pmid42136137, year = {2026}, author = {Bao, L and Zhao, F and Xu, W and Jiang, P and Zhang, Y and Luo, Y and Guan, W and Li, M and Chen, Q and Zhang, L and Kuang, H and Li, J and Liu, Y}, title = {Pharmacodynamics and mechanisms of triterpene components from the leaves of Astragalus mongholicus Bunge in the treatment of Alzheimer's disease.}, journal = {Natural product research}, volume = {}, number = {}, pages = {1-9}, doi = {10.1080/14786419.2026.2671969}, pmid = {42136137}, issn = {1478-6427}, abstract = {This study investigates the therapeutic potential and underlying mechanisms of triterpenoids (TR) derived from the leaves of Astragalus mongholicus Bunge for the treatment of Alzheimer's disease (AD). Eighteen triterpenoid compounds were identified in the TR fraction using UPLC-Q-TOF-MS. In the 3 × Tg-AD transgenic mouse model, the therapeutic efficacy of TR was assessed using a comprehensive approach that included the Morris water maze, histopathological analysis, transmission electron microscopy, and Western blotting. The findings revealed that TR significantly improved spatial learning and memory impairments, reduced hippocampal neuronal degeneration, and diminished the deposition of phosphorylated Tau (p-Tau) protein. Ultrastructural examination further confirmed that TR preserved mitochondrial integrity. Mechanistic studies showed that TR upregulated key mitophagy-related proteins in both PINK1/Parkin-dependent and -independent pathways. In conclusion, TR exerts neuroprotective effects by activating mitophagy through multiple pathways, highlighting its potential as a promising therapeutic candidate for AD. This study not only provides experimental evidence for the therapeutic potential of natural products targeting mitophagy in Alzheimer's disease but also expands the medicinal development value of the leaves of Astragalus mongholicus Bunge.}, } @article {pmid42136262, year = {2026}, author = {Khan, MA and Khan, ZA and Shoeb, F and Siddiqui, Z and Pandey, G and Fatima, G and Khan, RH and Khan, MM}, title = {Role of De Novo Lipogenesis in Neurodegeneration and Neurogenesis Disruption in Alzheimer's Disease and Treatment Perspective.}, journal = {Current neuropharmacology}, volume = {}, number = {}, pages = {}, doi = {10.2174/011570159X423516260216052123}, pmid = {42136262}, issn = {1875-6190}, abstract = {Progressive neurodegeneration, decline in neurogenesis, and cognitive dysfunction alongside amyloid-β plaque and neurofibrillary tangle formation are prominent pathological features of Alzheimer's Disease (AD). Although the underlying mechanism remains unclear, evidence suggests that surplus intracellular lipids/fatty acids could be the primary mediators. In this regard, increased levels of Saturated Fatty Acids (SFAs), Monounsaturated Fatty Acids (MUFAs), their triglyceride and ceramide derivatives have been reported in the brain of patients with AD. Further, converging evidence from basic and clinical studies suggests that de novo lipogenesis could be the main source of lipid/fatty acid accumulation in the brains of patients with AD. Although elevated cholesterol has long been suggested to induce inflammation and neurodegenera-tion in AD, recent evidence suggests that the effects of SFAs and their lipid derivatives, particularly ceramides, could be more detrimental. Consequently, de novo lipogenesis inhibitors could be the potential therapeutic targets for the early intervention in AD. Intriguingly, several studies have shown that treatment with various natural or synthetic compounds, which inhibit de novo lipogenesis, effectively reduced neurodegeneration, cognitive dysfunction, and inflammation in the model animals of AD. These compounds also increased neurogenesis while reducing lipid/fatty acid accumulation, suggesting that blocking lipid/fatty acid biosynthesis by inhibiting de novo lipogenesis could be an effective strategy in treating AD. Thus, while the study discusses the effects of various FDA-approved AD drugs and selected natural and synthetic inhibitors of de novo lipogenesis on neurodegeneration and neurogenesis in model animals, the doors are open for conducting clinical trials in patients with AD.}, } @article {pmid42136266, year = {2026}, author = {Gupta, S and Nihal, PM and Jawaid, T and Ashesh, AM and Bhise, MR and Rawat, M and Lohidasan, S and Wal, P and Kumar, A and Kumar, D and Gasmi, A}, title = {Exploring Mitochondrial Dysfunction and Protective Therapeutic Approaches to Counteract Its Role in Alzheimer's Disease Progression.}, journal = {Current neuropharmacology}, volume = {}, number = {}, pages = {}, doi = {10.2174/011570159X419571260226033536}, pmid = {42136266}, issn = {1875-6190}, abstract = {Alzheimer's disease (AD) is the primary cause of dementia, characterized by a progres-sive decrease in mental abilities and the accumulation of amyloid-beta (Aβ) peptides in the brain. The combination of these peptides leads to the development of neuritic plaques and neurofibrillary tangles that disrupt neural communication and eventually lead to the loss of neurons. One of the fac-tors that are involved in the development of AD is mitochondrial dysfunction. Disrupted function-ing of mitochondria leads to the production of less energy by the cells, increased oxidative stress, and accelerates the neurodegeneration process. Neurons that carry out their mitochondrial functions normally are required to keep the balance of calcium, in a reasonable energy production, and in the survival of the cells. Mitophagy, which guarantees the clearing of damaged mitochondria, is im-paired in AD. Cholinesterase blockers and NMDA receptor blockers are currently used as treat-ments, but these are not aimed at the underlying pathophysiology of the condition. New treatment approaches that are aimed at enhancing mitochondrial health, in contrast, are viable at providing a potential to decelerate or alter mitochondrial AD progression. The goals of these approaches include enhancement of the mitophagy process, alleviation of oxidative stress, and preservation of mito-chondrial health, which may disrupt major pathological events such as Aβ aggregation and tau hy-perphosphorylation. By concentrating on the replacement of mitochondria, scientists are moving in the right direction to develop therapies that will not only help control the symptoms but also cure the disease.}, } @article {pmid42136278, year = {2026}, author = {Sharma, A and Mittal, V and Sharma, D and Deswal, G and Das, A and Guarve, K and Grewal, AS}, title = {Therapeutic Insights into Natural Products for Modulating Neurodegenerative Disease Pathways.}, journal = {Central nervous system agents in medicinal chemistry}, volume = {}, number = {}, pages = {}, doi = {10.2174/0118715249405308251210104405}, pmid = {42136278}, issn = {1875-6166}, abstract = {INTRODUCTION: Neurodegenerative Disorders (NDs), such as Alzheimer's disease, Parkinson's disease, Huntington's disease, and Amyotrophic Lateral Sclerosis (ALS), are chronic and progressive conditions marked by the gradual loss of neuronal structure and function. These disorders lead to cognitive, motor, and sensory decline, significantly reducing quality of life and posing a major global health burden due to rising healthcare costs and the absence of curative therapies. This review aims to comprehensively explore the therapeutic potential of natural products in targeting cellular and molecular mechanisms underlying NDs, highlighting their neuroprotective roles and potential for disease modification.

METHODS: A comprehensive literature review was conducted using databases including PubMed, Scopus, Web of Science, and Google Scholar. Peer-reviewed articles, clinical trials, and experimental studies were analyzed to evaluate the therapeutic potential of natural products and their bioactive compounds in the management of NDs.

RESULTS: ND pathogenesis involves oxidative stress, neuroinflammation, mitochondrial dysfunction, and abnormal protein aggregation, ultimately leading to neuronal death. Current therapies largely provide symptomatic relief without altering disease progression. Natural products from plants, fungi, and marine sources demonstrate strong neuroprotective potential through multitargeted mechanisms. Bioactive compounds such as flavonoids, alkaloids, terpenoids, and polyphenols exhibit antioxidant, anti-inflammatory, anti-apoptotic, and neuroprotective activities. Key molecules, including curcumin, resveratrol, luteolin, quercetin, and catechins, modulate signaling pathways such as NF-κB, MAPK, PI3K/AKT, Nrf2, apoptosis, and autophagy, thereby reducing amyloid-beta aggregation, protecting dopaminergic neurons, improving mitochondrial function, and enhancing cognition in preclinical and clinical studies.

DISCUSSION: Natural products represent promising candidates for disease modification in NDs due to their multi-pathway actions and relatively low toxicity. However, major limitations, such as poor bioavailability, pharmacokinetic variability, and the lack of standardized formulations, hinder clinical translation. Innovative strategies, including advanced drug-delivery systems, structural modifications, and synergistic formulations, are needed to overcome these barriers.

CONCLUSION: Natural products hold significant therapeutic potential in managing neurodegenerative diseases by targeting multiple pathological mechanisms. Their integration into ND treatment could provide safer and more effective alternatives, but further well-designed clinical trials are essential to establish their efficacy and facilitate clinical application.}, } @article {pmid42136282, year = {2026}, author = {Singh, P and Bhardwaj, S and Nagarajan, K}, title = {Development and Assessment of Phytoconstituents-based Nanoemulsion as a Potent Combined Therapy for Neuroprotection in Scopolamine-induced Alzheimer's Disease Rat Model.}, journal = {Current neurovascular research}, volume = {}, number = {}, pages = {}, doi = {10.2174/0115672026450795260413103307}, pmid = {42136282}, issn = {1875-5739}, abstract = {INTRODUCTION: Nanoemulsions are increasingly recognized as effective carriers for delivering neuroprotective agents in the management of neurodegenerative conditions like Alzheimer's disease. Alzheimer's Disease (AD) is a chronic and progressive neurological disorder marked by memory impairment, cognitive dysfunction, oxidative damage, and degeneration of neurons. This study focuses on designing and evaluating a nanoemulsion-based drug delivery system combining Resveratrol and Ginkgo biloba to investigate their potential neuroprotective effects in a scopolamine- induced Alzheimer's model in Wistar rats.

METHODS: A total of nine water-in-oil nanoemulsion formulations (F1-F9) were developed using probe sonication and examined for various parameters, including droplet size, zeta potential, polydispersity index (PDI), entrapment efficiency, and in vitro drug release profiles.

RESULTS: Among these, Formulation F2, containing 25 mg of Resveratrol and 25 mg of Ginkgo biloba, showed the most favourable characteristics, including a high entrapment efficiency of 90.13%, maximum drug release of 92.33%, a particle size of 92.83 nm, and a zeta potential of 30.75 mV, suggesting good stability of the formulation. For the in vivo evaluation, rats were divided into six groups: normal control, negative control (scopolamine-treated), standard treatment group (Diazepam 2 mg/kg), and three test groups with different formulations. Behavioural studies using the Y-maze demonstrated that the Test Group 1 (treated with F2 formulation) had significantly improved spontaneous alternation behaviour, indicating enhanced cognitive performance. Biochemical analysis showed reduced malondialdehyde (MDA) levels and increased glutathione (GSH) levels, suggesting potent antioxidant activity. Additionally, histopathological examination of brain tissue revealed that the F2-treated group showed reduced neuronal damage and better preservation of hippocampal structure.

DISCUSSION: In rats treated with scopolamine, the optimized F2 nanoemulsion showed excellent physicochemical stability and markedly enhanced cognitive function. Strong antioxidant and neuroprotective effects of the combination formulation are indicated by decreased MDA levels, increased GSH levels, and intact hippocampus architecture.

CONCLUSION: The Resveratrol-Ginkgo biloba nanoemulsion (F2) successfully reduced oxidative stress and cognitive impairment, indicating its potential as a treatment for early-stage Alzheimer's disease. Additional research is needed to confirm its therapeutic application.}, } @article {pmid42136286, year = {2026}, author = {Tiwari, P and Kadiri, SK and Sulakhiya, K}, title = {Hyperprolactinemia and Tau Pathology: Unravelling Neuroendocrine Dysregulation for Therapeutic Targeting.}, journal = {Current neurovascular research}, volume = {}, number = {}, pages = {}, doi = {10.2174/0115672026467094260417052012}, pmid = {42136286}, issn = {1875-5739}, abstract = {BACKGROUND: Hyperprolactinemia, characterized by persistently elevated serum prolactin levels, is traditionally associated with reproductive and metabolic disturbances. Emerging evidence now implicates hyperprolactinemia in central nervous system dysfunction, particularly in the pathogenesis of neurodegenerative disorders. Chronic elevation of prolactin has been linked to tau pathology, a hallmark of Alzheimer's disease and related tauopathies, through mechanisms that promote tau hyperphosphorylation, microtubule destabilization, and neuronal compromise.

METHODOLOGY: This systematic review assesses the evidence on hyperprolactinemia and tau pathology. The overall literature search was performed in PubMed, Scopus, and Web of Science with the help of certain keywords that included prolactin, tau protein, neuroinflammation, oxidative stress, and dopaminergic signaling. The studies were narrowed down to a set of pre-established inclusion and exclusion criteria (original research, molecular and clinical data, relevance to neuropsychiatric disorders, non-English articles, reviews, animal studies that did not have a translational relevance). A clear study selection procedure was used, with independent screening and consensus-based resolution. The results generalize molecular, transcriptomic, neuroimaging, and clinical data to assess mechanistic connections and treatment prospects.

RESULTS: Neurons susceptible to tau accumulation under hyperprolactinemic states exhibit altered apoptotic signaling, impaired vesicular trafficking, and mitochondrial dysfunction. These disruptions correlate with increased neuroinflammation and oxidative stress, suggesting a mechanistic link between endocrine imbalance and tau-mediated neurotoxicity. Therapeutic agents such as dopamine agonists, selective kinase inhibitors, and prolactin receptor antagonists have the potential to restore neuroendocrine homeostasis and mitigate tau pathology.

DISCUSSION: The findings underscore hyperprolactinemia as a modifiable risk factor for cognitive decline. The neuroendocrine-tau axis represents a critical interface where hormonal dysregulation may precipitate neurodegenerative cascades. Clinical implications in the manuscript include that prolactin may serve as a biomarker of an early neurodegenerative process and that its role in the treatment approach includes dopamine agonists, prolactin receptor antagonists, and kinase inhibitors. This simplified methodology will ensure the highlights are original and have translational implications beyond mere abstract repetition.

CONCLUSION: Hyperprolactinemia-induced tau dysregulation presents novel opportunities for neuroprotective targeting. By bridging molecular mechanisms with clinical relevance, this review advocates for longitudinal studies to assess cognitive outcomes in hyperprolactinemic individuals. Emphasizing endocrine health may enhance cognitive resilience and inform future strategies for diagnosis, risk stratification, and therapeutic intervention in neurodegenerative diseases.}, } @article {pmid42136293, year = {2026}, author = {Ramesh, J and Jayanthi, B and Mohan, VK and Srinivasan, S and Vijayalakshmi, MK and Mohan, M}, title = {Targeted Nanotechnology Approaches to Bypass the Blood-brain Barrier in Neurodegenerative Disorders.}, journal = {CNS & neurological disorders drug targets}, volume = {}, number = {}, pages = {}, doi = {10.2174/0118715273444679260416064255}, pmid = {42136293}, issn = {1996-3181}, abstract = {Neurodegenerative diseases like Alzheimer's disease (AD), Parkinson's disease (PD), Amyotrophic Lateral Sclerosis (ALS), and Huntington's disease (HD) are a growing health burden across the world because of the progressive loss of brain cells and the ineffective nature of the available treatment. One significant challenge in the treatment of these conditions is the Blood- -Brain Barrier (BBB), a highly selective interface that limits the access of most therapeutic molecules to the central nervous system. Nanotechnology has become an attractive approach to addressing this difficulty, as it enables the delivery of drugs with high accuracy and actively engages in the repair of the BBB. This review provides an overall synthesis of focused nanotechnology solutions aimed at both circumventing and restoring BBB function in neurodegenerative illnesses. It discusses various nanoparticle (NP) platforms such as polymeric, lipid-based, micellar, metallic, and carbon-derived systems in the light of their physicochemical aspects, transport across the BBB, and therapeutic efficacy. Particular emphasis is put on the receptor-mediated transcytosis, neurovascular unit modulations, and the regulation of Wnt, Shh, and Tie-2 signalling pathways, which are BBB integrity pathways. The review incorporates mechanisms of BBB repair in combination with neuroprotective nanotherapies, rather than focusing solely on end repair. This review covers the role of targeted nanotechnology in the future of therapeutic approaches for neurodegenerative diseases. By connecting materials science, molecular neuroscience, and clinical innovation, it demonstrates how next-generation brain-targeted therapies can be developed using targeted nanotechnology.}, } @article {pmid42136299, year = {2026}, author = {Xia, B and Wu, S and Yu, W and Lü, Y}, title = {Research Progress on Intervention Strategies Targeting the Gut-Brain Axis in Alzheimer`s Disease.}, journal = {CNS & neurological disorders drug targets}, volume = {}, number = {}, pages = {}, doi = {10.2174/0118715273431295251201140053}, pmid = {42136299}, issn = {1996-3181}, abstract = {As the most common neurodegenerative disease in the world, Alzheimer's Disease (AD) is characterized by a complex pathogenesis and a lack of effective treatments. In recent years, breakthroughs in the Gut-Brain Axis (GBA) theory have provided a new direction for AD intervention. Studies have shown that AD patients commonly exhibit gut dysbiosis, accompanied by decreased Short-Chain Fatty Acid (SCFA) levels, endotoxin leakage, and increased systemic inflammation, which accelerate cognitive decline via neuroinflammation, Aβ deposition, and synaptic dysfunction. Based on this, intervention strategies targeting the GBA have emerged as a focus of research for slowing down the pathological process of AD. In this study, we systematically summarize the mechanisms linking gut microbiota dysbiosis to AD pathology. This includes the roles of metabolites (e.g., SCFA, LPS, and TMAO) in modulating neuroinflammation and Blood-Brain Barrier (BBB) permeability, as well as the critical involvement of vagal nerve pathways in gut-brain signaling. We further explored the potential of probiotics to improve cognitive function by restoring microbial homeostasis, enhancing anti-inflammatory effects, and elevating neurotrophic factor levels; dietary interventions (e.g., the Mediterranean and MIND diets) to reduce AD risk by modulating microbial composition and metabolic activity; and Fecal Microbiota Transplantation (FMT) to reduce Aβ plaque deposition and mitigate neuroinflammation. Despite promising findings, challenges persist, including discrepancies between animal models and human subjects, individual variability in microbiota composition, and an incomplete understanding of underlying mechanisms. In the future, it will be necessary to combine multiple technologies to develop personalized intervention protocols and optimize clinical translation processes, providing a theoretical basis for the precise treatment of AD.}, } @article {pmid42136342, year = {2026}, author = {Liu, CW and Shan, ZX and Li, WJ and Qu, QW and Hou, XQ}, title = {Potential Therapeutic Effects and Mechanisms of Estrogen on Diabetes, Alzheimer's Disease,and Their Comorbidity:A Review.}, journal = {Zhongguo yi xue ke xue yuan xue bao. Acta Academiae Medicinae Sinicae}, volume = {48}, number = {2}, pages = {328-337}, doi = {10.3881/j.issn.1000-503X.16649}, pmid = {42136342}, issn = {1000-503X}, mesh = {Humans ; *Alzheimer Disease/drug therapy ; *Estrogens/therapeutic use ; *Diabetes Mellitus/drug therapy ; Receptors, Estrogen/metabolism ; Animals ; }, abstract = {Estrogen is a lipid-soluble steroid hormone and one of the most important female sex hormones.It mainly functions by interacting with estrogen receptors,maintaining normal physiological and pathophysiological functions of the body,and playing a crucial role in regulating blood glucose homeostasis,metabolism,and physiological processes associated with brain learning and memory.Recent studies have shown that estrogen has potential therapeutic effects on diabetes,cognitive impairment and other diseases.It will provide new ideas and treatment strategies for diabetes,Alzheimer's disease,and their comorbidity by regulating the activity of estrogen and the interaction with estrogen receptors to modulate related pathological and physiological processes.This article reviews the latest research progress in the relationship between estrogen and these diseases,providing a new perspective and prospect for the prevention and treatment of diabetes,Alzheimer's disease,and their comorbidity.}, } @article {pmid42136344, year = {2026}, author = {Zhang, XT and Chen, SS and Liu, YW and Huang, HR and Yu, Y}, title = {Role of Brain Insulin Resistance in the Pathogenesis of Alzheimer's Disease.}, journal = {Zhongguo yi xue ke xue yuan xue bao. Acta Academiae Medicinae Sinicae}, volume = {48}, number = {2}, pages = {347-354}, doi = {10.3881/j.issn.1000-503X.16614}, pmid = {42136344}, issn = {1000-503X}, mesh = {*Alzheimer Disease/metabolism ; Humans ; *Insulin Resistance ; *Brain/metabolism ; }, abstract = {Alzheimer's disease (AD) is the most common type of dementia,in which brain insulin resistance (BIR) plays a key role.BIR affects the response of brain cells to insulin and is associated with cognitive decline and pathological features of AD.This study explores the role of BIR in the pathogenesis of AD and evaluates potential treatment strategies,aiming to provide new directions for the prevention and treatment of AD.}, } @article {pmid42136471, year = {2026}, author = {Sharma, S and Thakur, A and Paliwal, D and Mondal, R and Saini, S and Sahu, R and Kaushik, N and Tiwari, H}, title = {Exploring the Therapeutic Potential of Coumarin Scaffolds in Alzheimer's Disease: A Comprehensive Review.}, journal = {Mini reviews in medicinal chemistry}, volume = {}, number = {}, pages = {}, doi = {10.2174/0113895575443995260406045449}, pmid = {42136471}, issn = {1875-5607}, abstract = {Alzheimer's disease is a progressive and debilitating form of neurological disorder that affects millions of people across the globe. Alzheimer's disease is essentially defined by the presence of cognitive decline, memory impairments, and behavioral symptoms, and it is also defined by pathological hallmarks such as amyloid plaques, Tau protein inclusions, oxidative stress, & neuroinflammation. However, despite the vast progress made in the field of neuroscience and pharmacology, there is no permanent treatment available for Alzheimer's disease, and the existing treatments are only symptomatic in nature. This has led to the search for new innovative therapeutic approaches based on small molecules with multifunctional pharmacological properties. Among different molecules, Coumarin derivatives have been identified as promising therapeutic agents owing to their high structural diversity and potent ability to bind key molecular targets involved in AD pathogenesis. Coumarin derivatives have been found to have strong potential for modulating oxidative stress, inhibitng cholinesterase, reducing neuroinflammation, and interfering with amyloid-beta aggregation. Recent advancements in the synthesis and design of coumarin derivatives have shown that slight modifications in their structure can yieldsubstantial improvements in their efficacy and selectivity in the treatment of Alzheimer's disease. For coumarin derivatives to be used in the treatment of Alzheimer's disease, they need first to be able to cross the blood-brain barrier. To overcome this limitation, scientists have been working to improve lipophilicity, optimize molecular size and polarity, and design prodrugs. This review provides an updated account of the use of coumarin derivatives in the treatment of Alzheimer's disease. It focuses on their neuroprotective and, symptommodifying effects, and their use in dealing with the multifactorial nature of the disease. Moreover, this paper aims to give recent research findings and discuss the structure-activity relationships of these compounds. The knowledge gained from this review is expected to motivate further research endeavors in the development of stronger and more specific AD drugs.}, } @article {pmid42136472, year = {2026}, author = {Shrivastava, N and Husain, A and Haider, K}, title = {Substituted Benzofurans as Potent Anticancer Agents: Advances, Molecular Docking, and SAR Studies.}, journal = {Mini reviews in medicinal chemistry}, volume = {}, number = {}, pages = {}, doi = {10.2174/0113895575435772260422071930}, pmid = {42136472}, issn = {1875-5607}, abstract = {Benzofuran, an oxygen-containing fused heterocyclic aromatic compound, occurs naturally as a secondary metabolite from various plant sources like Rutaceae, Asteraceae, Cyperaceae, and Liliaceae. The derivatives of benzofuran possess a wide range of biological activities, including anticancer, anti-inflammatory, antioxidant, antibiotic, analgesic, anti-Alzheimer's, and immunosuppressive effects. Various synthetic methods are currently used to prepare various benzofuran derivatives. Its therapeutic significance is highlighted by the presence of the benzofuran core in several FDA-approved drugs. Due to the development of resistance in existing anticancer therapies, there is an urgent need for novel, effective, and safe therapeutic approaches. Many heterocyclic moieties and their structural hybrids have been explored for their potential biological activity and have attracted considerable attention as anticancer agents. Substituted benzofuran derivatives are emerging as lead candidates to meet the global challenges of cancer and its available treatment. Benzofuran has the chemical formula C8H6O. Structurally, it consists of a fused ring system: a benzene ring fused to a five-membered furan ring (with one oxygen). Both benzene and furan contribute to its aromatic character. Benzofuran heterocycle plays an important role in drug design and drug discovery due to its versatile nature. The current review summarizes the recent progress in the design, development, drug discovery, and pharmacological actions of benzofuran derivatives as anticancer agents; their molecular docking studies; and structure-activity relationships reported over the past five to six years, emphasizing fused heterocyclic analogues and their prospects to develop as lead molecules. A thorough understanding of the structure-activity relationship will provide a valuable framework for novel drug discovery and design.}, } @article {pmid42137472, year = {2026}, author = {Al-Karmalawy, AA and Attia, MI and Alnajjar, R and El-Shiekh, RA and Al Khatib, AO and Yousef, TA and Abdel-Sattar, E}, title = {Discovery of Caralluma-derived pregnane glycosides as potent and selective cholinesterase inhibitors: integrated in silico and in vitro evaluation.}, journal = {RSC advances}, volume = {16}, number = {27}, pages = {24903-24915}, pmid = {42137472}, issn = {2046-2069}, abstract = {Alzheimer's disease (AD) is the fourth leading cause of death among elderly people worldwide. It has a complex pathogenesis, making multitarget-directed ligands (MTDLs) a key therapeutic strategy. This study evaluated pregnane glycosides isolated from Caralluma species (Apocynaceae) as potential cholinesterase inhibitors targeting acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) enzymes for AD treatment. In silico molecular docking against AChE (PDB: 4EY7) and BuChE (PDB: 8CGO) identified caratuberside E and awdelioside B as top AChE binders (-11.09 and -11.49 kcal mol[-1], outperforming the cocrystal inhibitor at -9.52 kcal mol[-1]). For BuChE, caratuberside G and penicilloside C showed superior scores (-10.94 and -11.55 kcal mol[-1] vs. -8.89 kcal mol[-1] for the cocrystal). These results were validated by 200 ns molecular dynamics simulations (stable RMSD values) and MM-GBSA binding free-energy calculations, confirming strong interactions and favourable energetics. In vitro assays (using donepezil as reference) demonstrated potent inhibition: caratuberside E was most active against AChE (IC50 = 0.69 ± 0.07 µM), followed by awdelioside B (IC50 = 18.99 ± 0.06 µM); caratuberside G (IC50 = 1.59 ± 0.16 µM) and penicilloside C (IC50 = 12.38 ± 0.51 µM) excelled against BuChE. Collectively, these pregnane glycosides from Caralluma show promise as selective cholinesterase inhibitors and potential MTDLs for AD therapy.}, } @article {pmid42138018, year = {2026}, author = {Chen, CP and Zhang, T and E, ED and Xu, TY and Han, Q and Gao, X and Sun, J and Huang, Y and Yang, JH and Zhang, XQ}, title = {Targeting mGluR2/3 Signaling With LY341495 Restores Dentate Gyrus Function and Cognitive Performance in a Male Mouse Model of Alzheimer's Disease.}, journal = {CNS neuroscience & therapeutics}, volume = {32}, number = {5}, pages = {e70916}, pmid = {42138018}, issn = {1755-5949}, support = {82201322//National Natural Science Foundation of China/ ; LY24H090001//the Natural Science Foundation of Zhejiang Province/ ; 2024010317//Ningbo Top Medical and Health Research Program/ ; 2022020304//Ningbo Top Medical and Health Research Program/ ; 2023H017//Ningbo Science and Technology Project/ ; 2024L003//Ningbo Clinical Research Center for Emergency and Critical Diseases/ ; }, mesh = {Animals ; Male ; *Dentate Gyrus/drug effects/metabolism/pathology ; *Receptors, Metabotropic Glutamate/metabolism/antagonists & inhibitors ; *Alzheimer Disease/drug therapy/pathology/genetics/metabolism ; Disease Models, Animal ; *Xanthenes/pharmacology/therapeutic use ; Mice, Transgenic ; Mice ; *Amino Acids/pharmacology/therapeutic use ; Signal Transduction/drug effects ; Neurogenesis/drug effects ; Cognitive Enhancement ; *Excitatory Amino Acid Antagonists/pharmacology/therapeutic use ; }, abstract = {BACKGROUND: Aberrant metabotropic glutamate receptor 2/3 (mGluR2/3) signaling has been implicated in the synaptic and cognitive deficits observed in Alzheimer's disease (AD), yet the underlying regulatory mechanisms remain unclear. This study investigated the therapeutic potential of LY341495, a selective mGluR2/3 antagonist, in APP/PS1 transgenic mice, a widely used AD model.

METHODS: Male APP/PS1 mice were treated with the selective mGluR2/3 antagonist LY341495. Cognitive performance was evaluated using behavioral tests. Hippocampal dentate gyrus (DG) alterations were examined by immunohistochemistry and electrophysiology, including analyses of mGluR2/3 expression, excitatory synaptic activity, adult neurogenesis, calbindin expression, and amyloid-β plaque burden.

RESULTS: APP/PS1 mice exhibited pathological upregulation of mGluR2/3 in the DG, accompanied by altered presynaptic glutamatergic transmission, reduced neurogenesis, decreased calbindin expression, and deficits in recognition and spatial memory. LY341495 treatment attenuated the aberrant mGluR2/3 upregulation, enhanced excitatory synaptic activity, and improved calbindin levels and neurogenesis in the DG. Importantly, these changes were associated with significant reductions in DG amyloid-β plaque burden and marked improvements in cognitive performance.

CONCLUSIONS: This study highlights the novelty of linking mGluR2/3 inhibition to the restoration of calcium-buffering capacity, as reflected by calbindin expression and neurogenesis, processes critical for DG plasticity and resilience. These findings underscore the therapeutic potential of LY341495 as a novel intervention targeting mGluR2/3 signaling in AD.}, } @article {pmid42139159, year = {2026}, author = {Carvalho, MS and Barssotti, L and Santos, LMBD and Rosa, LRO and Gomes-Marcondes, MCC and Carneiro, EM and Barbosa, HCL and Zangerolamo, L}, title = {Tauroursodeoxycholic acid (TUDCA) ameliorates age-related skeletal muscle loss.}, journal = {The Journal of physiology}, volume = {604}, number = {12}, pages = {4795-4814}, doi = {10.1113/JP290683}, pmid = {42139159}, issn = {1469-7793}, support = {2021/13917-6//Fundação de Amparo à Pesquisa do Estado de São Paulo/ ; }, mesh = {Animals ; *Taurochenodeoxycholic Acid/pharmacology/therapeutic use ; *Muscle, Skeletal/drug effects/metabolism/physiology ; *Aging/drug effects/physiology ; Mice, Inbred C57BL ; Mice ; Male ; Sarcopenia ; Proto-Oncogene Proteins c-akt/metabolism ; }, abstract = {Ageing leads to changes in body composition, including increased adiposity and reduced skeletal muscle mass and force. The alterations in ageing skeletal muscle result from impaired proteostasis driven by factors such as chronic inflammation, hormonal changes and reduced nutrient absorption. Those age-related changes in body composition and skeletal muscle compromise mobility and increase the risk of falls, fractures and metabolic disorders. Tauroursodeoxycholic acid (TUDCA), a bile acid with known benefits in chronic diseases, has been shown by our group to improve cognition and metabolic homeostasis in ageing and Alzheimer's disease mouse models. Interestingly, in previous studies, TUDCA treatment was also associated with increased skeletal muscle mass in ageing mice, leading us to hypothesize that TUDCA could target skeletal muscle to reduce age-related muscle loss. To explore this, we treated 18-month-old C57BL/6 mice with TUDCA or vehicle for 20 days, using 3-month-old mice as a young control group. We demonstrate that TUDCA treatment decreases body weight while increasing skeletal muscle mass, restores muscle fibre size and preserves functional integrity. Additionally, TUDCA enhances skeletal muscle insulin sensitivity through increased AKT activation and reduces tissue inflammation. Such improvements collectively support the restoration of skeletal muscle proteostasis, as indicated by increased protein synthesis and phosphorylation of key anabolic signalling pathways, including ribosomal protein S6 kinase beta-1 (P70S6K) and eukaryotic translation initiation factor 4E-binding protein 1 (4EBP1). These findings contribute to a better understanding of TUDCA's actions on skeletal muscles of ageing mice and highlight its role as a promising strategy against age-related muscle loss. KEY POINTS: Tauroursodeoxycholic acid (TUDCA) treatment attenuates skeletal muscle loss in ageing mice. TUDCA improves skeletal muscle insulin sensitivity and restores AKT signalling. TUDCA exerts an anti-inflammatory effect in skeletal muscle of ageing mice. TUDCA emerges as a potential therapy for age-related skeletal muscle loss.}, } @article {pmid42139977, year = {2026}, author = {Soni, U and Pujari, R}, title = {Gentisic acid confers multimodal neuroprotection in experimental Alzheimer's disease by targeting oxidative stress, neuroinflammation, and protein aggregation.}, journal = {Phytomedicine : international journal of phytotherapy and phytopharmacology}, volume = {156}, number = {}, pages = {158276}, doi = {10.1016/j.phymed.2026.158276}, pmid = {42139977}, issn = {1618-095X}, mesh = {Animals ; *Alzheimer Disease/drug therapy/chemically induced/metabolism ; *Neuroprotective Agents/pharmacology/therapeutic use ; *Oxidative Stress/drug effects ; Humans ; Aluminum Chloride ; *Gentisates/pharmacology/therapeutic use ; Rats, Wistar ; Blood-Brain Barrier/drug effects/metabolism ; Male ; Rats ; Disease Models, Animal ; Amyloid beta-Peptides/metabolism ; Antioxidants/pharmacology ; Protein Aggregates/drug effects ; Galactose ; Neuroinflammatory Diseases/drug therapy ; Cell Line, Tumor ; Aluminum Compounds ; }, abstract = {BACKGROUND: Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by cognitive decline associated with oxidative stress, neuroinflammation, cholinergic dysfunction, and accumulation of amyloid-β (Aβ) and hyperphosphorylated tau (p-tau). Given the multifactorial nature of AD, phytochemicals with multi-target pharmacological properties are of growing therapeutic interest. Gentisic acid (GA; 2,5-dihydroxybenzoic acid) possesses established antioxidant and anti-inflammatory activities; however, its potential relevance in AD has not been comprehensively evaluated.

PURPOSE: This study investigated the neuroprotective potential of gentisic acid against Alzheimer-like pathology using integrated in vitro and in vivo experimental models.

STUDY DESIGN: A preclinical experimental study combining cell-based assays and an aluminium chloride (AlCl3) and D-galactose (D-Gal)-induced rat model of AD-like neurodegeneration was conducted.

METHODS: Blood-brain barrier (BBB) permeability of GA was assessed using a PAMPA-BBB assay. Neuroprotective effects were examined in AlCl₃-exposed SH-SY5Y cells. In vivo, Wistar rats received AlCl₃ and D-Gal to induce cognitive and biochemical alterations, followed by oral GA treatment. Behavioral paradigms such as open field, Morris water maze, novel object recognition, elevated plus maze and Y-maze tests were employed to assess spatial learning, recognition memory, and anxiety-like behavior. Oxidative stress markers, antioxidant enzymes, acetylcholinesterase activity, monoaminergic neurotransmitters, brain-derived neurotrophic factor (BDNF), pro-inflammatory cytokines, amyloid beta, and hyperphosphorylated tau protein levels were quantified. Histopathological evaluation of hippocampal and cortical regions was performed.

RESULTS: GA demonstrated adequate BBB permeability and concentration-dependent protection against AlCl₃-induced cytotoxicity in SH-SY5Y cells. In the rat model, GA (10, 30, and 100 mg/kg, per oral (p.o.) improved cognitive performance and attenuated anxiety-like behavior. Treatment with GA reduced lipid peroxidation (malondialdehyde), restored antioxidant defenses (superoxide dismutase, catalase and reduced glutathione), inhibited acetylcholinesterase activity, and normalized monoaminergic neurotransmitters (serotonin and dopamine). GA further elevated BDNF levels and suppressed pro-inflammatory cytokines (tumor necrosis factor-alpha and interleukin-1 beta). Notably, GA decreased cerebral Aβ and p-tau accumulation and preserved hippocampal and cortical architecture.

CONCLUSION: Gentisic acid exerts multi-modal neuroprotective effects, including antioxidant, anti-inflammatory, anti-cholinesterase, and anti-amyloidogenic actions, in experimental models of AD. These findings support its potential as a phytochemical candidate for further development in the prevention or adjunctive management of AD.}, } @article {pmid42141012, year = {2026}, author = {Gorin, BI and Pozdnyakov, SO and Potapova, KA and Tukhovskaya, EA and Gorchakov, DS}, title = {Efficacy and safety of DMB-I (latrepirdine) therapy in mild to moderate dementia in Alzheimer's disease: results of a multicenter, double-blind, randomized, placebo-controlled, clinical trial in three parallel groups.}, journal = {Scientific reports}, volume = {16}, number = {1}, pages = {}, pmid = {42141012}, issn = {2045-2322}, mesh = {Humans ; Female ; Male ; *Alzheimer Disease/drug therapy ; Double-Blind Method ; Aged ; Aged, 80 and over ; Treatment Outcome ; Quality of Life ; Middle Aged ; *Indoles/therapeutic use/adverse effects/administration & dosage ; Activities of Daily Living ; }, abstract = {Alzheimer’s disease (AD) is one of leading dementia causes, affecting over 50 million people worldwide. A multicenter, double-blind, randomized, placebo-controlled clinical trial in three parallel groups was conducted to evaluate efficacy and safety of Latrepirdine polymorph DMB-I in 26-week treatment of dementia in patients with AD. 135 patients of both sexes aged 60 to 90 years were randomized into three groups: DMB-I + placebo, 30 mg/day; DMB-I, 60 mg/day and Placebo. Treatment efficacy was assessed using Alzheimer’s disease Assessment Scale cognitive subscale (ADAS-cog), Mini-Mental State Examination (MMSE-2), quality of life questionnaire (QOL-AD), Clinical Global Impression scale (CGI) and Instrumental Activities of Daily Living score (IADL). Clinical parameters and adverse events (AEs) also assessed. The efficacy of DMB-I at a dose of 60 mg/day was demonstrated by assessing the primary efficacy criterion, namely, a significant change in the ADAS-cog score after 26 weeks of treatment compared with baseline. Severity of cognitive impairment dynamics on ADAS-cog, CGI and LADL scales was significantly improved in groups receiving DMB-I at both doses, compared with placebo. AEs overall incidence was similar between DMB-I and Placebo groups. 26-week therapy with DMB-I at both doses demonstrated efficacy and favorable safety profile. 60 mg/day dose was selected as optimal dose for further studies. Study retrospectively registered on Clinicaltrials.gov on February 27, 2024, NCT06292351.}, } @article {pmid42141074, year = {2026}, author = {Cai, C and Chong, YS and Liang, H and Hu, Y and Hu, Q and Chen, J and Sajikumar, S and Liu, F}, title = {Simvastatin rescues cognitive impairment in an Aβ1-42-induced model of Alzheimer's disease through the HDAC2-BDNF signaling pathway.}, journal = {Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology}, volume = {}, number = {}, pages = {}, pmid = {42141074}, issn = {1740-634X}, support = {2021J011433//Natural Science Foundation of Fujian Province (Fujian Provincial Natural Science Foundation)/ ; 82201668//National Natural Science Foundation of China (National Science Foundation of China)/ ; MOH-000641-00//MOH | National Medical Research Council (NMRC)/ ; MOH-001883-00//MOH | National Medical Research Council (NMRC)/ ; }, abstract = {Statins, renowned for their efficacy in treating cardiovascular diseases, have emerged as potential therapeutic agents for the prevention of Alzheimer's disease (AD). Among them, simvastatin (SV) has attracted considerable attention for its reported cognitive benefits in AD. However, the precise mechanisms by which SV modulates spatial cognitive function in AD remain unclear. In the present study, we used an AD model induced through intracerebroventricular administration of Aβ1-42 in male C57BL/6 mice. The cognitive performance were assessed using the Morris Water Maze (MWM) test, the Y-maze and the Novel Object Recognition (NOR) test. HDAC2 and BDNF expression levels were analyzed by Western blotting. Chromatin immunoprecipitation (ChIP) assays were performed to examine histone H4 acetylation (Ac-H4K5) at Bdnf promoters. Our results showed that SV treatment reversed cognitive impairments induced by Aβ1-42. Aβ1-42 administration increased HDAC2 expression, reduced histone H4 acetylation, and decreased BDNF levels in the dorsal hippocampus (dHPC), all of which were restored by SV treatment. Notably, viral overexpression of HDAC2 abolished the beneficial effects of SV, underscoring the critical role of HDAC2 in mediating its actions. Furthermore, blockade of BDNF signaling using TrkB-Fc attenuated the behavioral improvements induced by SV. In addition, SV treatment ameliorated Aβ1-42-induced deficits in neurogenesis and long-term potentiation (LTP). Together, these findings highlight the therapeutic role of SV in AD through epigenetic and synaptic mechanisms, and support further investigation into its clinical applicability.}, } @article {pmid42141084, year = {2026}, author = {Shahat, EA and Ayoub, IM and Bakr, RO and Gad, HA and Eldahshan, OA and Singab, ANB}, title = {Comparative analysis of volatile composition and anticholinesterase activity of Egyptian Hedychium coronarium and Alpinia zerumbet using chemometric assessment of extraction techniques.}, journal = {Scientific reports}, volume = {16}, number = {1}, pages = {}, pmid = {42141084}, issn = {2045-2322}, mesh = {*Alpinia/chemistry ; *Cholinesterase Inhibitors/pharmacology/chemistry/isolation & purification ; *Oils, Volatile/chemistry/pharmacology/analysis ; *Zingiberaceae/chemistry ; Plant Leaves/chemistry ; Gas Chromatography-Mass Spectrometry ; Antioxidants/chemistry/pharmacology ; Rhizome/chemistry ; *Volatile Organic Compounds/analysis/chemistry ; Principal Component Analysis ; }, abstract = {Hedychium coronarium and Alpinia zerumbet are rhizomatous plants belonging to the family Zingiberaceae. They are rich in essential oils. Hydrodistillation and headspace (HS) were employed for the extraction of the essential oils from the leaves and rhizomes of both plants. Essential oils were then analysed by GC/MS and the obtained results were subjected to chemometric analysis. The oil samples obtained by hydrodistillation were tested for their antioxidant and anti-cholinesterase activities using oxygen radical antioxidant capacity assay and colorimetric inhibition kit, respectively. Hydro-distilled oil from H. coronarium leaves showed the presence of forty-seven compounds (97.73%) compared to sixteen compounds (99.17%) in the HS volatiles. Meanwhile, hydro-distilled oil from H. coronarium rhizomes showed the presence of thirty-nine components (95.84%) compared to fifteen compounds (98.68%) in the HS volatiles with 1,8-cineole (41.69% and 58.41%) as the major component in both samples. A. zerumbet leaves oil showed the presence of nineteen compounds (94.54%) in the hydrodistilled oil and twenty-one compounds (99.53%) in the HS volatiles. Besides, the rhizomes hydrodistilled essential oil showed twenty-three compounds (91.85%) and sixteen compounds (100%) in the HS with 1,8-cineole (20.78% and 23.63%) representing the major component in both samples. Chemometric analysis of the results provided a clear and statistically robust discrimination between the hydrodistilled and headspace-isolated oil samples demonstrating that extraction method is a primary determinant of volatile profile. Principal component analysis score plot explained 75% of total variance and distinctly separated samples into four main clusters with key discriminating components β-pinene, and caryophyllene were the major responsible for the segregation of H. coronarium leaves by headspace and hydrodistillation extraction methods, respectively, besides, 1,8-cineole accounted for the discrimination of H. coronarium rhizomes extracted by hydrodistillation. Hierarchial cluster analysis (HCA) fully supported this classification, confirming consistent grouping patterns across both analyses. Importantly, A. zerumbet oils from both extraction methods clustered closely, indicating compositional stability, whereas H. coronarium samples showed strong method-dependent divergence. A. zerumbet rhizomes oil showed the strongest activity as anticholinesterase with IC50 of 0.54 ± 0.02 µg/mL while H. coronarium rhizomes showed the strongest antioxidant activity (10.06 ± 0.16 TE µM/L). H. coronarium leaves and A. zerumbet rhizomes showed anticholinesterase and antioxidant activities to such an extent that may make them a useful adjuvant in the treatment of cognitive diseases such as Alzheimer's.}, } @article {pmid42142416, year = {2026}, author = {Chiba, Y and Ide, K and Suzuki, S and Taguri, M and Suzuki, H and Abe, K and Yoshimi, A and Okuda, T and Saito, K and Mizushima, S and Yamanaka, T and Hishimoto, A and Sakurai, T and Arai, H and Asami, T and Odawara, T}, title = {Multimodal intervention benefits: Responder analysis of J-MINT PRIME Kanagawa trial.}, journal = {Archives of gerontology and geriatrics}, volume = {149}, number = {}, pages = {106289}, doi = {10.1016/j.archger.2026.106289}, pmid = {42142416}, issn = {1872-6976}, mesh = {Humans ; Female ; *Dementia/prevention & control ; Aged ; Male ; Combined Modality Therapy ; Mental Status and Dementia Tests ; Aged, 80 and over ; Cognitive Enhancement ; }, abstract = {INTRODUCTION: The J-MINT PRIME Kanagawa trial was an 18-month multimodal intervention (incorporating exercise, nutrition, and metabolic management) for dementia prevention. Because the primary analysis showed no significant benefits, we performed an exploratory responder analysis to identify responsive subpopulations.

METHODS: We analyzed the Full Analysis Set comprising 188 participants. Classification and regression tree (CART) analysis, applied to the intervention arm, identified baseline predictors of cognitive improvement. These rules were then applied to the entire cohort to evaluate treatment effects on the Mini-Mental State Examination (MMSE) using fully adjusted mixed-effects models for repeated measures (MMRM).

RESULTS: CART identified a "Target Group" (N = 108) characterized by baseline profiles such as an MMSE score < 28 or specific metabolic ranges (e.g., LDL-C < 135 mg/dL). Within this target group, the intervention significantly preserved MMSE trajectories compared with the control group (group × time interaction, P = 0.022). In contrast, the Non-Target Group (N = 80), consisting of high-functioning individuals (MMSE ≥ 28), exhibited no significant group × time interaction.

DISCUSSION: Multimodal interventions may effectively preserve global cognition in older adults with sub-threshold cognitive decline. Careful targeting of appropriate populations, while considering potential longitudinal measurement artifacts (e.g., practice effects), is essential. These findings provide a hypothesis-generating framework that warrants external validation in future prevention trials.}, } @article {pmid42142451, year = {2026}, author = {Razavi, A and Hou, J and Lin, SJ and Zhang, C and Kremen, WS and Fennema-Notestine, C and Elman, J and Holmans, P and Faraone, SV and Gaiteri, C and Hess, JL and Glatt, SJ}, title = {Predicted brain-regional gene expression patterns in individuals living with Alzheimer's disease.}, journal = {Neurobiology of aging}, volume = {166}, number = {}, pages = {29-40}, pmid = {42142451}, issn = {1558-1497}, mesh = {*Alzheimer Disease/genetics/metabolism/diagnosis ; Humans ; *Brain/metabolism ; *Transcriptome/genetics ; *Gene Expression/genetics ; Biomarkers/blood ; Female ; Disease Progression ; Male ; Aged ; }, abstract = {Studying brain gene expression in Alzheimer's Disease (AD) remains difficult as postmortem brain is difficult to access, cannot be used to guide donor treatment, may be confounded by environmental factors before and after death, and is difficult to link to early AD states or disease progression. To circumvent these limitations, several studies have tested blood transcriptome biomarkers for AD. However, gene-expression levels in the blood have limited correlation with those in the brain. To evaluate the potential of monitoring Alzheimer's progression with peripheral data, we used transcriptome-imputation to identify brain-region-specific AD-associated gene-expression differences in cohorts with blood-based transcriptome data. This approach provides a high-resolution image of AD-associated molecular differences in the brains of individuals actively living with disease. We analyzed eight AD studies (777 AD cases, 779 cognitively unimpaired controls), imputing transcriptomes in 10 brain regions via the Brain Gene Expression and Network Imputation Engine (BrainGENIE). Hundreds of differentially expressed genes (DEGs) associated with AD were identified in nine brain regions, with anterior cingulate cortex and amygdala showing the most differential expression. AD-associated genes were enriched in pathways such as proteostasis, mitochondrial dysfunction, and immune activation. We observed significant yet moderate concordance between imputed AD-associated changes and those directly measured in the dorsolateral prefrontal cortex and cerebellum. These transcriptomic changes can guide future in vitro studies focused on pathogenesis or be targets of novel therapeutic development. In conclusion, we demonstrated the scope and utility of brain expression imputation from the peripheral transcriptome, laying the groundwork for biomarker discovery and prospective AD studies.}, } @article {pmid42142620, year = {2026}, author = {Shang, X and Chen, SY and Zhang, XY and Regina, I and Zhang, T and Luo, J and Yan, YZ and Qiao-yuanYao, and Tong, F and Pan, LH}, title = {Insulin in brain: The physiological functions and therapeutic insights for neurodegenerative diseases.}, journal = {Life sciences}, volume = {398}, number = {}, pages = {124468}, doi = {10.1016/j.lfs.2026.124468}, pmid = {42142620}, issn = {1879-0631}, mesh = {Humans ; *Insulin/metabolism/therapeutic use/physiology/administration & dosage ; *Brain/metabolism/drug effects ; Animals ; *Neurodegenerative Diseases/drug therapy/metabolism/physiopathology ; Neuroprotective Agents/pharmacology ; Alzheimer Disease/drug therapy/metabolism ; Insulin Resistance ; Receptor, Insulin/metabolism ; Parkinson Disease/drug therapy/metabolism ; }, abstract = {This review highlight the function of insulin in the central nervous system in addition to its role in the periphery. The cerebral distribution and mechanisms of insulin and its receptor isoforms are reviewed in detail. We emphasize the essential roles of insulin in the maintenance of cerebral glucose homeostasis, modulation of cognitive performance, regulation of appetite, promotion of cerebrovascular angiogenesis, and exertion of neuroprotective effects. We demonstrate how insulin resistance exacerbates characteristic neuropathological features in Alzheimer's disease (AD) and Parkinson's disease (PD), while insulin-based interventions ameliorate these pathologies through multiple mechanisms including increasing the activity of insulin-degrading enzyme, suppressing Aβ neurotoxicity, and reducing α-synuclein deposition. The review also systematically examines the neuroprotective effects of insulin sensitizers and their potential to reduce the risk of AD, while noting the complexity of their bidirectional regulatory role in PD, which warrants further investigation. Notably, intranasal insulin administration emerges as a promising non-invasive therapeutic approach that bypasses the blood-brain barrier via olfactory and trigeminal pathways, suggesting significant potential for cognitive enhancement and neuropathological mitigation. Nonetheless, it must be noted that the optimal dosage, long-term safety, and sustained efficacy of insulin therapy remain unclear, and the current evidence is derived primarily from preclinical studies or small-scale clinical trials. In summary, this review paper underscores the critical physiological roles of insulin in the brain and outlines novel therapeutic strategies for using insulin in the treatment of AD and PD.}, } @article {pmid42142765, year = {2026}, author = {Feng, Y and Zhang, C and Wei, Y and Liu, E and Sun, H and Flatt, P and Gault, V and Irwin, N and Hölscher, C and Hao, L and Zhang, Z}, title = {A novel bifunctional peptide predicted to target neuropeptide Y4 and GLP-1 receptors alleviates cognitive deficits in 5 × FAD mice by modulating cGAS-STING-mediated neuroinflammation.}, journal = {Biochemical pharmacology}, volume = {251}, number = {Pt 1}, pages = {118074}, doi = {10.1016/j.bcp.2026.118074}, pmid = {42142765}, issn = {1873-2968}, abstract = {Effective disease-modifying therapies for Alzheimer's disease (AD) remain limited. Glucagon-like peptide-1 receptor (GLP-1R) activation has shown neuroprotective potential in AD, whereas the neuropeptide Y/pancreatic polypeptide-Y4 receptor (NPY/PP-Y4R) axis has been implicated in central homeostasis and inflammatory regulation, although its role in AD remains insufficiently defined. Here, we evaluated a rationally designed bifunctional peptide predicted to target both NPY4R and GLP-1R in 5 × FAD mice and LPS-stimulated BV2 cells. In vivo, NPY4/GLP-1 improved spatial learning and memory, working memory, and exploratory behavior, and was accompanied by reduced hippocampal Aβ burden (P < 0.05), alleviated neuronal injury (P < 0.01), improved synaptic integrity (P < 0.01), and attenuated mitochondrial abnormalities (P < 0.01). These changes were associated with lower hippocampal levels of cytosolic mitochondrial DNA (mtDNA) (P < 0.05), cGAS (P < 0.05), STING (P < 0.05), and phosphorylated IRF3 (P < 0.01), together with decreased IL-1β (P < 0.05) and increased IL-10 (P < 0.05) expression. In LPS-stimulated BV2 cells, NPY4/GLP-1 similarly reduced STING-related signaling (P < 0.05) and inflammatory responses (P < 0.05). Co-treatment with the STING inhibitor C-176 provided additional support for the involvement of STING-associated inflammatory signaling under in vitro inflammatory conditions. Molecular docking suggested that NPY4/GLP-1 may interact with both NPY4R and GLP-1R, providing a structural rationale for its bifunctional design. Collectively, these findings indicate that NPY4/GLP-1 exerts beneficial effects in AD-related models and that these effects are associated with attenuation of mtDNA-cGAS-STING-related neuroinflammatory signaling. This study provides initial evidence supporting further evaluation of this novel bifunctional peptide as a candidate therapeutic strategy for AD.}, } @article {pmid42143322, year = {2026}, author = {Gröbner, LS and Pietrzik, CU}, title = {Transport pathways across the blood-brain barrier for waste clearance and drug delivery.}, journal = {Fluids and barriers of the CNS}, volume = {23}, number = {1}, pages = {}, pmid = {42143322}, issn = {2045-8118}, mesh = {*Blood-Brain Barrier/metabolism ; Humans ; Animals ; *Low Density Lipoprotein Receptor-Related Protein-1/metabolism ; *Drug Delivery Systems ; Biological Transport/physiology ; *Receptors, Transferrin/metabolism ; }, abstract = {The blood-brain barrier (BBB) displays a highly organized and complex structure, which is important for maintaining brain homeostasis and protecting the brain from foreign molecules or pathogens. Receptor-mediated transcytosis (RMT) is one of the main delivery pathways across the BBB for molecules that cannot pass the barrier via, e.g. paracellular diffusion. For understanding the treatment options in neurodegenerative diseases such as Alzheimer´s disease (AD), it is important to investigate transport pathways and mechanisms at the BBB for a potential delivery of drugs, antibodies or other compounds across the BBB. This review provides an overview of the different transport variants across the BBB and how they can be targeted in order to promote internalization or secretion into or out of the brain. Therefore, we want to focus on two characterized proteins: the low-density lipoprotein receptor-related protein 1 (LRP1), which is a key mediator of amyloid β (Aβ) clearance from the brain during AD, and transferrin receptor 1 (TfR1), which is already used as a target for antibody-delivery into the brain. Additionally, this review discusses two other important proteins, which have been less frequently addressed in research regarding transport mechanisms: P-glycoprotein (P-gp) as another transporter at the BBB and proprotein convertase subtilisin/kexin type 9 (PCSK9), a well-known regulator of cholesterol homeostasis which promotes the degradation of the low-density lipoprotein receptor (LDLR) and LRP1. For these four main proteins, we aim to highlight existing approaches for targeting or inhibiting the aforementioned receptors or proteins. The approaches enable a higher penetration of the BBB, a better distribution in the brain, and ultimately fewer side effects of antibodies or nanoparticles. Here, we include lecanemab, trontinemab, dual TfR/CD98hc shuttles, evolocumab and alirocumab, immunoliposomes and other nanoparticles targeting TfR1 or LRP1. We will further highlight approaches which differ from these common ideas and demonstrate the current state of the art regarding drug delivery and waste clearance across the BBB.}, } @article {pmid42144109, year = {2026}, author = {Loukil, I and Vachon, A and Çaku, A and Plourde, M}, title = {Krill oil increases plasma omega-3 fatty acids more than fish oil in healthy adults: a double-blind randomized controlled trial.}, journal = {The American journal of clinical nutrition}, volume = {124}, number = {1}, pages = {101346}, doi = {10.1016/j.ajcnut.2026.101346}, pmid = {42144109}, issn = {1938-3207}, abstract = {BACKGROUND: Omega-3 fatty acids (ω-3 FAs), particularly EPA and DHA, are recognized for their health benefits. However, their circulating levels after supplementation may be modulated by several factors, including sex, carriage of the apolipoprotein E ε4 (APOE4) allele, and the chemical form of the supplement. Krill oil delivers ω-3 FAs primarily as phospholipids, whereas fish oil provides them as triglycerides.

OBJECTIVES: This study aimed to compare EPA and DHA concentrations after supplementation with krill oil and fish oil and assess whether sex and APOE4 genotype modify responses to supplementation.

METHODS: This double-blind, randomized clinical trial included 72 healthy adults (53 females, 19 males) matched for age and BMI. Participants received 1.1 g/d ω-3 FAs through either krill oil (n = 36) or fish oil (n = 36) for 12 wk. Plasma FAs were measured at baseline and at weeks 1, 2, 4, and 12 by GC-flame ionization detection. Differences in plasma ω-3 FAs concentrations by treatment, sex, and APOE4 status were analyzed.

RESULTS: Time-by-treatment interactions were significant for plasma delta over baseline concentrations of EPA (P = 0.0001) and DHA (P = 0.005), with krill oil resulting in ∼1.5-fold higher Δ EPA and Δ DHA compared with fish oil. The time-by-sex interaction was significant only for EPA (P = 0.026), with females having a 1.5-fold greater increase than males at 12 wk. After supplementation with either krill oil or fish oil, APOE4 carriers had 3-fold and 1.6-fold higher EPA and DHA, respectively, compared with baseline; however, these increases were not significantly different from those found in noncarriers.

CONCLUSIONS: Krill oil increased plasma ω-3 FAs more than fish oil, regardless of APOE4 genotype. Individuals with higher ω-3 FA requirements may achieve adequate enrichment with lower doses of krill oil compared with fish oil supplementation. This trial was registered at clinicaltrials.gov as NCT04279743.}, } @article {pmid42144687, year = {2026}, author = {Zhao, Q and Yu, Y and Wang, F and Wang, Y and Shao, P and Zhao, L}, title = {TARDBP Mediates the MAP3K11/SLC3A2/GPX4 Axis in Alzheimer's Disease Rats by Enhancing KRAS mRNA Stability.}, journal = {Journal of cellular and molecular medicine}, volume = {30}, number = {10}, pages = {e71181}, pmid = {42144687}, issn = {1582-4934}, support = {HAB202113//Huai'an Natural Science Research Program/ ; }, mesh = {Animals ; *Alzheimer Disease/metabolism/genetics/pathology ; Rats ; *Proto-Oncogene Proteins p21(ras)/genetics/metabolism ; PC12 Cells ; *RNA Stability/genetics ; *Phospholipid Hydroperoxide Glutathione Peroxidase/metabolism/genetics ; Reactive Oxygen Species/metabolism ; *DNA-Binding Proteins/metabolism/genetics ; Hippocampus/metabolism/pathology ; Male ; Amyloid beta-Peptides ; Iron/metabolism ; Ferroptosis/genetics ; Disease Models, Animal ; RNA, Messenger/genetics ; Signal Transduction ; Neurons/metabolism ; Rats, Sprague-Dawley ; }, abstract = {Ferroptosis is an emerging pathological mechanism in Alzheimer's disease (AD). The aim of the present study was to investigate the potential mechanisms by which TARDBP is involved in AD by promoting ferroptosis. An AD rat model was established by injecting homocysteine (Hcy). Memory function was assessed using the Morris water maze test and contextual fear conditioning test. Hippocampal neurons' morphology was observed by HE staining, and intracellular iron deposition in the hippocampus was evaluated by Perls' blue staining. PC12 cells were treated with 20 μM Aβ1-42 to establish an AD cell model in vitro. Cell viability was measured by MTT assay; LDH release, intracellular ROS levels and Fe[2+] concentrations were determined. The mRNA stability of KRAS was assessed by actinomycin D assay. Activation of the MAP3K11/SLC3A2/GPX4 pathway was assessed by Western blot. Treatment with Fer-1 or down-regulation of TARDBP improved memory function and reduced intracellular iron deposition in the hippocampus of AD rats. Furthermore, these interventions inhibited Aβ1-42-induced PC12 cell damage, ROS production and iron accumulation. Mechanistically, down-regulating TARDBP reduced the mRNA stability of KRAS, inhibited MAP3K11 expression and subsequently promoted the expression of SLC3A2 and GPX4. Conversely, up-regulation of KRAS reversed the protective effects induced by TARDBP knockdown in both AD rats and Aβ1-42-induced PC12 cells. TARDBP promotes the development of AD by enhancing the mRNA stability of KRAS, thereby mediating the MAP3K11/SLC3A2/GPX4 axis to induce ferroptosis.}, } @article {pmid42145109, year = {2026}, author = {Saxena, P and Kothiyal, P and Ratan, P}, title = {Evaluation of neuroprotective effects of Pyracantha crenulata (D. Don) M. Roem against aluminium chloride induced memory impairment of rats.}, journal = {Neurological research}, volume = {}, number = {}, pages = {1-14}, doi = {10.1080/01616412.2026.2673060}, pmid = {42145109}, issn = {1743-1328}, abstract = {Pyracantha crenulata, traditionally used in Himalayan folk medicine, valued for enhancing vitality, mental clarity, and combating age-related cognitive decline due to its antioxidant constituents.

AIM: This study evaluated the neuroprotective effect of hydroalcoholic extract of P. crenulata against aluminium chloride (AlCl3)-induced Alzheimer's disease in rats.

MATERIALS AND METHODS: Alzheimer's pathology was induced using AlCl3, and rats were treated with P. crenulata extract (250 and 500 mg/kg) for 21 days. Cognitive and behavioural performance were assessed using the Morris Water Maze (MWM) and Elevated Plus Maze (EPM). Biochemical parameters, including oxidative stress markers (SOD), cholinesterase activity (AChE), and myeloperoxidase levels (MPO), were measured. Histopathological examination of the hippocampus and cerebral cortex was conducted.

RESULTS: Aluminium intoxication led to marked deficits in learning and memory, as evidenced by performance in the Morris Water Maze and Elevated Plus Maze tests. Treatment with P. crenulata extract significantly enhanced spatial and long-term memory in a dose-dependent manner, with the higher dose producing the most pronounced improvement.

CONCLUSION: The findings of this study highlight the notable neuroprotective effects of P. crenulata, demonstrated through modulation of biochemical parameters and suppression of amyloid precursor protein and Tau, key pathological hallmarks of Alzheimer's disease, further validated by histopathological evidence.}, } @article {pmid42145110, year = {2026}, author = {Wimo, A and Jönsson, L}, title = {[Health economic aspects of dementia].}, journal = {Lakartidningen}, volume = {123}, number = {}, pages = {}, pmid = {42145110}, issn = {1652-7518}, mesh = {Humans ; *Dementia/economics/diagnosis/epidemiology/therapy ; Sweden/epidemiology ; Alzheimer Disease/economics/diagnosis ; Cost of Illness ; Health Care Costs ; Cost-Benefit Analysis ; }, abstract = {The societal costs of dementia in Sweden are very high: about SEK 90-100 billion per year. A purely demographic projection to 2050 gives a cost increase of about 80%. In addition to the costs, dementia also entails a loss of life expectancy for those with dementia and of quality of life for those affected and their relatives. At present, it is not possible to assess whether the antibody treatment against Alzheimer's disease is cost-effective in Sweden because no price is yet available. Blood-based biomarkers for Alzheimer's disease and other diagnostic methods, if included in the pricing basis for new drugs, can be a valuable addition to cost-effectiveness analyses.}, } @article {pmid42145619, year = {2026}, author = {Sherva, R and Bayly, H and Zhang, R and Harrington, K and Mez, J and Miller, MW and Tsuang, D and Wolf, E and Zeng, Q and Le Guen, Y and Tejeda, M and , and , and Gaziano, JM and Panizzon, MS and Hauger, RL and Merritt, VC and Farrer, LA and Logue, MW}, title = {A Genome-wide Association Study of Alzheimer's Disease and Dementia in a Large Multi-ancestry Military Cohort Identifies Many New Dementia-Associated Loci.}, journal = {medRxiv : the preprint server for health sciences}, volume = {}, number = {}, pages = {}, pmid = {42145619}, abstract = {INTRODUCTION: Biobank-scale cohorts of individuals with genetic data and diagnoses of Alzheimer's disease and related dementias (ADRD) have facilitated the discovery of additional risk loci via meta-analysis, with existing cohorts assembled specifically for ADRD genetic discovery. Cross-ancestry meta-analyses have further elucidated the overall genetic architecture of these dementias. Here, we include for the first time the European ancestry (EA) and Hispanic ancestry (HA) subset of the VA Million Veterans Program (MVP) along with the African ancestry (AA) MVP participants in a meta-analysis with a large-scale EA and AA meta-analysis.

METHODS: Independent genome-wide association studies (GWASs) were conducted in MVP participants using four phenotypes derived from electronic medical records and surveys: ADRD, prescriptions for common dementia medications, and self-reported maternal and paternal history of dementia (dementia by proxy). These GWASs were repeated in the EA, AA, and HA cohorts. MVP ancestry-specific and cross-ancestry meta-analyses were conducted. These were then meta-analyzed with existing GWAS results. Functionality of the peak variants was explored using brain-derived gene expression data and co-localization analysis.

RESULTS: Apart from the APOE region, 17, 4, and 3 genome-wide significant (GWS) loci were observed in the MVP EA, AA, and HA meta-analyses, respectively. When we meta-analyzed these with consortium results, we observed 72 loci in the EA GWAS, and 62 lead loci in the cross-ancestry meta-analysis. While most of these loci were known, 27 genes/regions were identified containing variants surpassing genome-wide significance for the first time: 7 EA specific, 12 in the cross-ancestry meta-analysis, and 8 driven by AA and HA cohorts. Several of these are members of pathways containing established ADRD risk genes, and several of the peak SNPs showed evidence for eQTL effects on their respective genes. Several of the novel SNPs showed significant eQTL effects in brain-derived mRNA-seq experiments. Additionally, there was a significant differential expression of the novel gene PAX7 in ADRD cases and controls.

DISCUSSION: MVP represents a large and unique primarily male cohort comprised of US Veterans from a range of backgrounds with a unique set of environmental exposures. The results generated here demonstrate the utility of biobank level cohorts for AD genetic discovery. Furthermore, our discovery of ADRD genes was enhanced by the inclusion of MVP data that provided an increase of underrepresented ancestry groups in contrast to prior cross ancestry GWASs. The new AD risk loci identified present potential new targets for dementia treatment confirmed that future large-scale analyses of AD genetic risk and prediction will be enhanced by the inclusion of MVP data.}, } @article {pmid42145636, year = {2026}, author = {Lorenzi, M and Custo, A and Frisoni, GB and Garibotto, V}, title = {A data-driven Alzheimer's disease progression simulator for retrospective validation and prospective Phase III power design.}, journal = {medRxiv : the preprint server for health sciences}, volume = {}, number = {}, pages = {}, doi = {10.64898/2026.05.03.26352317}, pmid = {42145636}, abstract = {Anti-amyloid immunotherapies have recently demonstrated the first significant slowing of cognitive decline in Alzheimer's disease (AD), yet clinical benefit varies markedly across drugs and scales with the completeness of amyloid clearance. Pharmacokinetic/pharmacodynamic (PK/PD) models are currently the standard tool for trial simulation, but they typically operate on single biomarkers and rely on drug-concentration assumptions, leaving the multi-scale cascade from amyloid clearance through tau, neurodegeneration, and cognition largely unmodelled. No existing framework has been jointly validated against the quantitative outcomes of multiple real-world phase III trials, spanning clearance kinetics, multi-modal biomarker trajectories, and statistical power. We present a trial simulation platform based on SimulAD, a disease progression model trained exclusively on longitudinal observational data from ADNI, with no access to trial-arm labels or drug-specific outcomes. SimulAD encodes intervention as piecewise amyloid clearance terms within a latent ordinary differential equation system that jointly governs amyloid, tau, structural MRI, and cognitive trajectories under the amyloid cascade hypothesis. We retrospectively simulated six landmark phase III anti-amyloid trials (TRAILBLAZER-ALZ2, CLARITY AD, EMERGE and ENGAGE, GRADUATE I and GRADUATE II) using a single trained model with trial-specific calibration limited to amyloid clearance kinetics. SimulAD reproduced published mean centiloid reductions within 5% error across all six trials and generated CDR-SB distributions broadly consistent with reported placebo and treated-arm outcomes. In a retrospective power analysis, calibrated simulations separated the three positive from the three null trials, with EMERGE near the decision boundary and ENGAGE and both GRADUATE trials below it. Across trials, higher amyloid-clearance rates were associated with larger calibrated clinical effects and lower estimated sample sizes. These results establish SimulAD as a valid disease-progression-centric trial simulator providing quantitative guidance on sample size planning and treatment kinetics optimisation that is grounded in the full multi-modal biomarker cascade of AD.}, } @article {pmid42146610, year = {2026}, author = {Shiferaw, TG and Sarkar, S and Baker, KM and Wooldridge, RS and Binfet, HM and Prozapas, VN and Ogbu, CP and Schepmoes, AA and Attah, IK and Niemeyer, CS and Sprenger, KG and Hassell, JE and Eckel, RH and Melchior, JT and Bruce, KD}, title = {ApoE Lipidation State Directs Immunometabolic Reprogramming of Human Microglia.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, doi = {10.64898/2026.05.04.722733}, pmid = {42146610}, issn = {2692-8205}, abstract = {INTRODUCTION: ApoE4 is the strongest genetic risk factor for Alzheimer's disease (AD). Emerging evidence suggests that ApoE4 increases AD risk by disrupting microglial metabolism and function. However, whether ApoE lipidation state contributes to microglial dysfunction remains poorly understood.

METHODS: Human microglia were treated with lipid-free or lipid-bound ApoE3 or ApoE4. Label-free live-cell holotomography and global proteomics were used to assess isoform- and lipidation-specific effects on lipid droplet dynamics, mitochondrial morphology, and microglial phenotype.

RESULTS: ApoE4 treatment resulted in fewer but enlarged lipid droplets and increased mitochondrial fragmentation compared to ApoE3, effects that were enhanced by lipid-bound ApoE4. Proteomic analyses revealed a strong type I interferon response in cells exposed to lipid-free ApoE, which was exacerbated by lipid-free ApoE4.

DISCUSSION: These findings indicate that lipid-bound ApoE4 drives metabolic reprogramming, whereas lipid-free ApoE4 promotes inflammatory signaling, identifying ApoE lipidation as a critical modifier of ApoE4-associated AD risk.}, } @article {pmid42146614, year = {2026}, author = {Lu, W and Caulfield, TR and Lee, E and Jeevaratnam, S and Wang, N and Bu, G and Kanekiyo, T and Li, Y}, title = {Discovery of a CI-994 derivative as a dual modulator of class I HDACs and Wnt/β- catenin signaling for Alzheimer's disease therapy.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {42146614}, issn = {2692-8205}, abstract = {Alzheimer's disease (AD) is a multifactorial disease with mixed pathologies. Consequentially, drugs targeting multiple pathological processes may offer synergistic benefits. While histone deacetylase (HDAC) inhibitors have demonstrated efficacy in alleviating AD-related pathologies in animal models, the neuroprotective Wnt/β-catenin signaling pathway remains compromised in AD brain. CI-994 is a class I HDAC inhibitor containing N-(2-aminophenyl)-benzamide. Our recent studies indicate that CI-994 is also an activator of Wnt/β-catenin signaling by stabilizing Wnt co-receptor LRP6. We herein use CI-994 as a scaffold to develop novel potent dual modulators of class I HDACs and Wnt/β-catenin signaling for AD therapy. Our lead compound, W2A-28, selectively inhibits class I HDAC1, 2 and 3 with IC50 values of 0.51 μM, 0.68 μM, and 0.22 μM, respectively, and shows no inhibitory activities on other HDACs. Furthermore, W2A-28 potently activates Wnt reporter activity with an EC50 value of 1.61 μM in Wnt-3A-expressing HEK293 cells. As expected, activation of Wnt/μ-catenin signaling by W2A-28 is associated with elevated LRP6 protein level. Importantly, W2A-28 displays excellent microsomal stability in both mouse and human liver microsomal stability assays, alongside high permeability and a lack of active efflux in MDR1-MDCKII models. Critically, W2A-28 treatment significantly enhances histone acetylation, activates Wnt/β-catenin signaling, and suppresses tau phosphorylation in AD patient-specific cerebral organoids carrying APOEε4/ε4 or APOEε3/ε4 with PSEN1 M146V mutation. Our findings position W2A-28 as a promising multi-target drug candidate for AD therapy.}, } @article {pmid42146852, year = {2026}, author = {D'Amelio, C and Feroleto, C and Caligiuri, C and Li Puma, DD and De Chiara, G and Paoletti, I and Codazzi, C and D'Alelio, F and Miraglia, F and Pappalettera, C and Nucci, L and Frasca, F and Ventura, L and Manca, A and Morrone, M and Leone, L and Deriu, F and Morotti, M and Grassi, C and Vecchio, F and Podda, MV}, title = {EEG-motor correlation as early Alzheimer's disease index in herpes simplex virus type-1-infected mice.}, journal = {Brain communications}, volume = {8}, number = {3}, pages = {fcag128}, pmid = {42146852}, issn = {2632-1297}, abstract = {Alzheimer's disease is a neurodegenerative disorder characterized by cognitive decline and memory impairment. Early treatment requires reliable tests to identify the initial manifestations for developing treatments that modify disease progression. Neuroinflammation has been implicated as a key driver of the onset and progression of Alzheimer's disease. Herpes simplex virus type-1 (HSV-1), a neurotropic virus that establishes latency within the central nervous system, has been associated with increased proinflammatory cytokines, cognitive impairment and Alzheimer's disease-like pathology in human and rodent brains. This study employed a murine model showing an Alzheimer's disease-related phenotype, induced by HSV-1 infection and recurrent reactivation through thermal stress, to investigate previously unexplored motor function impairments and their correlation with EEG changes predictive of Alzheimer's disease-like pathology. Mice were subjected to two (2×TS) or seven thermal stress (7×TS) HSV-1 reactivations to reproduce mild and severe cognitive impairments, respectively, and were tested for recognition memory using the Novel Object Recognition test and for spatial memory using the Y-maze test. Motor performance was assessed using grip strength and grid walking tests. Local field potential recordings, immunohistochemical, morphological and molecular analyses were performed to characterize the effects of HSV-1 on neural circuits. 2×TS HSV-1 mice showed a reduced preference index in Novel Object Recognition compared to mice receiving mock infection (i.e. vehicle inoculum), whereas 7×TS HSV-1 mice displayed severe cognitive decline across the different memory domains. Motor function was preserved after the second thermal stress but was impaired after the seventh thermal stress, with reduced forelimb force and increased foot faults starting from the fourth reactivation. Following the seventh reactivation, HSV-1 mice showed astrogliosis and phosphorylated Tau accumulation. In vivo, electrophysiological recordings revealed increased functional connectivity across frequency bands in 2×TS HSV-1 mice compared to controls, with negative correlations between total coherence and grip strength. Increased spine density in the frontal cortex of 2×TS HSV-1 mice supports early neuronal network alterations. From a translational perspective, we preliminarily evaluated comparable motor indices in healthy human participants, in patients with mild cognitive impairment, and in patients with Alzheimer's disease. As expected, both grip strength and dynamic balance were lower in patients with Alzheimer's disease compared to healthy and mild cognitive impairment subjects. Notably, grip strength was significantly reduced in mild cognitive impairment subjects, who displayed early motor impairment. Our findings highlight the potential of EEG-based biomarkers for early Alzheimer's disease detection and suggest motor indices as novel prognostic markers.}, } @article {pmid42146883, year = {2026}, author = {García-Alberca, JM and Mendoza, S and DE LA Guía, P and López DE LA Rica, M}, title = {Effectiveness of Souvenaid® combined with acetylcholinesterase inhibitors on caregiver burden in Alzheimer´s disease.}, journal = {Alzheimer's & dementia (New York, N. Y.)}, volume = {12}, number = {}, pages = {e70262}, pmid = {42146883}, issn = {2352-8737}, abstract = {INTRODUCTION: The burden experienced by caregivers of Alzheimer´s disease (AD) patients is a complex and stressful situation influenced by distinct variables, such as the patient´s need for monitoring, social isolation, mental or physical health problems, or financial challenges. In additon, behavioral and psychological symptoms of dementia are strongly associated with caregiver experiences of burden.

METHODS: This was a 12-month, retrospective, single-center, real-world study to evaluate the effectiveness of the combined treatment with Souvenaid and acetylcholinesterase inhibitors (AChEI) compared to treatment with either AChEI alone or Souvenaid alone on caregiver burden, anxiety and depression in patients, and AD patients attending a memory clinic. Assessments were conducted using the Zarit Burden Interview (ZBI), the Beck Depression Inventory (BDI), the State Trait Anxiety Inventory-State (STAI-S), and the Neuropsychiatric Inventory-Caregiver distress scale (NPI-D). A mixed model for repeated measures was conducted to evaluate differences from baseline to month 12 between caregivers in the three treatment groups.

RESULTS: At 12 months, caregiver burden, depression, anxiety levels, and the emotional distress in the context of behavioral and psychological symptoms of dementia (BPSD) improved in caregivers in the Souvenaid plus AChEI group (n = 70) compared to those in the AChEI group (n = 84) and those in the Souvenaid group (n = 66).The mean change for the ZBI score was found to be significantly higher in the Souvenaid plus AChEI group than in the AChEI group (p < 0.001) and the Souvenaid group (p < 0.001). In addition, there was a significant difference in the mean change for the BDI, STAI-S, and NPI-D scores between groups, favoring the Souvenaid plus AChEI group over the AChEI and Souvenaid groups.

DISCUSSION: In addition to assessing patients' cognitive, behavioral, and daily functioning, it is recommended regular monitoring of caregiver burden while providing support for patients with dementia. The combined treatment with Souvenaid and AChEI may have a significant impact on caregivers' experience of burden.}, } @article {pmid42147211, year = {2024}, author = {Prinz, A and Buerger, D and Krafft, J and Bergmann, M and Woll, A and Barisch-Fritz, B and Witte, K}, title = {Use of Immersive Virtual Reality in Nursing Homes for People With Dementia: Feasibility Study to Assess Cognitive, Motor, and Emotional Responses.}, journal = {JMIR XR and spatial computing}, volume = {1}, number = {}, pages = {e54724}, pmid = {42147211}, issn = {2818-3045}, abstract = {BACKGROUND: Physical activity interventions for people with dementia have shown promising effects in improving cognition and physical function or slowing disease-related decline. Immersive virtual reality (iVR), using head-mounted displays, facilitates realistic experiences by blurring the boundaries between VR and the real world. The use of iVR for people with dementia offers the potential to increase active time and improve dementia therapy and care through exercise interventions. However, the feasibility of using VR use in people with dementia, considering changes in motor, cognitive, psychological, and physiological parameters, remains insufficiently investigated.

OBJECTIVE: This study aims to investigate the feasibility of using iVR in people with dementia or mild cognitive impairment in nursing homes. Specifically, we examined changes in motor performance (balance and mobility), cognitive performance (global cognition and executive functions), emotional responses, and fear of falling using iVR.

METHODS: Utilizing a pre-post design, this study recruited 35 participants with mild-to-moderate dementia, assessed by the Mini-Mental State Examination (MMSE). Participants underwent a single session involving iVR exposure, with pre- and postexposure assessments and a feedback form, to exclude negative effects on cognitive and motor functions, mood, anxiety levels, and balance performance. The use of iVR involved 4 scenes, with a total length of 8 minutes. These scenes depicted a park with short and rather passive impressions presented as a 360° video in a head-mounted display. Before and after using the iVR, cognitive parameters were assessed using the Trail-Making Test A (TMT-A), motor parameters were assessed using the FICSIT-4 (Frailty and Injuries: Cooperative Studies of Intervention Techniques-4) and Timed-Up-and-Go (TUG) tests, and psychological parameters were assessed using the Dementia Mood Picture Test, State-Trait Anxiety Inventory, and Short Falls Efficacy Scale-International (Short FES-I). The Emotion Rating Scale and the duration of use were recorded during use, and a feedback questionnaire was completed afterward in addition to the posttests. Paired t tests and Wilcoxon tests were used to examine pre-post differences.

RESULTS: Of the 35 initial participants, 33 completed the study, which corresponds to a dropout rate of 6%. All 33 participants, who had a mean of 83.71 (SD 5.01) years, had dementia. They showed no statistically significant difference in cognitive and motor performance before and after iVR use. Thus, no negative effects on cognitive and motor functions, mood, anxiety levels, and balance performance were observed. The emotion rating scale also showed that 72% (n=24) felt joy and fun during iVR use, 100% (n=33) showed no emotions such as fear, sadness, or anger, and 93% (n=31) were attentive during iVR use.

CONCLUSIONS: The feasibility of using iVR for people with dementia can be rated positively. There were no changes in motor, cognitive, or emotional parameters that would increase the risk of falls or other negative emotional reactions during or after iVR use. Further studies are needed to investigate prolonged use in a more stimulating computer-generated environment and possible physical and cognitive tasks for people with dementia in nursing homes.

TRIAL REGISTRATION: German Clinical Trials Register DRKS00030616; https://drks.de/search/de/trial/DRKS00030616.}, } @article {pmid42147344, year = {2026}, author = {Geerts, H and Short, SM and Grant, A and van der Graaf, PH}, title = {Understanding quantitative effects of anti-amyloid therapies on tau biomarkers and functional outcome. Insights from a comprehensive mechanistic quantitative systems pharmacology study.}, journal = {Frontiers in pharmacology}, volume = {17}, number = {}, pages = {1813290}, pmid = {42147344}, issn = {1663-9812}, abstract = {INTRODUCTION: Anti-amyloid antibodies have the potential to become the standard of care in Alzheimer's Disease (AD) and large datasets from clinical trials allow the testing of predictive models on fluid biomarkers and functional outcomes. However, identifying an easily accessible biomarker to determine the time to switch to maintenance therapy, and identifying patient profiles with optimal cognitive benefit, are still unresolved issues in clinical practice.

METHODS: Predicted changes in monomers, oligomers, protofibrils and plaques were simulated using a well-validated Quantitative Systems Pharmacology model based on biophysical and biological assumptions of amyloid synthesis, aggregation and clearance. This model was combined with a previously calibrated computational neuronal network model of cognitive outcome in AD patients by introducing the effect of amyloid and tau oligomers on specific voltage- and ligand-gated ion channels, informed by preclinical studies.

RESULTS: The model accounted for 70% and 50% of the variance of clinically observed changes in plasma p-tau181 and Clinical Dementia Rating-Sum Of Boxes (CDR-SOB) respectively, in clinical trials of seven amyloid antibodies. We derived an antibody specific normalized decrease of plasma p-tau181 (-15% for donanemab, -45% for aducanumab and -75% for lecanemab) to determine trial duration for achieving central amyloid negativity. Using the concept of information processing bandwidth, the model suggests that anti-amyloid antibodies slow the cognitive worsening compared to placebo while at the same time lowering plasma p-tau181 levels by reducing neuronal firing. Finally, the model suggests that independently from the degree of amyloid reduction, the beneficial cognitive effect of treatment decreases with more advanced neuronal pathology and higher baseline tau-load. This provides a hypothesis for the impact of disease pathology and gender effect on functional outcomes with lecanemab and gantenerumab.

DISCUSSION: With further validation, this model has the capability to support optimization of clinical trial design for amyloid-tau combination therapy.}, } @article {pmid42147618, year = {2026}, author = {Sewell, DD and Kallenberg, G and Mandel, B and Mandvi, A and Asmus, L and Neel, IC and Heimler, G and Andrew, W and Lobatz, M}, title = {Enhancing Dementia Care in Primary Care: Impact of Targeted Training and Electronic Medical Record (EMR)-Integrated Algorithms.}, journal = {Cureus}, volume = {18}, number = {4}, pages = {e107031}, pmid = {42147618}, issn = {2168-8184}, abstract = {INTRODUCTION: The number of medical specialists whose training programs provide robust education in dementia diagnosis and treatment pales in comparison to the increasing number of individuals living with dementia. Primary care providers (PCPs) care for most older adults with cognitive concerns and dementia. Summarized here are the results of an effort to help PCPs care for these patients using targeted training and electronic medical record (EMR)-integrated clinical algorithms.

METHODS: Clinicians from two University of California San Diego Family Medicine Clinics completed assessments of dementia knowledge and comfort in caring for patients and family members impacted by dementia four times: enrollment, and approximately two, nine and 15 months after a three-component intervention: 1) training via four online educational modules (six hours total) on screening, evaluation, and care of patients with dementia; 2) integration of clinical algorithms into the EMR system and 3) access to mentoring from a more experienced peer.

RESULTS: Subjective assessment of comfort and competence of intervention group clinicians in working with patients with cognitive complaints significantly increased and was higher for intervention group PCPs than the comparison group PCPs. Evidence of completed AD8s (Eight-Item Informant Interview to Differentiate Aging and Dementia) at both clinics increased from baseline to post-intervention: 52.85% to 82.6% and 66.1% to 86.9%.

DISCUSSION: Training PCPs on dementia screening and diagnosis, and integration of algorithms into the EMR, improved clinician subjective competence and comfort in caring for patients with cognitive complaints and increased the AD8 completion rate. The small number of study participants mandates caution when interpreting these findings.}, } @article {pmid42148080, year = {2026}, author = {You, J and Liu, Q and Li, X}, title = {Anti-Aβ3-10 monoclonal antibody 7B8 improves cognitive function and protects the blood-brain barrier in APP/PS1 mice by regulating the HMGB-1/RAGE/NF-κB pathway.}, journal = {Frontiers in immunology}, volume = {17}, number = {}, pages = {1781351}, pmid = {42148080}, issn = {1664-3224}, mesh = {Animals ; *Blood-Brain Barrier/drug effects/metabolism ; Mice, Transgenic ; *Antibodies, Monoclonal/pharmacology ; Mice ; NF-kappa B/metabolism ; *Cognition/drug effects ; *Alzheimer Disease/drug therapy/metabolism/immunology ; Signal Transduction/drug effects ; *Amyloid beta-Peptides/immunology/metabolism ; Presenilin-1/genetics ; Amyloid beta-Protein Precursor/genetics ; Disease Models, Animal ; Male ; Humans ; Mice, Inbred C57BL ; Brain/metabolism ; }, abstract = {BACKGROUND: Alzheimer's disease (AD), the most prevalent dementia, is primarily underpinned by the amyloid cascade hypothesis. Passive Aβ immunotherapy effectively reduces cerebral Aβ deposition but is limited by severe side effects, including cerebral amyloid angiopathy (CAA), microhemorrhage, and amyloid-related imaging abnormalities (ARIA). Here, we investigated the efficacy and safety of a novel anti-A3-10 monoclonal antibody (7B8) in APP/PS1 double-transgenic mice, with a focus on its impacts on amyloid clearance, neuroinflammation, and blood-brain barrier (BBB) integrity.

METHODS: 7B8 was generated by immunizing mice with A3-10-KLH. Six-month-old APP/PS1 mice were intraperitoneally injected with 7B8 (10 mg/kg) weekly for 8 doses (7B8 group). Age-matched APP/PS1 mice treated with IgG and C57BL/6J mice served as negative and wild-type (WT) controls, respectively. One week after the final injection, behavioral tests were performed, followed by euthanasia for histological (left brain hemisphere) and biochemical (right brain hemisphere) analyses.

RESULTS: Compared with the IgG group, the 7B8 group exhibited significantly reduced cerebral Aβ deposition and improved cognitive function (both P < 0.05), comparable to the WT group. Notably, in these young 6-month-old APP/PS1 mice with early-stage amyloid deposition and minimal CAA pathology, 7B8 treatment did not increase microhemorrhage risk relative to the IgG control group (P > 0.05). Furthermore, 7B8 preserved vascular integrity by reducing perivascular Aβ40 deposition and smooth muscle actin damage, while enhancing endothelial cell fluorescence intensity (P < 0.05). At the molecular level, 7B8 upregulated vascular LRP-1 and BBB tight junction proteins (ZO-1, CLDN-5, Occludin), and downregulated RAGE expression (P < 0.05). It also suppressed microglial and astrocytic activation, reduced levels of IL-6 and cortical TNF-α, and inhibited the HMGB-1/RAGE/NF-κB signaling pathway (P < 0.05), without affecting global TNF-α or IL-1β levels.

CONCLUSION: 7B8 effectively alleviates cognitive impairment and clears cerebral and perivascular amyloid deposits in young APP/PS1 mice with early-stage AD pathology and minimal CAA, with no increased risk of microhemorrhage in this experimental setting. It also protects vascular structure and BBB integrity by inhibiting the HMGB-1/RAGE/NF-κB-mediated neuroinflammatory response. Given the limitations of evaluating CAA-related safety in young mice, future studies using mid-aged (12-15-month-old) APP/PS1 mice with prominent CAA will be conducted to fully characterize 7B8's safety profile. These findings highlight 7B8 as a promising candidate for safe and effective AD immunotherapy, providing new insights into the development of ARIA-minimizing strategies.}, } @article {pmid42148242, year = {2025}, author = {Khazaneha, M and Khadir, E and Motaghi, N and Arvan, H and Ebrahimi-Meimand, HA}, title = {Scientometric insights into neurology publications in Iran.}, journal = {Current journal of neurology}, volume = {24}, number = {1}, pages = {87-96}, pmid = {42148242}, issn = {2717-011X}, abstract = {Background: Undoubtedly, medical science has been born since the beginning of human creation. One of its important branches is neurology. Neurosciences in Iran, with a little delay from the first world, with the efforts of researchers, opened the way for the diagnosis and treatment of neurological diseases, and we reached the place where we are. Methods: In this bibliometric and scientometric study, we have evaluated the process of neurological science in Iran. By referring to the reliable indexes, we checked Web of Science (WoS), PubMed, and Scopus from 1963 onwards. We showed the published activities of Iranians in the form of charts and tables. Results: This study indicates the increasing growth of scientific studies in the field of neurology. In the field of neuroscience, the researchers are mostly aimed at the education and training of specialists and PhD students, and depending on the research facilities, as well as acquaintances and connections for the publication of articles. Diseases that have afflicted a large number of people causing them to suffer and limiting their activities, such as multiple sclerosis (MS), Alzheimer's, epilepsy, Parkinson's, and brain strokes have been the focus of researchers. Conclusion: Neurological studies have an increasing trend and can be divided into two basic sections, which are mainly done by neuroscientists and are based on the educational needs and training of specialists, but neurology studies and scientific publications are mainly done by neurologists and based on feeling the need and diseases in this field have been done.}, } @article {pmid42148368, year = {2026}, author = {Bailey-Taylor, MJ and Morrow, P and Hendrix, J and Galluzzi, KE and Sharafsaleh, G}, title = {Therapeutic Landscape of Early Symptomatic Alzheimer's Disease Translated into Everyday Practice for Geriatric Providers.}, journal = {Clinical interventions in aging}, volume = {21}, number = {}, pages = {585263}, pmid = {42148368}, issn = {1178-1998}, mesh = {Humans ; *Alzheimer Disease/drug therapy/diagnosis ; Disease Progression ; Biomarkers ; Cognitive Dysfunction/drug therapy ; Aged ; Antibodies, Monoclonal/therapeutic use/adverse effects ; }, abstract = {Alzheimer's disease (AD) accounts for 60-80% of all dementia cases. Recent advances in diagnostic biomarkers of early symptomatic AD (ie, mild cognitive impairment and mild dementia due to AD) and amyloid-targeting therapies (ATTs) have the potential to improve outcomes for patients with AD. Two ATTs (donanemab and lecanemab) are currently approved and available for use in the US. Both ATTs can slow disease progression as well as cognitive and functional decline in patients with early symptomatic AD. Treatment with ATTs is associated with specific safety concerns such as amyloid-related imaging abnormalities. Therefore, the benefit versus risk profile needs to be carefully considered when deciding whether to treat a patient with ATTs. This review aims to educate geriatric-trained health professionals regarding advances in the diagnosis and treatment of early symptomatic AD, including the optimal duration of treatment, management of adverse reactions, and patient counseling. It also discusses key considerations in care transitions and patient management in multidisciplinary settings to ensure continuous patient-centered care.}, } @article {pmid42148603, year = {2026}, author = {Xu, Q and Lu, J and Zhang, Z and Xu, D and Guo, C}, title = {Deep learning-based cognitive impairment brain imaging analysis: New methods, new technologies, and new paradigms.}, journal = {Neural regeneration research}, volume = {21}, number = {9}, pages = {4135-4147}, doi = {10.4103/NRR.NRR-D-25-00332}, pmid = {42148603}, issn = {1673-5374}, abstract = {Cognitive impairment arising from ischemic stroke, Alzheimer's disease, and Parkinson's disease presents distinct structural and network-level alterations. Brain magnetic resonance imaging offers a non-invasive and high-resolution approach to assess these changes, while deep learning provides powerful tools for automated analysis. Given that accurate lesion delineation, precise localization of abnormal regions, and reliable disease classification are fundamental to clinical decision-making. This review aims to explore the application of deep learning techniques to brain magnetic resonance imaging analysis of cognitive impairments caused by these disorders, with a focus on three core tasks: lesion segmentation, object detection, and image classification. Recent widely accepted findings indicate that ischemic stroke studies have achieved state-of-the-art lesion segmentation performance, with optimized U-shaped convolutional network (U-Net) and hybrid convolutional neural network-transformer models reaching Dice scores up to 0.911 in delineating focal damage. Alzheimer's disease research has advanced classification and staging accuracy by more than 10% compared with unimodal baselines through three-dimensional convolutional neural network, Transformers, and multimodal fusion, enabling more precise detection of diffuse cortical atrophy. Parkinson's disease imaging, despite lacking overt structural lesions, has leveraged ResNet and Vision Transformer backbones to identify subtle and spatially distributed abnormalities, improving early-stage differentiation. Persistent challenges include the scarcity of large, high-quality annotated datasets, substantial inter-site variability, high annotation costs, and limited interpretability, hindering clinical integration. Addressing these barriers will require advances in federated learning to mitigate data scarcity while preserving privacy, domain adaptation techniques to reduce inter-site variability, automated annotation, and low-resource training strategies to lower labeling costs, and explainable artificial intelligence to improve interpretability, thereby ensuring model robustness, privacy, and transparency. This review highlights emerging methods, innovative technologies, and novel paradigms that are redefining brain imaging analysis in cognitive impairment. Mechanistically, deep learning improves cognitive impairment analysis by integrating hierarchical and multiscale spatial features, modeling long-range functional connectivity disruptions, and fusing structural with functional imaging to better represent network-level pathology. In conclusion, aligning network architectures with disease-specific imaging characteristics and task requirements can greatly enhance the accuracy, robustness, and generalizability of magnetic resonance imaging analyses for cognitive impairment. Future work should focus on multimodal fusion, structure-function coupling, cross-disease evaluations, and embedding artificial intelligence tools into clinical workflows to support early detection, individualized treatment planning, and large-scale clinical adoption.}, } @article {pmid42148948, year = {2026}, author = {Li, X and Xiao, Y and Liu, F}, title = {Stevioside extends the healthspan and improves Alzheimer's disease and increases oxidative stress resistance via the mitochondrial unfolded protein response.}, journal = {Food & function}, volume = {17}, number = {11}, pages = {5021-5031}, doi = {10.1039/d6fo00251j}, pmid = {42148948}, issn = {2042-650X}, mesh = {Animals ; *Unfolded Protein Response/drug effects ; *Diterpenes, Kaurane/pharmacology ; *Oxidative Stress/drug effects ; Caenorhabditis elegans/drug effects/metabolism/genetics ; *Glucosides/pharmacology ; Longevity/drug effects ; *Mitochondria/metabolism/drug effects ; *Alzheimer Disease/drug therapy/metabolism ; Humans ; Caenorhabditis elegans Proteins/metabolism/genetics ; Reactive Oxygen Species/metabolism ; Superoxide Dismutase/metabolism ; }, abstract = {Increased evidence suggests that moderate activation of the mitochondrial unfolded protein response (UPR[mt]) can delay aging and ameliorate neurodegenerative pathologies. Stevioside (Ste), a natural zero-calorie sweetener extracted from Stevia rebaudiana, has gained global acceptance as a sugar substitute in the food industry. Accumulated studies indicate that stevioside exhibits a wide spectrum of biological effects, including anti-hyperglycemic, anti-hypertensive, anti-inflammatory, and antimicrobial activities. However, its potential roles in aging and neurodegenerative diseases remain poorly understood. In this study, the lifespan of Caenorhabditis elegans was found to be prolonged upon exposure to (1, 10, and 100 μM) stevioside in a dose-dependent manner. Furthermore, we found that stevioside extended the lifespan and healthspan in C. elegans via activation of the ATFS-1-mediated UPR[mt] pathway. Intriguingly, the amelioration of Alzheimer's disease-related phenotypes by stevioside was also mediated through the ATFS-1 pathway. Additionally, we found that stevioside increased the resistance of oxidative stress and reduced ROS levels and upregulated superoxide dismutase (SOD) activity in C. elegans via the ATFS-1 pathway. These results demonstrated that both the anti-aging and neuroprotective effects of stevioside in C. elegans required a functional ATFS-1-dependent mitochondrial unfolded protein response. Collectively, our work highlighted that stevioside might be a viable candidate for the prevention and treatment of aging and age-related diseases.}, } @article {pmid42149381, year = {2026}, author = {Han, L and Xiong, X and Fan, M and Zhang, L and Gao, S and Li, R and Wang, X and Xiao, X and Huang, C and Yang, J}, title = {Early-Life Psychological Stress Impairs Spatial Learning and Memory in Rats by Altering the Hippocampal Proteome.}, journal = {Behavior genetics}, volume = {56}, number = {3}, pages = {138-152}, pmid = {42149381}, issn = {1573-3297}, support = {82201342//National Natural Science Foundation of China/ ; xzy022023022//Xi 'an Jiaotong University Basic Research Student Project/ ; 2022PT-07//the Scientific Research and Sharing Platform Construction Project of Shaanxi Province/ ; }, mesh = {Animals ; *Hippocampus/metabolism ; Rats ; *Proteome/metabolism ; *Stress, Psychological/metabolism/physiopathology ; *Spatial Learning/physiology ; Male ; Maze Learning/physiology ; Memory/physiology ; Proteomics/methods ; Rats, Sprague-Dawley ; Spatial Memory/physiology ; }, abstract = {Early-life stress has been linked to anxiety, pessimism, and cognitive decline, all of which can have detrimental effects on individuals. One critical structure impacted by early-life stress is the hippocampus, which plays a vital role in regulating learning and memory functions. This study aims to elucidate the molecular mechanisms through which early-life psychological stress (ELPS) affects the learning and memory capabilities of the hippocampus in rats. In this study, ELPS model was applied on juvenile rats for 14 days. To evaluate the spatial learning and memory abilities of rats, the Morris Water Maze (MWM) test was adopted in this study. This study employed two-dimensional gel electrophoresis (2DE) and ultrahigh-performance liquid chromatographic-electrospray ionization quadrupole time-of-flight mass spectrometry (UPLC-ESI-Q-TOF-MS) techniques to reveal the proteomic map of the rat hippocampus. Subsequently, Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis and direct protein-protein interaction (PPI) network construction were performed to identify the biological pathways associated with the differentially expressed proteins (DEPs). ELPS treatment induced age-dependent spatial cognitive deficits. In juvenile rats, ELPS caused mild impairments in spatial learning, as reflected by increased escape latency during specific training days, but did not affect spatial memory. In contrast, adult rats exhibited significant and robust impairments in both spatial learning and spatial memory, with longer escape latency across training days, fewer platform crossings, and reduced time and distance in the target quadrant. These findings demonstrate that ELPS-induced cognitive dysfunction is far more pronounced in adult animals, representing persistent and progressive spatial learning and memory deficits. After therapy, 71 proteins were found in the hippocampal region, including 10 DEPs across the juvenile and adult groups post-treatment. Subsequent pathway analysis indicated the involvement of 4 DEPs in various pathways, including Biosynthesis of amino acids, Prion disease, HIF-1 signaling pathway, Distal axon, Alzheimer disease, and Necroptosis pathways. Our study revealed significant proteomic changes in the hippocampus of rats as they transitioned from juveniles to adults, including 10 consistently differentially expressed proteins. These proteomic alterations correspond to the age-dependent spatial cognitive deficits induced by ELPS-mild spatial learning impairment in juveniles and more pronounced deficits in both spatial learning and memory in adults-collectively supporting the lasting effects of ELPS on spatial cognitive function.}, } @article {pmid42149389, year = {2026}, author = {Gautam, AS and Singh, RK}, title = {Chrysin Ameliorated Neurochemical and Behavioural Changes Mediated By Combined Exposure of Interleukin-17 A With Amyloid Beta1-42 in Mice.}, journal = {Journal of neuroimmune pharmacology : the official journal of the Society on NeuroImmune Pharmacology}, volume = {21}, number = {1}, pages = {}, pmid = {42149389}, issn = {1557-1904}, mesh = {Animals ; *Amyloid beta-Peptides/toxicity/administration & dosage ; *Flavonoids/pharmacology ; *Peptide Fragments/toxicity/administration & dosage ; *Interleukin-17/toxicity/administration & dosage ; Male ; Mice ; Mice, Inbred BALB C ; Alzheimer Disease/metabolism ; Neuroprotective Agents/pharmacology ; Brain/drug effects/metabolism ; }, abstract = {Neuroinflammation is one of the major hallmarks of neurodegenerative diseases, including Alzheimer's disease (AD). Interleukin-17 (IL-17) cytokine and its downstream signaling have been shown to be implicated in preclinical and clinical models of AD. Moreover, the combination of recombinant IL-17 A with amyloid beta (Aβ1-42) has been shown to be involved in promoting neuroinflammation during AD pathology. Hence, it is speculated that IL-17 may exacerbate Aβ1-42-induced neuronal damage and inflammatory events in the brain. Although natural flavonoids have been reported to protect against neuroinflammation in AD, their role in IL-17 exacerbated Aβ1-42-induced responses has not been reported previously. The current research explored the ability of Chrysin in regulating the exacerbation of neuronal damage and inflammation during AD pathology induced due to the combination of recombinant mouse IL-17 A (rmIL-17 A) with Aβ1-42 in animals. Adult male BALB/c mice were exposed to intranasal Aβ1-42 (5 µg/10µL in phosphate-buffered saline (PBS)/animal) and rmIL-17 (4 µg/kg in 10 µL PBS/animal) from day 1 to day 14 on alternate days with therapeutic oral administration of Chrysin suspension (100 mg/kg) during the last 7 days. Oral treatment with Chrysin demonstrated significant protective effects in improving the memory functions of the animals, along with the modulation of neurodegenerative and neuroinflammatory signalling, microglial and astrocytic activation, and redox balance in the hippocampus and cortex areas of the animal brain tissues. These results supported the neuroprotective ability of Chrysin against the exacerbation caused by rmIL-17 A in Aβ1-42-induced AD in a mouse model.}, } @article {pmid42149841, year = {2026}, author = {Guu, TW and Li, WJ and Lee, SH and Hsu, CS and Chou, CN and Lack, L and Ma, WF}, title = {Facilitating the measurement and treatment of Behavioral and Psychological Symptoms of Dementia (BPSD) and understanding caregiver burden using wearable devices in Rural Taiwan-Protocol for a dyadic feasibility pilot study.}, journal = {PloS one}, volume = {21}, number = {5}, pages = {e0342136}, pmid = {42149841}, issn = {1932-6203}, mesh = {Humans ; Pilot Projects ; Taiwan ; *Wearable Electronic Devices ; *Caregivers/psychology ; *Dementia/psychology/therapy ; Female ; Male ; Quality of Life ; Aged ; Feasibility Studies ; Rural Population ; Surveys and Questionnaires ; *Alzheimer Disease/psychology/therapy ; Digital Health ; Middle Aged ; Actigraphy ; }, abstract = {INTRODUCTION: Alzheimer's disease (AD) prevalence rises with societal ageing. In clinical care, behavioral and psychological symptoms of dementia (BPSD)-including depression, agitation/aggression, apathy, and sleep disturbance-worsen patients' quality of life and substantially increase caregiver burden, more significantly than the cognitive symptoms. Standard BPSD assessments rely on caregiver-rated questionnaires that are cross-sectional and may be biased when caregivers are themselves older adults. Device-based measures (e.g., research-grade wrist actigraphy) can provide objective longitudinal data and novel features. In parallel, therapeutic wearables may improve sleep and mood in adults, and might improve BPSD if accepted by people living with dementia.

METHODS: This dyadic pilot study will recruit 20 participants (n = 10 AD patients; n = 10 caregivers) from outpatient services and affiliated day-care/dementia hubs in rural Taiwan. Participants will wear Geneactiv continuously for 8 weeks and Re-Timer ≥30 min/day for 4 weeks. Device-based data will be processed with GGIR, a well validated R-package designed for processing accelerometer data. Questionnaire assessments include Pittsburgh Sleep Quality Index (PSQI), Neuropsychiatry Inventory Questionnaire (NPI-Q), Caregiver Burden Inventory (CBI), and a semi-structured interview based on the Taiwanese version of Quebec User Evaluation of Satisfaction with Assistive Technology (T-QUEST) at prespecified timepoints.

DISCUSSION: Wearable devices may facilitate the measurement and treatment of specific BPSD, as well as reduce caregiver burden. If proven feasible even in rural Taiwan where both digital and health literacy and resources are limited, this model will inform how device-based dementia care model can be considered and applied in the context of global ageing.}, } @article {pmid42151697, year = {2026}, author = {Visentini, AE and Reichert, KP and Schetinger, MRC and Bottari, NB and Miron, VV and Castro, MFV and da Silveira, MV and Assmann, CE and Schirmann, AA and Morsch, VMM}, title = {Resveratrol as a potential natural compound to ameliorate cognitive impairment in aluminum-exposed mice: impacts on behavior, purinergic system, and brain inflammation.}, journal = {Metabolic brain disease}, volume = {41}, number = {1}, pages = {}, pmid = {42151697}, issn = {1573-7365}, mesh = {Animals ; *Resveratrol/therapeutic use/pharmacology ; Male ; Mice ; Aluminum Chloride ; *Cognitive Dysfunction/chemically induced/drug therapy/metabolism ; *Neuroprotective Agents/pharmacology/therapeutic use ; *Encephalitis/chemically induced/drug therapy/metabolism ; Antioxidants/therapeutic use/pharmacology ; *Receptors, Purinergic/metabolism ; *Behavior, Animal/drug effects ; *Aluminum/toxicity ; Brain/drug effects/metabolism ; Maze Learning/drug effects ; Aluminum Compounds ; }, abstract = {Aluminum (Al[3+]) accumulates in the brain and has been linked to neurodegeneration. When combined with citrate, its absorption increase, raising the risk of neurodegenerative disorders such as Alzheimer’s disease. Resveratrol (RSV), a polyphenol with anti-inflammatory, antioxidant, and neuroprotective properties, has been associated with aging prevention by reducing oxidative stress. This in vivo study aimed to determine whether RSV could protect male Swiss mice from Al[3+]-induced cognitive impairment, alterations in purinergic signaling, and brain inflammation. The study was conducted using 60 animals treated with aluminum chloride (AlCl3 50 mg/Kg, gavage), citrate (AlCl3 50 mg/Kg + CIT 100 mg/Kg, gavage), and resveratrol (AlCl3 50 mg/Kg + RSV 100 mg/Kg, gavage), along with their respective Controls, for 30 days every 48 h. Behavioral assessments included the open field test, object recognition test, and Y-maze test to evaluate cognitive performance. Enzymatic activity of purinergic pathways and levels of receptors and inflammation-related molecules were also analyzed. AlCl3 and AlCl3 + CIT induced an inflammatory response in mice, as evidenced by the modulation of purinergic system enzymes associated with inflammation. Al[3+] intoxication also triggered behavior alterations, which was modulated by CIT and alleviated by RSV treatment. Western blot findings revealed that AlCl3 and AlCl3 + CIT altered protein levels of purinergic receptors (A1R, A2AR, and P2 × 7R), the inflammasome protein NLRP3, the pro-inflammatory cytokine IL-1β, and the neurotrophic factor BDNF. RSV counteracted the toxic effects of Al[3+], providing neuroprotection against its toxicity and presenting itself as a potential therapeutic candidate for cognitive deficits.}, } @article {pmid42151713, year = {2026}, author = {Stijven, F and Mallinckrodt, C and Molenberghs, G and Alonso, A and Dickson, SP and Hendrix, SB}, title = {Time-Scale Target Parameters and Two-Step Estimation in Longitudinal Trials for Progressive Diseases.}, journal = {Statistics in medicine}, volume = {45}, number = {10-12}, pages = {e70591}, doi = {10.1002/sim.70591}, pmid = {42151713}, issn = {1097-0258}, support = {//Agentschap Innoveren en Ondernemen/ ; HBC.2022.0145//Johnson & Johnson Innovative Medicine/ ; }, mesh = {Humans ; Longitudinal Studies ; *Disease Progression ; Alzheimer Disease/drug therapy ; *Randomized Controlled Trials as Topic/methods/statistics & numerical data ; Models, Statistical ; Computer Simulation ; Time Factors ; Data Interpretation, Statistical ; }, abstract = {In progressive diseases such as Alzheimer's, treatments that slow progression should start early to preserve higher levels of functioning for a longer period. In corresponding clinical trials, treatment effects are usually expressed as mean differences on a clinical scale at fixed time points. Early in the disease course, however, these mean differences may appear small but may nonetheless correspond to an important slowing of disease progression. This complicates the appreciation of the relevance of observed treatment effects. We introduce a class of target parameters that quantify treatment effects on the time scale in longitudinal studies; for instance, in terms of time saved or percentage slowing of progression. We focus on data from randomized trials where the target parameters are identified under regularity assumptions. These target parameters remain well defined if treatment was not randomized, but additional untestable assumptions are required for identification. We propose general two-step estimators. In the first step, the data can be analyzed with standard methods for longitudinal data and standard software can thus be used. In the second step, summary statistics from the first step are used for inferences about the target parameters. The second step has been implemented in the TCT R package. We study the asymptotic properties and efficiency of these two-step estimators, and evaluate them in an extensive simulation study. These estimators are used in a phase 2/3 clinical trial for Alzheimer's disease, leading to important additional insights into the treatment effect.}, } @article {pmid42151732, year = {2026}, author = {Hammers, DB and Foster, E and Eloyan, A and Thangarajah, M and Taurone, A and Touroutoglou, A and La Joie, R and Beckett, L and Gao, S and Vemuri, P and Nudelman, KN and Kirby, K and Dage, JL and Aisen, P and Atri, A and Clark, D and Day, GS and Duara, R and Graff-Radford, NR and Grant, I and Honig, LS and Johnson, ECB and Jones, DT and Masdeu, JC and Mendez, MF and Parand, L and Womack, K and Musiek, E and Onyike, CU and Riddle, M and Rogalski, E and Salloway, S and Sha, SJ and Turner, RS and Wingo, TS and Wolk, DA and Dickerson, BC and Rabinovici, GD and Carrillo, MC and Apostolova, LG and , }, title = {Cognitive dispersion profiles and prediction of cognitive change in early-onset dementias: Results from LEADS.}, journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association}, volume = {22}, number = {5}, pages = {e71492}, pmid = {42151732}, issn = {1552-5279}, support = {AARG-22-926940/ALZ/Alzheimer's Association/United States ; LDRFP-21-818464/ALZ/Alzheimer's Association/United States ; K23 AG080071/ALZ/Alzheimer's Association/United States ; R56 AG057195/ALZ/Alzheimer's Association/United States ; U01AG6057195/ALZ/Alzheimer's Association/United States ; U24AG021886/ALZ/Alzheimer's Association/United States ; U01 AG016976/ALZ/Alzheimer's Association/United States ; P30 AG010133/ALZ/Alzheimer's Association/United States ; P50 AG008702/ALZ/Alzheimer's Association/United States ; P50 AG025688/ALZ/Alzheimer's Association/United States ; P50 AG005146/ALZ/Alzheimer's Association/United States ; P30 AG062421/ALZ/Alzheimer's Association/United States ; P30 AG062422/ALZ/Alzheimer's Association/United States ; P50 AG023501/ALZ/Alzheimer's Association/United States ; P30 AG010124/ALZ/Alzheimer's Association/United States ; P30AG066506/ALZ/Alzheimer's Association/United States ; P30 AG013854/ALZ/Alzheimer's Association/United States ; P50 AG005681/ALZ/Alzheimer's Association/United States ; P50AG047366/ALZ/Alzheimer's Association/United States ; R56AG057195/AG/NIA NIH HHS/United States ; }, mesh = {Humans ; Neuropsychological Tests/statistics & numerical data ; Female ; Male ; *Alzheimer Disease/psychology ; *Cognition/physiology ; Biomarkers ; *Dementia/psychology ; Age of Onset ; Disease Progression ; }, abstract = {INTRODUCTION: Research into cognitive dispersion - a cognitive process score measuring the intra-individual variability (IIV) across a single testing session - suggests utility in neurodegenerative populations. Given widespread deficits observed in sporadic early-onset Alzheimer's disease (EOAD), however, it is unclear if examining cognitive dispersion shows benefit in this condition.

METHODS: A total of 309 participants (188 amyloid-positive EOAD, 43 amyloid-negative early-onset dementia [EOnonAD], 78 cognitively normal [CN]) completed neuropsychological testing twice over 12 months. Dispersion-related differences among groups were assessed, as was cognitive dispersion's capacity to predict domain-specific cognitive trajectories, and its convergence with imaging biomarkers.

RESULTS: EOAD participants displayed higher cognitive dispersion than EOnonAD participants, and associations with EOAD-specific biomarkers. Additionally, cognitive dispersion was associated with 12-month reliable change across several cognitive domains.

DISCUSSION: These preliminary results examine cognitive dispersion in sporadic EOAD. When used with baseline cognitive performance, cognitive dispersion measures may enrich future clinical trials in EOAD by enhancing treatment monitoring over time.}, } @article {pmid42151912, year = {2026}, author = {Stuardo, N and Cáceres-Quezada, Á and Guzmán, D and Lamaizon, CM and Leal R, N and Koleske, AJ and Álvarez R, A}, title = {Abl kinase activation promotes axon initial segment disassembly and protein sorting defects in Alzheimer's disease.}, journal = {BMC biology}, volume = {}, number = {}, pages = {}, doi = {10.1186/s12915-026-02624-5}, pmid = {42151912}, issn = {1741-7007}, abstract = {BACKGROUND: Axon initial segment (AIS) dysfunction disrupts neuronal compartmentalization, which leads to pathological processes like Tau missorting in Alzheimer's disease (AD). However, the molecular mechanisms that destabilize the AIS scaffold are incompletely understood. Our group has previously shown that the Abl1 non-receptor tyrosine kinase is aberrantly activated in AD mouse models and promotes dendritic spine collapse, Tau hyperphosphorylation, and neuronal apoptosis. Given the important role of Abl1 in AD and its emerging significance in Tau pathology, we examined how it contributes to AIS collapse.

RESULTS: We find that activation of Abl1 by amyloid-β fibrils promotes AIS disruption, as determined by the loss of clustered AnkG in the proximal axon, and that this can be prevented by pharmacological inhibition of Abl kinases. Cytosolic extraction experiments show that active Abl1 associates to the AIS scaffold, and this association increases in response to amyloid-β fibril treatment. Furthermore, using expansion microscopy, we show that Abl1 localizes to the AIS in dissociated hippocampal cultures and in mouse brain slices. We find a decrease in AIS actin patches, key for maintenance of neuronal compartmentalization, following Abl kinase activation. Finally, we show that Abl1 activation promotes missorting of somatodendritic Rab11 into the axon and the axonal protein Tau into the somatodendritic compartment, indicating a bidirectional failure in AIS barrier function.

CONCLUSIONS: Taken together, our results show that Abl1 plays an important role in AIS destabilization and that its activation compromises protein compartmentalization in a primary neuron culture model of AD.}, } @article {pmid42151941, year = {2026}, author = {Luo, M and Zhao, FK and Wang, YM and Bian, J and Luo, Y}, title = {Bibliometric analysis of nanomaterials in the diagnosis and treatment of neurological and psychiatric disorders (1997-2025): trends and future directions.}, journal = {Journal of nanobiotechnology}, volume = {24}, number = {1}, pages = {}, pmid = {42151941}, issn = {1477-3155}, support = {Zunyi Science and Technology Talent Team Project [2024] No. 6//Zunyi Science and Technology Bureau/ ; No. 39 (2023)//Zunshi Science and Technology Cooperation Letter/ ; (QZYY-2024-094)//Science and technology research topic of traditional Chinese medicine and ethnic medicine of Guizhou Provincial Administration of Traditional Chinese Medicine/ ; No: 24QNMP019//Health Commission of Sichuan Province Medical Science and Technology Program/ ; 25MSZX259//Scientific Research Projects of the Sichuan Provincial Administration of Traditional Chinese Medicine/ ; 2026NSFSC1634//Sichuan Province Natural Science Foundation/ ; }, mesh = {Humans ; *Mental Disorders/diagnosis/therapy/drug therapy ; *Nervous System Diseases/diagnosis/therapy/drug therapy ; *Nanostructures/therapeutic use/chemistry ; *Bibliometrics ; Animals ; Oxidative Stress/drug effects ; Drug Delivery Systems ; }, abstract = {Nanomaterials have demonstrated substantial promise in the diagnosis and treatment of neurological and psychiatric disorders, offering novel strategies to overcome the limitations of traditional therapies. This review utilizes bibliometric analysis to evaluate global trends in nanomaterial research for neurological and psychiatric diseases, based on a corpus of 3,987 publications retrieved from the Web of Science Core Collection spanning from 1997 to August 2025. The analysis reveals a consistent upward trajectory in annual publications, reflecting substantial and growing international interest across diverse regions. Following an overview of global research dynamics, this review explores the pathogenesis of neurological and psychiatric disorders, such as Alzheimer's disease, Parkinson's disease, depression, and schizophrenia. The mechanisms underlying these conditions, including neuroinflammation, oxidative stress, protein aggregation, and neurotransmitter imbalances, are systematically discussed. Subsequently, the review focuses on how nanomaterials, including nanoparticles, nanocomposites, and nanocarriers, target these pathogenic mechanisms. The therapeutic applications of nanomaterials are evaluated with respect to their ability to modulate neuroinflammation, reduce oxidative stress, improve drug delivery to the brain, and facilitate the repair of neuronal damage. Despite the promising potential of nanomaterials, several challenges remain, including biocompatibility, targeted delivery, and scalability of treatment options. The review concludes by highlighting future directions for research, emphasizing the need for continued innovation in nanomaterial design and application to address these challenges and advance clinical treatments for neurological and psychiatric disorders.}, } @article {pmid42152119, year = {2026}, author = {Skácelíková, E and Vyhnálek, M and Děchtěrenko, F and Nikolai, T and Veverová, K}, title = {Willingness and barriers to blood-based biomarker testing of Alzheimer's disease in the general population in the Czech Republic.}, journal = {Alzheimer's research & therapy}, volume = {}, number = {}, pages = {}, doi = {10.1186/s13195-026-02070-z}, pmid = {42152119}, issn = {1758-9193}, support = {PTC-Gene-25-1439553//Alzheimer's Association - Part the Cloud Translational Research Program/ ; PTC-Gene-25-1439553//Alzheimer's Association - Part the Cloud Translational Research Program/ ; CZ.02.01.01/00/22_008/0004595//European Regional Development Fund, under the project "Beyond Security: Role of Conflict in Resilience-Building"/ ; }, abstract = {BACKGROUND: Blood-based biomarkers (BBBM) for Alzheimer's disease (AD) are entering clinical practice with new clinical practice guidelines and the first FDA-approved blood test. Their implementation will depend not only on assay performance but also on public willingness, trust, and understanding of probabilistic results. We examined attitudes towards BBBM in the general population and psychosocial factors that may facilitate or hinder uptake.

METHODS: We conducted an online cross-sectional survey among adults aged ≥ 35 years (M = 51.08, SD = 9.79) in the Czech Republic (N = 666). The survey assessed willingness to undergo BBBM testing, sociodemographic characteristics, experience with AD, depressive symptoms (Patient Health Questionnaire, PHQ-9), concerns about developing AD, and medical distrust (Medical Distrust Index, MDI). Logistic regression models (unweighted and weighted for gender and region) were estimated to examine the association with willingness. Open-ended responses were analyzed thematically to identify motivators and barriers.

RESULTS: Overall, 92.8% of participants reported that they would undergo BBBM testing. Greater concern about developing AD was the strongest facilitator (OR = 1.59-2.34). Having AD in a close family member was associated with lower willingness (OR = 0.31-0.43), as was higher medical distrust (MDI OR = 0.79 in the fully weighted model). Education, age, gender, depressive symptoms, and AD knowledge were not significantly associated with willingness. Qualitative analyses showed that participants viewed BBBM as a way to "take action in time", "know one's health status" and "prepare for the future", whereas fear of AD, preference "not to know", perceived lack of treatment, test uncertainty/"only probability", and privacy concerns were common barriers.

CONCLUSIONS: Public willingness to undergo BBBM testing is high, but psychosocial barriers, particularly familial experience of AD and medical distrust, may limit real-world uptake. Addressing these barriers through targeted education, probabilistic risk communication, and trusted primary-care pathways will be essential for the responsible implementation of BBBM in clinical practice.}, } @article {pmid42152645, year = {2026}, author = {Kishor, K and Arora, A and Yashika, and Yadav, S and Singh, A}, title = {Extracellular Vesicles in Alzheimer's Disease: Mechanisms, Immunotherapy Links, and Clinical Translation.}, journal = {Current pharmaceutical design}, volume = {}, number = {}, pages = {}, doi = {10.2174/0113816128464813260512100753}, pmid = {42152645}, issn = {1873-4286}, abstract = {Alzheimer disease (AD) is a progressive neurodegenerative disorder characterized by synaptic dysfunction, neuroinflammation, and cognitive impairment. Although amyloid-β and tau continue to serve as core biomarkers and therapeutic targets, the clinical efficacy of recent biologic agents targeting amyloid has led to a new paradigm in AD treatment. Nevertheless, emerging data show that lipid metabolism is an important and well-established aspect of AD pathophysiology rather than a new theory. Lipid processing in microglia, astrocytes, and neurons is disrupted, leading to chronic inflammation, impaired amyloid clearance, mitochondrial dysfunction, and synaptic dysfunction. This review critically analyzes how lipid accumulation and lipid droplet biology contribute to Alzheimer's disease using cellular, animal, and human studies. Special focus is placed on enzymatic regulators such as DGAT2, cholesterol transport, and neuron-glia metabolic linkages. This review synthesizes existing mechanistic and translational data to emphasize lipid dysregulation as a complementary therapeutic target and potential biomarker axis that may improve current amyloid- and taudirected therapeutic strategies.}, } @article {pmid42152660, year = {2026}, author = {Younas, S and Badshah, I and Akbar, K and Al-Otaibi, JS and Khan, H}, title = {3-(2,4-Dimethylbenzylidene)-6-chloroindolin-2-one Alleviates Memory Impairment in D-Galactose-induced Alzheimer Like Pathology in a Mouse Model.}, journal = {Current neuropharmacology}, volume = {}, number = {}, pages = {}, doi = {10.2174/011570159X434400260421062719}, pmid = {42152660}, issn = {1875-6190}, abstract = {INTRODUCTION: Oxidative stress and neuroinflammation are the main contributors to Alzheimer's disease (AD). The current study evaluated the neuroprotective efficacy of 3-(2,4- dimethylbenzylidene)-6-chloroindolin-2-one (DMO) against D-Galactose (GAL)-induced neuroinflammation, oxidative stress, and memory impairment in mice.

METHODS: Swiss Male albino mice weighing (25-30 g) were assigned to five experimental groups (n=6) (i) Normal group (received normal saline 0.9%) (ii) Control group (received GAL 100 mg/kg i.p) (iii) Standard group (received Donepezil 5 mg/kg + GAL 100 mg/kg i.p) (iv) Treatment group 1 (received DMO 5 mg/kg + GAL 100 mg/kg i.p) and Treatment group 2 (received DMO 10 mg/kg + GAL 100 mg/kg i.p) once daily for 8 weeks. After treatment, the mice were subjected to behavioral analysis, followed by sacrifice for further analysis.

RESULTS: DMO alleviated GAL-induced cognitive impairment as shown by the Morris water maze test (MWM), Y-maze, elevated plus maze (EPM), and open field (OF) test. Brain tissue histology showed reversal of distorted neuronal structures and decreased pyknosis upon DMO treatment. DMO also decreased the levels of Glutathione-S-Transferase (GST), reduced Glutathione (GSH), and catalase (CAT), concomitant with increased lipid peroxidase (LPO). Furthermore, levels of TNF-α and NF- ҡB, were significantly reduced in the DMO treatment groups as quantified by ELISA. In addition, Reverse transcription polymerase chain reaction (RT-PCR) showed a substantial decrease in the expression of β-amyloid and Tau protein.

DISCUSSION: The results showed that DMO inhibits D-gal induced oxidative stress, neuroinflammation and consequently alleviates memory impairment.

CONCLUSION: Our novel findings suggest that DMO could be a promising therapeutic modality for the treatment of brain aging-associated disorders.}, } @article {pmid42152670, year = {2026}, author = {Bjørklund, G and Izmailovich, M and Glushkova, N and Semenova, Y}, title = {Vitamin E in Alzheimer's Disease: A Perspective on Antioxidant Therapy.}, journal = {Current medicinal chemistry}, volume = {}, number = {}, pages = {}, doi = {10.2174/0109298673386940251024110821}, pmid = {42152670}, issn = {1875-533X}, abstract = {This study explores the relationship between vitamin E and Alzheimer's disease (AD), a neurodegenerative disorder characterized by cognitive decline, memory loss, and language impairment. Vitamin E is a fat-soluble antioxidant crucial in protecting cells from oxidative damage. The biochemistry and bioavailability of vitamin E are discussed, including its absorption, transport, and storage in the body. The section on interactions between vitamin E and other nutrients and herbals highlights how combining vitamin E supplements with other supplements or medications can affect its absorption, metabolism, and effectiveness. This study also discusses the potential therapeutic effects of vitamin E on AD, including its ability to reduce oxidative stress and inflammation, which are thought to play a role in the pathophysiology of AD. It explores the synergistic effects of vitamin E with pharmaceuticals and potential side effects, and covers the use of vitamin E in combination with other drugs for AD treatment, such as cholinesterase inhibitors and memantine, as well as the possible adverse effects of vitamin E supplementation. Overall, this study highlights the importance of vitamin E in preventing and managing AD and underscores the need for further research in this area.}, } @article {pmid42152699, year = {2026}, author = {Oba, GMJ and Sahu, R and Shah, K and Singh, AP}, title = {Interesting Potential Derivatives Based on the Coumarin Scaffold for the Treatment of Alzheimer's Disease.}, journal = {Mini reviews in medicinal chemistry}, volume = {}, number = {}, pages = {}, doi = {10.2174/0113895575449515260428094401}, pmid = {42152699}, issn = {1875-5607}, abstract = {As the most common and deadly age-related neurodegenerative disease, Alzheimer's Disease (AD) affects the vast majority of elderly individuals. As such, new drugs are being produced, and their safety is still being assessed. Coumarin-based medications are among the most important pharmacophores in both natural and synthetic medicinal compounds. Targeting several essential receptors or enzymes, this six-membered aromatic heterocycle, linked by two oxygen atoms, has numerous therapeutic applications in research and offers many opportunities for future improvements in anti-Alzheimer's drugs. Several coumarin compounds have been shown to inhibit not just enzymes and receptors but also a wide range of additional targets involved in the battle against AD. The expansion of new derivatives based on coumarins in conjunction with other moieties for the treatment of AD is the current focus of research. In order to help scientists design effective drugs with the right pharmacological activity, this study sheds light on the current therapeutic expansion of coumarin-based derivatives as well as their synthesis methods.}, } @article {pmid42152706, year = {2026}, author = {Karayat, M and Kaushik, N and Paliwal, D}, title = {Scopoletin as a Potential Therapeutic Agent for Neurodegenerative Disorders: Mechanisms and Perspectives.}, journal = {Current topics in medicinal chemistry}, volume = {}, number = {}, pages = {}, doi = {10.2174/0115680266399675251201111538}, pmid = {42152706}, issn = {1873-4294}, abstract = {Neurodegenerative diseases, such as Alzheimer's and Parkinson's, continue to pose significant challenges due to their complex aetiology and limited treatment options. Scopoletin, a naturally occurring coumarin found in a variety of medicinal plants, is being explored as a potential therapeutic agent because of its broad pharmacological profile. This review investigates scopoletin's neuroprotective potential, with particular emphasis on its antioxidant, anti-apoptotic, and cholinergic-regulating properties. It also highlights its ability to reduce oxidative stress, modulate neurotransmitter balance, and prevent protein aggregation, which are key pathological features of neurodegeneration. Despite promising preclinical findings, further research is required to establish its efficacy, optimise its bioavailability, and evaluate its safety in clinical settings. Overall, scopoletin demonstrates considerable potential as a neuroprotective compound, offering new avenues for the development of innovative therapeutics for neurodegenerative disorders. This comprehensive review aims to provide a foundation for future research and the advancement of scopoletin as a promising agent against neurodegeneration.}, } @article {pmid42157023, year = {2026}, author = {Rybicki-Kler, CI and Brooks, IAW and Jedrasiak-Cape, I and Deng, T and Avila, C and Brouns, E and Lekander, A and Ahmed, OJ}, title = {Reciprocal molecular and cellular cholinergic working memory impairments in Alzheimer's disease model mice.}, journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association}, volume = {22}, number = {5}, pages = {e71490}, doi = {10.1002/alz.71490}, pmid = {42157023}, issn = {1552-5279}, support = {R01MH129282/MH/NIMH NIH HHS/United States ; R34NS127101/NS/NINDS NIH HHS/United States ; P50NS123067/NS/NINDS NIH HHS/United States ; T32NS007222/NS/NINDS NIH HHS/United States ; T32NS076401/NS/NINDS NIH HHS/United States ; P30AG072931/AG/NIA NIH HHS/United States ; F31AG087629/AG/NIA NIH HHS/United States ; AARG-NTF-21-846572/ALZ/Alzheimer's Association/United States ; T32DC000011/DC/NIDCD NIH HHS/United States ; G102865/321033//Berger Endowment/ ; }, mesh = {Animals ; *Alzheimer Disease/genetics/metabolism/physiopathology ; Disease Models, Animal ; *Receptor, Muscarinic M1/metabolism/genetics ; *Memory, Short-Term/physiology ; Mice ; Mice, Transgenic ; *Memory Disorders/metabolism/genetics ; *Cholinergic Neurons/metabolism ; Acetylcholine/metabolism ; Humans ; }, abstract = {INTRODUCTION: The degeneration of basal forebrain cholinergic neurons is a key pathophysiological feature of Alzheimer's disease (AD). These cholinergic neurons target cortical neurons including those in the granular retrosplenial cortex (RSG) to facilitate essential cognitive functions. At the cellular level, acetylcholine supports working memory by inducing persistent firing that outlasts the stimulus, but how such cholinergic-induced persistent firing is altered in AD remains unknown.

METHODS: Using multiscale molecular and cellular analyses, we investigated neuron type-specific transcriptomic and physiological impairments of cholinergic persistent signaling in the RSG of 5xFAD mice.

RESULTS: Cholinergic inputs to RSG were reduced in 5xFAD mice. Expression of the Chrm1 gene encoding M1 muscarinic receptors was also reduced in RSG neurons, coupled with impaired cellular persistent firing.

DISCUSSION: The loss of M1 receptors suggests that allosteric M1 modulators being considered for treatment of AD symptoms may not be as effective on key cell types, necessitating further multiscale investigation.}, } @article {pmid42157276, year = {2026}, author = {Krick, KE and Chalk, JL and Lykins, JT and Wang, HP and Ferguson, CA and Shahid, SS and Weekman, EM and Wilcock, DM}, title = {TNF inhibition differentially impacts regional Abeta immunotherapy efficacy in the humanized hAb[SAA] mouse model.}, journal = {Alzheimer's research & therapy}, volume = {}, number = {}, pages = {}, doi = {10.1186/s13195-026-02084-7}, pmid = {42157276}, issn = {1758-9193}, support = {1RF1NS130834//Foundation for the National Institutes of Health/ ; }, abstract = {BACKGROUND: The FDA approval of amyloid beta (Aβ) targeting immunotherapies offered the first opportunity to clinically modify Alzheimer's disease progression and give patients back precious months in the course of disease progression. The administration of these therapeutics has uncovered a common side effect called Amyloid Related Imaging Abnormalities (ARIA). While often asymptomatic, these adverse events have potential to escalate, and their commonality has encouraged further studies to mitigate their incidence. Increases in immune activation are important in immunotherapy action, though heightened release of cytokines have also been shown in ARIA development. TNF has been shown in early studies to increase with immunotherapy administration and subsequent ARIA development and TNF itself has been implicated in blood brain barrier dysfunction which could contribute to hemorrhagic ARIA (ARIA-H) development.

METHODS: This study assessed hemorrhage outcomes in an aged mouse model using MRI and Prussian blue histology, explored transcriptomic and protein changes with NanoString nCounter and Meso Scale Discovery, and we performed immunohistochemical stains for microglia/macrophages, astrocytes, and pericyte changes.

RESULTS: In this study, we established ARIA-H pathology in a humanized mouse model (hAβ[SAA]) via chronic Aβ immunotherapy administration. We saw significant hemorrhagic lesions in our model, despite low levels of cortical cerebral amyloid angiopathy (CAA) suggesting a role for CAA as a risk factor for ARIA but potentially not its driver. We also explored the role of TNF in ARIA progression by inhibiting soluble TNF alongside immunotherapy administration as a potential combination therapeutic to address ARIA. With TNF inhibition, we saw a reduction of hemorrhages in the hippocampus, but not in the cortex, suggesting a regional effect. Further, we saw additional regional differences between the cortex and hippocampus with TNF inhibition including macrophage activation markers and amyloid levels, suggesting a differential role for TNF signaling in these areas and a potential heterogeneity of cellular responses in each region.

CONCLUSION: We induced ARIA without significant cortical CAA pathology and identified regional differences with TNF inhibition including a potential benefit of treatment in the hippocampus and possible detriment to pathology in the cortex.}, } @article {pmid42157624, year = {2026}, author = {Granberg, T and Blystad, I and Fällmar, D and Savitcheva, I and van Westen, D and Westman, E}, title = {[Brain imaging in cognitive disorders - from diagnosis to treatment and monitoring].}, journal = {Lakartidningen}, volume = {123}, number = {}, pages = {}, pmid = {42157624}, issn = {1652-7518}, mesh = {Humans ; *Cognition Disorders/diagnostic imaging/therapy ; Magnetic Resonance Imaging ; Tomography, X-Ray Computed ; *Neuroimaging/methods ; Brain/diagnostic imaging ; Alzheimer Disease/diagnostic imaging/therapy ; }, abstract = {Brain imaging is essential in the diagnostic workup of cognitive disorders. Computed tomography (CT) is usually the first-line method due to accessibility and patient comfort, whereas magnetic resonance imaging (MRI) offers higher diagnostic precision and is required before anti-amyloid therapy. MRI adds value by detecting microvascular pathology, enabling volumetric analysis, and ensuring safe monitoring of amyloid-related imaging abnormalities (ARIA). National Swedish MRI protocols and structured reporting templates support harmonized diagnostics and follow-up. Nuclear medicine methods are useful for complex cases to assess glucose metabolism, amyloid burden or dopamine transport function. With emerging treatment options for Alzheimer's disease, standardized imaging and close collaboration across specialties are essential for upscaling diagnostic routines and for safe and efficient care.}, } @article {pmid42157845, year = {2026}, author = {Bouton, J and Bretteville, A and Tresadern, G and Shaffer, P and Austin, N and Buijnsters, P and Cedervall, EP and Darville, N and Fonteyn, I and Leenaerts, J and Lamenca, CM and Mertens, L and Peeters, D and Velter, AI and Roosbroeck, YV and Ebneth, A and Bartolomé, JM and Trabanco, AA and Oehlrich, D}, title = {Discovery of 5‑Azaindole Inhibitors of O‑GlcNAcase for the Treatment of Alzheimer's Disease and Related Tauopathies.}, journal = {ACS medicinal chemistry letters}, volume = {17}, number = {5}, pages = {1096-1105}, pmid = {42157845}, issn = {1948-5875}, abstract = {Alzheimer's disease (AD) is a neurodegenerative disorder characterized by extracellular amyloid-β plaque accumulation and intracellular tau neurofibrillary tangles, with tau pathology correlating more closely with cognitive decline. Modulation of tau phosphorylation through the regulation of O-GlcNAcylation, a post-translational modification controlled by O-GlcNAcase (OGA), represents a promising therapeutic strategy. In this study, we report the optimization of a pyrimidine hit identified by high-throughput screening, leading to the discovery and optimization of a novel series of 5-azaindole-based OGA inhibitors. From this series, compound 24 was identified as an in vivo tool candidate that demonstrated a favorable pharmacokinetic profile and measurable brain exposure. Pharmacodynamic studies in murine models demonstrated that compound 24 induced a significant and transient elevation of brain O-GlcNAcylation levels, confirming the in vivo target engagement. These findings underscore the potential of 5-azaindole-based OGA inhibitors as a novel validated chemotype for modulation of O-GlcNAcylation.}, } @article {pmid42157881, year = {2026}, author = {Jabbari, S and Zakaria, ZA and de Menezes, IRA and Mohammadi, S}, title = {Rhamnazin attenuates Amyloid β-Peptide (1-42) induced spatial memory impairments by modulation of BDNF-ERK signaling pathway.}, journal = {3 Biotech}, volume = {16}, number = {6}, pages = {200}, pmid = {42157881}, issn = {2190-572X}, abstract = {Rhamnazin (Rham), a natural flavonoid, possesses various medicinal benefits including anti-inflammatory, antioxidant, antiangiogenic, and antibacterial activities. Additionally, Rham showed neuroprotective effects when assessed using the chronic stress-induced cognitive impairment assay. In this intriguing investigation, researchers delved into the working memory and spatial reference memory of Rham, utilizing a rat model of Alzheimer's disease (AD) induced by amyloid β1-42 (Aβ1-42). Administering Aβ1-42 directly into the ventricles led to notable cognitive impairments in behavioral assessments of rats with AD. However, chronic treatment of Rham (30, 60, and 120 mg/kg) once per day during five consecutive days improved the cognitive functions of AD-induced rats in a dose-dependent manner which was not observed following the acute Rham treatment. Concurrently, Rham administration also increased the levels of BDNF and phosphorylated ERK in the hippocampus. Moreover, the cognitive boost triggered by Rham was replicated through the overproduction of BDNF in the hippocampus. However, this effect was thwarted by either the bilateral delivery of lentiviruses expressing BDNF shRNA into the hippocampus or by a targeted injection of an ERK inhibitor. In conclusion, chronic treatment with Rham improves the cognitive deficits in AD-induced rats possibly via the upregulation of BDNF/ERK signaling pathway in hippocampus.}, } @article {pmid42157911, year = {2025}, author = {Waqar, Z and Sethi, P and Jain, D and Singh, K and Alsaidan, OA and Alzarea, SI and Gupta, JK and Saxena, S and Sharma, MC}, title = {Precision Medicine in Neurodegenerative Diseases: Genomic Approaches to Target Amyloid-β, Tau, and Alpha-Synuclein Pathways.}, journal = {Current genomics}, volume = {26}, number = {6}, pages = {469-494}, pmid = {42157911}, issn = {1389-2029}, abstract = {Neurodegenerative diseases, including Alzheimer's and Parkinson's disease, are characterized by the pathological aggregation of proteins such as amyloid-β, tau, and alpha-synuclein. These hallmark proteins play central roles in disease progression and represent promising targets for therapeutic intervention. Advances in precision medicine, driven by genomic technologies such as CRISPR-Cas systems, RNA-based therapies, and high-throughput sequencing, have enabled the development of tailored strategies to modulate these pathological pathways. This review examines the integration of genomic approaches in targeting amyloid-β, tau, and alpha-synuclein, emphasizing their potential to mitigate disease progression and improve patient outcomes. We highlight current progress in preclinical and clinical studies, discuss challenges associated with translating these therapies into clinical practice, and explore future directions for achieving therapeutic precision in neurodegenerative disorders. By examining the interplay of genetic, molecular, and therapeutic innovations, this review underscores the transformative potential of genomic medicine in addressing the unmet needs of neurodegenerative disease treatment.}, } @article {pmid42157943, year = {2026}, author = {Li, R and Yao, J and Peng, W and Zheng, L and Wu, X and Shui, X and Zheng, X and Tian, W and Wang, L and Zhou, Y and Ruan, X and Pan, X and Zhang, T and Liu, Y and Lee, TH and Chen, D}, title = {A Novel PROTAC Confers a Dual Benefit Against Amyloid and Tau Pathology in Alzheimer's Disease via DAPK1 Degradation.}, journal = {International journal of biological sciences}, volume = {22}, number = {9}, pages = {4724-4746}, pmid = {42157943}, issn = {1449-2288}, mesh = {Animals ; *Alzheimer Disease/metabolism/drug therapy ; *Death-Associated Protein Kinases/metabolism/genetics ; Mice ; *tau Proteins/metabolism ; Proteolysis Targeting Chimera ; Humans ; Female ; Phosphorylation ; Proteolysis ; Amyloid beta-Peptides/metabolism ; }, abstract = {Alzheimer's disease (AD) is a neurodegenerative disorder that is caused by multiple factors, characterized by a progressive decline in cognitive ability, extracellular amyloid-β (Aβ) plaques, and intracellular neurofibrillary tangles composed of hyperphosphorylated tau. Current treatment strategies can provide only symptomatic treatment or limited efficacy, highlighting the need to intervene in the upstream regulatory factors that drive both amyloid and tau pathologies. Death-associated protein kinase 1 (DAPK1) is a key driver upstream of both amyloid precursor protein processing and tau phosphorylation, simultaneously promoting amyloidogenesis and tau-mediated pathology in AD. In this study, we developed CP1, a bifunctional proteolysis-targeting chimera (PROTAC), to recruit E3 ubiquitin ligase to DAPK1, thereby inducing the ubiquitination and proteasomal degradation of DAPK1. CP1 efficiently eliminated the DAPK1 protein in primary cortical neurons without affecting its mRNA level, resulting in reduced Aβ generation and tau hyperphosphorylation. In vivo, upon systemic administration, CP1 effectively crossed the blood-brain barrier, degraded DAPK1, and consequently reduced the Aβ plaque burden and mitigated neuroinflammation in female 5xFAD mice. In a AAV-hTau-P301L tauopathy model, CP1 treatment suppressed tau hyperphosphorylation, preserved NeuN- and MAP2-positive neurons, attenuated astrocytic and microglial activation, and ultimately restored learning and memory abilities in both male and female mice. In summary, these findings demonstrate that degrading DAPK1 via a PROTAC strategy simultaneously mitigates both amyloid and tau pathology, indicating that CP1 is an effective candidate for disease-modifying therapy.}, } @article {pmid42158156, year = {2026}, author = {Li, R and Chen, Z and Jiang, Y and Yan, S and He, J and Yan, J and Zong, G and Yi, Z and Ren, X and Jia, B}, title = {Electroacupuncture for treating the cognitive symptoms of Alzheimer's disease: a randomized controlled trial.}, journal = {Frontiers in psychiatry}, volume = {17}, number = {}, pages = {1834514}, pmid = {42158156}, issn = {1664-0640}, abstract = {INTRODUCTION: The long-term efficacy of electroacupuncture (EA) in treating cognitive symptoms of Alzheimer's disease (AD) remains unclear, and its time-dependent relationship requires further investigation.

METHODS: Sixty-six patients were allocated to the EA or sham EA group, with stimulation for 20 minutes, for a 24-week treatment period, and were followed-up at 4 weeks. The primary outcome was the mean change in the Alzheimer's Disease Assessment Scale-Cognitive (ADAS-Cog) score. Activities of daily living and behavioral and psychological symptoms were also assessed.

RESULTS: After 24 weeks of intervention, patients demonstrated significant improvements in ADAS-Cog scores, with sustained benefits observed during the 4-week follow-up period. In addition, improvements were observed in activities of daily living and behavioral and psychological symptoms.

DISCUSSION: The use of EA as a promising nonpharmacological intervention for AD.

CLINICAL TRIAL REGISTRATION: https://www.chictr.org.cn/showproj.html?proj=151275, identifier (ChiCTR2200056329).}, } @article {pmid42158158, year = {2026}, author = {Pozuelo Moyano, B and Orgeta, V and von Gunten, A and Vandel, P and Ma, R and Stewart, R and Mueller, C}, title = {Late-life difficult-to-treat depression and dementia subtypes: a naturalistic cohort study using electronic health records.}, journal = {Frontiers in psychiatry}, volume = {17}, number = {}, pages = {1795874}, pmid = {42158158}, issn = {1664-0640}, abstract = {INTRODUCTION: Late-life difficult-to-treat depression (LL-DTD) and dementia frequently coexist in later life, but it remains unclear whether clinical and sociodemographic characteristics, as well as medication exposure patterns, differ across dementia subtypes among older adults with both conditions.

METHODS: We analysed anonymised electronic health records from a south London catchment area. We included patients aged ≥60 years at first recorded depression diagnosis with a dementia diagnosis. LL-DTD was defined as inadequate response to ≥2 antidepressant trials. Dementia diagnoses were classified as Alzheimer's disease (AD), vascular dementia (VD), mixed AD/VD, dementia with Lewy bodies (DLB), or other/unspecified dementia. Around the index depressive episode, we captured sociodemographics, depressive symptoms, physical comorbidity, and medication indicators. We used multivariate logistic regression to examine cross-sectional correlates distinguishing dementia subtypes (with AD as reference) within the LL-DTD and dementia sample. We conducted stratified analyses comparing non-AD versus AD dementia by the temporal order of dementia and depression diagnoses.

RESULTS: Among 890 older adults with LL-DTD and dementia, AD was the most common subtype (33.9%), followed by mixed AD/VD (22.5%), VD (22.2%), other/unspecified dementia (15.2%), and DLB (6.2%). Depressive symptom profiles and psychotropic treatment history were broadly similar across subtypes. Compared with AD, VD was associated with greater functional impairment, while greater physical comorbidity burden was more evident in VD and mixed AD/VD.

DISCUSSION: Somatic multimorbidity and functional impairment provided the clearest clinical separation between subgroups, while depressive symptom patterns and medication exposure appeared largely non-specific across dementia subtypes. This underscores the importance of multimorbidity and physical health burden in understanding heterogeneity of dementia outcomes in LL-DTD.}, } @article {pmid42158310, year = {2025}, author = {Jain, SK and Sharma, S and Singh, VK and Matreja, PS}, title = {Transplantation of human glial cells into murine brains: A systematic review of efficacy and safety in neurodegenerative disorders.}, journal = {Current journal of neurology}, volume = {24}, number = {2}, pages = {154-167}, pmid = {42158310}, issn = {2717-011X}, abstract = {Background: Neurodegenerative diseases impact millions of individuals globally. Over the years, brain research has predominantly focused on neurons, but attention is now shifting to glial cells, the brain's support cells, which play a vital role in neurodegenerative disorders. Therefore, glial cell transplantation represents a groundbreaking treatment approach for various neurodegenerative disorders, with the potential to restore neuronal function. We evaluated the evidence on the therapeutic effectiveness of human glial cell transplantation in neurodegenerative disorders. Methods: The literature review was performed in PubMed, Scopus, and Web of Science from 2000 to 2024. The authors independently reviewed the screened articles. The study outcomes on cell differentiation, long survival restoration of neuron function, and adverse outcomes were analyzed. Results: Study results highlight promising findings, including astrocytes improving motor function and slowing disease progression in neurodegenerative animal models through neurotrophic factor secretion and reduced inflammation. Similarly, microglia transplantation has demonstrated effectiveness in reducing α-synuclein toxicity in Parkinson's disease (PD), removing amyloid-β plaques in Alzheimer's disease (AD) models, and enhancing neuronal survival. Additionally, in demyelinating pathologies like multiple sclerosis (MS), oligodendrocyte transplantation promotes remyelination, restoring axonal conduction and enhancing functional outcomes. Cografting astrocytes with neuro progenitor cells significantly improved dopamine neuron engraftment and survival for at least 6 months post-transplantation. Conclusion: The transplantation of human glial cells offers promising therapeutic potential for neurodegenerative disorders, improving neuronal survival, restoring damaged circuits, and reducing disease progression.}, } @article {pmid42159155, year = {2026}, author = {Cummings, JL and Atri, A and Sano, M and Zetterberg, H and Scheltens, P and Knop, FK and Johannsen, P and Wichmann, CA and Abschneider, RM and Leon, T and Taylor, J and Feldman, HH}, title = {Plain language summary: the evoke(+) studies of semaglutide for early Alzheimer's disease.}, journal = {Neurodegenerative disease management}, volume = {}, number = {}, pages = {1-10}, doi = {10.1080/17582024.2026.2666332}, pmid = {42159155}, issn = {1758-2032}, } @article {pmid42159271, year = {2026}, author = {Shi, J and Du, Y and Wang, H and Zhang, N and Chen, W and Ni, J and Lu, X and Sun, Y and Wang, G and Liu, J and Zhang, W and Wei, M and Li, T and Zhou, B and Li, F and Wei, C and Yao, L and Xie, H and Tian, J and , }, title = {A paradigm of the diagnosis and treatment for the whole process of Alzheimer's disease.}, journal = {Annals of medicine}, volume = {58}, number = {1}, pages = {2672193}, pmid = {42159271}, issn = {1365-2060}, mesh = {Humans ; *Alzheimer Disease/diagnosis/therapy ; Biomarkers/metabolism/blood ; Disease Progression ; *Medicine, Chinese Traditional/methods ; Early Diagnosis ; Severity of Illness Index ; Practice Guidelines as Topic ; }, abstract = {INTRODUCTION: The clinical management of Alzheimer's disease (AD) is still constrained by the fact that its incompletely understood pathogenesis, difficulty in early diagnosis and the limited long-term treatment benefits so far. This article summarizes a regional perspective on the diagnosis and treatment of AD from the Alzheimer's Disease Chinese (ADC) guideline working group, aiming to improve the whole-process management of AD.

DISCUSSION: The article presents a comprehensive overview of a proposed diagnostic and therapeutic paradigm for AD, consisting of a three-dimensional diagnostic framework and a sequential therapy concept. Crucially, while biological biomarkers of AD are present at all stages, they may be unrelated to clinical severity. To address this, the diagnostic framework combines core clinical criteria with early-changing biomarkers, syndrome staging and traditional Chinese medicine (TCM)-based pattern phenotyping. This integrated, simplified and practical approach enhances diagnostic certainty and its correlation with clinical severity. This sequential therapy is a stage-adaptive treatment plan adjusted according to the disease progression, utilizing a dynamic, multi-target combination therapy. Unlike the existing unchanging single-target therapies, this approach provides specific mechanistic interventions tailored to each stage to prolong efficacy and delay disease progression.

CONCLUSIONS: This paradigm provides a whole-process, stage-oriented approach to AD diagnosis and management that may improve translational relevance, clinical applicability and continuity of care in real-world settings. Future cohort-based validation studies are needed to confirm its diagnostic performance and clinical benefits, and to refine its implementation.}, } @article {pmid42159313, year = {2026}, author = {Tajika, A and Omae, K and Sahker, E and Luo, Y and Takekita, Y and Furukawa, TA}, title = {Public acceptance and expectations for Lecanemab: Insights from a Smallest Worthwhile Difference study.}, journal = {Psychiatry and clinical neurosciences}, volume = {}, number = {}, pages = {}, doi = {10.1111/pcn.70082}, pmid = {42159313}, issn = {1440-1819}, abstract = {AIM: To determine the smallest worthwhile difference (SWD) for lecanemab, a disease-modifying drug for Alzheimer's disease (AD), among the general Japanese population using a benefit-harm trade-off method.

METHODS: We conducted an online survey with 658 participants to evaluate their preferences for the treatment effect of lecanemab, given its associated risks and high cost. We calculated SWD as the minimum required increase in the possibility of maintaining cognitive function (relative to the 50% without lecanemab) that patients would accept in exchange for the burdens of treatment (adverse effects, costs, other inconveniences). We examined the median SWD for two scenarios: a family member (SWD-families) and others (SWD-others), and analyzed subgroup differences.

RESULTS: The median SWD revealed a 15% increase for SWD-families and SWD-others. This value exceeds the drug's actual efficacy of an 8% increase. Notably, 17% of respondents reported zero SWD, driven by an intense fear of AD and possibly high expectations from media coverage. Including these participants, nearly half of the respondents considered the current effect worthwhile. No noticeable difference was found between the SWD-families and SWD-others.

CONCLUSION: Based on Japanese clinical scenarios, the public's median expectation for lecanemab exceeds its efficacy, though its current benefit remains acceptable to nearly half the population. These findings underscore that the SWD is shaped by psychological drivers, including fear and hope, rather than just reasoned evaluation. Clinicians must manage these expectations, accounting for highly heterogeneous treatment preferences. Future research should account for emotional factors that can overshadow a rational assessment of treatment value.}, } @article {pmid42160117, year = {2026}, author = {Chen, H and Wang, T and Xia, K and Li, X and Yao, X and Huang, W}, title = {Emerging Nanoreactors for Precision Disease Treatment: From Principles to Biomedical Applications.}, journal = {Small (Weinheim an der Bergstrasse, Germany)}, volume = {}, number = {}, pages = {e73859}, doi = {10.1002/smll.73859}, pmid = {42160117}, issn = {1613-6829}, support = {BK20251864//Basic Research Program of Jiangsu/ ; 62288102//Natural Science Foundation of China/ ; //Disciplinary Fund of the School of Pharmaceutical Sciences/ ; 20250285//Nanjing Tech University Teaching Reform Project/ ; }, abstract = {Inspired by natural cellular compartments, nanoreactors are spatially confined nanostructures that precisely regulate chemical and biological reactions and act as high-performance catalytic nanocontainers. Multifunctional integration of these systems surmounts the inherent limitations of conventional therapeutic modalities. This review focuses on recent breakthroughs in organic and organic-inorganic hybrid nanoreactors, highlighting three core effects: (1) the spatial confinement effect, which elevates the reactant concentration, accelerates mass transfer, lowers activation energy, modulates electronic states, and boosts reaction rates by orders of magnitude; (2) the synergistic effect of active sites, which enables efficient cascade reactions via spatially segregated or hierarchical catalytic architectures; (3) the stimuli-responsive effect, which dynamically controls catalysis and cargo release under endogenous (pH, enzymes, ROS) or exogenous (light, temperature) cues. Typical nanoreactors (liposomes, polymeric micelles/vesicles, mesoporous silica, protein cages, and organic-inorganic hybrids) are systematically discussed regarding structural merits and biomedical applications in treating diabetes, rheumatoid arthritis (RA), chronic wound healing, cancer, and Alzheimer's disease (AD). Current challenges and future perspectives are also addressed. Intelligent nanoreactors are expected to offer immense potential for disease diagnosis and therapy.}, } @article {pmid42160848, year = {2026}, author = {Zheng, M and Yang, M and Su, W and Tian, L and Gao, W}, title = {Targeting microglia: A new strategy for the treatment of Alzheimer's disease.}, journal = {Journal of neuroimmunology}, volume = {418}, number = {}, pages = {578966}, doi = {10.1016/j.jneuroim.2026.578966}, pmid = {42160848}, issn = {1872-8421}, abstract = {Alzheimer's disease (AD), a progressive neurodegenerative disorder characterized by amyloid-β (Aβ) plaques, neurofibrillary tangles, and chronic neuroinflammation, remains without curative therapies. Emerging evidence underscores microglia, the brain's resident immune cells, as pivotal players in AD pathogenesis, exerting dual roles in neuroprotection and neurotoxicity. This review synthesizes current knowledge on microglial dynamics, including their heterogeneous activation states (e.g., disease-associated microglia), metabolic reprogramming, aging-related dysfunction, and subset heterogeneity, which collectively influence Aβ clearance, tau propagation, and synaptic integrity. We highlight the interplay between microglial receptors-such as TREM2, APOE, and neurotransmitter receptors (e.g., cholinergic, glutamatergic, and cannabinoid receptors)-and AD pathology, emphasizing their roles in modulating neuroinflammation, phagocytosis, and neuronal excitotoxicity. Furthermore, we evaluate therapeutic strategies targeting microglia, including pharmacologic modulation of neuroinflammatory pathways, metabolic interventions, and cell transplantation, which aim to restore homeostatic microglial functions. Challenges in clinical translation, such as temporal specificity of interventions and microglial plasticity, are critically discussed. By integrating recent advances in single-cell genomics and neuroimmunology, this review provides a roadmap for developing microglia-centric therapies to disrupt the vicious cycle of neuroinflammation and neurodegeneration in AD, offering novel insights for future research and therapeutic innovation.}, } @article {pmid42160956, year = {2026}, author = {Yan, Y and Hu, D and Kong, L and Li, K and Su, J and Wu, Y and Zhan, H and Zhang, H and Sun, Y and Dou, X and Huang, P and Zhou, J}, title = {Reductions in neuropsychiatric symptoms after lecanemab treatment and their associations with imaging markers of β-amyloid clearance.}, journal = {The journal of prevention of Alzheimer's disease}, volume = {13}, number = {7}, pages = {100600}, pmid = {42160956}, issn = {2426-0266}, abstract = {BACKGROUND: Anti-amyloid-β (Aβ) therapies can slow cognitive decline and reduce cerebral amyloid burden in Alzheimer's disease (AD). Neuropsychiatric symptoms (NPS) are highly prevalent across the disease course and substantially contribute to disability and caregiver burden. However, whether Aβ clearance translates into improvements in NPS remains unclear.

METHOD: We enrolled 144 individuals with AD-related mild cognitive impairment or AD dementia who received intravenous lecanemab infusions. Standardized clinical rating scales, including the Neuropsychiatric Inventory, and amyloid PET were assessed at baseline (V0), 6 months (V1), and 12 months (V2). Longitudinal changes in clinical function and amyloid burden were analyzed.

RESULTS: Lecanemab treatment was associated with robust reductions in amyloid PET biomarkers and significant short-term reductions in NPS scores in patients who completed follow-up. Longitudinal analyses showed that reductions in total NPI scores were significantly associated with amyloid-β clearance in the insular cortex. Reductions in the hyperactivity subsyndrome were associated with amyloid reduction across a broader network, including the frontal and temporal lobes, striatum, and insular cortex.

CONCLUSIONS: In this real-world cohort, lecanemab was associated with short-term reductions in NPS. Changes in NPS severity were linked to regional amyloid-β clearance.}, } @article {pmid42161225, year = {2026}, author = {McNamara, O and Delany, T and Kwakowsky, A}, title = {Bumetanide as a potential treatment for neurodegenerative and neurodevelopmental disorders: A systematic review.}, journal = {Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie}, volume = {200}, number = {}, pages = {119533}, doi = {10.1016/j.biopha.2026.119533}, pmid = {42161225}, issn = {1950-6007}, mesh = {*Bumetanide/therapeutic use/pharmacology ; Humans ; Animals ; *Neurodegenerative Diseases/drug therapy/metabolism/physiopathology ; *Neurodevelopmental Disorders/drug therapy/metabolism/physiopathology ; *Sodium Potassium Chloride Symporter Inhibitors/therapeutic use/pharmacology ; Solute Carrier Family 12, Member 2/metabolism ; }, abstract = {Neurological disorders represent a major global health burden, affecting an estimated 3.4 billion individuals worldwide. Bumetanide, a clinically approved loop-diuretic and antagonist of the Na[+] -K[+]-Cl[-] cotransporter NKCC1, has recently emerged as a candidate for repurposing in the treatment of neurological disorders. Disrupted excitation-inhibition balance, driven in part by depolarizing GABAA receptor signaling resulting from altered chloride homeostasis, has been implicated across multiple neurodegenerative and neurodevelopmental conditions. This systematic literature review evaluated preclinical and clinical evidence for the efficacy of bumetanide across a range of neurological disorders, including Alzheimer's, Parkinson's, and Huntington's disease, autism spectrum disorder, schizophrenia, tuberous sclerosis, fragile X syndrome, Down syndrome, and Angelman syndrome. Across in vivo and ex vivo models, bumetanide frequently restored hyperpolarizing GABAergic activity and attenuated behavioral and cognitive abnormalities, although translational relevance is constrained by limited central nervous system penetration following systemic administration. Clinical evidence mainly comes from autism spectrum disorder, where some studies have reported modest improvements in behavioral outcomes and measurable neurophysiological changes, although findings remain inconsistent. Collectively, these findings suggest that NKCC1 inhibition represents a mechanistically relevant but clinically unproven therapeutic strategy. Further research is required to clarify the cellular mechanisms underlying bumetanide responsiveness, optimize delivery to the central nervous system, and identify biomarkers to stratify patients most likely to respond to treatment.}, } @article {pmid42161327, year = {2026}, author = {Vallikivi, JK and Kooyman, M and , and Kirby, J and Nigel Leigh, P and Iacoangeli, A and Al-Chalabi, A and Al Khleifat, A}, title = {CYP2D6 variants in amyotrophic lateral sclerosis: an association study of risk and survival.}, journal = {Brain : a journal of neurology}, volume = {}, number = {}, pages = {}, doi = {10.1093/brain/awag178}, pmid = {42161327}, issn = {1460-2156}, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease with limited therapeutic options. Riluzole remains the only widely available disease-modifying treatment for ALS, yet its survival benefit is modest and likely to vary substantially between patients. Cytochrome P450 2D6 (CYP2D6), is a highly polymorphic enzyme that contributes to interindividual variability in the metabolism of many drugs. CYP2D6 is also expressed in the brain, and experimental and translational studies indicate that brain CYP2D activity can influence local metabolism of neuroactive compounds. Accordingly, CYP2D6 poor function variants have been examined as susceptibility modifiers in the development of other neurodegenerative diseases, including Parkinson's disease and Alzheimer's disease, with heterogenous evidence; however, the role of CYP2D6 in ALS has not been established.}, } @article {pmid42161537, year = {2026}, author = {Fernández-Romero, L and Díez-Cirarda, M and Delgado-Alonso, C and Cabrera-Martin, MN and González-Rosa, JJ and Sanz-Nieto, C and Pérez-Macías, N and Balugo, P and Gómez-Ruiz, N and Matias-Guiu, J and Portolés-Pérez, A and Matias-Guiu, JA}, title = {Long-term effect of transcranial magnetic stimulation and transcranial electrical stimulation in primary progressive aphasia: study protocol for a randomised, double-blind clinical trial (RECONNECT-PLUS).}, journal = {BMJ open}, volume = {16}, number = {5}, pages = {e112999}, pmid = {42161537}, issn = {2044-6055}, mesh = {Humans ; Double-Blind Method ; *Transcranial Magnetic Stimulation/methods ; *Transcranial Direct Current Stimulation/methods ; *Aphasia, Primary Progressive/therapy ; Randomized Controlled Trials as Topic ; Female ; Male ; *Language Therapy/methods ; Treatment Outcome ; Aged ; Middle Aged ; }, abstract = {INTRODUCTION: Primary progressive aphasia (PPA) is a neurodegenerative syndrome associated with Alzheimer's disease and frontotemporal degeneration. Non-invasive brain stimulation (NIBS) is a promising treatment, especially associated with language therapy, but comparative efficacy and long-term effects between the different techniques (transcranial direct current stimulation (tDCS) and transcranial magnetic stimulation (TMS)) remain unknown. The present study aims to investigate the effects of non-invasive brain stimulation, alone or associated (tDCS/TMS/tDCS plus TMS) combined with language therapy delivered during a period of 6 months, in the progression of language impairment in PPA, compared with sham stimulation combined with language therapy.

METHODS AND ANALYSIS: The study is a randomised, double-blinded, parallel, sham-controlled clinical trial. Patients with PPA in early stages (global Clinical Dementia Rating equal to or less than 1) are eligible. They are to be randomised to one of the four treatment arms of the study (active tDCS-active TMS, active tDCS-sham TMS, sham tDCS-active TMS, sham tDCS-sham TMS). All patients will receive language therapy immediately after each session of NIBS, for 6 months. The primary outcome is the Mini-Linguistic State Examination. The secondary outcomes are naming of trained items, Addenbrooke's Cognitive Examination, Interview for Deterioration in Daily Living Activities, Clinical Dementia Rating including behaviour and language domains, Neuropsychiatric Inventory and regional brain metabolism. Exploratory substudies will be conducted including blood biomarkers, quantitative electroencephalography and spontaneous speech assessment.

ETHICS AND DISSEMINATION: The study is registered (ClinicalTrials.gov: NCT07158216) and approved by the Ethics Committee of the Hospital Clinico San Carlos (code 25/309-IC_P_CE). Patients will be enrolled after signing an informed consent form. Study outcomes will be disseminated through presentations at scientific conferences, publications in peer-reviewed journals and other academic forums.

TRIAL REGISTRATION NUMBER: NCT07158216.}, } @article {pmid42161925, year = {2026}, author = {Kim, DY and Kim, SM and Lee, C and Han, IO}, title = {O-GlcNAcylation reprograms microglial inflammatory states and attenuates Alzheimer's disease pathology.}, journal = {Cell death & disease}, volume = {}, number = {}, pages = {}, doi = {10.1038/s41419-026-08862-3}, pmid = {42161925}, issn = {2041-4889}, support = {RS-2024-00346770//National Research Foundation of Korea (NRF)/ ; }, abstract = {Chronic neuroinflammation, primarily driven by microglia, is a hallmark and key contributor to Alzheimer's disease (AD) progression. O-GlcNAcylation, a nutrient-sensitive post-translational modification, has emerged as a key regulator of cellular stress and inflammation, yet its role in microglial activation in AD remains unclear. We observed that hippocampal tissue from AD patients exhibits a marked reduction in O-GlcNAcylation, accompanied by enhanced pro-inflammatory M1 microglial polarization, elevated NF-κB signaling, and NLRP3 inflammasome activation. In an LPS-induced neuroinflammation model exhibiting AD-relevant inflammatory and cognitive features, as well as in in vitro microglial cultures, LPS exposure led to a pronounced decrease in O-GlcNAcylation, particularly within Iba1-positive microglia. Systemic or in vitro treatment with glucosamine (GlcN) effectively restored O-GlcNAc levels, suppressed M1-associated inflammatory pathways, and promoted an anti-inflammatory M2 phenotype. Mechanistically, GlcN enhanced O-GlcNAcylation of NF-κB subunits p65 and c-Rel, limiting their nuclear translocation and downstream pro-inflammatory gene expression. Notably, GlcN treatment ameliorated LPS-induced memory deficits and neuronal loss in mice. Collectively, these findings suggest that O-GlcNAcylation acts as a modulatory regulator of microglial activation and neuroinflammation in AD, and that enhancing O-GlcNAcylation may represent a potential therapeutic strategy to preserve immune homeostasis and neuronal integrity.}, } @article {pmid42162073, year = {2026}, author = {Zamani, NISM and Hamezah, HS and Mediani, A and Ghazali, M and Sadikan, MZ and Jam, FA}, title = {Selective elimination of amyloid-β-induced senescent neuroblastoma cells by Moringa oleifera leaf extract.}, journal = {Scientific reports}, volume = {}, number = {}, pages = {}, doi = {10.1038/s41598-026-53311-y}, pmid = {42162073}, issn = {2045-2322}, support = {Fundamental Research Grant Scheme (FRGS/1/2024/SKK10/MUCM/02/1)//Ministry of Higher Education, Malaysia/ ; (MUCM-MRB/001/2024)//MUCM-MRB joint seed grant/ ; }, abstract = {Accumulation of senescent cells (SnCs) in the ageing brain contributes to Alzheimer's disease (AD) progression by secreting a senescence-associated secretory phenotype (SASP) that exacerbates neuroinflammation and neurodegeneration. Senolytic agents that selectively eliminate SnCs have emerged as a potential therapeutic strategy; however, safer natural alternatives remain underexplored. In this study, we aimed to investigate the senolytic potential of Moringa oleifera leaf extract (MOL) in an in vitro AD-senescence model using SH-SY5Y cells exposed to amyloid-β (Aβ1-42) oligomers. SH-SY5Y cells exposed to 20 µM Aβ oligomers exhibited a senescent phenotype, characterised by increased senescence-associated β-galactosidase (SA-β-gal) positivity and upregulated nuclear expression of p21, p16, and γH2AX. Treatment with 300 µg/mL MOL significantly reduced the number of cells expressing senescence-associated molecular markers and induced apoptosis in SnCs, while attenuating the secretion of pro-inflammatory SASP cytokines, including IL-8 and TNF-α. Overall findings suggest that MOL extract preferentially targets SnCs and mitigates SASP-associated inflammation. These results support the potential of MOL as a natural compound with senolytic activity and provide a foundation for further development into its therapeutic relevance in AD.}, } @article {pmid42162487, year = {2026}, author = {Singh, A and Denkinger, MN and Leuzy, A and Dieckhoff, K and Liu, J and Marques, TM and Monuki, E and Stark, C and Grill, JD and Hom, C and Sultzer, D and Doran, E and Lott, I and Wood, K and Gawronski, B and Gonzalez, L and Choudhury, P and Atri, A and Beach, TG and Serrano, GE and Sajjadi, SA and Van Keuren-Jensen, K and Reiman, EM and Head, E and Ashton, NJ}, title = {A plasma protein signature for cerebral amyloid angiopathy.}, journal = {Acta neuropathologica}, volume = {151}, number = {1}, pages = {}, pmid = {42162487}, issn = {1432-0533}, support = {U24 NS072026/NS/NINDS NIH HHS/United States ; P30 AG019610/AG/NIA NIH HHS/United States ; P30 AG066519/AG/NIA NIH HHS/United States ; contract 211002//Arizona Department of Health Services/ ; contracts 4001, 0011, 05-901 and 1001//Arizona Biomedical Research Commission/ ; P30 AG072980/AG/NIA NIH HHS/United States ; }, mesh = {*Cerebral Amyloid Angiopathy/blood/pathology ; Humans ; Female ; Biomarkers/blood ; Male ; Aged ; Amyloid beta-Peptides ; Aged, 80 and over ; Brain/pathology ; }, abstract = {Cerebral amyloid angiopathy (CAA) is a cerebrovascular disorder characterized by the deposition of amyloid-β (Aβ) in the walls of leptomeningeal and cortical blood vessels that increases risk of intracerebral hemorrhages and progressive cognitive decline. More than 90% of individuals with Alzheimer's disease (AD) exhibit some level of CAA. Notably, in the new era of disease-modifying treatments for AD, CAA is a significant risk factor for amyloid-related imaging abnormalities (ARIA), an adverse event associated with anti-amyloid treatments. Therefore, there is great need for accessible, reliable and accurate in vivo biomarkers (e.g., blood-based) to improve antemortem identification of CAA that would improve risk stratification and reduce symptomatic ARIA. In this study, we employed the Nucleic Acid-Linked Immuno-Sandwich Assay (NULISA™) central nervous system panel for exploratory biomarker quantification in antemortem plasma of participants with neuropathological assessments for CAA from the Banner Sun Health Research Institute Brain and Body Donation Program (N = 251) and independently validated in the University of California Irvine Alzheimer Disease Research Center cohort (N = 110). We evaluated the differential protein expression in antemortem plasma sample taken < 5 years (mean 1.76 ± 1.3) from death using a logistic regression model. We further compared multi-biomarker models and found that a combination of CRP, IL4, CCL11, NPY and PDLIM5, plus demographic covariates showed an area under the curve (AUC) of 0.90 (95% CI 0.86-0.94) to identify neuropathologically confirmed CAA in the discovery cohort. In our independent replication, the antemortem plasma signature performed better than the basic demographics model showing a potential to predict CAA. The exploration and validation in antemortem plasma indicate that a multi-analyte panel, when combined with in vivo blood biomarkers for AD pathology, may be capable of identifying the presence of CAA and could have an meaningful impact on the clinical evaluation of patients under the investigation for cognitive decline. Further developments in biomarkers for this condition are crucial so that CAA identification could inform treatment decisions by highlighting ARIA risk.}, } @article {pmid42162953, year = {2026}, author = {Karthivashan, G and Wang, S and Wu, Q and Dahal, A and Li, X and Galleguillos, D and Sipione, S and Thinakaran, G and Kar, S}, title = {Native PLGA nanoparticles attenuate disease pathology via multiple pathways in 5xFAD Alzheimer's model.}, journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association}, volume = {22}, number = {5}, pages = {e71348}, pmid = {42162953}, issn = {1552-5279}, support = {MOP-84480//CIHR/Canada ; PJT-175090//CIHR/Canada ; //Alzheimer Society of Alberta and Northwest Territories/ ; RF1AG077610//National Institute on Aging, National Institutes of Health/ ; RF1AG079141//National Institute on Aging, National Institutes of Health/ ; //Ballermann Translational Research Fellowship/ ; //SynAD postdoctoral fellowships/ ; }, mesh = {Animals ; *Alzheimer Disease/pathology/drug therapy/metabolism/genetics ; *Nanoparticles/administration & dosage ; *Polylactic Acid-Polyglycolic Acid Copolymer/administration & dosage ; Male ; Disease Models, Animal ; Amyloid beta-Peptides/metabolism ; Mice, Transgenic ; Mice ; Brain/pathology/metabolism/drug effects ; Oxidative Stress/drug effects ; }, abstract = {INTRODUCTION: Elevated amyloid beta (Aβ) levels and aggregation contribute to neurotoxicity and development of Alzheimer's disease (AD), the leading cause of dementia in the elderly. While we reported that native poly(D,L-lactic-co-glycolic acid) (PLGA) nanoparticles, clinically used in drug delivery, suppress Aβ aggregation/toxicity, their effects in adult 5xFAD mice with advanced Aβ pathology remain unknown.

METHODS: We evaluated the effects of native PLGA in 8-month-old male 5xFAD mice via chronic intracerebroventricular (ICV) infusion using mini osmotic pumps. Cognitive function, amyloid level/burden, synaptic integrity, and neurodegenerative events were assessed along with transcript levels in brain tissues using bulk RNA sequencing (RNA-seq).

RESULTS: PLGA treatment reversed cognitive deficits, reduced Aβ levels/deposits, and attenuated neurodegenerative events. These effects were associated with modulation of Aβ production, oxidative stress, and lysosomal Aβ clearance. RNA-seq revealed transcriptional changes related to vesicle trafficking, immune activity, and redox regulation.

DISCUSSION: Native PLGA, by targeting different facets of the Aβ axis, offer unique therapeutic potential in treating AD-related pathology.}, } @article {pmid42162968, year = {2026}, author = {Reyna, NC and Hamilton, DA}, title = {Effects of Corticotropin-Releasing Factor 1 Receptor Antagonism on In Vivo Dentate Gyrus Long-Term Potentiation in the TgF344-AD Rat Model of Alzheimer's Disease.}, journal = {Hippocampus}, volume = {36}, number = {3}, pages = {e70103}, doi = {10.1002/hipo.70103}, pmid = {42162968}, issn = {1098-1063}, support = {P20AG068077/AG/NIA NIH HHS/United States ; }, mesh = {Animals ; *Dentate Gyrus/drug effects/physiopathology ; *Long-Term Potentiation/drug effects/physiology ; *Alzheimer Disease/physiopathology/drug therapy/pathology/genetics ; *Receptors, Corticotropin-Releasing Hormone/antagonists & inhibitors/metabolism ; *Pyrimidines/pharmacology ; Disease Models, Animal ; CRF Receptor, Type 1 ; Rats, Transgenic ; *Pyrroles/pharmacology ; Male ; Rats ; Rats, Inbred F344 ; Excitatory Postsynaptic Potentials/drug effects/physiology ; Perforant Pathway/drug effects/physiopathology ; }, abstract = {Alzheimer's disease (AD) is characterized by irreversible neurobiological deterioration and cognitive impairment. AD patients exhibit stress system abnormalities including upregulation of the corticotropin releasing factor type 1 receptor (CRF1) and elevated cortisol. Psychological distress increases the likelihood of AD diagnosis and hastens neurocognitive decline. Administration of the CRF1 antagonist, Antalarmin, reduces AD pathogenesis and anxiety-like behavior in models of AD. Motivated by these observations, the current study examined the potential contributions of CRF1 to altered synaptic plasticity in AD neuropathology and stress in the TgF344-AD rat model. In vivo electrophysiological recordings to assess long-term potentiation (LTP) in the perforant pathway to dentate gyrus synapses were performed in aged transgenic rats and wild-type (WT) controls (2-2.5 years). TgF344-AD rats had abnormal LTP measures of field excitatory post-synaptic potentials (fEPSP) and population spikes (PS). Treatment with Antalarmin did not alter LTP measures in TgF344-AD or WT rats. These observations indicate that LTP in TgF344-AD rats is reduced compared to WT rats and that acute treatment with a CRF1 antagonist did not rescue LTP deficits. Future research should further examine the mechanism of CRF1 in AD and implications of agonism or direct infusions of Antalarmin in vivo.}, } @article {pmid42163277, year = {2026}, author = {Lee, HJ and Seok, J and Kang, S and Oh, S and Hwang, JW and Kim, YJ and Seo, J and Hoe, HS}, title = {The insulin receptor inhibitor BMS-754807 alleviates neuroinflammation and Alzheimer's disease pathologies across human cellular and mouse models.}, journal = {Journal of neuroinflammation}, volume = {}, number = {}, pages = {}, doi = {10.1186/s12974-026-03855-7}, pmid = {42163277}, issn = {1742-2094}, support = {RS-2024-00357857//NRF/ ; RS-2024-00343370//KDRC/ ; H0501-25-1001//NIPA/ ; 20190058//Whanin Pharm Co., Ltd/ ; 26-BR-02-04, 26-BR-05-01, and 26-BR-06-01//KBRI funded by the Ministry of Science, ICT & Future Planning/ ; RS-2026-25492172//National Research Foundation of Korea/ ; }, abstract = {BACKGROUND: BMS-754807 is a dual inhibitor of insulin-like growth factor 1 receptor (IGF-1R) and insulin receptor (IR) that is in phase II clinical trials for the treatment of HR-positive and HER2-negative breast cancer. Because IGF-1R signaling regulates inflammatory responses, pharmacological modulation of IGF-1R may have therapeutic potential for Alzheimer's disease (AD); however, the effects of BMS-754807 on neuroinflammatory responses/AD pathology and cognitive function have not been fully investigated.

METHODS: We examined whether BMS-754807 modulates neuroinflammation and AD pathologies in multiple in vivo animal models and in vitro human models. BMS-754807 (20 mg/kg, i.p.) was systemically administered in wild-type mice challenged with LPS, 5xFAD mice, and PS19 transgenic mice. In addition, human-induced pluripotent stem cell (hiPSC)-derived microglia challenged with LPS and AD hiPSC-derived neurons were treated with 2.5 µM BMS-754807. For all models, the effects of BMS-754807 treatment were analyzed by real-time PCR, immunofluorescence staining, western blotting, ELISA, and/or activity assays.

RESULTS: BMS-754807 treatment significantly decreased p-IGF-IR (on-target) levels, LPS-induced proinflammatory cytokine production, and reactive oxygen species levels; restored HO-1 expressions; and inhibited AKT/STAT3 signaling in BV2 microglial cells. Similarly, BMS-754807 treatment reduced LPS-evoked proinflammatory cytokine expressions in primary microglial cells and primary astrocytes. In addition, BMS-754807 administration mitigated LPS-stimulated gliosis, microglial/astrocyte-associated dynamics, STAT3/NF-κB phosphorylation, and potentially NLRP3 inflammasome in vitro and/or in WT mice. Moreover, BMS-754807 treatment suppressed LPS-mediated proinflammatory responses through IGF-1R and NLRP3 in BV2 microglial cells. In 5xFAD mice, BMS-754807 administration downregulated IGF-1R phosphorylation, microgliosis/astrogliosis-related dynamics, and AKT/P38/STAT3 pathway. Notably, BMS-754807 treatment also diminished LPS-induced proinflammatory cytokine levels and STAT3/NF-κB signaling in human microglial models. Furthermore, BMS-754807 treatment decreased Aβ40/Aβ42 levels in hiPSC-derived AD neurons, and increased short-term spatial memory and reduced Aβ plaque accumulation by decreasing β-secretase (BACE1) activity in 5xFAD mice. Finally, in hiPSC-derived AD neurons and PS19 mice, BMS-754807 treatment significantly attenuated tau hyperphosphorylation, CaMKIIα phosphorylation, and tau-mediated astroglial activation.

CONCLUSIONS: Taken together, our results suggest that BMS-754807 exerts anti-inflammatory and potential disease-modifying effects by attenuating LPS/Aβ/tau-evoked glial activation and reducing Aβ and tau pathologies in both human cellular and mouse models of neuroinflammation and AD. Furthermore, BMS-754807 administration improved specific domains of cognitive function in vivo. These findings support pharmacological inhibition of IGF-1R as a potential therapeutic approach for neuroinflammation-associated diseases including AD.}, } @article {pmid42163384, year = {2026}, author = {Hsu, JL and Huang, SY and Wu, HC and Lin, KJ and Huang, KL and Huang, CC and Kim, S and Hsiao, IT}, title = {A clinically feasible framework to estimate tau pathology and clinical-biological discordance in the Alzheimer's disease spectrum.}, journal = {Alzheimer's research & therapy}, volume = {}, number = {}, pages = {}, doi = {10.1186/s13195-026-02083-8}, pmid = {42163384}, issn = {1758-9193}, support = {MOST 111-2314-B-182A-036-MY2, NSTC 112-2628-B-182-007-MY3, NSTC-113-2314-B-182-042-MY2, NSTC-114-2314-B-182-043, NSTC 114-2314-B-182A-061-MY3//National Science and Technology Council/ ; MOST 111-2314-B-182A-036-MY2, NSTC 112-2628-B-182-007-MY3, NSTC-113-2314-B-182-042-MY2, NSTC-114-2314-B-182-043, NSTC 114-2314-B-182A-061-MY3//National Science and Technology Council/ ; MOST 111-2314-B-182A-036-MY2, NSTC 112-2628-B-182-007-MY3, NSTC-113-2314-B-182-042-MY2, NSTC-114-2314-B-182-043, NSTC 114-2314-B-182A-061-MY3//National Science and Technology Council/ ; MOST 111-2314-B-182A-036-MY2, NSTC 112-2628-B-182-007-MY3, NSTC-113-2314-B-182-042-MY2, NSTC-114-2314-B-182-043, NSTC 114-2314-B-182A-061-MY3//National Science and Technology Council/ ; MOST 111-2314-B-182A-036-MY2, NSTC 112-2628-B-182-007-MY3, NSTC-113-2314-B-182-042-MY2, NSTC-114-2314-B-182-043, NSTC 114-2314-B-182A-061-MY3//National Science and Technology Council/ ; MOST 111-2314-B-182A-036-MY2, NSTC 112-2628-B-182-007-MY3, NSTC-113-2314-B-182-042-MY2, NSTC-114-2314-B-182-043, NSTC 114-2314-B-182A-061-MY3//National Science and Technology Council/ ; CORPG3P0281, CORPG3P0291, BMRP488//Chang Gung Memorial Hospital Research Fund/ ; CORPG3P0281, CORPG3P0291, BMRP488//Chang Gung Memorial Hospital Research Fund/ ; CORPG3P0281, CORPG3P0291, BMRP488//Chang Gung Memorial Hospital Research Fund/ ; CORPG3P0281, CORPG3P0291, BMRP488//Chang Gung Memorial Hospital Research Fund/ ; CORPG3P0281, CORPG3P0291, BMRP488//Chang Gung Memorial Hospital Research Fund/ ; CORPG3P0281, CORPG3P0291, BMRP488//Chang Gung Memorial Hospital Research Fund/ ; }, abstract = {BACKGROUND: Tau positron emission tomography (PET) is critical for biological staging and treatment stratification in Alzheimer's disease (AD), particularly in the era of anti-amyloid therapies where lower tau burden predicts greater clinical benefit. However, tau PET remains costly and inaccessible in many clinical settings. We aimed to develop and validate a clinically feasible framework to estimate global and regional tau burden using routinely available amyloid PET and clinical measures, aligned with the 2024 Alzheimer's Association (AA-2024) diagnostic framework, and to characterize clinical-biological discordance across the AD continuum.

METHODS: We conducted a cross-sectional study of 229 individuals spanning cognitively unimpaired, mild cognitive impairment, and dementia stages who underwent [[18]F]florbetapir amyloid PET, [[18]F]florzolotau tau PET, structural MRI, and cognitive assessment. Amyloid burden was quantified using the Centiloid (CL) scale (A+ defined as CL > 20). Tracer-specific tau thresholds for global and Braak-stage volumes were derived using two-component Gaussian mixture modeling. Logistic regression models incorporating CL, age, Mini-Mental State Examination (MMSE), and medial temporal lobe (MTL) volume were developed to classify high global tau burden and neocortical tau involvement. Among amyloid-positive individuals, biological staging was compared with clinical stage to assess discordance patterns.

RESULTS: Global and regional tau burden increased stepwise across clinical severity and amyloid strata. High global tau burden was uncommon in individuals with CL 21-60 (6.1%) but increased in CL 61-100 (22.6%) and > 100 (36.2%). A multivariable model integrating CL, age, MMSE, and relative MTL volume demonstrated good discrimination for high global tau burden (AUC = 0.87) and neocortical involvement (AUC = 0.84). Model robustness was confirmed by bootstrap resampling. Among amyloid-positive participants, 53.1% exhibited clinical-predominant AD, characterized by older age and higher cardiovascular risk despite relatively modest tau burden, indicating substantial clinical-biological discordance.

CONCLUSION: Routinely obtainable amyloid PET and clinical measures can approximate global and topographical tau burden with good accuracy and identify frequent clinical-biological discordance within the AD spectrum. This scalable framework provides a practical surrogate for tau PET in resource-limited settings and may support biological staging, therapeutic eligibility assessment, and precision treatment decision-making.}, } @article {pmid42163678, year = {2026}, author = {Jin, S and Liu, D and Ouyang, J}, title = {An Investigation of the Neurotoxic Mechanisms of Benzo[a]pyrene in Alzheimer's Disease Using an Integrated Approach of Network Toxicology and Machine Learning.}, journal = {Current neuropharmacology}, volume = {}, number = {}, pages = {}, doi = {10.2174/011570159X447239260407111712}, pmid = {42163678}, issn = {1875-6190}, abstract = {INTRODUCTION: Benzo[a]pyrene (BaP) exposure is increasingly associated with the progression of Alzheimer's Disease (AD), yet the specific molecular links remain poorly understood. This study utilizes an integrated computational framework, combining network toxicology, machine learning, and molecular dynamics simulations, to identify core biomarkers and elucidate the potential pathological interplay between BaP and AD.

METHODS: We began our analysis by identifying the intersection of targets and then created a Protein-Protein Interaction (PPI) Network to identify hub genes. To ensure accuracy, we selected final core molecular targets from the intersection of three distinct types of machine learning algorithms. To validate diagnostic value, immune cell infiltration data analysis was performed using the GSE138260 dataset. Finally, we used molecular docking and 100 ns dynamics to assess how BaP interacts with the core molecular target.

RESULTS: We identified four proteins associated with BaP and AD: CASP3 (Caspase 3), HTT (Huntingtin), TH (Tyrosine Hydroxylase), and PARK7 (DJ-1). These proteins signal neuronal apoptosis and neuro-immune dysregulation due to their involvement in pathways associated with these processes. The Receiver Operating Characteristic (ROC) analysis demonstrated strong diagnostic properties for these targets. Molecular docking data also showed BaP as the main target, with TH binding with a value of -10.02 kcal/mol. The stability of this BaP-TH complex was further confirmed by 100 ns molecular dynamics simulations.

DISCUSSION: The research reveals TH's critical effect on BaP-induced neurotoxicity. We also identify the potential molecular mechanisms contributing to Alzheimer's disease pathology via environmental exposure.

CONCLUSION: This research identifies several significant molecular interactions between BaP and AD. One major molecular target for BaP interaction with AD is tyrosine hydroxylase (TH). Our findings here create an opportunity for the development of therapeutics for the treatment of AD cases caused by exposure to environmental toxins.}, } @article {pmid42163745, year = {2026}, author = {Abdalla, EA and Fayed, AM and Hussein, MA and Abdel-Aziz, A and Mohamed, ZN}, title = {Multi-Target Neuroprotection of Salvia officinalis Aqueous Extract in a Scopolamine-Induced Model of Alzheimer's Disease: Comparative Efficacy Versus Donepezil.}, journal = {Current pharmaceutical design}, volume = {}, number = {}, pages = {}, doi = {10.2174/0113816128429239260312074215}, pmid = {42163745}, issn = {1873-4286}, abstract = {INTRODUCTION: Alzheimer's disease (AD) is a complex, age-related, neurodegenerative disorder that involves cognitive deterioration, oxidative stress, and neuroinflammation. Symptomatic relief is limited with conventional treatments such as donepezil, sparking a significant interest in multi-target botanicals. We examined the neuroprotective effects of Salvia officinalis aqueous extract (SAGE) on a scopolamine-induced animal model of AD and the related molecular mechanisms regarding GABRA5α, GSK-3β, and pERK pathways.

METHODS: SAGE was characterized using phytochemical profiling and antioxidant assays. IC50 values were determined in vitro for inhibitor activity against GABRA5α and GSK-3β. In vivo experiments included assessment of behavior (Morris water maze), assays for oxidative stress and inflammation, gene expression studies by qPCR, and histopathology of hippocampal tissue. Efficacy versus donepezil was compared. Statistical significance was based on one-way ANOVA followed by Tukey's post-hoc test (p < 0.05) for robust comparisons between all treatment groups.

RESULTS: The SAGE had strong antioxidant abilities and was able to inhibit GABRA5α and GSK-3β in a target-specific way. SAGE treatment greatly enhanced spatial learning and memory, retained the redox equilibrium, decreased neuroinflammatory markers, and normalized AChE activity. Gene expression was found to modulate favourably for GABRA5α, GSK-3β and pERK. Histological findings confirmed neuronal preservation. In all parameters, SAGE was more effective than donepezil. The present findings demonstrated the therapeutic potential of SAGE's phenolics to mitigate oxidative cascades, including those suggested as contributing factors to AD pathology.

DISCUSSION: The superior multi-modal efficacy of SAGE over donepezil due to its phenolic-rich phytochemical profile and capacity to modulate oxidative, inflammatory, and neuronal pathways is demonstrated. This is encouraging, and additional studies should be conducted to investigate pharmacokinetics, mechanistic and clinical significance.

CONCLUSION: S. officinalis AE strongly protects the brain against scopolamine-induced AD-like neuropathology in a superior way over standard treatment via altered multi-targets. Its characteristics promote its further development as a natural therapeutic candidate for AD treatment. There are however constraints, such as nodescription of the pharmacokinetic profiling and no tau/Aβ quantification. Prospective studies with these endpoints and chronic dosing schedules should now address the issue of long-term effectiveness and safety.}, } @article {pmid42164259, year = {2026}, author = {Giorelli, M}, title = {Reframing Alzheimer's disease as a complex adaptive system: More than an amyloid beta-tau connection.}, journal = {Alzheimer's & dementia (New York, N. Y.)}, volume = {12}, number = {}, pages = {e70256}, pmid = {42164259}, issn = {2352-8737}, abstract = {Alzheimer's disease (AD) is the leading cause of dementia, but simple models focusing on amyloid beta and tau only partially explain its variability and limited success in treatment. Evidence from systems biology, neuroimmunology, connectomics, and computational modeling supports viewing AD as a complex adaptive system, a multiscale network in which genetic, molecular, cellular, vascular, and environmental factors interact in complex, non-linear ways over time. In this perspective, disease paths develop from feedback-driven instabilities that spread across different levels, while resilience and compensatory mechanisms influence individual outcomes. This new understanding has important implications: diagnostic approaches should shift from static lesion biomarkers to longitudinal, multimodal measures of network states; treatments should combine pharmacological, metabolic, vascular, inflammatory, cognitive, and neuromodulatory strategies; and adaptive, model-informed algorithms should customize the timing and dosage to each patient's unique dynamics. Recognizing the complexity enables earlier detection of critical tipping points, targeted reinforcement of resilience, and personalized intervention plans, shifting AD care from late-stage, single-target methods to precision network medicine.}, } @article {pmid42164431, year = {2026}, author = {Schuller, AJ and Hager, MR and Briggs, AM and Rocha, SM and Yanouri, OA and Smith, EJ and Hall, SE and Montrose, LB and Tjalkens, RB}, title = {Treadmill training induces sex-dependent changes in hippocampal epigenetic patterns and plaque-associated microglial morphology in aged TgF344 rats.}, journal = {Frontiers in neuroscience}, volume = {20}, number = {}, pages = {1805957}, pmid = {42164431}, issn = {1662-4548}, abstract = {Alzheimer's disease (AD) is the most prevalent neurodegenerative disorder world-wide, characterized by progressive neuroinflammation, aberrant protein accumulation, and neuronal loss associated with cognitive decline. Although our understanding of the molecular mechanisms underlying AD pathogenesis has greatly increased in recent years, there remain limited treatment strategies and no cures for this disorder. Because of this, efforts have shifted toward identifying modifiable lifestyle factors which may decrease risk of onset or slow AD progression. One such approach which has shown promise in modulating the disease course is physical exercise. However, sex-specific effects of implementing such activity strategies in aged individuals after the onset of disease are less well studied. We sought to address this knowledge gap by characterizing hippocampal histopathology and DNA modification profiles of aged TgF344-AD rats following progressive treadmill-training. Reduced-representation bisulfite sequencing indicated 94 genes associated with differentially modified cytosines (DMCs) in exercised females (239 differentially modified regions, 54.6% hypermodified) and 87 DMC-associated genes in exercised males (216 differentially modified regions, 50.4% hypermodified) with unique functional enrichment for overrepresented pathways and protein interactions relevant to glial activation and synaptic plasticity. Using quantitative high-throughput slide scanning fluorescence microscopy we additionally examined this brain region for AD-relevant changes including neuronal and microglial density, microglial morphology, and accumulation of pathologic protein. This analysis revealed female-specific reductions in NeuN[+] and Iba1[+] cells in treadmill-trained animals, as well as sex- and exercise-dependent changes in plaque-associated microglial reactivity state. Together, these findings reveal that age of onset, biologic sex, and duration of physical exertion may be important factors in modulating the pathologic progression of AD.}, } @article {pmid42164617, year = {2026}, author = {Garnier-Crussard, A and Dadar, M and Villain, N and Charidimou, A and Boulouis, G and Cotton, F and Brickman, AM and Chételat, G}, title = {White matter hyperintensities in Alzheimer's disease in the era of anti-amyloid therapies.}, journal = {Alzheimer's & dementia (Amsterdam, Netherlands)}, volume = {18}, number = {}, pages = {e70349}, pmid = {42164617}, issn = {2352-8729}, abstract = {White matter hyperintensities (WMHs) are highly prevalent in Alzheimer's disease (AD) and arise from interacting vascular pathologies (including hypertensive small vessel disease and cerebral amyloid angiopathy) alongside inflammatory and neurodegenerative processes. In the era of anti-amyloid monoclonal antibodies, this heterogeneity is increasingly relevant for both treatment efficacy and safety. WMHs may signal mixed AD-vascular pathology that dilutes the cognitive benefit of amyloid-targeting therapies and may also index vulnerability of the neurovascular unit that predisposes to amyloid-related imaging abnormalities (ARIAs), although direct evidence remains limited. In this perspective, we synthesize current knowledge on the origins of WMHs in AD, review advanced magnetic resonance imaging and biomarker approaches that aim to refine lesion characterization in vivo, and discuss how WMHs should be interpreted in memory clinic practice when considering anti-amyloid therapies. We conclude with a research roadmap to integrate WMH phenotyping into precision risk-benefit assessment and ARIA prediction .}, } @article {pmid42164658, year = {2026}, author = {Liu, X and Jia, L and Wu, K and Chen, M and Sun, J and Yang, C and Xu, C and Sun, J and Wang, J and Dai, L}, title = {Exploring and Targeting the Connection of Iron and Copper Homeostasis to Neurodegenerative Diseases.}, journal = {MedComm}, volume = {7}, number = {}, pages = {e70766}, pmid = {42164658}, issn = {2688-2663}, abstract = {Iron (Fe) and copper (Cu) are vital micronutrients that regulate many critical physiological processes in the human body, with their homeostasis in the central nervous system (CNS) being essential for proper neuronal function. Disruptions in their metabolism and regulatory pathways have been associated with the pathogenesis of various forms of neurodegenerative diseases (NDDs) such as Alzheimer's disease (AD) and Parkinson's disease (PD). Despite growing research on metal homeostasis, the intricate molecular mechanisms that link iron and copper metabolism to the initiation and progression of NDDs remain insufficiently elucidated. In this review, we provide a systematic overview of the metabolic processes of iron and copper in the body and CNS, highlighting their interactions with many metal-binding proteins, including transporters, storage proteins, and important intrinsically disordered proteins (e.g., amyloid β-protein, tau, and alpha-synuclein) involved in NDDs. We further dissect the downstream effects of metal ion dyshomeostasis on cellular redox balance, neuroinflammation, autophagy, organelle interaction network, and cell death. Additionally, we discuss current therapeutic strategies aimed at targeting iron and copper dyshomeostasis, as well as the emerging role of artificial intelligence in this field of research. By integrating metal metabolism, metal-protein interactions, the effect of metal dyshomeostasis on downstream biological processes, and potential intervention strategies, this review serves as a comprehensive reference for understanding the pathogenesis of NDDs and offers new perspectives for developing effective therapeutics. Overall, this review underscores the significance of reinstating metal balance for the treatment of neurodegeneration.}, } @article {pmid42166005, year = {2026}, author = {Kariminejad-Farsangi, H and Kariminejad-Farsangi, H and Mir, Y and Sheibani, V and Joushi, S}, title = {Mechanistic insights into mesenchymal stem cell therapy for cognitive impairments in Alzheimer's disease models: a systematic review and meta-analysis.}, journal = {Molecular and cellular biochemistry}, volume = {}, number = {}, pages = {}, pmid = {42166005}, issn = {1573-4919}, abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder with limited treatment options that primarily offer symptomatic relief. Mesenchymal stem cells (MSCs) have shown promise in preclinical studies due to their neuroprotective, immunomodulatory, and regenerative properties. This systematic review and meta-analysis aimed to assess the effects of MSC therapy on cognitive performance and molecular pathology in animal models of AD.A systematic search was conducted in PubMed, Web of Science, Scopus, Embase, ProQuest, and gray literature sources. This study included in vivo interventional animal studies that evaluated the effects of MSCs on cognitive outcomes in Alzheimer's disease models using the Morris Water Maze test. The standardized mean difference (SMD) was used as the effect size, and data were synthesized using a random-effects model. Study quality was assessed using the SYRCLE risk of bias tool. Publication bias was evaluated through funnel plots, Egger's test, and the trim-and-fill method. Sensitivity analysis was performed using the leave-one-out method and further supported by a risk-of-bias-based approach.A total of 51 studies met the inclusion criteria, of which 37 were included in the meta-analysis. The findings indicated that MSC therapy significantly reduced escape latency (SMD = -1.18, 95% CI -1.46 to-0.89, I[2] = 56.81%, P = 0.00) and increased time spent in the target quadrant (SMD = 1.93, 95% CI 1.46 to 2.40, I[2] = 78.63%, P = 0.00). MSC treatment also led to an increase in hippocampal BDNF levels and a reduction in Aβ deposition and pro-inflammatory cytokines such as IL-1β and TNF-α. However, the effect on IL-6 levels was not statistically significant.MSCs Improve cognitive function and modulate pathological features in AD animal models. Further high-quality studies with standardized protocols and broader literature inclusion are needed to support clinical translation.}, } @article {pmid42166031, year = {2026}, author = {Xu, X and Ni, Z and Wang, YB and Fan, SS and Du, Y and Wang, X and Meng, XY}, title = {Decoding shared pathogenic networks of oxidative stress in neuropsychiatric disorders to prioritize multi-target therapeutics from natural products.}, journal = {Cell biology and toxicology}, volume = {}, number = {}, pages = {}, doi = {10.1007/s10565-026-10208-w}, pmid = {42166031}, issn = {1573-6822}, support = {2508085QC099//Natural Science Foundation of Anhui Province of China/ ; 2025AHGXZK40182//Natural Science Research Project for Youth of Higher Education Institutions of Anhui Province/ ; }, abstract = {BACKGROUND: Neurodegenerative and psychiatric disorders, including Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), and schizophrenia (SZ), are characterized by progressive neuronal loss and synaptic dysfunction. Despite their severity, effective disease-modifying treatments remain unavailable, largely due to the elusive nature of their underlying molecular mechanisms.

METHODS: To elucidate these mechanisms, we conducted an integrative systems biology analysis incorporating transcriptomic datasets, in silico proteomic networks, and inferred metabolomic profiles. Machine learning (ML) and deep learning (DL) models were employed to identify regulatory networks associated with oxidative stress, immune response, and synaptic signaling. Furthermore, network pharmacology approaches were applied to explore multi-target intervention strategies using bioactive compounds from traditional Chinese medicine (TCM).

RESULTS: Our integrative analysis revealed extensive overlap in dysregulated biological processes across all four disorders, particularly involving oxidative stress and immune activation. We identified TP53, NFE2L2, and PPP3CA as central regulatory hubs driving these pathologies. Notably, computational predictions highlighted that TCM-derived compounds, specifically stigmasterol and dodecanoic acid, exhibit promising multi-target effects for modulating these oxidative and inflammatory responses. Subsequent in vivo experimental validation was performed exclusively to corroborate the disease-associated pathways and core gene dysregulation in an Aβ42-induced AD model. These findings demonstrated molecular and behavioral phenotypes consistent with our multi-dimensional computational predictions, establishing a robust mechanistic rationale that merits future in vivo pharmacological validation for the predicted bioactive compounds.

CONCLUSION: This study highlights the utility of a multi-disease, multi-dimensional framework in uncovering shared pathogenic signatures. By integrating computational analytics with pharmacological modeling and experimental validation, we identified key regulatory genes and natural compounds with therapeutic potential. These findings provide a theoretical foundation for the development of multi-target, personalized treatment strategies against neurodegeneration.}, } @article {pmid42166820, year = {2026}, author = {Czarnota-Łydka, K and Kucwaj-Brysz, K and Cios, A and Mordyl, B and Głuch-Lutwin, M and Jastrzębska-Więsek, M and Partyka, A and Honkisz-Orzechowska, E and Karcz, T and Pakulska, J and Satała, G and Żesławska, E and Dąbrowska, M and Starek, M and Więcek, M and Kurowska, K and Pyka, P and Brunetti, L and Leuci, R and Piemontese, L and Nitek, W and Wesołowska, A and Carrieri, A and Handzlik, J}, title = {New chalcogen-optimized 1,3,5-triazines as dual 5-HT6R/FAAH modulators: A versatile approach to neurodegenerative disorders.}, journal = {European journal of medicinal chemistry}, volume = {315}, number = {}, pages = {118966}, doi = {10.1016/j.ejmech.2026.118966}, pmid = {42166820}, issn = {1768-3254}, mesh = {*Triazines/pharmacology/chemistry/chemical synthesis ; *Receptors, Serotonin/metabolism ; Humans ; Animals ; *Amidohydrolases/metabolism/antagonists & inhibitors ; *Neuroprotective Agents/pharmacology/chemistry/chemical synthesis ; *Chalcogens/chemistry/pharmacology ; Fatty Acid Amide Hydrolases ; Structure-Activity Relationship ; *Neurodegenerative Diseases/drug therapy/metabolism ; Molecular Structure ; Dose-Response Relationship, Drug ; Mice ; *Enzyme Inhibitors/pharmacology/chemistry/chemical synthesis ; }, abstract = {The clinical failure of selective serotonin 5-HT6 receptor (5-HT6R) antagonists in Alzheimer's disease (AD) highlights the need for multitarget therapeutic strategies addressing the multifactorial nature of neurodegeneration. Building upon our pioneering discovery of the first-in-class dual 5-HT6R/FAAH (fatty acid amide hydrolase) modulators among O-ether triazine compounds, we here report a comprehensive lead-optimization campaign centered on the triazine-based compound MR3b, identified as a promising lead in the search for AD treatment. Structural modifications based on scaffold contraction and chalcogen bioisosterism generated a focused library of 1,3,5-triazine derivatives with diversified GPCR and FAAH profiles. Several compounds displayed nanomolar affinities for 5-HT6R, 5-HT2AR, and D2R, alongside improved FAAH inhibition and antioxidant properties. Sulfur and selenium substitutions markedly enhanced receptor affinity and reduced cytotoxicity compared to the oxygen-containing lead. Selected compounds demonstrated significant neuroprotective effects in cellular models of AD-related pathology, including mitochondrial dysfunction, amyloid-β, and glutamate-induced toxicity. Furthermore, the thio-analogue 4c effectively reversed memory deficits in vivo, showing superior CNS penetration (Kp,brain = 0.78), an expanded therapeutic window (NOR test), and improved safety relative to MR3b. This study identified compound 4c as a second-generation lead and underscores the potential of multitarget triazine-based ligands combining serotonergic modulation and FAAH inhibition as potential disease-modifying candidates for AD and related neurodegenerative disorders.}, } @article {pmid42167685, year = {2026}, author = {Lee, YW and Cho, YE and Kim, SY and Cho, SY and Lee, SJ and Do, YJ and Lee, NH and Kim, DH and Ryu, JH and Bae, HJ and Park, SJ}, title = {Paeonol ameliorates scopolamine- and β-amyloid 1-42 oligomer-induced cognitive impairments through modulation of the TGR5-PKA-cAMP response element-binding-brain-derived neurotrophic factor pathway and inhibition of acetylcholinesterase.}, journal = {Neurochemistry international}, volume = {197}, number = {}, pages = {106188}, doi = {10.1016/j.neuint.2026.106188}, pmid = {42167685}, issn = {1872-9754}, mesh = {Animals ; *Acetophenones/pharmacology/therapeutic use ; *Amyloid beta-Peptides/toxicity ; *Scopolamine/toxicity ; Brain-Derived Neurotrophic Factor/metabolism ; *Peptide Fragments/toxicity ; Male ; Cyclic AMP-Dependent Protein Kinases/metabolism ; Mice ; *Acetylcholinesterase/metabolism ; Cyclic AMP Response Element-Binding Protein/metabolism ; Signal Transduction/drug effects/physiology ; *Cognitive Dysfunction/chemically induced/drug therapy/metabolism ; *Cholinesterase Inhibitors/pharmacology/therapeutic use ; }, abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder marked by cognitive decline, synaptic dysfunction, and cholinergic signaling deficits. Paeonol (2-hydroxy-4-methoxyacetophenone), a phenolic compound derived from Paeonia suffruticosa, has well-documented neuroprotective activity, but potential cognitive benefits and the underlying mechanisms have not been widely examined. Here, we investigated the potential of paeonol to improve cognitive function in scopolamine- and Aβ1-42 oligomer-induced mouse models of AD. Paeonol significantly improved the performance of both models in the Y-maze, novel object recognition, and passive avoidance tests, particularly at 10 mg/kg. Western blotting of excised brain tissue revealed that paeonol treatment reversed scopolamine- and Aβ1-42 oligomer-induced suppression of hippocampal PKA and cAMP response element-binding (CREB) phosphorylation and concomitantly enhanced brain-derived neurotrophic factor (BDNF) expression. Notably, paeonol also reversed scopolamine- and Aβ1-42-induced downregulation of Takeda G-protein-coupled receptor 5 (TGR5), an upstream regulator of the PKA-CREB-BDNF pathway, and molecular docking simulations predicted a possible paeonol-TGR5 interaction. Moreover, paeonol suppressed scopolamine-induced elevation of acetylcholinesterase activity with efficacy comparable to the clinical inhibitor donepezil. These findings support the potential of paeonol as a naturally sourced multitarget therapeutic agent for AD.}, } @article {pmid42167701, year = {2026}, author = {Hou, P and Li, X and Yan, Y and Lu, Q and Wang, J and Yuan, M and Wang, X and Wang, X}, title = {Polyethylene terephthalate microplastics activate AKT1 signaling and induce neurotoxic responses in SH-SY5Y cells.}, journal = {Toxicology and applied pharmacology}, volume = {513}, number = {}, pages = {117873}, doi = {10.1016/j.taap.2026.117873}, pmid = {42167701}, issn = {1096-0333}, mesh = {Humans ; *Proto-Oncogene Proteins c-akt/metabolism ; *Polyethylene Terephthalates/toxicity ; Signal Transduction/drug effects ; Cell Line, Tumor ; Cell Survival/drug effects ; Reactive Oxygen Species/metabolism ; *Microplastics/toxicity ; Phosphorylation ; *Neurons/drug effects/pathology/enzymology ; Molecular Docking Simulation ; Molecular Dynamics Simulation ; *Neurotoxicity Syndromes/etiology/pathology/enzymology ; Heterocyclic Compounds, 3-Ring ; }, abstract = {Microplastic exposure has emerged as a growing environmental health concern, with increasing evidence suggesting potential effects on the nervous system. However, the molecular basis by which polyethylene terephthalate (PET) contributes to Alzheimer's disease (AD)-related neurotoxicity remains unclear. This study examined whether PET induces neuronal injury by activating the AKT1 signaling pathway. Network toxicology integrating PubChem, STITCH, SwissTargetPrediction, OMIM, TTD, and GeneCards was used to identify PET-associated targets relevant to AD. Core targets were analyzed with Cytoscape, followed by GO and KEGG enrichment using R and clusterProfiler. Molecular docking and molecular dynamics simulations characterized the interaction between PET and AKT1. For in vitro validation, SH-SY5Y cells were treated with 100 μg/mL PET for 24 h or 48 h to detect cytotoxicity and molecular alterations. Four experimental groups were set in this study: Control, PET, PET + MK2206 (1 μM) and MK2206 (1 μM) single treatment groups. PET exposure reduced cell viability, increased intracellular reactive oxygen species (ROS) levels, and enhanced AKT phosphorylation at Ser473, while MK2206 attenuated these effects. These research results show that PET microplastics can induce neurotoxic reactions by activating the AKT1 pathway.}, } @article {pmid42168776, year = {2026}, author = {van Dyck, CH}, title = {Letter to the editor response for: "Schneider LS, Kennedy RE, Cutter G. Caution in interpreting disease-modification claims with lecanemab: selective reporting and causal inference. Alzheimer's & Dementia. 2026".}, journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association}, volume = {22}, number = {5}, pages = {e71485}, pmid = {42168776}, issn = {1552-5279}, } @article {pmid42170124, year = {2026}, author = {Patel, D and Patel, T and Patel, PN}, title = {Integrative Analysis of Pharmacological and Non-pharmacological Interventions in Alzheimer's Dementia.}, journal = {Cureus}, volume = {18}, number = {4}, pages = {e107386}, pmid = {42170124}, issn = {2168-8184}, abstract = {Alzheimer's dementia is a progressive neurodegenerative disorder in which cognitive decline, neuropsychiatric symptoms, and functional dependence emerge from a long preclinical and prodromal phase. Effective care increasingly requires an integrative approach: (1) disease-modifying pharmacology for selected patients early in the symptomatic course, (2) symptomatic pharmacotherapy for cognition and behavioral symptoms when benefits outweigh harms, and (3) non-pharmacological interventions that meaningfully affect quality of life, caregiver burden, safety, and functional outcomes across all stages. Recent advances, particularly anti-amyloid monoclonal antibodies, have reshaped early Alzheimer's treatment while raising new implementation challenges around biomarker confirmation, monitoring for amyloid-related imaging abnormalities (ARIA), and health-system capacity. Evidence also supports structured non-pharmacological strategies (e.g., cognitive stimulation, physical activity, caregiver programs, and environmental and behavioral approaches for agitation) as core therapies rather than "adjuncts." This narrative review synthesizes the evidence base and offers a practical, stage-based framework for combining pharmacological and non-pharmacological therapies, emphasizing person-centered goals, safety, feasibility, and equity.}, } @article {pmid42171909, year = {2026}, author = {Hammad, MO and Shady, T and Moanes, B and El-Sharkawy, AR and Galal, AM and Tawfeek, AE and El-Sisi, AEM and Sameh, A and Mahrous, S and Atya, N and Essam, A and El-Desouky, S and Abd El-Aziz, MH}, title = {Quinoa seed (Chenopodium quinoa W.) extract attenuates Alzheimer's disease-like neurodegeneration: Targeting the SLC7A11/GPX4 pathway.}, journal = {Molecular biology reports}, volume = {53}, number = {1}, pages = {}, pmid = {42171909}, issn = {1573-4978}, mesh = {Animals ; *Chenopodium quinoa/chemistry/metabolism ; *Alzheimer Disease/drug therapy/metabolism ; *Plant Extracts/pharmacology ; Male ; Rats ; Oxidative Stress/drug effects ; Seeds/chemistry ; *Phospholipid Hydroperoxide Glutathione Peroxidase/metabolism ; Disease Models, Animal ; *Amino Acid Transport System y+/metabolism ; Hippocampus/metabolism/drug effects ; Lipid Peroxidation/drug effects ; Ferroptosis/drug effects ; Antioxidants/pharmacology/metabolism ; Aluminum Chloride ; Signal Transduction/drug effects ; Iron/metabolism ; }, abstract = {BACKGROUND: Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by cognitive decline and hippocampal neuronal loss. Targeting ferroptosis-related pathways represents a promising therapeutic strategy.

OBJECTIVE: This study aimed to investigate the potential effect of quinoa (Chenopodium Quinoa W.) seed extract in an aluminum chloride (AlCl₃)-induced rat model of AD, with a particular focus on the SLC7A11/GPX4 antioxidant axis and NCOA4-mediated ferritinophagy.

METHODS: Adult male rats were randomly divided into four groups (n = 6): GI (Control), GII (AD), GIII (Quinoa + AD), and GIV (Alzemenda + AD). AD was induced by oral AlCl₃ administration. Quinoa extract and Alzemenda were administered concurrently with AlCl₃ throughout the experimental period. Behavioral performance was evaluated using the Morris Water Maze and Open Field Test. Oxidative stress markers, iron parameters, gene expression, and histopathological changes in the hippocampus were assessed.

RESULTS: GII exhibited significant cognitive impairment, increased lipid peroxidation, depletion of antioxidant defenses, downregulation of SLC7A11, and marked hippocampal iron deposition compared with GI. Treatment with quinoa (GIII) significantly improved learning and memory, restored GPX4 activity and GSH levels, upregulated SLC7A11 expression, and attenuated hippocampal iron deposition. GIV showed comparable behavioral and histological improvement. Systemic iron indices, as well as hippocampal FPN1 and NCOA4 expression, did not differ significantly among groups.

CONCLUSION: Quinoa seed extract exerts ameliorating effects in AlCl₃-induced AD by suppressing oxidative stress-associated neurodegeneration through preservation of the SLC7A11/GSH/GPX4 axis rather than modulation of iron export or ferritinophagy pathways.}, } @article {pmid42171931, year = {2026}, author = {Shukla, S and Singh, RK}, title = {Crosstalk between death-associated protein kinase 1-regulated mechanisms and dysfunctions in alzheimer's disease.}, journal = {Molecular biology reports}, volume = {53}, number = {1}, pages = {}, pmid = {42171931}, issn = {1573-4978}, mesh = {Humans ; *Alzheimer Disease/metabolism/genetics/pathology ; *Death-Associated Protein Kinases/metabolism/genetics ; Amyloid beta-Peptides/metabolism ; Animals ; Neurons/metabolism/pathology ; Reactive Oxygen Species/metabolism ; tau Proteins/metabolism ; Cell Death ; Signal Transduction ; Phosphorylation ; Autophagy ; }, abstract = {Alzheimer's disease (AD) is a chronic progressive neurocognitive disorder manifested by increased production and deposition of amyloid beta (Aβ), abnormal tau phosphorylation, and formation of neurofibrillary tangles (NFTs). In addition, the disease progression is found to be associated with neuronal cell death, elevated levels of reactive oxygen species, mitochondrial dysfunction, and loss of synaptic plasticity in specific regions of the brain. AD is seventh leading cause of death and over more than 70%-80% of 57 million people having dementia develop AD worldwide. The disease population is also severely increasing at an alarming rate globally. The currently available treatment strategies remain insufficient to cure the disease because AD involves very complex pathways during its progression. Death-associated protein kinase 1 (DAPK1) is identified as a promising next-generation therapeutic drug target for the management of AD. It belongs to a family of serine/threonine kinases that influences different hypotheses involved in AD pathogenesis, such as tauopathies, Aβ hypothesis, redox, and autophagy pathways. In this review, we highlight the involvement of DAPK1 in various molecular pathways associated with AD pathogenesis and the crosstalk between DAPK1 and synaptic dysfunction and neuronal cell death implicated in AD. Moreover, the various small molecules, microRNAs, and phytoconstituents have been discussed, which have the potential to be developed as a treatment strategy targeting DAPK1-related pathological pathways in AD.}, } @article {pmid42172039, year = {2026}, author = {Han, X and Xue, J and Zhang, Q and Li, R and Guo, X and Duan, Q and Sang, S}, title = {Nitric oxide-enhanced blood-brain barrier penetration and mitochondria-targeted antioxidant carbon dots for Alzheimer's disease.}, journal = {Journal of materials chemistry. B}, volume = {14}, number = {22}, pages = {6963-6981}, doi = {10.1039/d6tb00133e}, pmid = {42172039}, issn = {2050-7518}, mesh = {*Alzheimer Disease/drug therapy/metabolism ; *Carbon Quantum Dots/chemistry ; *Blood-Brain Barrier/metabolism/drug effects ; *Antioxidants/chemistry/pharmacology ; *Nitric Oxide/metabolism/chemistry/pharmacology ; *Mitochondria/metabolism/drug effects ; Animals ; Humans ; Amyloid beta-Peptides/metabolism/antagonists & inhibitors ; Reactive Oxygen Species/metabolism ; Oxidative Stress/drug effects ; Peptide Fragments/metabolism/antagonists & inhibitors ; Particle Size ; Caenorhabditis elegans/drug effects ; }, abstract = {Alzheimer's disease (AD) involves a complex pathogenesis in which the β-amyloid (Aβ) cascade and oxidative stress hypotheses interact through mitochondrial dysfunction, forming a vicious cycle that underscores the need for multi-targeted therapeutic strategies. In this study, multifunctional carbon dots (EMA-CDs) were rationally designed and synthesised via a simple one-pot hydrothermal approach to integrate antioxidant activity, nitric oxide (NO) release capability, and mitochondrial targeting. EMA-CDs exhibited potent reactive oxygen species (ROS) scavenging abilities, efficiently eliminating hydroxyl radicals, superoxide anions, and DPPH radicals with rates exceeding 80%. Their mitochondrial specificity further alleviated intracellular oxidative stress and neuroinflammation. Notably, EMA-CDs at low concentrations (80 µg mL[-1]) markedly inhibited Aβ42 aggregation and promoted fibril disassembly, achieving inhibition and depolymerisation efficiencies of approximately 97.1% and 99.4%, respectively. In addition, EMA-CDs promoted NO production, which in turn modulated the expression of MMP-9 and ZO-1 proteins. This led to a reversible and transient opening of the blood-brain barrier (BBB), resulting in an enhanced penetration efficiency with a cumulative rate of 65.4% over 12 h. Furthermore, in the C. elegans CL2006 model, EMA-CDs significantly alleviated Aβ42 plaque deposition and reduced intracellular ROS levels by approximately 55%. Moreover, EMA-CDs extended the mean lifespan of the worms by about 6 days and enhanced reproductive capacity to 1.25-fold of the control, demonstrating potent in vivo neuroprotective and antioxidative stress effects. Collectively, this study demonstrates that EMA-CDs function as a versatile therapeutic platform for AD treatment and provide a promising avenue for the development of multi-target nanotherapeutics and novel AD intervention strategies.}, } @article {pmid42172309, year = {2026}, author = {Unruh, D and Todtleben, J and Johnson, K and Schlichtmann, B and Szabo, M and Holland, M and Carlson, C and Hinson, J and Levin, S}, title = {Analytical and Clinical Validity of a High-Throughput, Fully Automated Immunoassay for Plasma Neurofilament Light Chain.}, journal = {The journal of applied laboratory medicine}, volume = {}, number = {}, pages = {}, doi = {10.1093/jalm/jfag052}, pmid = {42172309}, issn = {2576-9456}, abstract = {BACKGROUND: Neurofilament light chain (NfL) has emerged as a promising blood-based biomarker for neuroaxonal damage across neurological disorders. Clinical utility has been correlated with disease activity, treatment response, and prognosis. However, routine clinical laboratory implementation requires comprehensive analytical validation to ensure reliability and accuracy.

METHODS: A fully automated Access NfL research use only (RUO) immunoassay was evaluated on the DxI 9000 Immunoassay Analyzer from Beckman Coulter. Analytical validation in plasma assessed precision, analytical sensitivity, linearity, analytical specificity (interference), calibrator and sample stability, and method comparison to the Quanterix Simoa NfL assay. Clinical validity included comparisons of Alzheimer disease (Ad, N = 20) in plasma and multiple sclerosis (MS, N = 16) in serum, vs healthy controls (N = 20 and N = 23, respectively). Plasma-serum equivalence was validated.

RESULTS: The NfL assay met analytical criteria, with precision demonstrating coefficients of variation <3% across runs, a lower limit of quantification of 3.10 pg/mL, linearity with <12% deviation, and <10% interference. Plasma NfL samples remained stable for 18 h at room temperature (<7% difference) and refrigerated (<5%), and through 5 freeze-thaw cycles (<8%). Method comparison yielded high correlation (R2 = 0.981) with positive systematic proportional bias (Passing-Bablok slope = 3.02). Ad patients showed significantly elevated NfL levels (median 49.3 pg/mL, IQR: 28.9-67.8) vs controls (median 29.1 pg/mL, IQR: 22.6-33.8; P = 0.02). MS patients similarly demonstrated higher NfL (median 27.7 pg/mL, IQR: 22.5-50.6) vs controls (median 19.2 pg/mL, IQR: 15.1-25.6; P = 0.003).

CONCLUSIONS: The high-throughput Access NfL assay demonstrated analytical and clinical validity, supporting implementation in research and clinical laboratories.}, } @article {pmid42172661, year = {2026}, author = {Motisi Bertulli, A and Bezzio, C and Marsano, S and Corradini, I and Stranges, S and Matteoli, M and Armuzzi, A}, title = {Does inflammatory bowel disease play a role in cognitive decline? A systematic review.}, journal = {Journal of Crohn's & colitis}, volume = {20}, number = {5}, pages = {}, doi = {10.1093/ecco-jcc/jjag057}, pmid = {42172661}, issn = {1876-4479}, mesh = {Humans ; *Inflammatory Bowel Diseases/complications/psychology/drug therapy ; *Cognitive Dysfunction/etiology ; }, abstract = {BACKGROUND & AIMS: Inflammatory bowel disease (IBD) has been increasingly linked to cognitive impairment (CI) and dementia, yet the underlying mechanisms driving this association remain poorly understood and population, clinical and experimental studies show controversial results. Among others, factors such as chronic inflammation, gut-brain axis dysfunction, and psychological comorbidities have been proposed as contributors to cognitive deficits in IBD patients. The objective of this systematic review was to evaluate the existing literature on the relationship between IBD and cognitive function, considering observational and preclinical studies, with the aim to identify key factors influencing CI and potential clinical implications. The main focus of this review is on the use of IBD treatments, which may have a potential impact on CI.

METHODS: We conducted a systematic review according to PRISMA guidelines. PubMed and Scopus were searched from database inception up to August 30, 2024, for studies assessing cognitive performance in individuals with IBD. Clinical and epidemiological studies, genetic investigations (Mendelian Randomization and Genome-wide Association studies), and preclinical models examining memory, attention, and executive functions were included. Two reviewers independently extracted data and assessed methodological quality and risk of bias.

RESULTS: The research yielded 66 included studies, including 31 populations studies, 13 genetics studies, and 22 preclinical research studies. Our findings suggest that patients with IBD may exhibit impaired cognitive function, particularly in memory, attention, and executive processing. Disease activity, chronic inflammation and psychological stress appear to contribute to these deficits, while some treatment strategies seem to mitigate the risk of CI.

CONCLUSION: IBD is associated with CI and increased dementia risk, with biologics potentially mitigating neuroinflammation-related decline. More longitudinal studies and randomized clinical trials, also on intermediate endpoints, are needed to clarify the neuroprotective role of some therapies and optimize treatment strategies.}, } @article {pmid42172854, year = {2026}, author = {Copeland, EN and Mohammad, A and Baranowski, BJ and Marcella, BM and Beaudette, SM and MacPherson, REK and Fajardo, VA}, title = {Voluntary wheel running combined with low-dose lithium supplementation improves novel object recognition in male DBA/2 J mdx mice.}, journal = {Journal of trace elements in medicine and biology : organ of the Society for Minerals and Trace Elements (GMS)}, volume = {95}, number = {}, pages = {127893}, doi = {10.1016/j.jtemb.2026.127893}, pmid = {42172854}, issn = {1878-3252}, mesh = {Animals ; Male ; Mice ; Mice, Inbred mdx ; *Lithium/pharmacology/administration & dosage ; Glycogen Synthase Kinase 3/metabolism/antagonists & inhibitors ; *Physical Conditioning, Animal ; *Dietary Supplements ; Sarcoplasmic Reticulum Calcium-Transporting ATPases/metabolism ; Amyloid Precursor Protein Secretases/metabolism ; Phosphorylation/drug effects ; tau Proteins/metabolism ; *Recognition, Psychology/drug effects ; }, abstract = {BACKGROUND: Duchenne muscular dystrophy (DMD) is a severe neuromuscular disorder caused by a mutation to the dystrophin gene. Cognitive dysfunction is a lesser-known symptom of DMD; however, approximately one-third of patients experience it. Though the mechanisms underlying these dysfunctions are unknown, research points towards an Alzheimer's disease (AD)-like pathology in clinical and preclinical work. In a recent study, we previously demonstrated that inhibiting glycogen synthase kinase 3 (GSK3) through a combination of low-dose lithium supplementation and voluntary wheel running (VWR) improved muscle quality and function in the mdx mouse model of DMD. Interestingly, both VWR and GSK3 inhibition with lithium can exert neuroprotective effects against Alzheimer's pathology; however, whether this treatment can also benefit cognitive function in mdx mice remains unknown.

METHODS: Here, we conducted a brief follow-up study to determine whether inhibiting GSK3 with a combination of low-dose lithium supplementation and VWR would enhance novel object recognition in mdx mice, while also investigating potential mechanisms, including beta-secretase activity, Tau phosphorylation, and sarco(endo)plasmic reticulum calcium ATPase (SERCA) activity.

RESULTS: Our findings show that lithium and VWR treatment, on average, improved novel object recognition in mdx mice-a result that may be linked to enhanced SERCA activity within the hippocampus but not to any changes in beta-secretase activity or tau phosphorylation.

CONCLUSION: Taken together, these data point to the potential benefits of Li and VWR on cognitive function in mdx mice, highlighting the need for future research aimed at teasing out the potential mechanisms.}, } @article {pmid42172936, year = {2026}, author = {Li, Y and Li, H and Xu, Z and Zhou, SK and , }, title = {CLIS: Causality-inspired Longitudinal Image Synthesis and its application to Alzheimer's disease characterization.}, journal = {Medical image analysis}, volume = {112}, number = {}, pages = {104126}, doi = {10.1016/j.media.2026.104126}, pmid = {42172936}, issn = {1361-8423}, mesh = {*Alzheimer Disease/diagnostic imaging/pathology/cerebrospinal fluid ; Humans ; *Magnetic Resonance Imaging/methods ; *Image Interpretation, Computer-Assisted/methods ; Algorithms ; Longitudinal Studies ; Neural Networks, Computer ; Biomarkers/cerebrospinal fluid ; Brain/diagnostic imaging/pathology ; Generative Artificial Intelligence ; }, abstract = {Clinical decision-making relies heavily on causal reasoning and longitudinal analysis of clinical variables, which include demographic variables, biomarkers, measurements, etc., often stored in a tabular format, and visual medical images. For example, for a patient with Alzheimer's disease (AD), how might brain gray matter atrophy evolve over a year under a hypothetical change in the Aβ42 biomarker level in cerebrospinal fluid? Answering such hypothetical questions is important for diagnosis and follow-up treatment, yet these medical images are neither readily acquired nor effectively predicted by correlation-based image synthesis models. Hence, a Causality-inspired Longitudinal Image Synthesis (CLIS) model is valuable. Building such a CLIS model faces three primary challenges: mismatched dimensionality between high-dimensional images and low-dimensional tabular variables, inconsistent intervals in follow-up data, and the complexity of medical causal mechanisms. In this paper, we propose a CLIS model that addresses these challenges via a novel integration of generative imaging, continuous-time modeling, and structural causal models combined with a neural network. Specifically, we first depict dependencies among tabular variables - including demographics, clinical biomarkers, and brain volumes - using a tabular causal graph (TCG), and then extend this to a tabular-visual causal graph (TVCG) to synthesize brain MRIs in a causality-inspired manner. An independent variable is also introduced to explicitly model time intervals. We train our CLIS on the ADNI dataset and evaluate it on two additional AD datasets, demonstrating that the synthesized images are both high-quality and interpretable. Furthermore, the generated MRIs provide insights for AD characterization, illustrating the model's potential utility in clinical applications.}, } @article {pmid42174650, year = {2026}, author = {Dakhel, A and Vestin, J and Giedraitis, V and Nyholm, D and Ingelsson, M and Erlandsson, A}, title = {Characterization of a distinct form of vimentin in the neurodegenerative brain.}, journal = {Acta neuropathologica communications}, volume = {14}, number = {1}, pages = {}, pmid = {42174650}, issn = {2051-5960}, mesh = {*Vimentin/metabolism ; Humans ; *Brain/metabolism/pathology ; *Alzheimer Disease/metabolism/pathology ; Astrocytes/metabolism ; *Parkinson Disease/metabolism/pathology ; Female ; Aged ; Male ; alpha-Synuclein/metabolism ; Animals ; Aged, 80 and over ; Amyloid beta-Peptides/metabolism ; }, abstract = {Alzheimer's disease (AD) and Parkinson's disease (PD) are characterized by brain accumulation of aggregated proteins, leading to neuronal and glial dysfunction. Compelling data indicate that changes in vimentin expression, structure, and localization reflect alterations in cellular homeostasis and may correlate with disease progression. Yet, the involvement of abnormal vimentin in AD and PD remains unclear. Here, we have thoroughly characterized the distribution of modified, disease-associated vimentin in the AD and PD brain parenchyma, as well as in cerebrospinal fluid (CSF), hiPSC-derived astrocytes and organoids. For this purpose, we used the form-specific vimentin antibody [84-1], originally generated to recognize abnormal vimentin on the surface of sarcoma cells. The 84-1 vimentin reactivity pattern was characterized through immunohistochemistry and proximity ligation assay. Moreover, proteomic analysis, Western blot, and ELISA were performed to quantify 84-1 vimentin levels and gain insights into its molecular features. Our data demonstrate that 84-1 can identify a distinct population of vimentin in the human brain that shows low affinity to commonly used vimentin antibodies. The 84-1 vimentin is enriched in disease conditions and forms distinct deposits in the affected regions of the AD and PD brain, often colocalizing with pathological protein aggregates. Interestingly, the 84-1 vimentin pool consists mainly of cleaved proteoforms and reduction-resistant aggregates. Moreover, 84-1 vimentin levels are elevated in the CSF of AD and PD patients as well as in the culture medium of human astrocytes exposed to αSyn or Aβ fibrils. Taken together, our data highlights the importance of modified vimentin in neurodegeneration and presents 84-1 vimentin as a potential biomarker and future treatment target for AD and PD.}, } @article {pmid42174734, year = {2026}, author = {Xue, H and Bi, S and Wang, M and Zhu, X and Wang, F and Wang, Y and He, Y and Wang, Y and Liu, X and Cui, B and Li, N and Zhao, Z and Zhang, C and Wu, L and Qi, Z and Yan, S and Lu, J}, title = {Optimizing cutoffs for clinical interpretation of brain amyloid status using PET/MRI: a multisite study.}, journal = {Alzheimer's research & therapy}, volume = {}, number = {}, pages = {}, doi = {10.1186/s13195-026-02071-y}, pmid = {42174734}, issn = {1758-9193}, abstract = {BACKGROUND: Amyloid-β PET (Aβ-PET) imaging is playing an increasingly important role in the diagnosis and treatment of Alzheimer's Disease (AD). The Centiloid (CL) scale has been developed to standardize the measurements of Aβ PET imaging. Previous CL threshold settings were based on PET/CT, while our team's preliminary study found that CL values from PET/MRI are higher than those from PET/CT. Therefore, there is an urgent need to establish clinical interpretation cutoffs for Aβ status via PET/MRI to facilitate application in clinical practice.

METHODS: The clinical performance of Aβ PET/MRI and cerebrospinal fluid biomarkers were evaluated in a multisite cohort of 720 participants. Aβ-PET scans were visually read and quantified using CL method. A two-cutoff approach identified thresholds maintaining > 90% sensitivity/specificity and ≤ 20% intermediate cases, selected by maximal Youden index. Group comparisons of cerebrospinal fluid biomarkers and cognition used generalized linear models adjusted for age and sex.

RESULTS: The two-cutoff approach categorized Aβ-PET status as negative (CL ≤ 18.7), gray-zone (18.7-44.2), and positive (CL > 44.2). In Xuanwu cohort, it achieved an accuracy of 94.1%, a positive predictive value of 97.4%, a negative predictive value of 86.1%. In External cohort, the accuracy was 97.4%, positive predictive value 98.5%, negative predictive value 90.8%. Patients in the gray-zone group had lower cerebrospinal fluid(CSF) Aβ-42, Aβ-42/40 levels and a higher P-tau/Aβ-42 ratio.

CONCLUSIONS: This study established optimal CL-cutoff, providing a clinically applicable framework for interpreting Aβ PET/MRI findings. Incorporating a two-cutoff system facilitates the tracking of the AD continuum and supports individualized therapeutic decision-making.}, } @article {pmid42175737, year = {2026}, author = {Liang, S and Zhang, Q and Wang, X and Peng, L and Ji, X and Wang, J and Zhang, Y and Huang, J and Yang, J and Zhan, S and Xiao, Y and Liu, W and Chen, L}, title = {Electroacupuncture Improves the Learning and Memory by Modulating Hippocampal Glucose Metabolism through IGF1/IGF1R Signaling in Alzheimer's Disease.}, journal = {Advanced science (Weinheim, Baden-Wurttemberg, Germany)}, volume = {}, number = {}, pages = {e14241}, doi = {10.1002/advs.202514241}, pmid = {42175737}, issn = {2198-3844}, support = {82004440//National Natural Science Foundation of China/ ; 2024J09044//Fujian Provincial Natural Science Foundation of China/ ; 2025Y9600//Joint Funds for the innovation of science and Technology, Fujian Province/ ; 2024Y9533//Joint Funds for the innovation of science and Technology, Fujian Province/ ; 2023ZQNZD015//Health Service Research of Fujian Province/ ; }, abstract = {Alzheimer's disease (AD) is characterized by progressive cognitive decline and cerebral glucose hypometabolism. Emerging evidence suggests that modulating brain glucose metabolism represents a promising therapeutic strategy for AD. Here, we demonstrate that electroacupuncture (EA) improves cognitive function in 5×FAD mice by enhancing glucose metabolism in the hippocampus. EA treatment significantly attenuated learning and memory deficits and reduced β-amyloid (Aβ) deposition in 5×FAD mice. Further analysis revealed that these improvements were associated with enhanced hippocampal glucose metabolism and optimized information processing in the brain metabolic network. In addition, EA specifically activated the IGF1/IGF1R signaling pathway in the hippocampus, which promoted membrane translocation of GLUT3 and consequently enhanced neuronal glucose uptake. The glucose metabolic enhancement boosted tricarboxylic acid cycle activity and improved synaptic plasticity. Our findings establish a novel mechanism by which EA improves the learning and memory through the IGF1/IGF1R pathway, providing both theoretic and experimental support for the clinical application of EA in AD treatment.}, } @article {pmid42175774, year = {2026}, author = {Lin, Z and Jiang, Z and Chen, D and Liu, Y and He, Z and Ning, W and Wang, S and Guan, L}, title = {Novel Donepezil-Chalcone Hybrids as Potential Multifunctional Anti-Alzheimer's Disease Agents: Design, Synthesis, Computational Simulation, and In Vitro/In Vivo Biological Evaluation.}, journal = {Chemical biology & drug design}, volume = {107}, number = {5}, pages = {e70316}, doi = {10.1111/cbdd.70316}, pmid = {42175774}, issn = {1747-0285}, support = {22567024//The National Natural Science Foundation of China/ ; }, mesh = {*Alzheimer Disease/drug therapy/metabolism/pathology ; *Donepezil/chemistry/pharmacology ; Amyloid beta-Peptides/metabolism ; Animals ; Humans ; Molecular Docking Simulation ; Glycogen Synthase Kinase 3 beta/metabolism ; *Cholinesterase Inhibitors/chemistry/pharmacology/chemical synthesis/therapeutic use ; Drug Design ; Molecular Dynamics Simulation ; Peptide Fragments/metabolism ; Acetylcholinesterase/metabolism/chemistry ; Mice ; Butyrylcholinesterase/metabolism/chemistry ; *Neuroprotective Agents/chemistry/pharmacology/therapeutic use/chemical synthesis ; Amyloid Precursor Protein Secretases/metabolism/antagonists & inhibitors ; Aspartic Acid Endopeptidases/metabolism/antagonists & inhibitors ; *Chalcone/chemistry/pharmacology ; Protein Aggregates/drug effects ; }, abstract = {A novel series of donepezil-chalcone including pyridine, piperazine, phenylamide skeleton hybrids were designed, synthesized, and evaluated for their inhibitory activities against AChE and BChE. Subsequently, a subset of these derivatives was investigation to inhibit Aβ1-42 aggregation and promote Aβ1-42 disaggregation effects. Among them, compounds 8b, 8c, 8j, and 8ab possessing good activity were further assayed for their inhibitory effects on BACE-1 and GSK3β, as well as their PI displacement activity. 8b (AChE, IC50: 0.11 μM; BChE, IC50: 0.18 μM; Aβ1-42 aggregation, IC50: 3.40 μM; their ability to promote Aβ1-42 disaggregation, IC50: 4.53 μM; BACE-1, IC50: 1.82 μM; GSK3β, IC50: 0.98 μM) exhibited prominent bioactivities across the above assays. Meanwhile, the molecular docking and the molecular dynamics simulations were performed to analyze the interactions between 8b and the key amino acid residues of the target proteins, which verified the stability of the corresponding protein ligand complexes. Furthermore, 8b significantly attenuated the cytotoxicity induced by Fe[3+] and Cu[2+] in BV-2 microglial cells, L-Glu in HT-22 hippocampal neuronal cells, and Aβ1-42 in both BV-2 and SH-SY5Y neuroblastoma cells. Additionally, 8b reduced the levels of intracellular ROS and NO in LPS-stimulated BV-2 cells, demonstrating potent anti-inflammatory and neuroprotective properties. Acute toxicity tests in mice confirmed the safety profile of 8b. In in vivo studies, compound 8b effectively protected against neuroinflammation 8b ameliorated cognitive deficits in mice induced by AlCl3 combined with L-galactose, which was associated with the upregulation of p-GSK3β and the downregulation of p-Tau expression. In conclusion, 8b holds great potential as a promising multitarget-directed new lead compound for the treatment of AD.}, } @article {pmid42176081, year = {2026}, author = {Ibrahim, RW and AlSheikh, MH}, title = {Model Validation Pipeline Against Longitudinal Alzheimer's Biomarker Data.}, journal = {Neuroinformatics}, volume = {24}, number = {2}, pages = {}, pmid = {42176081}, issn = {1559-0089}, mesh = {*Alzheimer Disease/metabolism/diagnostic imaging/pathology ; Humans ; tau Proteins/metabolism ; Biomarkers/metabolism ; Amyloid beta-Peptides/metabolism ; *Brain/metabolism/pathology/diagnostic imaging ; Computer Simulation ; *Models, Neurological ; Connectome ; Neurons ; }, abstract = {This study develops a fractional-order model of Alzheimer's disease using a [Formula: see text]-generalized Atangana-Baleanu-Caputo (ABC) operator to capture the spatiotemporal dynamics of amyloid-beta and tau protein spread, coupled with a neuron regeneration mechanism. The fractional parameters α, [Formula: see text], and τ control memory depth, deformation of the kernel, and temporal scaling, respectively. Numerical simulations demonstrate that: (i) intermediate fractional orders [Formula: see text] produce biologically realistic propagation delays, (ii) lower [Formula: see text] values enhance nonlocal interactions and accelerate tau diffusion across the connectome, and (iii) increasing the scaling parameter τ slows accumulation, mimicking effective clearance or treatment response. Incorporating a treatment term with drug diffusion and decay reveals that sustained low decay rates ([Formula: see text]) markedly reduce tau concentrations and protect neuron populations. These findings show that the [Formula: see text]-ABC framework not only captures the hereditary and memory effects of Alzheimer's progression but also provides a flexible platform for simulating therapeutic interventions and predicting disease trajectories using real brain connectome data.}, } @article {pmid42176392, year = {2026}, author = {Baron, KG and Alcántara, C and López, I and Euler, M and Baucom, BRW and Bermudez, B and Arones, Y and Carbajal-Salisbury, S and Fabian, G and Grandner, M and Gorovoy, S and Lopez, S and Parthasarathy, S and Troxel, W}, title = {Protocol for Nuestro Sueño: A randomized trial of a couples-based intervention to improve PAP adherence and sleep health among Hispanic patients beginning positive airway pressure (PAP) and their partners.}, journal = {Sleep medicine}, volume = {145}, number = {}, pages = {109019}, doi = {10.1016/j.sleep.2026.109019}, pmid = {42176392}, issn = {1878-5506}, mesh = {Humans ; *Sleep Apnea, Obstructive/therapy ; *Hispanic or Latino ; *Continuous Positive Airway Pressure/methods ; Single-Blind Method ; Randomized Controlled Trials as Topic ; Adherence Interventions ; *Patient Compliance ; Female ; Male ; Pilot Projects ; Quality of Life ; Feasibility Studies ; Sleep Quality ; }, abstract = {BACKGROUND: Obstructive sleep apnea (OSA) is more common among Hispanic individuals and contributes to risk for cardiometabolic diseases, dementia and poor quality of life. Positive airway pressure (PAP) improves sleep and quality of life, and culturally adapted interventions are promising for increasing treatment engagement. The goal of this study is to test Nuestro Sueño, a culturally adapted couples-based intervention to promote positive airway pressure adherence and sleep health for Hispanic couples in which one partner is recently diagnosed with OSA.

METHODS: We are conducting a two-arm, parallel group, single blind, randomized controlled pilot/feasibility trial to compare our novel culturally adapted treatment to an information control (IC). Nuestro Sueño is a culturally adapted dyadic behavioral intervention based on a transdiagnostic model. The digital health program involves 3- weekly sessions delivered via telehealth with a community health worker. Content is focused on education about OSA and PAP, improving both partner's sleep quality, increasing partner support and communication, and couple-level goal-setting around sleep and PAP use. The IC includes standardized patient educational materials. Both groups receive the usual follow-up care. Assessments will be completed pre-treatment, 1 and 3 months after starting PAP. Our main outcomes are feasibility and treatment satisfaction. Secondary outcomes include comparing Nuestro Sueño to IC for PAP adherence, sleep quality (self-report and objective) and cognitive measures of memory, processing speed and verbal fluency.

DISCUSSION: Nuestro Sueño is a novel culturally adapted intervention focused on improving PAP adherence and sleep health among couples in which one partner is recently diagnosed with OSA. Results of this study will be used to inform the design of a subsequent fully adequately-powered clinical trial. If successful, this intervention could significantly advance current clinical practice in the treatment of OSA and sleep health more comprehensively as well as promote sleep health equity among Hispanic patients, who are more likely to face challenges to obtaining diagnosis and treatment for OSA.

TRIAL REGISTRATION: Clinicaltrials.gov, NCT06649929.}, } @article {pmid42177211, year = {2026}, author = {Sheikh, S and Shadin, M and Eity, TA and Oni, MIJ and Khatun, MM and Chowdhury, R and Bhuia, MS and Alfaifi, M and Altemani, FH and Altemani, AH and Saleh, N and Islam, MT}, title = {Lenalidomide ameliorates cognitive impairment via putative AChE inhibition: an in silico and in vivo study in a scopolamine-induced cognitive impairment model.}, journal = {Scientific reports}, volume = {}, number = {}, pages = {}, doi = {10.1038/s41598-026-49461-8}, pmid = {42177211}, issn = {2045-2322}, abstract = {Alzheimer's disease (AD) causes progressive cognitive decline, and current therapies provide limited benefit. This study evaluated the neuroprotective effects of lenalidomide (LLM), a thalidomide derivative, in a scopolamine-induced mouse model of cognitive impairment, with emphasis on its acetylcholinesterase (AChE) inhibitory potential. Mice received LLM (5, 10, and 20 mg/kg), donepezil (DNP) (3 mg/kg), or a combination and were assessed using Y-maze, passive avoidance, novel object recognition, and Morris water maze tests. In silico analysis, including molecular docking, 100 ns molecular dynamics simulation and ADMET profiling were performed to investigate the interaction of LLM with AChE. Memory performance showed a significant and dose-dependent improvement after the treatment of LLM. The 20 mg/kg dose exhibited effects comparable to DNP. LLM and DNP work together to increase effectiveness. Docking and simulation analyses revealed strong, stable binding to AChE while ADMET values indicated good drug-likeness. LLM exhibits neuroprotective and cognition enhancing effects in the scopolamine-induced model. In silico study also shows its potential as an AChE inhibitor. The study's anti-inflammatory mechanisms might also be helpful but need more exploration.}, } @article {pmid42177528, year = {2026}, author = {Chen, L and Lin, X and Fu, M and Chen, S and Yan, Z and Diao, Y and Chen, G and Huang, Z and Sun, Y and Lin, Y and Ye, Z and Zhou, Y and Ye, Q}, title = {Engineered neuronal exosomes mediate α-synuclein clearance to ameliorate Parkinson's disease.}, journal = {Journal of nanobiotechnology}, volume = {}, number = {}, pages = {}, doi = {10.1186/s12951-026-04552-6}, pmid = {42177528}, issn = {1477-3155}, support = {2023XH023//the Postdoctoral Research Project Startup Fund of Fujian Medical University Union Hospital/ ; 2024QH2020//the Startup Fund for Scientific Research of Fujian Medical University/ ; 2023Y9008//the Joint Funds for the Innovation of Science and Technology, Fujian Province/ ; 2024ZD01002//the Major Special Project of Fujian Provincial Health Technology Project/ ; U23A20423//the National Natural Science Foundation of China/ ; 2022Y2005//the Clinical Research Center for Precision Diagnosis and Treatment of Neurological Diseases of Fujian Province/ ; }, abstract = {Parkinson's disease (PD) is the second most common neurodegenerative disorder after Alzheimer's disease. A hallmark pathological feature of PD is the abnormal aggregation of α-synuclein (αSyn) into insoluble Lewy bodies. Consequently, developing strategies to inhibit αSyn aggregation in the brain has been a major research focus for PD treatment. This study developed a therapeutic approach using engineered neuronal exosomes. These exosomes were modified to extend their blood circulation half-life to 3.8 h and enhance targeting, with a 2.15 ± 0.09% brain signal proportion (vs. 0.78 ± 0.07% for free dye). They were then loaded with a self-developed αSyn aggregation-blocking peptide (sPep) as well as the antioxidant pyrroloquinoline quinone (PQQ). We investigated the therapeutic efficacy of this system in both in vitro and in vivo models of PD. Our experiments confirmed that the screened sPep effectively targeted and blocked αSyn aggregation both in vitro and in vivo. Neuronal exosomes, isolated by ultracentrifugation and hybridization, demonstrated strong abilities to cross the blood-brain barrier. In vivo studies revealed that the treatment significantly improved motor and cognitive functions in PD model mice. The underlying neuroprotective mechanisms included reducing αSyn aggregation, enhancing antioxidant capacity, ameliorating mitochondrial dysfunction, and suppressing cell apoptosis, collectively promoting the survival of dopaminergic neurons. These findings demonstrate that the engineered exosome-mediated delivery system exerts a protective effect against PD pathology.}, } @article {pmid42178013, year = {2026}, author = {Pattanaik, S and Sahu, PK and Paidesetty, SK and Prusty, SK and Pakeeraiah, K and Panda, PK and Lopamudra, }, title = {Design, synthesis, and inhibition of oxidative, amyloidogenic, and cholinergic dysfunction of saxagliptin-derived schiff bases against STZ-induced sporadic AD-like pathology.}, journal = {European journal of pharmacology}, volume = {1028}, number = {}, pages = {178987}, doi = {10.1016/j.ejphar.2026.178987}, pmid = {42178013}, issn = {1879-0712}, mesh = {Animals ; *Adamantane/analogs & derivatives/pharmacology/chemical synthesis/chemistry/therapeutic use ; *Oxidative Stress/drug effects ; *Alzheimer Disease/drug therapy/chemically induced/pathology/metabolism ; *Dipeptides/pharmacology/chemistry/chemical synthesis/therapeutic use ; Rats ; Streptozocin ; Male ; Schiff Bases/pharmacology/chemistry/chemical synthesis ; *Neuroprotective Agents/pharmacology/chemical synthesis/chemistry/therapeutic use ; *Drug Design ; Amyloid beta-Peptides/metabolism ; Molecular Docking Simulation ; Antioxidants/pharmacology/chemical synthesis ; *Dipeptidyl-Peptidase IV Inhibitors/pharmacology/chemical synthesis/chemistry ; Humans ; Rats, Wistar ; }, abstract = {Alzheimer's disease (AD) shares significant pathological convergence with diabetes, primarily through insulin resistance. This leads to oxidative stress, neuronal inflammation, plaque formation, cholinergic dysfunction, and impaired neuronal survival. Herein, we report 10 Saxagliptin (SXG, a potent DPP-IV inhibitor)-derived Schiff base derivatives that were virtually designed and screened. Five leads were prioritized using ADMET profiling and molecular docking, then synthesized via Schiff base condensation with selected aryl aldehydes to target AD progression associated with diabetes. Structural integrity, redox activity, and stability were confirmed by comprehensive characterization, including chromatographic and spectroscopic analyses, DFT calculations, and in vitro antioxidant assays. Neuroprotective potential was thus assessed in vivo by inducing AD-like pathology in rats with a single i.p. dose of STZ at 45 mg/kg, thereby reproducing brain insulin resistance, oxidative-nitrosative stress, and cholinergic dysfunction. Significant neurodegeneration in STZ-treated rats was evidenced by behavioral analyses, biochemical markers (AChE, Aβ42), oxidative stress indices (SOD, CAT, GSH, GPx, MDA, NO, MPO), and hippocampal histology. Treatment with SXG and derivatives at 0.5 mg/kg, orally, resulted in significant restoration of antioxidant defenses, inhibition of lipid peroxidation and NO overproduction, reduction of inflammatory oxidative bursts, and improved cognition in treated groups. Remarkably, derivatives 3c and 3e showed superior free-radical scavenging and greater regulation of redox biomarkers, which were associated with healthy, defined hippocampal cytoarchitecture and reduced neuronal pyknosis and necrosis compared with SXG. Additionally, 3e showed strong therapeutic efficacy by targeting oxidative stress, cholinergic, and amyloidogenic pathways synchronously.}, } @article {pmid42178051, year = {2026}, author = {Wang, C and Liu, J and Zhou, Y and Shan, X and Li, S and Ding, S and Zhuo, X and Li, Q and Yang, W and Zhang, X and Gu, L}, title = {Acacetin targets SNX5 to promote autophagy degradation of NLRP3 inflammasome against cognitive impairment in Alzheimer's disease.}, journal = {Biochemical pharmacology}, volume = {251}, number = {Pt 1}, pages = {118103}, doi = {10.1016/j.bcp.2026.118103}, pmid = {42178051}, issn = {1873-2968}, abstract = {Alzheimer's disease (AD) is a chronic, low-grade inflammatory neurodegenerative disorder. Inhibiting the NOD-, LRR- and pyrin domain-containing protein 3 (NLRP3) inflammasome is a potential therapeutic strategy for AD, but no approved NLRP3-specific inhibitors are available for clinical use, and current agents often cause significant side effects despite their anti-inflammatory benefits. Acacetin, is a flavonoid compound that can penetrate the blood-brain barrier, with potential for treating AD.The purpose of this study is to clarify the relationship between the anti-AD effect of acacetin and its mechanism of inhibiting NLRP3. Acacetin improved cognitive function and reduced neuronal damage in 3xTg mice. Further Acacetin directly binds to sorting nexin-5 (SNX5) and upregulates its expression. This, in turn, activates autophagy to degrade the NLRP3 inflammasome, alleviates inflammationin HT-22 cells and BV-2 cells. These findings suggest that Acacetin can exert an anti-AD effect by targeting SNX5 to activate autophagy and promote the degradation of the NLRP3 inflammasome, which underscore the importance of targeting SNX5 to suppress NLRP3 inflammasome activation in AD treatment.}, } @article {pmid42178053, year = {2026}, author = {Elkabes, S}, title = {Sexually dimorphic roles of toll-like receptors in the central nervous system.}, journal = {Brain, behavior, and immunity}, volume = {137}, number = {}, pages = {106830}, doi = {10.1016/j.bbi.2026.106830}, pmid = {42178053}, issn = {1090-2139}, abstract = {Many neurological and psychiatric diseases and disorders show sex differences in prevalence, incidence, disease manifestation and response to treatment. Yet, historically, most clinical and pre-clinical studies have been conducted disproportionately or exclusively in male subjects. In recent years, this research bias has been increasingly addressed through human and animal studies where both sexes are appropriately represented. These investigations have identified sex-specific disease mechanisms driven by a combination of distinct genetic, anatomical, physiological, hormonal and neural factors in males and females. Sexual dimorphism in immune function has long been recognized. Toll-like receptors (TLRs), important mediators of the innate immune response to pathogens and endogenous danger signals, play sex-biased roles in peripheral immunity. Toll-like receptors are also expressed in cells intrinsic to the central nervous system (CNS). They initiate, not only neuroinflammation in CNS infections and disease and injuries, but also influence neurodevelopment and normal aging. Emerging evidence indicates that TLRs expressed in CNS cells contribute to neural pathology in a sex-specific manner, a research area that warrants further investigations. The aim of the present review is to highlight the sex-specific contribution of TLRs expressed in the CNS to chronic pain, neurodegenerative diseases including Alzheimer's disease (AD) and Parkinson's Disease and psychiatric disorders including major depressive disorder (MDD). Major findings are highlighted, essential concepts, controversies and knowledge gaps are discussed, and potential future directions are proposed. Attention is drawn to the importance of advancing this research area given that neuroinflammation is a key player in many CNS pathologies and TLRs are the essential drivers of neuroinflammation.}, } @article {pmid42178337, year = {2026}, author = {Abaspour, N and Roghani, M and Bagheri, M and Khalili, M}, title = {Pioglitazone protects against trimethyltin hippocampal injury by reducing pyroptosis, mitochondrial dysregulation and ER stress.}, journal = {Scientific reports}, volume = {}, number = {}, pages = {}, doi = {10.1038/s41598-026-54103-0}, pmid = {42178337}, issn = {2045-2322}, support = {522458//shahed University/ ; }, abstract = {Hippocampus-specific neurotoxic trimethyltin (TMT) is routinely used to mimic a reliable murine phenotype of neurodegeneration as well as cognitive loss and is accordingly appropriate to analyze pathogenesis of the prevalent neurodegenerative disorders, i.e. Alzheimer's disease (AD), and to examine the effectiveness of novel therapeutics. Antidiabetic medication pioglitazone has exhibited neuroprotective effects with promising clinical indications for neurodegeneration-based illnesses. This study was accomplished for studying the neuroprotective effect of pioglitazone against TMT-initiated cognitive decline and allied hippocampal neurodegeneration. For this purpose, rats received intraperitoneal TMT (8 mg/kg) to generate a model of AD-like neurodegeneration and subsequently had oral daily administration of pioglitazone for 3 weeks (20 mg/kg). The acetylcholinesterase inhibitor and certified anti-AD drug donepezil (4 mg/kg) was similarly used as a positive control medicine. Pioglitazone treatment was accompanied by lower cognitive deficits in novel object recognition test and Barnes maze paradigm in addition to mitigation of astrogliosis severity with glial fibrillary acidic protein (GFAP) as its specific indicator and lower CA1 neuronal loss. Furthermore, pioglitazone partially normalized hippocampal factors of oxidative stress and neuroinflammation together with downregulation of pyroptotic parameters comprising caspase 1 and NLR family pyrin domain containing 3 (NLRP3). Moreover, less activity of acetylcholinesterase (AChE) and greater quantity of mitochondrial health-allied factors comprising peroxisome proliferator-activated receptor γ coactivator 1α (PGC1α), mitochondrial membrane potential (MMP), mitochondrial transcription factor A (TFAM), and peroxisome proliferator-activated receptor γ (PPARγ) were likewise detected after pioglitazone treatment. These advantageous properties of pioglitazone were accompanied by inferior quantity of specific AD-allied markers comprising presenilin1 (PSEN1) and hyperphosphorylated tau (p-tau) as well as downregulation of endoplasmic reticulum (ER) stress, as observed by lower levels of PKR-like ER kinase (PERK), C/EBP homologous protein (CHOP), glucose-regulated protein 78 (GRP78), and inositol-requiring enzyme 1α (IRE1α). While anti-AD donepezil treatment was associated with improvement of cognitive function, however, it was not capable to significantly yield most advantageous effects of anti-diabetic PPARg agonist pioglitazone. This study disclosed the underlying pathways for neuroprotective effect of pioglitazone in TMT neurodegeneration and AD-like phenotype.}, } @article {pmid42178577, year = {2026}, author = {Ruthirakuhan, M and Mills, M and Rosenberg, P and Haughey, N and Mintzer, J and Craft, S and Herrmann, N and Lerner, AJ and Levey, AI and Padala, PR and Porsteinsson, A and van Dyck, CH and Shade, D and Lanctôt, KL}, title = {Uncovering lipid biomarkers linked to methylphenidate efficacy in treating apathy in Alzheimer's disease: insights from the ADMET 2 trial.}, journal = {Alzheimer's research & therapy}, volume = {}, number = {}, pages = {}, doi = {10.1186/s13195-026-02055-y}, pmid = {42178577}, issn = {1758-9193}, support = {R01 AG046543/AG/NIA NIH HHS/United States ; R01 AG046543/AG/NIA NIH HHS/United States ; R01 AG046543/AG/NIA NIH HHS/United States ; R01 AG046543/AG/NIA NIH HHS/United States ; R01 AG046543/AG/NIA NIH HHS/United States ; R01 AG046543/AG/NIA NIH HHS/United States ; R01 AG046543/AG/NIA NIH HHS/United States ; R01 AG046543/AG/NIA NIH HHS/United States ; R01 AG046543/AG/NIA NIH HHS/United States ; R01 AG046543/AG/NIA NIH HHS/United States ; R01 AG046543/AG/NIA NIH HHS/United States ; R01 AG046543/AG/NIA NIH HHS/United States ; }, abstract = {BACKGROUND: Apathy is a prevalent neuropsychiatric symptom (NPS) in Alzheimer's disease (AD), linked to functional impairment and reduced quality of life. The Apathy in Dementia Methylphenidate Trial 2 (ADMET-2) found methylphenidate (MPH) had modest efficacy for treating apathy, but treatment responses varied. MPH blocks dopamine and noradrenaline transporters, inhibiting dopamine and noradrenaline reuptake. Lipids are closely tied to monamine transporter function through their structural and signaling roles in neurotransmission, neuroinflammation, and synaptic plasticity. This study aimed to identify lipid species associated with MPH response and explore lipid pathway disruptions in responders versus non-responders.

METHODS: Participants from ADMET-2 with baseline lipidomic data were included. Responders were defined by a ≥4-point improvement on the Neuropsychiatric Inventory Apathy subscale (NPI-A), or moderate-to-marked improvement on the ADCS-Clinicians Global Impression-Change (ADCS-CGIC). Baseline plasma samples underwent lipidomic profiling. Sparse Partial Least Squares Discriminant Analysis (sPLS-DA) in the MPH group was used to identify lipid species distinguishing responders from non-responders. Model performance was evaluated by area under the curve (AUC). Identified lipid species were analyzed in MetaboAnalyst for pathway enrichment. A secondary analysis in the placebo group assessed specificity of findings to MPH.

RESULTS: Of the 43 MPH-treated participants, 28 were NPI-apathy responders, and 10 were ADCS-CGIC responders. The PLS-DA model achieved robust discrimination between responders and non-responders (NPI-apathy: AUC = 0.82 +/- 0.05; ADCS-CGIC: AUC=0.84 +/- 0.07). Pathway analysis revealed disruptions in ceramide, phosphosphingolipid, and glycosphingolipid metabolism for NPI-apathy responders, and ceramide and glycosphingolipid metabolism for ADCS-CGIC responders. In 55 placebo-treated participants (30 NPI-apathy responders), an AUC of 0.79 +/- 0.05 was achieved, with pathway analysis indicating disruption in glycosphingolipid metabolism only.

CONCLUSIONS: This study demonstrates the utility of lipidomic profiling in identifying biomarkers of response to MPH in AD patients with apathy. The identified lipidomic species are broadly related to monoamine transporter function, reflecting their role in neurotransmission and synaptic plasticity. While glycosphingolipid metabolism appears broadly linked to changes in apathy, disruptions in ceramide and phospholipid metabolism may be specific to MPH treatment. Further study of these pathways may offer insights into the molecular mechanisms underlying apathy and treatment response, and could inform future biomarker-guided interventions.}, } @article {pmid42178732, year = {2026}, author = {Liu, C and Qin, X and Talisa, VB and Wang, J}, title = {Heterogeneous causal mediation analysis using Bayesian additive regression trees.}, journal = {Biometrics}, volume = {82}, number = {2}, pages = {}, pmid = {42178732}, issn = {1541-0420}, support = {R21AG087057/NH/NIH HHS/United States ; R01AG080590/NH/NIH HHS/United States ; S10OD028483/NH/NIH HHS/United States ; 2337612//National Science Foundation Faculty Early Career Development Program (CAREER) Award/ ; R305D200031//U.S. Department of Education Institute of Education Sciences Grant/ ; }, mesh = {Bayes Theorem ; Computer Simulation ; Alzheimer Disease/genetics ; Humans ; *Mediation Analysis ; Models, Statistical ; Regression Analysis ; Causality ; Apolipoproteins E/genetics ; Treatment Effect Heterogeneity ; }, abstract = {Causal mediation analysis provides insights into the mechanisms through which treatments affect outcomes. While mediation effects often vary across individuals, most existing methods focus solely on population-average effects, overlooking individual-level heterogeneity. To address this limitation, we propose a Bayesian regression tree ensemble method that flexibly models nonlinear relationships and captures treatment-by-mediator interactions in the mediation process. Using hierarchical posterior sampling, our approach provides credible intervals with nominal coverage rates for inferring heterogeneous mediation effects. Additionally, we leverage regression tree summaries to identify subgroups with distinct mediation effects and employ SHapley Additive exPlanation values to highlight key moderators and their influence on the mediation process. Comprehensive simulations demonstrate the method's accuracy in estimating and inferring heterogeneous mediation effects. Finally, we apply our method to investigate the heterogeneous mediation role of Alzheimer's disease pathology burden in the effect of apolipoprotein E genotype on late-life cognition.}, } @article {pmid42179062, year = {2026}, author = {Li, D and Dai, W and Li, X and Li, H and Li, L and Zhao, Y and Wang, X and Zhang, L}, title = {Amyloid-β suppresses oligodendrocyte differentiation in adult oligodendrocyte precursor cells (OPCs), with inflammatory gene changes distinguishing it from developmental OPCs.}, journal = {Journal of Alzheimer's disease : JAD}, volume = {}, number = {}, pages = {13872877261451403}, doi = {10.1177/13872877261451403}, pmid = {42179062}, issn = {1875-8908}, abstract = {BackgroundAlzheimer's disease (AD) involves white matter deterioration, but how amyloid-β (Aβ) affects oligodendrocyte lineage cells at different maturation stages remains unclear.ObjectiveTo determine whether Aβ impairs oligodendrocyte differentiation and myelination in adult oligodendrocyte precursor cells (OPCs) and to identify molecular correlates via RNA-seq.MethodsOligodendrocyte lineage cells were examined in plaque-associated regions of 8-month-old 5x familial Alzheimer's disease (FAD) mice by immunohistochemistry. Primary OPCs from neonatal and adult rats were cultured with or without amyloid-β1-42 oligomers (oAβ42) to assess differentiation. Myelination was evaluated in organotypic slice cultures. RNA-seq and qPCR were performed to identify oAβ42-induced gene expression changes.ResultsIn 5xFAD mice, Olig2[+] cells were reduced near plaques, with CC1[+] mature oligodendrocytes showing a pronounced decrease, while PDGFRα[+] OPCs remained unchanged. In vitro, oAβ42 inhibited differentiation of both neonatal and adult OPCs, with adult OPCs exhibiting intrinsically slower maturation. Slice cultures revealed selective hypomyelination (reduced myelin basic protein) after oAβ42 treatment. RNA-seq showed that oAβ42 induced a distinct transcriptomic profile in adult OPCs, with upregulated genes enriched in immune/inflammatory pathways. Core inflammatory genes Nr4a1 and Tnf were significantly upregulated, validated by qPCR.ConclusionsoAβ42 plaque pathology is associated with oligodendrocyte maturation blockade. Aβ impairs OPC differentiation in purified cultures accompanied by inflammatory transcriptional changes. These findings highlight oligodendrocyte dysfunction in AD white matter pathology and reveal a specific oAβ42 response in adult OPCs.}, } @article {pmid42179084, year = {2026}, author = {Kim, D and Jeong, H and Lim, HK and Ahn, SM and Song, M}, title = {Pharmacological targeting of the integrated stress response by 2BAct improves object recognition memory and reduces neuroinflammation in the 5xFAD model of Alzheimer's disease.}, journal = {Journal of Alzheimer's disease : JAD}, volume = {112}, number = {1}, pages = {367-379}, doi = {10.1177/13872877261450638}, pmid = {42179084}, issn = {1875-8908}, mesh = {Animals ; *Alzheimer Disease/drug therapy/metabolism/genetics/psychology ; *Integrated Stress Response/drug effects ; Disease Models, Animal ; *Recognition, Psychology/drug effects ; Mice ; *Neuroinflammatory Diseases/drug therapy/metabolism ; Mice, Transgenic ; tau Proteins/metabolism ; Amyloid beta-Peptides/metabolism ; Acetamides ; Cyclohexylamines ; }, abstract = {BackgroundAlzheimer's disease (AD) is a neurodegenerative disorder and the most common cause of dementia. The integrated stress response (ISR) contributes to impaired synaptic plasticity, neuronal dysfunction, and cognitive deficits in AD. However, research targeting the ISR as a therapeutic strategy for AD remains limited due to insufficient mechanistic insight.ObjectiveThis study aimed to evaluate the effects of 2BAct, an ISR inhibitor, on behavioral symptoms, amyloid-β (Aβ) and tau accumulation, and neuroinflammation in 5xFAD mice.MethodsTen-month-old 5xFAD mice received daily intraperitoneal (IP) injections of either 2BAct (10 mg/kg/day), donepezil (2 mg/kg/day; positive control), or vehicle for 23 consecutive days. Anxiety-like behavior and cognitive function were assessed using the open field test (OFT), novel object recognition test (NORT), and Morris water maze (MWM). Amyloid-β (Aβ), tau, and neuroinflammation markers were analyzed by immunofluorescence staining. ISR inhibition was evaluated by examining the phosphorylation level of eukaryotic initiation factor 2 alpha (eIF2α) using immunofluorescence staining and by analyzing ISR-related markers via RNA sequencing.Results2BAct treatment significantly improved object recognition performance and attenuated microglial activation and tau accumulation, without reducing Aβ burden. Reduced levels of phosphorylated eIF2α were also confirmed by immunofluorescence staining.ConclusionsThese findings suggest that 2BAct treatment improves cognitive performance and mitigates neuroinflammation while reducing tau accumulation. Although the therapeutic effects are limited, targeting the ISR with inhibitors such as 2BAct represents a potential therapeutic approach for AD. Further studies are required to elucidate the underlying molecular mechanisms and to address the limitations of ISR-based interventions.}, } @article {pmid42179740, year = {2026}, author = {Chen, R and Chiu, SY and DeSimone, JC and Wang, WE and Barmpoutis, A and Mcmillan, CT and Radhakrishnan, H and Irwin, DJ and Clark, L and Kantarci, K and Boeve, BF and Vaillancourt, DE}, title = {Automated Imaging Differentiation for Dementia: Including Alzheimer Disease Dementia and Dementia with Lewy Bodies.}, journal = {Neurology open access}, volume = {2}, number = {2}, pages = {}, pmid = {42179740}, issn = {2998-7601}, support = {P30 AG066506/AG/NIA NIH HHS/United States ; R01 NS058487/NS/NINDS NIH HHS/United States ; T32 NS082168/NS/NINDS NIH HHS/United States ; U01 NS119562/NS/NINDS NIH HHS/United States ; }, abstract = {BACKGROUND AND OBJECTIVES: Differentiation of Alzheimer's disease dementia (ADD) and dementia with Lewy bodies (DLB) remains a challenge. Free-water imaging has been investigated in neurodegenerative diseases and was found to be associated with neurodegeneration and neuroinflammation. This retrospective cohort study tested whether Automated Imaging Differentiation for Dementia (AIDD), combining diffusion free-water imaging (FWI) and support vector machine, predicts ADD vs DLB with high accuracy.

METHODS: Diffusion MRI data was rendered from ADNI, NACC, and PDBP. Free-water and free-water corrected fractional anisotropy were calculated for each participant using a bi-tensor model. Diffusion metrics were randomly assigned to training and testing sets. The primary outcome was the area under the curve (AUC) in the test set. AIDD was paired with antemortem MRI to predict postmortem pathology.

RESULTS: A total of 519 diffusion scans were processed with 258 ADD (mean age 73.7 (8.8), 50% male), 129 DLB (mean age 69.3, 88% male), and 132 controls (mean age 73.6 (6.8), 40% male). The machine learning sample included 387 scans,129 ADD with a mean age of 72.8 (8.7), 52.7% male; 129 DLB with a mean age of 69.3 (8.1), 87.6% male; and 129 controls with a mean age of 73.7 (6.8), 39.5% male). AIDD showed high training AUC for ADD vs DLB = 0.995 (95% CI, 0.985-1.000), ADD vs controls = 0.992 (95% CI, 0.982-1.000), DLB vs controls = 0.991 (95% CI, 0.983-0.999), and controls vs ADD/DLB = 0.990 (95% CI, 0.979-1.000). The testing AUCs were similar: ADD vs DLB = 0.995, ADD vs controls = 0.958, DLB vs controls = 0.939, controls vs ADD/DLB = 0.903. AIDD predictions were confirmed pathologically in a cohort of 13 patients.

DISCUSSION: This study demonstrates that machine learning in combination with free-water imaging can differentiate ADD, DLB, and normal aging with high clinical and pathological accuracy. Advancement in early detection of dementia can lead to more appropriate treatment plans, especially for DLB, and improved disease stratification that have hindered drug development trials.

CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that Automated Imaging Differentiation for Dementia, combining diffusion free-water imaging and machine learning accurately distinguishes Alzheimer's Disease from Dementia with Lewy bodies.}, } @article {pmid42179743, year = {2026}, author = {Yu, Z and Li, H and Wang, Y and Shen, F and Wang, Y}, title = {Aerobic exercise versus acupuncture as adjuncts to acetylcholinesterase inhibitors in Alzheimer's disease: a systematic review and Bayesian network meta-analysis.}, journal = {American journal of clinical and experimental immunology}, volume = {15}, number = {2}, pages = {37-49}, pmid = {42179743}, issn = {2164-7712}, abstract = {Acetylcholinesterase inhibitors (AChEIs) remain the standard therapy for Alzheimer's disease (AD), yet their cognitive and functional benefits are limited, creating a strong need for effective adjunctive treatments. Aerobic exercise and acupuncture have been proposed as promising complements to AChEIs because of their potentially synergistic neurotrophic and cholinergic effects. To compare these treatment combinations, we carried out a Bayesian network meta-analysis (BNMA) of randomized controlled trials (RCTs). These studies were sourced from major English and Chinese databases and examined cognitive and functional outcomes. In total, 37 RCTs were included, covering 2,188 participants. Among all, combined acupuncture (SUCRA = 78.92%) and fire needle therapy (SUCRA = 78%) demonstrated the highest probability of improving Mini Mental State Examination scores, while moderate intensity aerobic exercise ranked best for the Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog, SUCRA = 23.3%) and the Barthel Index (SUCRA = 71.1%). Combined acupuncture was ranked highest for the Alzheimer's Disease Assessment Scale-Activities of Daily Living (ADAS-ADL, SUCRA = 94.3%), although its effects did not reach statistical significance. Across analyses, heterogeneity was minimal (I[2] ≤ 4%), model convergence was stable, and no publication bias was detected. Overall, this BNMA suggests that combined or thermal acupuncture offers the strongest cognitive gains alongside AChEIs, whereas moderate-intensity aerobic exercise provides the most reliable functional support. Because overall functional improvements were modest and evidence for some interventions remains limited, the benefits appear selective rather than broad. Larger, standardized trials are needed to clarify these patterns and guide their use in practice.}, } @article {pmid42179865, year = {2026}, author = {Arp, AM and Bloom, GS and D'Abreu, A and Fansler, A and Meegan, K and Ratcliffe, S and Kapur, J and Manning, C}, title = {The use of memantine for prevention of Alzheimer's disease: Pilot feasibility study rationale and protocol.}, journal = {Contemporary clinical trials communications}, volume = {51}, number = {}, pages = {101644}, pmid = {42179865}, issn = {2451-8654}, abstract = {BACKGROUND: Alzheimer's disease (AD) affects over 6 million older adults in the Untiled States. Evidence suggests the neuropathology leading to the disorder begins decades earlier, calling for a preventative treatment that can be administered to at risk individuals. Memantine hydrochloride, an NMDA receptor antagonist, is a possible candidate for prophylactic treatment by diminishing excessive NMDA receptor activity.

METHODS: This is a 2-year, double-blind, randomized, placebo-controlled trial of memantine hydrochloride (1:1 randomization allocation using randomly permutated blocks of unequal size). Participants are APOε4 carriers slightly under the average age of AD symptom onset (50-65 years of age) with a positive family history of a first degree relative with AD. Amyloid PET scans are performed pre and post treatment. Cognitive assessments and physical and neurological examinations are completed at regular intervals throughout the feasibility trial.

DISCUSSION: This study will assess the feasibility of the use of memantine hydrochloride for prevention of AD. The primary aim is to determine feasibility of participants who a) enrolled among those found eligible, and b) completed the study among those randomized to a study arm. Exploratory aims include examination of cognitive and safety assessments. Although not powered to determine efficacy, the study will provide direction on design elements needed for a Phase III clinical trial. No formal hypotheses are included in this feasibility trial.

TRIAL REGISTRATION: Clinical Trials NCT05063851.}, } @article {pmid42180238, year = {2026}, author = {Wang, Y and Li, H and Zhou, J and Zhao, S and Yang, A and Li, Z}, title = {The clinical value of multimodal neuroimaging in monoclonal antibody therapy for Alzheimer's disease.}, journal = {Frontiers in neurology}, volume = {17}, number = {}, pages = {1761380}, pmid = {42180238}, issn = {1664-2295}, abstract = {Multimodal neuroimaging plays an indispensable role in the diagnosis, monitoring, and therapeutic evaluation of monoclonal antibody (mAb) therapies for Alzheimer's disease (AD). Structural MRI (sMRI) enables early detection of cerebral atrophy and amyloid-related imaging abnormalities (ARIA), a critical adverse effect associated with anti-Aβ immunotherapies. Positron emission tomography (PET) provides direct visualization and quantification of Aβ plaque clearance, serving as an objective biomarker of target engagement. Functional MRI (fMRI) has been investigated as a means to detect dynamic changes in brain network connectivity following treatment, though the evidence remains preliminary. The integration of these modalities significantly enhances diagnostic accuracy and allows for personalized assessment of treatment response. Furthermore, artificial intelligence (AI) technologies improve the efficiency and predictive power of imaging data analysis, supporting clinical decision-making. Despite these advances, challenges remain regarding the sensitivity and specificity of current imaging techniques, heterogeneity in treatment responses, and the need for long-term safety monitoring. Standardized imaging protocols, combined with multidisciplinary collaboration and robust AI-assisted modeling, are essential to optimize therapeutic outcomes and minimize risks in mAb-based AD treatment.}, } @article {pmid42180249, year = {2026}, author = {Miranda, DG and Carrouel, F and Attik, N and Araujo, GF and Lopes, NFDS and Marcucci, MC and Rodrigues, FP and Caires, GA and Vigerelli, H and Godoi, BH and Pacheco-Soares, C and Ramos, LP}, title = {Correction: Juglans regia and Pfaffia paniculata extracts: implications for periodontal disease treatment and correlation with Alzheimer's risk.}, journal = {Frontiers in cellular and infection microbiology}, volume = {16}, number = {}, pages = {1850828}, doi = {10.3389/fcimb.2026.1850828}, pmid = {42180249}, issn = {2235-2988}, abstract = {[This corrects the article DOI: 10.3389/fcimb.2025.1585438.].}, } @article {pmid42180526, year = {2026}, author = {Zhang, X and Yu, X and Sha, L and Li, Y and Qiao, Q and Yu, X and Xu, Q}, title = {Reblastatin as a neuroprotective agent in temporal lobe epilepsy and excitotoxic conditions of Alzheimer's disease and Parkinson's disease.}, journal = {Acta pharmaceutica Sinica. B}, volume = {16}, number = {5}, pages = {2964-2981}, pmid = {42180526}, issn = {2211-3835}, abstract = {Previous studies have shown that heat shock protein 90 (Hsp90) inhibitors can reduce seizures in temporal lobe epilepsy (TLE) by upregulating excitatory amino acid transporter 2 (EAAT2, also known as GLT-1). While the Hsp90 inhibitor 17-AAG is effective, its long-term use raises toxicity concerns. This study aimed to identify a safer Hsp90 inhibitor by screening benzenoid ansamycin derivatives for higher binding affinity and lower toxicity. Among nine natural benzenoid ansamycins and their derivatives screened, reblastatin emerged as the top candidate, exhibiting the highest binding affinity to Hsp90. Compared to geldanamycin and 17-AAG, reblastatin demonstrated significantly lower cytotoxicity in HEK293 and HepG2 cells. Like 17-AAG, reblastatin upregulated EAAT2 levels by disrupting the association among Hsp90, EAAT2, and the 20S proteasome. In a kainic acid-induced TLE mouse model, reblastatin reduced seizure frequency by 50%, with long-term treatment showing toxicity comparable to vehicle controls. Additionally, behavioral tests revealed neuroprotective effects of reblastatin in mouse models of Alzheimer's disease and Parkinson's disease. These findings collectively suggest that reblastatin is a promising Hsp90 inhibitor for treating TLE and excitotoxic conditions associated with neurodegenerative diseases.}, } @article {pmid42180530, year = {2026}, author = {Zhao, W and Lai, Y and Li, Z and Yuan, Z and Wen, Z and Zhang, L}, title = {Targeting non-apoptotic regulated cell death (RCD) to treat neurodegenerative diseases.}, journal = {Acta pharmaceutica Sinica. B}, volume = {16}, number = {5}, pages = {2601-2644}, pmid = {42180530}, issn = {2211-3835}, abstract = {Regulated cell death (RCD) is well-known as a controlled form of cell death regulated by one or more cascading signaling pathways. Over the past few decades, increasing evidence has implicated various non-apoptotic forms of RCD in neurons-including ferroptosis, parthanatos, necroptosis, pyroptosis, autophagic cell death, paraptosis, and cuproptosis-in the pathogenesis of neurodegenerative diseases (NDs) and their associated clinical manifestations. We provide an in-depth analysis of the associations between these RCDs and NDs, including Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), amyotrophic lateral sclerosis (ALS), and multiple sclerosis (MS), and highlight the potential of modulating non-apoptotic RCD subtypes as neuroprotective targets. Besides, we highlight the crosstalk mechanisms among different non-apoptotic RCDs in NDs and the key targets regulating the crosstalk, which hold significant promise for developing dual-functional inhibitors that precisely modulate the pathological microenvironment and overcome drug resistance. As our understanding of death signaling networks deepens, such strategies may lead to breakthrough therapies for multiple NDs. Moreover, we further discuss the emerging small molecule compounds targeting non-apoptotic RCDs and their current research progress in clinical trials for the treatment of NDs, which may provide novel directions for related drugs. This comprehensive analysis paves the way for future research and therapeutic strategies aimed at harnessing non-apoptotic RCD pathways to mitigate neurodegeneration and improve patient outcomes.}, } @article {pmid42180543, year = {2026}, author = {Yang, Y and Liu, J and Liu, J and Wei, S and Kong, X and Mu, W and Liu, Y and Zhang, N}, title = {Advances in immune cell-based therapeutic agents for the treatment of inflammation-related diseases.}, journal = {Acta pharmaceutica Sinica. B}, volume = {16}, number = {5}, pages = {2794-2837}, pmid = {42180543}, issn = {2211-3835}, abstract = {Inflammation-related diseases account for over 50% of global disease-associated mortality; the core pathological mechanisms of these diseases are closely linked to functional dysregulation of immune cells such as macrophages and T cells. Aberrantly activated immune cells excessively secrete inflammatory mediators, which drive chronic inflammatory cascades and trigger irreversible tissue damage. In recent years, immune cell-based therapeutic agents (ICTAs) have garnered significant attention due to their inherent targeting specificity and immunomodulatory capabilities, encompassing whole immune cells, cell membranes, or extracellular vesicles serving as active therapeutics or delivery carriers. This review systematically elaborates on strategies for constructing ICTAs through nanoengineering, genetic engineering, and membrane-fused engineering, while outlining their integrating applications with other delivery devices. Furthermore, we summarize the preclinical and clinical trial advancements of ICTAs in various diseases such as tumors, rheumatoid arthritis, diabetes, atherosclerosis, Alzheimer's disease, inflammatory bowel disease, ischemia/reperfusion injury, sepsis, and hemophagocytic lymphohistiocytosis. These insights establish an interdisciplinary design framework for developing clinically applicable ICTAs and propose novel therapeutic approaches for inflammation-related diseases.}, } @article {pmid42182271, year = {2026}, author = {Shee, S and Huang, M and Baghel, MS and Zheng, Y and Lun, S and Yadav, SK and Yadav, NN and Ruiz-Gonzalez, CE and Tyagi, S and Nuermberger, E and Jain, SK and Bhujwalla, ZM and Slusher, BS and Wong, PC and Bishai, W}, title = {BCG vaccination mitigates tau pathology and restores cognitive function in PS19 mice.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, doi = {10.64898/2026.05.12.724591}, pmid = {42182271}, issn = {2692-8205}, abstract = {UNLABELLED: Retrospective studies in patients with non-muscle invasive bladder cancer (NMIBC) have reported a significant reduction in Alzheimer's disease (AD) incidence (12-78%) among Bacillus Calmette-Guérin (BCG) recipients versus controls. To investigate the underlying mechanisms, we evaluated BCG in the PS19 mouse model of tauopathy. We found that BCG administration reduced hippocampal phospho-tau and microgliosis while preserving neuronal markers. In vivo volumetric T2-MRI demonstrated attenuation of brain atrophy accompanied by increased glutamate-weighted CEST-MRI signals. Functionally, BCG-treated mice showed improved performance in the novel object recognition test (NORT), as well as improved body-weight maintenance and survival. Transcriptomic profiling of the hippocampus revealed near complete normalization of the PS19 disease-associated gene expression signature towards that of healthy controls. Flow cytometric profiling of brain myeloid populations demonstrated a reduction in activated resident microglia, but total microglia cells remain elevated. Moreover, an increase of the co-stimulatory marker CD80 on the recruited peripheral myeloid cells ensues following BCG treatment. Consistent with this shift in myeloid state, primary brain myeloid cells from BCG-treated mice also exhibited enhanced phagocytosis of FITC-labeled tau fibrils and increased lactate production. Together, these findings indicate that BCG induces systemic and CNS myeloid cell reprogramming that limits neuroinflammation, enhances tau clearance, and rescues cognitive and neurodegenerative phenotypes in a tauopathy model. BCG is a safe, readily available therapy that merits consideration as a preventive agent against dementia.

ONE SENTENCE SUMMARY: BCG therapy prevents tauopathy in PS19 mouse model.}, } @article {pmid42182561, year = {2026}, author = {Iizuka, T and Watanabe, T and Kameyama, M}, title = {Aging modulates amyloid clearance kinetics during anti-amyloid therapy: evidence from real-world serial amyloid PET.}, journal = {Frontiers in aging neuroscience}, volume = {18}, number = {}, pages = {1801267}, pmid = {42182561}, issn = {1663-4365}, abstract = {BACKGROUND: Anti-amyloid antibodies have been shown to reduce cerebral amyloid burden in early Alzheimer's disease (AD), yet considerable interindividual variability in treatment-associated amyloid reduction has been observed. The biological factors underlying this variability remain unclear. In particular, the influence of aging on amyloid clearance dynamics during anti-amyloid therapy has not been well characterized in real-world clinical settings.

METHODS: We conducted a prospective observational study of 23 patients with early-stage AD receiving lecanemab who underwent serial [18]F-flutemetamol amyloid PET at baseline and after 6 and 12 months. Amyloid burden was quantified in centiloid units. Cognitive outcomes were assessed using the Mini-Mental State Examination (MMSE) and Clinical Dementia Rating-Sum of Boxes (CDR-SB). Baseline cerebral perfusion was evaluated using [123]I-IMP SPECT with three-dimensional stereotactic surface projection (3D-SSP) analysis.

RESULTS: All participants showed reductions in amyloid burden on serial PET; however, the magnitude of reduction varied substantially across individuals. Older patients tended to exhibit larger and more rapid reductions in amyloid burden, whereas younger patients demonstrated more modest decreases despite comparable baseline amyloid levels and standardized dosing. Amyloid reduction at 6 months strongly predicted the magnitude of reduction at 12 months, suggesting that early PET changes capture subsequent amyloid clearance trajectories. Cognitive decline occurred in a subset of patients despite substantial amyloid reduction and was associated with marked baseline temporo-parietal hypoperfusion on SPECT rather than insufficient amyloid removal.

CONCLUSION: In this real-world cohort, aging appeared to influence the observable kinetics of amyloid reduction during anti-amyloid therapy. Early serial amyloid PET may provide useful information regarding longer-term amyloid dynamics, while baseline perfusion imaging may help identify patients with substantial downstream neurodegenerative burden who remain at risk for cognitive decline despite amyloid clearance. These findings highlight biological heterogeneity in treatment response and underscore the value of multimodal imaging for monitoring disease-modifying therapies in AD.}, } @article {pmid42183357, year = {2026}, author = {Grabowska, ME and Chen, R and Zhou, Y and Vaidya, AU and Zhong, X and Guardo, C and Dickson, AL and Babanejad, M and Yan, C and Xin, Y and Mundo, S and Peterson, JF and Li, L and Embí, P and Feng, Q and Eaton, J and Wen, Z and Li, B and Wei, WQ}, title = {Integrating genetically predicted transcriptomic signatures with longitudinal real-world data enables scalable drug repurposing for Alzheimer's disease.}, journal = {Research square}, volume = {}, number = {}, pages = {}, pmid = {42183357}, issn = {2693-5015}, abstract = {Drug repurposing offers a potential strategy to expand treatment options for conditions with limited therapies, but advancing repurposing candidates toward clinical implementation remains a challenge. Large-scale data, together with advanced genetic and epidemiological methods, may help address this gap. Here, we present an integrative digital medicine approach that combines genetically predicted transcriptomic signatures and perturbation screening for candidate identification with multi-cohort real-world validation for systematic evaluation of prioritized candidates. We applied this approach to Alzheimer's disease (AD), a disease with substantial unmet clinical need and persistent difficulty in developing effective therapies. We constructed AD signatures from genetically predicted expression changes across bulk tissues and microglia, then queried Connectivity Map profiles to identify compounds predicted to oppose these signatures. Aspirin emerged as a reproducible candidate across multiple signatures and underwent further evaluation. We then examined its association with incident AD in longitudinal electronic health record data from Vanderbilt University Medical Center and the NIH All of Us Research Program, as well as national insurance claims data. Across independent cohorts, aspirin initiation before age 65 was consistently associated with lower risk of incident AD, with signals suggesting that cumulative exposure and APOE ε4 status may influence effect size. Transcriptomic analysis of human cortical organoids provided additional experimental support, showing that aspirin more strongly opposed AD-related neuronal pathway alterations in wild-type organoids than in an organoid model of AD. This integrative approach offers a scalable strategy for genetically informed drug repurposing that bridges candidate discovery and clinical evaluation.}, } @article {pmid42184087, year = {2026}, author = {Abdelaziz, AM and Shokr, MM and Fathy, MK and Fawzy, MN}, title = {Dysfunction of the CD38-Miro1 Axis Disrupts Astrocyte-neuron Mitochondrial Transfer in Alzheimer's Disease: Mechanisms and Therapeutic Restoration.}, journal = {Journal of molecular neuroscience : MN}, volume = {76}, number = {2}, pages = {}, pmid = {42184087}, issn = {1559-1166}, mesh = {Humans ; *Alzheimer Disease/metabolism ; *ADP-ribosyl Cyclase 1/metabolism ; *rho GTP-Binding Proteins/metabolism ; Animals ; *Astrocytes/metabolism ; *Neurons/metabolism ; *Mitochondria/metabolism ; *Mitochondrial Proteins/metabolism ; }, abstract = {Alzheimer's disease (AD) is characterized by early bioenergetic failure, contributing to synaptic dysfunction and neuronal vulnerability. This review examines a critical compensatory mechanism, the transfer of functional mitochondria from astrocytes to neurons, and its profound failure in AD. We detail the coordinated molecular cascade of this mitochondrial shunt, initiated by neuronal distress signals that activate astrocytic CD38. CD38-generated cyclic ADP-ribose triggers calcium release, which then binds to the mitochondrial Rho GTPase Miro1, modulating mitochondrial trafficking and promoting peripheral positioning via kinesin motor complexes for intercellular transport through tunneling nanotubes (TNTs). Transient, localized Ca[2+] signals bias mitochondria toward docking at the plasma membrane for export, whereas sustained pathologic Ca[2+] overload impairs trafficking via motor disengagement and Miro1 dysfunction. In AD, this rescue pathway is catastrophically disrupted by NAD+ depletion, Aβ-induced calcium dysregulation, tau-mediated microtubule instability, and oxidative stress, leading to inhibited CD38 signaling, Miro1 dysfunction/impairment, and TNT dismantlement. We systematically explain how this multi-level impairment initiates a vicious cycle of bioenergetic collapse. We also look at promising treatment options that could help restore this shunt, such as NAD+ augmentation to reactivate CD38, Miro1 stabilizers to help with trafficking, and interventions to keep TNT intact. Targeting the astrocyte-neuron mitochondrial shunt may represent an innovative, disease-modifying strategy that could transform the therapeutic framework from simple protein clearance to the proactive restoration of intercellular metabolic support, offering a promising direction for next-generation AD therapeutics.}, } @article {pmid42184266, year = {2026}, author = {Ix, M and Dodel, R and Ross, JA}, title = {Alpha-Synuclein-Specific RT-QuIC As a Tool for the Differential Diagnosis of Neurodegenerative Diseases Using Peripheral Tissues.}, journal = {Clinical chemistry}, volume = {}, number = {}, pages = {}, doi = {10.1093/clinchem/hvag037}, pmid = {42184266}, issn = {1530-8561}, abstract = {BACKGROUND: The diagnosis of neurodegenerative diseases (NDDs), such as Alzheimer disease (AD), Creutzfeldt-Jakob disease (CJD), Parkinson disease (PD), and other α-synucleinopathies, is traditionally based on clinical signs and symptoms. By the time symptoms emerge, neurodegeneration has already advanced, limiting the window for early treatment and research. Early diagnosis could improve therapeutic outcomes and deepen insights into disease onset, making the search for novel diagnostic tools and early biomarkers a major focus of current research. A key pathological hallmark of these prion-like diseases is the misfolding and aggregation of proteins such as prion protein, α-synuclein (αSyn), and tau, which are detectable early in the preclinical phase and are already used diagnostically.

CONTENT: The real-time quaking-induced conversion (RT-QuIC) assay is a thioflavin T-based in vitro method capable of detecting minute amounts of misfolded proteins in various biofluids with high sensitivity and specificity. It offers a promising approach for the early diagnosis of prion-like diseases. In recent years, RT-QuIC has been further developed, particularly to enhance the detection of αSyn-specific pathologies such as PD and related disorders. Additionally, increasing efforts have aimed to use peripheral and minimally invasive tissues or biofluids, such as skin, saliva, or nasal mucosa, for RT-QuIC analysis to support early and patient-friendly diagnostics.

SUMMARY: This review summarizes recent advances in αSyn-specific RT-QuIC, with a particular focus on peripheral sample materials. The diagnostic potential of this technique for α-synucleinopathies and other NDDs is discussed and its future applications in biomarker discovery are explored.}, } @article {pmid42184775, year = {2026}, author = {Feijão, JMS and Oliveira, DS and Chiussi, S and Pêgo, AP and Santos, SD and Moreira, FTC}, title = {NanoGold-enhanced biomimetic sensor for Tau-441 protein detection in serum for Alzheimer's disease diagnosis.}, journal = {Bioelectrochemistry (Amsterdam, Netherlands)}, volume = {172}, number = {}, pages = {109335}, doi = {10.1016/j.bioelechem.2026.109335}, pmid = {42184775}, issn = {1878-562X}, abstract = {Alzheimer's disease (AD) is the leading cause of dementia, and early identification of molecular biomarkers in blood offers a promising avenue for diagnosis and monitoring treatment. Tau-441 stands out as a particularly promising biomarker among the potential molecular targets. This research describes the development of a highly sensitive and cost-effective biomimetic sensor, capable of selectively detecting Tau-441 at femtomolar concentrations. This is achieved through the synergistic combination of gold nanoparticles (AuNPs) with molecularly imprinted polymer (MIP) technology. The MIP layer was sensitised by electropolymerising phenylenediamine (o-PDA) in the presence of Tau-441 and AuNPs onto a gold screen-printed electrode (Au-SPE) using cyclic voltammetry (CV). After polymerisation, the entrapped proteins were removed by proteolytic digestion, generating well-defined imprinted cavities within the polymer matrix. Scanning electron microscopy (SEM) and Raman analysis were conducted to monitor the surface modification of the Au-SPE working electrode. The device displayed linear responses to Tau-441 protein within the range 2.0 pg mL[-1] to 200 ng mL[-1], with a limit of detection of 1.51 fg mL[-1]. The analytical performance of the device was validated in complex matrices, including Cormay serum and cell media from primary cultures of hippocampal neurons, using a competitive assay. The platform showed high sensitivity, good reproducibility, and reliable performance in biologically relevant media, demonstrating strong robustness. Its excellent analytical characteristics, together with the potential for integration into portable electrochemical devices, make this sensor a promising tool for rapid and accurate point-of-care testing, enhancing the detection and monitoring of AD.}, } @article {pmid42185061, year = {2026}, author = {Huang, JY and Dong, WG and Guo, WQ and Yang, SM and Huang, ST and Huang, Y and Zhan, SJ and Lin, L and Wang, F and Liu, LL}, title = {[Effect of electroacupuncture on hippocampal myelin and Rac1/PAK1/LIMK1/cofilin signaling pathway in Alzheimer's disease mice].}, journal = {Zhen ci yan jiu = Acupuncture research}, volume = {51}, number = {5}, pages = {614-621}, doi = {10.13702/j.1000-0607.20250434}, pmid = {42185061}, issn = {1000-0607}, mesh = {Animals ; *p21-Activated Kinases/metabolism/genetics ; *Lim Kinases/metabolism/genetics ; *rac1 GTP-Binding Protein/metabolism/genetics ; *Alzheimer Disease/therapy/genetics/metabolism/psychology ; *Hippocampus/metabolism ; Male ; Mice ; Signal Transduction ; *Electroacupuncture ; Humans ; *Actin Depolymerizing Factors/metabolism/genetics ; *Cofilin 1/metabolism/genetics ; *Myelin Sheath/metabolism/genetics ; Neuropeptides ; }, abstract = {OBJECTIVES: To observe the effect of electroacupuncture (EA) on learning-memory ability, hippocampal myelin and RAS-associated C3 botulinum toxin substrate 1 (Rac1)/ P21-activated kinase 1 (PAK1)/ LIM kinase 1 (LIMK1)/ cofilin signaling pathway in senescence-accelerated mouse prone 8 (SAMP8) mice, so as to explore its mechanisms underlying improvement of Alzheimer's disease (AD) from the perspective of the cytoskeleton.

METHODS: Male SAMP8 (AD) mice were randomly divided into model group and EA group, with 9 mice in each group, and 9 male SAMR1 mice of the same age were used as the control group. The mice in the EA group received EA at "Dazhui" (GV14) and "Shenshu" (BL23) and punctured at "Baihui" (GV20) for 20 min, once per day, for 24 d, rest for 2 d after every 8 d of treatment. The Morris water maze test was used to observe the learning-memory ability. The Luxol fast blue (LFB) staining was used to observe the myelin sheath, and the phalloidin staining was used to observe the cytoskeleton in the hippocampus tissue. The mRNA expression levels of Rac1, PAK1, LIMK1, and cofilin were detected using real-time fluorescence quantitative PCR, and the protein expression levels of myelin basic protein (MBP), Rac1, PAK1, phosphorylated (p)-PAK1, LIMK1, p-LIMK1, cofilin, and p-cofilin in the hippocampal tissue were detected using Western blot.

RESULTS: Compared with the control group, the model group showed an obvious increase in the escape latency (P<0.01), and a significant decrease in the number of the original platform-crossing, the swimming time in the original platform quadrant, cytoskeleton fluorescence intensity, mRNA expression levels of Rac1, PAK1, LIMK1, and cofilin, and protein expression levels of MBP and Rac1, and the ratios of p-PAK1/PAK1, p-LIMK1/LIMK1, and p-cofilin/cofilin in the hippocampus tissue (P<0.01). Following EA intervention, the increased level of escape latency and the decreased levels of the number of the original platform-crossing, the swimming time in the original platform quadrant, cytoskeleton fluorescence intensity, and the expression levels of Rac1, PAK1, LIMK1, and cofilin mRNAs, and the expression levels of MBP and Rac1 proteins, and the ratios of p-PAK1/PAK1, p-LIMK1/LIMK1, and p-cofilin/cofilin were reversed (P<0.01, P<0.05). LFB staining showed disordered and loose arrangement of the fibers with vacuoles in the model group. Compared with the model group, the number of myelin fibers was increased with the fibers arranged in relatively regular order in the EA group, suggesting a reduction of the degree of demyelination.

CONCLUSIONS: EA can improve the learning-memory ability of SAMP8 mice, which may be related to its functions in up-regulating the activity of Rac1/PAK1/LIMK1/cofilin signaling, and promoting the cytoskeletal reorganization to improve myelin function.}, } @article {pmid42188341, year = {2026}, author = {Buccarello, L and Montagna, C and Di Matteo, S and Mangione, R and Carota, G and Sibbitts, J and Jarosova, R and Lunte, SM and Lazzarino, G and Caruso, G}, title = {The Bright and Dark Sides of Nitric Oxide in Neurodegenerative Diseases.}, journal = {Journal of personalized medicine}, volume = {16}, number = {5}, pages = {}, pmid = {42188341}, issn = {2075-4426}, abstract = {Nitric oxide (NO) plays an important role in neuronal communication, synaptic plasticity and vascular regulation. Due to its important function in neuronal homeostasis, NO imbalance is associated with neurodegeneration. Specifically, in Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), Parkinson's disease (PD) and frontotemporal lobar degeneration (FTLD), an excessive amount of NO, mostly produced by inducible NO synthase (iNOS), reacts with superoxide to form peroxynitrite, driving oxidative/nitrosative stress, mitochondrial dysfunction, and aberrant protein modifications. In AD, NO dysregulation promotes amyloid-β (Aβ) accumulation, tau hyperphosphorylation and synaptic loss, creating a self-perpetuating cycle of neuronal damage. NO's dual role, protective at physiological levels but harmful if overproduced, underscores the therapeutic potential of antioxidant compounds that restore the balance of NO/NOS (especially iNOS) while preserving physiological functions. However, despite the emerging role of antioxidant-based therapeutic approaches, clinical translation is limited by the complexity of NO signaling and the absence of safe, specific NOS inhibitors. By targeting the molecular switch from protective to toxic, NO activity may offer new personalized treatment avenues for neurodegenerative diseases.}, } @article {pmid42189237, year = {2026}, author = {Morbelli, SD and Bozzali, M and Cagnin, A and Cecchin, D and Chiti, A and Filippi, M}, title = {Precision pathways: optimising amyloid PET for sustainable Alzheimer's disease care.}, journal = {Journal of neurology}, volume = {273}, number = {6}, pages = {}, pmid = {42189237}, issn = {1432-1459}, mesh = {Humans ; *Alzheimer Disease/diagnostic imaging/metabolism/therapy/drug therapy ; *Positron-Emission Tomography/methods/standards ; *Amyloid beta-Peptides/metabolism ; *Precision Medicine/methods ; Biomarkers/metabolism ; }, abstract = {The approval of anti-amyloid therapies has reshaped Alzheimer's disease from a clinically defined syndrome to a biologically confirmed and treatment-oriented condition. This transition places biomarkers, particularly amyloid positron emission tomography (Aβ-PET), at the centre of diagnostic precision, patient selection, safety governance, and therapeutic monitoring. Aβ-PET provides high specificity for confirming cerebral amyloid pathology, especially in cases with discordant or inconclusive fluid biomarkers, and supports staging through semi-quantitative assessment using standardised Centiloid metrics. In patients considered for anti-amyloid therapies, baseline Aβ-PET refines eligibility and risk-benefit profiling when integrated with MRI and APOE genotyping. During treatment, longitudinal Aβ-PET enables objective assessment of pharmacodynamic target engagement and treatment-related amyloid clearance, supporting response-adapted strategies and, in selected cases, therapy discontinuation. Beyond its clinical role, Aβ-PET has strategic organisational and economic implications. Its value is maximised when embedded within structured, stepwise diagnostic pathways that use scalable fluid biomarkers for triage and reserve Aβ-PET for high-impact decisions. However, implementation is challenged by regional heterogeneity, capacity constraints, and limited harmonisation across centres. Coordinated hub-and-spoke models, quantitative standardisation, and prospective registry-based data collection are essential to ensure the equitable and sustainable integration of anti-amyloid therapies into clinical practice. Aβ-PET has evolved from a confirmatory diagnostic tool to a strategic instrument that enables biologically driven, outcome-oriented care for patients with Alzheimer's disease.}, } @article {pmid42190614, year = {2026}, author = {Subbiah Pillai Neelakanta Pillai, K and Abdul Hamid, NAW and Dafik, D and Ramasamy, S and Subramanian, SS and Sundaram, A and Suriyan, K}, title = {A voyage on computer aided intelligent algorithms for the segmentation of brain tissues for neurodisorder diagnosis.}, journal = {The International journal of neuroscience}, volume = {}, number = {}, pages = {1-23}, doi = {10.1080/00207454.2026.2680936}, pmid = {42190614}, issn = {1563-5279}, abstract = {Neurodisorders pose a considerable burden to global health, frequently requiring early treatment and diagnosis to avoid irreversible cognitive and motor impairments. Segmentation of brain tissue is an essential task in neurodiagnostics due to its inability to accurately separate grey matter, white matter and cerebrospinal fluid within imaging modalities like MRI and CT. This article reviews the progress of brain tissue segmentation techniques from manual and semi-automated approaches to sophisticated machine learning and deep learning algorithms. It discusses how these contemporary methodologies enhance segmentation quality, address difficult anatomical variation and optimize diagnostic accuracy in diseases like Alzheimer's, multiple sclerosis, traumatic brain injury and stroke. This research work compares supervised, unsupervised and deep learning paradigms on the basis of their advantages, disadvantages and potential use in clinical settings. In addition, it presents hybrid and ensemble methods that blend conventional and AI-based approaches to mitigate obstacles such as data heterogeneity, annotation limitations and interpretability. This survey details the revolutionizing potential of machine learning in neuroimaging and ultimately seeks to facilitate early diagnosis, treatment planning and individualized healthcare provision for neurological diseases.}, } @article {pmid42190844, year = {2026}, author = {Ma, X and Koppelmans, V and Akcicek, H and Akcicek, EY and Shen, J and Chen, L and Balu, N and Yuan, C and King, JB}, title = {SNAP MRI reveals association between distal cerebral arterial flow and cognitive function in an aging population.}, journal = {Magnetic resonance imaging}, volume = {132}, number = {}, pages = {110702}, doi = {10.1016/j.mri.2026.110702}, pmid = {42190844}, issn = {1873-5894}, mesh = {Humans ; Aged ; Male ; *Cerebrovascular Circulation/physiology ; Female ; *Aging ; *Magnetic Resonance Imaging/methods ; *Cognition/physiology ; *Cognitive Dysfunction/physiopathology ; Aged, 80 and over ; *Cerebral Arteries/physiopathology/pathology ; Reproducibility of Results ; Sensitivity and Specificity ; *Magnetic Resonance Angiography/methods ; *Cognition Disorders/physiopathology ; Blood Flow Velocity ; Neuropsychological Tests ; }, abstract = {OBJECTIVE: Impaired blood flow has recently been recognized as a critical contributor to cognitive impairment and dementia. It was reported that cerebral distal arterial flow measured from Simultaneous Non-contrast Angiography and Intraplaque Hemorrhage (SNAP) MRI is associated with post-treatment cognitive function improvement in carotid atherosclerosis patients. In this study, we aim to evaluate the value of SNAP-based measurements in assessing cerebrovascular function in an aging population.

MATERIALS AND METHODS: Neurovascular MRI data were collected on 36 aging participants (22 cognitively unimpaired and 14 impaired; 9 mild cognitive impairment (MCI) and 5 Alzheimer's Disease (AD)). Neurovascular MRI measurements, including white matter hyperintensities (WMH) volumes, cerebral blood flow (CBF), and SNAP-based distal cerebral arterial flow (dCAF) index, were quantified. Cognitive function was assessed using the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS).

RESULTS: Significant differences in the dCAF index were observed between cognitively unimpaired and impaired groups, and the dCAF index was significantly correlated with the RBANS total score. While CBF was significantly associated with dCAF index, there is no significant correlation of CBF or WMH with the RBANS score in this population.

CONCLUSION: Our findings suggest that the dCAF measured with SNAP MRI is valuable for evaluating the cognition-related cerebrovascular condition in an aging population.}, } @article {pmid42190921, year = {2026}, author = {Bhasha, S and Chintada, V and Munikumar, M and Maddineni, J and Nagulavancha, R and Malempati, T and Gadda, SS and Sankepally, KKR and Adi, PJ}, title = {Targeting tau-mitochondrial crosstalk in Alzheimer's disease with an Integrative multi-omics and artificial intelligence driven tools for the development of disease-modifying therapeutics.}, journal = {Ageing research reviews}, volume = {119}, number = {}, pages = {103186}, doi = {10.1016/j.arr.2026.103186}, pmid = {42190921}, issn = {1872-9649}, mesh = {*Alzheimer Disease/metabolism/drug therapy/pathology/genetics ; Humans ; *tau Proteins/metabolism ; *Mitochondria/metabolism/pathology/drug effects ; Multiomics ; *Artificial Intelligence ; Animals ; Proteomics ; Energy Metabolism ; }, abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative illness marked by cognitive impairment, synaptic dysfunction and neuronal death. Tau protein abnormalities and mitochondrial dysfunction are key features of its pathogenesis, and both are involved in driving disease development. Emerging evidence suggests that pathogenic tau not only destabilizes microtubules but also directly compromises mitochondrial dynamics, bioenergetics and quality control, ultimately aggravating neurodegeneration. However, the molecular processes by which tau disease causes mitochondrial failure are poorly known. In this review, we discuss the tau-mitochondria interplay in AD and highlight how integrated multi-omics and computational approaches are boosting the development of disease-modifying treatments. We conducted an extensive evaluation of recent literature in key scientific databases related to tau biology, mitochondrial dysfunction, mitophagy, transcriptomics, proteomics, metabolomics, and computational drug development in AD. The results demonstrate that hyperphosphorylated tau leads to inhibition of mitochondrial transport, changes in membrane potential, impairment of oxidative phosphorylation and increased generation of reactive oxygen species (ROS). Multi-omics analyses show coordinated changes in molecular pathways affecting energy metabolism, synaptic maintenance and neuronal survival. Furthermore, computational and AI-based methods have enabled the recognition of novel tau-interacting proteins, mitophagy modulators and treatment candidates. The tau-mitochondrial interaction is a key pathogenic axis in Alzheimer's disease and provides prospective avenues for harnessing multi-omics and computational techniques to create mechanism-based treatments to restore mitochondrial function and synaptic integrity. This integrative paradigm provides a basis for next-generation precision therapies for neurodegenerative network dysfunction.}, } @article {pmid42191654, year = {2026}, author = {Isei, MO and Okeowo, OM and Okoye, CN and Sobodu, TO}, title = {Enhancing global Alzheimer's disease drug outcomes by comprehensive African data integration.}, journal = {Journal of Alzheimer's disease : JAD}, volume = {}, number = {}, pages = {13872877261452117}, doi = {10.1177/13872877261452117}, pmid = {42191654}, issn = {1875-8908}, abstract = {Alzheimer's disease (AD) remains the leading cause of dementia worldwide and continues to pose a substantial therapeutic challenge. Although recent advances in disease-modifying treatments targeting amyloid-β pathology have generated cautious optimism, their translational impact is limited by persistent gaps in population and geographic representation within clinical trials. African populations, the most genetically diverse worldwide, remain markedly underrepresented in AD genomic and therapeutic studies. This gap limits the identification of ancestry-specific genetic risk factors and differential treatment responses and may contribute to the high attrition rates observed across AD drug development pipelines. We examine how the limited inclusion of African cohorts restricts insights into AD pathobiology and reduces the external validity of emerging therapeutic strategies. We highlight opportunities arising from the systematic integration of African population and clinical data, which have the potential to reveal novel biological mechanisms and expand the global relevance of candidate interventions. Persistent barriers, including insufficient research infrastructure and frequent substitution of African American cohorts for indigenous African populations, continue to obscure population-specific variation and hinder the development of a representative evidence base. Advancing the field will require coordinated and context-appropriate recruitment strategies, predictive modeling approaches grounded in region-specific data, and long-term investment in research capacity across the continent. A globally representative scientific framework that captures the full spectrum of human genetic heterogeneity is essential for accelerating progress in AD drug development. Integrating African population and data into clinical research will strengthen scientific rigor, enhance generalizability, and facilitate the development of globally equitable therapeutic strategies.}, } @article {pmid42191751, year = {2026}, author = {Okda, M and El-Masry, SM and Helmy, MW and Abbas, H}, title = {Herbosomal nanocarriers using natural-origin surfactants: a quercetin-based strategy for Alzheimer's disease and oxidative-stress-driven neurodegeneration.}, journal = {Scientific reports}, volume = {16}, number = {1}, pages = {}, pmid = {42191751}, issn = {2045-2322}, mesh = {*Quercetin/chemistry/pharmacology/administration & dosage ; *Oxidative Stress/drug effects ; *Alzheimer Disease/drug therapy/pathology/metabolism ; *Surface-Active Agents/chemistry ; Animals ; Antioxidants/chemistry/pharmacology/administration & dosage ; *Drug Carriers/chemistry ; Neuroprotective Agents ; Polysorbates/chemistry ; *Nanoparticles/chemistry ; }, abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by oxidative stress, neuroinflammation, and cholinergic dysfunction. Quercetin (QUE) is a multifunctional flavonoid with potent antioxidant and anti-inflammatory effects and proven neuroprotective, anticancer, antimicrobial, and hepatoprotective potential. However, its therapeutic translation, particularly in the management of Alzheimer's disease, is severely limited by low aqueous solubility, low bioavailability, and rapid metabolism. The current study aims to develop QUE-loaded herbosomes as an advanced phytophospholipid delivery system for AD treatment, with a focus on replacing the synthetic surfactant Tween 80 with natural-origin betaine surfactants to overcome the drawbacks of poor biocompatibility and chronic toxicity associated with conventional surfactants. QUE herbosomes were developed using the thin-film hydration method and evaluated for physicochemical characteristics, stability, and in vitro release behavior. Formulation variables were optimized to obtain herbosomal systems with favorable nanoscale properties and sustained drug release. DSC and FTIR analyses confirmed successful incorporation of quercetin within the vesicular structure. Compared with QUE suspension, the optimized QUE herbosomal formulations (F5 &F6) showed significantly higher effect in aluminum chloride-induced AD as evidenced by Behavioral testing, biochemical, and Histopathological analyses. These findings suggest that the developed QUE herbosomes with natural-origin surfactants offer a safe and biocompatible alternative to synthetic surfactant herbosomes, improving therapeutic outcomes in AD and holding promise for other oxidative stress-related neurodegenerative conditions.}, } @article {pmid42191803, year = {2026}, author = {Jalili, M and Babaei, P and Golshekan, M and Abedinzade, M and Andalib, S}, title = {Quercetin-loaded cellulose nanofibers improve memory, learning, and attenuate endoplasmic reticulum stress in a rat model of Alzheimer's disease.}, journal = {Scientific reports}, volume = {}, number = {}, pages = {}, doi = {10.1038/s41598-026-54595-w}, pmid = {42191803}, issn = {2045-2322}, abstract = {Alzheimer's disease (AD) lacks effective disease-modifying therapy. This study evaluated the neuroprotective efficacy of quercetin-loaded cellulose nanofibers (QNP) in a streptozotocin (STZ)-induced AD rat model, focusing on memory impairment and endoplasmic reticulum (ER) stress. Forty-eight male Wistar rats were randomly allocated to six groups (n = 8): Control, AD model (ICV STZ 3 mg/kg on days 1 and 3), STZ + empty cellulose nanoparticles, STZ + free quercetin (10 mg/kg IP), STZ + QNP (10 mg/kg IP, equivalent quercetin dose), and STZ + donepezil (1 mg/kg IP) for 14 days. Morris water maze testing revealed that QNP significantly reduced escape latency during acquisition (31%, P < 0.001 vs. AD model) and increased time spent in the target quadrant during the probe trial (P < 0.01). QNP treatment resulted in significantly greater improvement compared to an equivalent dose of free quercetin (P < 0.05). RT-PCR demonstrated XBP-1 mRNA splicing exclusively in the AD model group, indicating activation of the unfolded protein response (UPR). Both free quercetin and QNP completely prevented this splicing, demonstrating potent suppression of ER stress. Cellulose nanofiber-mediated delivery significantly enhances quercetin's bioavailability and therapeutic efficacy, ameliorating cognitive deficits in AD likely via mitigation of ER stress. QNP represents a promising, biocompatible nano-therapeutic strategy for Alzheimer's disease.}, } @article {pmid42192197, year = {2026}, author = {Liang, C and Zhou, Y and Zhuang, K and Wang, S and Zhong, L and Can, D and Lei, A and Li, H and Zhang, J and Leng, L}, title = {Microglial mitochondria transfer to astrocytes via GPNMB-enriched extracellular vesicles alleviates cognitive deficits in tauopathy mice.}, journal = {Nature neuroscience}, volume = {}, number = {}, pages = {}, pmid = {42192197}, issn = {1546-1726}, support = {2024J010001 to LL.//Natural Science Foundation of Fujian Province (Fujian Provincial Natural Science Foundation)/ ; }, abstract = {Alzheimer's disease (AD) is an irreversible neurodegenerative disease characterized by cognitive decline. The precise molecular mechanisms that underlie the pathogenesis of AD remain elusive. Here we show that glycoprotein nonmetastatic melanoma protein B (GPNMB) is produced by microglia and transferred to astrocytes through extracellular vesicles (EVs) in PS19 tau pathology mice. Tau is cleaved in microglia to generate N-terminal fragments that form a complex on mitochondria with Parkin/Nix and GPNMB, promoting the secretion of EVs containing mitochondria. Functional mitochondria transferred to astrocytes via EVs markedly improve astrocytic functions and attenuate the cognitive impairments and pathogenic features in PS19 mice. By contrast, microglial GPNMB deficiency eliminates mitochondrial EV secretion and mitochondrial transfer to astrocytes, thereby impairing astrocytic functions and exacerbating cognitive impairment in PS19-CcKO (CX3CR1 cre Gpnmb floxp) mice. GPNMB-enriched EVs from PS19 mice alleviate the pathological phenotypes of PS19 mice, offering potential insights for AD treatment.}, } @article {pmid42192211, year = {2026}, author = {Gaur, A and Wong, M and Chen, JJ and Kang, Y and Tahoulas, D and Jeor, K and Raguram, KH and Gallagher, D and Rapoport, M and Herrmann, N and Lanctôt, KL}, title = {Synaptic biomarkers in Alzheimer's disease dementia and mild cognitive impairment: A systematic review and meta-analysis.}, journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association}, volume = {22}, number = {5}, pages = {e71501}, pmid = {42192211}, issn = {1552-5279}, support = {PTCG-20-700751/ALZ/Alzheimer's Association/United States ; /CAPMC/CIHR/Canada ; //Toronto Rehabilitation Institute/ ; ASRP #21-11//Alzheimer Society Research Program/ ; }, mesh = {Humans ; *Alzheimer Disease/cerebrospinal fluid/blood ; *Biomarkers/cerebrospinal fluid/blood ; *Cognitive Dysfunction/cerebrospinal fluid/blood ; *Synapses/metabolism ; Synaptosomal-Associated Protein 25/cerebrospinal fluid ; }, abstract = {INTRODUCTION: Alzheimer's disease (AD) is characterized by synaptopathy, a neuropathological feature that can contribute to underlying cognitive decline. Here, we evaluate potential cerebrospinal fluid (CSF) and blood-based synaptic biomarkers in AD dementia and its earliest clinical stage, mild cognitive impairment (MCI).

METHODS: Articles that measured a subset of CSF and/or blood-based synaptic biomarkers in AD dementia, MCI, and/or healthy controls were included. A random-effects model was used to determine standardized mean differences and 95% confidence intervals.

RESULTS: In total, 65 study cohorts were included for meta-analysis and 12 for qualitative review. Several CSF (synaptosomal-associated protein 25 [SNAP-25], growth-associated protein 43 [GAP-43], neuronal pentraxin receptor, neuronal pentraxin-1, neuronal pentraxin-2, synaptotagmin-1, syntaxin-1B, and vesicle-associated membrane protein 2) and blood-based (SNAP-25, GAP-43, and synaptotagmin-1) synaptic biomarkers were altered in AD dementia and/or MCI.

DISCUSSION: Further evaluation of these identified biomarkers may enrich our understanding of AD pathophysiology and disease trajectory, as well as inform future treatment interventions.}, } @article {pmid42192558, year = {2026}, author = {Aggad, WS and Ghosh, R and Almohaimeed, HM and Mohammedsaleh, ZM and Saleh, FM and Almars, AI and Jyothi, SR and Panigrahi, R and Kumer, A and Dhara, B}, title = {Exosome-mediated gut-brain axis signaling in neurodegenerative diseases: Mechanisms, experimental evidence, and therapeutic perspectives-A narrative review.}, journal = {Animal models and experimental medicine}, volume = {}, number = {}, pages = {}, doi = {10.1002/ame2.70226}, pmid = {42192558}, issn = {2576-2095}, support = {PNURSP2026R213//Princess Nourah Bint Abdulrahman University/ ; }, abstract = {The stomach and the brain are connected by a sophisticated two-way communication mechanism called the gut-brain axis. Extracellular vesicles, particularly exosomes, that move bioactive substances between the stomach and the brain, such as proteins, lipids, metabolites, and microRNAs, may improve the gut-brain axis. In the past years, the role of exosome-mediated communication has been recognized as significant in relation to the etiology, continued progression, and potential treatment of neurodegenerative disorders. The authors of this review article present a summary of the current understanding of the relationship of gut microbiome, exosome biogenesis, and the pathophysiological development of neurodegenerative diseases. Evidence from laboratory studies, animal studies, and newly emerging human studies suggests that microbiome-based metabolites and inflammatory mediators may modulate how exosomes are produced, what they carry, and how they interact with the blood-brain barrier. These exosomal signals may impact neuroinflammation, neuronal signaling, and the spread of pathological proteins of neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and Huntington's disease. In addition, they examine some possible ways to target the gut-brain axis from a therapeutic perspective, including manipulating the gut microbiome, providing probiotics and/or prebiotics, performing fecal microbiota transplantation, and/or using engineered extracellular vesicles as vehicles for drug delivery. The authors also outline some of the methodological differences that make it difficult to assess the effects of exosomes.}, } @article {pmid42192778, year = {2026}, author = {Ramírez Hernández, E and Netzahualcoyotzi, C and Hurtado-Alvarado, G and Sánchez, JL and Pereyra Morales, A and Arredondo-Zamarripa, D and Hernández-Zimbrón, LF and Papy-Garcia, D and Guevara, J and Gutiérrez Ponce, N and Gomez-Henao, W and Garfias, Y and Ortiz Chavez, G and Zenteno, E}, title = {The Effect of Metabolic Syndrome on Alzheimer's Disease: Physical Activity as a Preventive and Therapeutic Measure.}, journal = {Brain sciences}, volume = {16}, number = {5}, pages = {}, pmid = {42192778}, issn = {2076-3425}, support = {PAPIIT IA208726//Universidad Nacional Autónoma de México/ ; PAPIIT IN222724//Universidad Nacional Autónoma de México/ ; PAPIIT IN204624//Universidad Nacional Autónoma de México/ ; }, abstract = {Epidemiological and clinical research on neurodegenerative diseases has shown that metabolic dysregulations increase the risk of developing Alzheimer's Disease (AD). Many metabolic changes can be grouped into metabolic syndrome (MetS), which is defined as the presence of three or more risk factors, including insulin resistance, hyperglycemia, hypertension, central obesity, and dyslipidemia. These changes cause systemic effects that are crucial in triggering neuroinflammation and neurodegeneration, key factors in AD development. All these factors impair energy metabolism in peripheral tissues and the brain by decreasing glucose utilization, leading to alterations in O-GlcNAcylation, glycosylation, mitochondrial function, oxidative stress, chronic inflammation, synaptic dysfunction, autophagy impairment, and blood-brain barrier (BBB) dysfunction. However, these factors are modified and largely influenced by lifestyle choices. A newer perspective emphasizes that regular exercise is vital for maintaining brain metabolism as we age. Current evidence suggests that engaging in physical activity for individuals with metabolic syndrome reduces their risk of Alzheimer's disease, enhances prognosis, and improves cognitive abilities. This review explores how metabolic syndrome relates to Alzheimer's and highlights possible strategies for prevention and treatment.}, } @article {pmid42192839, year = {2026}, author = {Valverde, HP and Clark, BJ and Hogeveen, J and Clark, VP}, title = {Noninvasive Brain Stimulation Techniques and Their Efficacy in Treating Cognition and Memory in Mild Cognitive Impairment and Alzheimer's Disease-A Systematic Review.}, journal = {Brain sciences}, volume = {16}, number = {5}, pages = {}, pmid = {42192839}, issn = {2076-3425}, abstract = {BACKGROUND/OBJECTIVES: The growing aging population is susceptible to cognitive and memory impairment, most commonly due to Alzheimer's disease, with no cures currently available. Noninvasive brain stimulation (NIBS) techniques may serve to improve cognition and delay catastrophic memory loss.

METHODS: A systematic review of NIBS research on cognitive impairment was carried out using PubMed, with additional backward citation searching. A total of 81 studies using NIBS were included.

CONCLUSIONS: The reviewed studies show that NIBS holds promise in improving memory deficits in patients with cognitive impairment. While the longevity of benefits from transcranial electrical stimulation appears limited, its short-term effects may provide benefits when used consistently. Transcranial magnetic stimulation appears to provide longer-lasting benefits. Transcranial focused ultrasound stimulation may also provide further benefits through more precise targeting of deeper brain structures compared to other NIBS techniques. Together, these results suggest that NIBS shows promise for the treatment of symptoms related to cognitive and memory impairment, and may help to alleviate some of the growing issues associated with the increasing level of Alzheimer's disease in an aging population.}, } @article {pmid42193043, year = {2026}, author = {Zamzuri, ZE and Kamaruzzaman, MA and Teoh, SL and Yahaya, MF}, title = {A Review of the Effect of Peripheral Amyloid β on the Central Nervous System.}, journal = {Current issues in molecular biology}, volume = {48}, number = {5}, pages = {}, pmid = {42193043}, issn = {1467-3045}, support = {FF-2025-443//Universiti Kebangsaan Malaysia Faculty of Medicine Fundamental Grants (GFFP)/ ; }, abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder classically defined by cerebral amyloid β (Aβ) plaque deposition and tau pathology. In recent years, AD has increasingly been recognized as a multisystem disorder rather than a purely brain-restricted condition, as mounting evidence indicates that Aβ metabolism is a dynamic, bidirectional process involving both central and peripheral compartments. Peripheral tissues, particularly platelets, liver, kidneys, and the gastrointestinal tract, contribute substantially to circulating Aβ levels and influence cerebral amyloid burden. Platelets are now considered the predominant source of peripheral Aβ, accounting for the majority of plasma Aβ under physiological and pathological conditions, while the liver and kidneys play critical roles in Aβ clearance through receptor-mediated uptake, enzymatic degradation and excretion. Disruption of these peripheral clearance pathways elevates circulating Aβ, increasing its transport into the brain via blood-brain barrier (BBB) mechanisms by enhanced RAGE-mediated influx and impaired LRP1-dependent efflux in AD. Peripheral Aβ entry into the central nervous system exacerbates neuroinflammation, mitochondrial dysfunction, and oxidative stress, thereby accelerating neuronal damage and disease progression. This review synthesizes updated evidence on peripheral sources of Aβ, differences between central and peripheral Aβ pools, mechanisms of Aβ transport across the BBB, pathological consequences of peripheral Aβ on the brain and emerging therapeutic strategies targeting peripheral Aβ metabolism, highlighting the importance of a systemic perspective in AD pathogenesis and treatment.}, } @article {pmid42193260, year = {2026}, author = {Virk, JP and Fernando, MG and Asih, PR and Martins, RN}, title = {Translational Feasibility of Curcumin for Treatment of Alzheimer's Disease: A Critical Appraisal of Clinical Challenges.}, journal = {Antioxidants (Basel, Switzerland)}, volume = {15}, number = {5}, pages = {}, pmid = {42193260}, issn = {2076-3921}, abstract = {The absence of robust and effective treatments for Alzheimer's disease remains a major challenge in modern medicine. As one of the leading causes of death, its increasing prevalence and complex chronic pathogenesis impose a substantial societal and healthcare burden, intensifying the need for effective therapeutic strategies. Current treatments remain limited, with minimal impact on cognitive decline in symptomatic patients. Curcumin, the bioactive ingredient in turmeric, has taken precedence over other natural products due to its potent antioxidative and anti-inflammatory properties. Numerous publications have extensively reported on the therapeutic effect of curcumin in animal models of Alzheimer's disease. However, no curcumin formulation has demonstrated consistent clinical efficacy against Alzheimer's or other neurodegenerative diseases to date. Over the years, many critics have argued that curcumin's undesirable chemical properties, mainly low bioavailability and rapid metabolism, pose significant barriers to its therapeutic use to target the brain. Considerable funding and research effort on emerging technologies such as nanoparticles and intranasal delivery continue to drive curcumin preclinical and clinical trials, prompting reflection on the rationale for continued investment. This narrative review critically dissects this disconnect, arguing that many purported benefits remain insufficiently substantiated, and identifying important opportunities where future research may hold promise for an effective treatment.}, } @article {pmid42193907, year = {2026}, author = {Albensi, BC and Adlimoghaddam, A}, title = {Targeting Mitochondrial Dysfunction in Alzheimer's Disease Neurons: Lithium Boosts Oxidative Phosphorylation.}, journal = {Cells}, volume = {15}, number = {10}, pages = {}, pmid = {42193907}, issn = {2073-4409}, support = {AARF-22-967198/ALZ/Alzheimer's Association/United States ; }, mesh = {Animals ; *Alzheimer Disease/metabolism/pathology/drug therapy ; *Oxidative Phosphorylation/drug effects ; *Mitochondria/metabolism/drug effects/pathology ; *Neurons/metabolism/drug effects/pathology ; Mice ; *Lithium/pharmacology/therapeutic use ; Mice, Inbred C57BL ; Electron Transport Complex IV/metabolism ; Mice, Transgenic ; Energy Metabolism/drug effects ; Oxygen Consumption/drug effects ; Hippocampus/pathology/metabolism ; }, abstract = {Alzheimer's disease (AD) is characterized by the accumulation of amyloid beta (Aβ) and neurofibrillary tangles in brain tissue; however, AD is multifactorial, and different etiopathogenic mechanisms involve factors that can affect mitochondrial function, which are associated with AD. While high-dose lithium is a well-established mood stabilizer, accumulating evidence suggests that low-dose lithium provides significant neuroprotection by reversing AD pathology, cognitive impairment, and inflammation. Despite these findings, there is limited information on how lithium affects brain energy metabolism. In the current study, we investigated the effect of lithium (0, 0.1, 1, and 10 mM) on mitochondrial function in AD neurons. Neuronal cells were isolated from the hippocampi of embryonic day 14-17 (E15-E17) control (C57BL/6) mice and 3xTg-AD mice. Mitochondrial oxygen consumption rate (OCR), mitochondrial Cytochrome C Oxidase (COX) activity, total ATP activity, and the expression of mitochondrial complex protein involved in oxidative phosphorylation (OXPHOS) were measured in control vs. 3xTg-AD in the presence and absence of lithium treatment. In the present study, lithium treatment significantly increased (p < 0.05) mitochondrial OCR, COX, total ATP, and levels of mitochondrial complex protein subunits (Complex I-V) in 3xTg-AD neurons. However, lithium had no effect on energy metabolism in control neurons. Together, these data indicate that lithium improves mitochondrial function under pathological states. Overall, these results have important implications for the treatment of disorders in which brain energy regulation is compromised, including AD. Particularly, our results highlight a role for lithium in regulating bioenergetics in early-stage AD and suggest that neuronal cells may be a crucial therapeutic target for preventing AD.}, } @article {pmid42193936, year = {2026}, author = {Sepehrimanesh, M and Melen, SV and Yeasmin, F and Ojo, VA and Walden, F and Urmee, H and Etheridge, J and Nasu, AK}, title = {Emerging Therapeutic Strategies for Neurodegenerative Diseases: A Comprehensive Review of Recent Advances and Future Directions.}, journal = {Cells}, volume = {15}, number = {10}, pages = {}, pmid = {42193936}, issn = {2073-4409}, mesh = {Humans ; *Neurodegenerative Diseases/therapy ; Animals ; Neuroprotective Agents/therapeutic use ; Genetic Therapy ; }, abstract = {Neurodegenerative diseases, including Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS; Lou Gehrig's disease), represent a growing global health burden characterized by progressive neuronal loss and functional decline. Despite decades of intensive research, effective disease-modifying therapies remain limited, underscoring the urgent need for innovative therapeutic strategies. This review highlights recent advances in the understanding of disease etiology and emerging treatment approaches, with a particular focus on modalities with translational potential. We discussed novel disease-modifying interventions, including gene and cell therapies, RNA-targeting strategies, and immunotherapies aimed at clearing misfolded proteins such as amyloid-β, tau, and α-synuclein. In parallel, we examined the evolving recognition of neuroinflammation and mitochondrial dysfunction as actionable therapeutic targets, alongside progress in precision medicine and biomarker-guided approaches that enable early diagnosis and individualized treatment. Additionally, we summarized developments in repurposed pharmacological agents, neuroprotective compounds, and lifestyle interventions, emphasizing the importance of integrative, multimodal strategies. Across AD, PD, and ALS, convergent molecular mechanisms, including protein misfolding, oxidative stress, and disrupted proteostasis, present opportunities for cross-disease therapeutic targeting. Finally, we addressed key challenges and future directions, including translating preclinical efficacy into clinical success, optimizing CNS-targeted delivery systems, and navigating ethical considerations surrounding gene editing and stem cell therapies.}, } @article {pmid42195086, year = {2026}, author = {André, Z and Kopániová, A and Gaštanová, B and Brandoburová, P and Režnáková, V and Fabian, M and Povinec, P and Hanes, J and Gmitterová, K}, title = {CSF Amyloid and Tau Biomarkers Distinguish Mixed from Vascular Dementia by Identifying Alzheimer's Disease Co-Pathology.}, journal = {Medicina (Kaunas, Lithuania)}, volume = {62}, number = {5}, pages = {}, pmid = {42195086}, issn = {1648-9144}, mesh = {Humans ; Biomarkers/cerebrospinal fluid/analysis ; *Dementia, Vascular/cerebrospinal fluid/diagnosis ; *tau Proteins/cerebrospinal fluid/analysis ; *Alzheimer Disease/cerebrospinal fluid/diagnosis ; *Amyloid beta-Peptides/cerebrospinal fluid/analysis ; Female ; Male ; Aged ; Mixed Dementias ; Diagnosis, Differential ; Peptide Fragments/cerebrospinal fluid ; ROC Curve ; Aged, 80 and over ; Middle Aged ; }, abstract = {Background and Objectives: Vascular dementia (VaD) and mixed dementia (MD) represent prevalent causes of cognitive decline in the elderly, as they share similar pathological pathways and clinical features. Distinguishing between these two conditions remains a challenge, due to their frequent clinical and neuroimaging overlap. Nevertheless, it is important from a prognostic perspective. Materials and Methods: The study comprised 114 participants, including patients with VaD (n = 33), MD (n = 26), Alzheimer's disease (AD; n = 26), and 29 cognitively healthy controls (C). We evaluated routinely used cerebrospinal fluid (CSF) biomarkers (total tau, p-tau181, Aβ1-42) and their ratios to assess inter-group differences, diagnostic accuracy, and correlations with cognitive score. Results: Patients with MD demonstrated significantly higher levels of t-tau and p-tau181, and lower levels of Aβ1-42, compared to VaD (p < 0.004 for all analyses). With the exception of p-tau181/t-tau, all calculated ratios enabled differentiation between these groups. ROC analysis confirmed the high diagnostic accuracy of CSF Aβ1-42 and t-tau (AUC 0.82 and 0.79 respectively) for detecting AD pathology in dementia patients. Furthermore, the t-tau/Aβ1-42, p-tau181/Aβ1-42 ratios were the most effective in differentiating AD-related from vascular pathologies (AUC 0.78 and 0.80 respectively), and in differentiating MD from VaD (AUC 0.79 and 0.77 respectively). A significant correlation was observed between CSF biomarkers (especially tau markers) and cognitive impairment severity. Conclusions: CSF biomarkers effectively differentiate mixed from vascular dementia by identifying underlying AD pathology independent of the clinical phenotype. This supports the use of CSF biomarkers in clinical practice to reveal the neurodegenerative component in patients with cerebrovascular disease, which is of fundamental importance for emerging disease-modifying treatment strategies in mixed neuropathologies.}, } @article {pmid42195382, year = {2026}, author = {Testa, C and Palmese, F and Boni, S and Domenicali, M and Lauretani, F}, title = {Clinical Trajectories of Neurodegenerative Diseases in Older Adults: A Three-Sphere Framework for Precision Geriatric Neurology.}, journal = {Life (Basel, Switzerland)}, volume = {16}, number = {5}, pages = {}, pmid = {42195382}, issn = {2075-1729}, abstract = {Neurodegenerative diseases are among the most consequential disorders of later life, not only because of their increasing prevalence, rising from approximately 1-2% at age 65 to over 30% by age 85, but also because they develop within the broader clinical context of ageing, multimorbidity, frailty, and polypharmacy. In older adults, these conditions rarely present as isolated and static diagnostic entities; rather, they unfold as dynamic clinical trajectories involving the progressive interaction of cognitive decline, behavioural-neuropsychiatric symptoms, and extrapyramidal-motor dysfunction. In this review, we propose a trajectory-based framework for the interpretation and management of major neurodegenerative disorders in later life, including Alzheimer's disease, frontotemporal dementia, Parkinson's disease and Parkinson's disease dementia, dementia with Lewy bodies, and vascular cognitive impairment. Building on a conceptual model organized around three major symptom spheres: cognitive, behavioural-neuropsychiatric, and extrapyramidal-motor, we argue that each disorder can be understood according to the relative predominance and temporal evolution of these domains. Alzheimer's disease is typically cognition-led, frontotemporal dementia behaviour-led, and Parkinsonian syndromes motor-led, whereas dementia with Lewy bodies shows early multidomain convergence across all three spheres simultaneously. Vascular and mixed dementias follow more heterogeneous trajectories shaped by lesion burden, network disruption, and copathology. This framework has direct implications for diagnosis, prognostic stratification, and treatment selection, because interventions targeting one sphere may destabilize another and generate prescription cascades, delirium, or functional decline. We further discuss how biomarker-based diagnosis, disease-modifying therapies, non-pharmacological interventions, multidisciplinary care, deprescribing strategies, and palliative planning can be integrated within a trajectory-based approach. Interpreting neurodegeneration through clinical trajectories rather than diagnostic labels alone offers a more realistic and therapeutically useful model for precision geriatric neurology across the full course of disease.}, } @article {pmid42196209, year = {2026}, author = {Mouaimi, M and Metaxas, A and Kourti, M}, title = {The Emerging Role of Dimethyl Fumarate in Alzheimer's Disease-A Systematic Review of Available Preclinical Studies.}, journal = {International journal of molecular sciences}, volume = {27}, number = {10}, pages = {}, pmid = {42196209}, issn = {1422-0067}, mesh = {*Dimethyl Fumarate/therapeutic use/pharmacology ; *Alzheimer Disease/drug therapy/metabolism ; Animals ; Humans ; NF-E2-Related Factor 2/metabolism ; Oxidative Stress/drug effects ; Antioxidants/pharmacology/therapeutic use ; Disease Models, Animal ; Amyloid beta-Peptides/metabolism ; tau Proteins/metabolism ; }, abstract = {Dimethyl fumarate (DMF), a fumaric acid ester, is approved for psoriasis and multiple sclerosis due to its antioxidant and anti-inflammatory properties mediated via Nrf2 activation. Nrf2 regulates genes that protect cells from oxidative stress, a key factor in neurodegenerative diseases such as Alzheimer's disease (AD), which is characterized by amyloid-β and tau accumulation and lipid peroxidation. This systematic review aimed to evaluate preclinical evidence for DMF as a potential therapeutic agent in AD models through Nrf2 activation. A comprehensive literature search of PubMed and Scopus (last search: December 2025) identified in vitro, in vivo, and combined preclinical studies assessing DMF in AD models. Studies were screened using predefined inclusion and exclusion criteria, and methodological quality was assessed using established tools. Results were synthesized narratively. Eighteen studies were ultimately included in the analysis. Across the included studies, DMF consistently activated the Nrf2 pathway, enhancing antioxidant and anti-inflammatory gene expression. DMF treatment reduced amyloid-β and tau protein levels, mitigated oxidative stress, and improved cognitive performance in animal models. However, the evidence is limited by heterogeneity in experimental models and methodological variability. In conclusion, preclinical evidence suggests DMF is a promising candidate for AD treatment by targeting oxidative stress and neuroinflammation via Nrf2 activation. Further preclinical studies, particularly on ferroptosis mechanisms, and well-designed clinical studies are warranted to clarify its full therapeutic potential. This review was not registered and the authors received no funding.}, } @article {pmid42196212, year = {2026}, author = {Jóźwiak-Bębenista, M and Stasiak, A and Sienkiewicz, M and Kwiatkowski, P and Kowalczyk, E}, title = {Psilocybin in Older Adults: Therapeutic Opportunities in Inflammation-Driven Disorders of Aging-From Depression to Neurodegeneration.}, journal = {International journal of molecular sciences}, volume = {27}, number = {10}, pages = {}, pmid = {42196212}, issn = {1422-0067}, support = {503/1-108-01/503-11-001//Medical University of Lodz/ ; }, mesh = {Humans ; *Aging/drug effects ; *Inflammation/drug therapy ; *Neurodegenerative Diseases/drug therapy ; *Depression/drug therapy ; *Psilocybin/therapeutic use/pharmacology ; Animals ; Aged ; *Hallucinogens/therapeutic use/pharmacology ; }, abstract = {Aging is associated with chronic, low-grade inflammation ("inflammaging"), which contributes to neuropsychiatric and neurodegenerative disorders such as depression, Alzheimer's disease, and Parkinson's disease. Conventional pharmacotherapies often provide limited benefit in older adults and are further complicated by polypharmacy and drug-drug interactions. Psilocybin, a serotonergic psychedelic acting primarily as a partial agonist at the 5-HT2A receptor and currently undergoing accelerated clinical development, has emerged as a potential multimodal therapeutic agent addressing these challenges. Acting via its active metabolite psilocin, 5-HT2A receptor-mediated signaling modulates cortical glutamatergic transmission, enhances tropomyosin receptor kinase B/brain-derived neurotrophic factor (TrkB/BDNF) pathways, and modulates neuroimmune cascades (includingnuclear factor kappa B (NF-κB), with convergent systems-level effects such as reorganization of the default mode network. Human studies report acute reductions in TNF-α with variable effects on IL-6 and CRP, consistent with an immunomodulatory profile. Pharmacokinetically, psilocybin shows properties advantageous in geriatric care: rapid onset, short half-life, and predominant phase-II glucuronidation, reducing interaction risk. Controlled studies demonstrate rapid antidepressant and anxiolytic effects in major depressive disorder, treatment-resistant depression, and existential distress, with emerging feasibility signals in neurodegeneration. Together, these findings support the hypothesis that a time-limited, mechanism-based intervention may improve mood and cognition while attenuating inflammation. This review integrates current evidence on psilocybin's neuroimmune and pharmacokinetic mechanisms relevant to aging, outlining its potential role in inflammation-related disorders and highlighting the need for targeted studies in older adults, who remain underrepresented in psychedelic research.}, } @article {pmid42196227, year = {2026}, author = {Kasprzak, A}, title = {Somatostatin in Aging: Correlations with Selected Central Nervous System and Gastrointestinal Tract Diseases.}, journal = {International journal of molecular sciences}, volume = {27}, number = {10}, pages = {}, pmid = {42196227}, issn = {1422-0067}, mesh = {Humans ; *Aging/metabolism ; *Somatostatin/metabolism ; Animals ; *Gastrointestinal Diseases/metabolism ; *Central Nervous System/metabolism ; }, abstract = {The hypothalamic-pituitary-somatotropic (HPS) axis, which includes growth hormone (GH) and insulin-like growth factor 1 (IGF-1), is one of three endocrine systems that show a decline in hormone concentration with age. Among the hypothalamic hormones involved in the aging process, GH-releasing hormone (GHRH) and somatostatin (SST) are most affected, resulting in several age-related changes. The pathophysiology of GH decline in the aging process is unclear, specifically, whether it results from decreased GHRH or increased SST levels. Similarly, it is not known whether quantitative changes in hypothalamic peptides (including SST) precede or follow age-related pathological behavioral changes. SST is produced mainly by cells of the central nervous system (CNS) and the gastrointestinal (GI) tract, which are functionally interconnected systems that undergo significant changes during aging. The physical changes in the aging organism are considered physiological, and experimental evidence indicates that a large proportion of these changes are the result of declining hormonal activity (including the SST system). It is particularly important to understand the role of SST in diseases of old age, which affect both cognitive processes and memory (e.g., Alzheimer's and Parkinson's diseases) and the proper functioning of the GI tract and pancreas (e.g., obesity, type 2 diabetes mellitus, and colorectal cancer). This narrative review discusses systemic and peripheral changes in SST production and secretion observed in aging individuals and their potential association with selected diseases of old age, especially CNS and GI tract diseases. Understanding the role of SST expression with age will enable the better application of this neuropeptide in the diagnosis and treatment of diseases of old age (including cancers).}, } @article {pmid42196498, year = {2026}, author = {Bianchi, VE and Visbal, LC and Devesa, J}, title = {Growth Hormone and Brain Regeneration: Evidence from Clinical Studies in Dementia, Traumatic Brain Injury, and Stroke: A Systematic Review.}, journal = {International journal of molecular sciences}, volume = {27}, number = {10}, pages = {}, pmid = {42196498}, issn = {1422-0067}, mesh = {Humans ; *Brain Injuries, Traumatic/drug therapy/metabolism/physiopathology ; *Stroke/drug therapy/metabolism/physiopathology ; *Dementia/drug therapy/metabolism ; *Growth Hormone/therapeutic use/metabolism/pharmacology ; Animals ; *Brain/drug effects/physiology/metabolism ; Insulin-Like Growth Factor I/metabolism ; *Regeneration/drug effects ; }, abstract = {Growth hormone (GH) and insulin-like growth factor 1 (IGF-1) play essential roles in the brain, influencing neuronal and dendritic growth, as well as neurotransmission. These effects persist throughout life. Numerous studies in animals and humans have demonstrated the beneficial effects of GH therapy on memory and cognitive function, as well as on the restoration of neuronal function following injury. All nerve cells, including neurons, glia, endothelial, epithelial, and perivascular cells, are affected by the actions of GH/IGF-1. IGF-1, in particular, has been associated with cognitive function. The GH-IGF-1 axis increases the proliferation of neuronal progenitor cells and the formation of new neurons, oligodendrocytes, and astrocytes. In this study, we searched databases such as PubMed, Google Scholar, and Embase for human clinical trials evaluating the effect of growth hormone (GH) therapy on dementia, Alzheimer's disease (AD), post-traumatic brain injury (PTI), and stroke. The following search terms were used: "GH and dementia," "GH and Alzheimer's disease," "GH and TBI," and "GH and stroke." Inclusion criteria were all randomized controlled trials and observational studies. Exclusion criteria included the lack of cognitive and memory assessments. We found 28 articles. Most studies show the beneficial effects of GH therapy on memory and recovery of brain function after traumatic injury and stroke; however, consistent data are still lacking. The limited number of clinical trials, the small number of patients, and the lack of data on plasma levels of sex hormones that clearly contribute to brain function are limiting factors. This is the case, for example, with androgens. Other critical factors are dosage and treatment duration. Prolonged administration and supraphysiological doses are more effective in inducing positive clinical changes. Growth hormone (GH) therapy is a very promising intervention for preventing and treating dementia and early-stage Alzheimer's disease, and it contributes significantly to the recovery of brain function in patients after traumatic injury and stroke. Further studies with more robust methodologies are needed to confirm these results.}, } @article {pmid42196596, year = {2026}, author = {Hasan, I and Tang, X and Xu, J}, title = {Glial Cells in Behavioral and Psychological Symptoms of Alzheimer's Disease.}, journal = {International journal of molecular sciences}, volume = {27}, number = {10}, pages = {}, pmid = {42196596}, issn = {1422-0067}, support = {82173798//National Natural Science Foundation of China/ ; }, mesh = {Humans ; *Alzheimer Disease/psychology/pathology/metabolism ; *Neuroglia/metabolism/pathology ; Animals ; Microglia/metabolism/pathology ; Astrocytes/metabolism/pathology ; Oligodendroglia/metabolism/pathology ; }, abstract = {Behavioral and psychological symptoms of dementia (BPSD) affect the majority of patients with Alzheimer's disease (AD), substantially increasing caregiver burden and the likelihood of institutionalization. The clinical management of BPSD remains challenging because of its poorly understood pathogenesis, the limited efficacy of conventional interventions, and significant safety concerns associated with current treatments. These limitations underscore the urgent need to identify novel therapeutic targets and develop glia-centered treatment strategies. As essential components of the central nervous system, glial cells maintain neural homeostasis, regulate neurotransmission, and mediate neuroinflammatory responses. Increasing evidence suggests that glial dysfunction contributes to the development of BPSD, thereby linking AD neuropathology and neuropsychiatric symptoms. Aberrant microglial activation, astrocytic dysfunction, and oligodendrocyte injury collectively compromise neural circuit integrity, disrupt neurotransmitter balance, and impair neuron-glia communication, ultimately promoting the progression of diverse BPSDs. Given the critical role of glial cells in regulating neurotransmitter systems, the dysregulation of which is closely associated with BPSD, this review summarizes the involvement of glial cells in BPSD, elucidates the underlying molecular mechanisms, and discusses recent advances in glia-based therapeutic strategies, thereby providing insights into the pathogenesis of BPSD in AD.}, } @article {pmid42196607, year = {2026}, author = {Wind-Mark, K and Kunze, LH and Willem, M and Palumbo, G and Giudici, C and Nuscher, B and Boening, G and Gildehaus, FJ and Lindner, S and Werner, RA and Franzmeier, N and Gnörich, JS and Brendel, M and Zatcepin, A}, title = {Tracking of Neuroinflammation Dynamics During Combined Anti-β-Amyloid Therapy (AAT) and Immunomodulation in a Preclinical Alzheimer's Disease Model.}, journal = {International journal of molecular sciences}, volume = {27}, number = {10}, pages = {}, pmid = {42196607}, issn = {1422-0067}, support = {EXC 2145 SyNergy - ID 390857198//German Research Foundation/ ; Medical & Clinician Scientist Program (MCSP)//Ludwig Maximilian University of Munich/ ; }, mesh = {Animals ; *Alzheimer Disease/drug therapy/immunology/diagnostic imaging/metabolism ; *Amyloid beta-Peptides/immunology/antagonists & inhibitors ; Mice ; Positron-Emission Tomography ; Disease Models, Animal ; Pioglitazone/pharmacology/therapeutic use ; *Neuroinflammatory Diseases/drug therapy/diagnostic imaging ; Receptors, GABA/metabolism ; *Antibodies, Monoclonal/pharmacology/therapeutic use ; *Immunomodulation/drug effects ; PPAR-gamma Agonists ; Mice, Transgenic ; Microglia/metabolism/drug effects ; Brain ; }, abstract = {Neuroinflammation is increasingly recognized as a key modulator of therapeutic response and adverse events in Alzheimer's disease (AD), especially during anti-amyloid-β (Aβ) monoclonal antibody (Aβ-mAb) treatment. We applied longitudinal translocator protein (TSPO) positron emission tomography (PET) to evaluate TSPO-associated neuroinflammatory responses to chronic Aβ-mAb therapy and their modulation by the peroxisome proliferator-activated receptor γ (PPARγ) agonist pioglitazone. App[NL-G-F] knock-in mice underwent TSPO-PET and Aβ-PET imaging at 5, 7.5, and 10 months of age across four treatment arms: placebo, Aβ-mAb, pioglitazone, and combination therapy. TSPO-PET detected early and progressive neuroinflammatory responses to Aβ-mAb that appeared lower with pioglitazone co-treatment. Both mono- and combination therapy were associated with altered temporal and spatial dynamics of the TSPO-PET signal. In addition, we applied a previously validated microglia desynchronization index based on TSPO-PET connectivity, which captured individual variation in regional TSPO-PET organization and correlated with cognitive performance. Together, TSPO-PET and its regional synchronicity can quantify longitudinal, region-specific treatment effects, which may help differentiate harmful from adaptive neuroinflammatory responses. These findings highlight the potential of TSPO-PET as a stratification biomarker to optimize therapeutic interventions. TSPO-PET therefore enables in vivo tracking of treatment-associated neuroinflammatory responses during anti-Aβ immunotherapy and provides a non-invasive framework for evaluating combination strategies targeting amyloid pathology and immune regulation in AD.}, } @article {pmid42198335, year = {2026}, author = {Lu, H and Yu, Y and Yang, Y and Li, H and Li, Y and Yu, T and Wang, S and Li, F and Cheng, X}, title = {Ginsenoside Rg1 Ameliorates the Learning and Memory Deficits of 5xFAD Mice by Inhibiting CCR3 Activity: Insights from In Vivo and In Vitro Investigations.}, journal = {Pharmaceuticals (Basel, Switzerland)}, volume = {19}, number = {5}, pages = {}, pmid = {42198335}, issn = {1424-8247}, support = {No.82374062//National Natural Science Foundation of China/ ; YDZX2023003//Central government-guided special fund project for local scientific and technological development/ ; KYZK2024Q24//Shandong University of Traditional Chinese Medicine Youth Science Research Fund Project/ ; }, abstract = {Background/Objectives: Alzheimer's disease (AD) is characterized by amyloid-beta accumulation and neuroinflammation, yet the molecular target of Ginsenoside Rg1 remains elusive. This study aimed to elucidate the neuroprotective mechanism of Ginsenoside Rg1, specifically investigating its interaction with C-C motif chemokine receptor 3 (CCR3). Methods: We utilized 5xFAD transgenic mice and CCR3-overexpressing BV2 microglial cells. Behavioral assessments, enzyme-linked immunosorbent assays, quantitative real-time polymerase chain reaction, molecular docking, and surface plasmon resonance were employed to evaluate cognitive function and molecular pathways. Results: Ginsenoside Rg1 treatment significantly ameliorated spatial learning and memory deficits. Quantitatively, Rg1 reduced cortical amyloid-beta 1-40 levels (p < 0.05) and bound directly to CCR3 with a dissociation constant of 3.599 × 10[-5] mol/L. This inhibition suppressed neuroinflammation and restored neurotrophic factors, including Brain-derived neurotrophic factor. Conclusions: CCR3 is a novel pharmacological target for Ginsenoside Rg1, providing a precise molecular basis for its neuroprotective effects. Future research should focus on clarifying the pharmacokinetic profile and brain bioavailability of Ginsenoside Rg1 to facilitate clinical translation.}, } @article {pmid42198353, year = {2026}, author = {Skroban, J and Kruk-Słomka, M and Popiołek, Ł}, title = {Exploring Acylhydrazones' Properties Against Neurodegenerative Diseases and Other Clinical Applications: A Review.}, journal = {Pharmaceuticals (Basel, Switzerland)}, volume = {19}, number = {5}, pages = {}, pmid = {42198353}, issn = {1424-8247}, abstract = {Neurodegenerative diseases are a serious problem for modern society, and their treatment remains an important issue discussed by the scientific community. One of the promising potential directions for modulating neurodegenerative processes is the use of acylhydrazones, a class of compounds that combine different bioactive fragments linked by an acylhydrazone moiety. So far, the biological properties of these compounds have been proven. They show antibacterial, antiviral, antifungal, antiparasitic, anticancer, anti-inflammatory and antioxidant activity. Many research papers focus on designing acylhydrazones that will find use in the treatment of neurodegenerative diseases by inhibiting the enzymatic activity of acetylcholinesterase (AChE), butyrylcholinesterase (BuChE), β-secretase 1 (BACE1) and monoamine oxidase (MAO), as well as inhibiting β-amyloid aggregation, exhibiting metal chelation and antioxidant properties. Recent studies have described the acylhydrazone-based dual (multi-target) inhibitors, which have demonstrated encouraging outcomes during in vitro evaluations. This review covers recent articles published in the years 2020-2025 and offers a comprehensive overview of the biological properties of the acylhydrazones and their multifunctional derivatives on neurodegenerative processes and/or neuroprotection, while emphasizing their universal nature, structural versatility and role as leading structures in the search for new drugs.}, } @article {pmid42198361, year = {2026}, author = {Silva, R and Monteiro, J and Ramalho, MJ and Andrade, S and Loureiro, JA and Pereira, MC}, title = {Advances in Strategies to Transport Nanoparticles Across the Blood-Brain Barrier for Drug Delivery into the Brain for the Treatment of Alzheimer's Disease.}, journal = {Pharmaceuticals (Basel, Switzerland)}, volume = {19}, number = {5}, pages = {}, pmid = {42198361}, issn = {1424-8247}, abstract = {Alzheimer's disease (AD) is a prevalent neurodegenerative disorder characterized by progressive dementia, constituting one of the leading causes of global mortality. Although the current treatments help attenuate the symptoms associated with AD, they are unable to stop the long-term progression of the disease, and consequently, no cure exists. One of the main reasons for the lack of cure and, therefore, one of the biggest challenges in its treatment, is the blood-brain barrier (BBB). This protective barrier limits the entry of foreign substances, including drugs, into the central nervous system. Different types of engineered nanoparticles (NPs) have been demonstrated to be able to penetrate this barrier and serve as efficient drug delivery systems (DDS) into the brain, making them a promising solution for future therapeutic development. Therefore, the purpose of this paper is to provide valuable insights into challenges faced by DDS in treating AD, highlight the nanotechnology-based approach, and discuss the advances in strategies being employed to enhance the crossing of NPs through the BBB. Furthermore, some up-to-date NP systems are presented, along with the latest therapeutic agents targeting AD, and finally, it underscores innovative approaches under investigation. Ultimately, the barriers hindering the clinical translation of NP-based strategies into human patients are discussed.}, } @article {pmid42198444, year = {2026}, author = {Badawi, GA and Shaaban, RS and Almutairi, JA and El-Masry, TA and Zaki, HF and Ibrahim, SM}, title = {Physical Exercise Enhances Melatonin Effect in D-Galactose/Aluminum Chloride-Induced Alzheimer's Disease of Ovariectomized Rats: Irisin Induction Associated with Upregulation of PPAR-γ/IGF-1/BDNF and Decreasing TNF-α/p38-MAPK/NLRP3/GFAP Pathway.}, journal = {Pharmaceuticals (Basel, Switzerland)}, volume = {19}, number = {5}, pages = {}, pmid = {42198444}, issn = {1424-8247}, support = {PNURSP2026R892//Princess Nourah bint Abdulrahman University Researchers Supporting Project/ ; }, abstract = {Background: Postmenopausal women are at high risk of Alzheimer's disease (AD) incidence and progression. Irisin, an exercise-induced myokine, has neuroprotective and antiaging effects against AD, especially in menopausal women suffering from insulin resistance (IR). For the first time, the novel role of irisin induced by melatonin (MTN) or/and physical exercise (PHE) was investigated in the current ovariectomized (OVX)/AD rat model by modulating brain neuroinflammation and IR-related markers. Methods: Fifty female Wistar rats were divided into five groups, with one representing a sham group. AD was induced in the other four bilateral OVX rat groups by daily intraperitoneal injection of D-galactose/AlCl3 (60 and 10 mg/kg, respectively) for 42 days. Group III-V: Animals were exposed to MTN (10 mg/kg/day; i.p.), PHE, and a combination of these, respectively, in the final 14 days of the experiment. Results: The OVX/AD rats showed significant deterioration in learning, memory, neurochemical, and histopathological examinations, while the MTN or/and PHE treatments significantly increased serum and brain irisin, improving memory in a Y-maze assessment. Thus, hippocampal histopathological alterations and IR-related markers decreased. In addition, suppressed hippocampal amyloid-beta protein expression and neuroinflammatory content of tumor necrosis factor-alpha (TNF-α), p38 mitogen-activated protein kinase (p38 MAPK), and NOD-like receptor protein-3 (NLRP3) were associated with an increase in peroxisome proliferator-activated receptor-gamma (PPAR-γ) protein expression and insulin-like growth factor-1 content in hippocampal tissues, collectively suppressing glial fibrillary acidic protein (GFAP) content, leading to an increase in brain-derived neurotrophic factor expression. Conclusions: Irisin induction may serve as a novel avenue in AD/menopause treatment and prevention via modulating the TNF-α/p38 MAPK/PPAR-γ/NLRP3/GFAP pathway.}, } @article {pmid42199014, year = {2026}, author = {Hao, L and Xing, Y and Han, Y}, title = {Status of diagnosis, treatment, and care of Alzheimer's disease continuum in China: A survey-based analysis.}, journal = {Journal of Alzheimer's disease : JAD}, volume = {}, number = {}, pages = {13872877261453551}, doi = {10.1177/13872877261453551}, pmid = {42199014}, issn = {1875-8908}, abstract = {BackgroundThe 2018 NIA-AA framework outlines a six-stage continuum from asymptomatic individuals to severe Alzheimer's disease (AD) dementia, but most Chinese research still focuses on dementia or broad diagnostic categories.ObjectiveTo map diagnosis, treatment, and care patterns across all six AD clinical stages in China and identify demographic, clinical, treatment and care-related factors associated with disease stage.MethodsWe conducted a nationwide, open online survey via official media channels targeting patients with clinician-confirmed AD and their caregivers. Data were collected via Questionnaire Star. Descriptive analyses, group comparisons, and ordinal logistic regression were performed to examine factors associated with NIA-AA stage.ResultsA total of 1116 valid responses were analyzed. Most participants were at Stage 2 or higher, with distribution of 0.4%, 9.1%, 16.0%, 24.8%, 26.6%, and 23.0%, across Stage 1-6. Overall, 64.5% had been diagnosed within five years. Neurology (66.4%) and memory clinics (19.2%) were the most frequently visited departments. Donepezil (52.2%) and Memantine (38.8%) were the most common medications, while 34.5% reported engaging in non-pharmacological interventions. Only 1.9% of patients receiving professional dementia institutional care. In logistic regression, disease duration (OR = 0.724, p = 0.006), stage at first outpatient visit (OR= 1.843, p < 0.001), and Donepezil use (OR = 1.394, p = 0.003) were independently associated with current NIA-AA stage.ConclusionsThis study provides the first nationwide, real-world description of diagnosis, treatment, and care across all NIA-AA stages in China. The findings highlight the need for improved primary-care screening, expanded memory-clinic access, and structured caregiver support to promote earlier detection and more equitable, stage-appropriate management of AD.}, } @article {pmid42199025, year = {2026}, author = {Wang, Y}, title = {Mesenchymal stem cell-mediated regulation of neuroinflammation and amyloid-β clearance: A promising therapeutic strategy for Alzheimer's disease.}, journal = {Journal of Alzheimer's disease : JAD}, volume = {}, number = {}, pages = {13872877261451894}, doi = {10.1177/13872877261451894}, pmid = {42199025}, issn = {1875-8908}, abstract = {Alzheimer's disease (AD) is a neurodegenerative disorder primarily characterized by cognitive decline. Its pathogenesis is complex, involving multiple pathological processes, including amyloid-β (Aβ) deposition, neuroinflammation, and synaptic dysfunction. In recent years, the role of mesenchymal stem cells (MSCs) in AD therapy has garnered significant attention. MSCs, through their multi-directional differentiation potential and paracrine effects, exhibit remarkable neuroprotective and anti-inflammatory properties, influencing AD progression. This review summarizes the potential mechanisms and effects of MSCs in AD treatment and explores precision therapeutic strategies based on MSC modulation.}, } @article {pmid42199075, year = {2026}, author = {Jin, L and Wang, X and Song, F and Hou, J and Bi, Y and Wen, X and Wang, X and Lai, F and Cheng, A}, title = {Quantitative AV-45 PET imaging for assessing treatment response to lecanemab and deep cervical lymphatic-venous anastomosis in Alzheimer's disease.}, journal = {Nuclear medicine communications}, volume = {}, number = {}, pages = {}, doi = {10.1097/MNM.0000000000002184}, pmid = {42199075}, issn = {1473-5628}, support = {no. 82001862//National Natural Science Founda tion of China/ ; }, abstract = {OBJECTIVES: This study aimed to validate the clinical utility of visual and software-based quantitative AV-45 PET analyses and compare treatment effects between lecanemab and deep cervical lymphatic-venous anastomosis (dcLVA).

METHODS: This retrospective cohort study included Alzheimer's disease patients who received 6-month lecanemab therapy or dcLVA surgery between July 2024 and 2025. AV-45 PET was performed 1 week before and 6 months after treatment. Standardized uptake value ratios (SUVRs) and centiloids (CLs) were obtained using visual and quantitative analyses. Agreement was assessed using Cohen's κ and intraclass correlation coefficients (ICC). Receiver operating characteristic (ROC) analysis evaluated diagnostic performance. Logistic regression used Informant Questionnaire on Cognitive Decline in the Elderly score greater than or equal to 3.3 as the outcome.

RESULTS: Baseline characteristics were comparable between groups (all P > 0.05). Visual assessment showed good agreement with centiloid quantification (κ = 0.72, ICC = 0.663). ROC analysis identified ΔCL as the optimal marker (area under the curve = 0.764, P = 0.026), with a cutoff of -11.5%. ΔCL ≥ -11.5% independently predicted cognitive decline in the lecanemab group (odds ratio = 10.281, 95% confidence interval = 1.289-82.005; P = 0.028). Cognitive decline was less frequent in the lecanemab group (23.5 vs. 81.8%; P < 0.001). ΔCL differed significantly between groups (P = 0.006), whereas ΔSUVR did not.

CONCLUSION: Visual and centiloid-based AV-45 PET analyses show good concordance for monitoring Alzheimer's disease treatment response. ΔCL is a robust marker of lecanemab efficacy, which is superior to dcLVA in reducing amyloid-β burden and delaying cognitive decline.}, } @article {pmid42199126, year = {2026}, author = {Wang, Y and Wang, Z and Zhao, J and Zhou, Y and Wei, D and Zhao, J and Sun, Z and Jiang, W}, title = {Mitochondrial transfer: A comprehensive analysis of mechanistic insights, preclinical applications, and technological innovations.}, journal = {Neural regeneration research}, volume = {}, number = {}, pages = {}, doi = {10.4103/NRR.NRR-D-25-01156}, pmid = {42199126}, issn = {1673-5374}, abstract = {Mitochondrial transfer, the intercellular exchange of functional mitochondria, is crucial for maintaining cellular homeostasis and promoting tissue repair, particularly in neurological disorders associated with mitochondrial dysfunction. This review addresses the mechanisms through which mitochondrial transfer occurs, including tunneling nanotubes, extracellular vesicles, gap junction channels, and cell fusion. Mitochondrial transfer and transplantation have demonstrated positive therapeutic effects in various disease models, such as cerebral hemorrhage, ischemic stroke, Alzheimer's disease, and multiple sclerosis. Exogenous mitochondria can integrate into recipient cells, enhancing adenosine triphosphate production, restoring redox balance, and improving cellular survival under stress conditions. However, clinical translation faces significant hurdles, including immune rejection, limited recipient cell uptake capacity, a lack of standardized manufacturing protocols, and unresolved ethical concerns regarding mitochondrial sourcing. To address these challenges, cutting-edge biotechnological strategies, such as mitochondrial surface modification, nanocarrier-based delivery, biomaterial-assisted transplantation, and the use of engineered vesicles, are being developed to enhance the precision, stability, and biocompatibility of mitochondrial delivery. Furthermore, innovative approaches, including CRISPR-based genome editing, 3D-bioprinted tissue models, and artificial intelligence-assisted predictive platforms, are being explored to enhance mitochondrial function and delivery efficiency. Current strategies to harness mitochondrial transfer include pharmacological agents that enhance mitochondrial dynamics, stem cell-based delivery of healthy mitochondria, and the aforementioned bioengineered platforms. In conclusion, the integration of mitochondrial transfer as a groundbreaking treatment option for neurological disorders relies on addressing two to three fundamental challenges. These include the establishment of standardized and scalable protocols for production and quality control, formulating approaches to minimize immune reactions and improve the efficiency of mitochondrial integration, and creating a well-defined ethical and regulatory framework for sourcing and utilizing mitochondria. The primary contribution of this work lies in its integrated analysis of mechanistic insights, preclinical applications, and technological innovations, providing a consolidated roadmap for advancing mitochondrial transplantation from bench to bedside.}, } @article {pmid42199136, year = {2026}, author = {Huang, Z and Zhu, Y and Li, X and Lei, X and Tang, L and Wen, D and Yao, S and Gong, J and Zang, G and Guo, Z}, title = {Dopamine, glutamate, and gamma-aminobutyric acid: Key hubs in neurotransmitters, signal transduction, and cognitive dysfunction.}, journal = {Neural regeneration research}, volume = {}, number = {}, pages = {}, doi = {10.4103/NRR.NRR-D-25-00849}, pmid = {42199136}, issn = {1673-5374}, abstract = {Neurotransmitters such as dopamine, glutamate, and gamma-aminobutyric acid (GABA) play crucial roles in regulating cognitive functions including learning, memory, and executive control. Dysregulation in synthesis, release, and metabolism of these neurotransmitters is implicated in the pathogenesis of various neurological disorders, such as Alzheimer's disease, Parkinson's disease, depression, and schizophrenia, leading to significant cognitive impairment. Recent research highlights that dopamine modulates reward processing, motivation, and memory through its synthesis via tyrosine hydroxylase and reuptake via the dopamine transporter. Glutamate, the primary excitatory neurotransmitter, mediates synaptic plasticity and cognitive processes through ionotropic and metabotropic receptors, while gamma-aminobutyric acid maintains inhibitory balance via GABA A and GABA B receptors. Notedly, interactions among these neurotransmitters, such as dopamine-Glu cross-talk through N-methyl-D-aspartate and dopamine receptors, and GABAergic regulation of dopaminergic activity, are critical for cognitive function. Existing detection techniques, including microdialysis, electrochemical sensors, and genetically encoded indicators, have advanced our understanding but still lack the spatiotemporal resolution needed to fully capture dynamic neurotransmitter interactions in real time. Although pharmacological interventions targeting these systems (e.g., L-3,4-dihydroxyphenylalanine, ketamine, GABAergic modulators) show potential, clinical applications are limited by significant side effects and variable efficacy. In summary, a multi-target approach, combining advanced detection methods with a deeper understanding of neurotransmitter crosstalk, may pave the way for more effective diagnostic and treatment interventions for cognitive disorders.}, } @article {pmid42199923, year = {2026}, author = {Putri, VA and Hapsari, RS and Amalia, R}, title = {L-α-GPC in Cognitive Decline: Mechanisms and Clinical Evidence in Neurodegenerative Disorders.}, journal = {Neuropsychiatric disease and treatment}, volume = {22}, number = {}, pages = {579603}, pmid = {42199923}, issn = {1176-6328}, abstract = {Neurodegenerative diseases such as Alzheimer's disease (AD), Parkinson's disease (PD), and vascular dementia are characterized by progressive neuronal loss, synaptic dysfunction, and cognitive decline. Despite the widespread use of symptomatic treatments, including acetylcholinesterase inhibitors and dopaminergic agents, these disorders remain incurable and lack disease-modifying therapies. L-α-Glycerylphosphorylcholine (L-α-GPC), a naturally occurring choline-containing phospholipid, has attracted interest for its dual roles as a precursor to acetylcholine biosynthesis and a modulator of neuroprotective signaling pathways. This narrative review summarizes current preclinical and clinical evidence regarding the mechanistic and clinical relevance of L-α-GPC in neurodegenerative disorders associated with cognitive impairment. Preclinical studies suggest that L-α-GPC can cross the blood-brain barrier, enhance cholinergic neurotransmission, upregulate neurotrophic factors such as brain-derived neurotrophic factor (BDNF), and modulate inflammatory responses, including those involving the α7 nicotinic acetylcholine receptor pathway. In animal models, L-α-GPC has been associated with improved cognitive performance, reduced neuroinflammation, and attenuation of amyloid-β and tau-related pathological features. Clinical studies have reported potential benefits of L-α-GPC, either as monotherapy or in combination with agents such as donepezil, in patients with AD, vascular dementia, mild cognitive impairment (MCI), and PD-related cognitive decline. However, the interpretation of these findings should be cautious because the available evidence remains heterogeneous, with notable variability in study design, dosage regimens, treatment duration, and outcome measures. Further well-designed, large-scale randomized controlled trials, together with biomarker-based assessments, are needed to clarify the therapeutic relevance and optimal clinical application of L-α-GPC in cognitive decline and neurodegenerative disorders. Overall, current evidence indicates that L-α-GPC may represent a promising adjunctive approach, although more robust validation is still required.}, } @article {pmid42201167, year = {2026}, author = {Bonny, G and Mahfooz, K and Garcia-Rates, S and Hasan, S and Greenfield, SA}, title = {Evaluating the Efficacy of Monoclonal Antibodies Against a Bioactive Peptide Involved in Alzheimer's Disease: A Methodological Approach.}, journal = {Methods and protocols}, volume = {9}, number = {3}, pages = {}, pmid = {42201167}, issn = {2409-9279}, abstract = {Antibody treatment for Alzheimer's disease is an evolving therapeutic strategy that ensures high affinity and specificity to the target antigen; however, current approaches have proven only partially successful. A 14-mer peptide, T14, is twice as high in Alzheimer's brains and has been identified as a primary driver in the neurodegenerative process. Previously, the polyclonal antibody Ab-19 was shown to be as effective as the T14 receptor blocker (NBP-14) in reducing the toxic calcium influx in PC12 cells. The aim of this study was to establish a thorough validation process in order to evaluate the efficacy of respective anti-T14 monoclonal antibodies in T14 detection and rescuing potential from T14-induced toxicity in PC12 cells. Subsequently, we assessed the binding affinity of the most promising antibody, THK-117, via quantitative indirect conjugated T14 ELISA assays. The level of efficacy shown proved to be comparable to the polyclonal antibody, yet with the additional advantage of robust manufacturing reproducibility and high binding specificity toward the T14 epitope. With a notably low EC50, THK-117 can be viewed as a promising candidate for humanization, offering a strong potential as a therapeutic monoclonal antibody for the treatment and prevention of Alzheimer's disease.}, } @article {pmid42201342, year = {2026}, author = {Aydın, Ş and Dalkılınç, E and Özdemir, S and Küçükler, S and Çomaklı, S and Adıgüzel, A}, title = {Neuroprotective effects of luteolin against aluminum-induced brain injury via chelation and antioxidant pathways.}, journal = {Naunyn-Schmiedeberg's archives of pharmacology}, volume = {}, number = {}, pages = {}, pmid = {42201342}, issn = {1432-1912}, abstract = {Aluminum (Al) is a widespread environmental neurotoxin linked to several neurodegenerative conditions through oxidative stress, inflammation, and apoptosis. Because it is present in food, water, pharmaceuticals, and consumer products, chronic exposure is nearly unavoidable and poses a public health concern. Luteolin (LUT), a natural flavone with antioxidant, anti-inflammatory, and metal-chelating properties, has emerged as a potential neuroprotective agent. This study investigated the protective effects of LUT against aluminum chloride (AlCl3)-induced neurotoxicity in rats. Sprague-Dawley rats received AlCl3 (4.2 mg/kg, i.p.) alone or together with LUT (25 or 50 mg/kg, p.o.) for 30 days. Behavioral performance was evaluated using novel object recognition and open-field tests. ICP-MS was employed to quantify brain Al levels, and complementary analyses were conducted to assess oxidative stress, neuroinflammation, apoptosis-related gene expression, neuroplasticity markers (BDNF, c-Fos), and cholinergic function (AChE). AlCl3 exposure significantly increased brain Al accumulation and induced oxidative stress, inflammation, apoptosis, and behavioral deficits. Although LUT co-treatment led to an apparent increase in total brain Al, this rise is likely attributable to the formation of Al-LUT complexes. This interpretation is supported by the marked reduction in Al-induced oxidative stress, apoptosis, and inflammation, accompanied by improved behavioral outcomes. This evaluation reveals that LUT provides protection in an environmental Al neurotoxicity model, offering insights beyond classical Alzheimer's disease contexts. Although its antioxidant and anti-inflammatory effects are well documented, evidence for its efficacy against environmentally induced Al neurotoxicity is still lacking.}, } @article {pmid42202469, year = {2026}, author = {Jessen, F and Dell'Agnello, G and Zimmer, JA and Sapin, C and Dichter, S and Doty, E and Epelbaum, S and Evans, CD and Hauck, PM and Khanna, R and Brooks, DA and Sims, JR and Agosta, F and , }, title = {Efficacy and safety of donanemab in the European eligible population: TRAILBLAZER-ALZ 2 post-hoc analyses.}, journal = {The journal of prevention of Alzheimer's disease}, volume = {13}, number = {8}, pages = {100605}, pmid = {42202469}, issn = {2426-0266}, abstract = {BACKGROUND: In the European Union (EU), donanemab is indicated in adults with early symptomatic Alzheimer's disease who are apolipoprotein E ε4 non-carriers or heterozygotes. Among these, patients without superficial siderosis at baseline, uncontrolled hypertension, or anticoagulant use are eligible.

OBJECTIVE: To assess efficacy and safety of donanemab in the EU-eligible population.

METHODS: A post-hoc conservative hybrid imputation method was implemented for clinical efficacy analyses during the TRAILBLAZER-ALZ 2 placebo-controlled period. In the 78-week long-term extension (LTE) participants in the early-start (randomised to donanemab) and delayed-start (randomised to placebo with donanemab initiation during the LTE) groups were compared to a propensity-weighted external control. Participants were switched to placebo after meeting amyloid-based treatment course completion criteria.

RESULTS: By 76 weeks, donanemab-treated participants in the EU-eligible population had a mean Clinical Dementia Rating Scale (CDR)-Sum of Boxes change from baseline difference from placebo of -0.7 points (95% confidence interval, -1.0, -0.4) and a 40.3% lower risk of disease progression to the next stage (per CDR-Global score). Treatment benefit increased over 154 weeks for non-carriers and heterozygotes, including those meeting treatment course completion criteria by 52 or 76 weeks. In the placebo-controlled period, 119 (19.5%) and 49 (8.0%) donanemab-treated eligible participants experienced amyloid-related imaging abnormalities-edema/effusion and infusion-related reactions, respectively. Safety findings were similar among donanemab-treated participants in the placebo-controlled period and LTE delayed-start group.

CONCLUSIONS: Consistent with previous TRAILBLAZER-ALZ 2 and LTE findings, donanemab significantly slowed disease progression compared to controls with a manageable safety profile in non-carriers and heterozygotes.}, } @article {pmid42202980, year = {2026}, author = {Sánchez-Valle, R and Alcolea, D and Amer Ferrer, G and Balasa, M and Casado Naranjo, I and Fortea, J and Lladó, A and Lleó, A and Montes, AM and Martinez Lozano, L and Martínez-Lage, P and Matias-Guiu, JA and Mendioroz, M and Perez Martinez, DA and Ripoll, GP and Riverol, M and Sanchez-Juan, P and Bondía, HV and , }, title = {Appropriate use recommendations of the Spanish Society of Neurology's Behavioural Neurology and Dementia Study Group on anti-amyloid antibodies in the treatment of Alzheimer disease.}, journal = {Neurologia}, volume = {}, number = {}, pages = {502075}, doi = {10.1016/j.nrleng.2026.502075}, pmid = {42202980}, issn = {2173-5808}, abstract = {INTRODUCTION: Two anti-amyloid monoclonal antibodies (mAb) have recently been approved by the European Commission for the treatment of Alzheimer disease (AD). In this context, the Spanish Society of Neurology's Behavioural Neurology and Dementia Study Group decided to issue a consensus statement gathering the recommendations of national experts on the appropriate use of anti-amyloid mAb. The document provides recommendations on practical aspects of the use of these drugs in Spain, which are intended to complement the indications described by regulators.

DEVELOPMENT: Fifty-seven members of the study group participated in the consensus process (January-September 2025), which includes recommendations on criteria for selecting candidates, adverse reactions, monitoring, criteria for suspension of treatment, shared physician-patient decision-making, and requirements of prescribing centres. All participants were invited to revise the complete document, specifically asked whether they agreed with the content of each section, and invited to share their comments.

CONCLUSIONS: The introduction of the first anti-amyloid mAb represents a paradigm shift in the management of AD, but is not free of challenges. The participating experts showed a high level of consensus on basic clinical and practical considerations, with the requirements of prescribing centres and criteria for treatment suspension being the areas that generated the most debate. Participants noted concerns about equity of access and implementation into current care, particularly if insufficient resources are allocated to this implementation. This document will require updates in line with new knowledge and/or approval of new drugs in this class.}, } @article {pmid42203570, year = {2026}, author = {Ho, NCW and Zhukovsky, P and Rajji, TK and Bowie, CR and Brooks, H and Butters, MA and Chen, Y and Fischer, CE and Flint, AJ and Herrmann, N and Lanctôt, KL and Lee, A and Mah, L and Marawi, T and Pollock, BG and Ryan, JD and Schoer, N and Ma, C and Voineskos, AN and Mulsant, BH and , }, title = {Brain Structures and Cognitive Decline: Moderation Analysis of the PACt-MD Randomized Clinical Trial of Brain Stimulation Plus Cognitive Remediation in Older Adults With Remitted Depression or Mild Cognitive Impairment.}, journal = {The American journal of geriatric psychiatry : official journal of the American Association for Geriatric Psychiatry}, volume = {34}, number = {8}, pages = {1005-1015}, doi = {10.1016/j.jagp.2026.04.008}, pmid = {42203570}, issn = {1545-7214}, mesh = {Aged ; Female ; Humans ; Male ; Middle Aged ; Brain/pathology ; Brain Cortical Thickness ; *Cognitive Dysfunction/therapy/diagnostic imaging/pathology ; *Cognitive Remediation/methods ; Double-Blind Method ; Executive Function ; Magnetic Resonance Imaging ; *Major Depressive Disorder/therapy/diagnostic imaging/pathology ; *Transcranial Direct Current Stimulation/methods ; }, abstract = {OBJECTIVE: To identify which patients with remitted major depressive disorder (rMDD) or mild cognitive impairment (MCI) benefit from cognitive remediation (CR) plus transcranial direct current stimulation (tDCS).

DESIGN: We conducted a moderator analysis to examine the effects of baseline brain magnetic resonance imaging (MRI) measures on the impact of CR + tDCS on cognitive decline in Prevention of Alzheimer's dementia with CR plus tDCS in MCI and Depression (PACt-MD), a double-masked randomized two-arm controlled trial with assessments at baseline, two months, and yearly for three to seven years.

SETTING: Five academic hospitals in Toronto, Canada.

PARTICIPANTS: A total of 246 participants with rMDD, MCI, or both, with an analyzable baseline MRI.

INTERVENTION: CR + tDCS or sham CR + sham tDCS.

MEASUREMENTS: Overall cortical thickness, overall fractional anisotropy, and cortical thickness in an a-priori composite region of interest (ROI); changes in global cognition, executive function, or verbal memory.

RESULTS: Overall cortical thickness moderated decline in global cognition (Χ² = 10.43, df = 3, p = 0.015); ROI cortical thickness moderated treatment-related changes in global cognition (Χ² = 29.05, df = 3, p <0.001), executive function (Χ² = 11.57, df = 3, p = 0.009), and verbal memory (Χ² = 16.08, df = 3, p = 0.001).

CONCLUSION: Future work needs to confirm that cortical thickness can be used to select adults at risk for dementia who are the most likely to benefit from CR + tDCS. CLINCIALTRIALS.

GOV IDENTIFIER: NCT02386670.}, } @article {pmid42204876, year = {2026}, author = {Khorsand, B and Teichrow, D and Ghanbarian, E and Zheng, L and Sajjadi, SA and Glover, CM and Grill, JD and Rabin, LA and Ezzati, A}, title = {Scalable markers for early cognitive decline: Plasma p-tau217, subjective cognitive concerns, and digital testing: Results from the A4/LEARN studies.}, journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association}, volume = {22}, number = {5}, pages = {e71505}, pmid = {42204876}, issn = {1552-5279}, support = {//public-private philanthropic partnership/ ; //National Institutes of Health/National Institute on Aging/ ; //Eli Lilly and Company/ ; //Accelerating Medicines Partnership/ ; //GHR Foundation/ ; //Avid and Cogstate/ ; }, mesh = {Humans ; Aged ; *Cognitive Dysfunction/diagnosis/blood ; *tau Proteins/blood ; Biomarkers/blood ; Female ; Male ; Aged, 80 and over ; Neuropsychological Tests ; Positron-Emission Tomography ; *Alzheimer Disease/blood ; Longitudinal Studies ; }, abstract = {INTRODUCTION: Amyloid positron emission tomography (PET) and cerebrospinal fluid (CSF) biomarkers confirm Alzheimer's disease (AD) pathology but are impractical for large-scale screening. Plasma phosphorylated tau at threonine 217 (p-tau217), subjective cognitive concerns, and computerized cognitive testing are non-invasive, scalable, and feasible to implement in large populations. We assessed their separate and combined predictive value for cognitive decline.

METHODS: We analyzed 1064 cognitively unimpaired adults (ages 65-85 years) from the Anti-Amyloid Treatment in Asymptomatic Alzheimer's Disease (A4; amyloid-positive) and Longitudinal Evaluation of Amyloid Risk and Neurodegeneration (LEARN; amyloid-negative) studies. Baseline assessments included apolipoprotein E (APOE) ε4 status, hippocampal volume, amyloid PET, plasma p-tau217, Cognitive Function Index (CFI), and Cogstate Computerized Battery (CCB). Cognitive impairment was defined as conversion from a Clinical Dementia Rating Global Score (CDR-GS) of 0 to ≥0.5 over 240 weeks.

RESULTS: During the follow-up, 34.1% developed cognitive impairment. Higher p-tau217, higher CFI, and lower CCB were associated with higher odds of converting to CDR-GS >0 across all cohorts.

DISCUSSION: P-tau217, CFI, and CCB each independently predict cognitive decline, offering practical, non-invasive tools for early AD risk stratification and trial enrichment.}, } @article {pmid42206050, year = {2026}, author = {Deng, HX and Cao, JL and Wu, Y and Jiang, SJ and Fang, QQ and Zhu, BY and Jiang, YJ}, title = {AI-driven insights into protein misfolding and innate immunity in neurodegenerative diseases.}, journal = {Frontiers in immunology}, volume = {17}, number = {}, pages = {1814357}, pmid = {42206050}, issn = {1664-3224}, mesh = {Humans ; *Neurodegenerative Diseases/immunology/metabolism ; *Immunity, Innate ; *Protein Folding ; Animals ; *Artificial Intelligence ; *Proteostasis Deficiencies/immunology ; }, abstract = {Neurodegenerative diseases encompass a diverse group of disorders ranging from adult-onset conditions such as Alzheimer's and Parkinson's disease to pediatric forms including neuronal ceroid lipofuscinoses (NCLs), Niemann-Pick type C (NPC), and infantile neuroaxonal dystrophy (INAD), all of which are characterized by protein misfolding and chronic neuroinflammation. During their occurrence and development, the innate immune system, especially the immune responses mediated by microglia in the central nervous system, plays a crucial regulatory role. Increasing evidence indicates that misfolded and abnormally aggregated proteins, such as β-amyloid (Aβ), Tau, α-synuclein, and TDP-43, are not only neurotoxic factors but can also act as damage-associated molecular patterns (DAMPs) recognized by innate immune receptors, thereby triggering persistent neuroinflammatory responses. However, traditional experimental and computational methods still have significant limitations in systematically analyzing the "protein misfolding-innate immune activation" mechanism. In recent years, artificial intelligence has made breakthrough progress in protein structure prediction, multi-conformation modeling, and integration of multi-omics data, providing a new research paradigm for revealing the intrinsic relationship between protein misfolding and innate immunity across the spectrum of neurodegenerative diseases. This article systematically reviews the latest applications of artificial intelligence in predicting the conformational characteristics of misfolded proteins, simulating the protein aggregation process, revealing the mechanism of innate immune perception, and reconstructing the regulatory network of neuroinflammation. It focuses on discussing the significance of deep learning models such as AlphaFold, I-TASSER, RoseTTAFold, Phyre2, and ESMFold in the field of protein structure prediction, as well as the related research on multi-modal AI technology in revealing the complex molecular mechanisms behind neurodegenerative diseases, such as combining AI with mathematical models to simulate the spread of misfolded proteins and further exploring the association with disease progression. The review also highlights the potential of AI to address the diagnostic challenges unique to pediatric neurodegenerative disorders, which, despite their rarity, collectively impose devastating lifelong burdens. In summary, AI tools not only deepen our understanding of the molecular mechanisms underlying both adult and childhood neurodegenerative diseases but also open up new avenues for developing innovative diagnostic tools and treatment methods.}, } @article {pmid42207225, year = {2026}, author = {Ed-Day, S and Kacimi, FE and El Gui, R and Didou, L and Ibouzine-Dine, L and El Kourchi, C and Boulbaroud, S and Haddan, A and Harhar, H and Azzaoui, FZ}, title = {Erythrina caffra extract restores memory, modulates cholinergic dysfunction, neuroinflammation, and attenuates oxidative stress in cadmium-induced alzheimer's disease-like pathology in rats.}, journal = {Molecular biology reports}, volume = {53}, number = {1}, pages = {}, pmid = {42207225}, issn = {1573-4978}, mesh = {Animals ; Oxidative Stress/drug effects ; *Plant Extracts/pharmacology ; *Alzheimer Disease/drug therapy/chemically induced/metabolism/pathology ; Rats ; Rats, Wistar ; Cadmium/toxicity ; Male ; *Erythrina/chemistry/metabolism ; *Memory/drug effects ; Antioxidants/pharmacology ; Hippocampus/drug effects/metabolism ; Neuroinflammatory Diseases/drug therapy/metabolism ; Disease Models, Animal ; Acetylcholine/metabolism ; Neuroprotective Agents/pharmacology ; }, abstract = {BACKGROUND: Cadmium (Cd) is a well-established neurotoxic heavy metal. Several epidemiological studies have highlighted its involvement in the pathogenesis of Alzheimer's disease (AD). AD is a multifactorial disorder influenced by environmental factors such as heavy metals. Erythrina caffra (E. caffra) is a medicinal plant rich in bioactive compounds with anti-inflammatory, antioxidant, and anticholinesterase properties. However, its protective potential against Cd-induced neurodegeneration remains insufficiently explored. This study investigated the effects of Cd on memory, cholinergic function, oxidative stress, and neuroinflammation, as key AD-related pathophysiological features, and evaluated the therapeutic potential of E. caffra seeds ethanolic extract.

METHODS AND RESULTS: AD-like alterations were induced in Wistar rats by intracerebroventricular (ICV) administration of cadmium chloride (CdCl2). Animals were treated with E. caffra ethanolic extract (2.5 mg/kg) or memantine (20 mg/kg) by oral gavage. Behavioral, neurobiochemical, and histological analyses were performed to assess memory, cholinergic function, oxidative stress, neuroinflammation, and neuronal integrity. Cd exposure significantly impaired memory and disrupted cholinergic function, as evidenced by reduced acetylcholine (ACh) levels in the hippocampus. Moreover, it induced oxidative stress, marked by decreased catalase (CAT), superoxide dismutase (SOD), and non-protein thiols (NPSH), alongside increased proinflammatory cytokines, including interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α), and hippocampal neuronal loss. Treatment with E. caffra and memantine significantly ameliorated these alterations.

CONCLUSIONS: E. caffra extract demonstrates neuroprotective effects against Cd-induced AD-like pathology by modulating oxidative stress, neuroinflammation, and cholinergic dysfunction. These findings suggest its potential as a promising therapeutic candidate for mitigating neurodegenerative processes associated with AD.}, } @article {pmid42207606, year = {2026}, author = {Papamicaël, C and Gembus, V and Gourand, F and Levacher, V}, title = {Redox Heterocyclic Platforms Engineered for Brain Drug Delivery and Beyond.}, journal = {Chemical record (New York, N.Y.)}, volume = {}, number = {}, pages = {e70162}, doi = {10.1002/tcr.70162}, pmid = {42207606}, issn = {1528-0691}, abstract = {Overcoming the blood-brain barrier remains one of the most formidable challenges in the diagnosis and treatment of central nervous system disorders. In this account, we showcase our contributions to the field of redox-responsive heterocycles, most notably 1,4-dihydroquinolines and 1,4-dihydropyridines, designed as powerful platforms for targeted brain delivery. Our work builds on the chemical delivery system and bioprecursor prodrug strategies pioneered by Bodor et al. We have focused on the development of redox-activated drug carriers and "bio-oxidizable" prodrugs, which enable efficient transport of neurotransmitters, neuropeptides, and radiotracers for advanced brain imaging, as well as cholinesterase and kinase inhibitors for the treatment of Alzheimer's disease. Last but not least, these versatile heterocyclic systems offer unprecedented perspectives in synthetic methodology, driving breakthrough advances in peptide synthesis and atroposelective amide bond construction.}, } @article {pmid42207745, year = {2026}, author = {Bhat, KMR and Lc, P and Thonse, NK and Potu, BK and Kateel, R}, title = {Neuroprotective Effects of Ginkgo biloba Extract in Neurological Disorders: Integrating Anti-Inflammatory and Antioxidant Mechanisms.}, journal = {Complementary medicine research}, volume = {}, number = {}, pages = {1-40}, doi = {10.1159/000552633}, pmid = {42207745}, issn = {2504-2106}, abstract = {BACKGROUND: Neurological disorders such as Alzheimer's disease, Parkinson's disease, epilepsy, and ischemic stroke are major causes of global disability and mortality. Neuroinflammation and oxidative stress play central roles in their pathogenesis. Ginkgo biloba extract (GBE), particularly the standardized formulation EGb 761, contains flavonoids and terpenoids that exert antioxidant, anti-inflammatory, and mitochondrial-protective effects. These pleiotropic actions position GBE as a promising candidate for neuroprotection.

SUMMARY: This narrative review synthesizes evidence from preclinical and clinical studies on the neuroprotective actions of GBE. Experimental data demonstrate that GBE attenuates oxidative stress by scavenging reactive oxygen species and enhancing endogenous antioxidant defenses, while simultaneously downregulating pro-inflammatory mediators through NF-κB inhibition and NLRP3 inflammasome suppression. Additional benefits include stabilization of mitochondrial function, modulation of neurotransmission, and prevention of apoptosis. Preclinical models consistently show improvements in cognition, motor function, and neuronal survival across diverse disease contexts. Clinical findings, however, are mixed: some randomized trials report improved cognition and functional outcomes in dementia and Parkinsonism, whereas others show no superiority over placebo. Variability in study design, extract standardization, and treatment regimens contribute to these discrepancies.

KEY MESSAGES: GBE exerts multifaceted neuroprotective effects through combined antioxidant, anti-inflammatory, mitochondrial, and neurotransmitter-modulating actions. Preclinical evidence strongly supports its role in mitigating pathological processes underlying Alzheimer's disease, Parkinson's disease, epilepsy, and ischemic injury. But clinical outcomes remain inconsistent. GBE holds potential as a safe, multi-target adjunctive therapy for complex central nervous system disorders, but translation into consistent clinical practice requires further validation.}, } @article {pmid42208269, year = {2026}, author = {Saxena, S and Kaur, J and Singh, TG and Kumar, M and Awasthi, A}, title = {Beyond the brain barrier: Hybrid nanoparticles orchestrating intelligent neuro-theranostics.}, journal = {Advances in colloid and interface science}, volume = {356}, number = {}, pages = {103954}, doi = {10.1016/j.cis.2026.103954}, pmid = {42208269}, issn = {1873-3727}, abstract = {Hybrid nanoparticles (HNPs) that integrate organic and inorganic components have been recognized as one of the most sophisticated solutions in the field of nanomedicine to surpass the physiological limitations of the blood-brain barrier (BBB). By the combination of biocompatibility, flexibility, and the capacity of functionalization of the organic shells with the magnetic, optical, or structural precision of the inorganic cores, HNPs provide receptor-mediated transport, controlled drug release, and multimodal imaging with high efficiency. This review details the molecular mechanisms of HNPs crossing the BBB, such as receptor-mediated, adsorptive, carrier-mediated, and biomimetic transcytosis, and also points to the role of the advanced conjugation chemistries like EDC/NHS coupling, thiol‑gold anchoring, click reactions, and redox-cleavable linkers in enhancing targeting fidelity. The therapeutic improvements in the major neurological diseases, i.e., Alzheimer's disease, Parkinson's disease, Huntington's disease, and glioblastoma, are discussed with the help of figures, which illustrate enhanced bioavailability, gene silencing, mitochondrial targeting, and integrated photothermal or magnetic responsiveness. Moreover, the review discusses potential diagnostic applications such as multimodal MRI/PET/NIR-II imaging, molecular biosensing, and theranostic nanoplatforms, which link the real time visualization with the targeted treatment. To conclude, we point out the upcoming directions comprising biomimetic coatings, AI guided nanoparticle design, stimuli responsive logic-gated systems, and clinically scalable biodegradable hybrids. In sum, HNPs embody a radically different strategy to precision neuro-nanomedicine, thereby providing a seamless avenue for diagnosis, targeted therapy, and continuous disease monitoring within a single intelligent nanosystem.}, } @article {pmid42208565, year = {2026}, author = {Serrano-Pozo, A and Escott-Price, V and Grinberg, LT and Pascoal, T and Suárez-Calvet, M and Dubois, B and Sperling, RA}, title = {Alzheimer's disease.}, journal = {Lancet (London, England)}, volume = {407}, number = {10544}, pages = {2241-2262}, doi = {10.1016/S0140-6736(26)00198-4}, pmid = {42208565}, issn = {1474-547X}, mesh = {Humans ; *Alzheimer Disease/diagnosis/therapy/epidemiology/prevention & control ; Biomarkers ; }, abstract = {Alzheimer's disease is the leading cause of dementia and among the top ten leading causes of death in high-income countries. Exponential advances in epidemiology, genetics, diagnostic imaging and fluid biomarkers, treatment, and prevention in the last decade reinforce the notion that we are entering a new era in the clinical management of Alzheimer's disease. However, far from triumphalism, this momentum should be accelerated to achieve the goals of preventing Alzheimer's disease and arresting its progression. In this Seminar, we summarise this progress and highlight unmet needs and areas of research priority.}, } @article {pmid42210357, year = {2026}, author = {Behzad, F and Leili, FR and Ebrahimi, MJ and Moafi, M and Kenari, PB and Alizadeh, A and Adeli, S and Khosravani, M and Jadidi Kouhbanani, MA and Fahanik-Babaei, J}, title = {Plant-mediated green nanoparticles: combining nanometal and biometabolite potential for Alzheimer's treatment.}, journal = {Biomedical engineering online}, volume = {}, number = {}, pages = {}, doi = {10.1186/s12938-026-01572-z}, pmid = {42210357}, issn = {1475-925X}, abstract = {Alzheimer's disease (AD) can cause cognitive and memory dysfunction due to insufficient acetylcholine (ACh). In principle, acetylcholinesterase (AChE) hydrolyzes ACh into acetic acid and choline, rendering the latter inactive. Acetylcholinesterase inhibitors (AChEI) are currently the main treatment strategy used to increase ACh availability and decrease the effects of cholinergic loss. The FDA has currently approved donepezil, rivastigmine, and galantamine (GAL) as AchEI drugs to treat AD. Among these drugs, only the alkaloid galantamine is found naturally among the AChEIs. The synergistic effect of plant metabolites and metal nanoparticles (MNPs) presents a promising avenue for AD treatment. Green synthesis approach leverages the unique properties of MNPs combined with the therapeutic potential of plant-derived compounds. In the present review, recent developments in nanotechnology, including the green synthesis of MNPs, have been discussed in relation to the treatment of AD. Given the recent advancements, we hope that the combination of nanotechnology and medicinal plants will eventually result in the development of highly successful strategies for the treatment of AD.}, } @article {pmid42210804, year = {2026}, author = {Devanand, DP and Huey, ED and Qian, M and Wei, R and Motter, JN and Nedic, L and Andrews, HF and Deliyannides, DA and Maayan, L and Graff, J and Deehan, E and Acosta, EP and Zanderigo, F and Goldberg, TE}, title = {Valacyclovir Treatment in Mild Cognitive Impairment: The VALMCI Randomized Clinical Trial.}, journal = {Alzheimer disease and associated disorders}, volume = {40}, number = {2}, pages = {69-76}, doi = {10.1097/WAD.0000000000000735}, pmid = {42210804}, issn = {1546-4156}, mesh = {Humans ; *Valacyclovir/therapeutic use ; Female ; *Cognitive Dysfunction/drug therapy/diagnostic imaging/virology ; Male ; *Antiviral Agents/therapeutic use ; Aged ; Double-Blind Method ; Positron-Emission Tomography ; Pilot Projects ; Treatment Outcome ; }, abstract = {BACKGROUND: Evidence from neuroscience, epidemiology, and electronic health records studies implicates herpes simplex viruses (HSV) as potentially etiologic for Alzheimer disease (AD).

METHODS: The VALMCI study was conducted in a research outpatient clinic specializing in memory disorders. The efficacy and side effects of valacyclovir 4 g/day were compared with placebo in a 12-month pilot, randomized, double-blind trial of participants with mild cognitive impairment (MCI), seropositivity to HSV1 or HSV2, and positive 18 F-florbetapir PET scan.

RESULTS: Totally, 42 of 50 participants (84%) completed the trial. In linear mixed-effects model analyses with age, sex, and apolipoprotein E e4 genotype as covariates, change in the primary outcome of 18 F-florbetapir PET mean SUVR was not significant with least-squares mean difference -0.01 (95% CI: -0.12 to 0.10; P =0.82). For secondary cognitive and functional outcomes, PACC composite z -score showed the least square mean difference 0.16 (95% CI: -0.17 to 0.49; P =0.32), and ADCS-ADL-PI score showed the least square mean difference 1.96 (95% CI: -0.43 to 4.34; P =0.11).

CONCLUSION: The results do not support the use of valacyclovir in the treatment of individuals with MCI with HSV seropositivity and PET amyloid positivity.}, } @article {pmid42211120, year = {2026}, author = {Song, H and Yang, M and Wu, S and Dai, Q and Qin, W and Xie, W and Chen, Y and Jiang, X and Zhang, X and Deng, X and Ouyang, C and Zhang, Y and Liu, X and Zhu, Y and Huang, G}, title = {Andrographolide attenuates microglial senescence in Alzheimer's disease mice by suppressing the STAT3 signaling.}, journal = {iScience}, volume = {29}, number = {6}, pages = {116033}, pmid = {42211120}, issn = {2589-0042}, abstract = {Andrographolide (AP), a diterpenoid extracted from Andrographis paniculata, has emerged as a promising treatment for Alzheimer's disease (AD) in preclinical studies, but the underlying mechanisms remain incompletely defined. Here, we demonstrated that AP treatment improved cognition performance and reduced amyloid-β (Aβ) plaque accumulation in 5×FAD transgenic mice of both sexes, by mitigating microglial senescence. Proteomic analysis revealed that AP markedly decreased cholesterol content in the cerebral cortex. Using an in vitro low-density lipoprotein-induced senescence model, we found that AP significantly alleviated senescence in BV2 microglia while enhancing their phagocytic capacity. Mechanistically, AP mitigated microglial senescence by inhibiting STAT3 signaling. Overall, these findings identify a previously unrecognized immunometabolic mechanism for AP in the treatment of AD.}, } @article {pmid42212431, year = {2026}, author = {Kim, JP and Lee, H and Kim, BH and Kang, H and Shin, D and Yim, S and Kim, S and Seo, SW and Kim, HN}, title = {Genetically prioritized druggable targets for amyloid-β pathology highlight ACE as a therapeutic candidate in Alzheimer's disease.}, journal = {Journal of Alzheimer's disease : JAD}, volume = {}, number = {}, pages = {13872877261454540}, doi = {10.1177/13872877261454540}, pmid = {42212431}, issn = {1875-8908}, abstract = {BackgroundAlzheimer's disease (AD) is characterized by a neuropathological cascade that begins with amyloid-β (Aβ) deposition. The recent success of disease-modifying drugs targeting Aβ has demonstrated that modulating amyloidopathy can yield clinical benefits, underscoring the need for additional drugs affecting amyloid pathology.ObjectiveTo identify novel drug targets associated with Aβ accumulation in AD using Mendelian randomization (MR) analysis of the druggable genome.MethodsWe performed MR analysis on expression quantitative trait loci (eQTLs) of the druggable genome in relation to Aβ accumulation using summary-data-based MR (SMR). Blood eQTL data were obtained from the eQTLGen consortium, and brain eQTL data from BrainMeta and PsychENCODE, while Aβ positron emission tomography (PET) genome-wide association study data were derived from 11,816 non-Hispanic White participants across 13 cohorts. Co-localization analysis was conducted to enhance the reliability of the MR results, and additional validation was performed using blood and brain protein quantitative trait loci (pQTLs) as instrumental variables.ResultsThe SMR and co-localization analyses revealed causal associations between the druggable genome and Aβ accumulation, with APH1B identified in blood eQTL data and ACE, APH1B, and CR1 identified in brain eQTL data. Further analysis using pQTL data confirmed causal associations for ACE and CR1, with ACE showing a negative association with Aβ PET uptake.ConclusionsThese findings highlight potential target genes for AD treatment, and the protective effect of ACE against amyloid pathology suggests that alternative medications to ACE inhibitors may be preferred for blood pressure management in the context of AD. Overall, our study demonstrates the potential of MR to facilitate drug repurposing for AD.}, } @article {pmid42213912, year = {2026}, author = {Wilson, S and Beswick, E and Popp, Z and Rahman, S and Bhogal, S and Whitfield, T and Low, S and Khan, R and Tolley, C and Walker, Z and Au, R and Slight, SP}, title = {Acceptability of Technologies to Support Early Dementia Detection: Qualitative Study With the Boston University Alzheimer's Disease Center Cohort.}, journal = {Journal of medical Internet research}, volume = {28}, number = {}, pages = {e84004}, pmid = {42213912}, issn = {1438-8871}, mesh = {Humans ; Aged ; Female ; *Dementia/diagnosis ; Male ; Boston ; *Alzheimer Disease/diagnosis ; Digital Health ; Cognitive Dysfunction/diagnosis ; Cohort Studies ; Aged, 80 and over ; Early Diagnosis ; Qualitative Research ; *Patient Acceptance of Health Care ; }, abstract = {BACKGROUND: Dementia is on the rise globally due to increasing life expectancies and population growth. Digital technologies may help detect early signs, enabling timely interventions to slow or reverse cognitive decline. However, to support the successful implementation of these digital technologies into health care settings, they must be acceptable to target users. Older adults and those with mild cognitive impairment (MCI) are at risk of developing dementia in later life and need to be able to use these technologies in order for this intervention to be approved and implemented in clinical practice.

OBJECTIVE: This study explored the perspectives of older adults and those living with a clinical diagnosis of MCI on the acceptability of using various digital technologies that have the potential to support early dementia detection.

METHODS: Participants were recruited from Boston University's Alzheimer's Disease Research Center. Participants selected at least 2 technologies from 9 different wearables and software to use for 2 weeks, at 3-month intervals, over a total duration of 2 years. A subgroup of self-selecting participants was interviewed after the first 2 weeks of use to gather initial perspectives regarding the acceptability of using the digital technologies. An inductive framework thematic analysis approach was used, assisted by NVivo (version 14.23.2; QSR International).

RESULTS: In total, 13 individuals living with a clinical diagnosis of MCI and 11 adults aged 65 years and older were interviewed. Our analysis identified five key themes: (1) gamification, (2) wearability, (3) user guidance, (4) burden of use, and (5) usefulness. Gamified apps were generally liked, although users with little experience of digital games needed time to adjust. Wearables resembling everyday accessories (eg, watches) were preferred, but complaints about tight or uncomfortable straps were frequently reported. Clear instructions were critical to support correct use, but many participants would have liked more troubleshooting support when technical issues arose. The use of 5 or more devices led to a high burden, especially when devices had practicality issues such as not being waterproof. Devices offering personal feedback were perceived as useful to satisfy personal interests, though some questioned their usefulness within health care. Participants raised concerns about losing valued personal interactions with health care professionals and questioned how their existing health conditions and treatment for such conditions may affect the validity of the data collected by the devices.

CONCLUSIONS: These findings can guide researchers in choosing appropriate devices and minimizing burden. Future work should explore the views of those experiencing digital exclusion to ensure equitable access to dementia-detection technologies.}, } @article {pmid42214568, year = {2026}, author = {Zhong, RF and Chen, ZQ and Li, SF and Jiang, JG}, title = {Neuroprotective effects of Uncaria rhynchophylla alkaloid extracts against amyloid-β toxicity via regulation of oxidative stress pathways.}, journal = {Journal of ethnopharmacology}, volume = {369}, number = {}, pages = {121918}, doi = {10.1016/j.jep.2026.121918}, pmid = {42214568}, issn = {1872-7573}, mesh = {Animals ; *Oxidative Stress/drug effects ; *Neuroprotective Agents/pharmacology/isolation & purification ; *Amyloid beta-Peptides/toxicity ; PC12 Cells ; *Uncaria/chemistry ; *Alkaloids/pharmacology/isolation & purification ; *Plant Extracts/pharmacology ; Caenorhabditis elegans/drug effects ; Rats ; Reactive Oxygen Species/metabolism ; Animals, Genetically Modified ; Cell Survival/drug effects ; Signal Transduction/drug effects ; Lipid Peroxidation/drug effects ; Hydrogen Peroxide ; Antioxidants/pharmacology ; Paralysis/chemically induced ; }, abstract = {Uncaria rhynchophylla is a important medicinal plant in Chinese traditional medicine for the treatment of neurological disorders, its alkaloid-rich constituents are considered the primary bioactive components responsible for its effects on the central nervous system.

AIM OF THE STUDY: This study aimed to investigate the neuroprotective effects of U. rhynchophylla alkaloid extract (URAs) against amyloid-β (Aβ)-induced neurotoxicity and oxidative stress, and elucidate underlying molecular mechanisms.

MATERIALS AND METHODS: URAs was prepared and characterized by LC-MS/MS for chemical profiling. The neuroprotective effects were evaluated using transgenic C. elegans CL2006 and CL2355, and H2O2-induced PC12 cells. In C. elegans, paralysis assay, Aβ deposition, and chemotaxis behavior were assessed. Oxidative stress markers including reactive oxygen species (ROS), lipofuscin accumulation, lipid peroxidation (MDA), and antioxidant enzyme activities (SOD, CAT) were measured. Quantitative real-time PCR was performed to examine the expression of genes of related signaling pathways. In PC12 cells, cell viability, ATP levels, and oxidative stress were evaluated.

RESULTS: URAs treatment significantly delayed Aβ-induced paralysis, reduced Aβ deposition, and improved chemotaxis behavior in transgenic C. elegans, while decreasing ROS, lipofuscin, and MDA, and increasing SOD and CAT activities. Furthermore, URAs modulated the expression of genes involved in Aβ metabolism, proteasome function, and antioxidant defense, and significantly suppressed the expression of p38 MAPK signaling pathway components.

CONCLUSION: Our findings demonstrate that URAs exert neuroprotective effects against Aβ toxicity and oxidative stress through multi-target mechanisms involving enhanced antioxidant defense, regulated proteostasis, highlighting their therapeutic potential for AD intervention.}, } @article {pmid42214747, year = {2026}, author = {Long, X and Shen, R and Yang, Y and Xu, Y and Wang, Y and He, Y and Xie, Y and Xie, X and Gao, D and Pang, X and Du, L}, title = {Isoquercetin-ligustrazine co-polymorph attenuates hypoxia-accelerated Alzheimer's disease by suppressing PERK-CHOP-mediated ER stress.}, journal = {Experimental neurology}, volume = {404}, number = {}, pages = {115856}, doi = {10.1016/j.expneurol.2026.115856}, pmid = {42214747}, issn = {1090-2430}, abstract = {Alzheimer's disease (AD), a neurodegenerative disorder predominantly affecting the elderly population, is frequently associated with hypoxic conditions, including obstructive sleep apnea and other age-related comorbidities. Arising from various pathological conditions, chronic hypoxia may contribute to the acceleration of AD progression. However, the precise mechanisms underlying hypoxia-induced cellular stress responses, particularly those involving ER stress and the PERK pathway, remain insufficiently explored. In this study, the therapeutic effects of a co-polymorph combining Isoquercetin and Ligustrazine (ILCP) on AD-related pathologies aggravated by chronic hypoxia were investigated. ApoE3/4 transgenic mice were exposed to hypoxic conditions for four weeks; results on oxidative stress levels, β-amyloid (Aβ) deposition, and neuronal apoptosis were assessed. Chronic hypoxia was found to intensify PERK pathway activity, elevate neuronal damage, and further aggravate AD-associated cognitive deficits. ILCP administration was associated with reduced PERK pathway activation, resulting in reduced oxidative stress, alleviated neuronal damage, and preserved synaptic plasticity. These findings support a role for PERK-CHOP signaling in hypoxia-driven AD pathology and suggest a potential link between ILCP treatment and modulation of this pathway.}, } @article {pmid42216035, year = {2026}, author = {Ibrahim, KS and Albaker, A and Abd-Elrahman, KS and Ferguson, SSG}, title = {Blocking estrogen receptors restores surface mGluR5 but not downstream signaling in female APP/PS1 Mice.}, journal = {Molecular brain}, volume = {}, number = {}, pages = {}, doi = {10.1186/s13041-026-01314-1}, pmid = {42216035}, issn = {1756-6606}, support = {195977/CAPMC/CIHR/Canada ; 148656/CAPMC/CIHR/Canada ; }, abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder that disproportionately affects women. Deposition of β-amyloid (Aβ), a hallmark of AD pathology, disrupts metabotropic glutamate receptor-5 (mGluR5) regulation of autophagy and accelerates disease progression in male AD mouse models. Yet, mGluR5 contribution to Aβ pathology is not observed in female AD mice, suggesting a distinct sex-selective profile. Given that estrogen receptors (ERs) form functional complexes with mGluR5 selectively in females, we assessed the role of ER activity in mGluR5 expression and downstream signaling in APPswe/PS1ΔE9 (APP/PS1) mice. We report here that mGluR5 cell surface expression is elevated in male but reduced in female APP/PS1 cortex relative to sex-matched wildtype controls, with total receptor expression remaining unchanged in both sexes. Treatment with the ER blocker, ICI 182,780, restored mGluR5 cell surface expression in female APP/PS1 mice but failed to rescue GSK3β and ULK1-regulated autophagy signaling. These findings indicate that male and female mGluR5 are embedded within intrinsically distinct signaling interactomes that are independent of ER regulation.}, } @article {pmid42216640, year = {2026}, author = {Kong, Y and Lv, X and Yang, Y and Li, Q and Dai, C and Lin, X and Liu, J and Li, J}, title = {Lactobacillus mucosae Reduces Neuronal Oxidative Stress in Alzheimer's Disease via the Regulation of CB2 Signaling.}, journal = {Journal of integrative neuroscience}, volume = {25}, number = {5}, pages = {48598}, doi = {10.31083/JIN48598}, pmid = {42216640}, issn = {0219-6352}, support = {Y20240038//Science and Technology Funds of Wenzhou/ ; }, mesh = {Animals ; *Oxidative Stress/drug effects/physiology ; *Alzheimer Disease/metabolism/drug therapy ; Male ; *Probiotics/pharmacology/administration & dosage ; *Signal Transduction/drug effects ; Disease Models, Animal ; *Receptor, Cannabinoid, CB2/metabolism/drug effects ; Mice, Transgenic ; Mice ; *Neurons/metabolism/drug effects ; *Lactobacillus ; }, abstract = {BACKGROUND: The probiotic Lactobacillus mucosae has been widely shown to have many positive effects. However, its neuroprotective effects and underlying mechanism in Alzheimer's disease (AD) remain elusive.

METHODS: Male APP/PS1 mice were treated for 4 weeks with L. mucosae WMU007, followed by the evaluation of cognitive function, neuronal damage, amyloid-β (Aβ) deposition, and Tau phosphorylation. RNA-seq coupled with Gene Ontology (GO) enrichment analysis implicated L. mucosae WMU007 in modulating oxidative stress in this AD model. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis and qPCR were performed to identify the specific mechanism by which this probiotic suppresses oxidative stress in the pathogenesis of AD. In addition, we quantified the levels of classical oxidative stress markers, such as superoxide dismutase 2 (SOD2) and glutathione peroxidase 4 (GPX4). We also examined the expression of cannabinoid receptor type 2 (CB2) and its key downstream regulators in the redox pathway, namely nuclear factor erythroid 2-related factor 2 (Nrf2) and heme oxygenase 1 (HO-1), in both animal and cellular models.

RESULTS: Our results showed that treatment with L. mucosae WMU007 significantly decreased cognitive impairment, neuronal damage, Aβ deposits, and Tau phosphorylation in APP/PS1 mice. Activation of CB2 was identified as the key mechanism by which L. mucosae WMU007 reduces oxidative stress in AD. In addition, L. mucosae WMU007 reduced oxidative stress and increased the levels of CB2 pathway-related proteins in vivo and in vitro.

CONCLUSIONS: These results indicate that L. mucosae WMU007 confers neuroprotection in AD by targeting CB2-mediated oxidative pathways, highlighting its therapeutic potential as a novel probiotic intervention.}, } @article {pmid42216664, year = {2026}, author = {Wen, T and Zhu, T and Zhou, LY and Ran, Z and Chen, L and Wang, WJ}, title = {Bibliometric analysis of natural medicine in the treatment of Alzheimer's disease: Trends, hotspots, and emerging research fields.}, journal = {Journal of Alzheimer's disease : JAD}, volume = {}, number = {}, pages = {13872877261451887}, doi = {10.1177/13872877261451887}, pmid = {42216664}, issn = {1875-8908}, abstract = {BackgroundAlzheimer's disease (AD) is a progressive neurodegenerative disorder whose global prevalence continues to rise, yet treatment options are still limited. Natural medicines, with their potential for multi-target intervention, have become a key direction in AD drug development. However, a systematic overview of research trends in this field based on bibliometric methods is currently lacking.ObjectiveThis study aims to summarize research progress on natural medicines for AD treatment using bibliometric analysis and to identify future research hotspots and trends.MethodsRelevant publications were retrieved from the Web of Science Core Collection. Data visualization and analysis were conducted using VOSviewer, CiteSpace, and R.ResultsA total of 3800 publications were included, involving contributions from 108 countries/regions, 4024 institutions, 18,729 authors, and 706 journals. Publication output showed steady growth, with China and India as the leading contributing countries. Institutions such as the Chinese Academy of Sciences and Kyung Hee University demonstrated high productivity and influence. The research focus has shifted from initial clinical pharmacology and molecular pathology to exploring multi-target mechanisms of natural medicines through network pharmacology and molecular docking. Promising natural agents include Ginkgo biloba, ginseng, curcumin, resveratrol, and Centella asiatica.ConclusionsResearch on natural medicines for AD has progressed steadily over the past two decades, with current emphasis on elucidating multi-target mechanisms using emerging technologies. However, clinical evidence remains limited. Future studies should strengthen multi-omics integration and clinical translation to foster innovative AD prevention and treatment strategies.}, } @article {pmid42216879, year = {2026}, author = {Pyun, J and Noor, A and Runwal, P and Mawal, C and Fuller, OK and Egan, CL and Febbraio, MA and Donnelly, PS and Short, JL and Bush, AI and Nicolazzo, JA}, title = {Cu(ATSM) Restores Blood-Brain Barrier Abundance of P-Glycoprotein and Improves Cognitive Function in the APP/PS1 Mouse Model of Alzheimer's Disease.}, journal = {ACS chemical neuroscience}, volume = {17}, number = {12}, pages = {2389-2405}, doi = {10.1021/acschemneuro.6c00252}, pmid = {42216879}, issn = {1948-7193}, mesh = {Animals ; *Alzheimer Disease/drug therapy/metabolism/pathology/genetics ; *Blood-Brain Barrier/drug effects/metabolism ; Mice, Transgenic ; *Thiosemicarbazones/pharmacology ; Disease Models, Animal ; Amyloid beta-Peptides/metabolism ; *ATP Binding Cassette Transporter, Subfamily B, Member 1/metabolism ; Amyloid beta-Protein Precursor/genetics/metabolism ; Mice ; *Organometallic Compounds/pharmacology ; Presenilin-1/genetics/metabolism ; Brain/drug effects/metabolism ; Humans ; *Cognition/drug effects ; Coordination Complexes ; Male ; Peptide Fragments/metabolism ; Copper/metabolism ; }, abstract = {Alzheimer's disease (AD) is a prevalent neurodegenerative disorder characterized by the accumulation of amyloid-beta (Aβ) peptides in the brain. P-glycoprotein (P-gp), a key efflux transporter at the blood-brain barrier (BBB), plays a crucial role in the clearance of Aβ. Using the APP/PS1 mouse model of familial AD, this study investigated the effect of copper diacetyl bis(4-methyl-3-thiosemicarbazone) (Cu(ATSM)) on brain microvascular abundance and function of P-gp and the associated effects on exogenous Aβ clearance, brain amyloid burden, and cognitive function. Compared to vehicle-treated 10 month-old APP/PS1 mice, Cu(ATSM) (30 mg/kg/day for 56 days) restored brain microvascular P-gp abundance (24.1%) and Cu concentrations (229.8%) as well as significantly reduced brain cortical concentrations of human Aβ42 (hAβ42) (42.1%) in APP/PS1 mice. Cu(ATSM) treatment led to a trend toward improved brain clearance (11.9%) of [125]I-Aβ42 that was cortically injected into APP/PS1 mice compared to vehicle-treated APP/PS1 mice. Importantly, Cu(ATSM) treatment led to significantly improved (43.8% p = 0.0087) learning and long-term spatial memory in APP/PS1 mice, assessed by the Barnes maze paradigm. Inductively coupled plasma mass spectrometric analysis revealed increased Cu concentrations in brain microvessel-enriched fractions. In APP/PS1 mice, Cu(ATSM) restored brain microvascular P-gp abundance, which was associated with lowered cortical hAβ42, and improved long-term spatial memory, indicating neurovascular target engagement accompanied by amyloid lowering and behavioral benefit. Together with established BBB penetration and ongoing safety and tolerability evaluation in neurodegenerative populations, these findings propose Cu(ATSM) as a potential therapeutic application of biometal modulation targeting neurovascular dysfunction and Aβ burden in AD.}, } @article {pmid42217307, year = {2026}, author = {Sharma, S and Kumar, V and Arulsamy, S and Kumar, S and Wadhwa, P}, title = {An integrated in silico approach to identify pyridine-based AChE and BChE inhibitors for Alzheimer's disease.}, journal = {Computers in biology and medicine}, volume = {212}, number = {}, pages = {111765}, doi = {10.1016/j.compbiomed.2026.111765}, pmid = {42217307}, issn = {1879-0534}, mesh = {*Cholinesterase Inhibitors/chemistry/pharmacology ; *Alzheimer Disease/drug therapy/enzymology ; *Pyridines/chemistry/pharmacology ; *Butyrylcholinesterase/chemistry/metabolism ; Humans ; *Acetylcholinesterase/chemistry/metabolism ; *Molecular Docking Simulation ; Molecular Dynamics Simulation ; }, abstract = {Among all the neural diseases Alzheimer's disease (AD) represents a major and critical global health challenge, along with limited diseases-altering therapeutic interventions efficacy. This study deploys collective approaches of in silico study which includes molecular docking, ADMET profiling, density functional theory (DFT), and MD simulations simulation to evaluate pyridine-based dual inhibitors which can target acetylcholinesterase (AChE PBD ID: 4EY7) and butyrylcholinesterase (BChE PDB ID: 6I0B). From a curated library of 55 ZINC-derived compounds, virtual screening using AutoDock Vina identified lead candidates exhibiting superior binding affinities (-11.5 to - 8.0 kcal/mol for AChE; - 10.9 to - 7.4 kcal/mol for BChE) compared to marketed drugs donepezil and tacrine. Compound 46 emerged as the top AChE inhibitor, while compound 49 demonstrated optimal BChE inhibition. DFT analysis at the B3LYP/6-31G(d) level revealed distinct electronic properties: compound 46 exhibited a wider HOMO-LUMO gap (5.32 eV) correlating with enhanced kinetic stability, whereas compound 49 displayed a narrower gap (5.10 eV) and elevated dipole moment, supporting target-selective binding. Extended MD simulations with 200 ns of total duration confirmed that compounds 46 and 49 (two complexes) have structurally stable conformations compared with each other; however, compound 49 was found to be thermodynamically more stable according to MM-PBSA predicted binding free energy (-54.96 ± 4.36 kcal/mol) than compound 46 (-44.73 + 4.85 kcal/mol). ADMET predictions showed good intestinal absorption and CNS permeability; however, it will be necessary to improve both the solubility of these compounds as well as their CYP3A4-related liability. This multi-tiered computational strategy was able to identify both compounds 46 and 49 as highly promising candidates for further experimental validation as dual cholinesterase inhibitors that will be incorporated into efforts to develop new AD treatment approaches.}, } @article {pmid42217970, year = {2026}, author = {Toma, C and Vujosevic, S}, title = {Optical coherence tomography and OCT-angiography in neurologic and neuro-ophthalmologic diseases: Current applications and future perspectives.}, journal = {Handbook of clinical neurology}, volume = {218}, number = {}, pages = {13-32}, doi = {10.1016/B978-0-443-22212-2.00022-7}, pmid = {42217970}, issn = {0072-9752}, mesh = {Humans ; *Tomography, Optical Coherence/methods/trends ; *Nervous System Diseases/diagnostic imaging ; *Eye Diseases/diagnostic imaging ; Retina/diagnostic imaging ; }, abstract = {Optical coherence tomography (OCT) and OCT-angiography (OCTA) have emerged as useful tools for noninvasive imaging in the neurologic field. This chapter elucidates their utility in detecting biomarkers for the diagnosis and monitoring of progression and response to treatment in different prevalent neurologic conditions. The retina, an extension of the central nervous system, presents a unique opportunity for monitoring brain pathology due to its accessibility. Through highly resolved scans of the retina and optic nerve, OCT and OCTA facilitate the identification of subtle clinical changes occurring during neuroinflammatory, neurodegenerative, and ischemic processes in disorders like multiple sclerosis, Alzheimer and Parkinson disease, anterior ischemic optic neuropathies, and papilledema. Peripapillary nerve fiber layer and macular internal retinal layer thickness on OCT, and vessel density in the superficial retina on OCTA seem to be the most sensitive parameters in detecting axonal injury and neurodegeneration. These metrics hold promise as surrogate markers for cerebral alterations. While OCT and OCTA show considerable potential, continued research is necessary to validate their reliability and clinical significance, considering potential confounding factors such as concurrent ophthalmic pathologies. Nonetheless, these advancements represent significant progress toward enhancing the diagnosis, management, and prediction of outcomes in various neuro-ophthalmic disorders.}, } @article {pmid42218511, year = {2026}, author = {Lin, H and Zhang, Y and Ni, R and Wang, M and Men, J and Ge, J and Lu, J and Wang, J and Zhang, H and Yang, Y and Zhang, Z and Zhu, Y and Zhao, H and Yen, TC and Wang, J and Shi, K and Rominger, A and Guan, Y and Fang, M and Yu, J and Jiang, J and Zuo, C}, title = {White matter [18]F-florbetapir retention predicts cognitive decline and treatment response in Alzheimer's disease.}, journal = {Alzheimer's research & therapy}, volume = {}, number = {}, pages = {}, doi = {10.1186/s13195-026-02098-1}, pmid = {42218511}, issn = {1758-9193}, support = {2022ZD0211606//STI2030-Major Projects/ ; 82021002, 82272039, and 82394434//National Natural Science Foundation of China/ ; }, abstract = {PURPOSE: White matter (WM) signal on [18]F-florbetapir positron emission tomography (PET) is often regarded as nonspecific, yet its biological significance remains unclear. This study aimed to characterize the trajectory, clinical significance, and biomarker correlates of normal-appearing white matter (NAWM) [18]F-florbetapir retention across the Alzheimer's disease (AD) continuum.

METHODS: We analyzed NAWM ¹⁸F-florbetapir retention in 672 participants across the AD continuum from the Alzheimer's Disease Neuroimaging Initiative and two Chinese cohorts. Longitudinal PET, plasma, and cerebrospinal fluid (CSF) biomarkers, as well as lecanemab treatment effects, were evaluated.

RESULTS: NAWM retention followed a distinct trajectory from cortical amyloid, increasing during preclinical stages and plateauing in symptomatic phases. Elevated NAWM ¹⁸F-florbetapir retention independently predicted cognitive decline, correlated with plasma p-tau217 and CSF p-tau/Aβ42 ratio, and showed significant reductions following lecanemab therapy. Combined assessment of cortical and NAWM PET improved diagnostic accuracy for amyloid positivity to 92%. NAWM retention also correlated strongly with plasma and CSF biomarkers in preclinical stages, and mediation analyses indicated that these fluid markers partly explained NAWM-cognition associations.

CONCLUSION: NAWM ¹⁸F-florbetapir retention represents a biologically valid and dynamic biomarker of AD progression, with potential utility for early detection, prognostication, and therapeutic monitoring.}, } @article {pmid42218670, year = {2026}, author = {Dong, Y and Xiao, X and Zhuang, XX and Wu, W and Fang, EF and Yang, G and Niu, Z and Lu, JH}, title = {AI-Driven discovery of brain-penetrant mTOR-independent autophagy enhancers for Alzheimer's disease.}, journal = {Autophagy}, volume = {}, number = {}, pages = {1-3}, doi = {10.1080/15548627.2026.2679639}, pmid = {42218670}, issn = {1554-8635}, abstract = {Current Alzheimer's disease therapies offer limited efficacy and are often accompanied by significant side effects, underscoring the urgent need for new treatment strategies. Enhancing autophagy represents a promising therapeutic approach, yet most known autophagy inducers act through the mTOR-dependent pathway, which broadly affects cellular metabolism and proliferation, and their clinical potential is further limited by poor blood-brain barrier (BBB) penetration. To address these twin challenges, an artificial intelligence (AI)-driven platform named DeepDrugDiscovery was developed, shifting the focus from traditional structure-based screening toward a mechanism-centric strategy for identifying mTOR-independent autophagy enhancers with brain penetrability. The platform screened over one million molecules and identified two lead compounds, Ombuin and 2-Hydroxycinnamic acid, which were experimentally shown to clear pathogenic tau and amyloid-β aggregates and restore memory function in both worm and mouse models of Alzheimer's disease. Notably, Ombuin exhibited robust brain exposure, confirming accurate BBB prediction. Released as an open-source resource, DeepDrugDiscovery demonstrates a scalable, AI-powered pipeline for discovering mechanism-based therapeutics.}, } @article {pmid42220121, year = {2026}, author = {Zhao, J and Tian, G and Qu, Y and Liu, Y and Wu, W and Dai, L and Zhang, G and An, F}, title = {Research Progress on Alzheimer's Disease with Classical Traditional Chinese Medicine Formulas.}, journal = {Current drug delivery}, volume = {}, number = {}, pages = {}, doi = {10.2174/0115672018401009251117113526}, pmid = {42220121}, issn = {1875-5704}, abstract = {Alzheimer's disease (AD) is caused by complex pathological changes and is a problem that cannot be ignored by the global public health system. Its main clinical manifestations include progressive cognitive impairment, mental and psychological changes, and, in advanced stages, paralysis and loss of self-care ability. The economic and psychological burdens imposed on AD patients and their caregivers have been progressively exacerbating, while the annual expenditures on AD treatment by nations worldwide and by the United Nations have demonstrated a consistent upward trend rather than a decline. The treatment of AD remains challenging, with currently limited therapeutic options available. The advantages of the multi-target, multi-component, safe, and low-toxicity characteristics of Traditional Chinese Medicine (TCM) have attracted public attention, providing ideas for the prevention and treatment of AD and for the development of new drugs. In this study, 27 TCM formulas reported to exhibit preventive and therapeutic effects on AD in basic or clinical research were identified and summarized. TCM can intervene in the progression of AD by clearing Aβ deposition, inhibiting Tau phosphorylation, reducing neuroinflammation, mitigating mitochondrial dysfunction and oxidative stress, and regulating gut microbiota. This review aims to provide evidence for further exploring the role and potential mechanisms of TCM in the prevention and treatment of AD, and to offer insights for the development of new anti-AD drugs.}, } @article {pmid42220134, year = {2026}, author = {Singh, I and Dheek, M and Usmani, A and Chauhan, SB and Sinha, A}, title = {Development, Optimization, and Characterization of Donepezil Hydrochloride-loaded Emulsomes with Nigella Sativa Oil for the Treatment of Alzheimer's Disease.}, journal = {Current neurovascular research}, volume = {}, number = {}, pages = {}, doi = {10.2174/0115672026444242260514094253}, pmid = {42220134}, issn = {1875-5739}, abstract = {INTRODUCTION: Alzheimer's disease is a progressive neurodegenerative disorder where conventional oral delivery of donepezil hydrochloride is limited by poor bioavailability and restricted brain access due to the blood-brain barrier. This study aims to develop an alternative nanocarrier-based delivery system to enhance therapeutic efficacy.

METHOD: Trestearin, phosphatidylcholine, and cholesterol formed a solid lipid core that was used to make emulsomes. TEM was used to characterize emulsomes, while FTIR spectroscopy was used for compatibility tests. The formulation was optimized using the 3-factor, 3-level Central Composite Design.

RESULT: The optimized emulsome formulation demonstrated a stable formulation with a mean particle diameter of 124 ± 3.25 nm, an entrapment efficiency of 74 ± 0.67%, a PDI of 0.209 ± 0.03, with a zeta potential of -0.130 mV. In vitro release study demonstrated a consistent drugrelease pattern, with 84 ± 1.24% of the medication released during the investigation.

DISCUSSION: Based on insights from the thesis, emulsomes incorporating Nigella sativa oil show enhanced neuroprotective potential due to the antioxidant and anti-inflammatory actions of thymoquinone. The intranasal route further supports improved brain targeting by bypassing the blood-brain barrier. The consistency of particle size, strong entrapment efficiency, and sustained drug release align with the reported advantages of emulsome-based formulations discussed in the thesis, reinforcing their promise as an effective approach for Alzheimer's treatment.

CONCLUSION: The central composite design optimization ensures a stable and effective delivery system for the donepezil hydrochloride-loaded emulsomes containing Nigella sativa oil with great potential for novel drug delivery in Alzheimer's disease.}, } @article {pmid42220141, year = {2026}, author = {Ahmed, I and Ansari, YA and Parveen, G and Shukla, K and Bhise, M and Singh, S and Shaikh, UP and Ahmed, R and Ansari, I and Kumar, A}, title = {Neuroprotective Phytochemicals Targeting Amyloid and Tau Pathologies.}, journal = {Current topics in medicinal chemistry}, volume = {}, number = {}, pages = {}, doi = {10.2174/0115680266446356260226085409}, pmid = {42220141}, issn = {1873-4294}, abstract = {The prevalence of Alzheimer's disease stands at more than 55 million individuals in the world, with estimates showing that the figure will increase to 152 million in 2050. Existing treatment methods are mostly symptomatic and do not address the underlying molecular disruptions, such as oxidative stress, mitochondrial dysfunction, and neuroinflammation. Neurodegeneration mediated by convergent pathways of these processes occurs through Aβ and hyperphosphorylated Tau. This is an overall review summarizing evidence from the PubMed, Scopus, and Web of Science databases as of 2025 on phytochemicals that can address both amyloid and tau pathologies simultaneously. This study presents a comprehensive assessment of more than 100 bioactive compounds across 7 chemical families with dual anti-amyloid and anti-tau effects, without prior reviews that address separate pathological targets or isolated classes of compounds with bioactivity. Major phytochemicals, such as curcumin, resveratrol, and epigallocatechin-3- gallate, suppress the activity of the beta-secretase, prevent the formation of amyloid fibrils, inhibit glycogen synthase kinase-3beta-mediated tau phosphorylation, and promote autophagy-lysosomal clearance. These molecules regulate NF-erythroid-2-related factor 2 signaling to inhibit reactive oxygen species and inhibit NF-κB-mediated neuroinflammation. Preclinical models show reductions in cognitive and neuropathological burden, but bioavailability and blood-brain barrier penetration pose barriers to clinical translation. Developed nanotechnology-based systems of delivery and structural modifications have potential in overcoming pharmacokinetic constraints. This represents a multi-target candidate therapy, a paradigm shift from the single-pathway therapeutics of the past, which may provide disease-modifying strategies beyond symptom management of Alzheimer's disease.}, } @article {pmid42220203, year = {2026}, author = {Eyre, B and Bonney, SK}, title = {A perivascular perspective on the immune impacts in cerebral amyloid angiopathy.}, journal = {Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism}, volume = {}, number = {}, pages = {271678X261454165}, pmid = {42220203}, issn = {1559-7016}, abstract = {Cerebral amyloid angiopathy (CAA) is one of the most common small vessel diseases. With the deposition of amyloid beta within the walls of cerebral blood vessels, CAA can result in damage to blood vessels over time and ultimately intracerebral haemorrhage (ICH). Not only is CAA a leading cause of ICH but CAA is commonly observed in Alzheimer's disease (AD), yet there are still no effective treatments for CAA. The pathophysiology of CAA has yet to be fully elucidated but we know the perivascular environment is heavily impacted by the deposition of amyloid within blood vessels. In recent years, there has been an increased interest in the role that perivascular clearance may play in the development of the disease. Additionally, the role of the immune system has also come into question, especially regarding CAA-related inflammation. In this review, we aim to discuss the immune impacts of CAA within the perivascular environment, and probe how specific cells within this environment may be involved in the pathogenesis of CAA. Importantly, we also consider how some of these immune cells may be key treatment avenues to explore.}, } @article {pmid42220275, year = {2026}, author = {Ou, J and Hou, K and Fu, Y and Luo, Y and Yu, Q and Shen, M and Jiang, S and Zhu, J and Wang, Y and Lin, K and Lin, Z and Fang, M}, title = {Brain microvascular endothelial cells: Beyond a barrier.}, journal = {Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism}, volume = {}, number = {}, pages = {271678X261454263}, pmid = {42220275}, issn = {1559-7016}, abstract = {The blood-brain barrier (BBB) has long been regarded as a passive, protective filter for the brain. This review re-evaluates the role of brain microvascular endothelial cells (BMECs)-from viewing them as static structural components to recognizing them as dynamic immunoregulatory sentinels within the neurovascular unit. BMECs actively sense inflammatory and pathogenic signals through pattern recognition receptors, integrate competing pathways such as Wnt/β-catenin and NF-κB, and make context-dependent decisions to balance barrier integrity with immune defense. In response to activation, they orchestrate neuroimmune communication by secreting chemokines, modulating adhesion molecules, and facilitating immune cell trafficking. Dysregulation of these functions contributes to the pathogenesis of various central nervous system disorders, including stroke, Alzheimer's disease, and multiple sclerosis, where BMECs dysfunction drives neuroinflammation and barrier breakdown. Further progress is required to resolve endothelial heterogeneity, develop precise tools for barrier function assessment, and define targeted interventions that modulate the immunoregulatory functions of BMECs in order to explain the mechanistic heterogeneity observed in neurological disorders. These efforts will deepen our understanding of the BBB's role in physiology and pathology, offering new strategies for the prevention and treatment of neurological diseases, and highlight BMECs as active participants in brain immunity and potential therapeutic targets.}, } @article {pmid42221048, year = {2026}, author = {Han, Y and Zhou, C and Wang, P and Karako, K and Song, P}, title = {The skin as a sentinel organ for neurodegeneration: An underrecognized target for dementia prevention.}, journal = {Intractable & rare diseases research}, volume = {15}, number = {2}, pages = {156-165}, pmid = {42221048}, issn = {2186-3644}, abstract = {Dementia prevention increasingly requires attention to modifiable systemic inflammatory stressors. In older adults, bullous pemphigoid (BP), herpes zoster (HZ), psoriasis, atopic dermatitis (AD), rosacea, prurigo nodularis (PN), and chronic pruritus are not merely disorders limited to the skin; they may signal or amplify neuroimmune vulnerability. Observational studies link BP with dementia and Alzheimer's disease, HZ with incident dementia and vascular cognitive injury, and psoriasis, AD, rosacea, or PN with smaller but biologically plausible cognitive risks. The proposed skin-brain axis integrates cytokine spillover, endothelial activation, blood-brain barrier dysfunction, BP180/ BP230 autoantigen sharing, varicellazoster virus neurotropism and vasculopathy, barrier failure, dysbiosis, itching-induced fragmented sleep, and medication or frailty-related cognitive toxicity. Clinically, cognitive impairment also worsens skin surveillance, hygiene, topical adherence, and recognition of pain, itching, infection, or blistering. Although causality and dementia prevention remain unproven, the evidence justifies proactive dermatological care in older adults and greater cognitive vigilance in older patients with severe inflammatory or pruritic dermatoses. Recombinant zoster vaccination, prompt antiviral therapy, steroid-sparing BP strategies, modern anti-inflammatory treatment for AD, psoriasis, and PN, and systematic attention to sleep, itching, caregiver capacity, and the medication burden are practical, low-regret steps while prospective brain-relevant trials are developed. This translational framework highlights mechanisms clinicians can now interrupt and endpoints investigators can soon measure. We propose that the skin should be recognized as a sentinel organ for neurodegeneration and that dermatological disease represents a potentially modifiable contributor to cognitive decline.}, } @article {pmid42221153, year = {2026}, author = {Nitrini, R}, title = {Diagnosis of Alzheimer's disease in asymptomatic individuals: a historical perspective.}, journal = {Dementia & neuropsychologia}, volume = {20}, number = {}, pages = {e2026487}, pmid = {42221153}, issn = {1980-5764}, abstract = {The diagnosis of Alzheimer's disease (AD) based on biomarkers of the pathological process represents a significant change from previous criteria, which required the presence of dementia for AD diagnosis. These new criteria create difficulties in disclosing the diagnosis of AD to asymptomatic individuals. A similar example exists in the history of cognitive and behavioral disorders, where the risk of developing dementia paralytica (DP), a form of neurosyphilis (NS), could be detected even in the asymptomatic phase. Treatment in this phase of DP or in its early symptomatic phase was successful due to the discovery of new therapeutic modalities and new evolutionary biomarkers, which are not yet widely available in AD. This type of biomarker was very important in NS and will certainly be in AD, allowing for faster and less expensive clinical trials.}, } @article {pmid42221535, year = {2026}, author = {Kogan, M and Frame, LA and Fahim Devin, M and Prather, C and Alchalabi, T and Ashraf, U and Darling Luczak, B and Fine, H and Ifateyo, A and Ledenac, M and Novak, SS and Yakel, J}, title = {The Integrative Personalized Functional Medicine Approach to Reverse Cognitive Decline: Academic Experience of the First 51 Patients Case Series.}, journal = {Global advances in integrative medicine and health}, volume = {15}, number = {}, pages = {27536130261452680}, pmid = {42221535}, issn = {2753-6130}, abstract = {Background: Alzheimer's disease (AD) and related dementias remain major public health challenges with limited treatment options. Personalized, multimodal integrative approaches have emerged as potential strategies for patients with mild cognitive impairment (MCI) and early-stage AD. Purpose: To describe outcomes from the first 51 participants enrolled in an academic integrative functional medicine program for cognitive decline. Research Design: Retrospective case series, chart analysis. Study Sample: Participants with MCI or AD enrolled at the GW Center for Integrative Medicine (n=51, 2017-2025); 22 remained in the program for ≥2.5 years for long-term cognitive analyses. Data Collection and/or Analysis: Participants underwent serial cognitive assessments [Montreal Cognitive Assessment (MoCA) and/or Boston Cognitive Assessment (BOCA), subset also completing CNS-Vitals and SLAMs at variable intervals]. MoCA was the prespecified primary outcome. Interventions included dietary modification, time-restricted eating, exercise, cognitive training, sleep optimization, individualized supplementation, hormonal management, and 40 Hz gamma-frequency sensory stimulation. Exploratory measures included volumetric brain MRI and Alzheimer's blood biomarkers (Aβ42/Aβ40, p-tau217, NfL) in a subset. Outcomes were summarized descriptively without formal statistical analyses. Results: Among participants with ≥2.5 years of follow-up, mean MoCA increased from 21.7 to 22.5, and 73% (16/22) demonstrated improvement (≥2-point increase) or stabilization (-1 to +1 points). Attrition was high; 29/51 discontinued within the first year, most commonly due to cost, program complexity, and lack of caregiver support. Conclusions: This program demonstrated encouraging preliminary findings of cognitive stabilization or improvement in participants with MCI or AD who remained enrolled. Controlled prospective trials are needed to determine efficacy and mechanisms.}, } @article {pmid42221706, year = {2026}, author = {Rangasamy, SB and Raha, S and Dasarathi, S and Pahan, K}, title = {Corrected Version: Sodium Benzoate, A Metabolite of Cinnamon and A Food Additive, Improves Cognitive Functions in Mice After Controlled Cortical Impact Injury.}, journal = {Journal of clinical & experimental immunology}, volume = {11}, number = {1}, pages = {11-26}, pmid = {42221706}, support = {I01 BX005002/BX/BLRD VA/United States ; IK6 BX004982/BX/BLRD VA/United States ; }, abstract = {Traumatic brain injury (TBI) is a major health concern, sometimes leading to long-term neurological disability, especially in children, young adults, and war veterans. Although the research investigators and clinicians have applied different treatment strategies or neurosurgical procedures to solve this health issue, we are still in need of effective therapy to halt the pathogenesis of brain injury. Earlier we have reported that sodium benzoate (NaB), a metabolite of cinnamon and a Food and Drug Administration-approved drug against urea cycle disorders and glycine encephalopathy, protects neurons in animal models of Parkinson's disease and Alzheimer's disease. This study was undertaken to examine the therapeutic efficacy of NaB in controlled cortical impact (CCI)-induced preclinical mouse model of TBI. Oral treatment with NaB, but not sodium formate (NaFO), was found to decrease the activation of microglia and astrocytes and inhibits the expression of inducible nitric oxide synthase (iNOS) in hippocampus and cortex of CCI-insulted mice. Further, administration of NaB also reduced the vascular damage and decreased the size of lesion cavity in the brain of CCI-induced mice. Importantly, NaB-treated mice showed significant improvements in memory and locomotor functions as well as displayed substantial reduction in depression like behaviors. These results delineate a novel neuroprotective property of NaB, highlighting its possible therapeutic importance in TBI.}, } @article {pmid42222332, year = {2026}, author = {Pluta, R and Ułamek-Kozioł, M}, title = {Genomic and proteomic conversion of brain ischemia to Alzheimer's disease.}, journal = {Frontiers in cell and developmental biology}, volume = {14}, number = {}, pages = {1804251}, pmid = {42222332}, issn = {2296-634X}, abstract = {Despite many years of extensive research into the etiology and treatment of Alzheimer's disease, based on the importance of amyloid and tau protein as causative factors, these studies have stalled, have not brought any breakthroughs and, most importantly, have not led to any final conclusions. Therefore, the ineffectiveness of the above-mentioned actions and the pressure from the community of people affected by Alzheimer's disease forced the scientific community to change its way of thinking about the etiopathogenesis of this disease. This situation has prompted a group of scientists who have been studying the effects of brain ischemia for years to focus on post-ischemic changes, which-similarly to Alzheimer's disease-predominate in the hippocampus, leading to the development of amyloid plaques, neurofibrillary tangles and ultimately to dementia. In this context, it has been proposed that brain ischemia may play an important role in driving amyloid and tau protein pathology in the development of Alzheimer's disease. In this review, we present an update of extensive experimental and clinical studies conducted over several years on the role of brain ischemia in the neuropathogenesis of Alzheimer's disease. Current advances in understanding the ischemic etiology of Alzheimer's disease have revealed dysregulation of Alzheimer's disease-associated genes, including secretases, amyloid precursor protein, apoptosis, autophagy, mitophagy, tau protein, α-synuclein, apolipoproteins, LRP1, and RAGE. This article presents the relationship between genes which dysregulation is a result of brain ischemia and the cellular and tissue neuropathology characteristic of Alzheimer's disease and their proteins. These observations clearly indicate that, following brain ischemia, changes occur in the expression of Alzheimer's disease-associated genes and in the folding of disease-associated proteins such as amyloid, tau protein, and α-synuclein. This leads to massive neuronal death and disruption of the neuronal network, ultimately leading to the development of Alzheimer's disease-like dementia. Data indicate common genomic and proteomic factors in brain ischemia and Alzheimer's disease. It seems that the brain ischemia model may be useful in determining the role of folding proteins and their genes dysregulation in Alzheimer's disease. In the future, manipulation of genes and proteins associated with ischemia and ischemia-induced Alzheimer's disease will likely provide new hope for developing causal therapies that are urgently needed to prevent or treat Alzheimer's disease. The innovative/novel approach to the etiology of Alzheimer's disease presented in this review will provide stakeholders with a glimpse into the future.}, } @article {pmid42222363, year = {2026}, author = {Roamcharern, N and Yubolphan, R}, title = {Overcoming the blood-brain barrier in Alzheimer's disease: translational perspectives on advanced drug delivery platforms.}, journal = {Frontiers in neuroscience}, volume = {20}, number = {}, pages = {1810486}, pmid = {42222363}, issn = {1662-4548}, abstract = {Alzheimer's disease (AD) is the leading cause of dementia worldwide and represents a growing public health challenge in aging societies. Despite extensive research efforts, currently approved therapies provide only limited symptomatic benefit and do not halt disease progression. A major obstacle to effective treatment is the blood-brain barrier (BBB), which severely restricts the brain delivery of most therapeutic agents. Nanoparticle-based drug delivery systems have emerged as a promising strategy to overcome BBB-related limitations by enabling precise control over physicochemical properties such as size, surface characteristics, and material composition. These properties can improve drug solubility, stability, pharmacokinetics, and targeted brain accumulation while reducing systemic toxicity. However, efficient BBB penetration and clinically feasible translation remain major challenges. This review summarizes key design principles for nanoparticles intended for AD therapy and highlights representative platforms with translational considerations, particularly lipid-based and polymer-based nanoparticles. In addition, alternative delivery strategies-including nose-to-brain nanoparticle systems and nanoparticles exploiting receptor-mediated and adsorptive-mediated transcytosis, as well as synaptic dysfunction targeting-are discussed. Collectively, this review outlines current advances and future directions for nanoparticle-mediated therapeutic delivery in AD.}, } @article {pmid42222852, year = {2026}, author = {Kale, D and Ramachandran, I and Lakshmi, S and Elumalai, P}, title = {In-vivo evaluation of neuroprotective effect of methanolic extract of Turbinaria ornatacombined with AKG against aluminium chloride-induced Alzheimer's in Wistar rats.}, journal = {3 Biotech}, volume = {16}, number = {6}, pages = {240}, pmid = {42222852}, issn = {2190-572X}, abstract = {UNLABELLED: The progressive neurodegenerative disease known as Alzheimer's disease (AD) is typified by behavioral abnormalities and cognitive deterioration. In the current investigation, the preventive potential of a combination formulation of alkyl glycerol (AKG) and Turbinaria ornata methanolic extract against aluminum chloride (AlCl3)-induced neurotoxicity in Wistar rats was examined. Groups 1 (control), 2 (AlCl3, 100 mg/kg), 3 and 4 (AlCl3 + T. ornata methanolic extract at low and high doses, respectively), and 5 and 6 (AlCl3 + T. ornata methanolic extract + AKG at low and high dosages, respectively) were the six groups that were part of the experimental design. Compared with the AlCl3-treated group, animals receiving the combined treatment, particularly Group 6, showed a significant restoration of antioxidant enzyme activities, including superoxide dismutase (SOD), catalase (CAT), and reduced glutathione (GSH), along with a significant reduction in the lipid peroxidation marker malondialdehyde (MDA) in brain and liver tissues. Exposure to AlCl3 caused learning and memory deficits and markedly hampered spontaneous locomotor and exploratory behavior; these effects were mitigated with combination therapy. Additionally, both the cortex and the hippocampus showed changed expression of important genes involved in the amyloid precursor protein (APP) processing pathway, according to qRT-PCR study. The combined treatment groups demonstrated significant modulation of APP pathway-related gene expression relative to the AlCl3 group, indicating an association between the observed biochemical and behavioral improvements and molecular changes in this experimental model. Overall, the results imply that AlCl3-induced neurobehavioral, biochemical, and molecular changes may be lessened by administering T. ornata methanolic extract and AKG together. To identify the independent or synergistic impacts of each component, more research including individual treatment groups is necessary, as the study is restricted to assessing the effects of the combination treatment.

SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s13205-026-04872-2.}, } @article {pmid42223785, year = {2026}, author = {Özkurt, Ç and Köse, S and Karasu, Ç and Kortholt, A and Kelicen-Uğur, P}, title = {Taliglucerase Alfa Reduces Amyloid-β Burden by Restoring Autophagic Pathways in a Neuronal Model of Alzheimer's Disease.}, journal = {Neurochemical research}, volume = {51}, number = {3}, pages = {}, pmid = {42223785}, issn = {1573-6903}, mesh = {Animals ; *Autophagy/drug effects/physiology ; *Amyloid beta-Peptides/metabolism ; *Alzheimer Disease/metabolism/drug therapy/pathology ; *Glucosylceramidase/pharmacology/therapeutic use ; Mice ; *Neurons/drug effects/metabolism ; Humans ; Hippocampus/drug effects/metabolism ; Peptide Fragments ; Cell Line ; Lysosomes/metabolism/drug effects ; Signal Transduction/drug effects ; Recombinant Proteins/pharmacology ; }, abstract = {Intraneuronal amyloid-beta (Aβ) accumulation and autophagic dysfunction are key pathological features of Alzheimer's disease (AD). Mutations in GBA1, which encodes the lysosomal enzyme β-glucocerebrosidase (GCase), are linked to several neurodegenerative disorders, but the role of GCase in AD remains incompletely understood. In this exploratory, proof-of-concept study, we investigated whether taliglucerase alfa (TAL), a recombinant human GCase, may influence intracellular Aβ accumulation by modulating autophagy pathways in a neuronal AD model. Endogenous Aβ accumulation was induced in mouse hippocampal neuronal cells (HT-22) by exposure to low-molecular-weight Aβ1-42 oligomer-enriched assemblies (oAβ1-42), followed by treatment with TAL. Soluble Aβ levels and selected components of the autophagy-lysosome pathway, including GCase, cathepsin B, p62/sequestosome-1 (p62/SQSTM1), and mammalian target of rapamycin (mTOR), were evaluated using Western blotting, ELISA, and RT-PCR. In this in vitro model, TAL treatment was associated with a reduction in intracellular monomeric Aβ levels. This observation was accompanied by changes in mTOR signaling and p62 levels, suggestive of modulation of autophagy-related processes. Overall, these results provide preliminary, hypothesis-generating evidence supporting a potential association between lysosomal GCase augmentation and Aβ-related and autophagy-associated processes in AD. Further studies, including expanded experimental validation and in vivo investigations, are required to clarify the underlying mechanisms and translational relevance.}, } @article {pmid42226198, year = {2026}, author = {Lee, HJ and Hoe, HS}, title = {The CDK4/6 inhibitor abemaciclib attenuates cognitive impairment and neuroinflammation via DYRK1A in human tau transgenic mice.}, journal = {Molecular brain}, volume = {}, number = {}, pages = {}, doi = {10.1186/s13041-026-01318-x}, pmid = {42226198}, issn = {1756-6606}, support = {RS-2024-00357857//National Research Foundation of Korea/ ; 26-BR-02-04, 26-BR-05-01, and 26-BR-06-01//KBRI funded by the Ministry of Science, ICT & Future Planning/ ; RS-2024-00343370//Korea Dementia Research Project through the Korea Dementia Research Center (KDRC)/ ; H0501-25-1001//NIPA (National IT Industry Promotion Agency) to support digital medical devices for AI-based Neurodevelopmental disorders/ ; RS-2026-25492172//NRF/ ; }, abstract = {We recently demonstrated that abemaciclib treatment modulates cognitive function, Alzheimer's disease (AD) pathology, and neuroinflammatory responses in wild-type mice treated with lipopolysaccharide and in 5xFAD mice. In this study, we investigated the influence of abemaciclib treatment on neuroinflammation and cognitive function in 6- or 9-month-old PS19 mice, a P301S mutant tauopathy model. We found that abemaciclib administration suppressed microglial activation in 6-month-old PS19 mice, whereas astrocytic activation was partially attenuated in the entorhinal cortex but not in the hippocampus. In addition, abemaciclib treatment improved short-term and recognition memory and the dendritic spine formation in 6- and 9-month-old PS19 mice. More importantly, abemaciclib administration enhanced short-term and recognition memory in a DYRK1A-dependent manner in 6-month-old PS19 mice. Collectively, our results suggest that abemaciclib treatment alleviates neuroinflammatory responses and cognitive impairment through DYRK1A in 6- or 9-month-old human tau transgenic PS19 mice, highlighting how this multi-kinase-targeting drug could be leveraged for the treatment of neurodegenerative diseases.}, } @article {pmid42227120, year = {2026}, author = {Gillet, JN}, title = {Overinvestment in ultra‑rare APOE variants and highly speculative apoE-inhibitor docking risks undermining translational progress in sporadic Alzheimer's disease.}, journal = {Journal of biomolecular structure & dynamics}, volume = {}, number = {}, pages = {1-9}, doi = {10.1080/07391102.2026.2671163}, pmid = {42227120}, issn = {1538-0254}, abstract = {Misclassification of ultra-rare and isoform-defining APOE variants, together with unsupported attempts to dock small-molecule 'inhibitors' to apolipoprotein E (apoE), continues to appear in the structural bioinformatics literature. Such inconsistencies stem from a broader misunderstanding of apoE as a highly flexible, two-domain protein with extensive intrinsically disordered regions (IDRs), a context essential for interpreting sequence variation. A recurring issue is the treatment of the pathogenic ε4 and protective ε2 substitutions as independent rare variants rather than as the canonical APOE isoform-defining polymorphism, a misinterpretation arising, for instance, from inconsistent minor-allele-frequency filtering and leading to overinterpretation of ultra-rare substitutions lacking established clinical relevance. Likewise, no experimental evidence supports stable interactions between apoE and small 'inhibitors' such as donepezil or other acetylcholinesterase drugs that provide only symptomatic benefit in Alzheimer's disease (AD). Docking such small ligands to apoE-frequently using incompatible homology models and outdated molecular-dynamics force fields ill-suited for proteins with large IDRs (e.g. AMBERff03)-tends to generate simulation-artifact cavities and non-biological ligand poses; compounding this, ligand protonation is frequently misassigned, such as the neutral state often attributed to donepezil, leading to meaningless structure-activity relationships. Collectively, these issues risk obscuring the well-established genetic architecture of APOE-associated AD and highlight the need for methodological rigor in in-silico structural modeling.}, } @article {pmid42227129, year = {2026}, author = {Andreev, AI and Neganova, ME and Aleksandrova, YR and Salikhova, DI and Belousova, EV and Shedenkova, MO and Sudina, AK and Maksimov, YM and Orlova, EA and Lapshina, MA and Popov, VS and Ahremenko, EA and Goldshtein, DV and Ustyugov, AA and Nebogatikov, VO}, title = {[Glial Progenitor Cell Therapy Improves Mitochondrial Function in the Hippocampus of 5xFAD Mice, but Does Not Restore the Multiscale Structure of Behavioral Stress Response].}, journal = {Molekuliarnaia biologiia}, volume = {60}, number = {2}, pages = {328-344}, doi = {10.7868/S3034555326020096}, pmid = {42227129}, issn = {0026-8984}, mesh = {Animals ; *Mitochondria/metabolism/pathology ; Mice, Transgenic ; *Alzheimer Disease/therapy/metabolism/genetics/pathology/physiopathology ; Mice ; *Hippocampus/metabolism/pathology/physiopathology ; Disease Models, Animal ; *Neuroglia/metabolism/transplantation/cytology ; Behavior, Animal ; *Stem Cell Transplantation ; Humans ; Amyloid beta-Protein Precursor/genetics ; }, abstract = {Cell therapy is increasingly used to treat a variety of medical conditions, including cancer, immune system disorders, and neurodegeneration. Stem cells secrete growth factors, signaling molecules, and extracellular vesicles, that can be used to treat neurological diseases and promote neuronal regeneration. Transgenic 5xFAD mice, which are a model for Alzheimer's disease (AD), were used in this study. The mice were 7 months old and received retro-orbital injections of glial progenitor cells (GPCs) once a week for 4 months. At 11 months, their behavior was analyzed using a multichannel actigraphy system. Brain tissues from the cortex, hippocampus, and midbrain were collected for postmortem analysis of mitochondrial respiratory chain enzyme activity. The results showed that the GPCs injection significantly improved the response of the hippocampal p2 mitochondrial fraction in 5xFAD mice to succinate, reaching a level observed in control animals. A similar trend was also observed for the cytochrome c oxidase complex. The oxygen consumption rate of mitochondria did not differ from that of clinically healthy mice after ascorbate/N,N,N',N'-tetramethyl-p-phenylenediamine dihydrochloride administration. A similar decrease in the efficiency of the electron transport chain was detected in the midbrain of 5xFAD mice, but no recovery was observed after GPCs treatment. Behavioral differences between non-transgenic and transgenic groups were observed in a multiparameter analysis using the actigraphy system. The behavior of transgenic mice in the treated and untreated groups was similar, while the behavior of non-transgenic mice varied. Additional analysis of locomotor activity and transient events in particular revealed that the activity of the GPCs-treated 5xFAD mice was differed fundamentally compared to other groups. Specifically, GPCs-treated mice exhibited greater number of transitions between intermediate activity states. In contrast, untreated mice showed transitions between extreme activity states, such as from low to high activity or vice versa. These findings suggest that changes in behavior and activity of the AD mice may be associated not only with hippocampal dysfunction, but also with disruptions in midbrain structures.}, } @article {pmid42227398, year = {2026}, author = {Wu, X and Zhang, K and Kan, C and Sheng, S and Jing, D and Han, F and Sun, X}, title = {Transmembrane Proteins in Neurodegeneration: Pathophysiology from Alzheimer's to Parkinson's Disease.}, journal = {Current neuropharmacology}, volume = {}, number = {}, pages = {}, doi = {10.2174/011570159X451846260403084025}, pmid = {42227398}, issn = {1875-6190}, abstract = {Neurodegenerative diseases, including Alzheimer's Disease (AD) and Parkinson's Disease (PD), represent a growing global health burden due to aging populations. These disorders are characterized by progressive neuronal dysfunction, protein aggregation, synaptic impairment, and neuronal loss. Transmembrane proteins, which regulate signal transduction, material transport, and cell communication, have emerged as key contributors to disease pathogenesis. In AD, amyloid precursor protein processing, N-methyl-D-aspartate receptor overactivation, and microglial receptor signaling drive β-amyloid accumulation, excitotoxicity, and neuroinflammation. In PD, α-synuclein aggregation, dopamine receptor dysregulation, mitochondrial dysfunction, and impaired iron homeostasis disrupt neuronal and synaptic integrity. Despite differences in clinical manifestations, both AD and PD share common mechanisms involving abnormal protein folding, altered calcium signaling, and oxidative and endoplasmic reticulum stress, largely mediated by transmembrane proteins. These shared pathways highlight the interconnected nature of these devastating conditions. These proteins also provide opportunities for therapeutic targeting and biomarker development. Current strategies include secretase inhibitors, N-methyl-D-aspartate receptor modulators, dopamine agonists, and emerging approaches targeting α-synuclein and other misfolded proteins. While challenges remain in achieving selectivity, delivery, and clinical efficacy, advances in molecular biology underscore the potential of transmembrane proteins as critical targets for diagnosis and treatment. Ongoing research continues to unravel their complex roles, and future studies will further elucidate their precise involvement in disease progression, offering hope for new interventions. This comprehensive review summarizes current knowledge on the structural and functional roles of transmembrane proteins in AD and PD, their contributions to shared pathological mechanisms, and their potential as biomarkers and therapeutic targets.}, } @article {pmid42227403, year = {2026}, author = {Yang, Z and Hou, X and Tan, Y and Tang, L and Ke, Z and Hu, Z and Ye, Q and Meng, H and Xu, Y and Chen, H}, title = {Neuro-navigated rTMS Targeting Left Angular Gyrus Promotes White-Gray Matter Remodelling to Improve Cognitive Function in Amnestic Mild Cognitive Impairment Patients: Evidence for Early Alzheimer.s Intervention.}, journal = {Current neuropharmacology}, volume = {}, number = {}, pages = {}, doi = {10.2174/011570159X438627260121063828}, pmid = {42227403}, issn = {1875-6190}, abstract = {INTRODUCTION: Repetitive Transcranial Magnetic Stimulation (rTMS), a non-invasive neuromodulation technique, has been increasingly applied in early intervention for amnestic Mild Cognitive Impairment (aMCI). However, the mechanism of changes in brain structure after rTMS treatment remains unclear.

METHODS: A total of 54 aMCI patients received neuro-navigation rTMS targeting the left angular gyrus for 4 weeks (rTMS group: n=28; sham group: n=26). All participants received multimodal MRI and cognitive assessments before and after rTMS. A white matter network was constructed, and Local Diffusion Homogeneity (LDH) was calculated to analyse white matter differences. Surface-based morphometry was used to detect cortical changes. In addition, the correlation between these structural alterations and improved cognitive function was analysed.

RESULTS: After rTMS, general cognitive function and episodic memory of aMCI patients significantly improved. Assortativity improved (P=0.039) while hierarchy decreased (P=0.036). Lower LDH was detected in the right hippocampus cingulum fasciculus, left inferior longitudinal fasciculus, right inferior/superior cerebellar peduncle, and right cingulum gyrus. The sulcus depth of the left medial orbitofrontal cortex, left superior frontal/parietal cortex, left middle/inferior temporal cortex, and right lateral occipital cortex was decreased. Improved general cognition was negatively correlated with decreased sulcus depth in left inferior temporal cortex (R=-0.585, P=0.001) and left superior parietal cortex (R=-0.447, P=0.017). Improved memory was negatively correlated with altered LDH in the right inferior cerebellar peduncle (R=-0.427, P=0.037).

DISCUSSION: Our study shows that neuro-navigated rTMS targeting the left angular gyrus can improve cognitive function and mood symptoms in aMCI patients by impacting brain structures, offering new biological evidence for its potential as an early AD intervention.

CONCLUSION: Neuro-navigated rTMS targeting the left angular gyrus improves aMCI cognition, linked to specific brain structural changes, supporting its early intervention value.}, } @article {pmid42227483, year = {2026}, author = {Shankar, M and Tiwari, P and Dubey, S}, title = {Phosphodiesterase-5 Inhibitors in Neurodegenerative Diseases: A Path to Cognitive Rescue.}, journal = {Current protein & peptide science}, volume = {}, number = {}, pages = {}, doi = {10.2174/0113892037397181251204145349}, pmid = {42227483}, issn = {1875-5550}, abstract = {Phosphodiesterase type 5 inhibitors (PDE5-Is) have emerged as potential therapeutic agents for neurodegenerative diseases, including Alzheimer's disease (AD), Parkinson's disease (PD), and multiple sclerosis (MS). Originally developed for cardiovascular disorders, PDE5-Is have gained significant attention for their neuroprotective effects due to their ability to modulate intracellular signaling pathways. These inhibitors exert their effects by increasing nitric oxide synthase expression, elevating cyclic guanosine monophosphate (cGMP) levels, and activating protein kinase G (PKG), leading to improved synaptic plasticity, neuronal survival, and cognitive enhancement. By targeting these molecular pathways, PDE5-Is help regulate neuroinflammation, oxidative stress, mitochondrial dysfunction, and neuronal apoptosis, which are key pathological features of neurodegenerative disorders. Several preclinical studies have demonstrated that PDE5-Is can reduce neuroinflammation, enhance neurogenesis, and improve mental performance in animal models of AD, PD, and MS. Additionally, these agents have shown promise in mitigating β-amyloid and tau pathology in AD, improving dopamine signalling in PD, and exerting immunomodulatory effects in MS. Furthermore, emerging research suggests that PDE5-Is may protect against neuronal cell death and improve cognitive function following cerebral ischemia by enhancing cerebral blood flow, reducing excitotoxicity, and promoting neurovascular coupling. Despite these promising findings, the clinical translation of PDE5-Is for neurodegenerative diseases remains in its early stages. Challenges, such as blood-brain barrier permeability, optimal dosing strategies, and long-term safety, must be addressed through further research. Nevertheless, given their multifaceted mechanisms of action, PDE5-Is represent a novel and exciting therapeutic approach that warrants deeper investigation in both preclinical and clinical settings for the treatment of neurodegenerative diseases.}, } @article {pmid42227779, year = {2026}, author = {Sharma, DK and Prasad, CS}, title = {Chitosan-based nanocarriers in Alzheimer's disease therapy: recent developments and future perspectives.}, journal = {Journal of drug targeting}, volume = {}, number = {}, pages = {1-18}, doi = {10.1080/1061186X.2026.2683967}, pmid = {42227779}, issn = {1029-2330}, abstract = {Alzheimer's disease (AD) is a neurological condition that worsens with time and causes behavioural problems, memory loss, and cognitive decline. It is a major global health concern. Alzheimer's complexity and the blood-brain barrier (BBB) limit effective disease-modifying treatments despite extensive research. The primary goal of conventional pharmacotherapies is to relieve symptoms; however, they frequently have low absorption, a short half-life, and peripheral adverse effects. The use of anti-Alzheimer medications in nanoparticles (NPs) is a potential remedy for these issues. Although many NPs are biocompatible and non-toxic, many are not biodegradable, making them unsuitable for CNS targeting. Chitosan (CS)-based NPs stand out among polymeric nanocarriers as stable, biodegradable delivery systems for central nervous system drugs. In this review, we examine the design, mechanisms of BBB penetration, drug-loading capacity, controlled-release behaviour, and therapeutic efficacy of CS-based delivery platforms, including nanoparticles, nanogels, lipid nanoparticles, polymeric micelles, nanoemulsions, and acetylcholinesterase inhibitor-loaded systems. Furthermore, the benefits of CS-based systems, including improved brain bioavailability, reduced toxicity, intranasal delivery, and support for multifunctional and stimuli-responsive therapeutics, are highlighted. All things considered, chitosan-based drug delivery systems offer a flexible and promising strategy for enhancing AD treatment results.}, } @article {pmid42228338, year = {2026}, author = {Chaudhary, B and Kumari, S and Sharma, P and Dhapola, R and Paidlewar, M and Vellingiri, B and Medhi, B and HariKrishnaReddy, D}, title = {Decoding neuroinflammation: the critical role of NLRP3 inflammasome in Alzheimer's disease.}, journal = {Inflammopharmacology}, volume = {}, number = {}, pages = {}, pmid = {42228338}, issn = {1568-5608}, abstract = {The hallmarks of Alzheimer's disease (AD), a progressive neurodegenerative disease, include tau tangles, amyloid-β (Aβ) plaques, cognitive impairment, and severe neuroinflammation. A key molecular mediator linking immunological activation and neurological pathology in AD is the NLRP3 inflammasome. This review explains the intricate role of the NLRP3 inflammasome in AD, including its structure, activation mechanisms, and regulatory signaling pathways. The pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs) that activate NLRP3 include oxidative stress, Aβ, mitochondrial dysfunction, ion fluxes, gut dysbiosis, and mitochondrial malfunction. Pro-inflammatory cytokines IL-1β and IL-18 are released when the inflammasome assembles with ASC and procaspase-1, leading to caspase-1 activation and pyroptosis. The article investigates both canonical and noncanonical pyroptosis pathways and provides detailed insights into how glial cells-specifically microglia and astrocytes-are involved in NLRP3-mediated neuroinflammation. It has been demonstrated that NLRP3 activation is modulated by several receptor-mediated signaling pathways, including NF-κB, TLR4, TREM2, purinergic, and MAP4K6, which intensify inflammatory responses in the AD brain. Furthermore, the review assesses preclinical and clinical research targeting NLRP3 and its upstream regulators, emphasizing potential treatment options as Simufilam, MCC950, OLT1177, and CY-09. This work highlights the therapeutic potential of the inflammasome and promotes the development of targeted anti-inflammatory treatments to ameliorate AD pathology by elucidating the molecular mechanisms linking NLRP3 to AD progression.}, } @article {pmid42229579, year = {2026}, author = {Wang, D and Fan, J and Wang, T and Tang, F and Yao, Q and Ye, X and Qi, X and Tian, M and Lin, X and Shi, J}, title = {Cerebellar rTMS ameliorates cognitive impairment in Alzheimer's disease: A randomized trial.}, journal = {Brain stimulation}, volume = {19}, number = {4}, pages = {103138}, doi = {10.1016/j.brs.2026.103138}, pmid = {42229579}, issn = {1876-4754}, abstract = {BACKGROUND: Developing effective neuromodulatory therapies for Alzheimer's disease (AD) is a critical unmet need. While repetitive transcranial magnetic stimulation (rTMS) shows promise, its optimal targets and mechanisms remain incompletely understood. The cerebellum, a key modulator of large-scale brain network dynamics, represents a novel therapeutic target for addressing the distributed cognitive network dysfunction in AD.

OBJECTIVE: This study aimed to evaluate the cognitive efficacy and safety of cerebellar rTMS in AD and to elucidate its potential mechanism of action through the lens of structural network topology.

METHODS: In this randomized, double-blind, sham-controlled trial, patients with AD were assigned to receive active or sham rTMS targeting the bilateral cerebellar Crus II region. Cognitive assessments were conducted at baseline, post-treatment (4 weeks), and at a 12-week follow-up. Diffusion tensor imaging (DTI) was employed to analyze changes in whole-brain structural network topology.

RESULTS: Compared to the sham group, the active rTMS group demonstrated significantly greater improvement in global and domain-specific cognitive function at 4 weeks, with benefits sustained at the 12-week follow-up. Response rates on the MMSE and MoCA were also significantly higher in the active group. Neuroimaging revealed that active rTMS enhanced global network efficiency, indicated by significant increases in global/local efficiency and clustering coefficient, alongside a decreased characteristic path length, signifying an optimization toward small-world topology. Furthermore, treatment selectively enhanced nodal efficiency within core hubs of the default mode, frontoparietal, and salience networks. Critically, these structural improvements correlated with cognitive gains; increased nodal efficiency in the precuneus and posterior cingulate cortex was associated with improved episodic memory and visuospatial function.

CONCLUSION: Cerebellar rTMS is a safe and effective intervention that confers sustained cognitive benefits in AD. Its therapeutic mechanism likely involves the reinforcement of structural connectivity and enhanced integrative capacity within supraordinate cognitive networks, particularly the default mode network, via cerebello-cortical pathways.}, } @article {pmid42229590, year = {2026}, author = {Reddy-Mazzitello, RM and Alexander, J and Skawratananond, S and Sehar, U and Mukherjee, U and Brownell, M and Ballada, S and Reddy, PH}, title = {Associations between posttraumatic stress and comorbidities of traumatic brain injury and substance use disorders with Alzheimer's disease in older veterans: A narrative review.}, journal = {Ageing research reviews}, volume = {120}, number = {}, pages = {103188}, doi = {10.1016/j.arr.2026.103188}, pmid = {42229590}, issn = {1872-9649}, abstract = {Posttraumatic stress disorder (PTSD) exhibits high rates of comorbidity with Substance Use Disorders (SUDs) and Traumatic Brain Injury (TBI), especially in older adults who are subject to the effects of psychological trauma due to combat exposure, health-related and psychosocial outcomes, and aging. This narrative review explores the associations between PTSD and comorbidities of psychoactive substance abuse and traumatic brain injuries on the incidence of Alzheimer's disease (AD) in veterans aged 55 > , according to existing literature. The account of genetic predisposition in reference to the presence of the Apolipoprotein e4 gene was also considered. Biomarkers of AD, including beta-amyloid and phosphorylated tau levels in cerebrospinal fluids (CSF), were analyzed in PTSD, TBI and SUD conditions. This review was conducted as a narrative summary utilizing three separate search engines. Inclusion of data was primarily determined by a single reviewer with a randomized 10 % of 49 selected studies cross screened by a second reviewer. Two additional independent reviewers incrementally cross-checked the 49 included studies at full-text stages for accuracy and consistency. The literature review found that PTSD and comorbidities of TBI and SUD may share increased incidence of AD and related dementia, however, a causal relationship cannot be implied. Conflicting results on CSF biomarker trends for each comorbidity and complications arising from genetic predispositions indicate a need for future studies to clarify the relationship between PTSD comorbidities on the onset of AD. Expanded biomarker analysis has not yet been assessed. Implications of this review may lead to alternative treatment and care methods for older adults/veterans suffering from psychological impairment to prevent the formation of comorbidities and lower existing elevated risks for AD onset and progression.}, } @article {pmid42229733, year = {2026}, author = {Kumari, N and Kumari, S and Sharma, P and Dhapola, R and Paidlewar, M and HariKrishnaReddy, D}, title = {From capillaries to cognition: decoding neurovascular unit dysfunction and cerebrovascular contributions in Alzheimer's disease.}, journal = {Biochemical pharmacology}, volume = {251}, number = {Pt 1}, pages = {118107}, doi = {10.1016/j.bcp.2026.118107}, pmid = {42229733}, issn = {1873-2968}, abstract = {Alzheimer's disease (AD), classically defined by abnormal amyloid-β and tau aggregation, is now also understood to profoundly disturb the brain's cerebrovascular system and the integrity of the neurovascular unit (NVU). An ever-growing body of evidence points to NVU dysfunction and neurovascular unit deficits as major contributors to AD pathology. NVU comprises neurons, glial cells, endothelial cells, and pericytes, which together orchestrate cerebral blood flow in the CNS and help maintain the structural and functional integrity of the blood-brain barrier (BBB). Its disruption increases neuronal damage and impairs clearance mechanisms in AD. Interactions between pericytes, astrocytes, smooth muscle cells, neurons, microglia, and NVU endothelial cells support cerebral perfusion, BBB integrity, and metabolic homeostasis. Major pathophysiological events involved in the development of early BBB leakage and neurovascular uncoupling in AD include endothelial impairment, breakdown of tight junctions, thickening of the basement membrane, degeneration of pericytes, and astrogliosis. Activated astrocytes and microglia further exacerbate NVU injury by releasing inflammatory mediators and ROS. Numerous molecular signaling cascades, including PI3K/Akt/mTOR, MAPK/ERK, and NF-κB pathways, are implicated in mechanistic interplay among metabolic perturbations, neuroinflammatory responses, and vascular endothelial damage. Emerging NVU-targeted therapeutic strategies include anti-inflammatory, antioxidant, and vasculoprotective drugs intended to restore BBB integrity, preserving neurovascular coupling, and promoting the removal of amyloid-β. This review synthesizes preclinical and clinical evidence elucidating mechanisms by which capillary-level perturbations lead to cognitive decline, while discussing therapeutic interventions aimed at restoring NVU integrity and preserving BBB architecture. The delineation of cerebral involvement in AD provides support for a potential for timely diagnosis and innovative approaches for treatment.}, } @article {pmid42229832, year = {2026}, author = {Singh, VB and Gupta, S and Sella, RN}, title = {Engineered EV-mediated delivery of an anti-amyloid peptide provides neuroprotection in an in vitro Alzheimer's disease model.}, journal = {International journal of pharmaceutics}, volume = {700}, number = {}, pages = {127043}, doi = {10.1016/j.ijpharm.2026.127043}, pmid = {42229832}, issn = {1873-3476}, mesh = {Animals ; *Alzheimer Disease/drug therapy/metabolism ; *Amyloid beta-Peptides/metabolism ; *Neuroprotective Agents/administration & dosage/pharmacology/chemistry ; PC12 Cells ; Mice ; Rats ; NIH 3T3 Cells ; *Extracellular Vesicles/metabolism ; Cell Survival/drug effects ; Drug Delivery Systems ; Reactive Oxygen Species/metabolism ; *Peptide Fragments ; Neurons/drug effects/metabolism ; }, abstract = {Alzheimer's disease is driven in part by amyloid-β (Aβ) aggregation, oxidative stress, and progressive neuronal dysfunction. Despite various attempts, therapeutic translation remains limited by inefficient delivery of bioactive molecules to neuronal cells. This study presents a surface-engineered extracellular vesicle (EV) platform designed for targeted peptide delivery, assessing its neuroprotective efficacy in an in vitro model of Alzheimer's disease. EVs were obtained from NIH/3T3 cells expressing Lamp2b-RVG and were surface-modified with the β-sheet breaker peptide H102 through CP05-CD63 affinity binding. ATR-FTIR, SERS Raman spectroscopy, high-resolution transmission electron microscopy, nanoparticle tracking analysis, zeta potential measurements, and EV marker profiling demonstrated successful peptide conjugation and vesicle integrity. Aggregated Aβ25-35 was utilized to assess neuronal toxicity in NGF-differentiated PC-12 cells. Peptide-modified EV demonstrated effective, time-dependent cellular uptake and significantly improved cell viability while decreasing membrane damage and intracellular reactive oxygen species levels in comparison to Aβ-treated controls. Treatment with Peptide-modified EV normalized the expression of key genes associated with Alzheimer's, such as APP, Bax, Sirt1, and Stat1, suggesting a coordinated modulation of amyloidogenic, apoptotic, oxidative, and inflammatory pathways. The results indicate that surface-engineered EVs facilitate efficient neuronal delivery of therapeutic peptides and offer multi-level cytoprotection against Aβ-induced neurotoxicity. This study emphasizes the capability of peptide-decorated EV as a multifunctional nanocarrier system for the treatment of Alzheimer's disease.}, } @article {pmid42230432, year = {2026}, author = {Liao, Y and Ye, S and Zhao, L and Zhou, M and Wen, Y and Zhu, Y and Huang, J and Zhang, L and Zhang, X and Guo, P and Xie, Y}, title = {Gain-of-function Modulation of TREM2 and its Impact on Amyloid-β and Tau Pathologies in Alzheimer's Disease: A Systematic Review and Meta-analysis of Animal Studies.}, journal = {Molecular neurobiology}, volume = {63}, number = {1}, pages = {}, pmid = {42230432}, issn = {1559-1182}, mesh = {Animals ; *Alzheimer Disease/metabolism/pathology ; *Amyloid beta-Peptides/metabolism ; *tau Proteins/metabolism ; *Receptors, Immunologic/metabolism ; *Membrane Glycoproteins/metabolism ; Humans ; Disease Models, Animal ; }, abstract = {Alzheimer's disease (AD) is characterized by amyloid-β (Aβ) deposition, hyperphosphorylated Tau accumulation, and chronic neuroinflammation, with microglial function playing a crucial role in modulating these pathological cascades. The microglial receptor TREM2 has emerged as a key regulator of microglial responses to AD-related pathology, and gain-of-function strategies targeting TREM2 have shown substantial therapeutic potential in preclinical models. However, outcomes of these strategies on Aβ and Tau pathologies have exhibited marked heterogeneity across studies, and no systematic integration of the relevant evidence so far. This deficiency has substantially hindered the rational development and clinical translation of TREM2-targeted therapeutic strategies. The objective of this study is to evaluate the effects of TREM2-targeted interventions on Aβ and Tau pathologies in AD animal models. A systematic search of PubMed, Embase, and Cochrane Library identified studies using AD animal models with TREM2-targeted interventions and reporting Aβ or Tau outcomes. This review was registered in PROSPERO (CRD420251131147). A total of 12 studies were included, with overall moderate risk of bias, mainly due to inadequate randomization and blinding. In APP/PS1 mice, TREM2 overexpression significantly reduced Aβ plaque number (SMD = - 0.87; 95% CI, - 1.28 to - 0.47) and plaque area (SMD = - 0.98; 95% CI, - 1.46 to - 0.50), with more pronounced effects observed in younger mice (≤ 7 months), where reductions in insoluble Aβ42 were also observed; phosphorylated Tau levels decreased as well. TREM2 agonist antibodies also reduced Aβ plaque number (SMD = - 2.03; 95% CI, - 2.83 to - 1.24). However, effects on Aβ plaque area, insoluble and soluble Aβ isoforms levels were inconsistent. Antibody treatment also attenuated Tau pathology and Aβ pathology in certain models, including 5XFAD mice or Tau transgenic mice. In addition, both TREM2 overexpression and agonist antibodies could reverse the cognitive impairment of AD animal models. This systematic review and meta-analysis provides the first comprehensive synthesis of preclinical evidence supporting TREM2 gain-of-function modulation as an AD therapeutic strategy targeting both Aβ and Tau pathologies. Our findings reveal that therapeutic efficacy is governed by disease stage, model pathological complexity, and intervention mode. These insights highlight the need for developing stage-specific and pathology-stratified strategies in translational research, establishing TREM2 as a condition-dependent yet promising immunotherapeutic target for AD.}, } @article {pmid42230965, year = {2026}, author = {Jörg, M and Walz, L and Nathal, S and Kristen, M and Lietz, C and Müller, M and Nguyen, VTT and Ruffini, N and Winz, ML and Gerber, S and Endres, K and Helm, M and Friedland, K}, title = {Sex-specific regulation of angiogenin in Alzheimer's disease.}, journal = {Molecular psychiatry}, volume = {}, number = {}, pages = {}, pmid = {42230965}, issn = {1476-5578}, support = {TRR319 RMaP (Project Id 439669440) TPB05//Deutsche Forschungsgemeinschaft (German Research Foundation)/ ; TRR319 RMaP (Project Id 439669440) TP A05//Deutsche Forschungsgemeinschaft (German Research Foundation)/ ; }, abstract = {Alzheimer's disease (AD) is a heterogeneous neurodegenerative disorder, highlighting the need to identify novel molecular regulators for effective treatment development. Angiogenin (ANG), a stress-responsive ribonuclease that inhibits apoptosis by generating 5'-tRNA fragments, is a candidate whose expression and regulation in AD is not understood. Here, we investigated ANG expression and regulation using AD cell and animal models, postmortem human brain tissue, and transcriptomic datasets (n = 645). We found that ANG is dysregulated in AD in a sex-dependent manner, altering downstream levels of 5'-tiRNA[Gly-GCC]. Our analysis revealed female-specific molecular subtypes, absent in males: Subtype 1 featured low ANG levels with increased inflammation and neuronal death; subtype 2 exhibited higher ANG expression and intermediate pathology; subtype 3, marked by the highest ANG levels, showed reduced inflammation, slower cognitive decline, and extended survival. These findings position ANG as a key modulator of neuroinflammation and apoptosis in AD, highlighting its potential as a treatment strategy.}, } @article {pmid42231842, year = {2026}, author = {Wiechmann, D and Günes, A and Kerz, E and Qiao, Y and Köhne, M and Sprick, U}, title = {Connected-speech digital biomarkers for monitoring transcranial pulse stimulation in Alzheimer's disease: A pilot study.}, journal = {Journal of Alzheimer's disease : JAD}, volume = {}, number = {}, pages = {13872877261456294}, doi = {10.1177/13872877261456294}, pmid = {42231842}, issn = {1875-8908}, abstract = {BackgroundAlzheimer's disease (AD) lacks effective disease-modifying therapies and scalable, ecologically valid biomarkers to monitor treatment response. Transcranial pulse stimulation (TPS) is an emerging non-invasive neuromodulation technique with potential to attenuate cognitive decline. Sensitive digital endpoints are needed to quantify intervention-related changes.ObjectiveTo develop and validate connected-speech-derived digital biomarkers as a longitudinal framework for monitoring TPS treatment response in AD.MethodsIn this open-label, single-arm pilot study, 32 patients with AD were compared to cognitively healthy controls. A three-stage framework was implemented: (1) machine-learning classification using linguistic features to derive a parsimonious biomarker panel; (2) construction of a Speech Composite Index (SCI) calibrated against the CERAD total score (CTS); and (3) longitudinal SCI tracking in a sub-cohort receiving TPS.ResultsThe classifier discriminated AD from controls with an AUROC of 0.879 and an F1-score of 0.825. The SCI showed strong convergent validity with global cognition (CTS: r = 0.76, p < 0.001; MMSE: r = 0.76, p < 0.001) and executive function (Stroop interference: r = -0.51, p = 0.015). Longitudinal modeling demonstrated a significant positive deviation from a CERAD-based progression reference (β_time = 0.057 z-units/month, p = 0.013), indicating relative stabilization of speech performance. Individual trajectories were heterogeneous (range -0.053 to +0.336) without significant demographic associations.ConclusionsConnected-speech-derived digital biomarkers can serve as scalable longitudinal endpoints for neuromodulatory interventions in AD. The SCI captures treatment-related dynamics and may support response stratification. Further validation in larger, sham-controlled multicenter studies is needed to establish clinical utility and specificity to TPS.}, } @article {pmid42231857, year = {2026}, author = {Rashidi-Ranjbar, N and Churchill, NW and Jerkic, M and Zomorrodi, R and Rotstein, O and Schneider, R and Andreazza, AC and Rajji, TK and Graham, SJ and Munoz, DG and Fornazzari, L and Lim, L and Norris, M and Schweizer, TA and Fischer, CE}, title = {A multimodal evaluation of transcranial photobiomodulation in mild cognitive impairment: Cognitive, metabolic, and neuroimaging outcomes of a pilot randomized controlled trial.}, journal = {Journal of Alzheimer's disease : JAD}, volume = {}, number = {}, pages = {13872877261453911}, doi = {10.1177/13872877261453911}, pmid = {42231857}, issn = {1875-8908}, abstract = {BackgroundMild cognitive impairment (MCI), a prodromal stage of Alzheimer's disease and related dementias (ADRD), represents a critical window for intervention. Although mitochondrial dysfunction is increasingly implicated in neurodegeneration, most therapies target downstream protein aggregation. Transcranial photobiomodulation (tPBM) delivers near-infrared light to enhance mitochondrial respiration.ObjectiveWe hypothesized that tPBM in MCI would be safe, feasible, and associated with improvements in cognition, mitochondrial function, and default mode network (DMN) functional connectivity (FC).MethodsWe conducted a single-blind, randomized, sham-controlled pilot trial (NCT05563298) in adults ≥50 years with MCI. Twenty participants were randomized 1:1 to active or sham devices. Active devices delivered pulsed 810-nm light for 20 min per session; shams emitted light for 2 seconds. Stimulation targeted DMN hubs and the olfactory bulb. Participants self-administered treatment at home six days per week for six weeks.ResultsAdherence was high (active 96.9%; sham 94.2%). Adverse events (AEs) were reported by 10 of 20 participants (4 active, 6 sham). No serious AEs occurred. Compared with sham, active tPBM produced greater improvement in global cognition (Mini-Mental State Examination; p = 0.03, d = 1.05) and episodic memory (California Verbal Learning Test-II long-delay recognition; p = 0.02, d = 1.09). Serum pyruvate and lactate increased with a reduced lactate-to-pyruvate (L/P) ratio (p = 0.007, d = -1.37). DMN FC increased (p = 0.014, d = 1.25), and plasma IL-6 declined (p = 0.02, r = -0.52).ConclusionsHome-based tPBM was safe, well tolerated, and feasible, with high adherence and mild AEs. Cognitive, metabolic, and network-level findings are consistent with enhanced mitochondrial efficiency and anti-inflammatory effects. These results support larger, double-blind, multicenter trials to evaluate tPBM as a mitochondria-targeted therapy in early ADRD.}, } @article {pmid42231859, year = {2026}, author = {Tsutsui, S and Stepanchuk, AA and Stys, JP and Black, SAG and Templeton, GW and Greiner, R and Stys, PK}, title = {Fluorescence spectroscopy and machine learning methods for detection of Alzheimer's disease from circulating white blood cells.}, journal = {Journal of Alzheimer's disease : JAD}, volume = {}, number = {}, pages = {13872877261453512}, doi = {10.1177/13872877261453512}, pmid = {42231859}, issn = {1875-8908}, abstract = {BackgroundAlzheimer's disease (AD) is the most common cause of dementia whose prevalence is projected to increase significantly in the coming decades. The recent advent of disease modifying therapies is a welcome development; however, it is also now apparent that early treatment maximizes the benefits of these drugs. Therefore, it is important to develop reliable methods of disease detection, preferably from an easily accessible matrix such as blood.ObjectiveTo develop a method for detecting AD from circulating white blood cells using spectral confocal microscopy.MethodsUsing K114-stained wild type and 5xFAD transgenic mouse cortical sections as proof-of-principle, spectral imaging of K114 fluorescence coupled with a signal processing/machine learning pipeline (spectral wavelet decomposition, dimensionality reduction, support vector machine classifier) can reliably distinguish non-plaque background parenchyma in the two strains. We then performed immunoprecipitation of Aβ from peripheral blood mononuclear cells (PBMCs) obtained from non-neurological controls and histopathologically-proven AD cases. We spectrally imaged the immunobeads labeled with K114, then used similar machine learning methods to classify control versus AD samples.ResultsNormal-appearing non-plaque 5xFAD background was reliably distinguished from wild type mouse brain. We could also classify AD with a high degree of reliability (area under the receiver operating curve = 0.95, p = 6.1e-5) and predict neuropathological scores from these blood elements (R = 0.89).ConclusionsOur spectral imaging method, together with automated machine learning analysis of spectral micrographs, using readily obtainable PBMCs from blood, represents a potentially useful approach for detection of AD in living subjects.}, } @article {pmid42231879, year = {2026}, author = {Nibila, Y and Sivagami, M}, title = {Artificial intelligence techniques for classification of Alzheimer's disease using neuroimaging data: a review.}, journal = {Frontiers in artificial intelligence}, volume = {9}, number = {}, pages = {1748985}, pmid = {42231879}, issn = {2624-8212}, abstract = {Alzheimer's disease (AD) is a gradually advancing brain disorder marked by memory impairment. The incurable, progressive nature of the disease leads to the dementia stage. Treatment is effective in the early stage, and it can be controlled but not cured. Artificial Intelligence (AI) learning models are used in medical science to detect and classify diseases into specific categories. Features are extracted from medical images and trained using AI learning models to perform an accurate diagnosis of AD. Recent advancements in machine learning (ML) and deep learning (DL) models have demonstrated significant potential in identifying AD across various data modalities, including neuroimaging, genetic information, and clinical assessments. This study focuses on the application of advanced ML and DL techniques in the identification and classification of AD, including regression models, decision trees, random forests, support vector machines (SVMs), k-nearest neighbors (KNNs), ensemble models, convolutional neural networks (CNNs), recurrent neural networks (RNNs), and generative adversarial networks (GANs). Each model is analyzed for its strengths, limitations, and performance metrics, with particular emphasis on the importance of data preprocessing and augmentation techniques to improve model accuracy and robustness. The review highlights that multimodal approaches, particularly the fusion of MRI and PET data, enhance classification accuracy compared to single-modality models. Additionally, transfer learning techniques have shown promise in overcoming data limitations by leveraging pretrained models. The review also highlights the critical role of evaluation metrics in assessing model performance, emphasizing the need for a diverse set that includes accuracy, precision, recall, F1-score, and Cohen's Kappa. The study identifies gaps in the current literature, including underreporting of certain metrics and the need for more comprehensive evaluations, and provides recommendations for future research. Finally, this study discusses the challenges and opportunities in the field, including improving model generalizability, enhancing interpretability, advanced data preprocessing and augmentation, integration with clinical workflows, and multimodal data fusion. This review provides consolidated information that may be useful for researchers, clinicians, and data scientists, offering insights into current trends, challenges, and future research directions in AI-driven AD detection.}, } @article {pmid42232224, year = {2026}, author = {Cortes-Flores, H and Torrandell-Haro, G and Brinton, RD}, title = {Anti-inflammatory and immunomodulatory therapies are associated with reduced risk of age-associated neurodegenerative diseases: impact of sex and treatment duration.}, journal = {Frontiers in aging neuroscience}, volume = {18}, number = {}, pages = {1818660}, pmid = {42232224}, issn = {1663-4365}, abstract = {INTRODUCTION: Neurodegenerative diseases (NDDs) including Alzheimer's disease (AD), Parkinson's disease (PD), multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS), and non-AD dementias share chronic neuroinflammatory mechanisms that contribute to neuronal injury and disease progression. While anti-inflammatory therapies (AITs) are associated with reduced neurodegenerative disease risk, knowledge regarding the impact of biological sex and treatment duration across multiple NDDs remains limited.

METHODS: We conducted a retrospective cohort analysis using a large propensity-score-matched population (n = 190,308; 95,154 treated vs. 95,154 untreated) to evaluate associations between long-term AIT exposure and incidence of major NDDs. Disease-specific and combined outcomes were assessed across drug classes (NSAIDs, corticosteroids, immunomodulators), sex, age, and therapy duration.

RESULTS: AIT exposure was associated with a significantly lower risk of developing any NDD (RR = 0.47, 95% CI 0.43-0.48, p < 0.0001) and was equally effective in both sexes. Risk reduction was observed for each age-associated disease: AD (RR = 0.40), non-AD dementia (RR = 0.51), PD (RR = 0.43), MS (RR = 0.25), and ALS (RR = 0.48). Among drug classes, immunomodulators conferred the greatest reduction (RR = 0.19), followed by corticosteroids (RR = 0.41) and NSAIDs (RR = 0.42). Duration analyses revealed a graded benefit, with RR declining from 0.94 (< 1 year) to 0.25 (> 6 years). Risk reduction was greatest in older participants (75-79 years).

DISCUSSION: Chronic use of anti-inflammatory or immunomodulatory therapies was associated with significantly reduced incidence of multiple neurodegenerative diseases in both sexes. The strongest effects were observed with immunomodulator use and prolonged therapy duration, suggesting that sustained modulation of systemic inflammation confers broad neuroprotective effects in both sexes. These findings highlight the potential of targeting immune-inflammatory pathways for neurodegenerative disease prevention and can inform prospective mechanistic and interventional studies.}, } @article {pmid42234329, year = {2026}, author = {Qi, JW and He, XY and Gu, YC and Luo, ZJ and Duan, R and Zhang, YD and Xie, Y and Jiang, T}, title = {Soluble TREM1 Contributes to Aging-Related Neurodegeneration via ROBO2/ERK Pathway.}, journal = {Molecular neurobiology}, volume = {63}, number = {1}, pages = {}, pmid = {42234329}, issn = {1559-1182}, mesh = {Animals ; *Aging/metabolism/pathology/blood ; *Receptors, Immunologic/metabolism ; Roundabout Proteins ; Hippocampus/pathology/metabolism ; *Triggering Receptor Expressed on Myeloid Cells-1/blood/metabolism ; *Nerve Degeneration/pathology/blood/metabolism ; *MAP Kinase Signaling System/physiology ; Solubility ; Neurons/metabolism ; *Neurodegenerative Diseases/pathology/metabolism/blood ; Male ; Humans ; Synapses/metabolism ; }, abstract = {Aging is recognized as the most significant risk factor for neurodegenerative diseases. Emerging evidence indicates that inflammation contributes to the progression of aging-related neurodegeneration. As a transmembrane immune receptor, triggering receptor expressed on myeloid cells 1 (TREM1) plays a crucial role in the regulation of inflammatory responses. Previously, our research group and others showed that the levels of a soluble form of TREM1 (sTREM1) were increased in the plasma or cerebrospinal fluid (CSF) of patients with Alzheimer's disease, the most common type of neurodegenerative disease among the elderly. Moreover, the elevated levels of CSF sTREM1 were closely associated with a more rapid rate of hippocampal degeneration in cognitively impaired older adults. However, the precise mechanisms by which sTREM1 contributes to aging-related neurodegeneration remain largely unclear. In this study, by utilizing senescence accelerated mouse prone 8 mice, an animal model of accelerated aging, we confirmed that serum sTREM1 levels were significantly increased during the aging process. Importantly, we demonstrated that roundabout guidance receptor 2 (ROBO2) functioned as a receptor for sTREM1 in hippocampal neurons, and its expression was also upregulated with aging. Additionally, we revealed for the first time that knockdown of neuronal ROBO2 mitigated aging-related hippocampal synaptic degeneration and cognitive impairments. Furthermore, we provided the first evidence that sTREM1 reduced the expression of synaptic proteins via the ROBO2/extracellular signal-regulated kinase pathway. These findings elucidated the mechanisms through which sTREM1 contributed to aging-related neurodegeneration and suggested that the inhibition of sTREM1-mediated signaling might represent a novel therapeutic strategy for the treatment of neurodegeneration and cognitive decline induced by aging.}, } @article {pmid42234971, year = {2026}, author = {Zhou, J and Zhu, X and Chen, W and Tan, J and Hong, L and Yang, L and Liu, Y and Zhai, T and Chen, K}, title = {The Dickkopf Protein Family in Non-Neoplastic Disorders: Emerging Roles and Therapeutic Targeting.}, journal = {Aging and disease}, volume = {}, number = {}, pages = {}, doi = {10.14336/AD.2025.1506}, pmid = {42234971}, issn = {2152-5250}, abstract = {The Dickkopf (DKK) family of secreted glycoproteins, comprising DKK1-4, serves as a pivotal regulator of the Wnt signaling pathway. Acting as canonical antagonists of the Wnt/β-catenin cascade, these proteins are indispensable for essential biological processes such as cellular proliferation, differentiation, development, and tissue homeostasis. In recent years, aberrant expressions of DKK proteins has been extensively documented in multiple cancers. Simultaneously, their pathophysiological roles and clinical relevance in non-oncological diseases have garnered growing attention. Disorders such as osteoporosis and arthritis, chronic kidney disease (CKD), myocardial injury, as well as neurodegenerative and dermatological conditions, including Alzheimer's disease (AD) and alopecia, have all been linked to DKK family members. These broad associations emphasize their substantial potential as diagnostic biomarkers and as promising therapeutic targets. This review provides a systematic synthesis of recent research within the past three years on the roles of the DKK protein family in diverse non-oncological diseases, further examining their prospective applications as biomarkers and therapeutic targets while addressing related challenges, with the aim of offering novel insights into diagnosis and treatment.}, } @article {pmid42235718, year = {2026}, author = {Oh, JM and Jeong, WK and Son, HJ and Kwon, YJ and Kim, SY and Oh, TW and Ji, M and Baek, M and Shin, WH and Kim, HJ and Choi, B and Kim, SH and Paik, MJ and Kim, H}, title = {Broussochalcone A alleviates cognitive impairment in scopolamine-induced mice as a potent β-amyloid aggregation inhibitor and changes blood and brain metabolite profiles.}, journal = {Journal of ethnopharmacology}, volume = {370}, number = {}, pages = {121958}, doi = {10.1016/j.jep.2026.121958}, pmid = {42235718}, issn = {1872-7573}, abstract = {Broussonetia papyrifera (BP) has been used for traditional medicine in amelioration of cognitive decline. Accumulation of β-amyloid (Aβ) plaques majorly contributed to the pathogenesis of Alzheimer's disease (AD).

AIM OF THE STUDY: This study aimed to investigate the role of broussochalcone A (BCA), a bioactive constituent of BP, in alleviation of cognitive impairment via Aβ aggregation inhibition in model mice.

METHODS: We screened a potent Aβ aggregation inhibitor from a herbal library and analyzed its effect on improving cognitive functions in model mice and principal protein expression. In addition, we compared the metabolite profiling of blood and tissues. We used the aggregation inhibition assay to screen 960 herbal compounds using Aβ42-, and a leading compound was selected based on drug-like properties. Animal behavioral tests including the Morris water maze were performed using scopolamine (SCO)-treated mice. Western blotting and histopathological analysis were performed. Key compounds in the blood, hippocampus, and cortex were analyzed to compare the metabolic profiles.

RESULTS: BCA was a potent Aβ aggregation inhibitor (IC50 = 1.75 ± 0.021 μM) with a predicted binding energy of -6.405 kcal/mol, and nontoxic to MDCK and SH-SY5Y cells. Molecular dynamics simulation revealed that the atomic contact numbers of BCA with Aβ were highly fluctuated during 100 ns; however, the transient contacts might prevent the aggregation. Cognitive function was significantly improved in BCA-treated mice in behavioral tests. Western blotting and histopathological analysis demonstrated that BCA treatment attenuated apoptosis, preserved hippocampal pyramidal neuron integrity, and alleviated SCO-induced spatial memory impairment. Metabolite profiling demonstrated that BCA modulated the metabolic pathways related to energy metabolism, redox homeostasis, amino acid turnover, and lipid metabolism in the serum and brain tissues, partially attenuating SCO-associated metabolic alterations.

CONCLUSIONS: BCA is a potent Aβ aggregation inhibitor and exhibits significant cognitive improvement, as well as neuroprotective effects, decreasing inflammation, and retaining neuron structures. In addition, BCA induced distinct metabolic alterations in the serum and brain tissues compared to SCO. These results strongly support the use of BCA as a promising candidate for the amelioration of cognitive impairment and application to AD therapeutics.}, } @article {pmid42235756, year = {2026}, author = {Shashwat, P and Kirthi, AV and Selvaraj, M and Karnwal, A and Dutta, J}, title = {Phytochemical engineered quantum dots as potential therapy to counter alpha synuclein aggregation in Parkinson's disease.}, journal = {Neurochemistry international}, volume = {198}, number = {}, pages = {106194}, doi = {10.1016/j.neuint.2026.106194}, pmid = {42235756}, issn = {1872-9754}, abstract = {Parkinson's disease (PD) is a prevalent neurodegenerative disorder that critically impairs human health and presently lacks effective cellular-level therapeutic interventions. The disease is primarily characterized by pathological aggregation of misfolded α-synuclein in presynaptic neurons, leading to dopaminergic neuronal loss. The limited efficacy of current pharmacological treatments stems largely from challenges in crossing the blood-brain barrier. Recent studies suggest that nano-phytomedicine approaches offer promising alternatives for PD management. Specifically, phytochemical-engineered carbon quantum dots (CQDs) show potential to modulate key pathological processes, including α-synuclein aggregation, mitochondrial dysfunction, oxidative stress, and neuronal degeneration. Evidence from related neurodegenerative models, such as Alzheimer's disease, reveals that multifunctional CQDs can scavenge reactive oxygen species, influence protein aggregation, and mitigate neurotoxicity. The synergistic integration of bioactive phytochemicals into CQDs could enhance drug bioavailability, pharmacokinetic properties, and cellular repair mechanisms while reducing toxicity. This review discusses the design strategies, therapeutic mechanisms, and biological interactions of phytochemical-engineered CQDs, emphasizing their potential as next-generation nanocarriers and intrinsic neurotherapeutic agents for PD treatment.}, } @article {pmid42236351, year = {2026}, author = {Hata, M and Miyazaki, Y and Takahashi, S and Ikeda, M}, title = {Temporal pattern of dementia with lewy bodies diagnostic labels around electroconvulsive therapy: A nationwide claims-based study.}, journal = {International psychogeriatrics}, volume = {}, number = {}, pages = {100224}, doi = {10.1016/j.inpsyc.2026.100224}, pmid = {42236351}, issn = {1741-203X}, abstract = {BACKGROUND: Electroconvulsive therapy (ECT) is widely used for severe depression. Dementia with Lewy bodies (DLB) may initially present with depressive symptoms, and ECT may be administered in some patients during the course of the disease. However, the timing of DLB diagnosis in relation to ECT treatment has not been well characterized.

METHODS: We conducted a retrospective cohort study using a nationwide administrative claims database in Japan, including records from 564 acute care hospitals between April 2008 and March 2025. Analyses were restricted to patients with a mood disorder diagnosis (ICD-10 F30-F39) recorded in the same month as the first ECT session, and patients with both DLB and Alzheimer disease (AD) diagnostic codes were excluded. The primary analysis examined the timing of recorded DLB diagnostic labels relative to ECT initiation, with AD diagnoses analyzed as a comparator.

RESULTS: Among 3733 patients who underwent ECT, 71 met the analytic criteria for DLB. The median interval between ECT initiation and the first DLB diagnosis was 8 days prior to ECT initiation. Recorded DLB diagnostic labels occurred significantly more often within ±90 and ±180 days of ECT initiation than AD diagnoses, whereas AD diagnoses were distributed more broadly across the observation period.

CONCLUSION: Recorded DLB diagnostic labels showed a distinct temporal pattern around ECT initiation. Clinical evaluation associated with ECT may facilitate recognition of underlying DLB in patients presenting with severe psychiatric symptoms. Clinicians should remain attentive to evolving DLB when treating late-life treatment-resistant mood disorders with ECT, as recognition of DLB may occur several years after treatment initiation.}, } @article {pmid42236499, year = {2026}, author = {Kumar, D and Walhekar, V and Shenoy, KM and Kini, SG}, title = {In silico investigation of thiazole-semicarbazide hybrids as dual GSK-3β/Tau inhibitors for Alzheimer's disease.}, journal = {Scientific reports}, volume = {}, number = {}, pages = {}, doi = {10.1038/s41598-026-55932-9}, pmid = {42236499}, issn = {2045-2322}, abstract = {AD is a widespread and debilitating neurodegenerative disorder, and existing treatments have demonstrated limited efficacy, emphasizing the need for novel therapeutic strategies. This study focused on the design of drug-like molecules with enhanced efficacy and minimized side effects by application of structure-based scaffold hopping and molecular hybridization strategies. Molecular docking was carried out on Glide module; Molecular dynamics simulation of 500 ns was executed employing Desmond and ADMET prediction was achieved by QikProp modules of Schrödinger. Through molecular docking studies targeting the GSK-3β and Tau enzymes, the compounds DVK5 and DVK11 were identified as promising inhibitors, showing favorable interactions within the active sites of these proteins, with docking energies of - 9.863 and - 8.994 kcal/mol, respectively. Molecular dynamics simulations further revealed that the DVK5 and DVK11 complexes exhibited stable interactions within the active sites of GSK-3β and Tau throughout a 500 ns simulation. Additionally, in silico ADMET analysis demonstrated that DVK10 exhibited an excellent human oral absorption rate of 75.175%, outperforming other compounds in the series. These findings strongly suggest the potential of DVK5 and DVK11 as dual inhibitors of GSK-3β and Tau, offering a basis for future drug development studies for the development of new lead compounds for AD treatment.}, } @article {pmid42239211, year = {2026}, author = {Patterson, C and Chattopadhyay, T and Thomopoulos, SI and Saykin, AJ and Davatzikos, C and Mormino, EC and Tosun, D and Beecham, GW and Biber, SA and Kukull, WA and Risacher, SL and Montine, TJ and Johnson, SC and Shen, L and Huang, H and Erus, G and Jun, GR and Mukherjee, S and Crane, PK and Cuccaro, ML and Archer, DB and Landman, BA and Toga, AW and Hohman, TJ and Thompson, PM}, title = {Predicting Autopsy-Confirmed Neuropathology across Clinical, Neuroimaging, and CSF Biomarkers using Machine Learning.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {42239211}, issn = {2692-8205}, abstract = {Accurate in vivo prediction of neuropathology is critical for advancing diagnosis and treatment of Alzheimer's disease and related dementias (ADRDs). As many individuals with ADRDs have mixed pathologies (β-amyloid, pathologic tau, cerebrovascular disease, vascular brain injury, pathologic TDP-43, hippocampal sclerosis, Lewy bodies), there is interest in determining how accurately we can infer these pathologic changes from clinical data, biofluid assays (e.g., CSF), and neuroimaging. Here we evaluated automated machine learning models trained on data curated by the AD Sequencing Project Phenotype Harmonization Consortium (N=7,894 individuals), to predict 26 autopsy-confirmed neuropathological outcomes. Predictors included in vivo clinical and cognitive composite scores, brain measures from 3D structural MRI and diffusion tensor imaging, image-derived measures of white matter hyperintensities (WMH), and CSF biomarkers. Predictive models were trained using ensemble learning with stratified cross-validation. We assessed performance using Spearman's rank correlation and Matthews correlation coefficient, to accommodate co-occurring pathologic changes. The added value of neuroimaging and CSF versus clinical features alone was quantified. Braak stage was among the most consistently predicted outcomes. CSF biomarkers best predicted β-amyloid and tau pathology, but diffusion MRI metrics best captured vascular brain injury and white matter injury, and outperformed clinical and cognitive measures and anatomical MRI in predicting Lewy body disease. Anatomical measures from structural MRI outperformed standard clinical assessments in assessing neurodegeneration and hippocampal sclerosis, and WMH complemented cognitive measures in predicting TDP-43 pathology. These results establish a baseline for comparing modalities for inferring neuropathology.}, } @article {pmid42239295, year = {2026}, author = {Kambali, M and Trushin, S and Wang, M and Nagarajan, R and Lyu, J and Trushina, E and Rudolph, U}, title = {A Small-Molecule Mitochondrial Complex I Modulator Improves Behavioral and Mitochondrial Dysfunction in Schizophrenia.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, doi = {10.64898/2026.05.19.726440}, pmid = {42239295}, issn = {2692-8205}, abstract = {Weak inhibition of mitochondrial complex I (mtCI) has been shown to have neuroprotective effects in cellular and animal models of Alzheimer's and Huntington's diseases, at least in part by enhancing mitochondrial biogenesis and function. Mitochondrial dysfunction has also been demonstrated in schizophrenia patients and mouse models of schizophrenia. We tested whether weak inhibition of mtCI would ameliorate mitochondrial and behavioral phenotypes in a mouse model of schizophrenia. In mice with four copies of the Gldc gene, 8 weeks of treatment with the weak mtCI inhibitor, the small-molecule tricyclic pyrone compound CP2, reversed spontaneous alternation deficits in the Y maze, startle habituation deficits, and social novelty deficits in the three-chamber social interaction test. Consistent with the mechanism of action, Western blots revealed that CP2 reverses the reduced expression of PGC-1α, a master regulator of mitochondrial biogenesis, and of the VDAC1, a primary gatekeeper for the exchange of metabolites, ions, and ATP between mitochondria and the cytosol. These findings suggest that the improvement of mitochondrial function may represent a novel strategy to reverse pathophysiological and behavioral deficits in schizophrenia.}, } @article {pmid42239568, year = {2026}, author = {El-Mokaddem, OK and Elmasry, GF and Mahmoud, WR and Abdel Ghany, LMA}, title = {Bridging the gap in Alzheimer's therapy: strategic design and SAR evolution of coumarin-based hybrids as potent MTDLs.}, journal = {RSC advances}, volume = {16}, number = {32}, pages = {29631-29660}, pmid = {42239568}, issn = {2046-2069}, abstract = {Due to their multitargeting potential, coumarin-based hybrid molecules represent a new and valuable drug development strategy for the treatment of Alzheimer's disease (AD). This review summarizes recent advances in the design, synthesis, and evaluation of coumarin hybrids as multi-target-directed ligands (MTDLs) for AD. This review covers various coumarin hybrid classes, including those incorporating triazole, thiazole, quinoline, chalcone, and other pharmacophores, highlighting their diverse mechanisms of action, such as acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) inhibition, amyloid-beta (Aβ) aggregation prevention, BACE-1 inhibition, MAO-B modulation, antioxidant activity, and metal ion chelation. Structure-activity relationship (SAR) studies have identified key structural features for optimal activity, including linker length, substitution patterns, and physicochemical properties influencing CNS penetration. Molecular docking and dynamics simulations reveal information about drug-target interactions and demonstrate the ability to engage multiple targets. Coumarin hybrids are already showing ecological in vivo efficacy in animal models, and also the desired safety window and metabolic stability make them potential clinical candidates. Future research directions include incorporating emerging therapeutic targets, advanced computational design, and a focus on the microbiome-gut-brain axis to develop more effective and disease-modifying AD therapeutics.}, } @article {pmid42240303, year = {2026}, author = {G, D and K, P and S, R and Vijaya Lakshmi, TR}, title = {Bobcat-optimized hybrid quantum-classical spike-driven network for MRI-based Alzheimer's stage prediction.}, journal = {The International journal of neuroscience}, volume = {}, number = {}, pages = {1-25}, doi = {10.1080/00207454.2026.2683880}, pmid = {42240303}, issn = {1563-5279}, abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder that severely affects memory, cognition, and behavioral functions, making early and accurate stage classification essential for timely clinical intervention and treatment planning. Conventional MRI-based diagnostic approaches are often limited by noise sensitivity, manual interpretation, and insufficient capability to model complex non-linear neuroimaging relationships across multiple disease stages. To address these limitations, this paper proposes a novel Hybrid Quantum-Classical Spike-Driven Network optimized with the Bobcat Optimization Algorithm(HQSDNet-BOA)for automated multistage AD classification using MRI data. The suggested framework introduces an integrated architecture that combines Square Root Sage-Husa Adaptive Robust Kalman Filtering(SRS-HARKF)for adaptive noise suppression and covariance stabilization, Graph-Enhanced Fuzzy Clustering (GEFC)for structurally consistent brain tissue segmentation, and a Hybrid Structural Graph Attention Network(HSGAN)for learning discriminative local-global anatomical representations. Moreover, Hybrid Quantum-Classical Spike-Driven Network (HQSDNet), which incorporates quantum convolutional learning, spike-driven transformers, and structural attention schemes, is designed to precisely identify nonlinear and spatial-temporal disease patterns. Bobcat Optimization Algorithm (BOA) is used for optimizing network parameters in real-time to ensure convergence efficiency and computational optimization. This study was performed using two datasets: ADNI (5,300 images representing five disease stages) and OASIS-3 (3,712 images representing three cognitive classes). The suggested HQSDNet-BOA yielded improved classification results with 98.8% accuracy, 98.0% precision, 98.5% recall, and 98.25% F1-score when applied to the ADNI dataset and outperformed the existing techniques in terms of computational speed. The obtained results confirm that the suggested framework provides a robust, efficient, and clinically relevant solution for accurate AD stage prediction and neuroimaging-based diagnostic support.}, } @article {pmid42243905, year = {2026}, author = {Qian, L and Cui, M and Wu, M and Song, B and Wang, P and Wu, M and He, T and Zhang, B and He, Y}, title = {Tea-derived natural nanodrug simultaneously enables real-time fluorescent tracking and noninvasive treatment of neuroinflammation in Alzheimer's disease.}, journal = {Journal of nanobiotechnology}, volume = {}, number = {}, pages = {}, doi = {10.1186/s12951-026-04642-5}, pmid = {42243905}, issn = {1477-3155}, support = {BK20240766//Natural Science Foundation of Jiangsu Province/ ; 22504095//National Natural Science Foundation of China/ ; 22393932//National Natural Science Foundation of China/ ; 2023M742532 and 2024T170625//China Postdoctoral Science Foundation/ ; 0002/2022/AKP, 0115/2023/RIA2//Macau University of Science and Technology Foundation/ ; 2023YFB3208202//National Key Research and Development Program of China/ ; }, abstract = {Neuroinflammation and glutamate-induced excitotoxicity are key drivers of synaptic dysfunction and cognitive decline in Alzheimer's disease (AD). However, chemically synthesized small-molecule drugs (e.g., memantine) often cause potential dose-dependent neurotoxicity, limited inflammation-targeting capability, and rapid systemic clearance, resulting in suboptimal therapeutic efficacy. Here, we introduce a tea-derived multifunctional natural nanodrug that enables real time fluorescence tracking and noninvasive treatment of neuroinflammation in AD. The natural nanodrug is derived from Pu-erh tea leaves, formulated with memantine and biomimetic vesicles for intranasal nebulized delivery. The tea-derived biomimetic nanodrug features intrinsic fluorescence, enabling real-time tracking at both cellular and tissue levels, with preferential colocalization in activated microglia and selective accumulation in neuroinflammatory brain regions. Remarkably, under matched nebulization conditions and nominal memantine loading, the tea-derived natural nanodrug shows an improved safety and efficacy relative to free memantine, significantly improving behavioral outcomes and reducing hippocampal damage. This noninvasive strategy enables efficient brain targeting and markedly restores hippocampal structure and cognitive performance in AD mouse models. Together, our study suggests new avenues and exciting opportunities for developing natural nanodrugs for noninvasively and precisely treating brain diseases including but not limited to AD.}, } @article {pmid42244738, year = {2026}, author = {Amontree, M and O'Leary, J and Wonnenberg, P and Nelson, M and Conant, K}, title = {4-methylumbelliferone attenuates amyloid pathology and learning deficits in the APP/PS1 mouse model.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {42244738}, issn = {2692-8205}, abstract = {4-Methylumbelliferone (4-MU) inhibits hyaluronic acid (HA) synthesis and is currently approved in Europe for biliary spasm. 4-MU administration reduces perineuronal nets (PNNs), and enzymatic degradation of PNNs in mouse models of Alzheimer's disease (AD) attenuates memory impairment. Although 4-MU has therapeutic efficacy in rodent models of fibrosis and cancer, it has not been examined in an Alzheimer's model. Here, we evaluated the impact of long-term 4-MU treatment in the APP/PS1 amyloid mouse model. From three months of age, mice were on either a vehicle or 4-MU-supplemented diet for 70 days or 52 weeks. Short and long-term 4-MU treatment decreased the soluble parenchymal Aβ1-42/Aβ1-40 ratio. Reductions in insoluble amyloid plaque were observed following 52 weeks of treatment. Extended 4-MU administration also reduced PNN intensity and ameliorated spatial memory deficits in APP/PS1 mice. These findings provide support for targeting brain extracellular matrix (ECM) as a therapeutic strategy for AD.}, } @article {pmid42245509, year = {2026}, author = {Wang, Z and Li, L and Dong, Y and Zhang, Y}, title = {The microbiota-tryptophan-brain axis in neurodegenerative diseases: pathogenic mechanisms, disease-specific roles, and translational therapeutics.}, journal = {Frontiers in microbiology}, volume = {17}, number = {}, pages = {1820111}, pmid = {42245509}, issn = {1664-302X}, abstract = {The pathogenesis of neurodegenerative diseases (NDDs) such as Alzheimer's disease (AD) and Parkinson's disease (PD) is very complex. Recent studies have shown that gut microbiota and their metabolites play a key role in the progression of these diseases. Tryptophan (Trp) is an essential amino acid, which mainly produces a variety of biologically active compounds in the intestine through the metabolism of indole pathway, Kynurenine pathway (KP) and serotonin pathway, including indole derivatives, Kynurenine (KYN) and serotonin (5-HT). These metabolites affect the central nervous system (CNS) through the Microbiota-gut-brain axis (MGBA) and affect CNS in a variety of mechanisms, including immune regulation, neuroprotection and maintenance of intestinal barrier function. They are involved in key pathological processes such as neuroinflammation, oxidative stress and pathological protein aggregation. This paper systematically reviews the mechanism of the role of Trp metabolites derived from gut microbiota in NDDs, and explores their specific roles in AD, PD, Amyotrophic Lateral Sclerosis (ALS) and Huntington's disease (HD), and summarizes the potential therapeutic value of the current pathway strategy. These strategies include nutritional intervention, targeted microbiome therapy [such as probiotic and fecal microbiota transplantation (FMT)], and metabolite-derived drugs. Future research must clarify its dynamic mechanism in the human body, develop relevant biomarkers, and promote personalized prevention and treatment strategies through clinical transformation, so as to provide a new direction for early intervention and treatment of NDDs.}, } @article {pmid42247667, year = {2026}, author = {Yu, J and Chen, Y and Bai, J and Zeng, J and Zhao, J and Fan, Y}, title = {Application of Focused Ultrasound in Alzheimer's Disease: A Bibliometric Analysis.}, journal = {The Journal of craniofacial surgery}, volume = {}, number = {}, pages = {}, pmid = {42247667}, issn = {1536-3732}, abstract = {OBJECTIVE: This study uses bibliometric analysis and knowledge mapping methods to systematically explore the emerging research frontiers and development trajectories of focused ultrasound (FUS) technology in the treatment of Alzheimer's disease (AD), and provides new clues and research directions for future research by exploring hotspots and new topics.

METHODS: A comprehensive literature search was conducted through the Science Citation Index Expanded Core Collection (WoSCC) database to identify relevant articles and reviews published between January 2014 and 2025 on the application of FUS technology in AD. For data analysis and visualization, we used VOSviewer software, CiteSpace, and the R package "bibliometrix" to conduct rigorous bibliometric analysis and build knowledge domain maps.

RESULTS: A total of 1531 papers involving 9220 contributors were identified between 2014 and 2025. The field demonstrated consistent growth (R2=0.9272), peaking in 2025 with 225 publications. China led in total output (475 papers), while the United States achieved the highest academic impact (12,965 citations, H-index: 56). The Chinese Academy of Sciences was the most prolific institution, whereas Harvard Medical School recorded the highest citation impact. The Journal of Alzheimer's Disease and Scientific Reports emerged as the leading publication venues, while Theranostics and Alzheimer's & Dementia provided high-prestige platforms. Tianfu Wang and Baiying Lei were the most productive authors, though Isabelle Aubert garnered the highest total citations. International collaboration analysis revealed a robust, multi-centric network anchored by the USA, China, Canada, and Italy. Co-citation analysis identified Leinenga G (2015) as the foundational study for ultrasound-mediated amyloid-beta clearance. Lipsman N (2018) marked a critical clinical inflection point, exhibiting a strong citation burst (17.3) that catalyzed a shift from preclinical models to human safety trials. Recent bursts extending into 2025 focus on multicenter clinical validation and long-term efficacy. Keywords analysis confirms that non-invasive blood-brain barrier (BBB) opening via microbubble-enhanced focused ultrasound (FUS) is the central research paradigm. Emerging frontiers have shifted from basic technical validation toward neuroinflammation, oxidative stress, tau pathology, and deep-learning-assisted diagnostics, reflecting an evolving focus on molecular mechanisms and precision neurosurgery.

CONCLUSIONS: Focused ultrasound technology has made significant progress in the field of Alzheimer's disease research and has become a research frontier with considerable therapeutic potential. With ongoing technological progress, the clinical translation of FUS is expected to bring new breakthroughs in AD treatment.}, } @article {pmid42247872, year = {2026}, author = {Fu, W and Lu, R and Wang, D and Sang, Z}, title = {Shared pathophysiology and therapeutic repurposing in Alzheimer's disease and type 2 diabetes: a critical review of convergent mechanisms and clinical challenges.}, journal = {Bioorganic chemistry}, volume = {180}, number = {}, pages = {110044}, doi = {10.1016/j.bioorg.2026.110044}, pmid = {42247872}, issn = {1090-2120}, abstract = {Alzheimer's disease (AD) and type 2 diabetes mellitus (T2DM) are two prevalent age-related disorders that share striking pathophysiological similarities, leading to the conceptualization of AD as a metabolic disorder often termed "type 3 diabetes." While numerous reviews have documented the epidemiological association between these diseases, a critical synthesis of the underlying molecular convergence-and its implications for therapeutic repurposing-remains fragmented. This review provides a comprehensive and critical analysis of the shared signaling pathways that underpin both AD and T2DM, including insulin resistance, oxidative stress, the AGE-RAGE axis, amyloidogenic protein misfolding (Aβ in AD and IAPP in T2DM), endoplasmic reticulum stress, and vasculopathy. By systematically examining each pathway, we highlight not only their disease-specific manifestations but also their intricate interconnections and the critical unresolved questions that hinder translational progress. We then critically evaluate the current evidence for repurposing major antidiabetic drug classes-insulin and its analogues, metformin, sulfonylureas, thiazolidinediones, incretin-based therapies (GLP-1 receptor agonists and DPP-4 inhibitors), and amylin receptor modulators-for AD treatment. Through this analysis, we identify key sources of clinical inconsistency, including patient heterogeneity (particularly APOE ε4 genotype), disease stage dependency, blood-brain barrier integrity, and off-target safety concerns. By integrating mechanistic insights with a rigorous assessment of clinical evidence, this review advances the understanding of AD as a metabolic disorder and provides a framework for future precision medicine approaches in cross-disease intervention. The synthesis presented here underscores that realizing the therapeutic potential of antidiabetic drugs in AD will require mechanism-guided patient stratification, early-stage intervention, and the development of brain-selective agents with improved efficacy and safety profiles.}, } @article {pmid42248234, year = {2026}, author = {Asmabi, V and Anoop, V}, title = {Multimodal neuroimaging-based deep learning framework for pattern analysis and early prediction of neurodegenerative diseases.}, journal = {Neuroscience}, volume = {610}, number = {}, pages = {36-48}, doi = {10.1016/j.neuroscience.2026.06.005}, pmid = {42248234}, issn = {1873-7544}, abstract = {Neurodegenerative diseases, such as Mild Cognitive Impairment (MCI) and Alzheimer's, pose significant challenges due to their progressive nature and late diagnosis. Early detection remains difficult, particularly when using conventional machine learning approaches that fail to capture complex spatial and temporal patterns in multimodal clinical data. Motivated by the need for accurate, scalable, and clinically applicable diagnostic tools, this study proposes a hybrid deep learning framework combining Convolutional Neural Networks (CNN) with Optimized Spatial-Temporal Bidirectional Gated LSTM (O‑SBGC‑LSTM). The framework is evaluated on 1,000 multimodal samples, achieving 94.8% accuracy, 93.9% precision, 94.2% recall, and a 94.0% F1-score, outperforming SVM (82.4%), Random Forest (85.7%), and CNN-LSTM (92.5%). Cross-validation confirms robustness (93.8-95.0% accuracy). The approach balances class performance across cognitively normal, MCI, and Alzheimer's cases. Future work will extend this framework to larger, multi-centre datasets and explore real-time clinical deployment, aiming to enhance early diagnosis, reduce misclassification, and support personalized treatment strategies for neurodegenerative disorders.}, } @article {pmid42248800, year = {2026}, author = {Miguel, ACC and Martins-Teixeira, L and Aliberti, MJR and Brucki, SMD and Caramelli, P and Laks, J and Nitrini, R and Rebello Pinho, PJDM and Suemoto, CK and Barbosa, MG and Ferri, CP}, title = {Bridging the gap: estimates of undetected dementia in Brazil.}, journal = {Age and ageing}, volume = {55}, number = {6}, pages = {}, doi = {10.1093/ageing/afag163}, pmid = {42248800}, issn = {1468-2834}, mesh = {Humans ; Brazil/epidemiology ; Male ; Female ; *Dementia/epidemiology/diagnosis ; Prevalence ; *COVID-19/epidemiology ; Aged, 80 and over ; Aged ; Middle Aged ; Alzheimer Disease/epidemiology/diagnosis ; Cholinesterase Inhibitors/therapeutic use ; SARS-CoV-2 ; }, abstract = {OBJECTIVE: To estimate the proportion of dementia underdiagnosis in Brazil and assess variations by age, sex and macro-economic regions.

METHODS: Diagnosed dementia cases were estimated using Brazilian Unified Health System (SUS) data on prescriptions for acetylcholinesterase inhibitors (AChEIs), as a proxy for recognised Alzheimer's disease (AD) cases. Estimates were adjusted for the proportion of AD among all dementias, treatment coverage and disease stages. Expected dementia prevalence was derived from national estimates. Underdiagnosis was calculated by comparing diagnosed to expected cases, stratified by sex, age group and region. Uncertainty interval (UI) bounds were calculated applying ±1 SD of the mean Delphi consensus prevalence for each stratum. Estimates were conducted for 2024 and repeated for 2019 and 2022 for pre- and post-COVID-19 pandemic comparison.

RESULTS: The overall proportion of dementia underdiagnosis among individuals aged ≥60 in 2024 was 84.3% (UI: 81.5-86.4). Proportions were higher among men (86.3%, UI: 83.5-88.2) than women (83.0%, UI: 79.9-85.2). Underdiagnosis peaked at 93.2% (UI: 92.3-93.7) in the 60-64-year age group, declined to 78.9% (UI: 78.1-79.6) among 85-89 years, then rose to 86.2% (UI: 85.7-86.7) among those ≥90 years. Proportions were highest in the poorest regions (North, Northeast and Central-West: 93.0%, UI: 91.4-94.1) and lowest in the richest (South and Southeast: 78.3%, UI: 74.3-81.2). Pre-pandemic (2019) underdiagnosis was slightly lower (81.6%, UI: 78.3-84.0) than in 2022 (84.9%, UI: 82.2-86.9) and 2024.

CONCLUSION: Dementia underdiagnosis in Brazil is high and unequally distributed, worsening after the COVID-19 pandemic. Expanding diagnostic access is critical to address disparities and improve care.}, } @article {pmid42248874, year = {2026}, author = {Kolypetri, P and da Silva, P and Francisco, RS and Frenkel, D and Cecere, RR and Kiliaan, PCJ and Montini, F and Saxena, S and Clementi, WA and Liu, X and Sun, C and Bergmark, RW and Singhal, T and Saraceno, TJ and Zimmermann, J and Gale, SA and Selkoe, DJ and Chitnis, T and Weiner, HL}, title = {Nasal administration of Protollin enhances monocyte phagocytosis and decreases CD8[+] T cell cytotoxicity in subjects with early Alzheimer's disease: a Phase 1 clinical trial.}, journal = {npj aging}, volume = {}, number = {}, pages = {}, doi = {10.1038/s41514-026-00397-3}, pmid = {42248874}, issn = {2731-6068}, support = {NIA R21AG072486/NH/NIH HHS/United States ; }, abstract = {Protollin, a nasal adjuvant, was evaluated in a randomized double-blind phase 1 study of 16 early Alzheimer's disease (AD) patients to determine safety and to assess its immunomodulatory effects. In a double-blind dose escalation study, subjects received nasal Protollin at doses of 0.1 mg, 0.5 mg, 1.0 mg, and 1.5 mg or placebo twice over a two-week period. Treatment was well-tolerated with minimal side effects. Transcriptomic and single-cell analyses demonstrated that prior to treatment, AD blood monocytes had downregulation of phagocytosis-related genes and an increased pro-inflammatory signature. These AD monocyte abnormalities were reversed by nasal Protollin beginning at a dose of 1.0 mg. Protollin induced a robust phagocytic gene signature, including upregulation of CD36, ITGAL, LYST, and FCGR1A. A similar phagocytic signature was observed in brain-infiltrating amyloid-clearing monocytes in an APP Tg mouse model treated with nasal Protollin. Protollin treatment decreased the expression of costimulatory molecules on monocytes and decreased CD8 [+] T cell activation and cytotoxicity. Our results provide the basis for a phase 2 study of nasal Protollin in subjects with AD in which nasal Protollin at a dose of 1.0 mg will be administered weekly over 6 months to modulate peripheral immunity and clear amyloid from the brain. ClinicalTrials.gov registration no NCT07187141.}, } @article {pmid42250049, year = {2026}, author = {Khan, Y and Rekha, A and Ballal, S and Maharana, L and Maqbool, M and Goyal, K and Mishra, R and Uniyal, P and Alam, P and Aljarba, TM and Gupta, G and Hussain, MS}, title = {Omics-driven strategies for identifying biomarkers in Alzheimer's disease.}, journal = {Metabolic brain disease}, volume = {41}, number = {1}, pages = {}, pmid = {42250049}, issn = {1573-7365}, mesh = {Humans ; *Alzheimer Disease/metabolism/genetics/diagnosis ; *Biomarkers/metabolism ; Multiomics ; *Metabolomics/methods ; *Proteomics/methods ; *Genomics/methods ; Animals ; Epigenomics/methods ; }, abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder with limited treatment options, mainly due to late diagnosis and partial understanding of its molecular aspects. Traditional biomarker discovery approaches have significantly contributed to AD diagnostics but suffer from limitations. The advent of omics technologies (genomics, epigenomics, transcriptomics, proteomics, and metabolomics) has revolutionized the search for novel biomarkers by enabling comprehensive molecular profiling. Genomic studies have identified risk-associated variants such as APOE4, while epigenomic alterations, including DNA methylation alterations, offer insight into gene regulation in AD. Transcriptomic analyses, particularly single-cell and spatial transcriptomics, have uncovered molecular pathways linked to neuroinflammation and synaptic dysfunction. Proteomic advancements, including mass spectrometry and extracellular vesicle profiling, have identified potential blood- and CSF-based biomarkers for early-stage detection. Metabolomic and lipidomic studies indicate that cerebral glucose hypometabolism, insulin resistance, mitochondrial damage, redox imbalance, and disrupted lipid homeostasis are centra contributors to AD pathogenesis rather than secondary considerations of the disease. These metabolic dysfunctions may precede overt neurodegeneration and influence amyloid processing, tau phosphorylation, neuroinflammatory activation, and synaptic loss, thereby generating clinically informative biomarker signatures in blood and cerebrospinal fluid. Within this metabolism-centered paradigm, integrative multi-omics approaches are particularly valuable because they not only enhance biomarker specificity, but also connect molecular signatures with bioenergetic and immune-mediated mechanisms of disease. Accordingly, integrative multi-omics approaches improve biomarker specificity and predictive power, thereby supporting the development of precision medicine and targeted therapeutic interventions. Nevertheless, important challenges remain, including data integration, reproducibility, and clinical translation.}, } @article {pmid42250112, year = {2026}, author = {Carrasco, M and Guzman, L and Barroso, E and Olloquequi, J and Cano, A and Ureña, J and Verdaguer, E and Prohens, R and Fortuna, A and Auladell, C and Ettcheto, M and Camins, A}, title = {Licochalcone a enhances cognitive resilience in APP/PS1 Mice by modulating glucose metabolism, Aβ burden, and neuroinflammation.}, journal = {GeroScience}, volume = {}, number = {}, pages = {}, pmid = {42250112}, issn = {2509-2723}, support = {PID2021-123462OB-I00//Ministerio de Ciencia e Innovación/ ; PID2023-146632OB-I00//Ministerio de Ciencia e Innovación/ ; PID2021-122473OA-I00//Ministerio de Ciencia e Innovación/ ; 2021 SGR 00288//Agència de Gestió d'Ajuts Universitaris i de Recerca/ ; Grant CB06/05/2004//CIBERNED/ ; CEX2021-001159-M//Institut de neurociencies/ ; EBLE-9051//Serra Hunter Contract/ ; UB-LE-9115//Serra Hunter Contract/ ; UB-LE-9035//Serra Hunter contract/ ; }, abstract = {Alzheimer's disease (AD) is a complex neurodegenerative disorder. Current therapeutic approaches targeting a single pathway have shown limited efficacy, highlighting the need for multi-target interventions. Licochalcone A (LCA), a chalcone of licorice root, has demonstrated anti-inflammatory and antidiabetic properties. However, its potential neuroprotective mechanisms in AD remain unclear. The present study aims to elucidate the beneficial effect of LCA against cognitive decline in an AD mouse model. For this purpose, five-month-old APPswe/PS1dE9 (APP/PS1) mice received intraperitoneal LCA (15 mg·kg[-1]·day[-1]) treatment for 4 weeks. Afterwards, cognitive function was assessed using Morris water maze (MWM) and Novel object recognition test (NORT). Metabolism was evaluated through glucose and insulin tolerance tests. Biochemical markers of synapses, neurogenesis, metabolism, Amyloid-β (Aβ) burden and neuroinflammation were analyzed using immunohistochemistry, Thioflavin-S staining, Golgi staining, Western blot, ELISA and RT-PCR. The results demonstrated that LCA significantly improved long-term memory in APP/PS1 mice, through MWM and NORT, accompanied by an increased dendritic spine density, upregulated PSD95 and spinophilin levels, and enhanced Ki67-positive cells in the hippocampus. Moreover, LCA treatment ameliorated glucose tolerance and initial insulin response while increasing Insr expression and GLUT1 protein levels. Furthermore, LCA-treated APP/PS1 mice showed reduced plaque burden and Aβ42 levels. Alongside, LCA demonstrated its anti-inflammatory effect by reducing glial reactivity, and Trem2 expression. In conclusion, the present study demonstrates the multiple therapeutic effects of LCA in APP/PS1 mice by simultaneously modulating glucose metabolism, reducing Aβ accumulation and attenuating neuroinflammation, ultimately enhancing cognitive resilience. These findings establish LCA as a promising multi-target compound for AD treatment.}, } @article {pmid42250142, year = {2026}, author = {Jalaiei, A and Kiani Darabi, AH and Sakkaki, E and Rezazadeh, M and Ghafouri-Fard, S}, title = {Molecular interplay between Non-coding RNAs and BDNF in Neurodegenerative Disorders: a systematic review.}, journal = {Molecular biology reports}, volume = {53}, number = {1}, pages = {}, pmid = {42250142}, issn = {1573-4978}, mesh = {*Brain-Derived Neurotrophic Factor/genetics/metabolism ; Humans ; *Neurodegenerative Diseases/genetics/metabolism ; MicroRNAs/genetics/metabolism ; *RNA, Untranslated/genetics/metabolism ; Animals ; Gene Expression Regulation ; RNA, Long Noncoding/genetics/metabolism ; }, abstract = {Brain-derived neurotrophic factor (BDNF), a member of the neurotrophin family, plays essential roles in nervous system development, neuronal maintenance, and neurogenesis. Aberrant BDNF concentrations, observed both peripherally and within the central nervous system (CNS), have been consistently implicated in the pathogenesis of a spectrum of neurodegenerative disorders (NDDs), including Alzheimer's disease, Parkinson's disease, Amyotrophic lateral sclerosis, Huntington's disease, and Multiple sclerosis. Non-coding RNAs (ncRNAs), such as microRNAs (miRNAs) and long non-coding RNAs (lncRNAs), regulate gene expression and are critical factors in cellular processes relevant to neurodegenerative disease pathobiology. Consequently, ncRNAs are posited as promising biomarkers and potential therapeutic modalities for CNS-related pathologies. However, robust empirical evidence substantiating ncRNA-mediated, post-transcriptional regulation of BDNF expression in the context of neurodegeneration remains relatively scarce. The objective of this systematic review is to provide a critical synthesis of the current literature on the diagnostic and prognostic utility of ncRNAs that modulate BDNF expression, specifically within the scope of neurodegenerative disorders. Furthermore, we will explore innovative therapeutic strategies centered on targeting BDNF-associated miRNAs for the treatment of these disorders.}, } @article {pmid42250492, year = {2026}, author = {Ahn, S and Salas, J and Cho, J and Scherrer, JF}, title = {Combined effect of anxiety disorder and insomnia on the risk of incident ADRD diagnosis.}, journal = {The journal of prevention of Alzheimer's disease}, volume = {13}, number = {8}, pages = {100621}, pmid = {42250492}, issn = {2426-0266}, abstract = {BACKGROUND: Anxiety disorders and insomnia are common modifiable conditions in older adults, but their independent and combined effects on the risk of incident Alzheimer's disease and related dementias (ADRD) remain unclear.

OBJECTIVES: To estimate the independent and combined associations of anxiety disorders and insomnia with the risk of incident ADRD.

DESIGN: Retrospective cohort study using an intention-to-treat approach with a 10-year follow-up period (2014-2023).

SETTING: De-identified electronic health record (EHR) data from 70 participating healthcare organizations within the TriNetX Research Network.

PARTICIPANTS: Adults aged ≥50 years without prior dementia who had regular ambulatory care during a three-year baseline period (n = 1,868,790).

MEASUREMENTS: Anxiety and insomnia were identified using ICD-based algorithms and categorized into four exposure groups: neither condition, anxiety only, insomnia only, and both. Incident ADRD was defined by two or more diagnostic codes within 12 months. Entropy balancing controlled for confounding, and weighted Cox proportional hazards models estimated hazard ratios (HRs).

RESULTS: At baseline, 4.1% had anxiety only, 3.8% had insomnia only, and 1.1% had both. Over follow-up, 2.3% developed ADRD. In weighted models, insomnia alone (HR: 1.12; 95% CI: 1.06-1.19), anxiety alone (HR: 1.49; 95% CI: 1.39-1.60), and co-occurring anxiety and insomnia (HR: 1.31; 95% CI: 1.06-1.62) were each associated with higher ADRD risk compared with neither condition. No significant effect modification by age, sex, or race was observed.

CONCLUSIONS: Anxiety and insomnia independently increase ADRD risk, though insomnia's contribution is very modest compared to the primary association demonstrated by anxiety. Co-occurrence does not confer additional risk beyond anxiety alone. Clinically, routine screening and treatment of anxiety and sleep disturbances represent actionable, broadly applicable strategies for ADRD prevention and healthy cognitive aging.}, } @article {pmid42251444, year = {2026}, author = {Contreras-Marciales, A and Mezquite-Garcia, D and Verdina, LA and Elnahrawy, A and Wolf, T and Guergues, J and Parikh, P and Hunter, ER and Hernandez Acosta, D and Stevens, SM and Hill, SE and Blair, LJ}, title = {FKBP51 inhibition by SAFit2 modulates tau pathology and cognitive deficits in PS19 mice.}, journal = {Alzheimer's research & therapy}, volume = {}, number = {}, pages = {}, doi = {10.1186/s13195-026-02107-3}, pmid = {42251444}, issn = {1758-9193}, support = {R01 NS073899/NS/NINDS NIH HHS/United States ; R01 NS073899/AG/NIA NIH HHS/United States ; I01 BX004626/BX/BLRD VA/United States ; AARG-22-974562/ALZ/Alzheimer's Association/United States ; }, abstract = {The accumulation of pathogenic tau protein is linked to cognitive decline and neuronal loss in Alzheimer's disease (AD), with tau oligomers identified as particularly neurotoxic. The 51 kDa FK506-binding protein (FKBP51) stabilizes these toxic tau oligomers and has been identified as a risk factor for several neurodegenerative diseases. FKBP51 levels increase with age and are especially high in AD brains, suggesting its involvement in disease progression. The development of the selective FKBP51 inhibitor, SAFit2, which can cross the blood-brain barrier, has shown promise in reducing stress hormones, improving stress responses, and mitigating protein-related pathologies in other neurodegenerative models. However, the effects of SAFit2 on tauopathies, such as those seen in AD, have not yet been investigated. Here, the effects of the FKBP51-selective inhibitor, SAFit2, were evaluated in PS19 tau transgenic mice. Mice received a 28-day regimen of SAFit2, followed by comprehensive behavioral, neuropathological, and proteomic analyses. SAFit2 demonstrated effective brain penetrance, with sex-dependent pharmacokinetics. Treatment slowed cognitive decline and depressive-like behavior, with pronounced benefits in male PS19 mice, including improved spatial memory and reduced tau oligomer burden. In females, SAFit2 promoted clearance of AT8-positive tau multimers with some benefit to recognition memory. Proteomic profiling revealed distinct molecular signatures underlying these sex-specific responses: males exhibited upregulation of RNA processing and ribosomal proteins, while females showed restoration of calcium signaling and synaptic drivers. Notably, behavioral recovery occurred independently of widespread neuroinflammation reversal. These findings provide the first in vivo evidence that FKBP51 inhibition by SAFit2 induces sex-specific remodeling of the brain proteome. This study also provides further evidence for the therapeutic benefits of targeting FKBP51 for tauopathies.}, } @article {pmid42251712, year = {2026}, author = {Reyzov, M and Valcheva-Kuzmanova, S}, title = {Neuropsychopharmacological effects of Aronia melanocarpa: A narrative review.}, journal = {Psychiatria Danubina}, volume = {38}, number = {1}, pages = {12-22}, doi = {10.24869/psyd.2026.12}, pmid = {42251712}, issn = {0353-5053}, mesh = {Animals ; Humans ; Cognitive Enhancement/methods ; *Photinia ; *Plant Extracts/pharmacology ; *Nootropic Agents/pharmacology ; }, abstract = {BACKGROUND: This narrative review examines the neuropsychopharmacological effects of Aronia melanocarpa (black chokeberry), focusing on its potential in the prevention and treatment of neuropsychiatric disorders such as anxiety, depression, and cognitive decline.

SUBJECTS AND METHODS: A comprehensive literature search across Web of Science, Scopus, and Google Scholar identified 29 original studies, based on in vitro, animal, and human research.

RESULTS: Findings demonstrated that Aronia melanocarpa, rich in polyphenols like anthocyanins and proanthocyanidins, exerts cognitive-enhancing, anxiolytic-like, and antidepressant-like effects. These outcomes are mediated by mechanisms involving antioxidant activity, modulation of neurotransmitter systems, inhibition of monoamine oxidases, reduction of neuroinflammation, modulation of gut microbiota, and upregulation of brain-derived neurotrophic factor (BDNF). Animal models of Alzheimer's disease and stress-induced disorders, along with human clinical trials, corroborated these effects.

CONCLUSIONS: The review underscores the therapeutic promise of Aronia melanocarpa nutraceuticals in neuropsychiatric health and highlights the need for further clinical validation.}, } @article {pmid42252274, year = {2026}, author = {Yu, Z and Wang, Y and Li, Y and Shen, F and Wang, Y}, title = {[Research progress on vascular endothelial growth factor C in meningeal lymphatic vessel-mediated clearance of amyloid β-protein].}, journal = {Zhejiang da xue xue bao. Yi xue ban = Journal of Zhejiang University. Medical sciences}, volume = {}, number = {}, pages = {1-8}, doi = {10.3724/zdxbyxb-2025-0549}, pmid = {42252274}, issn = {1008-9292}, abstract = {Alzheimer's disease (AD) is a neurodegenerative disorder characterized by the abnormal deposition of amyloid β-protein (Aβ) as a core pathological feature. Meningeal lymphatic vessels are crucial for Aβ clearance, and their dysfunction accelerates AD progression. Vascular endothelial growth factor C (VEGF-C), through activation of vascular endothelial growth factor receptor 3 and downstream pathways, synergistically promotes lymphangiogenesis, enhances lymphatic permeability, and regulates lymphatic fluid flow, thereby improving Aβ clearance efficiency. Genetic factors and aging-related declines in VEGF-C further impair meningeal lymphatic function, creating a vicious cycle. Although VEGF-C intervention has shown cognitive benefits in AD models, clinical translation faces challenges including non-specific activation of signaling pathways and interindividual variability. Future research should focus on precise regulation of VEGF-C and development of individualized AD therapeutic strategies targeting meningeal lymphatic vessels. This review summarizes the molecular mechanisms, influencing factors, and intervention strategies of VEGF-C in regulating meningeal lymphatic vessel function to promote Aβ clearance, aiming to provide insights for AD prevention and treatment.}, } @article {pmid42252335, year = {2026}, author = {Behl, T and Jayabalan, K and Ballal, S and Sahoo, S and Jayasingh Chellammal, HS and Gulati, M and Anand, K and Jha, SK and Gasmi, A}, title = {A Age Related Vascular Senescence: Mystery of Blood-brain Barrier Dysfunction in Neurodegeneration.}, journal = {Molecular neurobiology}, volume = {63}, number = {1}, pages = {}, pmid = {42252335}, issn = {1559-1182}, mesh = {Humans ; *Blood-Brain Barrier/pathology/physiopathology/metabolism ; *Aging/pathology ; Animals ; *Neurodegenerative Diseases/pathology/physiopathology ; }, abstract = {The pathophysiology of neurodegenerative illnesses is increasingly understood to be influenced by vascular aging, with blood-brain barrier (BBB) disruption emerging as a crucial mechanistic connection. Comprising endothelial cells, pericytes, astrocytes, and microglia, the BBB is a complex neurovascular unit (NVU) that strictly regulates molecular trafficking and shields neural tissue from circulating toxins and immune cells, therefore maintaining central nervous system homeostasis. The integrity of the BBB is compromised as people age due to structural and functional changes in the cerebrovasculature, such as endothelial senescence, pericyte loss, mitochondrial dysfunction, and persistent low-grade inflammation. These alterations speed up neuronal damage and encourage the development of classical proteinopathies like tau aggregation and amyloid-β by making it easier for neurotoxic proteins, immunological mediators, and metabolic waste to enter the brain parenchyma. BBB disruption is both an early occurrence and a factor in the development of neurodegenerative diseases including Alzheimer's disease, cerebral amyloid angiopathy, and vascular dementia. It exacerbates neuroinflammation, hinders clearance processes, and contributes to cognitive decline. Recent developments in single-cell omics, fluid biomarkers, and molecular imaging have made it possible to identify and characterize BBB failure in preclinical and clinical contexts, creating new opportunities for early diagnosis and treatment. Restoring BBB function and addressing vascular aging are two viable approaches to alter the course of neurodegenerative illnesses and enhance their prognoses. The processes, effects, and translational potential of vascular aging and BBB degradation in neurodegeneration are summarized in this review, which also identifies new treatment targets and research objectives for the future.}, } @article {pmid42252551, year = {2026}, author = {Chiatto, LM and Buccarello, L and Carota, G and Calabrò, RS and Rifici, C and Esposito, E and Ardizzone, A and Caruso, G}, title = {The Use of Statins in Parkinson's and Alzheimer's Disease: A 2021-2025 State-of-the-Art Review of Clinical and Preclinical Evidence.}, journal = {Pharmacology research & perspectives}, volume = {14}, number = {3}, pages = {e70280}, pmid = {42252551}, issn = {2052-1707}, mesh = {Humans ; *Alzheimer Disease/drug therapy ; *Hydroxymethylglutaryl-CoA Reductase Inhibitors/therapeutic use/pharmacology ; Animals ; *Parkinson Disease/drug therapy ; Drug Repositioning ; }, abstract = {Statins, widely prescribed for cardiovascular prevention, have emerged as potential disease-modifying agents in neurodegenerative disorders due to their pleiotropic effects on cholesterol metabolism, neuroinflammation, oxidative stress, and protein aggregation. Over the past decade, growing interest has focused on the potential repurposing of statins for Parkinson's disease (PD) and Alzheimer's disease (AD); however, clinical evidence remains heterogeneous and, in some cases, contradictory. This state-of-the-art review synthesizes clinical and preclinical studies published between 2021 and 2025 to critically evaluate the therapeutic potential and limitations of statins in PD and AD. Recent observational studies and large-scale cohort analyses suggest that long-term statin use may be associated with a reduced risk of incident PD and AD, as well as slower cognitive decline in selected patients' subgroups. However, these associations appear to depend on factors such as statin lipophilicity, treatment duration, and genetic background. Preclinical models provide mechanistic support, showing that statins can attenuate neuroinflammation, modulate microglial activation, reduce α-synuclein aggregation in PD models, and interfere with amyloid-β production and tau phosphorylation in AD models. Nevertheless, randomized controlled trials remain limited in number and often underpowered, and some reports indicate neutral or even adverse neurological outcomes, underscoring the complexity of cholesterol-dependent and cholesterol-independent mechanisms in the central nervous system (CNS). Collectively, the evidence from 2021 to 2025 highlights both the therapeutic promise and the unresolved challenges of statin repurposing in neurodegenerative diseases. Future research should prioritize well-designed clinical trials and biomarker-driven patient stratification to determine whether statins can be effectively leveraged as adjunctive disease-modifying therapies in PD and AD.}, } @article {pmid42252587, year = {2026}, author = {Jin, H}, title = {PET Molecular Probes for Neuroinflammation in Neurodegenerative Diseases: Progress and Prospects.}, journal = {ACS chemical neuroscience}, volume = {17}, number = {12}, pages = {2229-2237}, doi = {10.1021/acschemneuro.6c00338}, pmid = {42252587}, issn = {1948-7193}, mesh = {Humans ; *Neurodegenerative Diseases/diagnostic imaging/metabolism ; *Positron-Emission Tomography/methods ; Animals ; *Neuroinflammatory Diseases/diagnostic imaging/metabolism ; Receptors, GABA/metabolism ; *Molecular Probes/metabolism ; *Brain/metabolism/diagnostic imaging ; }, abstract = {Neuroinflammation is a central pathological process underlying neurodegenerative diseases, including Alzheimer disease (AD), Parkinson disease (PD), and amyotrophic lateral sclerosis. Positron emission tomography (PET) molecular probes now enable the noninvasive, quantitative visualization of neuroinflammatory processes in the living brain. This review surveys recent advances in PET probes targeting microglial activation markers─including the 18 kDa translocator protein (TSPO), the purinergic P2X7 receptor (P2X7R), colony-stimulating factor 1 receptor (CSF1R), and sphingosine-1-phosphate receptor 1 (S1PR1)─as well as astrocyte reactivity markers such as monoamine oxidase B (MAO-B) and imidazoline-2 binding sites (I2BS). I discuss the evolution from first-generation TSPO ligands to polymorphism-insensitive third-generation tracers, highlight emerging targets beyond TSPO, and evaluate the translational value of these probes for early diagnosis, disease staging, treatment monitoring, and drug development. Current challenges-including limited cellular specificity, genetic polymorphism effects, quantification difficulties, and clinical accessibility barriers─are analyzed alongside promising solutions. Integrating neuroinflammation PET into multimodal biomarker frameworks will be essential for advancing precision medicine in neurodegenerative diseases.}, } @article {pmid42253201, year = {2026}, author = {Tarkowska, A and Furmaga-Jabłońska, W and Pluta, R}, title = {Long-Term Consequences of Perinatal Asphyxia in the Development of Alzheimer's Disease.}, journal = {Current Alzheimer research}, volume = {}, number = {}, pages = {}, doi = {10.2174/0115672050432278251204130006}, pmid = {42253201}, issn = {1875-5828}, abstract = {Despite remarkable progress in medicine, perinatal asphyxia (PA) remains a significant clinical problem, and concerns regarding its long-term complications are increasingly being raised. Emerging evidence indicates that similar pathological pathways are activated following PA and during neurodegeneration in Alzheimer's disease (AD). These similarities involve various mechanisms, including alterations in AD-related proteins and their gene expression. Disturbances in neurotransmitter function can lead to excitotoxicity and cell death via necrosis and delayed apoptosis. Additionally, as observed in AD, dysregulation of autophagic processes has been reported. Pathological changes initiated by hypoxia in the newborn may trigger chronic neuroinflammation that persists long-term. Similarly, neuroinflammation plays a critical role in the pathogenesis of AD. Other common mechanisms include oxidative stress and mitochondrial dysfunction. Estrogens appear to have a protective effect in both PA and AD; however, ovaries exposed to PA may exhibit a reduced ovarian reserve, potentially diminishing neuroprotection later in life. Epigenetic modifications have also been proposed as a link between PA and AD. This review focuses on the changes that occur in the neonatal brain following PA, with particular emphasis on long-term consequences. We highlight common pathogenetic and causal pathways that may connect PA to the development of AD. Furthermore, we summarize key studies from the past 25 years addressing these topics and briefly discuss current research directions in the treatment of experimental and clinical PA.}, } @article {pmid42253387, year = {2025}, author = {Persaud, V and Wertheimer, AI}, title = {Assessing the Equitable Use of Formulary Drug Tier Systems: Consequences for Geriatric Patient Population Access and Accessible Medication.}, journal = {Innovations in pharmacy}, volume = {16}, number = {2}, pages = {}, pmid = {42253387}, issn = {2155-0417}, abstract = {Background: This study examines the implications of formulary drug tier systems on the accessibility and affordability of medications for the elderly/geriatric population within the New York metropolitan area. By systematically reviewing the Medicare insurance formularies and evaluating the most prescribed medicines with reported beneficial outcomes for ailments frequently experienced by the geriatric population, this research identifies disparities in drug tier placements and the cost of dispensing that may affect patient outcomes. The focus is on five prevalent conditions: Alzheimer's dementia, Chronic Obstructive Pulmonary Disease, Rheumatoid Arthritis, Ischemic Heart Disease, and Diabetes Mellitus Type 2 (T2DM). The findings aim to highlight the need for more equitable healthcare policies that consider the financial and medical needs of the elderly population. Methods: This study reviewed the formulary tier systems used by Medicare, the primary insurance provider for the elderly in New York City. The research focused on medications prescribed for Alzheimer's disease, COPD, rheumatoid arthritis, ischemic heart disease, and diabetes. Data on tier placements were extracted from Medicare Part D formularies, with a detailed examination of the criteria for tier assignment. The study identified the three most prescribed medications for each condition, using data from relevant health organizations and literature. An economic analysis was conducted to compare the costs associated with these medications, assessing the financial burden on patients. Results: The study revealed a prevalence of chronic conditions among New York City's elderly population. Medications commonly prescribed for these conditions were reviewed, with a focus on their placement within the Medicare Formulary Tier system and associated costs. The analysis highlighted substantial variations in cost and tier placement, affecting patient affordability and adherence. For example, Alzheimer's medications like galantamine and rivastigmine were found in higher tiers, leading to increased out-of-pocket expenses, while COPD treatments such as Symbicort and Trelegy Ellipta, although in preferred tiers, still imposed significant financial burdens. Rheumatoid arthritis drugs showed a wide cost range, with Humira in Tier 5 presenting the highest financial challenge. Similarly, ischemic heart disease and type 2 diabetes medications varied in affordability, with drugs like Eliquis and Steglatro positioned in higher tiers, significantly impacting patient costs and potential treatment adherence. Conclusion: Elderly patients in the United States, especially those dealing with chronic conditions are facing a substantial financial strain due to the increasing prices of prescription medications. Even with recent initiatives like the Inflation Reduction Act aimed at lowering expenses, the financial burden persists, causing issues with treatment adherence and negative health results. The results highlight the pressing requirement for more effective policy actions that support price transparency, promote the utilization of cost-effective generics, and deter the unwarranted classification of generic drugs in higher formulary tiers. It is crucial to handle these problems to guarantee fair access to medications for all elderly individuals, specifically those who qualify for both Medicare and Medicaid.}, } @article {pmid42253437, year = {2026}, author = {Harel, M and Leibovici, A and Itzhaki, N and Ravona-Springer, R and Moshier, E and Doniger, GM and Gottlieb, A and Bahat, Y and Bendlin, BB and Zeilig, G and Plotnik, M and Beeri, MS and Livny, A}, title = {Virtual reality-based cognitive-motor training in middle-aged adults at high Alzheimer's disease risk improves frontal cortex cerebral blood flow: A randomized controlled trial.}, journal = {Alzheimer's & dementia (New York, N. Y.)}, volume = {12}, number = {2}, pages = {e70265}, pmid = {42253437}, issn = {2352-8737}, abstract = {INTRODUCTION: Alzheimer's disease (AD) pathological processes begin decades before symptom onset. Early intervention in high-risk populations may be crucial for prevention. We investigated the effect of an intervention utilizing virtual reality (VR) cognitive-motor training on cerebral blood flow (CBF) and cognitive functioning in middle-aged adults at high AD risk due to parental history.

METHODS: In this randomized controlled trial, participants (n = 79) were randomly assigned to: VR cognitive-motor training while walking on a treadmill (VR+T, n = 24, treatment); VR cognitive training without treadmill (VR-T, n = 21, active control); treadmill walking while watching documentaries (TV+T, n = 20, active control); or no intervention (n = 14, passive control). Training consisted of 45-min sessions, twice weekly, for 12 weeks. CBF was measured at resting state using arterial spin labeling (ASL) at baseline, 3-month, and 6-month follow-up. Cognition was assessed using a comprehensive neuropsychological battery. We applied the intent-to-treat approach.

RESULTS: All groups improved in executive functions and memory over time (all p-values < 0.05), with no consistent between-group differences at follow-up. CBF of the VR+T group significantly increased at 3 months in the superior (p = 0.013, middle (p = 0.014), and inferior (p = 0.003) frontal gyri compared to the passive control group, which showed a decline in CBF over the same period. No significant differences in frontal CBF change were observed between VR+T and the TV+T active control group. This increase was sustained for 6 months in the superior (p = 0.035) and middle (p = 0.028) frontal gyri. In contrast, in the middle temporal gyrus, the VR+T group had lower CBF at 3 months, compared to the VR-T (p = 0.033) and to the passive control groups (p = 0.004).

DISCUSSION: Cognitive-motor VR training increased CBF in frontal regions susceptible to early AD-related changes in middle-aged adults at high AD risk. This intervention shows promise as a preventive approach and may be suitable for implementation as a home-based program for individuals at high risk.}, } @article {pmid42255952, year = {2026}, author = {Sonson, M and Yadollahikales, G and Flores, A and Lasner, I and Lee, S and Tan, Z and Quach, C and Kremen, S}, title = {From clinical trial to clinical experience: Lecanemab therapy in a real-world case series.}, journal = {Alzheimer's & dementia (Amsterdam, Netherlands)}, volume = {18}, number = {2}, pages = {e70365}, pmid = {42255952}, issn = {2352-8729}, abstract = {The approval of anti-amyloid therapies has expanded therapeutic options for patients with Alzheimer's disease (AD), but the pivotal trials that proved their efficacy restrict their applicability to a selected patient population. We describe a case series of seven patients with biomarker-confirmed AD pathology evaluated in an academic memory clinic and treated with lecanemab whose characteristics would have disqualified them from trial participation. Patient histories and outcomes are presented, accompanied by description of the clinical team's reasoning and application of published Appropriate Use Recommendations for each case. Overall, lecanemab was largely well tolerated, with no unexpected safety concerns and amyloid-related imaging abnormality rates comparable to trial data. Clinically, most patients remained stable over the treatment period, though some continued to decline. This series highlights the challenges and considerations in applying disease-modifying therapies beyond trial populations, emphasizing the need for real-world data to guide treatment in diverse AD presentations.}, } @article {pmid42255953, year = {2026}, author = {Wallace, A and Zhou, O and Hoang, MN and Porter, G and Padilla, C and Marshall, C}, title = {Lecanemab and amyloid-related imaging abnormalities: Real-world data from a single center experience.}, journal = {Alzheimer's & dementia (Amsterdam, Netherlands)}, volume = {18}, number = {2}, pages = {e70377}, pmid = {42255953}, issn = {2352-8729}, abstract = {INTRODUCTION: Lecanemab has demonstrated both safety and efficacy in clinical trials; however, routine clinical data are sparse. We contribute to the growing body of real-world safety data, with a special focus on amyloid-related imaging abnormalities (ARIA).

METHODS: We conducted a retrospective chart review of 146 patients treated with lecanemab according to appropriate-use recommendations at a specialty memory center clinic.

RESULTS: Real-world safety and efficacy data closely resemble published data in the Clarity-AD trial. Thirty-three patients (23%) discontinued treatment; all remaining patients completed at least 12 months of treatment. We observed a positive trend toward increasing ARIA edema/effusion (ARIA-E) with increasing mean arterial pressure and a mean amyloid clearance of -90.6 at 18 months.

DISCUSSION: When used according to appropriate-use recommendations, lecanemab is as safe as reported in the Clarity-AD trial. Further investigation into real-world data is necessary for a more complete evaluation of lecanemab's safety and efficacy.}, } @article {pmid42255958, year = {2026}, author = {Trudel, L and Therriault, J and Macedo, AC and Meeker, KL and Braskie, MN and Toga, AW and Gauthier, S and Vitali, P and Schindler, SE and O'Bryant, SE and Rosa-Neto, P}, title = {Eligibility for anti-amyloid treatment in a multiethnic community-based study.}, journal = {Alzheimer's & dementia (Amsterdam, Netherlands)}, volume = {18}, number = {2}, pages = {e70314}, pmid = {42255958}, issn = {2352-8729}, abstract = {INTRODUCTION: The approval of anti-amyloid monoclonal antibodies (mAbs), including lecanemab and donanemab, represents a significant advance in disease-modifying therapies (DMTs) for early Alzheimer's disease (AD). While appropriate use recommendations (AURs) have been established to guide clinical decision-making, the proportion of individuals with cognitive impairment in real-world, multiethnic populations meeting eligibility criteria remains unknown, as do potential differences in treatment-related risks across ethnic groups.

METHODS: We included 513 cognitively impaired individuals from the Health and Aging Brain Study-Health Disparities study, a multiethnic community-based cohort. Eligibility for lecanemab and donanemab was determined using published AUR criteria. Counts of amyloid-related imaging abnormalities were estimated based on apolipoprotein E (APOE) ε4 genotype and ethnicity using published incidence rates.

RESULTS: Only 15% of participants met eligibility criteria for lecanemab or donanemab. Black individuals had a numerically higher estimated ARIA burden, though differences were not statistically significant.

DISCUSSION: Few individuals in this community-based, multiethnic cohort met eligibility for anti-amyloid therapy, highlighting limited real-world applicability of current AURs.

HIGHLIGHTS: Only 15% of community-based individuals with MCI or dementia met eligibility criteria for lecanemab and donanemab.Black participants had numerically higher estimated ARIA cases, though not statistically significant.Current AUR criteria have limited real-world applicability across multiethnic populations.Broader inclusion criteria and real-world safety data are needed to ensure equitable, safe implementation.}, } @article {pmid42255964, year = {2026}, author = {Rosenbloom, M and Adams, C and Allen, B and Berry, B and Camargo, C and Cooper, G and Giles, S and Leahy, C and Sabbagh, M and Sadowski, M and Schreiber, C and Schulz, PE and Soria, J and Weisman, D and Frech, F and Jones, DR}, title = {Real-world use of lecanemab: patient pathway findings from a US multicenter study.}, journal = {Alzheimer's & dementia (Amsterdam, Netherlands)}, volume = {18}, number = {2}, pages = {e70376}, pmid = {42255964}, issn = {2352-8729}, abstract = {INTRODUCTION: To ensure Alzheimer's disease-modifying treatments can be initiated in diverse populations, efficient pathways to obtain timely diagnoses are required.

METHODS: This interim sub-analysis of a multicenter US study included cross-sectional surveys and interviews with neurologists at 12 diverse sites to assess real-world lecanemab use.

RESULTS: At survey completion, ∼1342 patients had received lecanemab. Most referrals originated from primary care. Amyloid pathology was confirmed primarily by positron emission tomography (58%) or cerebrospinal fluid (35%), with blood-based biomarkers (BBMs) increasingly used to reduce diagnostic delays. All sites performed apolipoprotein E4 (APOE ε4) testing to inform risk/benefit decisions. Infusions usually started within 6 months of diagnosis. Delayed/incomplete referrals were identified as the most significant barrier in the current patient pathway.

DISCUSSION: These findings demonstrate the feasibility of lecanemab integration in diverse clinical settings and highlight the importance of primary care physician engagement, optimization of referral pathways, and expanding BBM use in improving timely diagnosis, equitable access, and early treatment initiation.}, } @article {pmid42255966, year = {2026}, author = {Li, Y and Zhao, Y and Yang, A and Wang, Y and Xin, J and Chen, Y and Xing, X and Liu, F and Zou, Y and Zhao, W and Song, L and Gong, T and Wang, G}, title = {Lecanemab treatment modulates brain volume and cerebrospinal fluid pathways in early Alzheimer's disease: Insights from longitudinal magnetic resonance imaging.}, journal = {Alzheimer's & dementia (Amsterdam, Netherlands)}, volume = {18}, number = {2}, pages = {e70348}, pmid = {42255966}, issn = {2352-8729}, abstract = {INTRODUCTION: Lecanemab provides clinical benefits in early Alzheimer's disease (AD), but its longitudinal effects on brain structure, particularly cerebrospinal fluid (CSF) compartments, remain unclear. This study examined treatment-associated structural changes using longitudinal MRI.

METHODS: Thirty-one patients with mild cognitive impairment (MCI) or early AD underwent baseline and follow-up (1-7 months) 3D T1-weighted MRI during lecanemab treatment. Gray matter (GM), ventricular, choroid plexus (CP), and perivascular space (PVS) volumes were quantified. Longitudinal changes were analyzed with paired tests and linear mixed-effects models (LMMs).

RESULTS: Significant GM volume reductions were observed in AD-vulnerable regions (hippocampus, entorhinal cortex, precuneus), with increased CSF volumes. PVS volume showed a modest, non-significant decline. CP enlargement was associated with ventricular expansion.

DISCUSSION: Lecanemab treatment was associated with coordinated parenchymal and CSF-related structural changes. CP and PVS dynamics may represent potential MRI-based markers for monitoring early AD.}, } @article {pmid42256567, year = {2026}, author = {Rus Prelog, P and Zupan, M and Kovačič, A and Frol, S and Gregorič Kramberger, M}, title = {Amyloid-targeting treatment in Alzheimer's disease and concomitant antiplatelets: a clinical gray zone?.}, journal = {Frontiers in neurology}, volume = {17}, number = {}, pages = {1814289}, pmid = {42256567}, issn = {1664-2295}, } @article {pmid42256792, year = {2026}, author = {Dong, Y and Bai, X and Chen, Y and Wang, J and Cui, Q and Fan, L and Li, S and Qiu, Y}, title = {Timosaponin B-II attenuates hemorrhagic transformation-driven acceleration of alzheimer disease-related pathology after ischemic stroke.}, journal = {Biochemistry and biophysics reports}, volume = {46}, number = {}, pages = {102654}, pmid = {42256792}, issn = {2405-5808}, abstract = {Hemorrhagic transformation (HT) is a major complication of reperfusion therapy after ischemic stroke, but its impact on Alzheimer disease (AD) progression remains unclear. In this study, we used an early-stage APP/PS1 mouse model and found that HT following transient middle cerebral artery occlusion(tMCAO) aggravated cognitive impairment and promoted AD-like pathological changes, which were markedly attenuated by Timosaponin B-II (TB-II) treatment. TB-II effectively alleviated HT following tMCAO(tMCAO/HT)-induced cognitive and recognition memory deficits in APP/PS1 mice and reduced hippocampal Aβ42 production. In vitro, TB-II pretreatment reversed oxygen-glucose deprivation/reoxygenation (OGD/R) and hemin-induced increases in Aβ42 production and apoptotic propensity, as well as decreases in mitochondrial membrane potential and cell viability in N2a/APPswe cells. Mechanistically, TB-II activated NRF2, which in turn indirectly modulating GSK-3β-mediated APP phosphorylation and negatively regulated BACE1 transcription through binding promoter binding, ultimately suppressing amyloidogenic processing. Together, our findings suggest that TB-II may serve as a potential therapeutic agent against HT-associated acceleration of AD-like pathology after ischemia-reperfusion.}, } @article {pmid42257639, year = {2026}, author = {Kleiner, G and Lang, AE}, title = {Paratonia in Advanced Dementia: Deconstructing Scientific, Regulatory, and Health System Barriers to Botulinum Toxin A (BoNT-A) Treatment of Involuntary Muscle Resistance.}, journal = {Journal of the American Medical Directors Association}, volume = {}, number = {}, pages = {106285}, doi = {10.1016/j.jamda.2026.106285}, pmid = {42257639}, issn = {1538-9375}, abstract = {Paratonia, a movement disorder characterized by involuntary muscle resistance, affects nearly all people with advanced dementia and contributes to caregiver burden, hygiene complications, pressure injuries, and pain. With Alzheimer's disease and related dementias affecting 7.2 million Americans and projected to reach nearly 14 million by 2060, the clinical impact of paratonia will expand proportionally. Because the involuntary muscle resistance of paratonia is frequently misinterpreted as deliberate noncompliance, individuals may receive inappropriate pharmacologic management rather than targeted treatment of the underlying movement disorder. No treatments are currently approved specifically for paratonia-induced muscle postures. Passive motion therapy, which the Centers for Medicare & Medicaid Services quality standards promote for contracture prevention in nursing homes, showed no benefit for paratonia in a randomized controlled trial of individuals with advanced dementia. Furthermore, passive movement therapy may paradoxically reinforce abnormal motor patterns by triggering increased involuntary resistance, the defining feature of paratonia. Botulinum toxin A, in therapeutic use since 1989, with Food and Drug Administration approval, is an established treatment for post-stroke spasticity and cervical dystonia. These conditions, like paratonia, arise from distinct central nervous system pathologies but share a peripheral manifestation of involuntary sustained muscle contraction. Preliminary clinical evidence suggests potential safety and efficacy for paratonia-induced muscle postures. Despite the therapeutic rationale and preliminary evidence for safety and efficacy, pharmaceutical companies have not pursued regulatory approval for the paratonia indication. This article examines barriers to clinical development, including scientific uncertainties, knowledge gaps, infrastructure limitations, therapeutic nihilism, policy barriers, and pharmaceutical industry considerations. We propose coordinated stakeholder action across research, education, policy, and regulatory domains to establish pathways toward further research and, if warranted, clinical implementation.}, } @article {pmid42259049, year = {2026}, author = {Wang, C and Song, X and Chen, D and Su, J and Wang, Y and Huang, C and Wei, W}, title = {Gold-nanocube-based SERS sensor for accurate detection of Alzheimer's disease biomarkers: Aβ42 and MAO-B.}, journal = {Spectrochimica acta. Part A, Molecular and biomolecular spectroscopy}, volume = {362}, number = {}, pages = {128185}, doi = {10.1016/j.saa.2026.128185}, pmid = {42259049}, issn = {1873-3557}, abstract = {Considering the irreversible nature of Alzheimer's disease (AD), early diagnosis is of great importance for AD treatment. Both β-amyloid (Aβ) and monoamine oxidase B (MAO-B) are potential biomarkers for AD. This study developed a surface-enhanced Raman scattering (SERS) sensor using gold-nanocube (OX-AuNCs) to detect Aβ42 and MAO-B. OX-AuNCs, a type of gold-nanocube with open gaps, achieved a Raman enhancement factor of 8.99 × 10[8] due to numerous hot spots. The specific affinity between Thioflavin T (ThT) and Aβ42 inhibits ThT's intramolecular rotation, reducing its SERS signal. This reduced signal showed a linear correlation with Aβ42 concentrations from 66.70 pM to 0.20 μM, achieving a limit of detection (LOD) at 44.30 pM, while also distinguishing different aggregation levels of Aβ42. Interestingly, SERS intensity of phenethylamine (PEA) also decreased significantly when interacting with MAO-B. A linear relationship was found between the change in PEA intensity and MAO-B concentration (0.01-20.00 μg mL[-1]), yielding an LOD of 5.00 ng mL[-1]. The proposed SERS sensor effectively detected two potential AD biomarkers, Aβ42 and MAO-B, in artificial cerebrospinal fluid (ACSF) and human serum with satisfactory recovery rates, respectively. These results show promise for clinical diagnosis and drug screening for AD.}, } @article {pmid42259474, year = {2026}, author = {Ma, Z and Yang, Z and Xiao, Z and Huang, B and Wang, X}, title = {Unveiling the multi-target mechanisms of Zuo Gui Wan in Alzheimer's disease: An integrated study combining network pharmacology, Mendelian Randomization, and molecular docking.}, journal = {Brain research bulletin}, volume = {243}, number = {}, pages = {111972}, doi = {10.1016/j.brainresbull.2026.111972}, pmid = {42259474}, issn = {1873-2747}, abstract = {PURPOSE: Zuo Gui Wan (ZGW), a traditional Chinese medicine formula, shows neuroprotective potential, but the mechanisms underlying its therapeutic effects on Alzheimer's disease (AD) remain unclear. This study aims to identify the active components, molecular targets, and biological pathways of ZGW in AD using an integrated systems pharmacology approach combining network analysis and causal inference.

METHODS: Active ZGW ingredients and targets were sourced from TCMSP and BATMAN-TCM. Summary-data-based Mendelian Randomization (SMR) and colocalization analyses integrated eQTL and AD GWAS data to identify gene-AD associations. Network pharmacology, GO/KEGG enrichment, PPI analysis, and molecular docking were conducted. Selected targets were examined by CCK-8 assay and Western blot in an Aβ25-35-induced SH-SY5Y neuronal injury model treated with ZGW-containing rat serum.

RESULTS: We identified 134 bioactive ZGW compounds targeting 391 AD-related genes. SMR prioritized six targets (ACE, SRC, STAT1, LEP, EGFR, and MAPK3) associated with neuroinflammatory and cardiovascular pathways. Molecular docking suggested strong interactions between key compounds and targets, notably berberine with SRC (-10.53 kcal/mol) and compound 1 (PubChem CID: 137704703) with MAPK3 (-17.22 kcal/mol). In the Aβ-induced neuronal model, ZGW-containing serum partially restored cell viability, reduced ERK1/2 and STAT1 phosphorylation, and increased ACE expression.

CONCLUSION: Integrated computational analyses prioritized six potential AD-related targets of ZGW, including ACE, SRC, STAT1, LEP, EGFR, and MAPK3. Preliminary cellular experiments further supported the involvement of MAPK3/ERK and STAT1 signaling, with increased ACE expression observed after ZGW treatment. These findings provide mechanistic insight into the potential therapeutic effects of ZGW in AD.}, } @article {pmid42261768, year = {2026}, author = {Deng, R and Shargorodsky, A and Teopiz, K and Dri, CE and Wong, S and Le, GH and Zheng, YJ and McIntyre, RS}, title = {Lithium and long-term cognitive outcomes in bipolar disorder and early dementia: a systematic review.}, journal = {CNS spectrums}, volume = {31}, number = {1}, pages = {e18}, doi = {10.1017/S1092852926100996}, pmid = {42261768}, issn = {2165-6509}, mesh = {Humans ; *Bipolar Disorder/drug therapy/psychology ; *Lithium Compounds/therapeutic use ; *Cognitive Dysfunction/drug therapy ; *Antimanic Agents/therapeutic use ; *Dementia/drug therapy/psychology ; Randomized Controlled Trials as Topic ; *Alzheimer Disease/drug therapy/psychology ; Cognitive Enhancement ; }, abstract = {Cognitive impairment is a major determinant of disability in bipolar disorder (BD) and a defining feature of both mild cognitive impairment (MCI) and Alzheimer's disease (AD). Lithium, a first-line maintenance treatment for BD, is implicated in neuroprotective mechanisms including glycogen synthase kinase-3β inhibition, amyloid and tau modulation, and neurogenesis promotion. The overarching aim of this systematic review is to evaluate the long-term effects of lithium on cognition across BD, MCI, and early-to-moderate AD using randomized controlled trial (RCT) evidence. Online databases were searched from inception through May 2025 for RCTs reporting lithium's effect on cognitive outcomes in BD, MCI, or early-to-moderate AD with ≥8 weeks of follow-up. Risk of bias was assessed using the Cochrane RoB 2 tool. Eight RCTs met the inclusion criteria, ranging from 10 weeks to 3 years in duration. Across four BD trials, lithium did not exhibit consistent improvement or worsening on composite cognitive scores. Three of four MCI/AD trials reported attenuated global cognitive deterioration with low-dose lithium, especially when exposure was ≥12 months. Methodological limitations included small sample sizes, exploratory endpoints, and variable measures for cognitive function as well as lithium strategies. Lithium demonstrates preliminary signals of slower cognitive decline in MCI/AD. Available evidence suggests lithium has neutral effects on cognitive impairment in BD. Future adequately powered RCTs with cognition as a primary endpoint, functional measures, and biomarker outcomes are warranted to clarify lithium's role as a maintenance treatment in psychiatric disorders and its potential neuroprotective effects in neurodegenerative diseases.}, } @article {pmid42262554, year = {2026}, author = {Paulzen, M}, title = {[Dextromethorphan-bupropion for the treatment of agitation in Alzheimer's disease].}, journal = {Der Nervenarzt}, volume = {97}, number = {4}, pages = {411-414}, pmid = {42262554}, issn = {1433-0407}, } @article {pmid42263197, year = {2026}, author = {Miller, D and Lambert, S and Jordan, L and Butler, MJ and Sinvani, L and Perrin, A and Cheung, YK and Davidson, KW and Goodwin, AM}, title = {Multicomponent Behavior Change Technique Intervention for Caregivers of People With Alzheimer Disease and Related Dementias: Protocol for a Single-Arm, Personalized Behavioral Trial to Disrupt Sedentary Time.}, journal = {JMIR research protocols}, volume = {15}, number = {}, pages = {e82857}, pmid = {42263197}, issn = {1929-0748}, mesh = {Humans ; *Caregivers/psychology/statistics & numerical data ; *Sedentary Behavior ; *Alzheimer Disease/psychology/therapy ; *Behavior Therapy/methods ; *Dementia/psychology/therapy ; Text Messaging ; Walking ; }, abstract = {BACKGROUND: Sedentary behavior is associated with negative health outcomes. High levels of sedentary behavior are common among Alzheimer disease and related dementias (ADRD) caregivers already at risk of other adverse health effects, yet few interventions target sedentary behavior within this population. There is a need for trials intended to reduce time spent sedentary, which may be achievable by increasing the frequency of disruptions to sedentary time. Remotely delivered behavior change techniques (BCTs) may be effective for disrupting sedentary behavior in this population through short bursts of walking, although it is unclear how BCTs promote this behavior and potentially act via the hypothesized mechanism of behavioral automaticity.

OBJECTIVE: The goal of the trial is to examine whether a significant proportion of ADRD caregivers (≥50%) receiving an SMS text message-delivered BCT intervention form a habit to engage in hourly walking 4 times per day, with the broader objective of disrupting sedentary time in this population.

METHODS: This trial is a 12-week, decentralized, single-arm, National Institutes of Health Stage II behavioral trial. The trial will deliver a personalized, multicomponent BCT intervention to disrupt time spent sedentary by encouraging forming a habit of hourly walking among caregivers of persons with ADRD via the key mechanism of behavior change behavioral automaticity. The intervention includes 4 daily SMS text message-delivered BCT components previously used in interventions to disrupt sedentary behavior-Goal setting, Action planning, Prompts/cues, and Self-monitoring. Formation of an hourly walking habit is the primary outcome and will be defined as walking an additional 250 steps or more per hour for the same 4 consecutive hours as set up in a personalized walking plan on 7 consecutive days. Secondary outcomes include evaluating associations between habit formation and behavioral automaticity, and between longitudinal behavioral automaticity and habitual hourly walking over time. Additionally, heterogeneity of treatment effects will be evaluated. Exploratory analyses will examine potential moderating variables that may influence the intervention effect. The trial uses digital enrollment strategies, SMS text message intervention delivery, passive data collection via Fitbit (Google) devices, and online survey assessments to collect data remotely.

RESULTS: This study was funded by the National Institute on Aging in June 2024. Recruitment and data collection began in March 2025. As of August 2025, 40% (n=40) of the planned sample has been enrolled. Data collection is expected to be complete by June 2026. Data analysis and publication of results are expected by Fall and Winter 2026, respectively.

CONCLUSIONS: Results will have the potential to advance knowledge about the effectiveness of BCTs to form a habit of hourly walking and may provide opportunities for future public health impact to promote physical activity in caregivers of those living with ADRD.}, } @article {pmid42263407, year = {2026}, author = {Wasilah, H and Gidafie, A and Amelia, VL and Chung, MH}, title = {Effectiveness of morning blue light therapy on sleep and daytime symptoms in adults with primary and comorbid insomnia: A systematic review and meta-analysis of randomized control trials.}, journal = {International journal of nursing studies}, volume = {182}, number = {}, pages = {105588}, doi = {10.1016/j.ijnurstu.2026.105588}, pmid = {42263407}, issn = {1873-491X}, abstract = {BACKGROUND: Insomnia is the most prevalent sleep complaint, occurring as a primary or comorbid condition, increasing the public healthcare burden. Prior reviews examined the efficacy of blue light therapy in improving sleep among patients with a traumatic brain injury and young adults and reported conflicting results. A comprehensive evaluation of blue light therapy on sleep quality, sleep parameters, daytime sleepiness, and fatigue across adults with primary insomnia and insomnia with comorbid condition has not been fully established.

METHODS: This study was conducted in accordance with the PRISMA 2020 statement. We searched EBSCO, Embase, OVID, PubMed, Scopus, Trials.Gov, Web of Science, and PROSPERO for eligible studies published between the date of database inception and 16 April 2025. The Cochrane risk of bias tool was used to assess study quality. A random-effects model was employed to calculate the pooled effects. Subgroup analyses were performed to identify potential moderators.

RESULTS: We included 14 articles involving 444 insomniacs with a neurological disease (mild traumatic brain injury, Alzheimer's disease, or dementia) or medical disease (cancer, diabetes, or fibromyalgia) or with no comorbidity. Studies were conducted in several Asian and European countries, as well as the United States and Australia. The results indicated that blue light therapy improved subjective sleep quality [mean difference (MD) = -1.895], excessive daytime sleepiness (MD = -0.970), and several objective sleep parameters [sleep onset latency (Hedges' g = -0.545), waking after sleep onset (Hedges' g = -0.563), sleep efficiency (Hedges' g = 0.429), sleep fragmentation (Hedges' g = -1.228), and number of awakenings (Hedges' g = -0.614)]. Blue light therapy did not improve the fragmentation index, time in bed, or total sleep time and did not significantly reduce fatigue. The type of device, intervention duration, and light intensity moderated sleep quality. The intervention duration and frequency moderated sleep efficiency.

CONCLUSIONS: In adults with insomnia with diverse clinical backgrounds, blue light therapy may provide modest improvement in sleep quality and certain sleep parameters related to advancement and continuity of sleep (sleep fragmentation, sleep onset latency, waking after sleep onset, number of awakenings, and sleep efficiency), and may alleviate excessive daytime sleepiness. These findings suggest that blue light therapy may be considered potential non-pharmacological treatment for insomnia that can be implemented by healthcare providers in home or clinical settings. However, these findings should be interpreted with caution. Further studies are needed to confirm these findings.

REGISTRATION: The review was registered with PROSPERO (CRD420251027417).}, } @article {pmid42263916, year = {2026}, author = {Mengue Ngadena, YS and Njoupoue, MB and Zemo Gamo, F and Owona, PE and Bidingha A Goufani, R and Bouguem Yandja, PC and Akingbolabo Ogunlakin, D and Bilanda, DC and Chtita, S and Dzeufiet Djomeni, PD}, title = {Neuroprotective effects of aqueous extract of Pterocarpus mildbraedii Harms. on some biochemical markers in Alzheimer's disease using an AlCl3-induced rat model: Integrated ADMET, network pharmacology, molecular docking, and in vivo experimental validation.}, journal = {Journal of ethnopharmacology}, volume = {370}, number = {}, pages = {121962}, doi = {10.1016/j.jep.2026.121962}, pmid = {42263916}, issn = {1872-7573}, abstract = {ETHNOPHARMACOLOGY RELEVANCE: Neurodegenerative diseases such as Alzheimer's often lack effective conventional treatments. Phytotherapy is emerging as a promising approach to managing these conditions. Pterocarpus mildbraedii Harms. (P. mildbraedii), a plant from the Fabaceae family, which is traditionally used to treat convulsions, headaches, and fever. This study is designed to evaluate the neuroprotective effects of the aqueous extract of Pterocarpus mildbraedii Harms. on biochemical markers of Alzheimer's disease in an AlCl3-induced rat model using integrated ADMET, network pharmacology, molecular docking, and in vivo validation.

METHODS: We employed network pharmacology and in silico molecular docking to identify bioactive compounds and assess their binding affinities to key proteins: VCP, MAPK1, MMP9, PTGS1, IL6, and AR. The in vivo experiment lasted 56 days, with 30 animals divided into 5 groups (n = 6 per group). They received daily oral doses of distilled water (10 mL/kg), AlCl3 (75 mg/kg), Donepezil (5 mg/kg) after AlCl3, or P. mildbraedii bark water extract at 150 mg/kg (PM 150) and 300 mg/kg (PM 300) following AlCl3. On Days 23 and 51, all animals underwent open-field and Morris water maze tests. On Day 57, animals were sacrificed, and calcium levels, oxidative markers, and neurotransmitter levels were measured in homogenates from the amygdala, hippocampus, and prefrontal cortex. Histopathological analysis of the hippocampus and amygdala was also conducted.

RESULTS: In silico studies showed that the plant compounds pterocarpan and liquiritigenin bound strongly to VCP, MAPK1, and MMP9, with binding energies lower than those of reference inhibitors, indicating greater stability. In vivo, AlCl3 caused anxiety, locomotor issues (p < 0. 001), memory impairment (p < 0. 001), and disrupted GABA, ACh metabolism, and AChE activity. It also reduced antioxidant levels (p < 0.001), increased pro-oxidants (p < 0.001), and elevated calcium and Tau protein levels compared to the normal control. Treatment with Pterocarpus mildbraedii extract mitigated these effects, reducing anxiety and enhancing memory, locomotion, ACh, and GABA levels, as well as AChE activity. The extract notably decreased Tau protein and MDA concentrations by 80. 57% in the amygdala, 63. 80.57% in the prefrontal cortex, and 63.73. 50% in the hippocampus, and nitrites. It also significantly increased protein levels, GSH (by 6.95-fold in the amygdala, 80.48% in the prefrontal cortex, and 85.75% in the hippocampus), SOD, and catalase activities across brain regions compared with the AlCl3-treated group.

CONCLUSION: These findings suggest that Pterocarpus mildbraedii extract, with its antioxidant, anti-amnesic, and anxiolytic properties, offers neuroprotection and may have neuroprotective effects in Alzheimer 's-like neurotoxicity.}, } @article {pmid42264545, year = {2026}, author = {Vishwakarma, H and Chauhan, A and Kaur, L and Awasthi, A}, title = {Nanotechnology-enabled targeting strategies for neurodegenerative disorders: role of functionalized nanoparticles.}, journal = {The Journal of pharmacy and pharmacology}, volume = {78}, number = {6}, pages = {}, doi = {10.1093/jpp/rgag060}, pmid = {42264545}, issn = {2042-7158}, mesh = {Humans ; *Neurodegenerative Diseases/drug therapy/physiopathology/metabolism ; Animals ; *Nanoparticles ; Blood-Brain Barrier/metabolism ; *Drug Delivery Systems/methods ; Neuroprotective Agents/administration & dosage ; *Nanotechnology/methods ; Oxidative Stress/drug effects ; }, abstract = {BACKGROUND: Neurodegenerative disorders comprise a diverse group of progressive neurological diseases characterized by the gradual loss of neuronal structure and function. Conditions such as Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis arise from multifactorial mechanisms involving genetic susceptibility, environmental factors, and age-related cellular decline.

PATHOPHYSIOLOGY: Key pathogenic processes include oxidative stress, mitochondrial dysfunction, protein misfolding and aggregation, impaired axonal transport, Golgi fragmentation, and chronic neuroinflammation, all of which disrupt neuronal homeostasis and synaptic communication, ultimately leading to neuronal death. Hormonal imbalances further exacerbate these effects by promoting oxidative damage, inflammation, and metabolic dysfunction.

CHALLENGES IN THERAPY: Despite advances in understanding disease mechanisms, effective drug delivery remains challenging due to the restrictive nature of the blood-brain barrier.

Recent developments highlight the potential of nanoparticle-based drug delivery systems to overcome these limitations. Functionalized nanoparticles enhance blood-brain barrier penetration, improve targeting specificity, and enable controlled drug release. These systems can deliver neuroprotective agents, antioxidants, peptides, and gene therapies directly to affected brain regions. Thus, integrating disease pathophysiology with nanotechnology-based strategies offers a promising approach for improving therapeutic outcomes and advancing precision treatment in neurodegenerative disorders.}, } @article {pmid42265098, year = {2026}, author = {Belmont-Rausch, DM and Ludwig, MQ and Bentsen, MA and Hansen, SN and Secher, A and Holst, D and Moreno, J and Das, V and Egerod, KL and Bjerregaard, AM and Niss, K and Bau, S and Pyke, C and Dalgaard, K and Merkestein, M and Wichern, F and Hansen, CT and Polex-Wolf, J and Knudsen, LB and Pers, TH}, title = {Semaglutide attenuates neuroinflammation in male mice.}, journal = {Nature communications}, volume = {}, number = {}, pages = {}, doi = {10.1038/s41467-026-74038-4}, pmid = {42265098}, issn = {2041-1723}, support = {NNF18CC0034900//Novo Nordisk Fonden (Novo Nordisk Foundation)/ ; R190-2014-3904//Lundbeckfonden (Lundbeck Foundation)/ ; 8045-00091B//Det Frie Forskningsråd (Danish Council for Independent Research)/ ; R01 DK124238/DK/NIDDK NIH HHS/United States ; }, abstract = {Glucagon-like peptide-1 receptor agonists (GLP-1RAs) have shown promise in preclinical models of neurodegeneration, with emerging evidence suggesting these effects may be driven by modulation of neuroinflammation. However, the cellular mechanisms underlying GLP-1RA effects on neuroinflammation remain poorly understood. Here we show, using a mouse model of lipopolysaccharide-induced neuroinflammation, how semaglutide coordinates cellular responses to resolve neuroinflammation. We find that semaglutide in male mice prevents brain infiltration of neutrophils, excessive cytokine release, and suppresses neuroinflammation-associated transcriptional signatures specifically in microglia, endothelial cells, and a subset of pericytes. Mechanistically, we identify a subset of Glp1r-expressing neurons in the dorsal vagal complex that, upon semaglutide treatment, regulate genes involved in anti-inflammatory signaling. Semaglutide-modulated pathways overlap with inflammatory signatures found in human neurodegenerative diseases, including Alzheimer's disease, suggesting broad relevance for conditions involving neuroinflammation. Together, these findings reveal how GLP-1R signaling in male mice orchestrates resolution of neuroinflammation through coordinated multi-cellular programs.}, } @article {pmid42266233, year = {2026}, author = {Chen, Z and Zhang, Y and Zhu, X and Wu, H and Yu, T and Liu, Z}, title = {Comparative efficacy of exercise interventions on depressive symptoms and related outcomes in patients with Alzheimer's disease, cognitive impairment, and Parkinson's disease: a systematic review and network meta-analysis.}, journal = {Frontiers in physiology}, volume = {17}, number = {}, pages = {1825740}, pmid = {42266233}, issn = {1664-042X}, abstract = {BACKGROUND: Patients with Alzheimer's disease, cognitive impairment, and Parkinson's disease often experience depressive symptoms, which negatively impact quality of life and disease management. Exercise is an important non-pharmacological treatment in these populations; however, the relative efficacy of different exercise modalities remains unclear. This study used a systematic review and network meta-analysis to compare the effects of various exercise interventions on depressive symptoms and related outcomes.

METHODS: We systematically searched Chinese and English databases for randomized controlled trials evaluating exercise interventions in patients with Alzheimer's disease, cognitive impairment (including mild cognitive impairment and dementia), and Parkinson's disease. The primary outcome was depressive symptoms, assessed by using Geriatric Depression Scale (GDS) and Beck Depression Inventory (BDI); the secondary outcomes were cognitive function and motor function, assessed by using Mini-Mental State Examination (MMSE) and Unified Parkinson's Disease Rating Scale Part III (UPDRS III), respectively. Network meta-analysis was performed using Stata 16.0, and supplementary pairwise meta-analyses by disease type were conducted for the primary outcomes. RevMan 5.4 was used to assess the risk of bias, and the CINeMA framework was used to evaluate the credibility of the evidence.

RESULTS: A total of 23 randomized controlled trials involving 1,596 subjects were included. For the primary outcomes, no exercise modality showed an overall statistically significant advantage over the control group in improving depressive symptoms. For the secondary outcome, cognitive exercise significantly improved the MMSE scores compared with daily activities (MD = 3.50, 95% CI [2.29, 4.71]). For UPDRS III, no significant overall difference was observed between exercise interventions and the control group.

CONCLUSION: The available evidence does not provide stable or modestly consistent support for a clear overall benefit of different exercise interventions on depressive symptoms in patients with Alzheimer's disease, cognitive impairment, and Parkinson's disease. Cognitive exercise may help improve cognitive function, whereas the potential benefits of multicomponent exercise for motor function in Parkinson's disease should be interpreted with caution. In the future, large randomized controlled trials with clearer stratification, specific protocols, and standardized exercise prescriptions are needed to further define the optimal populations and intervention effects of different exercise modalities.

https://www.crd.york.ac.uk/prospero/, identifier CRD420261280926.}, } @article {pmid42266508, year = {2026}, author = {Khajuria, P and Kour, D and Sharma, K and Singh, L and Banoo, R and Manhas, D and Ramajayan, P and Nandi, U and B Bharate, S and Ahmed, Z and Kumar, A}, title = {AMPK-mediated autophagy induction by bisdemethoxycurcumin attenuates senescence and amyloid pathology in 3xTg-AD mice.}, journal = {Autophagy reports}, volume = {5}, number = {1}, pages = {2675164}, pmid = {42266508}, issn = {2769-4127}, abstract = {Alzheimer disease (AD) pathology is accompanied by increased senescence and reduced levels of autophagy in the brain. We investigated whether pharmacologically inducing autophagy could alter the senescent phenotype and ameliorate AD pathology. We discovered that Bisdemethoxycurcumin (BDMC), a natural compound found in Curcuma longa, stimulates autophagy in primary astrocytes. We found that autophagy and senescence exhibit an inverse relationship in aging astrocytes, with increased expression of senescent proteins and downregulation of autophagic proteins. However, treatment of aged astrocytes with BDMC reversed the senescent phenotype by ameliorating the impaired autophagy. Interestingly, the senescent phenotype persisted when autophagy was downregulated by knockdown of AMPK. Additionally, BDMC-induced autophagy aided in the removal of amyloid beta (Aβ) that was administered externally to the astrocytes. Further, to validate these results in a mouse model of AD, we confirmed that BDMC significantly penetrates the blood-brain barrier (BBB) in mice. Therefore, we administered 50 and 100 mg/kg b.w. of BDMC to transgenic 3xTg-AD mice for two months. In their hippocampus, the Control 3xTg-AD animals showed more senescent cells and lower autophagy levels. In contrast, autophagic proteins were significantly upregulated while senescence indicators, such as senescence-associated secretory phenotype (SASP) proteins, were sharply downregulated in the brain of treated animals. We discovered that the hippocampus of treated mice had a significantly lower Aβ load. These molecular changes in the brain were ultimately reflected in the improved working memory and neuromuscular coordination behavior of mice treated with BDMC. This study warrants further evaluation of BDMC for the management of AD.}, } @article {pmid42266879, year = {2026}, author = {Amuthan, S and Senthilkumar, NC}, title = {Ensemble Deep Learning Denoising (EDLD) model and optimized OTSU segmentation for Alzheimer's disease diagnosis using MRI images.}, journal = {Frontiers in artificial intelligence}, volume = {9}, number = {}, pages = {1743818}, pmid = {42266879}, issn = {2624-8212}, abstract = {Diagnosing Alzheimer's disease (AD) is necessary to determine treatment options. AD categorization using machine learning (ML) relies on difficult, manually specified features. The most important stage in AD diagnosis is denoising to restore image stability and quality. An ensemble image denoising technique that combines Attention Guided Convolutional Neural Network (AGCNN), Adaptive Denoising Autoencoder (ADAE), and Gaussian Deep Belief Network (GDBN) improves image denoising performance. The hybrid AGCNN reduces noise and aligns along the global route by combining global and local characteristics. In ADAE, the encoder learns picture representations using convolutional layers (CLs) while the decoder uses deconvolutional layers. In addition, the GDBN extends the standard Deep Belief Network (DBN) to Gaussian Restricted Boltzmann Machines (RBMs). Ensemble learning selects the approach with the greatest Peak Signal-to-Noise Ratio (PSNR) to integrate learning outcomes. After separating the background from the foreground by calculating the variances within the two groups, OTSU determines the threshold that minimizes the weighted sum of the variances. Levy Grasshopper Optimization Algorithm (LGOA) optimizes threshold selection by mimicking grasshopper swarming. VGG16, the DCNN model, is pre-trained for Alzheimer's datasets. The results are Sensitivity (SEN -95.86%), specificity (SPC - 94.93%), precision (PPV - 94.55%), F1-score (F1 - 95.21%), accuracy (ACC -95.87%), and Area Under the Receiver Operating Characteristic Curve (AUC - 96.45%) assess system and method performance.}, } @article {pmid42267529, year = {2026}, author = {Lohnes, BJ and Myskova, A and Tyagi, A and Hartwig, UF and Poddar, NK}, title = {Rewiring mTOR signaling in Alzheimer's disease: emerging mTOR modulators beyond oncology.}, journal = {Bioscience reports}, volume = {46}, number = {6}, pages = {}, pmid = {42267529}, issn = {1573-4935}, mesh = {Humans ; *Alzheimer Disease/drug therapy/pathology/enzymology/metabolism ; *TOR Serine-Threonine Kinases/metabolism/antagonists & inhibitors ; Signal Transduction/drug effects ; Animals ; *MTOR Inhibitors/therapeutic use ; }, abstract = {While Alzheimer's disease (AD) is the most common cause of dementia, curative treatments remain unavailable. Despite distinct pathologies between AD and cancer, shared dysregulation of the PI3K-AKT-mTOR signaling pathway promotes both disease states. mTOR activity significantly contributes to AD hallmarks, including amyloid-beta production, tau hyperphosphorylation, and altered metabolism and autophagy through mTOR-mediated signaling and downstream targets such as BACE-1, GSK-3β, and AChE. Consequently, mTOR-modulating compounds, demonstrating promising results in oncology, present a viable strategy to potentially halt or reverse AD progression. This review discusses the potential application of 37 mTOR pathway-modulating compounds, many originally developed for cancer treatment, given their shared molecular targets. We systematically classified the compounds based on their origin as marine, plant-derived, structural analogs, and synthetic compounds. This framework reveals a fundamental trade-off, as the structural novelty and pleiotropic effects of natural products are often counterbalanced by poor pharmacokinetics, whereas the pharmacological precision of synthetic compounds is frequently limited by compensatory feedback loops. Furthermore, we analyze translational challenges, including balancing efficacy with toxicity, limitations in blood-brain barrier penetration, and the need for patient stratification using robust biomarkers. We conclude that the most promising therapeutic approach for AD involves synergistically combining natural products with rational synthetic design. Leveraging natural products as a source of novel chemical scaffolds and employing targeted synthetic engineering to overcome their pharmacokinetic limitations, this strategy moves beyond blunt pathway inhibition. Ultimately, this enables a highly nuanced modulation of the mTOR network, providing the basis for future preclinical and clinical drug development in AD.}, } @article {pmid42267694, year = {2026}, author = {Verma, M and Mohd Siddique, MU and Singh, NK}, title = {Corrigendum to: Neuroactive Phytoconstituents of Glycyrrhiza glabra for the Treatment of Alzheimer's Disease.}, journal = {Current topics in medicinal chemistry}, volume = {26}, number = {4}, pages = {422}, doi = {10.2174/156802662604260406111327}, pmid = {42267694}, issn = {1873-4294}, abstract = {It has come to our notice that in the published version of this article [1], the reference [96] was cited erroneously. The author has now corrected the reference sequence, and it is now cited as [95]. The revised section is provided below. The original article can be found online at https://www.eurekaselect.com/article/145138.}, } @article {pmid42268277, year = {2026}, author = {Agaltsov, MV}, title = {[Sleep-disordered breathing in older adults: clinical features and effects on the nervous system and mental health].}, journal = {Zhurnal nevrologii i psikhiatrii imeni S.S. Korsakova}, volume = {126}, number = {5. Vyp. 2}, pages = {81-86}, doi = {10.17116/jnevro202612605281}, pmid = {42268277}, issn = {1997-7298}, mesh = {Humans ; *Sleep Apnea, Obstructive/therapy/epidemiology/physiopathology/complications/psychology/diagnosis ; Aged ; *Aging/physiology ; Female ; Mental Health ; Continuous Positive Airway Pressure ; }, abstract = {Obstructive sleep apnea (OSA) is a prevalent sleep-related breathing disorder characterized by upper airway collapse, intermittent hypoxemia, intrathoracic pressure fluctuations, and sleep fragmentation. In older adults, the clinical presentation and consequences of OSA differ from those observed in middle-aged individuals, necessitating age-specific management strategies. This review discusses age-related aspects of OSA epidemiology and pathophysiology, as well as associations with neurological and psychiatric outcomes in later life. Evidence demonstrates that OSA prevalence increases with age in both sexes, with postmenopausal hormonal and metabolic changes further elevating risk in women. Aging is associated with reduced slow-wave sleep, increased sleep fragmentation, and upper airway structural alterations, all of which may affect respiratory event patterns and arousals. Notably, excessive daytime sleepiness may be less prominent in older adults despite clinically significant OSA. Emerging data link OSA in older adults to cognitive decline, Alzheimer's disease biomarkers, and heightened risk of cerebrovascular disorders, although research specifically targeting elderly populations remains limited. Positive airway pressure (PAP) therapy may enhance mood, daytime functioning, and certain cognitive outcomes; however, current evidence is constrained by small sample sizes, short follow-up, and adherence challenges. Diagnosis and management of OSA in older adults require age-appropriate clinical interpretation and further longitudinal and interventional studies to elucidate causal relationships and the effects of treatment on neurodegenerative and cerebrovascular outcomes.}, } @article {pmid42268445, year = {2026}, author = {Mohasel-Roodi, M and Nozari, M and Baghalishahi, M and Shamsara, A}, title = {The protective effects of dexmedetomidine via AMPK/SIRT1 pathway activation in a rat model of alzheimer's disease: evidence from preliminary findings.}, journal = {Molecular biology reports}, volume = {53}, number = {1}, pages = {}, pmid = {42268445}, issn = {1573-4978}, mesh = {Animals ; *Dexmedetomidine/pharmacology/metabolism ; *Sirtuin 1/metabolism ; *Alzheimer Disease/drug therapy/metabolism ; Male ; Rats ; Rats, Wistar ; Disease Models, Animal ; *AMP-Activated Protein Kinases/metabolism ; Signal Transduction/drug effects ; Streptozocin ; *Neuroprotective Agents/pharmacology ; Neurons/drug effects/metabolism ; Hippocampus/metabolism/drug effects ; }, abstract = {BACKGROUND: Metabolic dysfunction and impaired energy signaling play critical roles in Alzheimer's disease (AD). The AMP-activated protein kinase (AMPK) / sirtuin-1 (SIRT1) pathway is a key regulator of neuronal energy homeostasis and survival. Dexmedetomidine (Dex), a selective α -2 adrenergic receptor agonist, has shown neuroprotective effects in acute neurological injury and energy homeostasis; however, its efficacy in metabolically driven AD models remains unclear.

METHODS: Forty-two adult male Wistar rats were randomly assigned to seven groups: control, sham, STZ, sham + Dex 25, STZ + Dex 25, STZ + Dex 50, and STZ + Dex 100 (n = 6/group). Sporadic AD was induced by bilateral intracerebroventricular injections of streptozotocin (STZ, 3 mg/kg) on days 1 and 3. Dex was administered intraperitoneally at doses of 25, 50, or 100 µg/kg following STZ injection. Hippocampal neuronal injury was assessed by Nissl staining, and AMPK and SIRT1 protein levels were evaluated using Western blot analysis 30 days after STZ administration.

RESULTS: STZ administration significantly increased neuronal injury in the hippocampal CA1 region and markedly reduced AMPK and SIRT1 expression compared with control and sham groups (p < 0.05-0.001). Dex treatment at all doses significantly attenuated CA1 neuronal damage, with the most pronounced histological protection observed at 25 µg/kg (p < 0.001). In parallel, Dex reversed STZ-induced downregulation of AMPK and SIRT1, with maximal molecular upregulation observed at 100 µg/kg (p < 0.05).

CONCLUSIONS: Dex mitigates STZ-induced hippocampal neurodegeneration, at least in part, through modulation of the AMPK/SIRT1 signaling pathway. These findings support the therapeutic potential of Dex in metabolically driven models of sporadic AD.}, } @article {pmid42268464, year = {2026}, author = {Mishra, H and Mishra, MK}, title = {Advances in anti-tau therapeutics for alzheimer's disease: immunotherapy, gene modulation, and combination approaches.}, journal = {Molecular biology reports}, volume = {53}, number = {1}, pages = {}, pmid = {42268464}, issn = {1573-4978}, mesh = {Humans ; *tau Proteins/antagonists & inhibitors/metabolism/genetics ; *Alzheimer Disease/therapy/genetics/metabolism/immunology ; *Immunotherapy/methods ; Animals ; Genetic Therapy/methods ; Oligonucleotides, Antisense/therapeutic use ; Combined Modality Therapy ; }, abstract = {Tau protein abnormalities are more detrimental to neurocognitive function and behaviour than amyloid plaque formation in patients affected by Alzheimer's Disease (AD) - the most common cause of dementia worldwide. Pathologically, tau misfolding, neurofibrillary tangle formation, hyper phosphorylation, and dissociation from microtubules lead to synaptic dysfunction and neuron death. With this understanding, tau is now a major therapeutic target; there is a growing research effort to assess immunotherapy, kinase inhibitors, and tau aggregation inhibitors, and evidence suggests that combination therapies may have synergistic effects. Although there are many challenges remaining, including poor late-stage trial efficacy and limited therapeutic access through the blood-brain barrier, the preliminary results from early preclinical and clinical studies suggest that tau pathology can be reduced and neuronal function improved. Additionally, RNA interference, antisense oligonucleotides, and other gene-based therapies are under investigation. Overall, tau-directed treatments show promise for the treatment of AD, with particular optimism about improvements in delivery systems and combination therapies that will lead to substantial therapeutic benefits and improved quality of life for patients with AD.}, } @article {pmid42268602, year = {2026}, author = {Moore, GJ and Bose, N and Henter, ID and Manji, HK}, title = {The 25-Year Evolution of Lithium as a Disease-Modifying Agent in Dementia: A Narrative Review.}, journal = {JAMA psychiatry}, volume = {}, number = {}, pages = {}, doi = {10.1001/jamapsychiatry.2026.1296}, pmid = {42268602}, issn = {2168-6238}, abstract = {IMPORTANCE: Lithium, a long-established cornerstone therapy for bipolar disorder, is a biologically plausible disease-modifying agent for neurodegenerative disorders, including mild cognitive impairment (MCI) and Alzheimer disease (AD).

OBSERVATIONS: Rather than targeting a single pathology like amyloid or tau, lithium acts across multiple cellular resilience pathways. Chronic lithium exposure induces the anti-apoptotic protein B-cell lymphoma 2 (Bcl-2), enhances brain-derived neurotrophic factor (BDNF) signaling, inhibits glycogen synthase kinase-3β (GSK-3β), stabilizes mitochondrial function, and reduces oxidative stress. These convergent mechanisms promote neuronal survival and synaptic integrity. In humans, proton magnetic resonance spectroscopy studies found that lithium increased N-acetylaspartate levels, consistent with improved neuronal viability, and structural magnetic resonance imaging (MRI) studies found that lithium preserved gray matter and/or reversed illness-related atrophy in hippocampal and corticolimbic regions. In addition, extensive evidence demonstrates that low-dose lithium (approximately 0.3mM)-significantly lower than traditional psychiatric doses (0.6-1.0mM)-exerts robust neurotrophic and neuroprotective effects. Preclinical models have found that these concentrations stimulate hippocampal neurogenesis, promote structural plasticity, and protect against proteotoxic injury. Furthermore, epidemiological studies have associated cumulative lithium exposure with reduced dementia risk, and early randomized clinical trials in MCI suggest cognitive stabilization and favorable tau biomarker changes at low, well-tolerated doses. The recent repletion hypothesis suggests that lithium may also function as a physiological trace element, but these findings await independent replication.

CONCLUSIONS AND RELEVANCE: These convergent data support a prospective clinical trial of low-dose lithium orotate to slow disease progression in MCI. Such an approach would prioritize established neuroprotective mechanisms while potentially mitigating the kidney and thyroid risks associated with higher-dose carbonate formulations. If low-dose lithium can indeed meaningfully alter disease trajectory, it would represent a much-needed, accessible, and inexpensive treatment that may be especially relevant in low- and middle-income countries.}, } @article {pmid42269217, year = {2026}, author = {Chae, HJ and Kwon, H and Son, SR and Moon, S and Park, AY and Bae, HJ and Jang, DS and Kim, DH}, title = {Fukinolic acid facilitates toxic amyloid-β oligomerization and exacerbates synaptic dysfunction.}, journal = {Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie}, volume = {200}, number = {}, pages = {119619}, doi = {10.1016/j.biopha.2026.119619}, pmid = {42269217}, issn = {1950-6007}, mesh = {Animals ; *Amyloid beta-Peptides/metabolism/toxicity/chemistry ; Long-Term Potentiation/drug effects ; Hippocampus/drug effects/metabolism/pathology/physiopathology ; *Synapses/drug effects/metabolism/pathology ; Alzheimer Disease/metabolism/drug therapy ; Neurons/drug effects/metabolism/pathology ; Mice ; Receptors, N-Methyl-D-Aspartate/metabolism ; Male ; Humans ; Mice, Transgenic ; Molecular Docking Simulation ; Synaptic Transmission/drug effects ; }, abstract = {Alzheimer's disease (AD) is characterized by the accumulation of amyloid-β (Aβ) aggregates that induce synaptic dysfunction and neuronal loss. Among the various Aβ species, soluble oligomers are considered the most neurotoxic forms and play a critical role in AD progression. Fukinolic acid (FA), a polyphenolic compound isolated from medicinal plants, has been reported to possess antioxidant and anti-inflammatory activities; however, its effects on Aβ aggregation have not been investigated. In the present study, we investigated whether FA modulates Aβ aggregation and synaptic dysfunction. Molecular docking analysis suggested that FA directly interacts with Aβ monomers at aggregation-prone regions. Consistent with this prediction, FA facilitated the formation of toxic Aβ oligomers and enhanced Aβ-induced neuronal cytotoxicity. The potentiation of Aβ toxicity by FA was abolished by an N-methyl-D-aspartate (NMDA) receptor antagonist, indicating the involvement of NMDA receptor-dependent signaling. Electrophysiological recordings showed that FA exacerbated Aβ-induced long-term potentiation (LTP) impairment in hippocampal slices without affecting basal synaptic transmission. In addition, FA administration increased Aβ deposition and reduced neuronal viability in the hippocampus of 5XFAD mice. FA treatment showed non-significant trends toward reduced hippocampal LTP and spontaneous alternation in the Y-maze test, indicating that further studies are required to determine whether FA affects synaptic and cognitive function in vivo. These findings suggest that FA promotes toxic Aβ oligomer formation and may aggravate Aβ-associated synaptic impairment through NMDA receptor-dependent mechanisms, highlighting the importance of evaluating the effects of natural compounds on Aβ pathology in AD.}, } @article {pmid42270143, year = {2026}, author = {Semiz, M and Millien, E and Simoes Loureiro, I}, title = {Comparing approaches to treating anomia in early Alzheimer's disease: Network model-based method vs. embodied cognition method.}, journal = {Neuropsychological rehabilitation}, volume = {}, number = {}, pages = {1-29}, doi = {10.1080/09602011.2026.2685294}, pmid = {42270143}, issn = {1464-0694}, abstract = {Semantic memory is affected early on in Alzheimer's disease (AD), leading to language difficulties such as anomia. Defined as the inability to find words during speech, anomia constitutes a real obstacle to the quality of life of AD patients. The aim of this research is to study the benefits of two treatment methods: the ESFA (Elaborated Semantic Feature Analysis) method, based on abstractive network models of semantic memory, and the TERM (Treatment by Embodied Reactivation of Memory) method, a new sensorimotor stimulations therapy based on the theory of embodied cognition. 19 patients with early-stage AD (MMSE ≥20/30) were distributed into two groups: ESFA group (N = 10, 7 women and 3 men; mean age = 82.7, SD = 4.52) and TERM group (N = 9, 8 women and 1 man; mean age = 81.78, SD = 7.26). Groups were equal, and comparisons were possible. While the ESFA method allows a broad improvement in both trained (W = -2.809; p = .005) and untrained (W = -2.194; p = .028) items, the TERM method seems to lead to an item-centered effect (W = -2.668; p = .008). Moreover, only with the TERM method, the benefits seem to be maintained (W = -1.715; p = .086). Further studies are still needed to further investigate the benefits of these two interesting methods.}, } @article {pmid42271174, year = {2026}, author = {Sdougkou, K and Rekka, E and Papagiannopoulou, D}, title = {Synthesis and Evaluation of Novel Cinnamic Acid Hybrids With Antiacetylcholinesterase, Antioxidant, and Anti-Inflammatory Properties.}, journal = {ChemMedChem}, volume = {21}, number = {11}, pages = {e70343}, pmid = {42271174}, issn = {1860-7187}, mesh = {*Anti-Inflammatory Agents/chemical synthesis/chemistry/pharmacology ; Cinnamates/chemical synthesis/chemistry/pharmacology ; *Acetylcholinesterase/metabolism ; Structure-Activity Relationship ; Antioxidants/chemical synthesis/chemistry/pharmacology ; *Cholinesterase Inhibitors/chemical synthesis/chemistry/pharmacology/therapeutic use ; Humans ; Animals ; Mice ; Lipid Peroxidation/drug effects ; Edema/chemically induced/drug therapy ; }, abstract = {Alzheimer's disease, one of the most widespread neurodegenerative disorders, is known for its multifactorial nature that makes it challenging to treat. In the present work, hybrid molecules were designed and synthesized combining the anti-acetylcholinesterase (AChE) activity of donepezil with the antioxidant and/or anti-inflammatory activity of selected cinnamic acids. In particular, the new derivatives were conjugated by Steglich esterification or amidation of suitable benzylpiperazine/piperidine moieties with ferulic, sinapic, 3,4-dimethoxycinnamic acids. All new molecules were evaluated for their activity in terms of AChE inhibition, while molecules that carried a phenolic group were also evaluated for their ability to inhibit lipid peroxidation. A representative group of compounds were studied in vivo for their anti-inflammatory activity with very encouraging results in paw-induced edema in mice. The 3,4-dimethoxycinnamic and sinapic acid esters with a two-carbon linker exhibited the strongest inhibition of AChE with nanomolar values of IC50. In addition, the sinapic esters demonstrated the highest antioxidant and anti-inflammatory activity. Thus, the above results indicate that the new sinapic acid derivatives based on donepezil combine anti-AChE, anti-inflammatory, and antioxidant activities, which warrant their further evaluation as new lead compounds in the treatment of related neurodegenerative diseases.}, } @article {pmid42272624, year = {2026}, author = {Pham, D and O'Brien, C and Florez-Bhandari, J and Faulstich, N and Ojo, T and Aloi, S and Goodwin, R and Roley, L and Nathaniel, SI and Nathaniel, TI}, title = {Risk factors associated with cancer and metabolic encephalopathy in Alzheimer's disease patients.}, journal = {Frontiers in aging neuroscience}, volume = {18}, number = {}, pages = {1810937}, pmid = {42272624}, issn = {1663-4365}, abstract = {BACKGROUND: Alzheimer's disease (AD) frequently coexists with risk factors that modify its clinical course. The combined presence of cancer and metabolic encephalopathy (ME) in AD represents a particularly vulnerable and understudied phenotype. We investigated whether cancer-associated risk profiles differ between AD patients with and without metabolic encephalopathy.

METHODS: We used multivariate logistic regression to identify clinical, vascular, pulmonary, neurocognitive, psychiatric, and treatment-related factors distinguishing (i) AD patients with metabolic encephalopathy with and without cancer (AD + ME ± C) and (ii) AD patients without metabolic encephalopathy with and without cancer (AD - ME ± C). Adjusted odds ratios (ORs) with 95% confidence intervals (CIs) were used to identify risk factors and phenotype-specific associations.

RESULTS: Of the total cohort, 10,516 patients had metabolic encephalopathy, and 118,253 did not. Cancer coexistence was present in 146 AD + ME patients and 1,167 AD - ME patients. Among AD + ME patients, cancer was strongly associated with cerebrovascular accident (OR = 3.47, 95% CI 2.16-5.59), secondary dementia (OR = 9.89, 95% CI 3.26-29.98), mild cognitive impairment (OR = 5.20, 95% CI 1.98-13.27), chronic obstructive pulmonary disease (OR = 7.66, 95% CI 5.20-11.29), and SSRI use (OR = 3.27, 95% CI 2.21-4.87). In contrast, memantine, buspirone, and valproate were associated with AD + ME without cancer. Among AD-ME patients, cancer was associated with dyslipidemia, peripheral vascular disease, congestive heart failure, arteriosclerosis, COPD, and cutaneous ulcers, reflecting chronic systemic illness.

CONCLUSION: Metabolic encephalopathy was associated with a different clinical profile in cancer-associated AD. Patients with ME exhibited increased systemic and neurologic vulnerability (e.g., vascular comorbidity and frailty indicators) rather than differences in baseline cognitive severity alone.}, } @article {pmid42273369, year = {2026}, author = {Offerdahl, JEV and Mor, DE}, title = {Toward common treatment strategies: convergent proteinopathies and mitochondrial dysfunction in Alzheimer's and Parkinson's diseases.}, journal = {Frontiers in neuroscience}, volume = {20}, number = {}, pages = {1846384}, pmid = {42273369}, issn = {1662-4548}, abstract = {Alzheimer's disease (AD) and Parkinson's disease (PD) are the two most prevalent neurodegenerative disorders (ND) globally, disproportionately affecting the elderly population. Traditionally viewed as distinct diseases, AD is defined by symptoms of cognitive impairment and dementia with amyloid-β and tau protein pathologies, while PD is defined by motor symptoms and eventual dementia with α-synuclein (α-syn) protein pathology. However, these pathologies are not unique to either disease, with a large fraction of AD patients displaying α-syn inclusions and PD patients displaying abnormal tau. Emerging evidence indicates that pathological tau and α-syn not only frequently coexist in AD and PD, but may engage in synergistic interactions that promote mitochondrial dysfunction, accelerate neurodegeneration, and worsen cognitive decline in both disorders. This review aims to provide both the prevailing views of AD and PD, as well as a detailed discussion of their commonalities with a focus on how tau and α-syn toxicities intersect at the mitochondrial level. Common features of mitochondrial impairment in AD and PD are discussed, including complex I deficiency, oxidative stress, impaired axonal transport, altered mitochondrial dynamics, and mitochondrial DNA damage. While prior reviews have often examined AD and PD independently, this review specifically focuses on the convergent and potentially synergistic interactions between tau and α-syn at the level of mitochondrial dysfunction, highlighting a shared mechanistic framework that may inform unified therapeutic strategies. By studying and understanding the mutual mechanisms underlying neurodegeneration in AD and PD, common treatment strategies can be identified.}, } @article {pmid42273802, year = {2026}, author = {Raket, LL and Lu, M and Evans, CD and Zimmer, JA and Sparks, J and Collins, EC and Shcherbinin, S and Wang, H and Nery, ESM and Epelbaum, S and Dell'Agnello, G and Brooks, DA and Sims, JR and Mintun, MA}, title = {Donanemab treatment effect by baseline tau burden and disease severity: Observations from the TRAILBLAZER-ALZ 2 trial.}, journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association}, volume = {22}, number = {6}, pages = {e71577}, pmid = {42273802}, issn = {1552-5279}, support = {//Eli Lilly and Company/ ; }, mesh = {Aged ; Female ; Humans ; Male ; *Alzheimer Disease/drug therapy/diagnostic imaging/metabolism ; Disease Progression ; Double-Blind Method ; Positron-Emission Tomography ; Severity of Illness Index ; *tau Proteins/blood/metabolism ; Treatment Outcome ; Antibodies, Monoclonal, Humanized ; }, abstract = {INTRODUCTION: Clinical trials indicate that disease-modifying therapies can slow clinical decline in Alzheimer's disease (AD), with earlier initiation associated with greater slowing.

METHODS: In the TRAILBLAZER-ALZ 2 trial, the treatment effect of donanemab on the Clinical Dementia Rating Scale Sum of Boxes (CDR-SB) score was assessed across disease stages defined by baseline tau PET, plasma P-tau217 levels, or predicted disease progression.

RESULTS: Donanemab-mediated slowing of disease progression occurred across baseline tau PET and plasma P-tau217 levels. Participants with lower baseline tau PET and P-tau217 showed greater slowing with donanemab versus placebo. Modeling CDR-SB scores indicated that earlier treatment (at the 25[th] percentile of baseline Predicted disease progression) delayed disease progression by 60% over 76 weeks, compared to 33% and 17% at the 50[th] and 75[th] percentiles.

DISCUSSION: Donanemab benefited participants with early symptomatic AD across clinical and pathological severities, with the greatest slowing in those treated earlier.

CLINICALTRIALS: gov Identifier: NCT04437511.}, } @article {pmid42274471, year = {2026}, author = {Yang, Y and Ma, Y and Wang, P and Guan, PP}, title = {Triptolide Reduces Cholesterol Synthesis and Alleviates Neuroinflammation by Inhibiting CD33 in Alzheimer's Disease Development and Progression.}, journal = {Biology}, volume = {15}, number = {11}, pages = {}, pmid = {42274471}, issn = {2079-7737}, support = {D2402007//Shenzhen Medical Research Fund/ ; GDRC202404//Natural Science Foundation of Top Talent of SZTU/ ; 2025ZDZX2061//Special projects in key areas of ordinary universities in Guangdong Province/ ; }, abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder, which has recently been found to be closely associated with neuroinflammation. As an anti-inflammatory drug, triptolide (TP), a natural diterpenoid from Tripterygium wilfordii, was selected in the current study for treating PS19 (tau[P301S] transgenic) mice, tauopathy AD mice. In addition, we have previously found that TP had the ability to reduce the level of cholesterol. However, the roles and mechanisms of TP in the above processes are not clear. To this end, we found that elevated cholesterol in serum and brain tissues upregulated the expression of apolipoprotein E (APOE) and sialic acid-binding Ig-like lectin 3 (CD33), leading to the activation of SH2-containing protein tyrosine phosphatase 1 (SHP-1). The activation of SHP-1 inhibits the signaling pathways of Janus kinase 1 (JAK1) and signal transducer and activator of transcription 6 (STAT6), which results in inhibition of the M2 polarization of microglia, which exacerbates neuroinflammation and cognitive decline in high-cholesterol diet (HCD)-fed mice. Conversely, TP treatment significantly inhibited the hepatic sterol regulatory element-binding protein 2 (SREBP2)/3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR) pathway, which reduced the cholesterol levels in the serum and brain. By depressing the levels of cholesterol, the axis of CD33 and SHP-1 was suppressed, which resulted in restoration of the activity of JAK1 and STAT6 pathways, leading to the transition of microglia from the M1 to the M2 phenotype. Of note, these observations demonstrate that TP alleviates the cognitive impairment of PS19 mice via depressing neuroinflammation. Altogether, our results revealed the mechanisms of TP in treating AD via CD33/SHP-1/JAK1/STAT6 pathways in a cholesterol-dependent manner.}, } @article {pmid42274838, year = {2026}, author = {Lior, N and Anna, P and Roni, H and Daniel, MM and Dan, F and Ronit, PK}, title = {APOE4-Expressing Astrocytes Exhibit Parkinson's Disease-Related Pathology.}, journal = {Molecular neurobiology}, volume = {63}, number = {1}, pages = {}, pmid = {42274838}, issn = {1559-1182}, mesh = {*Astrocytes/metabolism/pathology/drug effects ; alpha-Synuclein/metabolism ; Autophagy/drug effects ; *Apolipoprotein E4/metabolism/genetics ; *Parkinson Disease/pathology/metabolism/genetics ; Animals ; Humans ; Chloroquine/pharmacology ; }, abstract = {Parkinson's disease (PD) is characterized by motor symptoms that are mainly attributed to the progressive loss of dopaminergic neurons of the substantia nigra (SN). It is also characterized by abnormal inclusion vesicles, termed Lewy bodies (LBs), enriched with α-synuclein aggregates that may induce inflammation and neurotoxicity. The possibility that factors involved in other neurodegenerative diseases also affect PD-related pathologies, such as α-synuclein uptake, was examined. The apoe4 allele is a major genetic risk factor for Alzheimer's disease (AD) and has also been suggested to be involved in PD. Here, we examined the effects of APOE isoform expression on α-synuclein uptake and autophagy in astrocytes expressing the apoe3 or apoe4 alleles. Using multiple autophagy manipulations (EBSS, chloroquine, and rapamycin treatments), we found that α-synuclein uptake and autophagy readouts differ between APOE3 and APOE4 astrocytes, supporting a functional link between autophagy status and α-synuclein levels. Astrocytes expressing APOE4 exhibit reduced uptake of α-synuclein and reduced autophagy. Moreover, α-synuclein treatment inhibits autophagy mainly in APOE3-expressing cells. Additional experiments showed that the autophagy inhibitor chloroquine reduced α-synuclein uptake in APOE3 astrocytes but not in APOE4 astrocytes, while the autophagy enhancer rapamycin increased α-synuclein uptake in APOE4-expressing astrocytes. In addition, we found that Toll-like receptor 2 (TLR2) levels are elevated at both the mRNA and protein levels in APOE4-expressing astrocytes, whereas α-synuclein increased only TLR2 mRNA levels in APOE3-expressing astrocytes. Using the neurotoxin 1-methyl-4-phenylpyridinium (MPP[+]), we found that it affects cell growth in both APOE3 and APOE4-expressing astrocytes. MPP[+] treatment also reduced autophagy which was partially corrected by rapamycin. Taken together, these findings show that in astrocytes, APOE4 impairs α-synuclein uptake, which was emended by rapamycin and α-synuclein inhibits autophagy mainly in APOE3. These findings suggest that autophagy-targeting strategies can modulate astrocyte α-synuclein uptake; however, given the observed reductions in astrocyte cell number following rapamycin treatment, further optimization or examination of alternative autophagy modulators is needed.}, } @article {pmid42274866, year = {2026}, author = {Lefcourt, S and Kim, A and Huang, P and Weiss, C and , and Jones, C}, title = {Multi-scale Radiomic Fingerprint: Quantifying Spatial Changes in Biology.}, journal = {Journal of imaging informatics in medicine}, volume = {}, number = {}, pages = {}, doi = {10.1007/s10278-026-02041-8}, pmid = {42274866}, issn = {2948-2933}, support = {HT9425-23-1-0032//U.S. Department of Defense/ ; }, abstract = {Traditional radiomic studies build texture matrices using single-voxel increments. However, useful information may emerge when radiomic features are instead evaluated across multiple spatial scales. Moreover, basing these scales on physical units may produce results that are more interpretable to clinicians. We propose a multi-scale radiomic approach that defines texture distances in millimeter-based units to capture a more inclusive range of texture information, promote reproducibility, and improve clinician interpretability. We examine the variance in quantified radiomics across multiple spatial scales and diseases, including venous malformations, gliomas, Alzheimer's disease, brain metastases, and multiple sclerosis. We subsequently generated anisotropic counterparts to originally isotropic datasets to compare their performance in clinical predictive modeling. Finally, we evaluate differences between radiomic features captured at millimeter and voxel units. We discovered that the radiomic features captured at different millimeter scales were almost always statistically different (p < 0.05) across five diseases. Predictive modeling revealed that models trained on radiomics extracted from multiple millimeter scales consistently had a higher mean F1 across folds compared to those built from voxel scales. Roughly 93%, 90%, and 88% of texture metrics were statistically different between millimeter and voxel scales for venous malformations, Alzheimer's, and gliomas, respectively, suggesting that variations in spatial scale may capture differences in biology. We demonstrate that a multi-scale, millimeter-based alternative to fixed-distance voxel-based radiomics captures previously unacquired textural information while remaining clinically interpretable. This approach may have broad implications in all applications of clinical radiomic analysis, including disease diagnosis, monitoring, and treatment evaluation.}, } @article {pmid42274906, year = {2026}, author = {He, Y and Yi, T and Min, M and Xu, K and Lin, H and Xu, R and Deng, D and Xiao, X}, title = {Environmental Factors Drive Neurodegenerative Diseases Through Glutamate Excitotoxicity: A Convergent Mechanistic Pathway.}, journal = {Neuroscience bulletin}, volume = {}, number = {}, pages = {}, pmid = {42274906}, issn = {1995-8218}, abstract = {This review illustrates how environmental stressors disrupt glutamate homeostasis via specific mechanisms: lead-induced thiol modification, manganese mediated yin yang 1 (YY1)-histone deacetylases (HDAC) repression, PM2.5-triggered microglia-astrocyte crosstalk, and advanced glycation end products (AGEs)-receptor for advanced glycation end products (RAGE)-nuclear factor kappa-B (NF-κB) signaling from high-sugar diets. Together with genetic susceptibility and pigment epithelium-derived factor (PEDF), these factors impair astrocytic glutamate uptake, promoting synaptic glutamate accumulation. Subsequent N-methyl-D-aspartate (NMDA) and α-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid (AMPA) receptor overactivation triggers calcium overload, mitochondrial dysfunction, oxidative stress, and neuroinflammation-termed "degenerative excitotoxicity". Excitotoxicity manifests in Alzheimer's disease (amyloid-beta-excitatory amino acid transporter 2 (EAAT2) interplay), Parkinson's disease (subthalamic nucleus-driven excitatory storm), and amyotrophic lateral sclerosis (astrocytic failure versus neuronal cell-autonomous mechanisms). Future interventions need multi-target strategies, emerging technologies, and lifestyle modifications. This convergent framework offers a unified understanding linking environmental exposure to neurodegeneration and charts a roadmap toward mechanism-based prevention and treatment.}, } @article {pmid42275797, year = {2026}, author = {Lahiri, D and Kathir, S and Punjwani, Z and Liu, A and Pasvanis, S and Seixas-Lima, B and Roncero, CT and Chertkow, H and , }, title = {Application of a clinical scale for predicting Aβ-positivity in a multicentre Canadian dementia cohort: A necessity in the era of amyloid targeting treatment.}, journal = {Journal of the neurological sciences}, volume = {488}, number = {}, pages = {126047}, doi = {10.1016/j.jns.2026.126047}, pmid = {42275797}, issn = {1878-5883}, abstract = {BACKGROUND: Clinical Amyloid positivity Prediction Score (CAPS) is a clinical tool developed on a small Canadian cohort with clinical Alzheimer's Disease (AD) to help predict amyloid-beta (Aβ) positivity. The Comprehensive Assessment of Neurodegeneration and Dementia (COMPASS-ND) study is a national Canadian observational study of participants clinically diagnosed with various neurodegenerative disorders, including Alzheimer's syndrome, making it an ideal platform to validate CAPS on an independent but similar cohort of participants.

METHODS: Participants from the COMPASS-ND cohort with Subjective Cognitive Impairment (SCI), Mild Cognitive Impairment (MCI) or dementia due to AD, and a known Aβ status were included. CAPS was assigned to the individuals as follows: cognitive decline of >2 points/year on the Mini-Mental State Examination (MMSE) = 1-point, Neuropsychiatric Inventory Questionnaire (NPI-Q) ≥2 = 2 points, and low Fazekas score (0 or 1) = 1 points. A total CAP score ≥ 2 was considered indicative of Aβ positivity.

RESULTS: Total 86 participants fulfilled the inclusion criteria. Aβ + individuals had higher NPI-Q scores (2 vs 0.5, p = 0.005) and a lower baseline MMSE score (26.5 vs 28.0, p = 0.009). High WMH on brain MRI was reported more frequently in the Aβ- subgroup (50.0% vs 33.8%, p < 0.001). The frequency of people with a CAPS score of ≥2 is significantly higher in the Aβ + subgroup (75% vs 50%, p < 0.001). CAPS demonstrated a reasonable predictive value in this cohort, with 67% accuracy, and 73% sensitivity.

CONCLUSION: This validation study in a larger Canadian cohort showed that CAPS demonstrated reasonable accuracy in distinguishing between Aβ + and Aβ- subgroups.}, } @article {pmid42276063, year = {2026}, author = {Ishikawa, KI and Shiga, T and Hirose, T and Kuzumaki, N and Miyoshi, S and Yamaguchi, A and Tamune, H and Sarkar, AK and Nakai, K and Baba, K and Okabe, S and Hattori, N and Okano, H and Akamatsu, W}, title = {Suppression of ATM kinase signaling accelerates cellular senescence.}, journal = {Stem cell reports}, volume = {}, number = {}, pages = {102956}, doi = {10.1016/j.stemcr.2026.102956}, pmid = {42276063}, issn = {2213-6711}, abstract = {Cells derived from rejuvenated human induced pluripotent stem cells (hiPSCs) require extended culture periods to achieve functional maturation, and it remains difficult to recapitulate cellular senescence in these cells in vitro. This limitation hinders the accurate and efficient modeling of age-related neurodegenerative diseases. Here, we aimed to establish a simple approach to promote neuronal maturation and improve the efficiency of hiPSC-based disease modeling. Using a small-molecule inhibitor library, we identified an ATM kinase inhibitor, KU60019, that promotes both maturation-associated features and senescence-associated phenotypes in hiPSC-derived neurons and fibroblasts. KU60019 treatment promoted the manifestation of disease-relevant phenotypes in hiPSC models of age-related neurodegenerative diseases. Furthermore, senolytic analyses suggested that KU60019-induced senescent cells depend on pro-survival pathways, including HSP90-associated signaling. These findings suggest that KU60019 provides a simple and useful tool for accelerating phenotypic recapitulation in hiPSC models of age-related neurodegenerative diseases.}, } @article {pmid42276200, year = {2026}, author = {Alruwaili, NS and Al-Kuraishy, HM and Al-Gareeb, AI and Shokr, MM and Bogari, NM and Alhelfawi, S and Alruwaili, M and Batiha, GE}, title = {Beyond categorical boundaries: Common molecular and cellular pathways in autism spectrum disorder and schizophrenia.}, journal = {Progress in neuro-psychopharmacology & biological psychiatry}, volume = {148}, number = {}, pages = {111774}, doi = {10.1016/j.pnpbp.2026.111774}, pmid = {42276200}, issn = {1878-4216}, abstract = {Historically, ASD and schizophrenia have been classified as two distinct disorders, one being a neurodevelopmental disorder and the other a psychotic disorder. Recent studies, however, suggest that there may be substantial overlap between these disorders. Here, we will discuss some of the biological mechanisms involved in the development of these diseases that show similarities. These include dysregulation of the dopaminergic, serotonergic, glutamatergic, GABAergic, and acetylcholinergic systems; changes in BDNF signaling; histamine dysregulation; microglial activation; neuroinflammation; complement-mediated synapse elimination; gut-brain axis signaling; and endocannabinoid system dysfunction. It is important to note that the aforementioned biological mechanisms are present in several CNS disorders, such as major depressive disorder, Alzheimer's disease, and multiple sclerosis. While it is true that other CNS disorders share the same biological mechanisms as ASD and schizophrenia, the similarity between these disorders stands out for a particular reason. First, the biological mechanisms present in ASD and schizophrenia are significantly similar; second, their heritability is highly consistent; third, they have similar developmental trajectories; fourth, they exhibit similar circuit-level pathology; fifth, they share bidirectional epidemiological risks; and sixth, they follow a neurodevelopmental continuum. Recognizing this overlap has potential implications for early detection, biomarker development, and transdiagnostic treatment strategies, including repurposing medications such as memantine, α7-nicotinic agonists, and anti-inflammatory agents. However, longitudinal studies are needed to determine whether early targeting of shared pathways modifies long-term psychosis risk in ASD.}, } @article {pmid42276536, year = {2026}, author = {Kshirsagar, S and Reddy, AP and Reddy, PH}, title = {Restoration of mitochondrial dynamics and synaptic function by mitophagy enhancers in a tauopathy cell model.}, journal = {Mitochondrion}, volume = {91}, number = {}, pages = {102184}, doi = {10.1016/j.mito.2026.102184}, pmid = {42276536}, issn = {1872-8278}, abstract = {OBJECTIVES: To evaluate whether mitophagy enhancers-including urolithin A, actinonin, tomatidine, and nicotinamide riboside-can counteract mitochondrial dysfunction and synaptic damage induced by phosphorylated Tau in Alzheimer's disease.

METHODS: We Used immortalized mouse hippocampal primary HT22 neurons expressing mutant Tau (mTau-HT22). We treated cells with mitophagy enhancers and measured gene and protein levels of mitochondrial dynamics, biogenesis, mitophagy, synaptic markers, assessed cell viability, mitochondrial respiration, and examined mitochondrial morphology via transmission electron microscopy.

RESULTS: Compared to controls, mTau-HT22 cells exhibited increased mitochondrial fission and reduced fusion, diminished mitochondrial biogenesis, impaired mitophagy and synaptic gene expression, reduced cell survival, lower respiration, and fragmented mitochondria. Treatment with all mitophagy-enhancing compounds improved mitochondrial dynamics-, biogenesis-, and mitophagy-related marker expression together with mitochondrial functional outcomes, with urolithin A showing the strongest effects. Notably, a combined treatment of urolithin A with EGCG further enhanced respiratory function beyond single-agent treatments.

CONCLUSIONS: Mitophagy enhancers, particularly urolithin A alone or in combination with EGCG, restore mitochondrial and synaptic health in Tau-induced toxicity models. These findings position mitophagy enhancement as a potential therapeutic approach requiring further validation in Alzheimer's disease.}, } @article {pmid42276615, year = {2026}, author = {Jain, V and Bharti, S}, title = {Environmental toxins, PFAS exposure, and brain metabolism: A new angle in Alzheimer's disease pathophysiology.}, journal = {International review of neurobiology}, volume = {186}, number = {}, pages = {107-144}, doi = {10.1016/bs.irn.2026.01.011}, pmid = {42276615}, issn = {2162-5514}, mesh = {*Alzheimer Disease/metabolism/chemically induced ; Humans ; *Brain/metabolism/drug effects ; Animals ; *Fluorocarbons/toxicity/adverse effects ; *Environmental Pollutants/toxicity/adverse effects ; *Environmental Exposure/adverse effects ; Oxidative Stress/drug effects ; *Energy Metabolism/drug effects ; }, abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disease with a complicated cause and effect, usually associated with amyloid-β plaques, tau pathology, and neuroinflammation. Recent research indicates that changes in brain energy metabolism play a crucial role in the progression of AD. Additionally, persistent environmental toxins, particularly per- and polyfluoroalkyl substances (PFAS), have attracted considerable attention due to their widespread occurrence, ability to accumulate in living organisms, and neurotoxic effects. This chapter explores the connection between PFAS exposure and metabolic dysfunction in the brain as a potential new factor in the etiology of Alzheimer's disease. This study explored the potential impacts of PFAS on insulin signaling, lipid homeostasis, glucose metabolism, mitochondrial dynamics, and brain energy supply. The epidemiological associations between PFAS exposure and cognitive impairment are also examined, along with the mechanisms underlying oxidative stress, neuroinflammation, and dysregulation of metabolic systems. Finally, prevention, management, therapeutic approaches, and the research gap in PFAS-induced neurotoxicity are explored. Findings from this study emphasize the need to incorporate environmental toxicology into the Alzheimer's disease metabolic model for the sake of future treatment and preventive efforts.}, } @article {pmid42277155, year = {2026}, author = {Wang, L and Knox, S and Lawson, AB and Mollalo, A}, title = {Agricultural pesticide use and Alzheimer's disease dementia prevalence across US counties in a mixed supervised-unsupervised analysis.}, journal = {Scientific reports}, volume = {}, number = {}, pages = {}, doi = {10.1038/s41598-026-55678-4}, pmid = {42277155}, issn = {2045-2322}, abstract = {Agricultural pesticide use represents one of the most geographically patterned environmental systems, yet most prior research has focused largely on individual compounds rather than correlated exposure regimes. We conducted a cross-sectional analysis using modeled pesticide application intensity and Alzheimer's Disease (AD) dementia prevalence at the county-level across the United States. Stability-based Elastic Net screening and clustering were used to identify exposure groupings, and associations with AD prevalence were estimated using adjusted regression models. Out of 462 total pesticides screened, 112 demonstrated high selection stability and were grouped into 25 exposure clusters. Twenty clusters were significantly associated with AD dementia prevalence (p<0.05). The strongest positive associations were observed for a soil fumigation/nematicide system, an herbicide-dominant vegetation control regime, and a neuroactive insecticide system. Neuroactive insecticides and soil-intensive treatment systems were disproportionately represented among positively associated clusters, whereas systems dominated by phenoxy- and photosystem II inhibiting herbicides were more frequently aligned with inverse gradients. The fully adjusted model explained 59% of between-county variance (baseline R[2] = 0.44). Findings suggest that pesticide mixtures are associated with geographic heterogeneity in AD dementia prevalence and warrant higher-resolution, longitudinal investigation.}, } @article {pmid42277629, year = {2026}, author = {Chang, Y and Li, H and Liu, X and Li, X and Liu, J and Song, J and Fu, H and Xu, X and Wang, Y and Wang, Q and Ren, N and Chen, J and Deng, X and Zhang, X and Zuo, L and Zhou, B and Sun, X and Li, Z and Cao, Y and Wu, R and Jia, J and Qian, H and Wang, R}, title = {Lecanemab Reduces Neuropsychiatric Symptoms and Related Regional Brain Amyloid Load in Early Alzheimer's Disease: A Preliminary Prospective Study.}, journal = {CNS neuroscience & therapeutics}, volume = {32}, number = {6}, pages = {e70974}, pmid = {42277629}, issn = {1755-5949}, support = {82371999//the National Natural Science Foundation of China/ ; 2021ZD0201804//the Ministry of Science and Technology of the People's Republic of China/ ; 24BJZ14//Health Special Research Projects/ ; //Novel Medical Technologies and Innovative Services of Chinese PLA General Hospital/ ; }, mesh = {Humans ; Female ; Male ; *Alzheimer Disease/drug therapy/diagnostic imaging/psychology/metabolism ; Prospective Studies ; *Brain/drug effects/diagnostic imaging/metabolism ; Aged ; Positron-Emission Tomography ; Magnetic Resonance Imaging ; Neuropsychological Tests ; Preliminary Data ; Aged, 80 and over ; Psychiatric Status Rating Scales ; Amyloid beta-Peptides/metabolism ; *Amyloid/metabolism ; }, abstract = {AIM: This prospective study examined whether lecanemab was associated with changes in neuropsychiatric symptoms (NPS) and investigated their associations with cerebral amyloid burden in patients with early-stage Alzheimer's disease (AD).

METHODS: Fourteen eligible participants underwent amyloid positron emission tomography, magnetic resonance imaging, and neuropsychological assessments at baseline and following 6 months of lecanemab treatment. Neuropsychological assessments included the Clinical Dementia Rating, Mini-Mental State Examination (MMSE), Montreal Cognitive Assessment (MoCA), Hamilton Depression Rating Scale, Hamilton Anxiety Scale (HAMA), and Neuropsychiatric Inventory (NPI).

RESULTS: MMSE and MoCA remained stable, while amyloid burden decreased after 6 months of treatment (p < 0.05). HAMA, total NPI score, and NPI sub-scores for psychosis, hyperactivity, and apathy were also decreased (p < 0.05). Improvements in NPS were associated with lower amyloid burden in the hippocampus, amygdala, thalamus, inferior frontal gyrus (IFG), and anterior cingulate gyrus. These clinical improvements were associated with increased fractal dimension in the middle cingulate cortex and decreased sulcal depth in the IFG.

CONCLUSIONS: These findings suggest that, in early AD, lecanemab treatment may be associated with benefits beyond cognitive stabilization, including possible improvement in NPS, which may relate to amyloid clearance and structural changes in relevant brain regions.}, } @article {pmid42277961, year = {2026}, author = {Bonnar, O and Saadi, F and Sanchez-Mico, MV and Hanlin, LH and Vom Eigen, KA and Mumbi, N and Bacskai, BJ and Greenberg, SM and Holtzman, DM and van Veluw, SJ}, title = {Longitudinal multiphoton imaging of cerebral amyloid angiopathy in response to anti-ApoE4 immunotherapy in mice.}, journal = {Molecular neurodegeneration}, volume = {}, number = {}, pages = {}, doi = {10.1186/s13024-026-00957-x}, pmid = {42277961}, issn = {1750-1326}, support = {P01 AG078106/GF/NIH HHS/United States ; A2022051S//BrightFocus Foundation grant/ ; }, abstract = {BACKGROUND: There are no available treatments to halt or slow the progression of cerebral amyloid angiopathy (CAA), a disease neuropathologically characterized by the deposition of amyloid-β (Aβ) within the walls of the cerebrovasculature. Recently a novel therapeutic strategy has been described, targeting non-lipidated ApoE4 that co-deposits with Aβ, resulting in lower levels of Aβ across the brain. To understand the therapeutic potential for patients with CAA, we sought to determine if this global reduction in Aβ deposits corresponds to the active removal of existing aggregates in the vasculature and if so, whether this may improve vascular function over time.

METHODS: Cranial windows were implanted in 9-10-month-old 5xFAD mice expressing human APOE4 to facilitate chronic, unanesthetized imaging using in vivo multiphoton microscopy. Mice were treated weekly with anti-ApoE4 immunotherapy (HAE-4) or control IgG (50 mg/kg). Parenchymal and vascular Aβ burden as well as vascular function were measured in vivo before and during treatment. Post-mortem brains were assessed for CAA, parenchymal Aβ plaques and iron deposits. In a separate study, 5xFAD mice were treated with weekly HAE-4 or control IgG with the same doses of antibodies from 8 to 10 months of age in the absence of cranial windows.

RESULTS: Treatment with HAE-4 resulted in reduction of total Aβ plaque area post-mortem in mice and shrinkage of existing smaller plaques imaged with in vivo multiphoton microscopy. Vascular fibrillar Aβ under the cranial window conversely increased over time either with or without HAE-4 treatment and there was no treatment-associated improvement in vascular function in cortical arterioles in the areas measured in vivo. There was no evidence of hemorrhagic events linked to treatment, however there was significant immune cell activation. In 5xFAD mice treated without a cranial window, there was a reduction in plaques and CAA as previously described in HAE-4 vs. control treated mice.

CONCLUSIONS: Anti-ApoE4 immunotherapy, as shown previously, decreased the overall amount of Aβ. It also appeared to remove some existing plaque Aβ without measurable effects on vascular fibrillar Aβ deposits or vascular function in areas measured in vivo under a cranial window. The absence of treatment-associated hemorrhagic events may offer a comparative advantage relative to anti-Aβ immunotherapy.}, } @article {pmid42278193, year = {2026}, author = {Lourenço, KA and Dos Santos, MV and Araujo, AC and Guiguer, EL and Curi, R and Rocha, MG and Monteiro, ES and Yanaguizawa Junior, JL and Pithon-Curi, T and Quesada, K and de Abreu, LC and Marcondes, CO and Barbalho, SM and Valenti, VE and Miglino, MA}, title = {From Toxin to Therapy: Biomedical Applications of Bee Venom in Cancer, Diabetes, and Neurodegenerative Disorders.}, journal = {International journal of molecular sciences}, volume = {27}, number = {11}, pages = {}, pmid = {42278193}, issn = {1422-0067}, mesh = {Humans ; *Bee Venoms/therapeutic use/pharmacology/chemistry ; Animals ; *Neurodegenerative Diseases/drug therapy ; *Neoplasms/drug therapy ; *Diabetes Mellitus/drug therapy ; }, abstract = {Apitherapy is a complementary therapeutic approach based on the use of bee-derived products, particularly bee venom (BV), also known as apitoxin. Bee venom is a complex mixture of biologically active compounds, including peptides, enzymes, and biogenic amines, that exhibit diverse pharmacological activities. Major bioactive constituents such as melittin, apamin, adolapin, and phospholipase A2 have attracted increasing scientific interest due to their anti-inflammatory, antioxidant, antimicrobial, analgesic, and immunomodulatory properties. This review provides a comprehensive overview of the biological effects and therapeutic potential of bee venom in the management of chronic diseases, particularly diabetes, cancer, and neurological disorders. Evidence from experimental and clinical studies suggests that BV and its components can modulate multiple molecular pathways associated with oxidative stress, inflammation, apoptosis, and immune responses. These mechanisms contribute to potential benefits in glycemic control, tumor suppression, neuroprotection, and pain management. Additionally, bee venom has been investigated for its capacity to influence signaling pathways involved in cellular proliferation and survival, highlighting its potential as a complementary strategy in the treatment of complex diseases such as neurodegenerative disorders, including Parkinson's and Alzheimer's diseases. Despite these promising therapeutic effects, the clinical use of BV remains limited due to safety concerns, particularly the risk of allergic reactions, systemic toxicity, and anaphylaxis. Recent advances in drug delivery systems and nanotechnology may help improve the safety and efficacy of BV-based therapies by enabling targeted delivery and controlled dosing. Overall, bee venom represents a promising source of bioactive compounds with potential applications in translational and integrative medicine; however, further well-designed clinical trials and mechanistic studies are necessary to establish its safety, efficacy, and long-term therapeutic value.}, } @article {pmid42278362, year = {2026}, author = {Malenchini, M and Beretti, F and Gatti, M and Bertucci, E and Del Toro, E and Maraldi, T}, title = {Stem Cell-Derived Extracellular Vesicles Ameliorate the Neuron Mitochondrial Damage Induced by ROS-, LPS-Exposure: In Vitro Model of Neuron, Microglia, and Astrocyte Triple Co-Culture.}, journal = {International journal of molecular sciences}, volume = {27}, number = {11}, pages = {}, pmid = {42278362}, issn = {1422-0067}, mesh = {*Lipopolysaccharides/toxicity ; *Neurons/metabolism/drug effects ; *Mitochondria/metabolism/drug effects/pathology ; *Microglia/metabolism/drug effects ; *Reactive Oxygen Species/metabolism ; *Extracellular Vesicles/metabolism ; Coculture Techniques ; *Astrocytes/metabolism/drug effects/cytology ; Animals ; Humans ; Oxidative Stress/drug effects ; Hydrogen Peroxide ; Cell Survival/drug effects ; Cells, Cultured ; }, abstract = {Oxidative stress causes brain damage contributing to neurodegenerative and vascular diseases. In Alzheimer's disease (AD), elevated oxidative stress and mitochondrial damage are closely linked to misfolded protein accumulation. ROS also plays a major role in ischemic brain injury, particularly during reperfusion, impairing the blood-brain barrier and highlighting the association between vascular pathology and AD. To investigate perturbations in brain cells occurring in mixed dementia (AD combined with vascular dementia components), we used a triple culture system comprising neurons, astrocytes, and microglia and induced neuronal injury by combining LPS and H2O2 exposures. Cell viability assays revealed that neuronal death occurred mainly through apoptosis and DNA damage. In neurons and astrocytes exposed to LPS+H2O2, the expression of NADPH oxidase isoform 2, a major source of ROS, increased, along with FOXO3 and SOD2, a key mitochondrial ROS scavenger. Indeed, these changes were accompanied by altered mitochondrial morphology and integrity, as well as reduced neurite extension and thickness. The treatment with extracellular vesicles (EVs) derived from amniotic fluid stem cells was tested due to their rich content of antioxidant molecules. Interestingly, EVs reversed the negative effects of LPS+H2O2, suggesting the protective role against neuronal injury in vitro may be mediated by the EV-cargo.}, } @article {pmid42278468, year = {2026}, author = {Piekarczyk, N and Berezka, P and Domkowicz, K and Myślińska, D and Kaczor, JJ}, title = {Vitamin D3 and Dimethyl Fumarate Partially Restore Neurotrophic Signaling Without Altering Mitochondrial Integrity in the STZ-Induced Model of Sporadic AD.}, journal = {International journal of molecular sciences}, volume = {27}, number = {11}, pages = {}, pmid = {42278468}, issn = {1422-0067}, support = {531-D080-D248-25//Faculty of Biology/ ; }, mesh = {Animals ; *Cholecalciferol/pharmacology ; *Mitochondria/metabolism/drug effects ; Streptozocin/toxicity ; *Signal Transduction/drug effects ; Rats ; Male ; *Alzheimer Disease/metabolism/drug therapy/chemically induced/pathology ; *Dimethyl Fumarate/pharmacology ; Disease Models, Animal ; Brain-Derived Neurotrophic Factor/metabolism ; Hippocampus/metabolism/drug effects ; *Nerve Growth Factors/metabolism ; Proto-Oncogene Proteins c-akt/metabolism ; Oxidative Stress/drug effects ; Rats, Wistar ; }, abstract = {Alzheimer's disease (AD) is characterized by impaired neurotrophic support, oxidative stress, and metabolic dysfunction. Using the intracerebroventricular streptozotocin (ICV-STZ) rat model of sporadic AD, we investigated whether vitamin D3 (VitD3) and dimethyl fumarate (DMF), administered alone or in combination, modulate hippocampal neurotrophin-related signaling and redox balance. Animals were assigned to SHAM, STZ, VITD, DMF, and COMBO groups, representing control, ICV-STZ, VitD3-treated ICV-STZ, DMF-treated ICV-STZ, and combined VitD3 + DMF-treated ICV-STZ animals, respectively. Hippocampal neurotrophin processing (proBDNF and mature BDNF), downstream signaling (Akt and pAkt), IGF-1 content, mitochondrial oxoglutarate dehydrogenase (OGDH) content, citrate synthase (CS) activity, and glutathione peroxidase (GPx) activity were assessed. STZ administration showed a trend toward reduced mature BDNF content compared with the SHAM group (p = 0.07), whereas combined VitD3 and DMF treatment significantly increased mature BDNF content compared with the STZ group. The mature BDNF/proBDNF ratio was reduced in the STZ group compared with the SHAM group and tended to be higher in the COMBO group compared with the STZ group (p = 0.09). proBDNF content remained unchanged. IGF-1, pTrkB, total Akt, and pAkt content did not differ significantly between groups. The pAkt/Akt ratio showed a trend toward reduction in the STZ group compared with SHAM group (p = 0.09). GPx activity increased in the STZ group, while CS activity and OGDH content were not significantly altered. These findings indicate that STZ-induced neurodegeneration is characterized by redox-associated uncoupling of neurotrophic signaling rather than mitochondrial disruption. Combined VitD3 and DMF treatment partially modulated neurotrophic signaling, supporting a limited but measurable neuroprotective effect.}, } @article {pmid42278518, year = {2026}, author = {Ricci, S and Benuzzi, M and Fazzina, M and Cacialli, P}, title = {ZL006 Treatment Reduces Inflammation, Oxidative Stress, and Brain Aβ1-42 Accumulation and Rescues the Loss of PSD95 Synaptic Marker in Familial Alzheimer's Disease-Associated psen1-Deficient Zebrafish Model.}, journal = {International journal of molecular sciences}, volume = {27}, number = {11}, pages = {}, pmid = {42278518}, issn = {1422-0067}, support = {Cacialli-RFO2024//the Italian Ministry of University and Research (MIUR)/ ; }, mesh = {Animals ; Zebrafish ; *Amyloid beta-Peptides/metabolism ; *Oxidative Stress/drug effects ; *Presenilin-1/genetics/deficiency ; *Peptide Fragments/metabolism ; *Alzheimer Disease/metabolism/drug therapy/genetics/pathology ; *Zebrafish Proteins/genetics/metabolism ; Disease Models, Animal ; *Brain/metabolism/drug effects ; *Inflammation/drug therapy/metabolism ; Humans ; *Neuroprotective Agents/pharmacology ; }, abstract = {Familial Alzheimer's disease (FAD) is a rare form of Alzheimer's. FAD is mainly caused by one or multiple mutations in the genes encoding for amyloid precursor protein (APP), presenilin-1 (PSEN1), and presenilin-2 (PSEN2), with the majority occurring in PSEN1. Despite extensive research in animal models and numerous promising treatment trials, there is still no curative treatment for FAD. Recently, ZL006 (Med Chem Express cat. Number HY-100456) was shown to reduce over-produced nitric oxide and oxidative stress in ischemic stroke and could protect neurons against Aβ1-42-induced neurotoxicity (in vitro study). With this in mind, we tested ZL006 at different doses (10 μM, 25 μM, 50 μM and 100 μM) in zebrafish embryo injected with ctrl-MO and psen1-MO, investigating the effects on pathological phenotype in vivo. We showed that ZL006 exposure suppresses inflammation, oxidative stress and accumulation of Aβ1-42 in psen1-MO. In conclusion, our study showed that ZL006 was able to ameliorate the pathological phenotype of psen1-morphant zebrafish embryos, supporting its potential as a candidate for further investigations in the context of FAD treatment.}, } @article {pmid42278520, year = {2026}, author = {Kassenova, A and Svirin, E and Sitdikova, K and Chaprov, K and Tsoy, A and Munter, J and Nurzhanov, A and Kuznetsova, M and Veremeyko, T and Deykin, A and Ponomarev, E and Strekalova, T and Askarova, S}, title = {Effects of Wheat Malt Extract on Molecular and Behavioral Markers in Aged APP/PS1 and Wild-Type Mice.}, journal = {International journal of molecular sciences}, volume = {27}, number = {11}, pages = {}, pmid = {42278520}, issn = {1422-0067}, support = {AP23485236//Ministry of Science and Higher Education of the Republic of Kazakhstan/ ; Ref. No. 201223FD8829//The Faculty Development Competitive Research Grant Program, Nazarbayev Fund, Nazarbayev University/ ; FFSG-2024-0020//Scientific state assignment to the Centre for Collective Use IPAC RAS/ ; FZWG-2024-0003//The Scientific state assignment/ ; 101007642EU//The Marie Skłodowska-Curie PhytoApp within the European Union's Horizon 2020 research and innovation program (H2020-MSCA-RISE-2020)/ ; 101086453EU//The Marie Skłodowska-Curie Aqua-Synapse project within the European Union's Horizon 2020 research and innovation program (H2020-MSCA-RISE-2020)/ ; }, mesh = {Animals ; Mice, Transgenic ; Female ; *Alzheimer Disease/metabolism/genetics/drug therapy/pathology ; Mice ; *Presenilin-1/genetics/metabolism ; *Amyloid beta-Protein Precursor/genetics/metabolism ; *Triticum/chemistry ; *Plant Extracts/pharmacology ; Biomarkers/metabolism ; *Aging ; Disease Models, Animal ; Brain/metabolism/drug effects ; *Behavior, Animal/drug effects ; Plaque, Amyloid/metabolism/pathology ; Wheat Germ Agglutinins/pharmacology ; Astrocytes/metabolism/drug effects ; }, abstract = {Growing evidence suggests an important pathogenetic role of brain-specific gangliosides in the mechanisms underlying Alzheimer's disease (AD), the most common form of dementia. Nutritional strategies targeting ganglioside sialylation-for example, through agglutinin-mediated modulation-have therefore attracted increasing research interest. In particular, wheat malt extract (WME), a food-derived source of wheat germ agglutinin (WGA) with high affinity for gangliosides, may influence molecular pathways involved in AD pathogenesis. Twelve-month-old female APPswe/PS1E9 transgenic mice, a model of AD, and wild-type (WT) littermates received WME or tap water for three weeks. Behavioral performance was subsequently assessed. Amyloid plaque burden and astrocyte activation were evaluated using Congo red staining and GFAP immunoreactivity, respectively. Gene expression of selected AD markers in the brain was quantified by RT-qPCR. Aged WT mice exhibited robust, region-specific molecular responses to WME, including upregulation of activity-dependent and synaptic plasticity genes (Arc, Egr1, Bdnf, Syp), enhancement of metabolic and insulin-related signaling (Pgc1a, Sirt1, Igf1r, Irs2), increased Cldn5 expression, and reduced pro-inflammatory Il1β expression. APP/PS1 mice exhibited limited response to WME, suggesting more persistent transcriptional signatures of synaptic impairment, metabolic dysregulation, and neuroinflammation than in WT mice. We found no significant effects of WME treatment on amyloid plaque density and behavior in APP/PS1 mice. No effects on astrocyte activation were observed in either group. These findings demonstrate that dietary WME counteracts abnormal behaviors and molecular changes in neuron plasticity, metabolic, and vascular markers under conditions of normal aging but fails to improve the hallmarks of AD pathology. This highlights the potential of WGA-containing nutrients as a preventive nutritional approach targeting pathogenic mechanisms of aging and, potentially, AD pathology.}, } @article {pmid42278547, year = {2026}, author = {Pastén-Castrejón, NJ and Martínez-Orozco, H and Gutiérrez-Silerio, GY and Hernández-Montiel, HL and Maya-Arteaga, JP and Poblano-Paez, I and García-Solís, P and Díaz-Miranda, SY}, title = {Hippocampal, Microglial, Morphological, and Amyloid Profiles Following Thiamine Pyrophosphate Treatment in 3xTg-AD Mice.}, journal = {International journal of molecular sciences}, volume = {27}, number = {11}, pages = {}, pmid = {42278547}, issn = {1422-0067}, mesh = {Animals ; *Microglia/metabolism/drug effects/pathology ; *Alzheimer Disease/drug therapy/metabolism/pathology/genetics ; *Thiamine Pyrophosphate/pharmacology ; Mice, Transgenic ; *Hippocampus/metabolism/drug effects/pathology ; Female ; Mice ; *Amyloid beta-Peptides/metabolism ; Disease Models, Animal ; }, abstract = {Alzheimer's disease (AD) is characterized by the accumulation of amyloid-β (Aβ) and chronic neuroinflammation, with microglia playing a central role in its pathogenesis. Alterations in microglial metabolism have been proposed to contribute to AD-related inflammatory responses and reduced Aβ clearance, suggesting that thiamine-dependent pathways may be relevant in this context. Thiamine pyrophosphate (TPP), the active form of vitamin B1, is essential for glucose metabolism and mitochondrial function; however, its association with microglial changes in AD remains unclear. In this study, 9-month-old female triple-transgenic AD (3xTg-AD) mice and non-transgenic controls (NoTg) received TPP (2.0 mg/mL) or saline as a vehicle for six weeks via osmotic pumps. Nesting, a hippocampus-dependent behavioral test, as well analyses of Aβ burden, microglial morphology, and the expression of genes related to metabolic and immune pathways were evaluated. Differences in nesting behavior between experimental groups were observed, but TPP treatment was not associated with an evident change in 3xTg-AD mice. In the subiculum and CA1 regions of the hippocampus of female 3xTg-AD mice exposed to TPP, a lower Aβ burden was observed, and morphological variations in microglia were detected in both groups (3xTg-AD and NoTg). Additionally, in the brain of the TPP-treated group, some changes in mRNA gene expression were recorded. Together, these findings describe hippocampal microglial and amyloid profiles following TPP treatment in 3xTg-AD mice and provide a basis for further investigation of thiamine-dependent pathways in AD-related neuroinflammatory contexts.}, } @article {pmid42281500, year = {2026}, author = {Rashidi, SK and Dezfouli, MA and Khalili, H and Kiani, AKD}, title = {The role of gut microbiota in the neurobiology and treatment of Alzheimer's disease.}, journal = {General physiology and biophysics}, volume = {45}, number = {2}, pages = {129-151}, doi = {10.4149/gpb_2025042}, pmid = {42281500}, issn = {0231-5882}, mesh = {Humans ; *Alzheimer Disease/therapy/microbiology/physiopathology ; *Gastrointestinal Microbiome ; Animals ; *Brain/physiopathology ; Amyloid beta-Peptides/metabolism ; Probiotics/therapeutic use ; Fecal Microbiota Transplantation ; }, abstract = {Alzheimer's disease (AD) is the most common cause of dementia in the elderly population and characterized by progressive cognitive decline. The major pathological features of AD are the accumulation of extracellular amyloid-beta protein as neuritic plaques and intracellular hyperphosphorylated tau protein as neurofibrillary tangles. Studies have shown that gut microbiota are involved in several central nervous system disorders through regulation of neurotransmitter production, blood-brain barrier permeability and immune responses. The gut microbiota establishes a two-way communication between the gut and the brain through neural, endocrine, and immune pathways, which play a role in various neurological diseases, including AD. Alterations in the composition and function of the gut microbiota may influence neuroinflammation, amyloid-beta accumulation, and tau pathology. Targeting the balance of the gut microbiota through probiotics, prebiotics, and fecal microbial transplantation could be promising therapeutic approach against neurodegeneration. Understanding the complex relationship between the gut microbiota and AD pathobiology could pave the way for novel preventive and therapeutic strategies. Here, we summarized advances in the role of gut microbiota in AD pathobiology and updated rising concerns from recent reports. Moreover, the possibility of applying the capability of the gut microbiota as a promising treatment against AD has been discussed in this review.}, } @article {pmid42281759, year = {2025}, author = {Foye, G and Foye, E and Walter, S and Ptomey, LT}, title = {Research should be conducted with us, not on us: Perspectives on Alzheimer's disease clinical trials for persons with Down syndrome.}, journal = {Alzheimer's & dementia. Behavior & socioeconomics of aging}, volume = {1}, number = {4}, pages = {}, pmid = {42281759}, issn = {2997-3805}, abstract = {Life expectancy for individuals with Down syndrome (DS) has increased significantly over the past 60 years, drawing greater attention to Alzheimer's disease (AD), now the leading cause of death in this population. Despite a lifetime AD risk as high as 90%, individuals with DS have been historically excluded from AD research, exacerbating already-existing significant gaps in prevention, diagnosis, and treatment strategies. Although recent clinical trials have begun to address this, challenges in recruitment and retention persist due to accessibility barriers, safety concerns, and limited prior engagement. Meaningful inclusion requires centering the voices of both individuals with DS and their caregivers to ensure that researchers provide accessible studies, communicate with respect, and share results, which will result in greater trust in research. This perspective offers personal reflections from an adult with DS, her caregiver, and two researchers, offering practical insights for designing inclusive, respectful, and person-centered clinical trials.}, } @article {pmid42282197, year = {2026}, author = {Shao, Y and Yin, Y and Cheng, Y and McGeary, JE and Taveira, TH and Tsuang, DW and Logue, MW and Ayandeh, S and Ahmed, A and Zamrini, E and Zeng-Treitler, Q}, title = {Medication-Wide Association Study of Alzheimer's Disease and Related Dementias: Identifying Drug Candidates from Electronic Health Records through Explainable AI.}, journal = {medRxiv : the preprint server for health sciences}, volume = {}, number = {}, pages = {}, doi = {10.64898/2026.06.02.26354752}, pmid = {42282197}, abstract = {OBJECTIVE: Alzheimer's disease (AD) is a leading cause of death and disability, and treatment options for Alzheimer's disease and related dementias (ADRD) remain limited. We applied a data-driven, mechanism-agnostic Medication-Wide Association Study Plus (MWAS+) framework to identify candidate medications associated with ADRD using longitudinal electronic health record data and explainable artificial intelligence (AI).

METHODS: We used Veterans Health Administration electronic health record data from January 1999 to May 2022. The initial study population comprised 8,424,715 Veterans aged 65 years or older. Cases were defined by ADRD-related diagnosis codes or ADRD-related medication prescriptions, and controls were free of ADRD diagnosis and ADRD-related medication use. After exclusions and matching on sex, race, age at first encounter, and duration of follow-up, the primary analytic cohort included 505,817 matched case-control pairs (1:1; 1,011,634 Veterans). Longitudinal features were extracted from historical data up to 1 year before the index date and aggregated into 1-year intervals. We developed an upgraded Hybrid Value-Aware Transformer (HVAT 2.0) to jointly learn from longitudinal and nonlongitudinal clinical data while incorporating numerical values associated with clinical concepts, including cumulative medication dose. To enhance interpretability, we applied a medication-specific impact score method to estimate model-derived associations between medication exposure and ADRD risk.

FINDINGS: The model demonstrated stable performance across data partitions, with area under the receiver operating characteristic curve values of 0.791 in the training set, 0.772 in the validation set, and 0.775 in the testing set. Metolazone and varenicline were identified as the top 2 candidate medications with negative impact scores, suggesting potentially protective associations with new-onset ADRD. The impact score was -0.196 per unit of cumulative dose for metolazone (1800 mg) and -0.134 per unit for varenicline (280 mg). Although individual-level impact scores varied, most exposed patients had negative scores, including 12,020 of 12,480 metolazone users (96%) and 8,341 of 8,786 varenicline users (95%).

IMPLICATIONS: This study demonstrates the feasibility of combining a medication-wide association framework, longitudinal dose-aware modeling, and explainable AI to identify candidate medications for ADRD from real-world electronic health record data. The findings should be interpreted as signals for hypothesis generation rather than evidence of causality. This framework may support prioritization of repurposing candidates for expert review, follow-up cohort validation, and future clinical investigation.}, } @article {pmid42282265, year = {2026}, author = {Kwa, E and Ogilvie, CE and Kormos, NC and Green, AJE and Smith, TK and Gunn-Moore, FJ}, title = {The inhibitors of 17β-HSD10: are they any good?.}, journal = {RSC chemical biology}, volume = {}, number = {}, pages = {}, pmid = {42282265}, issn = {2633-0679}, abstract = {The advent of the first disease-modifying therapies for Alzheimer's disease (AD) has renewed optimism for effective prevention and treatment strategies. Growing mechanistic insights indicate that AD pathogenesis is multifactorial and non-linear, better conceptualized as a circular vortex in which interconnected pathological processes reinforce one another. This complexity highlights the necessity for multiple druggable targets and combination-based therapeutic approaches. A hallmark of AD is reduced cerebral glucose utilization, revealed by positron emission tomography studies, reflecting profound metabolic disruption and mitochondrial dysfunction. Among mitochondrial candidates, 17β-hydroxysteroid dehydrogenase type 10 (17β-HSD10), encoded by HSD17B10, has emerged as a protein of interest. Despite debate surrounding its substrate specificity due to conflicting in vitro data, its elevated expression in neurons and astrocytes within AD brains underscores its potential relevance. This review outlines chemical entities targeting both catalytic and non-catalytic functions of 17β-HSD10 and examines whether its inhibition offers biological efficacy and clarifies its metabolic roles in the living brain.}, } @article {pmid42282664, year = {2026}, author = {Fang, X and Border, JJ and Zhang, H and Morgan, GC and Gregory, A and Hanscom-Trofy, Y and Dong, R and Yang, J and Hwang, SH and Morisseau, C and Hammock, BD and Fan, F and Roman, RJ}, title = {Inhibition of Soluble Epoxide Hydrolase Rescues Cognitive Deficits by Preserving Neurovascular Integrity and Attenuating Glial- and Neuropathology in Diabetic-Related Dementia.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {42282664}, issn = {2692-8205}, abstract = {Diabetes mellitus (DM) is a major risk factor contributing to the development of Alzheimer's disease-related dementias (ADRD). While one of the early symptoms of both Alzheimer's disease (AD) and DM-related ADRD is a reduction in cerebral blood flow, the underlying biological mechanisms driving this decline remain to be fully elucidated. Genome-wide association studies have linked AD/ADRD to single-nucleotide polymorphisms in the gene encoding soluble epoxide hydrolase (sEH), an enzyme we previously reported to be upregulated in the brains of an AD rat model. Our previous work also demonstrated that chronic inhibition of sEH with 1-trifluoromethoxyphenyl-3-(1-propionylpiperidin-4-yl) urea (TPPU) preserves hippocampal-dependent spatial learning and memory and improves cerebral hemodynamics in both AD and DM-ADRD models. In the present study, we found that chronic TPPU treatment (1 mg/kg/day for 9 weeks) reduced brain sEH expression, improved cortical-based long-term non-spatial recognition memory involving both cortical and hippocampal networks, and reduced anxiety in DM-ADRD rats. TPPU improved brain perfusion and normalized impaired whisker-evoked functional hyperemia, an effect linked to upregulation of Kir2.1 expression in cerebral capillaries. Furthermore, TPPU restored tight junction proteins (ZO-1 and OCLN), mitigated capillary rarefaction, and suppressed astrocyte and microglial activation. At the cellular level, TPPU attenuated hippocampal neurodegeneration, restored the expression of synaptic proteins (PSD95 and SY38), and reduced levels of key pro-inflammatory chemokines, including MCP-1, RANTES, and MIP-1α, in DM-ADRD. In conclusion, TPPU preserves cognitive function in DM-ADRD by mitigating cerebrovascular dysfunction, neuroinflammation, and gliosis while protecting synaptic integrity and neuronal survival, representing a promising therapeutic strategy for DM-ADRD.}, } @article {pmid42283246, year = {2026}, author = {Fikry, H and Saleh, LA and Sadek, DR}, title = {Histological and Tissue-Level Outcomes of Stem Cell Therapies in Neurodegenerative Disorders: A Systematic Review.}, journal = {Clinical anatomy (New York, N.Y.)}, volume = {}, number = {}, pages = {}, doi = {10.1002/ca.70147}, pmid = {42283246}, issn = {1098-2353}, abstract = {Neurodegenerative diseases, which afflict millions worldwide and threaten public health, have no cure. Neurodegenerative diseases lack effective therapies, burdening society and the economy. Over the past 20 years, regenerative cell therapy (stem cell therapy) has advanced, opening novel neurodegenerative disease treatments. Thus, the current review aimed to systematically highlight experimental and clinical studies of potentially effective therapeutic strategies for stem cells and report histological, cellular, or ultrastructural outcomes following stem cell interventions in neurodegenerative diseases. PRISMA-compliant computerized literature searches of PubMed, Scopus, and Web of Science identified studies on embryonic, induced pluripotent, mesenchymal, or neural stem cells (NSCs) in neurodegenerative disease models and histological and tissue-level outcomes. Search terms included nervous system diseases, histology, neuron regeneration, stem cells, stem cell treatment, and transplantation. Peer-reviewed articles published between 2000 and 2025 were selected. Experimental animal and clinical studies that reported histological or tissue-level results after stem cell treatments were included. Eighty-six studies met the eligibility criteria, covering models of Parkinson's disease, Alzheimer's disease, amyotrophic lateral sclerosis (ALS), and Huntington's disease. Across these studies, stem cell therapies were linked to improved neuron survival, better synaptic structure, diminished gliosis, and some restoration of tissue structure. These effects depended on the type of stem cell used, the disease model, and how the treatment was given. Overall, the evidence suggests that stem cell therapies can lead to significant histological and tissue-level improvements in neurodegenerative diseases, supporting their potential for regeneration. Further standardized and translational studies are needed to clarify the underlying mechanisms and improve treatment strategies.}, } @article {pmid42283996, year = {2026}, author = {Totuk, O}, title = {Amyloid-Related Imaging Abnormalities in Anti-amyloid Therapy: Clinical Implications of Kinetics for Safer Use and Risk Stratification.}, journal = {Clinical drug investigation}, volume = {}, number = {}, pages = {}, pmid = {42283996}, issn = {1179-1918}, abstract = {Anti-amyloid monoclonal antibodies have emerged as disease-modifying therapies for Alzheimer's disease. However, their broader clinical adoption is limited by amyloid-related imaging abnormalities, a key safety concern. Traditionally viewed as an unavoidable and dose-dependent adverse effect, amyloid-related imaging abnormalities often lead to treatment interruption or the exclusion of high-risk patients from therapy. Emerging evidence now suggests that amyloid-related imaging abnormalities may instead reflect a transient modifiable cerebrovascular response, primarily influenced by the kinetics of amyloid clearance rather than the absolute magnitude of amyloid removal. Recent data from titration-based dosing strategies demonstrate that gradual amyloid mobilization can significantly reduce the incidence of amyloid-related imaging abnormalities without compromising amyloid positron emission tomography responses or downstream biomarkers. This kinetic perspective may support a more nuanced re-evaluation of patient groups previously deemed unsuitable for therapy, including APOE ε4 carriers, individuals with cerebral microbleeds, and patients on antithrombotic treatment. In this Current Opinion, we propose a pragmatic clinical framework that integrates amyloid clearance kinetics, magnetic resonance imaging-based risk stratification, and individualized protocols for treatment interruption and re-challenge. By reframing amyloid-related imaging abnormalities as a modifiable clinical decision-making challenge rather than an inherent toxicity, anti-amyloid therapies may be optimized for safer use; however, whether such approaches can enable broader and more inclusive treatment strategies remains to be established in prospective studies, particularly in high-risk populations.}, } @article {pmid42284682, year = {2026}, author = {O'Brien, EK and Cox, T and Fernandez, S and Bourgeat, P and Porter, T and Goudey, B and Doecke, JD and Masters, CL and Fripp, J and Nho, K and Villemagne, VL and Cruchaga, C and Rowe, CC and Saykin, AJ and Doré, V and Laws, SM}, title = {Predicting accumulation and age at onset of amyloid-β from genetic risk and resilience for Alzheimer's disease.}, journal = {EBioMedicine}, volume = {129}, number = {}, pages = {106329}, pmid = {42284682}, issn = {2352-3964}, abstract = {BACKGROUND: Accumulation of brain amyloid beta (Aβ), a key pathological hallmark of Alzheimer's disease (AD), begins decades before cognitive symptoms. Being able to predict the risk of Aβ accumulation, or the age at which Aβ exceeds a critical threshold, may enable intervention to delay or prevent onset of AD.

METHODS: Using published genome-wide association studies (GWASs), we developed polygenic scores (PGS) for AD risk (PGSrisk) and resilience (PGSresilience), and tested whether these predicted (i) if an individual is an Aβ accumulator ('Accumulator Status'), and (ii) in accumulators, the age at which brain Aβ exceeds a 20 centiloid (CL) threshold ('Age at onset of Aβ'; AAO-Aβ) in 2175 participants (1158 with AAO-Aβ) from the Alzheimer's Dementia Onset and Progression in International Cohorts (ADOPIC) study. We also performed GWASs on these traits to develop phenotype-specific PGSs.

FINDINGS: Higher genetic risk of AD predicted increased odds of Aβ accumulation (OR = 1.16; 95% CI = 1.05-1.29; p = 0.003) and younger AAO-Aβ (β = -1.32; SE = 0.31; p = 1.63 × 10[-5]). Higher genetic resilience to AD predicted later AAO-Aβ (β = 0.91; SE = 0.29; p = 0.002) but did not predict Aβ accumulation. These associations were independent of APOE ε4 status, the strongest genetic risk factor for AD. Phenotype-specific PGSs were not significantly associated with either trait.

INTERPRETATION: Polygenic scores, alongside other risk factors, may help identify individuals at risk of accumulating Aβ, and predict the age at which this exceeds a critical threshold. This could provide a window for administering disease-modifying treatment or lifestyle interventions to prevent or delay the onset of AD.

FUNDING: National Institutes of Health (R01-AG058676-01A1) and Australian National Health and Medical Research Council (GNT1161706; GNT2001320).}, } @article {pmid42288063, year = {2026}, author = {Zhao, H and Qian, S and Wang, Y and Yang, W}, title = {Information quality of Alzheimer's disease treatment videos on TikTok and related factors: A cross-sectional study.}, journal = {Journal of clinical neuroscience : official journal of the Neurosurgical Society of Australasia}, volume = {152}, number = {}, pages = {112144}, doi = {10.1016/j.jocn.2026.112144}, pmid = {42288063}, issn = {1532-2653}, abstract = {BACKGROUND: The increasing reliance on mobile internet for health information necessitates a critical evaluation of content quality. This study aimed to systematically assess the quality of Alzheimer's Disease (AD) treatment-related short videos on TikTok, a leading platform for health information dissemination.

METHOD: A total of 100 CE treatment videos from TikTok, retrieved on December 20, 2025, were comprehensively evaluated using established assessment tools. Specifically, the Journal of American Medical Association (JAMA) benchmark criteriaand themodified Decision-making Information Support Criteria for Evaluating the Reliability of Non-randomised Studies (mDIS) scorewere used to evaluate thereliabilityof the video content. TheGlobal Quality Score (GQS) was used to assess theoverall quality, and the Patient Education Materials Assessment Tool for Audio Visual Content (PEMAT-A/U)was used to evaluate understandability and actionability.

RESULTS: Neurologists were identified as primary contributors of high-quality content, while videos on experimental treatments like deep cervical lymphovenous anastomosis (LVA) generally exhibited lower quality. Videos from emerging first-tier cities and those uploaded by top-tier creators demonstrated superior audience engagement and often higher content quality. A significant positive correlation was found between video duration, audience engagement metrics, and content quality scores.

CONCLUSIONS: Neurologists play a crucial role in providing reliable AD treatment information on short video platforms. There is an urgent need to improve the quality of content on experimental treatments and to encourage longer, well-referenced videos. Platforms should enhance content moderation and explicitly label experimental therapies to ensure accurate and trustworthy public health education regarding AD.}, } @article {pmid42289507, year = {2026}, author = {Yazi, S and Ozen, B and Buldu, B and Yalcin, E and Karakose, O and Cakmak, O and Somunkiran, S and Yananli, HR and Sehirli, US and Kirazli, O}, title = {The effect of canagliflozin on hippocampal dendrite morphology in a model of Alzheimer's disease induced by intracerebroventricular injection of streptozotocin.}, journal = {Brain structure & function}, volume = {231}, number = {6}, pages = {}, pmid = {42289507}, issn = {1863-2661}, mesh = {Animals ; *Canagliflozin/pharmacology/administration & dosage ; *Alzheimer Disease/pathology/chemically induced/drug therapy ; Male ; Streptozocin/administration & dosage ; *Dendrites/drug effects/pathology ; Rats ; *Hippocampus/drug effects/pathology ; Disease Models, Animal ; Donepezil/pharmacology ; Dendritic Spines/drug effects/pathology ; Pyramidal Cells/drug effects/pathology ; *Sodium-Glucose Transporter 2 Inhibitors/pharmacology ; Rats, Wistar ; Rats, Sprague-Dawley ; }, abstract = {Alzheimer's disease (AD) and diabetes mellitus (DM) share common pathophysiological features. However, the effects of antidiabetic drugs on neurodegeneration are not completely known. Canagliflozin, a novel option for DM treatment, is a dual inhibitor of sodium glucose co-transporter type 2 (SGLT2) and acetylcholinesterase. The aim of this study is to examine the morphological features of dendrites and dendritic spines of pyramidal neurons in hippocampus of AD model treated with canagliflozin. The model of AD was obtained by intracerebroventricular injection of streptozotocin. Then, the rats were divided into 3 groups: vehicle, donepezil, and canagliflozin. The injections were i.c.v. administered for 7 days. Behavioral tests were performed to evaluate memory, anxiety, and motor functions. Brain tissues were processed by Golgi impregnation method. Pyramidal neurons in the CA1 region were examined using Neurolucida software. Dendritic branching, total dendrite length, dendritic spine density, and dendritic spine types were analyzed. Compared to the vehicle group, the donepezil group and the canagliflozin group exhibited significantly higher dendritic branches (p = 0.0273, p = 0.0195) and total dendrite length (p = 0.0171, p = 0.0360), respectively. The total dendritic spine density (p < 0.0001) and the mushroom-type dendritic spine density (p = 0.0001) were significantly low in the donepezil group compared to the vehicle group. However, canagliflozin did not induce any significant alterations in the dendritic spine density. Canagliflozin treatment was as effective as donepezil treatment on hippocampal dendrite morphology. This morphological framework, indicating dendritic plasticity and remodeling, serve to better understand the cellular effects of canagliflozin. Therefore, our study may contribute to the development of novel strategies for therapy of AD.}, } @article {pmid42291413, year = {2026}, author = {Sha, Y and Fu, H and Lu, K and Wang, G and Wang, Y}, title = {The role of YKL-40 in Alzheimer's disease pathology and drug targeting.}, journal = {PeerJ}, volume = {14}, number = {}, pages = {e21361}, pmid = {42291413}, issn = {2167-8359}, mesh = {Humans ; *Alzheimer Disease/drug therapy/metabolism/pathology ; *Chitinase-3-Like Protein 1/metabolism/antagonists & inhibitors ; Animals ; Biomarkers/metabolism ; Apoptosis ; Disease Progression ; }, abstract = {BACKGROUND: Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by the accumulation of amyloid-beta (Aβ) plaques, hyperphosphorylated tau tangles, and significant neuronal loss. Recent studies have implicated YKL-40, a glycoprotein commonly associated with inflammation and neural apoptosis, in the pathogenesis of AD.

METHODS: We conducted extensive searches across major scientific databases, including PubMed, Web of Science, and Embase. We selected peer-reviewed articles, review articles, and clinical studies focusing on YKL-40 in AD.

RESULTS: This review comprehensively analyses the multifaceted role of YKL-40 in AD, covering its cellular localization, biomarker associations, and pathological mechanisms. We also summarize the mechanistic pathways by which YKL-40 contributes to disease progression, highlighting its role in neuroinflammation, neural apoptosis, and disruption of the circadian regulation of immune responses. Moreover, the development of drugs that target YKL-40, such as humanized anti-YKL-40 antibodies and small molecules, offers promising strategies for blocking AD progression.

CONCLUSION: This review highlights the potential of YKL-40 as a novel drug target and its implications for enhancing diagnostic precision and treatment strategies in combating Alzheimer's disease.}, } @article {pmid42292330, year = {2026}, author = {Mukhopadhyay, D and Das, P and Angom, RS and Dutta, S and Li, Z and Castanedes-Casey, M and Kulkarni, T and Chakravarty, T and Wang, E and Dickson, D and Rachamala, HK}, title = {Vascular endothelial growth factor receptor-1 (VEGFR-1) knock-down is protective against hypoxia, Aβ1-42 oligomer and Aβ1-42 fibril -induced neuronal cell death: implications in AD pathogenesis.}, journal = {Frontiers in neuroscience}, volume = {20}, number = {}, pages = {1799391}, pmid = {42292330}, issn = {1662-4548}, abstract = {INTRODUCTION: Recent transcriptome analysis has demonstrated increased expression of Vascular Endothelial Growth Factor receptor-1 (VEGFR-1/FLT1) and in AD brain. Increased expression of VEGFR1 and its ligand VEGFB were associated with a more rapid rate of cognitive decline, providing evidence of a potential link between increased VEGFR-1 expression in AD pathogenesis. In this study, we explored the potential role of VEGFR-1 expression in neurons on AD pathology.

METHODS: To confirm VEGFR1 expression in AD brains, we first performed immunostaining in AD brain sections (AD - Braak stage V-VI, and normal controls - Braak 0-II). And to determine a potential detrimental role of neuronal VEGFR1 expression on AD associated pathologies, we exposed SH-SY5Y human neuroblastoma cells and mouse primary neurons to either hypoxia conditions (1%O2) or 5 μ Aβ1-42 oligomers or fibrils for 24, 28 and 72hrs.

RESULTS: In this study, we found preferential staining of VEGFR-1 in the neuropil and neuronal cell bodies both in AD and Control hippocampus and increased VEGFR-1 immunoreactivity in dystrophic neuritic processes in the vicinity of Thio-S positive amyloid plaques in AD brains. And treatment of SH-SY5Y human neuroblastoma cell line and mouse primary neurons, with either hypoxia conditions or Aβ1-42 oligomers, resulted in increased VEGFR-1 expression and cleaved caspase 3 activation, leading to neuronal toxicities/cell death. Similarly, treatment with Aβ1-42 fibrils also increased VEGFR-1 and cleaved caspase 3 protein levels in the SH-SY5Y cells whereas treatment with Aβ1-42 monomers had no effect on VEGFR-1 expression. In addition, we show that over-expression of VEGFR-1 intracellular domains in SH-SY5Y cells directly induced neuronal toxicities and importantly, siRNA-mediated knockdown of VEGFR-1 in neurons prevented the hypoxia, Aβ1-42 oligomer and Aβ1-42 fibril-induced toxicities and cell death phenotypes. Treatment with either hypoxia or Aβ1-42 oligomers also reduced expression of cell survival genes including VEGFR-2 and Hippo pathway YAP1 and siRNA-mediated VEGFR-1 knockdown in the neurons normalized expression of both VEGFR-2 and YAP1. Using differential gene expression analysis, we demonstrated upregulation of several inflammatory/interferon-stimulated genes (ISGs) as well as increased expression of genes involved in activation of oxidative stress and cell death pathways in response to Aβ1-42 oligomers treatment in mouse primary neurons. And siRNA-mediated VEGFR-1 knockdown in the mouse primary neurons, reduced gene expression of both the ISGs and oxidative stress/cell death pathways in response to Aβ1-42 oligomer treatment.

DISCUSSION: In summary, these results show that siRNA-mediated knockdown of VEGFR-1 in neurons significantly prevented hypoxia, Aβ1-42 oligomer and Aβ1-42 fibril-induced cellular toxicities and cell death phenotypes, indicating a potential detrimental role of aberrant VEGFR-1 expression and signaling in response to AD associated pathologies.}, } @article {pmid42292846, year = {2026}, author = {Lindemann, L and Lambotte, J and Rothe, J and Messer, J and Diener, C and Pichereau, S and Cantrill, C and Mueggler, T and Honer, M and Beck, J and Steinbrecher, T and Tortelli, R and Gerlach, I and Ratni, H and Rodriguez Sarmiento, RM and Baumann, K}, title = {Pharmacology of nivegacetor (RG6289), a potent and selective gamma secretase modulator in clinical development for the treatment of Alzheimer's disease.}, journal = {Frontiers in pharmacology}, volume = {17}, number = {}, pages = {1783414}, pmid = {42292846}, issn = {1663-9812}, abstract = {BACKGROUND: Alzheimer's Disease (AD) is a prevalent neurodegenerative disorder which involves a complex pathobiology driven by amyloid-beta (Aβ) and tau pathologies, among other factors. Aβ peptides are generated via β-secretase (BACE1) and γ-secretase cleavage of amyloid precursor protein (APP). While long isoforms like Aβ42 are neurotoxic and aggregation-prone, shorter isoforms (Aβ38, Aβ37) are non-amyloidogenic. γ-secretase modulators (GSMs) shift production from longer to shorter peptides which is expected to slow down or halt (prevent) amyloid accumulation and its downstream effects.

METHODS: The novel GSM nivegacetor was evaluated in vitro using cell lines overexpressing human wild-type APP, or human APP with the Swedish mutation K670N/M671L (APPSwe). The in vitro selectivity of nivegacetor was tested on Notch-1, a representative gamma secretase substrate other than APP. Additionally, nivegacetor was profiled for its selectivity on a range of pharmacological targets. In vivo studies tested a dose-response and a time course of nivegacetor on soluble Aβ levels in brain tissue of APPSwe transgenic mice. Furthermore, the impact of two ADAD mutations, PSEN1 E280A (Columbian) and PSEN2 N141I (Volga German), on nivegacetor's potency was tested. Moreover, nivegacetor was tested for possible effects on [[3]H]florbetaben binding to Aβ plaque pathology in human AD brain tissue sections.

RESULTS: Nivegacetor lowered the production of Aβ42 and Aβ40 and concomitantly increased levels of Aβ37 and Aβ38 in vitro and in vivo in mice. Nivegacetor did not inhibit Notch-1 and showed a favorable selectivity profile on a broad range of targets. When tested on two ADAD mutations, nivegacetor was equipotent on the PSEN1 E280A mutation and significantly less potent on the PSEN2 N141I mutation compared to wild-type gamma secretase. Nivegacetor did not interfere with the detection of amyloid plaques by [[3]H]florbetaben in human AD brain tissue, which is an important prerequisite for the use of florbetaben as a PET tracer in clinical trials.

CONCLUSION: Nivegacetor is a potent, orally bioavailable GSM with favorable properties and is currently under investigation as a clinical candidate in a Phase 2A clinical trial in individuals with prodromal and early sporadic AD, and in a Phase 2 clinical trial in individuals carrying the PSEN1 E280A ADAD mutation.}, } @article {pmid42293147, year = {2026}, author = {Pinky, and Neha, and Kaushik, M and Tiwari, P and El-Tanani, M and Rabbani, SA and Parvez, S}, title = {Propranolol reinstates mitochondrial dynamics and synaptic memory pathways through CaMKII/CREB-BDNF/ PKMζ cascades in an AD-like rat model.}, journal = {Frontiers in aging neuroscience}, volume = {18}, number = {}, pages = {1729046}, pmid = {42293147}, issn = {1663-4365}, abstract = {BACKGROUND: Alzheimer's disease (AD) is a major neurodegenerative disorder characterized by amyloid-β (Aβ) accumulation, neurofibrillary tangles, and progressive cognitive decline. Despite significant advances in understanding its pathophysiology, current therapeutic options provide limited symptomatic relief. The present study investigated the nootropic and anti-amnesic effects of propranolol (PRO) in a scopolamine (SCP)-induced AD-like rat model.

METHODS: Wistar rats received PRO (10, 30, or 50 mg/kg, p.o.) or donepezil (DPZ; 1 mg/kg) for 17 days. Cognitive deficits were induced by SCP (1 mg/kg, i.p.) administration from day 9 onward. Behavioral performance was assessed using the Novel Object Recognition (NOR) and Elevated Plus Maze (EPM) tests. Molecular and cellular analyses were conducted to evaluate synaptic plasticity markers (CaMKII, CREB, BDNF, PKMζ), mitochondrial function, oxidative stress parameters, and inflammatory markers (GFAP, TNF-α).

RESULTS: Propranolol treatment significantly improved long-term memory performance, enhanced recognition index, and attenuated anxiety-like behavior in SCP-treated rats. These behavioral effects were associated with upregulation of CaMKII-CREB-BDNF-PKMζ signaling, improvement in mitochondrial membrane potential (Δψm), reduction in reactive oxygen species (ROS) generation and Aβ1-42 accumulation, and decreased expression of GFAP and TNF-α.

CONCLUSION: The findings suggest that propranolol mitigates SCP-induced cognitive impairments, potentially through modulation of synaptic plasticity- related signaling, mitochondrial function, and neuroinflammatory responses. These results indicate the therapeutic potential of propranolol in experimental models of AD-related neurodegeneration, warranting further investigation.}, } @article {pmid42294918, year = {2026}, author = {Singh, M and Steinke, I and Crall, N and Tamhankar, S and Wibowo, FS and Xavier, J and Yue, Z and Pondugula, SR and Huang, CJ and Griffett, K and Smith, FT and Chowdhury, K and Suppiramaniam, V and Amin, RH}, title = {Design and Development of a Novel LXRβ/PPARδ Dual Agonist for Memory Impairment and Pathology in 3xTg-AD Animal Model of Alzheimer's Disease.}, journal = {ACS chemical biology}, volume = {}, number = {}, pages = {}, doi = {10.1021/acschembio.6c00240}, pmid = {42294918}, issn = {1554-8937}, abstract = {The rising prevalence of Alzheimer's disease (AD) underscores an urgent need for neuroprotective strategies that modulate cholesterol metabolism, neuroinflammation, improve pathology, and cognitive function. While Liver X receptors (LXRs) and peroxisome proliferator-activated receptors (PPARs) are validated targets for enhancing amyloid-β and tau clearance, clinical translation of first-generation LXR agonists has been hindered by LXRα-mediated hepatic steatosis and hypertriglyceridemia. Here, we report the structure-based design of AU403, a potent, isoform-selective LXRβ/PPARδ dual agonist designed to bypass LXRα-driven hepatotoxicity. Molecular modeling indicates that AU403 achieves LXRβ selectivity by engaging residues Phe329 and Leu330 while avoiding the corresponding LXRα residues Arg305 and Leu316. This structural precision translates to robust functional activity, with luciferase assays confirming potent activation of LXRβ (EC50 ≈ 45 nM) and PPARδ (EC50 ≈ 40 nM). Notably, AU403 exhibits a superior safety profile, circumventing hepatotoxicity, neutropenia, and hERG inhibition that have limited the clinical development of prior agonists. Furthermore, chronic administration of AU403 in 3xTg-AD mice significantly improved cognitive functions and reduced amyloid-β plaque burden, establishing AU403 as a promising dual-acting agonist for the treatment of Alzheimer's Disease.}, } @article {pmid42295086, year = {2026}, author = {Liu, Q and Lin, RR}, title = {Optimizing Antibody-Based Therapies for Alzheimer's Disease: From Clinical Limitations to Molecular Engineering Innovations.}, journal = {Aging and disease}, volume = {}, number = {}, pages = {}, doi = {10.14336/AD.2026.0292}, pmid = {42295086}, issn = {2152-5250}, abstract = {Antibody-based immunotherapy represents one of the most promising disease-modifying strategies for Alzheimer's disease (AD). Recent anti-amyloid-β (Aβ) antibodies have achieved robust plaque clearance and modest cognitive benefits in early AD, establishing clinical proof of concept. However, limited efficacy and safety concerns, particularly amyloid-related imaging abnormalities (ARIA), continue to restrict their therapeutic potential. This review outlines the current clinical status of antibody therapies targeting Aβ, tau, and neuroinflammatory pathways, and summarizes key antibody optimization strategies, including aggregation-state-selective targeting, Fc engineering, brain shuttle technologies, nanobody platforms, and nanotechnology-enabled delivery. We further discuss emerging concepts from tumor immunotherapy, such as antibody-guided protein degradation and conditionally active biologics, as potential avenues for next-generation AD treatment.}, } @article {pmid42295611, year = {2026}, author = {Guo, Y and Chen, P and Chen, S and Xu, N and Shi, J and Li, D and Zhang, P}, title = {Circ_0092222 is Enhanced in Alzheimer's Disease and Exacerbates Aβ-induced Neurotoxicity Through Sponging miR-331-3p.}, journal = {Molecular neurobiology}, volume = {63}, number = {1}, pages = {}, pmid = {42295611}, issn = {1559-1182}, mesh = {Female ; Humans ; Male ; *Alzheimer Disease/genetics/pathology/blood/metabolism ; *Amyloid beta-Peptides/toxicity ; Apoptosis/drug effects/genetics ; Cell Line, Tumor ; Cell Survival/drug effects ; *MicroRNAs/genetics/metabolism ; Neurons/metabolism/drug effects/pathology ; *Peptide Fragments/toxicity ; *RNA, Circular/genetics/metabolism ; *RNA, Competitive Endogenous/genetics/metabolism ; }, abstract = {This study aimed to explore the expression pattern of circ_0092222 in Alzheimer's disease (AD) and its role in Aβ-induced neuronal apoptosis. circ_0092222 was identified from the GEO dataset. Serum level of circ_0092222 in 95 AD patients and 100 controls was detected by reverse transcription quantitative real-time polymerase chain reaction (RT-qPCR). AD cell model was achieved by treating SH-SY5Y cells with Aβ25-35. Cell viability, cytotoxicity, apoptosis and inflammation were detected. The targeting relationship between circ_0092222 and miR-331-3p, and between miR-331-3p and SEC61A1 was verified by the dual-luciferase reporter gene assay. Pearson correlation and Logistic regression analysis were used to evaluate the relationship between variables and the risk factors for AD progression. Circ_0092222 expressions in AD patients were higher than that in the control group. Short years of education, low mini mental state examination (MMSE) score, low plasma Aβ42/40 ratio, and elevated circ_0092222 were independent risk factors for the progression of mild AD to moderate/severe. In cell experiments, the expression of circ_0092222 was upregulated. Knockdown of circ_0092222 could significantly reduce the apoptosis rate, lactate dehydrogenase (LDH) release, pro-inflammatory cytokine levels, and the expressions of Bax and cleaved caspase-3, and increase cell viability and Bcl-2 expression. Bioinformatics prediction and dual-luciferase reporter gene assay confirmed that circ_0092222 directly binds to miR-331-3p, and miR-331-3p directly targets SEC61A1. Functional rescue experiments demonstrated that circ_0092222 regulates Aβ25-35-induced neuronal injury by up-regulating SEC61A1 through sponging miR-331-3p. Inhibiting circ_0092222 can improve Aβ25-35-induced apoptosis and inflammation, suggesting that circ_0092222 may be a potential target for AD treatment.}, } @article {pmid42295692, year = {2026}, author = {Nath, R and Chakraborty, A and Akhtar, MJ and Maity, I and Ganguly, S and Nehra, B and Ashique, S and Khan, SA and Tariq, M and Bakshi, S and Debnath, B and Yasmin, S and Khalilullah, H and Ansari, MY}, title = {Recent trends in anti-Alzheimer's potential of novel biologically active isatin analogues: synthetic strategies, structural activity relationship studies and molecular docking insights.}, journal = {Molecular diversity}, volume = {}, number = {}, pages = {}, pmid = {42295692}, issn = {1573-501X}, abstract = {Alzheimer's disease is a progressive neurodegenerative illness i.e., characterized by cognitive decline, memory impairment, cholinergic dysfunction, oxidative stress, Aβ aggregation, tau hyperphosphorylation and neuroinflammation. Due to multifactorial nature of AD, conventional single-target therapeutic approaches exhibit limited clinical success. Hence, development of multifunctional small molecules emerged as a promising strategy for management of Alzheimer's diseases i.e., capable to modulate multiple pathological pathways simultaneously. Among various heterocyclic pharmacophores, isatin (1H-indole-2,3-dione) gained considerable attention due to its structural versatility, synthetic accessibility and broad spectrum of biological effects. Recent studies demonstrated that isatin-derived molecules possess significant inhibitory activity against acetylcholinesterase, butyrylcholinesterase, monoamine oxidase-A/B, β-secretase and amyloid aggregation pathways. Furthermore, hybridization of isatin core with pharmacologically active moieties like triazoles, coumarins, tacrine, benzylamine, piperazine, quinoline, hydrazones and melatonin afford more promising multitarget-directed ligands with improved BBB permeability, antioxidant potential and improved neuroprotective properties. Also, docking, MD simulation and ADMET analyses validated favorable binding interactions and drug-likeness characteristics of many isatin analogues. This review comprehensively summarizes recent advances in design, synthesis, biological evaluation, docking investigations and SAR studies of isatin-based anti-Alzheimer agents. In addition, key emphasis is placed on SAR trends which is responsible for promoted potency and selectivity including electron-withdrawing substitutions, linker optimization, hydrophobic interactions and dual-site binding with catalytic as well as peripheral anionic sites of target enzymes. Integration of hybrid isatin scaffolds with complementary pharmacophore combined with advanced in silico modeling and preclinical evaluation may pave the way for next-generation multifunctional therapeutics with improved efficacy and safety in treatment of Alzheimer's disease.}, } @article {pmid42297456, year = {2026}, author = {Alghamdi, A and Balafas, S and Bos, JHJ and van Munster, BC and Rafie, K and Dolga, AM and Hak, E}, title = {Association between the use of anti-herpetic drugs and subsequent initiation of Alzheimer's disease drug treatment: Dutch population-based inception cohort study.}, journal = {BMJ open}, volume = {16}, number = {6}, pages = {e114033}, pmid = {42297456}, issn = {2044-6055}, mesh = {Humans ; Female ; Aged ; *Alzheimer Disease/drug therapy/epidemiology ; Netherlands/epidemiology ; *Antiviral Agents/therapeutic use ; Retrospective Studies ; Male ; Middle Aged ; Aged, 80 and over ; Valacyclovir/therapeutic use ; Acyclovir/therapeutic use ; Famciclovir/therapeutic use ; Proportional Hazards Models ; Memantine/therapeutic use ; Donepezil/therapeutic use ; }, abstract = {OBJECTIVES: To examine whether exposure to anti-herpetic drugs (AHDs: acyclovir, valacyclovir, famciclovir) is associated with reduced risk of Alzheimer's disease (AD) treatment initiation.

DESIGN: Population-based retrospective matched cohort study.

SETTING: University Groningen community pharmacy database IADB.nl, covering approximately 125 Dutch pharmacies (1994-2024).

PARTICIPANTS: 262 757 adults aged 50-80 years without prior dementia or AD treatment. Exposed individuals with antiherpetic prescriptions (n=23 887) were matched 1:10 to unexposed controls (n=238 870) by age, sex and calendar time.

INTERVENTION: AHDs: acyclovir, valacyclovir, famciclovir.

MAIN OUTCOME MEASURES: Initiation of AD drug treatment, defined as at least two prescriptions for rivastigmine, donepezil, galantamine or memantine within 1 year. Cox proportional hazards models estimated HRs with 95% CIs, adjusted for comorbidities and medications. Analyses were stratified by period (1994-2018 vs 2019-2024) and drug type.

RESULTS: During follow-up, 2495 participants initiated AD treatment. The age of the participants was 65 (SD 9), and 59% were female. Any AHD exposure was associated with 90% reduced hazard of AD treatment (HR 0.09, 95% CI 0.07 to 0.13, p<0.001). Similar association was found in both periods: HR 0.14 (95% CI 0.09 to 0.20) in period one and HR 0.05 (95% CI 0.03 to 0.10) in period 2. All three AHDs were associated with a lower likelihood of future AD drug prescription: valacyclovir HR 0.10, acyclovir HR 0.09, famciclovir HR 0.07. The incidence rate of AD treatment initiation was substantially lower among AHD users compared with unexposed individuals overall (0.69/1000 person-years (py) vs 4.96/1000 py, p<0.001), with this association evident in both period 1 (0.65/1000 py vs 3.74/1000 py, p<0.001) and period 2 (0.81/1000 py vs 8.22/1000 py, p<0.001).

CONCLUSIONS: AHD exposure was consistently associated with markedly lower risk of AD treatment initiation, with similar findings observed in recent years. These findings support the hypothesis that herpesvirus reactivation may contribute to AD pathogenesis and suggest antiviral therapy could have preventive implications. Confirmation through prospective studies and randomised trials is needed.}, } @article {pmid42298279, year = {2026}, author = {Siengsukon, CF and Hand, LK and Nelson, E and Glaser, A and Ludwig, R and Russell, JA and Phadnis, MA and Dai, J and Bruce, J and Vidoni, ED and Drerup, M and Morris, J and Burns, JM}, title = {The impact of cognitive behavioral therapy for insomnia on cognitive performance and amyloid beta in older adults: A randomized controlled trial.}, journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association}, volume = {22}, number = {6}, pages = {e71591}, pmid = {42298279}, issn = {1552-5279}, support = {R01AG058530/AG/NIA NIH HHS/United States ; P30 AG072973/AG/NIA NIH HHS/United States ; T32 AG078114/AG/NIA NIH HHS/United States ; T32HL007028/NH/NIH HHS/United States ; T32HD057850//Eunice Kennedy Shriver National Institute of Child Health and Human Development/ ; }, mesh = {Humans ; *Cognitive Behavioral Therapy/methods ; *Amyloid beta-Peptides/metabolism ; Female ; *Sleep Initiation and Maintenance Disorders/therapy/psychology/metabolism ; Aged ; Male ; *Cognition/physiology ; Neuropsychological Tests ; Alzheimer Disease ; Aged, 80 and over ; Executive Function ; }, abstract = {INTRODUCTION: Insomnia is associated with increased risk for Alzheimer's disease (AD). It is unknown how cognitive behavioral therapy for insomnia (CBT-I) impacts two hallmarks of AD progression, cognitive performance and beta-amyloid (Aβ) burden.

METHODS: Cognitively normal older adults with symptoms of insomnia were randomized into CBT-I treatment (n = 100) or control (n = 100) groups. Cognitive performance was assessed at baseline, 6-weeks, and 1-year (1 year). Aβ burden was assessed in a subsample (n = 50).

RESULTS: No differences were observed between groups in change in cognitive performance, including speed of information processing (mean difference, 0.017; 95% confidence interval [CI], -0.1036 to 0.1376; p = 0.78), executive function (-0.0881; 95% CI, -0.2945 to 0.1182; p = 0.40), and memory (0.4068; 95% CI, -2.3965 to 3.2101; p = 0.77). No group differences were observed in Aβ deposition.

DISCUSSION: CBT-I did not improve cognitive performance or Aβ deposition by one year. Longer follow up is needed to understand the potential impact of CBT-I on AD risk.

CLINICAL TRIAL REGISTRATION: The study was registered on clinicaltrials.gov (NCT03954210) on 5/17/2019.}, } @article {pmid42298289, year = {2026}, author = {Amouyel, P and Andrieu, S and Bradshaw, A and Carmona, RC and Dumont, M and Grinberg, LT and Iwatsubo, T and Hansson, O and Jack, CR and Jicha, GA and Mahinrad, S and McDade, E and Mummery, CJ and Petersen, RC and Robinson, S and Schneider, JA and Shellcross, L and Smith, AG and Snyder, HM and Tapply, B and Teunissen, C and van der Flier, WM and Vellas, B and Wallon, D and Williamson, JD and Wilcock, D and Carrillo, MC}, title = {Provider and patient perspectives on the diagnosis and treatment of Alzheimer's disease: A global perspective from the Global Alzheimer's Leadership Series (GoALS).}, journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association}, volume = {22}, number = {6}, pages = {e71536}, pmid = {42298289}, issn = {1552-5279}, mesh = {*Alzheimer Disease/diagnosis/therapy ; Humans ; }, abstract = {Since 2016, the Alzheimer's Association and the Fondation Alzheimer have hosted Global Alzheimer's Leadership Series (GoALS) global think tanks, with world-leading experts for innovative discussions to advance Alzheimer's disease (AD) research and care. The second GoALS think tank, held in June 2024 in Paris, focused on the relationship between biological changes and clinical manifestations of AD in the context of the evolving therapeutic landscape. Discussions spanned real-world experiences of providers, patients, and their families, theoretical considerations, and health system challenges. The lived experience perspective was central to these discussions. The importance of shared decision-making, clear and transparent communication, and the need for real-world data to holistically support patients during their experiences were highlighted. This manuscript shares key insights from both the think tank meeting in Paris and a featured research session at the 2024 Alzheimer's Association International Conference that expanded the discussion themes for broader dissemination with the community.}, } @article {pmid42298621, year = {2026}, author = {Gezginer, I and Karakatsani, ME and Nanda, P and Chalasani, P and Kindler, D and Storz, R and Belau, M and Ni, R and Schratt, G and Deán-Ben, XL and Razansky, D}, title = {Transcranial pulse stimulation modulates spectral signatures of Alzheimer's disease in the 3×Tg-AD mouse model.}, journal = {Alzheimer's research & therapy}, volume = {}, number = {}, pages = {}, doi = {10.1186/s13195-026-02109-1}, pmid = {42298621}, issn = {1758-9193}, abstract = {BACKGROUND: Large-scale brain network dysfunction is increasingly recognized as an important feature of Alzheimer's disease (AD), offering insight into disease mechanisms and opportunities for targeted therapeutic intervention. The spectral features of this dysfunction remain poorly understood, and how neuromodulatory interventions interact with and reshape these frequency-resolved network signatures has yet to be explored.

METHODS: Triple-transgenic (3×Tg-AD) mice underwent resting-state functional MRI to assess functional connectivity, signal power, and variance across frequency bands after acute and longitudinal transcranial pulse stimulation (TPS), a low-intensity single-pulse neuromodulatory intervention. Novel object recognition testing was used to evaluate exploratory drive and short-term recognition memory following repeated TPS or sham treatment.

RESULTS: AD mice exhibited widespread functional connectivity loss accompanied by reduced low-frequency resting-state power and variance, together with a redistribution of spectral energy from slow-5 (0.01-0.027 Hz) to slow-4 (0.027-0.073 Hz) activity. TPS modulated these abnormalities by increasing low-frequency power, rebalancing slow-5/slow-4 fractional power, and strengthening network coherence, with the most prominent effects in cingulate, insular, piriform, and striatal regions. TPS effects showed a non-linear, region-dependent emergence across stimulation trains, with the strongest and most consistent modulation appearing after repeated stimulation. Similar spectral rebalancing was observed both after acute and longitudinal stimulation, persisting for up to 5 days. In addition, hippocampal regions that showed minimal acute responses exhibited delayed spectral changes at 24 h, with further modulation at 120 h. TPS-treated 3×Tg-AD mice did not show the decline in object exploration observed in sham-treated animals and showed an exploration-adjusted increase in novel object preference.

CONCLUSIONS: Frequency-specific neural dynamics are sensitive markers of AD-related dysfunction and may provide a useful framework for tracking disease-related network abnormalities. TPS selectively modulates low-frequency oscillatory activity and network coherence and is accompanied by preliminary behavioral changes, including preserved exploratory engagement and an exploration-adjusted increase in novel object preference in a separate behavioral cohort. This highlights the potential of combining neuromodulation with spectral network analysis to monitor disease-related network dysfunction and treatment-associated responses.}, } @article {pmid42299007, year = {2026}, author = {Imai, N and Yano, H and Ikegame, Y and Yasuda, S and Morishima, R and Okumura, A and Kumagai, M and Shinoda, J and Izumo, T}, title = {Cerebral Hyperperfusion with Lecanemab in Alzheimer's Disease Assessed by Amyloid PET and Arterial Spin Labeling.}, journal = {Current Alzheimer research}, volume = {}, number = {}, pages = {}, doi = {10.2174/0115672050453079260226065149}, pmid = {42299007}, issn = {1875-5828}, abstract = {INTRODUCTION/OBJECTIVE: Alzheimer's Disease (AD) is characterized by cognitive decline, amyloid-β deposition, and decreased Cerebral Blood Flow (CBF). Lecanemab, a monoclonal antibody targeting amyloid-β, slows cognitive decline in AD; however, its effects on CBF remain unclear. This study aimed to characterize CBF changes following lecanemab treatment and their association with baseline amyloid burden.

METHODS: Thirty patients with AD treated with lecanemab were analyzed retrospectively. Baseline amyloid deposition was quantified using the Centiloid scale, and patients were stratified into low, middle, and high groups. CBF was analyzed at baseline and at 8, 12, and 26 weeks using arterial spin labeling (ASL). Monoclonal antibody-triggered cerebral hyperperfusion (MATCH) was defined as a >20% CBF increase at week 8.

RESULTS: Seven patients were MATCH-positive (median CBF: 133.5% [125.5-167.8] of baseline). All MATCH-positive patients exhibited a decrease in CBF at week 12 compared to week 8. MATCH occurred in 6 of 10 patients in the middle Centiloid group. The low Centiloid group showed stable CBF, while the high Centiloid group showed a decreasing trend. The MATCHpositive group showed a significant deterioration in Instrumental Activities of Daily Living scores.

DISCUSSION: A transient CBF increase was closely associated with the middle Centiloid group. These CBF responses, including MATCH, may reflect amyloid removal, hyperperfusion, amyloidrelated imaging abnormalities, or immune responses.

CONCLUSIONS: CBF changes differed according to baseline amyloid burden. Understanding these therapy-related CBF changes is crucial for elucidating AD pathology, and ASL provides a practical, non-invasive method for longitudinal CBF monitoring in routine clinical practice.}, } @article {pmid42299502, year = {2026}, author = {Liu, M and Hong, H and Zhang, X and Ren, J and Tang, C}, title = {Targeting the Nrf2 Signaling Pathway: A Review of Traditional Chinese Medicine for Alzheimer's Disease.}, journal = {The American journal of Chinese medicine}, volume = {54}, number = {4}, pages = {1085-1113}, doi = {10.1142/S0192415X26500400}, pmid = {42299502}, issn = {1793-6853}, mesh = {*NF-E2-Related Factor 2/metabolism ; *Alzheimer Disease/drug therapy/genetics/etiology/metabolism ; Humans ; *Signal Transduction/drug effects/genetics ; *Drugs, Chinese Herbal/pharmacology/therapeutic use ; Oxidative Stress/drug effects/genetics ; *Medicine, Chinese Traditional ; Amyloid beta-Peptides/metabolism ; Animals ; tau Proteins/metabolism ; *Phytotherapy ; Phosphorylation/drug effects ; *Molecular Targeted Therapy ; }, abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder primarily characterized by β-amyloid (Aβ) deposition, Tau protein hyperphosphorylation, and chronic neuroinflammation. Current pharmacological interventions demonstrate limited therapeutic efficacy. The nuclear factor erythroid 2-related factor 2 (Nrf2) signaling pathway, a pivotal regulator of oxidative stress and neuroinflammation, plays a critical role in AD pathogenesis. Recent studies have revealed that traditional Chinese medicines (TCMs) and their bioactive constituents can modulate the Nrf2 signaling pathway to mitigate oxidative stress, suppress neuroinflammation, enhance Aβ clearance, and reduce Tau protein phosphorylation. By doing so, TCMs exert multi-targeted anti-AD effects. This review systematically summarizes the mechanisms and recent advances concerning the active ingredients of Nrf2 pathway-modulating TCMs, herbal medicines, and TCM formulations for the prevention and treatment of AD. Furthermore, it critically evaluates current research limitations and prospects for future research directions to provide a theoretical foundation for the development of novel anti-AD therapeutics derived from TCMs.}, } @article {pmid42299696, year = {2026}, author = {Brisendine, MH and Nieves-Esparcia, DQ and Willoughby, OS and Brown, B and Brown, JR and Braxton, DS and Henry, SN and McCoin, CS and Thyfault, JP and Morris, JK and Poelzing, S and Grange, RW and Jarome, TJ and Najt, CP and Drake, JC}, title = {Age-Dependent Remodeling of the Sciatic Nerve Proteome in 5xFAD Mice Can Be Attenuated by Exercise or Donepezil Treatment to Maintain Neuromuscular Function.}, journal = {Aging cell}, volume = {25}, number = {6}, pages = {e70595}, pmid = {42299696}, issn = {1474-9726}, support = {R01AG080731/AG/NIA NIH HHS/United States ; K02AG088474/AG/NIA NIH HHS/United States ; R00AG070104/AG/NIA NIH HHS/United States ; R01AG062548/AG/NIA NIH HHS/United States ; R01AG069781/AG/NIA NIH HHS/United States ; P20GM144269/GM/NIGMS NIH HHS/United States ; }, mesh = {Animals ; *Donepezil/pharmacology/therapeutic use ; Mice ; *Proteome/metabolism ; *Sciatic Nerve/metabolism/drug effects ; *Physical Conditioning, Animal ; *Aging ; Mice, Transgenic ; *Alzheimer Disease/metabolism/drug therapy ; Muscle, Skeletal/drug effects ; Male ; }, abstract = {Alzheimer's disease (AD) progresses along a continuum for years to possibly decades prior to cognitive decline. Although AD is primarily an age-related brain pathology, increasing evidence indicates dysfunction in peripheral nerves and skeletal muscle may manifest early in the disease progression. However, the underlying cause(s) for peripheral nerve dysfunction leading to impaired skeletal muscle torque production are not understood. Sciatic nerves from 5xFAD and wild-type (WT) mice were analyzed by tandem mass tag (TMT)-labeled proteomics at 3, 4, and 7 months, identifying proteome remodeling coincides with functional declines at 4 months particularly in pathways linked to mitochondrial turnover, calcium handling, and inflammation. We hypothesized either voluntary wheel running or donepezil treatment, begun prior to neuromuscular decline, would delay manifestation of neuromuscular impairment in 5xFAD mice. Separate cohorts, using 3-month-old 5xFAD mice and WT littermates, were given voluntary wheel access for 4 weeks or treated with the acetylcholinesterase inhibitor donepezil. We assessed tibial nerve stimulated plantar flexion torque and sciatic nerve compound (motor) neuron action potential (CNAP) in vivo at 4 months. Both exercise and donepezil attenuated in vivo nerve-stimulated muscle torque and CNAP dysfunction. Further, both exercise and donepezil attenuated the proteomic remodeling of the sciatic nerve through both shared and independent mechanisms that converged on mitochondria-centric pathways. Our findings in the 5xFAD model of AD support the notion that early phenotypes of AD are evident in the periphery that may have implications for timing of interventions.}, } @article {pmid42299743, year = {2026}, author = {Bélanger, E and Couch, E and Carroll, M and Gadbois, EA and Jutkowitz, E and Van Houtven, CH and Wetle, TT}, title = {Long-Term Perceptions of the Value of Amyloid PET Scans Among Cognitively Impaired Medicare Beneficiaries and Their Care Partners.}, journal = {International journal of geriatric psychiatry}, volume = {41}, number = {6}, pages = {e70226}, doi = {10.1002/gps.70226}, pmid = {42299743}, issn = {1099-1166}, support = {R01AG053934/NH/NIH HHS/United States ; //American College of Radiology Imaging Network/ ; /ALZ/Alzheimer's Association/United States ; }, mesh = {Humans ; *Positron-Emission Tomography/psychology/economics ; Male ; Female ; Aged ; United States ; Aged, 80 and over ; Medicare ; *Alzheimer Disease/diagnostic imaging ; *Caregivers/psychology ; Qualitative Research ; *Cognitive Dysfunction/diagnostic imaging ; Amyloid ; }, abstract = {OBJECTIVES: The objective of this study was to examine the long-term perceptions of the value of receiving an amyloid PET scan, a test used to diagnose Alzheimer's disease, among Medicare beneficiaries with cognitive impairment and their care partners.

METHODS: An exploratory qualitative research design was used. A total of 100 in-depth semi-structured interviews were conducted with a purposeful sample of CARE-IDEAS participants two to three years post-scan. A team of coders applied qualitative content analysis to identify content about the value of the scan, which was then analyzed using thematic analysis, and stratified by diagnostic category (mild cognitive impairment vs. dementia) and scan results (elevated amyloid vs. not elevated).

RESULTS: A majority of amyloid PET scan recipients and their care partners emphasized major benefits of receiving the scan including increased certainty about diagnosis, the ability to prepare for the future, potentially accessing treatment or trials, the ability to contribute to research, and limited procedural risks. Some participants also reported concerns about the cost of the scan, the lack of effective treatment options and clear prognostic information, the limited impact on their lives or treatment plans, and the emotional toll of living with the results. Their views and endorsements of the scan were shaped by their health and personal circumstances (e.g., seen as less relevant among those with rapidly declining health), and by their preference for more information and involvement in decision-making.

CONCLUSION: The perspectives of persons living with cognitive impairment and their care partners about the value of amyloid PET scans differed across disease trajectories and personal circumstances. These experiences should be taken into consideration when advising symptomatic patients on the benefits and drawbacks of biomarkers for Alzheimer's disease.}, } @article {pmid42299852, year = {2026}, author = {Beh-Pajooh, A}, title = {Identification of candidate diagnostic biomarkers and gene networks for moderate stages of Alzheimer's disease in fusiform gyrus exhibiting neurofibrillary tangles.}, journal = {Journal of Alzheimer's disease : JAD}, volume = {}, number = {}, pages = {13872877261452277}, doi = {10.1177/13872877261452277}, pmid = {42299852}, issn = {1875-8908}, abstract = {BackgroundAlzheimer's disease (AD) is a neurodegenerative disorder whose incidence grows with age and its development is gradual. However, if detected earlier there is much hope to prevent further exacerbation. In this study, NGS transcriptomics data from cases and controls with Braak scores of III-IV were investigated that all possessed neurofibrillary tangles (NFTs) in their fusiform gyrus.ObjectiveThe aim of this study was to discover the underlying mechanisms at gene level which could explain cognitive impairment by considering the presence of NFTs in both groups.MethodsDifferentially expressed genes (DEGs) were determined and ROC AUC were evaluated by leave-one-out cross-validation method on the diagnostic DEGs to detect candidate gene biomarkers. WGCNA was employed to identify co-expression modules with their trait association. Finally, in silico hybridization of lncRNAs from potential biomarkers with important AD-related microRNAs was carried out.ResultsHighly ranked potential diagnostic gene biomarkers revealed assessed AUC ranges of 80-90% in which RASGRF2-AS1 demonstrated the highest value. WGCNA demonstrated upregulated genes in favor of dephosphorylation of tau, proper proteostasis and vascular health in resilient controls whereas dysfunctional proteostasis, chronic protein misfolding, heightened cellular stress and tetrahydrobiopterin deficiency were attributed to cognitive impairment in AD patients. In silico analyses predicted some lncRNAs with a high possibility of acting as sponge for AD-related microRNAs.ConclusionsThis study discovered potential diagnostic gene biomarkers and transcriptional signatures that could explain the mechanisms of cognitive decline by considering the existence of NFTs, which could provide further insight for diagnosis and treatment of the disease.}, } @article {pmid42300138, year = {2026}, author = {Wolf, EJ and Zhao, X and Hao, S and Lawhorn, C and Carbaugh, J and Fortier, CB and Milberg, WP and Logue, MW and Miller, MW}, title = {PTSD Severity-Related Accelerated Aging, Hippocampal Volume, and CLDN5 DNA Methylation.}, journal = {Biopsychosocial science and medicine}, volume = {}, number = {}, pages = {}, doi = {10.1097/PSY.0000000000001501}, pmid = {42300138}, issn = {2998-8756}, abstract = {OBJECTIVE: The claudin-5 (CLDN5) gene is critical for blood brain barrier integrity and may link traumatic stress, accelerated aging, and neurological disease. Building on prior research showing associations between trauma exposure and PTSD with CLDN5 DNA methylation (DNAm), we tested if candidate CLDN5 DNAm loci were associated with advanced epigenetic aging in blood and brain tissue and with hippocampal volume.

METHODS: 1302 trauma-exposed individuals (Mage=44.23, SD=13.71; 76% male) underwent psychiatric diagnostic interviews and blood draws for obtaining epi/genetic information; 473 underwent magnetic resonance imaging of the brain. Data from 109 PTSD brain bank decedents with DNAm from ventromedial prefrontal cortex (vmPFC) were also examined (Mage-at-death=45.20, SD=14.21; 62% male).

RESULTS: All candidate loci were associated with metrics of epigenetic age in blood (p-adj range: .0396 to 4.5e-05) and these associations largely extended to postmortem vmPFC. There was an indirect association between PTSD severity and CLDN5 DNAm in blood at cg21872764 via GrimAge residuals (indirect β=.033, P=.040) that was diminished when the direct PTSD association was modeled. The CLDN5 probe cg17411190 in blood was negatively related to left and right hippocampal volume (p-adj=.042) and with volume of multiple hippocampal substructures. The association between PTSD severity and hippocampal volume was indirect via blood DNAm at cg17411190 (indirect β=-.011, P=.045).

CONCLUSIONS: PTSD severity-related accelerated aging may be associated with altered CLDN5 DNAm, which may signal neurodegeneration, such as reduced hippocampal volume. CLDN5 DNAm in blood may serve as a useful proxy for brain CLDN5 DNAm. Given that prior environmental enrichment and antidepressant studies show initial efficacy in altering CLDN5 expression, future studies could evaluate if PTSD treatment alters CLDN5 epigenetics and reduces risk for neurodegeneration.}, } @article {pmid42300608, year = {2026}, author = {Khorrami, S and Alifarsangi, A and Mohammed, LJ and Amshawee, AM and Zarrabi, A}, title = {Metal-based nanoparticles' potential in Alzheimer's disease diagnosis, therapy and theranostics.}, journal = {Nanoscale}, volume = {}, number = {}, pages = {}, doi = {10.1039/d5nr04613k}, pmid = {42300608}, issn = {2040-3372}, abstract = {Metal-based nanoparticles are emerging as a versatile platform to overcome critical challenges in the diagnosis and treatment of Alzheimer's disease (AD). This review provides a comprehensive synthesis of recent advances, structured around the three core domains of AD management: diagnostics, therapeutics, and theranostics. We discuss how the unique physicochemical properties of metals and metal oxides enable highly sensitive biosensing of amyloid and tau biomarkers, as well as high-contrast imaging modalities. The review then evaluates strategies for engineering metal-based nanoparticles to bypass the blood-brain barrier and achieve targeted accumulation, alongside their therapeutic roles in drug delivery, photothermal therapy, and modulating protein aggregation. Finally, we assess integrated theranostic systems that combine real-time imaging with targeted intervention. The key conclusion is that platforms based on metal-based nanoparticles, through their multifunctionality, offer a realistic pathway toward minimally invasive early diagnosis and targeted therapy. However, the field's future direction must prioritize rigorous standardization and advanced preclinical validation to translate these promising nanotechnologies from bench to bedside, ultimately advancing precision neurotheranostics for AD.}, } @article {pmid42300721, year = {2026}, author = {Song, BX and Schecter, J and Vieira, E and Gallagher, D and Diniz, BS and Fischer, CE and Flint, AJ and Herrmann, N and Kennedy, JL and Mah, L and Mulsant, B and Pollock, BG and Rajji, TK and Ma, C and Lanctôt, KL and , }, title = {Angiogenesis markers and cognitive response in a randomized trial of cognitive remediation plus transcranial direct current stimulation in older adults at risk of dementia.}, journal = {Journal of Alzheimer's disease : JAD}, volume = {}, number = {}, pages = {13872877261457934}, doi = {10.1177/13872877261457934}, pmid = {42300721}, issn = {1875-8908}, abstract = {BackgroundCognitive remediation (CR) combined with transcranial direct current stimulation (tDCS) has been shown to slow cognitive decline in older adults with mild cognitive impairment (MCI) or remitted major depressive disorder (rMDD). Dysregulated angiogenesis is implicated in early neurodegeneration and may influence response to these interventions.ObjectiveTo determine whether baseline plasma angiogenesis markers moderate short-term and long-term cognitive response to CR + tDCS in older adults at risk for dementia.MethodsNineteen angiogenesis-related plasma biomarkers were measured at baseline in participants from the PACt-MD randomized controlled trial. Participants received active or sham CR plus active or sham tDCS for 8 weeks, followed by semi-annual booster sessions and online CR between visits. Cognitive assessments occurred at baseline, 8 weeks, and yearly. Elastic net regression identified relevant markers and baseline variables associated with the 8-week cognitive change. For selected markers, treatment*marker interactions were tested using multivariable linear regression adjusted for relevant demographic, clinical, and genetic covariates. Significant interactions were further examined using likelihood ratio tests in linear mixed-effects models across follow-up.ResultsIn 271 participants, angiopoietin-2, endocan, and VCAM-1 were identified as relevant markers. Out of these three markers, only angiopoietin-2 interacted with treatment (β(SE) = 0.17(0.08), p = 0.04, padj = 0.11, f[2] = 0.02), with lower levels associated with greater 8-week cognitive improvement in the active treatment group, controlling for covariates. This moderating effect persisted during follow-up (χ[2]LRT(3) = 24.9, p < 0.001).ConclusionsLower baseline angiopoietin-2 may identify older adults with MCI or rMDD that are more likely to benefit from CR + tDCS.ClinicalTrials.gov; https://clinicaltrials.gov/study/NCT02386670; NCT02386670.}, } @article {pmid42300919, year = {2026}, author = {Peesapati, S and Chakraborty, S}, title = {Modeling the organizational heterogeneity of cholesterol-enriched microdomains in the neuronal membranes of gray and white matter of Alzheimer's brain: a computational lipidomics study.}, journal = {Soft matter}, volume = {}, number = {}, pages = {}, doi = {10.1039/d6sm00153j}, pmid = {42300919}, issn = {1744-6848}, abstract = {Alzheimer's disease (AD) is a leading cause of death among the elderly, with no existing treatment. The development of therapies is further hindered by a limited understanding of the molecular pathogenesis and the absence of reliable early-detection biomarkers. Neuroimaging and lipidomic studies reveal structural and biochemical alterations in both gray and white matter in AD patients, including disruptions in membrane organization and neuronal signaling pathways. In the present work, we employed lipidomics-guided modeling of membranes in gray and white matter regions under healthy and diseased (AD) conditions, and used all-atom molecular dynamics (MD) simulations to examine how AD-associated alterations in lipid composition influence the structure, spatial organization, and micro-heterogeneity of neuronal plasma membranes. The data suggest that Alzheimer's disease-associated lipid alterations in gray matter (GM) and white matter (WM) impact membrane thickness and microdomain distribution, highlighting the critical role of lipid composition in maintaining neuronal membrane homeostasis and function. Higher-order cholesterol-ceramide-sphingomyelin-enriched domains are more abundant in the neuronal membranes of the GM region under diseased conditions. Under AD-mimicking conditions, lipidomic analyses demonstrate that neuronal membranes in GM experience more substantial compositional and structural remodeling than those in WM. Our results show significant changes in membrane microdomain distribution across the lipid bilayers, and, interestingly, these changes are more pronounced in the gray matter than in the white matter. This study establishes a framework for modeling the tissue-specific lipidomics data to understand how disease-driven compositional changes affect the structure, organization, and dynamics of biological membranes.}, } @article {pmid42301522, year = {2026}, author = {Welikovitch, LA and Oakley, DH and Bennett, RE and Serrano-Pozo, A and Zhu, H and Ruiz-Uribe, NE and Zwang, TJ and Chibnik, LB and Gomez-Isla, T and Frosch, MP and Marks, DS and Salloway, S and Bernick, C and Greeley, D and Latimer, CS and Nolan, A and Hutchison, RM and Rubel, CE and Bussiere, T and Plowey, ED and Keene, CD and Hyman, BT}, title = {Neuropathological study of the effects of aducanumab anti-Aβ immunotherapy on patients with Alzheimer's disease.}, journal = {Acta neuropathologica}, volume = {151}, number = {1}, pages = {}, pmid = {42301522}, issn = {1432-0533}, support = {24AARF-1192364/ALZ/Alzheimer's Association/United States ; R01AG071567/NH/NIH HHS/United States ; UW ADRC P30 AG066509/NH/NIH HHS/United States ; P30AG062421//Massachusetts Alzheimer Disease Research Center/ ; W81XWH-21-S-TBIPH2//US Department of Defense/ ; }, mesh = {Humans ; *Alzheimer Disease/pathology/drug therapy/therapy/immunology ; *Antibodies, Monoclonal, Humanized/therapeutic use ; Female ; *Amyloid beta-Peptides/metabolism/immunology ; Male ; Aged ; *Brain/pathology/drug effects/metabolism ; Aged, 80 and over ; Neurofibrillary Tangles/pathology ; *Immunotherapy/methods ; Plaque, Amyloid/pathology ; tau Proteins/metabolism ; }, abstract = {Fluid and imaging biomarker data show that anti-amyloid (Aβ) antibodies promote the clearance of Aβ from the brains of patients with Alzheimer's disease (AD). We examined postmortem brain tissue of individuals who participated in aducanumab clinical trials and investigated the drug's effects on Aβ pathology and other AD phenotypes. The medial temporal lobe of six aducanumab clinical trial participants-who had extensive exposure to aducanumab and happened to die between 7 weeks and 5 years after their last antibody infusion-was compared with that of nine untreated AD patients matched for age, APOE genotype, and Braak neurofibrillary tangle stage, to determine how aducanumab impacts AD pathobiology. Patients treated with aducanumab displayed a robust reduction in Aβ burden. As observed in previous studies, Aβ was associated with non-arterial microvessels in aducanumab-treated patients, suggesting a redistribution of Aβ within the neuropil. Neuritic phospho-tau decreased in parallel with fewer Aβ plaques, but the density of PHF-1[+] and AT8[+] neurofibrillary tangles remained unchanged relative to the average untreated AD donor. Measures of microglial and astroglial reactivity were also comparable to those in untreated AD controls. These findings confirm aducanumab's potent ability to target and remove brain Aβ. On average, Aβ plaques increased in proportion to the length of time after the last dose, consistent with the idea that plaques gradually redeposit post-treatment. The selective reduction of neuritic, but not neurofibrillary tangle phospho-tau implies that Aβ-targeted antibodies such as aducanumab alleviate plaque-associated dystrophy but may not address established tangles. This study describes the long-term outcomes of anti-Aβ immunotherapy in AD.}, } @article {pmid42302727, year = {2026}, author = {Kim, MS and Kang, D}, title = {Why Deep Cervical Lymphovenous Anastomosis for Alzheimer Disease Lacks Scientific Foundation.}, journal = {The Journal of craniofacial surgery}, volume = {}, number = {}, pages = {}, doi = {10.1097/SCS.0000000000013042}, pmid = {42302727}, issn = {1536-3732}, abstract = {Deep cervical lymphovenous anastomosis (DCLVA) has been rapidly adopted as a surgical treatment for Alzheimer disease (AD), based on the hypothesis that enhancing cervical lymphatic drainage may promote glymphatic clearance of neurotoxic proteins. By mid-2025, an estimated 382 hospitals in China had performed the procedure before any randomized controlled trial was completed, prompting China's National Health Commission to prohibit its clinical use on the grounds of insufficient evidence. That prohibition addressed the absence of clinical trial data but did not articulate a specific physiological objection. Following a recent critical review of lymphovenous anastomosis in the lower extremity, the senior author investigated the status of this technique in the craniofacial region and found that its dominant application is not for head and neck lymphedema but for AD. This review identifies fundamental scientific gaps in the rationale for DCLVA in AD. The target pathology-cervical lymphatic insufficiency-has never been confirmed in living patients with AD. Preclinical evidence is contradictory: modulating dural lymphatic vessels in either direction does not alter amyloid pathology in mouse models. No study has controlled for confounding anesthetic effects. No standardized surgical protocol exists. Hemodynamic conditions at the anastomotic site during supine sleep-when glymphatic clearance is most active-have never been measured. Serious adverse events have already been reported. These gaps represent deficiencies in the fundamental science that must be resolved before clinical investigation can be justified.}, } @article {pmid42304162, year = {2026}, author = {Madhu, LN and Attaluri, S and Kotian, S and Upadhya, R and Somayaji, Y and Rao, S and Tarale, P and Ganesh, SV and Huard, C and Kodali, M and Shuai, B and Rao, VV and Shetty, AK}, title = {Human iPSC-NSC-Derived Extracellular Vesicles Can Alleviate Alzheimer's Disease-Linked Impairments in Mitochondria, mTOR Signaling, Autophagy, and Hippocampal Neurogenesis.}, journal = {Aging cell}, volume = {25}, number = {6}, pages = {e70590}, pmid = {42304162}, issn = {1474-9726}, support = {RF1AG074256/AG/NIA NIH HHS/United States ; R01AG075440/AG/NIA NIH HHS/United States ; }, mesh = {*Alzheimer Disease/metabolism/pathology ; *TOR Serine-Threonine Kinases/metabolism ; Humans ; Animals ; *Mitochondria/metabolism ; *Hippocampus/metabolism/pathology ; *Neurogenesis ; Mice ; Signal Transduction ; *Induced Pluripotent Stem Cells/metabolism ; *Autophagy ; Male ; *Extracellular Vesicles/metabolism/transplantation ; *Neural Stem Cells/metabolism ; Female ; }, abstract = {Intranasal (IN) administrations of extracellular vesicles (EVs) derived from human-induced pluripotent stem cell (hiPSC)-derived neural stem cells (hNSCs) have shown promise in reducing chronic neuroinflammation mediated by microglia and astrocytes in 5x familial Alzheimer's disease (5xFAD) mice, a model for early-onset Alzheimer's disease (AD). The current study rigorously investigated whether treatment with hiPSC-NSC-EVs could also alleviate several other neuropathological changes contributing to progressive cognitive decline. Three-month-old male and female 5xFAD mice received IN administrations of either hiPSC-NSC-EVs (~30 × 10[9]/week for 2 weeks) or vehicle. Two months later, the hippocampus of both male and female 5xFAD mice treated with the vehicle showed increased levels of markers of oxidative stress and mechanistic target of rapamycin (mTOR) signaling, altered expression of genes and/or proteins linked to mitochondria and autophagy, and diminished neurogenesis. In contrast, treatment with hiPSC-NSC-EVs restored levels of oxidative stress markers and the expression of genes and/or proteins linked to various mitochondrial complexes, mitochondrial biogenesis, fission, fusion, and mitophagy closer to naïve control levels, indicating alleviation of mitochondrial impairments. These improvements were accompanied by reduced phosphorylated mTOR levels and multiple autophagy markers matching those in naïve controls, suggesting a dampening of mTOR signaling and an enhancement of autophagy. Furthermore, mice treated with hiPSC-NSC-EVs showed increased hippocampal neurogenesis, associated with enhanced brain-derived neurotrophic factor signaling. Overall, the results highlight that IN administrations of hiPSC-NSC-EVs in the early stages of AD can help slow the progression of multiple neuropathological changes associated with cognitive decline in 5xFAD mice and potentially AD.}, } @article {pmid42304897, year = {2026}, author = {Kim, S and Park, SK}, title = {Fucoxanthin Promotes Longevity and Neuroprotection in Caenorhabditis elegans via DAF-16 and Autophagy Pathways.}, journal = {Rejuvenation research}, volume = {}, number = {}, pages = {15491684261460844}, doi = {10.1177/15491684261460844}, pmid = {42304897}, issn = {1557-8577}, abstract = {Identification of natural compounds that delay aging and prevent age-related neurodegeneration is a key goal in gerontology. Fucoxanthin, a marine-derived xanthophyll, exhibits potent antioxidant properties, yet its effects on organismal aging and specific molecular mechanisms remain underexplored. Here, we investigated the pro-longevity and neuroprotective effects of fucoxanthin using Caenorhabditis elegans. Fucoxanthin supplementation significantly extended the mean lifespan of wild-type nematodes by 12.1% and improved health span, as evidenced by delayed age-related motility decline and enhanced resistance to oxidative stress. Notably, this lifespan extension occurred without compromising reproductive fitness. Genetic analysis revealed that the beneficial effects of fucoxanthin require the FOXO transcription factor DAF-16 and the autophagy-essential gene bec-1. Furthermore, fucoxanthin treatment increased autophagic flux and upregulated the expression of SKN-1/Nrf2-dependent detoxification genes, hsp-16.2 and gst-4. In nematode models of Alzheimer's and Parkinson's disease, fucoxanthin significantly ameliorated Aβ-induced paralysis and protected against dopaminergic neurodegeneration and α-synuclein accumulation in a DAF-16-dependent manner. Collectively, our findings demonstrate that fucoxanthin acts as a multitarget geroprotector that promotes healthy aging through the coordinated activation of DAF-16 and autophagy, suggesting its potential as a therapeutic intervention for age-related decline.}, } @article {pmid42304917, year = {2026}, author = {Sinha, S and Gupta, S and Tiwari, P}, title = {Therapeutic Potential of Natural Chalcones Against Alzheimer's Disease: A Mechanistic Insight.}, journal = {Current neurovascular research}, volume = {}, number = {}, pages = {}, doi = {10.2174/0115672026454130260605061515}, pmid = {42304917}, issn = {1875-5739}, abstract = {INTRODUCTION: Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by cognitive deficits, amyloid-beta (Aβ) plaque deposition, tau hyperphosphorylation, oxidative stress, and chronic neuroinflammation. Therapeutic strategies are at present mainly symptomatic and do not modify the course of the disorder. Natural chalcones, precursors of flavonoids, are emerging as multi-target agents for neuroprotection since they have the ability to protect neurons and exert anti-inflammatory and antioxidant activities.

METHODS: A systematic literature search was performed in PubMed, Scopus, Web of Science, and Google Scholar utilizing keywords that associate chalcones with Alzheimer's disease. Studies were included if they reported in silico docking, in vitro assays, or mechanistic insights on AD-related targets (AChE, BACE1, GSK-3β, NF-κB). Data extraction included information about the compound's identity, structural changes, docking scores, enzyme inhibition, oxidative stress, and cytokine modulation. The findings were synthesized both qualitatively and quantitatively, with structure-activity relationship (SAR) analysis emphasizing patterns of hydroxylation and methoxylation. These helped in the rational design of chalcone derivatives, which showed potential as multi-target agents against AD pathology.

RESULTS: Several chalcones exhibited potent inhibition against AChE and BACE1, besides reducing reactive oxygen species (ROS) generation and preventing the release of pro-inflammatory cytokines. These findings demonstrate their potential to mitigate cholinergic deficits and neuroinflammatory signaling. SAR studies revealed a significant enhancement in bioactivity for certain hydroxylation and methoxylation substituents. This provides insights into the rational design of improved chalcone derivatives.

DISCUSSION: Chalcones display multifunctional properties and are able to modulate several AD pathological signatures, suggesting potential application in the prevention of AD symptoms. Their therapeutic importance is emphasized by their combined ability to target cholinergic dysfunction, oxidative stress, and neuroinflammation. The SAR analysis further supports the focused development of chalcone-based derivatives with improved potency.

CONCLUSION: The present study provides insights into the mechanistic basis of the neuroprotective activity of chalcones and paves the way for subsequent preclinical evaluation. The chalconebased strategy holds promise for the development of potential drug candidates for the treatment of neurodegenerative diseases such as Alzheimer's disease by addressing the multi-target nature of this complex disease.}, } @article {pmid42305190, year = {2026}, author = {Sedlacek Miskerikova, M and Houfkova, A and Benkova, M and Andrys, R and Janousek, J and Soukup, O and Musilek, K and Benek, O}, title = {Development of Novel 17β-HSD10 Inhibitors and Their Evaluation in an In Vitro Model of Alzheimer's Disease.}, journal = {ACS medicinal chemistry letters}, volume = {17}, number = {6}, pages = {1347-1354}, pmid = {42305190}, issn = {1948-5875}, abstract = {17β-hydroxysteroid dehydrogenase type 10 (17β-HSD10) is a multifunctional mitochondrial enzyme and a potential drug target for the treatment of various pathologies, including Alzheimer's disease (AD). In this study, five new benzothiazole-derived 17β-HSD10 inhibitors were developed based on structure-activity relationship (SAR) analyses of previously published compounds. To evaluate the inhibitory effects, cytotoxicity, and therapeutic potential of these new compounds, several enzyme- and cell-based methods were employed. All prepared compounds exhibited high inhibitory potential and confirmed good biomembrane permeation. Three inhibitors (9b, 9c, and 15a) showed lower IC50 values in both enzyme- and cell-based assays than the formerly published hit compounds. The compounds were also found to reduce the pathological effects associated with 17β-HSD10 overexpression, although not the combined pathological effects of 17β-HSD10 overexpression within an amyloid-β rich environment.}, } @article {pmid42305665, year = {2026}, author = {Vignesh Pandi, A and Malakar, V and Jeyabalan, JB and Sanjai, M and Shevate, K and Rajagopal, K and Prashantha Kumar, BR and Justin, A}, title = {Integrated computational-based design of putative dual TrkA/TrkB agonists for Alzheimer's disease: pharmacophore modelling, docking, MM/GBSA, DFT and dynamics studies.}, journal = {Frontiers in bioinformatics}, volume = {6}, number = {}, pages = {1779769}, pmid = {42305665}, issn = {2673-7647}, abstract = {BACKGROUND: The rapid progression of Alzheimer's disease (AD) is primarily caused by compromised neurotrophin functions and decreased tropomyosin receptor kinase expression in the basal forebrain area. The two main pathogenic features of AD are cholinergic-dependent cognitive dysfunctions and amyloidogenic-induced neurodegeneration. Concurrent stimulation of major neurotrophin signalling pathways, such as tropomyosin receptor kinases receptor A and B (TrkA and TrkB), may reduce amyloid-β-mediated neurotoxicity and cholinergic denervation in the basal forebrain, improving cognitive performance and re-establishing neuronal communication. The development of new medications with dual agonist action towards TrkA and B receptors holds enormous therapeutic potential for managing the symptoms of neurodegenerative diseases.

AIM: This study aims to develop novel dual TrkA/TrkB receptor agonists for the treatment of AD by enhancing neurotrophin signalling, reducing cholinergic denervation, and mitigating amyloid-β-induced neurotoxicity.

METHODS: An in silico drug discovery pipeline was employed, involving homology and pharmacophore modelling of amitriptyline, virtual screening of ChEMBL compounds, molecular docking, ADMET, MM/GBSA analysis, DFT calculations and molecular dynamics (MD) simulations for 100 and 300 ns to assess ligand stability and binding behaviour of the ligand-protein complexes.

RESULTS: Six novel optimised quinoline analogues (OP-1 to OP-6) were identified as computationally predicted dual TrkA/TrkB agonists by molecular docking (-8.90 to -5.07 kcal/mol), MM/GBSA (-40.47 to -30.71 kcal/mol), ADMET and DFT analysis. Furthermore, OP-1, OP-2, and OP-3 exhibit stable binding interactions over 300 ns of MD simulations. The optimised compounds demonstrated favorable computational binding profiles, predicted pharmacokinetic properties, and stable receptor-ligand interactions, identifying them as promising candidates for further experimental validation as potential dual TrkA/TrkB modulators in Alzheimer's disease.}, } @article {pmid42306035, year = {2026}, author = {Kalpaktsi, I and Panara, A and Mavroidi, B and Niforos, GG and Kalampaliki, AD and Vlachogianni, IC and Georgiou, EA and Fragopoulou, E and Tsarbopoulos, A and Skaltsounis, AL and Pelecanou, M and Palikaras, K and Gikas, E and Kostakis, IK}, title = {Novel hydroxytyrosol esters as potential anti-amyloid and neuroprotective agents for Alzheimer's disease.}, journal = {RSC medicinal chemistry}, volume = {}, number = {}, pages = {}, pmid = {42306035}, issn = {2632-8682}, abstract = {Alzheimer's disease (AD) is associated with the aggregation of β-amyloid (Aβ) peptides and oxidative stress, two interconnected processes that contribute to neuronal dysfunction and cognitive decline. Natural polyphenols such as oleuropein and its metabolite hydroxytyrosol display antioxidant and anti-amyloidogenic properties, but oleuropein suffers from limited stability due to glycosidic hydrolysis. To develop more robust and potent oleuropein analogs, we synthesized a series of hydroxytyrosol-based esters in which the secoiridoid glucoside scaffold of oleuropein was replaced by lipophilic substituents designed to enhance molecular stability and interactions with Aβ peptide. The compounds were evaluated for their ability to interact with Aβ40 using ESI-MS, circular dichroism (CD), and thioflavin-T fluorescence (ThT), along with complementary antioxidant assays. Most of the compounds formed stable non-covalent complexes with Aβ40, inhibited early aggregation events, and prevented the peptide's conformational transition from random coil to β-sheet. To assess biological efficacy and safety in vivo, the most promising analog (3b) was evaluated in Caenorhabditis elegans models of amyloid-β toxicity. Treatment with 3b exhibited no detectable toxicity in wild-type animals, as evidenced by normal development, growth, and reproductive efficacy. Importantly, 3b rescued lifespan shortening and locomotor deficits in transgenic nematodes expressing human Aβ42 pan-neuronally, while having no effect on control strains lacking Aβ42 expression. These findings demonstrate that 3b confers functional protection against amyloid-induced toxicity in vivo. Overall, our results identify the newly synthesized hydroxytyrosol-derived esters as promising multifunctional scaffolds that combine potent anti-aggregation activity with strong antioxidant properties and in vivo neuroprotective efficacy, supporting their further development as anti-amyloidogenic agents for AD therapy.}, } @article {pmid42306774, year = {2026}, author = {Rodriguez Martinez, PJ and Yslas, AR and Inoue, Y and Parsons, TM and Baker, SK and Lu, W and Raulin, AC and Kanekiyo, T}, title = {APOE3-Christchurch variant enhances neurovascular support functions of iPSC-derived mesenchymal stromal cells.}, journal = {Frontiers in molecular biosciences}, volume = {13}, number = {}, pages = {1778856}, pmid = {42306774}, issn = {2296-889X}, abstract = {Aging and neurodegenerative disorders like Alzheimer's Disease (AD) are associated with progressive dysfunction of the blood-brain barrier (BBB) and neurovascular unit (NVU), contributing to impaired vascular integrity and neuronal vulnerability. Apolipoprotein E (APOE) is a key regulator of neurovascular function, and the rare APOE3-R136S "Christchurch" variant (APOE3Ch) confers protection against AD. Mesenchymal stromal cells (MSCs) represent a promising cell-based therapy for the treatment of neurodegenerative diseases due to their paracrine effect exerted on vascular and neural cells. To investigate how APOE3Ch influences MSC-mediated neurovascular support, we used isogenic iPSC-derived MSCs (iMSCs) with homozygous APOE3Ch or APOE3. We found that APOE3Ch iMSCs have stronger immunosuppressive effect on LPS-induced NFκB activation of THP1 cells. APOE3Ch iMSCs also enhanced endothelial barrier resistance and angiogenic capacity compared to APOE3 iMSCs when directly co-cultured with endothelial cells. In addition, conditioned medium from APOE3Ch iMSCs promoted neurite outgrowth more efficiently than that from APOE3 iMSCs. Metabolic profiling revealed differences between APOE3Ch and APOE3 iMSCs, suggesting altered metabolic resilience. Together, these findings demonstrate that iMSCs support vascular and neuronal function through paracrine mechanisms and suggest that APOE3Ch variant improves specific aspects of MSC-mediated neurovascular support. This work highlights the potential of combining MSC-based therapies with protective APOE variants to target BBB and NVU dysfunction in aging and neurodegeneration.}, } @article {pmid42307825, year = {2026}, author = {Li, Y and He, X}, title = {Single-cell Transcriptomics Reveals that the SORBS1/FBXO22/BAG3 Axis Drives Astrocyte Senescence via Calcium Signaling and Affects Alzheimer's Disease-Related Neuronal Damage.}, journal = {Neuromolecular medicine}, volume = {28}, number = {1}, pages = {}, pmid = {42307825}, issn = {1559-1174}, mesh = {*Astrocytes/pathology/metabolism/physiology ; *Alzheimer Disease/pathology/metabolism/genetics ; *Cellular Senescence/genetics ; Humans ; *Neurons/pathology ; *Calcium Signaling/physiology/genetics ; *Adaptor Proteins, Signal Transducing/physiology/genetics ; Amyloid beta-Peptides/pharmacology/toxicity ; *Inhibitor of Apoptosis Proteins/physiology/genetics ; Animals ; Single-Cell Analysis ; Coculture Techniques ; Senescence-Associated Secretory Phenotype/genetics ; Single-Cell Gene Expression Analysis ; Cells, Cultured ; *Nerve Tissue Proteins/physiology/genetics ; Ubiquitination ; Transcriptome ; }, abstract = {In Alzheimer's disease (AD), senescent astrocytes fuel neuroinflammation and neuronal damage via the senescence-associated secretory phenotype (SASP). Calcium signaling plays a crucial role in this process, but the underlying molecular mechanisms remain elusive. We retrieved scRNA-seq data from the Gene Expression Omnibus (GEO) for AD and control brains. After cell-type annotation, we resolved astrocyte sub-clusters. Pseudotime trajectory and differential-expression analyses identified SORBS1 as a key senescence-related gene, which we followed with gene-set enrichment analysis. Next, we established an in vitro AD model by treating astrocytes with amyloid-β (Aβ). We evaluated astrocyte senescence using SA-β-gal staining, qRT-PCR, Western blot (WB) for senescence markers, and ELISA for SASP cytokines. We measured concentration of Ca[2+] with Fluo-4 AM probes. Subsequently, bioinformatic screening predicted FBXO22 as an interactor of SORBS1 and BAG3 as a ubiquitination substrate of FBXO22. We validated these interactions using Co-IP and in vitro ubiquitination assays. Finally, we constructed an astrocyte-neuron co-culture model. We detected neuronal cell viability, AChE activity, AD phenotype-related protein expression, apoptosis, and levels of inflammatory factors using MTT assay, specific kits, WB, flow cytometry, and ELISA, respectively, to assess neuronal damage. ScRNA-seq analysis revealed a marked reduction in astrocyte expression in AD brains, which may result from cellular senescence. The SASP gene SORBS1 was selectively up-regulated in astrocytes and significantly enriched in calcium-signaling pathways. Functional assays confirmed that SORBS1 accelerated astrocyte senescence. Mechanistically, SORBS1 interacted with FBXO22 to promote the ubiquitin-dependent degradation of BAG3, thereby amplifying calcium signaling, accelerating astrocyte senescence, and contributing to AD-related neuronal damage. We uncover a novel mechanism by which the SORBS1/FBXO22/BAG3 axis drives astrocyte senescence through the regulation of calcium signaling, thereby influencing AD-related neuronal damage. This finding provides a potential therapeutic target for AD treatment by targeting astrocyte senescence.}, } @article {pmid42307826, year = {2026}, author = {Soni, S and Sarkar, S and Tripathi, P and Maurya, S and Kaur, G and Haque, S}, title = {Neuroinflammation mediated repurposing of clemastine for Alzheimer's disease through network pharmacology, molecular dynamics, and experimental validation studies.}, journal = {Inflammopharmacology}, volume = {}, number = {}, pages = {}, pmid = {42307826}, issn = {1568-5608}, abstract = {BACKGROUND: Alzheimer's disease (AD) is a multifactorial neurodegenerative disorder with significant involvement of neuroinflammation, for which the current interventions are limited in efficacy. Certain antihistamines such as clemastine have neuroprotective properties beyond H1 receptor antagonism, including anti-inflammatory, antioxidant, remyelinating effects, modulates neuroinflammatory pathways. This study aims to investigate the neuroprotective potential of clemastine via in silico and in vivo studies for repurposing against AD.

METHODOLOGY: In silico analyses involved network pharmacology, molecular docking, and 100-ns molecular dynamic simulations along with principal component analysis and binding free energy calculations. Whereas, experimental studies involved treatment of clemastine (5 mg/kg and 10 mg/Kg, p.o.) for 14 days in lipopolysaccharide-induced neuroinflammatory (250 µg/Kg, i.p.) rat. Behavioral assessment was performed using Morris water maze (MWM) test. Biochemical parameters including acetylcholinesterase (AChE) activity, oxidative stress markers (MDA, SOD, CAT, GSH), and inflammatory biomarkers (NLRP3, TNF-α, IL-1β) were evaluated. Histopathological analysis of hippocampal CA3 region was performed using Nissl's staining.

RESULTS: Network analysis identified 52 overlapped targets between clemastine and AD. Hub genes such as GSK3β, DRD1, DRD2, CHRNA4, and SLC6A4 were associated with neurotransmission and kinase signaling pathways. Enrichment analysis highlighted PI3K/Akt, MAPK, and neuroactive ligand-receptor interaction pathways. Molecular docking and molecular dynamic simulations confirmed stable binding of clemastine with GSK-3β, PI3K, and NLRP3 proteins. Animal model studies demonstrated that clemastine significantly improved cognitive performance in MWM (p < 0.001), reduced AChE level (p < 0.0001), restored antioxidant enzyme levels, suppressed inflammatory mediators (p < 0.0001), and preserved hippocampal neuronal structure.

CONCLUSION: The study provides novel integrative evidence linking its antihistaminic action with simultaneous regulation of neuroinflammation through multi-target modulation of inflammation, oxidative stress, and neuronal signaling pathways, highlighting its potential as a promising repurposed therapeutic candidate for AD.}, } @article {pmid42307833, year = {2026}, author = {Sood, S and Singh, S and Singh, TG}, title = {PCSK9 in bridging metabolism and neurodegeneration: a new paradigm for alzheimer's treatment.}, journal = {Metabolic brain disease}, volume = {41}, number = {1}, pages = {}, pmid = {42307833}, issn = {1573-7365}, mesh = {Humans ; *Alzheimer Disease/metabolism/drug therapy ; *Proprotein Convertase 9/metabolism ; Animals ; Cholesterol/metabolism ; Amyloid beta-Peptides/metabolism ; *Brain/metabolism ; *Nerve Degeneration/metabolism ; }, abstract = {Proprotein convertase subtilisin-kexin type 9 (PCSK9) has recently emerged as a significant mediator that links metabolic dysfunction to neurodegeneration related to Alzheimer's disease (AD). It is a well-known and crucial component involved in cholesterol homeostasis. However, its function in the central nervous system (CNS) is still in its early stages. Normally, it is engaged with the breakdown of cholesterol in the body, but within the brain, PCSK9 has been seen to disrupt the homeostasis of cholesterol and its uptake. Receptors such as LDL receptor-related protein-1 (LRP-1) and low-density lipoprotein receptor (LDLR) are crucial for the survival of neurons, as they are responsible for the clearance of amyloid-β (Aβ) and peripheral lipid control. Elevated PCSK9 activity may promote degradation of these receptors, which eventually leads to deposition of Aβ near synapses along with reduced uptake of cholesterol by neurons, which may contribute to neurotoxicity and neuronal dysfunction. This review aims to explore the effect of elevated PCSK9 levels on the development as well as exacerbation of AD via different molecular mechanisms. Along with cholesterol dyshomeostasis, PCSK9 is found to be involved in glucose dysregulation, mechanistic target of rapamycin (mTOR) dysregulation, increased oxidative stress, neuroinflammation, reduced neurogenesis, affected Wnt-β-catenin signaling, and cholinergic signaling. Together, these mechanisms may contribute to AD progression. Preclinical studies show that pharmacological therapies targeting PCSK9 can give promising results by reducing neuroinflammation, modulating lipid homeostasis, and lowering Aβ accumulation. Therefore, modulation of PCSK9 represents a promising therapeutic strategy that warrants further mechanistic and clinical investigation in AD.}, } @article {pmid42308766, year = {2026}, author = {Kam, MK and Kim, JW and Choi, JY and Koh, YH and Jo, C}, title = {HSP90 is involved in curcumin-mediated inhibition of tau aggregation.}, journal = {Biochemical and biophysical research communications}, volume = {829}, number = {}, pages = {154140}, doi = {10.1016/j.bbrc.2026.154140}, pmid = {42308766}, issn = {1090-2104}, abstract = {Tau aggregation in neurons is a pathological hallmark of Alzheimer's disease (AD). The development of therapeutic drugs that inhibit tau aggregation in tauopathies, including AD, remains challenging. Herein, we developed a tau self-interaction reporter system using split Nanoluciferase (Tau-NLuc) in which luciferase activity is restored by the self-assembly of split Nanoluciferases following self-interaction between tau proteins. Curcumin (CCM), a phenolic organic compound, significantly reduced luciferase activity in the Tau-NLuc system, including mutant tau forms such as S396/404E and P301L, which are known aggregation-prone tau forms, suggesting that CCM may act as a potential inhibitor of tau aggregation. CCM did not alter the protein levels of phosphorylated tau as well as total tau, indicating that the reduction in luciferase activity by CCM did not originate from tau degradation, but rather from tau aggregation inhibition. Of note, CCM significantly increased heat shock protein (HSP) 90 dimer. The reduced luciferase activity in the Tau-NLuc system by CCM was recovered by knockdown of the HSP90 gene using a siRNA specific for HSP90 or treatment of an inhibitor of HSP90 NCT-58, supporting the involvement of HSP90. Intriguingly, hexahydrocurcumin (HHC), a derivative of CCM, did not reduce luciferase activity, nor did it induce the formation of the HSP90 dimer, suggesting that HSP90 dimer formation may contribute to the CCM-mediated inhibition of tau aggregation. Taken together, the results demonstrate that CCM inhibits tau aggregation with the involvement of HSP90, providing novel insights into the development of therapeutic strategies for AD.}, } @article {pmid42309020, year = {2026}, author = {Milà-Alomà, M and Hausle, I and Petersen, KK and Thropp, P and Schindler, SE and Tosun, D and , }, title = {The time interval from amyloid to tau PET positivity varies by age, sex and APOE-ε4 status.}, journal = {The journal of prevention of Alzheimer's disease}, volume = {13}, number = {8}, pages = {100622}, pmid = {42309020}, issn = {2426-0266}, abstract = {BACKGROUND: Alzheimer's disease (AD) progression varies widely among individuals. Identifying factors influencing timing of pathology and clinical progression is crucial for optimizing early intervention trials.

OBJECTIVES: To investigate how the estimated age at amyloid and tau PET positivity, and the time interval between these two key events ("amyloid-tau time interval"), relate to symptom onset and clinical progression, and to assess the effects of APOE-ε4 status and sex on these associations.

DESIGN: This analysis used data from the Alzheimer's Disease Neuroimaging Initiative (ADNI) and the Harvard Aging Brain Study (HABS).

SETTING: The ADNI is a multicenter observational cohort conducted at 55 sites across the United States; The HABS is a longitudinal, single-center observational cohort.

PARTICIPANTS: This study included participants with at least one positive amyloid PET scan (ADNI n = 792; HABS n = 104) or at least one positive tau PET scan (ADNI n = 212; HABS n = 48). All participants had information on sex, APOE-ε4 status, and longitudinal cognitive assessments.

MEASUREMENTS: We examined the influence of APOE-ε4 status, sex, and their interaction on the estimated age at biomarker positivity and the amyloid-tau time interval. Accelerated Failure Time (AFT) models were used to predict time to symptom onset (CDR > 0) based on estimated biomarker positivity age and the amyloid-tau time interval. Linear mixed-effects (LME) models evaluated differences in the rate of cognitive decline, as measured by CDR-SB, over five years following symptom onset according to estimated biomarker positivity age and amyloid-tau time interval. Additional models included interaction terms with sex or APOE-ε4 status.

RESULTS: The amyloid-tau time interval varied markedly between individuals and was shorter in APOE-ε4 carriers, women, and those with older age at amyloid PET positivity. APOE-ε4 carriers and women became amyloid and tau PET positive at younger ages. Following amyloid PET positivity, a shorter time to tau PET positivity predicted earlier symptom onset. After symptom onset, faster cognitive decline was observed in individuals with younger ages at amyloid or tau PET positivity. The time to symptom onset following tau PET positivity, or the rate of cognitive decline after symptom onset, were not influenced by the amyloid-tau time interval.

CONCLUSIONS: After becoming amyloid PET positive, APOE-ε4 carriers, women and older individuals may have a shorter window for detection and treatment before they become tau PET positive and develop symptoms. These findings should guide the identification of individuals at highest risk of rapid AD progression, enabling more efficient participant selection for clinical trials.}, } @article {pmid42309609, year = {2026}, author = {Mia, M and Dutta, A and Hossain, MM and Adhikari, J and Rahman, MM and Shibly, AZ}, title = {Exploring the neuroprotective, antioxidant, and anti-amyloid effects of Ganoderma lucidum compounds in Alzheimer's disease: insights from experimental and computational approaches.}, journal = {Journal, genetic engineering & biotechnology}, volume = {24}, number = {2}, pages = {100706}, pmid = {42309609}, issn = {2090-5920}, abstract = {Alzheimer's disease (AD) is characterized by amyloid-β (Aβ) aggregation and oxidative stress, with limited effective therapeutic options. This study evaluated the antioxidant, neuroprotective, and anti-amyloidogenic potential of Ganoderma lucidum, medicinal mushroom rich in bioactive compounds, including triterpenoids and sterols. Antioxidant activity was assessed using the DPPH assay, and neuroprotective effects were examined in Caenorhabditis elegans models (N2 and CL4176). The anti-Aβ potential of selected bioactive compounds was investigated through molecular docking, molecular dynamics simulations, and MM/GBSA analysis, along with ADMET predictions. The extract exhibited strong antioxidant effects, achieving 96.3% scavenging at 0.25 mg/mL. In C. elegans, treatment enhanced survival under oxidative stress by 25% at 0.5 mg/mL (p < 0.01) and delayed Aβ-induced paralysis, with 17.82% of worms remaining active at 68 h. Docking studies identified Epoxyganoderiol C (-7.8 kcal/mol), 5,6-Dihydroergosterol (-7.9 kcal/mol), and Ganoderiol A (-7.7 kcal/mol) as potent Aβ inhibitors, stabilized in molecular dynamics simulations with favorable RMSD, RMSF, Rg, and SASA profiles. MM/GBSA analysis confirmed strong binding affinities for 5,6-Dihydroergosterol, Epoxyganoderiol C, and Ganoderiol A against Aβ, with ΔG_bind values of - 71.66, -56.42, and - 45.45 kcal/mol, respectively. ADMET predictions indicated good drug-likeness, high gastrointestinal absorption, and no toxicity risks. In conclusion, G. lucidum extract demonstrated potent antioxidant and neuroprotective effects, while its bioactive key compounds-Epoxyganoderiol C, 5,6-Dihydroergosterol, and Ganoderiol A-showed favorable binding affinity and stability with Aβ, along with acceptable pharmacokinetic profiles. These findings suggest that G. lucidum and its bioactive constituents may serve as promising natural candidates for AD therapy.}, } @article {pmid42310298, year = {2026}, author = {Diaz Escarcega, R and M J, VK and Arizmendez, A and Tan, C and Urayama, A and Marrelli, SP and Morales, R and Wefel, JS and Zhang, C and McCullough, LD and Kim, N and Monchaud, D and Jung, SY and Tsvetkov, AS}, title = {Sex-linked helicases DDX3X and DDX3Y regulate G-quadruplex-associated stress in neurons.}, journal = {Cell death & disease}, volume = {}, number = {}, pages = {}, doi = {10.1038/s41419-026-08971-z}, pmid = {42310298}, issn = {2041-4889}, support = {4R01AG068292//U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; AFAR BIG21042//Glenn Family Foundation/ ; AFAR BIG21042//American Federation for Aging Research (American Federation for Aging Research, Inc.)/ ; }, abstract = {G-quadruplexes (G4s) are four-stranded nucleic acid structures that regulate virtually all nucleic acid-dependent cellular processes. At present, most functional studies involving G4s have focused on cancer cells. This study investigated how neurons respond to genotoxic stress induced by quarfloxin (CX-3543), a small molecule that stabilizes G4s. We found that quarfloxin treatment induced DNA damage in neurons, with double-strand breaks enriched in the nucleolus. Proteomic analysis revealed that quarfloxin promoted substantial protein changes, affecting networks associated with Alzheimer's, Parkinson's, and Huntington's diseases, and amyotrophic lateral sclerosis. Among the affected proteins, the G4 helicase DDX3X, encoded on the X chromosome, was upregulated, prompting further investigation of DDX3X and its Y-linked homolog DDX3Y in male and female neurons, respectively. RNA sequencing identified DDX3X- and DDX3Y-regulated gene networks involved in DNA damage responses, inflammation, cell cycle regulation, and stress-associated pathways, with notable sex-dependent differences. In human brain tissue, DDX3X expression and nuclear enrichment were increased in neurons from older females compared to younger individuals, with further elevation observed in Alzheimer's disease. Taken together, these findings identify DDX3X and DDX3Y as modulators of neuronal stress responses downstream of G4 stabilization and indicate that their induction is accompanied by activation of DNA damage response genes, as well as cell cycle- and inflammation-associated pathways, suggesting that sustained activation of these pathways may disrupt neuronal homeostasis. Our study provides insight into G4-dependent stress mechanisms in neurons and highlights sex-linked pathways that may contribute to brain aging and neurodegenerative disease vulnerability.}, } @article {pmid42310327, year = {2026}, author = {Varga, BT and Ernyey, AJ and Tajti, BT and Gáspár, A and Demeter, Z and Kollár, L and Kovács, P and Albert, M and Alpár, A and Gyertyán, I}, title = {Translational difficulties in establishing a pharmacologically induced neurovascular uncoupling model in rats.}, journal = {Scientific reports}, volume = {}, number = {}, pages = {}, doi = {10.1038/s41598-026-58244-0}, pmid = {42310327}, issn = {2045-2322}, abstract = {Neurovascular uncoupling (NVU) contributes to neurological disorders like Alzheimer's disease. While a mouse NVU model exists, a reliable rat model critical for cognitive research remains underdeveloped. To address this methodological gap, we investigated a pharmacological approach in rats using the same drugs (N-(methylsulfonyl)-2-(2-propynyloxy)-benzenehexanamide (MS-PPOH), L-NG-nitroarginine methyl ester (L-NAME), indomethacin) that proved to be efficacious in mice. The compounds were formulated as a cocktail solution and administered intraperitoneally for 13 days to aged, cognitively experienced Long-Evans rats. Our goal was to induce NVU while minimizing adverse systemic effects seen previously (e.g., hypertension, intestinal ulceration). The treatment induced only a modest (28%, non-significant) reduction in cerebral hyperaemia, with decreased prostaglandin E2 levels but unchanged 11,12-epoxyeicosatrienoic acid concentration in the brain. Cognitive effects were limited-transient impairment in the 5-choice task but no changes in spontaneous alternation, visual discrimination, cooperation, or motor learning. Significant adverse effects emerged: reduced food intake, weight loss, gastrointestinal malaise, and moderate renal toxicity. Our findings specifically highlight the challenges of achieving sufficient and symptomatically apparent NVU while minimizing systemic toxicity. While partial NVU occurred, this polypharmacy approach had major limitations. A reliable, industrially applicable rat NVU model remains urgently needed to accelerate antidementia drug development.}, } @article {pmid42311340, year = {2026}, author = {Li, G and Jiao, S and Zhou, Y and Cheng, X}, title = {Deep cervical lymphaticovenous anastomosis for Alzheimer's disease: theoretical foundations, regulatory suspension, and translational challenges.}, journal = {Frontiers in aging}, volume = {7}, number = {}, pages = {1849207}, pmid = {42311340}, issn = {2673-6217}, abstract = {Alzheimer's disease (AD) is a neurodegenerative disorder characterized by pathological changes in β-amyloid protein deposition, abnormal tau protein phosphorylation neurofibrillary tangles, and chronic neuroinflammation. Recent studies have shown that the glymphatic-meningeal-cervical lymphatic system pathway plays a crucial role in the clearance of intracranial metabolic waste. Dysfunction of this system may lead to a decrease in the clearance efficiency of Aβ and tau proteins. Deep cervical lymphaticovenous anastomosis (DCLVA) has been proposed as a novel surgical approach to enhance cervical lymphatic drainage, reduce Aβ/tau accumulation, and improve cognitive function in patients with AD. However, on 8 July 2025, the National Health Commission of China issued a notice prohibiting the clinical application of "deep cervical lymphaticovenous anastomosis" for the treatment of AD. This article provides a narrative review with critical appraisal of the theoretical basis, surgical mechanisms, and clinical evidence of DCLVA for AD. We objectively evaluate the strengths and limitations of current clinical studies, critically appraise the uncertainty of underlying physiology, and comprehensively analyze the potential risks, safety concerns, and translational obstacles that led to regulatory suspension. We further clarify unresolved scientific questions including pressure gradients, lymphatic contractility, reflux risk, anastomotic patency, and biomarker validation. By framing DCLVA within the context of its clinical prohibition, we provide clinicians and researchers with a balanced appraisal that acknowledges both the procedure's potential and the substantial gaps that must be addressed before widespread application can be justified.}, } @article {pmid42311735, year = {2026}, author = {Harikumar, N and Gupta, M and Al Janabi, T and Mand, KK}, title = {A Severe Symptomatic Case of Amyloid-Related Imaging Abnormalities After Donanemab Infusion.}, journal = {Cureus}, volume = {18}, number = {5}, pages = {e109045}, pmid = {42311735}, issn = {2168-8184}, abstract = {Amyloid-related imaging abnormalities (ARIA) are known complications of anti-amyloid monoclonal antibody therapy for Alzheimer's disease. Although many cases are asymptomatic, severe presentations can mimic stroke or toxic encephalopathy. This case highlights a rare presentation of ARIA with myoclonic movements and acute encephalopathy following donanemab infusion. We report a 75-year-old woman with Alzheimer's disease who developed acute confusion, hallucinations, and involuntary movements one day after her sixth donanemab infusion. Stroke workup was negative. MRI demonstrated findings consistent with both ARIA-E and ARIA-H. She was treated with high-dose intravenous methylprednisolone, followed by an oral prednisone taper, which resulted in gradual neurological improvement. Clinicians must maintain a high suspicion for ARIA in patients receiving anti-amyloid therapy who present with acute neurologic decline. Early MRI evaluation and prompt corticosteroid treatment may improve outcomes.}, } @article {pmid42312520, year = {2026}, author = {R, N and Dubey, S and Kumar, D and Walhekar, V and Tiwari, P}, title = {In Silico Prediction, Characterization, and Pre-clinical Appraisal of the Neuroprotective Effect of the Methanolic Extract of Cassytha filiformis.}, journal = {Current neurovascular research}, volume = {}, number = {}, pages = {}, doi = {10.2174/0115672026456568260601100209}, pmid = {42312520}, issn = {1875-5739}, abstract = {INTRODUCTION: Alzheimer's disease (AD) is a severe neurodegenerative disorder that progressively worsens with age. Medicinal plants have demonstrated potential for the management of AD. Cassytha filiformis, a native plant of the Indian subcontinent, has been reported to exhibit antioxidant activity, which could be beneficial in neurodegenerative disorders.

METHODS: This study evaluates the anti-neurodegenerative effect and possible mechanism of action of a methanolic extract of Cassytha filiformis (MECF). Two compounds, AC-2 and AC-4, were isolated from the extract and assessed for cognitive behavior using the Morris water maze and probe test, followed by evaluation of antioxidant, neurochemical, and anti-inflammatory parameters, as well as in silico studies.

RESULTS: Neurochemical abnormalities (acetylcholinesterase (AChE), NMDA (N-methyl-Daspartate), dopamine (DA)), neuro-inflammatory markers (TNF-α, IL-6), and antioxidant parameters (superoxide dismutase (SOD), lipid peroxidation (LPO), nitric oxide (NO)) were evaluated. Histological examination of brain cells assessed the regenerative impact of the isolated compounds. Antioxidant levels and neuroinflammation were significantly reduced (p < 0.05) in the MECF-, AC-2-, and AC-4-treated groups. Additionally, superoxide dismutase and catalase levels were significantly increased in the treated groups. Acetylcholine, NMDA, and dopamine levels showed marked improvement. Histopathological analysis revealed neuroregeneration in the test groups, and hematological evaluations supported these findings by demonstrating normalization of elevated blood profiles observed in the scopolamine-induced groups.

DISCUSSION: MECF and its isolated compounds, AC-2 and AC-4, exhibited notable antioxidant and neuro-anti-inflammatory properties, enhancing cognitive function, learning, and memory. The observed neuroprotective effects suggest a potential therapeutic role for these compounds in the management of AD.

CONCLUSION: Phenolic compounds present in AC-2 and AC-4 may be integral to the mechanism of action of MECF. Further investigations, including clinical validation, are necessary to explore the therapeutic potential of MECF, AC-2, and AC-4 in AD treatment.}, } @article {pmid42313307, year = {2026}, author = {Saini, K and Dhiman, P}, title = {Microglia-driven neuroinflammatory signaling in neurodegeneration: mechanisms and therapeutic opportunities.}, journal = {Molecular biology reports}, volume = {53}, number = {1}, pages = {}, pmid = {42313307}, issn = {1573-4978}, mesh = {Humans ; *Microglia/metabolism/pathology/immunology ; *Neurodegenerative Diseases/metabolism/therapy/pathology/immunology ; Animals ; Signal Transduction ; *Neuroinflammatory Diseases/metabolism/pathology/immunology ; Blood-Brain Barrier/metabolism ; Cytokines/metabolism ; Astrocytes/metabolism ; }, abstract = {Neuroinflammation has been identified as a major component to the pathogenesis and progression of many neurodegenerative illnesses, going beyond its traditional role as a protective immune response within central nervous system (CNS). There is growing evidence that persistent activation of peripheral immune pathways, microglia and astrocytes causes progressive neurodegeneration, synaptic loss and progressive neurodegeneration. This review examines the mechanisms of microglia- driven neuroinflammatory signaling and its involvement in major neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis and Huntington's disease. Key neuroinflammatory mechanisms covered in depth including microglial activation, astrocyte reactivity, peripheral immune cell infiltration, cytokine dysregulation, and blood brain barrier (BBB) disruption. This review also emphasizes the role of neuroinflammation in acute neurological symptoms and mental and cognitive impairments. Glial activation markers, inflammatory cytokines, BBB proteins and kynurenine pathway metabolites are emerging as promising biomarkers for disease diagnosis and monitoring. Additionally, the potential of new mathematical and systems level computational models to describe intricate neuroimmune interactions and forecast the course of disease and treatment results is investigated. Current and emerging therapies targeting neuroinflammation include anti-inflammatory and immunomodulatory drugs, lifestyle interventions, stem cell approaches, gene-editing technologies and nanoparticle-based drug delivery systems. Despite significant progress, translating preclinical findings into effective clinical therapies remains challenging. Future developments in integrative neuroimmune modeling, biomarker-guided therapies and precision medicine may make it possible to create individualized treatments plans targeted at reducing neuroinflammation and enhancing the course of neurodegenerative illnesses.}, } @article {pmid42314102, year = {2026}, author = {Ganesh, A and Smith, EE and Mostert, J and Strijbis, EM and Schoonheim, MM and Xia, C and Nadeau, Y and Leavitt, VM and Kalia, LV and Engelborghs, S and D'Haeseleer, M and McPherson, T and Cutter, GR and Koch, MW and , }, title = {Phase 2 Futility Trials in Alzheimer Disease and Mild Cognitive Impairment: A Cohort Analysis of the ADNI Data Set.}, journal = {Neurology}, volume = {107}, number = {1}, pages = {e218227}, doi = {10.1212/WNL.0000000000218227}, pmid = {42314102}, issn = {1526-632X}, mesh = {Humans ; *Alzheimer Disease/therapy ; *Cognitive Dysfunction/therapy ; Female ; Aged ; Male ; *Clinical Trials, Phase II as Topic ; Medical Futility ; Aged, 80 and over ; Longitudinal Studies ; Cohort Studies ; }, abstract = {BACKGROUND AND OBJECTIVES: The cost and complexity of phase 2 randomized-controlled trials (RCTs) hinder further development of promising treatment candidates for Alzheimer disease (AD). The Simon Two-Stage futility trial design, originally developed for oncology, offers a streamlined approach to evaluate potential disease-modifying therapies by comparing single-arm outcomes with historical controls, but is predicated on identifying outcome measures that reliably worsen with the natural history of the disease, with minimal risk of improvement. We sought to determine the feasibility of such futility trials in AD-associated dementia and mild cognitive impairment (MCI) using a large prospective cohort.

METHODS: We analyzed longitudinal data from the Alzheimer's Disease Neuroimaging Initiative (ADNI). Cognitive decline was assessed using AD Assessment Scale-Cognitive Subscale (ADAS-Cog 11 and ADAS-Cog 13), Clinical Dementia Rating-Sum of Boxes (CDR-SB), and Mini-Mental State Examination (MMSE) at 6, 12, and 24 months using different thresholds for worsening vs improvement. Binary logistic regression models examined baseline factors associated with cognitive worsening using different thresholds of worsening for each outcome of interest to assess what additional selection criteria may be needed for futility trials in AD-associated dementia vs MCI. Sample size estimates were derived based on expected rates of decline.

RESULTS: Among 2,665 participants (mean age 73.4 years [SD: 7.5], 1,260 [47.3%] female, 424 with AD-associated dementia), the CDR-SB exhibited the largest percentage of decline in AD-associated dementia and MCI, with 60.6% of patients with AD-associated dementia showing worsening when using a threshold of ≥1.0 points at 12 months vs 6.2% showing improvement. ADAS-Cog 11 and 13 showed similar decline patterns; for example, 41.7% with AD-associated dementia worsened by ≥ 5 points at 12 months on ADAS-Cog 13, whereas 5.8% improved. MMSE exhibited lower sensitivity; 25.8% with AD-associated dementia worsened by ≥ 5 points at 12 months, whereas 2.9% improved. Shorter trials (6-12 months) with 35-62 participants seemed feasible in AD-associated dementia, whereas MCI trials seemed to require 24 months and specific entry criteria based on age, apolipoprotein E ε4 status, and baseline CDR-SB performance.

DISCUSSION: Futility trials seem feasible in AD-associated dementia, offering a faster, cost-effective alternative to traditional phase 2 RCTs. CDR-SB seems to be the optimal primary outcome. Further validation in clinical trial data sets is warranted.}, } @article {pmid42314597, year = {2026}, author = {Li, Y and Yang, XF and Yang, SY and Wang, L and Sun, YZ and Tan, WX and Yang, Z and Zheng, YZ and Wang, J and Jin, HW and Zeng, KW and Tu, PF}, title = {Millepurpan from Astragali Radix binds condensin SMC2 to reverse microglial cell cycle arrest and metabolic reprogramming in neuroinflammation.}, journal = {Bioorganic chemistry}, volume = {180}, number = {}, pages = {110089}, doi = {10.1016/j.bioorg.2026.110089}, pmid = {42314597}, issn = {1090-2120}, abstract = {Microglia are key immune cells in the central nervous system, whose dysfunction contributes to neuroinflammation and neurological disorders. Astragali Radix (AR), the root of Astragalus membranaceus (Fisch.) Bge. var. mongholicus (Bge.) Hsiao, is known for neuroprotective effects, yet its active compounds remain underexplored. This study reports the first isolation of Millepurpan (MPP) from AR extract and reveals its potent anti-inflammatory effects in BV-2 microglial cells stimulated with lipopolysaccharide (LPS). Binding assays show MPP targets the ATPase head domain of structural maintenance of chromosomes 2 (SMC2), a condensin complex subunit, inducing steric hindrance that obstructs the ATP-binding pocket. LPS suppresses SMC2 nuclear translocation, causing p21-mediated G0/G1 arrest; MPP restores nuclear SMC2 and promotes G1/S transition. Seahorse metabolic analysis indicates MPP reverses LPS-induced glycolytic reprogramming, an effect abolished by Palbociclib co-treatment, highlighting cell cycle progression's role in metabolic regulation. In vivo, MPP crosses the blood-brain barrier, reduces microglial hyperactivation, and protects neurons in LPS-treated C57BL/6 mice. Immunofluorescence confirms MPP rescues nuclear SMC2 depleted by LPS, supporting its anti-neuroinflammatory action. Reanalysis of single-cell RNA sequencing datasets indicates dysregulation of SMC2 and downstream genes in Alzheimer's disease patients, suggesting SMC2 as a potential biomarker for neuroinflammation. Together, findings reveal an SMC2-mediated pathway whereby MPP binding promotes SMC2 nuclear translocation, mitigating neuroinflammation via regulation of microglial cell cycle and metabolic homeostasis. Given cell cycle regulation's importance in cellular homeostasis, SMC2 emerges as a promising therapeutic target, and MPP as a candidate agent for neuroinflammatory disorder treatment.}, } @article {pmid42315374, year = {2026}, author = {da Silva, AMP and de Siqueira Lima, DV and Figueiroa Souza, R and Lopes, VHP and Januario Campos Cardoso, L and Ornelas Pinto, EL and Gonçalves, OR and Braga, C and Cal, H and Haddad, DS and Vasconcelos, SMM and Duarte, FS and Perry, G and Anghinah, R}, title = {Cannabinoids Treatment for Agitation in Alzheimer's Disease: A Systematic Review and Meta-Analysis With Bayesian and Sequential Trial Analyses.}, journal = {The American journal of geriatric psychiatry : official journal of the American Association for Geriatric Psychiatry}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.jagp.2026.05.016}, pmid = {42315374}, issn = {1545-7214}, abstract = {OBJECTIVE: Agitation and related neuropsychiatric symptoms are common in Alzheimer's disease (AD) and contribute to caregiver burden, functional decline, and institutionalization. Cannabinoid-based therapies have been investigated as potential symptomatic interventions, but evidence remains limited by small trials, heterogeneous formulations, and variable outcome reporting. We aimed to evaluate the efficacy, cognitive outcomes, and safety of cannabinoid-based therapies in AD.

METHODS: This systematic review and meta-analysis were prospectively registered in PROSPERO and conducted following PRISMA 2020 guidelines. PubMed, Embase, and the Cochrane Central Register of Controlled Trials were searched through April 2025 for randomized placebo-controlled trials evaluating cannabinoid-based therapies for agitation or neuropsychiatric symptoms in AD. One nonrandomized open-label study was retained as supplementary evidence for sensitivity analyses. Primary efficacy analyses were restricted to randomized between-group contrasts. Outcomes included Neuropsychiatric Inventory (NPI) total score, Cohen-Mansfield Agitation Inventory-Short Form (CMAI-SF), NPI agitation/aggression, Mini-Mental State Examination (MMSE), and safety outcomes. Random-effects meta-analyses were complemented by Bayesian models and Trial Sequential Analysis.

RESULTS: Seven studies met the inclusion criteria, including six randomized trials and one open-label prospective cohort, with 221 participants enrolled. Cannabinoid-based therapies showed lower neuropsychiatric symptom and agitation scores than placebo in randomized between-group analyses: NPI total score (standardized mean difference [SMD], -0.31; 95% confidence intervals [CI], -0.47 to -0.15; k = 4), CMAI-SF (SMD, -0.40; 95% CI, -0.69 to -0.10; k = 3), and NPI agitation/aggression (SMD, -0.47; 95% CI, -0.69 to -0.25; k = 3). Bayesian posterior probabilities for lower symptom scores exceeded 95%. MMSE findings did not support a consistent cognitive benefit. Somnolence was the principal safety signal (risk ratios, 2.25; 95% CI, 1.43-3.54), with Trial Sequential Analysis suggesting sufficient accrued information for this outcome. Falls and fatigue were imprecisely estimated.

CONCLUSIONS: Cannabinoid-based therapies showed lower agitation and neuropsychiatric symptom scores than placebo in AD, with somnolence as the main safety concern. Interpretation remains limited by few trials, heterogeneous formulations and outcome instruments, short follow-up, and concentrated statistical weight. Larger randomized trials with formulation-specific protocols, longer follow-up, active comparators, and systematic safety monitoring are needed.}, } @article {pmid42315445, year = {2026}, author = {Yassine, HN and Pour, SG and Juarez, M and Arrelanas, IC and Ali, N and Dikeman, D and Sanchez, A and Park, J and Kerman, B and Duro, MV and Asante, I and Louie, S and Kono, N and D'Orazio, LM and Chui, H and Mack, WJ and Harrington, MG and Braskie, MN and Schneider, LS}, title = {CNS target engagement of high-dose DHA supplementation in older adults at risk for dementia: a randomised, double-blind, placebo-controlled trial.}, journal = {EBioMedicine}, volume = {}, number = {}, pages = {106316}, doi = {10.1016/j.ebiom.2026.106316}, pmid = {42315445}, issn = {2352-3964}, abstract = {BACKGROUND: APOE ε4 carriers have increased Alzheimer's disease risk and altered omega-3 metabolism. No large-scale prevention trials have tested high-dose docosahexaenoic acid (DHA) supplementation specifically in non-demented APOE ε4 carriers with low baseline omega-3 intake for early intervention.

METHODS: We conducted a phase IIa 24-month, randomised, double-blind, placebo-controlled trial (NCT03613844) at the University of Southern California between September 2018 and May 2024. Participants aged 55-80 years without dementia, low dietary DHA intake (<200 mg/day), and ≥1 dementia risk factor were stratified by cerebrospinal fluid (CSF) collection willingness into lumbar puncture (LP) or no-LP arms. Within each arm, participants were randomised 1:1 to receive 2 g/day DHA or placebo, stratified by APOE ε4 status. Primary outcome was the 6-month CSF DHA-to-arachidonic acid (AA) ratio change. Secondary and exploratory outcomes included 24-month neuroimaging and cognitive measures.

FINDINGS: Of 739 screened individuals, 365 participants were randomised (181 LP arm, 184 no-LP arm). Mean age was 66.4 years (SD 5.7), 210 (58%) were female, 142 (39%) were Hispanic, 173 (47%) were APOE ε4 carriers. DHA supplementation increased CSF DHA/AA ratio at 6 months vs placebo (0.17 [95% CI 0.15-0.18] vs -0.02 [95% CI -0.04 to -0.0004]; difference 0.19 [95% CI 0.16-0.21]; p < 0.0001), independent of APOE ε4 status (interaction p = 0.71). Dropout was 38%, mainly due to COVID-19. No treatment differences were observed in brain volumes or cognitive performance over 24 months. Adverse events were comparable between groups, with no serious adverse events attributed to treatment.

INTERPRETATION: High-dose DHA achieved CNS target engagement in non-demented older adults with low baseline omega-3 intake, independent of APOE ε4. Despite biochemical target engagement, no differences in cognition or brain structure were observed over 24 months. Future research should prioritise brain DHA metabolism over further supplementation trials.

FUNDING: National Institute on Aging (R01AG057684) and the ADDF (GC-201711-2014197).}, } @article {pmid42315518, year = {2026}, author = {Dar, NJ and Soriano-Castell, D and Maher, P}, title = {Sustained dysregulation of iron and glutathione homeostasis induces chronoferroptosis, a persistent ferroptotic adaptation in neuronal cells.}, journal = {Cell death discovery}, volume = {}, number = {}, pages = {}, doi = {10.1038/s41420-026-03208-6}, pmid = {42315518}, issn = {2058-7716}, support = {R01AG067331//Foundation for the National Institutes of Health (Foundation for the National Institutes of Health, Inc.)/ ; R01AG069206//Foundation for the National Institutes of Health (Foundation for the National Institutes of Health, Inc.)/ ; }, abstract = {Although iron accumulates in brain regions impacted by neurodegenerative diseases such as Alzheimer's and Parkinson's, how chronic elevated iron levels contribute to neuronal dysfunction remains unclear. Here, we show that sustained iron overload, but not acute exposure, leads to a state of ferroptotic stress where nerve cells remain viable but become hypersensitive to oxidative injury. Retinoic acid-differentiated SH-SY5Y neuronal cells were exposed to acute (6-8 h) or chronic (9 days) iron loading to model transient versus prolonged age-related iron stress. While acute iron exposure produced minimal biochemical changes and did not sensitize cells to oxidative or ferroptotic challenges, chronic iron exposure induced ferritin upregulation, mitochondrial superoxide accumulation, suppression of GPX4 expression, elevated lipid peroxidation and loss of cellular glutathione (GSH). In addition, chronic but not acute GSH depletion by buthionine sulfoximine (BSO) recapitulated the iron-induced phenotype. Cells under chronic ferroptotic stress exhibited increased sensitivity not only to the ferroptosis inducer RSL-3 but also to hydrogen peroxide. Ferrostatin-1 significantly mitigated these effects suggesting that lipid peroxidation drives this state. Together, these findings demonstrate that, in contrast with acute exposure, chronic disruption of iron homeostasis with consequent GSH depletion remodels cellular redox homeostasis over time, inducing a state we term chronoferroptosis: a persistent ferroptotic adaptation characterized by coordinated alterations in iron-handling and antioxidant defense proteins that may represent early vulnerability to neurodegenerative pathology. Thus, these studies highlight the importance of sustained stress paradigms for modeling the progressive nature of neurodegenerative diseases.Graphical abstract illustrating how prolonged iron or BSO exposure drives a persistent ferroptotic stress state in RA differentiated SH-SY5Y cells. These cells were subjected to either acute exposure for 6-8 h or chronic exposure for 9 days. Acute iron or BSO treatment caused minimal biochemical changes and did not increase vulnerability to oxidative or ferroptotic challenges. In contrast, chronic exposure stimulated ferritin production, mitochondrial superoxide buildup, GSH depletion, reductions in GPX4 expression and increased lipid peroxidation without altering cell viability. However, these chronically stressed neuronal cells became markedly more sensitive to secondary stressors such as RSL-3 or hydrogen peroxide resulting in decreases in cell viability, whereas viability was not altered in acutely treated cells.}, } @article {pmid42316324, year = {2026}, author = {Figueiredo, EV and Azevedo, CV and Penitente, AR and Pedrosa, VR and Camilo da Silva, VR and Longo, BM}, title = {Impact of sex differences on microglial function in Alzheimer's disease.}, journal = {Alzheimer's research & therapy}, volume = {}, number = {}, pages = {}, doi = {10.1186/s13195-026-02099-0}, pmid = {42316324}, issn = {1758-9193}, support = {2022/00249-8//Fundação de Amparo à Pesquisa do Estado de São Paulo/ ; 001//Coordenação de Aperfeiçoamento de Pessoal de Nível Superior/ ; 312904/2021-5//Conselho Nacional de Desenvolvimento Científico e Tecnológico/ ; }, abstract = {Aging is the strongest risk factor for Alzheimer's disease (AD), a multifactorial neurodegenerative disorder characterized by amyloid-β (Aβ) accumulation, tau pathology (hyperphosphorylated tau and neurofibrillary tangles [NFTs]), and associated neuroinflammatory processes. Age-related cellular and molecular stressors, including mitochondrial dysfunction, genomic instability, and chronic low-grade inflammation, progressively increase vulnerability to neurodegeneration. In parallel, sex is increasingly recognized as a biological variable that shapes AD risk, clinical course, and neuropathological burden. Women account for roughly two-thirds of AD cases, a disparity not fully explained by longevity. Multiple factors likely contribute, including hormonal transitions across the lifespan (particularly menopausal estrogen decline), sex chromosome-linked immune regulation, sex-dependent interactions between genetic risk factors (e.g., APOE4 and TREM2) and brain aging, and differences in vascular risk, cognitive reserve, and sociocultural exposures that influence disease expression and detection. Microglia, the brain's resident immune cells, are sexually dimorphic, and respond to Aβ and tau pathology, modulating inflammatory signaling, synaptic remodeling, and neurovascular dysfunction implicated in AD. Emerging human and experimental evidence indicate that microglial activation states, immunometabolism, and functional responses differ between males and females and may contribute to sex-specific AD trajectories. Here, we synthesize current evidence supporting microglial sexual dimorphism across aging and AD, highlight possible candidates (hormonal signaling, immuno-aging, disease-associated microglial states, and immunometabolic remodeling), and discuss key knowledge gaps toward sex-informed precision approaches for prevention and treatment.}, } @article {pmid42316357, year = {2026}, author = {Ma, L and Geng, Y and Wang, L and Zhang, G and Xu, S and Wang, Z}, title = {Rational Design of Sequentially Activated Dual-Locked Near-Infrared Fluorescent Probe for Simultaneous Imaging of Cerebral Amyloid-β Plaques and ClO[-] in Alzheimer's Disease.}, journal = {Analytical chemistry}, volume = {98}, number = {25}, pages = {18943-18953}, doi = {10.1021/acs.analchem.6c01603}, pmid = {42316357}, issn = {1520-6882}, mesh = {*Alzheimer Disease/diagnostic imaging/metabolism ; Animals ; *Fluorescent Dyes/chemistry/chemical synthesis ; *Amyloid beta-Peptides/metabolism/analysis/chemistry ; Mice ; *Plaque, Amyloid/diagnostic imaging ; *Hypochlorous Acid/analysis ; *Peptide Fragments/analysis/metabolism ; Humans ; *Optical Imaging ; Fluorescent Chemosensor Compounds ; Mice, Transgenic ; Boron Compounds/chemistry ; }, abstract = {Alzheimer's disease (AD) is a complex neurodegenerative disorder mediated by multiple pathological factors, including amyloid-β (Aβ) plaque deposition and oxidative stress. Herein, we report a new class of sequentially activated dual-lock-responsive fluorescent probes, D-BDY and T-BDY, which were designed by integrating pyrrole-based electron-donating units and molecular rotors into the BODIPY scaffold. This strategic design enabled photoinduced electron transfer (PET) and twisted intermolecular charge transfer (TICT) modulated fluorescence responses to both Aβ1-42 aggregates and hypochlorite (ClO[-]). The probes exhibited remarkable fluorescence enhancement (50-100-fold) when exposed to a mixed solution containing both ClO[-] and Aβ1-42 aggregates. Confocal imaging and staining of Aβ-containing brain slices revealed that the probes preferentially bind to the dense β-sheet-rich cores of plaques, and their colocalization with thioflavin-T (ThT) was further enhanced following ClO[-] activation. Furthermore, in vivo imaging in an APP/PS1 transgenic AD mouse model demonstrated that D-BDY successfully crossed the blood-brain barrier (BBB), enabling real-time monitoring of Aβ1-42 plaques and the oxidative microenvironment. The observed fluorescence intensity exhibited a strong correlation with pathological severity and was significantly attenuated upon antioxidant treatment. These results established D-BDY as a promising single-molecule dual-locked fluorescent probe capable of sensitively visualizing Aβ1-42 aggregation and ClO[-]-related oxidative stress in vivo, offering a valuable tool for AD diagnosis and pathological progression monitoring.}, } @article {pmid42317872, year = {2026}, author = {Singh, G and Singh, G and Shreya, and Kumari, A and Aran, KR}, title = {Nutrients and bioactive compounds as modifiers of neurodegenerative trajectories: molecular mechanisms, translational barriers, and precision nutrition.}, journal = {Frontiers in nutrition}, volume = {13}, number = {}, pages = {1819432}, pmid = {42317872}, issn = {2296-861X}, abstract = {The Neurodegenerative diseases (NDs) such as Alzheimer's disease (AD), Parkinson's disease (PD), Multiple sclerosis (MS), and Amyotrophic lateral sclerosis (ALS) are a growing health burden across the world with minimal disease-modifying treatment and therapy. It is emerging that neurodegeneration is not only a progressive loss of neurons, but also a nutrient-sensitive systems-level dysfunction that takes the form of redox imbalance, chronic neuroinflammation, mitochondrial dysfunction, impaired proteostasis, and synaptic loss. The aging brain are more prone to metabolic vulnerability, and subclinical deficiencies in essential nutrients and bioactive dietary compounds may exacerbate cellular stress responses that contribute to disease progression. It summarizes the existing data on the effects of nutrients like vitamins, minerals, polyunsaturated fatty acids, and various phytochemicals in modulating neuronal homeostasis by regulating oxidative signaling, inflammatory cascades, mitochondrial resilience, autophagy, and synaptic plasticity. These nutrient-mediated effects collectively influence neuronal survival, synaptic integrity, and cognitive function by affecting disease susceptibility and progression. Additionally newer metabolites of the marine and microbiome act as new neuroactive agents. The evidence from in-vitro and preclinical models, translation to clinical benefit remains inconsistent due to heterogeneity in study design, bioavailability, blood- brain barrier penetration, dosing strategies and disease stage. This review highlights emerging potential of precision nutrition frameworks that integrate nutrigenomics, metabolomics, and microbiome interactions, and individualized metabolic profiling to enable context-dependent and stage-specific interventions. Moreover, conceptualizing neurodegeneration as a nutrient-sensitive, systems level disorder, propose a mechanistically informed and integrative approach that combine targeted nutritional strategies with pharmacological and lifestyle therapies to more effectively modify neurodegenerative trajectories.}, } @article {pmid42317884, year = {2026}, author = {Azinge, N and Elkomi, R and Bisrat, M and Gillani, SF and Deverapalli, M and Beyene, E and Michael, MB and Deonarine, A}, title = {Proton Pump Inhibitors Versus H2 Blockers and the Risk of Incident Dementia in Adults Younger Than 65.}, journal = {Cureus}, volume = {18}, number = {5}, pages = {e109101}, pmid = {42317884}, issn = {2168-8184}, abstract = {BACKGROUND: Proton pump inhibitors (PPIs) and histamine-2 receptor antagonists (H2 blockers) are routinely prescribed for the long-term management of chronic acid-related gastrointestinal conditions. Although prior research has explored a potential link between PPI exposure and cognitive decline, findings across studies have been inconsistent, and most investigations have concentrated on elderly populations.

OBJECTIVE: This study aimed to evaluate whether PPI therapy, relative to H2 blocker therapy, was associated with differential incident dementia risk among adults below the age of 65 who carry diagnoses warranting sustained acid suppression.

METHODS: A retrospective cohort analysis was performed using data from the TriNetX Global Collaborative Network. Eligible participants were adults aged 18-65 with a confirmed diagnosis of gastroesophageal reflux disease with esophagitis (ICD-10-CM K21.0) or Barrett's esophagus (ICD-10-CM K22.7), and documented treatment with either a PPI (ATC code A02BC) or an H2 blocker (ATC code A02BA). All individuals with pre-existing dementia were excluded. Cohorts were balanced via 1:1 propensity score matching on age, sex, and baseline psychiatric and neurodevelopmental diagnoses. The main outcome, incident dementia, was captured through ICD-10 diagnostic codes encompassing Alzheimer's disease (G30), dementia secondary to other diseases (F02), unspecified dementia (F03), and other degenerative nervous system disorders (G31). Analyses included risk ratios, odds ratios, Kaplan-Meier survival curves, and Cox proportional hazards regression.

RESULTS: Following propensity score matching, each treatment group comprised 197,187 patients. New-onset dementia was recorded in 368 individuals (0.19%) assigned to the PPI group and 607 individuals (0.31%) in the H2 blocker group. Relative to H2 blocker use, PPI therapy was linked to a meaningfully lower likelihood of developing dementia (risk ratio 0.61, 95% CI 0.53-0.69; odds ratio 0.61, 95% CI 0.53-0.69). Kaplan-Meier analyses corroborated these findings, with a significantly reduced dementia hazard observed among PPI-treated patients (hazard ratio 0.63, 95% CI 0.55-0.72; log-rank p < 0.001).  Conclusion: In this propensity-matched sample of adults younger than 65 years with chronic acid-related diagnoses, PPI therapy did not elevate the risk of incident dementia relative to H2 blockers and was, in fact, associated with a statistically lower observed risk. These results should reassure clinicians and patients regarding the cognitive safety profile of PPIs when sustained acid suppression is medically necessary.}, } @article {pmid42318047, year = {2026}, author = {Wei, YT and Li, L and Xie, WT and Wang, Y and Zhao, YR and Zhang, RZ and Ma, L and Yan, XK}, title = {Altered Effective Connectivity Within the Frontoparietal Network in Alzheimer's Disease and Its Modulation by Acupuncture: A Resting-State fMRI Study.}, journal = {Neuropsychiatric disease and treatment}, volume = {22}, number = {}, pages = {601136}, pmid = {42318047}, issn = {1176-6328}, abstract = {PURPOSE: Alzheimer's disease (AD) is increasingly prevalent, yet how acupuncture modulates cognitive brain networks remains unclear. We used resting-state fMRI (rs-fMRI) to examine whether acupuncture prescription regulates effective connectivity within the frontoparietal network (FPN) in AD.

PATIENTS AND METHODS: Sixty AD patients were randomized to donepezil alone (drug group) or acupuncture plus donepezil (acupuncture group) for 6 weeks (n=30/group). Seven healthy controls were scanned once. Global cognition was assessed with MoCA-B. Independent component analysis identified the FPN, and Granger causality analysis quantified directed effective connectivity before and after treatment.

RESULTS: Both interventions improved MoCA-B (P<0.05), with larger gains in the acupuncture group (P<0.05). Relative to controls, AD showed FPN disruption with compensatory reorganization. Decreased connectivity was observed from the left middle temporal gyrus (MTG) to the right inferior parietal lobule (IPL), and from the left median cingulate/paracingulate gyri (P<0.05). Increased connectivity emerged from the right IPL and left cingulate/paracingulate to the left MTG, and from the right IPL to the left medial frontal gyrus (orbital part) (P<0.05). The right IPL and left MTG were core FPN nodes. Post-treatment, the drug group showed reduced right IPL→left orbital medial frontal connectivity, whereas the acupuncture group showed reduced right IPL→left MTG connectivity (P<0.05). Between-group comparisons indicated acupuncture-specific modulation of right insula→left MTG and left precuneus→left MTG connectivity (P<0.05).

CONCLUSION: Acupuncture combined with donepezil provides superior cognitive benefits and selectively reshapes directed FPN interactions, supporting a network-level mechanism involving frontal-parietal-temporal integration.}, } @article {pmid42318437, year = {2026}, author = {Dinnerstein, E}, title = {"Doctor, if it were you, which would you choose?": Navigating personal preference questions in anti-amyloid immunotherapy selection.}, journal = {Alzheimer's & dementia (Amsterdam, Netherlands)}, volume = {18}, number = {2}, pages = {e70373}, pmid = {42318437}, issn = {2352-8729}, abstract = {The approval of lecanemab and donanemab represents a watershed moment in Alzheimer Disease (AD) treatment, yet clinicians face a novel challenge: guiding patients through treatment selection when head-to-head comparative data are absent. When confronted with the question "What would you do if you were me?", clinical providers must balance evidence-based medicine with the therapeutic alliance. This perspective examines the ethical, practical, and relational dimensions of responding to personal preference queries in the context of anti-amyloid immunotherapy selection, offering a framework for authentic engagement that honors both professional boundaries and patient-centered care.}, } @article {pmid42318555, year = {2026}, author = {Yadollahi Khales, A and Ghaedi, K and Esmaeili, F and Noorbakhshnia, M and Etemadifar, M}, title = {Plasma lncRNA signature of upregulated ATP2B1-AS1 and downregulated RPL21P28 correlates with diagnosis and cognitive severity in Alzheimer's disease.}, journal = {Frontiers in aging neuroscience}, volume = {18}, number = {}, pages = {1739935}, pmid = {42318555}, issn = {1663-4365}, abstract = {BACKGROUND: The non-invasive biomarkers have considerable effects in determination and treatment of Alzheimer's disease (AD). The specificity and stability of the circulating long non-coding RNAs (lncRNAs) have made them suitable options in disease management. The aim of this study was discovering and clinically confirming a new plasma lncRNA signature and the underlying regulatory mechanisms.

METHODS: In a two-stage research, the preliminary bioinformatic screen of public transcriptomic data (GEO: GSE63060) found candidate lncRNAs. Then the level of the major candidates, ATP2B1-AS1 and RPL21P28, were validated by Real-Time qPCR in plasma of 25 AD patients and 25 healthy controls. The diagnostic performance was appraised by the Receiver Operating Characteristic (ROC) curve analysis and the presumed functions were described by a competing endogenous RNA (ceRNA) network.

RESULTS: Our study established concurrent ATP2B1-AS1 upregulation and RPL21P28 downregulation in Alzheimer's patient plasma (p < 0.001). This highly discriminatory two-lncRNA signature produced an area under the curve (AUC) of 0.81 for ATP2B1-AS1 and 0.83 for RPL21P28. Based on MMSE scores, the expressions of both lncRNAs were significantly correlated with the level of cognitive impairment. These lncRNAs were also showed a correlation to important regulation mechanisms by our ceRNA network analysis, with RPL2B1P28 linked to synaptic functional genes and ATP2B1-AS1 to neurodevelopment.

CONCLUSION: ATP2B1-AS1 and RPL21P28 plasma levels present specific AD biomarker signature. These lncRNAs show great potentials in designing a non-invasive blood test that can be used for early diagnosis and disease follow-up. It also establishes new areas for intervention therapy research.}, } @article {pmid42319641, year = {2026}, author = {Jetsonen, V and Välimäki, T and Selander, T and Kuvaja-Köllner, V and Martikainen, J and Koivisto, AM}, title = {Different family caregiver- and care recipient-related factors are associated with the cost of care in the early, mild, and moderate stages of Alzheimer's disease in Finland: A 5-year ALSOVA study.}, journal = {The European journal of health economics : HEPAC : health economics in prevention and care}, volume = {}, number = {}, pages = {}, pmid = {42319641}, issn = {1618-7601}, abstract = {PURPOSE: Alzheimer's disease (AD) accounts for a significant proportion of health and social care costs. We studied family caregiver (FC), care recipient (CR), and formal care provider-related factors, which are associated with the cost of care in different stages of AD in Finland.

METHODS: A 5-year follow-up was conducted with 231 individuals with AD (CRs) and their FCs as a part of the ALSOVA project. The data was collected between 2002 and 06. Significant factors associated with costs were identified using a stepwise backward elimination procedure. Neuropsychiatric symptoms were measured with the Neuropsychiatric Inventory (NPI).

RESULTS: Across all stages of AD, each additional year of CR's education was associated with a 3.4% reduction in costs (rate ratio [RR] 0.966, 95% CI 0.940-0.993). Conversely, a one-point increase on the Neuropsychiatric Inventory was associated with a 1.8% increase in costs (RR 1.018, 95% CI 1.011-1.025). CR's neuropsychiatric symptoms (RR 1.028, 95% CI 1.010-1.047) and male FC (RR 1.756, 95% CI 1.266-2.437) were associated with increased total costs in early AD, CR's comorbidities (RR 1.138, 95% CI 1.068-1.212) and FC's burden (RR 1.032, 95% CI 1.012-1.053) in mild AD and FC being a spouse (RR 1.451, 95% CI 1.105-1.905) in moderate AD. No formal care provider-related factors were associated with total costs in any stage of AD.

CONCLUSIONS: This study reveals several factors that may be manageable to control the costs of AD. Comprehensive prevention, evaluation, and treatment of a CR's neuropsychiatric symptoms and comorbidities should be executed early. Informal care can act as a substitute for formal care in early-stage AD, and supportive measures toward FCs should be considered.}, } @article {pmid42320774, year = {2026}, author = {Ren, L and Liu, S and Sun, X and Zhang, Y and Wang, P and Liu, L and Chen, LL}, title = {Ditan Decoction alleviates glutamate excitotoxicity in an Aβ-induced Alzheimer's disease-like model through the regulation of ERBB2/PI3K/AKT signaling pathway.}, journal = {Journal of ethnopharmacology}, volume = {371}, number = {}, pages = {122084}, doi = {10.1016/j.jep.2026.122084}, pmid = {42320774}, issn = {1872-7573}, abstract = {Alzheimer's disease (AD), as the most prevalent form of dementia among the elders, poses a major global health challenge. Ditan Decoction (DTD), a classic prescription from traditional Chinese medicine, demonstrates potent capacity against neurological disorders. Nevertheless, the specific components of DTD and its mechanisms in treating AD remain unclear.

AIM OF THE STUDY: The study was designed to investigate the underlying substance basis and molecular mechanisms of DTD in treating Aβ1-42-induced cognitive decline in rats.

MATERIALS AND METHODS: The AD model rats established by Aβ1-42 injection were subjected to cognitive function assessment through Y-maze, Morris water maze and novel object recognition tests. Neuronal damage and dendritic spine integrity were evaluated by Nissl and Golgi staining. The constituent assignment of DTD in vitro and in vivo was accomplished by LC-MS, and potential targets for AD treatment were predicted through network pharmacology, broad-target metabolomics, molecular docking and molecular dynamics simulations. Immunofluorescence and neurotransmitter assay served to analyze neuronal activation levels and glutamate content. Protein expressions of signal pathway were detected in hippocampus and validated by serum pharmacology in HT22 cells using Western blot analysis.

RESULTS: DTD treatment significantly alleviated the cognitive dysfunction in AD model rats. LC-MS analysis identified 268 compounds in DTD, with 23 active ingredients absorbed in vivo. Integrated analyses combining network pharmacology, metabolomic profiling, molecular docking, and molecular dynamics simulations indicated that DTD may exert therapeutic effects against AD by lowering glutamate levels in hippocampus via the regulation of ERBB2/PI3K/AKT signaling pathways. DTD upregulated the expression of ERBB2 and p-AKT, reduced glutamate-induced neuronal activation levels and hippocampal glutamate content, and elevated the level of synaptic proteins PSD95, Syn1 and NR2A/B, thereby improving the structural and functional integrity of synapses. Cell tests confirmed that DTD alleviated glutamate-induced excitotoxicity and synaptic dysfunction in HT22 cells via ERBB2/PI3K/AKT pathway, which was abolished by ERBB2 inhibitor AG-825 and PI3K inhibitor LY294002.

CONCLUSIONS: This study elucidates the neuroprotective mechanism of DTD within AD model rats. DTD improves synaptic dysfunction by reducing hippocampal glutamate concentrations and counteracting glutamate-mediated excitotoxicity via the ERBB2/PI3K/AKT signaling pathway.}, } @article {pmid42320781, year = {2026}, author = {Bashaw, AG and Roman-Ortiz, C and Gao, SX and Schier, LA and Borner, T and Kanoski, SE}, title = {Glucagon-like peptide-1 signaling in learning and memory: evidence, mechanisms, and therapeutic implications.}, journal = {Biological psychiatry}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.biopsych.2026.06.006}, pmid = {42320781}, issn = {1873-2402}, abstract = {Glucagon-like peptide-1 (GLP-1) is primarily known for its role in glucose homeostasis and food intake control, and GLP-1 analogs (either as monotherapy or dual agonists) are commonly used for Type 2 Diabetes and obesity treatment in humans. Beyond these functions, the receptor for GLP-1 (GLP-1R) is widely expressed throughout the brain, including in the hippocampus and interconnected regions that contribute to learning and memory processes. Here we review emerging evidence supporting a role for GLP-1 signaling in promoting learning and memory function, particularly in dementia and other conditions that present hippocampal dysfunction. Evidence is synthesized from preclinical rodent models revealing that GLP-1 analog treatment improves deficits in memory function and hippocampal neuronal signaling processes in various models of dementia, aging, and metabolic disruption. While findings from human clinical trials and meta-analyses also show promise for GLP-1 analog-based treatment for memory disorders, results thus far are mixed, with many studies underpowered and/or lacking comprehensive memory evaluation. We describe several distinct yet non-mutually exclusive neurobiological mechanisms via which GLP-1R signaling can enhance memory, including blood-brain barrier penetration and direct action on hippocampal GLP-1Rs, improved peripheral and central insulin sensitivity, vagus nerve GLP-1R activation, and peripheral metabolic and inflammatory improvements. We conclude by emphasizing important considerations for future clinical trials for GLP-1 analogs in the treatment of Alzheimer's and other memory disorders, including focusing on metabolically vulnerable individuals, stratifying results by cardiovascular and metabolic status, and leveraging existing GLP-1 analogs and drug delivery approaches towards maximizing bioavailability and brain penetrance.}, } @article {pmid42321014, year = {2026}, author = {Kehmeier, MN and Famiano, A and Cullen, AE and Leonhardt, T and Ferguson, SJ and Snyder, M and McCurdy, CE and Tyrrell, DJ and Alkayed, NJ and Walker, AE}, title = {APOE4 negates the effects of ovarian hormones on cerebrovascular endothelial and mitochondrial function.}, journal = {The Journal of physiology}, volume = {}, number = {}, pages = {}, doi = {10.1113/JP290852}, pmid = {42321014}, issn = {1469-7793}, support = {//John L. Luvaas Family Fund/ ; 23PRE1023169//AHA/ ; //Endocrine Technologies Core/ ; R01AG064106//HHS, National Institutes of Health/ ; P51OD011092//HHS, National Institutes of Health/ ; S10OD026701//HHS, National Institutes of Health/ ; }, abstract = {The APOEε4 allele and oestrogen deficiency independently predispose females to an increased risk of vascular and metabolic impairments, but their cerebrovascular effects are less understood. The purpose of this study was to determine the interaction between APOE genotype and oestrogen on cerebrovascular endothelial and mitochondrial function. We studied young female homozygous APOEε3 and APOEε4 mice (n = 19-20/group; ∼6 months old) that were fed a high-fat diet and were ovariectomized (OVX), OVX and supplemented with 17β-oestradiol, or left intact. In APOEε3 mice, OVX was associated with impaired posterior cerebral artery endothelium-dependent dilatation, which was rescued by 17β-oestradiol. However, in APOEε4 mice, there was no effect of OVX or 17β-oestradiol on cerebral artery endothelial function. Carotid artery passive stiffness was greater with OVX and lower with 17β-oestradiol treatment in APOEε3 mice, but there was no impact of OVX or 17β-oestradiol in the APOEε4 mice. In cerebral arteries and arterioles, 17β-oestradiol led to higher mitochondrial complex I respiration in APOEε3 but not APOEε4 mice. These functional differences were concomitant with group differences in mitochondrial DNA copy number, antioxidant enzymes and pro-inflammatory factors. Overall these results indicate that the APOE genotype modulates the impact of OVX and oestradiol on the cerebral vasculature. We found that 17β-oestradiol enhances cerebrovascular endothelial and mitochondrial function in OVX APOEε3 mice but not in APOEε4 mice. This suggests that 17β-oestradiol supplementation may have more cerebrovascular benefits for APOEε4 non-carriers. KEY POINTS: Females have twice the risk of Alzheimer's disease than males, and the APOEε4 genetic variant has a greater risk for Alzheimer's disease than the APOEε3 variant. The risk for Alzheimer's disease increases after menopause in females, suggesting that the loss of female sex hormones may play a role. There are highly inconsistent results among past studies examining the interaction between APOE genotype and oestrogens on brain outcomes, and their impact on the vasculature has not been studied. We aimed to determine the impact of APOEε4 genotype on the cerebrovascular response to ovariectomy and oestradiol. We found that oestradiol improved cerebral artery endothelial function and mitochondrial respiration in ovariectomized APOEε3 mice following ovariectomy. In contrast APOEε4 mice were resistant to the beneficial effects of ovarian hormones on cerebrovascular and mitochondrial function. This research suggests that APOE genotype may be a consideration when weighing the risks and benefits of prescribing hormone replacement therapy to postmenopausal females.}, } @article {pmid42321855, year = {2026}, author = {Gheibi, FS and Hosseini, L and Kalejahi, P and Dastgiri, S and Shafiee-Kandjani, AR and Noorazar, SG}, title = {Therapeutic potential of AdipoRon in cognitive, depressive, and anxiety disorders: a systematic review and meta-analysis.}, journal = {Molecular brain}, volume = {19}, number = {1}, pages = {}, pmid = {42321855}, issn = {1756-6606}, mesh = {Animals ; *Piperidines/therapeutic use/pharmacology ; *Anxiety Disorders/drug therapy ; Humans ; *Cognition/drug effects ; *Cognition Disorders/drug therapy ; *Depression/drug therapy ; *Depressive Disorder/drug therapy ; }, abstract = {Rising cases of cognitive disorders, depression, and anxiety underscore the need for new treatments, given the limited effectiveness and side effects of current options. AdipoRon targets adiponectin receptors and shows promise for protecting the brain, reducing inflammation, and supporting metabolism. This review examines preclinical data to determine whether AdipoRon consistently improves mood and cognitive function and to identify the underlying neurobiological pathways. We conducted a comprehensive literature search using PubMed, Embase, Web of Science, and Scopus, with no time limit, up to August 30, 2025. The quality of the selected studies was evaluated using the Collaborative Approach to Meta-Analysis and Review of Animal Studies (CAMARADES) checklists and the SYRCLE risk of bias tool. The studies found that AdipoRon treatment significantly reduced immobility in the forced swim test and had a significant anxiolytic effect in the open field test, especially in chronic unpredictable mild stress models. It also improved recognition memory in the novel object recognition test in models of Alzheimer's and Parkinson's diseases. Additionally, AdipoRon increased the expression of synaptic proteins, such as synaptophysin and PSD-95, in rodent models of these diseases. It also modulated the production of inflammatory cytokines. This review establishes AdipoRon's capacity to resolve depressive, anxious, and cognitive deficits in rodent models. Because the meta-analyses were based on a limited number of studies and substantial heterogeneity was observed across studies, the findings should be interpreted with caution. However, further well-designed preclinical and clinical investigations are essential to confirm these findings.}, } @article {pmid42322185, year = {2026}, author = {Lozupone, M and Dibello, V and Sardone, R and Zupo, R and Castellana, F and Bortone, I and Lampignano, L and Di Matteo, M and Moramarco, G and Dellegrazie, F and Daniele, A and Solfrizzi, V and Panza, F}, title = {Evaluating emerging amyloid-β centric drugs for the treatment of Alzheimer's disease.}, journal = {Expert opinion on emerging drugs}, volume = {}, number = {}, pages = {}, doi = {10.1080/14728214.2026.2693701}, pmid = {42322185}, issn = {1744-7623}, abstract = {INTRODUCTION: The amyloid cascade hypothesis provided a compelling rationale for Alzheimer's disease (AD) drug development, but many amyloid-β (Aβ)-targeted agents failed to show benefit. The present review article evaluated emerging Aβ-directed therapies, focusing on mechanisms, clinical efficacy, safety, and regulatory progress.

AREAS COVERED: The recent approvals of lecanemab and donanemab offered the first convincing evidence that reducing Aβ burden can modestly slow cognitive decline in early AD. Beyond these first-generation monoclonal antibodies, the pipeline includes next-generation antibodies with enhanced brain penetration (trontinemab), therapies designed also for presymptomatic intervention (remternetug tested for secondary prevention), and novel approaches targeting galectin-3 to disrupt Aβ aggregation and neuroinflammation. Active immunotherapies like UB-311 and small molecules such as ALZ-801, avoiding amyloid-related imaging abnormalities (ARIA), broaden the therapeutic horizon with potentially safer and more accessible options, but with no proven efficacy.

EXPERT OPINION: Clinical benefits for Aβ-centric therapies are modest, ARIA pose ongoing safety concerns, and high costs coupled with intensive monitoring limit accessibility. Regulators have begun to restrict approval to genetically defined subgroups according to apolipoprotein E genotype, underscoring the need for precision medicine. Therefore, while Aβ-centric therapies are incremental, they represent essential steps toward combination and precision strategies in the treatment of AD.}, } @article {pmid42322653, year = {2026}, author = {Cui, S and Jiang, Q and Chen, S}, title = {Locus coeruleus-norepinephrine system dysfunction: A new concept in cognitive aging and neurodegenerative diseases.}, journal = {Neural regeneration research}, volume = {}, number = {}, pages = {}, doi = {10.4103/NRR.NRR-D-25-00910}, pmid = {42322653}, issn = {1673-5374}, abstract = {The role of the locus coeruleus in aging and neurodegenerative diseases has recently attracted attention. There is growing evidence of changes in the locus coeruleus-norepinephrine system in aging and neurodegenerative diseases, including increased tau accumulation, an inverted U-shaped pattern in the neuromelanin signal, and altered functional connectivity. This review summarizes the research applications and advancements in the study of cognitive aging and dysfunction of the locus coeruleus-norepinephrine system in neurodegenerative diseases. Recent evidence has suggested pathologic protein accumulation, locus coeruleus degeneration, reduced neuromelanin signal, and altered functional connectivity in neurodegenerative diseases in both human and animal models. Notably, the specific regions affected and the severity of these changes can vary subtly among different neurodegenerative disorders. Additionally, recent studies have shown a link between alterations in the locus coeruleus-norepinephrine system and both Alzheimer's and Parkinson's diseases. The possible mechanisms include promoting pathological protein accumulation, pro-inflammatory responses, synaptic plasticity dysfunction, oxidative stress, and blood- brain barrier dysfunction. Advanced experimental technologies have recently been applied to investigate the role of the locus coeruleus-norepinephrine system in aging, Alzheimer's disease, and Parkinson's disease. These advanced technologies, including optogenetic or chemogenetic methods and omics analysis help uncover the effects of specific locus coeruleus activation patterns and the locus coeruleus-related circuit mechanisms underlying its vulnerability during aging and neurodegenerative diseases. Thus, therapies targeting the locus coeruleus-norepinephrine system, including drugs and vagus nerve stimulation, have the potential for clinical application. Many studies have demonstrated the effects of adrenoreceptor-targeted drugs on cognitive function and Parkinson's disease, although some showed no effects. Limited data are available for norepinephrine-targeted drugs, which have demonstrated less-than-ideal results. Recent studies have demonstrated that vagus nerve stimulation can improve cognitive function in Alzheimer's disease and reduce the symptoms of Parkinson's disease, including gait function, suggesting that vagus nerve stimulation could be a new supplementary treatment for neurodegenerative diseases. Overall, the evidence reviewed suggests that the locus coeruleus-norepinephrine system is disrupted during aging and neurodegenerative diseases, and that this disruption can aggravate disease progression. Thus, the locus coeruleus-norepinephrine system is a potential therapeutic target in slowing disease progression. Future studies should focus on the locus coeruleus-norepinephrine system and use advanced experimental and neuroimaging technologies to reveal early pathological alterations and the underlying mechanisms of its vulnerability during aging and neurodegenerative diseases, along with exploring potential therapeutic approaches.}, } @article {pmid42322910, year = {2026}, author = {Liu, R and Wei, M and Xu, L and Qu, Z and Yu, JQ and Liu, Y and Zhang, WN and Zhang, D and Zhuang, C}, title = {A Keap1-Nrf2 protein-protein interaction inhibitor 4-95 ameliorates cognitive dysfunction by suppressing neuronal ferroptosis.}, journal = {Bioorganic chemistry}, volume = {180}, number = {}, pages = {110134}, doi = {10.1016/j.bioorg.2026.110134}, pmid = {42322910}, issn = {1090-2120}, abstract = {Alzheimer's disease (AD) is a severe neurodegenerative disorder. With current therapies failing to halt clinical progression, identifying novel disease-modifying therapeutics is of paramount urgency. Although ferroptosis has emerged as a crucial driver of AD pathogenesis, effective pharmacological strategies targeting this pathway remain limited. Bioinformatic analysis revealed close associations among ferroptosis, oxidative stress, the Keap1-Nrf2 pathway, and AD. Compound 4-95, a selective Keap1-Nrf2 protein-protein interaction (PPI) inhibitor, significantly alleviated Erastin and RSL-3-induced ferroptosis in SH-SY5Y and HT-22 cells. In Aβ1-42-treated cell models, 4-95 dose-dependently decreased Aβ and p-Tau expression, while increasing the anti-ferroptotic proteins GPX4 and SLC7A11. Keap1 and GPX4 knockdown verified that 4-95 inhibits ferroptosis via the Keap1-Nrf2-GPX4 axis. In vivo, 4-95 markedly improved cognitive and spatial memory deficits in Aβ1-42-induced AD mice, promoted Nrf2 nuclear translocation, upregulated the downstream antioxidant targets HO-1 and NQO1, and attenuated neuronal injury. Collectively, the study reveals a new mechanism of a Keap1-Nrf2 PPI inhibitor that mitigates AD pathogenesis by directly inhibiting ferroptosis. This novel mechanism underscores a new class of disease-modifying candidates for AD treatment, representing a new therapeutic strategy for this devastating disorder.}, } @article {pmid42323643, year = {2026}, author = {Bouveret, Z and Pruvost, L and Trédan, O and Le Romancer, M and Poulard, C}, title = {How post-translational modifications impact glucocorticoid receptor function in human pathologies.}, journal = {Cell communication and signaling : CCS}, volume = {}, number = {}, pages = {}, doi = {10.1186/s12964-026-03015-7}, pmid = {42323643}, issn = {1478-811X}, support = {ANR-22-CE13-0001-01//Agence Nationale de la Recherche/ ; }, abstract = {Glucocorticoid receptor (GR) is a member of the nuclear hormone receptor family, which acts as a transcription factor when bound by glucocorticoid (GC) ligands. GR is expressed in nearly all tissue types and regulates essential processes such as inflammation, immune regulation and metabolism. Given its ubiquitous role, GR has frequently been associated with a wide range of illnesses, particularly in the fields of allergy, pulmonary, dermatology, rheumatology, or ophthalmology. It was reported that GCs either contribute to their development or serve as part of their treatment, making them the most prescribed drugs worldwide. GR activity and signaling is finely regulated by a network of post-translational modifications (PTMs). Indeed, PTMs can alter GR behavior and function by modifying its localization, stability, interaction with other proteins and transcriptional activity. Aside from the well-characterized phosphorylation events, additional PTMs are implicated in GR activity and their dysregulation has been described in various diseases. This review provides an integrated overview of current knowledge on GR PTMs, highlighting both mechanistic insights and their relevance in disease. We will present how aberrant PTMs contribute to extremely prevalent diseases, such as cancer, chronic inflammatory diseases, Alzheimer's disease and other neurological diseases. Special attention will be given to the specific readers of these PTMs and to the enzymes catalyzing these modifications, as they represent promising therapeutic targets.}, } @article {pmid42323655, year = {2026}, author = {Monteverdi, A and Cotta Ramusino, M and Conca, F and Augello, A and Totaro, C and Grasso, PA and Castelnovo, A and Lorenzi, RM and Terzaghi, M and Farina, LM and Costa, A and Pichiecchio, A and Cappa, SF and Gandini Wheeler-Kingshott, C and Palesi, F and D'Angelo, E}, title = {Virtual brain and electroencephalography explain the variance of memory alterations in mild cognitive impairment.}, journal = {Alzheimer's research & therapy}, volume = {}, number = {}, pages = {}, doi = {10.1186/s13195-026-02114-4}, pmid = {42323655}, issn = {1758-9193}, abstract = {BACKGROUND: Mild Cognitive Impairment (MCI) is a heterogeneous clinical condition characterized by a wide spectrum of cognitive and behavioural manifestations. Despite numerous studies, the link between neuropsychological performance and pathophysiological signatures of the disease-including Aβ and tau accumulation along with altered excitation/inhibition (E/I) balance and brain rhythms-remains elusive.

METHODS: Here Aβ/tau biomarkers were used to distinguish positive (MCI[+]- prodromal Alzheimer's disease) and negative (MCI[-]) subjects in a cohort of 30 MCI patients (18 MCI[+] and 12 MCI[-]). Virtual brain models based on high-field magnetic resonance imaging data were then developed to determine the inter-node coupling and E/I profile in resting-state networks, while node spectral information was obtained from source analysis of high-density electroencephalography (HD-EEG). Finally, virtual brains and HD-EEG parameters, creating brain digital twins of individual subjects, were correlated with cognitive performance.

RESULTS: While virtual brain simulations did not reveal E/I differences between MCI[+] and MCI[-], a positive correlation emerged between synaptic parameters of the limbic network and verbal episodic memory for both groups. EEG power spectral density revealed a lower high-frequency/low-frequency ratio in MCI[+] largely due to a reduced alpha band in the default mode, limbic, attention, frontoparietal, visual and somatomotor networks. A strong correlation emerged between multimodal parameters and memory functions, supporting that brain digital twin simulations can effectively explain the variability of neuropsychological performance in MCI patients beyond the sensitivity of individual techniques alone. In particular, the combination of HD-EEG and virtual brain parameters explained more than 90% of variance for episodic memory patients' scores, confirming the compound origin of memory performance involving network specific E/I levels and electroencephalographic activity acting in concert.

CONCLUSIONS: This multimodal and multiparametric analysis combining virtual brain modelling with HD-EEG and molecular data enhances the stratification of MCI patients and could be used to develop digital biomarkers of progression to dementia, opening new perspectives for personalized prognosis and treatment.}, } @article {pmid42324743, year = {2026}, author = {Sakagami, S and Yoshida, Y and Uemura, S and Kumamoto, T and Tsukamoto, R and Nishi, T and Kawano, S and Fukuoka, K and Ino, H and Hamamura, K and Ohdo, S and Matsunaga, N}, title = {Benzbromarone as a Novel Candidate for Preventing Alzheimer's Disease: Evidence From Real-World Data Screening and in Vitro Validation.}, journal = {Clinical and translational science}, volume = {19}, number = {7}, pages = {e70650}, pmid = {42324743}, issn = {1752-8062}, mesh = {Humans ; *Benzbromarone/therapeutic use/pharmacology ; *Alzheimer Disease/prevention & control/epidemiology ; *Drug Repositioning ; Female ; Male ; Japan/epidemiology ; *Uricosuric Agents/pharmacology/therapeutic use ; Aged ; Amyloid beta-Peptides/metabolism ; Aged, 80 and over ; Incidence ; Cell Line, Tumor ; }, abstract = {Drug development for Alzheimer's disease (AD) remains challenging, with only a 0.4% success rate from Phase I trials to regulatory approval. Drug repositioning leverages existing approved drugs to identify promising drug alternatives, particularly when combined with real-world data (RWD) and target trial emulation. In this study, we comprehensively screened 1,241 approved drugs using a large-scale Japanese claims database (n = 2,090,465; 2005-2023). We identified patients newly prescribed a study drug and applied an active-comparator, new-user design. We used propensity score-based inverse probability of treatment weighting (IPTW) to balance the covariates. The primary outcome was incident AD, defined using ICD-10 codes (F00 and G30). We estimated cumulative incidence using IPTW-adjusted Kaplan-Meier analysis and Cox proportional hazards models and conducted sensitivity analyses using Fine-Gray competing risk models, empirical calibration with negative control outcomes, and E-value estimation. We performed in vitro validation using Aβ-Tet-ON SH-SY5Y cells and quantified Aβ expression using western blotting. Benzbromarone, a uricosuric agent, was associated with a decreased risk of AD onset (adjusted HR: 0.54, 95% CI: 0.41-0.71, p < 0.05 post-FDR correction); this association remained robust across sensitivity analyses. In vitro, benzbromarone reduced Aβ protein expression in SH-SY5Y cells in a dose-dependent manner, even following transcriptional blockade, suggesting a posttranscriptional regulatory mechanism. In conclusion, using a combined approach of RWD-based pharmacoepidemiology and in vitro validation, we identified benzbromarone as a novel candidate potentially associated with reduced AD risk. Our findings highlight the potential of drug repositioning strategies to accelerate AD drug discovery, promoting further mechanistic and clinical investigations.}, } @article {pmid42324842, year = {2026}, author = {Ugale, V and Sharon, N and Salunkhe, C and Salunkhe, J and Lokwani, D and Patil, K and Reddy, PN and Kulkarni, P}, title = {Naphthalene-4H-Chromene Molecular Hybrids as Dual Cholinesterase Inhibitors for the Treatment of Alzheimer's Disease.}, journal = {Drug development research}, volume = {87}, number = {5}, pages = {e70338}, doi = {10.1002/ddr.70338}, pmid = {42324842}, issn = {1098-2299}, support = {RGSTC/File-2024/DPP-309/CR-20/332//Rajiv Gandhi Science and Technology Commission/ ; TAR/2021/000140//Department of Science and Technology (DST)-Science and Engineering Research Board (SERB)/ ; CRG/2022/004365//Department of Science and Technology (DST)-Science and Engineering Research Board (SERB)/ ; KBCNMU/RGSTC/Sanction Order/199//Kavayitri Bahinabai Chaudhari North Maharashtra University (KBCNMU)/ ; }, mesh = {*Cholinesterase Inhibitors/pharmacology/chemistry/therapeutic use/chemical synthesis ; Animals ; *Alzheimer Disease/drug therapy ; Mice ; *Naphthalenes/chemistry/pharmacology ; *Benzopyrans/chemistry/pharmacology ; Acetylcholinesterase/metabolism ; Butyrylcholinesterase/metabolism ; Molecular Docking Simulation ; Male ; Humans ; Scopolamine ; Cell Line ; Structure-Activity Relationship ; }, abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by cognitive decline associated with cholinergic dysfunction. Herein, we have designed and synthesized series of 4-(naphthalen-1-yl)-4H-chromene derivatives 4(a-n) by a one-pot three-component reaction with adequate synthetic yield and purity. Naphthalene-chromene hybrids were synthesized by formation of two C─C bonds and one C─O bond in a single synthetic step. All synthesized compounds were tested for safety and efficacy using in vitro and in vivo studies. Compounds were found devoid of cytotoxicity in BV-2 cells. Most of the synthesized compounds have shown moderate to good inhibitory activity against cholinesterase enzymes. These compounds were found to be more selective towards acetylcholinesterase (AChE) compared to butyrylcholinesterase (BuChE). Compound 4 m has shown highest inhibitory potency against AChE (AChE, IC50 = 1.08 µM; BuChE, IC50 = 82.59 µM). The prototype compound (4 m) from in-vitro screening was found to be safe in acute oral toxicity followed by histopathological analysis. Compound 4 m was evaluated for in vivo efficacy in scopolamine-induced cognitive impairment model in mice. It significantly reversed the cognitive deficit in neurobehavioral tests. Pre-treatment with 4 m have balanced key biochemical markers involved in the oxidative stress and cognitive functions. The compound 4 m alleviated neuronal tissue damage caused by scopolamine as indicated in the histological study. Molecular docking analysis also reconfirmed the binding affinity of 4 m at cholinesterase enzymes. Taken together, these findings supported the emergence of 4 m as a potential cholinesterase inhibitor for the treatment of AD.}, } @article {pmid42325226, year = {2026}, author = {Alhowail, AH and Al Mouslem, AK and Almatrafi, MA and Aldubayan, MA}, title = {Semaglutide in cognitive dysfunction: neuroprotective potential, clinical trial limitations, and a prevention-focused framework.}, journal = {Frontiers in aging neuroscience}, volume = {18}, number = {}, pages = {1851072}, pmid = {42325226}, issn = {1663-4365}, abstract = {Metabolic dysfunction is increasingly recognized as a pivotal factor in cognitive decline and neurodegenerative diseases, such as Alzheimer's disease (AD). Glucagon-like peptide-1 receptor agonists (GLP-1RAs), notably the long-acting agonist semaglutide, exhibit significant metabolic efficacy and pronounced neuroprotective effects across a broad spectrum of preclinical models. This is corroborated by extensive epidemiological studies that consistently link GLP-1RA use with a decreased incidence of dementia. Nevertheless, promising preclinical and observational findings have not been mirrored in clinical success for the treatment of established AD. Recent negative outcomes from the pivotal phase 3 EVOKE and EVOKE+ trials, which demonstrated no clinical benefit of oral semaglutide in patients with early AD, have resulted in a notable translational paradox. This review critically examines the mechanistic, preclinical, epidemiological, and clinical evidence concerning the impact of semaglutide on cognitive function to reconcile these conflicting findings. Preclinical studies have revealed complex neuroprotective mechanisms, including suppression of neuroinflammation, restoration of metabolic function, and activation of pro-survival pathways. Conversely, clinical trials in symptomatic AD have been unsuccessful, although modest and clinically insignificant changes in cerebrospinal fluid biomarker levels have been observed. We propose the hypothesis that the current body of evidence is consistent with a prevention-focused model, wherein semaglutide's primary value may lie in modifying the upstream metabolic and inflammatory drivers of neurodegeneration, such as those prevalent in vascular and metabolic cognitive impairment, rather than reversing established amyloid-driven AD pathology. This hypothesis, however, remains speculative and requires prospective validation in appropriately designed trials. This review seeks to resolve the apparent contradictions in the literature and propose future research directions centered on appropriate patient populations and therapeutic windows.}, } @article {pmid42325271, year = {2026}, author = {Liang, C and Jiang, W and Chen, J and Turner, JA and Calhoun, VD and Abbott, CC and Jiang, R and Fu, Z and Wu, L and Wang, X and Qi, S and Yuan, Y}, title = {Longitudinally altered default mode network and insula multimodal brain pattern in end-stage renal disease during sustained hemodialysis treatment.}, journal = {iScience}, volume = {29}, number = {6}, pages = {116008}, pmid = {42325271}, issn = {2589-0042}, abstract = {Hemodialysis (HD) is the predominant treatment for end-stage renal disease (ESRD). Despite the efficacy of HD, the neurobiological underpinnings underlying high-risk complications remain unclear. In this study, using unsupervised fusion of functional and structural MRI, we identified a longitudinally altered default mode network (DMN)-insula pattern in ESRD receiving HD over 1-year follow-up (n = 39). This pattern was associated with cognition, and its related genes were enriched in biological processes involving DNA damage and repair, energy metabolism, and cellular activation. The baseline DMN-insula pattern demonstrated potential predictive value for follow-up cognition in ESRD. More importantly, these brain-cognition associations were validated in independent high-risk complications cohorts, including major depressive disorder (n = 60), mild cognitive impairment (n = 291), and Alzheimer's disease (n = 77) by extracting the corresponding brain features and assessing their correlations with cognition. Collectively, this study may help researchers better understand the underlying mechanisms of ESRD receiving HD from a multimodal neuroimaging and molecular perspective.}, } @article {pmid42325273, year = {2026}, author = {Hao, W and Yu, X and Zhou, Q and Jia, Y and Su, X and Yu, Y and Wang, Y and Wang, J and Liu, C}, title = {Different modulation patterns of theta and gamma dual-site HD-tACS on cognitive impairment.}, journal = {iScience}, volume = {29}, number = {6}, pages = {116138}, pmid = {42325273}, issn = {2589-0042}, abstract = {Alzheimer's disease (AD) is characterized by impaired local network integration and long-range connections. Theta and gamma oscillations are critical for cognitive function, so this study used dual-site fronto-temporoparietal junction (TPJ) high-density transcranial alternating current stimulation (HD-tACS) to explore its frequency-specific effects on brain networks and cognition. Thirty-six AD patients were randomized 1:1:1 to 6Hz-tACS, 40Hz-tACS and sham stimulation targeting bilateral fronto-TPJ cortex for four weeks. Cognitive functions were assessed at baseline, post-treatment and 8-week follow-up. TMS-EEG and voxel-based distance-related functional connectivity analysis evaluated network changes. Both active stimulation groups showed sustained cognitive improvements for eight weeks compared to the sham stimulation group (all p < 0.017). 40Hz-tACS also enhanced language function (p < 0.025). 6Hz-tACS increased anterior functional connections and anterior-to-posterior information flow, while 40Hz-tACS increased posterior connections and posterior-to-anterior flow, closely linked to cognitive improvements. These effects are oscillation frequency-dependent, supporting cognitive improvement in AD.}, } @article {pmid42325435, year = {2026}, author = {Liu, C and Zhu, Z and Lin, H and Bush, WS and Jenq, RR and Cominelli, F and Pillai, JA and Haines, JL and Zhu, X and Xu, R and Williams, SM and Cheng, F and Zhang, L}, title = {The gut-brain axis in Alzheimer's disease: early detection, microbial metabolites, mechanisms, and therapeutic opportunities.}, journal = {Frontiers in molecular biosciences}, volume = {13}, number = {}, pages = {1735332}, pmid = {42325435}, issn = {2296-889X}, abstract = {Alzheimer's disease (AD), the leading cause of dementia worldwide, imposes a growing clinical and societal burden, yet no therapies have been proven to alter its progression despite decades of intensive research. As traditional targets have yielded limited success, attention has shifted to modifiable upstream pathways, notably the gut-brain axis, a bidirectional system linking gut microbiota with CNS function. Emerging evidence indicates that microbial dysbiosis may influence key processes leading to AD, including neuroinflammation, amyloid and tau pathology, and cognitive decline. While microbiome composition is associated with AD, it remains unclear at which stage-preclinical, mild cognitive impairment (MCI), or AD dementia-these differences first arise, or how specific risk bacteria and metabolites contribute to progression. The precise roles of these microbes and metabolites in AD pathology or brain resilience also remain poorly understood, and few microbiome-targeted treatments have been validated in humans. Existing reviews often overlook host-specific factors that influence microbiome composition and confound associations with AD. To bridge these gaps, we summarize human studies published in the past 5 years. The literature suggests that gut microbial changes may precede clinical symptoms, with consistent dysbiosis observed in AD patients. We adopt a microbiome-centered perspective emphasizing bacteria-driven and metabolite-driven mechanisms, each playing distinct yet complementary roles in neural and bloodstream pathways. These pathways offer potential targets for microbiome-based prevention and treatment but require more human validation. Future studies should leverage longitudinal, multi-omics approaches and artificial intelligence (AI) tools while rigorously accounting for confounders to improve early detection and develop personalized therapies for AD.}, } @article {pmid42325550, year = {2026}, author = {Li, X and Chen, H and Xu, P and Guo, X and Gao, J and Yao, D and Wang, Y and Wang, T and Liu, B and Yuan, J}, title = {Exosomes: A new frontier in the treatment of neurological diseases.}, journal = {iScience}, volume = {29}, number = {7}, pages = {116331}, pmid = {42325550}, issn = {2589-0042}, abstract = {Exosomes (Exos) are an essential class of extracellular vesicles enriched with a wide range of biologically active molecules, which gives them a unique advantage in participating in intercellular signaling and communication and serving as carriers for drug delivery. Exo-based diagnostic and therapeutic strategies are currently hot topics in disease research. Owing to their naturally low immunogenicity, good biocompatibility, ability to penetrate the blood‒brain barrier (BBB), and engineered modifications, exos have significant advantages and possible applications in the treatment of nervous system diseases. Due to the serious harm of neurological diseases to human health, they have been widely studied by researchers. Exos can be administered in a variety of ways, including intranasal administration, intracranial administration, local stereotactic injection, and encapsulation in biomaterials, each of which has its own advantages and disadvantages. However, several requirements need to be met before exo-based therapies can be implemented, such as the standardization of isolation and purification techniques, an in-depth understanding of the mechanism of action, and safety assessments and regulation for clinical translation. The aim of this review is to provide a comprehensive overview of the biogenesis, molecular composition, function, and delivery modes of exos and their therapeutic roles and mechanisms in neurological diseases (e.g., multiple sclerosis (MS), Alzheimer's disease (AD), Parkinson's disease (PD), and stroke) and to discuss the current challenges and future perspectives to support ongoing research and clinical applications.}, } @article {pmid42327033, year = {2026}, author = {Mostowfi, N and Foreman, R and Wang, J and Khoury, R and Albanese, A and Ma, QL and Cohn, W and Petzinger, G and Jakowec, M and Ahmed, SK and Seidler, PM}, title = {Tau Disaggregation by a CNS-Permeable Small Molecule Reduces Fibril and Oligomer Burden and Preserves Proteostasis and Behavior.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, doi = {10.64898/2026.06.09.731185}, pmid = {42327033}, issn = {2692-8205}, abstract = {Pathological tau aggregates drive neuronal dysfunction in Alzheimer's disease (AD) and related tauopathies, yet no approved therapy eliminates existing tau neurofibrillary tangles. Here, we report the development of a coumarin-based small-molecule series that disaggregates tau fibrils and oligomers through a stacking-driven co-assembly mechanism. Structure-activity relationships identified PT-13 as a lead compound that inhibits tau seeding by AD brain-derived matter and reduces aggregate burden measured across both fibrillar and oligomeric tau species. Mechanistic studies demonstrate that disaggregation does not generate soluble oligomeric intermediates, addressing a central question in the field. PT-13 is brain-penetrant and well tolerated in vivo. In a tauopathy mouse model, PT-13 treatment reduces tau pathology while preserving behavioral function, proteasome capacity, and synaptic integrity. These findings establish small-molecule tau disaggregation as a viable therapeutic strategy and provide a molecular framework for the design of aggregate-directed therapeutics in neurodegeneration.}, } @article {pmid42327192, year = {2026}, author = {Fulghum, K and Hayir, A and Ankeriasniemi, R and Shaddy-Gouvion, C and Vang, CM and Salathe, SF and Queathem, ED and Hughey, CC and Haeri, M and Thyfault, JP and Puchalska, P and Crawford, PA}, title = {Diet-Dependent Cognitive Benefits of Exogenous Ketone Body Precursor, (R,S)-1,3,-Butanediol, in a Mouse Model of Tauopathy.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, doi = {10.64898/2026.06.03.729999}, pmid = {42327192}, issn = {2692-8205}, abstract = {Alzheimer's disease and related tauopathies are escalating public health threats, particularly in the context of obesity and metabolic dysfunction, which accelerate cerebral glucose hypometabolism, tau pathology, neurodegeneration, and cognitive decline. Ketogenic therapies reconfigure systemic fuel metabolism, with emerging evidence for neuroprotection. (R,S)-1,3-butanediol (BD) raises circulating D- and L-β-hydroxybutyrate (βOHB) concentrations. To evaluate whether BD improves cognitive function across dietary contexts, male and female tau-transgenic mice and littermate controls received 10% BD in drinking water for 20 or 30 weeks starting at 6 weeks of age. BD rapidly induced ketosis (1.5-3.0 mM βOHB) in chow-fed mice, with L-βOHB contributing to ∼75% of the circulating βOHB pool. Despite minimal effects of BD on body weight and glucose homeostasis, and no effect on histopathological tau signal, 20-week BD treatment improved memory to control levels in chow-fed female tauopathy mice. Isotope-tracing untargeted metabolomics revealed that BD-treatment differentially affected glucose-derived [13] C-enrichment of metabolites in brains of male and female mice. BD-induced cognitive benefits in tau-transgenic mice were abrogated when mice were maintained on BD for 30 weeks on standard chow or when mice were administered BD over 20 weeks while maintained on a high-fat, Western diet, Notably, BD-induced ketosis was blunted in mice consuming Western diet. Moreover, intermittent ketogenic diet-induced ketosis failed to improve cognition in Western diet-fed tauopathy mice. These results suggest BD-induced ketosis extends cognitive benefits in a manner dependent on biological sex and nutritional metabolic status. Taken together, these data contextualize the roles of βOHB as modulators of cognitive resilience in tauopathy.}, } @article {pmid42328129, year = {2026}, author = {Yang, Z and Chen, Y and Li, S and Lei, X and Wu, X and Wang, Y and Deng, S}, title = {Overcoming Biological Barriers: A Comprehensive Review of Advanced Melatonin Delivery Systems for Therapeutic Applications.}, journal = {International journal of medical sciences}, volume = {23}, number = {7}, pages = {2462-2485}, pmid = {42328129}, issn = {1449-1907}, mesh = {*Melatonin/administration & dosage/pharmacokinetics/chemistry/therapeutic use ; Humans ; *Drug Delivery Systems/methods ; Animals ; Neurodegenerative Diseases/drug therapy ; Blood-Brain Barrier/drug effects/metabolism ; Drug Carriers/chemistry ; Neoplasms/drug therapy ; Antioxidants/administration & dosage/pharmacokinetics ; Nanoparticles/chemistry ; }, abstract = {Melatonin is a pleiotropic hormone with well-documented antioxidant, anti-inflammatory, neuroprotective, and immunomodulatory properties, making it a promising candidate for the treatment of diverse diseases including neurodegenerative disorders, cardiovascular diseases, cancer, and sleep disturbances. However, its clinical translation has been hampered by several biopharmaceutical limitations, including poor aqueous solubility, extensive hepatic first-pass metabolism, rapid systemic clearance, and low oral bioavailability. Additionally, physiological barriers such as the blood-brain barrier, stratum corneum, and mucosal epithelia restrict its accumulation at target sites. In recent years, nanotechnology-based drug delivery systems have emerged as powerful tools to overcome these challenges. This review provides a comprehensive overview of advanced melatonin nanocarriers with a focus on their design principles, formulation strategies, and therapeutic applications. A central theme of this review is the integration of carrier design with biological barrier circumvention and administration routes-elucidating how specific nanocarrier platforms address the shortcomings of conventional immediate- and prolonged-release melatonin formulations through spatial and temporal control over drug distribution. We summarize recent preclinical progress in melatonin nanocarriers for a wide range of disease models, including Alzheimer's disease, Parkinson's disease, myocardial infarction, retinal degeneration and glaucoma, depression, and various cancers, with emphasis on the relationship between administration routes and therapeutic outcomes. Finally, critical challenges in clinical translation are addressed, including large-scale manufacturing, long-term toxicity evaluation, regulatory considerations, and the development of chronotherapy-compatible delivery systems. By integrating insights from materials science, pharmaceutics, and nanomedicine, this review aims to provide a rational framework for the future design and clinical application of melatonin-based nanotherapeutics.}, } @article {pmid42328310, year = {2026}, author = {Hosseinpoor-Dashatani, S and Ebrahimi, N}, title = {Global trends in Alzheimer's disease randomized controlled trials: a bibliometric analysis.}, journal = {Dementia & neuropsychologia}, volume = {20}, number = {}, pages = {e20250423}, pmid = {42328310}, issn = {1980-5764}, abstract = {UNLABELLED: Alzheimer's disease (AD) is the most common form of dementia worldwide, creating substantial clinical and socioeconomic burdens. Randomized controlled trials (RCTs) provide the highest level of evidence to evaluate interventions, yet global publication trends and thematic evolution have not been systematically analyzed.

OBJECTIVE: As far as we are aware, there has been no bibliometric analysis that has thoroughly assessed RCTs in AD, despite their pivotal influence on the development of treatment and prevention strategies. Therefore, in this study, we conducted a bibliometric mapping analysis of global RCTs on AD.

METHODS: A bibliometric analysis of human RCTs on AD from September 2010 to September 2025 was conducted using PubMed and Web of Science. VOSviewer was employed for keyword co-occurrence, co-authorship mapping, and co-citation analyses to identify research themes, collaborations, and temporal trends.

RESULTS: A total of 4,482 RCTs were identified, revealing five main themes: pharmacological interventions, lifestyle and prevention strategies, pathophysiological mechanisms, cognitive and behavioral interventions, and clinical trial methodology. After 2015, focus shifted from traditional pharmacology to multidomain, prevention-oriented, and precision-driven approaches. Emerging topics included digital health, gut microbiome, and machine learning. Collaboration networks highlighted the dominance of the US and Europe, with rapid growth in Asia and emerging regions.

CONCLUSION: Findings indicate a paradigm shift in AD RCTs toward integrative, technology-enabled designs, emphasizing both pharmacological and non-pharmacological strategies. These trends can guide future global research priorities and intervention development.}, } @article {pmid42328628, year = {2026}, author = {Castro E Silva, JH and Marangon, D and Boccazzi, M and Raffaele, S and Cignitti, N and Bavetta, M and Arisi, I and Fumagalli, M and Abbracchio, MP and Lecca, D}, title = {The GPR17 agonist galinex restores oligodendrocyte maturation under inflammatory conditions.}, journal = {Frontiers in pharmacology}, volume = {17}, number = {}, pages = {1838997}, pmid = {42328628}, issn = {1663-9812}, abstract = {INTRODUCTION: Chronic neuroinflammation disrupts oligodendrocyte differentiation and limits effective remyelination across multiple neurological disorders. Among the molecular regulators integrating inflammatory cues with oligodendrocyte maturation, G protein-coupled receptor 17 (GPR17) has emerged as a critical checkpoint. Physiologically, GPR17 expression is low in early oligodendrocyte precursor cells (OPCs), peaks in immature oligodendrocytes, and is subsequently downregulated to allow terminal maturation. Under neuroinflammatory conditions, GPR17 expression persists, suggesting a possible role in impaired oligodendrocyte maturation and defective myelination. Here, we tested whether receptor modulation by the selective GPR17 agonist Galinex (GAL) can support oligodendrocyte maturation under inflammatory conditions.

METHODS: Differentiating oligodendroglial cultures were exposed to a pro-inflammatory cytokine cocktail composed of TNFα, IL-1β, and IFNγ. We first identified a subtoxic inflammatory condition, defined as cytokine exposure that did not cause overt loss of cell viability, and assessed oligodendrocyte maturation, myelin-associated marker expression, GPR17 expression, and transcriptional remodelling. Publicly available transcriptomic signatures from neuroinflammatory mouse models and human Alzheimer's disease and multiple sclerosis brains were used for cross-comparison. The effect of GAL was then evaluated by molecular, morphological, and functional readouts, including a synthetic nanofiber myelination assay.

RESULTS: Subtoxic cytokine exposure consistently impaired oligodendrocyte morphological maturation, reduced the expression of myelin-associated markers, and was accompanied by increased GPR17 expression. Transcriptomic analysis revealed coordinated remodelling of pathways related to protein synthesis and proteostasis, mitochondrial metabolism, lipid homeostasis, and inflammatory/immunogenic-like responses, together with senescence- and DNA damage-associated features. Cross-comparison with disease-associated transcriptomic signatures showed significant overlap with neuroinflammatory modules, supporting the relevance of the inflammatory pathways engaged in our model. GAL treatment partially restored terminal maturation-associated features and oligodendrocyte morphology. Moreover, in the nanofiber assay, GAL significantly increased the length of MBP-positive segments compared with CTK-treated cells, suggesting improved wrapping/myelination-like capacity after inflammatory challenge.

DISCUSSION: Together, this study establishes a controlled in vitro model linking inflammatory cytokine exposure, disease-associated transcriptional alterations, and impaired oligodendrocyte differentiation. Our findings indicate that pharmacological modulation of GPR17 can promote oligodendrocyte maturation and wrapping features under non-permissive inflammatory conditions. This strategy should be considered as an oligodendroglial-directed approach that may complement anti-inflammatory or immunomodulatory interventions.}, } @article {pmid42329240, year = {2026}, author = {Xu, Z and Ding, J and Su, X and Wang, G and Xie, K and Zhao, Y and Xiong, C and McDade, E and Schneider, LS and Liu, L}, title = {Subgroup identification via Interaction Tree and Mixed Model for Repeated Measures with application to Alzheimer's disease.}, journal = {Biometrics}, volume = {82}, number = {2}, pages = {}, pmid = {42329240}, issn = {1541-0420}, support = {UL1 TR002345/GF/NIH HHS/United States ; R21 AG084054/GF/NIH HHS/United States ; 5928//Washington University CTFRP/ ; }, mesh = {*Alzheimer Disease/drug therapy/therapy ; Humans ; Computer Simulation ; *Models, Statistical ; *Precision Medicine/methods ; Treatment Effect Heterogeneity ; Longitudinal Studies ; Algorithms ; }, abstract = {In precision medicine, subgroup identification is crucial for designing personalized treatments. This research focuses on subgroup identification in longitudinal clinical trials by integrating the Interaction Tree (ITree) with the Mixed Model for Repeated Measures (MMRM). Our ITree-MMRM approach retains the flexibility of tree-based methods in capturing nonlinear treatment interactions for heterogeneous treatment effects, while adhering to Food and Drug Administration guidelines for assessing treatment effects at the conclusion of longitudinal studies using MMRM. Additionally, we explore various options for tuning parameters and employ bootstrap methods to prune trees, reducing the risk of overoptimism. We demonstrate that our method outperforms existing subgroup identification techniques in simulations. The ITree-MMRM model is applied to an Alzheimer's disease clinical trial to identify subgroups with long-term treatment responses.}, } @article {pmid42329254, year = {2026}, author = {Paliwal, S and Bhardwaj, JS and Taliyan, R}, title = {Exploring the Neuroprotective Potential of 5-Azacytidine on the Streptozotocin-Induced Rat Model of Alzheimer's Disease.}, journal = {ACS chemical neuroscience}, volume = {}, number = {}, pages = {}, doi = {10.1021/acschemneuro.6c00234}, pmid = {42329254}, issn = {1948-7193}, abstract = {Alzheimer's disease (AD) associated with insulin resistance represents a major challenge in sporadic neurodegeneration, where impaired neuronal survival and synaptic plasticity are compounded by aberrant DNA methylation. Epigenetic silencing of Wnt pathway genes under insulin-resistant conditions exacerbates β-amyloid accumulation, tau hyperphosphorylation, and oxidative stress. The present study aimed to establish insulin-resistant AD models and evaluate the mechanistic potential of DNA methyltransferase (DNMT) inhibition, with a specific focus on canonical Wnt/β-catenin restoration. An in vitro AD model was generated by exposing SHSY-5Y cells to streptozotocin (STZ, 400 μM), resulting in elevated DNMT1, Aβ1-42, and sFRP1 levels, alongside reduced β-catenin and survivin expression. Treatment with the DNMT1 inhibitor 5-azacytidine (5-AZA), employed here as a mechanistic probe rather than a therapeutic candidate, reversed these changes, restoring Wnt signaling and attenuating amyloid burden. In vivo, intracerebroventricular administration of STZ (3 mg/kg) in rats induced an insulin-resistant AD-like pathology characterized by cognitive decline, increased pTau and acetylcholinesterase activity, and reduced neuroprotective markers. 5-AZA treatment improved memory and behavior, decreased pTau and AChE levels, and enhanced ADAM10, TREM2, BDNF, and antioxidant activity. Histological analysis further revealed preservation of neuronal layers and structural integrity. Collectively, these findings demonstrate that DNMT inhibition, exemplified by 5-AZA as a mechanistic tool, can mitigate STZ-induced molecular and behavioral alterations by relieving hypermethylation-mediated repression and supporting partial reactivation of canonical Wnt/β-catenin signaling. While 5-AZA itself is not a viable therapeutic option, the results highlight DNMT inhibition as a promising disease-modifying strategy in insulin resistance-associated AD.}, } @article {pmid42330346, year = {2026}, author = {Nie, C and Yang, R and Wang, X and Jia, P and Zhang, X and Dai, Y and Bai, X and Duan, S and Li, Y and Zheng, P and Tian, X and Jiang, L and Wang, C}, title = {Lilrb4a Suppression Reprograms Microglia to Mitigate APOE4-Associated Amyloid Plaques and Cerebral Amyloid Angiopathy in Association With a PPAR-Linked Pro-Clearance State.}, journal = {Advanced science (Weinheim, Baden-Wurttemberg, Germany)}, volume = {}, number = {}, pages = {e24167}, doi = {10.1002/advs.202524167}, pmid = {42330346}, issn = {2198-3844}, support = {82271470//National Natural Science Foundation of China/ ; LG-GG-202401-ADA010100//Lingang Laboratory AD Special Project/ ; 2023NSCQ-MSX3605//Natural Science Foundation of Chongqing Municipal Bureau of Science and Technology/ ; //National Science Fund for Excellent Young Scholars/ ; KZD-JI202400406//Scientific and Technological Research Program of Chongqing Municipal Education Commission/ ; STI2030-Major Projects 2021ZD0202400//Key Technologies Research and Development Program/ ; }, abstract = {The mouse gene Lilrb4a, an ortholog of human leukocyte immunoglobulin-like receptor B4 (LILRB4), is markedly upregulated in microglia in Alzheimer's disease models and has been implicated in Apolipoprotein E (APOE)-related signaling. However, its contribution to amyloid pathology under an APOE4 background remains unclear. Here, 5xFAD mice carrying human APOE4 were used to assess the impact of Lilrb4a reduction by genetic deletion or antisense oligonucleotide treatment. Both approaches significantly reduced cortical amyloid plaque burden and APOE4-associated cerebral amyloid angiopathy without altering amyloid-β (Aβ) production. Bulk RNA sequencing identified enrichment of peroxisome proliferator-activated receptor (PPAR)-related and broader metabolic pathways in Lilrb4a-deficient mice. Consistently, biochemical analyses showed reduced p-SHP-2, NF-κB-p65, and p-STAT1, increased p-STAT3, and induction of anti-inflammatory and clearance-associated effectors, including Arg-1, TGF-β, and Cyp2e1. In primary microglia, pharmacological interrogation supported a functional contribution of PPAR-γ signaling to the enhanced Aβ uptake and degradation associated with Lilrb4a suppression, whereas PPAR-γ agonism recapitulated key pro-clearance phenotypes in vitro and attenuated amyloid pathology in vivo. Together, these data support Lilrb4a as an APOE4-associated microglial checkpoint candidate linked to impaired amyloid clearance and identify a PPAR-linked pro-clearance program as a potential downstream component of this response.}, } @article {pmid42330959, year = {2026}, author = {Du, Y and Sun, C and Wu, L and Wu, Z and Tong, Y and Tian, H and Mao, Y and Shi, X and Ding, H and Xie, W and Yao, W and Chen, S and Gao, X}, title = {Oral GLP-1 receptor agonist promotes astrocyte-neuron lactate and lipid transfer with neuroprotective effects.}, journal = {Cell metabolism}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.cmet.2026.05.014}, pmid = {42330959}, issn = {1932-7420}, abstract = {Glucagon-like peptide-1 receptor (GLP-1R) activation is widely assumed to regulate the metabolic disorder in Alzheimer's disease (AD). However, direct evidence for this hypothesis is lacking, and currently, there is no oral GLP-1R agonist with effective blood-brain barrier-penetrating ability. Here, we show that a candidate peptide, OHP2, an oral GLP-1R agonist with blood-brain barrier permeability, exhibits promising therapeutic potential for AD. OHP2 primarily activates GLP-1R on astrocytes, leading to increased aerobic glycolysis and driving lactate release. Astrocyte-derived lactate is taken up by neurons and elevates histone H3 lysine 9 lactylation (H3K9la), which in turn facilitates lipid transport from neurons back to astrocytes. This astrocyte-neuron metabolic coupling sustains continuous aerobic glycolysis and offers a potential treatment strategy for AD. The H3K9la derived from OHP2 links glucose and lipid metabolic cycle and facilitates metabolic coupling between astrocytes and neurons, which leads to remission of metabolic disturbances in AD. Thus, our study provides a new candidate molecule for drug research in treating AD and illustrates that intracerebral GLP-1R activation, which facilitates astrocyte-neuron metabolic coupling, may be a potential approach for the treatment of AD.}, } @article {pmid42332435, year = {2026}, author = {He, W and Zhang, K and Jia, X and Lv, Y and Cheng, T and Han, L and Xia, Y and Zhang, X and Zhai, W and Yang, F and Wang, S and Jin, L}, title = {Design, Biological Characterization, and Discovery of the Brain-Penetrant NLRP3 Inhibitor Based on a [1,2,4]Triazolo[1,5-a]pyrimidine Scaffold for the Treatment of Central Nervous System Diseases.}, journal = {Journal of medicinal chemistry}, volume = {}, number = {}, pages = {}, doi = {10.1021/acs.jmedchem.6c00839}, pmid = {42332435}, issn = {1520-4804}, abstract = {NLRP3 inflammasome is a critical cytosolic multiprotein complex central to the innate immune response. Upon activation, NLRP3 oligomerizes and recruits the adapter protein ASC; this scaffold recruits and activates pro-caspase-1. Active caspase-1 catalyzes the proteolytic maturation and secretion of the potent pro-inflammatory cytokines IL-1β and IL-18, and induces a programmed cell death called pyroptosis. Dysregulated or chronic NLRP3 inflammasome activation is a major driver of pathogenesis in a wide spectrum of peripheral inflammatory diseases, including gout, pericarditis, atherosclerosis, nonalcoholic steatohepatitis, and NLRP3 gain-of-function autoinflammatory disorders known as CAPS, as well as neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, and multiple sclerosis. Herein we described the discovery of NLRP3 inhibitors based on the [1,2,4]triazolo[1,5-a]pyrimidine scaffold. Represented by compound 25, this scaffold exhibited exceptional potency, favorable physicochemical properties, and desirable pharmacokinetic profiles, including good brain penetration. Compound 25 showed potential as a candidate for the treatment of Parkinson's disease.}, } @article {pmid42332767, year = {2026}, author = {Ye, J and Deng, Y and Zhang, B and Li, C and Guo, X and Yue, R and Wan, H and Hao, Y and Xiao, S}, title = {HDAC7 acts as an astrocytic mediator of Aβ pathology that directly engages IKK to drive astrocyte neurotoxicity and neurodegeneration in Alzheimer's disease.}, journal = {Alzheimer's research & therapy}, volume = {}, number = {}, pages = {}, doi = {10.1186/s13195-026-02121-5}, pmid = {42332767}, issn = {1758-9193}, support = {82101493//National Natural Science Foundation of China/ ; 82474227//National Natural Science Foundation of China/ ; 2025A1515012551//Basic and Applied Basic Research Foundation of Guangdong Province/ ; JCYJ20240813141825034//Shenzhen science and technology research and development funds/ ; 20231121103959001//Shenzhen Science and Technology Innovation Commission/ ; 2023SHIBS0003//Shenzhen-Hong Kong Institute of Brain Science-Shenzhen Fundamental Research Institutions/ ; }, abstract = {BACKGROUND: Astrocytes undergo reactive transformations in response to pathological stimuli and play a critical role in neuronal loss associated with Alzheimer's disease (AD). However, the intrinsic mechanisms through which astrocytes detect amyloid-β (Aβ) pathology and develop neurotoxic properties remain inadequately understood. The dysregulation of class IIa Histone deacetylases (HDACs) has been implicated in astrocyte dysfunction under pathological conditions. This study aims to elucidate the role of HDAC7 as an astrocytic mediator of Aβ that drives the formation of neurotoxic reactive astrocytes, and to propose HDAC7 as a potential therapeutic target for mitigating neuronal loss and cognitive deficits in AD.

METHODS: We examined HDAC7 expression in APP/PS1 mice of varying ages using RT-qPCR, Western blotting, and immunostaining analysis. Astrocyte-specific HDAC7 overexpression and knockdown were achieved through adeno-associated virus (AAV) delivery (GfaABC1D promoter) in wild-type (WT) and APP/PS1 mice, followed by behavioral tests, immunostaining, RT-qPCR, and RNA-seq. Mechanistic studies were conducted using primary astrocytes derived from WT and Hdac7[flx/flx] mice, employing co-immunoprecipitation, Western blotting, and neuron viability assays. Pharmacological inhibition of HDAC7 in APP/PS1 mice was performed via intraperitoneal injection of TMP195, and the effects on neurotoxic reactive astrocytes, neuronal and synaptic loss, and behavioral performance were measured.

RESULTS: HDAC7 was selectively upregulated in plaque-adjacent astrocytes in APP/PS1 mice. Overexpression of HDAC7 specifically in astrocytes was sufficient to induce a neurotoxic transcriptional profile, neuronal loss, and cognitive deficits in both WT and young APP/PS1 mice. Mechanistically, upon Aβ stimulation, the upregulated HDAC7 directly interacted with and deacetylated IKKα and IKKβ, resulting in the activation of IKK, translocation of NF-κB to the nucleus, and subsequent expression of neurotoxic genes. This neurotoxic conversion was dependent on IKK activity, as IKK inhibition nullified the effects in astrocytes overexpressing HDAC7. Conversely, astrocytic HDAC7 knockdown or treatment with TMP195 attenuated IKK-NF-κB signaling, reduced the presence of neurotoxic reactive astrocytes, and rescued neurodegeneration and cognitive deficits in APP/PS1 mice.

CONCLUSIONS: HDAC7 acts as an intrinsic effector within astrocytes, responding to Aβ pathology and converting astrocytes into a neurotoxic state through direct interaction with IKK. Targeting HDAC7 presents a promising strategy for astrocyte-directed therapeutic interventions in Alzheimer's disease.}, } @article {pmid42332768, year = {2026}, author = {Lee, CY and Hsu, CW and Tseng, PT and Fang, YY and Stubbs, B and Thompson, T and Carvalho, AF and Lin, YH and Kao, YC and Yang, FC and Hsu, TW and Liang, CS}, title = {Real-world effectiveness of monoclonal antibody lecanemab versus acetylcholinesterase inhibitors in Alzheimer's disease: a target trial emulation.}, journal = {Alzheimer's research & therapy}, volume = {}, number = {}, pages = {}, doi = {10.1186/s13195-026-02095-4}, pmid = {42332768}, issn = {1758-9193}, abstract = {BACKGROUND: Acetylcholinesterase inhibitors (AChEIs) provide symptomatic relief in Alzheimer's disease (AD), whereas lecanemab may modify disease progression; however, real-world evidence on its safety and clinical impact remains limited. Therefore, this study aimed to compare the safety and effectiveness of initiating lecanemab versus AChEIs in patients with mild cognitive impairment (MCI) or AD.

METHODS: Using the TriNetX US electronic health record network, we conducted a retrospective cohort study including individuals diagnosed with MCI or AD between July 2023 and September 2025. A target trial emulation with 1:1 propensity score matching and Cox models estimated comparative risks.

RESULTS: Lecanemab was associated with a fivefold higher incidence of neuroimaging abnormalities than AChEIs, while 1-year treatment persistence was similar (53.4% vs 52.5%). After matching, 589 patients were included in each cohort. Compared with AChEIs, lecanemab was associated with significantly lower risks of behavioral and psychological symptoms of dementia (BPSD) (HR, 0.52; 95% CI, 0.36-0.77) and emergency visits (HR, 0.66; 95% CI, 0.51-0.85), but a higher risk of hospitalization (HR, 1.31; 95% CI, 1.03-1.67). Lecanemab was also associated with lower use of antipsychotics (HR, 0.47; 95% CI, 0.32-0.70), antidepressants (HR, 0.60; 95% CI, 0.43-0.85), melatonin/orexin antagonists (HR, 0.61; 95% CI, 0.42-0.88), antibiotics (HR, 0.61; 95% CI, 0.44-0.86), and antifungals (HR, 0.57; 95% CI, 0.37-0.88), whereas steroid use was higher among lecanemab users (HR, 2.19; 95% CI, 1.55-3.10).

CONCLUSIONS: Compared with an AChEI-based conventional care strategy, lecanemab initiation was associated with comparable treatment persistence and lower observed risks of BPSD, emergency visit as well as reduced use of psychotropic and infection-related medications in exploratory analyses. However, the higher incidence of neuroimaging abnormalities associated with lecanemab, along with increased risks of hospitalization and corticosteroid use, likely reflects proactive clinical monitoring and management of amyloid-related imaging abnormalities (ARIA). While residual confounding cannot be excluded and results warrant cautious interpretation, these exploratory findings warrant further validation in biomarker-confirmed cohorts and head-to-head randomized trials.}, } @article {pmid42332917, year = {2026}, author = {Lee, YS and Roh, S and Moon, H and Steele, JS and Yoon, DP and Warne, DK}, title = {If a Family Member Develops Alzheimer's Disease: Gender Differences in Help-Seeking Intentions Among American Indians.}, journal = {Journal of applied gerontology : the official journal of the Southern Gerontological Society}, volume = {}, number = {}, pages = {7334648261459708}, doi = {10.1177/07334648261459708}, pmid = {42332917}, issn = {1552-4523}, abstract = {This study examined psychosocial factors associated with help-seeking intentions if and when a family member developed Alzheimer's disease (AD) among American Indian populations, focusing on gender differences. Guided by Andersen's behavioral model of health service use, predisposing, enabling, and need factors were considered as potential sources for AD help-seeking intentions. Multivariate regression analyses were conducted on a sample of 226 American Indian adults residing in South Dakota. Subjective norms and family support were positively associated with help-seeking intentions for both men and women. Gender differences emerged. American Indian women were more likely than men to intend to seek help for a family member with AD if the need arose, while self-confidence in completing medical forms was positively associated with help-seeking intentions among American Indian men only. Identifying common and gender-specific AD intervention strategies can promote timely help-seeking and improve treatment outcomes in American Indian communities.}, } @article {pmid42333278, year = {2026}, author = {Ravella, B and Theli, A and Gadde, EC and Ravipati, H}, title = {Jejunal Diverticulitis With Contained Perforation and Abscess Successfully Managed With Conservative Therapy: A Case Report and Review of the Literature.}, journal = {Cureus}, volume = {18}, number = {6}, pages = {e111181}, pmid = {42333278}, issn = {2168-8184}, abstract = {Jejunal diverticulosis is a rare condition that predominantly affects elderly individuals and is often asymptomatic. However, complications such as diverticulitis, perforation, and abscess formation can result in significant morbidity. Perforated jejunal diverticulitis has traditionally been managed surgically, although increasing evidence supports conservative treatment in selected patients. We report a case of a 74-year-old female with hypothyroidism, hyperlipidemia, and Alzheimer's dementia who presented with acute bilateral lower abdominal pain and nausea. Laboratory evaluation demonstrated leukocytosis, elevated inflammatory markers, and lactic acidosis. CT of the abdomen and pelvis revealed jejunal diverticulitis with focal perforation and an adjacent 2.4 × 3.6 cm gas-containing abscess. Given her hemodynamic stability and absence of generalized peritonitis, she was managed nonoperatively with bowel rest, IV fluids, ceftriaxone, and metronidazole. The patient improved clinically with normalization of inflammatory markers and was discharged on oral antibiotics. Follow-up imaging demonstrated complete resolution of the abscess and eventual resolution of inflammatory changes without surgical intervention. This case contributes to the growing body of evidence supporting conservative management of contained perforated jejunal diverticulitis and highlights the importance of careful patient selection and longitudinal radiographic follow-up.}, } @article {pmid42333463, year = {2026}, author = {Lee, N and Youn, K and Moon, M and Lee, DS and Kim, DH and Ho, CT and Jun, M}, title = {Fucoxanthin enhances AMPK/mTOR-dependent autophagic flux and attenuates ferroptosis in Alzheimer's disease models.}, journal = {Food & function}, volume = {}, number = {}, pages = {}, doi = {10.1039/d6fo01264g}, pmid = {42333463}, issn = {2042-650X}, abstract = {Alzheimer's disease (AD) is characterized by amyloid-β (Aβ) accumulation, impaired proteostatic clearance, and oxidative damage, all of which contribute to neuronal dysfunction and disease progression. Fucoxanthin (FX), a marine-derived carotenoid abundant in brown algae, has shown antioxidant and neuroprotective potential. However, its role in autophagy-lysosome dysfunction and ferroptosis-associated oxidative injury under amyloidogenic conditions remains unclear. In this study, the effects of FX were investigated in APP Swedish mutant-expressing Neuro2a (SweAPP N2a) cells treated with 0.1-5 μM FX and in 5XFAD transgenic mice orally administered FX at 200 mg kg[-1]. FX treatment increased LC3-II expression and reduced p62 accumulation in SweAPP N2a cells, indicating enhanced autophagic degradation. FX also increased the expression of the lysosomal markers LAMP1 and cathepsin D (CTSD), suggesting enhanced lysosome-associated degradative capacity. These responses were accompanied by AMPK activation and suppression of mTOR signaling, together with increased autophagic flux as confirmed by bafilomycin A1-based analysis. Moreover, FX significantly reduced intracellular ROS levels and lipid peroxidation marker 4-hydroxynonenal (4-HNE), while modulating ferroptosis-associated proteins, including GPX4 and FTH1. Consistent with the cellular findings, FX administration in 5XFAD mice modulated autophagy-lysosome-related and ferroptosis-associated proteins in the brain and significantly reduced ThS-positive amyloid plaque burden. Collectively, these findings demonstrate that FX enhances autophagy-lysosome-associated proteostatic regulation through AMPK/mTOR signaling and attenuates ferroptosis-linked oxidative injury under amyloidogenic conditions. These results provide mechanistic evidence supporting the role of FX as a marine-derived bioactive compound for modulating AD-related pathological processes.}, } @article {pmid42333562, year = {2026}, author = {Srivastava, V and Chakraborty, S and Srivastava, R}, title = {Toll-Like Receptor-Mediated Neuroinflammation and Its Role in Neurocognitive Functions.}, journal = {Current reviews in clinical and experimental pharmacology}, volume = {}, number = {}, pages = {}, doi = {10.2174/0127724328415188260605204430}, pmid = {42333562}, issn = {2772-4336}, abstract = {Toll-like receptors (TLRs) are a family of pattern recognition receptors that recognise both pathogen-associated and damage-associated molecular patterns. While their expression was initially believed to be restricted to immune cells, accumulating evidence now demonstrates their presence across multiple neural cell types. Due to their significant involvement in neuroinflammatory and neurodegenerative processes, TLRs have garnered growing attention for their potential contributions to neurocognitive disorders, including Alzheimer's disease, Parkinson's disease, stroke, amyotrophic lateral sclerosis, and other forms of dementia. Potential treatment targets for lowering neuroinflammation and slowing the evolution of neurocognitive diseases include TLR signalling pathways, namely the MYD88-dependent and TRIF-dependent cascades. To initiate signalling, Toll-like receptors (TLRs) recruit specific adaptor molecules that activate the transcription factors NF-κB and IRFs, which regulate the induction of innate immune responses. Over the past decade, a combination of genetic, biochemical, structural, cellular, and bioinformatics approaches has been utilised to elucidate the detailed molecular mechanisms underlying TLR signalling. These studies have clarified how TLRs interact with cytosolic innate immune sensors to orchestrate effective immunological reactions. The function of different TLRs expressed in various brain immune cells and their contribution to the pathophysiology of neuroinflammation are described. This paper discusses the involvement of TLRs in autoimmune and neuroinflammatory circumstances like multiple sclerosis (MS), bacterial meningitis, viral encephalitis, stroke, Alzheimer's disease, and Parkinson's disease. It is intended for TLR biologists and immunologists studying neuroinflammation, as well as neuroscientists delving into central nervous system processes mediated by TLRs.}, } @article {pmid42333570, year = {2026}, author = {Abubakar, MD and Gupta, J and Daksh, R and Chavan, PR and Alom, S and Mondal, A and Azizuddin, S and Pal, B and Murti, K and Kumar, D and Kumar, N}, title = {Neurodegenerative Disease Molecular Therapeutics based on Structural Activity Connections of Microglia Activation and Priming: A Comprehensive Review.}, journal = {Current topics in medicinal chemistry}, volume = {}, number = {}, pages = {}, doi = {10.2174/0115680266405995260414053514}, pmid = {42333570}, issn = {1873-4294}, abstract = {INTRODUCTION: In neurodegenerative diseases (NDDs) such as Alzheimer's (AD) and Parkinson's (PD), neuroinflammation plays a crucial role in the development and advancement of these disorders by contributing to the buildup of defective protein folding. Native immune response cells, known as microglial cells, enhance neuroinflammation by altering their shape and producing cytokines that promote inflammation. Inflammation in NDDs causes synapse pathology and dysfunction, although microglia-synapse relationships are unclear. Microglial structural activity alters physiology and architecture, causing functional changes and degeneration. Neurodegeneration and protein accumulation trigger microglial priming, which activates and regenerates microglia, resulting in heightened inflammatory responses. The biological activities and structural activation of microglia are studied to improve NDD therapy.

METHODS: An exhaustive search was conducted using the internet databases of PubMed, ScienceDirect, Google Scholar, DOAJ, and Wiley to identify any papers that discussed microglial activation, priming of this process, and molecular intervention in NDDs. First, molecular, preclinical, and clinical data were carefully reviewed for extraneous or redundant references, then narratively merged to offer a conceptual overlay.

RESULTS: This review examines the role of microglial cells in NDDs, highlighting potential interventions such as peptide- and RNA-based therapies, NF-κB, TLR4, JAK inhibitors, antibodies, and biologics.

DISCUSSION: The results suggest that stimulating microglial cells and enhancing neuron connections may improve treatment outcomes. The review indicates that translational research should be conducted to connect molecular pathways with clinically effective medicines.

CONCLUSION: Targeting microglia- and astrocyte-driven molecular markers could help resolve neuroinflammation and facilitate reliable therapeutic interventions in the progression of NDDs.}, } @article {pmid42334062, year = {2026}, author = {Corriveau-Lecavalier, N and Falgàs, N and Putcha, D and Graff-Radford, J and Yong, KXX and Boon, BDC and Mohanty, R and Westman, E and Groot, C and Jones, DT and Grinberg, LT and Rabinovici, GD and Whitwell, JL and Apostolova, LG and Murray, ME and Hammers, DB and Schindler, SE and Atonsdottir, I and Rhodus, EK and Schott, JM and Illán-Gala, I and Chukwuanugo, O and Guerra, JJL and Peters, R and Abner, EL and Abdelnour, C and Lladó, A and La Joie, R and de Souza, LC and Rezaii, N and Shir, D and Pijenburg, YAL and Carrillo, MC and Dickerson, BC and Aisen, P and Ossenkoppele, R and Raman, R}, title = {Improving the clinical trial landscape for patients with atypical variants of Alzheimer's disease: a call to action.}, journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association}, volume = {22}, number = {6}, pages = {e71521}, pmid = {42334062}, issn = {1552-5279}, support = {JR22/00014//Instituto de Salud Carlos III/ ; R01-AG50603/GF/NIH HHS/United States ; R01-AG075802/GF/NIH HHS/United States ; P30 AG 062677/GF/NIH HHS/United States ; }, mesh = {Humans ; *Alzheimer Disease/therapy/diagnosis ; *Clinical Trials as Topic ; Disease Progression ; }, abstract = {Patients with atypical variants of Alzheimer's disease (AD) often present at a younger age with predominantly non-amnestic impairments and a more aggressive disease course. Historically, individuals with atypical presentations have not been included in large-scale clinical trials, which typically focus on late-onset, sporadic amnestic-predominant AD. Consequently, treatment options and research efforts specific to atypical AD remain limited. The emergence of amyloid-targeting therapies that slow disease progression underscores these challenges, as evidence supporting their efficacy in early-onset amnestic and non-amnestic AD variants is scarce. This perspective article argues that atypical AD represents an excellent disease model for clinical trials and proposes strategies to address critical gaps in clinical trial design for this population. Key considerations include optimizing participant selection approaches, establishing syndrome-specific or surrogate biological and clinical endpoints, and fostering advocacy to enhance early and accurate diagnosis, equitable representation, and outcomes for these populations.}, } @article {pmid42334485, year = {2026}, author = {Coleman, JS and Capstick, RA and Chang, S and Rios, DJ and Bubser, M and Thompson Gray, AD and Zagol-Ikapitte, I and Krishnan, S and Cho, HP and Rodriguez, AL and Niswender, CM and Boutaud, O and Garcia, GP and Elder, GA and Engers, DW and Jones, CK and Lindsley, CW}, title = {Discovery of VU6066098: A Selective and CNS-Penetrant mGlu2 NAM with Robust Antidepressant-, Antipsychotic-, and Procognitive-like Activity in Rodents.}, journal = {ACS chemical neuroscience}, volume = {}, number = {}, pages = {}, doi = {10.1021/acschemneuro.6c00324}, pmid = {42334485}, issn = {1948-7193}, abstract = {Herein, we report the discovery and development of an optimized mGlu2 Negative Allosteric Modulator (NAM) in vivo tool compound, VU6066098, based on a novel, structurally distinct chemotype. VU6066098 is a potent, selective, and CNS-penetrant mGlu2 NAM with excellent rat PK (CLp = 23.9 mL/min/kg, t1/2 = 2.2 h, %F = 100, Kp = 1.28, Kp,uu = 0.25), making it ideal to explore the therapeutic potential of selective mGlu2 inhibition in preclinical rat models. In a rat forced swim test, VU6066098 displayed an oral minimum effective dose (MED) of 1 mg/kg and was equi-efficacious to ketamine. In amphetamine-induced hyperlocomotion, VU6066098 displayed an oral minimum effective dose (MED) of 30 mg/kg. While in the preclinical cognitive tasks of rat novel object recognition and acquisition of contextual fear conditioning, VU6066098 produced robust dose-dependent effects at oral minimum effective doses (MED) of 3 mg/kg and 0.3 mg/kg, respectively. In a blast-related traumatic brain injury (TBI) model, administration of VU6066098 at a dose of 10 mg/kg IP was effective acutely, and the effect on NOR memory was sustained up to 30 days postdose. Thus, mGlu2 NAMs show therapeutic potential for the treatment of a broad range of affective and cognitive symptoms associated with Major Depressive Disorder, Alzheimer's disease, TBI, and acute psychosis; moreover, these data strongly support further optimization of mGlu2 NAMs for future clinical development.}, } @article {pmid42336161, year = {2026}, author = {Zhang, Y and Zhang, X and Huang, J and Sun, Z}, title = {Lamivudine ameliorates neuropathology in 5×FAD mice via coordinated inhibition of the cGAS-STING pathway with enhancement of mitophagy.}, journal = {Brain research bulletin}, volume = {243}, number = {}, pages = {112014}, doi = {10.1016/j.brainresbull.2026.112014}, pmid = {42336161}, issn = {1873-2747}, abstract = {Alzheimer's disease is a neurodegenerative disorder for which there is currently no effective treatment available. Epidemiological and clinical evidence suggests that lamivudine, a nucleoside reverse transcriptase inhibitor, is associated with a reduced risk of Alzheimer's disease and shows potential in alleviating neuroinflammation. This study therefore aims to employ AD mouse models to further investigate the molecular mechanisms by which lamivudine ameliorates AD-related phenotypes. In this study, we showed that lamivudine administration inhibited cGAS-STING activation and attenuated mitochondrial damage in the 5 ×FAD mouse model, as supported by improved mitochondrial morphology and enhanced mitophagy. These changes were associated with improved spatial memory, alongside reduced neuronal apoptosis and synaptic loss. Our findings underscore the neuroprotective potential of lamivudine in AD via coordinated preservation of mitochondrial integrity and suppression of innate immune signaling, suggesting its promise for clinical translation in neurodegenerative disorders.}, } @article {pmid42336952, year = {2026}, author = {Arabhalvaei, V and Rajaei, SN and Alinaghi, MM and Talebi, M and Dashti, F and Abachi, SF and Khodayar, Z and Jafroodi, AR and Jamalaldin, M and Mehboodi, M and Maleki, MH and Rahimi, A and Baziyar, P}, title = {Investigation of the effects of sodium butyrate on SH-SY5Y neurons treated with amyloid beta42 and lipopolysaccharide: A computational and experimental study.}, journal = {Scientific reports}, volume = {}, number = {}, pages = {}, doi = {10.1038/s41598-026-59446-2}, pmid = {42336952}, issn = {2045-2322}, abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by amyloid beta42 (Aβ42) aggregation, neuroinflammation, and synaptic dysfunction. This study combines computational and experimental approaches to investigate the neuroprotective effects of sodium butyrate (NaB). Differentiated SH-SY5Y neurons were exposed to lipopolysaccharide (LPS) and Aβ1-42 to model AD-like conditions, and the potential protective effects of NaB were evaluated. MD simulations indicated that NaB may be associated with destabilization of organized Aβ42 fibrils. Alterations in RMSD, Rg, and SASA values indicated structural instability of Aβ42 fibrils in the presence of NaB. Treatment with NaB (10 and 50 µM) significantly improved cell viability compared to the LPS + Aβ group (p < 0.001) and attenuated apoptosis, as evidenced by reduced expression of Bax, Caspase-3, and FOXO3a (p < 0.0001), alongside upregulation of the anti-apoptotic marker Bcl-2 (p < 0.01). Moreover, NaB markedly increased the expression of neuroprotective and antioxidant genes, including BDNF, Nrf2, SIRT1, and CREB (p < 0.001), thereby restoring pathways involved in neuronal survival, oxidative stress defense, and synaptic plasticity. Collectively, these effects mitigated LPS + Aβ-induced cytotoxicity, suggesting that NaB exerts its neuroprotective action through epigenetic regulation of stress-response and plasticity networks. Our findings provide robust evidence supporting sodium butyrate as a promising therapeutic candidate for preventing or slowing AD-related neuronal degeneration and highlight its potential translational relevance for future in vivo and clinical investigations.}, } @article {pmid42337598, year = {2026}, author = {Labrador-Espinosa, MA and Franzmeier, N and Karagianni, S and Moscoso, A and Schöll, M}, title = {Clinico-biological trajectories stratified by combined tau biomarkers in preclinical Alzheimer's disease.}, journal = {Alzheimer's research & therapy}, volume = {18}, number = {1}, pages = {}, pmid = {42337598}, issn = {1758-9193}, mesh = {Humans ; Female ; *tau Proteins/blood/metabolism ; *Alzheimer Disease/diagnostic imaging/blood/metabolism/drug therapy/pathology ; Positron-Emission Tomography ; Aged ; Biomarkers/blood ; Male ; Amyloid beta-Peptides/metabolism ; Brain/diagnostic imaging/metabolism/pathology ; Magnetic Resonance Imaging ; Disease Progression ; Antibodies, Monoclonal, Humanized/therapeutic use ; Cognitive Dysfunction/diagnostic imaging ; Longitudinal Studies ; }, abstract = {BACKGROUND: Tau pathology biomarkers provide prognostic indicators of neurodegeneration and cognitive decline in Alzheimer's disease (AD), making them crucial to early patient stratification for disease-modifying interventions. Plasma p-tau217 indexes early tau pathophysiology, whereas FDA/EMA-approved [[18]F]flortaucipir PET (tau-PET) visual assessments indicate advanced neurofibrillary tangle pathology. Here, we identified concordant and discordant profiles based on combined plasma p-tau217 status and tau-PET visual assessments in cognitively unimpaired amyloid-β (Aβ)-positive older adults and investigated whether these profiles delineate distinct longitudinal trajectories of Aβ and tau accumulation, neurodegeneration, and cognitive decline.

METHODS: We included 330 cognitively unimpaired Aβ-PET-positive participants (72.2 ± 4.8 years; 58% female; 48% randomized to receive solanezumab) from the A4 Study, who underwent plasma p-tau217 and tau-PET at baseline. Plasma positivity (T1 +) followed A4 core criteria as previously reported (≥ 0.28 U/mL), while tau-PET positivity (T2 +) was determined by three expert visual readers with strong inter-rater agreement (κ = 0.954). Participants were stratified as T1[- / +]T2[- / +] at baseline and were followed for 5.0 ± 1.7 years. Baseline and longitudinal differences in regional Aβ- and tau-PET SUVR, MRI-measured gray-matter (GM) volume, and cognitive performance were examined using ANCOVA and mixed-effects models. All models accounted for treatment, with additional sensitivity analyses excluding treated participants.

RESULTS: At baseline, 57% were negative-concordant (T1 - T2 - : n = 187), 24% were discordant (T1 + T2 - : n = 53; T1 - T2 + : n = 27), and 19% were positive-concordant (T1 + T2 + : n = 63). T1 + T2 + profile constituted the highest-risk state, showing the greatest baseline cortical Aβ burden, the strongest neocortical tau progression (fronto-temporo-parietal pattern; p(FDR) < 0.05), marked baseline atrophy with accelerated longitudinal GM loss in overlapping regions, and the fastest cognitive decline (PACC: d = -1.84, p < 0.001). Consistently, T1 + T2 + exhibited the highest hazard of progression to more advanced clinico-biological stages over follow-up (HRClinical = 3.03, HRBiological = 9.98; p < 0.001). Discordant profiles showed comparatively limited progression, suggesting earlier or low-tau states. Results were essentially unchanged after excluding treated participants.

CONCLUSIONS: Integrating plasma p-tau217 with tau-PET visual assessment reveals clinically meaningful tau-biomarker heterogeneity in preclinical AD. Our findings highlight the value of combining these biomarkers to refine early risk prediction and support prioritization strategies for prevention trials. The frequency of discordance also motivates refining tau-PET visual assessments beyond binary classification (e.g., ordinal/semi-quantitative staging) to better capture subtle early tau signal.}, } @article {pmid42337797, year = {2026}, author = {Soni, H and Sutherland, GT and Hofer, MJ}, title = {The complement system in Alzheimer's disease: evaluating biomarker potential in a complex neuroimmune context.}, journal = {Journal of neuroinflammation}, volume = {}, number = {}, pages = {}, doi = {10.1186/s12974-026-03927-8}, pmid = {42337797}, issn = {1742-2094}, abstract = {Neuroinflammatory processes are increasingly recognised as important modulators of Alzheimer's disease (AD) progression, driving interest in immune-related biomarkers beyond classical pathological measures. Among these, the complement system has attracted attention because of its interactions with amyloid-β (Aβ) and tau pathology, genetic associations with AD risk, and evidence of activation within affected brain regions. However, these biological observations do not directly translate into straightforward biomarker signals. Complement activity is highly dynamic, spans multiple activation and regulatory states, and may reflect both central and peripheral immune processes. This complexity limits interpretation when complement markers are assessed in isolation, as age, systemic inflammation, vascular comorbidity, and blood-brain barrier integrity can influence measured levels. Current evidence does not support complement-derived biomarkers as stand-alone diagnostic classifiers comparable to established amyloid, tau, and neurodegeneration (AT(N)) measures. Their independent or additive value within multimodal biomarker frameworks remains unclear, partly because of cohort heterogeneity, incomplete assay harmonisation, uncertain tissue-source attribution, and limited longitudinal validation. This review critically evaluates complement-derived measures as biologically informative markers of neuroimmune activity in AD, distinguishing biological plausibility from analytical and clinical utility. We argue that their most defensible current role is within multimodal biomarker frameworks, where they may provide context-specific information on inflammatory state rather than function as independent diagnostic, staging, or treatment-monitoring tools. Progress toward clinical application will require rigorous standardisation, mechanistic clarification, and validation across large, longitudinal, and diverse cohorts.}, } @article {pmid42337854, year = {2026}, author = {Lee, S and Choi, BJ and Park, MH and Park, S and Kim, J and Jin, HK and Shim, H and Jeon, JW and Bae, JS}, title = {A novel antibody against CD300c ameliorates cognitive deficits and reduces pathology in the late-stage of APP/PS1 mouse model.}, journal = {Journal of Alzheimer's disease : JAD}, volume = {}, number = {}, pages = {13872877261458360}, doi = {10.1177/13872877261458360}, pmid = {42337854}, issn = {1875-8908}, abstract = {BackgroundA major pathological hallmark of Alzheimer's disease (AD), the most common cause of dementia, is the accumulation of amyloid-β (Aβ) plaques. However, currently approved therapeutic agents fail to fundamentally halt disease progression and have limitations in terms of efficacy, sustainability, and safety. CD300c is an immunoregulatory molecule that modulates monocyte differentiation and activates macrophages. We recently developed a fully human anti-CD300c antibody, CB201, demonstrating its therapeutic potential in early and late 5xFAD mice.ObjectiveThis study investigated the efficacy of CB201 in late-stage AD using the APP/PS1 transgenic mouse model. We analyzed the effects of administering CB201 on changes in memory and cognitive function and Aβ and tau protein accumulation in the brain.MethodsTo assess long- and short-term memory improvements, behavioral tests were conducted using the Morris water maze and fear conditioning. Immunostaining was performed to quantify changes in Aβ and tau accumulation.ResultsCB201-treated late-stage AD mice demonstrated improved cognitive performance and memory, comparable to wild-type controls. Histopathological analysis further revealed that CB201 treatment reduced Aβ and tau accumulation.ConclusionsCB201 exerts significant therapeutic effects on functional impairments and pathological alterations in late-stage AD. These results confirm CB201 as a potential immunotherapeutic for the treatment of AD.}, } @article {pmid42337953, year = {2026}, author = {Chang, A and Kim, M and Glittenberg, M and Qu, W and Li, D and Li, L}, title = {HDL-mimetic peptide treatment reverses APOE4-induced transcriptomic and lipidomic alterations in the brain of humanized APOE mice.}, journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association}, volume = {22}, number = {6}, pages = {e71568}, pmid = {42337953}, issn = {1552-5279}, support = {AG058081/NH/NIH HHS/United States ; AG056976/NH/NIH HHS/United States ; AG059654/NH/NIH HHS/United States ; AG081426/NH/NIH HHS/United States ; AG077772/NH/NIH HHS/United States ; T32AG029796//NIH training grant/ ; //College of Pharmacy, University of Minnesota/ ; }, mesh = {Animals ; *Brain/metabolism/drug effects ; Mice ; *Apolipoprotein E4/genetics/metabolism ; *Lipid Metabolism/drug effects ; Lipidomics ; Mice, Transgenic ; Humans ; *Transcriptome/drug effects ; *Lipoproteins, HDL/pharmacology ; Alzheimer Disease/genetics/metabolism ; *Peptides/pharmacology ; Apolipoproteins E/genetics ; Disease Models, Animal ; Apolipoprotein A-I ; }, abstract = {INTRODUCTION: The apolipoprotein E4 (APOE4) allele is the strongest genetic risk factor for late-onset Alzheimer's disease (AD). ApoE4 has reduced lipidation capacity and impaired lipid transport, disrupting neuronal maintenance. The high-density lipoprotein (HDL)-mimetic peptide 4F offers a potential therapeutic strategy.

METHODS: To investigate how APOE4 alters brain gene expression and lipid metabolism and to evaluate the therapeutic potential of 4F, we performed dual-omics analysis in APOE4/4 and APOE3/3 mice treated intraperitoneally with D-enantiomer of 4F (D4F) or vehicle for 12 weeks from 10 to 13 months of age.

RESULTS: APOE4/4 mice showed widespread transcriptomic and lipidomic alterations, including downregulation of lipid metabolism and synaptic pathways, increased ceramides, sphingomyelins, and cholesteryl esters, with decreased diglycerides and triglycerides. D4F treatment shifted relevant gene expression and lipid profiles toward APOE3/3 levels.

DISCUSSION: These findings reveal molecular mechanisms underlying APOE4-driven dysregulation and support the therapeutic potential of HDL-mimetic peptides to mitigate APOE4-associated alterations in AD.}, } @article {pmid42338509, year = {2026}, author = {Malvankar, SR and Wolfe, MS}, title = {The γ-secretase complex: from discovery to a therapeutic target.}, journal = {RSC chemical biology}, volume = {}, number = {}, pages = {}, pmid = {42338509}, issn = {2633-0679}, abstract = {γ-Secretase is an intricate intramembrane aspartyl protease that cleaves within the transmembrane domain of ∼150 substrates and is considered the 'proteasome of the membrane'. This enzyme consists of four different subunits, with presenilin being the catalytic subunit. This review provides a brief overview of γ-secretase as a proteolytic enzyme, from its biochemistry and biology to its roles in disease and potential as a therapeutic target. A detailed discussion on the discovery and structure of γ-secretase is followed by a survey of its substrates, including the most studied amyloid precursor protein and the Notch1 receptor, and a description of substrate processing and sequence specificity. The role of γ-secretase in human biology and pathology is also detailed, with a particular focus on Alzheimer's disease (AD), in which the pathogenicity of the γ-secretase product amyloid-β peptide is still a matter of controversy. Lastly, the potential of γ-secretase inhibitors and modulators for the treatment of AD and other diseases is considered.}, } @article {pmid42338648, year = {2026}, author = {Riaz, R and Fatima, M and Ramzan, S and Rathi, D and Fatima, F and Farooq, M and Shaukat, A and Khaliq, N and Akilimali, A}, title = {FDA Approval of Donanemab-azbt: A New Dawn in Alzheimer's Disease Treatment.}, journal = {Health science reports}, volume = {9}, number = {6}, pages = {e72688}, pmid = {42338648}, issn = {2398-8835}, abstract = {BACKGROUND: Alzheimer's disease (AD) is a neurodegenerative condition marked by the accumulation of beta-amyloid plaques and neurofibrillary tangles, leading to neuronal death and cognitive decline. Acetylcholinesterase inhibitors (AChEIs) such as donepezil, galantamine, and rivastigmine are commonly used to enhance cognitive function by increasing acetylcholine levels, but they can cause side effects like nausea, bradycardia, and headaches. NMDA receptor antagonists, like memantine, reduce glutamatergic activity and are used to manage symptoms, yet are also associated with adverse effects including dizziness and agitation. Recently, monoclonal antibodies such as aducanumab have been developed to target amyloid-beta aggregates, though they are associated with amyloid-related imaging abnormalities (ARIA).

AIMS: This article aims to summarize current pharmacological approaches to AD and to highlight the emerging role of Donanemab-azbt, an FDA-approved monoclonal antibody for early symptomatic AD, in reducing amyloid plaques and slowing cognitive decline.

METHODS: This overview synthesizes data from clinical trials and therapeutic experience with acetylcholinesterase inhibitors, NMDA receptor antagonists, and monoclonal antibodies, with a particular focus on Donanemab-azbt, its mechanism of targeting amyloid-beta aggregates, and its efficacy and safety profile in early symptomatic AD.

RESULTS: Donanemab-azbt has demonstrated efficacy in clinical trials, significantly reducing amyloid plaque burden and slowing cognitive decline in patients with early symptomatic AD. However, its use may result in ARIA and other adverse effects, necessitating careful clinical and radiological monitoring during treatment.

CONCLUSION: Despite the risks of ARIA and other adverse events, Donanemab-azbt represents a promising addition to AD therapy, offering the potential for improved outcomes in patients with early symptomatic disease and expanding the therapeutic options beyond traditional symptomatic treatments.}, } @article {pmid42338764, year = {2026}, author = {Li, N and Peng, X and Xiong, W and Yang, C and Wang, W}, title = {Neuroprotective effects of Ershiwuwei Shanhu pills on APP/PS1 mice through antioxidant enhancement, anti-apoptosis, and MAPK pathway regulation.}, journal = {Translational neuroscience}, volume = {17}, number = {1}, pages = {20250396}, pmid = {42338764}, issn = {2081-3856}, abstract = {OBJECTIVES: Alzheimer's disease (AD) involves cognitive impairment, neuronal degeneration, oxidative imbalance, and abnormal MAPK signaling. This study investigated the protective effects of Ershiwuwei Shanhu Pills (ESP) on cognition, oxidative stress, neuronal apoptosis, and MAPK pathway regulation in APP/PS1 mice.

METHODS: Sixty mice were used, including 50 APP/PS1 transgenic mice randomly assigned to five groups: untreated AD model, donepezil (0.5 mg/kg), and low- (100 mg/kg), medium- (200 mg/kg), or high-dose (400 mg/kg) ESP. Ten wild-type C57BL/6J mice served as normal controls. All treatments were administered orally for 60 days. Cognitive performance was assessed by the Morris water maze. Hippocampal pathology and apoptosis were evaluated by histology and TUNEL staining, while oxidative stress markers, AD-related proteins, and MAPK phosphorylation were measured via ELISA and Western blot.

RESULTS: ESP treatment improved learning and memory performance, reduced hippocampal neuronal damage, and decreased neuronal apoptosis. Antioxidant enzyme activities (SOD, CAT, GSH, GSH-PX) increased, whereas MDA and GSSG levels decreased. Circulating Aβ1-40, Aβ1-42, TAU181, and γ-secretase levels were reduced. ESP also downregulated phosphorylation of JNK, ERK, and p38. The medium-dose group showed therapeutic effects comparable to donepezil.

CONCLUSIONS: ESP exerts neuroprotective effects in APP/PS1 mice by alleviating oxidative stress, inhibiting neuronal apoptosis, and modulating MAPK signaling. These findings suggest ESP as a promising multi-target therapeutic strategy for AD.}, } @article {pmid42339068, year = {2026}, author = {La Joie, R and Blazhenets, G and Maiti, P and Chiotis, K and Eloyan, A and Kirby, K and Hammers, D and Koeppe, RA and Ackley, SF and Robison, J and Soleimani-Meigooni, DN and Carrillo, MC and Dickerson, BC and Apostolova, LG and Rabinovici, GD and , }, title = {Identification of patients receiving amyloid-targeting therapies in observational studies using amyloid PET trajectories: Insights from LEADS.}, journal = {Alzheimer's & dementia (Amsterdam, Netherlands)}, volume = {18}, number = {2}, pages = {e70408}, pmid = {42339068}, issn = {2352-8729}, abstract = {INTRODUCTION: As amyloid-targeting therapies (ATTs) enter clinical care, observational cohorts must accurately ascertain ATT exposure. We developed an approach to flag mis/undocumented ATT in the Longitudinal Early-Onset Alzheimer's Disease Study using longitudinal amyloid positron emission tomography (PET).

METHODS: We analyzed 742 [[18]F]florbetaben PET from 270 participants with early-onset Alzheimer's disease. Using PET acquired before US Food and Drug Administration (FDA) approval of ATTs, we quantified Centiloid (CL) variability between two consecutive scans (PET "segments") to determine unusual CL decline thresholds that were then applied to post-FDA approval segments.

RESULTS: Pre-FDA approval segments increased by a median of 4.1 CL/year (whole cerebellum reference) and 3.6 CL/year (composite reference); unusual CL decline thresholds, defined as mean - 2 standard deviations of the pre-approval distributions were -15.8 and -9.4 CL/year, respectively. When applied to segments acquired post-FDA approval, extreme declines were observed in 59% to 78% of treated (n = 54) versus 4% to 8% of untreated segments (n = 344).

DISCUSSION: Longitudinal amyloid PET analyses can help identify ATT exposure in observational studies.}, } @article {pmid42339400, year = {2026}, author = {Williams, T and Jang, SR and Lanctôt, KL and Kang, A and Bloudek, L and Wang, G}, title = {Simulation of long-term lecanemab treatment effect on Alzheimer's disease progression.}, journal = {Alzheimer's & dementia (New York, N. Y.)}, volume = {12}, number = {2}, pages = {e70274}, pmid = {42339400}, issn = {2352-8737}, abstract = {INTRODUCTION: Anti-amyloid therapies such as lecanemab have demonstrated statistically significant slowing of decline on the Clinical Dementia Rating-Sum of Boxes (CDR-SB) in patients with early Alzheimer's disease (AD) in pivotal trials. Converting treatment differences on CDR-SB into time saved from disease progression may help convey clinical relevance for patients and caregivers more effectively.

METHODS: Disease progression models were developed using Alzheimer's Disease Neuroimaging Initiative and National Alzheimer's Coordinating Center data. A 37% treatment-related time delay, derived from the Clarity AD trial, was applied to estimate long-term efficacy of lecanemab.

RESULTS: Natural progression models estimated 11.5 to 13.7 years from mild cognitive impairment due to AD to severe AD. When starting treatment at CDR-SB 3.2, lecanemab delayed progression to severe AD by 2.5 to 3.7 years when assuming patients remained on treatment and 2.0 to 3.0 years when accounting for treatment discontinuation. Results were consistent across different datasets.

DISCUSSION: Projections suggest lecanemab substantially delays clinical progression of AD, preserving patients' time in earlier stages of AD.}, } @article {pmid42339401, year = {2026}, author = {Burke, J and Weerman, A and Hanson, M and Zhang, Q and Monfared, AAT and Mattke, S}, title = {Travel barriers to amyloid-targeting infusion access among older adults.}, journal = {Alzheimer's & dementia (New York, N. Y.)}, volume = {12}, number = {2}, pages = {e70282}, pmid = {42339401}, issn = {2352-8737}, abstract = {INTRODUCTION: Amyloid-targeting treatments (ATT) for Alzheimer's disease require regular infusions and caregiver accompaniment for approximately 80% of patients. Travel time to infusion sites and caregiver availability can therefore impede access to care, especially in rural and lower income populations.

METHODS: We conducted a survey in a nationally representative Internet panel with more than 2300 adults aged ≥65 years to estimate willingness to travel for bi-weekly infusion treatment, and access to an accompanying caregiver. Addresses of respondents and infusion sites were geocoded and driving times to the nearest infusion centers were calculated using Google Maps road network data. To estimate potential access gains under subcutaneous (SC) delivery, we estimated access by relaxing the travel and accompaniment requirements in a scenario analysis.

RESULTS: Median willingness-to-travel time was 97.5 minutes (interquartile range [IQR]: 67.5-187.5 minutes) one way for bi-weekly infusions over a 5-year period. Approximately 90% of respondents were willing to travel the required time to reach an infusion site. However, 18% indicated that it would be unlikely that they could identify someone to accompany them. When caregiver accompaniment was incorporated as a constraint, 75% met both the travel and caregiver criteria. In regression analysis, respondents with annual incomes above $60,000 and those residing in metropolitan areas were 9 and 19 percentage points more likely, respectively, to meet travel and caregiver criteria. In a scenario analysis, SC delivery increased overall access by up to 33%, in relative terms, with larger proportional gains for low income and rural respondents.

DISCUSSION: A meaningful number of individuals in a nationally representative sample live farther from their nearest site than they would be willing to travel, and obstacles to access worsen if individuals need a caregiver to accompany them, as is common among early-stage AD patients. Treatments that do not require infusion delivery could improve equitable access to care.}, } @article {pmid42339433, year = {2024}, author = {Jellinger, KA}, title = {Mild cognitive impairment in Parkinson's disease: current view.}, journal = {Frontiers in cognition}, volume = {3}, number = {}, pages = {1369538}, pmid = {42339433}, issn = {2813-4532}, abstract = {Parkinson's disease (PD), the most common motor movement disorder and second most common neurodegenerative disorder after Alzheimer's disease (AD), is often preceded by a period of mild cognitive impairment (MCI), which is associated with impairment of a variety of cognitive domains including executive function, attention, visuospatial abilities and memory. MCI, a risk factor for developing dementia, affects around 30% of de novo PD patients and can increase to 75% after more than 10 years. While 30-40% remain in the MCI state, up to 60% will convert to dementia. Characteristic findings are slowing of EEG rhythms, frontotemporal hypoperfusion, decreased functional connectivity in the default mode and attentional networks, prefrontal and basal-ganglia-cortical circuits, which often manifests prior to clinical symptoms and overt brain atrophy. The heterogeneity of cognitive phenotypes suggests that a common neurodegenerative process affects multiple functional neuronal networks and neuromodulatory systems that may be superimposed by Lewy body and Alzheimer's-related or other co-pathologies. Sparse neuropathological data for PD-MCI revealed a heterogenous picture with various morphological changes similar to MCI in other diseases. This review highlights the essential epidemiological, clinical, neuroimaging and morphological changes in PD-MCI, available biomarkers, and discusses the heterogenous pathobiological mechanisms involved in its development. In view of its complex pathogenesis, well-designed longitudinal clinico-pathological studies are warranted to clarify the alterations leading to MCI in PD, which may be supported by fluid and neuroimaging biomarkers as a basis for early diagnosis and future adequate treatment modalities of this debilitating disorder.}, } @article {pmid42340126, year = {2026}, author = {Thunell, J and Tysinger, B and Baumgart, M and Carrillo, M and Crimmins, E and Goldman, D and Heun-Johnson, H and Jacobson, M and Joyce, G and Leaf, D and Neumann, LTV and Zissimopoulos, J}, title = {The cost of dementia in the United States in 2026.}, journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association}, volume = {22}, number = {6}, pages = {e71480}, pmid = {42340126}, issn = {1552-5279}, support = {U01AG086827/AG/NIA NIH HHS/United States ; }, mesh = {Humans ; United States ; *Dementia/economics/epidemiology ; *Cost of Illness ; Aged ; *Health Care Costs/statistics & numerical data ; Quality of Life ; Female ; Middle Aged ; Male ; Caregivers/economics ; Health Expenditures/statistics & numerical data ; }, abstract = {INTRODUCTION: Comprehensive cost measurement is essential for an effective policy response to societal dementia costs.

METHODS: Using dynamic microsimulation, the Health and Retirement Study, and other national data, we quantified the 2026 cost of dementia in the United States.

RESULTS: In 2026, 5.7 million (95% confidence interval [CI] [5.6, 6.0]) US adults aged 51 and older are living with dementia, supported by 5.2 million (95% CI [4.9, 5.5]) care partners. Total costs are $818 billion (B, 95% CI [759, 866]), driven by quality-of-life losses for persons with dementia ($320B, 95% CI [269, 363]) and care partners ($15B 95% CI [6, 25]). Unpaid care ($237B, 95% CI [220, 253]), earnings losses ($23B), and out-of-pocket costs combined with quality-of-life losses account for 80% of costs and are borne by families. Governments cover 70% of healthcare costs ($222B, 95% CI [209, 237]).

DISCUSSION: The costs of dementia fall on families, highlighting limited policy and work supports. Treatment innovation may increase medical costs but reduce caregiver burden and improve quality of life.

HIGHLIGHTS: The costs of dementia in the United States in 2026 are $818 billion. Quality-of-life losses are the largest driver of dementia's total burden. Individuals and families bear over three times the cost versus health systems. Methods enable analysis of treatment, care, and policy innovations on future costs.}, } @article {pmid42340306, year = {2026}, author = {Brookman, R and Christensen, J and Maurice, OR and Aghaei, M and Cass, A and Monzaviyan, S and Shatnawi, E and Carter, M and Tran, J and McIlwain, N and Garrido, S and Siette, J and Strutt, P and Harris, CB}, title = {Measures used to evaluate psychosocial interventions in dementia care: A narrative review and synthesis.}, journal = {Journal of Alzheimer's disease : JAD}, volume = {}, number = {}, pages = {13872877261459125}, doi = {10.1177/13872877261459125}, pmid = {42340306}, issn = {1875-8908}, abstract = {Psychosocial interventions are widely used in dementia care, yet standardized outcome measurement remains highly variable, and recent frameworks emphasize outcomes prioritized by people living with dementia and their care partners. This narrative, measurement-focused review does not appraise or synthesize treatment effects. Instead, it aims to map outcome measures to the International Consortium for Health Outcomes Measurement (ICHOM) dementia set plus an additional carer-wellbeing domain, to organize them into a taxonomy of wellbeing domains that highlights patterns and gaps in measurement practice. Eligible studies included participants with Alzheimer's disease and related dementias, evaluated a psychosocial intervention, and reported standardized pre- and post-intervention outcome measures at short and/or long-term follow-up. A total of 136 studies met inclusion criteria. Interventions encompassed arts and creative therapies, cognitive and reminiscence approaches, education and psychosocial support, physical and movement-based therapies, sensory and relaxation therapies, environmental and daily living support, and animal/robot-assisted programs. Outcome measures clustered on neuropsychiatric symptoms (205 instances) and cognitive functioning (146 instances), with fewer measures of social functioning (22 instances) and health-related quality of life (13 instances). Measurement approaches were highly variable (43 distinct neuropsychiatric measures, 47 cognitive measures, 14 social functioning measures). Outcomes were predominantly assessed using short-term measures, with some long-term follow-up, and few observational in-the-moment measures capturing engagement, enjoyment, reciprocity or mastery. This review presents a taxonomy of outcome measures that highlights the mismatch between current evaluation practices and person-centered psychosocial priorities in dementia care, and guides more purposeful measure selection.}, } @article {pmid42341593, year = {2026}, author = {Wik, E and Dahlén, AD and Julku, U and Xiong, M and Michno, W and Syvänen, S and Sehlin, D}, title = {Brain interstitial fluid pharmacokinetics and therapeutic effect of a BBB penetrating amyloid beta antibody measured by microdialysis.}, journal = {Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics}, volume = {23}, number = {4}, pages = {e00949}, doi = {10.1016/j.neurot.2026.e00949}, pmid = {42341593}, issn = {1878-7479}, abstract = {The disease-modifying antibody lecanemab for treating Alzheimer's disease (AD) was initially designed to target amyloid-beta (Aβ) protofibrils, i.e. soluble aggregates of Aβ, but it has also been successful in clearing insoluble amyloid plaques in clinical studies. Therefore, this study aimed to investigate how a brain penetrating, bispecific murine variant of lecanemab (RmAb158-scFv8D3) distributes in the brain and interacts with different pools of aggregated Aβ in APP transgenic mice. The alpha-synuclein targeting antibody RmAbSynO2-scFv8D3 was used as control. Further, by performing in vivo high cut-off microdialysis in freely moving animals, brain interstitial fluid (ISF) was continuously collected across 24 h to assess concentrations of free antibody in the brain. Post mortem distribution of the antibodies was analyzed by sequential extraction of brain tissue. RmAb158-scFv8D3 showed rapid ISF clearance as well as a redistribution from brain extracts containing small, soluble Aβ species toward brain extracts containing insoluble, plaque-associated Aβ with time. A treatment effect was detected already at 12 h post injection, whereby the RmAb158-scFv8D3-treated animals showed lower concentrations of the smallest, most soluble Aβ aggregates. Collectively, these findings suggest that within the first 24 h after a single injection of the bispecific RmAb158-scFv8D3 antibody we can capture the antibody's initial brain distribution and interactions with both soluble Aβ aggregates and insoluble, plaque-associated Aβ. These interactions mediate a swift reduction of soluble Aβ, while clearance of insoluble Aβ requires longer treatment time.}, } @article {pmid42343047, year = {2026}, author = {Jiang, Z and Zhang, J and Zhang, X and Xie, C and Chen, X and Ma, G and Lu, X and Ai, Y and Jia, T}, title = {Targeting NOX4 with Quercetagetin-PLGA nanomaterials: a novel therapeutic strategy for Alzheimer's disease.}, journal = {Naunyn-Schmiedeberg's archives of pharmacology}, volume = {}, number = {}, pages = {}, pmid = {42343047}, issn = {1432-1912}, abstract = {This study aims to address NOX4 (NADPH oxidase 4)-driven oxidative injury in Alzheimer's disease (AD) and the poor bioavailability of the natural flavonoid Quercetagetin, we developed an α7 nicotinic acetylcholine receptor (α7-nAChR)-targeted, Quercetagetin-loaded PLGA nanocarrier (PLGA@Quercetagetin@α7-nAChR) for receptor-mediated delivery, NOX4 suppression, and neuroprotection. Using the GSE97760 dataset, bioinformatic screening combined with LASSO regression was performed to identify candidate targets. Single-cell RNA sequencing (scRNA-seq) with pseudotime analysis was applied to delineate cell type-resolved and trajectory-associated expression patterns. Nanoparticles were fabricated by a double-emulsion method and characterized for physicochemical properties. In an Aβ-induced HT-22 neuronal injury model, genetic perturbation, western blotting, and flow cytometry were used to validate the pathogenic role of NOX4 and to evaluate the pharmacological efficacy of the nanoplatform. NOX4 emerged as the key gene, showing enriched expression in oligodendrocytes and endothelial cells and an increase along the inferred disease-associated trajectory. In vitro, Aβ stimulation upregulated NOX4, whereas NOX4 knockdown or Quercetagetin treatment alleviated Aβ-induced cytotoxicity and apoptosis. The nanoparticles exhibited an average diameter and sustained drug release over 72 h. α7-nAChR targeting enhanced neuronal uptake by ~ fivefold, markedly reduced NOX4 mRNA levels, and decreased the apoptotic rate from 18.3% to 5.0%. Notably, encapsulation also mitigated the hepatorenal toxicity observed with high-dose free Quercetagetin. These in vitro findings suggest NOX4 as a potential target in AD, and the PLGA@Quercetagetin@α7-nAChR nanoplatform shows improved cellular uptake and reduced short-term toxicity compared to free drug. However, claims regarding brain targeting and translational potential are limited by the absence of in vivo validation, non-targeted controls, drug exposure normalization, and key formulation parameters (e.g., encapsulation efficiency). Future in vivo studies are required to substantiate this targeted strategy for AD.}, } @article {pmid42343519, year = {2026}, author = {Zhou, B and Zhu, C and Chen, X and Li, J and Gao, D and Wu, A and Tao, L and Yuan, X and Yang, G and Chen, X and Xie, M and Cheng, L and Wang, X}, title = {[Mechanism of moxibustion at the governor vessel for regulating autophagy against Alzheimer's disease via lncRNA-RP4-mediated Wnt/β-catenin pathway].}, journal = {Zhongguo zhen jiu = Chinese acupuncture & moxibustion}, volume = {46}, number = {6}, pages = {929-947}, doi = {10.13703/j.0255-2930.20250309-k0001}, pmid = {42343519}, issn = {0255-2930}, mesh = {Animals ; *Alzheimer Disease/therapy/genetics/metabolism/physiopathology ; *RNA, Long Noncoding/genetics/metabolism ; *Moxibustion ; *Autophagy ; Mice ; Humans ; *Wnt Signaling Pathway ; Male ; Mice, Inbred C57BL ; *beta Catenin/metabolism/genetics ; Mice, Transgenic ; MicroRNAs/genetics/metabolism ; Acupuncture Points ; Membrane Proteins/genetics/metabolism ; }, abstract = {OBJECTIVE: To observe the effect of moxibustion at the governor vessel on lncRNA-RP4/miR-939-5p and Bnip3 in APP/PS1 double transgenic mice mediated by Wnt/β-catenin pathway, and to explore the mechanism of moxibustion in the treatment of Alzheimer's disease (AD).

METHODS: Sixty 6-month-old APP/PS1 mice were randomly divided into a model group, a rapamycin group, a moxibustion+ 3-methyladenine (3-MA) group and a moxibustion group, with 15 mice in each group. Fifteen C57BL/6J mice of the same age were used as the control group. The rapamycin group was given intraperitoneal injection of rapamycin (2 mg/kg). The moxibustion group was given moxibustion at "Baihui" (GV20),suspended moxibustion at "Fengfu" (GV16) and "Dazhui" (GV14) for 20 min. The moxibustion+3-MA group was injected with 1.5 mg/kg 3-MA on the basis of the moxibustion group. After 6 consecutive treatments, rest for 1 d, and lasted 2 weeks.HEK293T cells were cultured in vitro and transfected with miR-939-5p and its empty plasmid, and transfected with lncRNA-RP4 and Bnip3 wild-type and mutant. HT22 cells cultured in vitro were randomly divided into a control group and a model (Aβ 1-42) group. The lncRNA-RP4 overexpression group, the lncRNA-RP4 knockdown group, the miR-939-5p mimic group, the miR-939-5p inhibitor group, the Bnip3 overexpression group, the Bnip3 knockdown group and the corresponding empty plasmid group were set up, and transfection was performed on the basis of the model group. Morris water maze test was used to detect the learning and memory ability of mice. HE staining was used to observe the morphology of hippocampus in each group. The structure of nerve cells, the number and structure of autophagic vacuoles and autophagic lysosomes in hippocampal CA1 region of mice in each group were observed by transmission electron microscopy. The expression of Aβ 1-42 protein in hippocampus was detected by immunohistochemistry. The expression of mTOR, TFEB, P62, Wnt3 a, β-catenin, GSK-3β, lncRNA-RP4, miR-939-5 p and Bnip3 mRNA in hippocampus of mice in each group was detected by real-time fluorescence quantitative PCR. Western blot was used to detect the expression of mTOR, TFEB, P62, LC3 B-Ⅰ,LC3 B-Ⅱ, CTSB, Lamp1, V-ATPase, Wnt3a, β-catenin, GSK-3β and Bnip3 protein in hippocampus of mice in each group.Dual luciferase assay was used to verify the targeting relationships among lncRNA-RP4, miRNA-939-5p and Bnip3 in HEK293T cells. The concentration of Aβ 1-42 in HT22 cells of each group was detected by ELISA. The expression of lncRNA-RP4, miR-939-5p, Bnip3, Wnt3a, β-catenin and GSK-3β mRNA in HT22 cells of each group was detected by real-time fluorescence quantitative PCR. The expression of Bnip3, Wnt3a, β- catenin and GSK-3β protein in HT22 cells of each group was detected by Western blot.

RESULTS: Compared with the model group, the escape latency of the rapamycin group and the moxibustion group was shortened (P<0.05), and the number of crossing the platform was increased (P<0.05).The number of hippocampal neurons was large, and a small amount of cell necrosis was observed. The cells were arranged in an orderly manner with clear boundaries. Some neurons were deformed, atrophied and irregular, and autophagic vacuoles increased. The expression of A β 1-42 protein, mTOR, P62, GSK-3β mRNA and protein, and miR-939-5p mRNA in hippocampus was decreased (P<0.05), while the expression of TFEB, Wnt3a, β-catenin, Bnip3 mRNA and protein, LC3B-Ⅰ, LC3B-Ⅱ, CTSB, Lamp1, V-ATPase protein, and lncRNA-RP4 mRNA was increased (P<0.05). Compared with the rapamycin and moxibustion groups, the escape latency of the moxibustion+3-MA group was prolonged (P<0.05), and the number of crossing the platform was decreased (P<0.05). The number of hippocampal neurons decreased slightly, the cell necrosis was more, the cell arrangement was irregular, the boundary was blurred, and a small amount of autophagic vacuoles and more deformed neurons were occasionally seen. The expression of A β 1-42 protein, mTOR, P62, GSK-3β mRNA and protein, and miR-939-5p mRNA in hippocampus increased (P<0.05), while the expression of TFEB, Wnt3a, β-catenin,Bnip3 mRNA and protein, LC3B-Ⅰ, LC3B-Ⅱ, CTSB, Lamp1, V-ATPase protein, and lncRNA-RP4 mRNA decreased (P<0.05). Dual luciferase assay confirmed that there was a targeting relationship among lncRNA-RP4, miR-939-5p and Bnip3.After the intervention of lncRNA-RP4 in vitro, compared with the model group, the expression of Aβ 1-42 protein,miR-939-5p mRNA, GSK-3 β mRNA and protein in the lncRNA-RP4 overexpression group was decreased (P<0.05), and the expression of lncRNA-RP4 mRNA, Bnip3, Wnt3a, β-catenin mRNA and protein was increased (P<0.05). The expression of Aβ 1-42 protein, miR-939-5p mRNA, GSK-3 β mRNA and protein in lncRNA-RP4 knockdown group was increased (P<0.05), while the expression of lncRNA-RP4 mRNA, Bnip3, Wnt3a and β-catenin mRNA and protein was decreased (P<0.05). Compared with the lncRNA-RP4 overexpression group, the expression of Aβ 1-42 protein, miR-939-5p mRNA, GSK-3 β mRNA and protein in the lncRNA-RP4 knockdown group was increased (P<0.05), and the expression of lncRNA-RP4 mRNA, Bnip3, Wnt3a, β-catenin mRNA and protein was decreased (P<0.05). After intervention with miR-939-5p, compared with the model group, the expression of Aβ 1-42 protein, miR-939-5p mRNA, GSK-3 β mRNA and protein in the miR-939-5p mimic group was increased (P<0.05), and the expression of lncRNA-RP4 mRNA, Bnip3, Wnt3a,β-catenin mRNA and protein was decreased (P<0.05). The expression of A β 1-42 protein, miR-939-5p mRNA, GSK-3 β mRNA and protein in miR-939-5p inhibitor group was decreased (P<0.05), while the expression of lncRNA-RP4 mRNA,Bnip3, Wnt3a and β-catenin mRNA and protein was increased (P<0.05). Compared with the miR-939-5p mimic group, the expression of Aβ 1-42 protein, miR-939-5p mRNA, GSK-3β mRNA and protein in the miR-939-5p inhibitor group was decreased (P<0.05), and the expression of lncRNA-RP4 mRNA, Bnip3, Wnt3a, β-catenin mRNA and protein was increased (P<0.05). After Bnip3 intervention, compared with the model group, the expression of Aβ 1-42 protein,miR-939-5p mRNA, GSK-3 β mRNA and protein in the Bnip3 overexpression group was decreased (P<0.05), while the expression of lncRNA-RP4 mRNA, Bnip3, Wnt3a and β-catenin mRNA and protein was increased (P<0.05). The expression of A β 1-42 protein, miR-939-5p mRNA, GSK-3 β mRNA and protein in the Bnip3 knockdown group was increased (P<0.05), while the expression of lncRNA-RP4 mRNA, Bnip3, Wnt3a and β-catenin mRNA and protein was decreased (P<0.05). Compared with the Bnip3 overexpression group, the expression of Aβ 1-42 protein, miR-939-5p mRNA,GSK-3β mRNA and protein in Bnip3 knockdown group was increased (P<0.05), and the expression of lncRNA-RP4 mRNA, Bnip3, Wnt3a, β-catenin mRNA and protein was decreased (P<0.05).

CONCLUSION: Moxibustion at the governor vessel ameliorates AD cognitive deficits by activating the lncRNA-RP4/miR-939-5p/Bnip3 axis, enhancing Wnt/β-catenin pathway, restoring autophagosome-lysosome activity, promoting autophagy, accelerating A β 1-42 clearance, and improve cognitive dysfunction of AD. This study elucidates a novel epigenetic mechanism underlying moxibustion's therapeutic efficacy in AD.}, } @article {pmid42343674, year = {2026}, author = {Feng, ZP and Xiao, J and Yu, CC and Zhang, X and Yu, ZX and Pan, YK and Yang, S and Shen, F}, title = {[Mechanism of electroacupuncture at "Neiguan" (PC6) and "Jianshi" (PC5) in ameliorating blood-brain barrier damage in APP/PS1 mice based on the nucleus tractus solitarius-locus coeruleus neural circuit].}, journal = {Zhen ci yan jiu = Acupuncture research}, volume = {51}, number = {6}, pages = {677-687}, doi = {10.13702/j.1000-0607.20250903}, pmid = {42343674}, issn = {1000-0607}, mesh = {Animals ; *Electroacupuncture ; *Locus Coeruleus/metabolism ; *Blood-Brain Barrier/metabolism ; Male ; Mice ; *Solitary Nucleus/metabolism ; Mice, Inbred C57BL ; *Alzheimer Disease/therapy/metabolism/genetics/physiopathology ; *Acupuncture Points ; Humans ; Disease Models, Animal ; }, abstract = {OBJECTIVES: To observe the role of tyrosine hydroxylase (TH)-positive neurons in the nucleus tractus solitarius (NTS) and locus coeruleus (LC) in electroacupuncture (EA)-mediated improvement of blood-brain barrier (BBB) damage in APP/PS1 mice, so as to explore the mechanism of the NTS[TH]-LC neural circuit underlying the effect of EA on prevention and treatment of Alzheimer's disease (AD).

METHODS: (1) Eight 4-month-old male C57BL/6 mice served as the control group, and 16 age-matched male APP/PS1 mice were randomly divided into the model and EA groups (n=8). The EA group received EA stimulation at "Neiguan" (PC6) and "Jianshi" (PC5) once every other day for 4 weeks. After intervention, Morris water maze and novel object recognition tests were used to evaluate learning and memory abilities. Western blot was performed to detect the expression levels of hippocampal tight junction proteins, including Occludin, Claudin-5, and zonula occludens-1 (ZO-1). Immunofluorescence was used to assess the co-localization of TH/c-Fos in NTS and LC, as well as TH/norepinephrine (NE) co-localization in LC. (2) Five TH-cre mice received retrograde tracing virus injection into LC to observe whether TH-positive neurons in NTS project to LC. (3) Twenty-one 7-month-old APP/PS1 mice were injected with chemogenetic activation virus (AAV2/9-hSyn-DIO-hM3D-mCherry-WPRE-hGH-pA) or empty virus (AAV2/9-Ef1α - DIO-mCherry-WPRE-hGH-pA) into the NTS, and AAVretro-TH-CRE-WPRE-hGH-pA virus into the LC. After 21 d of virus expression, 6 mice injected with empty virus were taken as mCherry+CNO+EA group;3 mice from the activation virus group were randomly selected for brain slice patch-clamp to verify virus functionality. The remaining mice were randomly divided into 2 groups (n=6):hM3D+CNO+EA, and hM3D+saline+EA groups. EA was applied to PC6 and PC5 once daily for 15 d. After intervention, learning and memory abilities were evaluated by Morris water maze and novel object recognition tests. BBB permeability was detected by Evans blue (EB) staining. Immunofluorescence was used to measure TH/c-Fos and TH/NE co-localization in the LC.

RESULTS: (1) Compared with the control group, the model group showed significantly impaired learning and memory abilities (P<0.01), decreased expressions of hippocampal Occludin, Claudin-5, and ZO-1 (P<0.01), and increased TH/c-Fos co-localization (c-Fos expression in TH-positive neurons) in NTS and LC, as well as TH/NE co-localization in LC (P<0.01). Compared with the model group, the EA group exhibited improved learning and memory abilities (P<0.05, P<0.01), increased expressions of hippocampal tight junction proteins (P<0.01), and reduced TH/c-Fos and TH/NE co-localization (P<0.01, P<0.05). (2) Retrograde tracing confirmed that TH-positive neurons in NTS project to LC. (3) Compared with the mCherry+CNO+EA group and hM3D+saline+EA group, the hM3D+CNO+EA group showed significantly impaired learning and memory (P<0.01), increased EB content in brain tissue, and elevated TH/c-Fos and TH/NE co-localization in the LC (P<0.01).

CONCLUSIONS: EA at PC6 and PC5 can ameliorate BBB damage and learning/memory deficits in AD mice, and its mechanism may be related to inhibiting the activation of the NTS[TH]-LC neural circuit.}, } @article {pmid42346109, year = {2026}, author = {Huang, H and Xu, K and Lardellia, M}, title = {Ketone-Dependent Restoration of Autophagy and Mitochondrial Quality Control Through VPS35 in a Drosophila Model of C99-Induced Neurodegeneration.}, journal = {Cells}, volume = {15}, number = {12}, pages = {}, pmid = {42346109}, issn = {2073-4409}, mesh = {Animals ; *Mitochondria/metabolism/drug effects/ultrastructure ; *Autophagy/drug effects ; *Vesicular Transport Proteins/metabolism ; Disease Models, Animal ; *Ketones/pharmacology/metabolism ; Humans ; Neurons/metabolism/drug effects ; *Amyloid beta-Protein Precursor/metabolism ; Drosophila melanogaster/metabolism ; *Drosophila Proteins/metabolism ; Alzheimer Disease/metabolism ; }, abstract = {BACKGROUND: Early endolysosomal and autophagic defects are among the earliest cellular alterations observed in Alzheimer's disease (AD). However, the molecular mechanisms linking amyloid precursor protein (APP) metabolism to vesicle trafficking dysfunction remain incompletely understood. The APP-derived fragment C99 has emerged as a potential upstream mediator of intracellular toxicity, but its impact on organelle homeostasis and its modulation by metabolic interventions remain unclear.

METHODS: To investigate these mechanisms, we expressed human C99 in Drosophila neurons and examined intracellular pathology using ultrastructural analysis, fluorescent reporters of autophagy and mitochondrial turnover, and proteomic interactome mapping. The effects of the ketone body β-hydroxybutyrate (BHB) were evaluated to assess the impact of metabolic intervention.

RESULTS: Neuronal C99 expression induced pronounced vesicular abnormalities, impaired autophagic turnover, and disrupted mitochondrial quality control. Transmission electron microscopy revealed extensive accumulation of enlarged vesicular compartments, accompanied by reduced mitochondrial turnover and accumulation of aged mitochondria. BHB treatment restored autophagic cargo clearance, improved mitochondrial turnover, and normalized vesicular ultrastructure. These protective effects required neuronal ketone transport, indicating a neuron-intrinsic metabolic mechanism. Proteomic analysis of the C99-associated interactome revealed that ketone treatment remodels networks enriched for vesicle trafficking and proteostasis pathways. Network prioritization identified the retromer component VPS35 as a candidate regulatory hub. Functional analyses demonstrated that depletion of VPS35 abolished the BHB-dependent restoration of autophagy, mitochondrial turnover, and vesicle morphology.

CONCLUSIONS: Ketone treatment restores mitochondrial quality control and autophagic homeostasis through a VPS35-dependent mechanism in C99-induced neurodegeneration. These findings provide mechanistic insight into how metabolic interventions may restore intracellular homeostasis in Alzheimer's disease.}, } @article {pmid42346783, year = {2026}, author = {Gomes-Bispo, A and Cardoso, C and Afonso, C and Lourenço, HM and Pedro, S and Moniz, P and Bandarra, NM}, title = {Marine Lipids and Alzheimer's Disease: Biochemistry, Bioaccessibility/Bioavailability, Metabolism, and Health Effects.}, journal = {Marine drugs}, volume = {24}, number = {6}, pages = {}, pmid = {42346783}, issn = {1660-3397}, support = {MAR-016.9.1-FEAMPA-00008//Mar 2030/ ; 101060712//European Commission/ ; PRR - FF 483//Government of Portugal/ ; }, mesh = {Humans ; *Alzheimer Disease/drug therapy/metabolism ; Animals ; *Lipids/chemistry/pharmacology/pharmacokinetics/therapeutic use ; *Aquatic Organisms/chemistry ; Biological Availability ; Lipid Metabolism ; }, abstract = {Due to its high prevalence and significant impact on modern society, Alzheimer's disease (AD) is one of the most important neurodegenerative disorders. It is more common among individuals over the age of 65, and its incidence has increased sharply as a result of rising life expectancy. Several factors have made it challenging to identify an effective treatment for AD. One major difficulty lies in its complexity, as the mechanisms involved in its progression are not yet fully understood. Nevertheless, the role of diet and lipids has been highlighted by numerous studies, underscoring their potential influence on this pathology. Due to the intricacy of its biochemical and metabolic interactions, this subject continues to be of particular interest, highlighting the need for further research. In this sense, this comprehensive and updated review aimed to elucidate these aspects, especially regarding marine-derived lipids, whose bioactive potential may become an irreplaceable tool in the management of AD, whether in terms of its treatment or prevention.}, } @article {pmid42347121, year = {2026}, author = {Xiao, D and Duvvuri, A and Makrigiannis, LV and Fuller, C}, title = {The Neuroprotective Role of Exercise in Alzheimer's Disease: An Integrative Review of Animal and Human Studies.}, journal = {Neurology international}, volume = {18}, number = {6}, pages = {}, pmid = {42347121}, issn = {2035-8385}, abstract = {Alzheimer's disease (AD), the leading cause of dementia, is characterized by progressive cognitive decline along with hallmark brain pathologies including amyloid-beta accumulation, hyperphosphorylated tau, neuroinflammation and neuronal mitochondrial dysfunction. As current pharmaceutical treatments only provide modest symptomatic improvement, there is an urgent need for effective non-pharmaceutical treatment options for the prevention or slowing down of this disease. This review synthesizes results from randomized controlled trials, observational studies, and animal model research on the ability of exercise to influence cognitive functions, brain structural changes, inflammatory processes, and neuroplasticity-related pathways. Exercise has demonstrated the capacity to enhance neurotrophic signaling, improve the regulation of mitochondria, improve cerebrovascular function and reduce pro-inflammatory cytokine levels in preclinical and mild cognitive impairment (MCI) subjects. Additionally, aerobic and resistance training has been shown to enhance physical performance and functional capacity. Furthermore, mind-body, dual-task and multimodal types of interventions may also provide additional cognitive and psychological benefits. Although the overall cognitive effect of exercise in individuals with established AD is generally small, it has been demonstrated that exercise can contribute to maintaining brain health through multiple interconnected metabolic, vascular and molecular pathways, thereby preserving cognitive reserve and slowing disease progression, particularly when initiated during early to midlife prior to the onset of AD symptoms. Therefore, future research will require establishing stage-specific exercise recommendations based on modality type, intensity and duration to achieve optimal clinical outcomes.}, } @article {pmid42348056, year = {2026}, author = {Zhang, C and Long, W and Ni, J and Chen, Z and Wu, X and Li, M and Du, F and Zhao, Y and Shen, J and Cho, CH and He, X and Xiao, Z}, title = {The Biological Basis, Mechanisms of Action, and Optimization Strategies of Exosomes Derived from Mesenchymal Stem Cells for the Treatment of Alzheimer's Disease.}, journal = {Molecular neurobiology}, volume = {63}, number = {1}, pages = {}, pmid = {42348056}, issn = {1559-1182}, mesh = {*Exosomes/metabolism/transplantation ; Humans ; *Alzheimer Disease/therapy/metabolism/pathology ; Animals ; *Mesenchymal Stem Cells/metabolism ; }, abstract = {Alzheimer's disease (AD) is a complex neurodegenerative disorder whose pathological process involves multiple mechanisms, including Aβ deposition, tau protein abnormalities, neuroinflammation, synaptic damage, and neuronal loss. Current therapeutic approaches remain ineffective in halting disease progression; therefore, the development of multi-targeted, low-immunogenicity therapeutic strategies with efficient brain delivery is of great significance. Mesenchymal stem cell-derived exosomes (MSC-derived exosomes) inherit the immunomodulatory, neuroprotective, and tissue-repairing properties of MSCs, and possess good biocompatibility and the potential to cross the blood-brain barrier. Studies have shown that MSC-derived exosomes exert therapeutic effects by modulating neuroinflammation, promoting neurogenesis and synaptic plasticity, reducing Aβ deposition and tau pathology, and regulating multiple AD-related signaling pathways. At the same time, the molecular composition and functions of MSC-derived exosomes derived from different tissues exhibit heterogeneity, and their therapeutic efficacy is influenced by factors such as the source cells, culture conditions, preparation processes, and administration methods. In recent years, strategies such as engineered surface modification, functional molecule loading, three-dimensional culture, microenvironment pretreatment, large-scale production, as well as intranasal administration and biomaterial delivery systems have provided new directions for enhancing the brain-targeting ability, stability, yield, and therapeutic efficacy of MSC-derived exosomes. This review summarizes the biological basis of MSC-derived exosomes, their mechanisms of action in AD treatment, and optimization strategies, providing a reference for their further development and translational application as a cell-free therapeutic approach for AD.}, } @article {pmid42348083, year = {2026}, author = {Yildirim, C and Cevik, S and Bal, R and Kaplan, DS and Yilmaz, SG and Ulusal, H and Bekerecioglu, S}, title = {Vitexin Protects Against Scopolamine-Induced Cognitive Impairment by Preserving Synaptic Integrity and Modulating Nrf2/HO-1 and NF-κB Signaling Pathways.}, journal = {Molecular neurobiology}, volume = {63}, number = {1}, pages = {}, pmid = {42348083}, issn = {1559-1182}, mesh = {Animals ; *Apigenin/pharmacology/therapeutic use ; Male ; *NF-kappa B/metabolism ; *Signal Transduction/drug effects ; *NF-E2-Related Factor 2/metabolism ; *Synapses/drug effects/metabolism/pathology ; Rats, Wistar ; *Cognitive Dysfunction/chemically induced/drug therapy/prevention & control/metabolism ; Scopolamine ; Oxidative Stress/drug effects ; *Neuroprotective Agents/pharmacology/therapeutic use ; *Heme Oxygenase-1/metabolism ; Rats ; Maze Learning/drug effects ; *Heme Oxygenase (Decyclizing)/metabolism ; Hippocampus/drug effects/metabolism/pathology ; }, abstract = {Alzheimer's disease is characterized by progressive cognitive decline driven by oxidative stress, neuroinflammation, and synaptic dysfunction. This study investigated the neuroprotective effects of vitexin in a scopolamine (Sco)-induced rat model of cognitive impairment. Forty-two male Wistar rats were randomly assigned to six groups (n = 7 per group): saline, Sco (2 mg/kg/day, i.p.), Sco + vitexin (30 mg/kg/day, oral), Sco + donepezil (1.5 mg/kg/day, i.p.), vitexin alone, and donepezil alone. All treatments were administered for 14 consecutive days. Behavioral assessments using the morris water maze and elevated plus maze revealed that Sco significantly impaired spatial learning and memory while increasing anxiety-like behaviors. Vitexin treatment markedly improved these deficits, with efficacy comparable to donepezil. Biochemically, Sco elevated acetylcholinesterase activity, lipid peroxidation, and oxidative/nitrosative stress markers (TOS, OSI, MDA, Peroxynitrite, NO, and NOS) while decreasing total antioxidant status (TAS). Vitexin reversed these changes. Western blot and immunofluorescence analyses demonstrated that Sco reduced hippocampal BDNF, GDNF, PSD95, and synaptophysin levels and increased GFAP, IL-6, TNF-α, NF-κB p65, and COX-2 expression. Vitexin restored neurotrophic and synaptic proteins, suppressed astrocyte activation and inflammatory signaling, and activated the Nrf2/HO-1 pathway. These findings were further supported by qRT-PCR analysis of BDNF, GDNF, GPX4, and NF-κB. In conclusion, vitexin exerts significant neuroprotective and synaptoprotective effects against Sco-induced cognitive impairment by simultaneously restoring redox balance, suppressing neuroinflammation, and preserving synaptic integrity. These results position vitexin as a promising therapeutic candidate for neurodegenerative disorders, including Alzheimer's disease.}, } @article {pmid42348482, year = {2026}, author = {Xue, D and Peng, J and Yue, L and Qi, W}, title = {Understanding Discrepancies and Predictors of Self- versus Proxy-Rated Quality of Life in Chinese Community-Dwelling Older Adults with Mild Dementia: A Cross-Sectional Study.}, journal = {Dementia and geriatric cognitive disorders}, volume = {}, number = {}, pages = {1-19}, doi = {10.1159/000553237}, pmid = {42348482}, issn = {1421-9824}, abstract = {BACKGROUND: Accurate evaluation of quality of life (QoL) is essential for optimal dementia management, yet notable discrepancies exist between patient self-rated and proxy-rated QoL. This study aimed to analyse the discrepancies and agreement between self-rated and proxy-rated QoL and identify their independent predictors among community-dwelling persons with mild dementia (PwMD).

METHODS: This cross-sectional study included 129 PwMD and their primary caregivers. Assessments included sociodemographic information, the QoL-Alzheimer's Disease scale, Mini-Mental State Examination, Geriatric Depression Scale, Activities of Daily Living, Functional Activities Questionnaire and Neuropsychiatric Inventory Questionnaire. Differences and agreement were analyzed using Wilcoxon tests, Spearman correlations, and intraclass correlation coefficients (ICC). Independent predictors were identified through multiple linear regression.

RESULTS: Patients rated their QoL significantly higher than their caregivers did, with poor-to-fair agreement at the total, dimensional and item levels (ICC = 0.11-0.50). Higher depressive symptoms (β = -0.354, p = 0.001), lower severity of elation (β = 0.214, p = 0.013), and greater disinhibition (β = -0.174, p = 0.041) independently predicted poorer self-rated QoL. By contrast, greater neuropsychiatric symptom severity (β = -0.283, p < 0.001), poorer Activities of Daily Living function (β = -0.230, p = 0.006), and polypharmacy (β = -0.208, p = 0.009) predicted lower proxy-rated QoL.

CONCLUSION: Self- and proxy-rated QoL reflect distinct evaluative perspectives in PwMD. Self-reports are influenced by emotional and psychological states, whereas proxy ratings are shaped by observable symptoms, functional dependency and treatment burden. These findings suggest the need to integrate both assessment perspectives in clinical practice.}, } @article {pmid42349060, year = {2026}, author = {Changchien, TC and Zul, DD and Cheng, KD and Mathurin, TV and Dagbue, AC and Fang, YY and Liang, CS and Yeh, WC and Hsu, TW}, title = {Lithium versus valproate in bipolar disorder: Associations with dementia, mortality, suicide attempt, and end-stage renal disease in adults aged 45 years and older - a propensity score-matched retrospective cohort study.}, journal = {Psychiatry research}, volume = {364}, number = {}, pages = {117284}, doi = {10.1016/j.psychres.2026.117284}, pmid = {42349060}, issn = {1872-7123}, abstract = {BACKGROUND/OBJECTIVE: Patients with bipolar disorder (BD) are at increased risk of dementia. However, few studies have directly compared subsequent dementia risk between BD patients treated with lithium and valproate, the two first-line mood stabilizers.

METHODS: This retrospective cohort study used the TriNetX collaborative network, which aggregates de-identified electronic health records across the United States. Adults aged≧45 years with BD who initiated lithium or valproate for the first time between 2000 and 2025 were included. 1:1 propensity score matching was applied. The primary outcome was all-cause dementia, and secondary outcomes were Alzheimer's disease, vascular dementia, unspecified dementia (ICD10 code: F03), mortality, suicide attempt, and ESRD.

RESULTS: After applying exclusion criteria and matching, 3056 patients remained in each group. Lithium use was associated with a lower risk of all-cause dementia than valproate use (207 [7.1%] vs 311 [10.8%]; Relative risk [RR], 0.658; 95% confidence interval [CI], 0.556-0.778; Hazard ratio [HR], 0.689; 95% CI, 0.578-0.822; both P<.001). Lithium use was also associated with lower risks of unspecified dementia (HR, 0.677; 95% CI, 0.530-0.865; P=.002) and suicide attempt (HR, 0.594; 95% CI, 0.399-0.885; P=.010). Although the relative risk of Alzheimer disease was lower in the lithium group, the adjusted hazard ratio did not reach statistical but marginal significance. No significant between-group differences were observed for vascular dementia, mortality, or ESRD.

LIMITATIONS: Residual confounding may persist due to the observational design, and dementia diagnoses relied on clinical coding within electronic health records.

CONCLUSIONS: In this large, compliance-verified cohort, lithium treatment was associated with lower risks of dementia compared to valproate, without excess ESRD or mortality risk. These findings support lithium as a preferred long-term mood stabilizer for preserving cognitive outcomes in older adults with bipolar disorder, though observational data preclude causality inferences.}, } @article {pmid42349617, year = {2026}, author = {Li, Q and Liu, X and Xing, R and Qi, F and Li, X and Wang, K and Chen, L}, title = {5-Methoxyseselin inhibits neuronal ferroptosis and β-amyloid production in female APP/PS1 transgenic mice.}, journal = {Biochemical pharmacology}, volume = {251}, number = {Pt 2}, pages = {118188}, doi = {10.1016/j.bcp.2026.118188}, pmid = {42349617}, issn = {1873-2968}, abstract = {Nrf2 signaling dysregulation drives progressive cognitive decline in Alzheimer's disease (AD), as the brain's endogenous defenses fail to neutralize oxidative stress and ferroptotic neuronal attrition. Here, we report that 5-Methoxyseselin (5-Met), a natural coumarin derivative, is a nuclear factor erythroid 2-related factor 2 (Nrf2) inducer that facilitates glutathione peroxidase 4 (GPX4)-mediated lipid-repair machinery. Mechanistically, 5-Met may bind to Kelch-like ECH-associated protein 1 (Keap1), thereby disrupting the Keap1-Nrf2 inhibitory interaction and promoting Nrf2 stabilization. This leads to upregulated GPX4 expression and subsequent suppression of neuronal ferroptosis in APP/PS1 mice. Consistently, 5-Met treatment effectively protected N2a cells from ferroptotic challenges induced by ferric ammonium citrate (FAC), erastin, or RSL3 via upregulating GPX4 expression. Furthermore, 5-Met modulated β-amyloid (Aβ) homeostasis by inhibiting β-amyloid precursor protein-cleaving enzyme 1 (BACE1)-mediated Aβ production and enhancing low-density lipoprotein receptor-related protein 1 (LRP1)-mediated Aβ efflux. In addition, 5-Met treatment improved cognitive performance in APP/PS1 mice. Collectively, these findings identify 5-Met as a multi-target neuroprotective agent that restores Aβ homeostasis and inhibits neuronal ferroptosis, suggesting it may be a therapeutic compound for AD.}, } @article {pmid42349816, year = {2026}, author = {Abdel-Aal, RA and Abdelnabi, S and Badary, DM and Hussein, AMR}, title = {Effect of Metformin on Anti-Alzheimer Activity of Rivastigmine in Aluminum Chloride-Induced Alzheimer's Disease in Rats: A Behavioral, Biochemical, Immunohistopathological Evidence of Crosstalk between Amyloid, Tau, Autophagy, and Apoptosis.}, journal = {European journal of pharmacology}, volume = {}, number = {}, pages = {179087}, doi = {10.1016/j.ejphar.2026.179087}, pmid = {42349816}, issn = {1879-0712}, abstract = {AIM: This study investigates how the anti-Alzheimer's effectiveness of rivastigmine (RIVA) is affected by the antidiabetic drug metformin (MET).

METHOD: ology: Male rats were randomly divided into a control group, an Alzheimer's disease (AD) group receiving aluminum chloride (AlCl3), a RIVA-treated group, a MET-treated group, and a RIVA+MET combination group. Cognitive performance was assessed using passive avoidance (PA), the radial arm maze (RAM), the Morris water maze (MWM), and novel object recognition (NOR) tests. Hippocampal microtubule-associated protein tau (MAPT), beta-site APP cleaving enzyme 1 (BACE1), acetylcholinesterase (AChE), and autophagy marker Sequestosome 1 (SQSTM1/p62) were measured, while amyloid-beta (Aβ) and caspase-3 expression were analyzed immunohistochemically. Histopathology and electron microscopy were used to assess neuronal integrity.

RESULTS: MET, RIVA, and their combined treatment mitigated the neurodegenerative alterations induced by AlCl3. The combination of MET+RIVA failed to yield significant differences in behavioral performance [PA, RAM, MWM, and NORT], MAPT levels, and AChE activity compared with the treatment with RIVA monotherapy. However, the combination therapy showed significant reductions in hippocampal BACE1, Aβ deposition, and SQSTM1/p62 levels, indicating enhanced suppression of amyloidogenic processing and improved autophagy. Although differences between MET+RIVA combination and RIVA monotherapy were not statistically significant for these markers, the combination markedly reduced caspase-3 immunoreactivity compared with the diseased group, indicating greater attenuation of apoptosis.

CONCLUSION: These results highlight the crosstalk among the amyloid, tau, autophagy, and apoptotic pathways in AD and suggest that the MET+RIVA combination showed promising molecular improvements but no clear behavioral superiority, indicating the need for further optimization.}, } @article {pmid42351553, year = {2026}, author = {Hong, B and Tao, T and Li, Y and Gu, Z and Zhang, H and Chen, J and Yue, L}, title = {Prediction of Antipsychotic Drug Doses for BPSD in Alzheimer's Disease Using Deep Learning Techniques.}, journal = {Diagnostics (Basel, Switzerland)}, volume = {16}, number = {12}, pages = {}, pmid = {42351553}, issn = {2075-4418}, support = {STI2030-Major Projects-2022ZD0213100//National Natural Science Foundation of China/ ; STI2030-Major Projects-2022ZD029000//National Natural Science Foundation of China/ ; NA//the integrated innovation team project of Shanghai Mental Health Center/ ; JCYJ-SHFY-2022-014//Shanghai Pilot Program for Basic Research-Chinese Academy of Science, Shanghai Branch/ ; 20Y11906800//Shanghai Science and Technology Committee/ ; No.KCXFZ20211020163408012//Shenzhen Science and Technology Program/ ; NA//the Program of High-Level Medical Talents, National Health Commission of China/ ; 2023-TX-018//the Programe of Chen Frontier Lab for AI and Mental Health (TCCI) - Shanghai Mental Health Center (SMHC)/ ; SHDC12025118//Shanghai Shen-Kang Hospital Development Center/ ; SHDC22025303//Shanghai Shen-Kang Hospital Development Center/ ; NA//the Integrated Innovation Team Project of Shanghai Mental Health Center/ ; NA//The Scientific Research Program of FuRong Laboratory/ ; 19MC1911100//Shanghai Clinical Research Center for Mental Health/ ; 13dz2260500//Shanghai Key Laboratory of Psychotic Disorders/ ; }, abstract = {Background/Objectives: Antipsychotic dosing for behavioral and psychological symptoms of dementia (BPSD) in Alzheimer's disease remains empirical and variable. This study develops a deep learning model to predict individualized antipsychotic doses from structural MRI. Methods: A transfer learning approach with a cascaded ResNet (Cas-ResNet) was used. The model was first pre-trained on a large healthy aging dataset (CBMFM, n = 646) for brain age prediction, then fine-tuned on a BPSD dataset (SMHC, n = 86) to predict the defined daily dose (DDD) of antipsychotics. Model interpretability was performed using Grad CAM to identify predictive brain regions. Results: The proposed model achieved a mean absolute error of 0.19 and a Pearson correlation of 0.66 between predicted and actual doses, outperforming baseline 3DCNN, VGG, and DenseNet. Key contributing regions included the left inferior temporal gyrus, right parahippocampal gyrus, right putamen, left middle temporal gyrus, and left caudate. Conclusions: This proof-of-concept study demonstrates that deep learning can predict personalized antipsychotic doses from structural MRI, offering an objective tool to standardize BPSD pharmacotherapy and reduce empirical prescribing. The identified brain regions provide neurobiological insights into treatment response.}, } @article {pmid42351734, year = {2026}, author = {Dragomir, AF and Barbu, AC and Stoleru, S and Zugravu, A and Dumitrescu, MC and Bazar, G and Ghita, CIV and Fratea, S and Stoleru, CM and Coman, OA and Fulga, I}, title = {Comparative Effects of Donepezil and Tacrine on Recall-Related Exploratory Behavior in a Subacute Lipopolysaccharide-Induced Neuroinflammatory Model of Cognitive Impairment.}, journal = {Biomedicines}, volume = {14}, number = {6}, pages = {}, pmid = {42351734}, issn = {2227-9059}, abstract = {Background/Objectives: Neuroinflammation is increasingly recognized as an important contributor to Alzheimer-like cognitive impairment. Lipopolysaccharide (LPS) is commonly used in experimental models to trigger systemic immune activation and behavioral alterations associated with neuroinflammation. This study aimed to validate a subacute LPS-induced model of recall-phase impairment and to compare the effects of donepezil and tacrine on recall-related exploratory behavior in rats. Methods: Male Wistar rats were tested in a two-trial Y-maze paradigm consisting of an acquisition trial followed by a recall trial 24 h later. In the validation experiment, rats received saline or LPS 1 mg/kg intraperitoneally for four consecutive days. In the intervention experiment, rats received saline, LPS, or LPS combined with donepezil 1 or 3 mg/kg or tacrine 3 or 5 mg/kg. The primary recall-phase outcome was the unknown/known arm time ratio (U/K time ratio). Additional outcomes included arm times, arm entries, U/K entry ratios, discrimination indices, and mean time per entry. Results: Repeated LPS administration significantly reduced the U/K time ratio, decreased time- and entry-based discrimination indices, reduced time spent in the unknown arm, and decreased unknown-arm entries, without significantly altering acquisition-phase behavior, total entries, or mean time per entry. In the intervention experiment, donepezil 1 mg/kg and tacrine 5 mg/kg significantly increased the U/K time ratio compared with LPS. Discrimination indices and entry-based measures further supported a treatment-related shift toward novelty-directed exploration, while total arm entries and mean time per entry were not significantly changed. Conclusions: Subacute LPS administration produced a measurable recall-phase exploratory impairment in the Y-maze. Donepezil and tacrine attenuated several components of this impairment, with partially distinct dose-related behavioral profiles.}, } @article {pmid42351738, year = {2026}, author = {Sarwar, T and Rehman, AA and Arif, H and Alwanian, WM and Alharbi, HOA and Rahmani, AH}, title = {Biophysical and Computational Insights into Alpha-1 Antitrypsin Aggregation and Its Inhibition by Natural Polyphenols.}, journal = {Biomedicines}, volume = {14}, number = {6}, pages = {}, pmid = {42351738}, issn = {2227-9059}, abstract = {Background/Objectives: Protein misfolding and amyloid fibril formation underlie several degenerative diseases, including Alzheimer's disease and Parkinson's disease. Alpha-1 antitrypsin (A1AT), a serpin protein, is particularly prone to misfolding, with polymerization and aggregation implicated in alpha-1 antitrypsin deficiency and associated hepatic and pulmonary disorders. In this study, we examined the structural changes in A1AT induced by the fluorinated alcohol, trifluoroethanol (TFE), and assessed the inhibitory effects of two natural polyphenols, amentoflavone (AMF) and theaflavin (TF), on aggregation and fibril formation. Methods: A library of selected phytocompounds was virtually screened against the crystal structure of A1AT (PDB 3NE4) using AutoDock Vina to elucidate their binding affinity towards it. Based on binding affinities, two compounds, AMF and TF, were selected for further studies. Protein aggregation was induced with TFE, and the protective effects of AMF and TF were evaluated using protease inhibitory activity, intrinsic fluorescence, turbidity, Rayleigh scattering, ANS fluorescence, and ThT fluorescence assays. Furthermore, 100 ns molecular dynamics simulation and MM-PBSA calculations were performed to assess the stability and binding interactions of the A1AT-ligand complexes. Results: Pre-treatment of A1AT with AMF or TF significantly inhibited TFE-induced aggregation in a dose-dependent manner, with AMF being consistently more effective. ThT fluorescence analysis revealed a ~60-65% decrease in aggregate formation upon treatment with polyphenols, with IC50 values estimated at ~40 µM for AMF and ~50 µM for TF, both of which are statistically significant. Molecular docking and 100 ns molecular dynamics simulation also revealed stable A1AT-polyphenol interactions, with AMF exhibiting greater binding affinity and greater attenuation of solvent-induced conformational perturbation. Conclusions: Collectively, our findings show that TFE causes A1AT misfolding via a molten globule-like intermediate, resulting in fibril formation at 30-40% TFE, and natural polyphenols AMF and TF inhibited aggregation in a concentration-dependent manner. These observations suggest the potential of AMF and TF as lead scaffolds for anti-aggregation strategies, as modulators of amyloidogenic processes.}, } @article {pmid42352265, year = {2026}, author = {Tian, M and Feng, R and Gong, C and Ben, X and Ma, Z and Yi, X and Guo, Q}, title = {Intranasal Adipose-Derived MSC Extracellular Vesicles Confer Sustained Cognitive Improvement and Suppress Alzheimer's Pathology in APP/PS1 Mice.}, journal = {Biomolecules}, volume = {16}, number = {6}, pages = {}, pmid = {42352265}, issn = {2218-273X}, support = {ZDYF2024SHFZ137//Department of Science and Technology of Hainan Province/ ; 823QN246//Department of Science and Technology of Hainan Province/ ; 82301632//National Natural Science Foundation of China/ ; QCQTXM202213//Department of Science and Technology of Hainan Province/ ; }, mesh = {Animals ; *Alzheimer Disease/therapy/pathology/metabolism/genetics ; *Extracellular Vesicles/metabolism/transplantation ; Administration, Intranasal ; Mice ; Female ; Mice, Transgenic ; *Mesenchymal Stem Cells/metabolism/cytology ; Amyloid beta-Protein Precursor/genetics/metabolism ; Amyloid beta-Peptides/metabolism ; Presenilin-1/genetics/metabolism ; Cognition ; Disease Models, Animal ; *Adipose Tissue/cytology ; Hippocampus/metabolism/pathology ; Humans ; Cognitive Enhancement ; }, abstract = {Alzheimer's disease (AD) lacks effective disease-modifying therapies, and extracellular vesicles (EVs) derived from adipose-derived mesenchymal stromal cells (ADMSCs) have emerged as promising therapeutic candidates. In this study, we investigated the brain biodistribution and dose-dependent effects of intranasally administered ADMSC-EVs in female APP/PS1 mice, with age-matched wild-type mice and vehicle-treated transgenic mice serving as controls. EV biodistribution was assessed using PKH26 labeling, cognitive performance was evaluated using the Morris water maze, Y-maze, and novel object recognition tests, and hippocampal amyloid pathology and plasma AD-related biomarkers were analyzed. Intranasally delivered ADMSC-EVs rapidly reached multiple brain regions, including the hippocampus, improved learning and memory performance, and reduced hippocampal amyloid-β 1-42 (Aβ42) deposition and plaque burden. These effects followed a nonlinear dose-response pattern, with reduced efficacy at low doses and no additional benefits at high doses. Notably, partial behavioral and pathological benefits persisted after treatment cessation. Together, these findings show that intranasal ADMSC-EVs exert therapeutic effects in APP/PS1 mice and support the importance of dose optimization and post-treatment durability in the development of EV-based interventions for AD.}, } @article {pmid42352894, year = {2026}, author = {Janpaijit, S and Verma, K and Widoyanti, AAE and Tencomnao, T and Prasansuklab, A}, title = {Exploring Mechanistic Targets of Areca catechu Against Neurodegenerative Diseases Through an Integrated Network Pharmacology, Molecular Docking, and Experimental Approaches.}, journal = {International journal of molecular sciences}, volume = {27}, number = {12}, pages = {}, pmid = {42352894}, issn = {1422-0067}, support = {Fundamental Fund//Thailand Science Research and Innovation Fund, Chulalongkorn University/ ; }, mesh = {Molecular Docking Simulation ; Animals ; Network Pharmacology/methods ; *Areca/chemistry ; *Neurodegenerative Diseases/drug therapy/metabolism ; *Neuroprotective Agents/pharmacology/chemistry ; Humans ; Caenorhabditis elegans/drug effects ; *Plant Extracts/pharmacology/chemistry ; Mice ; Microglia/drug effects/metabolism ; Alzheimer Disease/drug therapy/metabolism ; }, abstract = {Alzheimer's disease (AD) and Parkinson's disease (PD) are the two most prevalent neurodegenerative disorders, while the therapeutic efficacy of current drugs for both diseases remains limited, with unfavourable side effects. The fruit of Areca catechu L. (AC) is recognised as a popular chewing item across China and Southeast Asia and has been used for centuries as a traditional remedy, ranging from relieving digestive issues to depression. The neuroprotective role of AC has been underscored in previous studies; however, its mechanisms of action remain unclear. The present study aimed to investigate anti-neurodegenerative mechanisms of AC for the treatment of AD and PD. An integrated approach combining untargeted metabolite profiling, network pharmacology, bioinformatics analysis, and molecular docking was utilised. Experimental validation was performed using in vitro cell-based and in vivo models. The study revealed TNF-α, IL-1β, IL-6, CASP3, MAPK3, and AKT1 as top-ranked hub targets by which AC exerts its action on AD and PD. Enrichment analyses of these genes identified significant biological and functional pathways involved in neuroinflammation, apoptosis, and AD. Experimental validation showed that AC extracts significantly downregulated hub gene expressions in the neuroinflammatory BV-2 microglia cell model and prolonged the survival of the transgenic Caenorhabditis elegans AD model. Docking analysis suggested lucidine B, oxolucidine B, solanocapsine, evodiamine, and liquiritigenin are the principal phytocompounds underlying the neuroprotective properties of AC. The findings revealed the pharmacological mechanisms of AC and highlighted its potential value as an effective, multitargeting natural agent to address challenges in AD and PD therapies.}, } @article {pmid42352925, year = {2026}, author = {Czubowicz, K and Motyl, JA and Wencel, A and Strosznajder, RP}, title = {The Role of Sphingosine-1-Phosphate Signaling in Cerebral Ischemia/Reperfusion Injury and Alzheimer's Disease Pathology.}, journal = {International journal of molecular sciences}, volume = {27}, number = {12}, pages = {}, pmid = {42352925}, issn = {1422-0067}, support = {the statutory budget of MMRI PAS, under theme No. 7//Mossakowski Medical Research Institute, Polish Academy of Sciences/ ; }, mesh = {Humans ; *Alzheimer Disease/metabolism/pathology/drug therapy ; *Lysophospholipids/metabolism ; *Sphingosine/analogs & derivatives/metabolism ; Animals ; *Reperfusion Injury/metabolism/pathology/drug therapy ; *Signal Transduction ; *Brain Ischemia/metabolism/pathology ; Sphingosine-1-Phosphate Receptors/metabolism ; Sphingosine 1 Phosphate Receptor Modulators/therapeutic use ; }, abstract = {Sphingosine-1-phosphate (S1P) is a pleiotropic bioactive sphingolipid that regulates key cellular processes, like proliferation, apoptosis, inflammation, and vascular homeostasis. S1P acts as a signaling molecule both inside and outside cells by interacting with five G-protein-coupled S1P receptors (S1PR1-S1PR5). Accumulating evidence indicates that dysregulation of S1P signaling is implicated in the pathophysiology of cerebral ischemia/reperfusion (I/R) injury and Alzheimer's disease (AD). In I/R injury, S1P signaling regulates vascular permeability, immune cell infiltration, and neuronal survival and death. In AD, alterations in S1P metabolism are associated with β-amyloid deposition, tau hyperphosphorylation, synaptic dysfunction, and sustained neuroinflammation. S1P receptor (S1PR) modulators represent promising therapeutic agents in both preclinical and clinical studies. Fingolimod was the first oral disease-modifying therapy approved for the treatment of multiple sclerosis and, at the same time, the first S1PR modulator introduced into clinical practice. New selective S1PR-targeting agents, including siponimod and ozanimod (S1PR1 and S1PR5), as well as the S1PR1-selective agent ponesimod, have also been approved for clinical use. In addition to their immunomodulatory properties, S1PR modulators have direct effects in the central nervous system, facilitating the maintenance of blood-brain barrier integrity, reducing microglial activation, and enhancing neuronal survival pathways. Building on this knowledge, we discuss the role of S1P signaling, highlighting recent advances in S1PR modulators as promising therapeutic agents for cerebral I/R injury and AD.}, } @article {pmid42353002, year = {2026}, author = {Kanubaddi, KR and Yaung, CL and Harn, HJ and Chiou, TW and Hsu, SX and Wijaya, I and Lin, SZ and Wuli, W}, title = {Astragalus and Cordyceps Derivatives in the Treatment of Aging-Related Chronic Diseases and Neurodegenerative Disorders.}, journal = {International journal of molecular sciences}, volume = {27}, number = {12}, pages = {}, pmid = {42353002}, issn = {1422-0067}, mesh = {Humans ; *Neurodegenerative Diseases/drug therapy/metabolism ; *Cordyceps/chemistry ; Animals ; *Aging/drug effects ; Chronic Disease/drug therapy ; *Astragalus Plant/chemistry ; *Drugs, Chinese Herbal/therapeutic use/chemistry ; }, abstract = {Aging is associated with a rising burden of chronic metabolic, cardiovascular, musculoskeletal, and neurodegenerative diseases that share interconnected pathological mechanisms, including oxidative stress, chronic inflammation, mitochondrial dysfunction, metabolic imbalance, and immune dysregulation. Because these disorders arise from complex and overlapping biological disturbances, conventional single-target therapies often provide only limited benefit. In this context, traditional Chinese herbal medicines, characterized by multi-component and multi-target actions, are being re-evaluated using modern pharmacological and systems biology approaches. Among these, Astragalus membranaceus and Cordyceps species have attracted attention as representative tonic medicines with long-standing traditional use and growing biomedical relevance. Their principal bioactive constituents, including polysaccharides, saponins, flavonoids, sterols, and nucleoside derivatives such as cordycepin, exert pleiotropic effects on inflammatory signaling, redox homeostasis, mitochondrial function, metabolic regulation, and immune responses. This review summarizes current evidence on bioactive derivatives from Astragalus and Cordyceps in aging-related chronic and neurodegenerative disorders, including diabetes, cardiovascular dysfunction, osteoarthritis, cancer, Alzheimer's disease, and Parkinson's disease. It focuses on mechanistic findings from cellular and animal studies and critically discusses key translational challenges, such as compositional variability, poor bioavailability, lack of standardized preparation, limited clinical validation, and safety concerns related to toxicity and herb-drug interactions.}, } @article {pmid42353032, year = {2026}, author = {Shahabian, L and Kynigopoulos, D and Papacharalambous, R and Ioannou, E and Dionysiou, S and Christou, S and Picolos, M and Pipis, M and Panayiotou, E}, title = {Semaglutide Selectively Improves Metabolic and Cognitive Function in 5xFAD Mice.}, journal = {International journal of molecular sciences}, volume = {27}, number = {12}, pages = {}, pmid = {42353032}, issn = {1422-0067}, mesh = {Animals ; Semaglutide ; *Alzheimer Disease/drug therapy/metabolism ; Mice ; Male ; *Cognition/drug effects ; Female ; Disease Models, Animal ; *Glucagon-Like Peptides/pharmacology ; Mice, Transgenic ; Diet, High-Fat/adverse effects ; Amyloid beta-Peptides/metabolism ; Adiponectin/metabolism ; Glucagon-Like Peptide-1 Receptor/metabolism ; Hippocampus/metabolism/drug effects ; Body Weight/drug effects ; }, abstract = {Alzheimer's disease (AD) and metabolic syndrome often occur together, sharing characteristics such as insulin resistance, dyslipidemia, and chronic inflammation. Metabolic dysfunction frequently precedes cognitive decline, indicating that early intervention might alter the disease's progression. We investigated whether the GLP-1 receptor agonist semaglutide (SMGL) influences metabolic impairment and AD pathology in an AD mouse model. Male and female 5xFAD and wild-type (WT) mice on regular (RD) or high-fat diets (HFD) were administered SMGL for 13 weeks. SMGL-treated groups exhibited significant, context-dependent effects. In metabolically challenged 5xFAD HFD mice, treatment led to reduced body weight, improved glucose tolerance, normalized cholesterol levels, and a restored balance of adiponectin and leptin. These improvements were associated with reduced Aβ40 and Aβ42 levels, restored GLP-1 receptor expression, increased synaptophysin and βIII-tubulin levels, and enhanced spatial memory. SMGL also decreased Iba1 and CD68 immunoreactivity in the hippocampus and cortex, reduced macrophage infiltration, and lowered CD36 expression in visceral adipose tissue (VAT), indicating coordinated anti-inflammatory effects. WT RD mice showed minimal metabolic responses and a modest decline in Y-maze performance, suggesting that excessive GLP-1 receptor activation may disrupt neuronal homeostasis when metabolic status is normal. SMGL acts as a context-specific metabolic and neuroprotective agent, offering the greatest benefits under conditions of metabolic dysfunction. These findings in a preclinical model suggest that targeting early metabolic disturbances provides a testable hypothesis for attenuating AD-related neurodegeneration, though further translational studies are required.}, } @article {pmid42353174, year = {2026}, author = {Lee, S and Yoo, YJ and Kim, G and Kim, E and Yun, S and Kim, J and Ryu, H and Chung, W}, title = {Kilovoltage Energy Significantly Enhances the Therapeutic Efficacy of Low-Dose Radiation in a 3xTg-AD Mouse Model of Alzheimer's Disease.}, journal = {International journal of molecular sciences}, volume = {27}, number = {12}, pages = {}, pmid = {42353174}, issn = {1422-0067}, support = {RS-2023-00253427//Ministry of Science and ICT/ ; RS-2022-NR070632, RS-2026-255417//Ministry of Science and ICT/ ; RS-2024-00467661//Ministry of SMEs and Startups/ ; RS-2024-00441564//Ministry of SMEs and Startups/ ; RS-2025-02317308//Ministry of Science and ICT/ ; BT250232//Seoul R&BD Program/ ; KHU-20251295//Kyung Hee University in 2025/ ; }, mesh = {Animals ; *Alzheimer Disease/radiotherapy/metabolism/pathology ; Disease Models, Animal ; Mice ; Mice, Transgenic ; Amyloid beta-Peptides/metabolism ; tau Proteins/metabolism ; Brain/metabolism/radiation effects/pathology ; Male ; }, abstract = {Low-dose radiation (LDR) has emerged as a promising therapeutic modality for Alzheimer's Disease (AD). Although different irradiation protocols have been explored, the optimal parameters for maximizing therapeutic efficacy remain unclear. Radiation energy has been shown to influence radiobiological responses, with more pronounced effects at lower energy ranges. We therefore investigated whether kilovoltage LDR (KLDR) provides superior therapeutic efficacy compared with megavoltage LDR (MLDR) in a murine model of AD(3xTg-AD). To this end, we directly compared the efficacy of MLDR and KLDR in AD model mice to identify an optimal irradiation strategy for LDR treatment with potential relevance to clinical translation in AD. X-rays with 110-kV or 6-MV energy were applied to the brain of AD model mice at an early-stage of disease progression (26-28 weeks age; 0.6 Gy × 5 fractions for 2.5 weeks). After LDR treatment, cognitive function was assessed in AD model mice using passive avoidance (PA) test and novel object recognition (NOR) test. In addition, different molecular markers associated with inflammation, amyloid-beta (Aβ) plaques, tau burden, and neuronal and synaptic degeneration were analyzed in the brain of AD model mice. KLDR (110 kV) significantly inhibited cognitive decline in AD model mice, as demonstrated by both the PA and NOR tests. In addition, KLDR significantly reduced hippocampal levels of GFAP, Iba-1, and pro-inflammatory cytokines (TNF-α, IL-6, and IL-1β), while increasing anti-inflammatory cytokines (TGF-α, TGF-β, and IL-10), and was associated with marked reductions in Aβ and tau levels. Furthermore, the expression levels of Aβ40 and Aβ42 were quantified by ELISA following KLDR and MLDR treatment, revealing a statistically significant reduction in the KLDR group. The degeneration of neurons and synapses was significantly suppressed also at the kilovoltage energy level. Conversely, MLDR (6 MV) exerted minimal effects and did not produce statistically significant improvements. Taken together, our findings demonstrate that radiation energy level is a key determinant of LDR therapeutic efficacy in AD model mice, with KLDR showing significantly greater effectiveness in improving AD-related pathological features than MLDR. Therefore, KLDR may be recommended as a novel radiation protocol for AD treatment.}, } @article {pmid42353197, year = {2026}, author = {Honjo, A and Yako, H and Kasai, M and Chiba, M and Satsuka, A and Kato, T and Yagi, M and Nishi, A and Miyamoto, Y and Yamauchi, J}, title = {Hesperetin Rescues Amyloid Beta-Induced Defects in Neurite Outgrowth Under In Vitro Mild Cognitive Impairment-like Cellular Conditions.}, journal = {International journal of molecular sciences}, volume = {27}, number = {12}, pages = {}, pmid = {42353197}, issn = {1422-0067}, mesh = {*Amyloid beta-Peptides/metabolism/toxicity ; Animals ; *Hesperidin/pharmacology ; *Neuronal Outgrowth/drug effects ; *Cognitive Dysfunction/metabolism/drug therapy/pathology ; *Peptide Fragments ; Mice ; Neurons/drug effects/metabolism ; *Neurites/drug effects/metabolism ; Cell Differentiation/drug effects ; Cell Line ; }, abstract = {Accumulation of aggregated amyloid beta (Aβ) species is a defining pathological hallmark of Alzheimer's disease and is associated with extensive neuronal structural abnormalities. Mild cognitive impairment (MCI), a transitional stage between normal aging and the onset of dementia, is thought to represent an early phase of this pathological continuum. Studies at the cellular level suggest that the conditions impair the maintenance of established neuronal processes/networks and restrict their capacity for elongation or re-elongation. They may also attenuate the activation and process extension of quiescent neural progenitor or stem-like cells. These early cellular changes precede overt neurodegeneration in neural tissue and are likely to contribute to cognitive decline. They highlight the importance of in vitro models for identifying molecular targets involved in recovery from disease. In this study, we investigated the effects of aggregated Aβ (25-35) on neuronal process elongation and associated intracellular events in the N1E-115 cell line, a widely used model of neuronal differentiation. Addition of aggregated Aβ to cultured N1E-115 cells attenuated process elongation in a concentration-dependent manner. This morphological impairment was accompanied by decreased expression of neuronal differentiation markers. In contrast, at the half-maximal inhibitory concentration for process elongation, long-term cultured cells did not exhibit apparent process retraction or degenerative morphology. This mild but progressive impairment, without extensive cell death, is consistent with the cellular features of early-stage conditions rather than advanced Alzheimer's pathologies. Similar results were observed in primary cortical neurons. Aβ also decreased the level of GTP-bound Ras and phosphorylation of the downstream mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK). Furthermore, treatment with hesperetin, a bioactive flavonoid compound, recovered the Aβ-induced inhibition of neuronal process elongation. Hesperetin also restored Ras and MAPK/ERK states, suggesting that its effects are associated, at least in part, with modulation of signaling through Ras and MAPK/ERK. Our findings suggest that hesperetin may serve as a useful molecular probe for modulating early cellular responses associated with Alzheimer's disease-related pathology. This in vitro model might serve as a useful platform for investigating the molecular target candidates involved in recovery from nervous system disorders.}, } @article {pmid42353204, year = {2026}, author = {Olajide, AT and Aunsorn, S and Kehinde, SA and Kaewmanee, T and Chusri, S}, title = {From Tradition to Translation: A Critical Appraisal of Bacopa monnieri for Neuroprotection from Preclinical and Clinical Perspectives and Challenges in Utilization.}, journal = {International journal of molecular sciences}, volume = {27}, number = {12}, pages = {}, pmid = {42353204}, issn = {1422-0067}, support = {67A307000040//National Science, Research, and Innovation Fund (NSRF) and Mae Fah Luang University (Fundamental Fund Grant)/ ; }, mesh = {*Bacopa/chemistry ; Humans ; Animals ; *Neuroprotective Agents/therapeutic use/pharmacology/chemistry ; *Alzheimer Disease/drug therapy ; *Plant Extracts/therapeutic use/pharmacology/chemistry ; *Neuroprotection/drug effects ; Cognitive Enhancement ; }, abstract = {Dementia, and more specifically Alzheimer's disease (AD), is a progressive neurodegenerative disorder that has become a growing health menace in the world with an escalation in incidence as well as enormous social and economic consequences. Existing pharmacological treatment including cholinesterase inhibitors and N-methyl-D-aspartate (NMDA) receptor antagonists are not very effective in reducing the symptoms and fail to prevent the disease process. The non-pharmacological treatment interventions such as diet, exercise and cognitive training have supportive effects and cannot be used as standalone treatments. Therapeutic gap has resulted in increased interest in complementary and alternative therapies, especially that of pleiotropic action of herbal medicines. Bacopa monnieri (BM) is an Ayurvedic herb that has historically been used to treat memory enhancement and now has both preclinical and clinical evidence supporting its ability to modulate neurotransmission, reduce oxidative stress and suppress neuroinflammation. However, such difficulties as low bioavailability, instability of the environmental factors, and variations in formulations restrict its clinical applicability. New technologies with a lot of potential such as microencapsulation technology can provide the solution to this problem by increasing stability, solubility, and targeted delivery of compounds that will increase treatment efficacy. This narrative review is a synthesis of the existing information on the pathogenesis of dementia, therapeutic approaches, and the effectiveness of BM as a complementary intervention. It points out links between traditional medicine and modern neuroscience, strengths and limitations of on-going evidence, gaps that need further research, such as long-term clinical trials, standardized formulations, and discovery of the role of BM in the gut-brain axis. BM is a prime example of how herbal medicines can be used as a complement to conventional treatment and play a role in multi-modal approaches aimed at reducing the cognitive impairment associated with dementia.}, } @article {pmid42353279, year = {2026}, author = {Jorda, A and Alvarez-Gamez, K and Vergani, S and Paba, I and Perez, M and Aldasoro, M and Vila, JM and Valles, SL}, title = {Insulin Regulates AKT/GSK-3β Signalling, Tau Phosphorylation, and Redox Homeostasis in SH-SY5Y Neuroblastoma Cells.}, journal = {International journal of molecular sciences}, volume = {27}, number = {12}, pages = {}, pmid = {42353279}, issn = {1422-0067}, support = {CIAICO/2023/143//Generalitat Valenciana/ ; }, mesh = {Humans ; *Glycogen Synthase Kinase 3 beta/metabolism ; *tau Proteins/metabolism ; *Proto-Oncogene Proteins c-akt/metabolism ; *Insulin/pharmacology/metabolism ; Phosphorylation/drug effects ; *Signal Transduction/drug effects ; Cell Line, Tumor ; *Neuroblastoma/metabolism/pathology ; Oxidative Stress/drug effects ; Oxidation-Reduction/drug effects ; Homeostasis/drug effects ; Apoptosis/drug effects ; Cell Survival/drug effects ; NF-E2-Related Factor 2/metabolism ; }, abstract = {Insulin (Ins) regulates multiple intracellular signalling pathways involved in cell survival, oxidative stress responses, and tau phosphorylation. Dysregulation of these pathways has been implicated in neurodegenerative disorders, including Alzheimer's disease (AD). The present study evaluated the effects of insulin on protein kinase B/glycogen synthase kinase-3 beta (AKT/GSK-3β) signalling, tau phosphorylation, and oxidative stress-related markers in SH-SY5Y neuroblastoma cells. Cell metabolic activity was assessed using the (diphenyltetrazolium bromide) MTT assay, while cell number and viability were evaluated by Trypan Blue exclusion, necrosis by lactate dehydrogenase (LDH) release, and apoptosis by Caspase-3 activity. Western blot analysis was performed to evaluate the expression of phosphorylated AKT (p-AKT), phosphorylated GSK-3β (p-GSK-3β Ser9), phosphorylated TAU (pTAU), nuclear factor erythroid 2-related factor 2 (NRF2), manganese superoxide dismutase (Mn-SOD), and copper/zinc superoxide dismutase (Cu/Zn-SOD). Lipid peroxidation was determined by measuring malondialdehyde (MDA) levels using a colorimetric/fluorometric assay. Insulin treatment increased MTT reduction (31.25%) and cell metabolic activity (119.15%) while reducing LDH release (19.2%) and Caspase-3 activity (31.26%). In addition, insulin significantly increased p-AKT (34.2%) and p-GSK-3β (Ser9) (19.9%) levels. A reduction in pTAU levels (53.39%) was also observed following insulin treatment. Furthermore, insulin increased NRF2 expression (18.77%), Cu/Zn-SOD (37.29%), and Mn-SOD (50.16%) and reduced MDA levels (13.95%). These findings indicate that insulin modulates signalling pathways associated with tau phosphorylation and cellular redox regulation in SH-SY5Y cells. Insulin treatment was associated with increased AKT and GSK-3β phosphorylation, reduced tau phosphorylation, and changes in oxidative stress-related markers in SH-SY5Y neuroblastoma cells. These findings support a role for insulin in the modulation of molecular pathways implicated in cellular stress responses and tau regulation. Further studies using differentiated neuronal models and disease-relevant conditions are required to determine the relevance of these observations to neurodegenerative disorders.}, } @article {pmid42353615, year = {2026}, author = {ALNasser, MN and Carter, WG}, title = {Phytochemicals as NMDA Receptor Inhibitors and Their Potential for Treating Excitotoxicity-Related Neurotoxicity: A Systematic Review.}, journal = {Current issues in molecular biology}, volume = {48}, number = {6}, pages = {}, pmid = {42353615}, issn = {1467-3045}, support = {KFU260924//King Faisal University/ ; }, abstract = {Excitotoxicity caused by excessive activation of glutamate receptors, particularly N-methyl-D-aspartate receptors (NMDARs), significantly contributes to neuronal damage in neurodegenerative diseases (NDDs), such as Alzheimer's, Parkinson's, and Huntington's diseases. This systematic review aimed to evaluate the effects of plant extracts and phytochemicals on NMDAR-mediated excitotoxicity and to summarize their proposed neuroprotective mechanisms. The review protocol was registered in PROSPERO (CRD42024528160). A systematic search of Medline, Embase, Web of Science Core Collection, and PubMed identified 323 records, with an additional 7 records identified through manual searching that specifically considered in vitro and in vivo inhibitors of NMDAR excitotoxicity using plant extracts and isolated phytochemicals. Twenty-seven studies demonstrated that plant extracts and phytochemicals attenuate excitotoxicity through multiple mechanisms, including inhibition of NMDAR-induced currents, reduction of intracellular calcium influx, modulation of NMDAR expression, attenuation of oxidative stress, and mitochondrial dysfunction. However, the evidence base was largely dominated by in vitro and ex vivo studies, with limited in vivo validation, restricting translational relevance. Risk-of-bias assessment using an adapted version of the Office of Health Assessment and Translation (OHAT) Risk of Bias Tool indicated that 4 studies had a low overall risk of bias, 12 had low to moderate risk, and 11 were at moderate risk, with key limitations related to inadequate reporting of blinding, randomization, and allocation concealment. In contrast, exposure characterization, outcome assessment, and confounding control were generally strong across studies. Although the findings support the mechanistic neuroprotective potential of certain plant extracts and phytochemicals against NMDAR-mediated excitotoxicity, further well-designed in vivo and clinical studies are required to establish their therapeutic relevance for the treatment of neurodegenerative diseases.}, } @article {pmid42353761, year = {2026}, author = {Xu, J and Ashebir, YA and Shao, Y}, title = {Molecular Basis of Synergistic Causal Effect of Dual GLP-1R and GIPR Agonists for Risk Reduction in Diabetic Retinopathy, Alzheimer Disease, and Coronary Artery Disease in Diabetic Patients.}, journal = {Genes}, volume = {17}, number = {6}, pages = {}, pmid = {42353761}, issn = {2073-4425}, support = {U01OH012486/CC/CDC HHS/United States ; P30AG066512/AG/NIA NIH HHS/United States ; }, mesh = {Humans ; *Coronary Artery Disease/genetics/drug therapy/prevention & control ; *Alzheimer Disease/genetics/drug therapy/prevention & control ; *Glucagon-Like Peptide-1 Receptor Agonists ; *Diabetic Retinopathy/genetics/drug therapy/prevention & control ; *Diabetes Mellitus, Type 2/drug therapy/genetics/complications ; *Receptors, Gastrointestinal Hormone/agonists/genetics ; Glucagon-Like Peptide-1 Receptor/genetics ; Glycated Hemoglobin/metabolism ; Male ; Hypoglycemic Agents/therapeutic use/pharmacology ; Female ; }, abstract = {Background: The dual agonism of glucagon-like peptide-1 receptor (GLP-1R) and glucose-dependent insulinotropic polypeptide receptor (GIPR) becomes a groundbreaking treatment for type 2 diabetes (T2D) that achieves robust glycemic control and maintains body weight. It also induces potential risk reduction in diabetic retinopathy (DR), Alzheimer disease (AD), and heart diseases including coronary artery disease (CAD) in treated T2D patients. To date, the molecular basis underpinning the remarkable causal treatment effects and synergy of the dual agonism of GLP-1R and GIPR on risk reduction in T2D, CAD, DR and AD has not been systematically investigated. Methods: To elucidate the treatment effects and potential synergy of dual GLP-1R/GIPR agonism on risk reduction in T2D, CAD, DR and AD while minimizing the impact of confounders, we used a robust cis-Mendelian randomization (cis-MR) with a principal component-based generalized method of moments (PC-GMM) where blood-based glycated hemoglobin (HbA1c), high- and low-density lipoprotein cholesterol (HDL-c, LDL-c), and BMI were used as mediating biomarkers. Results: Our cis-MR analyses confirmed a synergistic causal protective effect of dual GLP-1R/GIPR agonism on T2D via HbA1c reduction [OR = 0.17; 95% CI = (0.11, 0.26); p = 3.68 × 10[-17]] which is more significant than either GLP-1R agonism or GIPR agonism alone. Similarly, the causal protective effect of dual GLP-1R/GIPR agonism via HbA1c reduction was also significant for DR [OR = 0.20; 95% CI = (0.11, 0.36); p = 9.22 × 10[-8]]. Further, our multivariate cis-MR (or cis-MVMR) analyses revealed that after adjusting for HbA1c, a synergistic protective effect on DR via a reduction in LDL-c is significant in dual GLP-1R/GIPR agonism [OR = 0.57; 95% CI = (0.29, 0.94)], while the protective effect on DR of LDL-c reduction is non-significant in either GLP-1R agonism or GIPR agonism alone. Also, after adjusting for HbA1c, the multivariate cis-MR results showed significant protective effects on AD via a reduction in LDL-c in GLP-1R/GIPR agonism [OR = 0.44; 95% CI = (0.25, 0.81)]. Importantly, the multivariate cis-MR results also revealed that dual GLP-1R/GIPR agonism has significant protective effects on CAD via both a reduction in BMI [OR = 0.46; 95% CI = (0.28, 0.75)] and an improvement in HDL [OR = 0.59; 95% CI = (0.39, 0.90)]. This is in support of the hypothesis that dual GLP-1R/GIPR agonism has a synergistic protective effect on CAD that is stronger than that of GLP-1R agonism alone, which yielded a non-significant causal effect for both HDL and BMI, and GIPR agonism alone also yielded a non-significant causal effect for HDL when adjusted for BMI. Conclusions: These novel findings have significant implications for repurposing dual incretin agonism in terms of diabetic drugs to serve as a unifying, precision prevention strategy against CAD, DR and AD as leading drivers of mortality and morbidity in diabetic patients.}, } @article {pmid42356271, year = {2026}, author = {Sarti, G and Tognozzi, G and Magni, G and Lana, D and Rossi, F and Traini, C and Vannucchi, MG}, title = {The Multiple Functions of Amyloid Beta in the Gut Epithelium and the Role of the Microbiota: A Study in the APP/PS1 Animal Model Subjected to Chronic Synbiotic Treatment.}, journal = {Nutrients}, volume = {18}, number = {12}, pages = {}, pmid = {42356271}, issn = {2072-6643}, support = {PRIN2022SC_VANNUCCHI//Ministero dell'università e della ricerca/ ; VANMBANCAITALIA23//Bank of Italy/ ; 58513_CHIARA TRAINIRICATEN24//University of Florence/ ; }, mesh = {Animals ; *Synbiotics/administration & dosage ; *Amyloid beta-Peptides/metabolism ; Disease Models, Animal ; *Intestinal Mucosa/metabolism/microbiology ; *Alzheimer Disease/microbiology/metabolism ; Mice, Transgenic ; *Gastrointestinal Microbiome/physiology ; Intestinal Barrier Function ; Colon/metabolism/microbiology ; Amyloid beta-Protein Precursor/genetics/metabolism ; Mice ; Presenilin-1/genetics ; Ileum/metabolism/microbiology ; Tight Junctions/metabolism ; Male ; }, abstract = {Background:/ Over the past decade, increasing evidence has shifted attention from the brain to the gut microbiota (MB) as a source and site of systemic dissemination of amyloid-β (Aβ), an APP derivative responsible for plaque formation in the brains of Alzheimer's disease (AD) patients. Furthermore, AD patients and APP/PS1 mice, a transgenic model of AD, exhibit dysbiosis. Objectives: Using APP/PS1 mice treated from 2 to 8 months of age, we studied ileal and colonic epithelial integrity, intestinal barrier (IB) integrity assessed through tight junction (TJ) protein expression, local immune system, the presence/increase in Aβ expression in enterocytes, and the protective effects of synbiotic treatment. Methods: The tissue was stained with Periodic Acid-Schiff and Alcian Blue to evaluate epithelial morphology and mucus production, and immunohistochemistry was performed to assess TJs, immune markers, and Aβ expression. Results: Our results demonstrate that colonic and ileal epithelium of 8-month-old APP/PS1 mice displays IB impairment in term of alterations of goblet cells staining and TJ protein expression and signs of immune involvement. The ileum was more severely affected, showing a reduced epithelial surface area, decreased lysozyme production, and fewer tuft cells. Long-term synbiotic treatment largely prevented APP/PS1 mouse changes and caused a significant increase in Aβ expression in all treated mice. Conclusions: These findings support the belief in early intestinal involvement in AD and highlight the potential of the microbiota as a target for early intervention aimed at modifying the progression to neurodegeneration. Increased epithelial Aβ labeling after treatment raises the possibility of intestinal management of Aβ, which requires further validation.}, } @article {pmid42357346, year = {2026}, author = {Costanzi, E and Fontana, L and Giroldo, F and Coco, S}, title = {Advancing MSC-EV Therapies: Harnessing Preconditioning and Mito-EVs to Tackle Neuroinflammation and Neurodegeneration.}, journal = {Pharmaceutics}, volume = {18}, number = {6}, pages = {}, pmid = {42357346}, issn = {1999-4923}, support = {P2022LR49L//Ministry of Universities and Research/ ; 202229X8HW//Ministry of Universities and Research/ ; }, abstract = {Neuroinflammation plays a central role in the onset and progression of neurodegenerative disorders. Several disease-modifying therapies have been developed to target neuroinflammatory pathways in specific disorders. However, their ability to stop disease progression or restore neuronal and mitochondrial homeostasis remains limited. This is still a major unmet clinical need. In this context, mesenchymal stromal cell (MSC)-derived Extracellular Vesicles (EVs) have emerged as a promising cell-free therapeutic strategy due to their ability to modulate immune responses and promote neuroprotection through the delivery of bioactive cargo. Recent evidence has identified a distinct subset of EVs, known as mitochondrial EVs (mito-EVs), which carry mitochondrial DNA, proteins, and functional components. These vesicles may uniquely influence cellular bioenergetics, redox balance, and neuroinflammatory signaling, offering additional therapeutic potential compared to conventional MSC-EVs. This review summarizes the role of MSC-derived EVs in neuroinflammatory disorders, with a particular focus on mito-EVs. It also discusses preconditioning strategies to enhance EV efficacy, including hypoxic, inflammatory, pharmacological priming and genetic engineering approaches. Finally, we critically evaluate current preclinical evidence regarding the treatment of major neurodegenerative disorders, including Alzheimer's disease, Parkinson's disease, Multiple Sclerosis, and Amyotrophic Lateral Sclerosis, as well as Traumatic Injury, highlighting the key challenges for clinical translation.}, } @article {pmid42357417, year = {2026}, author = {Sharma, N and An, SSA}, title = {Multitarget Actions of Pentacyclic Triterpenic Acids in Alzheimer's Disease: Mechanistic Insights.}, journal = {Molecules (Basel, Switzerland)}, volume = {31}, number = {12}, pages = {}, pmid = {42357417}, issn = {1420-3049}, support = {RS-2021-NR060117//Ministry of Education/ ; RS-2025-02292973//Ministry of Oceans and Fisheries/ ; }, mesh = {*Alzheimer Disease/drug therapy/metabolism ; Humans ; *Neuroprotective Agents/therapeutic use/pharmacology/chemistry ; *Pentacyclic Triterpenes/therapeutic use/pharmacology/chemistry ; Animals ; Amyloid beta-Peptides/metabolism ; Phytochemicals/chemistry/pharmacology/therapeutic use ; tau Proteins/metabolism ; }, abstract = {Alzheimer's disease (AD) is a complex neurodegenerative disorder with features of amyloid-beta (Aβ) accumulations, tau hyperphosphorylation, oxidative stress, neuroinflammation, and synaptic losses. Despite extensive therapeutic investigations for many decades, the clinical treatment options remained largely symptomatic, while anti-amyloid antibody therapies were expensive and had limited accessibility. A subclass of triterpenoids generated from plants, pentacyclic triterpenic acids (PTAs), exhibited a variety of pharmacological properties. The neuroprotective effects of some important PTAs in AD models were reviewed in this study. These phytochemicals displayed a multimodal neuroprotection by lowering amyloid and tau, improving mitochondrial function, inhibiting inflammation, and improving synaptic plasticity and cognition. However, the neuroprotective mechanisms of several PTAs remained poorly characterized. In addition, most evidence were preclinical, while poor bioavailability and the limited clinical validation hindered the therapeutic translation. Studies were needed to evaluate these phytochemicals in AD, improve their pharmacokinetics, and enhance brain delivery. Their diverse bioactivities and encouraging preclinical findings suggest these compounds may serve as promising lead candidates for future drug development in neurodegenerative diseases.}, } @article {pmid42358353, year = {2026}, author = {Nowar, R and Velma, GR and Fu, J and Kidwai, A and Bauc, G and Ackerman-Berrier, M and Thatcher, GRJ and Brady, ST and Ben Aissa, M}, title = {Inhibition of pathogenic tau signaling via blocking of the phosphatase-activating domain by novel small molecules.}, journal = {Frontiers in pharmacology}, volume = {17}, number = {}, pages = {1829420}, pmid = {42358353}, issn = {1663-9812}, abstract = {INTRODUCTION: Tau pathology is a major feature of Alzheimer's disease (AD) and multiple other adult-onset neurodegenerative diseases. Aberrant exposure of an N-terminal phosphatase-activating domain (PAD) is characteristic of pathological tau, representing a toxic gain of function. Exposure of the PAD in pathological tau leads to dysregulation of protein phosphatase 1/glycogen synthase kinase 3 (PP1/ GSK3β) signaling, inhibition of fast axonal transport, synaptic dysfunction, and altered transcription, along with other pathological consequences. Previous studies showed that TNT1, an antibody against the PAD, blocked toxicity of pathogenic forms of tau.

METHODS: In this article, we describe a high-throughput screen for small molecules that block TNT1 binding to the PAD in an AlphaLISA screen and bind specifically to the PAD in surface plasmon resonance assays. Candidate PAD ligands (PADis) were identified, and initial biochemical and biophysical optimization produced PADis with increased affinity and selectivity. Three candidate PADis were evaluated in neuronal (rat E18 embryonic cortical neurons) and non-neuronal cells (HEK293T human embryonic kidney cells) using a nano-bioluminescence resonance energy transfer (nanoBRET) assay to assess PP1 binding and cell toxicity.

RESULTS AND DISCUSSION: All three compounds prevented PP1 binding to PAD and neurite degeneration due to pathological tau in primary cultured cortical neurons. The final candidates had an IC50 value between 10 and 20 nM in neurons with low cytotoxicity, CC50 > 75 μM in primary cultured neurons, and 40-100 μM in non-neuronal cells. PADi treatment of primary cultured neurons transfected with pathogenic tau restored axonal growth and prevented neurodegeneration. These studies establish a novel approach to therapeutics for Alzheimer's disease and tauopathies.}, } @article {pmid42358562, year = {2026}, author = {Cribb, L and Moreno-Betancur, M and Sarant, J and Wolfe, R and Pase, MP and Rance, G and Mielke, MM and Murray, AM and Owen, A and Woods, RL and Zhou, Z and Wu, Z and Sheets, KM and Chong, TT and Shah, RC and Ryan, J}, title = {The effect of treating hearing loss with hearing aids on plasma biomarkers of Alzheimer's disease and related dementias.}, journal = {Alzheimer's & dementia (Amsterdam, Netherlands)}, volume = {18}, number = {2}, pages = {e70397}, pmid = {42358562}, issn = {2352-8729}, abstract = {BACKGROUND: Though evidence indicates that treating hearing loss with hearing aids (HAs) could reduce dementia risk, the effects on biomarkers of Alzheimer's disease and related dementias (ADRD) remain unknown.

METHODS: Observational data from Aspirin in Reducing Events in the Elderly (ASPREE) study participants without dementia and with hearing problems were used. We emulated two target trials to estimate the effect of (1) new HA prescription and (2) the frequency of HA use on plasma ADRD biomarkers after 7 years using targeted maximum likelihood estimation, with multiple imputation for missing data.

RESULTS: There was a median of 2842 individuals (mean 75 years, 48% female) across imputed datasets, and 735 new HA prescriptions. Estimated treatment effects were close to null for phosphorylated tau181, neurofilament light chain, glial fibrillary acidic protein, and amyloid beta 42/40. There was little evidence of effect modification (e.g., by apolipoprotein E ε4 genotype).

DISCUSSION: In older people with hearing loss, HA prescription and frequency of use had minimal association with levels of ADRD biomarkers.}, } @article {pmid42358604, year = {2026}, author = {Hindle, A and Chen, Y and Yin, X and Manczak, M and Decourt, B and Neugebauer, V}, title = {Transsynaptic complex dysfunction in the hippocampus of Alzheimer's disease patients.}, journal = {Frontiers in aging neuroscience}, volume = {18}, number = {}, pages = {1837327}, pmid = {42358604}, issn = {1663-4365}, abstract = {INTRODUCTION: Alzheimer's disease (AD) involves not only amyloid-β and tau pathology but synaptic dysfunction and impaired autophagy, though the underlying mechanisms and their relationship to AD progression are not well understood. Transsynaptic complexes involving presynaptic neurexins (Nrxn1/2/3), secreted cerebellins (Cbln1/2/3/4), and postsynaptic glutamate delta receptors (GluD1/2) play critical roles in organizing synapses and synaptic plasticity. Studies in pain models have reported that treatment with recombinant Cbln1 rescues AMPA glutamate receptor imbalance, promotes autophagy, and inhibits hyperexcitability and pain behaviors. Here we tested the novel hypothesis that dysregulation of Cbln-GluD-based transsynaptic complexes may occur in the brain of AD patients, providing insights into disease progression and potential avenues for therapeutic development.

METHODS: We analyzed human hippocampal tissues from the TTUHSC Garrison Brain Bank and the NIH NeuroBioBank for expression of transsynaptic complex components in addition to autophagy and neuroplasticity pathways. Their expression in hippocampus was compared between control samples of Braak stages 0/1 and AD samples showing either mild (Braak stage 2) or severe (Braak stages 5/6) neurofibrillary tangle pathology. Co-immunoprecipitation was used to examine protein-protein interactions.

RESULTS: We found significantly decreased protein levels of Cbln1 and GluD2 in AD hippocampus. In the autophagy pathway, PIST and beclin-1 were decreased in AD hippocampus. Co-immunoprecipitation revealed interactions between GluD1 and PIST and between PIST and beclin-1, suggesting possible regulatory interactions between transsynaptic complex elements and autophagy in human hippocampus. We further observed decreased BDNF, consistent with diminished neuroplasticity. Finally, cofilin phosphorylation was decreased in AD, suggesting disruption of trafficking and formation of cofilin-actin rods.

DISCUSSION: These results suggest that the homeostasis of signaling molecules important for synaptic integrity is disrupted in the human hippocampus at both early- and late-stage AD. The loss of transsynaptic complex expression is accompanied by the downregulation of autophagy and neuroplasticity markers that are known to be linked to AD pathology.}, } @article {pmid42359179, year = {2026}, author = {Saito, T and Fukaya, H and Omodaka, S and Yazawa, Y}, title = {An Elderly Patient With Status Epilepticus Caused by a Dural Arteriovenous Fistula.}, journal = {Cureus}, volume = {18}, number = {5}, pages = {e109568}, pmid = {42359179}, issn = {2168-8184}, abstract = {Dural arteriovenous fistulas (DAVFs) are a rare cause of epilepsy. Therefore, they can be misdiagnosed or overlooked. We report a case of an 84-year-old female with Alzheimer's disease who developed status epilepticus as the initial manifestation of the left transverse sinus DAVF. On admission, symptomatic epilepsy secondary to Alzheimer's disease was suspected, and medical therapy was started; however, clinical improvement was limited. Magnetic resonance imaging and magnetic resonance angiography findings provided clues for the diagnosis of the left transverse sinus DAVF. Endovascular treatment led to improvement in behavioral symptoms and electroencephalography findings with no seizure recurrence. One month later, she returned to her baseline condition. This case highlights the importance of including DAVF in the differential diagnosis of seizures in older adults and of recognizing that invasive endovascular therapy may offer a curative option.}, } @article {pmid42360038, year = {2026}, author = {Bouges, S and Alagoz, E and Gutierrez-Meza, D and Noell, D and Hollnagel, F and Oby, A and Flowers-Benton, S and Fischer, B and Gooding, DC and Anthony, RL and Carter, FP and Ennis, GE and Van Hulle, C and Zuelsdorff, M and Lambrou, NH and James, TT and Umucu, E and Carlsson, CM and Asthana, S and Gleason, CE and Passmore, SR}, title = {Engendering trustworthiness in the community: Strategies for researchers.}, journal = {Journal of Alzheimer's disease : JAD}, volume = {}, number = {}, pages = {13872877261458800}, doi = {10.1177/13872877261458800}, pmid = {42360038}, issn = {1875-8908}, abstract = {BackgroundDespite significant advances in Alzheimer's disease treatment, underrepresentation of ethnoracialized groups in clinical trials limit the generalizability of study findings. Though mistrust in health care research is a known barrier to clinical trial participation, methods are needed to quantitate this multidimensional subjective term. This study investigated how Black participants view trustworthiness.ObjectiveTo provide an overview of participants' views of a trustworthy study design and investigator.MethodsThis qualitative study utilized focus group discussions with Black participants 45 years and older. Transcripts were coded by three researchers by means of content analysis. After central categories were identified using concept mapping, we constructed a conceptual model of trust to reflect participants' views of trustworthiness.ResultsParticipants self-identified as Black, were a mean age of 62, and predominantly female (80%). Focus group analysis revealed that a trustworthy study design and its impact as well as a trustworthy investigator were central categories of trustworthiness. Comprehensive study outlines, detailed information on the disease being studied, and sharing of study results improved participants' willingness to be involved in studies. Participants also value researchers who are scientifically and culturally competent, knowledgeable, attentive and who engage in education and sharing comprehensive resources on diseases impacting vulnerable populations.ConclusionsThese findings suggest that trustworthy features of the study design and researcher characteristics can provide a foothold to build trust with a population whose mistrust of research is well-documented. Further research on trustworthiness is necessary to develop tools to create a framework for building a trustworthy research environment.}, } @article {pmid42360204, year = {2026}, author = {Prasad, G and Srivastava, M and Singh, V}, title = {Nanotheranostics for Alzheimer's Disease: The Rising Promise of Fluorescent Carbon Dots.}, journal = {ACS biomaterials science & engineering}, volume = {}, number = {}, pages = {}, doi = {10.1021/acsbiomaterials.6c00290}, pmid = {42360204}, issn = {2373-9878}, abstract = {Alzheimer's disease is a commonly observed neurodegenerative disease among older adults worldwide nowadays. It is characterized by a gradual decline in neuronal structural features and function in the brain owing to the aggregation and deposition of prion protein (amyloid beta), hyperphosphorylation of tau proteins, the production of excessive reactive oxygen species, and elevated levels of metal ions. However, various traditional drugs have been developed and used, but some of them have mild or severe side effects, and a few of them are incapable of crossing the complex blood-brain barrier. Due to this reason, these traditional drugs had only modest success in clinical studies. Early diagnosis is also one of the most concerning prospects for Alzheimer's disease treatment. As a result, preparation of such materials capable of crossing the blood-brain barrier and detecting early-stage changes that lead to symptoms in Alzheimer's disease is in demand in the biomedical field. Carbon dots have recently grabbed the attention for the remediation of Alzheimer's and other neurodegenerative diseases, due to their ability to cross the blood-brain barrier because of their zero-dimensional structure, apart from possessing various fascinating properties like, biocompatibility, low cytotoxicity, non-invasiveness, water dispersibility, tunable emission, surface functionalization and, enhanced physicochemical characteristics foster targeted drug delivery, early diagnosis, and higher therapeutic efficacy. In this review, we outline the latest developments in the use of carbon dots for both imaging and therapeutic strategies in Alzheimer's disease, and conclude with a thorough evaluation of their future applications in the management of neurodegenerative diseases.}, } @article {pmid42361162, year = {2026}, author = {Muela-Zarzuela, I and Alcocer-Gómez, E and Suarez-Rivero, JM and Low, E and Ishaq, A and Azkargorta, M and Luque-Sierra, A and Martin, F and Elortza, F and Astorga-Gamaza, A and Antón, R and Bali, S and Tamargo-Azpilicueta, J and Guerra-Castellano, A and Díaz-Moreno, I and Joachimiak, LA and Oroz, J and Ruiz-Cabello, J and von Zglinicki, T and Sanz, A and Cordero, MD}, title = {NLRP3 haploinsufficiency unmasks a compensatory NLRP1-NLRP3 interaction that drives accelerated aging in mice.}, journal = {Science advances}, volume = {12}, number = {26}, pages = {eaec9499}, pmid = {42361162}, issn = {2375-2548}, mesh = {Animals ; *NLR Family, Pyrin Domain-Containing 3 Protein/genetics/metabolism ; *Haploinsufficiency ; *Aging/genetics/metabolism ; Mice ; Inflammasomes/metabolism/genetics ; *Adaptor Proteins, Signal Transducing/metabolism/genetics ; Mice, Knockout ; NLR Proteins ; *Apoptosis Regulatory Proteins/metabolism/genetics ; Inflammation/genetics/metabolism/pathology ; }, abstract = {The NLRP3 inflammasome has been implicated in a wide range of human diseases, including cardiovascular, metabolic, neurodegenerative (such as Alzheimer's disease), and other age-related conditions. This has positioned NLRP3 as a promising pharmacological target. Numerous studies have shown that complete NLRP3 ablation can prevent or mitigate these diseases. However, total elimination of NLRP3 is not a feasible therapeutic strategy for the millions of patients affected by these degenerative disorders. Consequently, drug development efforts have focused on partial inhibition of NLRP3 using compounds that reduce its expression or activity. Paradoxically, although many studies have used Nlrp3 knockout mouse models, Nlrp3 haploinsufficient mice-more representative of the effects of pharmacological inhibition-are rarely included and remain poorly characterized. Here, we report the long-term effects of Nlrp3 haploinsufficiency during aging. Although no overt differences were observed in early life, by 16 months of age, Nlrp3 heterozygous mice exhibited signs of accelerated inflammatory aging, driven by compensatory overexpression of NLRP1. Mechanistic studies provide evidence of a previously unidentified interaction between NLRP1 and NLRP3, forming a hybrid inflammasome that drives NLRP1-mediated inflammatory overactivation when NLRP3 expression is reduced. Accordingly, anti-inflammatory treatment provided notable but moderate improvement of the inflammatory phenotype, whereas genetic inhibition of Nlrp1 more consistently reduced inflammation and extended health span. Our findings reveal a previously unidentified compensatory interaction between NLRP1 and NLRP3 and suggest that multiinflammasome inhibition may offer a more effective strategy for treating aging and age-related diseases.}, } @article {pmid42361582, year = {2026}, author = {Li, Z and Bai, X and Li, J and Geng, W and Xing, X and Liang, J and Li, J and Li, J}, title = {Network meta-analysis of different traditional Chinese medicine therapies as adjuvant treatments for Alzheimer's disease.}, journal = {Complementary therapies in clinical practice}, volume = {64}, number = {}, pages = {102075}, doi = {10.1016/j.ctcp.2026.102075}, pmid = {42361582}, issn = {1873-6947}, abstract = {BACKGROUND AND PURPOSE: Alzheimer's disease (AD) is a major global health challenge. While various traditional Chinese medicine (TCM) therapies are widely used as adjuncts to conventional Western medicine, their relative efficacy and safety remain unclear due to the lack of direct comparisons. This network meta-analysis aimed to compare and rank different TCM adjuvant therapies for AD, to inform evidence-based clinical decision-making.

METHODS: Randomized controlled trials (RCTs) evaluating TCM therapies as adjuncts to conventional Western medicine (CWM) for AD were searched in eight databases, including the China National Knowledge Infrastructure (CNKI), Wanfang Data, PubMed, and Web of Science, from inception to January 1, 2025. Two independent reviewers performed study selection, data extraction, and risk-of-bias assessment using the Cochrane risk-of-bias tool for randomized trials (RoB 2.0). Network meta-analysis was conducted using RevMan 5.4 and Stata 16.0.

RESULTS: Thirty-one RCTs involving 3221 patients with AD were included, comprising seven interventions: CWM plus Chinese herbal medicine (CHM), CWM plus acupuncture (Acup), CWM plus Chinese patent medicine (CPM), CWM plus Acup and acupoint application (AA), CWM plus Acup and CPM, CWM plus Acup and CHM, and CWM alone. For clinical total effective rate, CWM + Acup + AA ranked first [odds ratio (OR) = 10.71; 95% confidence interval (CI), 3.44-33.33; surface under the cumulative ranking curve (SUCRA), 94.5%]. For Mini-Mental State Examination (MMSE) score, CWM + CHM + Acup ranked first [standardized mean difference (SMD) = 3.01; 95% CI, 1.65-4.37; SUCRA, 97.2%]. For Activities of Daily Living (ADL) score, CWM + Acup + AA ranked first (SMD = 4.10; 95% CI, 1.18-7.02; SUCRA, 99.2%). For Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog) score, CWM + CHM + Acup ranked first (SMD = 2.43; 95% CI, 0.43-4.43; SUCRA, 89.3%). CWM + CPM ranked first for interleukin (IL)-1β (SMD = 1.73; 95% CI, 0.82-2.65; SUCRA, 83.8%), IL-6 (SMD = 3.47; 95% CI, 2.29-4.65; SUCRA, 96.3%), and tumor necrosis factor-alpha (TNF-α) (SMD = 3.71; 95% CI, 2.86-4.56; SUCRA, 100%). For serum superoxide dismutase (SOD), CWM + (CHM + Acup) ranked first (SMD = 2.78; 95% CI, 0.87-4.69; SUCRA, 94.1%).

CONCLUSION: Available evidence suggests that CPM added to CWM may offer advantages for inflammatory biomarkers, while acupuncture-based combinations may be advantageous for selected clinical and functional outcomes. Treatment choice should therefore be guided by the therapeutic target and the certainty of the supporting evidence. Because several comparisons were supported by few studies and overall certainty was low to very low for major outcomes, these findings require confirmation in rigorously designed trials.}, } @article {pmid42362040, year = {2026}, author = {Xu, W and Cao, J and Liu, Y and Wei, Z and Zha, X and Xie, S and Liu, X and Wang, W and Zhang, C and , }, title = {LPI alleviates Alzheimer's disease pathology via the GPR55 receptor.}, journal = {Neuroscience}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.neuroscience.2026.06.035}, pmid = {42362040}, issn = {1873-7544}, abstract = {Lysophosphatidylinositol (LPI) is an endogenous GPR55 agonist, yet its role in Alzheimer's disease (AD) remains unclear. Here, we performed serum metabolomic profiling in 5xFAD mice and observed a reduction in multiple LPI species prior to the onset of overt Aβ pathology, and this decrease was further corroborated in human cohort samples. Exogenous LPI treatment reduced cerebral Aβ deposition, improved performance in learning and memory behavioral tasks, reduced pathological microglial aggregation, inhibited astrocyte proliferation, and ameliorated hippocampal oxidative stress. Mechanistically, administration of the GPR55 antagonist ML191 blocked the protective effects of LPI, while the GPR55 agonist O-1602 recapitulated these benefits, indicating that LPI acts through GPR55. Collectively, our findings suggest that reduced LPI represents an early metabolic vulnerability in the 5xFAD model and establish the LPI-GPR55 axis as a potential therapeutic target for early intervention in AD.}, } @article {pmid42362770, year = {2026}, author = {Lee, S and Baratono, SR and Ha, J and Burt, GT and Palm, ST and Drew, WJ and Zide, BS and Chiulli, NM and Lariviere, S and Zhang, S and Yeo, BTT and Fox, MD and Sperling, RA and Donovan, NJ and Siddiqi, SH}, title = {Atrophy in preclinical Alzheimer's disease maps to a network that predicts longitudinal decline.}, journal = {Molecular psychiatry}, volume = {}, number = {}, pages = {}, pmid = {42362770}, issn = {1476-5578}, support = {2T32MH016259-34//U.S. Department of Health & Human Services | NIH | National Institute of Mental Health (NIMH)/ ; }, abstract = {Brain atrophy may precede cognitive and functional impairment in Alzheimer's disease (AD), but at this "preclinical" stage, it remains unclear whether atrophy localizes to specific brain networks and whether such localization is associated with clinical outcomes. We investigated cortical thickness in 1778 cognitively unimpaired (CU) older adults with amyloid-β (Aβ) PET from the A4 (Anti-Amyloid Treatment in Asymptomatic Alzheimer's Disease) and LEARN (Longitudinal Evaluation of Amyloid Risk and Neurodegeneration) studies, with a subset (N = 445) with tau PET. We estimated the networks disrupted by each individual's cortical thinning using a large normative connectome database (N = 1000), and tested whether this preclinical AD atrophy network is associated with clinical manifestations and longitudinal cognitive (PACC) and functional (CDR) trajectories. Distinct networks connected to atrophy patterns were associated with Aβ and regional tau in CU older adults. These networks were similar to a previously published atrophy network for AD dementia (Aβ: r = 0.817, P = 0.006; tau: r = 0.712, P = 0.046). Atrophy connectivity to this preclinical AD network was associated with higher Aβ and tau, independent of total cortical atrophy, and cross-sectionally with lower cognition, greater subjective cognitive decline, and increased anxiety; longitudinally, it predicted faster cognitive and functional decline over ~5 years. After tau adjustment, the functional-decline effect was preserved while the cognitive-slope effect was largely attenuated. Atrophy in preclinical AD localizes to a network resembling AD dementia, and is independently associated with AD pathologies, clinical outcomes, and longitudinal decline. Network-level neurodegeneration is detectable and clinically informative in preclinical AD, supporting future network-based research and therapeutic development.}, } @article {pmid42363162, year = {2026}, author = {Ma, X and Yuan, M and Gao, Y and Guo, Z and Liang, J and Yan, F and Wang, S and Qiu, H and He, S and Li, Y and Wang, Y}, title = {40 Hz biparietal transcranial alternating current stimulation for Alzheimer's disease: a prospective study.}, journal = {BMC medicine}, volume = {}, number = {}, pages = {}, doi = {10.1186/s12916-026-04983-w}, pmid = {42363162}, issn = {1741-7015}, support = {2021ZD0201800 and 2021ZD0201801//the Brain Science and Brain-like Intelligence Technology Research Projects of China/ ; LNB202204//the senile disease prevention project of Hebei Province/ ; XH202402//the "Spark" Research Project Outstanding Fund of the First Hospital of Hebei Medical University/ ; 20231065//the Medica science research subject of Hebei Provincial Health Commission/ ; }, abstract = {BACKGROUND: Alzheimer's disease (AD) is characterized by dysfunction in multiple cognitive domains. Patients with AD demonstrate a relative attenuation and dysregulation of theta and gamma oscillations in the temporal and parietal lobes at an early stage. Transcranial alternating current stimulation (tACS) has been shown to modulate neural oscillations in different regions of the brain, affecting higher cognitive functions such as motor function, memory, and learning.

OBJECTIVE: To observe the clinical efficacy and after-effects of biparietal 40 Hz tACS in treating AD patients, to analyze its safety and feasibility, and to deeply explore the effects of tACS on time-varying brain networks and dynamic functional connectivity.

METHODS: In the study, patients with mild AD who were treated in the First Hospital of Hebei Medical University from October 2022 to August 2023 were recruited, randomly divided into tACS group or Sham group, and then respectively received either biparietal 40 Hz tACS or sham stimulation for 15 consecutive days, each lasting 30 min. Neuropsychological assessment scales were collected to assess the efficacy at three time points: pre-stimulation, post-stimulation, and 10-week follow-up. Additionally, transcranial magnetic stimulation with electroencephalography (TMS-EEG) and functional magnetic resonance imaging (fMRI) were collected to explore time-varying brain networks and functional connectivity.

RESULTS: Patients with AD exhibited improvements in global cognition, memory, language, attention, and executive functions following tACS treatment compared with those before treatment. Additionally, the neuropsychiatric inventory scores were decreased significantly after tACS treatment. The clinical efficacies were not obvious in Sham group. These results indicated that tACS treatment had significant short-term efficacy and good stability. The brain time-varying EEG network patterns were analyzed using the adaptive directed transfer function. The analysis showed enhanced information flows from the temporal and prefrontal regions and from the posterior to anterior regions after tACS treatment. In contrast, decreased information flow was observed from the left to right frontal regions. The fMRI analysis revealed enhanced connectivity within default mode network and between default mode network and Frontoparietal network after active treatment.

CONCLUSIONS: The 40 Hz biparietal tACS is a potentially safe and effective treatment for AD with certain long-term efficacy by modulating dynamic functional connectivity.

TRIAL REGISTRATION: The trial was retrospectively registered at the Chinese Clinical Trial Registry (registration number: ChiCTR2500115019).}, } @article {pmid42363270, year = {2026}, author = {Bathini, P and Schilling, S and Rahfeld, JU and Holtzman, DM and Saido, TC and Lemere, CA}, title = {Early binding of anti-amyloid antibodies to CAA drives complement activation, inflammation and ARIA in mice.}, journal = {Molecular neurodegeneration}, volume = {}, number = {}, pages = {}, doi = {10.1186/s13024-026-00965-x}, pmid = {42363270}, issn = {1750-1326}, support = {23AARF-1029815/ALZ/Alzheimer's Association/United States ; AG078106/NH/NIH HHS/United States ; 1RF1 AG058657, 1R01NS136122/NH/NIH HHS/United States ; }, abstract = {Anti-amyloid antibody treatment for Alzheimer's disease is linked to Amyloid-Related Imaging Abnormalities (ARIA), including vasogenic edema (ARIA-E) and microhemorrhages (ARIA-H), especially in ApoE ε4/4 carriers. To investigate mechanisms underlying ARIA, we examined the binding and temporal vascular effects of immunization with 3D6, the precursor to the anti-amyloid antibody bapineuzumab, in two aged Alzheimer's disease amyloid mouse models. Acutely, 3D6 bound to cerebral amyloid angiopathy (CAA), resulting in C1q binding and classical complement activation. Weekly short-term immunization over 7 weeks resulted in elevated CAA- and plaque-associated complement deposition, red blood cell extravasation and microhemorrhages, and was accompanied by significant transcriptomic changes in genes related to complement, inflammation, vascular dysfunction, and endothelial lipid responses. Longer-term dosing over 13-15 weeks further increased complement deposition and was associated with blood-brain barrier disruption, MMP-9 upregulation, and microhemorrhages, accompanied by reduced amyloid burden and modest CAA clearance. C3 levels correlated with microhemorrhage severity. Perivascular macrophages co-localized with complement-decorated CAA in 3D6-treated mice. These findings implicate complement activation as an early key driver of ARIA and suggest that therapeutic targeting of complement may reduce ARIA risk.}, } @article {pmid42363277, year = {2026}, author = {Caminiti, SP and Fernandes, M and Zaccone, C and Malito, R and Chiaravalloti, A and Manfredi, N and Camedda, R and Giuliano, FD and D'Amelio, M and Mercuri, NB and Perani, D and Liguori, C}, title = {Altered brain glucose metabolism and connectivity in young adults with obstructive sleep apnea.}, journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association}, volume = {22}, number = {2}, pages = {e71211}, pmid = {42363277}, issn = {1552-5279}, support = {//Ministry of University and Research (MUR)/ ; //National Recovery and Resilience Plan (NRRP)/ ; //Ministero dell'Università e della Ricerca/ ; //NEXTGENERATIONEU/ ; }, mesh = {Humans ; *Sleep Apnea, Obstructive/metabolism/diagnostic imaging ; *Glucose/metabolism ; Positron-Emission Tomography ; Female ; Male ; *Brain/metabolism/diagnostic imaging ; Fluorodeoxyglucose F18 ; Polysomnography ; Adult ; Young Adult ; Neural Pathways/metabolism/diagnostic imaging ; Magnetic Resonance Imaging ; Brain Mapping ; }, abstract = {INTRODUCTION: Obstructive sleep apnea syndrome (OSAS) is a recognized risk factor for neurodegenerative disorders. However, a causal link between OSAS and brain damage has yet to be established.

METHODS: Thirty cognitively normal patients with moderate-to-severe OSAS, free from systemic or neurological comorbidities, were enrolled and underwent [18]F-fluorodeoxyglucose positron emission tomography imaging. Their scans were compared to those of cognitively normal, OSAS-free controls from the Alzheimer's Disease Neuroimaging Initiative database. Additional analyses included commonality mapping, correlations with polysomnographic parameters, and seed-based metabolic connectivity of major resting-state networks.

RESULTS: Group-level analyses showed fronto-parietal glucose hypometabolism and cerebellar glucose hypermetabolism in patients with OSAS compared to controls. Cerebellar glucose hypermetabolism was associated with reduced rapid eye movement sleep latency and duration. Seed-based connectivity analysis revealed alterations in attentional and limbic networks.

DISCUSSION: Moderate-to-severe OSAS may represent a cause of brain dysfunction, highlighting the importance of its early diagnosis and appropriate treatment to prevent worsening brain damage and possible future neurodegenerative processes.

HIGHLIGHTS: Moderate-to-severe obstructive sleep apnea syndrome (OSAS) is associated with altered brain glucose metabolism. Cerebellar glucose hypermetabolism is associated with rapid eye movement sleep impairment. Attentional and limbic networks connectivity is disrupted in moderate-to-severe OSAS. Early recognition of patients with moderate-to-severe OSAS has the potential to overcome the risk of worsening brain damage that may lead to neurodegeneration.}, } @article {pmid42363810, year = {2026}, author = {Sato, K and Niimi, Y and Ihara, R and Suzuki, K and Iwata, A and Iwatsubo, T}, title = {Potential and biases of large language model simulation for public surveys on Alzheimer's disease therapies.}, journal = {Journal of Alzheimer's disease : JAD}, volume = {}, number = {}, pages = {13872877261464182}, doi = {10.1177/13872877261464182}, pmid = {42363810}, issn = {1875-8908}, abstract = {BackgroundWhile large language models (LLMs) have a potential to simulate public-opinion, their reliability for sensitive medical topics like novel Alzheimer's disease (AD) treatments remains unclear.ObjectiveThis study compared LLM-generated and human answers on AD-therapy dilemmas; assessed model and prompting parameter influences; and identified demographic bias.MethodsUsing survey data on late 2023 from 1671 Japanese Trial Ready Cohort Webstudy participants who are presumably cognitively unimpaired, LLM persona profiles guided four LLMs (Gemini-1.5-flash, Gemini-2.0-flash, GPT-4.1-mini, GPT-4o-mini). The models answered a binary question about acceptance towards patient-prioritization or a 5-point Likert question on concern about amyloid-related imaging abnormalities (ARIA) under varied prompt settings. Aggregate similarity was measured with Jensen-Shannon Divergence (JSD) for binary and Earth Mover's Distance (EMD) for Likert scale; while individual agreement used Cohen's κ and Spearman's ρ.ResultsWhile some LLM models achieved fair group-level agreement in both tasks (JSD ≤ 0.05, EMD < 1.0), individual agreement was negligible across any LLM settings (κ, ρ ≈ 0). Adding detailed attributes like living condition, clinical status, or related personal opinions offered limited improvement. Performance was largely stable for most demographic levels, but deteriorated for minority subgroups, such as those with low education or requiring long-term care.ConclusionsOur study demonstrates that current LLMs can approximate aggregate attitudes toward novel AD therapies but cannot predict individual opinions. They can amplify biases in some small subgroups. LLMs may be useful for pre-testing public survey in the field of AD/dementia treatment but should not replace authentic human data.}, } @article {pmid42363912, year = {2026}, author = {Zhou, S and Lee, T and Ji, X and Mackenzie, KR and Li, F}, title = {Characterizing the Reactive Metabolites of Colony-Stimulating Factor 1 Receptor Inhibitor PLX5622 in Liver Microsomes and Mice.}, journal = {Chemical research in toxicology}, volume = {}, number = {}, pages = {}, doi = {10.1021/acs.chemrestox.6c00282}, pmid = {42363912}, issn = {1520-5010}, abstract = {Colony-stimulating factor 1 receptor (CSF1R) is a receptor tyrosine kinase involved in cell growth and differentiation, particularly in macrophages and microglia. CSF1R inhibitors are under investigation for various diseases, including cancer, autoimmune/inflammatory diseases, and neurodegenerative disorders. PLX5622 is a highly specific, brain-penetrant, and orally bioavailable CSF1R inhibitor that is being evaluated in a clinical trial for rheumatoid arthritis and considered as an attractive candidate for the treatment of Alzheimer's disease (AD). Drug metabolism significantly influences both the efficacy and safety of therapeutic agents. In particular, bioactivation leading to the formation of reactive metabolites is often implicated in adverse drug effects. In this study, we investigated the metabolism and potential bioactivation of PLX5622 in mouse and human liver microsomes (MLM/HLM) and mice using LC-MS-based metabolomic approaches. Reduced glutathione (GSH) and methoxyamine (NH2OMe) were used to capture reactive intermediates. In total, 12 PLX5622-GSH adducts and five NH2OMe adducts were identified in both HLM and MLM, along with 22 nontrapped metabolites generated from demethylation, hydroxylation, and carbon-carbon cleavage reactions. PLX5622-GSH-related adducts in mice were also assessed and 8 GSH adducts were detected in mouse liver, confirming the occurrence of bioactivation in vivo. Using recombinant human cytochrome P450 (CYP) enzymes and selective chemical inhibitors in liver microsomes, CYP3A was determined to be the primary enzyme responsible for the metabolic activation of PLX5622. These insights into the metabolic pathways of PLX5622 are valuable for further study of its safety and potential drug interactions of CYP3A. Future studies using human primary hepatocytes or physiologically human-relevant models such as liver-on-a-chip systems are warranted to confirm clinical relevance and better predict in vivo outcomes.}, } @article {pmid42364023, year = {2026}, author = {Ebrahimbabaei, A and Hekmat, AS and Javanmardi, K}, title = {Neurotherapeutic roles of the protective arm of the renin-angiotensin system: from inflammation to cognitive rescue.}, journal = {Molecular biology reports}, volume = {53}, number = {1}, pages = {}, pmid = {42364023}, issn = {1573-4978}, mesh = {Humans ; *Renin-Angiotensin System/drug effects/physiology ; Animals ; *Inflammation/metabolism ; Proto-Oncogene Mas ; Angiotensin-Converting Enzyme 2/metabolism ; Receptor, Angiotensin, Type 2/metabolism ; Receptors, G-Protein-Coupled/metabolism ; *Cognition/drug effects/physiology ; Signal Transduction ; Angiotensin I/metabolism ; Peptide Fragments/metabolism ; Peptidyl-Dipeptidase A/metabolism ; Neuroinflammatory Diseases/metabolism ; Proto-Oncogene Proteins/metabolism ; Blood-Brain Barrier/metabolism ; Brain/metabolism ; Oxidative Stress ; Oligopeptides ; }, abstract = {The renin-angiotensin system (RAS), traditionally recognized for its role in regulating blood pressure and fluid homeostasis, is increasingly understood to exert important effects across multiple organ systems, including the central nervous system (CNS). A local brain RAS contributes to neurovascular regulation, inflammation, oxidative stress, synaptic plasticity, and cognitive function. This review critically summarizes the neurotherapeutic relevance of the protective RAS arm, particularly the angiotensin-converting enzyme 2 (ACE2)-angiotensin-(1-7)-Mas receptor axis, the angiotensin II type 2 receptor (AT2R), and the alamandine/Mas-related G protein-coupled receptor D (MrgD) pathway. Experimental evidence suggests that these pathways may counterbalance angiotensin II type 1 receptor signaling by reducing neuroinflammation, oxidative injury, vascular dysfunction, and neuronal loss in models of ischemic stroke, Alzheimer's disease, Parkinson's disease, and multiple sclerosis. The strongest evidence remains preclinical, with most data derived from cell culture and animal models, whereas human evidence is still indirect and largely based on observational or early translational studies of RAS-modifying drugs. Important uncertainties remain regarding blood-brain barrier penetration, receptor-specific signaling, disease-stage dependency, systemic vascular effects, and reproducibility across models. Therefore, protective RAS signaling should be considered a promising but still exploratory therapeutic framework rather than an established treatment strategy for neurological disease. Future work should prioritize selective brain-penetrant agonists, validated biomarkers of central RAS activity, and rigorously designed clinical trials to determine whether modulation of ACE2-angiotensin-(1-7)-Mas, AT2R, or alamandine/MrgD signaling can produce clinically meaningful neuroprotection.}, } @article {pmid42364272, year = {2026}, author = {Cawthray, J}, title = {From PET to targeted radionuclide therapy in the Brain: The emerging role of radiometal-based platforms.}, journal = {Journal of inorganic biochemistry}, volume = {283}, number = {}, pages = {113397}, doi = {10.1016/j.jinorgbio.2026.113397}, pmid = {42364272}, issn = {1873-3344}, abstract = {Radiometal-based radiopharmaceuticals have become central to the advancement of molecular imaging and targeted radionuclide therapy, offering powerful tools for the diagnosis and treatment of diseases affecting the brain. The unique chemical versatility of radiometals - encompassing a broad range of coordination chemistries, physical half-lives, and emission properties - combined with an expanding repertoire of targeting biomolecules enables highly tunable and increasingly modular imaging and therapeutic platforms. In particular, positron emission tomography (PET) using radiometal-labelled tracers provides sensitive, quantitative, and non-invasive assessment of molecular processes in vivo, while radiometal-based therapeutic agents enable the selective delivery of cytotoxic radiation to diseased tissue. This review examines recent progress in the application of radiometal-based radiopharmaceuticals for brain disorders, with a focus on neuro-oncology - including primary brain tumours and brain metastases - as well as neurodegenerative diseases such as Alzheimer's disease and Parkinsons disease. Key challenges unique to brain applications are discussed, including the restrictive nature of the blood-brain barrier, heterogeneous target expression, and off-target biodistribution. Recent advances in chelator development, emerging antigen targets, alternative routes of administration, and strategies to improve brain delivery are highlighted. While imaging agents continue to lead therapeutic development in this space, reflecting the need for accurate disease characterisation, recent progress underscores the potential of radiometal-based therapies for brain disease. In particular, immunoPET has emerged as a powerful tool for evaluating target expression, biodistribution, and treatment response. Collectively, these developments position radiometal-based radiopharmaceuticals as a promising and evolving platform enabling personalised treatment strategies for neurological disorders.}, } @article {pmid42364425, year = {2026}, author = {Rodrigues, EA and Dionizio, A and Rosa, CM and Campos, DHS and Damatto, FC and Reyes, DRA and Souza, LM and Santos, PP and Gatto, M and Borim, PA and Pagan, LU and Araújo, TT and Buzalaf, MAR and Cunha, TM and Okoshi, K and Okoshi, MP}, title = {Effects of SGLT2 inhibitor dapagliflozin on the heart of rats with long-standing Type 1 diabetes mellitus: Protein profile.}, journal = {Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie}, volume = {201}, number = {}, pages = {119719}, doi = {10.1016/j.biopha.2026.119719}, pmid = {42364425}, issn = {1950-6007}, abstract = {UNLABELLED: Sodium-glucose cotransporter 2 (SGLT2) inhibitors have beneficial outcomes on the renal and cardiovascular system in diabetes mellitus (DM) patients. As most clinical trials were performed in Type 2 DM, the effects of SGLT2 inhibition in Type 1 DM are not completely clarified.

OBJECTIVE: To evaluate the effects of long-standing SGLT2 inhibitor dapagliflozin on the protein profile in rats with a Type 1 DM model.

METHODS: Male Wistar rats were divided into Control (C), DM, and DM treated with dapagliflozin (DM+DAPA) for 30 weeks. DM was induced by a single injection of streptozotocin (40 mg/kg); dapagliflozin was added to chow (5 mg/kg/day). Label-free mass spectrometry was used to assess left ventricular proteome. The bioinformatic tools used were STRING, Cytoscape, Cluster Marker, and ClueGO.

STATISTICAL ANALYSIS: ANOVA and Tukey or Kruskal-Wallis and Dunn.

RESULTS: Dapagliflozin attenuated body weight loss (C 574 ± 43; DM 339 ± 31*; DM+DAPA 413 ± 30*# g; p < 0.05 * vs C; # vs DM) and reduced glycemia [C 108 (101-111); DM 554 (529-562)*; DM + DAPA 343 (237-416)*# mg/dL; p < 0.05 * vs C; # vs DM]. Most proteins identified in the networks downregulated in DM vs C were upregulated in DM + DAPA vs DM. Proteins related to energy metabolism (CKm, Ak1, Atp5pf, Mdh1, Idh2), excitation-contraction coupling (Actc1, Casq2, Serca1, Serca2a), and oxidative stress (Sod1, Sod2) were upregulated in DM + DAPA. KEGG pathways enriched in DM vs Control included gap junction, necroptosis, and fatty acid degradation (upregulated), and Alzheimer's disease, cardiac contraction, and glycolysis/gluconeogenesis (downregulated). In DM + DAPA vs DM, upregulated pathways included Parkinson's disease, cardiac contraction, citrate cycle, necroptosis, and cyclic guanosine monophosphate-dependent protein kinase (PKG) signaling pathway; downregulated proteins were linked to ketone body metabolism.

CONCLUSION: Dapagliflozin modulates cardiac protein abundance by attenuating DM-induced changes in Type 1 DM rats.}, } @article {pmid42364498, year = {2026}, author = {Hu, H and Zhao, S and Xu, L and Ma, Z and Ma, R and Huang, F and Shi, L}, title = {Sequential targeting nanochaperone disrupts positive feedback loop of mitochondrial dysfunction for Alzheimer's disease therapy.}, journal = {Biomaterials}, volume = {335}, number = {}, pages = {124408}, doi = {10.1016/j.biomaterials.2026.124408}, pmid = {42364498}, issn = {1878-5905}, abstract = {Mitochondrial dysfunction is recognized as a key pathogenic mechanism of Alzheimer's disease (AD), involving a self-perpetuating feedback loop with three aspects: upstream β-amyloid protein (Aβ), downstream calcium ion (Ca[2+]) and reactive oxygen species (ROS). However, current therapeutic strategies only focus on one aspect and fail to address multiple factors within this cycle. Moreover, the lack of targeted approaches to the mitochondria within damaged neurons further limits their application. Herein, we developed a sequential targeting nanochaperone to selectively target damaged neuronal mitochondria and disrupt this vicious cycle for AD treatment. In this strategy, with the sequence mediation of damaged neuron-targeting and mitochondria-targeting peptides decorated on surface, the nanochaperone can first localize to the damaged neurons in AD brain and then translocate to mitochondria within them. Subsequently, this nanochaperone can effectively bind upstream Aβ proteins and inhibit their aggregation toxicity to mitochondria through the synergic effect of chaperone-mimicking microdomains and Aβ-targeting peptide on surface, thereby halting downstream mitochondrial Ca[2+] dyshomeostasis and ROS overload in the damaged neuron. Furthermore, the modified mitochondria-targeting peptide with antioxidant property can further scavenge overproduced ROS and regulate Ca[2+] homeostasis, which in turn contributes to reducing the Aβ-induced mitochondrial damage. Consequently, the nanochaperone efficiently restores the mitochondrial dysfunction by disrupting the self-amplifying feedback loop of "Aβ-Ca[2+]-ROS" in the AD mitochondrial microenvironment, resulting in the significant alleviation of neuronal damage and cognitive deficits in 5xFAD transgenic mice. Taken together, our work presents a novel therapeutic strategy against mitochondrial dysfunction for AD treatment.}, } @article {pmid42364649, year = {2026}, author = {Lamichhane, B and Niraula, A and Merindol, N and Gélinas, SE and Lagüe, P and Ricard, S and Germain, H and Desgagné-Penix, I}, title = {A Golgi-localized N-methyltransferase and reversible aldo-keto reductases coordinate dual terminal routes in galanthamine biosynthesis.}, journal = {The Plant journal : for cell and molecular biology}, volume = {126}, number = {6}, pages = {e70910}, pmid = {42364649}, issn = {1365-313X}, support = {CRC-2023-00353//Canada Research Chairs/ ; }, mesh = {*Galantamine/biosynthesis/metabolism ; *Methyltransferases/metabolism/genetics ; *Golgi Apparatus/metabolism/enzymology ; *Plant Proteins/metabolism/genetics ; *Alcohol Oxidoreductases/metabolism/genetics ; *Liliaceae/enzymology/metabolism/genetics ; *Amaryllidaceae/enzymology/metabolism/genetics ; }, abstract = {Galanthamine, a therapeutic Amaryllidaceae alkaloid produced exclusively by species within the Amaryllidoideae subfamily, is a key treatment for early-stage symptoms of Alzheimer's disease. Elucidating its biosynthetic pathway is essential for strategies aimed at enhancing production through metabolic engineering. Galanthamine derives from the metabolic precursor 4'-O-methylnorbelladine, which undergoes cytochrome P450-mediated para-ortho' C-C phenol coupling to yield nornarwedine. Two competing terminal routes have been proposed: (i) reduction of nornarwedine to norgalanthamine, followed by N-methylation, or (ii) N-methylation of nornarwedine to narwedine prior to reduction. Here, we identify three aldo-keto reductase (AKR) candidates (LaAKR1, LaAKR2, and LaAKR3) and three N-methyltransferase (NMT) candidates from Leucojum aestivum: LaNMT, homologous to coclaurine N-methyltransferase-like (NMT-like), and two γ-tocopherol methyltransferases (TMT) homologs, LaTMT1 and LaTMT2. Subcellular localization studies revealed distinct compartmentalization, with LaNMT targeted to the ER-cytosol, LaTMT1 to plastids, and LaTMT2 to the Golgi apparatus. In vitro, LaTMT2 methylated both nornarwedine and norgalanthamine, with a kinetic preference for nornarwedine. LaTMT1 methylated γ-tocopherol to α-tocopherol (vitamin E). All three AKRs catalyzed reversible interconversions between nornarwedine and norgalanthamine, and between narwedine and galanthamine, with LaAKR3 favoring the reduction reaction whereas LaAKR1 the oxidation reaction. These findings identify LaTMT2 and LaAKRs as key branch-enabling enzymes, reconcile long-standing models of galanthamine biosynthesis, and provide a strategic target for metabolic engineering strategies to enhance galanthamine production.}, } @article {pmid42365183, year = {2026}, author = {Park, DK and Constant, AB and Honig, LS and Marder, KS and Provenzano, FA and , }, title = {Machine learning classification and regional differentiation of neuropathologically-confirmed Alzheimer's disease and comorbid Lewy body disease.}, journal = {Communications medicine}, volume = {}, number = {}, pages = {}, doi = {10.1038/s43856-026-01652-0}, pmid = {42365183}, issn = {2730-664X}, abstract = {BACKGROUND: Alzheimer's disease (AD) and dementia with Lewy bodies (DLB) co-occur frequently, and growing evidence, including neuropathology, supports synergistic interplay between the diseases. We tested whether a single T1-weighted MRI scan may differentiate neuropathologically confirmed comorbid AD/DLB and AD controls using heterogeneously acquired neuroimaging.

METHODS: We obtained structural neuroimaging, on two groups, AD with and without DLB pathology. Convolutional neural networks are trained across dimensions. We introduce a triple-ensemble strategy consisting of majority voting schemes within a variety of plane permutations. In addition, we conduct voxel-wise statistical analyses.

RESULTS: Here we show convolutional neural networks record a classification accuracy of 0.820 and an f1 score of 0.79 in identifying comorbid DLB/AD from AD patients. Prediction accuracy is higher proximal to date of death, while the trained model largely outperforms clinical baseline diagnosis. The slice-level performance varies depending on the sampled brain location, with sensitivity highest in the temporal lobe and specificity highest in the occipital lobe. In DLB/AD, gray matter is relatively preserved though atrophy is observed in the occipital lobe, suggesting that the comorbidity differentially affects brain loss and may accelerate it in the occipital lobe.

CONCLUSIONS: This study demonstrates how machine learning approaches can address diverse neuroimaging data from clinical sources to differentiate neurodegenerative diseases using a true gold standard of neuropathological confirmation. The frameworks utilized here can be extended to other diseases that are frequently co-occurring and feasibly extend to single scan diagnostic clinical utility of scans already being acquired.}, } @article {pmid42365511, year = {2026}, author = {Song, A and Zhao, Y and Wu, S and Xu, X}, title = {Frequency-specific effects of pulsed magnetic field on BV2 microglial cell function.}, journal = {Electromagnetic biology and medicine}, volume = {}, number = {}, pages = {1-9}, doi = {10.1080/15368378.2026.2694326}, pmid = {42365511}, issn = {1536-8386}, abstract = {The objective of this study was to investigate the effects of pulsed magnetic field (PMF) at different frequencies on phagocytosis, migration, and the expression of inflammatory factors in microglia. BV2 microglia were subjected to PMF at different frequencies for 3 d, twice daily. The changes of cell viability, phagocytosis and migration after magnetic stimulation were detected. The mRNA and protein levels of TNF-α and IL-1β were determined using RT-PCR and ELISA. The nuclear translocation of NF-κB P65 and intracellular Ca2+ level was detected through immunofluorescence. PMF at different frequencies did not affect microglial viability. Stimulation at all frequencies enhanced the ability of microglia to phagocytosis and migration. The mRNA expression level of IL-1β and TNF-α was significantly decreased by magnetic stimulation at 20 Hz and 40 Hz. However, only the protein level of IL-1β was significantly reduced by magnetic stimulation at 20 Hz, while TNF-α remained unaffected. Magnetic stimulation at 20 Hz and 40 Hz inhibited the nuclear translocation of NF-κB P65 and increased the intracellular Ca2+ level. Repetitive magnetic stimulation can modulate the secretion of inflammatory cytokines and enhance the phagocytosis and migration capacity of microglia in a frequency-dependent manner. This variation may be linked to differences in the activation of NF-κB and calcium in microglia.}, } @article {pmid42366338, year = {2026}, author = {Dey, AK and Al-Amin, MY and Ferdous, R and Alam, AHMK and Rahman, AA and Hossen, MB and Mollah, MNH and Sadik, MG}, title = {Isolation and identification of hasubanan alkaloids having anti-cholinesterase and antioxidant activity from the stem Stephania japonica.}, journal = {BMC complementary medicine and therapies}, volume = {}, number = {}, pages = {}, doi = {10.1186/s12906-026-05447-7}, pmid = {42366338}, issn = {2662-7671}, support = {37-01-0000-073-04-012/2019//University Grants Commission of Bangladesh/ ; }, abstract = {BACKGROUND: A recent report showed that Stephania japonica chloroform fraction has potential anticholinesterase and antioxidant activities and is able to improve learning and memory in mice. Therefore, the aim of the present study was to isolate and identify compounds from the chloroform fraction with cholinesterase inhibitory and antioxidant activity that may be useful as new candidates for the treatment of AD.

METHODS: Chromatographic methods were used for isolation of compounds and the isolated compounds were analyzed by spectroscopic methods for structure elucidation. Acetyl- and butyryl-cholinesterase inhibitory activity were evaluated for by Ellman's method and the antioxidant activity by several in vitro models such as DPPH and hydroxyl radicals scavenging, reducing power, total antioxidant activity, and inhibition of brain lipid peroxidation. The interaction of cholinesterase enzymes and isolated compounds were examined by molecular docking studies.

RESULTS: Bioactivity guided approach led to the isolation of four compounds from the chloroform fraction and identified as aknadinine, aknadilactam, aknadicine and stephisoferuline on the basis of their [1]H-NMR and [13]C-NMR spectral data. All the compounds were of hasubanan type. They showed significant inhibition against acetylcholinesterase and butyrylcholinesterase, with at least two fold increased affinity for butyrylcholinesterase than acetylcholinesterase. The IC50 values of the alkaloids were in the range of 9.36-14.89 µg/mL against acetylcholinesterase and 3.97-6.66 µg/mL against butyrylcholinesterase. Kinetic analysis revealed that all the four compounds exhibited mixed type of inhibition against both acetylcholinesterase and butyrylcholinesterase. The interaction of compounds with several amino acids of enzymes was supported by molecular docking studies. All the hasubanan alkaloids showed antioxidant activity in all in vitro assays and inhibited peroxidation of brain lipid. The IC50 values of the compounds for scavenging of DPPH and hydroxyl radicals, and lipid peroxidation inhibition were found to be in the range of 5.1-40.91, 10.44-19.41, and 20.60-31.72 µg/mL, respectively.

CONCLUSION: The hasubabanan alkaloids isolated from S. japonica may represent a new class of anti-cholinesterase compounds. The multitargeted activity of hasubanan alkaloids may lead to new candidates for the treatment of AD.}, } @article {pmid42366543, year = {2026}, author = {Sui, Z and Feng, A and Gong, Y and Zha, S and Lv, Y and Zheng, Q and Li, L and Wang, Y}, title = {Predicting cognitive function in Alzheimer's clinical trials via amyloid β-protein biomarkers.}, journal = {British journal of clinical pharmacology}, volume = {}, number = {}, pages = {}, doi = {10.1002/bcp.70665}, pmid = {42366543}, issn = {1365-2125}, support = {2025ZHYL037//Shanghai Municipal Health Commission Smart Healthcare Special Project/ ; 2024YFC3506600//National Key R&D Program of China/ ; LSLSKL20240203//Open Research Program of the State Key Laboratory of Integration and Innovation of Classic Formula and Modern Chinese Medicine/ ; }, abstract = {OBJECTIVES: This study investigates the association between amyloid-β (Aβ) biomarkers and clinical cognitive outcomes and quantitatively elucidates their relationship, providing robust evidence supporting the amyloid hypothesis and advancing the development of novel anti-amyloid therapeutics, such as aducanumab, lecanemab and donanemab.

METHODS: Placebo-controlled randomized clinical trials reporting Aβ-related biomarkers and cognitive function clinical outcomes were retrieved from PubMed, EMBASE and Cochrane Library. Pearson correlation analysis was first used to screen indices, and then a model-based meta-analysis (MBMA) using non-linear mixed-effect modelling was established to predict cognitive function based on biomarkers while examining relevant factors affecting the relationship.

RESULTS: Primary outcomes included changes in the Clinical Dementia Rating Scale Sum of Boxes (CDR-SB) and the Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-COG-11). The analysis included 57 articles representing 93 417 subjects, with a modelling subset of 18 246 patients providing paired biomarker-endpoint data for Alzheimer's disease or mild cognitive impairment. Results showed significant correlations between the standard uptake value ratio (SUVR) of β-amyloid plaques and CDR-SB, centiloid and CDR-SB, and SUVR and ADAS-COG-11. Three prediction models of cognitive function scales based on imaging index of β-amyloid plaques were established and found to be significantly impacted by factors such as baseline CDR-SB, treatment duration and the proportion of patients receiving basic treatment.

CONCLUSIONS: This study clarified the correlation and established predictive models for CDR-SB and ADAS-COG-11 based on amyloid imaging. This research identifies potential biomarkers and model-derived benchmarks for future dose selection and decision-making in Alzheimer's drug development, potentially accelerating the development of new treatments.}, } @article {pmid42366747, year = {2026}, author = {Abed, H}, title = {Postoperative Experiences After Dental Treatment Under General Anesthesia in People Living With Alzheimer's Disease: A Descriptive Study With Caregiver and Staff Reports.}, journal = {Special care in dentistry : official publication of the American Association of Hospital Dentists, the Academy of Dentistry for the Handicapped, and the American Society for Geriatric Dentistry}, volume = {46}, number = {4}, pages = {e70201}, doi = {10.1111/scd.70201}, pmid = {42366747}, issn = {1754-4505}, mesh = {Humans ; *Anesthesia, General ; *Alzheimer Disease/complications ; Female ; Aged ; *Caregivers/psychology ; Male ; Aged, 80 and over ; *Anesthesia, Dental ; Postoperative Complications/epidemiology ; Middle Aged ; *Dental Care for Chronically Ill ; Anesthesia Recovery Period ; }, abstract = {AIMS: To describe the demographic and clinical characteristics of people living with Alzheimer's disease (AD) undergoing dental treatment under general anesthesia, to summarize peri-recovery challenges reported by healthcare staff, and to describe caregiver-reported postoperative experiences at three time points. The occurrence of postoperative delirium or hallucinations was also descriptively examined.

METHODS: In this single-center descriptive study, postoperative information was obtained through structured telephone contacts with caregivers and relevant clinical staff at three time points (immediate recovery, 2 days, and 2 weeks). Responses were analyzed using inductive content analysis and summarized descriptively.

RESULTS: Participants (n = 14) were elderly and predominantly in the moderate to late stages of AD, with substantial dependence on caregivers. Staff-reported observations indicated that agitation and behavioral disturbance during emergence and early recovery were the most prominent challenges. Resistance to care with monitoring devices was also noted. Caregivers reported increased pain, agitation, and care demands within the first 48 h following general anesthesia. By one week, most caregivers reported physical recovery and behavioral improvement. No documented cases of postoperative delirium or hallucinations were identified.

CONCLUSIONS: In this exploratory descriptive study, dental treatment under general anesthesia in people living with AD was followed by short-term postoperative behavioral and physical challenges that generally improved within one week. Given the small sample size and descriptive design, findings should be interpreted cautiously.}, } @article {pmid42367372, year = {2026}, author = {Cabán, M and Brown-Bradley, C and Wetmore, JB and Ottman, R and Siegel, K}, title = {Latinos' beliefs regarding the role played by nonmedical factors in the quality of Alzheimer's disease care: Findings from a NYC community-based sample.}, journal = {SSM. Qualitative research in health}, volume = {9}, number = {}, pages = {}, pmid = {42367372}, issn = {2667-3215}, abstract = {Latinos represent the fastest-growing subpopulation in the United States and are expected to experience the steepest increase in the coming decades in adults 65 and older living with Alzheimer's disease (AD). However, they also have a higher likelihood of delayed diagnosis, greater difficulty in accessing specialist referrals, treatments and support services and have fewer long-term and nursing care options than non-Latino Whites. A New York City community-based sample of Latinos completed qualitative interviews in English (63%) or Spanish (37%). We investigated participants' beliefs regarding Latinos' access to quality AD-related care. Data were coded by three team members using ATLAS.ti and thematic analysis was conducted by the senior qualitative team members. The results are organized along the care continuum from diagnosis through medical, supportive, and long-term care. The data revealed that participants (n = 155) believed a combination of nonmedical factors contributed to Latinos being diagnosed at a more advanced stage of AD and receiving poorer quality of care once diagnosed than non-Latino Whites. These included: limited financial assets, restricted health insurance coverage, cultural values and tendencies, limited availability of providers who understood their background and experiences or spoke Spanish, and to a lesser extent prejudice or discrimination. These findings are important because expectations of poor care may deter care seeking or once diagnosed may influence patients' level of engagement in care and treatment adherence. They have implications for enhancing patient-centered care for Latinos with AD as it emphasizes the incorporation of their perspectives when assessing the quality of care being delivered.}, } @article {pmid42367689, year = {2026}, author = {Liu, Y and Zhao, J and Shi, Z}, title = {Anti-Metabotropic Glutamate Receptor 5 Autoimmune Encephalitis with a Typical Alzheimer's Disease Biomarker Profile: A Case of Rapidly Progressive Dementia Unresponsive to Cholinesterase Inhibitors.}, journal = {Case reports in neurology}, volume = {18}, number = {1}, pages = {280-284}, pmid = {42367689}, issn = {1662-680X}, abstract = {INTRODUCTION: The distinction between neurodegenerative and autoimmune causes of rapidly progressive dementia can be challenging, particularly when atypical Alzheimer's disease (AD) biomarkers are present. We present a case of anti-metabotropic glutamate receptor 5 (mGluR5) autoimmune encephalitis (AE) initially misdiagnosed as AD due to concordant clinical, imaging, and biomarker findings.

CASE PRESENTATION: A 51-year-old woman developed progressive memory decline, apathy, and stereotyped paper-folding behavior over 2 years. She was diagnosed with rapidly progressive AD and treated with donepezil and memantine without improvement. Initial workup showed hippocampal neurodegeneration on magnetic resonance imaging/MRS and elevated plasma phosphorylated tau181, tau217, and GFAP - consistent with an AD biomarker profile. Neurological examination later revealed bilateral pyramidal signs. Re-evaluation identified serum anti-mGluR5 antibodies. Treatment with intravenous methylprednisolone and immunoglobulin led to marked improvement in cognition and behavior within 2 weeks.

CONCLUSION: This case demonstrates that anti-mGluR5 AE can manifest with a biomarker profile highly suggestive of AD, leading to prolonged misdiagnosis. It underscores the importance of considering AE in treatment-refractory or atypical dementia, even in the presence of supportive AD biomarkers, and highlights the potential for significant recovery with timely immunotherapy.}, } @article {pmid42367849, year = {2026}, author = {Gabal, E and Nguyen, TKO and Kovalenko, T and Gao, H and Rappaport, N and Funk, C and Baloni, P and Trushina, E}, title = {Mitochondrial Complex I Modulator Restores Network Resilience in Advanced Alzheimer's Disease Through Metabolic Reprogramming.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, doi = {10.64898/2026.06.14.732179}, pmid = {42367849}, issn = {2692-8205}, abstract = {Mitochondrial dysfunction and lipid dysregulation are among the earliest abnormalities in Alzheimer's disease (AD), yet their mechanistic interplay and therapeutic potential remain poorly understood. Here, we investigated whether restoration of mitochondrial function can reverse metabolic dysfunction and promote resilience in advanced-stage AD. Female APP/PS1 mice were treated with the brain-penetrant mitochondrial complex I (mtCI) modulator CP2 beginning at 19 months of age, when pathology and cognitive deficits were well established. To define the metabolic mechanisms underlying therapeutic response, we developed iMiceBrain , the first brain-specific genome-scale metabolic model of the mouse brain, and integrated transcriptomics, targeted metabolomics, lipidomics, and metabolic network analyses. CP2 treatment broadly reprogrammed AD-associated molecular signatures and restored pathways involved in mitochondrial function, glucose utilization, lipid metabolism, synaptic activity, and cellular stress responses. Metabolic modeling identified enhanced mitochondrial substrate flexibility, activation of fatty acid utilization, restoration of pyruvate dehydrogenase flux, and normalization of cholesterol metabolism as key features of the therapeutic response. Lipidomic analyses further demonstrated correction of disease-associated alterations in cholesteryl esters, phospholipids, and sphingolipids. Together, these findings demonstrate that mild mtCI modulation restores metabolic resilience by coordinating mitochondrial and lipid metabolism, establishing it as a disease-modifying therapeutic strategy for AD.}, } @article {pmid42367992, year = {2026}, author = {Haynes, KA and Pandey, RS and Doud, EH and Cope, ZA and Little, GJ and Williams, SP and Nepali, U and Quinney, SK and Nagar, A and Charbe, NB and da Silva, L and Dage, JL and Duong, DM and Seyfried, NT and Sasner, M and Lamb, BT and Oblak, AL and Territo, PR and Carter, GW and Sukoff Rizzo, SJ}, title = {Molecular mechanisms underlying amyloid lowering by aducanumab: differential and comparative effects of sex and IgG reveal the post-treatment disease brain.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, doi = {10.64898/2026.06.16.731973}, pmid = {42367992}, issn = {2692-8205}, abstract = {INTRODUCTION: Improving the predictive validity of preclinical studies for Alzheimer's disease (AD) requires rigorous evaluation of therapeutic efficacy, safety, and sex-specific responses in translationally relevant models. As amyloid-targeting monoclonal antibodies continue to advance clinically, there is an urgent need to define the molecular milieu that persists after amyloid is reduced and disease progression continues. Leveraging the NIA-funded MODEL-AD Preclinical Testing Core, we investigated the biochemical, functional, and multi-omic signatures associated with chronic administration of murine chimeric aducanumab (chAdu) in 5XFAD mice, including the contribution of IgG-mediated effects.

METHODS: Male and female 5XFAD mice were treated weekly with chAdu beginning at 8 months of age and compared to age-and sex-matched murine IgG2aκ isotype (IgG) and saline controls. Plasma and brain pharmacokinetics, amyloid-beta (Aβ), behavioral assessments, and treatment-emergent anti-drug antibodies (ADAs) were quantified. Post-treatment transcriptomic and proteomic analyses were performed to assess molecular pathways associated with chAdu and IgG exposure following 17-week treatment.

RESULTS: chAdu produced sex-dependent changes in Aβ, including increased plasma Aβ42:40 and reductions in brain Aβ which were associated with mild behavioral impairments in the absence of improvements in cognitive function. IgG control treatment produced similar reductions, indicating biologically active IgG-mediated processes independent of Aβ-targeted specificity. Treatment-emergent ADAs occurred in 10% of chAdu-treated mice and were associated with reduced drug exposure and efficacy. Multi-omics analyses confirmed sex-dependent and IgG-mediated effects at both the transcriptomic and proteome level revealing disease-associated genes and proteins not altered despite reductions in amyloid with treatment.

DISCUSSION: These findings demonstrate sex-dependent PK and pharmacodynamic responses to chAdu, identify biologically meaningful IgG-driven effects, and reveal molecular signatures that persist after amyloid reduction. This work provides biological insights into pathways that may remain insufficiently addressed following amyloid lowering; revealing novel targets for future drug discovery to prevent and treat disease.}, } @article {pmid42368200, year = {2026}, author = {Chong, AEY and Sasmita, AO and Koh, RY and Ling, APK}, title = {Neuroprotective effects of ursodeoxycholic acid in Parkinson's disease and Alzheimer's disease.}, journal = {Neuroprotection (Chichester, England)}, volume = {4}, number = {2}, pages = {111-130}, pmid = {42368200}, issn = {2770-730X}, abstract = {Neurodegenerative diseases (NDDs) including Parkinson's disease (PD) and Alzheimer's disease (AD), are progressive disorders characterised by shared pathological features, including mitochondrial dysfunction, oxidative stress, apoptosis, neuroinflammation, neurotoxic protein buildup, and impaired protein clearance. Current treatments can only relieve disease symptoms but cannot delay the disease progression. Ursodeoxycholic acid (UDCA), a hydrophilic bile acid traditionally used in hepatology, has recently gained attention for its neuroprotective properties. This review critically evaluates UDCA's mechanisms of action, including the restoration of mitochondrial function, inhibition of apoptosis, reduction of oxidative stress and neuroinflammation, and enhancement of autophagy in both PD and AD models. In vitro and in vivo studies demonstrate UDCA's ability to preserve neuronal integrity, improve motor and cognitive outcomes, and reduce toxic protein aggregates. Although early-phase clinical trials, such as the UDCA for Parkinson's (UP) study in PD, show promising mitochondrial benefits and safety, clinical evidence in AD remains limited. Future directions emphasise the need for large-scale trials, personalised medicine, improved central nervous system (CNS) delivery strategies, or dietary interventions to modulate UDCA production from the gut microbiome. While not a first-line treatment, UDCA represents a compelling mitochondrial stabiliser with disease-modifying potential in NDDs.}, } @article {pmid42368467, year = {2026}, author = {Ji, T and Wang, L and Weng, X and Lu, C and Gao, Y and Yu, K and He, J and Shen, X and Gao, X}, title = {Protective effect of baicalein from Pinellia ternate on Alzheimer's disease cell injury: a network pharmacology, molecular docking, and molecular dynamics study.}, journal = {Frontiers in aging neuroscience}, volume = {18}, number = {}, pages = {1848282}, pmid = {42368467}, issn = {1663-4365}, abstract = {INTRODUCTION: Alzheimer's disease (AD) constitutes the primary leading cause of dementia. Pinellia ternata (Thunb.) Breit. is a traditional Chinese herb with unclarified potential therapeutic effects against AD. This study aimed to explore the therapeutic potential and underlying mechanism of Pinellia ternata (Thunb.) Breit. in the treatment of AD.

METHODS: The bioactive components and corresponding targets of Pinellia ternata (Thunb.) Breit. were screened from TCMSP, Herb, and SymMap databases. AD-related targets were retrieved from OMIM, GeneCards, and TTD databases, and key targets were obtained via target intersection analysis. Functional enrichment analyses were performed to identify the main signaling pathways involved in the targets. Core targets and major bioactive components were further screened, and molecular docking as well as dynamics simulations were conducted to verify the binding affinity between key components and core targets. In vitro cell experiments using BV2 cells were implemented to validate the therapeutic effect of the core bioactive component.

RESULTS: A total of 13 bioactive components and 99 corresponding targets of Pinellia ternata (Thunb.) Breit. were identified, and 29 key AD-related targets were screened out through target intersection. Enrichment analysis results showed that these key targets were mainly enriched in neuroactive ligand-receptor interaction and calcium signaling pathways. PTGS2, CASP2, and AKT1 were determined as core therapeutic targets, with β-sitosterol and baicalein identified as the principal bioactive components of Pinellia ternata (Thunb.) Breit. against AD. Molecular docking and dynamics simulations verified the strong binding affinity between baicalein and PTGS2. In vitro experimental results further demonstrated that baicalein pretreatment could relieve the inhibitory effect of Aβ1-42 on BV2 cell proliferation.

DISCUSSION: Pinellia ternata (Thunb.) Breit. exerts therapeutic effects on AD via a synergistic mechanism characterized by multi-component, multi-target, and multi-pathway regulation. The active ingredient baicalein targeting PTGS2 is a crucial material basis for its anti-AD effect. The findings of this study elucidate the potential mechanism of Pinellia ternata (Thunb.) Breit. in AD treatment and provide a reliable theoretical foundation for subsequent in-depth research and clinical exploration of the herb as a therapeutic agent for AD.}, } @article {pmid42368893, year = {2026}, author = {Xie, J and Li, Y and Lu, J and Wang, W and Hou, Y and Huang, Y and Wu, H and Zhou, Y and Li, J}, title = {Mechanisms of electroacupuncture for the treatment of Alzheimer's disease by activating Wnt/β-catenin pathway to improve blood-brain barrier function.}, journal = {IBRO neuroscience reports}, volume = {21}, number = {}, pages = {106-113}, pmid = {42368893}, issn = {2667-2421}, abstract = {AIMS: In this study, we used APP/PS1 mice as a research vehicle to illustrate that electroacupuncture can improve the blood-brain barrier function by activating the Wnt/β-catenin pathway for the treatment of Alzheimer's disease (AD).

METHODS: 18 7-month-old SPF APP/PS1 male double-transgenic mice were selected as AD model mice and randomly divided into model group, electroacupuncture group and donepezil hydrochloride group, with 6 mice in each group, and 6 C57BL/6 J male mice as normal group. After the end of the intervention, the mice in each group were subjected to Morris water maze behavioural test. After the behavioural test, the pathological morphology of hippocampal tissue was observed by HE staining method, Aβ was detected in the hippocampal region of mice by IHC method, the mRNA expression of Axin2 and Dkk1 was detected in hippocampal tissue by Real-time PCR method, and the tight junction protein, Claudin-5, was detected in hippocampal region of mice by Western Blot method. Claudin-5, Occludin protein with active β-catenin, p-GSK3β protein expression in mouse hippocampus by Western Blot.

RESULTS: EA can improve the learning ability of APP/PS1 mice, restore the morphology and structure of the hippocampus, reduce the positive expression of Aβ in the hippocampus, down-regulate the expression of Axin2 and Dkk1 mRNA, and elevate the expression of the tight junction-related proteins, Claudin-5, Occludin with active β-catenin, and p-GSK3β.

CONCLUSION: EA can improve the expression of blood-brain barrier-related molecules in AD mice by regulating the expression of molecules related to the Wnt/β-catenin pathway, which is beneficial to the early treatment of AD.}, } @article {pmid42369233, year = {2026}, author = {Ding, S and Johns, E and Orlichenko, A and Fredericks, C and Zhao, Y}, title = {A NOVEL BAYESIAN FRAMEWORK UNCOVERING BRAIN CONNECTIVITY-TO-SHAPE RELATIONSHIP IN PRECLINICAL ALZHEIMER'S DISEASE.}, journal = {The annals of applied statistics}, volume = {20}, number = {2}, pages = {1429-1451}, pmid = {42369233}, issn = {1932-6157}, abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by amyloid-beta plaques and tau tangles, with significant pathological changes occurring in subcortical brain regions. While previous research has focused primarily on volumetric reductions in areas such as the hippocampus, thalamus, and caudate, emerging evidence suggests that their fine-grained shape deformations may offer greater sensitivity to early disease pathology. Moreover, understanding how these shape alterations influence brain functional connectivity (FC) networks could provide critical insights into the neurobiological mechanisms underlying the progression of AD. In this context, we propose a novel statistical approach, the Connectivity-on-Shape Regression (COSR) model, designed to investigate the spatially varying impact of brain subcortical shape on FC, accounting for the intrinsic modularity of functional networks. Under a Bayesian framework, COSR employs a relaxed-thresholded Gaussian process prior model to promote feature selection and integrates a stochastic block model to capture the unknown modular organization of FC. To facilitate the practical application of COSR with vertex-level shape measurements, we develop a computationally efficient variational inference approach to achieve posterior inference. Extensive simulations demonstrate the superiority of COSR over existing alternatives in accurately uncovering connectivity-to-shape associations and identifying neurobiological signals. Applying COSR to data from the Anti-Amyloid Treatment in Asymptomatic Alzheimer's study, we discover meaningful neural structural-functional relationships in amyloid-positive individuals, highlighting the potentially complex interplay between structural and functional brain alterations during this crucial preclinical stage of AD.}, } @article {pmid42369461, year = {2026}, author = {Mukumbi, K and Liu, Y and Shi, Z and Liu, E and Toyli, A and Hung, GU and Chen, QH and Sha, Q and Chiu, PY and Zhou, W}, title = {Low-Density Lipoprotein Cholesterol and Dementia Risk: Integrating Mendelian Randomization and Target Trial Emulation Within the Heart-Brain Axis.}, journal = {medRxiv : the preprint server for health sciences}, volume = {}, number = {}, pages = {}, doi = {10.64898/2026.06.10.26355413}, pmid = {42369461}, abstract = {BACKGROUND: The heart-brain axis links cardiovascular and neurodegenerative disease through shared vascular and inflammatory mechanisms. Although low-density lipoprotein cholesterol (LDL-C) is an established causal factor in atherosclerotic cardiovascular disease (ASCVD), its relationship with dementia remains uncertain, with midlife elevations associated with increased risk but late-life associations often appearing null or inverse. To address this cholesterol paradox, we integrated mendelian randomization (MR) with an active-comparator new-user target trial emulation.

METHODS: We applied a triangulated causal inference framework integrating two-sample MR with observational target trial emulation. Genetic variants associated with LDL-C were used as instrumental variables to evaluate Alzheimer's disease (AD), Dementia with Lewy bodies (DLB), Frontotemporal dementia (FTD), and any dementia (AnyDem), with causal estimates derived using inverse-variance weighted models and sensitivity analyses for heterogeneity and pleiotropy. In parallel, an active-comparator new-user design compared statin versus ezetimibe initiation among adults aged ≥60 years using propensity score (PS) overlap weighting and Cox proportional hazards models to evaluate cardiovascular and dementia outcomes.

RESULTS: Genetically predicted LDL-C was associated with increased risk of DLB (OR 1.65, 95% CI 1.30-2.10; p<0.001), but not AD or AnyDem; FTD estimates were inconsistent. Sensitivity analyses suggested heterogeneity and possible pleiotropy for DLB. In the observational analysis (n=6,977), statin initiation was associated with higher risks of ASCVD (HR 1.26, 95% CI 1.11-1.45) and AnyDem (HR 1.66, 95% CI 1.16-2.38), although estimates attenuated after lipid adjustment and lagged analyses, suggesting residual confounding, treatment selection, and reverse causation in late-life observational associations.

CONCLUSIONS: These findings suggest that LDL-C reflects accumulated vascular and metabolic risk rather than a direct causal driver of AD or overall dementia, although a subtype-specific association was observed for DLB. Late-life associations appeared influenced by timing, reverse causation, and treatment selection, warranting cautious interpretation.}, } @article {pmid42369569, year = {2026}, author = {Liu, T and Zhang, Y and Hou, W and Hao, H and Geng, A and Zhao, G and Zhang, Y}, title = {From cellular heterogeneity to precision medicine: single-cell multi-omics in CNS disease research.}, journal = {Frontiers in cellular neuroscience}, volume = {20}, number = {}, pages = {1848558}, pmid = {42369569}, issn = {1662-5102}, abstract = {Single-cell sequencing and multi-omics technologies are revolutionizing research on central nervous system (CNS) diseases by enabling high-resolution analysis of cellular heterogeneity and molecular dynamics. Traditional technologies (e.g., bulk sequencing, routine histology) often lack cellular resolution, fail to capture heterogeneity among individual cells, and struggle to reveal subtle molecular changes in early pathogenesis, limiting their ability to clarify complex CNS disease mechanisms and develop precise diagnostic tools. This review comprehensively summarizes the latest advances in single-cell multi-omics methodologies, including genomics, transcriptomics, proteomics, metabolomics, and spatial omics, and their applications in elucidating the pathogenesis, diagnosis, and treatment of common CNS disorders. Representative diseases such as ischemic stroke, Alzheimer's disease, Parkinson's disease, viral meningitis, bacterial meningitis, multiple sclerosis, autism spectrum disorder, and depression are used as examples to discuss the current status and future prospects of single-cell multi-omics technologies in CNS disease research. Currently, these technologies have enabled the identification of rare pathogenic cell subsets, the mapping of cell-specific molecular pathways, and the discovery of potential diagnostic biomarkers in several common CNS disorders, though their clinical translation is still hindered by technical costs and standardization issues. In the future, the integration of single-cell multi-omics with spatial transcriptomics, artificial intelligence, and clinical data is expected to further decode the complex pathogenesis of CNS disorders, accelerate the development of targeted therapies, and promote the shift toward personalized medicine in CNS disease management-aligning with translational goals of neuropsychopharmacology.}, } @article {pmid42370069, year = {2026}, author = {Timashkov, A and Andreev, S and Safonova, A and Zangieva, S and Kadieva, D and Zinchenko, O}, title = {The inconsistent effects of tDCS in rehabilitation and cognitive enhancement: sources of variability and paths to personalization.}, journal = {Frontiers in human neuroscience}, volume = {20}, number = {}, pages = {1817726}, pmid = {42370069}, issn = {1662-5161}, abstract = {BACKGROUND/AIMS: Transcranial direct current stimulation (tDCS) has emerged as a promising intervention in both rehabilitation and cognitive enhancement, yet its effects remain inconsistent across studies. This variability has raised questions about the underlying mechanisms influencing tDCS efficacy.

METHODS: In this review, we address the issue of the inconsistent effect of tDCS on motor and cognitive domains across studies in healthy individuals and those with neurodegenerative disorders. A review of literature in the field was conducted using PubMed and Google Scholar.

RESULTS: Research indicates that individual anatomical differences among subjects may contribute to the inconsistent outcomes observed, as variations in current density at targeted brain regions and genetic variations responsible for the stimulation effect. Understanding the factors that contribute to the inconsistent effects of tDCS will be essential for enhancing its application in clinical settings and maximizing its potential benefits in cognitive rehabilitation and enhancement.

CONCLUSION: Future research should focus on optimizing tDCS parameters and exploring individualized approaches to treatment, taking into account the diverse responses observed in different populations.}, } @article {pmid42370305, year = {2026}, author = {Maiese, K}, title = {Dementia, mood disorders, and aging: Bridging new avenues of care through shared biological pathways.}, journal = {Aging advances}, volume = {3}, number = {3}, pages = {142-151}, pmid = {42370305}, issn = {3050-6743}, abstract = {With advancing age and lifespan throughout the globe in both developed and developing nations, the risk for developing cognitive loss and mood disorders increases significantly to the extent that after reaching the age of 65, this risk almost doubles every 5 years thereafter. As a result, a corresponding rise in non-communicable diseases will impact individuals with dementia and mood disorders involving Alzheimer's disease, multiple sclerosis, depression, and anxiety. On a clinical basis, multiple risk factors and presentations that involve the loss of intellectual capacity with the onset of mental health conditions, mood disorders preceding dementia, sleep fragmentation initiation, perivascular pathway disruptions, and circadian clock dysfunction can occur in both cognitive loss and mood disorders, but a much broader scope of shared underlying cellular pathways form the underpinning for the connection of these disorders that rests upon metabolic disorders, such as diabetes mellitus. Cognitive impairment and mood disorders can precede one another as well as coexist with related co-morbidities that involve metabolic disorders with diabetes mellitus, but present treatment strategies for these disorders are primarily symptomatic in nature and rely upon disease-altering therapies that may slow disease progression but also may be accompanied by disabling complications. Given these challenges, the institution of innovative avenues is critical at this juncture to address the mutual cellular mechanisms for the treatment of disorders involving Alzheimer's disease, multiple sclerosis, depression, and anxiety. The pathways of cell senescence and telomere biology with aging, cellular metabolic dysfunction, apolipoprotein E, oxidative stress, programmed cell death with autophagy, ferroptosis, and pyroptosis, mechanistic target of rapamycin, glucagon-like peptide-1 receptor agonism, mammalian forkhead transcription factors of the "O" class, and mitochondrial dynamics offer a compelling potential to bridge these underlying pathways into unifying strategies for transition into efficacious clinical care for dementia and mood disorders. Tempered with this enthusiasm for these mutual disease mechanisms is the complexity of these pathways that will require meticulous oversight of the interdependence among pathway components and their ultimate biological impact on clinical outcomes.}, } @article {pmid42370776, year = {2026}, author = {Salazar, BH and Hoffman, KA and Ong, M and Welk, B and Stoffel, JT and Wood, D and Stampas, A and Khavari, R}, title = {Engineering Advances in Neurogenic Lower Urinary Tract Dysfunction (NLUTD): Current State and Future Directions - A Report From the Neurogenic Bladder Research Group (NBRG).}, journal = {Neurourology and urodynamics}, volume = {}, number = {}, pages = {}, doi = {10.1002/nau.70356}, pmid = {42370776}, issn = {1520-6777}, support = {1R13DK138734/DK/NIDDK NIH HHS/United States ; }, abstract = {BACKGROUND AND OBJECTIVE: Neurogenic lower urinary tract dysfunction (NLUTD), stemming from neurodegenerative diseases or injuries such as cerebrovascular accidents, spinal cord injuries, and Alzheimer's disease, significantly impacts quality of life. Symptoms, including urinary frequency, urgency, incontinence, and retention, are managed with devices ranging from catheters to sacral neuromodulation. This Neurogenic Bladder Research Group (NBRG) report explores the intersection between clinical, basic science, and engineering research in personalized NLUTD treatment, identifies critical gaps for future investigation, and examines how interdisciplinary collaboration can drive engineering solutions to improve care.

METHODS: In December 2024, NBRG convened its annual meeting, gathering experts from engineering, clinical practice, research, and patient advocacy to discuss challenges in NLUTD research and explore collaborative solutions.

RESULTS: Enhanced collaboration between clinicians and engineers offers promise for improving NLUTD care. Clinicians provide critical insight into patient needs but often lack time for sustained research, while engineers contribute technical innovation yet may lack clinical exposure. Integrating patient perspectives emerged as a key theme, ensuring that technologies are practical, acceptable, and aligned with end-user needs. Discussions emphasized expanding programs that support cross-disciplinary, multi-institutional research and identifying funding pathways tailored to interdisciplinary efforts. Strategies to enhance patient involvement and foster inclusive research that reflects patient diversity and socio-demographic factors influencing care were also discussed.

CONCLUSION: Institutional support, interdisciplinary collaboration, and the active engagement of patients are key to advancing clinical care and NLUTD treatments.}, } @article {pmid42371177, year = {2026}, author = {Li, R and Zhang, T and Ren, D and Zhu, H and Xu, J and Xiao, L}, title = {Bushen Huoxue Acupuncture alleviates alzheimer's disease progression via the E3 ubiquitin ligase SMURF2‑mediated ubiquitination of LAPTM5.}, journal = {Metabolic brain disease}, volume = {41}, number = {1}, pages = {}, pmid = {42371177}, issn = {1573-7365}, support = {2024JJ5544//Hunan Provincial Natural Science Foundation of China/ ; }, mesh = {Animals ; *Ubiquitin-Protein Ligases/metabolism ; *Alzheimer Disease/metabolism/therapy ; *Ubiquitination/physiology ; Mice ; Microglia/metabolism ; *Acupuncture Therapy/methods ; Disease Progression ; *Membrane Proteins/metabolism ; Male ; Humans ; }, abstract = {This study investigated the therapeutic potential and mechanism of Bushen Huoxue Acupuncture (BSHXA) against Alzheimer's disease (AD) using integrated in vivo and in vitro approaches. In eight-month-old SAMP8 mice, BSHXA treatment significantly improved cognitive performance, alleviated hippocampal neuronal damage and neuroinflammation, and downregulated LAPTM5 expression. Complementary in vitro experiments in lipopolysaccharide (LPS)-stimulated BV2 microglia demonstrated that LAPTM5 knockdown reduced apoptosis, pathological protein accumulation, and pro-inflammatory M1 polarization. Through bioinformatic prediction and Co-IP assays, SMURF2 was identified as an E3 ubiquitin ligase directly interacting with LAPTM5 and promoting its ubiquitin-dependent degradation. SMURF2 overexpression in vitro reproduced protective effects similar to LAPTM5 knockdown. Importantly, in vivo knockdown of SMURF2 abolished the therapeutic benefits of BSHXA. Collectively, these findings demonstrate that BSHXA ameliorates AD progression by upregulating SMURF2, which promotes the ubiquitination and subsequent degradation of LAPTM5, thereby suppressing microglial M1 polarization, inhibiting neuroinflammatory responses, and attenuating AD pathologies. The SMURF2-LAPTM5 axis is established as a key mechanistic pathway underlying the neuroprotective effects of BSHXA.}, } @article {pmid42371218, year = {2026}, author = {Kurmi, S and Parab, SB and Godad, A and Waghmare, P and Doshi, G}, title = {Neuroprotective Effects of Tenoxicam and Phenethyl Isothiocyanate in an Aβ1-42-Induced Rat Model of Alzheimer's Disease: Modulation of NF-κB/NLRP3 Signaling and Redox Homeostasis.}, journal = {Molecular neurobiology}, volume = {63}, number = {1}, pages = {}, pmid = {42371218}, issn = {1559-1182}, mesh = {Animals ; Amyloid beta-Peptides/toxicity ; Male ; *Alzheimer Disease/drug therapy/metabolism/pathology ; *NF-kappa B/metabolism ; Rats, Wistar ; *Isothiocyanates/pharmacology/therapeutic use ; *Piroxicam/analogs & derivatives/pharmacology/therapeutic use ; *Signal Transduction/drug effects ; *Neuroprotective Agents/pharmacology/therapeutic use ; Disease Models, Animal ; Peptide Fragments/toxicity ; *NLR Family, Pyrin Domain-Containing 3 Protein/metabolism ; Oxidation-Reduction/drug effects ; *Homeostasis/drug effects ; Oxidative Stress/drug effects ; Rats ; }, abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by cognitive decline, neuroinflammation, oxidative stress, and amyloid pathology, yet effective disease-modifying therapies remain limited. This study asked whether combined targeting of inflammatory and oxidative stress pathways could offer enhanced neuroprotection in an Aβ1-42-induced rat model of AD. Tenoxicam, an oxicam-class non-steroidal anti-inflammatory drug with COX-linked anti-inflammatory activity, and phenethyl isothiocyanate (PEITC), a natural compound known for antioxidant and Nrf2-activating properties, were selected on the basis of their complementary mechanisms; however, their combined potential in this model has not been sufficiently explored, providing the rationale for this hypothesis-driven investigation. Male Wistar rats were assigned to control, disease, standard, tenoxicam, PEITC, and combination treatment groups. Cognitive performance was evaluated using the Morris Water Maze, Y-maze, and Novel Object Recognition tests, while neuroinflammatory and oxidative stress markers, including NF-κB, NLRP3, IL-1β, Nrf2, catalase, and malondialdehyde, were assessed alongside histopathological examination of hippocampal integrity and molecular docking against COX-2, NF-κB, and NLRP3. Aβ1-42 administration induced significant cognitive impairment, neuroinflammation, oxidative stress, and neuronal damage. Tenoxicam and PEITC improved behavioral performance, reduced inflammatory signaling, restored antioxidant defenses, and preserved hippocampal architecture, with the combination showing the most pronounced effects. These findings provide preclinical evidence that dual modulation of inflammatory and redox pathways may represent a promising multi-target approach for AD and support further evaluation of this combinatorial strategy.}, } @article {pmid42374285, year = {2026}, author = {Pedersen, EK and Nielsen, A and Nicolaisdóttir, DR and Øksnebjerg, L and Tannebæk, K and Janbek, J and Waldemar, G and Nielsen, TR}, title = {Associations between a psychosocial intervention and quality of life and caregiver-related outcomes in family caregivers of people with dementia: the Danish DemTool trial.}, journal = {BMC geriatrics}, volume = {}, number = {}, pages = {}, doi = {10.1186/s12877-026-07835-7}, pmid = {42374285}, issn = {1471-2318}, abstract = {BACKGROUND: People with dementia often need comprehensive support, depending on the stage of the disease, from both family members and healthcare professionals. Caring for a person with dementia can be stressful and impact the caregiver's health and wellbeing. Studies show that family caregivers of people with dementia frequently experience stress, depression, and reduced quality of life. We aimed to assess the association between the psychosocial intervention (DemTool) and caregiver wellbeing and quality of life among family caregivers of people with dementia.

METHOD: DemTool trial was a pragmatic, cluster-controlled trial. The intervention was delivered by primary care dementia coordinators across 30 Danish municipalities from 2020 to 2023, with 15 serving as the intervention group and 15 as treatment as usual. The primary outcome measures were the Neuropsychiatric Inventory Caregiver Distress Scale (NPI-D) and the European Quality of Life Visual Analog Scale (EQ VAS). Both measures were completed at baseline and follow-up, alongside secondary quality of life outcomes. To estimate group differences in primary and secondary outcomes, we applied analysis of variance (ANOVA) and analysis of covariance (ANCOVA).

RESULTS: A total of 245 family caregivers were included in the study (181 in the intervention group and 64 in the treatment-as-usual group). Most participants were females caring for a spouse. Baseline scores for caregiver wellbeing and quality of life were similar across groups. The DemTool intervention was associated with a significant between-group difference in change from baseline in caregiver-related quality of life as measured by the Carer Experience Scale (CES), favoring the intervention. This was evident in the analysis adjusted for baseline scores (p = 0.05) and remained significant when further adjusting for caregiver-related covariates (p = 0.02). No statistically significant between-group differences were observed for the remaining wellbeing and quality-of-life outcomes.

CONCLUSION: No effects of DemTool were found on traditional health-related quality-of-life outcomes. However, a positive association was found between the intervention and the CES, underlining the importance of selecting outcomes that are directly related to the targeted effects of the intervention.

TRIAL REGISTRATION: The study protocol was registered in the ClinicalTrials.gov system, registration number: NCT07355829.}, } @article {pmid42374501, year = {2026}, author = {Bregman, N and de Barros, NP and Nathan, T and Levy, MH and Sima, D and Van Eyndhoven, S and Bar-David, A and Aizenstein, O and Niry, D and Atlan, L and Awad, AA and Ash, E and Omer, N and Shiner, T}, title = {Lecanemab in practice: AI-derived MRI predictors of benefit and Amyloid Related Imaging Abnormalities (ARIA).}, journal = {Alzheimer's research & therapy}, volume = {}, number = {}, pages = {}, doi = {10.1186/s13195-026-02127-z}, pmid = {42374501}, issn = {1758-9193}, abstract = {INTRODUCTION: Lecanemab, a monoclonal antibody targeting amyloid beta, has demonstrated meaningful clinical benefits in early Alzheimer's disease (AD), yet real-world data is needed to optimize patient selection and enhance safety monitoring, particularly with respect to amyloid-related imaging abnormalities (ARIA). Integration of quantitative and AI-derived MRI biomarkers may improve risk stratification and prediction of clinical trajectory.

METHODS: We conducted a retrospective real-world study of eighty-two patients with biomarker-confirmed early AD who initiated lecanemab at Tel Aviv Sourasky Medical Center between November 2023 and June 2025. Baseline MRI included volumetric T1-weighted imaging and susceptibility-weighted imaging (SWI). Automated whole-brain, regional cortical, and hippocampal volumes, and percentiles were extracted using FDA-cleared AI tools (icobrain by icometrix). Microhaemorrhage (MH) burden was assessed by both human and AI-assisted reads. Cognitive outcomes were evaluated using change in Mini-Mental State Examination (MMSE). Linear regression models assessed MRI predictors of cognitive response, and multivariable logistic regression identified predictors of ARIA.

RESULTS: Patients exhibited significantly lower cerebral volumes at treatment initiation. Mean whole brain percentile, mean gray-matter (GM) percentile, and mean white matter percentile were 11.45%, 8.6% and 38% respectively. Higher baseline GM volume predicted less MMSE decline at 12 months (β = 0.64, FDR-corrected p < 0.003). Hippocampal and white-matter volumes were not associated with cognitive outcomes. Seventeen patients (20.7%) developed ARIA. Baseline MH burden was the strongest predictor of ARIA (human rated OR=3.48 per MH, p=0.015, icobrain rated OR=3.25, p=0.01), while APOE ε4 carriage showed a strong directional trend which did not reach significance. Aspirin use and hypertension were not associated with ARIA. Agreement between icobrain and experts for MH ratings was excellent with a single-measure intraclass correlation coefficient (ICC) of 0.89 (95% CI: 0.83-0.93).

CONCLUSIONS: AI-derived MRI markers, particularly GM volume and MH burden, provide valuable predictors of cognitive response and ARIA risk in patients treated with lecanemab. Integrating quantitative neuroimaging into clinical workflows may enhance personalized treatment decisions and improve real-world implementation of Amyloid-targeting therapies.}, } @article {pmid42375090, year = {2026}, author = {Lee, HY and Hossain, MK and Jang, GH and Lee, H and Kim, YM and Chae, HJ}, title = {Behavioral and Biochemical Evaluation of a Curcumin-Loaded Nano-Liposomal Formulation in a Scopolamine-Induced Mouse Model of Cognitive Impairment.}, journal = {Biomolecules & therapeutics}, volume = {34}, number = {4}, pages = {866-881}, doi = {10.4062/biomolther.2026.062}, pmid = {42375090}, issn = {1976-9148}, abstract = {Scopolamine-induced cognitive impairment in mice models acute cholinergic dysfunction associated with early functional features of Alzheimer's disease (AD). This study evaluated the neuroprotective potential of curcumin-loaded nanoliposomes (Cur-NL), a bioavailable curcumin formulation, using behavioral, molecular, and biochemical approaches. Male mice received oral Cur-NL (250, 500, or 1000 mg/kg) for 30 days, followed by a single intraperitoneal injection of scopolamine (2 mg/kg). Cognitive performance was assessed by the open field test and Barnes maze. Acetylcholinesterase (AChE) activity, acetylcholine (ACh) levels, hippocampal gene expression, and reactive oxygen species (ROS) accumulation were analyzed to investigate underlying mechanisms. Cur-NL significantly improved spatial learning and memory and restored cholinergic balance by normalizing AChE activity and ACh levels. Treatment also attenuated hippocampal neuroinflammation, oxidative stress, and ROS accumulation. Cur-NL modulated genes related to amyloid processing and synaptic plasticity, suppressing App and Bace1 and upregulating Adam10 and Bdnf. Network analyses supported the involvement of cholinergic, inflammatory, and synaptic signaling pathways. These findings indicate that Cur-NL confers multitarget neuroprotection in a scopolamine-induced model and may serve as a candidate for managing early cholinergic-related cognitive decline. Important limitations should be acknowledged: curcumin concentrations in plasma and brain were not quantified, and a free-curcumin comparator was not included. The findings should therefore be interpreted as evidence of efficacy of the tested Cur-NL preparation, not as a comparative demonstration of nano-liposomal superiority over free curcumin. Direct pharmacokinetic and head-to-head comparative studies are required to establish the formulation-specific contribution of nano-liposomal delivery.}, } @article {pmid42375607, year = {2026}, author = {Lee, N and Youn, K and Kwon, H and Kim, DH and Ho, CT and Jun, M}, title = {Fucoxanthin attenuates carbonyl stress and neuroinflammation by modulating MGO/RAGE/NF-κB axis in Aβ-induced models.}, journal = {Frontiers in pharmacology}, volume = {17}, number = {}, pages = {1811183}, doi = {10.3389/fphar.2026.1811183}, pmid = {42375607}, issn = {1663-9812}, abstract = {INTRODUCTION: Amyloid-β (Aβ) accumulation is a central pathological feature of Alzheimer's disease (AD) and a major driver of disease progression. Recent evidence suggests that carbonyl stress associated with Aβ plays a critical role in AD pathology by promoting neuroinflammation and neuronal damage. In particular, methylglyoxal (MGO), a highly reactive carbonyl compound, contributes to activation of the receptor for advanced glycation end products (RAGE) and NF-κB-dependent inflammatory signaling, leading to synaptic dysfunction. The present study investigated whether fucoxanthin, a marine-derived carotenoid, attenuates Aβ-induced carbonyl stress and inflammatory responses associated with MGO/RAGE/NF-κB-related signaling.

METHODS: PC12 neuronal cells were pretreated with fucoxanthin (0.1-5 μM) and exposed to aggregated Aβ25-35 (10 μM) to assess its effects on carbonyl stress-associated inflammatory signaling. In parallel, an Aβ1-42 intracerebroventricular injection mouse model was used to validate the in vitro findings. Mice were orally administered fucoxanthin (100 or 200 mg/kg/day) for 15 days and assessed for serum MGO levels, hippocampal RAGE/NF-κB activation, microglial activation, and synaptic marker expression.

RESULTS: Fucoxanthin significantly reduced the expression of pro-inflammatory mediators, including COX-2, iNOS, IL-1β, and TNF-α in Aβ-exposed neuronal cells. This anti-inflammatory effect was associated with inhibition of NF-κB nuclear translocation and downregulation of RAGE expression. Consistent with these in vitro findings, fucoxanthin treatment in Aβ1-42-injected mice alleviated systemic and hippocampal carbonyl stress, as evidenced by decreased serum MGO levels and suppression of hippocampal RAGE/NF-κB activation. These effects were accompanied by reduced microglial activation (Iba-1) across hippocampal subregions and significant restoration of both presynaptic and postsynaptic markers, indicating preservation of synaptic integrity.

CONCLUSION: These findings demonstrate the neuroprotective role of fucoxanthin in mitigating Aβ-induced carbonyl stress by targeting the MGO/RAGE/NF-κB axis, thereby suppressing neuroinflammation and preserving synaptic integrity in Aβ-induced cellular and mouse models. Fucoxanthin emerges as a promising pharmacological candidate targeting carbonyl stress-associated mechanisms in AD.}, } @article {pmid42376449, year = {2026}, author = {Vukmir, RB}, title = {Alzheimer's disease and related dementia: evaluation, diagnosis and acute care management.}, journal = {Frontiers in neurology}, volume = {17}, number = {}, pages = {1743770}, doi = {10.3389/fneur.2026.1743770}, pmid = {42376449}, issn = {1664-2295}, abstract = {IMPORTANCE: The patient presenting with memory loss often requires a complex, extensive multidisciplinary specialty evaluation that may begin in the primary care, emergency department, or general neurology setting. The analysis begins with a suspicion or concern regarding cognitive performance raised by the patient, family, or provider. Ideally, a better understanding will empower the primary care and general neurology communities to screen for and appropriately diagnose, treat, or refer patients with dementia.

METHODS: The thematic focus of this narrative review is diagnosis, imaging, and treatment of Alzheimer's disease and related dementia (ADRD). Information was abstracted from the National Library of Medicine MEDLINE/PubMed database. Medical Subject Headings (MeSH) heading search terms included dementia and, more specifically, Alzheimer's disease. The search targeted primary research, preferentially compared to reviews, consensus statements, or case reports if feasible.

OBSERVATIONS: Delirium typically represents an acute or subacute fluctuating change in mental status, often temporally related to acute illness. While dementia is typically associated with a more chronic progressive presentation of cognitive change without the presence of concurrent illness. However, subacute or dementia presentations may be exacerbated in that setting as well.

CONCLUSION AND RELEVANCE: The diagnosis, management, and therapy of Alzheimer's disease and related dementia is undergoing rapid change in imaging and now the utility of blood-based biomarkers. As more amyloid-modifying therapy is administered, the acute care systems should be knowledgeable of the treatment course and potential for complications.}, } @article {pmid41449667, year = {2026}, author = {Günaydin, C and Hackett, NR and Wakim, V and Sondhi, D and Kaminsky, SM and Crystal, RG}, title = {Prime Editing of Alzheimer's Disease High-Risk APOE4 Allele by Brain-Directed Adeno-Associated Virus Vectors.}, journal = {Human gene therapy}, volume = {37}, number = {9-10}, pages = {403-411}, doi = {10.1177/10430342251401888}, pmid = {41449667}, issn = {1557-7422}, mesh = {*Dependovirus/genetics ; Animals ; *Alzheimer Disease/genetics/therapy ; Humans ; *Apolipoprotein E4/genetics ; *Genetic Vectors/genetics/administration & dosage ; Mice ; *Gene Editing/methods ; *Brain/metabolism ; Alleles ; Genetic Therapy ; Apolipoprotein E3/genetics ; }, abstract = {Common variants of the apolipoprotein E (APOE) gene have a major impact on the risk of developing Alzheimer's disease (AD). Relative to homozygotes with the common E3 allele, the APOE4 variant (C112R) increases risk by 3.5-fold in E3/E4 heterozygotes and 15-fold in E4 homozygotes. Since the E3 and E4 alleles differ only by a single nucleotide, gene editing of E4 to E3 is a potential strategy to reduce AD risk in E4 homozygotes. Because the APOE pool in the brain is separate from systemic APOE, editing to treat AD would ideally be directed to the brain. Following in vitro optimization of prime editing guide RNAs, efficient prime editing expression cassettes were inserted into the adeno-associated virus (AAV) split-intein system and packaged into pairs of AAV vectors for in vivo editing. The AAV vectors were administered to human homozygous APOE4-targeted replacement mice (TRE4), and APOE4 to APOE3 editing efficiency was assessed after 4 weeks. The prime editing construct designated APOE3/4-3_10 was the most efficient at APOE4 to APOE3 conversion, both in liver following intravenous delivery and in brain following intrahippocampal delivery. To assess brain-wide editing, two AAV capsids were compared, including AAVrh.10 with administration either directly to the hippocampus or to the cerebrospinal fluid via the cisterna magna and AAV-CAP.B10 administered intravenously. Other than minor differences in APOE4/3-3_10 mediated E4 to E3 editing in the cerebellum, the different capsids and routes yielded similar editing efficacy throughout the brain. This may represent a candidate treatment to reduce the risk of AD.}, } @article {pmid41450541, year = {2025}, author = {Chen, C and Shao, Q and Zhou, S}, title = {Exploring the Mahuang Fuzi Xixin Decoction's mechanism for treating Alzheimer's disease using molecular docking and network pharmacology.}, journal = {Frontiers in aging neuroscience}, volume = {17}, number = {}, pages = {1688316}, pmid = {41450541}, issn = {1663-4365}, abstract = {OBJECTIVE: Explore the potential mechanism of Mahuang Fuzi Xixin Decoction (MFXD) in the treatment of Alzheimer's disease (AD) using network pharmacology, molecular docking approaches, and test its efficacy by in vitro experiments.

METHODS: Active components of MFXD were screened from TCMSP, BATMAN-TCM, and TCMID, with corresponding targets obtained from SwissTargetPrediction and TCMSP. AD-related differential genes were retrieved from GEO. Intersection targets were identified via Venn diagrams, followed by GO/KEGG enrichment analyses, PPI network construction, and molecular docking. In vitro validation experiments were carried out using PC12 cells induced by Aβ25-35 to simulate the pathological state of AD. For the detection of cell viability, the CCK-8 assay was employed to evaluate the protective effect of MFXD and its active components on damaged PC12 cells. Western blot analysis was used to determine the protein expression levels of key molecules involved in AD-related signaling pathways, including phosphorylated p-NF-κB p65, NF-κB p65, p-GSK-3β, GSK-3β, MMP-9, p-Tau, and Tau. Additionally, the ELISA was utilized to measure the secretion level of TNF-α in the supernatant of Aβ25-35-induced PC12 cells, so as to assess the anti-inflammatory effect of MFXD.

RESULTS: Thirty-seven active components and 230 targets of MFXD were identified, along with 4913 AD-related differentially expressed genes from GEO dataset GSE122063, yielding 47 intersection targets. GO annotation enriched these targets in processes like reactive oxygen species metabolism, components like extracellular matrix, and functions like neurotransmitter binding; several pathways were enriched in the KEGG analysis, such as TNF signaling pathway, calcium signaling pathway, and NF-κB signaling pathway. The intersection target PPI network identified MMP9, EGFR, FOS as core targets. Molecular docking results indicated that quercetin binds to the three core targets (MMP9, EGFR, FOS), while luteolin binds preferentially to EGFR and MMP9. In vitro, Aβ25-35-induced PC12 cells treated with quercetin/luteolin had concentration-dependent viability increases (all P < 0.001); 15% MFXD-containing serum restored viability to ≥ 95% (P < 0.001 vs. AD model, comparable to DHCL). Western blot showed AD model had elevated p-NF-κB p65/NF-κB p65, MMP9/β-actin, p-Tau/Tau and reduced p-GSK-3β/GSK-3β (all P < 0.05); MFXD reversed these (all P < 0.05), while DHCL only inhibited p-NF-κB p65/NF-κB p65. ELISA showed MFXD and DHCL both reduced AD model's TNF-α (all P < 0.001).

CONCLUSION: MFXD potentially exerts anti-AD effects through a multi-component, multi-target, multi-pathway approach. Its key active components (quercetin, luteolin) may act by modulating the core target MMP9. Also, MFXD can simultaneously regulate several pathways, such as the TNF signaling pathway, Calcium signaling pathway, and NF-κB signaling pathway, and target Tau protein-related pathology by restoring the phosphorylation level of GSK-3β to suppress abnormal hyperphosphorylation of Tau, and thereby alleviating pathological damage in AD.}, } @article {pmid41450657, year = {2025}, author = {Zhao, Y and Xi, E and Wang, Z and Gao, N and Sun, H and Zhu, G}, title = {Nanoamplifier Agents Transiently Rise the Metabolism of β‑Amyloid Peptide in Urine for the Early Diagnosis of Alzheimer's Disease.}, journal = {JACS Au}, volume = {5}, number = {12}, pages = {6169-6178}, pmid = {41450657}, issn = {2691-3704}, abstract = {Alzheimer's disease (AD) is the most common form of dementia without effective treatment. Therefore, early diagnosis for timely treatment and delayof the onset of AD are critical. At present, detecting β-amyloid (Aβ) in cerebrospinal fluid is still the most important clinical method. However, the invasive detection method is harmful and difficult to promote. Recent research has shown that Aβ was found not only in blood and cerebrospinal fluid, but also in urine, which could be used for noninvasive testing. Compared with blood/cerebrospinal fluid, the background proteins in urine are very low, but unfortunately the content of Aβ is even lower. Therefore, if the concentration of Aβ is increased with the background proteins maintained at the low level, urine could be an ideal noninvasive early detection target for AD. Gold nanoparticles (AuNP) with ultrasmall size (<6 nm) could be rapidly metabolized by the kidneys and excreted with urine, and easily regulated by the metabolic pathway between kidneys and liver by changing their size. After screening, we found 3 nm AuNP had the highest renal metabolic efficiency, and by modifying with kidney targeting peptides and Aβ antibody 6E10, the complex system (P6-Au) acted as a "Aβ-targeting renal metabolic carrier", which both metabolized rapidly through the kidneys and increased the concentration of Aβ in urine. After tail vein injection of P6-Au, the Aβ content in the urine of 5×FAD transgenic mice increased by more than 20 times within the next 24 h, which resulted in the diagnosis time being advanced from the ninth month to the fifth month and provided a new approach for early detection of AD.}, } @article {pmid41451412, year = {2025}, author = {Li, S and Qian, W and Zhang, Z and Chen, Y and Hou, X and Min, B and Zhou, H and Zhu, X and Ling, J and Yang, W and Cao, S}, title = {Comprehensive safety assessment of donepezil: pharmacovigilance analysis based on the FDA adverse event reporting system.}, journal = {Frontiers in neurology}, volume = {16}, number = {}, pages = {1655216}, pmid = {41451412}, issn = {1664-2295}, abstract = {BACKGROUND: Alzheimer's disease (AD) has a growing global prevalence, and the need for safe and effective treatments is urgent. Donepezil is commonly used therapeutic agents for AD but has safety controversies. The objective of this study was to thoroughly evaluate donepezil's adverse event profile using actual data.

METHODS: In this study, reports of donepezil-related adverse events were collected from the first quarter of 2004 to the fourth quarter of 2024 through the FAERS database. The association of donepezil-induced adverse events was disproportionality analyzed using Reporting odds Ratios (ROR) and Proportional Reporting Ratio (PRR) and Bayesian Confidence Propagation Neural Network (BCPNN) and Multi-item Gamma Poisson Shrinker (MGPS), among other methods.

RESULTS: A total of 26,120 ADRs with donepezil as the "first suspect" were retrieved during the reporting period. The most common AEs included nausea, vomiting, syncope, and dizziness, which were consistent with the labeling of the medication and clinical trials. Unintended major AEs such as fall, hypotension, tremor, cognitive disorder, mania, and the highest signal of pleurothotonus were also detected. The reports also collected were characterized by a high proportion of female patients (51.3%) and the time of AE induction within 30 days (41%).

CONCLUSION: Donepezil treatment needs to focus on cardiovascular and neurological adverse events, especially for women, elderly patients, or patients with co-morbidities, cardiac monitoring and dose adjustment should be strengthened. Clinics need to balance efficacy and risk, develop individualized dosing regimens, and explore novel therapeutic strategies to improve long-term safety.}, } @article {pmid41451871, year = {2025}, author = {Yang, T and Huhe, H and Williams, SP and Kaur, S and Ay, YA and Davis-Gilbert, ZW and Cary, GA and Paisie, C and Butler, RR and Wiley, J and Betarbet, R and Fu, H and Duong, D and Seyfried, NT and Leal, K and Carter, GW and Edwards, A and Levey, AI and Capener, JL and Drewry, DH and Hossain, MA and Oh, HJ and Axtman, AD and Sukoff Rizzo, SJ and Longo, FM and , }, title = {PAK1 inhibitor NVS-PAK1-1 preserves dendritic spines in amyloid/tau exposed neurons and 5xFAD mice.}, journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association}, volume = {21}, number = {12}, pages = {e71033}, pmid = {41451871}, issn = {1552-5279}, support = {U54 AG065187/AG/NIA NIH HHS/United States ; //PhRMA Foundation/ ; //Archer Fund/ ; //Jean Perkins Foundation/ ; //NIH grants NIA U54AG065187/ ; //Applebaum Foundation Fund/ ; //The SGC is a registered charity that receives funds from Bayer AG, Boehringer Ingelheim/ ; }, mesh = {Animals ; *Dendritic Spines/drug effects/pathology/metabolism ; *p21-Activated Kinases/antagonists & inhibitors/metabolism ; *tau Proteins/metabolism ; *Amyloid beta-Peptides/metabolism/toxicity ; Mice, Transgenic ; *Alzheimer Disease/pathology/metabolism/drug therapy ; *Neurons/drug effects/metabolism ; Hippocampus/drug effects/pathology ; Disease Models, Animal ; Mice ; Female ; Humans ; Dibenzazepines ; Pyrrolidines ; }, abstract = {INTRODUCTION: Synaptic spine loss in Alzheimer's disease (AD) contributes to cognitive decline. p21-activated kinase 1 (PAK1), a regulator of spine integrity, is aberrantly activated in AD. We investigated whether PAK1 inhibition might preserve dendritic spines in vitro and in vivo.

METHODS: Oligomeric amyloid beta (oAβ) or tau (oTau) were applied to hippocampal neurons ± NVS-PAK1-1, a selective PAK1 inhibitor. NVS-PAK1-1 was orally administered to 5xFAD mice. The effects of NVS-PAK1-1 treatment on PAK1 activity, spine density, and the proteome were assessed using phospho-PAK1 (pPAK1) western blotting, Golgi staining, and mass spectrometry for proteomic analyses.

RESULTS: NVS-PAK1-1 prevented oAβ and oTau-induced spine loss in vitro. In 5xFAD mice, NVS-PAK1-1 demonstrated brain exposure after oral administration and reduced PAK1 activation, prevented spine loss, and partially normalized synaptic proteomic signatures in females in absence of alterations in brain or plasma Aβ.

DISCUSSION: PAK1 inhibition enhances spine resilience in AD models, supporting its therapeutic potential.

HIGHLIGHTS: p21-activated kinase 1 (PAK1) inhibitors prevent oligomeric amyloid beta (oAβ) and oligomeric tau-induced spine loss and dendritic degeneration in cultured mouse hippocampal neurons. NVS-PAK1-1, a selective PAK1 inhibitor, protects against oAβ-induced spine loss in a dose-dependent manner (EC50 = 2 nM). Oral administration of NVS-PAK1-1 achieves brain penetration and bioavailability in normal CD-1 mice, and target engagement in 5xFAD mice. Chronic NVS-PAK1-1 treatment mitigates spine loss in the somatosensory cortex of 6-month-old 5xFAD female mice. Chronic treatment with NVS-PAK1-1 restores proteomic abundance of actin cytoskeleton and dendritic spine-associated proteins, including cofilin 2 and pyruvate dehydrogenase kinases, downstream of PAK1 in young 5xFAD female mice showing spine resilience. Clinical oncology trials with other PAK1 inhibitors support potential repurposing or novel compound development for Alzheimer's disease trials.}, } @article {pmid41451887, year = {2025}, author = {Lynch, SY and Jia, J and Miles, N and Boiser, J and Buhl, DL and Graff, O and Zadikoff, C}, title = {ABBV-552 in patients with mild Alzheimer's disease: a randomized phase IIb trial.}, journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association}, volume = {21}, number = {12}, pages = {e70994}, pmid = {41451887}, issn = {1552-5279}, mesh = {Humans ; *Alzheimer Disease/drug therapy ; Male ; Aged ; Female ; Middle Aged ; Aged, 80 and over ; Double-Blind Method ; Treatment Outcome ; Dose-Response Relationship, Drug ; Mental Status and Dementia Tests ; }, abstract = {INTRODUCTION: This proof-of-concept, dose-finding phase IIb trial evaluated treatment with ABBV-552 compared with placebo in participants with clinically diagnosed mild Alzheimer's disease (AD).

METHODS: Participants aged 50 to 90 years with a Mini-Mental State Examination score of 20 to 26 and a global Clinical Dementia Rating score of 0.5 to 1.0 were randomized 1:1:1:1 to placebo or ABBV-552 (1, 5, or 15 mg) daily. The primary endpoint was the change from baseline in the 14-item Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog 14) at week 12.

RESULTS: Two hundred sixty-three participants were randomized. The least-squares mean difference (vs placebo) in change from baseline at week 12 in ADAS-Cog 14 total score (95% confidence interval) for ABBV-552 1 mg was -0.02 (-1.87, 1.83), nominal p = 0.9819; 5 mg, -0.42 (-2.25, 1.42), nominal p = 0.6545; 15 mg, 0.25 (-1.58, 2.08), nominal p = 0.7860. Treatment-emergent adverse events occurred in 48.5% of ABBV-552 recipients versus 42.2% in the placebo group; no safety concerns were identified.

DISCUSSION: ABBV-552 did not demonstrate a meaningful difference versus placebo on the primary endpoint.

HIGHLIGHTS: ABBV-552 is a small molecule that modulates the SV2A receptor in neurons ABBV-552 may enhance synaptic efficiency leading to improved cognition in patients with Alzheimer's disease (AD) Participants with mild AD were treated with either placebo, 1 mg, 5 mg, or 15 mg of ABBV-552 covering an estimated 35% to 80% SV2A receptor occupancy in a phase II randomized clinical trial Results failed to show efficacy over placebo as measured by ADAS-Cog 14 at week 12 ABBV-552 was generally safe and well tolerated.}, } @article {pmid41452267, year = {2026}, author = {Cai, X and Huang, Y and Wang, T and Gao, J and Tang, Y and Zhu, C and Rong, S}, title = {Mesoporous PdPt Nanozymes with Target Peptides and Cascade Reactive Oxygen Species Scavenging for Boosting Alzheimer's Disease Treatment.}, journal = {ACS nano}, volume = {20}, number = {1}, pages = {1267-1277}, doi = {10.1021/acsnano.5c17413}, pmid = {41452267}, issn = {1936-086X}, mesh = {*Alzheimer Disease/drug therapy/metabolism ; *Reactive Oxygen Species/metabolism ; *Amyloid beta-Peptides/metabolism/antagonists & inhibitors/chemistry ; Humans ; Porosity ; *Palladium/chemistry ; *Platinum/chemistry ; Animals ; Oxidative Stress/drug effects ; Particle Size ; *Peptides/chemistry/pharmacology ; Surface Properties ; }, abstract = {Alzheimer's disease (AD) is an age-related neurodegenerative disease that has become a major health problem nowadays. Inhibiting the aggregation of amyloid-β (Aβ) peptides has made progress in AD treatments. Here, we synthesized mesoporous PdPt nanozymes to immobilize target peptide KLVFFAED for high-efficiency AD treatment. Thanks to the high surface area of the mesoporous nanospherical structure of PdPt nanozymes, lots of KLVFFAED were grafted with a concentration as high as 439.2 μg mL[-1], amplifying inhibition activity against Aβ aggregations. Importantly, the system has a pre-eminent photothermal property in the near-infrared region and exhibits the ability to photothermally disintegrate Aβ aggregates. Moreover, the integrated superoxide dismutase/catalase mimetic activity of PdPt nanozymes also achieves cascade reactive oxygen species (ROS) scavenging to alleviate oxidative stress and neuroglial damage, thus delaying the progression of AD. Therefore, the designed system can simultaneously block Aβ aggregation, destabilize Aβ fibrils, and clear ROS, which together enhance the therapeutic effects, providing important insights into the applications of nanozymes for AD therapy.}, } @article {pmid41452429, year = {2025}, author = {Heidari, Z and Zakaee, A and Vafadar, A and Alavimanesh, S and Charami, H and Jamali, Z and Jahromi, AH and Rakhsha, A and Savardashtaki, A}, title = {An overview of gene and cell therapy approaches for Alzheimer's disease.}, journal = {Metabolic brain disease}, volume = {41}, number = {1}, pages = {10}, pmid = {41452429}, issn = {1573-7365}, mesh = {*Alzheimer Disease/therapy/genetics ; Humans ; *Genetic Therapy/methods ; *Cell- and Tissue-Based Therapy/methods ; Animals ; }, abstract = {Alzheimer's disease (AD), acknowledged as the leading cause of dementia, is defined by the accumulation of amyloid plaques and neurofibrillary tangles (NFTs) in the brain. This condition presents a significant challenge to global health due to its complex and multifaceted characteristics. Pharmacological treatments for AD mainly focus on relieving symptoms instead of addressing the fundamental progression of the condition. Currently, there are three cholinesterase inhibitors (ChEIs) that can be used for the treatment of AD: donepezil, rivastigmine, and galantamine, along with the N-methyl-D-aspartate (NMDA) receptor antagonist memantine. Although these medications can improve cognitive function and assist patients in their daily activities, it is crucial to understand that they do not halt the progression of the disease itself. Recently, innovative therapeutic strategies have been introduced for the treatment of this disease. Cell and gene therapies hold remarkable potential for the treatment of AD. Gene therapy, in particular, enables the precise modulation of AD-related genes, enhances neuroprotective factors, and mitigates the accumulation of amyloid plaques. Additionally, cell-based therapies utilizing mesenchymal stromal cells (MSCs), neural stem cells (NSCs), and induced pluripotent stem cells (iPSCs) are designed to replace lost neurons, modulate immune responses, and restore functional neural networks. Together, these innovative techniques represent significant advancement in the treatment of AD, instilling hope for enhanced patient outcomes and a higher quality of life. In this review, we emphasize the innovative cell and gene strategies, along with in vitro and preclinical studies, that explore the potential of gene and cell-based therapies as treatments for AD.}, } @article {pmid41452714, year = {2025}, author = {Zhang, J and Zhu, D and Hu, M and Pan, M and Chen, C}, title = {A Combination of Low-Dose Δ[9]-THC and Celecoxib as a Therapeutic Strategy for Alzheimer's Disease.}, journal = {Aging and disease}, volume = {}, number = {}, pages = {}, doi = {10.14336/AD.2025.1206}, pmid = {41452714}, issn = {2152-5250}, support = {R01 NS076815/NS/NINDS NIH HHS/United States ; }, abstract = {Alzheimer's disease (AD) is the leading cause of dementia in the elderly, and no effective therapies are currently available to prevent, treat, or halt its progression. Δ[9]-Tetrahydrocannabinol (Δ[9]-THC), the primary psychoactive compound in marijuana, has been considered a potential therapeutic agent, but clear evidence for its ability to prevent cognitive decline is lacking. Previous studies have demonstrated that Δ[9]-THC-induced cognitive impairments are associated with the induction of cyclooxygenase-2 (COX-2). In this study, we aimed to evaluate whether Δ[9]-THC alone or in combination with Celecoxib, a selective COX-2 inhibitor, could reduce neuropathology and improve cognitive function in AD model animals. We observed that Δ[9]-THC (3.0 mg/kg), either alone or with Celecoxib (1.0 mg/kg), significantly reduced Aβ and tau pathologies, enhanced synaptic marker expression, and prevented the onset of cognitive decline. Notably, the combination treatment produced greater improvements in spatial learning and effectively mitigated Δ[9]-THC-induced neuroinflammatory responses. Furthermore, Δ[9]-THC reversed or attenuated the dysregulated expression of synaptic and immune/inflammation-related genes and restored the downregulated expression of genes linked to AD observed in both AD patients and AD animal models, with greater efficacy when combined with Celecoxib in AD model mice. These findings suggest that the combination of low-dose Δ[9]-THC and Celecoxib holds promise as an early intervention strategy for preventing AD onset or treating mild cognitive impairment (MCI). Importantly, both Δ[9]-THC (in the form of Dronabinol and Nabilone) and Celecoxib are FDA-approved medications already in clinical use, supporting the strong translational potential of this combination therapy and its feasibility for rapid advancement to clinical trials to assess its efficacy in preventing or delaying AD onset in humans.}, } @article {pmid41453655, year = {2026}, author = {Basri, R and Al-Kuraishy, HM and Fawzy, MN and Alruwaili, M and Batiha, GE}, title = {PACAP: A promising disease-modifying target for Alzheimer's disease.}, journal = {Life sciences}, volume = {386}, number = {}, pages = {124176}, doi = {10.1016/j.lfs.2025.124176}, pmid = {41453655}, issn = {1879-0631}, mesh = {*Pituitary Adenylate Cyclase-Activating Polypeptide/metabolism ; Humans ; *Alzheimer Disease/drug therapy/metabolism ; Animals ; *Neuroprotective Agents/pharmacology/therapeutic use ; Blood-Brain Barrier/metabolism ; }, abstract = {Alzheimer's disease (AD) is a significant public health threat, and current therapeutic approaches provide only minimal symptomatic benefit without slowing its progression. This review covers evidence for the expanding involvement of pituitary adenylate cyclase-activating polypeptide (PACAP), an endogenous neuropeptide with significant and consistent neuroprotective properties in various experimental models of AD. We consolidate evidence that PACAP works via multiple pathways to negate primary pathological events in AD by shifting the metabolism of amyloid precursor protein from the amyloidogenic into non-amyloidogenic, inhibiting tau hyperphosphorylation, controlling neuroinflammation, and promoting synaptic plasticity. The reduced level of PACAP in clinical studies of AD patients supports its therapeutic relevance. Although concerns about PACAP pharmacokinetics and blood-brain barrier (BBB) penetration persist as serious obstacles, recent development of stable analogs and innovative delivery systems holds promise for circumventing these limitations. We also consider how established drugs (metformin, linagliptin, and statins) might provide a degree of neuroprotection in part-seeking through PACAP-related pharmacology. Taken together, the cumulative available evidence places PACAP not only as yet another promising therapeutic candidate but rather as a master regulator of neuroprotection, tackling AD's multifaceted nature. Restoration of PACAP signaling is a very distinct method to intervene in disease development, which offers immeasurable benefit in comparison to symptom relief treatment.}, } @article {pmid41454086, year = {2025}, author = {Mi, X and Shan, K and Ye, X and Cheng, R}, title = {AAD-2004 through clearing H2O2 reduces astrocyte proliferation and promotes neural regeneration after spinal cord injury.}, journal = {Scientific reports}, volume = {16}, number = {1}, pages = {3371}, pmid = {41454086}, issn = {2045-2322}, support = {ZKKY2023003//Zhejiang Medical Association/ ; 2024KY658//Scientific Research Program of Zhejiang Medical Technology/ ; }, mesh = {*Spinal Cord Injuries/drug therapy/metabolism/pathology/physiopathology ; Animals ; *Hydrogen Peroxide/metabolism ; *Astrocytes/drug effects/metabolism ; *Nerve Regeneration/drug effects ; Cell Proliferation/drug effects ; Mice ; *Neuroprotective Agents/pharmacology ; Oxidative Stress/drug effects ; Disease Models, Animal ; Cells, Cultured ; }, abstract = {To assess the effect of AAD-2004 on spinal cord injury (SCI) and to explore its mechanism, we employed an in vitro model using OGD/R-challenged astrocytes to investigate the effects of AAD-2004 against cell death (terminal deoxynucleotidyl transferase dUTP nick-end labeling, tunel), oxidative stress (H2O2 level), and the expression of the key neuroprotective factor MAP2.AAD-2004[2-hydroxy-5-[2-(4-trifluoromethylphenyl)-ethylaminobenzoic acid] is a hydrogen peroxide(H2O2) scavenger primarily used for the treatment of amyotrophic lateral sclerosis and Alzheimer disease that has demonstrated certain neuroprotective properties. In parallel, modified allen's method was adopted, further exploring the potential molecular mechanism in vivo. Based on these conditions, histological and behavioral analysis were performed by Nissl staining, basso mouse scale and footprint analysis. The level of molecules associated with glial scar formation, nerve regeneration, axonal regeneration and H2O2 level were analyzed using western blot, immunofluorescence staining and H2O2 kit. AAD-2004 significantly improved the movement function after SCI and inhibited the proliferation of astrocytes, thus preventing the formation of glial scar by inhibiting of H2O2. At the same time, AAD-2004 promoted nerve regeneration, and the effect was due to neuronal regeneration and axonal regeneration pathways. The expression levels of GFAP and vimentin were significantly downregulated in AAD-2004-treated, and the expression level of Ki67 and PH3 were downregulated. The mean fluorescence intensity of neuronal regeneration (Neun[+]and MAP2[+]) and axonal regeneration-related (NF[+] and GAP43[+]) were significantly upregulated after AAD-2004 treatment. Scavenging H2O2 level is a viable therapeutic strategy, and that AAD-2004 is prospective, and that scavenging H2O2 facilitated nerve regeneration and inhibited glial scar formation for SCI.}, } @article {pmid41454738, year = {2026}, author = {Takeda, T and Toritsuka, M and Tamakoshi, H and Iwata, N and Makinodan, M}, title = {Immune involvement in neuropsychiatric disorders: Insights from single-cell transcriptomic studies.}, journal = {Psychiatry and clinical neurosciences}, volume = {80}, number = {4}, pages = {241-249}, pmid = {41454738}, issn = {1440-1819}, support = {JPMJMS239F-1-2//Moonshot Research and Development Program/ ; 21gm6310015h0002//Japan Agency for Medical Research and Development/ ; 21uk1024002h0002//Japan Agency for Medical Research and Development/ ; 21wm04250XXs0101//Japan Agency for Medical Research and Development/ ; 22gm1510009h0001//Japan Agency for Medical Research and Development/ ; 24gm1910004s0402//Japan Agency for Medical Research and Development/ ; 24wm0625510h0001//Japan Agency for Medical Research and Development/ ; 23H04173//Japan Society for the Promotion of Science/ ; 24K02386//Japan Society for the Promotion of Science/ ; }, mesh = {Humans ; *Single-Cell Analysis/methods ; *Mental Disorders/immunology/genetics ; *Transcriptome/immunology ; *Gene Expression Profiling ; Sequence Analysis, RNA ; }, abstract = {Neuropsychiatric disorders pose profound challenges to both research and treatment, largely due to their clinical heterogeneity and the limited understanding of their underlying biological mechanisms. While bulk RNA sequencing (bulk RNA-seq) has been widely used to study gene expression, it cannot resolve cell-type-specific signals or detect rare cellular subpopulations. In contrast, single-cell RNA sequencing (scRNA-seq) and single-nucleus RNA sequencing (snRNA-seq) have emerged as transformative technologies, enabling transcriptomic profiling at single-cell resolution. These approaches have revealed immunological alterations across a wide range of disorders. This review introduces recent findings from sc/snRNA-seq studies of immune-related mechanisms in psychiatric disorders-including schizophrenia, bipolar disorder, major depressive disorder, autism spectrum disorder, and attention-deficit/hyperactivity disorder-as well as in neurological conditions such as Alzheimer's disease, Parkinson's disease, dementia with Lewy bodies, multiple sclerosis, and anti-NMDA receptor encephalitis. While sc/snRNA-seq overcome averaging effects of bulk RNA-seq by resolving cell types, these methods still face challenges. We outline a roadmap that integrates bulk RNA-seq and sc/snRNA-seq to mitigate the remaining gaps.}, } @article {pmid41455134, year = {2026}, author = {Du, O and Wu, YJ and Li, MY and Du, JR}, title = {The role of HMGB1 in central nervous system (CNS) diseases: mechanisms and therapeutic perspectives.}, journal = {Cytokine}, volume = {198}, number = {}, pages = {157099}, doi = {10.1016/j.cyto.2025.157099}, pmid = {41455134}, issn = {1096-0023}, mesh = {Humans ; *HMGB1 Protein/metabolism ; *Central Nervous System Diseases/metabolism/therapy/pathology ; Animals ; Biomarkers/metabolism ; }, abstract = {Central nervous system (CNS) diseases represent a major global health burden and are among the leading causes of disability and mortality worldwide. The pathological mechanisms underlying CNS disorders are complex and multifactorial, involving processes such as neuroinflammation, oxidative stress, neuronal damage, and synaptic dysfunction. High-mobility group box 1 (HMGB1), a member of the high-mobility group box (HMGB) protein family, is predominantly localized in the nucleus under physiological conditions, where it contributes to DNA repair, transcriptional regulation, and other cellular functions. However, in various CNS pathologies-including stroke, traumatic brain injury (TBI), Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), glioblastoma (GBM), epilepsy, depression, multiple sclerosis (MS), and schizophrenia-HMGB1 is released or secreted into the extracellular space. There, it plays a key role in regulating neuroinflammation, cell death, cell migration, and tissue damage and repair, thereby contributing to disease pathogenesis and progression. HMGB1 not only functions as a critical regulator in the progression of CNS diseases but also serves as a biomarker for predicting poor clinical outcomes. Moreover, a growing body of evidence indicates that therapeutic strategies targeting HMGB1 can significantly alleviate pathological damage in various CNS disorders, highlighting its potential as a promising therapeutic target. This review comprehensively summarizes the structure, post-translational modifications, release mechanisms, and receptor systems of HMGB1, along with its roles and mechanisms in CNS diseases. It also discusses the potential of HMGB1 as a biomarker and examines emerging HMGB1-targeted therapeutic strategies, aiming to provide a theoretical foundation for the treatment and drug development of CNS disorders.}, } @article {pmid41455863, year = {2025}, author = {Elbermawy, Y and El-Desouky, S and Arafa, RK and Elfarrash, S and Bassiouny, A}, title = {Synergistic Neuroprotection in Tauopathic Mice via Green-Synthesized Silver Nanoparticles Co-delivering Methylene Blue and Moringa oleifera.}, journal = {Molecular neurobiology}, volume = {63}, number = {1}, pages = {331}, pmid = {41455863}, issn = {1559-1182}, mesh = {Animals ; *Methylene Blue/pharmacology/administration & dosage/therapeutic use ; *Moringa oleifera/chemistry ; *Metal Nanoparticles/chemistry/administration & dosage ; *Silver/chemistry/pharmacology ; *Neuroprotective Agents/pharmacology/administration & dosage/therapeutic use ; *Neuroprotection/drug effects ; Mice, Transgenic ; Mice ; *Green Chemistry Technology/methods ; *Tauopathies/drug therapy/pathology/metabolism ; Glycogen Synthase Kinase 3 beta/metabolism ; Plant Extracts/administration & dosage/pharmacology ; tau Proteins/metabolism ; }, abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder with limited therapeutic options.Most current treatments target only a single pathogenic pathway. We developed an innovative green-synthesized silver nanoparticle formulation for the co-delivery of methylene blue (MB), a tau aggregation inhibitor, and Moringa oleifera (MO) extract, an antioxidant and anti-inflammatory agent. Silver nanoparticles act as multifunctional carriers, improving drug stability and brain delivery, yielding the combined formulation MOMB-Ag-NPs. MOMB-Ag-NPs were synthesized and characterized using ultraviolet-visible spectroscopy (UV-Vis), transmission electron microscopy (TEM), scanning electron microscopy (SEM), and energy-dispersive X-ray (EDX) analysis. Homozygous P301S tau transgenic mice were assigned to four groups: saline (0.9%, i.p.), MB (4 mg/kg/day, i.p.), MO (260 mg/kg/day, oral), or MOMB-Ag-NPs (4 mg/kg/day MB equivalent, i.p.) for 60 days. In vitro GSK-3β inhibition assays and molecular docking analyses assessed mechanistic interactions. Neuroprotective efficacy was evaluated through survival, behavioral tests, immunohistochemistry, ELISA, and Western blotting. MOMB-Ag-NPs displayed spherical morphology (10-25 nm), high stability, and efficient MB encapsulation (EE 54.7%, DL 93.5%). Both MO and MB inhibited GSK-3β in vitro (IC50 = 9.41 and 65.77 µg/mL), corroborated by molecular docking. In vivo, MOMB-Ag-NPs significantly improved locomotor activity, and cognitive performance. Treated mice showed reduced astrogliosis, decreased pro-inflammatory cytokines (TNF-α, IL-6), enhanced autophagy (LC3β), increased antioxidant defenses (SOD), and differential modulation of the AKT/GSK-3β pathway. This study provides novel evidence that a green-synthesized MB and MO nanoformulation exerts synergistic neuroprotective effects in tauopathy mice, highlighting the translational promise of multitarget strategies for AD treatment.}, } @article {pmid41455872, year = {2025}, author = {Marei, HE}, title = {Epigenetic Editing in Neurological and Neuropsychiatric Disorders: Pioneering Next-Gen Therapeutics for Precision Gene Control.}, journal = {Molecular neurobiology}, volume = {63}, number = {1}, pages = {330}, pmid = {41455872}, issn = {1559-1182}, mesh = {Humans ; *Epigenesis, Genetic/genetics ; *Gene Editing/methods ; *Nervous System Diseases/genetics/therapy ; Animals ; *Mental Disorders/genetics/therapy ; *Genetic Therapy/methods ; *Precision Medicine/methods ; Epigenome Editing ; }, abstract = {Epigenetic editing has emerged as a promising approach in the treatment of neurological and neuropsychiatric disorders, enabling the precise and enduring modification of genes associated with these conditions. Interventions that focus on chromatin, such as programmable systems like CRISPR/dCas9, zinc-finger proteins, and TALEs linked to epigenetic effector domains, enable the modification of DNA methylation, histone modifications, and noncoding RNA control at specific loci. This work integrates current progress in understanding the epigenetic landscape of neurological neuropsychiatric disorders, highlighting the functions of DNA methylation (de novo vs maintenance, active versus passive demethylation), histone remodeling, and context-dependent gene regulation. We emphasize that the dysregulation of these processes is essential to diseases such as Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), and major psychiatric disorders. Innovative therapeutic approaches, including KRAB- and TET-based repressors, "hit-and-run" epigenome editing, and targeted noncoding RNA regulation, are analyzed alongside translational methodologies that utilize gene therapy vectors, nanoparticle delivery systems, and inducible expression mechanisms. We also examine proof-of-concept studies that demonstrate how to prevent gene expression and alter the transcriptional networks of diseased cells in living organisms. We identify current challenges, including off-target effects, delivery issues, inadequate understanding of long-term stability, and the need for reliable diagnostics, while highlighting the translational promise of combining epigenetic clearance with biogenesis and repair. This review is aimed at providing a comprehensive and critical examination of the molecular principles, therapeutic strategies, and translational obstacles associated with epigenetic editing in neurological and neuropsychiatric disorders, thereby facilitating the development of next-generation precision therapies.}, } @article {pmid41456355, year = {2026}, author = {Haixia, T and Bo, X}, title = {Exercise impact on IRE1α signaling: Novel insights into Alzheimer's disease prevention and treatment.}, journal = {Biochemical and biophysical research communications}, volume = {797}, number = {}, pages = {153156}, doi = {10.1016/j.bbrc.2025.153156}, pmid = {41456355}, issn = {1090-2104}, mesh = {*Alzheimer Disease/prevention & control/therapy/metabolism/pathology ; Humans ; *Signal Transduction ; Endoplasmic Reticulum Stress ; *Endoribonucleases/metabolism ; Animals ; *Protein Serine-Threonine Kinases/metabolism ; *Exercise/physiology ; }, abstract = {Endoplasmic reticulum stress (ERS) and its downstream signaling play a central role in neuroinflammation in Alzheimer's disease (AD). Among them, IRE1α, as a key sensor of ER stress, is a pivotal molecule connecting stress to inflammation. Its aberrant activation drives neuroinflammation, which in turn exacerbates Aβ deposition, Tau pathology, and cognitive decline. Therefore, targeting the IRE1α signaling pathway has become a potential strategy for AD intervention. Recent studies suggest that exercise can alleviate ER stress and directly or indirectly inhibit the excessive activation of IRE1α, thereby reducing its downstream inflammatory signals. This review aims to systematically elucidate the pathogenic mechanism of the IRE1α inflammatory signaling pathway in AD. It also focuses on exploring the evidence of the neuroprotective effect of exercise through regulating this pathway, providing new theoretical basis and direction for exercise-based prevention and treatment of AD.}, } @article {pmid41456527, year = {2026}, author = {Li, X and Ji, W and Wu, X and Cai, J and Zheng, M and Zhang, X and Liu, P and Wang, G and Li, X and Wang, S and Huo, Z and Wang, Q and Song, Z and Li, D and Zhou, S and Sun, H and Ma, X and Zou, L and Gao, W}, title = {Cerebralcare Granule® restores intracranial lymphatic drainage system to support proactive brain health in Alzheimer's disease models.}, journal = {Phytomedicine : international journal of phytotherapy and phytopharmacology}, volume = {150}, number = {}, pages = {157617}, doi = {10.1016/j.phymed.2025.157617}, pmid = {41456527}, issn = {1618-095X}, mesh = {Animals ; *Alzheimer Disease/drug therapy/metabolism ; Mice, Transgenic ; Mice ; Disease Models, Animal ; *Drugs, Chinese Herbal/pharmacology ; *Brain/drug effects/metabolism ; Amyloid beta-Peptides/metabolism ; Blood-Brain Barrier/drug effects ; Aquaporin 4/metabolism ; Male ; Lymphangiogenesis/drug effects ; Glymphatic System/drug effects ; Donepezil/pharmacology ; Mice, Inbred C57BL ; }, abstract = {BACKGROUND: Impairment of the intracranial lymphatic drainage system significantly contributes to Alzheimer's disease (AD) by facilitating the accumulation of neurotoxic amyloid-β (Aβ) and tau proteins. Restoring lymphatic function offers a promising preventive strategy against early-stage AD pathology.

PURPOSE: This study aimed to evaluate the effects and mechanisms of Cerebralcare Granule® (CG), a traditional Chinese medicine formula, on cognitive impairment and pathological markers in AD mouse models by modulating intracranial lymphatic clearance pathways.

METHODS: Six-month-old APP/PS1 transgenic mice and wild-type controls received oral administration of CG or donepezil for two months. Behavioral assessments included the Morris water maze, open field, Y-maze, novel object recognition, and passive avoidance tests. Immunohistochemistry, immunofluorescence, and Western blot analyses were used to assess Aβ deposition, glymphatic clearance, astrocytic aquaporin-4 (AQP4) polarization, meningeal lymphangiogenesis, and blood-brain barrier integrity. Tracer-based in vivo imaging confirmed improved CSF influx and efflux dynamics. Brain-penetrant compounds of CG were identified using UPLC-MS/MS, MALDI-TOF-MS imaging, and network pharmacology.

RESULTS: CG treatment significantly improved cognitive performance, reduced Aβ burden, enhanced glymphatic transport, and promoted meningeal lymphatic drainage in APP/PS1 mice. CG restored perivascular AQP4 polarization, improved cerebrospinal fluid-interstitial fluid exchange, facilitated waste removal to cervical lymph nodes, and protected the integrity of the blood-brain barrier. Major brain-penetrant compounds-paeoniflorin, rhynchophylline, and ethyl gallate-were found to target lymphatic signaling pathways (AQP4, VEGFC, VEGFR3, PROX1) effectively.

CONCLUSION: CG exerts protective effects against cognitive impairment and AD pathology by reinforcing the structural and functional integrity of the intracranial lymphatic drainage system, highlighting a novel therapeutic avenue for proactive brain health management in early-stage AD.}, } @article {pmid41456743, year = {2026}, author = {Tait, S and Fratini, F and Boussadia, Z and Gaddini, L and Marra, M and Le Pera, L and Venturini, G and Ferrante, A}, title = {Investigation of dipyridamole-elicited signaling in the brain of Niemann Pick type C mice: A multi-omic study.}, journal = {Brain research bulletin}, volume = {234}, number = {}, pages = {111708}, doi = {10.1016/j.brainresbull.2025.111708}, pmid = {41456743}, issn = {1873-2747}, mesh = {Animals ; *Niemann-Pick Disease, Type C/metabolism/drug therapy/genetics ; *Dipyridamole/pharmacology ; Mice ; Hippocampus/metabolism/drug effects ; *Signal Transduction/drug effects ; Mice, Knockout ; Cerebellum/metabolism/drug effects ; Disease Models, Animal ; Niemann-Pick C1 Protein/genetics ; *Brain/metabolism/drug effects ; Male ; Mice, Inbred C57BL ; Multiomics ; }, abstract = {Niemann Pick type C1 (NPC1) is a rare, fatal disorder characterized by endo-lysosomal (EL) lipid accumulation that leads to damage of both peripheral organs and central nervous system, with cerebellum and hippocampus being particularly affected. Currently very few therapeutic options exist in Europe for NPC. In fact, miglustat is the only approved drug and L-acetylleucine was recently granted for marketing authorization by European Medicine Agency. Thus, the identification of new treatments is mandatory. We have previously demonstrated that dipyridamole (DIP), an approved medicine that is clinically employed as an antiplatelet agent, could rescue recognition memory and increase hippocampal expression of calbindin. On the contrary, the drug was unable to improve cerebellar-dependent motor function. In order to elucidate the mechanism of these region-specific changes induced by DIP, in this work we performed a multi-omic analysis of genes and proteins modulated by the treatment in the hippocampus and cerebellum of a mouse model of NPC1 (Npc1[-/-]). Our results revealed that DIP significantly affected various pathways in the hippocampus at protein level, but it had no significant impact on pathways in the cerebellum (either at gene or protein level). Interestingly, the most affected pathways in the hippocampus of Npc1[-/-] mice administered with DIP were those related to cGMP-PKG activation and to mitochondrial function. Our results paved the way to test DIP in experimental models of other neurodegenerative disorders, such as Alzheimer's disease that is similarly marked by hippocampal and mitochondrial dysfunctions.}, } @article {pmid41457120, year = {2025}, author = {Jiang, T and Ma, W and Dong, W and Zhou, H and Mao, X}, title = {Ferroptosis-associated transcriptional factors in neurological diseases: molecular mechanisms and therapeutic prospects.}, journal = {Experimental & molecular medicine}, volume = {57}, number = {12}, pages = {2763-2781}, pmid = {41457120}, issn = {2092-6413}, mesh = {*Ferroptosis/genetics ; Humans ; *Nervous System Diseases/metabolism/therapy/etiology/pathology ; Animals ; *Transcription Factors/metabolism/genetics ; Iron/metabolism ; Lipid Peroxidation ; }, abstract = {Ferroptosis, a newly discovered type of regulatory cell death with iron-dependent accumulation of lipid peroxides, is widely discussed in a plethora of neurological disorders such as Alzheimer's disease, Parkinson's disease, epilepsy, stroke, traumatic brain injury and spinal cord injury. There are many preclinical and clinical evidences supporting the critical role of ferroptosis in these neurologic conditions, despite the molecular machinery by which ferroptosis modulates brain dysfunction remains uncharacterized. Transcription factors (TFs) are core components of the machinery that manipulates ferroptosis process genetically. Until now, there is no report on the summarization of role of ferroptosis-associated TFs in neurological diseases. Therefore, here we provided the basic knowledge regarding the regulation of TFs on ferroptotic processes including iron metabolism, antioxidant defense and lipid peroxidation. In addition, we also discussed the recent advances in our understanding of ferroptosis-related TFs in the emerging hallmarks of neurological diseases. The fact that Nrf2 activator RTA-408 is approved for clinical evaluation (phase 2 clinical trial) of its efficacy and safety in patients with Alzheimer's disease supports this notion. Future research on proteolysis-targeting chimera (PROTAC) and gene therapy holds promise for optimization of neurological disease treatment.}, } @article {pmid41457949, year = {2025}, author = {Chen, Q and Wen, Q and Zhong, T and Liu, J and Gao, H}, title = {Deep cervical lymphaticovenous anastomosis for Alzheimer's disease: A narrative review.}, journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association}, volume = {21}, number = {12}, pages = {e71038}, pmid = {41457949}, issn = {1552-5279}, support = {No.B2025292//Medical Scientific Research Foundation of Guangdong Province/ ; GMUCR2025-02028//Plan on enhancing scientific research in GMU，Guangdong, China/ ; }, mesh = {Humans ; *Alzheimer Disease/surgery ; *Lymphatic Vessels/surgery ; *Anastomosis, Surgical/methods ; *Glymphatic System/surgery ; Amyloid beta-Peptides/metabolism ; }, abstract = {Alzheimer's disease (AD) is a common neurodegenerative disorder with limited treatment options. Recent discoveries of the glymphatic system and meningeal lymphatic vessels (MLVs) have highlighted their critical role in clearing metabolic waste-including amyloid beta and tau proteins-from the brain. Dysfunction of these systems contributes to AD pathogenesis by impairing the clearance of neurotoxic proteins. Deep cervical lymphaticovenous anastomosis (dcLVA) is an innovative microsurgical technique designed to enhance cerebral waste drainage by anastomosing deep cervical lymphatic channels to adjacent veins. This narrative review synthesizes current evidence on the mechanisms, applications, and emerging perspectives of dcLVA for AD. Early studies suggest potential short-term improvements in cognitive scores and neuroimaging biomarkers after surgery, with an acceptable safety profile. However, the evidence is limited to small prospective cohorts and case reports, underscoring the need for larger, randomized controlled trials to validate its efficacy and long-term benefits. dcLVA represents a promising surgical intervention for select patients, particularly those with moderate-to-severe AD who have failed conventional pharmacotherapy, but it requires careful patient selection and further investigation. HIGHLIGHTS: This review proposes deep cervical lymphaticovenous anastomosis (dcLVA) as a mechanism driven surgery that may enhance clearance of amyloid beta (Aβ) and tau through the brain, meningeal, and deep cervical drainage pathways. Early human evidence from a single arm cohort and case reports suggests short term cognitive and imaging signals with acceptable perioperative safety. dcLVA is not recommended as a first line option for early Alzheimer's disease (AD) and may be considered for moderate to severe AD or for patients who are refractory to pharmacotherapy and have objective evidence of drainage impairment. Standardized patient selection and longitudinal imaging and biomarker monitoring are recommended, including Aβ and tau positron emission tomography (PET), diffusion tensor imaging (DTI) analysis along the perivascular space, and cerebrospinal fluid (CSF) or plasma panels. Systemic safety remains an important uncertainty, and future trials should include longitudinal surveillance of hepatic, renal, and hematologic function. Multicenter randomized controlled trials (RCTs) are urgently needed with 12 month Clinical Dementia Rating Sum of Boxes (CDR SB) as a primary endpoint, transparent reporting, and evaluation of combination strategies with anti Aβ therapies.}, } @article {pmid41457950, year = {2025}, author = {Algeciras-Schimnich, A and Theobald, JP and Figdore, DJ and Ashrafzadeh Kian, S and Bornhorst, JA}, title = {False positive plasma p-tau217 results associated with heterophilic antibody interference: A potential clinical pitfall.}, journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association}, volume = {21}, number = {12}, pages = {e71045}, pmid = {41457950}, issn = {1552-5279}, mesh = {Humans ; *tau Proteins/blood/immunology ; *Alzheimer Disease/blood/diagnosis ; *Antibodies, Heterophile/blood ; False Positive Reactions ; Amyloid beta-Peptides/blood ; Biomarkers/blood ; Immunoassay ; Phosphorylation ; Female ; Male ; Aged ; Peptide Fragments ; }, abstract = {INTRODUCTION: Plasma phosphorylated tau at threonine 217 (p-tau217) has emerged as one of the most promising blood-based biomarkers for Alzheimer's disease (AD). While rare, heterophilic antibodies (HAb) are a persistent potential confounding factor in immunoassays.

METHODS: Potential HAb interference in the Lumipulse G pTau217 assay in samples exhibiting concentrations > 10 pg/mL were investigated. Samples were subjected to HAb blocking reagent (HBT), and in some cases, polyethylene glycol (PEG) precipitation and serial dilutions.

RESULTS: In 14 of the 15 suspected HAb cases, HBT treatment greatly reduced measured p-tau217 concentrations. and in one of three specimens selected for further investigation, reduced Aβ42 concentrations PEG precipitation in the three selected samples also reduced p-tau217 concentrations, while serial dilution yielded mixed effects. Control specimens were unaffected by sample treatment or dilutions.

DISCUSSION: HAb may result in falsely elevated p-tau217 and p-tau217/Aβ42 ratio. HAb interference should be considered in cases of unusually high p-tau217 concentrations prior to clinical interpretation.

HIGHLIGHTS: Potential heterophile antibody (HAb) interference in the Lumipulse p-tau217 immunoassay was investigated. Investigation was performed using HAb blocking reagent, and in some cases also using PEG precipitation . Patients with p-tau217 concentrations > 10 pg/mL exhibited positive HAb interference in 14 of 15 cases. HAb interference can lead to falsely positive p-tau217/Aβ42 ratios.}, } @article {pmid41458258, year = {2026}, author = {Jing, C and Li, J and Yu, D and Chao, M and Yan, H and Ge, K and Ma, G and Wang, J and Gao, F and Zhang, G}, title = {Heterotrimetallic Au@Cu2Se nanozymes target inflamed neurons via suppression of oxidative stress and apoptosis to alleviate Alzheimer's disease.}, journal = {Materials today. Bio}, volume = {36}, number = {}, pages = {102646}, pmid = {41458258}, issn = {2590-0064}, abstract = {Neuronal dysfunction mediated by oxidative stress and amyloid-β (Aβ) deposition is widely recognized as a core mechanism in the pathogenesis of Alzheimer's disease (AD). Aβ oligomers specifically interact with key mitochondrial proteins-such as alcohol dehydrogenase, cyclophilin D, and ATP synthase-markedly increasing reactive oxygen species (ROS) production, which leads to mitochondrial membrane potential collapse and disruption of energy metabolism. Although cuprous selenide and gold nanospheres can mimic the catalytic activities of glutathione peroxidase (GPx) and superoxide dismutase (SOD), effectively scavenge excess ROS, restore mitochondrial membrane potential, and promote ATP synthesis through synergistic action, their therapeutic potential is limited by poor targeting specificity in vivo. Moreover, while antioxidant nanoagents show promise in mitigating oxidative stress, their non-specific distribution often necessitates high doses, raising potential off-target toxicity concerns and reducing treatment efficacy. Therefore, developing a delivery system that combines multifunctional neuroprotection with precise targeting to diseased microenvironments remains an urgent need. To address this, we functionalized the surface of Au@Cs nanoparticles with hyaluronic acid (HA) to construct a CD44-targeted Au@Cs-HA-PEG nanosystem. By taking advantage of the high expression of CD44 in microglia and astrocytes under inflammatory conditions, the precise targeting of inflammatory regions in the brains of AD model mice was promoted. In vitro experiments demonstrated that Au@Cs-HA-PEG effectively reduced ROS levels in HT22 cells, reversed mitochondrial membrane potential attenuation, and restored neuronal function. In vivo results showed that these nanoparticles achieved rapid brain enrichment, significantly reduced Aβ plaque deposition and neuroinflammation, and markedly improved learning, memory, and cognitive abilities in AD mice. In conclusion, this study confirms that the Au@Cs-HA-PEG nanosystem ameliorates cognitive dysfunction in AD mice by regulating ROS homeostasis, offering a novel strategy and experimental foundation for targeted therapy of Alzheimer's disease.}, } @article {pmid41460031, year = {2026}, author = {Fu, C and Kan, Y and Guo, K and Jiang, L and Zhang, Y and Dong, H and Xie, J}, title = {Tenuigenin ameliorates Alzheimer's disease by targeting MAP2K1: integrated evidence from network pharmacology and experimental validation.}, journal = {Neuroreport}, volume = {37}, number = {2}, pages = {53-66}, doi = {10.1097/WNR.0000000000002239}, pmid = {41460031}, issn = {1473-558X}, support = {gzwkj2025-129//Science and Technology Fund Project of the Guizhou Provincial Health Commission/ ; gzwkj2025-130//Science and Technology Fund Project of the Guizhou Provincial Health Commission/ ; 20222121020675//Project of the Heilongjiang Provincial Health and Family Planning Commission/ ; }, mesh = {*Alzheimer Disease/drug therapy/metabolism ; Humans ; Network Pharmacology/methods ; *Neuroprotective Agents/pharmacology ; *Drugs, Chinese Herbal/pharmacology ; Molecular Docking Simulation ; Amyloid beta-Peptides/metabolism ; Cell Line, Tumor ; }, abstract = {OBJECTIVE: Alzheimer's disease (AD) is a prevalent neurodegenerative disorder primarily characterized by progressive cognitive impairment and synaptic dysfunction. Despite substantial research efforts, effective therapeutic options remain limited. Tenuigenin (TEN), a principal bioactive constituent isolated from the traditional Chinese medicinal herb Polygala tenuifolia, has demonstrated promising neuroprotective effects.

METHODS: This study adopted a comprehensive multitiered approach, combining network pharmacology, machine learning, molecular modeling, and in-vitro experiments, to elucidate the therapeutic targets and mechanisms of TEN in AD. Computational analyses identified mitogen-activated protein kinase kinase 1 (MAP2K1) as a critical target, mediating the effects of TEN. Gene set enrichment analysis indicated that TEN could activate the 26S proteasome pathway, promoting the degradation of neurotoxic proteins, such as amyloid-β (Aβ), thereby reducing their pathological accumulation.

RESULTS: Immune infiltration analysis further revealed that TEN could modulate the distribution of activated natural killer cells and M0 macrophages, playing a role in restoring immune balance in the AD microenvironment. Molecular docking and dynamics simulations demonstrated strong binding affinity and structural compatibility between TEN and MAP2K1. Experimental validation using Aβ-treated SH-SY5Y cells indicated that TEN significantly enhanced cell viability and suppressed MAP2K1 protein expression.

CONCLUSION: In conclusion, this study provided the first integrated evidence that TEN exerts neuroprotective effects in AD by targeting MAP2K1. These findings highlight the multitarget, multipathway therapeutic potential of TEN and support its development as a natural agent for AD prevention and treatment.}, } @article {pmid41460033, year = {2026}, author = {Hu, XH and Jin, Q and Xie, JL and Wu, CL and Pan, JP}, title = {Docosahexaenoic acid modulates microglial autophagy via miR-589-5p/toll-like receptor 4 axis in Alzheimer's disease.}, journal = {Neuroreport}, volume = {37}, number = {2}, pages = {77-85}, doi = {10.1097/WNR.0000000000002236}, pmid = {41460033}, issn = {1473-558X}, mesh = {*Alzheimer Disease/metabolism ; *Autophagy/drug effects ; *MicroRNAs/metabolism ; *Docosahexaenoic Acids/pharmacology ; *Toll-Like Receptor 4/metabolism/drug effects ; Humans ; *Microglia/drug effects/metabolism ; Animals ; Male ; Mice ; Female ; Aged ; Amyloid beta-Peptides ; Cell Line ; }, abstract = {OBJECTIVE: To investigate the neuroprotective mechanism by which docosahexaenoic acid (DHA) promotes microglial autophagy via the miR-589-5p/toll-like receptor 4 (TLR4) axis in Alzheimer's disease.

METHODS: In vitro, BV2 microglial cells were treated with Aβ25-35 to establish an Alzheimer's disease model and subjected to DHA treatment with or without miR-589-5p inhibition and TLR4 overexpression. Cytotoxic effects were assessed by methylthiazolyldiphenyl-tetrazolium bromide assays. Autophagy markers (LC3-II/I ratio, Beclin1, and p62) were evaluated by Western blot and immunofluorescence. The miR-589-5p/TLR4 interaction was assessed using dual luciferase assays. For clinical validation, peripheral blood samples from healthy controls, patients with mild Alzheimer's disease, and patients with severe Alzheimer's disease (n = 30 each) were analyzed for miR-589-5p and TLR4 mRNA expression via quantitative reverse transcription PCR (qRT-PCR).

RESULTS: In cellular assays, DHA significantly enhanced autophagy by increasing the LC3-II/I ratio and Beclin1 expression while decreasing p62 levels (P < 0.05). Mechanistic validation showed that miR-589-5p inhibition abolished DHA's autophagy-promoting effects, while TLR4 overexpression reversed these benefits. Conversely, miR-589-5p mimic treatment rescued autophagy even under TLR4 overexpression conditions. Dual-luciferase assays confirmed that miR-589-5p directly targets TLR4. Clinically, qRT-PCR analysis revealed that miR-589-5p expression was downregulated and TLR4 expression was upregulated in Alzheimer's disease patients compared to healthy controls, and these alterations were correlated with disease severity (P < 0.05).

CONCLUSION: DHA enhances microglial autophagy via a novel miR-589-5p/TLR4 regulatory axis, a potential Alzheimer's disease therapy and biomarker for Alzheimer's disease progression.}, } @article {pmid41460506, year = {2026}, author = {Bernard, PJ and Więckowska, A and Grosjean, S and Godyń, J and Sałat, K and Detka, J and Palacz, N and Tyrybon, W and Jończyk, J and Szałaj, N and Zaręba, P and Martin, H and Maj, M and Jozwiak, K and Marco-Contelles, J and Ismaili, L}, title = {First Sustainable One-Pot Tandem Hantzsch Multicomponent Reaction/Click Reaction Approach for Novel Multitarget-Directed Ligands in Alzheimer's Disease.}, journal = {ACS chemical neuroscience}, volume = {17}, number = {2}, pages = {404-422}, doi = {10.1021/acschemneuro.5c00806}, pmid = {41460506}, issn = {1948-7193}, mesh = {*Alzheimer Disease/drug therapy ; Animals ; Ligands ; Mice ; *Cholinesterase Inhibitors/pharmacology/chemical synthesis/chemistry ; *Neuroprotective Agents/pharmacology/chemical synthesis/chemistry ; *Dihydropyridines/pharmacology/chemical synthesis/chemistry ; Click Chemistry/methods ; *Calcium Channel Blockers/pharmacology/chemical synthesis/chemistry ; Tacrine/pharmacology ; Antioxidants/pharmacology/chemical synthesis ; Disease Models, Animal ; Male ; Scopolamine ; }, abstract = {This study explores novel multitarget-directed ligands (MTDLs) showing anticholinesterase, antioxidant, neuroprotective, and calcium channel inhibitory activities, as promising compounds for Alzheimer's disease (AD) treatment. The rational design combined dihydropyridines (DHPs), known for calcium channel blocking and neuroprotective properties, with tacrine, a cholinesterase inhibitor. The key innovation of this work lies in the one-pot tandem Hantzsch multicomponent/click reaction used to synthesize new 18 DHPs IIIa-r. This sustainable and original approach aligns with green chemistry principles by reducing waste, energy consumption, and derivatives formation. Notably, DHP IIIj and IIIk demonstrated a multitarget profile and effectively reversed scopolamine-induced amnesia in a mouse model, showcasing its antiamnesic properties. These results suggested that DHP IIIj and IIIk hold promise as innovative therapeutic candidates for AD, validating the potential of MTDL strategy and highlighting the one-pot tandem synthesis as a significant advancement in medicinal chemistry.}, } @article {pmid41460605, year = {2026}, author = {Fassbender, RV and Kehm, C and Otta, AL and Fink, GR and Onur, OA}, title = {Repetitive transcranial magnetic stimulation enhances alpha power in Alzheimer's disease patients.}, journal = {Journal of Alzheimer's disease : JAD}, volume = {109}, number = {3}, pages = {1242-1257}, pmid = {41460605}, issn = {1875-8908}, mesh = {Humans ; *Alzheimer Disease/therapy/physiopathology/psychology ; *Transcranial Magnetic Stimulation/methods ; Male ; Female ; Aged ; *Alpha Rhythm/physiology ; Single-Blind Method ; Electroencephalography ; Neuropsychological Tests ; Middle Aged ; Aged, 80 and over ; Brain/physiopathology ; Memory, Episodic ; }, abstract = {BackgroundWith Alzheimer's disease (AD) presenting an ongoing challenge, innovative treatment methods are essential. Repetitive transcranial magnetic stimulation (rTMS) has emerged as a promising noninvasive intervention, particularly targeting alpha band oscillations associated with AD-related cognitive decline.ObjectiveThis study aimed to investigate the effects of low-intensity rTMS over posterior cortical areas on alpha band oscillations and memory performance in AD patients compared to age-matched healthy controls.MethodsIn a single-blinded, sham-controlled rTMS-EEG study, we examined 14 amyloid-positive AD patients and 14 age-matched healthy controls. Continuous EEG was recorded at rest (eyes closed) before, during, and after stimulation. During stimulation, participants completed an episodic memory task.ResultsWe were able to demonstrate that during rTMS alpha power increased compared to sham, with a notable 25% increase observed in AD patients. However, comparison of memory performance under the sham and stimulation conditions revealed no significant stimulation effect.ConclusionsThese findings support and extend current knowledge of noninvasive brain stimulation mechanisms. Our results suggest that alpha frequency-tuned rTMS over posterior cortical areas can modulate pathological brain activity in AD patients even at low intensities. Given the limited sample size and moderate effect sizes, results should be interpreted with caution. Nevertheless, our results warrant further studies with long-term EEG-rTMS protocols to evaluate the potential therapeutic benefit.}, } @article {pmid41460672, year = {2026}, author = {Sun, L and Wei, G and Ji, F and Ding, Y and Fan, J and Xu, Y and He, C and Zhou, Y and Liu, Z and Sun, Z and Zhou, D}, title = {Proteome-wide association study identifies novel Alzheimer's disease-associated proteins.}, journal = {Journal of Alzheimer's disease : JAD}, volume = {109}, number = {4}, pages = {1733-1747}, doi = {10.1177/13872877251409352}, pmid = {41460672}, issn = {1875-8908}, mesh = {Humans ; *Alzheimer Disease/genetics/blood ; Male ; Female ; Genome-Wide Association Study ; Aged ; *Proteome/genetics ; Longitudinal Studies ; Hippocampus/pathology ; Cognitive Dysfunction/genetics/blood ; Aged, 80 and over ; Cross-Sectional Studies ; Protein Interaction Maps ; Proteomics ; Cohort Studies ; }, abstract = {BackgroundAlzheimer's disease (AD) is a progressive neurodegenerative disease with limited prevention and treatment options.ObjectiveWe aimed to identify proteins with genetically regulated plasma levels associated with AD and its related phenotypes.MethodsWe conducted a proteome-wide association study (PWAS) using Olink-based plasma proteomes (N = 45,540) from the UK Biobank Pharma Proteomics Project (UKB-PPP) and a large-scale genome-wide association study for AD (N case = 85,934, N control = 401,577). To validate and expand these findings, we conducted longitudinal analyses of AD and mild cognitive disorder (MCD) over a 13.7-year follow-up, along with genetic-based PWAS analyses and cross-sectional studies on hippocampal volume. Protein-protein interaction networks were constructed to explore mechanistic association.ResultsWe identified 30 AD-associated plasma proteins by PWAS, including 17 previously reported and 13 novel candidates (including FES, LRP11, and HDGF). Longitudinal cohort studies supported the role of PILRB and FES in AD and/or MCD. Additionally, the genetically determined higher levels of LRP11 were found to be associated with an increased hippocampal volume, including its subdivisions, along with a reduced risk of AD. In contrast, higher plasma levels of HDGF were linked to a decreased hippocampal volume, accompanied by an increased risk of AD. Protein-protein interaction analysis linked PILRA, PILRB, FES, and LRP11 to several pathological proteins associated with AD, including BIN1, ABCA7, and SORL1.ConclusionsThis study identified 13 novel candidates, with potential roles in hippocampal volume and AD risk, providing insights into disease mechanisms.}, } @article {pmid41461311, year = {2025}, author = {Li, R and Wu, X and Yao, J and Chen, J and Shui, X and Zheng, X and Tian, W and Wang, L and Zhou, Y and Zhang, T and Chen, D and Liu, Y and Lee, TH}, title = {Selective degradation of DAPK1 via a novel hydrophobic tagging attenuates tau pathology in Alzheimer's disease.}, journal = {Journal of advanced research}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.jare.2025.12.037}, pmid = {41461311}, issn = {2090-1224}, abstract = {INTRODUCTION: The upregulation of death-associated protein kinase 1 (DAPK1) is involved in tau hyperphosphorylation, neuronal apoptosis and cognitive dysfunction, which are key pathological features of Alzheimer's disease (AD). This result suggests that DAPK1 is novel therapeutic target for AD.

OBJECTIVES: This study aimed to evaluate the efficacy and mechanism of action of CJ1, a novel hydrophobic tagging (HyT)-based degrader, in targeting DAPK1 and alleviating in AD.

METHODS: A library of HyT-based bifunctional molecules was synthesized and systematically screened for their ability to degrade DAPK1 in vitro. CJ1 emerged as the most potent candidate degrader of DAPK1, and its capacity to induce DAPK1 degradation via the proteasome system was further evaluated. Its effects on tau phosphorylation and neuronal viability were evaluated in multiple cellular models. The in vivo efficacy of systemic CJ1 administration was assessed in two tau-related pathology (tauopathy) mouse models, AAV-hTau-P301L and hTau transgenic mice. Behavioral, biochemical, and histological analyses were performed to evaluate cognitive function, tau pathology, neuroinflammation, neurodegeneration, and safety.

RESULTS: CJ1 selectively promoted the posttranslational degradation of DAPK1 by the proteasome system without affecting DAPK1 mRNA expression. In vitro studies demonstrated that CJ1 significantly reduced tau phosphorylation at multiple AD-related sites. In vivo, CJ1 effectively penetrated the blood-brain barrier, decreased the levels of both the soluble and insoluble forms of hyperphosphorylated tau, and suppressed the formation of neurofibrillary tangles. Additionally, CJ1 treatment restored synaptic and dendritic structures, enhanced spatial learning and memory, attenuated neuroinflammatory responses, preserved neuronal populations, and produced no evidence of systemic toxicity.

CONCLUSION: CJ1 functions as a potent and selective degrader of DAPK1, exerting neuroprotective effects by reducing tau hyperphosphorylation and preserving neuronal structural integrity. These findings support DAPK1 as a promising therapeutic target and suggest that further preclinical studies are warranted to evaluate CJ1 as a potential treatment for tauopathies associated with AD.}, } @article {pmid41461684, year = {2025}, author = {Saremi, M and Safari, S and Alikhani, MY and Komaki, A and Siadat, SD and Asghari, B}, title = {Evidence for neuroprotection by Bacillus coagulans ATCC 7050 via synaptic plasticity and oxidative balance in Alzheimer's disease.}, journal = {Scientific reports}, volume = {15}, number = {1}, pages = {44690}, pmid = {41461684}, issn = {2045-2322}, support = {Grant Number: 140303292888//Vice Chancellor for Research and Technology, Hamadan University of Medical Sciences/ ; }, mesh = {Animals ; *Alzheimer Disease/metabolism/physiopathology ; *Oxidative Stress/drug effects ; Male ; *Neuronal Plasticity/drug effects ; Rats ; Rats, Wistar ; *Bacillus coagulans/physiology ; Disease Models, Animal ; Hippocampus/metabolism ; Amyloid beta-Peptides ; *Probiotics/pharmacology/administration & dosage ; Long-Term Potentiation ; *Neuroprotection ; Superoxide Dismutase/metabolism ; Memory, Short-Term ; Glutathione Peroxidase/metabolism ; Malondialdehyde/metabolism ; }, abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by cognitive decline, synaptic impairment, and oxidative stress. Probiotics with antioxidant and anti-inflammatory properties have been proposed as potential adjunctive strategies. This study examined whether oral administration of Bacillus coagulans ATCC 7050 could attenuate hippocampal oxidative stress, modulate synaptic plasticity, and influence spatial working memory in an Aβ1-42-induced rat model of AD. Adult male Wistar rats were assigned to Sham, AD, BC (probiotic only), and AD + BC groups. Working memory was assessed by Y-maze, synaptic function by perforant path-dentate gyrus long-term potentiation (LTP) recordings, and oxidative status by hippocampal malondialdehyde (MDA), superoxide dismutase (SOD), and glutathione peroxidase (GPx) assays. AD rats exhibited reduced alternation percentage, impaired LTP (fEPSP slope and PS amplitude), elevated MDA, and decreased SOD and GPx activities versus Sham. B. coagulans treatment improved alternation percentage without affecting total entries, preserved PS amplitude from 30 min post-HFS, reduced MDA, and restored SOD activity, with partial GPx recovery. fEPSP slope remained reduced. These findings suggest B. coagulans ATCC 7050 mitigates oxidative stress, preserves neuronal excitability, and improves working memory in an Aβ-based AD model, supporting further investigation of its potential as a safe adjunct in early-stage disease.}, } @article {pmid41461739, year = {2025}, author = {Palachai, N and Buranrat, B and Pariwatthanakun, C and Noisa, P and Mairuae, N}, title = {Neuroprotective effects of Cratoxylum formosum (L.) leaf extract on β-amyloid-induced injury in human neuroblastoma SH-SY5Y cells.}, journal = {Scientific reports}, volume = {15}, number = {1}, pages = {44730}, pmid = {41461739}, issn = {2045-2322}, support = {//the Faculty of Medicine, Mahasarakham University/ ; //Thai Traditional Medical Knowledge Fund/ ; }, mesh = {*Clusiaceae ; *Plant Extracts/chemistry/pharmacology/therapeutic use ; Drug Evaluation, Preclinical ; Humans ; Cell Line, Tumor ; *Alzheimer Disease/drug therapy ; Oxidative Stress/drug effects ; *Amyloid beta-Peptides ; *Neuroprotective Agents/analysis/pharmacology/therapeutic use ; MAP Kinase Signaling System/drug effects ; Flavonoids/analysis ; Peptide Fragments ; }, abstract = {In Alzheimer's disease (AD), Amyloid beta peptide (Aβ), the primary constituent of senile plaques, has been documented as triggering oxidative stress and leading to the death of neuronal cells. Therefore, this research aims to investigate how the Cratoxylum formosum (L.) leaf extract mitigates oxidative stress and cellular damage induced by Aβ in SH-SY5Y cells. The SH-SY5Y cells were treated with Cratoxylum formosum (L.) extract both with and without Aβ25-35. Neuroprotection was evaluated through viability and lactate dehydrogenase (LDH) assays, accompanied by an analysis of various mechanisms including caspase-3/7 activity, levels of reactive oxygen species (ROS), phosphorylation of protein kinase B (Akt), extracellular signal-regulated kinase 1/2 (ERK1/2), and cAMP-responsive element binding protein (CREB), expression of B-cell lymphoma 2 (Bcl-2) proteins, as well as catalase (CAT) and superoxide dismutase (SOD) activities. Results indicated an escalation in oxidative stress in cells exposed to Aβ, evidenced by increased ROS levels. Aβ further exacerbated caspase-3/7 activity, LDH release, and a decline in cell viability. Conversely, treatment with Cratoxylum formosum (L.) extract exhibited a concentration-dependent reduction in Aβ-induced neurotoxicity, manifesting in enhanced cell survival, reduced LDH release and ROS production, and suppression of caspase-3/7 activity. Moreover, it led to increased phosphorylation of Akt, ERK1/2, CREB, upregulated expression of Bcl-2 proteins, and enhanced activity of SOD and CAT. High-performance liquid chromatography (HPLC) analysis identified chlorogenic acid, 1,5-dicaffeoylquinic acid, and ferulic acid as the major phenolic constituents of Cratoxylum formosum (L.) extract. These results imply that the extract may provide protective effects against Aβ-induced neurotoxicity, although further studies are required to clarify its role in AD.}, } @article {pmid41462867, year = {2025}, author = {Fonseca, N and Nunes, M and Silva, PMA and Bousbaa, H and Ricardo, S}, title = {Galanthamine Fails to Reverse P-gp-Mediated Paclitaxel Resistance in Ovarian Cancer Cell Lines.}, journal = {Biomedicines}, volume = {13}, number = {12}, pages = {}, pmid = {41462867}, issn = {2227-9059}, abstract = {Background: Ovarian cancer has the poorest prognosis of all gynecological malignancies, largely due to its chemoresistance, which poses significant treatment challenges. In this context, drug repurposing emerges as an innovative strategy that employs non-cancer treatments to interact with various signaling pathways, enhancing chemotherapy efficacy while minimizing toxicity. This study investigated the cytotoxic effects of galanthamine, currently used as an Alzheimer's disease, as a potential treatment for high-grade serous carcinoma, both individually and in combination with paclitaxel. Methods: The Presto Blue assay, viability marker assessments, immunocytochemical analysis of apoptosis, and a cumulative assay were employed to evaluate the functionality of P-glycoprotein. Results: The results indicated that galanthamine did not demonstrate cytotoxic or synergistic effects in either high-grade serous carcinoma cell line tested, suggesting that it is not a viable strategy for overcoming paclitaxel resistance in this context. The immunocytochemistry analysis indicated that galanthamine does not affect the expression of proteins related to cell viability and proliferation and is not associated with chemoresistance. Additionally, functional assays showed that galanthamine treatment did not affect its drug efflux function at the cellular level. Conclusions: Overall, the results indicate that galanthamine is unsuitable for reversing paclitaxel resistance despite some literature suggesting its potential interaction with P-glycoprotein.}, } @article {pmid41462869, year = {2025}, author = {Sarbu, M and Ica, R and Biricioiu, MR and Dehelean, L and Zamfir, AD}, title = {Glycosphingolipids in Dementia: Insights from Mass Spectrometry and Systems Biology Approaches.}, journal = {Biomedicines}, volume = {13}, number = {12}, pages = {}, pmid = {41462869}, issn = {2227-9059}, support = {PN-IV-P2-2.1-TE-2023-0175//UEFISCDI/ ; UAV-IRG-1-2025-8//Aurel Vlaicu University of Arad, Romania/ ; }, abstract = {This narrative literature review synthesizes recent evidence on glycosphingolipid (GSL) dysregulation in dementia, emphasizing discoveries enabled by mass spectrometry (MS) and systems biology. Focusing on the research published within the last decade, we selected studies that are relevant to GSL alterations in dementia and notable for their methodological advances. The findings were conceptually integrated to emphasize key molecular, analytical, and systems-level aspects across the major dementia types. The results from MS-based glycolipidomics in Alzheimer's disease, dementia with Lewy bodies, frontotemporal dementia, Parkinson's disease dementia, and Huntington's disease consistently indicate altered GSL metabolism and shared molecular vulnerabilities in neuronal lipid regulation. At the same time, distinct GSL signatures differentiate individual dementias, reflecting the disease-specific mechanisms of neurodegeneration. The literature also reveals that recent advances in high-resolution MS and integrative analytical workflows have shifted GSL research from descriptive to mechanistic, facilitating the detailed mapping of species linked to neuroinflammation, protein aggregation, and synaptic dysfunction. Systems-level analyses combining MS data with other omics approaches increasingly depict GSLs as active regulators of neuronal function rather than inert membrane components. At the same time, emerging trends position GSLs as promising early biomarkers and potential therapeutic targets, while the growing use of artificial intelligence in MS data analysis is accelerating the detection of their subtle patterns, improving cross-disease comparisons. Together, these results reinforce the major role of MS-based platforms in discovering dementia-associated GSLs, identifying therapeutic targets, and influencing future strategies for diagnosis and treatment.}, } @article {pmid41463053, year = {2025}, author = {N F Guimarães, G and Dos Santos Cardoso, F and Gamboa, L and W Barrett, D and Gonzalez-Lima, F}, title = {Abdominal Photobiomodulation and the Gut-Brain Axis: A Systematic Review of Mechanistic and Translational Evidence.}, journal = {Biomedicines}, volume = {13}, number = {12}, pages = {}, pmid = {41463053}, issn = {2227-9059}, abstract = {Background/Objectives: Bidirectional communication between the gut and brain is central to neurological and psychiatric health, and abdominal photobiomodulation (PBM) has emerged as a promising non-invasive way to modulate this axis by targeting intestinal mitochondria, epithelial integrity, and the microbiota. We systematically reviewed preclinical and clinical evidence on abdominal PBM, alone or in combined protocols, reporting microbiome, metabolic, or neurobehavioral outcomes. Methods: Following PRISMA 2020 recommendations, we searched MEDLINE, Scopus, Web of Science, and ScienceDirect through May 2025 for animal and human studies applying PBM to the abdomen and reporting gut-related, metabolic, or brain-related outcomes. Results: Nine studies met the eligibility criteria (five human, four animal). Human trials, mainly in Parkinson's and Alzheimer's disease, used 630-904 nm light and reported gains in mobility, balance, cognition, and olfaction; one trial also showed microbiota modulation with a decreased Firmicutes:Bacteroidetes ratio. Animal models revealed cognitive improvement, reduced neuroinflammation, dopaminergic neuroprotection, and microbial rebalancing. Mechanistic findings converged on enhanced mitochondrial bioenergetics, redox and anti-inflammatory signaling, vagal activation, and short-chain fatty acid-mediated effects. Conclusions: Current evidence, though limited by small samples, heterogeneous dosimetry, combined treatment sites, and few sham-controlled human trials, suggests that abdominal PBM can influence the gut-brain axis through converging mitochondrial, immune, and microbial mechanisms. Adequately powered randomized trials with standardized dosimetry, validated mechanistic biomarkers, and integrative multi-omics analyses are needed to clarify causal pathways and optimize translational applications.}, } @article {pmid41463129, year = {2025}, author = {Eroglu, B and Velez, D and Jones, K and Deak, F and Eroglu, A}, title = {Amelioration of Alzheimer's Disease Pathology in Zebrafish by Photobiomodulation.}, journal = {Biomedicines}, volume = {13}, number = {12}, pages = {}, pmid = {41463129}, issn = {2227-9059}, support = {R01 AG062655/AG/NIA NIH HHS/United States ; }, abstract = {Background/Objectives: The zebrafish is a widely used research model due to its characteristics, such as being transparent during development, sharing 70% of its genes with humans, and having conserved features of vertebrate aging, including deterioration of mitochondrial and cognitive functions. While affecting approximately 15% of the world population, neurodegenerative diseases, such as Alzheimer's disease (AD), are currently incurable, requiring testing of alternative treatment strategies. Hence, this study was conducted to test the hypothesis that an optimized photobiomodulation (PBM) therapy improves AD pathology through its multifaceted beneficial effects, including enhancing mitochondrial function and reducing oxidative stress and neuroinflammation. Methods: A pharmacological zebrafish model of AD was developed by adding small amounts (100 nM) of okadaic acid (OKA) directly to fish tanks for nine days. Next, some of OKA-treated and control zebrafish were subjected to an optimized near-infrared PBM therapy while others remain untreated. Results: When examined after OKA treatment, zebrafish brains displayed histological hallmarks of AD including, neurofibrillary tangles, vacuoles, and neuroinflammation. Behavioral tests using a T-maze revealed that OKA-treated zebrafish spent significantly less time in the reward arm than untreated controls (15.2% vs. 50%). In contrast, a sequential PBM therapy significantly reduced formation of neurofibrillary tangles, vacuoles, neuroinflammation, and improved mitochondrial biogenesis in brains of OKA-treated zebrafish while also improving their cognitive function as evidenced by being able to recall the reward arm and spending more time there similar to controls (55 and 57%, respectively). Conclusions: These findings suggest that (1) a fast, cost-effective zebrafish AD model can be developed using OKA treatment and (2) PBM therapy holds promise to ameliorate AD pathology.}, } @article {pmid41465142, year = {2025}, author = {Machowska, M and Leszek, J and Mikołajczyk-Tarnawa, A and Głowacka, K and Trypka, E and Rąpała, M and Piechota, J and Wiela-Hojeńska, A}, title = {The Diagnostic Reliability of BIN1 and TOMM40 Genotyping in Assessing Dementia Risk.}, journal = {Genes}, volume = {16}, number = {12}, pages = {}, pmid = {41465142}, issn = {2073-4425}, support = {RPDS.01.02.01-02-0002/20//Regional Operational Programme of the Lower Silesian Voivodeship 2014-2020, co-financed by the European Union, European Regional Development Fund/ ; }, mesh = {Humans ; *Mitochondrial Precursor Protein Import Complex Proteins/genetics ; Male ; Female ; Aged ; *Cognitive Dysfunction/genetics/diagnosis ; *Tumor Suppressor Proteins/genetics ; Polymorphism, Single Nucleotide ; *Adaptor Proteins, Signal Transducing/genetics ; *Alzheimer Disease/genetics/diagnosis ; *Nuclear Proteins/genetics ; Genotype ; *Dementia/genetics/diagnosis ; *Membrane Transport Proteins/genetics ; Genetic Predisposition to Disease ; Case-Control Studies ; Aged, 80 and over ; Middle Aged ; }, abstract = {OBJECTIVES: Alzheimer's disease (AD) and other dementias represent a growing public health concern, highlighting the need for reliable biomarkers for early diagnosis and treatment monitoring. This study evaluated the potential utility of BIN1 and TOMM40 genotyping in diagnosing mild cognitive impairment (MCI) and early-stage dementia.

METHODS: The BIN1 rs744373 and TOMM40 rs2075650 polymorphisms were genotyped in a cohort of 105 individuals diagnosed with MCI or dementia and in 164 cognitively healthy controls. Genotype distributions were compared between the groups, and the potential role of these variants in diagnostic assessment was explored.

RESULTS: A significantly higher frequency of the TOMM40 rs2075650 GG genotype was observed in patients with AD compared with cognitively healthy controls. In contrast, no statistically significant differences in genotype distribution were found among individuals with mild MCI, vascular dementia, or mixed dementia. Furthermore, the distribution of BIN1 rs744373 alleles did not differ significantly across the analyzed groups.

CONCLUSIONS: Data on the effects of BIN1 rs744373 and TOMM40 rs2075650 polymorphisms in MCI and dementia remain limited and inconsistent. In our study, significant differences were observed only for the TOMM40 rs2075650 GG genotype and G allele, which were more frequent in Alzheimer's disease patients than in controls. No significant associations were found for MCI, vascular dementia, or mixed dementia, nor for the BIN1 rs744373 polymorphism. These results suggest that TOMM40 rs2075650 genotyping may serve as an additional marker for assessing AD risk.}, } @article {pmid41465466, year = {2025}, author = {Xu, C and Owen, JE and Gislason, T and Benediktsdottir, B and Ye, J and Robinson, SR}, title = {Limited Microvascular Remodelling Occurs in the Aged Human Hippocampus in Obstructive Sleep Apnoea.}, journal = {International journal of molecular sciences}, volume = {26}, number = {24}, pages = {}, pmid = {41465466}, issn = {1422-0067}, support = {Not applicable//RMIT University/ ; }, mesh = {Humans ; *Sleep Apnea, Obstructive/pathology/physiopathology/therapy ; Male ; Middle Aged ; Female ; Aged ; *Hippocampus/blood supply/pathology ; *Microvessels/pathology/physiopathology ; Adult ; *Aging/pathology ; *Vascular Remodeling ; Continuous Positive Airway Pressure ; }, abstract = {In mice, intermittent hypoxia is associated with an increase in microvessels in the hippocampus, whereas in humans with obstructive sleep apnoea (OSA), microvessels are lost from the heart and retina. The present study investigated microvascular changes in the hippocampus of patients with OSA, and whether patient age or use of continuous positive airway pressure (CPAP) influence microvascularisation. Using autopsy samples from 31 people with confirmed OSA, microvessels were immunolabelled and quantitatively analysed. Compared to the Low OSA group, the High OSA group had larger mean microvessel diameters in the fimbria and CA4, and greater mean microvessel length in the fimbria, which are indicative of microvascular remodelling. An absence of angiogenesis was indicated by similar mean vessel counts in both OSA severity groups. Increased age was associated with microvascular remodelling in the fimbria only. Treatment with CPAP was not associated with changed patterns of microvascularisation. We conclude that: (i) no evidence was found for angiogenesis in the human hippocampus in OSA or ageing; (ii) increased OSA severity is associated with microvascular remodelling in the fimbria and CA4; (iii) microvascular remodelling does not appear to be influenced by CPAP use; (iv) limited adaptability of the microvasculature may underpin the vulnerability of the hippocampus to hypoxic injury, particularly in severe OSA.}, } @article {pmid41465832, year = {2025}, author = {Pilśniak, J and Węgrzynek-Gallina, J and Bednarczyk, B and Buczek, A and Pilśniak, A and Chmiela, T and Jarosińska, A and Siuda, J and Holecki, M}, title = {The Role of Glucagon-like Peptide-1 Receptor Agonists in Alzheimer's and Parkinson's Disease: A Literature Review of Clinical Trials.}, journal = {Life (Basel, Switzerland)}, volume = {15}, number = {12}, pages = {}, pmid = {41465832}, issn = {2075-1729}, abstract = {Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are widely used in the treatment of type 2 diabetes and obesity due to their metabolic effects. Emerging evidence suggests they may also have neuroprotective effects, indicating their potential as disease-modifying therapies in neurodegenerative disorders such as Alzheimer's disease (AD) and Parkinson's disease (PD). Preclinical studies in animal models have demonstrated that GLP-1RAs can reduce neuroinflammation, oxidative stress, neuronal apoptosis, and pathological protein aggregation, while enhancing glucose metabolism and mitochondrial function. This narrative review analyzed results from human clinical trials evaluating GLP-1RAs in AD and PD, based on a search of four databases (Web of Science, Medline, Embase, and Clinical Trials). The analysis included eleven studies. In AD, clinical trials suggest that GLP-1RAs such as liraglutide and semaglutide may enhance brain glucose metabolism, facilitate glucose transport across the blood-brain barrier, and benefit neuronal networks. However, most studies did not demonstrate improvements in cognitive functions or radiological markers. Short-term clinical trials of GLP-1RAs, including exenatide and lixisenatide, demonstrated promising effects on motor and selected non-motor symptoms in patients with PD, but their disease-modifying effects remain unproven. GLP-1RAs showed a favorable safety profile. Despite promising findings, small study populations, heterogeneous protocols, and short observation periods limit definitive conclusions. Further larger, long-term studies are needed, particularly to clarify the risk-benefit balance, weight control, and long-term outcomes.}, } @article {pmid41466363, year = {2026}, author = {de Magalhães, CG and Moldakozhayev, A and Lopez, MV and Bowman, GL and Chhatwal, JP and Kellis, M and Mohs, R and Nisenbaum, L and Quiroz, YT and Raju, RM and Sperling, RA and Moqri, M and Gladyshev, VN}, title = {The Right Person, the Right Treatment, at the Right Time in Alzheimer's Disease: Insights From the 2025 Brain Aging Symposium.}, journal = {Aging cell}, volume = {25}, number = {1}, pages = {e70351}, pmid = {41466363}, issn = {1474-9726}, support = {K08 AG086586/AG/NIA NIH HHS/United States ; }, mesh = {Humans ; *Alzheimer Disease/therapy/pathology/metabolism ; *Brain/pathology/metabolism ; *Aging/pathology ; Biomarkers/metabolism ; }, abstract = {On October 22nd, 2025, Brain Aging Symposium took place at Harvard Medical School bringing together leading researchers from academia and partner organizations to discuss recent advances in measuring and monitoring human brain aging trajectories, with a particular focus on Alzheimer's disease (AD). A central theme emerged: achieving "the right treatment for the right person and the right time" through precision medicine approaches. Key advances included the unprecedented validation of plasma-based biomarkers, particularly brain-derived p-Tau217 that can identify seeding AD pathology with remarkable specificity, making large-scale screening newly feasible. Integrating multi-level "omic" modalities, spanning genetic information, molecular biomarkers of nutrition, lipid and protein signatures, neuroimaging measures, cognitive assessments, and lifestyle factors, enhances disease risk modeling and trajectory prediction beyond the capacity of any single marker. Early findings highlight critical roles for nutritional and lipid metabolism, and myelin integrity in brain aging, with cell and sex-specific vulnerabilities identified in response to nutrition, social isolation, and metabolic stress. Computational approaches that combine single-cell genomics, epigenomics, and artificial intelligence have been shown to accelerate causal discovery and therapeutic development. However, significant challenges remain: current biomarkers explain only half the variance in cognitive decline, racial and ethnic differences in biomarker levels lack mechanistic understanding, and scalable tools for comprehensive brain aging assessment are needed. The symposium underscored that preventing AD will require intervening during the preclinical asymptomatic phase. These multimodal screening platforms, coupled with mechanistically driven therapeutics, reduction in modifiable risk factors, including nutrition, vascular health, and social determinants of health, could profoundly impact the field.}, } @article {pmid41467376, year = {2026}, author = {Alexandrova, EG and Abakumova, TR and Ziganshina, LE}, title = {Use of nootropics in Alzheimer's disease: An analysis of regulatory positions and drug policies in the countries of the Commonwealth of Independent States.}, journal = {The International journal of risk & safety in medicine}, volume = {37}, number = {2}, pages = {257-264}, doi = {10.1177/09246479251410817}, pmid = {41467376}, issn = {1878-6847}, mesh = {*Alzheimer Disease/drug therapy ; Humans ; *Nootropic Agents/therapeutic use ; Russia ; United States ; United Kingdom ; Practice Guidelines as Topic ; }, abstract = {ObjectiveTo analyse regulatory positions and drug policies of the Commonwealth of Independent States (CIS), compared to those of the EU, UK, USA i of the nootropics, used in Russia for Alzheimer's disease.MethodsWe searched E-library to reveal the list of nootropics used and studied in Russia for Alzheimer's disease. We assessed official pharmaceutical registries of nine countries for registration status of identified nootropics, 7 National Essential Medicines Lists (EML), and four clinical practice guidelines (CPG) on Alzheimer's disease. We compared the results of Russia with other countries regulatory and policy positions.ResultsE-Library searches identified 11 nootropicspiracetam, citicoline, idebenone, vinpocetine, choline alfoscerate, Cerebrolysin®, Kortexin®, ethylmethylhydroxypyridine succinate, glycine, nicergoline, nimodipine. Eight nootropic have registration for use in all CIS countries (excluding idebenone, nimodipine), four (piracetam, nimodipine, nicergoline, idebenone) - in UK, nimodipine - in the USA, and idebenone - in EU. National EMLs included: nine nootropics (Russia), 8 - Belarus and Kazakhstan, 4 - Uzbekistan, 2 - Armenia. The studied nootropic agents are not included on the WHO Model EML and on the National EML of the Kyrgyz Republic. They are not listed in the CPG for Treatment of dementia and Alzheimer's disease in the USA, the EU, and the UK. Russian CPGs for Alzheimer's disease recommend Cerebrolysin® and choline alfoscerate.ConclusionsThe studied nootropics are registered for use and listed on National EMLs of Russia, Armenia, Belarus, Kazakhstan, Uzbekistan. None is included on the WHO Model EML and the National EML of Kyrgyzstan, Only CPG of the RF recommend using two nootropics as adjuvant therapy of Alzheimer's disease, Cerebrolysin® and choline alfoscerate. CPG of the European Union, the United Kingdom, and the USA do not mention nootropics as potential treatment options for Alzheimer's disease.}, } @article {pmid41467438, year = {2025}, author = {Zhao, J and Wang, J and Guo, X}, title = {Organoids: Key advances, optimization, and technological iterations in their application to neurodegenerative diseases.}, journal = {Neural regeneration research}, volume = {}, number = {}, pages = {}, doi = {10.4103/NRR.NRR-D-25-00924}, pmid = {41467438}, issn = {1673-5374}, abstract = {Organoid technology, as an innovative approach, has shown great potential in disease modeling, target screening, and the development of treatment strategies. However, traditional organoids still have three major limitations in research: the absence of specific cell types, the lack of blood-brain barrier structure, and insufficient reproducibility of experimental results. In recent years, researchers have gradually overcome these limitations by introducing innovative techniques such as advanced culture methods, microfluidic systems, bioprinting, organoid transplantation, and assembloid construction. This progress has facilitated the widespread application of organoids in the study of neurodegenerative diseases. This paper aims to systematically review the technological innovations of organoids in the study of neurodegenerative diseases. By summarizing classical organoid construction strategies and their limitations, it emphasizes the value of organoids in comprehensive applications within neurodegenerative disease research. In this review, we focus on five specific neurodegenerative diseases: Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, and frontotemporal dementia. Research in these diseases demonstrates that organoids improve experimental accessibility and reduce development cycles in disease modeling, target discovery, and therapeutic strategy formation. Using customized equipment and gene editing techniques, these organoids can be tailored to specific needs, providing pathophysiologically relevant disease models and enhancing our understanding of neurodegenerative diseases. Although organoid technology has demonstrated significant advantages in disease research, its potential for treating neurodegenerative diseases has not yet been fully explored, which may become an important direction for future research.}, } @article {pmid41467972, year = {2026}, author = {Chang, ST and Wu, HY and Chiu, YL and Chuang, YF}, title = {Anti-herpetic treatment reduces dementia risk: A systematic review and meta-analysis.}, journal = {Journal of Alzheimer's disease : JAD}, volume = {109}, number = {4}, pages = {1590-1602}, doi = {10.1177/13872877251409323}, pmid = {41467972}, issn = {1875-8908}, mesh = {Humans ; *Antiviral Agents/therapeutic use ; *Dementia/prevention & control/epidemiology ; *Herpes Simplex/drug therapy ; Herpes Zoster/drug therapy ; }, abstract = {BackgroundHuman herpesvirus (HHV) infections, particularly for herpes simplex virus (HSV) and varicella-zoster virus (VZV), may increase dementia risk, yet the protective effects of anti-herpetic medications remained unclear.ObjectiveThis systematic review and meta-analysis of observational studies aimed to examine the association between anti-herpetic medications and dementia, focusing on HSV or VZV-related infections.MethodsThis study followed PRISMA guidelines (CRD42022368318). Cohort or nested case-control studies published from databases' inception to December 2024 were systematically searched in PubMed, MEDLINE, Embase, Cochrane Library, PsycINFO, and Web of Science. Eligible studies evaluated anti-herpetic medications (e.g., acyclovir, famciclovir, ganciclovir, valacyclovir, valganciclovir) and dementia risk in non-demented adults aged ≥50. Pooled adjusted hazard ratios (aHR) and 95% confidence intervals (CIs) were analyzed using random-effects models. Subgroup and meta-regression analyses were performed to explore potential sources of heterogeneity and effect modifiers.ResultsFourteen cohort studies involving more than 10 million older adults were included. To demonstrate the effects of anti-herpetic medications in various clinical scenarios, the meta-analysis compared: diagnosed and treated versus diagnosed but untreated (aHR=0.77, 95% CI: 0.67-0.89); treated versus untreated regardless of diagnosis (aHR=0.90, 95% CI: 0.87-0.94); and diagnosed and treated versus neither diagnosed nor treated (aHR=0.87, 95% CI: 0.78-0.97). Subgroup analysis and meta-regression identified infection severity as a significant modifier (p < 0.0001), explaining 89.01% of heterogeneity.ConclusionsThis systematic review and meta-analysis reveals notable protective effect of anti-herpetic medication usage on dementia, and the effect is especially pronounced in patients with severe alpha herpesvirus infections.}, } @article {pmid41468784, year = {2026}, author = {Palanivel, V and Salkar, A and Shenoy, A and Eva, TA and Perera, R and Chitranshi, N and Gupta, V and You, Y and Mirzaei, M and Graham, SL and Gupta, V and Basavarajappa, D}, title = {Neuropeptide Y at the crossroads of neurodegeneration: Mechanistic insights and emerging therapeutic strategies.}, journal = {Neuropeptides}, volume = {115}, number = {}, pages = {102583}, doi = {10.1016/j.npep.2025.102583}, pmid = {41468784}, issn = {1532-2785}, mesh = {Humans ; *Neuropeptide Y/metabolism ; *Neurodegenerative Diseases/metabolism ; Animals ; Signal Transduction/physiology ; Oxidative Stress/physiology ; Receptors, Neuropeptide Y/metabolism ; }, abstract = {Neuropeptide Y (NPY), a widely distributed and highly conserved neuropeptide, plays a central role in the regulation of diverse physiological processes, including stress responses, energy homeostasis, vascular tone, and immune modulation, via activation of its receptor subtypes. Beyond its physiological roles, the dysregulation of NPY expression has been documented in several neurodegenerative disorders, including Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, Machado-Joseph disease, and retinal disorders such as diabetic retinopathy and glaucoma. These alterations in NPY levels and receptor activity highlight its potential not only as a biomarker for disease progression but also as a promising therapeutic target. Previous evidence revealed that NPY exerts neuroprotection by alleviating excitotoxicity, oxidative stress, mitochondrial dysfunction, and neuroinflammation while concurrently facilitating neurogenesis, synaptic plasticity, and cellular resilience. NPY activates receptor-mediated intracellular signaling cascades like PI3K/Akt, MAPK/ERK, and p38K, that control cellular survival, proteostasis, and inflammation and thereby influence disease trajectories. Understanding NPY operation with these mechanisms can unveil new avenues for targeted therapy. Current insights into the complex roles of NPY in neurodegeneration are discussed in this review, and their implications in diagnostic and treatment strategies are addressed.}, } @article {pmid41469664, year = {2025}, author = {Yu, X and Xiao, H and Bao, S and Dong, Y and Dong, Z and Zhao, J and Wang, G and Meng, X and Wang, F}, title = {Cigarette smoke-induced lung-brain barrier dysfunction drives neurocognitive impairment via inflammatory spill-over.}, journal = {Journal of neuroinflammation}, volume = {23}, number = {1}, pages = {10}, pmid = {41469664}, issn = {1742-2094}, support = {2024CX129//the Graduate Innovation Fund of Jilin University/ ; Not applicable//the Medical Basic Research Innovation Center of Airway Disease in North China/ ; Not applicable//Key Laboratory of Pathobiology/ ; 20200601011JC//Key Laboratory of Precision Infectious Diseases, Jilin Province/ ; 2022C036//Engineering Laboratory for Precision Prevention and Treatment of Common Diseases, Jilin Province/ ; 20230204055YY//Department of Science and Technology of Jilin Province: Key Scientific and Technological Research and Development Projects/ ; }, mesh = {Animals ; Female ; Mice ; *Blood-Brain Barrier/metabolism/pathology/drug effects ; Mice, Inbred BALB C ; *Lung/metabolism/pathology/drug effects ; *Pulmonary Disease, Chronic Obstructive/metabolism ; Brain ; }, abstract = {BACKGROUND: Although the association between cigarette smoke (CS)-induced chronic obstructive pulmonary disease (COPD) and neurocognitive disorders is recognized, the underlying mechanisms remain unclear. To date, no studies have linked alterations in lung and brain barrier permeability to the “spill-over” of inflammatory factors in CS induced COPD-related neurocognitive disorders (COPD-NCDs). METHODS: Using GWAS data, a two-sample Mendelian randomization (MR) analysis was conducted to explore the genetic associations between COPD and neurocognitive disorders (dementia, Alzheimer’s disease, etc.). A BALB/c female mouse model with CS exposure (9 cigarettes/day × 24 weeks) was established. Cognitive functions were evaluated using open field tests, novel object recognition tests, and Morris water maze tests. Histopathological changes were observed by HE and Masson staining. Cellular and molecular profiles in brain tissues were analyzed by single-cell RNA sequencing. Levels of inflammatory factors were detected by ELISA. Barrier permeability changes in the lungs and brain were assessed by using Evans Blue staining. Tight junction proteins in lung and brain tissues were measured by immunofluorescence and Western blotting. RESULTS: MR analysis revealed causal associations between COPD and Alzheimer’s disease, dementia, depression, anxiety, and Parkinson’s disease. CS-exposed mice exhibited COPD phenotypes (emphysema, reduced lung function) and cognitive impairments (memory deficits, anxiety-like behaviors). Activation of microglia/astrocytes and decreased neuronal/synaptic marker expression were observed in the hippocampus. Increased leakage of Evans blue staining in the lungs and brain, along with downregulated expression of tight junction proteins (Occludin, Claudin1, ZO-1), indicated increased blood-brain barrier (BBB) permeability. Elevated levels of inflammatory factors (IL-1β, IL-6, TNF-α) were detected in lung tissues, brain tissues and serum. CONCLUSIONS: CS exposure disrupts lung barrier function, leading to the “spill-over” of inflammatory factors to the brain via the lung-brain axis. This increases BBB permeability, triggering neuroinflammation, impairing hippocampal neuronal and synaptic function, and ultimately causing neurocognitive disorders. This study elucidates a novel mechanism of COPD-NCDs, which may provide new targets for the treatment of COPD-NCDs.}, } @article {pmid41469705, year = {2025}, author = {Li, T and Zhang, J and Song, H and Zhang, R and Fan, F and Huang, Z and Zeng, ML and Peng, BW and Zhang, J}, title = {Border-associated macrophages: an emerging perspective from physiological basis and multi-disease roles to the mechanism of vascular cognitive impairment and dementia.}, journal = {Journal of neuroinflammation}, volume = {22}, number = {1}, pages = {302}, pmid = {41469705}, issn = {1742-2094}, support = {82501747//the Natural Science Foundation of China/ ; 82571371//the Natural Science Foundation of China/ ; 2025AFC006//the Natural Science Foundation of Hubei Province/ ; PTXM2025032//Medical Sci-Tech Innovation Platform of Zhongnan Hospital, Wuhan University/ ; ZY2023Z018//Key projects of Traditional Chinese Medicine Scientific research in 2023-2024 by Hubei Provincial Administration of Traditional Chinese Medicine/ ; }, mesh = {Humans ; *Cognitive Dysfunction/pathology/immunology/metabolism ; *Dementia, Vascular/pathology/immunology/metabolism/physiopathology ; Animals ; *Macrophages/pathology/metabolism/immunology ; *Brain/pathology/immunology/metabolism ; }, abstract = {Brain border-associated macrophages (BAMs) are resident immune cells at the border of the central nervous system (CNS), and their physiological functions and roles in neurological diseases have been widely reported. However, the specific mechanisms by which BAMs contribute to vascular cognitive impairment and dementia (VCID) remain unclear. This article systematically reviews the subsets, origin and differentiation, molecular markers of BAMs, and their research progress in various brain diseases such as hypertension, Alzheimer's disease (AD), and stroke. On this basis, this article deeply analyzes the potential hypotheses of BAMs' involvement in the pathogenesis of VCID, including their regulation of neurovascular unit (NVU) homeostasis, their core role in neuroimmune inflammation, their impact on the lipid metabolism pathways in the CNS, and their involvement in the pathogenesis of vascular risk factor-related cognitive impairment (VRFCI). The mechanistic hypotheses proposed in this article aim to provide new perspectives for understanding the pathophysiology of VCID and may open up new directions for the development of early intervention and targeted treatment strategies.}, } @article {pmid41471033, year = {2025}, author = {Park, YC and Seol, E and Lee, J and Hong, JH and Jung, JG and Sunwoo, J}, title = {Pharmacokinetic Evaluation of GB-5001, a Long-Acting Injectable Formulation of Donepezil, in Healthy Korean Participants: Population Pharmacokinetics with Phase 1 Study.}, journal = {Pharmaceutics}, volume = {17}, number = {12}, pages = {}, pmid = {41471033}, issn = {1999-4923}, support = {Not applicable//G2GBIO Inc./ ; }, abstract = {Background/Objectives: Oral donepezil, an acetylcholinesterase (AChE) inhibitor for Alzheimer's disease, faces adherence challenges. Long-acting injectable (LAI) formulations like GB-5001 aim to enhance adherence by reducing dosing frequency. This Phase 1, open-label, active-controlled, dose-escalation study evaluated the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of GB-5001 in healthy male adults. Methods: Participants were assigned to cohorts receiving GB-5001A or GB-5001D (LAI formulations) via intramuscular (IM) or subcutaneous (SC) injection, or oral Aricept[®]. Safety, PK, and PD (AChE inhibition) were assessed. The influence of CYP2D6 phenotype was explored, and modeling/simulation was performed. Results: Fifty healthy male participants completed the study. After IM administration, GB-5001A (70 mg, 140 mg, 280 mg) showed dose-dependent increases in exposure (AUCinf and Cmax), resulting in significantly extended exposure compared to oral Aricept[®] 10 mg. No serious adverse events were reported; the most common AEs were mild injection site reactions, which occurred in all treatment groups except the GB-5001A IM 70 mg group and the Aricept group. GB-5001A also demonstrated sustained AChE inhibition. Conclusions: GB-5001A, an LAI donepezil, showed favorable safety, dose-proportional PK, and sustained plasma exposure. It achieved a 3-4-fold longer half-life than oral donepezil. These findings, supported by modeling, highlight GB-5001A's potential as a once-monthly IM alternative for Alzheimer's disease treatment.}, } @article {pmid41471079, year = {2025}, author = {Trasca, DM and Dorin, PI and Carmen, S and Varut, RM and Singer, CE and Radivojevic, K and Stoica, GA}, title = {Artificial Intelligence in Biomedicine: A Systematic Review from Nanomedicine to Neurology and Hepatology.}, journal = {Pharmaceutics}, volume = {17}, number = {12}, pages = {}, pmid = {41471079}, issn = {1999-4923}, abstract = {Background/Objectives: This review evaluates the expanding contributions of artificial intelligence (AI) across biomedicine, focusing on cancer therapy and nanomedicine, cardiology and medical imaging, neurodegenerative disorders, and liver disease. Core AI concepts (machine learning, deep learning, artificial neural networks, model training/validation, and explainability) are introduced to frame application domains. Methods: A systematic search of major biomedical databases (2010-2025) identified English-language original studies on AI in these four areas; 203 articles meeting PRISMA 2020 criteria were included in a qualitative synthesis. Results: In oncology and nanomedicine, AI-driven methods expedite nanocarrier design, predict biodistribution and treatment response, and enable nanoparticle-enhanced monitoring. In cardiology, algorithms enhance ECG interpretation, coronary calcium scoring, automated image segmentation, and noninvasive FFR estimation. For neurological disease, multimodal AI models integrate imaging and biomarker data to improve early detection and patient stratification. In hepatology, AI supports digital histopathology, augments intraoperative robotics, and refines transplant wait-list prioritization. Common obstacles are highlighted, including data heterogeneity, lack of standardized acquisition protocols, model transparency, and the scarcity of prospective multicenter validation. Conclusions: AI is emerging as a practical enabler across these biomedical fields, but its safe and equitable use requires harmonized data, rigorous multicentre validation, and more transparent models to ensure clinical benefit while minimizing bias.}, } @article {pmid41471351, year = {2025}, author = {Makhaeva, GF and Utepova, IA and Rudakova, EV and Kovaleva, NV and Boltneva, NP and Zyryanova, EY and Musikhina, AA and Lazarev, VF and Vladimirova, SA and Guzhova, IV and Ganebnykh, IN and Astakhova, TY and Timokhina, EN and Chupakhin, ON and Charushin, VN and Richardson, RJ}, title = {1-Azinyl-1'-Alkenylferrocenes with Anticholinesterase, Antioxidant, and Antiaggregating Activities as Multifunctional Agents for Potential Treatment of Alzheimer's Disease.}, journal = {Pharmaceuticals (Basel, Switzerland)}, volume = {18}, number = {12}, pages = {}, pmid = {41471351}, issn = {1424-8247}, support = {24-63-00016//Russian Science Foundation/ ; }, abstract = {Background/Objectives: This study focused on synthesizing novel alkenyl derivatives of azinylferrocenes and evaluating their potential as Alzheimer's disease (AD) therapeutics. Methods: 1-Azinyl-1'-acetylferrocenes were obtained by regioselective acetylation of azinylferrocenes, followed by the Wittig reaction or reduction of 1-azinyl-1'-acetylferrocenes and subsequent dehydration of the resulting alcohols. The synthesized compounds underwent the following biological activity testing relevant to AD: inhibition of acetylcholinesterase (AChE), butyrylcholinesterase (BChE), and off-target carboxylesterase (CES); antioxidant capacity (ABTS and FRAP assays); inhibition of Aβ42 self-aggregation (thioflavin method); blocking AChE-induced β-amyloid aggregation (propidium displacement); and cytotoxicity in SH-SY5Y and MSC-Neu cells (MTT assay). Results: Quinoline and bipyridine derivatives demonstrated effective cholinesterase inhibition, especially quinoline 7b (AChE IC50 3.32 μM; BChE IC50 3.68 μM), while acridine derivatives were poor inhibitors. Quantum chemical (QC) calculations predicted that acridine derivatives were especially prone to form stable dimers. Molecular docking into protein targets generated by an AlphaFold3 reproduction code showed that these dimers were too bulky to access enzyme active sites, yet they could bind to protein surfaces to inhibit Aβ42 self-aggregation and displace propidium from the AChE peripheral anionic site. All compounds showed high antioxidant activity in ABTS and FRAP assays, with quinoline derivatives being 2-4 times more potent than Trolox. QC calculations supported these findings. Quinoline and bipyridine derivatives also exhibited low cytotoxicity and scant CES inhibition. Conclusions: Overall, the synthesized ferrocenes, particularly the quinoline and bipyridine derivatives, appear promising for further research as multifunctional therapeutic agents targeting AD due to their anticholinesterase, antiaggregating, and antioxidant activities combined with low toxicity.}, } @article {pmid41471864, year = {2025}, author = {Cao, S and Shi, X and Chen, Y and Liu, T and Hu, J and Dong, X and Chen, H and Dai, J and Yin, H}, title = {Gut Microbiota-Targeted Photobiomodulation Ameliorates Alzheimer's Pathology via the Gut-Brain Axis: Comparable Efficacy to Transcranial Irradiation.}, journal = {Microorganisms}, volume = {13}, number = {12}, pages = {}, pmid = {41471864}, issn = {2076-2607}, support = {62175261//National Natural Science Foundation of China/ ; 2023YFB3609103//National Key R&D Program of China/ ; 2021-I2M-1-058//Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences/ ; 24JCZDJC00240//Natural Science Foundation of Tianjin/ ; }, abstract = {Alzheimer's disease (AD) is a major neurodegenerative disorder with limited effective and affordable therapies. Photobiomodulation (PBM) offers a safe, non-invasive treatment strategy, yet conventional transcranial PBM (tc-PBM) is restricted by low skull penetration. To overcome this limitation, gut microbiota-targeted PBM (gm-PBM) has been proposed to modulate the gut-brain axis, though its efficacy and mechanisms remain unclear. Here, six-month-old APPswe/PS1dE9 mice received gm-PBM or tc-PBM (810 nm, 25 mW/cm[2], 20 min/day for 4 weeks). Behavioral testing revealed that both treatments improved spatial learning and memory, while histological analyses showed reduced amyloid-β deposition and microglial shift toward an anti-inflammatory phenotype. Notably, gm-PBM specifically enriched short-chain fatty acid-producing bacteria, elevated propionate, butyrate, and secondary bile acids, and restored intestinal barrier integrity, whereas tc-PBM induced minimal microbiota changes. These findings suggest that gm-PBM confers neuroprotective effects comparable to or exceeding tc-PBM through modulation of the gut microbiota-metabolism-immune axis, highlighting its potential as a non-invasive and cost-effective therapeutic approach for AD.}, } @article {pmid41473097, year = {2025}, author = {Kang, MH and Kang, MA and Jeon, HJ and Shin, HC and Moon, H and Lee, DG and Park, HM}, title = {Evaluation of the safety and efficacy of a donepezil depot injection in dogs with canine cognitive dysfunction.}, journal = {Frontiers in veterinary science}, volume = {12}, number = {}, pages = {1724060}, pmid = {41473097}, issn = {2297-1769}, abstract = {Canine cognitive dysfunction (CCD) is an age-related neurodegenerative disorder for which effective treatments remain limited, and objective diagnostic and therapeutic assessment tools using biomarkers or neuroimaging are still lacking compared with human Alzheimer's disease. This study evaluated the safety and efficacy of a long-acting donepezil depot injection in dogs with CCD, using behavioral scores and serum neurofilament light chain (NfL) as primary outcomes, with baseline MRI for diagnostic support. Thirty-two dogs with clinically diagnosed CCD were randomly assigned to a high-dose group (n = 11), a low-dose group (n = 11), or a control group (n = 10). Diagnosis was established based on the Canine Cognitive Dysfunction Rating Scale (CCDR), the CAnine DEmentia Scale (CADES), and DISHAA scoring, and baseline MRI was performed in selected dogs with owner consent. A single intramuscular injection of donepezil depot was administered on day 0, and evaluations were conducted on days 14 and 28. The high-dose group showed significant improvements in CCDR, CADES, and DISHAA at both 14 and 28 days, whereas the low-dose group improved primarily at day 28, with earlier effects limited to CADES (p < 0.05). At day 28, both treatment groups had significantly lower serum NfL levels than controls (p < 0.05), while within-group values remained stable. Quality-of-life scores improved in activity, sociability, overall condition, and global QoL. Adverse events were mild and transient. These findings suggest that a single intramuscular injection of long-acting donepezil depot demonstrates favorable safety and potential efficacy in dogs with CCD, with improvements in behavioral scores and NfL supporting its therapeutic potential and highlighting the value of integrating clinical and biomarker-based assessments in future CCD management.}, } @article {pmid41473323, year = {2025}, author = {Salian, VS and Veerareddy, V and Tang, X and Xiao, Y and Kalari, KR and Kashyap, PC and Kandimalla, KK}, title = {Molecular Mechanisms Underlying the Regulation of VCAM-1 Expression by the Short-Chain Fatty Acid Butyrate.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, doi = {10.64898/2025.12.15.694447}, pmid = {41473323}, issn = {2692-8205}, support = {R01 NS125437/NS/NINDS NIH HHS/United States ; }, abstract = {Over the past decade, cerebrovascular inflammation has been increasingly recognized as a contributor to the progression of neurodegenerative diseases, particularly Alzheimer's disease (AD). One of the molecular hallmarks of cerebrovascular inflammation is the increased expression of vascular cell adhesion molecule (VCAM)-1 on blood-brain barrier (BBB) endothelial cells. Exposure to amyloid beta (Aβ) peptides, one of the primary hallmarks of AD, and pro-inflammatory cytokines such as tumor necrosis factor-alpha (TNF-α) induces VCAM-1 expression on the BBB endothelium, which facilitates extravasation of leukocytes into the brain thereby promoting an inflammatory response. Therefore, it is crucial to explore therapeutic agents that can inhibit VCAM-1 expression induced by Aβ and TNF-α. Short-chain fatty acids, such as butyrate, produced by the gut microbiota as byproducts of dietary fiber metabolism, are recognized for their anti-inflammatory properties. In this study, we successfully tested the hypothesis that butyrate mitigates Aβ and TNF-α-induced VCAM-1 expression in polarized human cerebral microvascular endothelial cell monolayers, a widely used BBB in vitro model. Our findings indicated that pre-treatment with butyrate significantly reduced Aβ42 and TNF-α mediated upregulation of VCAM-1. Furthermore, we have shown STAT3/GATA6 axis as a key mediator of anti-inflammatory effects of butyrate. These findings provide mechanistic insight into butyrate's protective role and highlight its potential to mitigate Aβ and TNF-α-induced cerebrovascular inflammation in AD.}, } @article {pmid41473419, year = {2026}, author = {Tonegawa-Kuji, R and Karavani, E and Danziger, M and Zhang, P and Hou, Y and Zhou, Y and Bykova, M and Pieper, AA and Rosen-Zvi, M and Cummings, J and Cheng, F}, title = {Critical evaluation of real-world evidence of repurposable medicines in the Alzheimer's disease drug development pipeline using a target trial emulation.}, journal = {Alzheimer's & dementia (New York, N. Y.)}, volume = {12}, number = {1}, pages = {e70193}, pmid = {41473419}, issn = {2352-8737}, support = {P20 GM109025/GM/NIGMS NIH HHS/United States ; R35 AG071476/AG/NIA NIH HHS/United States ; }, abstract = {INTRODUCTION: Repurposing Food and Drug Administration (FDA)-approved drugs could accelerate treatment development for Alzheimer's disease (AD).

METHODS: Using the MarketScan claims database (2011 to 2020), we applied a trial emulation approach in two base cohorts: (1) individuals with mild cognitive impairment (MCI cohort) and (2) individuals aged ≥70 years (over-70 cohort). We evaluated drugs represented in clinical trials for AD, comparing them with same-class or active comparators. Covariate-adjusted hazard ratios (HRs) were estimated using inverse-probability-weighted Cox models.

RESULTS: A total of 6 out of 38 (16%) drugs in the MCI cohort and 10 out of 53 (19%) drugs in the over-70 cohort were associated with a lower AD incidence versus same-class comparators. Active comparator analyses indicated that bupropion (vs escitalopram; HR 0.57, 95% confidence interval [CI] [0.49, 0.66]), trazodone (vs sertraline; HR 0.82, 95% CI [0.74, 0.91]), venlafaxine (vs escitalopram; 0.72, 95% CI [0.62, 0.84]), and zolpidem (vs lorazepam; HR 0.69, 95% CI [0.56, 0.85]) were associated with a lower AD incidence in the MCI cohort; these four plus liraglutide were associated with a lower incidence of AD dementia in the over-70 cohort (vs metformin; HR 0.74, 95% CI [0.59, 0.93]).

DISCUSSION: This is the first comprehensive set of trial emulations for FDA-approved drugs that are represented in AD trials. Findings may inform future trial designs.

HIGHLIGHTS: Repurposing FDA-approved drugs originally developed for other diseases could accelerate treatment development for AD.We identified repurposable drugs that are in current or complete clinical trials of AD and emulated trials for these agents using a large-scale insurance claims-based database.Among 54 drugs evaluated, 6/38 (16%) drugs in the MCI cohort and 10/53 (19%) in the over-70 cohort were associated with reduced AD incidence versus same-class comparators. Active comparator analyses indicated that bupropion, trazodone, venlafaxine, and zolpidem were associated with reduced AD incidence in the MCI cohort; these four plus liraglutide were associated with a lower incidence of AD dementia in the over-70 cohort.A minority of repurposed table drugs that are in current or completed clinical trials for AD and meet criteria for inclusion in this study showed no effect in our trial emulation studies.This is the first comprehensive set of trial emulations for FDA-approved drugs that are represented in AD trials. Building on our findings, integrating real-world evidence can inform future trials and accelerate drug development for AD.}, } @article {pmid41474058, year = {2026}, author = {Naftchi-Ardebili, K and Singh, K and Popelka, GR and Pauly, KB}, title = {A deep-learning model for one-shot transcranial ultrasound simulation and phase aberration correction.}, journal = {Medical physics}, volume = {53}, number = {1}, pages = {e70259}, pmid = {41474058}, issn = {2473-4209}, support = {R01 Grant EB032743//National Science Foundation/ ; }, mesh = {*Deep Learning ; Humans ; *Image Processing, Computer-Assisted/methods ; Skull/diagnostic imaging ; Ultrasonography ; Tomography, X-Ray Computed ; }, abstract = {BACKGROUND: Transcranial ultrasound is a promising non-invasive neuromodulation technique with applications, including neuronal activity modulation, blood-brain barrier opening, targeted drug delivery, and thermal ablation. Its ability to deliver focused ultrasound waves to precise brain regions has led to over 50 clinical trials targeting conditions such as opioid addiction, Alzheimer's disease, dementia, epilepsy, and glioblastoma. However, skull heterogeneity complicates accurate focal spot prediction and energy delivery, requiring rapid yet precise phase aberration correction in clinical workflows.

PURPOSE: To address the trade-off between computational efficiency and accuracy in current focus prediction methods, we introduce TUSNet, a deep learning framework for rapid and accurate transcranial ultrasound pressure field and phase aberration correction computation.

METHODS: TUSNet, an end-to-end neural network, was trained to predict both 2D transcranial ultrasound pressure fields and phase corrections. TUSNet was trained on 180432 synthetic skull Computed Tomography (CT) segments, and tested on 1232 real skull CT segments. Its performance was benchmarked against k-Wave, a MATLAB-based acoustic simulation package, evaluating computation speed, focal spot accuracy, phase correction accuracy, and pressure magnitude estimation.

RESULTS: TUSNet computed pressure fields and phase corrections in 21 ms, which is over 1200 × $\times$ faster than k-Wave, while achieving 98.3% accuracy in peak pressure magnitude estimation and a mean focal positioning error of only 0.18 mm relative to k-Wave ground truth. End-to-end training took approximately 8 h on 4x NVIDIA A100 80 GB GPUs.

CONCLUSIONS: TUSNet demonstrates that deep learning can provide accurate and rapid estimates of phase aberrations and transcranial pressure fields, offering a promising direction for accelerating ultrasound treatment planning. While the present validation is based on simulated, noise-free ultrasound fields, the results establish a foundation that future experimental studies can build on to assess performance under real-world clinical conditions.}, } @article {pmid41475761, year = {2026}, author = {Mei, J and Shi, X and Chen, M and Li, Z and Cui, Y and Fang, C and Wu, X and Chen, X and Zeng, K and Yang, L}, title = {Chitosan/selenium nanoparticles Pickering emulsion prolong quercetin retention time to ameliorates cognitive disorder: Focus on restoring the metabolic disorder and gut microbiota.}, journal = {Carbohydrate polymers}, volume = {375}, number = {}, pages = {124804}, doi = {10.1016/j.carbpol.2025.124804}, pmid = {41475761}, issn = {1879-1344}, mesh = {*Quercetin/chemistry/pharmacology/administration & dosage/pharmacokinetics ; Animals ; *Gastrointestinal Microbiome/drug effects ; *Chitosan/chemistry ; Emulsions/chemistry ; *Nanoparticles/chemistry ; *Selenium/chemistry ; Mice ; Male ; Mice, Inbred C57BL ; *Cognitive Dysfunction/drug therapy ; Brain/metabolism/drug effects ; }, abstract = {Gut microbiota influence brain inflammation and cognitive impairment by regulating lipid metabolism. The therapeutic efficacy of quercetin (Que) in Alzheimer's disease (AD) treatment is significantly limited by its poor water solubility and short residence time in vivo. Herein, Chitosan (CS) modified selenium nanoparticles was used to prepare a high-loading Pickering emulsion (Que-CS/Se-PE), improving bioaccessibility of Que. Simulated gastrointestinal fluid experiments demonstrate that Que-CS/Se-PE exhibits strong stability under acidic conditions. In vitro digestion studies indicate that Que-CS/Se-PE enables QUE to target intestinal fluids and release slowly. In vivo imaging revealed that the gastrointestinal retention time of Que-CS/Se-PE was up to 48 h. In HFD + D-gal-induced mice, Que-CS/Se-PE treatment reduced serum TC and brain TNF-α levels by 40.8 % and 31.5 %, respectively, indicating substantial improvement in lipid metabolism and neuroinflammation. Behavioral tests showed that Que-CS/Se-PE improved cognitive performance, with preference index elevated by 2.1-fold. Moreover, the relative abundances of Akkermansia, Lactobacillus, and Bacteroidota increased by 2.7-, 17.8-, and 4.7-fold, respectively. In conclusion, Que-CS/Se-PE exhibits interfacial stability, excellent adhesion, and sustained-release properties, significantly prolonging the retention time of quercetin in vivo and enhancing its bioavailability. Furthermore, it modulates lipid metabolism and gut microbiota, and finally ameliorates cognitive impairment in obesity and age-related AD.}, } @article {pmid41476028, year = {2026}, author = {Zhang, W and Liu, H and Zhang, C and Li, Y and Fang, K and Zhou, Y and Weng, L and Fang, L and Luo, Y and Xiao, H and Zhou, L and Jiao, B and Shen, L}, title = {Six-month follow-up of ARIA-H and iron deposition in real-world lecanemab therapy for Alzheimer's disease: Evidence from a Chinese 7T MRI cohort.}, journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association}, volume = {22}, number = {1}, pages = {e71044}, pmid = {41476028}, issn = {1552-5279}, support = {U22A20300 82371434//National Natural Science Foundation of China/ ; 2021ZD0201803//STI2030-Major Projects/ ; 2023YFC3603700//the National Key R&D Program of China/ ; 2024JJ2097//the Outstanding Youth Fund of Hunan Provincial Natural Science Foundation/ ; 2024PT5108//the Scientific Research Program of FuRong Laboratory/ ; SMIDF-150-2025A19//the Brain Health Youth Fund of Shanghai Medical Innovation & Development Foundation/ ; }, mesh = {Humans ; *Alzheimer Disease/drug therapy/diagnostic imaging/metabolism ; *Magnetic Resonance Imaging/methods ; Male ; Female ; *Iron/metabolism ; Aged ; Amyloid beta-Peptides/blood ; Follow-Up Studies ; Biomarkers/blood ; *Brain/diagnostic imaging/metabolism/drug effects ; tau Proteins/blood ; Cohort Studies ; China ; Middle Aged ; Peptide Fragments/blood ; East Asian People ; }, abstract = {INTRODUCTION: With the approval of lecanemab for treating Alzheimer's disease (AD), there is an urgent need to evaluate its safety and treatment effects on biomarkers in real-world practice.

METHODS: Patients receiving lecanemab (n = 72) underwent routine 3T and 7T magnetic resonance imaging (MRI) for amyloid-related imaging abnormality (ARIA) monitoring. Longitudinal changes of iron deposition assessed by quantitative susceptibility mapping (QSM) and its association with plasma biomarkers were further evaluated.

RESULTS: With use of 7T MRI, we identified characteristic perivascular features and detected ARIA with hemorrhages/hemosiderin deposition (ARIA-H) ≈4 months earlier than with 3T. QSM detected post-treatment regional susceptibility reductions. Decreased susceptibility in the temporal, frontal lobes, and the thalamus was associated with plasma amyloid beta 42 (Aβ42) and tau phosphorylated at threonine 217 (p-tau217) changes.

DISCUSSION: 7T MRI provides superior ARIA-H detection and iron dynamics monitoring, supporting its role in risk stratification and therapy assessment for lecanemab-treated patients. Iron deposition measured by QSM may serve as a promising neuroimaging marker for amyloid-targeting treatments.

HIGHLIGHTS: Using 7T magnetic resonance imaging (MRI), this study for the first time visualized amyloid-related imaging abnormality with hemorrhages/hemosiderin deposition (ARIA-H) at a submillimeter resolution, characterized by aggregated, clustered cerebral microbleeds in a perivascular distribution, suggesting overlapping pathology with cerebral amyloid angiopathy. The susceptibility-weighted imaging sequence on 7T MRI enabled detection of ARIA-H up to 4 months earlier. Plasma amyloid beta 42 (Aβ42) and tau phosphorylated at threonine 217 (p-tau 217) levels are sensitive biomarkers for amyloid targeted therapy. Quantitative susceptibility mapping (QSM) analysis demonstrated reduced cortical iron burden post-treatment, which has significant associations with plasma Aβ42 and p-tau 217 levels, highlighting QSM-derived iron quantification as a promising neuroimaging indicator for amyloid-targeted therapeutics.}, } @article {pmid41476179, year = {2025}, author = {Taheri, E and Raeeszadeh-Sarmazdeh, M}, title = {Evaluating the effect of minimal TIMP variants on protecting and transport across the rat brain microvascular cells (RBMEC).}, journal = {Scientific reports}, volume = {16}, number = {1}, pages = {1020}, pmid = {41476179}, issn = {2045-2322}, support = {P30 GM145646/GM/NIGMS NIH HHS/United States ; }, mesh = {Animals ; Rats ; *Blood-Brain Barrier/metabolism/drug effects ; *Endothelial Cells/metabolism/drug effects ; Matrix Metalloproteinase 9/metabolism ; *Brain/blood supply/metabolism ; *Microvessels/cytology/metabolism ; *Tissue Inhibitor of Metalloproteinase-3/metabolism/genetics/pharmacology ; *Tissue Inhibitor of Metalloproteinase-1/metabolism/genetics/pharmacology ; Tight Junctions/metabolism ; *Tissue Inhibitor of Metalloproteinases/metabolism/genetics/pharmacology ; Zonula Occludens-1 Protein/metabolism ; Cells, Cultured ; Biological Transport ; Capillary Permeability ; }, abstract = {Tissue inhibitors of metalloproteinases (TIMPs), endogenous inhibitors of matrix metalloproteinases (MMPs), can be tailored to regulate MMP activity and mitigate the disruptive effects of specific MMPs when dysregulated in diseases. MMPs, especially MMP-9, are major contributors to the degradation of extracellular matrix components, leading to BBB disruption in neurological disorders. The upregulation of MMPs undermines blood-brain barrier (BBB) integrity and drives neuroinflammation. Engineering minimal protein variants offers enhanced modularity, tissue penetration, and BBB permeability. Minimal TIMP variants were engineered, aiming to improve their therapeutic reach across both sides of the BBB, particularly when delivery to the brain is essential. In this study, we assessed the protective effects of mTC1 and mTC3 on BBB integrity using an in vitro model of rat brain microvascular endothelial cells (RBMECs). Barrier function was evaluated following treatment with recombinant MMP-9, either alone or co-treated with native TIMP-1, TIMP-3, or the engineered minimal variants. MMP-9 induced a dose-dependent increase in BBB permeability, reflected by a decrease in trans-endothelial electrical resistance (TEER) and increased paracellular transport of fluorescent tracers. Co-treatment with TIMP-1, TIMP-3, mTC1, or mTC3 significantly attenuated MMP-9-mediated disruption of tight junctions of RBMECs, preserving TEER values and reducing permeability. Immunofluorescence staining for tight junction proteins, ZO-1 and occludin, further validated the preservation of endothelial integrity in the presence of wild-type human TIMPs and engineered TIMP variants. These findings underscore the potential of engineered minimal TIMPs as molecular tools to stabilize the BBB and support their future application in mechanistic studies focused on BBB protection.}, } @article {pmid41476782, year = {2025}, author = {Zhu, Y and Liu, H and He, M and Xu, Z and Sun, L and Wu, Z and Niu, X and Huang, S and Wang, J and Ran, X}, title = {Epidemiology and Risk Factors Characteristics of Alzheimer's Disease in Southwestern China: A Cross-Sectional Study.}, journal = {Clinical interventions in aging}, volume = {20}, number = {}, pages = {2685-2704}, pmid = {41476782}, issn = {1178-1998}, mesh = {Humans ; *Alzheimer Disease/epidemiology ; China/epidemiology ; Female ; Male ; Risk Factors ; Aged ; *Cognitive Dysfunction/epidemiology ; Cross-Sectional Studies ; Aged, 80 and over ; Middle Aged ; Prevalence ; Rural Population ; Sex Factors ; Age Factors ; Educational Status ; Comorbidity ; Logistic Models ; }, abstract = {BACKGROUND: To address the regional heterogeneity of Alzheimer's disease, a large-scale epidemiological study of 12,421 elderly individuals was conducted in southwestern China to depict its unique risk characteristics.

METHODS: A total of 12,421 subjects were selected via cluster sampling from southwestern China after low quality data were filtered out. On the basis of investigations and medical imaging examinations, three groups were distinguished: the AD, mild cognitive impairment (MCI), and normal control groups. The risk factors for AD and MCI were analysed via a multivariate logistic regression model.

RESULTS: This study identifies a high burden of cognitive impairment in southwestern China, with 22.07% of adults aged ≥60 years exhibiting cognitive decline and 5.81% diagnosed with Alzheimer's disease rates surpassing national and global averages. Key risk factors included age >80 years, female sex, low education, rural residence, surgical history, and urological comorbidities. These findings underscore the need for region-specific prevention strategies, prioritizing older, less-educated rural women through combined cognitive and vascular interventions, while integrating cognitive screening into primary care in underserved areas for early detection and intervention.

CONCLUSION: Elderly individuals in southwestern China exhibit a high prevalence of cognitive impairment, with AD associated with complex risk factors including established contributors like advanced age, dementia family history, alcohol abuse, and multisystem comorbidities-while notably identifying surgical history and urolithiasis as region specific risk signals. These findings underscore regional, environmental, and ethnic influences on AD pathogenesis, requiring tailored prevention/treatment. Future priorities include integrating brief cognitive screening into primary care, targeting high-risk groups (eg, undereducated rural elderly women), and establishing prospective cohorts to clarify causal links between urolithiasis, surgical history, and cognitive decline for refined region-adapted AD prevention.}, } @article {pmid41477167, year = {2025}, author = {Garcia, ML and Denton, AR and Jackson, NL and Scofield, MD and McMahon, LL}, title = {Pharmacologically increasing O-GlcNAcylation increases complexity of astrocytes in the dentate gyrus of TgF344-AD rats.}, journal = {Frontiers in aging neuroscience}, volume = {17}, number = {}, pages = {1690410}, pmid = {41477167}, issn = {1663-4365}, abstract = {BACKGROUND: Alzheimer's disease (AD) pathology begins two or three decades prior to the onset of cognitive symptoms and is characterized by amyloid-β (Aβ) and hyperphosphorylated tau (pTau) accumulation, reactive glial cells, increased inflammation, and neuronal degeneration in later stages. Preclinical studies report that increasing the post-translational modification, O-GlcNAcylation, involving the addition of a single N-acetylglucosamine (GlcNAc) moiety to serine or threonine residues, can reduce amyloidogenic processing of amyloid precursor protein (APP) and compete with serine phosphorylation on tau, decreasing hyperphosphorylated tau accumulation. Protein O-GlcNAcylation can have anti-inflammatory effects, suggesting the possibility that increasing O-GlcNAcylation may decrease reactive gliosis and other pathological changes in AD.

METHODS: This study aimed to assess the possible beneficial effects of pharmacologically enhancing O-GlcNAcylation by inhibiting O-GlcNAcase (OGA), the enzyme responsible for the removal of O-GlcNAc moieties, on progressive AD pathology using female TgF344-AD rats. The selective OGA inhibitor thiamet-G [TMG; 10 mg/kg, subcutaneously (s.c.)] was administered three times per week for 3 months starting at 6 months of age, a time point when Aβ pathology is evident in the hippocampus. Western blot analysis was used to measure protein levels of GFAP, Iba-1, and Aβ. Immunohistochemistry and confocal imaging were used to assess Aβ plaques, astrocyte and microglia complexity, and degeneration of tyrosine hydroxylase-positive (TH+) axons.

RESULTS: In TgF344-AD rats, we found significantly increased astrocyte complexity, defined as increased process length and branches, increased numbers of microglia, loss of noradrenergic axons (NA), and significant Aβ plaques compared to WT, confirming previous work by us and others. Notably, pharmacologically increasing O-GlcNAcylation further increased astrocyte complexity in TgF344-AD rats, specifically those located in close proximity to Aβ plaques, while microglia morphology and Aβ staining were unaffected. O-GlcNAcylation was not able to lessen the loss of TH + axons in TgF344-AD rats, although fewer dystrophic axons were observed, suggesting a possible beneficial effect.

DISCUSSION: Our findings demonstrate that increasing O-GlcNAcylation in TgF344-AD rats using a cyclical treatment protocol at a time when Aβ pathology is already significant does not provide broad beneficial effects on Aβ accumulation, microglial reactivity, or noradrenergic axon loss, although there appears to be fewer dystrophic axons. Importantly, increasing O-GlcNAcylation in TgF344-AD rats has dual beneficial effects on astrocyte reactivity. Astrocytes in close proximity to Aβ plaques are more complex with longer processes and more branches compared to those in saline-treated TgF344-AD rats at the same distance, enabling them to surround plaques and protect nearby neurons. Astrocytes located at more distal locations from plaques are less reactive than those at the same distance in saline-treated TgF344-AD rats, permitting a less pathological local environment for nearby neurons. Our findings offer new insights into the possible mechanisms that might contribute to the beneficial therapeutic effects of increasing O-GlcNAcylation during progressive AD pathology.}, } @article {pmid41477168, year = {2025}, author = {Xiao, Y and Li, H and Han, X and Liu, Y and Sun, J and Sun, C and Wang, Y and Ye, T and Cheng, X}, title = {Qi-Fu-Yin ameliorates physiological frailty in male 5xFAD mice through remodeling the gut microbiota and modulating the cerebral cortex metabolism.}, journal = {Frontiers in aging neuroscience}, volume = {17}, number = {}, pages = {1622286}, pmid = {41477168}, issn = {1663-4365}, abstract = {INTRODUCTION: Alzheimer's disease (AD) is a neurodegenerative disease that can only be managed rather than cured, bringing a substantial burden to society. Frailty and cognition are intertwined in a cycle of decline, affecting the prognosis of AD. Qi-Fu-Yin (QFY) is a classic prescription in traditional Chinese medicine for dementia. While most studies have focused on cognitive impairment, research on physiological frailty remains relatively scarce in AD, especially in 5xFAD mice. We aimed to investigate the impacts of QFY on the physiological frailty of male 5xFAD mice.

METHODS: Male 5xFAD mice received QFY, followed by grip strength test, rotarod test, grading score of frailty, lipofuscin staining, SA-β-gal and Aβ co-staining. The metabolite alteration and the intestinal flora composition were analyzed by non-targeted metabolomics and 16S rRNA sequencing. Moreover, Spearman's correlation analysis was used to integrate behavioral results, differentially expressed metabolites, and altered bacterial genera.

RESULTS: We discovered that QFY improved grip strength, riding time, score of frailty, lipofuscin deposition, SA-β-gal, and Aβ in male 5xFAD mice. The results of untargeted metabolomics showed that metabolites such as proline, PS (18:1/18:0), and PFSA-CI were downregulated in the male 5xFAD mice compared with C57BJ/6JXSJL mice, while PE (18:1/18:1) was upregulated. QFY treatment reversed these changes, restoring metabolite levels toward those of C57BJ/6JXSJL mice. Arginine and proline metabolism, alanine, aspartate and glutamate metabolism, and butyrate metabolism were filtered out as the important metabolic pathways between the C57BJ/6JXSJL mice and the male 5xFAD mice, as well as between the 5xFAD mice and the 5xFAD mice with QFY treatment. Moreover, Ruminococcaceae, Subdoligranulum, Bacteroides, Alistipes, Rikenellaceae_RC9_gut_group, and Odoribacter, which were lower in male 5xFAD mice, were improved after QFY intervention.

DISCUSSION: The differential intestinal flora might improve the metabolism of brain tissue as well as muscle strength and coordination through Short-chain fatty acids (SCFAs). The differential metabolites caused by QFY intervention also have an improving effect on physiological frailty. We suggest that QFY exerts protective impacts against the physiological frailty in AD by adjusting the muscle-gut-brain axis.}, } @article {pmid41477525, year = {2025}, author = {Zheng, M and Hong, X and Liao, P and Huang, H and Zhang, Y and Xu, W and Li, H}, title = {Plant-Derived Exosome-Like Nanoparticles: A Promising Therapeutic for Neurological Disorders and Drug Delivery.}, journal = {International journal of nanomedicine}, volume = {20}, number = {}, pages = {15769-15791}, pmid = {41477525}, issn = {1178-2013}, mesh = {Humans ; *Exosomes/chemistry ; *Nanoparticles/chemistry ; Animals ; *Nervous System Diseases/drug therapy ; Blood-Brain Barrier/metabolism ; *Drug Delivery Systems/methods ; *Plants/chemistry ; }, abstract = {Neurological disorders, including ischemic stroke, Alzheimer's disease, and Parkinson's disease, exhibit high incidence rates and pose significant health challenges. Current pharmacological treatments often fail to adequately address clinical needs due to obstacles such as limited penetration of the blood-brain barrier and suboptimal efficacy. Plant-derived exosome-like nanoparticles (PELNs) have emerged as promising therapeutic agents due to their superior biocompatibility, low toxicity, ability to traverse the blood-brain barrier, and abundance of lipids, microRNAs, and other bioactive compounds. This review provides a comprehensive overview of recent advancements in PELNs preparation technologies, elucidates the mechanisms of action of their principal bioactive components, and explores their therapeutic applications across various neurological disorders, thereby offering a theoretical foundation for the development of related treatment strategies. Nonetheless, researches on PELNs continue to encounter significant challenges. At the production level, there is an absence of standardized isolation protocols, and the yields remain inadequate to satisfy clinical requirements. Clinically, the efficacy in humans has yet to be established, and the available safety data are insufficient. Technically, the lack of standardized storage conditions and the susceptibility of biological stability to external factors further complicate the field. This review delineates these challenges to offer insights for advancing both fundamental research and the clinical translation of PELNs.}, } @article {pmid41477735, year = {2026}, author = {Tsai, HR and Lin, YJ and Loh, CH and Lee, YC and Huang, HK}, title = {Risk of Alzheimer Disease and Related Dementia after Retinal Vascular Occlusion: A Nationwide Cohort Analysis.}, journal = {Ophthalmology. Retina}, volume = {10}, number = {2}, pages = {117-127}, doi = {10.1016/j.oret.2025.10.017}, pmid = {41477735}, issn = {2468-6530}, mesh = {Humans ; Male ; Female ; *Alzheimer Disease/epidemiology/etiology ; Taiwan/epidemiology ; Aged ; Risk Factors ; Incidence ; *Retinal Vein Occlusion/complications/epidemiology ; Retrospective Studies ; Follow-Up Studies ; Risk Assessment/methods ; Middle Aged ; *Retinal Artery Occlusion/complications ; Aged, 80 and over ; *Population Surveillance ; *Dementia, Vascular/epidemiology/etiology ; }, abstract = {PURPOSE: To evaluate the risk of developing Alzheimer disease (AD) and related dementia in patients with newly diagnosed retinal vascular occlusion.

DESIGN: A nationwide population-based cohort study using claims data from Taiwan's National Health Insurance Research Database (NHIRD).

PARTICIPANTS AND CONTROLS: A total of 39 540 individuals with diagnoses of retinal vascular occlusion between 2011 and 2019 in Taiwan and 395 400 age- and sex-matched nonretinal vascular occlusion individuals without prior diagnoses of any dementia.

METHODS: Patients with newly diagnosed retinal vascular occlusion were identified in the NHIRD, and baseline characteristics were collected. The study endpoints, including AD, vascular dementia (VD), and all-cause dementia, were determined by ≥2 separate outpatient diagnoses or a single discharge diagnosis. Inverse probability of treatment weighting (IPTW) was applied to balance baseline covariates and control potential confounders. Cox proportional hazards models were used to estimate the hazard ratio (HR) for each outcome.

MAIN OUTCOME MEASURES: Development of AD, VD, and all-cause dementia.

RESULTS: After IPTW, 38 522 patients with retinal vascular occlusion and 395 740 nonretinal vascular occlusion individuals were included. Patients with retinal vascular occlusion had increased risks of AD (HR, 1.57; 95% confidence interval [CI], 1.39-1.80), VD (HR, 1.76; 95% CI, 1.58-1.95), and all-cause dementia (HR, 1.58; 95% CI, 1.50-1.65). Both retinal artery occlusion and retinal vein occlusion were associated with increased risks of AD (HR, 1.59; 95% CI, 1.14-2.23; and HR, 1.58; 95% CI, 1.39-1.80, respectively), VD (HR, 1.79; 95% CI, 1.32-2.43; and HR, 1.77; 95% CI, 1.59-1.98, respectively), and all-cause dementia (HR, 1.62; 95% CI, 1.42-1.86; and HR, 1.58; 95% CI, 1.52-1.67, respectively).

CONCLUSIONS: Patients with retinal vascular occlusion had moderately increased risks of AD and related dementias. Therefore, monitoring for dementia symptoms in patients with retinal vascular occlusion may facilitate earlier detection and intervention.

FINANCIAL DISCLOSURE(S): The authors have no proprietary or commercial interest in any materials discussed in this article.}, } @article {pmid41477911, year = {2026}, author = {Yu, W and Zhuang, D and Wang, K and Qu, Y}, title = {JWX-A1223 attenuates cognitive deficits and tau protein hyperphosphorylation via the Akt/GSK3β pathway in APP/PS1 mice.}, journal = {Archives of physiology and biochemistry}, volume = {}, number = {}, pages = {1-12}, doi = {10.1080/13813455.2025.2610481}, pmid = {41477911}, issn = {1744-4160}, abstract = {BACKGOUND: Alzheimer's disease (AD) is a neurodegenerative disorder marked by cognitive decline, affecting memory, thinking, and behaviour. Its neuropathology includes amyloid plaques and neurofibrillary tangles in the brain.

MATERIALS: Amyloid plaques consist of misfolded beta-amyloid protein, while tangles are made of hyperphosphorylated tau protein.

METHOD: After treatment with JWX-A1223, the APP/PS1 mice showed significant cognitive improvement in the Morris water maze test. They had shorter escape latency, reduced swimming distance, and longer stay time in the target quadrant, indicating enhanced spatial learning and memory.

RESULTS: The treatment with JWX-A1223 also significantly reduced the phosphorylation levels of tau protein at Ser202, Ser396 and Ser404 sites in the cerebral cortex and hippocampus of mice, while increasing the phosphorylation levels at Ser473 site of Akt and Ser9 site of GSK3β.

CONSLUSION: It indicates that by regulating the activity of the Akt/GSK3β pathway, it alleviates the excessive phosphorylation of tau protein and thereby improves cognitive impairment.}, } @article {pmid41477991, year = {2026}, author = {Hu, H and Cheng, Q and Li, D and Li, Y and Li, X and Chen, Y and Guo, Y and Tian, S and Jiang, Y and Chen, Y and Liu, Y and Li, S}, title = {Ponicidin ameliorates Alzheimer's disease through dual inhibition of RIPK1-mediated neuroinflammation and necroptosis.}, journal = {International immunopharmacology}, volume = {171}, number = {}, pages = {116095}, doi = {10.1016/j.intimp.2025.116095}, pmid = {41477991}, issn = {1878-1705}, mesh = {Animals ; *Receptor-Interacting Protein Serine-Threonine Kinases/metabolism/antagonists & inhibitors ; *Alzheimer Disease/drug therapy/metabolism ; Necroptosis/drug effects ; Mice ; Mice, Transgenic ; Disease Models, Animal ; Cell Line ; Microglia/drug effects ; Humans ; *Anti-Inflammatory Agents/pharmacology/therapeutic use ; *Neuroinflammatory Diseases/drug therapy ; Neurons/drug effects ; Male ; Mice, Inbred C57BL ; *Neuroprotective Agents/pharmacology/therapeutic use ; }, abstract = {Ponicidin (Pon), a diterpenoid isolated from Rabdosia rubescens, exhibits a broad range of pharmacological activities, including anti-inflammatory effects. However, its therapeutic potential in Alzheimer's disease (AD), particularly in modulating receptor-interacting protein kinase 1 (RIPK1)-mediated neuroinflammation and necroptosis, remains underexplored. This study aims to investigate the mechanism through which Pon targets RIPK1 to alleviate AD pathogenesis. The interaction between Pon and RIPK1 was confirmed using bio-layer interferometry (BLI) and drug affinity responsive target stability (DARTS) assays. In vitro, the effects of Pon on inflammatory responses and necroptosis were evaluated in BV2 microglial cells (BV2 cells) and HT22 hippocampal neuronal cells (HT22 cells) using Enzyme-linked immunosorbent assay (ELISA), Reverse transcription quantitative real-time polymerase chain reaction (RT-qPCR), Western blotting (WB), and flow cytometry. In vivo, Pon's therapeutic efficacy was assessed in the 5 × FAD transgenic mouse model of AD through behavioral tests, histological analysis, and biochemical assays. Pon was found to bind RIPK1 with high affinity (KD = 135 nM) and enhance RIPK1's resistance to proteolytic degradation. In microglial cells, Pon effectively inhibited the release of pro-inflammatory cytokines interleukin-6 (IL-6) and tumor necrosis factor alpha (TNF-α) by disrupting the RIPK1-janus kinase 1 (JAK1)-signal transducer and activator of transcription 1 (STAT1) signaling pathway. In neurons, Pon suppressed RIPK1-mediated necroptosis by blocking the RIPK1-RIPK3-mixed lineage kinase domain-like protein (MLKL) cascade. Behavioral analysis of 5 × FAD mice revealed that Pon treatment significantly improved cognitive function, reduced amyloid-beta (Aβ) plaque deposition, and alleviated neuroinflammation and necroptosis in the brain. Pon exerts dual neuroprotective effects by targeting RIPK1, mitigating both neuroinflammation and necroptosis, two critical pathological processes in AD. These findings underscore Pon's potential as a disease-modifying therapy for AD and provide a foundation for the clinical development of natural product-derived RIPK1 inhibitors in neurodegenerative diseases.}, } @article {pmid41478424, year = {2026}, author = {Zhang, Y and Chen, L and Jin, J and Xin, Y and Wang, J and Zhang, A}, title = {Therapeutic application of fecal microbiota transplantation for neurological diseases: Exploring novel mechanisms and perspectives.}, journal = {Experimental neurology}, volume = {398}, number = {}, pages = {115631}, doi = {10.1016/j.expneurol.2025.115631}, pmid = {41478424}, issn = {1090-2430}, mesh = {Humans ; *Fecal Microbiota Transplantation/methods/trends ; *Nervous System Diseases/therapy ; *Gastrointestinal Microbiome/physiology ; Animals ; }, abstract = {Recently, fecal microbiota transplantation (FMT) has garnered widespread attention as an emerging therapeutic approach in the field of neurological disorders. In this study, we review the research progress of FMT in treating neurological disorders. First, the development, safety, and efficacy of FMT are introduced. Subsequently, the application and potential mechanisms of FMT in neurodegenerative diseases (such as Parkinson's disease and Alzheimer's disease), neurodevelopmental disorders (such as autism spectrum disorder and attention deficit hyperactivity disorder), and other neurological conditions are elaborated in detail. Particularly, we explore the pivotal role of the microbiota-gut-brain axis in FMT for treating neurological disorders, as well as how FMT influences neurological function by regulating the gut microbiota and its metabolites, immune system and inflammatory responses, and neurotransmitters. However, FMT also faces numerous challenges in the treatment of neurological disorders, such as ethical issues, safety concerns, and standardization problems. Therefore, this review also prospects the future development directions of FMT in the treatment of neurological diseases, including personalized therapy and combination therapies. FMT may be a feasible and promising option for treating various neurological disorders, but a comprehensive understanding of its working principles and continuous improvement of its application in clinical practice are still ongoing.}, } @article {pmid41478465, year = {2026}, author = {Bandarupalli, T and Noonan, C and Hansen, K and Weaver, R and Baumann, K and Banks, WA and Erickson, MA and Rhea, EM}, title = {Acute peripheral versus central inhibition of insulin receptors differentially alters cytokine and blood-brain barrier responses to an inflammatory stimulus.}, journal = {Brain, behavior, and immunity}, volume = {133}, number = {}, pages = {106251}, doi = {10.1016/j.bbi.2025.106251}, pmid = {41478465}, issn = {1090-2139}, mesh = {Animals ; *Blood-Brain Barrier/metabolism/drug effects ; Male ; Mice ; *Receptor, Insulin/antagonists & inhibitors/metabolism ; *Cytokines/metabolism ; *Inflammation/metabolism ; Lipopolysaccharides/pharmacology ; Insulin Resistance/physiology ; Brain/metabolism/drug effects ; Insulin/metabolism ; Peptides ; }, abstract = {The blood-brain barrier (BBB)'s role in protecting the brain from exposure to harmful circulating factors has led to its disruption being implicated in neurodegenerative diseases such as vascular dementia and Alzheimer's disease. Insulin resistance, defined by an impaired response to insulin, is a common feature of metabolic disorders and neurodegenerative diseases. Importantly, individuals can possess peripheral insulin resistance independent of central insulin resistance and vice versa. States of insulin resistance, like diabetes mellitus for peripheral insulin resistance and Alzheimer's disease for central insulin resistance, are associated with inflammation and BBB disruption. However, the contributions of acute impairment of insulin receptor signaling solely in the periphery versus the brain to inflammation and BBB disruption are not clear. As central vs peripheral insulin resistance could have different effects on inflammation, we characterized the effects of acute central versus peripheral insulin receptor inhibition with or without an inflammatory insult, using lipopolysaccharide (LPS) as a prototypic immune stimulus. Male CD-1 mice were treated with an insulin receptor antagonist (S961), peripherally (intraperitoneal) or centrally (intranasal). This treatment was then followed by an intraperitoneal administration of either saline or LPS 30 min later, at a single 3 mg/kg dose known to cause inflammation and BBB disruption. Assays of BBB disruption and brain and serum collection were done 28 h after the injections. Metabolic hormones, cytokines, and the acute phase protein serum amyloid a (SAA) were then measured in serum and brain homogenates. In the absence of LPS, central S961 reduced serum hormones including ghrelin, gastric inhibitory peptide (GIP), and glucagon. Peripheral S961 significantly increased many cytokines in both brain and blood, whereas central S961 decreased serum SAA and increased a few cytokines. BBB integrity was not affected by S961 alone, but central S961 decreased LPS-induced BBB disruption and also lowered serum levels of SAA. These findings highlight the differential effects of peripheral versus central insulin receptor inhibition on cytokine responses and BBB integrity in the presence and absence of acute inflammation, elucidating differences in the molecular mechanisms for insulin receptor signaling depending on the location of signaling dysfunction. The results suggest a potential neuroprotective role of acute central insulin inhibition during acute inflammation.}, } @article {pmid41478541, year = {2026}, author = {Zafar, I and Khan, MS and Jamal, A and Shafiq, S and Bahwerth, FS and Khan, NU}, title = {Precision therapeutic strategies for Alzheimer's disease: Amyloid β-targeted foundations and multimodal next-generation approaches.}, journal = {Molecular and cellular neurosciences}, volume = {136}, number = {}, pages = {104070}, doi = {10.1016/j.mcn.2025.104070}, pmid = {41478541}, issn = {1095-9327}, mesh = {*Alzheimer Disease/metabolism/drug therapy/therapy ; Humans ; *Amyloid beta-Peptides/metabolism ; Animals ; *Precision Medicine/methods ; Blood-Brain Barrier/metabolism ; }, abstract = {Alzheimer's disease (AD) is the leading cause of dementia and a significant unmet medical challenge, pathologically characterized by amyloid β (Aβ) aggregation, tau hyperphosphorylation, synaptic dysfunction, and chronic neuroinflammation. Although Aβ has long been a central therapeutic target, clinical translation has historically been hindered by late-stage intervention, inadequate blood-brain barrier (BBB) penetration, and the molecular heterogeneity of AD. Recent advances with Aβ-targeted monoclonal antibodies, particularly lecanemab and donanemab, have provided the first clinical evidence of disease modification, demonstrating robust amyloid clearance and measurable slowing of cognitive decline in early-stage AD. These results validate the Aβ hypothesis but also highlight persistent barriers, including amyloid-related imaging abnormalities (ARIA), questions about the durability of benefit, challenges in patient stratification, and the high economic burden of biologics. To overcome these limitations, next-generation strategies are emerging that extend beyond single-pathway targeting toward multimodal and precision-based frameworks. Innovative approaches include tau-directed therapies to prevent the propagation of neurofibrillary tangles, immunomodulatory strategies to enhance microglial clearance of aggregated proteins, and neuroprotective interventions to counteract oxidative and inflammatory stress. Concurrently, nanotechnology-based drug delivery systems are being engineered to efficiently traverse the BBB and deliver multifunctional payloads, while artificial intelligence (AI)- driven discovery platforms are accelerating target identification, biomarker integration, and patient stratification. Future perspectives emphasize the importance of preclinical-stage intervention, long-term efficacy trials, and the adoption of personalised treatment paradigms that integrate genomic, biomarker, and digital profiling to optimise outcomes. Collectively, these advances signal a paradigm shift in AD therapeutics, positioning Aβ-targeted therapies as a foundation while paving the way for combination strategies that more effectively address the disease's multifactorial nature.}, } @article {pmid41478817, year = {2026}, author = {Qi, L and Zheng, F and Tu, M and Abdullah, R and Zhao, Y and Su, X and Zhou, D and Peng, G}, title = {Safety profiles of lecanemab: A systematic review and meta-analysis of randomized controlled trials and real-world evidence.}, journal = {The journal of prevention of Alzheimer's disease}, volume = {13}, number = {3}, pages = {100473}, pmid = {41478817}, issn = {2426-0266}, mesh = {Humans ; Randomized Controlled Trials as Topic ; *Alzheimer Disease/drug therapy ; *Antibodies, Monoclonal, Humanized/adverse effects/therapeutic use ; Amyloid beta-Peptides ; }, abstract = {BACKGROUND: Safety profiles of lecanemab, an anti-amyloid-β antibody for the treatment of early Alzheimer's disease (AD), remain uncertain and may vary between randomized controlled trials (RCTs) and real-world evidence (RWE) studies.

OBJECTIVES: This systematic review and meta-analysis aimed to evaluate the safety, tolerability, and acceptability of lecanemab based on findings from both RCTs and emerging RWE studies.

METHODS: We systematically searched major databases and clinical trial registries from their inception to June 2025. Random-effects meta-analyses were performed to estimate the pooled incidence of key safety outcomes, including amyloid-related imaging abnormalities (ARIA), infusion-related reactions (IRRs), and treatment discontinuation (due to ARIA, adverse events [AEs], or any cause). The risk of ARIA according to the ApoE4 genotype was assessed via relative risk (RR). This study was registered with PROSPERO (No. CRD420251110679).

RESULTS: A total of two RCTs and five RWE studies encompassing 1576 patients were included. The pooled ARIA incidence was 19% (95% CI: 16%-23%), which was significantly modulated by ApoE4 status (RR 1.45 for heterozygotes, 3.54 for homozygotes vs noncarriers) and the pooled symptomatic ARIA incidence was 3% (95% CI: 2%-4%). IRRs occurred in 26% (95% CI: 19%-34%), with heterogeneity reduced in patients receiving specific pre-infusion prophylaxis. The pooled rate of discontinuation due to AEs was 8% (95% CI: 5%-11%), with discontinuation due to ARIA occurring in 5% (95% CI: 3%-7%) of patients in RWE studies.

CONCLUSIONS: Lecanemab-related ARIA demonstrates a clear ApoE4 gene-dose effect, supporting routine ApoE4 genotyping before treatment. Standardizing pre-infusion prophylaxis may reduce variability in IRRs incidence, while prompt recognition and management of ARIA are critical for improving treatment tolerability. These findings provide important evidence to support the safe clinical use of lecanemab.}, } @article {pmid41478818, year = {2026}, author = {Mummery, CJ and Li-Hsian, CC and Lasagna-Reeves, CA and Ossenkoppele, R and Rowe, CC and Scharre, DW and Wang, H and Kyaga, S and Cummings, JL}, title = {Tau in Alzheimer's disease: Shaping the future patient journey.}, journal = {The journal of prevention of Alzheimer's disease}, volume = {13}, number = {2}, pages = {100447}, pmid = {41478818}, issn = {2426-0266}, support = {P20 GM109025/GM/NIGMS NIH HHS/United States ; R35 AG071476/AG/NIA NIH HHS/United States ; }, mesh = {Humans ; *Alzheimer Disease/metabolism/drug therapy/diagnosis ; *tau Proteins/metabolism ; Biomarkers/metabolism ; }, abstract = {Alzheimer's disease is a complex and multifactorial disease characterized by two key pathological hallmarks: amyloid-beta plaques and tau neurofibrillary tangles. Recent progress has led to the development and approval of disease-targeted therapies for Alzheimer's disease in the form of anti-amyloid-beta monoclonal antibodies. However, findings suggest that amelioration of multiple pathological drivers may be required to maximize clinical effect. An increasing body of evidence suggests that tau is a critical player in Alzheimer's disease pathophysiology, contributing significantly to neurodegeneration and cognitive decline. There are now several tau-targeting drugs in clinical development. In this review, we build on research and advancements in the field of tau to envision how an increasing focus on tau could shape the future Alzheimer's disease patient journey. We highlight the potential of tau as both a promising therapeutic target and a valuable biomarker, with the potential to inform treatment decisions and provide insight into disease trajectories. We also consider what a greater focus on tau may bring to an already evolving patient care pathway characterized by an increased influx of patients presenting earlier in the disease continuum, changes in workflow and infrastructural requirements, and increased complexity in treatment decision-making, treatment administration, treatment monitoring, and patient tracking. This review underscores the critical changes that may be required and knowledge gaps to be elucidated to ensure healthcare system preparedness for additional classes of disease-targeted therapy to move toward a next-generation, individualized treatment approach to Alzheimer's disease diagnosis and care.}, } @article {pmid41478820, year = {2026}, author = {Wang, P and Wu, X and Sun, F and Zhang, H and Jiang, Y and Wang, Q and Ding, H and Zhou, Y and Liu, F and Liu, H}, title = {Multi-omics integration reveals shared genetic architecture between metabolic markers and gray matter atrophy in Alzheimer's Disease.}, journal = {The journal of prevention of Alzheimer's disease}, volume = {13}, number = {2}, pages = {100452}, pmid = {41478820}, issn = {2426-0266}, mesh = {Humans ; *Alzheimer Disease/genetics/pathology/metabolism/diagnostic imaging ; *Gray Matter/pathology/diagnostic imaging/metabolism ; Genome-Wide Association Study ; Atrophy/genetics/pathology ; Neuroimaging ; Biomarkers/metabolism ; Brain/pathology/diagnostic imaging/metabolism ; Glucose/metabolism ; Multiomics ; }, abstract = {BACKGROUND: Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by widespread gray matter volume (GMV) reductions. Emerging evidence links glucose and lipid metabolic dysregulation to AD pathophysiology. However, the extent to which AD-related GMV alterations and metabolic traits share a common genetic basis remains poorly understood.

OBJECTIVES: To explore the shared genetic architecture between GMV alterations in AD and metabolites related to glucose and lipid metabolism, aiming to provide biological insights into the prevention and treatment of AD.

DESIGN: This is a multimodal, cross-disciplinary study combining neuroimaging meta-analysis, transcriptome-neuroimaging association analysis, conjunctional false discovery rate (conjFDR) analysis, and functional enrichment analysis to identify the shared genetic architecture between AD-related brain structural alterations and metabolic traits.

SETTING: Public databases and European populations.

PARTICIPANTS: The meta-analysis included 49 studies (1945 CE patients and 2598 controls). The largest genome-wide association study (GWAS) summary statistics were used for AD (Ncase = 39,918; Ncontrol =358,140), two glycemic traits-glucose (GLU, N = 459,772) and glycated hemoglobin (HbA1c, N = 146,864), and three lipid traits (N = 1320,016)-high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), and triglycerides (TG).

MEASUREMENTS: We conducted a voxel-based morphometric meta-analysis of GMV in AD by systematically reviewing 49 neuroimaging studies, identified through a literature search in PubMed and Web of Science using a predefined search strategy. Building upon these neuroanatomical findings, we performed a transcriptome-neuroimaging association analysis using data from the Allen Human Brain Atlas to identify genes spatially correlated with GMV alterations. To further explore the shared genetic architecture, we integrated GWAS summary statistics for AD and five metabolic markers using conjFDR analysis. Finally, functional enrichment analyses were performed to elucidate the biological relevance of the identified genes through this integrative framework.

RESULTS: Consistent GMV reductions in AD were observed in the bilateral middle temporal gyrus, right superior temporal gyrus, and other key subcortical regions. The conjFDR analysis identified 20, 17, 78, 87, and 82 genes shared between AD-related GMV reductions and GLU, HbA1c, HDL-C, LDL-C, and TG, respectively. Notably, 6 genes were shared across all five metabolic markers. Enrichment analysis implicated these genes in biological processes related to Aβ aggregation and phosphatidylinositol metabolism.

CONCLUSIONS: This study reveals a convergent genetic architecture underlying AD-related GMV atrophy and metabolic dysfunction. These findings may offer novel insights into the molecular interplay between systemic metabolism and neurodegeneration in AD and highlight potential targets for therapeutic strategies.}, } @article {pmid41478829, year = {2026}, author = {Meade, J and Mesa, H and Alamgir, S and Bieniecka, I and Liu, L and Zhang, Q}, title = {Synaptic toxicity of OGA inhibitors and the failure of ceperognastat.}, journal = {The journal of prevention of Alzheimer's disease}, volume = {13}, number = {2}, pages = {100456}, pmid = {41478829}, issn = {2426-0266}, mesh = {Animals ; *Hippocampus/drug effects/metabolism ; *Synapses/drug effects ; Mice ; Male ; Neuronal Plasticity/drug effects ; tau Proteins/metabolism ; Mice, Inbred C57BL ; *Enzyme Inhibitors/toxicity/pharmacology ; Phosphorylation/drug effects ; }, abstract = {O-GlcNAcase inhibitors (OGAi) have emerged as a promising therapeutic strategy in Alzheimer's disease (AD) by enhancing O-GlcNAcylation, which competes with tau phosphorylation and reduces tau aggregation. However, the Phase II clinical trial failure of ceperognastat, marked by accelerated cognitive decline in the treatment group, has raised significant safety concerns. Here, we examined the acute synaptic effects of three structurally distinct OGAi compounds-ceperognastat, ASN90, and MK8719-in mouse hippocampal slices. Electrophysiological recordings revealed suppression of both short- and long-term synaptic plasticity, including paired-pulse facilitation/depression and long-term potentiation. Immunohistochemical analysis confirmed disrupted synaptic protein levels (increased PSD-95, reduced Synaptophysin 1) and a biphasic shift in tau phosphorylation. These convergent findings suggest a class-wide synaptotoxic mechanism and call for a great caution in the development of disease-modifying therapies in AD. We argue that preclinical drug screening for synaptic functionality is essential in CNS-targeted therapeutic pipelines.}, } @article {pmid41479956, year = {2025}, author = {Massara, M and Vedovelli, L and Masina, F and M J Edelstyn, N and Silvia Bisiacchi, P and Di Rosa, E}, title = {From cigarettes to compulsions: a longitudinal study in de novo Parkinson's disease.}, journal = {Frontiers in psychology}, volume = {16}, number = {}, pages = {1708535}, pmid = {41479956}, issn = {1664-1078}, abstract = {INTRODUCTION: Parkinson's disease (PD) is the second most common neurodegenerative disorder after Alzheimer's disease. Among the environmental and lifestyle factors associated with disease onset, cigarette smoking represents one of the most paradoxical. While substantial evidence has demonstrated a protective effect of smoking against the development of PD, smoking appears to worsen symptomatology, particularly by exacerbating impulsive-compulsive behaviors (ICBs) in people with PD (PwPD). However, longitudinal studies examining the effects of cigarette smoking on the progression of PD remain limited. Moreover, recent studies often involve mixed samples of treated and untreated PwPD, potentially confounding the impact of dopamine replacement therapy with that of smoking on ICBs.

METHODS: In the present study, we investigated a cohort of de novo PwPD, tracking their motor, cognitive, affective, and behavioral outcomes over 5 years, to better clarify the role of smoking in disease progression. Data were obtained from the Parkinson's Progression Markers Initiative and included 166 PwPD (119 non-smokers and 47 former smokers) and 79 healthy controls (48 non-smokers and 31 former smokers).

RESULTS: Our results revealed that a significantly higher percentage of former-smoker PwPD (28%) exhibited at least one ICB compared to non-smoker PwPD (13%; Pearson's [2](1) = 5.45, p = 0.02). No other significant differences between non-smokers and former smokers emerged in motor or non-motor symptoms, either in PwPD or in healthy individuals.

DISCUSSION: In conclusion, the novelty of our findings lies in showing that smoking-related influences on impulsive-compulsive behaviors in PD are most evident at the de novo stage, before any dopaminergic treatment. This temporal specificity may help resolve previous inconsistencies in the literature and underscores the importance of distinguishing between environmental and pharmacological effects on symptom development.}, } @article {pmid41480410, year = {2026}, author = {Tang, S and Luo, W and Wu, S and Yuan, M and Wen, J and Zhong, G and Shen, L and Jiang, W and Cheng, C and Wu, X and Xiao, X}, title = {Hippocampus-targeted BDNF gene therapy to rescue cognitive impairments of Alzheimer's disease in multiple mouse models.}, journal = {Genes & diseases}, volume = {13}, number = {2}, pages = {101649}, pmid = {41480410}, issn = {2352-3042}, abstract = {Brain-derived neurotrophic factor (BDNF) can protect neurons from apoptosis and maintain normal synaptic structures, indicating a significant potential for Alzheimer's disease (AD) treatment. However, the method of in vivo BDNF delivery requires further optimization, and the therapeutic efficacy of BDNF in AD animal models needs to be further evaluated. Here, we demonstrated that a newly engineered adeno-associated virus (AAV) serotype termed AAVT42 showed better tropism for neurons than AAV9 in the central nervous system (CNS). We analyzed the therapeutic potentials of AAVT42-delivered BDNF in three AD mouse models: amyloid precursor protein/presenilin-1 (APP/PS1), rTg4510, and 3 × Tg. Long-term BDNF expression in the hippocampus mitigated neuronal degeneration or loss in these AD mice, and alleviated their cognitive impairment, with no discernible effect on amyloid-β deposition or tau phosphorylation. Furthermore, transcriptomic analysis in 3 × Tg mice revealed that BDNF orchestrated the up-regulation of genes associated with neuronal structural organization and synaptic transmissions, such as Neuropeptide Y (Npy), Corticotropin-releasing hormone (Crh), Tachykinin precursor 1 (Tac1), and the down-regulation of Bone morphogenetic proteins (Bmps). Our study highlighted the efficacy of AAVT42 in gene delivery to CNS and validated the therapeutic benefits of BDNF in treating AD, which will be useful for future translational research on AD treatment using an AAV delivery system.}, } @article {pmid41480618, year = {2025}, author = {Hu, G and Gogzheyan, C and Panja, S and Sil, S and Gendelman, HE}, title = {Extracellular vesicle-based therapies for neurodegenerative diseases.}, journal = {NeuroImmune pharmacology and therapeutics}, volume = {4}, number = {4}, pages = {377-390}, pmid = {41480618}, issn = {2750-6665}, support = {R01 MH121402/MH/NIMH NIH HHS/United States ; R01 NS034239/NS/NINDS NIH HHS/United States ; }, abstract = {Extracellular vesicles (EVs) are mediators of neurodegeneration and emerging therapeutic tools for central nervous system disorders. On the one hand, they help spread beta amyloid, tau, α-synuclein, TDP-43, and mutant SOD1, contributing to the signs and symptoms of Alzheimer's, Parkinson's, Amyotrophic lateral sclerosis, and Huntington's Diseases. By activating glial cells, they promote chronic neuroinflammation through carrying cytokines, inflammasomes, and chemokines. On the other hand, EVs' ability to transport neuroregulatory products and cross the blood-brain barrier makes them ideal vehicles for drug delivery. Their function can be surface-modified to deliver targeted therapies, including anti-inflammatory and neuroprotective regulatory RNAs, proteins, and lipids, as well as factors that help maintain neural homeostasis. Notably, we suggest that colostrum-derived EVs, enriched with growth factors and immune-regulatory microRNAs, offer a natural, scalable, and biocompatible source for neuroprotective treatment. Although EVs can act as "Janus-faced" entities - serving both as disease initiators and versatile therapeutic vehicles - controlling their activity can enable immune-based therapeutics for neurodegenerative diseases.}, } @article {pmid41481312, year = {2026}, author = {Banik, A and Amaradhi, R and Sau, M and Rawat, V and Dingledine, R and Ganesh, T}, title = {Antagonism of the EP2 Receptor Reveals Sex-Specific Protection in a Two-Hit Mouse Model of Alzheimer's Disease.}, journal = {ACS chemical neuroscience}, volume = {17}, number = {2}, pages = {392-403}, pmid = {41481312}, issn = {1948-7193}, support = {U01 AG052460/AG/NIA NIH HHS/United States ; U01 AG088113/AG/NIA NIH HHS/United States ; UG3 NS127386/NS/NINDS NIH HHS/United States ; UH3 NS127386/NS/NINDS NIH HHS/United States ; }, mesh = {Animals ; *Alzheimer Disease/metabolism/drug therapy ; *Receptors, Prostaglandin E, EP2 Subtype/antagonists & inhibitors/metabolism ; Mice ; Male ; Disease Models, Animal ; Female ; Mice, Transgenic ; Brain/drug effects/metabolism ; Maze Learning/drug effects ; Sex Characteristics ; Microglia/drug effects/metabolism ; }, abstract = {Neuroinflammation is evident in Alzheimer's disease (AD) brains, exacerbating the pathology and ensuing cognitive deficits in patients. The prostaglandin-E2 receptor EP2 emerged as a neuroinflammatory target in several neurodegenerative diseases, including AD. Antagonism of EP2 mitigates neuroinflammation and cognitive deficits in status epilepticus and stroke models. Here, we investigated the efficacy of a potent and selective EP2 antagonist TG11-77.HCl on the cognitive behavior and neuroinflammation in a two-hit 5xFAD mouse model of AD. We exposed adult 5xFAD mice on B6SJL genetic background and their nontransgenic littermates to a low dose of lipopolysaccharide and administered TG11-77.HCl or the vehicle in the drinking water for 12 weeks. Mice were subjected to Morris water maze and Y-maze testing during their last week of drug treatment. Blood samples were subjected to complete blood count (CBC) analysis and brain tissues were processed to examine the levels of inflammatory transcripts and glial marker expression (mRNA), followed by the quantification of congophilic amyloid deposition and microglial activation (IBA[+]) in the brain by immunohistochemistry. TG11-77.HCl treatment enhanced the spatial memory performance and ameliorated mRNA expression of proinflammatory mediators, chemokines, and cytokines in the neocortex of 5xFAD males only and attenuated astroglia and microglia activation in both male and female 5xFAD mice and the congophilic amyloid load in 5xFAD males only. CBC analysis revealed no changes in peripheral inflammation, irrespective of sex, on treatment with TG11-77.HCl. This study reveals sex-specific protection of selective EP2 antagonism in a two-hit mouse model of AD and supports a prudent therapeutic strategy against neuroinflammation and associated cognitive impairment in AD.}, } @article {pmid41481335, year = {2026}, author = {Noreen, S and Nazir, R and Khan, M and Shah, SA}, title = {Schiff Base Complex rescues mice against scopolamine-induced cognitive dysfunction.}, journal = {Drug and chemical toxicology}, volume = {}, number = {}, pages = {1-11}, doi = {10.1080/01480545.2025.2606103}, pmid = {41481335}, issn = {1525-6014}, abstract = {Alzheimer's disease (AD) is a common and debilitating neurodegenerative disease characterized by progressive cognitive impairment, and oxidative stress is a recognized contributor. Despite numerous studies, effective treatments remain scarce. This study synthesized and assessed the neuroprotective effects of a Schiff base complex, Copper(II) 4-(benzylideneamino)-3-hydroxynaphthalene-1-sulfonic acid [Cu(BAHN)2], against scopolamine-induced (SCOP) cognitive and synaptic deficits in adult albino mice. Eight-week-old male BALB/c mice were randomly split into 4 groups: (1) controls (normal saline, 0.9%), (2) SCOP (1 mg/kg), (3) SCOP and Schiff base complex (30 mg/kg) and (4) Schiff base complex alone (30 mg/kg). Cognitive function was assessed using the Morris Water Maze (MWM) and Y-maze test. To assess the biochemical effects of the complex, antioxidant enzyme activities, and western blot analyses were performed. Treatment with the Schiff base complex significantly restored the activity of important antioxidant enzymes-catalase (CAT), peroxidase (POD), superoxide dismutase (SOD) and reduced glutathione (GSH) which were decreased by SCOP exposure. In addition, lipid peroxidation (LPO) rates were decreased. The complex also counteracted SCOP-induced decreases in both pre- and post-synaptic proteins, in line with improved behavioral performance in both cognitive challenges. Mechanistically, the compound activated phosphorylated Akt (p-Akt) and upregulated Nrf2 signaling, as well as downregulating nuclear factor kappa B (NF-kB) and interleukin-1β (IL-1β), show a decrease in neuroinflammation. In summary, these data suggest that the Schiff base complex reduces the oxidative, inflammatory, and synaptic deleterious effects of SCOP, probably, by regulating the p-Akt/Nrf2 pathway. Additional mechanistic studies are needed to understand its potential therapeutic implications in dementia.}, } @article {pmid41481960, year = {2026}, author = {Fazal, F and Dar, NJ and Ahamad, S and Khan, S and Bano, N and Saha, S and Nazir, A and Bhat, SA}, title = {cGAS-STING signaling in Alzheimer's disease: Microglial mechanisms and therapeutic opportunities.}, journal = {Molecular aspects of medicine}, volume = {107}, number = {}, pages = {101444}, doi = {10.1016/j.mam.2025.101444}, pmid = {41481960}, issn = {1872-9452}, mesh = {Humans ; *Alzheimer Disease/metabolism/drug therapy/pathology/etiology ; *Nucleotidyltransferases/metabolism ; *Membrane Proteins/metabolism ; *Signal Transduction/drug effects ; *Microglia/metabolism/pathology/drug effects ; Animals ; STING Protein ; Cyclic Guanosine Monophosphate-Adenosine Monophosphate Synthase ; }, abstract = {Alzheimer's disease (AD) is increasingly recognized as a neuroinflammatory disorder driven by microglial dysfunction. The cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway plays a critical role in neuroinflammation and has been strongly implicated in the pathology of AD. Chronic activation of cGAS-STING contributes to neurodegeneration by driving persistent type I interferon release and excessive pro-inflammatory cytokine production. However, the pathway exhibits context-dependent effects. Transient activation promotes antiviral defense, autophagy, and cellular quality control in the central nervous system. Sustained engagement exacerbates neuroinflammation and synaptic loss. Preclinical studies demonstrate that pharmacological inhibitors (such as NR, TSG, H-151, TDI-6750, TDI-8246) mitigate amyloid beta and tau pathology, attenuate microglial reactivity, and enhance cognitive outcomes. Yet, its essential physiological roles, including antimicrobial immunity and autophagy regulation, pose challenges for therapeutic targeting. This potentially disrupts neuroimmune homeostasis. In this review, we highlight the role of cGAS-STING in AD and explore its potential as a therapeutic target using small-molecule drug candidates. Despite these promising findings, challenges remain, including optimizing blood-brain barrier (BBB) penetration, ensuring immune specificity, and addressing long-term safety concerns. Due to these challenges, no cGAS-STING inhibitors have entered clinical trials for AD. However, the future of AD treatment may involve modulation of neuroinflammatory pathways, with cGAS-STING inhibitors playing a central role in reshaping neuroimmune homeostasis.}, } @article {pmid41482107, year = {2026}, author = {Chen, X and Yao, H and Ma, S and Zhu, H and Xu, Y and Zhu, Y and Ying, Y and Wang, L and Zhang, Q and Zheng, C and Zhou, Y and Tong, Z and Huang, K and Shentu, Y}, title = {FGF22/FGFR2/YAP modulates ferroptosis to suppress neurodegeneration and cognitive impairment in Alzheimer's disease.}, journal = {Experimental neurology}, volume = {398}, number = {}, pages = {115630}, doi = {10.1016/j.expneurol.2025.115630}, pmid = {41482107}, issn = {1090-2430}, mesh = {Animals ; *Alzheimer Disease/metabolism/pathology/drug therapy ; *Receptor, Fibroblast Growth Factor, Type 2/metabolism ; *Ferroptosis/drug effects/physiology ; Mice ; YAP-Signaling Proteins ; *Cognitive Dysfunction/metabolism/drug therapy/pathology ; *Adaptor Proteins, Signal Transducing/metabolism ; *Fibroblast Growth Factors/pharmacology/therapeutic use/metabolism ; Male ; Cell Cycle Proteins ; Mice, Transgenic ; Amyloid beta-Peptides/toxicity ; Mice, Inbred C57BL ; Signal Transduction/drug effects ; Humans ; Peptide Fragments ; }, abstract = {Ferroptosis, a programmed cell death triggered by iron accumulation and lipid peroxidation, has been increasingly recognized as a critical mechanism underlying neurodegenerative processes, including Alzheimer's disease (AD). The mechanosensitive regulator YAP is implicated in AD progression and ferroptosis. Here we confirmed that FGF22, a fibroblast growth factor, amelitorated cognitive deficits in β-Amyloid (1-42) (Aβ1-42) treated AD model mice through the FGFR2/YAP pathway, which was further ascertained by various biochemical analyses. Additionally, FGF22 treatment effectively reduced ferroptosis and neuronal apoptosis, thereby attenuating synaptic impairments and neuronal injury in the AD model mice and Aβ1-42-exposed HT22 cells. Collectively, the data presented herein implicate FGF22 as a potential neuroprotective agent in AD models, with its efficacy likely mediated through engaging of the FGFR2/YAP signaling axis.}, } @article {pmid41482111, year = {2026}, author = {Zheng, R and Liu, X and Liao, Z and Wan, R and Qiu, G and Li, M and Tang, C and Zhou, R and Song, J}, title = {Electroacupuncture ameliorates tau-driven cognitive decline by modulating NF-κB/NLRP3 inflammasome signaling in P301S mice.}, journal = {Experimental neurology}, volume = {398}, number = {}, pages = {115637}, doi = {10.1016/j.expneurol.2025.115637}, pmid = {41482111}, issn = {1090-2430}, mesh = {Animals ; *Electroacupuncture/methods ; *NLR Family, Pyrin Domain-Containing 3 Protein/metabolism ; Mice ; *Inflammasomes/metabolism ; *NF-kappa B/metabolism ; *tau Proteins/genetics/metabolism ; Mice, Transgenic ; Signal Transduction/physiology ; *Cognitive Dysfunction/therapy/metabolism/genetics ; Male ; Mice, Inbred C57BL ; *Tauopathies/metabolism ; }, abstract = {Alzheimer's disease (AD) progression is driven by a vicious cycle wherein pathological Tau hyperphosphorylation promotes microglial activation and NF-κB/NLRP3 inflammasome signaling, leading to excessive secretion of proinflammatory cytokines that reciprocally exacerbate Tau pathology. While pharmacological NLRP3 inhibitors hold therapeutic potential for AD, critical barriers-including poor blood-brain barrier penetration, suboptimal target selectivity, and safety concerns-persist. This study investigated whether electroacupuncture (EA), a non-pharmacological neuromodulatory approach, could disrupt this Tau-inflammasome cycle. Using P301S Tau transgenic mice, two EA regimens were tested at the GV20 (Baihui) acupoint: 6-month-old mice receiving a 1-month EA intervention, and 6-month-old mice undergoing a prolonged 3-month EA intervention. Cognitive function was evaluated via Y-maze, novel object recognition (NOR), and Morris water maze (MWM) tests, while corticospinal function was assessed using tail-suspension limb-clasping scoring. Hippocampal Tau pathology and inflammatory signaling were analyzed by Western blot and immunohistochemistry, targeting total Tau, phosphorylated Tau, NF-κB, NLRP3, caspase-1, IL-1β, IL-18, TNF-α, and microglial morphology. Short-term (1-month) EA treatment significantly improved spatial working memory and recognition memory. Mechanistically, EA reduced p-Tau levels, suppressed NF-κB activation (decreased p-P65/P65 ratio), downregulated NLRP3 inflammasome components (NLRP3, cleaved caspase-1) and proinflammatory cytokines (IL-1β, IL-18 and TNF-α), and mitigated microglial hyperactivation. Importantly, long-term (3-month) EA treatment persistently suppressed p-Tau accumulation and neuroinflammation, thereby consolidating cognitive benefits even in P301S mice with severe corticospinal dysfunction. These findings establish EA as a multi-targeted immunomodulatory strategy that attenuates Tau-driven neuroinflammation through the TNF-α/NF-κB/NLRP3 signaling axis, highlighting its potential as a safe, non-pharmacological adjunct or alternative therapy for AD and related tauopathies.}, } @article {pmid41482153, year = {2026}, author = {Yan, Y and Su, J and Xie, M and Kong, Y and Wang, C and Yuan, G and Fang, Y and Hwang, K and Kim, CY and Han, H and Zhang, Z}, title = {Low Intensity Ultrasound-facilitated exosome delivery promotes hippocampal neurogenesis in Alzheimer's disease.}, journal = {Brain stimulation}, volume = {19}, number = {1}, pages = {103015}, doi = {10.1016/j.brs.2025.103015}, pmid = {41482153}, issn = {1876-4754}, mesh = {*Alzheimer Disease/therapy/metabolism ; Animals ; *Neurogenesis/physiology ; *Hippocampus/metabolism ; *Exosomes ; Mice ; Female ; *Ultrasonic Waves ; Humans ; Mice, Transgenic ; Doublecortin Protein ; Mesenchymal Stem Cells ; Disease Models, Animal ; }, abstract = {BACKGROUND: Low-intensity ultrasound (LIUS) and human adipose-tissue mesenchymal stem cell-derived exosomes (hADSC-Exos) have shown neuroprotective potential, but their combined effects in Alzheimer's disease (AD) remain unclear.

OBJECTIVE: To evaluate the safety and efficacy of intranasal hADSC-Exos alone or combined with LIUS in APP/PS1 mice, and explore underlying molecular mechanisms.

METHODS: Female APP/PS1 mice (30 weeks) were randomized into five groups (n = 6). Treatments included intranasal hADSC-Exos, LIUS, or both for 2 months. Behavioral tests, histology, and hippocampal RNA-seq were performed.

RESULTS: LIUS enhanced Exo uptake in HT22 cells by ∼8 % without toxicity. Combined treatment improved learning and memory (escape latency ↓45 s→20 s; P < 0.01), increased neurogenesis markers (GFAP/SOX2, DCX, Ki67), and reduced amyloid and microglial activation. RNA-seq identified 93 specific DEGs in the combination group, with enrichment in synaptic and mitochondrial pathways. Fos and Kcnj13 were top DEGs and both downregulated after therapy (P < 0.05).

CONCLUSIONS: Intranasal hADSC-Exos combined with LIUS is safe, enhances brain delivery, and synergistically improves cognition and neurogenesis in AD mice. The Fos-Kcnj13 axis may mediate these effects, suggesting a promising noninvasive therapeutic strategy.}, } @article {pmid41482856, year = {2026}, author = {Kalita, R and Sarma, A and Baruah, H and Zaman, A and Goswami, D}, title = {Nose to Brain Delivery of Curcumin Loaded Therapeutic Nanostructures for Neurodegenerative Diseases.}, journal = {Biopharmaceutics & drug disposition}, volume = {47}, number = {1}, pages = {12-36}, doi = {10.1002/bdd.70021}, pmid = {41482856}, issn = {1099-081X}, mesh = {*Curcumin/administration & dosage/pharmacokinetics ; *Neurodegenerative Diseases/drug therapy/metabolism ; Administration, Intranasal ; Humans ; Animals ; *Brain/metabolism/drug effects ; *Neuroprotective Agents/administration & dosage/pharmacokinetics ; *Nanostructures/administration & dosage ; Blood-Brain Barrier/metabolism ; Drug Delivery Systems ; Drug Carriers ; }, abstract = {Neurodegenerative diseases are progressive disorders that damage and eventually kill neurons in the central nervous system (CNS). In recent years, various research has been done on reliable and effective treatment methods for the most common neurodegenerative diseases such as Parkinson's, Alzheimer, and Migraine diseases. Different neurodegenerative disorders such as Huntington's disease, Alzheimer's disease, Parkinson's disease, amyotrophic, Lewy body disease can be treated by curcumin, which is a strong antioxidant polyphenol with neuroprotective and anti-amyloid properties. However, Blood-brain barrier (BBB) and blood cerebrospinal fluid barrier restricts the permeation of curcumin to the brain leads poor distribution of the drug in brain tissue. The intranasal pathway holds promise for enhancing the treatment of CNS disorders since it bypasses the BBB and increases the brain bioavailability of drug. As nanotechnology continues to improve, research on the delivery of drug through intranasal route has grown significantly in last 10 years. Several nanocarriers have been developed such as nano-emulsions, microspheres, dendrimers, liposomes, carbon-based nanoformulation, and nanoparticles to deliver curcumin to the brain via intranasal route for the treatment of neurodegenerative diseases. This study provided a thorough analysis of several curcumin nano-formulations used in intranasal pathway as a novel treatment for neurodegenerative diseases.}, } @article {pmid41483724, year = {2026}, author = {Strain, JF and Rahmani, M and Phuah, CL and Dierker, D and Luo, J and Owen, C and Vlassenko, AG and Jafri, H and Bourgeat, P and Fripp, J and Jin, L and Moulder, K and Benzinger, T and Xiong, C and Lee, JM and Weiner, M and Masters, CL and Morris, JC and Womack, K and Goyal, MS and , }, title = {Regional growth rates of white matter hyperintensities are associated with beta-amyloid burden.}, journal = {Neurobiology of aging}, volume = {160}, number = {}, pages = {22-32}, pmid = {41483724}, issn = {1558-1497}, support = {P30 AG066444/AG/NIA NIH HHS/United States ; R01 AG089239/AG/NIA NIH HHS/United States ; P01 AG003991/AG/NIA NIH HHS/United States ; P01 AG026276/AG/NIA NIH HHS/United States ; U19 AG024904/AG/NIA NIH HHS/United States ; UL1 TR000448/TR/NCATS NIH HHS/United States ; R01 AG043434/AG/NIA NIH HHS/United States ; R01 AG073210/AG/NIA NIH HHS/United States ; R01 AG058676/AG/NIA NIH HHS/United States ; U01 AG024904/AG/NIA NIH HHS/United States ; R01 EB009352/EB/NIBIB NIH HHS/United States ; P30 NS098577/NS/NINDS NIH HHS/United States ; RF1 AG073210/AG/NIA NIH HHS/United States ; }, mesh = {Humans ; Female ; Male ; Aged ; *White Matter/pathology/metabolism/diagnostic imaging ; *Amyloid beta-Peptides/metabolism ; Magnetic Resonance Imaging ; Risk Factors ; Aged, 80 and over ; Middle Aged ; Positron-Emission Tomography ; Longitudinal Studies ; *Brain/pathology/metabolism ; }, abstract = {There is increasing evidence for an association between white matter hyperintensities (WMH) and brain beta-amyloid deposition. How WMH are longitudinally associated with brain beta-amyloid burden requires further investigation, particularly with respect to co-existent vascular risk factors and differences across white matter regions. We measured WMH on MRI and vascular risk factors in a combined neuroimaging data set of cognitively normal and individuals with dementia comprised of the ADNI, AIBL and OASIS3 studies, which includes harmonized centiloid estimates of beta-amyloid burden from PET imaging. WMH were measured using the TrUE-Net algorithm. Vascular risk factors were extracted from provided clinical data and used to calculate individual revised Framingham Stroke Risk Profile (FSRP) scores. Linear mixed effects modelling was used to determine the relationship between the growth rate of WMH and baseline beta-amyloid burden, controlling for age, sex, APOE4 status, and vascular risk factors. 1243 participants [49 % female, mean age 71.7 y (SD 7.6 y)] had at least 3 brain MRIs. Linear mixed models demonstrate robust independent cross-sectional relationships between WMH and baseline beta-amyloid burden (beta coefficient=0.27, p < 0.001), age (beta coefficient=0.04, p < 0.001) and vascular risk factors (beta coefficient=0.25, p < 0.001). Growth rates of WMH increased with baseline beta-amyloid burden (slope=0.021, p < 0.001) and decreased with anti-hypertensive medications (slope=-0.019, p = 0.002), above and beyond age, APOE4 status, and other vascular risk factors. The longitudinal association for beta-amyloid burden persisted in a similar analysis for parietal WM. Our study suggests that in Alzheimer disease research cohorts, WMH progression is associated with age and beta-amyloid burden, particularly in parietal white matter, and slowed by anti-hypertensive treatment.}, } @article {pmid41484306, year = {2026}, author = {Huang, H and Wu, J and Fang, Z and Wang, Y and Xie, J and Guan, Y}, title = {Recent Advances of the Role of Dl-3-n-Butylphthalide in the Treatment of Alzheimer's Disease.}, journal = {Molecular neurobiology}, volume = {63}, number = {1}, pages = {340}, pmid = {41484306}, issn = {1559-1182}, support = {202510159035//Innovation and Entrepreneurship Training Program for China Medical University Students/ ; }, mesh = {Humans ; *Benzofurans/therapeutic use/pharmacology ; *Alzheimer Disease/drug therapy/metabolism ; Animals ; Oxidative Stress/drug effects ; }, abstract = {Alzheimer's disease (AD) is a prevalent neurodegenerative disorder affecting approximately 55.2 million individuals globally, with complex pathogenesis involving amyloid-β (Aβ) aggregation, tau pathology, neuroinflammation, oxidative stress, and synaptic dysfunction. Current treatments offer only symptomatic relief without halting disease progression. Dl-3-n-butylphthalide (NBP), a small-molecule compound originally derived from celery seeds, has emerged as a promising multi-target therapeutic candidate for AD. Preclinical studies demonstrate that NBP exerts its therapeutic effects in AD by alleviating oxidative stress, enhancing superoxide dismutase (SOD) and glutathione activities, suppressing neuroinflammation by inhibiting NLRP3 inflammasome activation and pro-inflammatory cytokine release (e.g., IL-1β, TNF-α), reducing Aβ deposition and tau hyperphosphorylation, promoting autophagy, and improving synaptic plasticity. A meta-analysis of six trials (n = 851) confirmed that NBP improves Mini-Mental State Examination (MMSE) and Montreal Cognitive Assessment (MoCA) scores with a favorable safety profile, primarily mild gastrointestinal symptoms and transient liver enzyme elevations. This review systematically summarizes recent advances in NBP research, integrating both preclinical mechanisms and clinical evidence, and highlights its potential as a novel multi-target strategy for AD treatment. Further large-scale, long-term trials are warranted to validate its efficacy and explore optimized delivery systems and combination therapies.}, } @article {pmid41484454, year = {2026}, author = {Ibrahim, M and Khalil, AM and Attia, H and Alseekh, S and Mohamed, AF and El-Yamany, MF}, title = {Gut Microbiome-Sphingolipid Metabolism-Brain Axis Interactions: Neuroprotective Effects of Amitriptyline as Functional Inhibitor of Acid Sphingomyelinase in a Mouse Model of Tauopathy.}, journal = {Journal of neuroimmune pharmacology : the official journal of the Society on NeuroImmune Pharmacology}, volume = {21}, number = {1}, pages = {3}, pmid = {41484454}, issn = {1557-1904}, mesh = {Animals ; *Sphingomyelin Phosphodiesterase/antagonists & inhibitors/metabolism ; *Gastrointestinal Microbiome/drug effects/physiology ; Mice ; *Amitriptyline/pharmacology/therapeutic use ; Mice, Transgenic ; *Tauopathies/metabolism/drug therapy ; *Brain/drug effects/metabolism ; *Neuroprotective Agents/pharmacology/therapeutic use ; *Sphingolipids/metabolism ; Disease Models, Animal ; Male ; Mice, Inbred C57BL ; }, abstract = {Tauopathies are neurodegenerative diseases characterized by accumulation of hyperphosphorylated tau protein (P-tau). The gut microbiota (GM) is symbiotic with the host and altered in neurodegenerative diseases. Amitriptyline (AMI) is a functional inhibitor of acid sphingomyelinase (ASM) which is abnormally highly expressed in brains of Alzheimer patients. Little data is known about the role of colonic ASM in management of tauopathy. Therefore, the aim of this study was to investigate the role of AMI on reversing gut dysbiosis, ceramide levels, colonic inflammation and intestinal barrier disruption in tauopathy through the bidirectional gut-brain axis. P301S transgenic mice were administered AMI for 35 days. Colonic ASM, ceramides, inflammation and membrane integrity were assessed besides fecal microbiome analysis and serum lipopolysaccharides to assess intestinal membrane disruption. Levels of hippocampal P-tau, protein phosphatase 2 A and neurogenesis were assessed along with cognitive behavior. AMI treatment significantly reduced colonic ASM, ceramide levels, increased abundance of Harryflintia, Dubosiella, and Parasutterella and decreased abundance of Lactobacillus, Lachnoclostridium, Oscillibacter, Oscillospiracea UCG-003, Colidextribacter, Roseburia, Butyricicoccus, and Sphingomondales. In contrast, P301S mice displayed an altered GM profile with enriched Firmicutes and Clostridia, and low proportions of Bacteroidota- a phylum associated with intestinal barrier protection-, and Ruminococcaceae. Also, AMI treatment decreased inflammation and restored colonic membrane integrity with subsequent decrease in serum lipopolysaccharides, P-tau in hippocampus and improvement in cognitive behaviour and neurogenesis. The current results indicate that AMI has neuroprotective effects against tauopathy through modulation of ASM activity, associated ceramide levels, GM composition, colonic inflammation and membrane integrity through bidirectional gut-brain axis.}, } @article {pmid41484627, year = {2026}, author = {Jia, H and Ma, L and Liu, J and Gao, M and Liang, X and Zhang, F and Gao, Y and Liu, M and Jiang, W and Wei, M and Zhong, X}, title = {Organelle stress in NLRP3 inflammasome: a central mediator of neurodegenerative diseases.}, journal = {Molecular neurodegeneration}, volume = {21}, number = {1}, pages = {8}, pmid = {41484627}, issn = {1750-1326}, mesh = {*NLR Family, Pyrin Domain-Containing 3 Protein/metabolism ; Humans ; *Neurodegenerative Diseases/metabolism ; *Inflammasomes/metabolism ; Animals ; Mitochondria/metabolism ; *Organelles/metabolism ; Reactive Oxygen Species/metabolism ; }, abstract = {Organelle stress and NLRP3 inflammasome activation have been established as pivotal contributors to inflammatory responses and play a significant role in the pathogenesis of neurodegenerative diseases (NDDs), including Alzheimer’s disease (AD) and Parkinson’s disease (PD). However, the involvement of multiple organelles and their interorganellar signaling in NLRP3 inflammasome activation has not yet been systematically elucidated. The causal mechanisms by which these organelles promote NLRP3 activation and subsequently drive the progression of NDDs remain unclear. Furthermore, therapeutic interventions targeting this pathway require urgent and comprehensive investigation. This article comprehensively reviews the mechanisms by which organelle-derived stress signals, such as mitochondrial reactive oxygen species (mtROS), cathepsin B (CTSB), and calcium ions (Ca2+), induce NLRP3 inflammasome activation. It further examines the pivotal role of organelle-specific NLRP3 localization and post-translational modifications in the activation of the NLRP3 inflammasome. Finally, we outline NLRP3-mediated inflammatory processes in NDDs, focusing on events directly induced by organelle stress and interactions. These processes are not merely consequences of NDD progression but also critical factors accelerating disease deterioration. Potential therapeutic strategies targeting the organelle-NLRP3 axis are proposed, which may provide novel theoretical foundations and promising avenues for the prevention and treatment of NDDs.}, } @article {pmid41484644, year = {2026}, author = {Kim, T and Hong, YJ and Kim, M and Bae, Y and Lee, SB and Kim, SH and Lee, MA and Ko, E and Park, JW and Yang, DW}, title = {Impact of dose and compliance of antidementia medications on long-term outcomes in Alzheimer's disease: a nationwide real-world study.}, journal = {Alzheimer's research & therapy}, volume = {18}, number = {1}, pages = {24}, pmid = {41484644}, issn = {1758-9193}, mesh = {Humans ; *Alzheimer Disease/drug therapy/mortality/epidemiology ; Male ; Female ; Aged ; Aged, 80 and over ; *Cholinesterase Inhibitors/therapeutic use/administration & dosage ; Republic of Korea/epidemiology ; Treatment Outcome ; *Memantine/therapeutic use/administration & dosage ; Disease Progression ; *Nootropic Agents/therapeutic use/administration & dosage ; Middle Aged ; *Medication Adherence ; Dose-Response Relationship, Drug ; }, abstract = {BACKGROUND: Antidementia medications are widely prescribed for Alzheimer's disease (AD), but their long-term real-world effectiveness remains uncertain. This study investigated whether long-term outcomes differ according to medication dosage and compliance using nationwide data.

METHODS: Data from the Korean National Health Insurance Service (NHIS) covering 47 million individuals were analyzed. Prescription data for acetylcholinesterase inhibitors and memantine were analyzed for dosage and compliance. Among 1,704,547 dementia cases (2010-2016), 466,773 patients with clinically diagnosed AD were included. Medication dosage and compliance during the first three years after diagnosis were categorized to define optimal versus suboptimal treatment. Clinical outcomes included progression to moderate to severe dementia, institutionalization, and mortality. Multivariable logistic regression identified factors associated with outcomes.

RESULTS: Patients who maintained optimal dosage and compliance during the first three years after diagnosis showed a lower rate of progression to moderate to severe dementia than those receiving suboptimal treatments consistently across all classification criteria. Regression analyses revealed that optimal compliance and dosage were strongly associated with reduced progression (OR 0.807 and 0.704, respectively; p < 0.0001) and early mortality within five years. In contrast, mortality and institutionalization rates were not significantly different between groups except that mortality within five years.

CONCLUSIONS: Both medication dosage and persistence were independently associated with better long-term outcomes in AD. Maintaining optimal treatment during the early disease period may delay disease progression and improve survival within five years. This nationwide real-world study provides robust evidence supporting the importance of sustained, adequate antidementia therapy in clinical practice.}, } @article {pmid41484932, year = {2026}, author = {Nitzan, K and Bentulila, Z and Bregman-Yemini, N and Ayalon, N and David, D and Break, E and Sarne, Y and Doron, R}, title = {Sex-dependent effects of ultra-low-dose-THC preventive treatment on neuroinflammation and cognitive decline in 5xFAD mice.}, journal = {Biology of sex differences}, volume = {17}, number = {1}, pages = {20}, pmid = {41484932}, issn = {2042-6410}, support = {3-2021-2022b//National Institute for Psychobiology in Israel, Hebrew University of Jerusalem/ ; }, mesh = {Animals ; Male ; Female ; *Cognitive Dysfunction/prevention & control/drug therapy ; Mice ; *Neuroinflammatory Diseases/prevention & control ; *Dronabinol/administration & dosage/pharmacology/therapeutic use ; *Alzheimer Disease/prevention & control/drug therapy ; *Sex Characteristics ; Mice, Transgenic ; Hippocampus/drug effects ; Disease Models, Animal ; *Neuroprotective Agents/administration & dosage/pharmacology ; Prefrontal Cortex/drug effects ; }, abstract = {BACKGROUND: Alzheimer's disease (AD) remains the most prevalent cause of dementia, yet no existing treatment effectively prevents its onset. Current therapies primarily aim to slow disease progression or manage symptoms, leaving a critical gap in preventive strategies. Recent findings suggest that ultra-low-dose tetrahydrocannabinol (ULD-THC) may exert neuroprotective effects without the adverse consequences associated with chronic THC use. This study investigates whether preventive ULD-THC treatment can mitigate neuroinflammation and early cognitive decline in the 5xFAD mouse model of AD, with a specific focus on sex differences in treatment response.

METHODS: Male and female 5xFAD mice received monthly ULD-THC injections from 3 to 5 months of age, before significant pathology emerged. At 6 months, behavioral assessments were conducted, followed by molecular analyses of hippocampal and prefrontal cortex (PFC) tissue.

RESULTS: Results indicated that ULD-THC attuned AD-related cognitive decline in both males and females, with sex-specific neuroinflammatory responses. Males exhibited reduced hippocampal inflammation, whereas females showed reduced inflammation in the PFC, suggesting distinct neuroprotective mechanisms across sexes.

CONCLUSIONS: These findings highlight ULD-THC's potential as a preventive strategy for AD, emphasizing the importance of sex-dependent therapeutic approaches. By attenuating neuroinflammatory processes before cognitive deficits fully manifest, ULD-THC offers a novel, biologically targeted approach to AD prevention. Future research should explore its long-term efficacy and translational potential in clinical settings.}, } @article {pmid41485137, year = {2026}, author = {Zhu, Z and Steward, A and Dehsarvi, A and Roemer-Cassiano, SN and Dewenter, A and Biel, D and Hirsch, F and Frontzkowski, L and Pescoller, J and Klonowski, M and Gnörich, J and Pontecorvo, MJ and Shcherbinin, S and Schöll, M and Buckley, R and Ossenkoppele, R and Xie, F and Guo, T and , and Höglinger, G and Brendel, M and Franzmeier, N}, title = {Defining patient-centered amyloid PET thresholds for the onset of tauopathy in Alzheimer's disease.}, journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association}, volume = {22}, number = {1}, pages = {e71064}, pmid = {41485137}, issn = {1552-5279}, support = {AARG-22-973496/ALZ/Alzheimer's Association/United States ; //Gerhard and Ilse Schick Foundation/ ; BMBF 01KU2203//ERAPerMed/ ; }, mesh = {Humans ; *Positron-Emission Tomography ; Male ; *Alzheimer Disease/diagnostic imaging/metabolism ; Female ; *Tauopathies/diagnostic imaging/metabolism ; Aged ; tau Proteins/metabolism ; Aged, 80 and over ; *Amyloid/metabolism ; Sex Factors ; Age Factors ; Brain/diagnostic imaging/metabolism ; Carbolines ; }, abstract = {INTRODUCTION: Amyloid-induced tauopathy drives clinical decline in Alzheimer's disease (AD). Because age and sex shape tau trajectories, defining patient-centered amyloid thresholds for tauopathy onset could facilitate pre-tauopathy AD identification and aid treatment decisions and prognosis.

METHODS: By including two samples (Alzheimer's Disease Neuroimaging Initiative [ADNI, n = 301]; and 18F-AV-1451-A05 [A05, n = 143]), we explored whether age and sex affect tauopathy transition and determined patient-centered amyloid positron emission tomography (PET) thresholds that mark tauopathy onset.

RESULTS: We found a consistent amyloid PET × age interaction on global tau PET increase in men (ADNI/A05: p = 0.0078/0.018), with younger men showing faster amyloid-associated tau accumulation. We then established patient-centered, amyloid PET-inferred tauopathy transition cut-offs. Women reached this transition at lower amyloid PET levels, and these cutoffs predicted both earlier onset and accelerated cognitive decline (p < 0.001).

DISCUSSION: This study highlights the effect of age and sex on the amyloid-to-tauopathy transition, establishes patient-centered amyloid PET thresholds for tauopathy onset, and links these thresholds to accelerated cognitive decline.

HIGHLIGHTS: Younger age is related to faster amyloid-related tau accumulation in men. We defined a series of amyloid positron emission tomography (PET) thresholds to enable patient-centered inference of amyloid-related tauopathy. Crossing the amyloid PET-defined tauopathy phase is associated with more progressive tau deposition and cognitive decline.}, } @article {pmid41485354, year = {2026}, author = {Lin, X and Tang, L and Hu, Z}, title = {Causal relationship between tractography-based brain white matter structural connectome and risk of psychiatric disorders: A bidirectional Mendelian randomization study.}, journal = {Psychiatry research. Neuroimaging}, volume = {357}, number = {}, pages = {112131}, doi = {10.1016/j.pscychresns.2025.112131}, pmid = {41485354}, issn = {1872-7506}, mesh = {Humans ; Mendelian Randomization Analysis ; *White Matter/diagnostic imaging/pathology ; *Connectome/methods ; *Mental Disorders/diagnostic imaging/genetics/pathology ; Diffusion Tensor Imaging ; *Brain/diagnostic imaging/pathology ; Male ; }, abstract = {AIM: This study sought to explore the causal link between 206 tractography-derived white matter connectivity metrics in the brain and the risk of nine psychiatric disorders, employing a bidirectional two-sample Mendelian randomization (MR) approach.

METHOD: Summary datasets of 9 psychiatric disorders including anxiety disorder, Alzheimer's disease (AD), major depressive disorder (MDD), autism spectrum disorder (ASD), bipolar disorder (BD), schizophrenia, Tourette syndrome(TS), attention-deficit hyperactivity disorder (ADHD), and cannabis use disorder (CUD) were used. MR analyses were performed using the inverse variance weighted (IVW), weighted median, MR-Egger, MR-PRESSO, and MR-robust adjusted profile score (MR-RAPS) method.

RESULTS: Forward MR analysis showed that the left-hemisphere dorsal attention network to the right-hemisphere limbic network connectome was causally associated with a 32 % higher risk of anxiety disorder [odds ratio(OR) = 1.32; 95 % confidence interval (CI): 1.16, 1.51). Reverse MR analysis indicated that AD was associated with a 7 % higher risk for the left-hemisphere limbic network to the right-hemisphere control network connectome(OR = 1.07; 95 % CI: 1.03, 1.10).

CONCLUSIONS: Our MR analysis reveals causal relationships between brain white matter structural connectivity and psychiatric disorders, advancing our knowledge of the neural mechanisms that contribute to psychiatric disorders and providing evidence for targeted interventions in psychiatric treatment.}, } @article {pmid41485573, year = {2026}, author = {Pi, G and Zhang, L and Lei, H and Zhong, T and Zhang, F and Lu, Y and Qiu, X and Qi, Y and Dong, Y and Zhu, R and Qin, Q and Wang, J and Sarapultsev, A and Luo, S and Cheng, X and Yang, Y and Wang, JZ and Hu, D}, title = {Ursolic acid reduces Aβ-driven aggression via Gab1-mediated autophagy and dorsal hippocampal circuit modulation in Alzheimer's disease.}, journal = {Journal of advanced research}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.jare.2025.12.054}, pmid = {41485573}, issn = {2090-1224}, abstract = {INTRODUCTION: Aggression is one of the most debilitating neuropsychiatric symptoms in Alzheimer's disease (AD), posing significant challenges for both patients and caregivers. However, the underlying mechanism remains unclear, and effective therapeutic strategies are lacking.

OBJECTIVES: This study aimed to investigate the neural circuit mechanisms underlying amyloid-beta (Aβ)-driven aggression in AD and explore the therapeutic potential of ursolic acid (UA) in alleviating this behavior.

METHODS: A combination of virus tracing, electrophysiological recording, in vivo Ca2 + recording, and a aggressive behavior test was utilized to investigate the neural circuit vulnerable to Aβ-driven aggression. optogenetic or chemogenetic manipulation was used to identify the regulation of the neural circuit on aggressive behavior. Proteomics and molecular targeting were employed to explore the underlying mechanisms of Aβ-driven aggression and evaluate UA's effects.

RESULTS: We identified that Aβ accumulation drove hyperexcitability of dorsal hippocampal CA3 (dCA3) neurons projecting to the dorsal lateral septum (dLS), thereby triggering aggressive behavior in the 5xFAD mouse model. Optogenetic activation of the dCA3-dLS circuit in wild-type mice induced aggression, whereas either optogenetic or chemogenetic inhibition of this projection alleviated aggression in 5xFAD animals. Proteomic profiling of dCA3 tissue identified Grb2-associated binding protein 1 (Gab1) as a key mediator upregulated in 5xFAD mice and normalized by ursolic acid (UA) treatment. UA reduced Aβ plaque burden, restored autophagic flux (increasing LC3B-II and decreasing p62), and suppressed dCA3-dLS circuit hyperactivity, resulting in durable attenuation of aggressive behavior. Viral knockdown of Gab1 in dCA3 mimicked UA's effects on autophagy, Aβ clearance, circuit excitability, and aggression, whereas Gab1 overexpression blocked UA's benefits.

CONCLUSION: Together, these results define a novel Gab1-dependent autophagy-circuit mechanism for Aβ-induced aggression and establish UA as a promising candidate for alleviating neuropsychiatric symptoms in AD.}, } @article {pmid41485615, year = {2026}, author = {Kabiri, S and Gholizadeh Dangheralou, P and Khazaeifard, F and Rostami Mehr, S and Mansouri, SM and Rahimi Rad, N and Abbasi-Maleki, S}, title = {Evaluation of neurobiochemical and behavioral responses to carvone nanoemulsion: A neuroprotective approach for Alzheimer's disease-associated dementia in a rat model.}, journal = {Brain research}, volume = {1875}, number = {}, pages = {150143}, doi = {10.1016/j.brainres.2026.150143}, pmid = {41485615}, issn = {1872-6240}, mesh = {Animals ; *Alzheimer Disease/drug therapy/metabolism ; Rats ; *Neuroprotective Agents/pharmacology/administration & dosage ; Brain-Derived Neurotrophic Factor/metabolism ; Disease Models, Animal ; Emulsions ; Male ; *Cyclohexane Monoterpenes/pharmacology/administration & dosage ; Malondialdehyde/metabolism ; *Behavior, Animal/drug effects ; Antioxidants/pharmacology ; *Dementia/drug therapy ; }, abstract = {BACKGROUND: Antioxidant supplements have emerged as promising strategies to mitigate the impact of Alzheimer's disease (AD) and associated dementia. We explored the neuroprotective potential of Carvone nanoemulsion (CANO) using a rat model of AD-associated dementia.

METHOD: Our experimental groups comprised non-AD control rats (CON), untreated AD rats (AD), and AD rats treated with CANO at two different dosages: 40 mg/kg (CANO40) and 80 mg/kg (CANO80). We assessed various behavioral parameters, malondialdehyde (MDA) and brain-derived neurotrophic factor (BDNF) levels,ferric-reducing ability of plasma (FRAP).

RESULTS: AD induction caused a significant reduction in step-through latency (P < 0.001), center time (P < 0.001), the number of visits (P < 0.001), and total distance traveled (P < 0.001), time spent in open arms (P < 0.001), and both FRAP (P < 0.001) and BDNF levels (P < 0.001) in comparison to the CON group, while elevating escape latency, time in target zone and platform location latency, and MDA levels (P < 0.001). Treatment with CANO, particularly at the CANO80 dosage, significantly improved these parameters compared to the AD group, resulting in decreased time in the target zone (P < 0.001), escape latency (P < 0.001), and platform location latency (P < 0.001) and higher FRAP (P < 0.05) and BDNF levels (P < 0.05), along with decreased MDA levels (P < 0.05).

CONCLUSION: CANO, especially at the 80 mg/kg dosage, shows promise in alleviating symptoms associated with AD-associated dementia. However, further research is warranted to validate and expand upon these findings.}, } @article {pmid41486173, year = {2026}, author = {Silva-Llanes, I and Smith, LA and Abdelkader-Guillén, A and Jiménez-Villegas, J and Sarrió, D and Moreno-Bueno, G and Lastres-Becker, I}, title = {GASDERMIN D-mediated pyroptosis as a therapeutic target in TAU-dependent frontotemporal dementia mouse model.}, journal = {Journal of biomedical science}, volume = {33}, number = {1}, pages = {6}, pmid = {41486173}, issn = {1423-0127}, support = {PID2022-136854OB-I00//Ministerio de Ciencia, Innovación y Universidades/ ; PID2022-137065OB-I00//Ministerio de Ciencia, Innovación y Universidades/ ; CB16/12/00295//Centro de Investigación Biomédica en Red de Cáncer/ ; CB06/05/0089//Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas/ ; }, mesh = {Animals ; *Pyroptosis/genetics ; Mice ; *tau Proteins/metabolism/genetics ; Disease Models, Animal ; Humans ; *Phosphate-Binding Proteins/metabolism/genetics ; Mice, Transgenic ; *Intracellular Signaling Peptides and Proteins/metabolism/genetics ; *Frontotemporal Dementia/genetics/metabolism/drug therapy/pathology ; Male ; Female ; Alzheimer Disease/genetics ; Mice, Inbred C57BL ; Aged ; Hippocampus/metabolism ; Gasdermins ; }, abstract = {BACKGROUND: Recent research has revealed a strong connection between neuroinflammation and TAU protein-related neurodegeneration. A key discovery shows that the NLRP3 inflammasome, when activated, can significantly impact TAU pathology and subsequent neuronal death. This process involves pyroptosis, a lytic form of programmed cell death driven by inflammasome activation, leading to GASDERMIN D (GSDMD) cleavage and the subsequent release of inflammatory molecules IL-1β and IL-18. In this study, we explore the role of pyroptosis and GSDMD in Alzheimer's disease (AD) and tauopathy models, focusing on the TAU-induced neuroinflammatory process and its correlation with synaptic plasticity loss.

METHODS: Hippocampal tissue from AD patients at Braak stage II-III has been analyzed using qPCR to assess pyroptosis-related gene expression. To determine the role of TAU in pyroptosis and neuroinflammation, we used two different models: one based on intracerebral injection of an adeno-associated virus that specifically overexpresses TAU in the neurons of the hippocampus (AAV-TAU[P301L]), and a transgenic mouse model Tg-TAU[P301S] at 8 and 10 months of age. Gene expression, protein levels, and neuroinflammation markers were evaluated using qPCR and immunofluorescence. Additionally, both genetic (GSDMD-deficient mice) and pharmacological (dimethyl fumarate, DMF) interventions targeting pyroptosis have been explored to assess their impact on neuroinflammation and synaptic plasticity.

RESULTS: AD patients exhibited increased expression of pyroptosis-related genes, supporting the involvement of pyroptosis in neurodegeneration. Furthermore, TAU overexpression induced pyroptosis in both mouse models, and GSDMD protein levels increased alongside reactive microglial morphology. Our data supports that TAU-induced neuroinflammation correlated with synaptic plasticity impairment. GSDMD deficiency significantly reduced pyroptosis-related markers associated to TAU, but unexpectedly worsened synaptic plasticity deficits, suggesting GSDMD may play a dual role in inflammation and synaptic function. Finally, we showed that DMF treatment suppressed pyroptosis gene expression, reduced GSDMD levels, and alleviated neuroinflammation, correlating with improved synaptic marker expression.

CONCLUSION: Our findings demonstrate that TAU-induced pyroptosis contributes to neuroinflammation and synaptic dysfunction. While GSDMD inhibition mitigates inflammation, its absence exacerbates synaptic impairment, highlighting its complex role in tauopathies. Our results indicate that DMF treatment could offer a promising therapeutic avenue to modulate pyroptosis and neuroinflammation, and restore synaptic integrity in tauopathies.}, } @article {pmid41486697, year = {2026}, author = {Pan, H and Cheng, X and Zhang, J and Hou, K and Murray, KA and Manglani, K and Zhu, C and Hsu, HK and Mekkittikul, M and Halladay, T and Mirbaha, H and Elezi, G and Abskharon, R and Sawaya, MR and Bombino, A and Williams, CK and DeTure, M and Dickson, DW and Vinters, HV and Whitelegge, JP and Harran, PG and Cole, GM and Frautschy, SA and Eisenberg, DS}, title = {In Vitro and In Vivo Evaluation of Small-Molecule Disassemblers of Pathological Tau Fibrils.}, journal = {ACS chemical neuroscience}, volume = {17}, number = {2}, pages = {450-464}, doi = {10.1021/acschemneuro.5c00940}, pmid = {41486697}, issn = {1948-7193}, support = {I01 BX005919/BX/BLRD VA/United States ; R01 AG066212/AG/NIA NIH HHS/United States ; }, mesh = {Animals ; *tau Proteins/metabolism/drug effects ; Humans ; *Tauopathies/metabolism/drug therapy/pathology ; Mice ; *Alzheimer Disease/metabolism/drug therapy/pathology ; Mice, Transgenic ; Brain/metabolism/drug effects/pathology ; Disease Models, Animal ; *Protein Aggregation, Pathological/metabolism/drug therapy ; }, abstract = {Aggregation of the microtubule-binding protein tau is the histopathological hallmark of Alzheimer's disease (AD) and other neurodegenerative diseases, which are collectively known as tauopathies. Tau aggregation in AD patients is correlated with neuron loss, brain atrophy, and cognitive decline, and pro-aggregation tau mutations are sufficient to cause neurodegeneration and dementia in humans and tauopathy model mice. Thus, reversing tau aggregation is a potential therapeutic avenue for AD. In a previous study, we discovered CNS-11, a small molecule that disaggregates AD patient brain-extracted tau fibrils in vitro. In this study, we identify two chemical analogs of CNS-11, named CNS-11D and CNS-11G, that disaggregate AD patient brain-extracted tau fibrils and prevent seeding in a tau aggregation cell culture model. We also demonstrate that 8 weeks of treatment with either CNS-11D or CNS-11G reduces levels of insoluble tau in a mouse model of tauopathy. Our work defines the properties of two small molecules that diminish aggregation of tau in vivo and provides further support for structure-based methods to target tau for treatment of AD.}, } @article {pmid41486988, year = {2025}, author = {Ranjbari, F and Dadkhah, M and Pirdel, Z and Fathi, F}, title = {Margatoxin Peptide: Preparation and the Potential Use for Biological Applications in Cancer and Neurological Disorders.}, journal = {Protein and peptide letters}, volume = {32}, number = {11}, pages = {791-802}, doi = {10.2174/0109298665415268251024053300}, pmid = {41486988}, issn = {1875-5305}, mesh = {Humans ; *Scorpion Venoms/chemistry/pharmacology/therapeutic use ; *Neoplasms/drug therapy/metabolism/pathology ; Animals ; *Peptides/chemistry/pharmacology/therapeutic use ; *Antineoplastic Agents/chemistry/pharmacology/therapeutic use ; *Nervous System Diseases/drug therapy/metabolism ; *Potassium Channel Blockers/chemistry/pharmacology/therapeutic use ; Kv1.3 Potassium Channel/antagonists & inhibitors/metabolism ; *Neurodegenerative Diseases/drug therapy/metabolism ; Scorpions/chemistry ; }, abstract = {Scorpion venom compounds are known to contain nucleotides, polypeptides, mucoproteins, lipids, biogenic amines, and other unidentified macromolecules. Several peptides in scorpion fluids have demonstrated a wide range of biological activities with strong specificity for their targeted sites. Margatoxin, isolated from the venom of the scorpion, exhibits desirable properties, including high selectivity, good permeability, and stability in cancer cells, which can be achieved at picomolar doses, thereby blocking voltage-gated K[+] channels. This narrative review consolidates results from an extensive literature search conducted in major electronic databases up to September 2024. Important studies were identified using keywords associated with scorpion venom peptides, Kv1.3 channels, cancer treatment, and neurodegenerative disorders. The amino acids that make up Margatoxin have an effective molecular function in blocking voltage-gated K[+] channels 1.3. Due to the abnormally high expression of voltage-gated K[+] channel 1.3 in various types of cancers, blockers of this channel can inhibit apoptosis, metabolic changes, tumor angiogenesis, invasion, and migration. On the other hand, these channel blockers have emerged as a promising therapeutic approach for neurological disorders, such as Alzheimer's and Parkinson's diseases. The strong efficacy and targeted action of margatoxin further position it as a promising drug candidate. As the number of individuals affected by cancer and neurological conditions continues to rise, research into scorpion venom peptides like margatoxin may lead to innovative therapeutic options for future treatments.}, } @article {pmid41486993, year = {2026}, author = {Cai, M and Yan, S and Sun, Y and Huo, Q and Dai, X}, title = {miRNAs: Promising Biomarkers for Alzheimer's Diagnosis and Treatment.}, journal = {Current Alzheimer research}, volume = {}, number = {}, pages = {}, doi = {10.2174/0115672050427877251118111643}, pmid = {41486993}, issn = {1875-5828}, abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by amyloid-beta (Aβ) plaque deposition, neurofibrillary tangles of hyperphosphorylated tau protein, and chronic neuroinflammation, leading to synaptic dysfunction and cognitive decline. Current diagnostic methods rely on clinical symptoms and limited biomarkers, while available treatments only provide symptomatic relief without halting disease progression. MicroRNAs (miRNAs), small non-coding RNAs of 19-22 nucleotides, have emerged as crucial regulators of gene expression through post-transcriptional mechanisms and show distinct dysregulation patterns in AD patients' blood, cerebrospinal fluid (CSF), and brain tissues. Key miRNAs such as miR-132, miR-146a, miR-34a, and miR-125b demonstrate consistent alterations in expression levels, correlating with disease progression and offering potential as non-invasive diagnostic tools. This review comprehensively examines the dual role of miRNAs as diagnostic biomarkers and therapeutic targets for AD. We also provide an analysis of specific miRNA signatures in different biofluids (plasma, serum, CSF) and brain regions that correlate with disease stages, highlighting their potential for early and non-invasive diagnosis. Therapeutically, miRNAs modulate multiple AD-related pathways, including neuroinflammation via NF-κB signaling, Aβ production through BACE1 inhibition, and tau phosphorylation via GSK3β regulation. miRNAs also influence synaptic plasticity, mitochondrial function, and autophagy, presenting multifaceted opportunities for intervention. However, challenges, including miRNA heterogeneity, stability, and targeted delivery, remain critical impediments. Advances in nanocarriers, exosomal miRNAs, and viral vectors show promise in overcoming these obstacles, enabling precise miRNA modulation. In addition, we underscore the need for standardized protocols, further validation in clinical cohorts, and the development of cost-effective detection methods to translate miRNA-based approaches into practical diagnostics and therapies. By integrating miRNA biomarkers with existing diagnostic tools and exploring combinatorial therapeutic strategies, researchers can harness the potential of miRNAs to revolutionize AD intervention, paving the way for early detection and effective treatment of this devastating disease.}, } @article {pmid41487012, year = {2026}, author = {Verma, R and Bahadur, S}, title = {A Comprehensive Review of Naringin Loaded Nano Drug Delivery System in Treatment of CNS Disorders.}, journal = {Current pharmaceutical design}, volume = {}, number = {}, pages = {}, doi = {10.2174/0113816128407188251116030341}, pmid = {41487012}, issn = {1873-4286}, abstract = {Citrus fruits are an abundant source of the polyphenolic phytoconstituent naringenin, which belongs to the class of flavanones. NRG shows a lot of potential as a drug for treating a number of CNS disorders, such as neuroprotective activity, antiamyloidosis, antiparkinson, antialzheimer activity, and more. However, naringenin's hydrophobic nature, which results in limited absorption, limits its therapeutic potential. In this article, we provide an outline of the variety of nanocarriers employed for delivering naringenin as carriers. Some of them include solid lipid nanoparticles, liposomes, micelles, polymeric nanoparticles, nanostructured lipid carriers, nanosuspensions, and nanoemulsions, among others. These formulations of naringenin nanomedicine have been used for the potential treatment of a series of CNS disorders. Based on various research reports, it can be said that with the right nanocarriers, naringenin proves to be a promising therapeutic alternative for the treatment of several CNS ailments, including neurological diseases, Alzheimer's, Parkinson's disease, cerebral ischemia, etc. Therefore, the present manuscript highlights the various aspects of naringenin and its pharmacological activities. Further, naringenin-loaded nanocarriers have been enlisted and discussed in detail.}, } @article {pmid41487496, year = {2025}, author = {Cheng, R and Kim, J}, title = {Intranasal delivery of iron chelators and management of central nervous system disease.}, journal = {Frontiers in pharmacology}, volume = {16}, number = {}, pages = {1709259}, pmid = {41487496}, issn = {1663-9812}, abstract = {Brain iron dyshomeostasis plays a critical role in the pathology of multiple central nervous system (CNS) disorders, including neurodegenerative and neuropsychiatric diseases. Iron chelators such as deferoxamine (DFO) and deferiprone (DFP) have demonstrated therapeutic potential in mitigating disease progression in these conditions. However, systemic administration is hindered by poor blood-brain barrier (BBB) permeability, dose-limiting toxicity, and poor patient compliance due to frequent dosing regimens. In recent years, intranasal (IN) drug delivery has emerged as a promising strategy to bypass the BBB, providing a direct nose-to-brain delivery route via olfactory and trigeminal pathways while minimizing systemic exposure. This review provides a comprehensive summary of the current status of iron chelation therapy for CNS disorders with a focus on pharmacokinetics, efficacy, and translational potential of IN administration. While IN DFO has been extensively studied in preclinical models of Alzheimer's disease and stroke, recent developments have expanded the scope to other chelators such as DFP. We compare traditional systemic routes, including oral and intravenous, with intranasal administration, highlighting their respective advantages and limitations for CNS delivery. With ongoing advances in formulation and delivery technologies, IN iron chelators provide a promising alternative for the treatment of CNS disorders characterized by impaired iron homeostasis in the brain.}, } @article {pmid41487944, year = {2026}, author = {Rus Prelog, P and Zupan, M and Gregorič Kramberger, M and Frol, S}, title = {The Concomitant Use of Selective Serotonin Reuptake Inhibitors and Anti-Amyloid Treatment in Alzheimer's Disease: Balancing Benefits and Risks.}, journal = {Dementia and geriatric cognitive disorders extra}, volume = {16}, number = {1}, pages = {1-3}, pmid = {41487944}, issn = {1664-5464}, } @article {pmid41488323, year = {2025}, author = {Lotlikar, MS and Zellmer, JC and Bhattacharyya, R}, title = {Sigma receptors and mitochondria-associated ER membranes are converging therapeutic targets for Alzheimer's disease.}, journal = {Frontiers in neuroscience}, volume = {19}, number = {}, pages = {1733659}, pmid = {41488323}, issn = {1662-4548}, abstract = {Alzheimer's disease (AD) begins decades before clinical symptoms emerge. The "amyloid hypothesis" suggests that amyloid-β (Aβ) deposition initiates a cascade of tau hyperphosphorylation, neuroinflammation, and neuronal loss leading to cognitive decline. The recent success of anti-Aβ therapies such as Leqembi in prodromal or mild cognitive impaired patients underscores the importance of early intervention and Aβ clearance. However, safety and cost limitations highlight the need for alternative therapeutic strategies. Small-molecule modulators of Sigma-1 and Sigma-2 receptors (σ1R and σ2R) have emerged as promising candidates for AD treatment. σ1R agonists exhibit neuroprotective and anti-amnestic effects under pathological conditions without affecting normal cognition. Beyond AD, σ1R is implicated in several neurodegenerative diseases including ALS (amyotrophic lateral sclerosis), Parkinson's, and Huntington's diseases, stroke, and epilepsy. σ1R plays a key role at mitochondria-associated ER membranes (MAMs)-specialized lipid raft-like domains that form functional membrane contact sites between the endoplasmic reticulum (ER) and mitochondria. β-secretase (BACE1), γ-secretase, and their substrates APP and palmitoylated APP (palAPP) localize in the MAMs, promoting amyloidogenic Aβ production. MAMs serve as dynamic hubs for inter-organelle communication, calcium signaling, and lipid metabolism. The "MAM hypothesis" proposes that MAM dysregulation drives early AD pathology and persists throughout disease progression, contributing to neurofibrillary tangle formation, calcium imbalance, and neuroinflammation. This review aims to summarize the current understanding of σ1R-mediated regulation of MAMs and its neuroprotective mechanisms, highlighting potential therapeutic opportunities for targeting σ1R in AD and other neurodegenerative disorders.}, } @article {pmid41488470, year = {2026}, author = {Cho, Y and Lee, J and Choi, BY and Yun, JH and Han, S and Baek, SH and Park, J and Cho, Y and Kim, HK and Kim, E and Palomera, LF and Lim, J and Jeon, Y and Im, J and Hong, JM and Kim, TK and Kim, SH and Yim, JH and Jo, DG}, title = {Ramalin Ameliorates Alzheimer's Disease Pathology by Targeting BACE1, HDAC6, and MAPK Pathways.}, journal = {MedComm}, volume = {7}, number = {1}, pages = {e70518}, pmid = {41488470}, issn = {2688-2663}, abstract = {Aberrant deposition of β-amyloid (Aβ) and hyperphosphorylated tau, along with neuroinflammation, are key drivers of Alzheimer's disease (AD) pathology. Here, we identify ramalin, a natural antioxidant, as a promising therapeutic agent that alleviates AD pathology by modulating β-site APP cleaving enzyme 1 (BACE1), histone deacetylase 6 (HDAC6), and the mitogen-activated protein kinases (MAPK) pathway. Ramalin reduced BACE1 protein levels, independently of its transcription, translation, or enzymatic activity, an effect mediated by inhibition of HDAC6. Consistently, HDAC6 knockout similarly decreased BACE1 levels, highlighting HDAC6 as a key regulator of BACE1. Ramalin further suppressed neuroinflammatory responses by downregulating inducible nitric oxide synthase (iNOS) and the NLR family pyrin domain containing 3 (NLRP3) inflammasome. In AD mouse models, ramalin treatment significantly attenuated neuroinflammation, Aβ plaque burden, and tau hyperphosphorylation, while improving cognitive performance. Notably, ramalin reversed Aβ oligomer-induced synaptic transmission impairment and restored synaptic vesicle recycling in hippocampal neurons. Transcriptomic analysis identified modulation of the MAPK pathway, with reduced phosphorylation of c-Jun N-terminal kinase (JNK) and extracellular signal-regulated kinase (ERK) implicated in tau pathology. These findings establish ramalin as a disease-modifying intervention that provides neuroprotection through concurrent regulation of BACE1, HDAC6, and MAPK signaling pathway. Collectively, our findings highlight ramalin as a compelling disease-modifying candidate with the potential to drive a breakthrough approach targeting AD pathology.}, } @article {pmid41488982, year = {2025}, author = {Ressa, R and Ettinger, J and Chowdhury, E and Graham, L and Ndirangu, K and Mancebo, JZ and Bodnar, C}, title = {A value assessment of patient-level outcomes and productivity loss for intravenous and subcutaneous lecanemab for patients with early Alzheimer's disease.}, journal = {Journal of medical economics}, volume = {29}, number = {1}, pages = {118-134}, doi = {10.1080/13696998.2025.2609499}, pmid = {41488982}, issn = {1941-837X}, mesh = {Humans ; *Alzheimer Disease/drug therapy ; Injections, Subcutaneous ; Markov Chains ; Patient Preference ; Administration, Intravenous ; Cost-Benefit Analysis ; Caregivers ; Efficiency ; Decision Support Techniques ; }, abstract = {AIMS: Intravenous (IV) lecanemab is approved for the treatment of patients with early Alzheimer's disease (AD); a subcutaneous (SC) option may offer additional benefits. We assessed the overall value of SC treatments, and direct/indirect outcomes associated with IV and SC lecanemab.

METHODS AND MATERIALS: For the narrative review, PubMed was searched (February 2025) for studies comparing patient preferences for IV/SC treatment administration published between 2015-2025. Study eligibility was determined using patient, intervention, comparator, outcomes, and study criteria. For the decision-analytic model, a Markov model was developed with four lecanemab treatment scenarios. Scenarios one to three included IV initiation (10 mg/kg biweekly) to month 18, followed by either IV initiation continued (10 mg/kg biweekly), SC maintenance (250 mg weekly) or IV maintenance (10 mg/kg every 4 weeks). Scenario four included SC initiation (500 mg weekly) for an 18-month period, followed by SC maintenance (250 mg weekly). Outcomes were administration time/frequency; patient, caregiver, and healthcare professional time; and caregiver productivity loss.

RESULTS: Forty-three publications reported patient treatment preferences. Most (88.4%) reported that patients preferred SC over IV. Key reasons for this were time savings (n = 13/43 studies; 30.2%), convenience (n = 11/43; 25.6%), treatment frequency (n = 12/43; 27.9%). Two studies (n = 2/43; 4.7%) reported an IV preference over SC; for three studies (n = 3/43; 7.0%), treatment preference was driven by administration frequency. Decision-analytic modeling of lecanemab treatment scenarios revealed that IV initiation to IV maintenance had the lowest number of administrations, whereas SC initiation to SC maintenance had the lowest number of treatment hours and caregiver productivity losses.

LIMITATIONS: Caution must be taken when generalizing these results for all AD patients.

CONCLUSIONS: SC treatments show value as a therapeutic option. IV and SC lecanemab availability may offer benefits to patients, caregivers, and society, and improve shared decision making.}, } @article {pmid41490027, year = {2026}, author = {Yang, JW and Jiang, J}, title = {Association between varicella-zoster virus and Alzheimer's disease: A systematic review and meta-analysis of comprehensive evidence from infection, treatment to prevention.}, journal = {Journal of Alzheimer's disease : JAD}, volume = {110}, number = {1}, pages = {74-85}, doi = {10.1177/13872877251411573}, pmid = {41490027}, issn = {1875-8908}, mesh = {Humans ; *Alzheimer Disease/prevention & control/epidemiology/virology ; Antiviral Agents/therapeutic use ; *Herpesvirus 3, Human ; *Varicella Zoster Virus Infection/complications/prevention & control/epidemiology/drug therapy ; *Herpes Zoster/prevention & control ; Risk Factors ; Vaccination ; }, abstract = {BackgroundThe association between varicella-zoster virus (VZV) infection and Alzheimer's disease (AD) risk has shown inconsistent results. Given difficulties in early diagnosis and limited therapeutic options for AD, identifying modifiable risk factors is significant for prevention.ObjectiveTo systematically evaluate the impact of VZV infection on AD risk and explore protective effects of antiviral treatment and vaccination.MethodsWe searched PubMed and Web of Science databases up to April 2025. The Newcastle-Ottawa Scale assessed study quality. Random-effects models were used for meta-analysis using risk ratios (RR) as the primary effect measure, with sensitivity and subgroup analyses conducted.ResultsTwenty-one studies were included. Meta-analysis showed: (1) herpes zoster patients had significantly higher AD risk (RR = 1.12, 95% CI: 1.01-1.24, p = 0.04); (2) patients receiving antiviral treatment had lower AD risk (RR = 0.55, 95% CI: 0.37-0.82, p = 0.003); (3) vaccinated individuals had lower AD risk (RR = 0.72, 95% CI: 0.68-0.78, p < 0.0001). The strongest association occurred in the >70 years age group, demonstrating age as an important effect modifier.ConclusionsThis meta-analysis provides systematic evidence supporting that VZV infection increases AD risk while confirming protective effects of antiviral treatment and vaccination. These findings support including herpes zoster vaccination in preventive healthcare for elderly populations.}, } @article {pmid41490207, year = {2026}, author = {Liu, Y and Su, H and Guan, T and Li, X and Dong, C and Hu, Z and Zhang, Y}, title = {Risk prediction of progression from normal cognitive function to Alzheimer's disease in elderly aged 65 and above based on deep learning methods.}, journal = {Journal of Alzheimer's disease : JAD}, volume = {109}, number = {4}, pages = {1764-1777}, doi = {10.1177/13872877251410937}, pmid = {41490207}, issn = {1875-8908}, mesh = {Humans ; *Alzheimer Disease/diagnosis/psychology ; *Deep Learning ; Aged ; Male ; *Disease Progression ; Female ; Aged, 80 and over ; *Cognition/physiology ; Risk Assessment ; Risk Factors ; Proportional Hazards Models ; Neuropsychological Tests ; }, abstract = {BackgroundAlzheimer's disease (AD) is a severe neurological disorder for which a complete cure is not currently available. Therefore, predicting the risk of AD in elderly individuals with normal cognitive function is crucial for early prevention, treatment, and family-provided daily care preparation.ObjectiveThis study aimed to establish a risk prediction model for the progression from normal cognitive function to AD in elderly via deep learning (DL) methods to provide a reference for clinical decision-making and the development of screening tools for the early diagnosis of AD.MethodsDeepSurv, DeepHit, and Cox models were constructed, and the consistency index (C-index), integrated Brier score (IBS), and area under the ROC curve (AUC) were used to evaluate the accuracy, calibration and discriminative power of the three prediction models.ResultsThe overall predictive ability of the model was relatively stable, with concordance indices of 0.82 (DeepSurv), 0.83 (DeepHit), and 0.81 (Cox) and IBSs of 0.08, 0.07, and 0.05, respectively. From the perspective of the C-index indicator, the consistency of the deep learning model was better than that of the Cox model.ConclusionsRisk prediction models for the progression from normal cognitive function to AD can be established using easily obtainable early-stage predictors, which are expected to be used for rapid screening of the risk of developing AD in elderly after clinical validation.}, } @article {pmid41490210, year = {2026}, author = {Giuffrè, GM and Battisti, F and Tudor, AM and Lenkowicz, J and Avitabile, A and Rosati, AM and Martellacci, N and Patarnello, S and Torelli, F and Cesario, A and Marra, C}, title = {Redefining management of mild cognitive impairment and Alzheimer's disease through the shift from clinical to clinical-biological diagnosis: Insights from a single-center experience.}, journal = {Journal of Alzheimer's disease : JAD}, volume = {109}, number = {4}, pages = {1945-1954}, doi = {10.1177/13872877251411461}, pmid = {41490210}, issn = {1875-8908}, mesh = {Humans ; *Alzheimer Disease/diagnosis/therapy ; *Cognitive Dysfunction/diagnosis/therapy ; Male ; Female ; Aged ; Retrospective Studies ; Aged, 80 and over ; Cohort Studies ; Middle Aged ; Neuropsychological Tests ; Biomarkers ; Mental Status and Dementia Tests ; *Disease Management ; }, abstract = {BackgroundAlzheimer's disease (AD) diagnosis has shifted from a purely clinical framework to a clinical-biological paradigm, driven by biomarker integration. This evolution is motivated by the wider availability of reliable biomarkers and the advent of disease-modifying treatments.ObjectiveTo assess changes over time in clinical characteristics, diagnostic pathways, and healthcare resource utilization in a real-world cohort of individuals with cognitive impairment attending a Memory Clinic.MethodsThis secondary data retrospective observational study analyzed two patient cohorts with newly diagnosed cognitive impairment: one from 2017-2019 and another from 2021-2023. Anonymized medical records and structured hospital data were examined using natural language processing to extract demographic and clinical information, diagnostic pathways, treatment patterns and comorbidities.ResultsThe 2021-2023 cohort was significantly younger, exhibited higher baseline Mini-Mental State Examination scores, and underwent more instrumental assessments than the 2017-2019 cohort. These findings likely reflect a shift in public awareness and attitudes toward cognitive health. AD diagnoses increased in both cohorts over time, while mild cognitive impairment diagnoses declined. The use of diagnostic combinations was more frequent in the recent cohort, in which clinical-biological diagnoses were significantly more prevalent.ConclusionsThis study provides real-world insights into the evolving landscape of cognitive impairment diagnostics and care, underscoring a shift toward earlier, biologically grounded diagnosis, supporting precision medicine in AD care. The expanded use of biomarkers reflects evolving practice standards and prepares the ground for disease-modifying therapies in AD.}, } @article {pmid41490490, year = {2026}, author = {Wang, W and Huang, R and Lv, L and Ma, X and Li, Z and Zhang, Y and Wu, J and Wu, S and Xu, J and Hu, Y and Turck, CW and Li, H and Hu, X}, title = {Long-term effects of forty-hertz auditory stimulation as a treatment of Alzheimer's disease: Insights from an aged monkey model study.}, journal = {Proceedings of the National Academy of Sciences of the United States of America}, volume = {123}, number = {2}, pages = {e2529565123}, pmid = {41490490}, issn = {1091-6490}, mesh = {Animals ; *Alzheimer Disease/therapy/pathology/cerebrospinal fluid ; Macaca mulatta ; tau Proteins/cerebrospinal fluid ; Disease Models, Animal ; Amyloid beta-Peptides/cerebrospinal fluid ; *Acoustic Stimulation/methods ; Male ; Female ; *Aging ; Humans ; Brain/pathology ; }, abstract = {Based mainly on rodents studies, forty-hertz (40-Hz) physical stimulation has been regarded as a potential noninvasive treatment for Alzheimer's disease (AD). Considering the brain differences between rodents and humans, the effects of 40-Hz physical stimulation need to be further validated using nonhuman primates before its clinical application. Here, we took advantage of a rare opportunity to expose nine aged rhesus monkeys (26 to 31 y old) to 40-Hz auditory stimulation. Given the strong correlation between cerebrospinal fluid (CSF) Aβ and Tau concentrations and corresponding AD pathology in brain parenchyma in clinical practice, we investigated the effects of 40-Hz stimulation on AD pathology by monitoring changes in CSF Aβ and Tau concentrations. Our results revealed that 7 consecutive days of 40-Hz auditory stimulation triggered a rapid and significant increase of Aβ levels by more than 200%, but no effect on Tau levels in the CSF. Additionally, we observed that the elevation of CSF Aβ levels persisted for more than 5 wk after cessation, which had not been reported in any previous studies. After this, a pathological examination of the temporal cortices of 4 of the experimental monkeys was carried out and the data demonstrated that all of them had prevalent extracellular Aβ senile plaque pathology, whereas Tau pathology was negative or very weak. These results provide a good explanation for the differences between the CSF Aβ and Tau protein levels. Together, these first-time results from monkeys suggest that 40-Hz auditory stimulation has strong potential of a noninvasive AD treatment method.}, } @article {pmid41491073, year = {2026}, author = {Wasim, R and Azmi, S and Ahmad, A and Srivastava, A}, title = {NLRP3 inflammasome and Alzheimer's disease: bridging inflammation and neurodegeneration.}, journal = {Inflammopharmacology}, volume = {34}, number = {2}, pages = {951-966}, pmid = {41491073}, issn = {1568-5608}, mesh = {*Alzheimer Disease/metabolism/drug therapy/pathology/immunology ; Humans ; *NLR Family, Pyrin Domain-Containing 3 Protein/metabolism ; Animals ; *Inflammasomes/metabolism ; *Inflammation/metabolism/pathology ; Neuroinflammatory Diseases/metabolism ; }, abstract = {The progressive neurodegenerative disease known as Alzheimer's disease (AD) is characterized by widespread neuronal death, memory loss, and cognitive decline. The NLRP3 inflammasome has emerged as a key modulator of neuroinflammation, which is increasingly implicated in the pathophysiology of AD. In response to endogenous and pathogenic danger signals, the innate immune system's multiprotein complex known as the NLRP3 inflammasome is activated. Pyroptosis and neuroinflammatory cascades are eventually triggered by its activation, which causes caspase-1 to be cleaved and pro-inflammatory cytokines like interleukin-1β and interleukin-18 to be released. NLRP3 activation is strongly stimulated by tau aggregation and β-amyloid plaques in AD, which accelerates neuronal damage and prolongs chronic inflammation. The control and activation of inflammasomes are involved in both canonical and non-canonical pathways as well as mitochondrial dysfunction. Significantly, animal models indicate that NLRP3's therapeutic potential is highlighted by the reduction of amyloid burden and amelioration of cognitive decline that results from its inhibition or genetic deletion. Small-molecule inhibitors and natural substances that can alter NLRP3 activity have been discovered recently, providing intriguing approaches to AD treatment. Despite tremendous advancements, issues with medication selectivity and blood-brain barrier penetration still need to be resolved before these discoveries can be used in clinical settings. Comprehending the complex relationship between NLRP3 activation and Alzheimer's pathology may open the door to new, focused treatments meant to slow or stop the progression of the illness.}, } @article {pmid41491579, year = {2026}, author = {Kamali, M and Ansari, M and Nooraee, P and Tajadini, H and Kamali, H and Dehesh, T and Ashrafzadeh, A and Sharififar, F}, title = {Preliminary clinical evaluation of capsules containing standard hydroalcoholic extract of Myrtus communis L. in patients with mild to moderate Alzheimer' disease: a randomized, double-blind parallel-group clinical trial.}, journal = {BMC complementary medicine and therapies}, volume = {26}, number = {1}, pages = {40}, pmid = {41491579}, issn = {2662-7671}, mesh = {Humans ; *Alzheimer Disease/drug therapy ; Male ; Female ; *Plant Extracts/therapeutic use ; *Myrtus ; Aged ; Double-Blind Method ; Capsules ; Aged, 80 and over ; Cognition/drug effects ; Phytotherapy ; }, abstract = {BACKGROUND: This study evaluated the effectiveness of Myrtus communis L. extract, known for its antioxidant and anticholinesterase properties, to enhance cognitive function and mitigate disease progression in individuals with mild to moderate Alzheimer's disease (AD).

METHODS: Fifty elderly patients with mild to moderate AD residing in a Kerman nursing home were enrolled in a randomized, placebo-controlled trial conducted between November 2019 to February 2020. Participants were randomly assigned to either an intervention group (n = 25), receiving M. communis L. capsules (500 mg each capsule), or a control group (n = 25), receiving placebo capsules. Cognitive function was assessed at baseline and after four weeks using the Mini-Mental State Examination (MMSE) and Clinical Dementia Rating (CDR) scales. Statistical analyses, performed using SPSS version 22, considered a significance level of p < 0.05.

RESULTS: All fifty patients completed the four-week trial. Baseline characteristics-including sex, mean age, and education level-were well-matched between the intervention and control groups. After four weeks of treatment, the intervention group demonstrated a statistically significant improvement in cognitive function, as evidenced by significantly higher MMSE scores compared to the placebo group (23.4 ± 0.25 vs. 19.6 ± 0.25; p < 0.0001). Concurrently, the intervention group exhibited a significant reduction in dementia severity, indicated by lower CDR scores compared to the control group (0.8 ± 0.04 vs. 1.5 ± 0.04; p < 0.0001).

CONCLUSIONS: These findings suggest that M. communis L. holds promise as a potential complementary therapy for AD, capable of improving cognitive function and potentially slowing disease progression. However, further research is necessary to corroborate these results, elucidate the underlying mechanisms of action, and optimize treatment parameters before definitive conclusions can be drawn.

TRIAL REGISTRATION: irct.ir, ID: 20170702034861N8. Registered on 26/08/2019.}, } @article {pmid41493656, year = {2026}, author = {Cicero, CE and Angelini, L and Abbadessa, G and Bruno, M and Fiume, G and Nucera, B and Ornello, R and Arabia, G and Giuliano, L and Guarnieri, B and Lugaresi, A and Perani, D and Sacco, S and Tassorelli, C and Nicoletti, A and Pellecchia, MT and , }, title = {Sex and gender-related differences in neurological diseases: current challenges and recommendations for clinical practice.}, journal = {Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology}, volume = {47}, number = {1}, pages = {108}, pmid = {41493656}, issn = {1590-3478}, mesh = {Humans ; *Nervous System Diseases/therapy/epidemiology ; Female ; *Sex Characteristics ; Male ; Pregnancy ; }, abstract = {Neurological diseases include a large variety of conditions ranging from inflammatory, vascular and neurodegenerative disorders to epilepsy and headache. The impact of sex and gender on various aspects of these conditions (epidemiology, risk factors, pathophysiology, clinical features, treatment, and management of pregnancy and breastfeeding) is still not entirely taken into consideration, despite a rapidly increasing body of evidence. This position paper covers six neurological conditions (Alzheimer's Disease, Cerebrovascular disease, Parkinson's disease, Epilepsy, Headache disorders, Multiple Sclerosis) providing an overview of available evidence on sex and gender differences, identifying knowledge gaps and providing recommendations for clinical practice and future studies. We recommend taking into consideration modifiable sex and gender specific risk factors, the role of hormones across women's lifespan and a personalized treatment approach based on gender. We also recommend that future efforts should be devoted to increase the representation of women in clinical studies, to promote sex and gender-based guideline production and to better characterize the safety profile in pregnancy of newer drugs.}, } @article {pmid41493675, year = {2026}, author = {Usman, AS and Manoharan, SD and Che Mohd Nassir, CMN and Abdul Hamid, H and Hein, ZM and Norazit, A and Murthy, J and Zainol, M and Kamaruzzaman, MA and Chiroma, SM and Mustapha, M and Mohd Moklas, MA and Mehat, MZ}, title = {Neuroprotective Effects of Ficus deltoidea in Alzheimer's Disease-Like Rat Model: Insights from Behavior, Histology, and Amyloid Pathology.}, journal = {Molecular neurobiology}, volume = {63}, number = {1}, pages = {345}, pmid = {41493675}, issn = {1559-1182}, support = {(FRGS/1/2021/SKK0/UPM/02/15)//the Ministry of Higher Education under the Fundamental Research Grant Scheme/ ; }, mesh = {Animals ; *Alzheimer Disease/pathology/drug therapy/metabolism ; *Ficus/chemistry ; *Neuroprotective Agents/pharmacology/therapeutic use ; Male ; Rats, Wistar ; Disease Models, Animal ; *Plant Extracts/pharmacology/therapeutic use ; Plaque, Amyloid/pathology/drug therapy ; Amyloid beta-Peptides/metabolism ; Hippocampus/pathology/drug effects/metabolism ; Amyloid Precursor Protein Secretases/metabolism ; Maze Learning/drug effects ; Rats ; *Behavior, Animal/drug effects ; Spatial Memory/drug effects ; Aspartic Acid Endopeptidases/metabolism ; }, abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder marked by cognitive decline, memory impairment, and accumulation of amyloid-β (Aβ) plaques. While current treatments offer limited efficacy, medicinal plants such as Ficus deltoidea (FD), a traditional remedy, have shown promise due to their neuroprotective and anti-inflammatory properties. An AD-like phenotype was induced in male Wistar rats using D-galactose and aluminum chloride over 70 days. FD extract was administered orally at 50, 100, and 200 mg/kg. Spatial memory was evaluated using the T-maze test. Histological analyses of the hippocampi's Cornu Ammonis 1 and 3 (CA1 and CA3) regions were conducted via hematoxylin and eosin (H&E) staining, and Aβ plaques deposition was assessed with Congo red. Enzyme-linked immunosorbent assay (ELISA) was used to quantify hippocampal levels of Aβ (1-42) and β-secretase-1 (BACE-1). FD treatment significantly enhanced spatial memory, preserved pyramidal neuron integrity in CA1 and CA3, and reduced amyloid plaque formation. Biochemically, FD markedly decreased hippocampal Aβ (1-42) and BACE-1 concentrations in a dose-dependent manner. Thus, FD exhibits multi-target neuroprotective effects in an AD-like model, potentially via modulation of amyloidogenic pathways. Further studies are warranted to explore its mechanisms and therapeutic potential in other brain regions implicated in AD.}, } @article {pmid41493713, year = {2026}, author = {Hoveizi, E and Doraghi, K and Rostami, E}, title = {Fabrication and Characterization of Resveratrol-Loaded Solid Lipid Nanoparticles: Evaluation of Neuroprotective, Neurobehavioral, and Molecular Outcomes.}, journal = {Molecular neurobiology}, volume = {63}, number = {1}, pages = {346}, pmid = {41493713}, issn = {1559-1182}, support = {SCU.SB1403.12464//Shahid Chamran University of Ahvaz/ ; }, mesh = {*Resveratrol/pharmacology/administration & dosage/chemistry ; Animals ; *Nanoparticles/chemistry/ultrastructure ; *Neuroprotective Agents/pharmacology/administration & dosage/chemistry ; Male ; Rats ; Oxidative Stress/drug effects ; *Lipids/chemistry ; Antioxidants/pharmacology ; Neural Stem Cells/drug effects/metabolism ; *Behavior, Animal/drug effects ; Rats, Sprague-Dawley ; Interleukin-1beta/metabolism ; Memory/drug effects ; }, abstract = {Neurodegenerative processes involve oxidative stress, inflammation, and disrupted signaling, which contribute to cognitive decline. Resveratrol offers neuroprotection but suffers from poor solubility and bioavailability. Solid lipid nanoparticles (SLNs) can improve solubility, stability, and neural targeting, thereby enhancing efficacy. This study investigates whether SLN/resveratrol treatment modulates neuroprotective targets (HSP70, IL-1β) and antioxidant enzymes (CAT, GPX, SOD) in vitro and whether it improves inactive avoidance memory in an animal model. SLNs were produced by melting tripalmitin and palmitic acid, adding resveratrol, Tween, and butanol, then combining with water and stirring for 1 day. The resulting formulations were characterized using FTIR, electron microscopy, and DLS. Neural stem cells (NSCs) were treated with SLNs, resveratrol, and SLN/resveratrol, and the expression of oxidative stress enzymes, HSP70, and IL-1β was analyzed. In vivo, a passive avoidance memory model was induced in rats via electrical destruction of the nucleus basalis of Meynert. Molecular analysis showed that resveratrol increased HSP70 expression by 3.1-fold and significantly decreased IL-1β levels. SLN treatment had no notable effect on these genes, but the SLN/resveratrol increased HSP70 expression by fourfold and significantly reduced IL-1β. Resveratrol significantly upregulated the antioxidant enzymes CAT and GPX, whereas SLNs alone had no effect. The SLN/resveratrol also markedly enhanced CAT and GPX levels. Behavioral tests demonstrated that the SLN/resveratrol treatment improved passive avoidance memory in the Alzheimer's model. Collectively, these results indicate that SLN/resveratrol robustly enhances neuroprotection by modulating signaling pathways, reducing oxidative stress, and improving memory, with the SLN delivery system potentially increasing bioavailability and neural exposure.}, } @article {pmid41494605, year = {2026}, author = {Viqueira, L and Navarro, E and Negredo, P and Bernal, JA and Rodríguez-Franco, MI and Tortosa, E and López, MG}, title = {Long-term NRF2-driven microglial repopulation mitigates microgliosis, neuronal loss and cognitive deficits in tauopathy.}, journal = {Brain, behavior, and immunity}, volume = {133}, number = {}, pages = {106253}, doi = {10.1016/j.bbi.2026.106253}, pmid = {41494605}, issn = {1090-2139}, mesh = {Animals ; *Microglia/metabolism ; *NF-E2-Related Factor 2/metabolism ; *Tauopathies/metabolism/pathology ; Mice ; *Cognitive Dysfunction/metabolism ; Neurons/metabolism/pathology ; *Gliosis/metabolism ; Disease Models, Animal ; Hippocampus/metabolism ; Male ; tau Proteins/metabolism ; Mice, Transgenic ; Mice, Inbred C57BL ; Cognition/physiology ; }, abstract = {Tauopathies, including Alzheimer's disease, feature chronic microglial reactivity that drives neuroinflammation and disease progression. Pharmacological microglial depletion and subsequent repopulation using colony-stimulating factor 1 receptor inhibitors have emerged as a potential therapeutic strategy to reprogram dysfunctional microglia. Despite promising short-term results, the long-term efficacy and pharmacological modulation of repopulated microglia remain poorly understood. Here, we investigated the long-term effects of microglial repopulation alone and in combination with the activation of the cytoprotective nuclear factor erythroid 2 p45-related factor 2 (NRF2) in an in vivo AAV-hTau[P301L] induced model. Integrating different behavioural, immunohistological and transcriptomic analysis, we evaluated cognitive function, tau pathology, neuronal survival and glial reactivity. We found that, whereas microglial repopulation alone did not significantly affect disease progression, NRF2-driven microglial replenishment sustained cognitive function, prevented hippocampal neuronal loss and restored microglial phenotype. Transcriptomic analyses further revealed that the combined treatment modulated tau- associated mitochondrial gene expression changes. These results highlight the importance of shaping the fate of self-renewed microglia and propose NRF2-mediated microglial repopulation as a potential pharmacological strategy for the treatment of tauopathies.}, } @article {pmid41495456, year = {2026}, author = {Chen, Z and Bi, S and Shan, Y and Wang, F and Wang, Y and Qi, Z and Wang, T and Li, X and Li, S and Xiao, H and Wang, S and Cui, B and Qi, Z and Han, Y and Yan, S and Lu, J and , }, title = {MRI-to-PET synthesis via deep learning for amyloid-β quantification in Alzheimer's disease.}, journal = {European radiology}, volume = {36}, number = {6}, pages = {5125-5137}, pmid = {41495456}, issn = {1432-1084}, support = {82102010//National Natural Science Foundation of China/ ; 82394434//National Natural Science Foundation of China/ ; }, mesh = {*Alzheimer Disease/diagnostic imaging/metabolism ; *Positron-Emission Tomography/methods ; Humans ; *Deep Learning ; *Magnetic Resonance Imaging/methods ; *Amyloid beta-Peptides/metabolism ; Generative Adversarial Networks ; Imaging, Three-Dimensional ; Generative Artificial Intelligence ; }, abstract = {OBJECTIVES: Amyloid-β (Aβ) PET is crucial for diagnosing and monitoring Alzheimer's disease (AD), but its high cost and radiation exposure limit its use. Deep learning techniques make it possible to generate PET from structured MRI data. In this study, we built a deep learning model to generate 3D synthetic Aβ PET images from structural MRI.

MATERIALS AND METHODS: The generative adversarial network with share parameters (ShareGAN) model was trained and tested with 1009 Aβ PET and paired MRI images from the Alzheimer's Disease Neuroimaging Initiative database and three tertiary hospitals in China. The 3D synthetic model operates on the whole volume rather than 2D image slices, realistically reproducing minor discrepancies between neighboring image planes. ShareGAN-based PET images were evaluated using quantitative metrics and visual assessment. Pearson correlation coefficient and Bland-Altman analyses were used to assess the correlation and concordance between synthetic and real PETs.

RESULTS: 3D Synthetic PET images showed high similarity and correlation with real Aβ PET in external testing sets 1 and 2 in terms of structural similarity index measure (0.898, 0.899), peak signal-to-noise ratio (34.690, 34.725), mean absolute error (0.031, 0.031), and standardized uptake value ratio (R = 0.758, 0.828). The diagnostic accuracy of PET positive or negative status in external testing sets 1 and 2 was 88.5% and 89.4%, respectively.

CONCLUSION: MRI-based 3D synthetic Aβ PET images can serve as a safe and cost-effective tool for Aβ status visualization, providing PET-eligible patients with Aβ PET-like imaging analysis to guide subsequent real Aβ PET scans.

KEY POINTS: Question Amyloid-β (Aβ) PET limitations (high cost, radiation, limited access) hinder early Alzheimer's disease (AD) detection. Clinical practice urgently requires a suitable supplementary method for Aβ pathology assessment. Findings AI-synthesized 3D Synthetic Aβ PET from structural MRI demonstrated strong consistency with real PET and effectively triaged high-risk patients for confirmatory scans. Clinical relevance This non-invasive, cost-effective method holds the promise of enabling wider Aβ pathology screening, reduces unnecessary PET scans, and supports early intervention in resource-limited settings, while preserving diagnostic rigor for treatment decisions.}, } @article {pmid41495612, year = {2026}, author = {Yang, G and Zhu, D and Zhang, K}, title = {Nose-brain axis: A bridge from the nasal cavity to the central nervous system.}, journal = {Neural regeneration research}, volume = {21}, number = {9}, pages = {4012-4019}, doi = {10.4103/NRR.NRR-D-25-01770}, pmid = {41495612}, issn = {1673-5374}, abstract = {The nose-brain axis is a direct pathway linking the nasal cavity to the central nervous system. Odors, as well as exogenous substances such as pathogens, inflammatory mediators, and drugs, can enter the cranial cavity through pathways including the olfactory nerve, trigeminal nerve, and humoral routes, thereby enabling signal transmission and material exchange from the peripheral nasal cavity to the central nervous system. In recent years, advances in multimodal visualization technologies have made it possible to dynamically monitor the nose-brain axis from the molecular level to the tissue level, providing important means for revealing its functional characteristics and pathological changes. Owing to the existence of the nose-brain axis, nasal inflammation can, through neuro-immune interactions, activate central microglia and astrocytes and induce neuroinflammation, thus promoting the onset and progression of central nervous system diseases. In addition, the nose-brain axis offers a unique route for the treatment of central nervous system disorders. Intranasal drug delivery can bypass the blood-brain barrier, act directly on the central nervous system, increase intracranial drug bioavailability, and produce rapid effects, providing new ideas for treating cross-system diseases. This review systematically summarizes the anatomical pathways of the nose-brain axis, visualization monitoring technologies, and mechanisms by which nasal inflammation affects the central nervous system. It also reviews advances in intranasal drug delivery for emotional disorders, migraine, Parkinson's disease, and Alzheimer's disease, aiming to provide new strategies for studying the mechanisms by which nasal inflammation influences the central nervous system and for cross-system targeted therapy.}, } @article {pmid41496361, year = {2026}, author = {Huzián, O and Nagy, LI and Hackler, L and Knapp, L and Kocsis, ÁK and Szöts, I and Tamás, G and Puskás, LG and Molnár, G}, title = {Novel drug candidate binds to delta subunit containing GABAA receptors and improves spatial memory.}, journal = {Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie}, volume = {195}, number = {}, pages = {118970}, doi = {10.1016/j.biopha.2026.118970}, pmid = {41496361}, issn = {1950-6007}, mesh = {Animals ; *Receptors, GABA-A/metabolism/genetics ; *Spatial Memory/drug effects/physiology ; Male ; Mice ; Scopolamine ; Mice, Inbred C57BL ; Protein Subunits/metabolism ; Mice, Knockout ; Cognitive Enhancement ; }, abstract = {The hydroxyquinoline derivative Q134R is a promising drug candidate for the treatment of Alzheimer's disease with cytoprotective and cognition-enhancing properties. Radioligand binding assays showed that Q134R reduced [[35]S]TBPS binding, consistent with modulation of the picrotoxin site or conformational states that regulate TBPS accessibility. Electrophysiological recordings in mouse brain slices revealed that Q134R significantly increased tonic inhibitory currents in cortical neurogliaform and dentate gyrus granule cells, both known to express delta subunit-containing GABAA receptors. This effect was abolished in mice deficient in the GABAA delta subunit confirming the delta subunit dependency of Q134R's action. Furthermore, in a scopolamine-induced amnesia model, Q134R treatment significantly improved spatial memory performance in wild-type mice, but not in mice lacking in the delta subunit. These results suggest that Q134R enhances tonic inhibition through delta subunit-containing GABAA receptors, which may contribute to the modulation of memory processes and serve as a protective mechanism in early-stage neurodegenerations. These receptor-mediated effects likely contribute to its broader therapeutic efficacy and may complement its previously reported interactions with signaling pathways such as NFAT and HIF-1.}, } @article {pmid41496364, year = {2026}, author = {Facchinetti, R and Valenza, M and Ciarla, C and Steardo, L and Serviddio, G and Palombelli, G and Verkhratsky, A and Steardo, L and Canese, R and Cassano, T and Scuderi, C}, title = {Ultramicronized palmitoylethanolamide restores astrocyte-neuron metabolic coupling and Klotho/FGF21 signaling in a triple-transgenic mouse model of Alzheimer's disease.}, journal = {Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie}, volume = {195}, number = {}, pages = {118965}, doi = {10.1016/j.biopha.2025.118965}, pmid = {41496364}, issn = {1950-6007}, mesh = {Animals ; *Astrocytes/drug effects/metabolism ; *Alzheimer Disease/drug therapy/metabolism/genetics ; *Palmitic Acids/pharmacology ; Mice, Transgenic ; *Ethanolamines/pharmacology ; Signal Transduction/drug effects ; Klotho Proteins ; *Fibroblast Growth Factors/metabolism ; *Neurons/drug effects/metabolism ; Disease Models, Animal ; Amides ; Mice ; Glutamic Acid/metabolism ; Taurine/metabolism ; ADAM17 Protein/metabolism ; Lactic Acid/metabolism ; }, abstract = {Alzheimer's disease (AD), a multifactorial neurodegenerative disorder, is characterized by metabolic deficiency, neuroinflammation, and synaptic impairment. Astrocyte-neuron metabolic coupling regulates cerebral energy homeostasis through key metabolites such as lactate, glutamate, and taurine. We investigated the therapeutic potential of ultramicronized-palmitoylethanolamide (um-PEA) in restoring the homeostasis of these metabolites in the triple transgenic (3 ×Tg-AD) mouse model of AD. Using in vivo magnetic resonance imaging and spectroscopy (MRI/MRS) combined with Western blot, we evaluated the effects of chronic um-PEA treatment on lactate-glutamate dynamics and taurine metabolism in the frontal cortex and hippocampus of 6- and 12 month-old mice. Our findings demonstrate that 3 ×Tg-AD mice exhibit lactate accumulation, glutamine/glutamate imbalance, and taurine depletion, alongside reduced expression of metabolic processes regulators such as FGF21, Klotho, and insulin receptor. Treatment with um-PEA successfully restored these metabolic changes by: (i) rebalancing lactate-glutamate metabolism, (ii) increasing taurine synthesis and transport, (iii) upregulating FGF21, Klotho, and insulin receptor expression, and (iv) modulating the metalloproteases ADAM10 and ADAM17, which regulate Klotho processing. These results identify um-PEA as a promising metabolic modulator capable of mitigating AD-related neurodegenerative processes. By targeting astrocyte-neuron metabolism and enhancing both FGF21 and Klotho pathways, um-PEA holds significant potential as an adjunctive therapeutic strategy for AD.}, } @article {pmid41496378, year = {2026}, author = {Zhao, Y and Lu, H and Jiang, X}, title = {Advance in neuroprotective effects of proanthocyanidins (PCs): Structure, absorption, bioactivities, mechanism, and perspectives.}, journal = {Pharmacological research}, volume = {223}, number = {}, pages = {108082}, doi = {10.1016/j.phrs.2025.108082}, pmid = {41496378}, issn = {1096-1186}, mesh = {*Proanthocyanidins/chemistry/pharmacology/pharmacokinetics/therapeutic use ; Humans ; *Neuroprotective Agents/chemistry/pharmacokinetics/pharmacology/therapeutic use ; Animals ; *Nervous System Diseases/drug therapy/metabolism ; Gastrointestinal Microbiome/drug effects ; }, abstract = {With the global population growing and aging, along with increasing environmental, metabolic, and lifestyle-related risk factors, the worldwide incidence of stroke, Alzheimer's disease (AD) and other dementias, meningitis, and other neurological disorders-along with associated mortality-has risen significantly. Proanthocyanidins (PCs), which are oligomers and polymers of flavan-3-ols, are widely distributed across the plant kingdom, including in grape seeds, cinnamon, apples, cranberries, lotus seeds, and pine bark. They represent the second most abundant class of polyphenols in nature, after lignin. A substantial body of preclinical evidence indicates that PCs exert significant neuroprotective effects through multiple mechanisms. This review provides a systematic overview of the sources, structural characteristics, and bioavailability of PCs, with a focus on their pharmacological mechanisms in nervous system disease. Specifically, it examines their roles in regulating oxidative stress, neuroinflammation, protein homeostasis, apoptosis, autophagy, and key signaling pathways, including Nrf2/HO-1, CREB/BDNF, PI3K/Akt, MAPK, and NF-κB. Furthermore, this review systematically summarized the distinct structural forms of PCs, including monomers, dimers, trimers, and polymers, and explores their structure-activity relationships (SARs) in modulating the gut-brain axis. Additionally, recent advances in PCS-based nano-delivery systems and clinical studies related to neurological disorders are summarized. Growing evidence indicates that microbial metabolism in the gut serves as a key mechanism underlying their neuroprotective effects. Finally, the potential applications of PCs as promising dietary supplements or therapeutic agents for the prevention and treatment of nervous system diseases are discussed, along with existing challenges and future perspectives.}, } @article {pmid41498479, year = {2026}, author = {Sachdev, PS and Bentvelzen, AC and Gustafson, D and Hansra, GK and Hosoki, S and Jiang, J and Lennon, MJ and Moro, MA and Saks, DG and Samaras, K and Kovacic, JC and Kalaria, R}, title = {Vascular Cognitive Impairment and Dementia: Clinical Features, Neuropathology, and Biomarkers.}, journal = {Journal of the American College of Cardiology}, volume = {87}, number = {1}, pages = {52-76}, doi = {10.1016/j.jacc.2025.11.008}, pmid = {41498479}, issn = {1558-3597}, mesh = {Humans ; Biomarkers/blood ; *Dementia, Vascular/diagnosis/pathology ; *Cognitive Dysfunction/diagnosis/etiology/pathology ; Risk Factors ; *Cerebrovascular Disorders/complications ; *Brain/pathology ; }, abstract = {Vascular cognitive impairment and dementia (VCID), ie, cognitive impairment secondary to cerebrovascular disease (CeVD), is the second most common form of dementia after Alzheimer's disease (AD), accounting for 15% to 20% of all cases. CeVD, in fact, contributes to dementia alongside other neuropathologies in up to 75% of dementia cases. CeVD and AD not only frequently co-occur in the brain, but they may also interact, and some VCID risk factors (midlife hypertension and diabetes) also increase AD risk. Because CeVD and cardiovascular disease share risk factors and pathophysiology, the cardiovascular clinician is likely to encounter both in the clinic. Moreover, common cardiac disorders, such as atrial fibrillation, heart failure, acute coronary syndrome, and valvular disease, increase VCID risk. There have been recent developments in the diagnostic criteria for VCID, with advances in risk biomarkers, treatment, and prevention of cognitive impairment and dementia. The diagnosis of VCID is a 2-step process, with the initial identification of a cognitive syndrome followed by the establishment of a predominantly vascular etiology, guided by clinical history and examination and substantiated by neuroimaging, preferably magnetic resonance imaging. Clinical presentations include an acute onset, a stepwise decline, a fluctuating course if caused by multiple strokes, or a gradual slow progression if attributable to cerebral small vessel disease. Cognitive deficits can be found in several domains, such as information-processing speed, attention, executive function, and emotional lability, sometimes referred to as the subcortical syndrome, often seen in the early stages of VCID without cortical infarcts. The diagnosis is supported by the identification of large and small infarcts, lacunes, white matter hyperintensities, dilated perivascular spaces and cerebral microbleeds using magnetic resonance imaging. This part 1 of a 2-part JACC review series describes the clinical features, pathophysiology, and biomarkers of VCID for cardiovascular clinicians who have a critical role in its early identification, management, and prevention in their patients.}, } @article {pmid41498480, year = {2026}, author = {Goodall, LS and Lennon, MJ and Sachdev, PS and Gorelick, PB and Kovacic, JC and Samaras, K}, title = {Current and Emerging Therapeutic Approaches for Vascular Cognitive Impairment and Dementia.}, journal = {Journal of the American College of Cardiology}, volume = {87}, number = {1}, pages = {77-100}, doi = {10.1016/j.jacc.2025.09.1502}, pmid = {41498480}, issn = {1558-3597}, mesh = {Humans ; *Dementia, Vascular/therapy/prevention & control ; *Cognitive Dysfunction/therapy ; Risk Factors ; Nootropic Agents/therapeutic use ; Cognitive Enhancement ; }, abstract = {Cardiovascular risk factors contribute to the majority of dementia cases, with about 20% directly attributable to vascular cognitive impairment and dementia (VCID). VCID treatment developments have been slow compared with Alzheimer's disease (AD), which now has several FDA-approved symptom- and disease-modifying agents. In the second part of this JACC Seminar Series, advances and new perspectives on the management and prevention of VCID are reviewed. There is reasonable evidence that cognitive enhancers (donepezil, galantamine, and memantine) modestly improve cognition in vascular dementia (VaD), the most severe form of VCID, especially if there is associated AD pathology. Antidepressants may benefit those with depression and stroke, but they have poor efficacy in those with depression and VaD alone. Behavioral, social, and environmental interventions are first-line therapies for managing VCID-associated agitation and psychosis. Second-line antipsychotics have not been trialed in those with VaD alone, but are beneficial where AD and VaD co-exist, with risperidone and quetiapine effective in reducing psychosis and agitation. Primary prevention of VCID includes identifying and managing cardiometabolic risk factors along with manifestations of covert cerebrovascular disease. Both primary and secondary VCID prevention involve management of cardiovascular risks, specifically hypertension, diabetes mellitus, smoking, atrial fibrillation, obesity, and sedentariness. Management of vascular risk factors may moderately reduce the risk of incident cognitive impairment. Novel interventions currently being evaluated in clinical trials are discussed. The discovery and utilization of VCID and AD biomarkers will enhance the specificity and effectiveness of interventions such that a precision-medicine approach to disease-specific medical therapy may be taken.}, } @article {pmid41498900, year = {2026}, author = {Lin, ZY and Cai, LL and Lin, JX and Zheng, GY}, title = {Tiaobu Xinshen Recipe Improves Cognitive Deficits by Alleviating Synaptic Ultrastructure Degradation and Reducing Amyloid β in Transgenic Mice of Alzheimer's Disease.}, journal = {Chinese journal of integrative medicine}, volume = {32}, number = {4}, pages = {332-339}, pmid = {41498900}, issn = {1993-0402}, mesh = {Animals ; *Alzheimer Disease/drug therapy/pathology/complications/physiopathology ; Mice, Transgenic ; *Synapses/ultrastructure/drug effects ; *Drugs, Chinese Herbal/therapeutic use/pharmacology ; *Amyloid beta-Peptides/metabolism ; Male ; Amyloid Precursor Protein Secretases/metabolism ; Maze Learning/drug effects ; Insulysin/metabolism ; Mice ; Amyloid beta-Protein Precursor/metabolism ; *Cognitive Dysfunction/drug therapy ; Neprilysin/metabolism ; CA1 Region, Hippocampal/ultrastructure/drug effects/pathology ; *Cognition Disorders/drug therapy/complications ; Memory/drug effects ; }, abstract = {OBJECTIVE: To investigate the effect of Tiaobu Xinshen Recipe (TXR) on cognitive function of 5xFAD transgenic mice and explore the potential mechanisms.

METHODS: Six-month-old male wild-type (WT) mice and 5xFAD transgenic mice were randomly divided into vehicle (0.9% NaCl), TXR (granules, 4.18 g/kg) and donepezil (0.625 mg/kg) groups using a random number table, respectively, which were given intragastric administration once a day for 60 d. Spatial learning and memory performance was tested with modified Morris water maze (MMWM) test. Synaptic ultrastructure in the hippocampal CA1 region was observed by transmission electron microscopy. The levels of amyloid β (Aβ), the major amyloid precursor protein (APP)-cleaving enzymes and Aβ-degrading enzymes including β-secretase, α-secretase, neprilysin (NEP) and insulin-degrading enzyme (IDE), were detected by immunohistochemistry staining and Western blot, respectively.

RESULTS: In MMWM test, when compared with the 5xFAD-vehicle group, 5xFAD-TXR group demonstrated a significantly shorter escape latency to the platform and increased number of platform crossings and time spent in target quadrant (P<0.05 or P<0.01). The ultrastructure of synapse in the hippocampal CA1 region of mice in the 5xFAD-TXR group was significantly changed, including increased numbers of mitochondria and synaptic vesicles, intact synaptic membrane, and thickened postsynaptic density. The Aβ load was markedly decreased in the cerebral cortex and hippocampus CA1 subregion of TXR-treated 5xFAD mice (P<0.05). TXR treatment decreased APP levels and increased IDE expression in brains of 5xFAD mice (P<0.01). However, TXR treatment had no effect on α- and β-secretase, and NEP in 5xFAD mice (P>0.05).

CONCLUSION: TXR improves cognitive dysfunction in 5xFAD mice by alleviating synaptic ultrastructure degradation and reducing Aβ.}, } @article {pmid41499301, year = {2026}, author = {Mohasel-Roodi, M and Nozari, M and Shamsara, A and Basiri, M and Mirzaie, V and Baghalishahi, M}, title = {Effects of Dexmedetomidine on the Behavioral Outcomes in Streptozotocin-Induced Alzheimer's Disease Rats.}, journal = {Brain and behavior}, volume = {16}, number = {1}, pages = {e71196}, pmid = {41499301}, issn = {2162-3279}, support = {402000357//Kerman Neuroscience Research Center, Kerman University of Medical Sciences/ ; }, mesh = {Animals ; *Dexmedetomidine/pharmacology/administration & dosage ; *Alzheimer Disease/drug therapy/chemically induced ; Streptozocin/pharmacology ; Male ; Rats, Wistar ; Rats ; Disease Models, Animal ; *Adrenergic alpha-2 Receptor Agonists/pharmacology/administration & dosage ; *Neuroprotective Agents/pharmacology/administration & dosage ; *Behavior, Animal/drug effects ; Maze Learning/drug effects ; Anxiety/drug therapy ; }, abstract = {INTRODUCTION: Alzheimer's disease (AD) is a progressive and prevalent neurodegenerative disorder characterized by progressive cognitive decline and memory impairment. Intracerebroventricular (ICV) administration of streptozotocin (STZ) in rodents recapitulates key features of sporadic AD, including brain insulin resistance and oxidative stress. Dexmedetomidine (Dex), a highly selective α2-adrenergic receptor agonist, has demonstrated neuroprotective and anti-inflammatory properties, suggesting its potential utility as a therapeutic approach for AD.

METHODS: Seventy adult male Wistar rats were randomly allocated to seven experimental groups: Control, Sham, STZ, Sham + Dex (25 µg/kg), and STZ + Dex (25, 50, 100 µg/kg). Cognitive performance and anxiety-like behaviors were evaluated using the open-field test (OFT), elevated plus maze (EPM), Y-maze test, and Morris water maze (MWM).

RESULTS: In the Y-maze, STZ-treated rats exhibited significant reductions in spontaneous alternation behavior (p = 0.002), which were significantly reversed by Dex (25 µg/kg, p = 0.002). In the MWM, the STZ administration resulted in prolonged escape latencies and increased path lengths compared with Control animals (p < 0.05). Treatment with Dex (25 µg/kg) significantly improved spatial learning and memory retention (p < 0.05). No significant differences were observed in locomotor activity and anxiety-related behaviors in the OFT or EPM.

CONCLUSIONS: These findings indicate that Dex at 25 µg/kg attenuates STZ-induced cognitive deficits, likely through neuroprotective and anti-inflammatory mechanisms. The results highlight Dex as a promising candidate for AD therapy, though further research is required to elucidate its underlying molecular pathways. The study supports the potential repurposing of Dex for neurodegenerative disorders.}, } @article {pmid41499318, year = {2026}, author = {Melrose, J}, title = {Roles for Electrochemical Proton Gradients in Mitochondrial Energy Production and Neurosensory Processes in Health and Disease.}, journal = {Developmental neurobiology}, volume = {86}, number = {1}, pages = {e70006}, doi = {10.1002/dneu.70006}, pmid = {41499318}, issn = {1932-846X}, support = {//Melrose Personal Research Fund/ ; }, mesh = {Humans ; Animals ; *Mitochondria/metabolism ; *Energy Metabolism/physiology ; *Protons ; *Proton-Motive Force/physiology ; Oxidative Stress/physiology ; *Nervous System Diseases/metabolism ; Brain/metabolism ; }, abstract = {This study reviews the roles of proton electrochemical gradients in ubiquitous mitochondrial energy production systems in cellular activation and functions in neurosensory signaling. Proton electrochemical gradients crucially shaped the evolution of life. The emergence of the proton-motive force in mitochondria was fundamental in energy production and central to the function of eukaryotic cells. Dysfunctional mitochondria, however, result in impaired formation of proton gradients and a wide spectrum of diseases. This is particularly prominent in tissues with high energetic demands, such as muscle and nervous tissues. Oxidant stress generated by dysfunctional proton conductance in the brain results in Alzheimer's and Parkinson's disease, muscular sclerosis, amyotrophic sclerosis, and Huntington's disease. In these disorders, oxidative stress, protein misfolding, and neuroinflammation lead to dysfunctional neuronal activity, neuronal damage, and death. Advancements in nanozyme-engineered synthetic enzymes offer a promising innovative approach to the treatment of these disorders. Nanozymes target proton conductance and the oxidant species they generate, scavenging oxygen free radicals and restoring redox balance, and offer neuronal protection and functional recovery of brain tissues. Neural injury and associated neurological diseases affect almost 1 billion people globally, so there is a clear need to develop effective methods that stimulate neural repair and regeneration. Glycosaminoglycans with proton capture and transport properties regulate intercellular signaling processes, synaptic functions, and cellular communication. Electroconductive hydrogels are showing impressive results in neural repair and regeneration. Glycosaminoglycans, particularly keratan sulfate, show useful electroconductive proton capture and transport properties, suggesting they may be worth evaluation in such procedures.}, } @article {pmid41499862, year = {2026}, author = {Nadais, A and Castro, C and Martins, I and Trigo, D and Nunes, C and Henriques, AG and de Lourdes Pereira, M and da Cruz E Silva, OAB}, title = {Nanoparticle-mediated Zn delivery impacts neural protein phosphatase activity.}, journal = {Biomaterials advances}, volume = {182}, number = {}, pages = {214675}, doi = {10.1016/j.bioadv.2025.214675}, pmid = {41499862}, issn = {2772-9508}, mesh = {*Zinc Oxide/chemistry ; Humans ; Phosphorylation/drug effects ; *Nanoparticles/chemistry ; *Zinc/chemistry/administration & dosage/pharmacology ; *Neurons/drug effects/metabolism/enzymology ; Animals ; *Phosphoprotein Phosphatases/metabolism ; Alzheimer Disease/metabolism/drug therapy/pathology ; tau Proteins/metabolism ; }, abstract = {In recent years, the use of nanoparticles (NPs) in diagnosis and treatment of different disorders has been a matter of intensive research. Due to their physical and chemical properties, zinc oxide nanoparticles (ZnO NP) have been explored in a range of biological applications, including cancer and neurological diseases. Regarding the latter, while some studies report protective effects of ZnO NP in cultured cells and animal models, others indicate that these NPs have a harmful impact on the brain, such as promoting oxidative stress and cell death. Previous results from our group have suggested beneficial effects for zinc (Zn) cations in both modulating protein aggregation and on Alzheimer's disease (AD) pathology. In this context, the effect of encapsulated Zn as a nanoparticle on protein aggregation and its influence on protein phosphorylation events associated with AD were explored. The results herein presented show that ZnO NP contributed to a decrease in protein aggregation in neuronal cells. However, these NPs were also found to decrease PP1 and PP2A activity, potentially contributing to increased phosphorylation of tau and APP, which are AD pathology hallmarks. In conclusion, while the use of NPs as a Zn delivery system may offer benefits by reducing aggregate formation, they also appear to induce undesired molecular changes, like those observed in AD. Therefore, a holistic approach should be incorporated as we move forward in this research line, as their effects on distinct cellular processes may be dual edged.}, } @article {pmid41501420, year = {2026}, author = {Wang, XY and Zhou, WS and Gaur, U and Zhen, XC and Zheng, WH}, title = {Sigma-1 receptor positive allosteric modulator promotes neuronal survival and improves cognitive deficits in AD mice via sigma-1 receptor/ERK pathway.}, journal = {Acta pharmacologica Sinica}, volume = {47}, number = {4}, pages = {888-902}, pmid = {41501420}, issn = {1745-7254}, mesh = {Animals ; *Receptors, sigma/metabolism/agonists ; Sigma-1 Receptor ; *Alzheimer Disease/drug therapy/metabolism ; *Neurons/drug effects/metabolism ; *Neuroprotective Agents/pharmacology/therapeutic use ; Humans ; Cell Survival/drug effects ; Rats ; Apoptosis/drug effects ; *MAP Kinase Signaling System/drug effects ; Reactive Oxygen Species/metabolism ; Male ; Amyloid beta-Peptides/metabolism ; Allosteric Regulation/drug effects ; Mice ; PC12 Cells ; Mice, Transgenic ; Oxidative Stress/drug effects ; }, abstract = {The sigma-1 receptor is an important new therapeutic drug target for Alzheimer's disease (AD). Here, we reported that SOMCL-668, a novel selective and potent sigma-1 receptor allosteric modulator, is neuroprotective in AD both in vitro and in vivo. SOMCL-668 promoted PC12 cells against Aβ-induced intracellular reactive oxygen species (ROS) accumulation, mitochondrial membrane potential hyperpolarization and neuronal apoptosis. Similar results were obtained in SH-SY5Y and primary cortical culture neurons. The mechanistic study showed that SOMCL-668 stimulated the phosphorylation of ERK and CREB, while pharmacological inhibition or knockout of ERK via CRISPR-Cas9 attenuated its protective effects. Further studies with the sigma-1 receptor agonists/antagonists and knockout of sigma-1 receptor via CRISPR-Cas9 indicated that the sigma-1 receptor is essential for the effect of SOMCL-668. In 3xTg-AD mice, SOMCL-668 improved the learning and memory deficits, inhibited neuronal apoptosis and oxidative stress, reduced Aβ deposition and tau protein phosphorylation via ERK/CREB pathway. Moreover, pretreatment with sigma-1 receptor antagonist BD1047 blocked the effect of SOMCL-668. These results demonstrated that SOMCL-668 provides neuroprotection in AD and its effect is mediated by the sigma-1 receptor/ERK/CREB pathway. Our findings support that SOMCL-668 can be utilized as a potential drug for the prevention and treatment of Alzheimer's disease.}, } @article {pmid41501928, year = {2026}, author = {Li, E and Song, F and Coppola, Q and Yack, L and Le, M and Javed, S and Pandher, N and Prufer, I and Mayzel, O and Heuer, HH and Koestler, M and Miller, BL and Boxer, AL and Vandevrede, L and Grinberg, LT and Walsh, CM and Neylan, TC}, title = {Treatment of Disturbed Sleep in Progressive Supranuclear Palsy: a randomized, remote, double-blinded, 6-week cross-over design study protocol comparing zolpidem, suvorexant, and placebo.}, journal = {Trials}, volume = {27}, number = {1}, pages = {105}, pmid = {41501928}, issn = {1745-6215}, support = {A130340//Rainwater Charitable Foundation/ ; }, mesh = {Humans ; Cross-Over Studies ; *Supranuclear Palsy, Progressive/complications/physiopathology/drug therapy/diagnosis ; Double-Blind Method ; *Triazoles/therapeutic use/adverse effects ; *Azepines/therapeutic use/adverse effects ; *Zolpidem/therapeutic use/adverse effects ; *Sleep/drug effects ; *Orexin Receptor Antagonists/therapeutic use/adverse effects ; *Sleep Wake Disorders/drug therapy/etiology/physiopathology/diagnosis ; Treatment Outcome ; *Sleep Aids, Pharmaceutical/therapeutic use/adverse effects ; Time Factors ; Randomized Controlled Trials as Topic ; Polysomnography ; *Hypnotics and Sedatives/therapeutic use/adverse effects ; }, abstract = {BACKGROUND: Prior research identified profound sleep disruption in progressive supranuclear palsy (PSP). The hypothalamus and brainstem, areas that help regulate sleep/wake patterns, are among the earliest affected brain regions in PSP disease progression. Comparing polysomnography and quantitative-neuropathology metrics, we identified relative sparing of wake-promoting nuclei in PSP compared to Alzheimer's disease, though PSP had more disrupted sleep. It led to the hypothesis that PSP patients have hyperinsomnia (or hyposomnia, little sleep) due to degeneration of sleep nuclei with a preservation of sleep neurons, causing a system unbalance. A higher neuronal count of wake-promoting nuclei was associated with greater nocturnal wake, regardless of disease. Specifically, orexinergic wake-promoting neurons in the lateral hypothalamus, previously described as the sleep-on/off switch, are relatively spared in PSP. Thus, we hypothesized that an orexinergic antagonist may be more effective in treating sleep/wake issues in PSP than other hypnotic medications. This study protocol was established to test the safety and efficacy of an orexinergic antagonist (suvorexant) targeting the wake-promoting system and contrasts it with a GABAergic receptor agonist (zolpidem) targeting sleep-promoting systems and placebo.

METHODS: This is a remote clinical trial, designed as a double-blind, cross-over, within-subject 6-week trial, with 3 one-week-long conditions, separated by 1-week washout periods. The order of the 3 regimens is randomized and counterbalanced: placebo (microcrystalline cellulose), 15 mg/day suvorexant, 5 mg/day zolpidem. Participants are recruited from doctor and study referrals, registries, and support groups. Once onboarded, the trial coordinator maintains communication with the participant/caregiver throughout the 6 weeks. Assessments include neurological interviews, cognitive testing, and subjective questionnaire packets. Sleep and circadian rhythms are assessed through ambulatory EEG and actigraphy monitoring devices worn by the participant throughout the trial.

DISCUSSION: The study design aims to reduce participant and caregiver burden, while improving accessibility to such a study. Administering a remote clinical trial for a rare disease, however, creates unique issues that would otherwise be absent from in-person studies. Particularly, a symptom rather than disease-modifying trial is challenging to recruit for when potential disease-modifying therapeutics are available. Needing to coordinate with non-associated medical offices to attain medical records or prescriptions can cause frustrations for the potential participant, medical office, and study team. In recruitment, onboarding, and trial maintenance, this study design relies on consistent communication to support participant enrollment and satisfaction.

TRIAL REGISTRATION: Treatment of Disturbed Sleep in Progressive Supranuclear Palsy (PSP); NCT04014389. Registered on June 2, 2019.}, } @article {pmid41502301, year = {2026}, author = {Abhyankar, SD and Xiao, Y and Mahajan, N and Luo, Q and Cummins, TR and Oblak, AL and Lamb, BT and Corson, TW and Bhatwadekar, AD}, title = {Müller Glial Kir4.1 Channel Dysfunction in APOE4-KI Model of Alzheimer's Disease.}, journal = {Glia}, volume = {74}, number = {3}, pages = {e70119}, pmid = {41502301}, issn = {1098-1136}, support = {R01EY027779-S1/EY/NEI NIH HHS/United States ; R01EY032080/EY/NEI NIH HHS/United States ; //Research to Prevent Blindness, Unrestricted Grant/ ; DK064466/DK/NIDDK NIH HHS/United States ; G20240315-8762//Sigma Xi Grants in Aid of Research/ ; //NIH T32, Peter J. Roach Award, Center for Diabetes and Metabolic Diseases, Indiana University School of Medicine/ ; }, mesh = {Animals ; *Potassium Channels, Inwardly Rectifying/metabolism/genetics ; Kcnj10 Channel ; *Ependymoglial Cells/metabolism/pathology ; *Alzheimer Disease/metabolism/pathology/genetics ; *Apolipoprotein E4/genetics/metabolism ; Disease Models, Animal ; Rats ; Mice, Transgenic ; Mice ; Membrane Potential, Mitochondrial/physiology/drug effects ; Mitochondria/metabolism ; Cells, Cultured ; Oxidative Stress/physiology ; Patch-Clamp Techniques ; Humans ; }, abstract = {Alzheimer's disease (AD), particularly late-onset AD (LOAD), affects millions worldwide, with the apolipoprotein ε4 (APOE4) allele being a significant genetic risk factor. Retinal abnormalities are a hallmark of LOAD, and our recent study demonstrated significant age-related retinal impairments in APOE4-knock-in (KI) mice, highlighting that retinal impairments occur before the onset of cognitive decline in these mice. Müller cells (MCs), key retinal glia, are vital for retinal health, and their dysfunction may contribute to retinal impairments seen in AD. MCs maintain potassium balance via specialized inwardly rectifying K[+] channels 4.1 (Kir4.1). This study posits that Kir4.1 channels will be impaired in APOE4-KI, resulting in MC dysfunction. Additionally, we demonstrate that MC dysfunction in APOE4-KI stems from alterations in mitochondrial dynamics and oxidative stress. Kir4.1 expression and function were studied using immunofluorescence and through the whole-cell voltage clamp, respectively. In parallel, rat Müller cells (rMC-1) were used to create an in vitro model for further mechanistic studies. MitoQ was used to evaluate its potential to mitigate APOE4-induced deficits. APOE4 retinas and APOE4-transfected rMC-1 significantly reduced Kir4.1 expression, K+ buffering capacity, and increased mitochondrial damage. APOE4-transfected rMC-1 showed reduced mitochondrial membrane potential (ΔΨm) and increased mitochondrial reactive oxygen species (ROS). MitoQ treatment significantly reduced mitochondrial ROS and restored Kir4.1 expression in APOE4-expressing cells. Our results demonstrate that APOE4 causes mitochondrial dysfunction and MC impairment, which may contribute to retinal pathology in AD. MitoQ restored mitochondrial health and Kir4.1 expression in APOE4-expressing rMC-1, suggesting targeting mitochondria may offer a promising therapeutic strategy for AD.}, } @article {pmid41502346, year = {2026}, author = {Chang, YY and Zheng, XH and Wang, MW and Zhang, QW and Gao, YT and Wang, YN and Sun, YT and Fan, HH and Li, X and Du, LD and Xie, XM and Pang, XB}, title = {Morroniside Modulates Microglia Polarization via the CX3CL1/CX3CR1/PU.1 Axis in ApoE4 Transgenic Mice.}, journal = {Phytotherapy research : PTR}, volume = {40}, number = {2}, pages = {783-799}, doi = {10.1002/ptr.70177}, pmid = {41502346}, issn = {1099-1573}, support = {251111313400//Key R&D Program of Henan Province/ ; 252300421379//Natural Science Foundation of Henan/ ; 25B350004//Key Scientific Research Projects of Henan Higher Education Institutions/ ; 82501727//Natural Science Foundation of China/ ; 22508091//Natural Science Foundation of China/ ; }, mesh = {Animals ; *Microglia/drug effects/metabolism ; Mice, Transgenic ; Mice ; Proto-Oncogene Protein Spi-1 ; *Alzheimer Disease/drug therapy/metabolism ; *CX3C Chemokine Receptor 1/metabolism ; Trans-Activators/metabolism ; *Glycosides/pharmacology ; *Chemokine CX3CL1/metabolism ; Proto-Oncogene Proteins/metabolism ; Apolipoprotein E4/genetics/metabolism ; Disease Models, Animal ; Male ; Neuroprotective Agents/pharmacology ; Amyloid beta-Peptides/metabolism ; Signal Transduction/drug effects ; Mice, Inbred C57BL ; }, abstract = {Microglia monitor disease stimulation, neuronal apoptosis, and neural repair, and their overactivation-induced inflammation plays a key role in the pathogenesis of Alzheimer's disease (AD). Morroniside (Mor), an iridoid glycoside compound in Cornus officinalis, is one of the effective active components. The effects of Mor on antioxidant stress, antiapoptosis, and nerve repair function have been widely studied, but the mechanism of Mor in AD treatment remains unclear. To study the neuroprotective effects of Mor and elucidate the molecular mechanisms underlying its improvement of AD symptoms, we used ApoE4 transgenic mice and ApoE4-transfected BV2 cells as models of AD, focusing on microglia phenotype, function, and neuroinflammation. The 10-month-old mice were randomly divided into the ApoE3 control group (ApoE3 + Veh), the ApoE4 model group (ApoE4 + Veh), and the ApoE4 + Mor 10, 20, and 40 mg/kg groups as in vivo models. The in vitro BV2-ApoE model was constructed via lentiviral transfection. The effects of Mor on cognitive function of AD models were assessed through behavioral tests, western blot, immunofluorescence staining, and ELISA to measure changes of related pathological and inflammatory factors. Mor improved the cognitive function of ApoE4 transgenic mice by reducing Aβ plaques in the brain, improving the structural lesions of hippocampal neurons, and increasing synaptic plasticity in the brain of AD mice. In addition, Mor promoted the transformation of microglia from the M1 to the M2 phenotype, inhibited the activation of the CX3CR1/PU.1 signaling axis, and alleviated the dysfunction of microglia both in vitro and in vivo. CX3CR1 siRNA and PU.1 siRNA were used further to verify the regulatory effect of Mor on microglia phenotype. Our findings indicate that Mor can inhibit neuroinflammation, reduce Aβ accumulation, and improve synaptic damage in ApoE4 mice via the CX3CL1/CX3CR1/PU.1 pathway regulating the phenotype and function of microglia. This study provides a new therapeutic candidate for the prevention and treatment of AD.}, } @article {pmid41502722, year = {2025}, author = {Wu, H and Huang, N and Wang, K and Mi, J and Liu, Z and Wang, J and Sang, Z and Tan, Z}, title = {Development of Novel 3‑Phenylpropanamide Derivatives as BChE Inhibitors for the Treatment of Alzheimer's Disease.}, journal = {ACS omega}, volume = {10}, number = {48}, pages = {59522-59534}, pmid = {41502722}, issn = {2470-1343}, abstract = {Alzheimer's disease (AD) is a prevalent neurodegenerative degenerative disorder among the elderly, featured by progressive cognitive decline and memory impairment. Due to its complex pathogenesis, there is still no effective therapeutic drug to date. Recently, selective BChE inhibition has been regarded as a potent approach for treating AD. In this work, we conducted structural optimization and structure-activity relationship studies on the previously obtained lead compound EMC-4f, and obtained the potential selective BChE inhibitor 12a (eqBChE, IC50 = 1.3 μM; huBChE, IC50 = 0.95 μM). The in vitro results exhibited that 12a showed good BBB permeability. Moreover, 12a demonstrated significant neuroprotective effects on l-Glu/Aβ25-35-induced HT22 cells injury. Further, the in vivo tests suggested that 12a remarkably alleviated mice cognitive impairment induced by scopolamine. Therefore, these data present that 12a is a promising BChE inhibitor against AD.}, } @article {pmid41502736, year = {2025}, author = {Biswal, B and Pattnaik, S and Satapathy, BS and Maharana, L}, title = {Luliconazole-Loaded Nanoliposomes as a Repurposing Strategy to Combat Memory Dysfunction in LPS-Induced Alzheimer's Rats.}, journal = {ACS omega}, volume = {10}, number = {48}, pages = {59655-59674}, pmid = {41502736}, issn = {2470-1343}, abstract = {Alzheimer's disease (AD) is a major neurodegenerative disorder with no definitive cure. Out of several proposed pathophysiology, microbial infection has recently been identified as one of the key pathogenic contributors for the development and progression of AD. In this context, the present study aims at a repurposing strategy through luliconazole (a potent imidazole derivative)-loaded optimized nanoliposomal carriers to treat AD. Optimized luliconazole-loaded nanoliposomes (LuNLs) were developed by the conventional thin-film hydration method followed by characterization in terms of FESEM, AFM, zeta potential, average size, loading %, and drug release (in vitro). The in vivo effectiveness of the LuNLs was investigated in LPS-induced AD rats. Molecular docking and simulation analysis demonstrated a favorable docking score between luliconazole and selected AD proteins. Spherical, nanosized (52.42 nm), negatively charged (-29.9 mV) LuNLs were reported showing a sustained drug release up to 24 h. An in vivo behavioral study depicted improved cognitive behavior in the LuNLs-treated group as compared to control groups. In vivo antioxidant activity in terms of SOD, MDA, and GSH inhibition by LuNLs was found comparable to that of standard formulation-treated groups, depicting the neuroprotective behavior of LuNLs. The histopathological observation of brain tissue in the LuNLs/control group further substantiated the in vivo behavioral study data. Based on the reports, luliconazole may be used as a viable, efficacious alternative for the treatment of AD, though further preclinical studies are highly warranted.}, } @article {pmid41505203, year = {2026}, author = {Lyketsos, CG and Peters, ME}, title = {Neuropsychiatric symptoms in Alzheimer's disease: Past, present, and future.}, journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association}, volume = {22}, number = {1}, pages = {e71077}, pmid = {41505203}, issn = {1552-5279}, support = {P30AG066507//Johns Hopkins Alzheimer's Disease Research Center/ ; }, mesh = {Humans ; *Alzheimer Disease/psychology/complications ; *Cognitive Dysfunction/psychology ; *Depression/etiology ; Disease Progression ; }, abstract = {Noncognitive neuropsychiatric symptoms (NPS; e.g., depression, agitation) are nearly universal throughout the course of Alzheimer's disease (AD), cause significant adverse impact to patients and caregivers, and are associated with more rapid progression to severe dementia. Although the importance and presence of NPS was recognized by Dr. Alois Alzheimer himself, it was a series of research roundtables in the 2010s that propelled the understanding and treatment of NPS in AD forward. The mild behavioral impairment (MBI) construct was developed as a complementary behavioral analogue to mild cognitive impairment, solidifying the importance of NPS prior to dementia onset. Neurobiological underpinnings of NPS are being studied and the NPS treatment pipeline includes novel therapeutics, repurposing of existing pharmaceuticals, and non-pharmacologic interventions. The Alzheimer's Disease Research Centers and The National Alzheimer's Coordinating Center, being recognized in this special issue, have played a pivotal role in the recognition and study of NPS in AD. HIGHLIGHTS: Noncognitive neuropsychiatric symptoms (NPS) are nearly universal throughout the course of Alzheimer's disease (AD), cause significant adverse impact to patients and caregivers, and are associated with more rapid progression to severe dementia. A series of research roundtables in the last decade and a half have propelled the understanding and treatment of NPS in AD forward. The mild behavioral impairment (MBI) construct was developed as a complementary behavioral analogue to mild cognitive impairment, solidifying the importance of NPS prior to dementia onset. Neurobiological underpinnings of NPS are being studied and the treatment pipeline includes novel therapeutics, repurposing of pharmaceuticals, and non-pharmacologic interventions. The Alzheimer's Disease Research Centers and The National Alzheimer's Coordinating Center have played a pivotal role in the recognition and study of NPS in AD.}, } @article {pmid41505228, year = {2026}, author = {Head, E and Cohen, A and Fortea, J and McGlinchey, E}, title = {Novel insights into Alzheimer's disease through the study of individuals with Down syndrome.}, journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association}, volume = {22}, number = {1}, pages = {e71074}, pmid = {41505228}, issn = {1552-5279}, support = {U19AG068054//NIH/NIA/ ; U19AG068054//NIH/NIA/ ; P30AG066519//NIH/NIA/ ; RF1AG079519//NIH/NIA/ ; U19AG068054//NIH/NIA/ ; P30AG066519//NIH/NIA/ ; RF1AG079519//NIH/NIA/ ; R01AG056850//NIH/NIA/ ; R21AG056974//NIH/NIA/ ; R01AG061566//NIH/NIA/ ; 1R01AG081394//NIH/NIA/ ; R61AG066543//NIH/NIA/ ; //Fondo de Investigaciones Sanitario/ ; INT21/00073//Carlos III Health Institute/ ; PI20/01473//Carlos III Health Institute/ ; PI23/01786//Carlos III Health Institute/ ; //Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED) Program 1/ ; //Fondo Europeo de Desarrollo Regional/ ; SLT006/17/00119//Department de Salut de la Generalitat de Catalunya/ ; //Fundación/ ; IIBSP-DOW-2020-151//Tatiana Pérez de Guzmán el Bueno/ ; H2020-SC1-BHC-2018-2020//Horizon 2020-Research and Innovation Framework Programme/ ; HPE-ADRD 24HPE1284307//Alzheimer Association/ ; }, } @article {pmid41506537, year = {2026}, author = {Liang, YZ and Jiang, MZ and Xu, XT and Zhu, T and Guo, H and Ding, L and Zhong, H and Bao, J and Qin, LQ and Li, YH}, title = {Ameliorating effect and mechanism of p-coumaric acid liposome on cognitive dysfunction and mitochondrial damage under intermittent hypoxia.}, journal = {Life sciences}, volume = {387}, number = {}, pages = {124197}, doi = {10.1016/j.lfs.2026.124197}, pmid = {41506537}, issn = {1879-0631}, mesh = {Animals ; Liposomes ; *Mitochondria/drug effects/metabolism/pathology ; *Hypoxia/complications/drug therapy/metabolism ; Mice ; *Propionates/pharmacology/administration & dosage ; Alzheimer Disease/drug therapy/metabolism ; *Cognitive Dysfunction/drug therapy/metabolism/etiology ; Amyloid beta-Peptides/metabolism ; Neuroprotective Agents/pharmacology/administration & dosage ; *Coumaric Acids/pharmacology ; Male ; Disease Models, Animal ; Cognitive Enhancement ; }, abstract = {AIMS: Alzheimer's disease (AD) has become a global public health problem. Mitochondrial dysfunction contributes to AD pathogenesis, and adequate oxygen supply is essential to maintain mitochondrial homeostasis. P-coumaric Acid (CA) is a polyphenol with anti-hypoxia and anti-AD properties. In this study, CA was formulated into a biomimetic liposome (CA-Lip) to enhance its therapeutic efficacy, and the underlying mechanisms were studied.

MATERIALS AND METHODS: APP/PS1 mice were divided into four groups: AD group, hypoxia treatment group (AD-HY group), hypoxia + CA treatment group (CA group), hypoxia + CA-Lip treatment group (CA-Lip group). Age-matched wild-type littermates were used as controls. Mice in the hypoxia treatment groups were exposed to a hypoxia chamber for 6 h daily for 8 weeks. Cognitive performance and mitochondrial function were subsequently evaluated to determine the ameliorating effects and mechanisms of CA-Lip.

RESULTS: Cognitive impairment and mitochondrial dysfunction were more pronounced in the AD-HY group than in the AD group. CA-Lip produced greater neuroprotective effects than CA. Mechanistic analyses showed that CA-Lip reduced amyloid-β (Aβ) accumulation, enhanced mitochondrial biogenesis (upregulation of PGC-1α expression), maintained mitochondrial dynamics (upregulation of MFN2 expression, and downregulation of DRP1 expression), inhibited excessive mitophagy (downregulation of PINK1 and Parkin expression), enhanced cell autophagy (upregulation of ATG7 and LC3B expression and downregulation of mTOR and P62 expression), and reduced neuronal apoptosis.

CONCLUSIONS: CA-Lip effectively ameliorates hypoxic cognitive impairment by reducing Aβ generation and improving mitochondrial function.}, } @article {pmid41506734, year = {2026}, author = {, and , }, title = {[Guidelines for the management of chronic insomnia comorbid with common neuropsychiatric disorders in adults (2025 edition)].}, journal = {Zhonghua nei ke za zhi}, volume = {65}, number = {1}, pages = {18-44}, doi = {10.3760/cma.j.cn112138-20250911-00539}, pmid = {41506734}, issn = {0578-1426}, support = {2021YFC2501400//National Key Research and Development Program of China/ ; }, mesh = {Humans ; *Sleep Initiation and Maintenance Disorders/therapy/complications ; Comorbidity ; *Mental Disorders/complications/therapy ; Adult ; }, abstract = {Chronic insomnia frequently co-occurs with common neuropsychiatric disorders, including migraine, stroke, Alzheimer's disease, Parkinson's disease, epilepsy, generalized anxiety disorder, depressive disorder, body distress disorder, post-traumatic stress disorder, and disorders due to use of alcohol. The prevalence of these neuropsychiatric disorders is hiher among patients with chronic insomnia than in the general population, and the conditions mutually exacerbate each other. Comorbidities not only exacerbate the severity and increases the relapse risk of each condition but also lead to a poorer prognosis, more severe impairment of social functioning, a higher all-cause mortality risk, and greater treatment challenges. Therefore, the Sleep Disorders Group, Chinese Society of Neurology and Sleep Medicine Group,China Neurologist Association have convened experts in relevant fields, based on current medical evidence, to establish guideline for the management of Chinese adults with chronic insomnia comorbid with the aforementioned 10 categories of common neuropsychiatric disorders. The aim is to standardize clinical practice and improve treatment effectiveness and cure rates.}, } @article {pmid41507065, year = {2026}, author = {De Rui, M and Salerno Trapella, G and Ceolin, C and Ceccato, F and Antonelli, G and Ravelli, A and Andreuzza, R and Conti, E and Sarlo, M and Coin, A and Zanforlini, BM and Bertocco, A and Curreri, C and Tizianel, I and Mapelli, D and Sergi, G and Devita, M}, title = {Effect of cognitive training on cortisol levels in patients with neurocognitive disorders.}, journal = {The journals of gerontology. Series B, Psychological sciences and social sciences}, volume = {81}, number = {2}, pages = {}, pmid = {41507065}, issn = {1758-5368}, mesh = {Humans ; *Hydrocortisone/metabolism/analysis ; Female ; Male ; *Cognitive Training ; Aged ; Saliva/chemistry ; *Neurocognitive Disorders/metabolism/therapy ; }, abstract = {OBJECTIVES: Elevated cortisol levels are linked to a greater risk and faster progression of neurocognitive disorders (NCDs). While interventions such as exercise and mindfulness have shown benefits in reducing cortisol, the impact of cognitive training (CT) on cortisol regulation remains unexplored. This study investigated whether CT affects cortisol levels and secretion patterns in individuals with minor or major NCD and compared its effects with those of pharmacological treatment.

METHODS: Sixty-two older adults with NCD and 43 healthy controls were recruited from the University Hospital of Padua in Italy. Among patients with NCD, 34 underwent CT (CT-NCD group), and 28 received pharmacological treatment (PH-NCD group). Salivary cortisol was measured at six points during the day, at baseline, and at 3 months (T1) and 6 months (T2) post-intervention.

RESULTS: Compared with pharmacological treatment (PH), CT showed a larger percentage decrease of daily cortisol exposure area under the curve (AUC) from baseline; however, the between-group difference did not remain statistically significant after covariate adjustment, and the only robust time-point effect was in the afternoon (F(1,47)=5.13; p = .028). Morning values decreased within groups, but between-group differences in the CAR were not significant; at bedtime, CT showed only a trend towards lower cortisol than PH (p = .071). Median morning values changed from 7.75 to 6.20 in CT and from 5.80 to 5.15 in PH.

DISCUSSION: Cognitive training may help lower cortisol levels and enhance cognitive function in NCD patients, suggesting its potential as a nonpharmacological tool to modulate hypothalamic-pituitary-adrenal axis activity. Larger randomized studies are needed to confirm and extend these findings.}, } @article {pmid41508060, year = {2025}, author = {Sun, CX and Han, XY and Xiao, YT and Liu, YX and Ye, TY}, title = {[Research progress on prevention and treatment of Alzheimer's disease with Danggui Shaoyao San].}, journal = {Zhongguo Zhong yao za zhi = Zhongguo zhongyao zazhi = China journal of Chinese materia medica}, volume = {50}, number = {22}, pages = {6215-6226}, doi = {10.19540/j.cnki.cjcmm.20250626.601}, pmid = {41508060}, issn = {1001-5302}, mesh = {*Drugs, Chinese Herbal/administration & dosage/therapeutic use ; *Alzheimer Disease/drug therapy/prevention & control/metabolism/genetics ; Humans ; Animals ; Amyloid beta-Peptides/metabolism/genetics ; }, abstract = {Alzheimer's disease is a neurodegenerative disorder associated with aging. In traditional Chinese medicine(TCM), it is classified as a syndrome of root deficiency and branch excess. Danggui Shaoyao San, a classic formula traditionally used to treat gynecological disorders, has the effects of promoting blood circulation, removing blood stasis, opening orifices, awakening the mind, strengthening the spleen, resolving phlegm, and tonifying Qi to nourish the spirit. Modern clinical studies have found that Danggui Shaoyao San can slow the progression of Alzheimer's disease and has great potential for clinical application. Recent studies indicate that Danggui Shaoyao San treats Alzheimer's disease through multi-target and multi-level mechanisms. These include clearing amyloid β(Aβ) plaques and abnormally phosphorylated tau protein, maintaining brain-gut homeostasis, reducing oxidative stress, and regulating autophagy. Its key components, paeoniflorin and ferulic acid, have also been reported to exert antioxidant, anti-inflammatory, and anti-apoptotic effects, eliminate pathological products, and regulate the cholinergic system in the brain. This paper traces the classic formula of Danggui Shaoyao San, conducts a theoretical integration of ancient and modern medical systems, and systematically summarizes and analyzes the research related to the treatment of Alzheimer's disease using Danggui Shaoyao San and its key components. It aims to provide a valuable reference for further research and modern application of Danggui Shaoyao San in the treatment of Alzheimer's disease.}, } @article {pmid41508178, year = {2025}, author = {Hou, WX and Liu, YX and Miao, JR and Zhu, ZK and Yin, Y and Liu, JL and Zhao, DY}, title = {[Mechanism of Liuwei Dihuang Pills in enhancing GPNMB expression to regulate FcγRⅡB/c-Src pathway for prevention and treatment of Alzheimer's disease].}, journal = {Zhongguo Zhong yao za zhi = Zhongguo zhongyao zazhi = China journal of Chinese materia medica}, volume = {50}, number = {21}, pages = {6062-6071}, doi = {10.19540/j.cnki.cjcmm.20250805.401}, pmid = {41508178}, issn = {1001-5302}, mesh = {Animals ; *Alzheimer Disease/genetics/drug therapy/metabolism/prevention & control ; *Drugs, Chinese Herbal/administration & dosage ; Mice ; Male ; *Membrane Glycoproteins/genetics/metabolism ; Humans ; Signal Transduction/drug effects ; *Receptors, IgG/metabolism/genetics ; Hippocampus/drug effects/metabolism ; *src-Family Kinases/metabolism/genetics ; Amyloid beta-Peptides/metabolism/genetics ; }, abstract = {This study investigated the effect of Liuwei Dihuang Pills on the Fcγ receptor Ⅱ-b(FcγRⅡB)/c-Src tyrosine kinase(c-Src) pathway in senescence-accelerated mouse prone 8(SAMP8) by regulating the expression of the glycoprotein non-metastatic melanoma protein B(GPNMB) and explored the mechanism of the kidney-tonifying and essence-strengthening therapy in the treatment of Alzheimer's disease.(1) For the effects of Liuwei Dihuang Pills on the learning and memory ability, hippocampal β-amyloid protein(Aβ), GPNMB, and autophagy function in SAMP8 mice, eight seven-month-old male senescence-accelerated mouse resistant 1(SAMR1) mice were used as a control group, and 16 male SAMP8 mice of the same age were randomly divided into a model group and a Liuwei Dihuang Pills group. The Liuwei Dihuang Pills group was given 2.36 g·kg~(-1) concentrated Liuwei Dihuang Pills solution by gavage, while the control group and the model group were given the same volume of normal saline twice a day for four consecutive weeks. The learning and memory ability of mice in each group was detected by the Morris water maze experiment; the expression level of Aβ in the hippocampus of mice were detected by enzyme-linked immunosorbent assay(ELISA) and immunohistochemistry; the expression of GPNMB in the hippocampus of mice was detected by immunofluorescence and Western blot; the expression level of ubiquitin-binding protein p62 and microtubule-associated protein light chain 3(LC3) Ⅱ/LC3Ⅰ in the hippocampus of mice was measured by Western blot.(2) For the regulatory effect of GPNMB on the FcγRⅡB/c-Src pathway, eight seven-month-old male SAMR1 mice were used as a control group, and 24 male SAMP8 mice of the same age were randomly divided into a model group, an LV-Vector group, and an LV-GPNMB~(OE) group. The bilateral hippocampus of the LV-Vector group and LV-GPNMB~(OE) group was injected with LV-Vector and LV-GPNMB~(OE) of 2 μL/each side, respectively. Western blot was used to detect the expression level of p62, LC3Ⅱ/LC3Ⅰ, FcγRⅡB, Src homology 2 protein tyrosine phosphatase 1(SHP-1), and c-Src proteins in the hippocampus of mice.(3) For the effect of Liuwei Dihuang Pills in regulating the FcγRⅡB/c-Src pathway by increasing the GPNMB expression, 32 seven-month-old male SAMP8 mice were randomly divided into a model group, a Liuwei Dihuang Pills group, a Liuwei Dihuang Pills + LV-NC group, and a Liuwei Dihuang Pills + LV-shGPNMB group. The bilateral hippocampus of the Liuwei Dihuang Pills + LV-NC group and Liuwei Dihuang Pills + LV-shGPNMB group was injected with LV-NC and LV-shGPNMB, respectively, before the drug treatment. Western blot was used to detect the expression level of p62, LC3Ⅱ/LC3Ⅰ, FcγRⅡB, SHP-1, and c-Src proteins in the hippocampus of mice. The results showed that(1) compared with those of the control group, the escape latency of the model group was significantly increased, and the time spent in the target quadrant and the effective area was significantly decreased. The expression level of Aβ, GPNMB, and p62 in the hippocampus was significantly increased, and the level of LC3Ⅱ/LC3Ⅰ was significantly decreased. Compared with those of the model group, the escape latency of the Liuwei Dihuang Pills group was significantly shortened, and the time spent in the target quadrant and the effective area was significantly increased. The level of Aβ was significantly decreased, and the expression level of GPNMB was significantly increased. The expression level of p62 was significantly decreased, and the level of LC3Ⅱ/LC3Ⅰ was significantly increased.(2) Compared with those of the control group, the expression level of p62, FcγRⅡB, SHP-1, and c-Src proteins in the hippocampus of the model group was significantly increased, and the level of LC3Ⅱ/LC3Ⅰ was significantly decreased. Compared with those of the model group, the expression level of p62, FcγRⅡB, SHP-1, and c-Src in the LV-GPNMB~(OE) group was significantly decreased, and the level of LC3Ⅱ/LC3Ⅰ was significantly increased.(3) Compared with those of the model group, the expression level of p62, FcγRⅡB, SHP-1, and c-Src in the Liuwei Dihuang Pills group was significantly decreased, and the level of LC3Ⅱ/LC3Ⅰ was significantly increased. Compared with those of the Liuwei Dihuang Pills group, the expression level of p62, FcγRⅡB, SHP-1, and c-Src in the Liuwei Dihuang Pills + LV-shGPNMB group was significantly increased, and the level of LC3Ⅱ/LC3Ⅰ was significantly decreased. These results indicate that Liuwei Dihuang Pills can inhibit the FcγRⅡB/c-Src pathway by up-regulating the GPNMB expression, thereby increasing autophagy levels, enhancing neuroprotective ability, and alleviating Alzheimer's disease.}, } @article {pmid41508200, year = {2025}, author = {Zhang, YX and Wang, J and Chen, QQ and Zhang, JL and Wang, Q and Long, YL and Zhou, SJ and Gong, ZP and Zheng, L and Huang, Y and Li, YT}, title = {[Study on quality markers of Pleione yunnanensis for "same treatment for different diseases" in liver inflammation and Alzheimer's disease based on UHPLC fingerprint and network pharmacology].}, journal = {Zhongguo Zhong yao za zhi = Zhongguo zhongyao zazhi = China journal of Chinese materia medica}, volume = {50}, number = {20}, pages = {5684-5696}, doi = {10.19540/j.cnki.cjcmm.20250710.202}, pmid = {41508200}, issn = {1001-5302}, mesh = {Chromatography, High Pressure Liquid ; *Alzheimer Disease/drug therapy/genetics/metabolism ; *Drugs, Chinese Herbal/chemistry ; Network Pharmacology ; Humans ; Molecular Docking Simulation ; Biomarkers/analysis ; Quality Control ; *Hepatitis/drug therapy/genetics ; }, abstract = {This study aims to screen quality markers(Q-markers) of Pleione yunnanensis for the treatment of liver inflammation and Alzheimer's disease(AD) based on the concept of "same treatment for different diseases" using ultra-high-performance liquid chromatography(UHPLC) fingerprinting combined with network pharmacology and molecular docking, and to perform quantitative analysis of the identified Q-markers. The UHPLC fingerprints of 15 batches of P. yunnanensis were established and subjected to similarity evaluation, cluster analysis(CA), principal component analysis(PCA), and orthogonal partial least squares discriminant analysis(OPLS-DA) to identify characteristic components responsible for quality variations. Network pharmacology and molecular docking were employed to explore the potential active components, related targets, and signaling pathways underlying the "same treatment for different diseases" mechanism for liver inflammation and AD. Based on the criteria of effectiveness, specificity, and measurability, Q-markers of P. yunnanensis were identified and quantified. Ten common peaks were identified in the UHPLC fingerprints of 15 batches, with eight components identified. Similarity scores ranged from 0.774 to 0.987. Chemical pattern recognition analysis identified that shancigusin H, militarine, and gymnoside Ⅴ were the major characteristic components contributing to quality differences among batches. RESULTS:: of network pharmacology and molecular docking revealed that dactylorhin A and militarine were the key active components exerting anti-inflammatory and neuroprotective effects. These components acted on 13 core targets, including SRC, CASP3, and CTNNB1, and regulated signaling pathways such as the PI3K-Akt signaling pathway and arachidonic acid metabolism. Based on the effectiveness, specificity, and measurability of Q-marker, dactylorhin A and militarine were selected as the Q-markers of P. yunnanensis. Quantitative analysis demonstrated that the content of dactylorhin A ranged from 0.527% to 2.21%, and militarine ranged from 0.731% to 2.58% across the 15 batches. The UHPLC fingerprint method and Q-marker-based quantification approach are robust and reliable, providing experimental evidence for quality control and standardization of P. yunnanensis.}, } @article {pmid41508224, year = {2025}, author = {Ma, YJ and Deng, SX and Liao, ZH and Gao, MH and Ding, HX and Xu, ZQ and Lu, YT and Yang, C and Wang, Q}, title = {[Treatment of Alzheimer's disease from gut-brain interactions based on theory of "spleen deficiency leading to obstruction of nine orifices"].}, journal = {Zhongguo Zhong yao za zhi = Zhongguo zhongyao zazhi = China journal of Chinese materia medica}, volume = {50}, number = {19}, pages = {5330-5339}, doi = {10.19540/j.cnki.cjcmm.20250618.501}, pmid = {41508224}, issn = {1001-5302}, mesh = {*Alzheimer Disease/drug therapy/physiopathology/metabolism ; Humans ; *Brain/physiopathology/drug effects/metabolism ; *Spleen/physiopathology/drug effects ; Animals ; Medicine, Chinese Traditional ; Drugs, Chinese Herbal/therapeutic use ; Gastrointestinal Microbiome ; }, abstract = {Alzheimer's disease(AD) is the most common form of dementia. The decline in sensory function is associated with pathological damage in specific brain regions during the early stages of AD. Such decline often precedes cognitive impairment, worsens as the pathology progresses, and constitutes a high-risk factor for the onset of AD. According to traditional Chinese medicine(TCM), all orifices are connected to the brain, and the brain governs all orifices. The mind originates from and depends on both the brain and orifices, with their physiological and pathological states being closely interconnected. In AD, dysfunction of the sensory orifices is closely linked to the later-stage manifestations of impaired mental clarity and consciousness. The theory that "spleen deficiency leading to obstruction of nine orifices" emphasizes that insufficiency of the spleen and stomach is the root cause of orifice dysfunction. Both internal and external pathogenic factors in AD can damage the spleen and stomach, leading to the abnormal movement of turbid substances generated by these organs, which may transform into turbid toxins. This, in turn, gradually impairs the orifices, brain, and mind, thereby exacerbating the progression of AD. The digestive, absorptive, and transport functions of the spleen and stomach are similar to those of the gut microbiota. Spleen deficiency is a core pathological factor in diseases associated with gut microbiota dysbiosis. Such dysbiosis can lead to dysfunction in the neural, metabolic, and immune pathways involved in gut-brain interactions, constituting the biological basis for the TCM concept that "spleen deficiency leading to obstruction of nine orifices". Under the guidance of this theory, employing spleen-strengthening and cognition-enhancing drugs alongside aromatic orifice-opening drugs to support spleen function, and using ingredients that promote dampness elimination, lubrication, and blood stasis resolution to dispel pathogenic factors from the orifices, can help restore the structural balance of the gut microbiota, regulate related metabolic and immune dysfunctions, and ultimately delay the progression of AD. This article explores the etiology, pathogenesis, and therapeutic strategies of AD based on the theory of "spleen deficiency leading to obstruction of nine orifices", and interprets its biological significance from the perspective of gut-brain interactions, aiming to provide new insights for the prevention and treatment of AD.}, } @article {pmid41509242, year = {2025}, author = {Kumari, R and Bowen, C and Srivastava, U and Brandelli, AD and Kumar, P and Kour, D and Malepati, S and Jang, WE and Bromwich, M and Zeng, H and Sing, A and Sloan, SA and Wulff, H and Rangaraju, S}, title = {Kv1.3 inhibition alleviates neuropathology via neuroinflammatory and resilience pathways in a mouse model of Aβ pathology.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, doi = {10.64898/2025.12.25.696456}, pmid = {41509242}, issn = {2692-8205}, support = {R01 AG071587/AG/NIA NIH HHS/United States ; R01 AG075820/AG/NIA NIH HHS/United States ; R01 NS114130/NS/NINDS NIH HHS/United States ; }, abstract = {Inhibition of voltage-gated potassium channel Kv1.3 is a therapeutic strategy to curb microglia-mediated neuroinflammation in neurodegeneration, although the cellular and signaling mechanisms of disease-modification by Kv1.3 blockers are unclear. In this study, we delineate protective mechanisms of Kv1.3 blockade in a mouse model of Alzheimer's disease (AD) pathology using comprehensive transcriptomics and proteomics profiling of brain, corresponding with neuropathological effects of two translationally relevant Kv1.3 blockers, namely small molecule PAP-1 and peptide ShK-223. Following 3 months of treatment, both molecules reduced Ab plaque burden. Single nuclear RNA seq (snRNA seq) of brain nuclei showed that PAP-1 disproportionately impacted oligodendrocytes and microglia and increased crosstalk between neurons and astrocytes with endothelial cells. In contrast, ShK-223 had pronounced effects on glutamatergic neurons and astrocytes. Both blockers increased expression of myelination genes in oligodendrocytes and synaptic genes in neurons. Neuroprotective effects of PAP-1 were further confirmed by bulk brain transcriptomics and proteomics whereby PAP-1 increased levels of synaptic, cognitive resilience and mitochondrial proteins, while decreasing glial and immune pathways including STAT1/3 phosphorylation. Using proximity labeling and co-immunoprecipitation, we found that Kv1.3 interacts with STAT1/3 in microglia. Using microglial cell lines and primary microglia, we discovered a preferential functional coupling between Kv1.3 and type 2 but not type 1 IFN signaling. Brain-level disease modification by Kv1.3 blockade was reflected in the cerebrospinal fluid (CSF) via reduced levels of neurofilament-light (NEFL) and resilience protein RPH3A, both of which are increased in human AD CSF. Together, this study demonstrates functional links between Kv1.3 channels and type 2 IFN signaling and reveals distinct cellular effects of Kv1.3 blockers in AD pathology that correspond with reduced neuropathology and neuroinflammation, augmentation of resilience and neuro-vascular pathways, along with biomarkers of therapeutic effect.}, } @article {pmid41509252, year = {2026}, author = {Jesudason, CD and Rangel-Barajas, C and Beach, CJ and Beck, DE and Caballero-Floran, IH and Clayton, WB and Da Silva, L and David, JC and Doolen, S and Faulkner, AN and Hamdani, AK and Huhe, H and Huynh, K and Imhoff, RD and Javens-Wolfe, J and Mason, ER and Moussaif, M and Singhal, K and Soni, DM and van Buuren-Milne, M and Williams, SP and Angus, SP and Chu, S and Dage, JL and Hipskind, PA and Johnson, TS and Kaddurah-Daouk, R and Lamb, BT and Meikle, PJ and Mesecar, AD and Palkowitz, AD and Quinney, SK and Sukoff Rizzo, SJ and Oblak, AL and Richardson, TI}, title = {Optimization and Characterization of SHIP1 Ligands for Cellular Target Engagement and Activity in Alzheimer's Disease Models.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {41509252}, issn = {2692-8205}, support = {T32 AG071444/AG/NIA NIH HHS/United States ; U01 AG088021/AG/NIA NIH HHS/United States ; U54 AG065181/AG/NIA NIH HHS/United States ; T32 CA272370/CA/NCI NIH HHS/United States ; P30 CA082709/CA/NCI NIH HHS/United States ; R01 AG081322/AG/NIA NIH HHS/United States ; }, abstract = {Src homology 2 domain-containing inositol 5-phosphatase 1 (SHIP1), encoded by the gene INPP5D, is a lipid phosphatase that negatively regulates immune receptor signaling in hematopoietic cells and microglia. Here, we describe a pyridyl-pyrazole-piperidine scaffold and the lead compound 3-((2-chlorobenzyl)oxy)-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyridine (32), which demonstrates SHIP1 target engagement, brain exposure, and evidence of a central pharmacodynamic response in vivo. Structure-activity relationship studies, guided by biochemical and cellular assays using multiple human and murine protein constructs and cells, identified SHIP1-active ligands. A thermal shift assay using full-length SHIP1 was used to assess compounds for cellular target engagement, while studies in IL-4 conditioned THP-1 cells was used to demonstrate changes in downstream AKT signaling. Targeted lipidomics revealed changes in the overall phosphoinositide pool consistent with SHIP1 target engagement and reduction of phospho-AKT levels. In a protein-lipid overlay assay, compound 32 induced changes in the relative association of SHIP1 with multiple phosphatidylinositols on a membrane surface. In high-content cellular imaging assays, compound 32 enhanced the uptake of myelin/membrane debris and fibrillar amyloid by primary murine microglia, phenocopying a genetic model with reduced SHIP1 expression. Finally, oral administration of compound 32 resulted in brain exposure sufficient to alter gene expression and reduce IL-1β levels as pharmacodynamic markers of microglial activation and neuroinflammation in an amyloidosis mouse model of Alzheimer's disease. Collectively, these results define a scaffold with SHIP1 target engagement, CNS exposure, and in vivo activity, providing a foundation for the optimization of brain-penetrant SHIP1 ligands suitable for further mechanistic studies and therapeutic development for the treatment of Alzheimer's disease.}, } @article {pmid41509358, year = {2026}, author = {Jati, S and Kal, S and Munoz-Mayorga, D and Tang, K and Sahoo, D and Chen, X and Mahata, SK}, title = {Catestatin ameliorates tauopathy and amyloidogenesis via adrenergic inhibition.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {41509358}, issn = {2692-8205}, support = {I21 RX004398/RX/RRD VA/United States ; P30 NS047101/NS/NINDS NIH HHS/United States ; R21 AG091126/AG/NIA NIH HHS/United States ; R01 AG074273/AG/NIA NIH HHS/United States ; R21 AG078635/AG/NIA NIH HHS/United States ; R01 AG078185/AG/NIA NIH HHS/United States ; R21 AG080246/AG/NIA NIH HHS/United States ; R01 GM138385/GM/NIGMS NIH HHS/United States ; UG3 TR003355/TR/NCATS NIH HHS/United States ; R01 AI155696/AI/NIAID NIH HHS/United States ; }, abstract = {Neurodegenerative disorders like Alzheimer's disease (AD), Corticobasal Degeneration (CBD), and Progressive Supranuclear Palsy (PSP) are characterized by Tau aggregation, synaptic dysfunction, neuroinflammation, and progressive cognitive decline. Although metabolic dysregulation and neuropeptide imbalance have been linked to these disorders, the functional consequences of such imbalance and its potential for therapeutic reversal remain poorly understood. Our previous work identified chromogranin A (CgA), which encodes a pro-hormone for several metabolic peptides, as a key regulator of Tau pathology. Here, we investigate Catestatin (CST), a CgA-derived peptide that is a potent inhibitor of catecholamine release and has been shown to increase insulin sensitivity and lower peripheral blood pressure. We report significant reductions in CST levels in the hippocampus and cortex of AD brains, as well as in the frontal cortex of CBD and the basal ganglia of PSP. Supplementing CST in cortical neuronal cultures and organotypic slice cultures (OTSC) decreased Tau phosphorylation and aggregation. In vivo, CST administration in PS19 Tauopathy mice reduced pathological Tau species, attenuated gliosis, and improved cognitive function. CST treatment also lowered amyloid plaque burden and neuroinflammation in 5xFAD mice. Mechanistically, CST decreased epinephrine (EPI) levels in both PS19 and 5xFAD mice and suppressed downstream protein kinase A (PKA) hyperactivation in PS19 and OTSC. These findings reveal a previously unrecognized neuropeptidergic mechanism linking CST deficiency to elevated adrenergic receptor (ADR)-EPI-PKA stress signaling and Tauopathy-driven neurodegeneration, suggesting CST replacement as a promising therapeutic approach.}, } @article {pmid41510223, year = {2025}, author = {Jiang, L and Tucker, A and Sepehri, C and Patel, D and Wang, Q and Yuan, S and Sherman, E and Chen, Y and Beh, J and Downey, A and Goldberg, D and Gniadzik, W and Ma, X}, title = {Inhibition of N6-Methyladenosine Accumulation by Targeting METTL3 Mitigates Tau Pathology and Cognitive Decline in Alzheimer's Disease.}, journal = {Research square}, volume = {}, number = {}, pages = {}, pmid = {41510223}, issn = {2693-5015}, support = {R01 AG091577/AG/NIA NIH HHS/United States ; }, abstract = {Dysregulation of N6-methyladenosine (m6A) modification of RNA has emerged as a novel feature of Alzheimer's disease (AD). Here, we investigate the relationship between m6A modification and AD pathology, and the therapeutic potential of modulating excessive m6A via its "writer" methyltransferase METTL3 in a humanized P301S tau transgenic mouse model of AD (PS19). We observed significantly elevated m6A levels in human post-mortem AD frontal cortex tissue compared to healthy controls, which positively correlated with hyperphosphorylated tau and amyloid-β (Aβ) deposition. These effects were recapitulated in the PS19 tau mice model of AD. Importantly, treatment of PS19 mice with the METTL3 inhibitor STM2457 reduced excessive m6A, alleviated tau pathology, and attenuated neurodegeneration. Behavioral assessments further demonstrated that STM2457-treated PS19 mice exhibited significantly improved learning and memory relative to untreated PS19 mice. Our results identify m6A as a critical contributor to AD pathogenesis and demonstrate that pharmacological inhibition of METTL3 represents a promising therapeutic strategy to improve cognition in AD.}, } @article {pmid41510304, year = {2025}, author = {Wang, Y and Zhou, M and Tang, Z and Xiong, C and Asken, B and Yang, B and Su, J and Zhou, X and Song, Q}, title = {CauReL: Dynamic Counterfactual Learning for Precision Drug Repurposing in Alzheimer's Disease.}, journal = {Research square}, volume = {}, number = {}, pages = {}, pmid = {41510304}, issn = {2693-5015}, support = {R01 LM014156/LM/NLM NIH HHS/United States ; OT2 OD025315/OD/NIH HHS/United States ; OT2 OD026551/OD/NIH HHS/United States ; OT2 OD026552/OD/NIH HHS/United States ; OT2 OD026549/OD/NIH HHS/United States ; OT2 OD025337/OD/NIH HHS/United States ; OT2 OD025277/OD/NIH HHS/United States ; OT2 OD026555/OD/NIH HHS/United States ; OT2 OD026550/OD/NIH HHS/United States ; OT2 OD026553/OD/NIH HHS/United States ; OT2 OD023205/OD/NIH HHS/United States ; OT2 OD025276/OD/NIH HHS/United States ; OT2 OD026557/OD/NIH HHS/United States ; OT2 OD026554/OD/NIH HHS/United States ; U24 OD023163/OD/NIH HHS/United States ; OT2 OD023206/OD/NIH HHS/United States ; OT2 OD026556/OD/NIH HHS/United States ; R01 GM153822/GM/NIGMS NIH HHS/United States ; U24 OD023176/OD/NIH HHS/United States ; OT2 OD026548/OD/NIH HHS/United States ; R35 GM151089/GM/NIGMS NIH HHS/United States ; U2C OD023196/OD/NIH HHS/United States ; U24 OD023121/OD/NIH HHS/United States ; R01 CA241930/CA/NCI NIH HHS/United States ; }, abstract = {Alzheimer's disease has few effective therapies, and decades of amyloid- and tau-focused trials have delivered only modest benefit with substantial toxicity. Drug repurposing using real-world data offers a faster and lower-risk route to new treatments, yet current approaches typically average effects across populations, model disease onset and progression separately, and provide little insight into which patients are most likely to benefit. We present CauReL, a dynamic counterfactual representation learning framework that enables transparent, patient specific estimation of treatment effects from large-scale electronic health records for precision drug repurposing in AD. CauReL first learns balanced latent representations of treated and untreated patients using Integral Probability Metric regularization, then jointly predicts two clinically linked outcomes, incident AD and time from mild cognitive impairment (MCI) to AD, to generate paired counterfactual outcomes for every individual. A counterfactual explanation module quantifies how clinical features shape benefit at the patient level, and uplift trees transform complex heterogeneity into simple, rule-based subgroups suitable for trial enrichment and clinical decision support. Using independent cohorts from OneFlorida+ and All of Us, we screened outpatient prescriptions with at least 20 percent exposure among 28,605 individuals with mild cognitive impairment, of whom 4,990 progressed to Alzheimer's disease. CauReL substantially improved covariate balance and distributional overlap across drug cohorts and achieved strong predictive accuracy for both incidence (AUC greater than 0.90) and progression timing (C index 0.81 to 0.84; Spearman 0.80 to 0.86). Twenty drugs showed consistent protective associations, with four emerging as highly reproducible across both networks, the metabolic agents liraglutide and empagliflozin and the neuroactive agents entacapone and amantadine. These drugs were associated with meaningful absolute risk reductions and clinically significant delays in progression from mild cognitive impairment to Alzheimer's disease. Metabolic drugs produced the strongest benefits in individuals with diabetes, obesity, or cardiovascular disease, whereas neuroactive drugs provided broadly consistent protection across most subgroups. CauReL is available as an open source Python package with a companion web server for direct application to new cohorts or disease settings (https://caurel.site/). This work delivers a scalable and interpretable framework for prioritizing repurposable drugs and designing targeted clinical trials for the patients most likely to benefit.}, } @article {pmid41510365, year = {2026}, author = {Wang, Y and Alexander, GC and Mehta, HB}, title = {Treatment of type 2 diabetes among medicare beneficiaries with and without alzheimer's disease: A retrospective cohort study.}, journal = {Journal of diabetes and metabolic disorders}, volume = {25}, number = {1}, pages = {25}, pmid = {41510365}, issn = {2251-6581}, abstract = {PURPOSE: While Alzheimer's disease (AD) and type 2 diabetes mellitus (T2DM) commonly co-occur in older adults, little is known regarding whether and how the treatment of T2DM varies by AD status. This study aimed to compare and contrast T2DM treatment among individuals with and without AD.

METHODS: We conducted a retrospective cohort study using 20% Medicare Fee-for-Service claims data from 2016 to 2020. The primary outcome was initiation of any antidiabetic medication within one year of T2DM diagnosis, and we also examined initiation patterns across specific drug classes. We used multivariable logistic regression to estimate adjusted odds ratios for the association between AD and treatment initiation.

RESULTS: Among 388,359 beneficiaries newly diagnosed with T2DM, 9,584 had AD. Within one year, overall treatment initiation was lower for individuals with AD compared to those without. At initiation, individuals with AD were more likely to receive insulin and less likely to receive metformin, sodium-glucose cotransporter 2 (SGLT2) inhibitors, or glucagon-like peptide-1 (GLP-1) receptor agonists. In adjusted models, AD was associated with lower odds of antidiabetic treatment initiation, and among those initiating treatment, lower odds of initiating newer agents such as GLP-1 receptor agonists and SGLT2 inhibitors.

CONCLUSION: Beneficiaries with AD were less likely to initiate antidiabetic therapy, particularly newer agents. Future work could explore the basis for these differences.}, } @article {pmid41510572, year = {2026}, author = {Tang, C and Han, K and Wen, X and Zhang, J and Sun, W and Yue, X and Shi, L and Liu, Z and Zhao, J and Yan, C and Liu, M and Yao, Z and Kong, Z and Liu, Y and Fu, Z and Zhao, X and Yang, Z and Han, M and Chen, C and Xing, Z and Zhou, X and Yang, F and Zhang, Y and Jiang, X}, title = {Synthetic Disaggregators Enhance Central-Peripheral Amyloid-β Clearance in Alzheimer's Disease.}, journal = {Advanced materials (Deerfield Beach, Fla.)}, volume = {38}, number = {11}, pages = {e20002}, doi = {10.1002/adma.202520002}, pmid = {41510572}, issn = {1521-4095}, support = {2024YFA0918400//National Key Research and Development Program of China/ ; 82350125//National Natural Science Foundation of China/ ; 82425056//National Natural Science Foundation of China/ ; 82173763//National Natural Science Foundation of China/ ; 82303810//National Natural Science Foundation of China/ ; ZR2022ZD18//Fundamental Research Funds of Shandong Province/ ; ZR2023QH224//Natural Science Foundation of Shandong Province/ ; 2022M721967//China Postdoctoral Science Foundation/ ; 2024T170524//China Postdoctoral Science Foundation/ ; SYS202202//Shandong Provincial Laboratory Project/ ; NO.tsqnz20221165//Taishan Scholar Foundation of Shandong Province/ ; 2025CXPT177//Key R&D Program of Shandong Province/ ; 2025CXPT177//Key R&D Program of Shandong Province/ ; }, mesh = {*Alzheimer Disease/metabolism/pathology/drug therapy ; Animals ; *Amyloid beta-Peptides/metabolism/chemistry ; Mice ; Macrophages/metabolism/drug effects ; Nanoparticles/chemistry ; Humans ; Phagocytosis/drug effects ; *Protein Aggregates/drug effects ; Brain/metabolism/pathology ; }, abstract = {Pathogenic amyloid-β (Aβ) accumulation defines Alzheimer's disease (AD), directly inflicting neuronal damage and driving chronic neuroinflammation. While both central microglia and peripheral macrophages are critical for Aβ clearance, their functional impairment in AD inexorably leads to escalating Aβ burden and disease progression. We here report an in situ engineered synthetic Aβ disaggregator (SAD) delivered to macrophages via neuroprotective DHA-based lipid nanoparticles (DLNPs). This platform transcends current therapeutic limitations by not only potently dismantling neurotoxic Aβ aggregates but also by fundamentally reprogramming peripheral macrophages to enhance Aβ clearance. Specifically, our results demonstrate that DLNPs effectively reprogram peripheral macrophages to produce and secrete cerebral-penetrating SAD both in vitro and in vivo. The SAD can promote cerebral Aβ disaggregation, thereby inhibiting neuroinflammatory pathology progression. Moreover, the DLNPs efficiently reprogram the peripheral macrophages to enhance phagocytosis, further facilitating drainage of Aβ and reducing cerebral Aβ accumulation in mouse models. Collectively, these findings uncover a dual-action mechanism of SAD through the synergistic interplay of direct Aβ disaggregation and enhanced macrophage-mediated clearance. In sum, our findings establish that the central-peripheral targeting therapeutic strategy significantly reversed AD pathology, highlighting the therapeutic potential of mRNA-based in situ fusion protein in AD treatment.}, } @article {pmid41510716, year = {2026}, author = {Bano, A and Khan, AA and Kushwaha, SP and -, A and Zaidi, SMH and Misbahul Hasan, S and Fatima, A}, title = {Indole Scaffolds in Neurological Therapeutics: Synthesis, Structure-Activity Relationships and Drug-Receptor Interactions.}, journal = {Mini reviews in medicinal chemistry}, volume = {}, number = {}, pages = {}, doi = {10.2174/0113895575415521251021091530}, pmid = {41510716}, issn = {1875-5607}, abstract = {INTRODUCTION: Indole is a privileged heterocyclic scaffold that plays a crucial role in medicinal chemistry due to its strong ability to bind to various biological receptors and interact with diverse molecular targets. Indole exhibits both biological and chemical significance. Its structural versatility allows for precise chemical modifications, making it an essential framework in drug discovery. This review discusses the structure-activity relationships, synthesis, and interactions of indole derivatives, particularly in relation to targets within the central nervous system.

METHODS: A detailed literature survey was conducted using databases such as Google Scholar, Elsevier, PubMed, ACS, PubChem, ScienceDirect, and RSC to understand the structural modifications of indole derivatives and their therapeutic potential. Both research and review articles related to indole- based compounds were thoroughly studied to prepare this review article.

RESULTS: There are over 40 FDA-approved drugs containing an indole nucleus used to treat various diseases, underscoring its potential in neurotherapeutics. This review highlights innovative synthetic strategies, including green chemistry approaches, that improve the drug-likeness and bioavailability of indole derivatives. Indole continues to be an indispensable scaffold in the development of novel therapeutics aimed at addressing the growing burden of neurological disorders.

DISCUSSION: This review aims to provide a comprehensive analysis of the therapeutic potential of indole-based compounds for the treatment of neurological disorders. However, challenges like blood-brain barrier permeability and long-term safety must be addressed for clinical success. Nonetheless, this review will help in designing and developing newer indole-based molecules in the discovery of neurological drug development.

CONCLUSION: Due to its broad spectrum of biological activities and favorable pharmacokinetic properties, indole is an impressive scaffold for the treatment of various neurological disorders. Indole demonstrates remarkable therapeutic potential against a range of central nervous system-related conditions, including Alzheimer's disease, epilepsy, migraine, stroke, Parkinson's disease, prion disease, amyotrophic lateral sclerosis, and Huntington's disease.}, } @article {pmid41510718, year = {2026}, author = {Prabakaran, A and Sivaperuman, A and Natarajan, R and Nagarajan, NC and Solomon, VR}, title = {Innovative Approaches to Alzheimer's Treatment: Utilizing Tacrine Hybrids to Inhibit Amyloid Beta Aggregation as a Strategic Focus.}, journal = {Mini reviews in medicinal chemistry}, volume = {}, number = {}, pages = {}, doi = {10.2174/0113895575422492251116190843}, pmid = {41510718}, issn = {1875-5607}, abstract = {Alzheimer's disease (AD) is a complex and progressive brain disorder marked by memory loss, cognitive decline, and behavioral changes. One of its defining features is the build-up of amyloid plaques, clumps of β-amyloid (Aβ) peptides, in the brain, along with the formation of neurofibrillary tangles. These Aβ peptides are generated when the amyloid precursor protein (APP) is cleaved by enzymes, with β-secretase (BACE1) playing a key role in the first step of this process. Because BACE1 starts the cascade that leads to harmful Aβ build-up, it has become an important target in the search for effective Alzheimer's treatments. As Aβ accumulates in neurons, it disrupts communication between brain cells and triggers oxidative stress, which worsens damage and accelerates disease progression. This is often exacerbated by imbalances in metal ions, such as copper and iron. While tacrine, an early acetylcholinesterase inhibitor, has shown benefits in managing AD symptoms, its limitations have led researchers to explore improved versions. One promising direction is the development of tacrine-based hybrid molecules. By combining tacrine with other chemical groups that have anti-β-amyloid (Aβ) effects, antioxidant properties, and metal-chelating properties, scientists aim to create compounds that target multiple aspects of the disease simultaneously. This review examines the emerging potential of tacrine hybrids, particularly their capacity to inhibit BACE1 and prevent Aβ aggregation, providing new hope for more effective and disease-modifying therapies for Alzheimer's disease.}, } @article {pmid41510728, year = {2026}, author = {González-Jiménez, KA and Herrera-Mayorga, EV and Paredes Sánchez, FA and Niño-García, N and Torres-Castillo, JA and Martínez-Padrón, HY and Sánchez-Sánchez, M}, title = {New Drug Therapies Against Targeting Neurodegenerative Diseases: A Comprehensive Review.}, journal = {Central nervous system agents in medicinal chemistry}, volume = {}, number = {}, pages = {}, doi = {10.2174/0118715249397580251117044621}, pmid = {41510728}, issn = {1875-6166}, abstract = {Neurodegenerative diseases encompass well-characterized behavioral, cognitive, and movement disorders that affect older people, impacting all facets of daily life. In Alzheimer's disease, specific antibodies targeting the β-amyloid protein (aducanumab, lecanemab, and others) are gaining special interest due to the approval of the first particular drugs against this disease. In Parkinson's disease, most drugs were approved several decades ago; however, new Phase II clinical trials point to monoclonal antibodies as a promising approach, and the report of alkaloids also suggests various therapeutic targets against this disease. Pick's disease has a low prevalence; currently, no drugs are approved by government agencies. However, thanks to molecular tools, it has been possible to elucidate therapeutic targets implicated in the appearance of the disease. α-synuclein is the main therapeutic target in Lewy body disease; most of the reported molecules are in clinical Phases I and II. Additionally, drug repositioning may emerge as a viable option in the search for effective treatments against this disease. In amyotrophic lateral sclerosis, the appearance of newly approved drugs such as tofersen and edaravone, and some others in clinical Phase II (bosutinib), opens a new era in the understanding and treatment of this condition. Altered emotions and progressive damage in some brain regions characterize schizophrenia and vascular dementia. Combinations of tricyclic drugs are a trend that aims to increase the cognitive performance of patients with schizophrenia. In vascular dementia, numerous in vivo trials with molecules of different natures (flavonoids and lactones) have yielded positive results, delaying the progression of the disease. This review examines recent reports on molecules evaluated in vivo and in vitro models of the primary neurodegenerative diseases.}, } @article {pmid41510732, year = {2026}, author = {Adhikari, B and Venkatesh, DN and Puri, V and Sharma, A}, title = {Therapeutic Implications of Nutraceutical Nanotechnology for the Treatment of Chronic Diseases.}, journal = {Current drug metabolism}, volume = {}, number = {}, pages = {}, doi = {10.2174/0113892002415344251122122358}, pmid = {41510732}, issn = {1875-5453}, abstract = {Nanotechnology possesses therapeutic value in managing chronic disease, but it has limitations like as solubility, stability, and targeted delivery in clinical applications. The review explores how nanotechnology-based delivery systems improve the efficacy, bioavailability, and targeted actions of nutraceutical compounds. Health benefits, sustainable nanotechnology, market size, and growth forecasts have shown positive results in this industry over the last two decades. The disease-like respiratory, diabetes, Alzheimer's and Parkinson's, and breast cancer top focused sectors for this nutraceuticals sector. Most literature has been collected from 2020-2025 using PubMed, Scopus, Google Scholar, and Web of Science. The different criteria included preclinical, clinical, and nanotechnology-integrated nutraceutical studies. The liposomes, dendrimers, nanoemulsions, and polymeric nanoparticles significantly enhance the stability and delivery of key bioactive as example like curcumin, resveratrol, and omega-3. Early-stage clinical trials show promise for diseases like Alzheimer's, diabetes, and cancer. Nanotechnology is the reshaping of nutraceutical therapy, through regulatory, toxicology, and large-scale validation gaps persist. Future work must focus on green synthesis, long-term safety, and harmonized approval pathways. Despite this, the industry still needs collaboration between academic researchers, scientists, and regulatory bodies to start the next generation of clinical trials and treatments that can reduce the risk of diseases and death in the future.}, } @article {pmid41510854, year = {2026}, author = {Tyagi, S and Murali, N and Singh, SK and Babtiwale, SR and Padhi, BK and Lakshmi, NRA and Gandhi, AP}, title = {A Systematic Review to Evaluate the Effect of Neflamapimod on Cognitive Function and Progression of Dementia.}, journal = {Neurology India}, volume = {74}, number = {1}, pages = {12-19}, doi = {10.4103/neurol-india.Neurol-India-D-25-00227}, pmid = {41510854}, issn = {1998-4022}, mesh = {Humans ; *Dementia/drug therapy ; *Cognition/drug effects ; Disease Progression ; *Alzheimer Disease/drug therapy ; }, abstract = {Treatment options for dementia mainly comprise of symptomatic treatment, as no disease-modifying therapy currently exists that directly reduces the pathology. This systematic review assessed the effectiveness of neflamapimod (VX-745), a p38α kinase inhibitor, as a therapeutic agent for treating dementia, including Alzheimer's disease (AD) and Lewy Body Dementia (LBD). The systematic review evaluated the therapeutic effect of neflamapimod on dementia. Five electronic databases were included in the systematic review: PubMed, Embase, ProQuest, Cochrane Library, and Web of Science, which were searched until May 5, 2024. Two independent reviewers conducted title and abstract screening, followed by full-text review and data extraction, with disagreements resolved by a third reviewer. The risk of bias in the included studies was assessed using the ROB 2.0 tool. PROSPERO Registration ID: CRD42024542377. The review identified clinical results, biomarker effects, and mechanistic insights from two key trials. Due to the inclusion of only two eligible studies with varying methodologies and outcome measures, a meta-analysis could not be performed. While the primary cognitive outcomes, such as "neuropsychological test battery (NTB)" and "Hopkins Verbal Learning Test-Revised (HVLT-R)" were not statistically different, episodic memory, executive function, attention, gait dysfunction, and motor issues showed improvements, especially in patients with elevated plasma tau181, a marker for AD pathology. Biomarker analysis also indicated a statistically significant reduction in cerebrospinal fluid (CSF) tau and phosphorylated tau biomarkers, which are closely related to neuroinflammation and synaptic impairment in dementia. The findings of the current review suggested that while the cognitive effects of neflamapimod remain uncertain, its ability to influence disease-specific biomarkers makes it a potential drug to be used in dementia. This review connects biological and clinical outcomes, paving the way for future advancements in dementia treatment strategies.}, } @article {pmid41511339, year = {2025}, author = {Yu, H and Josi, RR and Khanna, A and Khismatullin, DB}, title = {Low-Density Lipoproteins Induce a Pro-Inflammatory, Chemotactic Mox-like Phenotype in THP-1-Derived Human Macrophages.}, journal = {Cells}, volume = {15}, number = {1}, pages = {}, pmid = {41511339}, issn = {2073-4409}, support = {R01 HL127092/HL/NHLBI NIH HHS/United States ; 1R01HL127092-01A1/NH/NIH HHS/United States ; }, mesh = {Humans ; *Lipoproteins, LDL/pharmacology/metabolism ; *Macrophages/metabolism/drug effects ; Phenotype ; *Chemotaxis/drug effects ; THP-1 Cells ; *Inflammation/pathology/metabolism ; Mast Cells/metabolism/drug effects ; Interleukin-6/metabolism/pharmacology ; Cytokines/metabolism ; Cell Adhesion/drug effects ; Cell Differentiation/drug effects ; Atherosclerosis ; Tumor Necrosis Factor-alpha/metabolism ; }, abstract = {Murine macrophages exposed to oxidized low-density lipoprotein (oxLDL) polarize into a distinct Mox phenotype characterized by impaired phagocytic and chemotactic function. Although implicated in atherosclerosis, this phenotype has not been confirmed in human macrophages. Drawing parallels to human tumor-associated macrophages, and in contrast to the murine cell response, we hypothesize that LDL/oxLDL induces a hybrid Mox-like state in human macrophages, marked by the simultaneous secretion of pro-inflammatory cytokines and anti-inflammatory factors, potentially exacerbating vascular inflammation and atherogenesis. To test this, THP-1 human monocytes were differentiated into resting macrophages, then polarized into M1-like and M2-like phenotypes, followed by treatment with native LDL, oxLDL, IL-6, or their combinations. ELISA results showed that oxLDL or LDL with IL-6 polarized resting and M1-like macrophages into a Mox-like phenotype that secreted TNF-α and TGF-β1 at levels comparable to M1- and M2-like cells, respectively. The pro-inflammatory nature of Mox-like macrophages was supported by increased THP-1 adhesion to vascular endothelial cells exposed to the macrophage-conditioned media. In microfluidic assays, LUVA human mast cells migrated toward media from Mox-like macrophages, indicating enhanced chemotaxis. In summary, the pro-inflammatory Mox-like state is triggered in human macrophages by oxLDL or LDL combined with IL-6, a key regulator of the inflammatory acute-phase response. Unlike in murine cells, this state is marked by high chemotactic activity driven by TGF-β1 secretion, which promotes mast cell recruitment and contributes to atherosclerotic plaque development and Alzheimer's disease.}, } @article {pmid41511604, year = {2026}, author = {Babaker, MA and Alazabi, NI and Yousef, EM and Haredy, SA and Algohary, AM and Mansour, DF and Ahmed-Farid, OA}, title = {Taurine Mitigates Spironolactone-Induced Hyperkalemia and Cognitive Dysfunction: A Biochemical and Histological Study in a Rat Model.}, journal = {Applied biochemistry and biotechnology}, volume = {198}, number = {3}, pages = {1962-1993}, doi = {10.1007/s12010-025-05513-9}, pmid = {41511604}, issn = {1559-0291}, mesh = {Animals ; *Taurine/pharmacology ; Male ; *Hyperkalemia/chemically induced/drug therapy/metabolism/pathology ; Rats, Sprague-Dawley ; Rats ; *Spironolactone/adverse effects/pharmacology ; Disease Models, Animal ; *Cognitive Dysfunction/chemically induced/drug therapy/pathology/metabolism ; Neuroprotective Agents/pharmacology ; }, abstract = {Spironolactone (SPR), a widely used potassium-sparing diuretic, frequently causes hyperkalemia, leading to significant cardiovascular and neurological complications. Taurine, a semi-essential amino acid with known antioxidant and neuroprotective effects, was hypothesized to mitigate these adverse effects. This study investigated taurine's efficacy against SPR-induced hyperkalemia and associated cognitive dysfunction in a rat model. Adult male Sprague-Dawley rats were treated for four weeks with SPR, SPR + galantamine (an AChE inhibitor widely used in the treatment of Alzheimer's disease), or SPR + varying concentrations of taurine, followed by assessment of cognitive, biochemical, and histopathological alterations. SPR administration significantly increased serum potassium levels (~7.5 mEq/L), induced cognitive deficits, disrupted neurotransmitter balance (e.g., altered GABA and glutamate levels), and caused reactive astrocytic swelling in key brain regions. Taurine demonstrated a dose-dependent protective effect against SPR-induced neurotoxicity by mitigating hyperkalemia and associated cognitive impairments. Biochemically, taurine restored neurotransmitter balance by increasing GABA and reducing the excitotoxic glutamate levels. Histological analysis further confirmed taurine's neuroprotective effects, showing preserved cortical structures and reduced astrogliosis, especially at the highest concentration (5%). Our correlation analysis reveals complex regulatory mechanisms underlying neurotransmitter balance in the brain. These findings suggest taurine as a promising therapeutic agent for alleviating SPR-induced neurological side effects. Further studies are needed to explore taurine's long-term effects and clinical applications in managing hyperkalemia-related cognitive dysfunctions.}, } @article {pmid41513181, year = {2026}, author = {Vyas, J and Jamenis, AS and Kaku, K and Shah, Y and Miner, KM and Bhatia, TN and Kim, RE and Bai, R and Hamel, E and Leak, RK and Gangjee, A}, title = {Discovery of multitargeting single agents as a novel route to the potential treatment of neurodegenerative diseases.}, journal = {Bioorganic & medicinal chemistry letters}, volume = {133}, number = {}, pages = {130536}, pmid = {41513181}, issn = {1464-3405}, support = {R21 AG068608/AG/NIA NIH HHS/United States ; }, mesh = {Animals ; Humans ; *Drug Discovery ; Molecular Structure ; *Neurodegenerative Diseases/drug therapy ; *Protein Kinase Inhibitors/chemistry/pharmacology/therapeutic use ; Structure-Activity Relationship ; }, abstract = {There are no cures for neurodegenerative diseases. The biggest hurdle to treating these disorders is that their clinical manifestation is rooted in multiple physiological processes. Therefore, efficacious pharmaceutical options will likely require two or more agents with different mechanisms of action. However, drug combinations have significant drawbacks, including overlapping toxicities and unique pharmacokinetic properties, particularly the rate and extent of central nervous system (CNS) penetration. A single agent with multiple mechanisms of action could overcome these drawbacks. We have recently discovered first-in-class novel single agents (compounds 1 and 2) that mildly inhibit clinically important kinases and subtly favor microtubule stability at concentrations that show no evidence of neuronal toxicity in primary neurons, while maintaining their ability to penetrate the CNS in vivo. It is important to note that the effects of these analogs are mild and are predicated on avoiding neurotoxicity. These multitargeting single agents provide a new structural modality with the potential to influence treatments for Parkinson's and Alzheimer's disease and serve as lead compounds for further optimization.}, } @article {pmid41513640, year = {2026}, author = {Abdulkhaliq, AA and Kim, B and Almoghrabi, YM and Khan, J and Ajoolabady, A and Ren, J and Bahijri, S and Tuomilehto, J and Borai, A and Pratico, D}, title = {Amyloid-β and Tau in Alzheimer's disease: pathogenesis, mechanisms, and interplay.}, journal = {Cell death & disease}, volume = {17}, number = {1}, pages = {21}, pmid = {41513640}, issn = {2041-4889}, mesh = {Humans ; *Alzheimer Disease/pathology/metabolism ; *Amyloid beta-Peptides/metabolism ; *tau Proteins/metabolism ; Animals ; Brain/metabolism/pathology ; }, abstract = {Alzheimer's disease (AD) is a devastating neurodegenerative disease and the most prevalent type of dementia characterized by pathological deposition of amyloid-β plaques/deposits and tau tangles within the brain parenchyma. This progressive ailment is featured by irreversible cognitive impairment and memory loss, often misdiagnosed as the consequence of old age in elderlies. Pathologically, synaptic dysfunction occurs at the early stages and then progresses into neurodegeneration with neuronal cell death in later stages. In this review, we aimed to critically discuss and highlight recent advances in the pathological footprints of amyloid-β and tau in AD. Specifically, we focused our attention on the interplay and synergistic effects of amyloid-β and tau in the pathogenesis of AD. We hope that our paper will provide new insights and perspectives on these pathological features of AD and spark new ideas and directions in AD research and treatment.}, } @article {pmid41514416, year = {2026}, author = {Tian, Q and Liu, M and Zhong, F and Liu, X and Lü, Y}, title = {Lecanemab treatment for mild alzheimer's disease with high risk of cerebral hemorrhage: a case report.}, journal = {BMC neurology}, volume = {26}, number = {1}, pages = {76}, pmid = {41514416}, issn = {1471-2377}, mesh = {Humans ; Male ; *Alzheimer Disease/drug therapy/complications/diagnostic imaging/genetics ; Aged ; *Cerebral Hemorrhage/diagnostic imaging ; *Antibodies, Monoclonal, Humanized/therapeutic use ; }, abstract = {BACKGROUND: Lecanemab has been approved for the treatment of mild cognitive impairment due to Alzheimer's disease (AD) and mild AD dementia based on the efficacy in slowing cognitive decline and preliminary safety data from the phase Ⅲ Clarity AD trial. However, this trial excluded patients with high risk of cerebral hemorrhage, such as individuals with intracranial aneurysms or > 4 microhemorrhages.

CASE PRESENTATION: A 70-year-old male with mild AD, intracranial aneurysm, microhemorrhages, and APOE ε3/ε4 genotype received lecanemab after multidisciplinary evaluation and informed consent. Over six months of intensive monitoring, cognitive function stabilized with no deterioration, daily activities were preserved, microhemorrhages remained stable (with one new small lesion noted at 3 months), and no aneurysm rupture or severe adverse events (including amyloid-related imaging abnormalities) occurred.

CONCLUSIONS: This case suggests that, despite hemorrhage risks, lecanemab may have a manageable risk-benefit profile in selected real-world AD patients under intensive monitoring and multidisciplinary care, with its application beyond clinical trial criteria requiring more nuanced and individualized consideration.}, } @article {pmid41514478, year = {2026}, author = {Noman, M and Qadir, H and Ahmed, S and Rehman, NU and Shah, FA and Riaz, M and Ahmad, N and Ul-Haq, Z and Irshad, N}, title = {Santonin Attenuates Alzheimer's-Like Pathology via Multitarget Modulation of the NLRP3 Inflammasome, BDNF Signaling, and Amyloidogenic Pathways: An Integrated Experimental and Computational Study.}, journal = {ACS chemical neuroscience}, volume = {17}, number = {2}, pages = {465-477}, doi = {10.1021/acschemneuro.5c00957}, pmid = {41514478}, issn = {1948-7193}, mesh = {Animals ; *NLR Family, Pyrin Domain-Containing 3 Protein/metabolism/drug effects ; *Alzheimer Disease/metabolism/drug therapy/pathology ; *Brain-Derived Neurotrophic Factor/metabolism/drug effects ; Signal Transduction/drug effects ; Amyloid beta-Peptides/metabolism ; *Inflammasomes/metabolism/drug effects ; Molecular Docking Simulation ; *Neuroprotective Agents/pharmacology ; Male ; Brain/drug effects/metabolism/pathology ; Rats ; Humans ; Acetylcholinesterase/metabolism ; }, abstract = {Alzheimer's disease (AD) is a neurodegenerative disorder and the predominant cause of dementia, characterized by amyloid β (Aβ) plaques and tau tangles that disrupt neurons in memory-related brain regions. This study explores the therapeutic potential of santonin using integrated in silico, in vitro, and in vivo approaches. Molecular docking identified santonin as a promising acetylcholinesterase, NOD-like receptor family, pyrin domain-containing 3 (NLRP3), brain-derived neurotrophic factor (BDNF), and nuclear factor kappa B (NF-κB) ligand with significant binding affinities and supportive interaction scores supported by molecular dynamics simulations with significant multitarget therapeutic relevance. In vitro assays demonstrated that santonin has measurable inhibition of cholinesterase enzymes, showing significant effects on butyrylcholinesterase and acetylcholinesterase enzymes. Behavioral analysis revealed that santonin produced dose-dependent improvements in memory and exploratory behaviors, indicating significant neuroprotective effects against streptozotocin (STZ)-induced impairments. Histological analysis showed that santonin preserved neuronal architecture, enhanced neuronal density, and reduced Aβ deposition in STZ-treated brains using hematoxylin and eosin, Congo red, and Nissl analysis. These effects were evident in the cortical and hippocampal regions. Santonin exhibited strong antioxidant effects, mitigating induced enzyme depletion and oxidative marker elevation. Santonin effectively mitigated STZ-induced Aβ buildup and provided protective effects. Santonin modulated marker expression in STZ-treated brains by reducing the amyloid precursor protein, Tau, toll-like receptor 4, NLRP3, discs large MAGUK scaffold protein 4, and BDNF. Santonin reduces neuroinflammation and neurotrophic signaling in the early stages of AD, which suggests that it may be used as a treatment. However, more research is needed to confirm its effectiveness.}, } @article {pmid41515488, year = {2026}, author = {Huang, Y and Li, X and Dai, L and Cheng, M and Zhao, L and Shen, Y and Xie, J and Luo, X}, title = {Antioxidant, Anti-Inflammatory, and Chemical Composition Analysis of In Vitro Huperzia serrata Thallus and Wild Huperzia serrata.}, journal = {Molecules (Basel, Switzerland)}, volume = {31}, number = {1}, pages = {}, pmid = {41515488}, issn = {1420-3049}, support = {20232ACB2050009//Natural Science Foundation of Jiangxi Province, China/ ; 32060074//National Natural Science Foundation of China/ ; 20204BCJ22024//Major Academic and Technical Leader Training Project of Jiangxi Province/ ; }, mesh = {*Antioxidants/pharmacology/chemistry ; *Anti-Inflammatory Agents/pharmacology/chemistry ; *Huperzia/chemistry ; Animals ; *Plant Extracts/chemistry/pharmacology ; Mice ; Alkaloids/chemistry/pharmacology ; Sesquiterpenes/chemistry/pharmacology ; RAW 264.7 Cells ; }, abstract = {Huperzine A is a preferred treatment option for Alzheimer's disease. Huperzia serrata (Thunb. ex Murray) Trev. (H. serrata) has garnered significant attention for its ability to produce Huperzine A (HupA). However, natural populations of wild H. serrata (WH) are rapidly declining. Fortunately, our group obtained two types of H. serrata thalli (OT and ST) capable of stably producing Huperzine A, which have the potential to serve as an alternative resource to WH. To evaluate the feasibility of this strategy, we conducted a comprehensive assessment of both WH and H. serrata thallus. The results indicated that compared to WH, ST and OT exhibited stronger anti-inflammatory and antioxidant activities, with lower cytotoxicity. Notably, ST demonstrated a strong radical scavenging activity, reaching 93.23% (DPPH at 0.2 μg/mL) and 99.87% (ABTS at 4 μg/mL), and reduced nitrite production from 10.29 μM to 6.51 μM at 50 µg/mL. GC-MS and widely targeted metabolomics analyses revealed that the higher antioxidant and anti-inflammatory activities for ST and OT were due to higher concentrations of phenolic acids and flavonoids compared to WH. In addition, the HupA content in ST reached 36.56% of that found in WH. KEGG enrichment analysis revealed that the flavonoid, phenylalanine, and phenylpropanoid biosynthesis pathways may be involved in regulating the antioxidant activity. P-coumaroyl quinic acid and caffeoyl quinic acid are the crucial metabolites for antioxidant activity. These findings suggested that the H. serrata thallus could serve as a sustainable alternative to WH.}, } @article {pmid41516246, year = {2025}, author = {Kvetnoy, I and Kheyfets, O and Safaniev, L and Kheifets, V and Mironova, E and Kvetnaia, T and Mazzoccoli, G and Prashchayeu, K and Gavrilova, A}, title = {Signaling Molecules and Diagnosis of Cognitive Disorders: Current State and Prospects.}, journal = {International journal of molecular sciences}, volume = {27}, number = {1}, pages = {}, pmid = {41516246}, issn = {1422-0067}, mesh = {Humans ; *Biomarkers/metabolism ; *Signal Transduction ; *Cognition Disorders/diagnosis/metabolism ; *Alzheimer Disease/diagnosis/metabolism ; Animals ; *Dementia, Vascular/diagnosis/metabolism ; Amyloid beta-Peptides/metabolism ; tau Proteins/metabolism ; }, abstract = {Cognitive disorders present significant medical and social challenges nowadays, due to their high prevalence, progressive course and a lack of effective methods for treatment of neurodegenerative diseases and comorbid pathologies. An important area of research is the identification of molecular biomarkers that reflect early pathophysiological changes and facilitate a more accurate biological characterization of cognitive impairment. This study provides an overview of the most relevant signaling molecules for diagnosing cognitive disorders. It presents data on the effectiveness of using comprehensive panels of molecular biomarkers in clinical practice, including β-amyloid, CD34, claudin, DRP1, endothelin-1, NF-kB, PINK1, RAGE, S100, α-synuclein, and tau protein, in patients with Alzheimer's disease (AD) and vascular dementia (VD). The study results demonstrate that cumulative changes in the expression of signaling molecules reflect various neurodegenerative and vascular-associated biological processes. The data obtained are comparative in nature and require further validation before potential clinical application.}, } @article {pmid41516328, year = {2026}, author = {Cipriano, GL and Floramo, A and Argento, V and Oddo, S and Artimagnella, O}, title = {Mutant Tau (P301L) Enhances Global Protein Translation in Differentiated SH-SY5Y Cells by Upregulating mTOR Signalling.}, journal = {International journal of molecular sciences}, volume = {27}, number = {1}, pages = {}, pmid = {41516328}, issn = {1422-0067}, support = {RRC-2025-23686388//Ministero della Salute/ ; }, mesh = {Humans ; *tau Proteins/genetics/metabolism ; *TOR Serine-Threonine Kinases/metabolism/genetics ; *Signal Transduction ; *Protein Biosynthesis ; Up-Regulation ; Cell Line, Tumor ; Cell Differentiation ; Neurons/metabolism ; *Mutation ; Sirolimus/pharmacology ; }, abstract = {Altered protein synthesis plays a key role in ageing and multiple neurodegenerative diseases. In Alzheimer's disease and other tauopathies, the intracellular accumulation of hyperphosphorylated Tau disrupts several cellular processes, including mRNA translation. Although Tau interacts with ribosomal proteins and modulates translational selectivity, its effects on global protein synthesis remain poorly understood. Studies report reduced translation in later disease stages but increased translation early in pathology. To clarify Tau's impact in human neurons, we used SH-SY5Y cells overexpressing the P301L mutant form of Tau and quantified global protein synthesis using the SUnSET (Surface Sensing of Translation) puromycin-incorporation assay. We found that Tau-P301L expression greatly increased global translation by upregulating mTOR/S6 pathway. These effects were abolished by rapamycin treatment, indicating that Tau-driven translational upregulation is mTOR-dependent. Given that impaired translational control can disrupt synaptic plasticity and memory, Tau-induced alterations in protein synthesis may contribute to tauopathy progression and identify mTOR signalling as a potential therapeutic target.}, } @article {pmid41517524, year = {2025}, author = {Abboud, I and Xu, E and Xu, S and Alhasany, A and Wang, Z and Wu, X and Astraea, N and Jiang, F and Hu, ZJ and Chan, JW}, title = {Emerging Oculomic Signatures: Linking Thickness of Entire Retinal Layers with Plasma Biomarkers in Preclinical Alzheimer's Disease.}, journal = {Journal of clinical medicine}, volume = {15}, number = {1}, pages = {}, pmid = {41517524}, issn = {2077-0383}, support = {K25 AG071840/AG/NIA NIH HHS/United States ; R01 NS132766/NS/NINDS NIH HHS/United States ; UL1 TR001872/NH/NIH HHS/United States ; }, abstract = {Background/Objectives: Alzheimer's disease (AD) is the leading cause of dementia, which is an inevitable consequence of aging. Early detection of AD, or detection during the pre-AD stage, is beneficial, as it enables timely intervention to reduce modifiable risk factors, which may help prevent or delay the progression to dementia. On the one hand, plasma biomarkers have demonstrated great promise in predicting cognitive decline. On the other hand, in recent years, ocular imaging features, particularly the thickness of retinal layers measured by spectral-domain optical coherence tomography (SD-OCT), are emerging as possible non-invasive, non-contact surrogate markers for early detection and monitoring of neurodegeneration. This pilot study aims to identify retinal layer thickness changes across the entire retina linked to plasma AD biomarkers in cognitively healthy (CH) elderly individuals at risk for AD. Methods: Eleven CH individuals (20 eyes total) were classified in the pre-AD stage by plasma β-amyloid (Aβ)42/40 ratio < 0.10 and underwent SD-OCT. A deep-learning-derived automated algorithm was used to segment retinal layers on OCT (with manual correction when needed). Multiple layer thicknesses throughout the entire retina (including the inner retina, the outer retina, and the choroid) were measured in the inner ring (1-3 mm) and outer ring (3-6 mm) of the Early Treatment Diabetic Retinopathy Study (ETDRS). Relationships between retinal layers and plasma biomarkers were analyzed by ridge regression/bootstrapping. Results: Results showed that photoreceptor inner segment (PR-IS) thinning had the largest size effect with neurofilament light chain. Additional findings revealed thinning or thickening of the other retinal layers in association with increasing levels of glial fibrillary acidic protein and phosphorylated tau at threonine 181 and 217 (p-tau181 and p-tau217). Conclusions: This pilot study suggests that retinal layer-specific signatures exist, with PR-IS thinning as the largest effect, indicating neurodegeneration in pre-AD. Further research is needed to confirm the findings of this pilot study using larger longitudinal pre-AD cohorts and comparative analyses with healthy aging adults.}, } @article {pmid41517810, year = {2026}, author = {Lee, S and Chang, JW}, title = {From Ablation to Neuromodulation Platform: The Evolving Role of Magnetic Resonance-Guided Focused Ultrasound in Functional Neurosurgery.}, journal = {Journal of clinical neurology (Seoul, Korea)}, volume = {22}, number = {1}, pages = {17-41}, pmid = {41517810}, issn = {1738-6586}, support = {/HI/NHLBI NIH HHS/United States ; }, abstract = {Magnetic resonance-guided focused ultrasound (MRgFUS) has rapidly evolved from an experimental concept into a versatile platform in functional neurosurgery. Initially pioneered as a noninvasive thermal ablation modality for essential tremor, MRgFUS has since gained regulatory approval and demonstrated durable long-term efficacy. Its clinical applications have expanded to include Parkinson's disease, chronic pain, psychiatric disorders, and investigational use in dystonia, epilepsy, and brain tumors. Beyond lesioning, low-intensity focused ultrasound enables reversible neuromodulation and transient blood-brain barrier opening, facilitating drug and gene delivery in conditions such as Alzheimer's disease and glioblastoma. Comparative analyses highlight MRgFUS as an incisionless alternative to traditional modalities like deep brain stimulation, radiofrequency ablation, and radiosurgery, offering unique advantages in precision, safety, and patient acceptability while retaining certain limitations, including irreversibility and eligibility constraints due to skull properties. Emerging innovations-such as dual-target strategies, staged bilateral procedures, adaptive focusing technologies, and integration with immuno- or gene therapies-are expanding its therapeutic potential. Collectively, these advances position MRgFUS as not only an ablative tool but also a transformative neuromodulation platform with broad implications for the treatment of movement disorders, neuropsychiatric disease, and neurodegeneration.}, } @article {pmid41517961, year = {2026}, author = {Vilor-Tejedor, N and Danso, S and Albanus, RD and Billingsley, K and Evans, TE and Lee, LY and Wang, S and Jiang, J and Liu, H and Ross, J and Chilla, G}, title = {Advancing global dementia research through equity and inclusion.}, journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association}, volume = {22}, number = {1}, pages = {e71069}, pmid = {41517961}, issn = {1552-5279}, support = {//Intramural Research Programs of the National Institute on Aging (NIA)/ ; R01AG081693//National Institutes of Health (NIH), Department of Health and Human Services/ ; RYC2022-038136-I//Spanish Ministry of Science and Innovation-State Research Agency,/ ; //la Caixa Foundation/ ; 25AARF-1377279 (2025-2029)//Alzheimer's Association Research postdoctoral fellowship/ ; 23S06083-001//European Union FEDER/ ; 1ZIANS003154//National Institutes of Health (NIH), Department of Health and Human Services/ ; Z01-AG000949//National Institutes of Health (NIH), Department of Health and Human Services/ ; //National Institute of Neurological Disorders and Stroke (NINDS)/ ; VCID-UMD-26-1514428//AD Strategic Fund: Vascular Contributions to Cognitive Impairment and Dementia-Understanding Mechanisms of Dysfunction/ ; //Ajuntament de Barcelona/ ; WE.03-2024-07(2025-2027)//Alzheimer's Association Research postdoctoral fellowship/ ; //Alzheimer's Disease Data Initiative/ ; P30AG072976//National Institutes of Health (NIH), Department of Health and Human Services/ ; PID2022-143106OA-I00//European Union FSE+/ ; P30 AG072976/AG/NIA NIH HHS/United States ; }, mesh = {Humans ; *Dementia ; Diversity, Equity, Inclusion ; *Biomedical Research ; Workforce Diversity ; Global Health ; }, abstract = {Despite the global burden of dementia, research remains dominated by high-income, Western populations, limiting the generalizability and equity of findings. In this Perspective, we highlight the importance of diversity and inclusion in dementia research, not only in study participants but also in the researchers, study design, and funding priorities. We describe how the lack of representation creates knowledge gaps and delays progress in prevention, diagnosis, and treatment. We also present examples of initiatives that are working to change this, including the Alzheimer's Disease Data Initiative and the William H. Gates Sr. Fellowship program, which supports open science, international collaboration, and early-career researchers from underrepresented regions. These efforts demonstrate that diversity is not only an ethical goal, but a scientific need. More inclusive and global research could lead to discoveries that are more generalizable, more globally applicable, and better able to inform strategies to address dementia across all communities. HIGHLIGHTS: Prioritize representation in datasets across ethnicity, geography, sex/gender, and socio-economic status. Support early-career researchers from underrepresented regions with long-term funding and mentorship. Standardize and adapt tools (cognitive, clinical, genomic) across cultural and linguistic contexts. Promote open science through equitable, federated data sharing platforms, and embed community engagement from research design to dissemination. Value diversity as a driver of discovery, not as a confounder.}, } @article {pmid41517979, year = {2026}, author = {Bachhav, SS and Florian, H and Boiser, J and Wang, Y and Shiller, DD and Graab, U and Lynch, SY and Graff, O and Xiong, H}, title = {Safety, Tolerability, and Pharmacokinetics of Single Doses of ABBV-916, an Anti-Amyloid Antibody, in Healthy Participants.}, journal = {Clinical and translational science}, volume = {19}, number = {1}, pages = {e70419}, pmid = {41517979}, issn = {1752-8062}, mesh = {Humans ; Male ; Female ; Double-Blind Method ; Healthy Volunteers ; Adult ; *Amyloid beta-Peptides/immunology/antagonists & inhibitors ; Middle Aged ; Dose-Response Relationship, Drug ; *Antibodies, Monoclonal, Humanized/administration & dosage/pharmacokinetics/adverse effects ; Infusions, Intravenous ; Alzheimer Disease/drug therapy ; Injections, Subcutaneous ; Young Adult ; }, abstract = {Amyloid-beta (Aβ) plaque brain clearance is one of the promising disease-modifying treatment approaches to slow cognitive decline in Alzheimer's disease (AD). ABBV-916, an anti-amyloid antibody, was being developed as an early AD disease-modifying treatment. A phase 1, randomized double-blind, placebo-controlled single ascending dose (SAD) study investigated the safety, tolerability, pharmacokinetics (PK), and immunogenicity of ABBV-916 in healthy participants. Five groups of participants were enrolled and randomized 6:2 to receive ABBV-916 (100, 300, 1000, or 3000 mg) or placebo by intravenous (IV) infusion or subcutaneous (SC) injection (300-mg dose only). After dosing, participants were followed for 20 weeks for assessments. Cerebrospinal fluid (CSF) samples were collected after dosing 1000 mg IV for determination of ABBV-916 levels in the CSF. ABBV-916 single doses up to 3000 mg were well tolerated in healthy participants. No clinically significant laboratory findings, amyloid-related imaging abnormalities, or serious adverse events were reported. The ABBV-916 PK profile exhibited dose-related increases in maximum concentration and area under the plasma concentration-time curve with terminal elimination half-life ranging from 29 to 40 days across the cohorts. The estimated absolute bioavailability after SC dosing was 51%. The average CSF-to-serum partition ratio was 0.12% (range 0.10%-0.21%). Positive anti-drug antibody was detected in < 7% of participants, which was transient, at low titer, and did not affect ABBV-916 PK. This study demonstrated desirable safety, tolerability, and PK profile of ABBV-916 after single-dose administration in healthy participants. The data supported further evaluation of ABBV-916 multiple IV and SC doses in patients with AD.}, } @article {pmid41518096, year = {2026}, author = {Mai, D and Li, Z and Cao, Z and Lin, P and Tan, J and Li, R and Ye, Q}, title = {Metabolomics-Driven Integration of Traditional Chinese Medicine for Neurological Disorders: From Precision Diagnosis to Therapeutic Innovation.}, journal = {Phytotherapy research : PTR}, volume = {40}, number = {2}, pages = {829-843}, doi = {10.1002/ptr.70182}, pmid = {41518096}, issn = {1099-1573}, support = {20251026//Guangdong Provincial Department of Traditional Chinese Medicine/ ; SEZYY2023A13//the Second Traditional Chinese Medicine Hospital of Guangdong Province/ ; }, mesh = {Humans ; *Medicine, Chinese Traditional/methods ; *Metabolomics/methods ; *Nervous System Diseases/diagnosis/metabolism/therapy/drug therapy ; Animals ; *Drugs, Chinese Herbal/therapeutic use ; }, abstract = {Neurological disorders are leading causes of disability and death worldwide, yet many patients still face delayed diagnosis, limited disease-modifying options and substantial treatment-related adverse effects. Traditional Chinese medicine (TCM) provides holistic, multi-target interventions through acupuncture, herbal formulas and adjunctive therapies, but its mechanisms remain insufficiently defined. Metabolomics, which enables system-wide profiling of small-molecule metabolites, offers an objective way to characterise disease-related metabolic networks and quantify the global effects of TCM. We systematically searched PubMed, Web of Science and China National Knowledge Infrastructure for studies published between January 2005 and June 2025 that evaluated TCM-related interventions for neurological disorders and reported metabolomic outcomes. Peer-reviewed animal and clinical studies were included, whereas reviews, conference abstracts, methodological-only papers and non-neurological studies were excluded. Across Alzheimer's disease (AD), Parkinson's disease (PD), multiple sclerosis (MS), ischaemic stroke (IS), epilepsy and high-altitude cerebral oedema (HACE), consistent alterations were identified in amino acid, lipid and energy-related pathways, such as nicotinamide and lysophosphatidylcholine species in AD, branched-chain amino acids in PD and phenylalanine and asymmetric dimethylarginine in MS. Metabolomics studies indicate that acupuncture and herbal formulas can jointly modulate neurotransmitter balance, cerebral energy metabolism, oxidative stress, neuroinflammation and blood-brain barrier integrity. Emerging spatial metabolomics based on mass spectrometry imaging links individual TCM components, including ginsenosides and Astragalus membranaceus-Carthamus tinctorius decoctions, to region-specific metabolic reprogramming in the cortex, hippocampus and thalamus. However, most metabolite-disease associations are correlative and are constrained by small sample sizes, heterogeneous designs and lack of technical standardisation. Metabolomics therefore provides a quantitative framework to dissect the multi-target mechanisms of TCM in neurology and to connect molecular changes with functional outcomes. Standardised workflows, larger multicentre clinical studies and integration of spatial metabolomics, multi-omics and artificial-intelligence-based analysis are required to translate these findings into TCM-informed precision diagnosis and personalised treatment for neurological disorders.}, } @article {pmid41518572, year = {2026}, author = {Zhang, Z and Zhang, M and Cao, Z and Zhao, H and Li, X and Luo, P}, title = {Fibrillarin: bridging ribosome biogenesis and apoptosis in cellular stress and disease.}, journal = {Apoptosis : an international journal on programmed cell death}, volume = {31}, number = {1}, pages = {11}, pmid = {41518572}, issn = {1573-675X}, support = {82171363//National Natural Science Foundation of China/ ; }, mesh = {Humans ; *Apoptosis/genetics ; *Ribosomes/metabolism/genetics ; *Stress, Physiological ; *Chromosomal Proteins, Non-Histone/metabolism/genetics ; Tumor Suppressor Protein p53/metabolism/genetics ; Animals ; *Neoplasms/genetics/metabolism/pathology ; Cell Nucleolus/metabolism ; *Neurodegenerative Diseases/genetics/metabolism/pathology ; }, abstract = {Nucleolar stress has emerged as a critical regulatory mechanism linking ribosome biogenesis defects to apoptotic cell death in various pathological conditions. Fibrillarin (FBL), the catalytic component of box C/D small nucleolar ribonucleoproteins, participates in multiple forms of programmed cell death through both p53-dependent and p53-independent pathways across diverse disease contexts including cancer and neurodegeneration. In malignancies including breast cancer, colorectal cancer, and hepatocellular carcinoma, FBL overexpression promotes apoptosis resistance, whereas in Alzheimer's disease and ALS/FTD, FBL dysfunction contributes to pathological neuronal death. Dysregulation of FBL can lead to excessive apoptosis or apoptosis resistance depending on cellular context and disease state. Various cellular stressors trigger aberrant FBL function, disrupting rRNA processing and ribosome assembly, which then activates nucleolar stress responses that culminate in cell death through ribosomal protein-MDM2-p53 axis activation or selective translational control of survival factors in a context-dependent manner. Therefore, targeting FBL-mediated apoptotic pathways is considered an important avenue for the treatment of various cancers and neurodegenerative diseases. In this review, we summarize the major and recent findings focusing on the mechanisms of FBL-regulated apoptosis in disease pathogenesis and provide a systematic overview of current therapeutic strategies targeting nucleolar stress pathways, including RNA polymerase I inhibitors and precision medicine approaches based on p53 status, which may provide important therapeutic targets that merit further investigation.}, } @article {pmid41518808, year = {2026}, author = {Qu, J and Jiang, X and Ma, Y and Sheng, X and Pi, C and Wang, Y and Xu, Q and Li, R and Wang, P and Qian, D and Wang, J and Yi, Z and Yi, J and Wen, L and Liu, S}, title = {Unveiling the gut-brain axis: How chronic exposure to arsenic-induced microglial pyroptosis drives Alzheimer's disease-like pathology.}, journal = {Journal of hazardous materials}, volume = {503}, number = {}, pages = {141087}, doi = {10.1016/j.jhazmat.2026.141087}, pmid = {41518808}, issn = {1873-3336}, mesh = {Animals ; *Microglia/drug effects/pathology ; *Alzheimer Disease/chemically induced/pathology/metabolism ; Mice ; *Pyroptosis/drug effects ; *Arsenic/toxicity ; Male ; Gastrointestinal Microbiome/drug effects ; *Brain/drug effects/pathology/metabolism ; Cognitive Dysfunction/chemically induced ; Mice, Inbred C57BL ; *Brain-Gut Axis/drug effects ; Signal Transduction/drug effects ; }, abstract = {Arsenic, a pervasive environmental contaminant in groundwater, poses a severe global threat to public health. Chronic arsenic exposure has been linked to neurological impairment, however, its specific pathogenic mechanism and whether the gut-brain axis plays a key role remain unclear. This study investigated the role of gut microbiota and its metabolite indoxyl sulfate (IS) in mediating chronic exposure to arsenic-induced cognitive impairment and Alzheimer's disease (AD)-like pathology, with a specific focus on microglial pyroptosis. We found that chronic arsenic exposure induced cognitive dysfunction and intestinal barrier injury, disrupted gut microbiota composition, promoted IS accumulation in serum and brain, and activated the AhR/NF-κB/NLRP3 signaling pathway, triggering microglial pyroptosis and elevating AD-like pathological markers in mice. Meanwhile, fecal microbiota transplantation (FMT) from arsenic-exposed mice recapitulated cognitive impairment, elevated IS levels, and neuroinflammation in recipient mice. Furthermore, arsenic upregulated hepatic IS-synthesis genes (CYP2E1, Sult1d1) and downregulated renal IS-excretion gene (ABCG2). In vitro, arsenic and IS co-exposure promoted M1 polarization and enhanced pyroptosis by activating the AhR/NF-κB/NLRP3 signaling pathway, while suppressing phagocytosis-related proteins (TREM2, SYK and CD36). Furthermore, SiAhR treatment could alleviated microglial inflammatory injury and enhancing the microglia's phagocytic capacity induced by arsenic and IS co-exposure in BV2 cells through inhibiting the AhR/NF-κB/NLRP3-mediated pyroptosis signaling pathway. In conclusion, chronic arsenic exposure induced cognitive impairment and AD-like pathological via the gut microbiota-AhR-pyroptosis cascade, where in IS accumulation served a key mediator. These findings provide new insights into preventing arsenic-related cognitive damage.}, } @article {pmid41518900, year = {2026}, author = {Loraine, A and Farr, SA and Niehoff, ML and Larrea, IG and Ganev, Y and Samanta, J and Rahman, K and Crider, AM and Sandoval, K and Witt, KA}, title = {Dual sigma receptor 1 and 2 modulator improves memory behavior in mouse model of age-related cognitive decline.}, journal = {The Journal of pharmacology and experimental therapeutics}, volume = {393}, number = {2}, pages = {103795}, pmid = {41518900}, issn = {1521-0103}, support = {R16 NS140308/NS/NINDS NIH HHS/United States ; }, mesh = {Animals ; *Receptors, sigma/metabolism ; Sigma-1 Receptor ; Mice ; Male ; Disease Models, Animal ; *Memory/drug effects ; *Aging/drug effects ; Hippocampus/drug effects/metabolism ; Maze Learning/drug effects ; Behavior, Animal/drug effects ; Cognitive Enhancement ; *Indoles/pharmacology/therapeutic use ; }, abstract = {Sigma-1 (S1R) and sigma-2 (S2R) receptors are promising targets for treating Alzheimer disease (AD), playing important roles in cognitive function, with potential to mitigate neuropathology. The dual S1R/S2R receptor modulator (+/-)-cis-1-n-Butyl-8-methoxy-1,2,3a,4,5,9b-hexahydrobenz[e]indole hydrochloride (BBZI) was evaluated in the senescence-accelerated mouse prone 8 model of cognitive decline and AD as to behavior and hippocampal expression effects. Chronic BBZI treatment (0, 0.001, 0.01, 0.1, 1.0, or 10 mg/kg, i.p. daily, 27-days) was evaluated using a behavioral battery including open field activity (day-15), elevated plus maze (day-16), Y-maze (day-22), T-maze foot-shock avoidance (days 20 and 27), and novel object recognition (days 23 and 24). No changes were observed in open field, elevated plus maze, Y-maze, or novel object recognition tests at any dose of BBZI as compared with vehicle. BBZI enhanced T-maze foot-shock memory retention at 0.1 (P < .05, Bonferroni) and 1.0 mg/kg (P < .001, Bonferroni) compared with vehicle (day-27). In a separate cohort, a single-injection of BBZI (0, 0.001, 0.01, 0.1 & 1.0 μg, i.c.v.) with testing 7-days later showed a significant effect in the T-maze foot-shock test (P = .011) and enhanced memory retention behavior at 0.01 μg compared with vehicle (P < .05, Bonferroni). Poly(A) RNA sequencing evaluation of hippocampal tissue 24-hours after intracerebroventricular administered BBZI (1.0 μg/μL) versus vehicle showed unique gene expression changes, with notable effects relevant to mitochondrial energetics and synaptic function. Gene enrichment analysis identified affiliations with pathways involved in neurodegenerative disease. This data supports dual S1R/S2R receptor modulation as a promising strategy for AD treatment and identifies potential gene pathways involved. SIGNIFICANCE STATEMENT: Dual sigma receptor 1 and 2 modulator BBZI improved memory behavior in senescence-accelerated mouse prone 8 mice. Evaluation of senescence-accelerated mouse prone 8 hippocampal tissue 24 hours after BBZI (1.0 μg/μL i.c.v.) versus vehicle administration identified gene changes related to mitochondrial energetics and synaptic function. BBZI to mitigates cognitive decline behavior, impacting hippocampal genes critical for brain function.}, } @article {pmid41519166, year = {2026}, author = {Zhao, P and Cao, Z and Rozpędek-Kamińska, W}, title = {Receptor tyrosine kinases in Alzheimer's disease: Mechanistic insights and therapeutic implications.}, journal = {Neurochemistry international}, volume = {193}, number = {}, pages = {106117}, doi = {10.1016/j.neuint.2026.106117}, pmid = {41519166}, issn = {1872-9754}, mesh = {Humans ; *Alzheimer Disease/drug therapy/enzymology/metabolism ; Animals ; *Receptor Protein-Tyrosine Kinases/metabolism/antagonists & inhibitors ; *Protein Kinase Inhibitors/therapeutic use/pharmacology ; Amyloid beta-Peptides/metabolism ; tau Proteins/metabolism ; Tyrosine Kinase Inhibitors ; }, abstract = {Alzheimer's disease (AD) is a complex neurodegenerative disorder whose pathogenesis remains incompletely understood. It is considered one of the most costly, fatal, and socially burdensome diseases of the twenty-first century. Previous studies have shown that receptor tyrosine kinases (RTKs) play an important role in the pathological progression of AD. RTKs regulate amyloid-beta (Aβ) deposition and Tau hyperphosphorylation, thereby influencing neuronal survival, synaptic plasticity, and spatial cognitive function in patients with AD. From a therapeutic perspective, RTK-targeted interventions offer new avenues for AD treatment. Inhibiting specific RTKs can reduce Aβ production and pathological Tau phosphorylation, thereby slowing disease progression. Conversely, activating selected neuroprotective RTKs can promote neuronal survival, restore synaptic function, and ameliorate cognitive impairment. Several small-molecule inhibitors and monoclonal antibodies targeting RTKs have already demonstrated promising therapeutic potential in preclinical studies. Overall, this review systematically summarizes the clinical features and mechanisms of AD, as well as the current applications and future challenges of RTK-based research in neurodegenerative diseases, providing theoretical guidance for the development and repurposing of novel multi-pathway RTK-directed therapies.}, } @article {pmid41519243, year = {2026}, author = {Sharma, K and Shahid, M and Patel, R and Islam, A}, title = {Insights into mechanism of ionic liquids for protein stability: Future implications for neurodegeneration treatment.}, journal = {Ageing research reviews}, volume = {117}, number = {}, pages = {103024}, doi = {10.1016/j.arr.2026.103024}, pmid = {41519243}, issn = {1872-9649}, mesh = {Humans ; *Ionic Liquids/therapeutic use/chemistry/pharmacology ; *Neurodegenerative Diseases/drug therapy/metabolism ; Animals ; Protein Stability/drug effects ; }, abstract = {Neurodegenerative diseases are characterized by a gradual loss of neurons, cellular dysfunction, loss of intricate synaptic networks and brain damage, which are going to be the second leading cause of death in future. These proteinopathies are marked by abnormal amyloid fibril deposition, aberrant aggregation of misfolded proteins via polymerization, where protein aggregates serve as key pathological hallmarks in Alzheimer's, Parkinson's, and multiple system atrophy disorders. These toxic aggregates accumulate in the brain and disrupt neuronal function, targeting motor neurons, spinal cord, and ultimately leading to respiratory failure and death. As population ages, the prevalence of these neuronal disorders rises significantly, emphasizing to approach effective treatment for risk reduction. In the pursuit of developing effective anti-amyloidogenesis therapeutic agents, ionic liquids (ILs) continue to receive the least attention. ILs have emerged as promising substitute for conventional solvents, owing to their unique physicochemical properties that facilitate protein refolding, mitigate denaturation, amyloidogenesis, and prevent aggregation. This review critically addresses intricate IL-protein interactions, dictated by anions-cations composition of ILs, their polarity, hydrophobicity, kosmotropicity, chaotropicity, amphiphillicity, and network, which modulate protein behavior and support structural and functional integrity. This article also underscores the need for precision in IL selection, ensuring their properties align with the desired structural outcome. We showcase ILs as a promising therapeutic avenue for neurodegenerative diseases, demonstrating their potential to modulate pathological protein aggregation and enhance protein homeostasis. Lastly, this review of outstanding research works, account for current lacunae that will guide future perspectives for the rational designing of IL for protein stabilization and offers new strategies for addressing underlying mechanism of ageing disorders.}, } @article {pmid41519279, year = {2026}, author = {Cai, M and Wang, S and Liu, M and Lai, B and Chen, C and Ding, J and Wang, X}, title = {Elevated FKBP5 expression associates with epilepsy-related molecular changes and promotes neuronal hyperexcitability.}, journal = {Brain research}, volume = {1874}, number = {}, pages = {150157}, doi = {10.1016/j.brainres.2026.150157}, pmid = {41519279}, issn = {1872-6240}, mesh = {Animals ; Neurons/metabolism ; *Tacrolimus Binding Proteins/metabolism/genetics ; Kainic Acid/pharmacology ; Hippocampus/metabolism ; *Epilepsy/metabolism/physiopathology ; Tacrolimus Binding Protein 5 ; Male ; Glutamic Acid/metabolism ; Astrocytes/metabolism ; Mice ; Cells, Cultured ; Disease Models, Animal ; Mice, Inbred C57BL ; }, abstract = {OBJECTIVE: Epilepsy is one of the neurological disorders, characterized by recurrent, spontaneous seizures arising from neuronal hyperexcitability and hypersynchrony in the brain. The mechanisms of epilepsy are intricate and remain elusive. FKBP5 has emerged as a significant protein implicated in neurological disorders such as Alzheimer's disease (AD) and Parkinson's disease (PD). This study aims to investigate the role of FKBP5 in a kainic acid (KA)-induced intrahippocampal epilepsy model and assessed how FKBP5 gain-of-function and FKBP51 inhibition influence neurotransmitter dynamics and neuronal excitability.

METHODS: We examined the expression of FKBP5 in the hippocampus of the kainic acid (KA)-induced epilepsy model. To explore the impact of FKBP5 on neuronal activity, we overexpressed FKBP5 in primary cortical neurons and astrocytes, assessing extracellular glutamate levels in neuron-astrocytes co-cultures with or without the FKBP51-selective inhibitor SAFit2 (250 nM). Intrinsic excitability, voltage-gated Na[+] currents, and network activity were evaluated using whole-cell patch-clamp recordings and high-density microelectrode arrays (HD-MEAs).

RESULTS: We observed an elevated level of FKBP5 in the hippocampus of a kainic acid (KA)-induced chronic epilepsy mouse model, whereas cortical FKBP5 did not show clear changes across the examined post-insult time points.. Moreover, FKBP5 overexpression induced a remarkable increase in the extracellular glutamate level in co-cultured primary cortical neurons and astrocytes. Intriguingly, FKBP5 overexpression modifies the electrophysiological properties of primary neurons, resulting in increased intrinsic excitability and enhanced Na[+] currents. Additionally, the network activity exhibits hyperexcitability with FKBP5 overexpression. Notably, SAFit2 treatment was also associated with elevated extracellular glutamate in the co-culture system, while intracellular FKBP5 and EAAT2 protein levels showed no significant group differences in the current dataset.

CONCLUSION: These findings suggested that FKBP5 played a significant role in regulating neuronal excitability and extracellular glutamate homeostasis. However, due to discrete sampling and the lack of continuous seizure monitoring, the present in vivo data do not establish a definitive causal contribution of FKBP5 to epileptogenesis, warranting future studies integrating longitudinal EEG and cell-type-specific manipulations.}, } @article {pmid41520099, year = {2026}, author = {Mao, C and Wang, W and Huang, X and Wu, M and Wang, Y and Wang, T and Qiu, Y and Chu, S and Jin, W and Jiang, Y and Bao, J and You, Y and Li, Y and Dong, L and Feng, F and Huo, L and Qiu, L and Gao, J}, title = {Real world clinical practice of lecanemab at PUMCH dementia cohort: focus on dynamic imaging and biomarker evolution.}, journal = {Alzheimer's research & therapy}, volume = {18}, number = {1}, pages = {32}, pmid = {41520099}, issn = {1758-9193}, support = {2021-I2M-1-020//CAMS Innovation fund for medical sciences (CIFMS)/ ; 2022-PUMCH-A-254//National High Level Hospital Clinical Research Funding/ ; 2020YFA0804500, 2020YFA0804501//National Key Research and Development Program of China/ ; }, mesh = {Humans ; Male ; Female ; Aged ; Biomarkers/blood/cerebrospinal fluid ; Magnetic Resonance Imaging ; Middle Aged ; Positron-Emission Tomography ; Aged, 80 and over ; tau Proteins/metabolism ; Amyloid beta-Peptides/metabolism ; Neuropsychological Tests ; Adult ; *Antibodies, Monoclonal/therapeutic use ; *Cognitive Dysfunction/drug therapy/diagnostic imaging ; Brain/diagnostic imaging/drug effects ; Cohort Studies ; *Alzheimer Disease/drug therapy/diagnostic imaging ; Treatment Outcome ; *Dementia/drug therapy/diagnostic imaging ; }, abstract = {BACKGROUND: Lecanemab is an anti-Aβ antibody approved in China for mild cognitive impairment (MCI) and mild dementia. Real-world application requires comprehensive assessment beyond MMSE scores, considering factors like ARIA risk. This single-center, real-world study aims to evaluate its efficacy in an expanded population, observe biomarker changes, and assess its safety profile in clinical practice.

METHODS: We recruited adults aged 40-90 with early AD from the PUMCH Dementia Cohort. A total of 42 patients received lecanemab treatment, of whom 29 completed the 6-month treatment evaluation. Participants had confirmed amyloid and tau pathology and met clinical criteria (CDR ≤ 1, CDR-SB ≤ 8and MMSE ≥ 18). Comprehensive assessments included neuropsychological testing, CSF and plasma biomarkers (Lumipulse G1200), multi-sequence 3T MRI (volumetric and ALPS index analysis), and amyloid/tau PET imaging (Centiloid quantification). All were monitored for adverse reactions. Matched control groups (matched for sex, age, APOE genotype, disease severity, and baseline therapy) were established for comparison of longitudinally changes in cognitive function, daily living ability and structure MRI.

RESULTS: Treatment was effective even for patients with lower MMSE scores but still classified as having mild dementia by CDR. A significant median Centiloid reduction of 30.9 was observed, with a 24.1% amyloid PET negativity rate after six months. While scores on cognitive and functional scales (CDR-SB, ADL) significantly worsened, indicating disease progression, the rate of progression was significantly slower compared to the control group. Structural MRI showed significant volume reduction in multiple brain regions and increased ventricular volume post-treatment, with no statistically significant change in the ALPS value. The rate of brain volume reduction is faster than that in the control group. Plasma biomarker dynamics (Aβ42, GFAP) indicated effective disease-modifying therapy. Greater Centiloid reduction was linked to more brain volume loss, higher baseline Centiloid levels, higher plasma Aβ42 increase and older age of onset. APOE ɛ4 homozygotes showed less Centiloid reduction. A favorable safety profile was observed, with a 7.1% incidence of asymptomatic, mild ARIA.

CONCLUSIONS: This study confirms the clinical efficacy, biomarker changes, and safety profile of lecanemab treatment over a 6-month period, demonstrating its positive therapeutic value and a favorable safety profile in the Chinese population with AD.}, } @article {pmid41520543, year = {2026}, author = {Xue, R and Wang, F and Zhang, B and Wu, J and Zhang, N and Sun, C}, title = {Carrier-free nanoassembly with dual antioxidant and anti-inflammatory activities camouflaged by melanoma cell membrane for tau-targeted therapy of Alzheimer's disease.}, journal = {Biomaterials}, volume = {329}, number = {}, pages = {123970}, doi = {10.1016/j.biomaterials.2025.123970}, pmid = {41520543}, issn = {1878-5905}, mesh = {Animals ; *Alzheimer Disease/drug therapy/pathology/metabolism ; *Antioxidants/therapeutic use/pharmacology/chemistry ; *tau Proteins/metabolism ; *Anti-Inflammatory Agents/therapeutic use/pharmacology/chemistry ; *Melanoma/pathology/metabolism ; *Cell Membrane/metabolism ; Humans ; Mice ; Selenium/chemistry/therapeutic use ; Oxidative Stress/drug effects ; Blood-Brain Barrier/metabolism/drug effects ; Cell Line, Tumor ; *Nanocomposites/chemistry ; }, abstract = {Targeting phosphorylated tau (p-tau) across the blood-brain barrier (BBB) represents a critical prerequisite for attenuating tau pathology and disease progression in Alzheimer's disease (AD) by alleviating oxidative stress and neuroinflammation. To address this challenge, we developed a novel carrier-free selenium-based nanoassembly stabilized by hydroxyl-rich fingolimod (FTY720), a sphingosine analogue. Following camouflaging with melanoma cell membranes and further functionalizing with T807, the resulting nanocomposite (FSMT) demonstrated robust capacity for BBB crossing and target p-tau both in vitro and in vivo. Additionally, FTY720 and nano-selenium exert remarkable antioxidant and anti-inflammatory effects by modulating the GSK-3β and NF-κB signaling pathways, respectively, thereby attenuating tau hyperphosphorylation and preventing neuronal cell death. In an okadaic acid-induced AD mouse model, the FSMT treatment not only significantly ameliorated oxidative stress and neuroinflammation, but also improved spatial learning and memory impairments. The reduction in abnormal tau aggregation following treatment was confirmed by PET-CT imaging. Overall, this p-tau-targeted biomimetic nanocomposite demonstrated excellent biocompatibility and therapeutic efficacy, presenting a translatable strategy for treating AD and other neurological disorders through analogous mechanisms.}, } @article {pmid41520868, year = {2026}, author = {Bajinka, O and Jallow, L and Ozdemir, G}, title = {A multi-target therapeutic framework for Alzheimer's disease: an integrative mechanistic review.}, journal = {Neuroscience}, volume = {596}, number = {}, pages = {143-157}, doi = {10.1016/j.neuroscience.2026.01.010}, pmid = {41520868}, issn = {1873-7544}, mesh = {Humans ; *Alzheimer Disease/metabolism/therapy/diagnosis/drug therapy ; Animals ; Amyloid beta-Peptides/metabolism ; tau Proteins/metabolism ; Biomarkers/metabolism ; Neuroinflammatory Diseases/metabolism ; }, abstract = {BACKGROUND: Alzheimer's disease (AD) is increasingly recognized as a multifactorial network disorder in which amyloid and tau pathology interact with mitochondrial dysfunction, neuroinflammation, metabolic impairment, vascular dysregulation, and synaptic failure. This review provides an integrative, systems-level synthesis of these mechanisms with emphasis on diagnostic and therapeutic implications.

METHODS: A structured narrative review was conducted using PubMed, Scopus, Web of Science, and Embase (2010-2025). Eligible studies included clinical trials, biomarker validation studies, cohort analyses, and mechanistic investigations. Evidence was synthesized by mechanistic domain with focus on cross-system interactions and translational relevance.

FINDINGS: Convergent data indicate that soluble Aβ species, tau propagation, glial dysregulation, insulin resistance, mitochondrial bioenergetic failure, lipid imbalance, and BBB dysfunction form a self-reinforcing neurodegenerative network. Diagnostic advances-including plasma p-tau181/217, Aβ42/40 ratio, GFAP, sTREM2, neuronal exosomes, and multimodal machine-learning models-enable earlier staging and refinement of therapeutic selection. Therapeutic development is shifting from linear amyloid removal to multi-target strategies incorporating anti-tau agents, glial-modulating compounds, metabolic and microbiome interventions, medical nutrition, and multidomain lifestyle programs. Across trials, combined strategies targeting interacting mechanisms demonstrate stronger biomarker and cognitive effects than single-axis approaches.

CONCLUSIONS: AD management requires a systems-oriented therapeutic architecture in which interventions are selected based on mechanistic dominance, biomarker stage, and potential synergy. We outline a multi-target strategy integrating amyloid/tau modulation, neuroimmune regulation, metabolic-vascular stabilization, and synaptic support. Future work should prioritize biomarker-guided stratification, treatment sequencing, and prevention-oriented combination designs.}, } @article {pmid41521126, year = {2026}, author = {Sankhe, K and Ruthirakuhan, M and Andreazza, AC and Brawman-Mintzer, O and Craft, S and Herrmann, N and Ismail, Z and Lerner, AJ and Levey, AI and Mintzer, J and Padala, PR and Perin, J and Porsteinsson, AP and Rosenberg, PB and Shade, D and Tumati, S and van Dyck, CH and Lanctôt, KL}, title = {Peripheral biomarkers associated with apathy and predicting response to methylphenidate: Secondary analysis of the Apathy in Dementia Methylphenidate Trial 2 (ADMET2) study.}, journal = {International psychogeriatrics}, volume = {}, number = {}, pages = {100181}, pmid = {41521126}, issn = {1741-203X}, support = {R01 AG046543/AG/NIA NIH HHS/United States ; }, abstract = {BACKGROUND: In Apathy in Dementia Methylphenidate Trial 2 (ADMET2), apathy in Alzheimer's disease improved with methylphenidate (MPH) in a randomized, placebo-controlled trial, though response varied. Here we evaluated serum biomarkers for their association with apathy and with treatment response.

METHODS: All ADMET2 participants with available blood samples were included. Markers of inflammation [interleukin (IL)-6, IL-10, Tumor Necrosis Factor (TNF)], oxidative stress [lipid hydroperoxide (LPH), 4-hydroxynonenal (4-HNE), 8-isoprostane (8-ISO)] and neuronal injury [neurofilament light (NfL), S100B] were assessed and values log-transformed. Neuropsychiatric Inventory-apathy (NPI-A) measured apathy. Least Absolute Shrinkage and Selection Operator (LASSO) regression was performed for feature selection of baseline markers predicting NPI-A at Month-6 (M6). Univariate analyses examined individual biomarker effects and multivariable models evaluated their combined effects. Treatment interactions, baseline and change in biomarker levels in treatment responders (≥4 change in NPI-A) and remitters (M6 NPI-A=0) were explored.

RESULTS: In the ADMET2 biomarker subset (n = 44, MPH:21, age:75 years, MMSE:20.2), higher baseline TNF was associated with higher M6 NPI-A [B(SE)= 6.86 (1.71), p = .0003], and multivariable models found lower baseline TNF [B(SE)= 8.28(1.61), p < .001] and higher baseline S100B [B(SE)= -6.41(1.95), p = .002] were associated with lower M6 NPI-A. Exploratory analyses suggested that higher baseline NfL significantly interacted with treatment to predict lower M6 NPI-A [B(SE)= -8.36(4.21), p = .05], only when adjusting for cognition. MPH remitters had lower baseline TNF [B(SE)= -0.27(0.10), p = .02], higher baseline NfL [B(SE)= 0.33(0.14), p = .03], and a greater decrease in IL-6 [B(SE)= -0.44 (0.17), p = .02].

CONCLUSIONS: Inflammatory and neuronal injury biomarkers may have prognostic value and may potentially inform treatment response and remission outcomes in apathy. Apathy in Dementia Methylphenidate Trial 2 (ADMET2), NCT02346201, https://clinicaltrials.gov/study/NCT02346201.}, } @article {pmid41521630, year = {2026}, author = {K, A and B, SK and Reddy, SG and Kugabalasooriar, S}, title = {Innovations in Nanobot and Microbot Propulsion for Targeted CNS Drug Delivery Across the Blood-Brain Barrier.}, journal = {Critical reviews in analytical chemistry}, volume = {}, number = {}, pages = {1-30}, doi = {10.1080/10408347.2025.2612631}, pmid = {41521630}, issn = {1547-6510}, abstract = {The transport of therapeutic molecules to the brain is one of the largest challenges of contemporary medicine because of the restrictive nature of the blood-brain barrier (BBB), which blocks the penetration of almost all biological therapeutics and most small-molecule drugs. This is a major limitation to the treatment of such neurological diseases as Parkinson's disease (PD), glioblastoma, and Alzheimer's disease. To beat these obstacles, there must be advanced delivery systems that can be precise, be released under control, and move without being invasive. Over the past decade, there have been innovations in micro and nanorobotic technologies, which provide a groundbreaking model that incorporates innovations in materials science, analytical chemistry, and biomedical engineering. Such engineered nanorobots are magnetically controlled, polymeric, or biologically derived nanorobots, which can be magnetically, acoustically, optically, or chemically controlled, and can cross the BBB with greater specificity. It has also been possible to follow the behavior of nanorobots at a direct visualization level in biological systems due to the development of analytical tools, especially imaging, real-time monitoring, and in situ sensing, which allows the behavior of nanorobots to be evaluated rigorously in terms of motions, shape transformation, and drug release profiles. The present review gives a detailed description of the propulsion-based nanorobotic drug delivery systems to the central nervous system (CNS), including structural components, modes of actuation, and protocols of analysis. The review explains that the combined effects of physicochemical features, external stimuli, and interactions between biointerfaces influence permeability via the BBB and accuracy of therapeutic response.}, } @article {pmid41522368, year = {2026}, author = {Scheltens, P and Atri, A and Feldman, HH and Zetterberg, H and Sano, M and Johannsen, P and Colombo, TL and Bardtrum, L and Jeppesen, R and Hansen, CT and Cummings, JL}, title = {Baseline characteristics from evoke and evoke+: Two phase 3 randomized placebo-controlled trials of semaglutide in participants with early-stage symptomatic Alzheimer's disease.}, journal = {Alzheimer's & dementia (New York, N. Y.)}, volume = {12}, number = {1}, pages = {e70200}, pmid = {41522368}, issn = {2352-8737}, support = {P20 GM109025/GM/NIGMS NIH HHS/United States ; R35 AG071476/AG/NIA NIH HHS/United States ; }, abstract = {INTRODUCTION: The glucagon-like peptide-1 receptor agonist semaglutide may impact neuroinflammation and reduce neurodegeneration. We present baseline characteristics of participants enrolled in the evoke (NCT04777396) and evoke+ (NCT04777409) trials, referred to as "evoke (+)" hereafter.

METHODS: Evoke (+) are two ongoing global, multicenter, randomized, double-blind, parallel-group, placebo-controlled phase 3 trials investigating semaglutide in participants with early-stage symptomatic Alzheimer's disease (AD) with confirmed amyloid positivity (by positron emission tomography or cerebrospinal fluid testing). Inclusion criteria are the same for both trials, except that by design, evoke+ also includes participants with significant small vessel pathology. Both trials include a 12-week screening phase before randomization (1:1) to receive oral semaglutide titrated to 14 mg or placebo for 156 weeks. Baseline data were summarized and analyzed descriptively. Additionally, data were pooled and assessed by five main geographical regions.

RESULTS: Evoke (+) recruited 9996 participants from 566 sites in 40 countries. The mean (standard deviation) age of participants was 71.8 (7.1) and 72.6 (7.1) years in evoke and evoke+, respectively; more participants were female than male (female: 53.0% and 51.9%, respectively) and most had a Clinical Dementia Rating (CDR) global score of 0.5 (72.8% and 71.4%; CDR global score of 1: 26.5% and 27.6%). Both trial populations had similar demographics, and clinical and cognitive baseline characteristics, except that 2.8% of participants in evoke+ had magnetic resonance imaging-documented significant small vessel pathology as per protocol inclusion criteria. Regional-level data demonstrated some differences in AD treatment characteristics, including cholinesterase inhibitor use of 41.7% in North America versus 61.6% in Asia.

DISCUSSION: Evoke (+) are the only large-scale, phase 3 trials investigating the longer-term efficacy and safety of semaglutide in early AD as a potential disease-modifying treatment. The baseline characteristics from evoke (+) reflect a varied, global population with early-stage symptomatic AD. Primary readouts are expected in the second half of 2025.

HIGHLIGHTS: evoke and evoke+ are the only large-scale randomized controlled trials (RCTs) investigating the longer-term efficacy and safety of semaglutide in early AD.Baseline characteristics reflect a varied, global population.The trials' primary readouts are expected in the second half of 2025.}, } @article {pmid41522370, year = {2026}, author = {Foley, KE and Weekman, EM and Wilcock, DM}, title = {Acute anti-Aβ antibody exposure induces microglial changes and significantly alters chemokine signaling.}, journal = {Alzheimer's & dementia (New York, N. Y.)}, volume = {12}, number = {1}, pages = {e70201}, pmid = {41522370}, issn = {2352-8737}, abstract = {INTRODUCTION: While the anti-amyloid-lowering immunotherapies provide the first disease-targeting therapies for the treatment of Alzheimer's disease, there remain harmful adverse events causing hesitation among patients, families, physicians, and regulatory bodies. Though these drugs have been repeatedly proven to lower brain amyloid plaque burden, the specific cellular mechanisms and pathways by which the immunotherapy impacts the brain remain unclear.

METHODS: This study aimed to transcriptionally profile the brain's immediate immune response to anti-amyloid beta (anti-Aβ) antibodies. To evaluate acute cellular priorities, we intracranially injected anti-Aβ antibody (3D6) or an isotype-matched control immunoglobulin G (IgG) antibody and performed single-cell sequencing analysis after 3 days.

RESULTS: We found reduced numbers of a motile microglia cluster and homeostatic microglia in the 3D6 antibody-injected cortex compared to the IgG-injected cortex. It was also found that chemokine/cytokine signaling was enriched across homeostatic-proinflammatory microglia, interferon-responding microglia, and disease-associated microglia 2 (DAM2) following 3D6 antibody injection. We explored "CCL" signaling, which suggested a change in outgoing signaling coordinated by all microglia types targeting homeostatic microglia, surprisingly not targeting DAM1 or DAM2. We then analyzed enriched signaling pathways clustered by k-means river plots and identified pathways enriched and dampened with acute 3D6 treatment.

DISCUSSION: Together these data supply evidence for significant involvement of microglia in the anti-Aβ response in the brain after just 3 days. Most interestingly, there are changes in cytokine/chemokine signaling across microglia subtypes, specifically with communication in CCL pathways targeting homeostatic microglia and T cells. These acute signaling changes provide novel insights and generate unique hypotheses on the brain's immediate immune reaction to anti-Aβ antibody.

HIGHLIGHTS: Intracranially injected anti-amyloid beta (anti-Aβ) antibody promotes an immediate microglial response.3D6 exposure resulted in fewer homeostatic and motile microglia subtypes.Acute 3D6 enriches for chemokine/cytokine signaling pathways.}, } @article {pmid41522467, year = {2026}, author = {Williams, DM and Heikkinen, S and Hiltunen, M and , and Davies, NM and Anderson, EL}, title = {The proportion of Alzheimer's disease attributable to apolipoprotein E.}, journal = {NPJ dementia}, volume = {2}, number = {1}, pages = {1}, pmid = {41522467}, issn = {3005-1940}, abstract = {Variation in the APOE gene strongly affects Alzheimer's disease (AD) risk. However, the proportion of AD burden attributable to this variation requires clarification, which would help to elucidate the scope of strategies targeting apolipoprotein E (APOE) for AD prevention and treatment. We estimated the extents to which clinically diagnosed AD, AD neuropathology and all-cause dementia are attributable to the common APOE alleles in four large studies. First, we used data on 171,105 and 289,150 participants aged ≥60 years from UK Biobank (UKB) and FinnGen, respectively. AD and all-cause dementia were ascertained from linked electronic health records in these cohorts. Second, we examined amyloid-β positivity from amyloid positron emission tomography scans of 4415 participants of the A4 Study. Third, we analysed data from the Alzheimer's Disease Genetics Consortium (ADGC), where neuropathologically confirmed AD cases were compared to pathology-negative, cognitively intact controls (N = 5007). In each analysis, we estimated outcome risk among carriers of APOE risk alleles ε3 and ε4, relative to individuals with an ε2/ε2 genotype, and calculated attributable fractions to show the proportions of the outcomes due to ε3 and ε4. For AD, fractions ranged from 71.5% (95% confidence interval: 54.9%, 81.7%) in FinnGen to 92.7% in the ADGC (82.4, 96.5%). In A4, 85.4% (17.5, 94.5%) of cerebral amyloidosis was attributable to ε3 and ε4. The proportions of all-cause dementia attributable to ε3 and ε4 in UKB and Fin-Gen were 44.4% (95% CI: 18.2%, 62.2%) and 45.6% (30.6%, 56.9%), respectively. Without strong underlying risks from APOE ε3 and ε4, almost all AD and half of all dementia would not occur. Intervening on APOE should be prioritised to facilitate dementia prevention.}, } @article {pmid41523330, year = {2025}, author = {Raphael, DL}, title = {Neuropsychiatric symptoms in mild cognitive impairment and early Alzheimer's disease: Clinical pattern and diagnostic implications.}, journal = {AIMS neuroscience}, volume = {12}, number = {4}, pages = {676-705}, pmid = {41523330}, issn = {2373-7972}, abstract = {BACKGROUND: Alzheimer's disease (AD) and mild cognitive impairment (MCI) are widely recognized for their hallmark cognitive deficits, typically characterized by progressive cognitive deterioration. However, neuropsychiatric symptoms (NPS), including depression, apathy, anxiety, irritability, and sleep disturbances, are increasingly prevalent in the early stages of these conditions and significantly influence the disease trajectory and patient outcomes. Importantly, neuropsychiatric symptoms often precede overt memory loss by several years, with subtle mood and behavioral disturbances serving as early pre-diagnostic markers of an underlying Alzheimer's pathology. Their presence complicates the diagnosis, accelerates the disease progression, and intensifies the caregiver burden. However, distinguishing NPS arising from neurodegeneration and primary psychiatric disorders remains a profound diagnostic challenge, thus delaying timely intervention and obscuring early disease recognition.

OBJECTIVE: This structured narrative review examines the diagnostic complexities, clinical impact, and current management of NPS in early-stage Alzheimer's disease (AD) and Mild Cognitive Impairment (MCI), alongside the biological underpinnings, clinical relevance, diagnostic challenges, and treatment perspectives. We argue that understanding and managing NPS is essential to improve the clinical outcomes, reduce the caregiver burden, and guide therapeutic innovation.

METHODS: A structured narrative review of peer-reviewed studies published between 2012 and 2025 was conducted using PubMed, MEDLINE, Scopus, PsycINFO, Google Scholar, and CINAHL. The included studies investigated NPS prevalence, neurobiological correlations, and management strategies in individuals with AD or MCI.

FINDINGS: NPS affects up to 80% of individuals with early AD or MCI, often preceding cognitive decline. The current management strategies heavily rely on non-pharmacological interventions such as caregiver support, behavioral activation, and structured routines, while pharmacological options remain limited by modest efficacy and safety concerns.

DISCUSSION: Advancing knowledge of NPS and their association with cognitive decline is critical to establish more precise diagnostic criteria and to inform personalized therapeutic approaches. Future research should emphasize biomarker-driven diagnostics and the development of novel, targeted interventions that simultaneously address cognitive and neuropsychiatric domains to optimize outcomes for patients and caregivers. This study contributes to the field by reframing NPS as potential early biomarkers in the trajectory of MCI and dementia progression.}, } @article {pmid41524345, year = {2025}, author = {Yusupov, FA and Abdykadyrov, MS}, title = {[Neurogenesis in neurodegeneration: multifactorial regulation, mechanisms of impairment, and therapeutic strategies].}, journal = {Zhurnal nevrologii i psikhiatrii imeni S.S. Korsakova}, volume = {125}, number = {12}, pages = {14-21}, doi = {10.17116/jnevro202512512114}, pmid = {41524345}, issn = {1997-7298}, mesh = {Humans ; *Neurogenesis/physiology/drug effects ; *Alzheimer Disease/physiopathology/therapy ; *Parkinson Disease/physiopathology/therapy ; *Neurodegenerative Diseases/physiopathology ; Animals ; Brain/physiopathology ; Hippocampus ; }, abstract = {OBJECTIVE: To systematize current data on neurogenesis and its role in the pathogenesis of neurodegenerative conditions, such as Alzheimer's disease and Parkinson's disease, with a focus on molecular mechanisms of regulation, the nature of disorders in neurodegeneration, and the evaluation of therapeutic approaches aimed at stimulating neurogenesis.

MATERIAL AND METHODS: Research papers published in scientific databases, mainly Scopus, PubMed, and Google Scholar, over the past 5 years were used for this review. Special attention was paid to studies on neurogenesis and its role in the pathogenesis of neurodegenerative diseases. The review included studies that met the following criteria: publications from the past five years reporting current neurogenesis data, using clearly identified experimental and clinical techniques, published in peer-reviewed international journals with a high impact factor, and providing reliable statistics to support the results.

UNLABELLED: Studies with a limited sample size and insufficient statistical significance, those lacking a transparent methodology or exhibiting a low level of data reproducibility, reviews without a clear focus on neurogenesis or its connection to neurodegenerative diseases, and studies providing insufficient information on the applied technologies and analysis methods were excluded.

RESULTS: Modern research has significantly expanded the understanding of neurogenesis and its role in neurodegenerative diseases. Neurogenesis has been confirmed to occur in specific areas of the adult brain, including the hippocampus, where it is involved in cognitive processes such as learning, memory consolidation, spatial adaptation, cognitive flexibility, and regulation of affective behavior. However, the extent and functional significance of neurogenesis in different brain regions remain a matter of debate. The effect of neurodegenerative diseases on neurogenesis varies: in Alzheimer's disease, studies in animal models demonstrate its impairment; however, data on humans are inconsistent: a decrease in neurogenesis is observed in the early stages of the disease, but in some cases, its increase is reported, likely as a compensatory mechanism. Factors influencing neurogenesis in Alzheimer's disease include β-amyloid and tau protein accumulation, neuroinflammation, mitochondrial dysfunction, and oxidative stress. Parkinson's disease is associated with a decrease in neurogenesis in the subventricular zone and hippocampus due to the degeneration of dopaminergic neurons and the accumulation of α-synuclein; however, deep brain stimulation is able to enhance neuronal proliferation. Therapeutic strategies include pharmacological approaches aimed at stimulating neurogenesis, such as the use of neurotrophic factors, acetylcholinesterase inhibitors, selective serotonin reuptake inhibitors, Wnt and EGFR signaling pathway modulators, uric acid, and MFG-E8, as well as non-pharmacological methods, including physical activity, enriched environment, cognitive training, electrical stimulation, and music therapy.

CONCLUSION: Neurodegenerative diseases are a significant problem in modern healthcare, requiring an in-depth study of the mechanisms of neurogenesis and its role in pathogenesis. Despite conflicting evidence on neurogenesis in adult humans, animal model studies and cellular technologies demonstrate prospects for its therapeutic stimulation. Pharmacological and non-pharmacological methods, including the use of neurotrophic factors, electrical stimulation, and cognitive training, as well as cellular and gene therapy, are the basis of new intervention strategies. However, the issues of controlling the differentiation and integration of new neurons, as well as the ethical aspects associated with the use of stem cells, remain unresolved. Further interdisciplinary research aimed at studying the regulatory mechanisms of neurogenesis and its therapeutic potential may lead to the development of effective treatment strategies that can slow or even reverse the progression of neurodegenerative diseases. It highlights the need to integrate advanced technologies and approaches in modern neuroscience and clinical practice.}, } @article {pmid41524357, year = {2025}, author = {Guzanova, EV and Zorkova, AV and Sorokina, TA and Goncharov, VV and Voronina, DS and Beschastnova, IA}, title = {[Frequency of nutritional deficiency in patients with Alzheimer's disease and Parkinson's disease].}, journal = {Zhurnal nevrologii i psikhiatrii imeni S.S. Korsakova}, volume = {125}, number = {12}, pages = {113-119}, doi = {10.17116/jnevro2025125121113}, pmid = {41524357}, issn = {1997-7298}, mesh = {Humans ; *Alzheimer Disease/complications ; Male ; Aged ; Female ; *Malnutrition/epidemiology/etiology/diagnosis/diet therapy ; Aged, 80 and over ; Middle Aged ; *Parkinson Disease/complications ; Nutritional Status ; Nutrition Assessment ; }, abstract = {OBJECTIVE: To determine the incidence of nutritional deficiencies in patients with Alzheimer's disease (AD) and Parkinson's disease (PD) and, if identified, to correct them.

MATERIAL AND METHODS: 111 patients with neurodegenerative diseases AD and PD aged 50 to 89 years) were examined. Patients were examined twice: at the initial visit and 2 months later. During the first visit, a neurological examination and neuropsychological assessment were performed, and anxiety and depression levels were determined. Nutritional status was assessed using the Mini Nutritional Assessment (MNA) questionnaire, and body mass index (BMI) was calculated. For laboratory confirmation of malnutrition, hemoglobin, albumin, lipid profile, urea, and creatinine levels were assessed. All patients at risk of malnutrition were given dietary recommendations. The patient's family discussed adherence to a dietary regimen and maintaining a nutritious diet. To treat malnutrition, patients were also recommended to receive enteral nutrition supplements at a rate of 30-35 kcal/kg of body weight for outpatients (a total of at least 400 kcal/day) and 1 g of protein/kg of body weight/day. For this purpose, Fresubin protein was used, individually adjusted from 2 to 6 measuring spoons (12-36 g of protein). In the presence of dysphagia, depending on the severity of the swallowing disorder, a diet with a modified consistency was prescribed: Fresubin Cream 2 kcal, Fresubin Yogurt, Fresubin Condensed Level 2, and Fresubin Condensed Level 1. At the second visit (2 months later), treatment effectiveness was assessed.

RESULTS: Among the examined patients, AD was diagnosed in 66 (59.5%) patients, and PD in 45. (40.5%). malnutrition/risk of malnutrition was detected in 31 (28%) patients. In the group of patients with AD who had malnutrition/risk of malnutrition, 15 (62.5%) patients had malnutrition, 9 (37.5%) had the risk of malnutrition. Among patients with PD, 3 (42.9%) patients were diagnosed with malnutrition, 4 (57.1%) had the risk of malnutrition. Patients with AD who had moderate and severe dementia had significantly more often malnutrition and risk of malnutrition (p<0.05). Patients with PD at a more severe stage of the disease and, accordingly, with more pronounced movement disorders, had significantly more often malnutrition and the risk of malnutrition (p<0.05). A moderate correlation was obtained between dysphagia, oral apraxia, tooth loss, chewing disorder and malnutrition and the risk of malnutrition in patients with AD and PD (r=0.3, p<0.001). The value of laboratory parameters, such as increased creatinine, decreased albumin and hemoglobin, statistically significantly correlated with malnutrition and the risk of malnutrition (p<0.05). The study found a statistically significant association between depression, affective disorders, and malnutrition and the risk of malnutrition in patients with AD and PD (p<0.05). When examining patients malnutrition and the risk of malnutrition at the second visit, BMI increased in all patients.

CONCLUSION: Malnutrition and the risk of malnutrition occur in more than a quarter of patients with AD and PD. The risk of malnutrition increases in moderate and severe stages of the disease. Malnutrition is more common in AD compared to PD. Malnutrition and the risk of malnutrition were significantly associated with the presence of depression, affective disorders, as well as with chewing disorders, tooth loss, dysphagia, and oral apraxia. Early recognition of the risks of malnutrition is important for the timely correction of modifiable factors for the development of malnutrition, including the organization of adequate nutrition for the patient, dental prosthetics, Adjustment of the treatment regimen for the underlying disease, treatment of depressive episodes, and affective disorders. If a diagnosis of malnutrition is made, it is necessary to calculate and replenish the patient's energy and fluid needs, including the inclusion of additional enteral nutrition in the comprehensive treatment strategy.}, } @article {pmid41524585, year = {2026}, author = {Hu, G and Li, W and Lei, X and Yao, Y and Ye, S}, title = {Aloe-emodin attenuated Aβ-induced tau phosphorylation by autophagy-NLRP3 inflammasome pathway.}, journal = {Neuroreport}, volume = {37}, number = {3}, pages = {95-105}, doi = {10.1097/WNR.0000000000002246}, pmid = {41524585}, issn = {1473-558X}, support = {82205235//the National Natural Science Foundation of China/ ; 2022AH050502//The Key Project Foundation of Natural Science Research of Anhui University of Chinese Medicine/ ; 2022rcyb028//The Talent Support Program of Anhui University of Traditional Chinese Medicine/ ; YQYB2024028//Anhui Province 2024 Action Project for Training Young and Middle aged Teachers in Universities/ ; }, mesh = {Animals ; *Autophagy/drug effects ; *tau Proteins/metabolism/drug effects ; *NLR Family, Pyrin Domain-Containing 3 Protein/metabolism/drug effects ; PC12 Cells ; *Anthraquinones/pharmacology ; Rats ; *Amyloid beta-Peptides/metabolism ; Phosphorylation/drug effects ; *Inflammasomes/metabolism/drug effects ; Signal Transduction/drug effects ; Cell Survival/drug effects ; Alzheimer Disease/metabolism ; Neuroprotective Agents/pharmacology ; }, abstract = {OBJECTIVE: Anthraquinone derivative aloe-emodin, extracted from Chinese herbs has been confirmed with various pharmacological effects, including anti-inflammatory and neuroprotective properties, particularly in Alzheimer's disease, but the exact mechanism of action remains unclear.

METHODS: In this study, the PC12 cells were induced by amyloid β-protein (Aβ) to establish an in vitro model of Alzheimer's disease. The 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyltetrazolium bromide, 5-ethynyl-2'-deoxyuridine staining, transmission electron microscopy, real-time quantitative PCR, western blot, ELISA, coimmunoprecipitation (Co-IP), and immunofluorescence were employed to evaluate effect of aloe-emodin on the survival and expression of related genes and proteins in PC12 cells induced by Aβ.

RESULTS: We found that 5 μM aloe-emodin significantly enhanced cell survival and proliferation. It also increased the mRNA and protein expression of Beclin-1 and LC3II, while decreasing the mRNA expression of P62, PI3K, AKT, mechanistic target of rapamycin (mTOR), NOD-like receptor protein 3 (NLRP3), and caspase-1, as well as the protein expression of P62, NLRP3, cleaved-caspase-1, p-PI3K, p-AKT, p-mTOR, interleukin-18 (IL-18), and IL-1β. Additionally, aloe-emodin reduced the intensity of p-tau fluorescence. The Co-IP results demonstrated a direct interaction between NLRP3 and LC3. Interestingly, aloe-emodin exhibited effects comparable to those of RAPA, an mTOR inhibitor.

CONCLUSION: These findings demonstrate that aloe-emodin offers neuroprotective benefits by reducing NLRP3-mediated inflammation and promoting autophagy, thereby providing a novel perspective on the treatment of Alzheimer's disease.}, } @article {pmid41524814, year = {2026}, author = {Tripathi, P and Shah, J}, title = {Valacyclovir Mitigates Amyloid Plaque Deposition, P-Tau Aggregation, and Neuroinflammation in Streptozotocin induced Alzheimer's Disease Rat Model.}, journal = {Molecular neurobiology}, volume = {63}, number = {1}, pages = {356}, pmid = {41524814}, issn = {1559-1182}, support = {GSBTM/MD/PROJECTS/SSA/4887/2016-17//Gujarat State Biotechnology Mission, Government of Gujarat, India./ ; }, mesh = {Animals ; *Valacyclovir/pharmacology/therapeutic use ; *Alzheimer Disease/drug therapy/metabolism/pathology/chemically induced ; Streptozocin ; Male ; Disease Models, Animal ; *Plaque, Amyloid/drug therapy/pathology/metabolism ; *tau Proteins/metabolism ; *Neuroinflammatory Diseases/drug therapy/pathology/metabolism ; Amyloid beta-Peptides/metabolism ; Amyloid Precursor Protein Secretases/metabolism ; Oxidative Stress/drug effects ; *Protein Aggregates/drug effects ; Neuroprotective Agents/pharmacology/therapeutic use ; Rats, Wistar ; Rats ; Aspartic Acid Endopeptidases/metabolism ; }, abstract = {Alzheimer's Disease (AD), a leading cause of dementia, is a known neurodegenerative disorder. Affecting millions of people worldwide, AD pathogenesis involves diverse risk factors such as lifestyle, environmental, and metabolic conditions that accelerate sporadic AD. Very recently, backed with substantial evidence, herpes simplex virus-1 (HSV-1) has been recognized as a potential causative factor that may play a pivotal role in sporadic AD. Latent virus is estimated to activate key underlying pathways, preferably Aβ and p-tau, to cause AD. Additionally, Antivirals such as Valacyclovir have emerged to impart a potential neuroprotective role in AD. Present research aimed to explore the neuroprotective role and mechanism of Valacyclovir in the streptozotocin-induced Alzheimer's disease model in rats. A single dose of 3 mg/kg ICV (intracerebroventricular) Streptozotocin (STZ) was administered to induce AD in rats. Two doses of Valacyclovir, i.e., 100 mg/kg and 150 mg/kg were evaluated with Donepezil 5 mg/kg as standard. Post 21 days of treatment, Valacyclovir demonstrated dose-dependent improvement in neurobehavioral parameters. Further, AD-specific parameters i.e. Aβ1-40 and Aβ1-42, p-tau, and BACE-1 were significantly (p < 0.001) reduced with parallel reduction in inflammatory (p < 0.001) and oxidative stress markers. Additionally, Valacyclovir also increased the levels of amyloid clearance enzymes i.e., neprilysin (NEP) (p < 0.001) and insulin-degrading enzyme (IDE) (p < 0.001). Results suggest promising neuroprotective action of valacyclovir via reducing Aβ-amyloid protein, p-Tau, BACE-1, as well as demonstrating anti-inflammatory and antioxidant activity.}, } @article {pmid41524953, year = {2026}, author = {O'Mara, A and Mody, BP and Mammi, M and Simjian, T and Ghattas, K and Kaliki, S and Le, NPM and Liew, A and Migliore, M and Mekary, RA}, title = {The effect of GLP-1 receptor agonists on cognition in nondiabetic patients with mild cognitive impairment or alzheimer's disease: a meta-analysis of randomized controlled trials.}, journal = {Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology}, volume = {47}, number = {1}, pages = {149}, pmid = {41524953}, issn = {1590-3478}, mesh = {Humans ; *Alzheimer Disease/drug therapy/psychology ; *Cognitive Dysfunction/drug therapy ; *Glucagon-Like Peptide-1 Receptor Agonists ; *Randomized Controlled Trials as Topic ; Cognitive Enhancement ; *Cognition/drug effects ; }, abstract = {BACKGROUND: Currently, the cognitive impact of Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) remains unclear in non-diabetic patients with Alzheimer’s disease (AD) and mild cognitive impairment (MCI), despite their widespread use for type 2 diabetes. This meta-analysis summarized cognitive outcomes from randomized controlled trials (RCTs) of GLP-1 RAs in non-diabetic patients with AD or MCI. METHODS: PubMed, Cochrane Library, and Embase were searched for studies through October 27, 2024. Pooled standardized mean differences (SMD) and 95% confidence intervals (CI) were calculated using random-effects models. Sensitivity analyses addressed variations in cognitive assessment methodologies. Between-study heterogeneity was evaluated using the I[2] index. RESULTS: Four RCTs comprising 112 patients (61 placebo, 51 treatment) were included. For cognitive tests where higher scores indicate better outcomes, no significant difference was observed between GLP-1 RA and placebo groups (pooled SMD: -0.10, 95% CI: -0.53, 0.34; I[2] = 23.9%). Sensitivity analyses yielded consistent results. Analysis of the Alzheimer’s Disease Assessment Scale–Cognitive subscale from two studies, where lower scores indicate better outcomes, similarly showed no significant treatment effect (SMD: 0.07, 95% CI: -0.47, 0.62; I[2] = 0%). CONCLUSION: There was no evidence that GLP-1 RAs improved cognitive outcomes compared to placebo in non-diabetic patients with AD or MCI. Further research is needed to clarify their neuroprotective potential and explore alternative therapeutic strategies for cognitive decline.}, } @article {pmid41526725, year = {2026}, author = {Li, R and Berlowitz, D and Mez, J and Silver, B and Wang, X and Hu, W and Goodwin, R and Keating, H and Liu, W and Lin, H and Yu, H}, title = {Early prediction of Alzheimer's disease using longitudinal electronic health records of US military veterans.}, journal = {Communications medicine}, volume = {6}, number = {1}, pages = {23}, pmid = {41526725}, issn = {2730-664X}, support = {I01 HX003711/HX/HSRD VA/United States ; I01 HX003969/HX/HSRD VA/United States ; R01 AG080670/AG/NIA NIH HHS/United States ; R01 DA056470/DA/NIDA NIH HHS/United States ; }, abstract = {BACKGROUND: Early prediction of Alzheimer's disease is important for timely intervention and treatment. We examine whether machine learning on longitudinal electronic health record notes can improve early prediction of Alzheimer's disease.

METHODS: From Veterans Health Administration records (2000 to 2022), we studied 61,537 individuals diagnosed with Alzheimer's disease and 234,105 without, aged 45-103 years, 98.4% were male. From clinical notes, we quantified the frequency of subjective cognitive decline and Alzheimer's disease-related keywords, and applied statistical machine learning models to assess their ability to predict future diagnosis.

RESULTS: Here we show that Alzheimer's-related keywords (e.g., "concentration," "speaking"), occur more often in notes of individuals who later develop Alzheimer's disease than in controls. In the 15 years preceding diagnosis, cases demonstrate an exponential increase in keyword mentions (from 9.4 to 57.7 per year), whereas controls show a slower, linear increase (8.2 to 20.3). These trends are consistent across demographic subgroups. Random forest models using these keywords for prediction achieve an area under receiver operating characteristic curve from 0.577 at ten years before diagnosis to 0.861 one day before diagnosis, consistently outperforming models using only structured data.

CONCLUSIONS: Signs and symptoms of early Alzheimer's disease are reported in clinical notes many years before a clinical diagnosis is made and the frequency of these signs and symptoms, approximated by keywords, increases the closer one is to the diagnosis. A simple keyword-based approach can capture these signals and can help identify individuals at high risk of future Alzheimer's disease.}, } @article {pmid41527082, year = {2026}, author = {Du, Y and Wu, L and Mao, Y and Chen, S and Gao, X}, title = {IL-27, a metabolic regulator secreted by astrocytes in response to GLP-1RA OHP2, modulates microglial reprogramming in Alzheimer's disease by regulating cGAS lactylation.}, journal = {Journal of neuroinflammation}, volume = {23}, number = {1}, pages = {58}, pmid = {41527082}, issn = {1742-2094}, support = {82473834//National Natural Science Foundation of China,China/ ; 82373780//National Natural Science Foundation of China,China/ ; CPU2022PZQ10//"Double First-Class" University Project/ ; }, mesh = {Animals ; *Astrocytes/metabolism/drug effects ; *Alzheimer Disease/metabolism/pathology ; *Microglia/metabolism/drug effects ; Mice ; Humans ; *Interleukins/metabolism ; cGAS-STING Signaling Pathway ; Cells, Cultured ; Metabolic Reprogramming ; Mice, Inbred C57BL ; }, abstract = {Microglia-mediated neuroinflammation, considered one of the most plausible pathogenic hypotheses underlying Alzheimer’s disease (AD), plays a pivotal role in the initiation and progression of this devastating condition. Recently, glucagon-like peptide-1 receptor agonists (GLP-1RAs) have demonstrated promising neuroprotective effects in both preclinical and clinical studies. Previously, we developed an orally-administered GLP-1RA peptide called OHP2, which is capable of crossing the blood-brain barrier for the treatment of AD. OHP2 has been shown to effectively reduce brain inflammation in AD mouse models. In this study, we discovered that OHP2 treatment induced IL-27 secretion from astrocytes and modulated microglial reprogramming from the neurotoxic M1 phenotype to the neuroprotective M2 phenotype through glycolysis/cGAS lactylation clock/mTOR pathway, thereby alleviating excessive neuroinflammation. These findings provide a rationale for further pharmacological investigations into OHP2 and suggest that IL-27 may hold significant implications for AD therapy as a metabolic regulator.}, } @article {pmid41527161, year = {2026}, author = {Cheng, CM and Tsai, MJ and Tseng, CC and Lin, YS and Lin, YS and Chen, LY and Liu, MN and Fuh, JL}, title = {Pharmacological management of agitation in dementia: An evidence-based review with expert consensus.}, journal = {Journal of the Chinese Medical Association : JCMA}, volume = {89}, number = {3}, pages = {187-197}, pmid = {41527161}, issn = {1728-7731}, mesh = {Humans ; Aberrant Motor Behavior in Dementia ; Antipsychotic Agents/therapeutic use ; Consensus ; *Dementia/drug therapy/complications ; *Psychomotor Agitation/drug therapy/etiology ; }, abstract = {Agitation is a frequently occurring and challenging neuropsychiatric symptom of Alzheimer's disease (AD) that substantially affects quality of life, caregiver burden, and healthcare utilization. Nonpharmacological interventions, especially trigger identification, environmental adjustments, and supportive activities, remain the first-line approach for treating agitation. Pharmacological treatment should be considered only when nondrug measures are insufficient or when agitation causes severe distress or safety risks. This consensus integrates evidence up to June 2025, the Taiwan Ministry of Health and Welfare approval status, and expert opinion from Taipei Veterans General Hospital. Among the approved agents, brexpiprazole demonstrated the strongest evidence and most favorable safety profile. Risperidone and aripiprazole are effective, but require careful monitoring for cerebrovascular and extrapyramidal risks. Selected antidepressants, particularly citalopram and agomelatine, should be considered when safety is prioritized. Anticonvulsants, acetylcholinesterase inhibitors, and memantine have limited efficacy and should be reserved for refractory cases. Long-term or routine pharmacological use is not supported by current evidence. Future research should focus on identifying responsive patient subgroups, optimizing dosing strategies, and integrating medications into individualized, multidisciplinary care plans.}, } @article {pmid41527496, year = {2026}, author = {Kalita, T and Shakya, A and Ghosh, SK and Singh, UP and Bhat, HR}, title = {Microwave-Assisted Synthesis and In Vitro Anti-Alzheimer Evaluation of Novel 1,3,5-Triazine-Nicotinic Hydrazide Derivatives as Acetylcholinesterase and Butyrylcholinesterase Inhibitors.}, journal = {Journal of biochemical and molecular toxicology}, volume = {40}, number = {1}, pages = {e70685}, doi = {10.1002/jbt.70685}, pmid = {41527496}, issn = {1099-0461}, mesh = {*Cholinesterase Inhibitors/pharmacology/chemical synthesis/chemistry ; *Alzheimer Disease/drug therapy/enzymology ; *Acetylcholinesterase/metabolism/chemistry ; Animals ; Humans ; *Butyrylcholinesterase/metabolism/chemistry ; *Triazines/chemistry/pharmacology/chemical synthesis ; *Microwaves ; Molecular Docking Simulation ; *Hydrazines/chemistry/pharmacology/chemical synthesis ; Cell Line, Tumor ; Rats ; Male ; }, abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder posing major global health challenges due to its complex pathophysiology and increasing prevalence among the elderly. In the present work, the molecular hybridization technique was utilized to design and synthesize nicotinic hydrazide-1,3,5-triazine hybrids. Accordingly, this study aimed to design, perform in silico screening, synthesize, and evaluate the in vitro and in vivo anti-AD potential of the proposed compounds. Docking studies revealed that the compounds displayed key interactions with catalytic site and peripheral anionic site residues. Based on binding affinity, ten compounds were synthesized and characterized using different spectroscopic techniques. In vitro AChE and BChE inhibitory assays revealed that the compound 4A36 showed the highest inhibitory ability with log IC50 values of 5.97 μM against AChE and 4.57 μM against BChE. In addition, cytotoxicity screening revealed that 4A36 was non-toxic in SH-SY5Y neuroblastoma cells in the concentration range of 15.625-250 µg/mL. Acute oral toxicity evaluation of the compound revealed no adverse effects up to 175 mg/kg b.w. Further, in vivo studies using the scopolamine-induced model further validated the therapeutic promise of the compound. At a dose of 30 mg/kg b.w., the compound demonstrated significant improvements in learning and memory, reduced MDA levels with concurrent elevation of antioxidant enzymes SOD and Catalase, and reduced AChE activity in hippocampal tissue. Histopathological observations revealed that treatment groups, especially at higher dose (30 mg/kg b.w.), preserved the granular layer of the dentate gyrus and improved neuronal integrity compared to the disease control. These findings indicate that 4A36 at a dose of 30 mg/kg b.w. may be considered as a promising lead compound in AD.}, } @article {pmid41527522, year = {2026}, author = {Richardson, TI and Klein, RC and Huang, K and Zhang, J and Mesecar, AD and Dage, JL and Clayton, B and Lamb, BT and Palkowitz, AD}, title = {Next-generation Alzheimer's therapeutics: target assessment and enablement at the Indiana University School of Medicine-Purdue University TREAT-AD Center.}, journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association}, volume = {22}, number = {1}, pages = {e70964}, pmid = {41527522}, issn = {1552-5279}, support = {U54AG065181/AG/NIA NIH HHS/United States ; }, mesh = {Humans ; *Alzheimer Disease/drug therapy ; Indiana ; *Drug Discovery/methods ; Computational Biology ; United States ; Universities ; Schools, Medical ; }, abstract = {The incidence of Alzheimer's disease (AD) continues to increase, despite decades of effort to develop disease-modifying therapies. In response, the National Institute on Aging (NIA) established the TaRget Enablement to Accelerate Therapy Development for Alzheimer's Disease (TREAT-AD) centers to address the gap between basic research and translational drug discovery. Situated within a robust AD research environment, the Indiana University School of Medicine (IUSM)-Purdue University TREAT-AD Center is one of two National Institutes of Health (NIH)-supported centers funded to accomplish this mission. With a focus on novel biological targets beyond amyloid and tau, our center has assembled the necessary components of a drug discovery engine: project and data management, bioinformatics and computational science, structural biology and biochemistry, assay development and pharmacology, and molecular design and synthesis of small molecules, antibodies, and oligonucleotides. Our objective is to deliver Target Enabling Packages (TEPs) within an open science framework, making data, methods, and research tools broadly accessible through the AD Knowledge Portal. HIGHLIGHTS: The Indiana University School of Medicine (IUSM)-Purdue TREAT-AD Center develops Target Enabling Packages (TEPs) to advance novel targets for the treatment of Alzheimer's disease (AD). The center is overseen by an administrative core and operates through four technical cores - bioinformatics, structural biology, assay development, and medicinal chemistry - within a milestone-driven and open science framework. Multi-omics, systems biology, and machine learning (ML) approaches guide the nomination of high-priority targets beyond amyloid and tau. Cross-core workflows provide structural insights into novel biological targets, validated assays, biomarkers, and molecular probes that enable lead optimization. All data, methods, and tools are openly shared through the AD Knowledge Portal to accelerate global efforts in AD drug discovery.}, } @article {pmid41527663, year = {2025}, author = {Barbati, SA and Carota, G and Partsinevelos, K and Di Pietro, L and Privitera, A and Cardaci, V and Graziani, A and Mangione, R and Lazzarino, G and Tavazzi, B and Di Pietro, V and Maiani, E and Bellia, F and Amorini, AM and Lazzarino, G and Baba, SP and Caruso, G}, title = {Preclinical evidence and therapeutic perspectives on carnosine for the treatment of neurodegenerative disorders.}, journal = {AIMS neuroscience}, volume = {12}, number = {4}, pages = {444-513}, pmid = {41527663}, issn = {2373-7972}, abstract = {Carnosine (β-alanyl-L-histidine) is an endogenous dipeptide widely distributed in mammalian tissues, especially skeletal and cardiac muscle cells, and, to a lesser extent, in the brain. While early interest in carnosine was given because of its role in muscle cell metabolism and athletic performance, it has more recently gained attention for its potential application in several chronic diseases. Specifically, brain aging and neurodegenerative disorders have received particular attention, as a marked reduction in carnosine levels has been described in these conditions. Carnosine exerts a wide range of biological activities, including antioxidant, anti-inflammatory, anti-glycation, metal-chelating, and neuroprotective properties. Mechanistically, it acts by inhibiting the production of advanced glycation end products (AGEs), buffering cellular pH, and regulating intracellular nitric oxide signaling and mitochondrial function. Its safety profile, the lack of toxicity, and significant side effects support its application for long-term therapeutic use. In this review, we aim to recapitulate and discuss the effects, dosages, and administration routes of carnosine in preclinical in vivo models, with a particular focus on neurodegenerative disorders where it has been shown to reduce oxidative stress, suppress neuroinflammation, modulate protein aggregation, and preserve cognitive function, all key features of neurodegeneration. Despite promising findings, there are gaps in the knowledge on how carnosine affects synaptic plasticity, neuronal remodeling, and other processes that play a central role in the pathophysiology of neurodegenerative disorders. Additionally, clinical translation remains challenging due to inconsistencies across in vivo studies in terms of dosage, treatment duration, routes of administration, and disease models, which affect reproducibility and cross-study comparability. Therefore, while carnosine emerges as a multifunctional and well-tolerated molecule, further research is needed to clarify its therapeutic relevance in human diseases. In this review, we also address future perspectives and key methodological challenges that must be overcome to effectively translate carnosine's biological potential into clinical practice.}, } @article {pmid41527682, year = {2026}, author = {Zohud, O and Lone, IM and Midlej, K and Iraqi, FA}, title = {The complexity of dementia development and its comorbidities: The collaborative cross-mouse population for multivarious tasks approach.}, journal = {Animal models and experimental medicine}, volume = {9}, number = {1}, pages = {72-88}, pmid = {41527682}, issn = {2576-2095}, support = {//A core fund from Tel Aviv University/ ; }, mesh = {Animals ; *Dementia ; Mice ; *Disease Models, Animal ; Comorbidity ; Humans ; Autoimmune Diseases/complications ; Gene-Environment Interaction ; Inflammation ; Neurodegenerative Diseases ; }, abstract = {The rising incidence of dementia and associated neurodegenerative disorders poses a growing public health challenge. These conditions have traditionally been studied as isolated central nervous system disorders; however, emerging evidence suggests that broader systemic factors, including chronic inflammation, immune dysregulation, metabolic dysfunction, and genetic susceptibility, may also play a role. This review examines the interconnection between autoimmune diseases and metabolic syndromes in the pathogenesis and exacerbation of neurodegeneration. Conditions such as rheumatoid arthritis, systemic lupus erythematosus, and type 1 diabetes mellitus have been associated with a heightened risk of developing dementia through chronic immune activation, blood-brain barrier disruption, and neuroinflammatory signaling. Similarly, metabolic disorders such as diabesity promote insulin resistance and oxidative stress, accelerating cognitive decline. The review also discusses glaucoma as a neurodegenerative condition with autoimmune features, underscoring the need for expanded classification and treatment strategies. A key focus is the utilization of the Collaborative Cross (CC) mouse model, which enables the study of gene-environment interactions across genetically diverse backgrounds. Findings from CC mice reveal strain-dependent susceptibility to inflammation, cognitive impairment, and gut-brain axis dysfunction, providing a translational bridge to human variability. This review highlights the importance of integrating precision-based approaches to dementia research that consider systemic influences. Advancing our understanding of these multiorgan interactions holds potential for designing precision-based therapeutic approaches to postpone the onset or reduce the incidence of neurodegenerative conditions.}, } @article {pmid41527739, year = {2026}, author = {Le, J and Hu, X and Jiang, Y and Wang, Q and Ma, Q and Cui, W}, title = {Insights into phosphoproteomic studies and prospects of phosphoproteins as biomarkers for brain disorders.}, journal = {Journal of Alzheimer's disease : JAD}, volume = {110}, number = {1}, pages = {5-25}, doi = {10.1177/13872877251411546}, pmid = {41527739}, issn = {1875-8908}, mesh = {Humans ; *Phosphoproteins/metabolism ; *Proteomics/methods ; Biomarkers/metabolism ; *Brain Diseases/metabolism/diagnosis ; Animals ; Phosphorylation ; }, abstract = {The dysregulation of phosphorylation networks plays a critical role in the pathogenesis of a wide spectrum of brain disorders, including Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, traumatic brain injury, ischemic stroke, drug abuse, major depressive disorder, and schizophrenia. Notably, phosphorylated isoforms of microtubule-associated protein tau and neurofilament heavy polypeptide are already utilized in clinical diagnostics, highlighting the promise of protein phosphorylation signatures as biomarkers for prediction, diagnosis, prognosis, and treatment monitoring. Recent advances in deep phosphoproteomic technologies now facilitate the comprehensive mapping of phosphorylation alterations across diverse biological samples and disease stages. This review summarizes current phosphoproteomic studies aimed at identifying biomarkers for brain disorders and elaborates on the promising application of phosphorylated proteins in this context.}, } @article {pmid41527747, year = {2026}, author = {Heo, RJ and Negida, A and Barrett, MJ and Chrenka, EA and Bayram, E and Kane, JPM and Werner, AM and Rossom, RC and Wyman-Chick, KA}, title = {Cholinesterase inhibitors for patients with dementia: Patterns of prescribing and disparities in treatment.}, journal = {Journal of Alzheimer's disease : JAD}, volume = {109}, number = {4}, pages = {1917-1924}, pmid = {41527747}, issn = {1875-8908}, support = {R00 AG073453/AG/NIA NIH HHS/United States ; R01 NS142622/NS/NINDS NIH HHS/United States ; }, mesh = {Humans ; *Cholinesterase Inhibitors/therapeutic use ; Female ; Male ; *Dementia/drug therapy ; Galantamine/therapeutic use ; Aged ; Rivastigmine/therapeutic use ; Aged, 80 and over ; Donepezil/therapeutic use ; *Practice Patterns, Physicians'/statistics & numerical data ; *Healthcare Disparities ; Lewy Body Disease/drug therapy ; Alzheimer Disease/drug therapy ; Dementia, Vascular/drug therapy ; }, abstract = {BackgroundCholinesterase inhibitors (ChEIs) are cornerstones of the symptomatic treatment of Alzheimer's disease (AD) and dementia with Lewy bodies (DLB) and are also prescribed for vascular dementia (VaD). Despite their widespread use, patterns of ChEI prescribing are unclear.ObjectiveOur objective was to examine the prevalence, timing, and types of ChEI prescriptions before and after dementia diagnosis.MethodsWe analyzed electronic health record and claims data for patients diagnosed with AD, DLB, or VaD between October 2015 and August 2022 from a large U.S. healthcare system. ChEI claims (donepezil, rivastigmine, galantamine) were identified in the ±3 years surrounding dementia diagnosis. Repeated measures logistic regression was used to estimate the likelihood of ChEI fills by time-period, dementia type, and time x dementia type interaction to determine if change in prescription patterns significantly differed by diagnosis.ResultsAmong 3166 eligible patients, DLB had the highest prevalence of ChEIs both pre-and post-diagnosis compared to patients with AD and VaD. Post-diagnosis, donepezil was the most common, while galantamine use was sparse. After adjusting for demographics, patients with VaD had lower rates of ChEIs relative to AD (OR: 0.34, 95% CI 0.26-0.45). In the fully adjusted model, females (OR: 0.81, 95% CI: 0.71-0.91) and patients from ethnoracially minoritized populations (OR: 0.74, 95% CI: 0.62-0.88) were less likely to fill ChEI prescriptions.ConclusionsDonepezil was the most frequently filled ChEI across dementias. Patients with DLB had the highest prevalence of ChEIs pre- and post-diagnosis. The potential disparities in treatment we identified should be investigated further.}, } @article {pmid41528665, year = {2026}, author = {Kumar, A and Rakshit, D and Saharia, N and Tiwari, P and Mugale, MN and Mishra, A}, title = {Dietary Isoflavone Biochanin A Attenuates Aluminium Chloride-Induced Sporadic Alzheimer's Disease and Associated Neurobehavioral Alterations Through NRF2-HO1 Pathway Activation and NLRP3 Inflammasome Suppression.}, journal = {Molecular neurobiology}, volume = {63}, number = {1}, pages = {359}, pmid = {41528665}, issn = {1559-1182}, mesh = {Animals ; Aluminum Chloride/toxicity ; *Alzheimer Disease/chemically induced/drug therapy/metabolism/pathology ; *NLR Family, Pyrin Domain-Containing 3 Protein/metabolism ; *NF-E2-Related Factor 2/metabolism ; *Inflammasomes/metabolism/drug effects ; *Genistein/pharmacology/therapeutic use ; Male ; Signal Transduction/drug effects ; Oxidative Stress/drug effects ; *Heme Oxygenase-1/metabolism ; Mice ; *Behavior, Animal/drug effects ; Mice, Inbred C57BL ; }, abstract = {Alzheimer's disease (AD), a debilitating neurodegenerative disorder, currently lacks effective curative treatments. Growing evidence implicates aluminium, a widely prevalent environmental metal, in the pathogenesis of AD due to its ability to induce oxidative stress, neuroinflammation, cholinergic dysfunction, and amyloid-beta (Aβ) deposition, ultimately leading to cognitive decline. Biochanin A (BCA), a naturally occurring isoflavone, exhibits well-documented antioxidant, anti-inflammatory, and neuroprotective activities, including acetylcholinesterase (AChE) inhibition. However, its specific therapeutic potential in AD models has remained largely unexplored. This study evaluates the protective effects of BCA against aluminium chloride (AlCl3)-induced AD-like pathology in mice. Animals received daily oral administration of AlCl3 (100 mg/kg) for 6 weeks, with or without concurrent BCA treatment (5, 10, and 20 mg/kg). During the final week, comprehensive neurobehavioral assessments were conducted. Thereafter, hippocampal tissues were analyzed for biochemical, molecular, and elemental analyses, and intact brains were examined histologically. AlCl3 exposure significantly impaired neurobehavioral performance, elevated oxidative stress, disrupted cholinergic function, intensified neuroinflammation, promoted amyloid aggregation, and induced neurodegeneration. Notably, BCA supplementation dose-dependently ameliorated these pathological alterations. BCA treatment improved neurobehavioral deficits (P < 0.05), reduced oxidative markers (P < 0.01), restored cholinergic function by lowering AChE activity (P < 0.01), attenuated inflammatory mediators (P < 0.01), reduced amyloid and aluminium deposition (P < 0.001), and alleviated AlCl3-induced neurodegeneration. Overall, our findings indicate that BCA confers neuroprotection primarily through activation of the NRF2-HO-1 signaling pathway and through suppression of the NLRP3 inflammasome, highlighting its promise as a potential therapeutic candidate for AD.}, } @article {pmid41530008, year = {2026}, author = {Feldman, OJ and Herrmann, N and Ruthirakuhan, M and Gallagher, D and L G Verhoeff, NP and Kiss, A and Black, SE and Lanctôt, KL}, title = {Assessment of clinical factors that predict response to nabilone for agitation in Alzheimer's disease: A post hoc analysis of a randomized placebo-controlled trial.}, journal = {International psychogeriatrics}, volume = {}, number = {}, pages = {100183}, doi = {10.1016/j.inpsyc.2026.100183}, pmid = {41530008}, issn = {1741-203X}, abstract = {INTRODUCTION: Previously, nabilone showed a medium effect size for treating agitation in moderate-to-severe Alzheimer's disease (AD), but response varied. These post hoc analyses aimed to identify a group of clinical characteristics that predicted treatment response.

METHODS: Data from a double-blind, placebo-controlled crossover trial in AD agitation were used. Nineteen clinical characteristics were categorized (presence/absence) and evaluated for relation to agitation response (change on Cohen-Mansfield Agitation Inventory (CMAI)). Characteristics with a ≥ 8 point response difference between categories were included in a multivariable analysis model to calculate individual predicted response. Linear mixed-effects models with Satterthwaite's approximation evaluated the impact of treatment on the relationship between predicted and observed responses.

RESULTS: Thirty-nine participants (77 % male, mean [SD] age 87 [10.2], standardized Mini-Mental State Exam (sMMSE) 6.5 [6.8]) were enrolled. Variable selection identified five characteristics related to greater nabilone efficacy: higher pain (Pain Assessment in Advanced Dementia score ≥3) (difference [SE] in CMAI response = -18.8 [3.2]), greater appetite and eating disorders (-16.4 [5.5]), greater apathy (-14.0 [5.5]), less cognitive impairment (sMMSE greater than 10) (-16.5 [4.2]) and no concomitant cholinesterase inhibitors (-13.9 [4.4]). For those with a predicted response in the top tertile based on those five characteristics, 82 % responded, compared with 40 % in the lowest tertile. A treatment-by-tertile interaction (F(2,29) = 8.48, p = 0.001) indicated observed treatment response varied across tertiles.

CONCLUSION: A reliable clinical profile of persons with AD related agitation likely to respond to nabilone may be established with additional research.}, } @article {pmid41530554, year = {2026}, author = {Taylor, WD and Gerlach, AR and Szymkowicz, SM and Gujral, S and Andreescu, C}, title = {Remission is insufficient: predictors and mechanistic models of recurrence in late-life depression.}, journal = {Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology}, volume = {}, number = {}, pages = {}, pmid = {41530554}, issn = {1740-634X}, support = {UL1 TR000445/TR/NCATS NIH HHS/United States ; K23 MH125074/MH/NIMH NIH HHS/United States ; R01 MH121620/MH/NIMH NIH HHS/United States ; K01 MH133913/MH/NIMH NIH HHS/United States ; R01 MH108509/MH/NIMH NIH HHS/United States ; R01 MH123662/MH/NIMH NIH HHS/United States ; UL1 TR002243/TR/NCATS NIH HHS/United States ; R01 MH121619/MH/NIMH NIH HHS/United States ; R33 MH122464/MH/NIMH NIH HHS/United States ; }, abstract = {While achieving remission is the goal of acute antidepressant treatment, recurrence of new depressive episodes following remission is unfortunately common in clinical populations with Major Depressive Disorder, including older adults with Late-Life Depression (LLD). The neurobiological factors underlying this risk are poorly understood, limiting our ability to identify potential preventive mechanistic targets. Beyond the limited prognostic utility achieved from individual psychiatric history, it remains challenging to clinically stratify individual risk. This review examines factors influencing the recurrence of depressive episodes following remission in LLD, focusing on cognitive, behavioral, social, and environmental aspects. It additionally considers neuroimaging-based biomarkers related to recurrence risk as well as discussing evidence for and limits of maintenance treatment to prevent recurrence. The paper proposes possible mechanisms contributing to recurrence, including physiological and behavioral responses to stressors, the influence of Alzheimer's disease neuropathology, and conceptualizing repeat depressive episodes within the accelerated aging hypothesis of LLD. A dynamical landscape model of depression recurrence is proposed to elucidate the interplay between different mood states, resilience, and treatment response. This synthesis then highlights avenues for future research, focusing on areas of potential significance ranging from risk stratification to tertiary prevention efforts that may improve both long-term affective and cognitive symptoms.}, } @article {pmid41530949, year = {2025}, author = {Chen, Y and Liu, Y}, title = {Eosinophils: pathological mechanisms and novel targeted therapeutic strategies across multiple disease spectrums.}, journal = {Journal of leukocyte biology}, volume = {118}, number = {1}, pages = {}, doi = {10.1093/jleuko/qiag009}, pmid = {41530949}, issn = {1938-3673}, support = {LHDMY23H160001//Zhejiang Provincial Natural Science Foundation of China/ ; }, mesh = {Humans ; *Eosinophils/pathology/immunology/metabolism ; Animals ; *Molecular Targeted Therapy ; }, abstract = {Eosinophils are a type of white blood cell belonging to the granulocyte family. Their cytoplasm contains eosinophilic granules that hold various biologically active substances. They perform diverse functions, participating in inflammatory responses, immune defense, and tissue repair. Eosinophils are implicated in the pathogenesis of multiple diseases, including infectious diseases, allergic disorders, and hematological conditions. Moreover, increasing research in recent years has revealed significant associations between eosinophils and autoimmune diseases, solid tumors, coronary atherosclerotic heart disease, and even Alzheimer's disease. They participate in disease onset and progression through the release of toxic proteins, cytokines, and chemokines, as well as through interactions with other cells. Focusing on the biological characteristics and functions of eosinophils facilitates the elucidation of disease mechanisms associated with related disorders. This, in turn, provides further direction for eosinophil-targeted research and therapeutic strategies, including the research and development of drugs that modulate their function, targeted therapies, immunotherapies, and cell therapies. This paper provides a comprehensive review of the structure, function, and role of eosinophils in related diseases, along with potential future therapeutic strategies. It aims to deepen the understanding of researchers and clinicians, thereby facilitating their application in further research, as well as in clinical disease diagnosis and treatment analysis.}, } @article {pmid41531227, year = {2026}, author = {Samudra, N and Vemuri, M and Weitlauf, J}, title = {Menopause, cognition, and Alzheimer's disease risk.}, journal = {Current opinion in obstetrics & gynecology}, volume = {38}, number = {2}, pages = {131-138}, doi = {10.1097/GCO.0000000000001087}, pmid = {41531227}, issn = {1473-656X}, abstract = {PURPOSE OF REVIEW: Cognitive symptoms are common throughout the menopause transition. This review outlines a comprehensive clinical approach, grounded in recent findings, to guide clinicians in addressing menopause-related cognitive concerns and neurodegenerative disease risk for midlife women.

RECENT FINDINGS: Research highlights the benefits of lifestyle and psychosocial interventions for cognitive symptoms during the menopause transition. Addressing underlying medical and mental health conditions, as well as difficulties with sleep, chronic stress, and vasomotor symptoms, can ameliorate symptoms and reduce risk for future dementia. Cognitive changes during the menopause transition do not typically indicate dementia. A subset of women, including apolipoprotein ε4 (APOE ε4) carriers and those who experience early menopause, face heightened risk. Alzheimer's disease biomarkers are clinically available and may change in some women during the menopause transition, particularly in APOE ε4 carriers, but our understanding of these changes, as well as their relationship to menopause hormone therapy, is evolving. There is presently insufficient evidence for the role of menopause hormone therapy for the treatment of menopause-related cognitive symptoms or neurodegenerative disease prevention.

SUMMARY: While typically transient, cognitive symptoms in menopause can benefit from addressing comorbid medical and psychosocial conditions. Research into dementia risk related to changes in the menopause transition is ongoing.}, } @article {pmid41531459, year = {2025}, author = {Fischer, BL and Van Hulle, CA and Norton, DL and Wyman, MF and Ennis, G and Lambrou, NH and Bouges, S and Gooding, DC and Gleason, CE}, title = {Mild Behavioral Impairment is Associated With Incident Cognitive Decline Among Dementia-Free, Racially Diverse Older Adults: Data From the African Americans Fighting Alzheimer's in Midlife (AA-FAIM) Study.}, journal = {The American journal of geriatric psychiatry. Open science, education, and practice}, volume = {8}, number = {}, pages = {43-53}, pmid = {41531459}, issn = {2950-3868}, support = {R01 AG074231/AG/NIA NIH HHS/United States ; R01 AG062307/AG/NIA NIH HHS/United States ; R56 AG062307/AG/NIA NIH HHS/United States ; P30 AG062715/AG/NIA NIH HHS/United States ; R01 AG054059/AG/NIA NIH HHS/United States ; }, abstract = {OBJECTIVES: To determine whether MBI associates with worse cognitive performance over time and with incident cognitive decline in an older, racially/ethnically diverse cohort at early stages of cognitive change.

DESIGN: This observational cohort study followed participants from the Wisconsin Alzheimer's Disease Research Center Clinical Core (WADRC) for up to 13 visits.

SETTING: An urban university research center.

PARTICIPANTS: Participants from the WADRC Clinical Core were included in this convenience sample if they were without dementia, had undergone at least 1 cognitive assessment, and completed measures of cognitive, clinical and affective function.

MEASUREMENTS: MBI was assessed using the Neuropsychiatric Inventory. Linear mixed effects models (LME) were fit to cognitive outcomes Trailmaking Tests A and B (TMT-A, B) and Wechsler Logical Memory (LM). Cox proportional hazard models assessed whether MBI was related to risk for incident global Clinical Dementia Rating Scale (CDR >0).

RESULTS: N = 584 participants with mean age 64.6 years, range 46-92.6 years, 59.4% female and 17% African American. LME results indicated participants with MBI exhibited worse age-associated decline on TMT-B, compared to those without MBI (beta=0.008, p = 0.01, CI: 0.002, 0.01, t(337) = 2.4, p = 0.01). MBI at baseline was associated with a significant hazard ratio (HR) indicating an increased risk of decline on the CDR (HR: 2.84; HR 95% CI: 1.68 - 4.81; p = 0.0001).

CONCLUSIONS: MBI associated with worse cognitive performance and incident cognitive decline in a racially diverse, older adult sample at early stages of cognitive change. Increased awareness of the late life emergence of neuropsychiatric symptoms is warranted to assist in identification and improve prognostication and treatment of neurodegenerative disease.}, } @article {pmid41531784, year = {2025}, author = {Zhang, Y and Ren, Y and Zhu, X and Liu, T and Han, R and Fang, Y and Zhao, Z and Mao, F and Wang, Y and Li, X and Li, X}, title = {Research Progress on Idebenone in Neurodegenerative Diseases.}, journal = {Aging medicine (Milton (N.S.W))}, volume = {8}, number = {6}, pages = {624-633}, pmid = {41531784}, issn = {2475-0360}, abstract = {In recent years, significant progress has been made in understanding the therapeutic potential of idebenone (IDE), a synthetic analogue of Coenzyme Q10, in neurodegenerative diseases (NDs). This review comprehensively examines the pharmacological properties of IDE and its emerging applications in various NDs, with particular emphasis on Alzheimer's disease, Parkinson's disease, Friedreich's ataxia, and Huntington's disease. We elucidate IDE's multifaceted neuroprotective mechanisms, including its potent antioxidant activity that reduces reactive oxygen species production, its ability to enhance mitochondrial bioenergetics, and its regulatory effects on cellular metabolism. Additionally, we critically evaluate current clinical research findings and discuss the translational potential of IDE in ND therapeutics. The accumulated evidence strongly supports IDE as a promising mitochondrial-targeted agent capable of mitigating disease symptoms and modifying disease progression in multiple neurodegenerative disorders. This review highlights both the current achievements and future directions for IDE-based interventions in ND treatment.}, } @article {pmid41531926, year = {2025}, author = {Jerath, R and Malani, V}, title = {The fading self in space-disruption of default spatial representation across neurological disorders.}, journal = {Frontiers in systems neuroscience}, volume = {19}, number = {}, pages = {1655500}, pmid = {41531926}, issn = {1662-5137}, abstract = {Neurological disorders stem from an intermingled change to self-in-space. While many of these disorders present as spatial deficits-contralateral neglect syndrome, for example-they manifest from the same etiology: disruption to the brain's "default spatial representation" (DSR). DSR is a basic internally generated representation of space that delineates where the self is located in space-without attentional focus from an external drive. We review how pathologic disintegration of DSR is associated with anomalous activation and connectivity within distinct large-scale brain networks (e.g., the default mode network and a comprehensive attention-networked system), leading to a heterogeneous presentation of clinically assessed outcomes. The outcomes include psychogenic paralysis of limbs, left-side neglect, rectified sense of other locations, disorders of consciousness, symptoms related to autism spectrum disorder, Alzheimer's disease, schizophrenia, and depersonalization/derealization disorder. By consolidating evidence from neuroimaging, lesion-symptom mapping, and computational assessment, we aim to reconceptualize these disorders not as separate and independent maladies, but as manifestations of a deeper, shared etiology, supporting a network-based assessment strategy for diagnosis and treatment that seeks to restore self-in-space.}, } @article {pmid41531938, year = {2026}, author = {Mandloi, U and Giri, N and Kumar, S and Modi, G}, title = {Theranostic advances in Alzheimer's disease: structure-guided design of near-infrared fluorescent probes targeting amyloid-β and cholinergic dysfunction.}, journal = {RSC medicinal chemistry}, volume = {17}, number = {2}, pages = {806-819}, pmid = {41531938}, issn = {2632-8682}, abstract = {Alzheimer's disease (AD) is a complex neurodegenerative disorder, with unmet clinical challenges due to the lack of early diagnosis and an efficient treatment. Theranostics, an integrated approach that combines diagnosis and therapy, has emerged as a viable option, particularly with the use of near-infrared fluorescence probes (NIRFPs), which allow real-time in vivo imaging and therapeutic monitoring. This review article discusses recent breakthroughs in the rational design of alkene-bridged donor-π-acceptor (D-π-A) NIRFPs that target AD hallmarks such as amyloid-β (Aβ) aggregation and cholinergic dysfunction. We specifically focused on multifunctional probes like THK-565 (fluorescent compound), and a dihydrotetramethyl-indocyanine theranostic near-infrared probe (DTNP), which exhibit high blood-brain barrier (BBB) permeability, target selectivity, and dual imaging/therapeutic capabilities. Furthermore, emerging probes can distinguish between Aβ and cholinesterase (ChEs) with high resolution and low toxicity. Together, these molecular imaging technologies provide a game-changing platform for detection of early-stage AD and multiple intervention approaches. We explore structure-activity connections, molecular processes, and future directions for the clinical translation of NIRFP-based theranostic agents in AD.}, } @article {pmid41531988, year = {2025}, author = {Benin, BM and Hillyer, T and Csubak, BA and Aguirre, N and Dengler-Crish, CM and Kang, C and Shin, WS}, title = {Investigation of Three Flavonoids as Potent Tau Aggregation Inhibitors and In vivo Demonstration of Myricetin.}, journal = {Pharmacological research. Natural products}, volume = {9}, number = {}, pages = {}, pmid = {41531988}, issn = {2950-1997}, support = {R01 AG076699/AG/NIA NIH HHS/United States ; R03 NS135326/NS/NINDS NIH HHS/United States ; }, abstract = {Neurodegenerative disorders, including Alzheimer's disease (AD), are characterized by the formation and propagation of neurotoxic tau aggregates, which arise from the misfolding and subsequent aggregation of tau proteins into fibrillary structures. While tau-targeting agents represent a promising therapeutic strategy for the prevention and treatment of various neurodegenerative diseases, they currently constitute a limited subset of the treatments undergoing clinical trials. In this study, we report the potent anti-aggregation and filament disassembly effects of three flavonols: myricetin, quercetagetin, gossypetin. We observed remarkable nanomolar-to-low-micromolar 50% inhibitory concentrations (0.57-1.21μM) and low 50% disassembly concentrations (7.5-14μM) using tau seeds derived from AD mouse model brains. Furthermore, we validated that myricetin treatment was associated with a reduction in overall phosphorylated tau (p-Tau) burden in vivo in the 3xTg AD mouse model. Notably, these reductions were associated with enhanced performance in Y-maze assessments of spatial learning and memory, supporting further preclinical evaluation, including direct brain pharmacokinetic studies and mechanism-driven investigations relevant to tauopathy therapy.}, } @article {pmid41533031, year = {2026}, author = {Tan, FHP and Najimudin, N and Azzam, G and Zainuddin, A and Shamsuddin, S and Mohd Kasihmuddin, MS}, title = {Geroprotective effects of Salvianolic acid A through redox and detoxification pathway activation in an aging Drosophila Alzheimer's model.}, journal = {Biogerontology}, volume = {27}, number = {1}, pages = {39}, pmid = {41533031}, issn = {1573-6768}, mesh = {Animals ; *Alzheimer Disease/metabolism/drug therapy/genetics ; Drosophila melanogaster ; *Aging/drug effects/metabolism ; Oxidation-Reduction ; Amyloid beta-Peptides/metabolism/genetics ; Disease Models, Animal ; *Lactates/pharmacology ; *Caffeic Acids/pharmacology ; Animals, Genetically Modified ; Oxidative Stress/drug effects ; *Neuroprotective Agents/pharmacology ; Peptide Fragments/metabolism/genetics ; Humans ; Antioxidants/pharmacology ; Longevity/drug effects ; }, abstract = {Alzheimer's disease (AD) is characterized by the accumulation of amyloid-β42 (Aβ42) neurotoxic peptides that cause oxidative stress and neurodegeneration. The current study examined the neuroprotective properties of salvianolic acid A (SalA), an antioxidant polyphenol, in a Drosophila melanogaster model of AD. Transgenic flies expressing human Aβ42 were assayed for eye morphology, life span, and locomotor function after SalA diet supplementation. RNA-seq and RT-qPCR were used to quantify transcriptional regulation with SalA treatment. Aβ42 expression resulted in classic AD phenotypes, including retinal degeneration, shortened lifespan, and compromised climbing ability. Partial rescue of the rough-eye phenotype, significant prolongation of lifespan, and improved locomotor function in aging flies were induced by SalA treatment. Transcriptome profiling showed the upregulation of glutathione metabolism-associated, cytochrome P450 activity-associated, and antioxidant defence-associated genes, while muscle development-associated, cell adhesion-associated, and apoptosis-associated genes were downregulated. Network analysis identified a SalA-responsive gene module enriched in detoxification and immune pathways that was conducive to enhanced cellular resistance to Aβ42 toxicity. These findings identify a redox-regulated aging mechanism whereby SalA maintains neuronal and systemic homeostasis during aging. SalA inhibits Aβ42-induced neurotoxicity in Drosophila via promoting redox equilibrium and detoxification. These findings present SalA as a potential multi-target lead drug for AD and other age-related neurodegenerative diseases.}, } @article {pmid41533472, year = {2025}, author = {Shah, A and Kalu, U and Chen, D and Slomkowski, M and Hobart, M and Such, P and Grossberg, GT}, title = {Brexpiprazole side-effect profile in people with agitation in Alzheimer's dementia: a plain language summary.}, journal = {Current medical research and opinion}, volume = {41}, number = {12}, pages = {2369-2377}, doi = {10.1080/03007995.2025.2608578}, pmid = {41533472}, issn = {1473-4877}, } @article {pmid41535445, year = {2026}, author = {Schnieder, M and von Arnim, CAF}, title = {[Polypharmacy in patients with neuropsychiatric symptoms].}, journal = {Innere Medizin (Heidelberg, Germany)}, volume = {67}, number = {3}, pages = {289-294}, pmid = {41535445}, issn = {2731-7099}, mesh = {Humans ; *Polypharmacy ; *Dementia/drug therapy/epidemiology ; Aged ; *Delirium/drug therapy/epidemiology ; Alzheimer Disease/drug therapy/epidemiology ; Antipsychotic Agents/therapeutic use/adverse effects ; Risk Factors ; Germany ; *Depressive Disorder/drug therapy/epidemiology ; }, abstract = {Dementia, delirium, and depression are the main geriatric psychiatric syndromes, and their prevalence is increasing significantly due to demographic aging. At the same time, multimorbidity and polypharmacy lead to increased interaction rates and a higher frequency of side effects, as well as reduced adherence. In Germany, the number of dementia cases is projected to rise from the current 1.8 million to 2.8 million by 2050. The most common etiologies are Alzheimer's disease and vascular dementia. Progressive cognitive and motor function loss often results in apraxia and dysphagia, which complicate pharmacotherapy. Acetylcholinesterase inhibitors (donepezil, rivastigmine, galantamine) and memantine are used therapeutically. Newly approved amyloid antibodies (lecanemab, donanemab) show efficacy in the early stages of Alzheimer's disease, but carry the risk of amyloid-associated imaging abnormalities (ARIA). Dementia is considered a predisposing risk factor for delirium, which is characterized by fluctuations in attention and consciousness. Delirogenic factors include polypharmacy as well as other medications such as opioids and benzodiazepines. Due to the increased risk of mortality and stroke, neuroleptics should only be administered to geriatric patients when strictly indicated, in minimal doses, and for a limited duration. Non-pharmacological interventions take precedence. Selective serotonin reuptake inhibitors (SSRIs) are considered the first-line treatment for depressive disorders in older adults, while tricyclic antidepressants should be avoided. Regular medication reviews, reduction of anticholinergic burden, and technical aids to facilitate medication intake are essential for optimizing treatment adherence.}, } @article {pmid41535708, year = {2026}, author = {Yu, MJ and Xiong, RQ and Wu, JW and Li, YC and Xie, JX and Zhou, HP and Ye, GY and Chang, Y and Huang, KB and Pan, SY}, title = {β-Hydroxybutyrate improves glymphatic system function and alleviates cerebral edema in mice after ischemic stroke.}, journal = {Acta pharmacologica Sinica}, volume = {47}, number = {4}, pages = {903-916}, pmid = {41535708}, issn = {1745-7254}, mesh = {Animals ; *Brain Edema/drug therapy/etiology/metabolism ; Male ; *Glymphatic System/drug effects/metabolism ; *3-Hydroxybutyric Acid/therapeutic use/pharmacology ; Aquaporin 4/metabolism ; Mice, Inbred C57BL ; *Ischemic Stroke/drug therapy/complications/metabolism ; Mice ; Diet, Ketogenic ; Infarction, Middle Cerebral Artery/complications ; Membrane Proteins/metabolism ; Calcium-Binding Proteins/metabolism ; Muscle Proteins ; }, abstract = {Cerebral edema is a severe complication following ischemic stroke. Recent studies have highlighted the crucial role of the glymphatic system (GS) in the clearance of water and macromolecules. GS dysfunction involving the disorders of AQP4 polarization may be crucial in the pathophysiology of cerebral edema. β-Hydroxybutyrate (BHB), the main component of the ketone body, has been shown to alleviate neurological deficits by restoring GS function in subarachnoid hemorrhage models and to reduce Aβ deposition in Alzheimer's disease models. In this study we investigated the effects of BHB on cerebral edema following ischemic stroke and its mechanisms. The mice were fed a ketogenic diet (KD) or a normal diet for 4 weeks before transient middle cerebral artery occlusion (MCAO). Alternatively, the mice received BHB (5 g·kg[-1]·d[-1]) or vehicle post-MCAO. By using brain section analysis, transcranial macroimaging, two-photon in vivo imaging and MRI, we demonstrated that both KD and BHB treatment significantly enhanced GS function under normal and MCAO conditions. BHB reduced cerebral edema and infarct volume post-MCAO. Notably, delayed BHB treatment initiated 10 h post-MCAO still improved GS function, but did not influence infarct volume. Furthermore, we revealed that BHB increased α1-syntrophin expression and H3K27ac levels in α1-syntrophin (Snta1) enhancer, restoring AQP4 polarization. In addition, BHB also reduced HDAC3 expression and elevated p300 expression. These results suggest that a KD and BHB treatment enhance GS function in mice and that BHB also mitigates brain edema after MCAO. The potentiation of GS function by BHB is likely mediated by the inhibition of HDAC3 activity and the increase in p300 activity, which upregulate α1-syntrophin expression and restore AQP4 polarization.}, } @article {pmid41536056, year = {2026}, author = {Dong, J and Xu, L and Xu, X and Shi, B and Wang, Q and Xu, J and Xu, C and Kuang, H and Qu, A}, title = {Chiral Spindle-like Nanorods Reprogram Neuroinflammation by Catalyzing α-Ketoglutarate Biosynthesis.}, journal = {Journal of the American Chemical Society}, volume = {148}, number = {3}, pages = {3654-3671}, doi = {10.1021/jacs.5c19753}, pmid = {41536056}, issn = {1520-5126}, mesh = {Animals ; *Ketoglutaric Acids/metabolism ; Mice ; Humans ; *Nanotubes/chemistry ; *Alzheimer Disease/drug therapy/metabolism ; *Neuroinflammatory Diseases/metabolism/drug therapy ; Disease Models, Animal ; Reactive Oxygen Species/metabolism ; }, abstract = {Alzheimer's disease (AD) is the most prevalent cause of dementia worldwide, and breakthroughs in effective intervention strategies are urgently needed. Here, we report that chiral spindle-like Fe7Se8 nanorods (NRs) promote α-ketoglutarate (AKG) biosynthesis, providing a new potential route for AD intervention through modulation of neuroimmune homeostasis. Oral administration of L-NRs significantly restored intestinal microbiota homeostasis in 3 × Tg AD model mice, markedly enriched Lactobacillus johnsonii, and enhanced biosynthesis of the metabolite AKG, which reversed cognitive impairment and neuronal degeneration in 5 × FAD mice. Moreover, AKG levels in the clinical serum and cerebrospinal fluids were found to be significantly lower in patients with AD than in healthy controls. Mechanistic studies revealed that L-NRs efficiently promoted AKG biosynthesis through scavenging reactive oxygen species (ROS) to restore the activities of three enzymes in the biosynthesis pathway. Crucially, these NRs are broken down by gastric juice into smaller nanoparticles and subsequently into ions in the intestines. Further studies explored that AKG crossed the blood-brain barrier via cooperatively mediated transport proteins, targeted microglial phenotypic switching, reprogrammed the neuroinflammatory microenvironment, and ultimately ameliorated cognitive deficits and neuronal pathological alterations. Our findings suggest that AKG might serve as a therapeutic drug for the precise treatment of neurodegenerative diseases.}, } @article {pmid41536422, year = {2025}, author = {Thaliath, A and Pillai, JA}, title = {Non-Cognitive Symptoms in Alzheimer's Disease and Their Likely Impact on Patient Outcomes. A Scoping Review.}, journal = {Current treatment options in neurology}, volume = {27}, number = {}, pages = {}, pmid = {41536422}, issn = {1092-8480}, support = {P30 AG072959/AG/NIA NIH HHS/United States ; }, abstract = {PURPOSE OF REVIEW: Increased understanding of the pathophysiology of Alzheimer's disease (AD) has led to development of disease modifying therapies. The therapies primarily target measures of cognitive decline since AD has been thought of as a cognitive disorder. However, the non-cognitive symptoms seen in AD contribute to overall quality-of-life. This scoping review was undertaken to further our understanding of the non-cognitive features of AD.

RECENT FINDINGS: The non-cognitive symptoms in AD range from changes in sensory perception, systemic changes, and neuropsychiatric manifestations. We targeted the following non-cognitive domains: vision, olfaction, GI, muscle, sleep, circadian rhythm, immune and behavioral symptoms as it relates to AD for this review. Non-cognitive features impact the ability of individuals to perform their activities of daily living, have safety implications and lead to increased caregiver burden. The review explores non-pharmacological and pharmacological measures targeted at the non-cognitive changes in AD.

SUMMARY: Non-cognitive symptoms contribute to significant disease burden in Alzheimer's disease. It is important to screen for and provide supportive care for these symptoms to help improve clinical care. Incorporation of non-cognitive features of AD in clinical trials will help ascertain the true societal and economic impact of AD and that of potential therapeutics.

OPINION STATEMENT: Alzheimer's disease (AD) is primarily recognized as a disorder of cognition; however, non-cognitive symptoms significantly contribute to disease burden and clinical presentation. These manifestations particularly behavioral symptoms and systemic changes beyond the central nervous system impact patients' quality of life and increase caregiver stress. Often, such symptoms necessitate a transition from home-based care to more intensive settings, such as memory care facilities. As AD prevalence rises alongside an aging population, the shortage of dedicated memory care providers in community settings challenges access and quality of care. Improved awareness and early recognition of non-cognitive features among healthcare professionals can aid identification of modifiable systemic issues and allow timely behavioral management during clinical encounters. Treatment of these symptoms requires a multifaceted approach, incorporating pharmacological and non-pharmacological strategies. Non-pharmacological interventions, including tailored behavioral approaches and environmental modifications, can enhance quality of life for individuals with AD and reduce caregiver burden especially where specialized medical resources are limited.}, } @article {pmid41537461, year = {2026}, author = {Choi, KY and Kang, S and Cook, S and Li, D and Choi, YY and Seo, EH and Han, X and Park, JE and Lee, S and Lee, S and Chung, JY and Chong, A and Choi, SM and Ha, JM and Song, MK and Lee, JS and Choo, IH and Kim, JH and Song, HC and Kim, BC and Kim, H and Farrer, LA and Gim, J and Jun, GR and Lee, KH}, title = {The Gwangju Alzheimer's & Related Dementias (GARD) cohort: Over a decade of Asia's largest longitudinal multimodal study.}, journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association}, volume = {22}, number = {1}, pages = {e70981}, pmid = {41537461}, issn = {1552-5279}, support = {25-BR-03-05//the KBRI Basic Research Program through the Korea Brain Research Institute, funded by the Ministry of Science and ICT/ ; NRF-2014M3C7A1046041//the Original Technology Research Program for Brain Science of the National Research Foundation funded by the Korean government, MSIT/ ; RS-2024-00407198//Brain Pool program funded by the Ministry of Science and ICT through the National Research Foundation of Korea/ ; 2023-ER1007-01//Korea National Institute of Health research project/ ; //by the Technology Innovation Program (20022810, Development and Demonstration of a Digital System for the evaluation of geriatric Cognitive impairment) funded By the Ministry of Trade, Industry & Energy (MOTIE, Korea)/ ; RS-2024-00433283//the Technology Innovation Program funded by the Ministry of Trade, Industry & Energy, Republic of Korea/ ; HR22C141105//Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health & Welfare, Republic of Korea/ ; }, mesh = {Humans ; Longitudinal Studies ; *Alzheimer Disease/epidemiology/diagnostic imaging/diagnosis/genetics ; Female ; *Cognitive Dysfunction/epidemiology/diagnosis ; Aged ; Male ; Republic of Korea/epidemiology ; Disease Progression ; Multiomics ; Biomarkers ; Middle Aged ; Magnetic Resonance Imaging ; Neuroimaging ; Cohort Studies ; Proteomics ; Aged, 80 and over ; }, abstract = {INTRODUCTION: Alzheimer's disease (AD) is a major public health concern in Korea, with a high prevalence among older adults. A community-based longitudinal study is essential for tracking disease progression, identifying biomarkers, and developing targeted prevention and treatment strategies. The Gwangju Alzheimer's & Related Dementias (GARD) cohort was established to address these needs through a multimodal approach.

METHODS: Participants aged ≥60 years undergo comprehensive clinical evaluations, neuroimaging, and biospecimen collection for multi-omics analyses (genomics, transcriptomics, proteomics, and metagenomics) at baseline and systematic follow-up visits.

RESULTS: From over 17,000 screened individuals, 12,877 were enrolled. Baseline diagnoses include 5,123 cognitively unimpaired (CU), 3,250 mild cognitive impairment (MCI), and 2,125 AD dementia. The resource includes magnetic resonance imaging scans (n = 10,843) and extensive multi-omics data: genomic (n = 10,775), proteomic (n = 116), and microbiome (n = 595).

DISCUSSION: The integrated GARD dataset provides a powerful and scalable resource for identifying novel biomarkers, understanding disease heterogeneity, and advancing precision medicine for AD.

HIGHLIGHTS: Gwangju Alzheimer's & Related Dementias (GARD) is a large-scale, longitudinal, community-based cohort study in South Korea. The study focuses on early detection and monitoring of dementia progression. GARD includes cognitive testing, imaging, biospecimens, and multi-omics data. We aim to identify Korean-specific biomarkers predictive of cognitive decline. Supports East Asian insights and fills gaps in global Alzheimer's research.}, } @article {pmid41537771, year = {2026}, author = {Wang, N and Sun, Z and Chen, F and Tian, X and Li, J and He, X}, title = {Mangiferin Alleviates Formaldehyde-Induced Tau Hyperphosphorylation and Cognitive Impairment in Mice via the PI3K/AKT/GSK3β Pathway: Insights From Network Pharmacology and Experimental Validation.}, journal = {FASEB journal : official publication of the Federation of American Societies for Experimental Biology}, volume = {40}, number = {2}, pages = {e71346}, doi = {10.1096/fj.202503159R}, pmid = {41537771}, issn = {1530-6860}, support = {202401AT070082//Yunnan Fundamental Research Projects/ ; 202301BA070001-032//Yunnan Fundamental Research Projects/ ; }, mesh = {Animals ; *Proto-Oncogene Proteins c-akt/metabolism ; Mice ; *Glycogen Synthase Kinase 3 beta/metabolism ; *Phosphatidylinositol 3-Kinases/metabolism ; *Formaldehyde/toxicity ; Phosphorylation/drug effects ; *tau Proteins/metabolism ; Network Pharmacology ; Male ; Molecular Docking Simulation ; *Cognitive Dysfunction/chemically induced/metabolism/drug therapy ; Signal Transduction/drug effects ; Hippocampus/metabolism/drug effects ; Protein Interaction Maps ; Xanthones ; }, abstract = {Studies have demonstrated that accumulation of formaldehyde (FA) in the body can result in Alzheimer's disease (AD) like changes including cognitive impairment, Aβ deposition, and Tau hyperphosphorylation. Mangiferin (MGF), a natural flavonoid compound, has been suggested in previous reports to have potential in the treatment of AD. This study integrated network pharmacology and in vivo experiments to elucidate the therapeutic potential and mechanisms of MGF in mitigating FA-induced neurotoxicity. Potential overlapping targets between MGF and AD were identified using jvenn. Functional enrichment analysis of these targets was performed with DAVID. A protein-protein interaction (PPI) network was constructed using STRING and visualized in Cytoscape to identify hub genes. Molecular docking simulations with AutoDock were then employed to assess binding affinity. Subsequently, for experimental validation, a mouse model of FA-induced neurotoxicity was established. Spatial memory and cognitive function in mice were evaluated using the Y-maze and novel object recognition tests. The expression levels of key pathway-related proteins in the cortex and hippocampus were analyzed via immunohistochemistry (IHC) and Western blotting (WB). Network analysis identified AKT1 and GSK3β as key targets, and molecular docking confirmed strong binding affinity between MGF and these proteins. Experimental validation demonstrated that MGF dose-dependently improved spatial memory and cognitive performance in FA-exposed mice, reduced neuronal apoptosis, and suppressed Tau hyperphosphorylation at Thr181, Ser396, and Ser404. Mechanistically, MGF activated the PI3K/AKT pathway, leading to GSK3β inactivation through Ser9 phosphorylation. These findings highlight MGF as a promising therapeutic candidate for AD by targeting the PI3K/AKT/GSK3β axis.}, } @article {pmid41538772, year = {2026}, author = {Liao, YS and Wai, T and Liao, TY and Chang, HL and Chang, YL and Fu, LC}, title = {Mild Cognitive Impairment Detection System Based on Unstructured Spontaneous Speech: Longitudinal Dual-Modal Framework.}, journal = {JMIR medical informatics}, volume = {14}, number = {}, pages = {e80883}, pmid = {41538772}, issn = {2291-9694}, mesh = {Humans ; *Cognitive Dysfunction/diagnosis ; *Speech/physiology ; Aged ; Female ; Male ; Longitudinal Studies ; Memory, Episodic ; Neuropsychological Tests ; Aged, 80 and over ; ROC Curve ; }, abstract = {BACKGROUND: In recent years, the incidence of cognitive diseases has also risen with the significant increase in population aging. Among these diseases, Alzheimer disease constitutes a substantial proportion, placing a high-cost burden on health care systems. To give early treatment and slow the progression of patient deterioration, it is crucial to diagnose mild cognitive impairment (MCI), a transitional stage.

OBJECTIVE: In this study, we use autobiographical memory (AM) test speech data to establish a dual-modal longitudinal cognitive detection system for MCI. The AM test is a psychological assessment method that evaluates the cognitive status of subjects as they freely narrate important life experiences.

METHODS: Identifying hidden disease-related information in unstructured, spontaneous speech is more difficult than in structured speech. To improve this process, we use both speech and text data, which provide more clues about a person's cognitive state. In addition, to track how cognition changes over time in spontaneous speech, we introduce an aging trajectory module. This module uses local and global alignment loss functions to better learn time-related features by aligning cognitive changes across different time points.

RESULTS: In our experiments on the Chinese dataset, the longitudinal model incorporating the aging trajectory module achieved area under the receiver operating characteristic curve of 0.85 and 0.89 on 2 datasets, respectively, showing significant improvement over cross-sectional, single time point models. We also conducted ablation studies to verify the necessity of the proposed aging trajectory module. To confirm that the model not only applies to AM test data, we used part of the model to evaluate the performance on the ADReSSo dataset, a single time point semistructured data for validation, with results showing an accuracy exceeding 0.88.

CONCLUSIONS: This study presents a noninvasive and scalable approach for early MCI detection by leveraging AM speech data across multiple time points. Through dual-modal analysis and the introduction of an aging trajectory module, our system effectively captures cognitive decline trends over time. Experimental results demonstrate the method's robustness and generalizability, highlighting its potential for real-world, long-term cognitive monitoring.}, } @article {pmid41539386, year = {2026}, author = {Hector, A and Leduc, T and da Costa Caiado, MJ and Delignat-Lavaud, B and Dufort-Gervais, J and Daneault, C and Des Rosiers, C and Bourguignon, C and Lina, JM and Fernandes, K and Brouillette, J and Mongrain, V}, title = {Electrocorticographic, astrocytic and transcriptomic signatures in the triple transgenic mouse model of Alzheimer's disease submitted to stearoyl-CoA desaturase inhibition.}, journal = {Neuropharmacology}, volume = {289}, number = {}, pages = {110835}, doi = {10.1016/j.neuropharm.2026.110835}, pmid = {41539386}, issn = {1873-7064}, mesh = {Animals ; *Alzheimer Disease/genetics/drug therapy/physiopathology/metabolism ; *Astrocytes/drug effects/metabolism ; Mice, Transgenic ; Female ; *Transcriptome/drug effects ; Disease Models, Animal ; *Stearoyl-CoA Desaturase/antagonists & inhibitors/metabolism ; Electrocorticography ; Sleep/drug effects/physiology ; Presenilin-1/genetics ; Mice ; Brain/drug effects/metabolism ; Enzyme Inhibitors/pharmacology ; Amyloid beta-Protein Precursor/genetics ; Humans ; Mice, Inbred C57BL ; }, abstract = {Alzheimer's disease (AD) is associated with cognitive deficits and sleep disturbances. Research suggests the involvement of dysfunctions in lipid metabolism in the brain of AD patients and animal models. The inhibition of stearoyl-CoA desaturase (SCD), a lipid-converting enzyme, was shown to restore memory in triple transgenic (3xTg)-AD mice. In the brain, astrocytes regulate the synthesis of specific lipids. This project tested whether the inhibition of SCD restores sleep in 3xTg-AD mice, and whether this associates with modifications in lipids, astrocytic function and the transcriptome. Wild-type (WT) and 3xTg-AD female mice received a SCD inhibitor (SCDi) or vehicle, which was followed by an electrocorticographic (ECoG) recording. Brain slices were stained for lipid droplets, astrocytic markers or processed for spatial transcriptomics. The reduced time spent awake (increased time spent in slow wave sleep) in 3xTg-AD mice was not restored by SCDi treatment. Rhythmic and scale-free ECoG activities were markedly altered in 3xTg-AD mice for all wake/sleep states, and SCDi changed these ECoG signatures differently in mutant in comparison to WT mice. GFAP-positive cell density and lipid droplet count were elevated in hippocampal CA1, and rescued by SCDi. The treatment also rescued the expression of several genes in a manner mainly overlapping between brain regions. The findings suggest that the multiple wake/sleep alterations in 3xTg-AD mice are not mitigated by SCD inhibition, but that this treatment can revert changes in hippocampal astrocytes, lipids and in the brain transcriptome. This work will benefit the understanding of the AD pathophysiology and associated sleep disturbances.}, } @article {pmid41540303, year = {2026}, author = {Abd El-Fattah, MA}, title = {Challenges and Opportunities of Drug Delivery for Treatment of Alzheimer's Disease.}, journal = {AAPS PharmSciTech}, volume = {27}, number = {1}, pages = {78}, pmid = {41540303}, issn = {1530-9932}, mesh = {*Alzheimer Disease/drug therapy/metabolism ; Humans ; *Drug Delivery Systems/methods ; Blood-Brain Barrier/metabolism/drug effects ; Nanoparticles/chemistry ; Animals ; Amyloid beta-Peptides/metabolism ; Brain/metabolism/drug effects ; }, abstract = {Alzheimer's disease (AD) is a neurodegenerative disorder characterized by progressive deterioration in cognitive functions. It represents a global health concern with increasing prevalence and devastating outcomes for the quality of life that could ultimately lead to death. AD is associated with deposition of β-amyloid (Aβ) plaques and intracellular buildup of tau proteins forming neurofibrillary tangles (NFTs), which are the main characteristics for AD brain tissues. Approved AD therapy is based mainly on symptomatic relief, and conventional medicaments often fail due to either low bioavailability, limited solubility, or failure to cross blood-brain barrier (BBB). The complexity in AD pathophysiology opens windows for many therapeutic options. So, lecanemab was recently approved by FDA as the first disease-modifying therapy. However, drug delivery to the brain remains challenging due to the nature of BBB. Hence, more extensive research is essential to develop disease-modifying therapies and also to find drug delivery strategies to ensure simplified administration and successful brain delivery. This review article summarizes AD pathogenesis with the corresponding treatment targets. It emphasizes innovative drug delivery strategies and novel formulation approaches to deliver medicines across BBB. The use of recent advancements in drug delivery to deliver medicaments across BBB are highlighted, with focus given to novel drug delivery systems and formulation of nanoparticles for brain targeting. The use of nutraceuticals, gene therapy, and stem cell therapy are is covered.}, } @article {pmid41540476, year = {2026}, author = {Zhang, Y and Zhang, F and Yin, H and Sun, Y and Wang, Y and Ren, Z and Jiang, J and Zeng, L}, title = {hUC-MSC-derived exosomes ameliorate Alzheimer's disease pathology through lncRNA-9969-mediated multi-target protection involving neuronal autophagy and microglial modulation.}, journal = {Alzheimer's research & therapy}, volume = {18}, number = {1}, pages = {34}, pmid = {41540476}, issn = {1758-9193}, support = {YDZJ202301ZYTS536//the Science and Technology Department of Jilin Province/ ; }, mesh = {Animals ; *Exosomes/metabolism/transplantation ; *Alzheimer Disease/pathology/metabolism/therapy/genetics ; Humans ; *RNA, Long Noncoding/metabolism/genetics ; *Microglia/metabolism/pathology ; Mice ; *Mesenchymal Stem Cells/metabolism ; *Autophagy/physiology ; *Neurons/metabolism/pathology ; Male ; Amyloid beta-Peptides/metabolism ; Disease Models, Animal ; Mice, Transgenic ; }, abstract = {BACKGROUND: Alzheimer's disease is characterized by intertwined pathologies including neuroinflammation, driven by microglial dysfunction, and metabolic disturbances such as lipid dyshomeostasis. Mesenchymal stem cell-derived exosomes (MSC-Exos) hold therapeutic promise, Still, it is unknown whether they can simultaneously address these co-occurring impairments via specific molecular cargos, such as long non-coding RNAs (lncRNAs).

METHODS: Transcriptome sequencing of exosomes derived from human umbilical cord mesenchymal stem cells (hUC-MSCs) revealed high expression of the long noncoding RNA ENST00000629969 (hereinafter referred to as lncRNA-9969). We isolated exosomes from hUC-MSCs (WT-Exo) and established human umbilical cord blood mesenchymal stem cells stably knocked down for lncRNA-9969 via siRNA, from which corresponding exosomes (KD-Exo) were isolated. Cross-species analysis identified the mouse homolog of lncRNA-9969 as ENSMUST00000200021 (hereinafter referred to as lncRNA-0021). Cellular experiments employed an Aβ₂₅₋₃₅-induced SH-SY5Y cell model to evaluate the protective effects of exosomes. In animal experiments, 6-month-old APP/PS1 mice received biweekly tail vein injections of WT-Exo or KD-Exo for 4 weeks. Phenotypic and mechanistic analyses were subsequently conducted using the Morris water maze, Western blot, immunofluorescence, qPCR, and transmission electron microscopy.

RESULTS: In Aβ-injured SH-SY5Y cells, WT-Exo significantly attenuated cellular damage and promoted Aβ clearance, whereas the protective effect of KD-Exo was markedly reduced. In APP/PS1 mice, WT-Exo treatment significantly improved spatial memory deficits and upregulated hippocampal expression of synaptic proteins synaptophysin (Syn) and brain-derived neurotrophic factor (BDNF). Molecular mechanism studies demonstrated that lncRNA-0021 directly binds mmu-miR-6361. Through this ceRNA mechanism, exosome-delivered lncRNA activated the mTOR/p70S6K autophagy pathway, regulated lipid metabolism-related genes, promoted microglial polarization toward the protective M2 phenotype, and suppressed pyroptosis. These beneficial changes were not observed in the KD-Exo-treated group.

CONCLUSIONS: hUC-MSC-derived exosomes exert neuroprotective effects by delivering functional lncRNA-9969. Its highly conserved homolog in mice, lncRNA-0021, achieves coordinated multi-target regulation of neuroinflammation, pyroptosis, and metabolic disturbances by sequestering miR-6361 and activating downstream signaling pathways. This study elucidates the central role of exosomal lncRNAs in AD pathology and provides new insights for developing RNA-based multi-target therapeutic strategies.}, } @article {pmid41540481, year = {2026}, author = {Si, X and Tian, S and Chen, Y and Li, X and Wu, G and Yao, Y and Wang, M}, title = {Investigating the molecular mechanisms of glutamine metabolism and mitochondria-related biomarkers in Alzheimer's disease through transcriptomics and experimental validation.}, journal = {European journal of medical research}, volume = {31}, number = {1}, pages = {274}, pmid = {41540481}, issn = {2047-783X}, support = {22JR5RA994//Natural Science Foundation of Gansu Province, China/ ; CY2022-MS-A07//Cuiying Scientific and Technological Innovation Program of Lanzhou University Second Hospital, China/ ; }, abstract = {BACKGROUND: Alzheimer's disease (AD) is a prevalent neurodegenerative disorder. This study aims to identify biomarkers associated with glutamine metabolism-related genes (GRGs) and mitochondria-related genes (MRGs) in AD through bioinformatics analysis, offering insights for prevention and treatment strategies.

METHODS: Candidate genes were first picked out through differential gene expression profiling, construction of weighted gene co-expression network analysis (WGCNA), and interaction network analysis. Biomarkers were then filtered using machine learning algorithms. For these biomarkers, expression verification and receiver operating characteristic (ROC) curve analysis were carried out. These biomarkers underwent GeneMANIA analysis, subcellular and chromosomal localization, enrichment analysis, along with immune infiltration assessment, establishment of a multi-layered molecular regulatory network, and prediction of potential therapeutic agents by leveraging drug-gene interaction databases. Finally, the consistency was validated by reverse transcription quantitative polymerase chain reaction (RT-qPCR).

RESULTS: Initially, 10 candidate genes were identified through bioinformatics analysis. Machine learning, expression validation, and ROC analysis pinpointed SNCA and PPP2R1A as biomarkers (AUC > 0.7). These biomarkers were associated with 20 functionally similar genes and were active in the nucleus and cytoplasm. SNCA was located on chromosome 4, and PPP2R1A on chromosome 19. Enrichment analysis unveiled their involvement in pathways such as olfactory transduction. Additionally, these biomarkers influenced immune cells; for instance, there was a positive correlation between PPP2R1A and type 2 T helper cells (cor = 0.66, P = 1.03 × 10[-5]). A molecular regulatory network demonstrated that these biomarkers were regulated by 134 miRNAs, and 72 potential drugs targeting these biomarkers were identified. RT-qPCR confirmed the expression consistency with bioinformatics results.

CONCLUSION: This study ultimately identified SNCA and PPP2R1A as biomarkers for AD, providing a theoretical foundation and potential targets for the diagnosis and treatment of AD.}, } @article {pmid41540503, year = {2026}, author = {Song, C and Wu, PY and Huffman, WJ and David-Bercholz, J and Bedolla, A and Velagapudi, R and Njoroge, A and Rodriguiz, RM and Wetsel, WC and Rendina, D and Bilbo, SD and Chiang, W and Ogu, JC and Gelbard, HA and Yang, T and Grill, WM and Terrando, N}, title = {Electrical stimulation of the vagus nerve improves amyloid pathology in delirium superimposed on dementia.}, journal = {Bioelectronic medicine}, volume = {12}, number = {1}, pages = {2}, pmid = {41540503}, issn = {2332-8886}, support = {AARF-24-1313412/ALZ/Alzheimer's Association/United States ; 2019-AARG-643070/ALZ/Alzheimer's Association/United States ; R01-AG057525, R01-AG083979A1, RF1-AG079138, R21-AG055877/NH/NIH HHS/United States ; }, abstract = {BACKGROUND: Delirium and delirium superimposed on dementia (DSD) are common complications affecting patients suffering from ongoing neurodegenerative pathologies. Peripheral surgical trauma can trigger neuroinflammation and ensuing DSD via mechanisms that remain poorly understood. Given the multifactorial therapeutic effects of neuromodulation, including vagal nerve stimulation, we have tested a minimally invasive approach to combat DSD following orthopedic surgery. METHODS: We performed orthopedic surgery on 5xFAD and CVN-AD mice and tested the efficacy of minimally invasive percutaneous vagus nerve stimulation (pVNS). We applied immunohistochemical, biochemical, and behavioral assays to evaluate the impact of surgery on postoperative delirium on DSD pathology in Alzheimer’s disease-like mice. To confirm the role of systemic factors in neuroinflammation and amyloid-β dyshomeostasis, we conducted experiments using interleukin-6 (IL-6), a cytokine commonly upregulated in postoperative delirium and in vitro co-culture assays for validation. RESULTS: In AD-like mice surgery induced acute changes in amyloid-β; perioperative treatment with pVNS effectively reduced amyloid-β load, plaque sphericity, and neuronal loss. The rescue of these pathological hallmarks led to improved delirium-like behavior, as demonstrated by the 5-choice serial reaction time task on postoperative days 1 and 2. pVNS improved microglial morphology, particularly near amyloid-β plaques. Acute isolation of microglial cells from 5xFAD mice after surgery indicated that pVNS partially enhanced key Disease-Associated Microglia (DAM) markers. The contribution of pro-inflammatory cytokines to amyloid-β aggregation was validated using an in vitro transwell culture model following Cytomix exposure, which also caused endothelial barrier disruption. Finally, we isolated IL-6 as a well-established biomarker of postoperative delirium and described its role in DSD pathology following systemic administration. CONCLUSION: These findings establish a role for neuromodulation after pVNS in regulating perioperative immunity and advance a new paradigm for perioperative interventions in patients at risk for DSD.}, } @article {pmid41540543, year = {2026}, author = {Singh, NK and Kumar, Y and Chandra, M and PadmaPriya, G and Sharma, Y and Mishra, S}, title = {Betanin: A Natural Phytomolecule for the Intervention of Neurological Disorders.}, journal = {Current topics in medicinal chemistry}, volume = {}, number = {}, pages = {}, doi = {10.2174/0115680266398457251014040532}, pmid = {41540543}, issn = {1873-4294}, abstract = {Betanin is widely consumed around the globe either as beetroot directly or as one of the key ingredients in food and pharmaceutical preparations. The health benefits of Betanin, including the treatment of numerous neurological diseases and brain cancer, have been reported extensively. Betanin has gained global attention due to notable anti-inflammatory, antioxidant, and anti-cancer activities. Recently, there has been growing attention on the usage of Betanin to prevent or delay the onset of neurodegenerative disorders. This review recapitulates available information from various recent pre-clinical studies on Betanin in several neurological diseases, such as Parkinson's disease, Alzheimer's disease, aging, brain stroke, anxiety, and neuropathic pain. Betanin exhibits remarkable neuroprotective effects via activation of the Nrf2 signaling pathway, inhibition of the production and expression of pro-inflammatory mediators and reactive oxygen species, along with suppression of the NF-κB signaling pathway. Taking betanin as part of a healthy diet may aid in the management of various brain-related disorders. This review focuses on the neurological conditions for which betanin has shown therapeutic potential, highlighting its beneficial properties, cellular and molecular mechanisms of action, and its relevance in light of current research. Based on the available evidence, betanin could be considered a promising candidate and lead compound in the drug development process for the prevention, treatment, and management of several neurological disorders in the future.}, } @article {pmid41540706, year = {2026}, author = {Zhang, S and Huang, T and Yang, C and Chen, J and Lü, T and Zhang, J}, title = {[Sulforaphane reduces reactive astrocyte-mediated neuron apoptosis in vitro by inhibiting the MAPK/NF-κB signaling pathway in Aβ42 oligomer-activated astrocytes].}, journal = {Nan fang yi ke da xue xue bao = Journal of Southern Medical University}, volume = {46}, number = {1}, pages = {191-199}, pmid = {41540706}, issn = {1673-4254}, mesh = {*Isothiocyanates/pharmacology ; Sulfoxides ; *Apoptosis/drug effects ; *Astrocytes/drug effects/cytology/metabolism ; *Amyloid beta-Peptides ; Humans ; *Neurons/drug effects/cytology ; Signal Transduction/drug effects ; Tumor Necrosis Factor-alpha/metabolism ; Cell Line, Tumor ; Animals ; NF-kappa B/metabolism ; Peptide Fragments ; Mice ; Interleukin-6/metabolism ; Coculture Techniques ; MAP Kinase Signaling System/drug effects ; }, abstract = {OBJECTIVES: To explore the effects of sulforaphane (SFN) on Aβ42-activated U87 astrocyte-mediated apoptosis of SH-SY5Y neurons in vitro.

METHODS: U87 cells treated with different concentrations of Aβ42, SFN or both were examined for changes in cell activity, IL-6 and TNF-α mRNA expression, release of IL-6 and TNF-α proteins, and expressions of p-p38, p-p65 and GFAP using CCK-8 assay, RT-qPCR, ELISA and Western blotting. SH-SY5Y neurons were co-cultured with U87 astrocytes treated with Aβ42 alone or in combination with SFN or SB203580 for 24 h, and the changes in Bax protein expression levels and viability of SH-SY5Y cells were examined. The effects of Aβ42, SFN, and their combination were also observed in astrocytes isolated from mouse brain tissues, and the indirect effects of astrocyte treatmentt on viability of the co-cultured primary neurons were assessed.

RESULTS: The viability of U87 astrocytes increased significantly following treatment with 1.25 μmol/L Aβ42 but decreased after Aβ42 treatment above 5 μmol/L. SFN treatments for 24 h below 5 μmol/L did not significantly affect U87 cell viability. Aβ42 treatment significantly increased protein expressions of p-p38, p-p65 and GFAP, mRNA expression levels of IL-6 and TNF-α, and IL-6 and TNF-α levels in culture supernatant of U87 cells. SH-SY5Y cells co-cultured with Aβ42-treated U87 cells showed significantly increased protein expressions of Bax, and exhibited lowered viability following co-culture with 5 μmol/L Aβ42-treated U87 cells. The isolated mouse astrocytes showed lowered viability following Aβ42 treatment above 10 μmol/L, but SFN treatment below 5 μmol/L for 24 did not obviously affect the cell viability. The primary neurons co-cultured with Aβ42-treated mouse astrocytes showed significantly lower cell viability than those co-cultured with the astrocytes treated with Aβ+SFN or Aβ+SB203580.

CONCLUSIONS: SFN attenuates astrocyte-mediated neuron apoptosis by inhibiting the MAPK/NF-κB signaling pathway in Aβ42 oligomer-activated astrocytes.}, } @article {pmid41540764, year = {2026}, author = {Kanwal, A and Azeem, B and Nasir, H and Mumtaz, F and Ashraf, N and Amin, MHJ and Kanwal, W and Khan, BW}, title = {Exploring Adjunctive Novel Therapeutic Approach of KarXT (Xanomeline-Trospium Chloride) for Managing Psychotic Symptoms in Patients With Schizophrenia and Alzheimer's Disease.}, journal = {Brain and behavior}, volume = {16}, number = {1}, pages = {e71182}, pmid = {41540764}, issn = {2162-3279}, mesh = {Humans ; *Alzheimer Disease/drug therapy/complications ; *Schizophrenia/drug therapy/complications ; *Psychotic Disorders/drug therapy ; *Antipsychotic Agents/pharmacology/therapeutic use ; Quality of Life ; }, abstract = {BACKGROUND: Acute psychotic symptoms like delusions and hallucinations are of major concern while treating patients with schizophrenia and alzheimer's psychosis, primarily impacting their daily life functioning and quality of life. The traditional antipsychotic medications, commonly prescribed to manage these symptoms, cause significant side effects with limited efficacy, requiring novel therapeutic agents that can overcome this challenge. While there is no definitive cure, symptomatic treatment can help relieve some of the symptoms and improve the quality of life of people with alzheimer's disease (AD).

METHOD: A comprehensive literature search of PubMed, scopus, google scholar, and ClinicalTrials.gov was conducted to identify studies on xanomeline-trospium chloride (KarXT) in schizophrenia and AD psychosis. After screening 802 unique records, 39 studies-including preclinical, clinical, and observational investigations-were included in this narrative review. Only English-language publications up to February 2025 were considered.

RESULT: KarXT, with its dual action on the M1 and M4 receptors and mAChR antagonism, greatly helps reduce the severity of the positive and negative symptoms, as it resulted in an 8.4-point greater reduction on the PANSS scale. Side effects were minimal and did not account for the discontinuation of treatment.

CONCLUSION: Psychosis is a common feature of schizophrenia and AD, most often caused by high concentrations of dopamine in the brain, characterized by hallucinations, delusions, and disorganized thinking, resulting in markedly reduced quality of life for the patient and associated caregiver. Conventional treatments targeting dopamine receptors produce extrapyramidal symptoms and metabolic side effects, leading to noncompliance with medication. KarXT, with its dual action on M1 and M4 receptors and mAChR antagonism, greatly helps reduce the severity of the positive and negative symptoms. The side effects experienced were minimal and did not account for the discontinuation of treatment.An overview of the mechanism of action, clinical trials, and classical findings of KarXT for the management of psychotic symptoms in patients with schizophrenia and alzheimer's disease.}, } @article {pmid41541199, year = {2026}, author = {Salah, RS and El-Sayed, NF and El-Hussieny, M and Mansour, ST and Othman, M and Fouad, MA and Rashdan, HRM and Ewies, EF and Gharib, HSA and Elsayed, GH}, title = {Design and synthesis of new phosphazine and triazole derivatives for treatment of Alzheimer's disease: modulating ROS/JNK and Wnt/β-catenin signaling pathways.}, journal = {RSC advances}, volume = {16}, number = {4}, pages = {3077-3100}, pmid = {41541199}, issn = {2046-2069}, abstract = {Alzheimer's disease (AD) is a multifactorial neurodegenerative disorder characterized by progressive cognitive impairment and the accumulation of amyloid-β (Aβ) peptides. In this study, a novel series of triazole and phosphazine derivatives were synthesized and evaluated for neuroprotective activity in an aluminum chloride (AlCl3)-induced rat model of AD. Among the synthesized compounds, 3a, 6a, and 6c were structurally characterized and selected for in vivo biological evaluation. Behavioral, biochemical, molecular, and histopathological assessments were conducted to determine their efficacy, with Rivastigmine used as a reference drug. Compounds 3a and 6c significantly improved cognitive and memory performance, decreased Aβ1-42 production, and reduced reactive oxygen species (ROS) generation. Furthermore, both compounds inhibited the activation of JNK and Puma, promoted Beclin-1 expression, and activated Wnt/β-catenin signaling, as evidenced by increased expression levels of Wnt7a, β-catenin, LRP6, and FZD4, alongside decreased expression levels of GSK-3β and BACE1. Molecular docking studies supported these findings, revealing strong binding affinities of the active compounds, particularly 3a, to the JNK3 active site. Molecular dynamic simulations were performed on the best docking pose of the most potent compound 3a to confirm the formation of a stable complex with JNK3. Compounds 3a, 6a, and 6c demonstrated favorable pharmacokinetic profiles, with predicted good oral bioavailability, blood-brain barrier permeability, and non-substrate behavior toward P-glycoprotein. They are expected to maintain therapeutic availability in systemic circulation, as indicated by the predicted plasma protein binding below 90%, moderate to high steady-state volume of distribution, and lack of substrate affinity for cytochrome P450 enzymes CYP2C9 and CYP2D6. These results suggest that compounds 3a and 6c may serve as promising multi-target therapeutic candidates for AD by modulating oxidative stress, apoptosis, autophagy, and Wnt/β-catenin signaling pathways.}, } @article {pmid41543367, year = {2026}, author = {Bhagunde, P and Penner, N and Willis, BA and Bell, R and Charil, A and Irizarry, MC and Hersch, S and Reyderman, L}, title = {Brain Amyloid Plaque Levels Affect Clinical Progression in Alzheimer Disease: Assessment of Amyloid PET and Change in CDR-SB Utilizing Semi-Mechanistic Model.}, journal = {CPT: pharmacometrics & systems pharmacology}, volume = {15}, number = {2}, pages = {e70173}, pmid = {41543367}, issn = {2163-8306}, mesh = {Humans ; *Alzheimer Disease/drug therapy/diagnostic imaging/metabolism ; Positron-Emission Tomography ; Disease Progression ; *Antibodies, Monoclonal, Humanized/therapeutic use/administration & dosage/pharmacology ; *Plaque, Amyloid/drug therapy/diagnostic imaging/metabolism ; Amyloid beta-Peptides/metabolism ; *Brain/metabolism/diagnostic imaging/drug effects ; Male ; Aged ; Female ; Double-Blind Method ; Models, Biological ; }, abstract = {Lecanemab is a humanized IgG1 monoclonal antibody binding with high affinity to protofibrils of amyloid-beta (Aβ) protein. In clinical studies, lecanemab has been shown to reduce amyloid markers in early symptomatic Alzheimer's disease and slow decline on clinical endpoints of cognition and function. Nonlinear mixed-effects modeling assessed the correlation between amyloid PET and change in CDR-SB using data from lecanemab phase 2 study (Study 201) and phase 3 study (Study 301; Clarity AD). Data from placebo-treated subjects were used to establish a disease-progression model; the effect of amyloid reduction on disease progression was defined using data from lecanemab-treated subjects. CDR-SB scores were used with beta regression to fit a Richard's function parameterized in terms of baseline CDR-SB, intrinsic rate of disease progression, shape, and precision of the beta distribution. Simulations were conducted to evaluate the impact of lecanemab treatment over 4 years. Baseline CDR-SB was predicted by diagnosis and baseline mini-mental state examination (BMMSE) score. Intrinsic rate of disease progression was predicted by amyloid PET and BMMSE. Amyloid PET was a better predictor of drug effect than lecanemab exposure, demonstrating amyloid reduction as a surrogate marker of efficacy. Simulations projected the difference in CDR-SB between lecanemab and placebo treated subjects continued increasing over 4 years. Patients with low baseline amyloid and less severe disease were projected to have slower disease progression and better outcomes with lecanemab treatment.}, } @article {pmid41543510, year = {2026}, author = {Dumoulin, D and Ghrayeb, M and Côté, S and Garneau, D and Chai, L and Frost, EH and Fülöp, T and Beauregard, PB}, title = {Bidirectional relationship between the biofilm of Porphyromonas gingivalis and the amyloid-beta peptide.}, journal = {Microbiology spectrum}, volume = {14}, number = {3}, pages = {e0198125}, pmid = {41543510}, issn = {2165-0497}, support = {2019-AUDC-263669//Fonds de recherche du Québec/ ; 316403//Fonds de Recherche du Québec - Santé/ ; //Ministère des relations internationales et de la Francophonie/ ; }, mesh = {*Porphyromonas gingivalis/physiology/metabolism/genetics ; *Biofilms/growth & development ; *Amyloid beta-Peptides/metabolism ; Humans ; Alzheimer Disease/microbiology/metabolism ; *Peptide Fragments/metabolism ; Bacteroidaceae Infections/microbiology/metabolism ; Periodontitis/microbiology ; Extracellular Matrix/metabolism ; }, abstract = {UNLABELLED: Periodontitis and Porphyromonas gingivalis infections are significant risk factors for the onset of Alzheimer's disease (AD). Despite the reliance of P. gingivalis on its biofilm for its survival and virulence, the impact of the extracellular matrix on AD's neuropathological hallmarks has never been examined. In this study, we report a bidirectional relationship between the amyloid-beta (Aβ) peptide, which plays a central role in AD, and the biofilm of P. gingivalis. Using multiple fluorescent markers for biofilm components, we observed that Aβ1-40 inhibited biofilm formation while Aβ1-42 increased extracellular matrix production. Also, using thioflavin T staining and atomic force microscopy, we observed co-aggregation of the biofilm and monomeric Aβ1-40, resulting in faster aggregation and significant changes in aggregate structure. Our findings propose mechanistic explanations for the role of P. gingivalis as a risk factor for AD and offer potential mechanisms for microbial involvement in AD etiology.

IMPORTANCE: While the etiology of Alzheimer's disease has been studied extensively for the past 50 years, its exact causes remain unknown. Our current understanding is that the accumulation of multiple genetic and environmental risk factors would lead to the onset of the disease. Porphyromonas gingivalis is a bacterium that produces biofilm and elicits periodontitis, a chronic infection of the gums that constitutes a risk factor for Alzheimer's disease. While studies have looked at the effects of P. gingivalis in triggering Alzheimer's symptoms in animal models, none have explored the impact of the biofilm, which is essential in this bacterium. Our study seeks to bridge that gap by demonstrating a bidirectional relationship between P. gingivalis biofilm and amyloid beta, one of the brain lesions involved in Alzheimer's disease. By understanding the risk factors involved in Alzheimer's disease and their impact, we aim to provide valuable insights on prevention and treatment.}, } @article {pmid41544372, year = {2026}, author = {Rosenberg, A and Solomon, A and Bonnard, A and Daniilidou, M and Hagman, G and Hall, A and Matton, A and Öhlund-Wistbacka, U and Westman, E and Kivipelto, M}, title = {Preparing for the implementation of anti-amyloid therapies in Europe: Assessing real-world eligibility for lecanemab and donanemab in a Swedish memory clinic.}, journal = {The journal of prevention of Alzheimer's disease}, volume = {13}, number = {3}, pages = {100476}, pmid = {41544372}, issn = {2426-0266}, mesh = {Humans ; Sweden ; Female ; *Alzheimer Disease/drug therapy/genetics ; *Eligibility Determination ; Male ; Aged ; Apolipoprotein E4/genetics ; *Antibodies, Monoclonal/therapeutic use ; *Amyloid beta-Peptides/antagonists & inhibitors ; Aged, 80 and over ; Antibodies, Monoclonal, Humanized ; }, abstract = {Lecanemab and donanemab are the first anti-Aβ treatments to receive approval in Europe. Eligibility criteria are strict, eg., APOE ε4/4 carriers are excluded. Successful implementation in public healthcare hinges on accurate estimates of eligibility rates in settings which will be the first to roll out the treatments (specialized memory clinics with early disease stages). We applied the appropriate use recommendations (AUR) to assess treatment eligibility in a Swedish tertiary memory clinic where Aβ and APOE assessments are routinely performed. Of the full cohort (N = 410), 26 and 25 patients met the AUR criteria for lecanemab and donanemab, respectively (6 %; partial overlap between the groups). After excluding APOE ε4/4 carriers in line with the European guidelines, only 14 and 13 patients remained eligible (3 %). In clinics with younger populations, a significant percentage of potentially eligible patients are likely to have the APOE ε4/4 genotype. These findings are important to inform the implementation of anti-Aβ treatments.}, } @article {pmid41546373, year = {2026}, author = {Massoumzadeh, P and Tiemann Powles, S and Naghashzadeh, M and Rizzo, J and Hu, J and Yaeger, L and Alkelani, H and Wang, Q and Chen, G and Dolatshahi, M and Joseph-Mathurin, N and Benzinger, TLS}, title = {Sex differences in Alzheimer's disease: a systematic review of two decades of neuroimaging research.}, journal = {The British journal of radiology}, volume = {99}, number = {1180}, pages = {702-713}, pmid = {41546373}, issn = {1748-880X}, support = {P30 AG066444/AG/NIA NIH HHS/United States ; P01 AG003991/AG/NIA NIH HHS/United States ; P01 AG026276/AG/NIA NIH HHS/United States ; K01 AG080123/AG/NIA NIH HHS/United States ; R01 AG054567/AG/NIA NIH HHS/United States ; UF1 AG032438/AG/NIA NIH HHS/United States ; R01 AG074909/AG/NIA NIH HHS/United States ; R01 AG052550/AG/NIA NIH HHS/United States ; UL1 TR002345/TR/NCATS NIH HHS/United States ; U19 AG032438/AG/NIA NIH HHS/United States ; /NH/NIH HHS/United States ; R01AG074909/AG/NIA NIH HHS/United States ; K01AG080123/AG/NIA NIH HHS/United States ; UL1TR002345/TR/NCATS NIH HHS/United States ; }, mesh = {Humans ; *Alzheimer Disease/diagnostic imaging/genetics ; *Neuroimaging/methods ; Female ; Biomarkers ; Sex Factors ; Male ; Disease Progression ; Brain/diagnostic imaging ; Positron-Emission Tomography ; }, abstract = {OBJECTIVES: Given the heterogeneous nature of Alzheimer's disease (AD) and its higher prevalence in females, it is crucial to understand sex-related differences in AD presentation and changes in the brain.

METHODS: This systematic review investigates sex differences in AD and summarizes key findings from neuroimaging studies over the past two decades to examine how genetics, hormones, and lifestyle factors influence neuroimaging biomarkers and their correlation with cognitive decline and AD progression. A comprehensive literature search was conducted across several databases for human studies from 2004 to 2024 related to AD, biological sex differences, and neuroimaging.

RESULTS: After a 3-step review process, the final extraction included 120 peer-reviewed studies using various neuroimaging modalities, such as MRI, amyloid-beta PET, tau-PET, and fluorodeoxyglucose (FDG) PET, to investigate sex as a biological predictor variable in adults with or at risk for AD. Over 90% of the reviewed studies identified clear sex-specific patterns of imaging biomarkers related to cognitive reserve, hormonal changes, APOE-ɛ4 genotype, inflammation, vascular health, and lifestyle factors. Machine learning studies increasingly incorporate sex as a key variable, revealing sex-specific biomarkers and improving model performance in predicting disease status and progression.

CONCLUSIONS: Considering biological sex in AD research is essential for improving diagnostic accuracy, tailoring interventions, and health outcomes.

ADVANCES IN KNOWLEDGE: This systematic review identifies sex-specific patterns in neuroimaging biomarkers of AD, influenced by cognitive reserve, hormones, APOE-ɛ4 genotype, inflammation, vascular health, and lifestyle. Recognizing these differences is crucial for understanding, diagnosis, and treatment efficacy.}, } @article {pmid41546910, year = {2026}, author = {Elyasi, L and Wężyk, M}, title = {Exosome-derived microRNAs from stem cells from human exfoliated deciduous teeth (SHED): Emerging therapeutics for neurodegenerative disorders.}, journal = {Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie}, volume = {195}, number = {}, pages = {119001}, doi = {10.1016/j.biopha.2026.119001}, pmid = {41546910}, issn = {1950-6007}, mesh = {Humans ; *Exosomes/metabolism/genetics ; *Neurodegenerative Diseases/therapy/genetics/metabolism ; *Tooth, Deciduous/cytology/metabolism ; *MicroRNAs/genetics/metabolism ; Animals ; *Stem Cells/metabolism ; *Stem Cell Transplantation/methods ; Tooth Exfoliation ; }, abstract = {Neurodegenerative diseases (NDDs) cause progressive damage of brain structures, resulting in a loss of function and, eventually, the patient's death. Current therapeutic strategies are limited to late stages of the disease, culminating in palliative care, while tackling the underlying causes of neurodegeneration could halt or at least slow down the disease at an early stage. In this vein, stem cell transplantation therapies are emerging as a promising alternative, as such as cells can penetrate the central nervous system, engraft, differentiate, and secrete neurotrophic, neuro-regenerative, and neuroprotective factors. Stem cells derived from human exfoliated deciduous teeth (SHED) have demonstrated significant regenerative potential in various biological systems and pathological conditions, showing high proliferative capacity and multipotency to differentiate into neuronal cells both in vivo and in vitro, apparently functioning through exosome-derived microRNAs (exos-miRs). Here, we summarize recent reports on specific miRs from SHED's exosomes, which exert diverse regulatory functions counteracting oxidative stress, and provide immunomodulatory and neurotrophic benefits contributing to the treatment of neurodegeneration in NDDs. We discuss clinical and preclinical evidence supporting the potential of SHED cells in the treatment of NDDs, including Alzheimer's disease (AD), Parkinson's disease (PD), multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS), spinal cord injury, focal cerebral ischemia, and peripheral nerve damage. We also highlight that the use of SHED in NDDs treatment remains largely underexplored, opening a wide field for further research. We suggest deeper studies on the role of SHED-exos-miRs in NDDs, including their proneurotrophic activity, reduction of genotoxic neuronal stress, and disruption of proinflammatory signaling pathways.}, } @article {pmid41547241, year = {2026}, author = {Reichau, K and Crouzier, L and Gehrig, T and Flake, A and Schaller, E and Meunier, J and Bertrand-Gaday, C and Chatonnet, A and Zvejniece, L and Sotriffer, C and Maurice, T and Decker, M}, title = {Targeting neuroinflammation by activation of the sigma-1 receptor (S1R) and inhibition of butyrylcholinesterase (hBChE) leads to highly potent anti-amnesic compounds in an Alzheimer's disease mouse model.}, journal = {European journal of medicinal chemistry}, volume = {305}, number = {}, pages = {118486}, doi = {10.1016/j.ejmech.2025.118486}, pmid = {41547241}, issn = {1768-3254}, mesh = {Animals ; *Receptors, sigma/metabolism/agonists ; *Alzheimer Disease/drug therapy/metabolism ; *Butyrylcholinesterase/metabolism ; Mice ; Sigma-1 Receptor ; Disease Models, Animal ; Humans ; *Cholinesterase Inhibitors/pharmacology/chemistry/chemical synthesis/therapeutic use ; Structure-Activity Relationship ; Dose-Response Relationship, Drug ; *Neuroprotective Agents/pharmacology/chemistry/chemical synthesis ; *Neuroinflammatory Diseases/drug therapy/metabolism ; Molecular Structure ; *Amnesia/drug therapy/metabolism ; Male ; Amyloid beta-Peptides ; }, abstract = {Alzheimer's disease (AD) is a neurodegenerative disorder for which no effective preventative or curative treatment has yet been identified. Due to the multifactorial nature and complex pathophysiology of the disease, we developed a multi-target ligand that both inhibits human butyrylcholinesterase (hBChE), a key enzyme linked to β-amyloid plaque formation, and activates the sigma-1 receptor (S1R), which modulates neuroinflammatory and protective pathways. To this end, a series of isoindolines were designed and synthesized, and their biological activities were evaluated. The most promising compound, 7c, exhibited significant dual activity, achieving nanomolar IC50 values against hBChE and potent S1R activation. Subsequent in vivo studies in an Aβ25-35 mouse model revealed a remarkable improvement in cognitive deficits in both short- and long-term memory at an effective dose of 0.01 mg/kg in WT Swiss-OF1 mice. This dose is 10-fold lower compared to single-target compounds 7a and 7b of this isoindoline series. The lack of neuroprotective effects in BChE knock-out (KO) mice confirmed the involvement of BChE inhibition in the pharmacological effects of compound 7c in WT mice. Further combinatorial studies employing a two-drug combination demonstrated synergy in the neuroprotective effect of addressing the two targets.}, } @article {pmid41548335, year = {2026}, author = {Dong, W and Yuan, Q and Wu, B and Gao, S and Zhang, Y and Pan, Y and Zhou, K and Jiang, H}, title = {Age at type 2 diabetes onset and risk of dementia: The modifying role of genetic susceptibility and mitochondrial function.}, journal = {The journal of nutrition, health & aging}, volume = {30}, number = {3}, pages = {100780}, pmid = {41548335}, issn = {1760-4788}, mesh = {Humans ; *Diabetes Mellitus, Type 2/epidemiology/genetics/complications ; Middle Aged ; Female ; *Genetic Predisposition to Disease ; *Dementia/epidemiology/genetics/etiology ; Male ; *Mitochondria/physiology/genetics ; Age of Onset ; Aged ; Prospective Studies ; China/epidemiology ; DNA, Mitochondrial/genetics ; Risk Factors ; Genetic Risk Score ; }, abstract = {OBJECTIVES: To assess dementia risk after incident type 2 diabetes (T2D) by age at diagnosis and evaluate modification by treatment, genetic susceptibility, and mitochondrial function.

DESIGN: Prospective 1:1 age- and sex-matched cohort study using inverse-probability-weighted Cox models.

SETTING: Kunshan Aging Research with E-health (KARE) cohort in China (2018-2024).

PARTICIPANTS: 42,514 adults without diabetes or dementia at baseline, including 21,257 incident T2D cases and 21,257 non-diabetic controls.

MEASUREMENTS: Outcomes were all-cause dementia, Alzheimer's disease (AD), and vascular dementia (VaD) from linked medical records and annual examinations. T2D onset age was grouped as 45-54 years, 55-64 years, and persons 65 years and older. In genotyped participants (n = 14,455), a T2D polygenic risk score (PRS) and blood mitochondrial DNA copy number (mtDNA-CN) were examined.

RESULTS: Over a median 3.67 years, incident T2D was associated with higher risks of all-cause dementia (adjusted hazard ratio [AHR] 1.95, 95% CI 1.71-2.21), AD (2.21, 1.88-2.59), and VaD (1.57, 1.20-2.07). Glucose-lowering treatment was associated with lower dementia risk versus no treatment. Among patients aged 55-64 years, the low-PRS/low-mtDNA-CN subgroup had the highest AD risk (AHR 2.41, 95% CI 1.12-5.19).

CONCLUSION: Age at T2D onset was associated with variation in dementia risk. Earlier diagnosis and treatment were associated with lower observed cognitive risk, while genetic susceptibility and mitochondrial function may inform individualised risk stratification.}, } @article {pmid41548526, year = {2026}, author = {Moon, SY and Chen, TF and Lee, BC and Moon, WJ and Kandiah, N and Kumar, S and Park, YH and Inaba, K and Dash, A}, title = {A regional framework for the detection and management of ARIA with anti-amyloid therapies in early Alzheimer's disease in Asia.}, journal = {The journal of prevention of Alzheimer's disease}, volume = {13}, number = {3}, pages = {100477}, pmid = {41548526}, issn = {2426-0266}, mesh = {Humans ; *Alzheimer Disease/drug therapy/diagnostic imaging ; Asia ; Amyloid beta-Peptides ; }, abstract = {Alzheimer's disease (AD) is a growing public health concern in Asia, with an increasing prevalence driven by demographic shifts and rising life expectancy. The introduction of anti-amyloid monoclonal antibodies such as lecanemab and donanemab marks a pivotal transition from symptomatic management of AD to disease-modifying approaches, but their clinical use requires careful monitoring for amyloid-related imaging abnormalities (ARIA), a key safety consideration that presents either as vasogenic edema or as microhemorrhages and superficial siderosis. ARIA has been observed in varying frequencies across global and Asian clinical trial populations, underscoring the need for region-specific guidance. With our early clinical experiences in South Korea, Taiwan and Singapore serving as archetypes in Asia, we outline a framework for the detection and management of ARIA in Asian healthcare settings, accounting for disparities in imaging infrastructure, genetic factors, and clinician experience. Pre-treatment risk stratification, standardized imaging protocols, and severity-based treatment modifications are central to the framework, highlighting the critical role of multidisciplinary collaboration involving neurologists, geriatricians, psychiatrists, and radiologists in ensuring accurate detection and management of ARIA. Additionally, the paper highlights the role of pharmacovigilance, real-world evidence generation, physician education, and healthcare system preparedness in optimizing the safety and efficacy of anti-amyloid therapies in Asia. The proposed framework aims to ensure safe and effective use of anti-amyloid therapies while mitigating ARIA-related risks, thereby optimizing therapeutic outcomes for early AD in diverse healthcare settings across Asia.}, } @article {pmid41548619, year = {2026}, author = {Shao, S and Zu, R and Lu, H and Yuan, Y and Chen, Y and Wu, C and Yang, Y and Shao, S and Ma, H and Zhang, Z and Sun, Y}, title = {Kai-Xin-San alleviates Alzheimer's disease by targeting the DHFR-mediated folate-mitochondrial axis.}, journal = {Journal of ethnopharmacology}, volume = {361}, number = {}, pages = {121230}, doi = {10.1016/j.jep.2026.121230}, pmid = {41548619}, issn = {1872-7573}, mesh = {Animals ; *Alzheimer Disease/drug therapy/metabolism ; *Mitochondria/drug effects/metabolism ; *Tetrahydrofolate Dehydrogenase/metabolism ; Mice, Transgenic ; *Folic Acid/metabolism ; *Drugs, Chinese Herbal/pharmacology/therapeutic use ; Mice ; Male ; Humans ; Cell Line ; Disease Models, Animal ; *Neuroprotective Agents/pharmacology ; }, abstract = {Kai-Xin-San (KXS) is a classical herbal formula first recorded in the Tang Dynasty and has been used for more than 1000 years for cognitive impairment and dementia.

AIM OF THE STUDY: To investigate whether KXS granules (KXSG) alleviate mitochondrial dysfunction in AD by engaging dihydrofolate reductase (DHFR) -linked folate metabolism.

MATERIALS AND METHODS: The pharmacodynamic effects of KXSG were evaluated in APP/PS1 transgenic mice using behavioral testing, neuropathological assessment, and ultrastructural examination of mitochondria. Pathways and candidate targets were first prioritized by brain-tissue DIA proteomics, and were further supported by a network pharmacology analysis based on putative brain-penetrant constituents. Mechanistic validation was performed both in vivo using APP/PS1 transgenic mice and in vitro using an APP-overexpressing HT22 cell model. Mitochondrial function, folate-cycle-related indices, and target protein expression were assessed in both systems, and pharmacological inhibition of DHFR with methotrexate was employed to probe causality.

RESULTS: KXSG treatment improved learning and memory performance, preserved hippocampal neuronal integrity, and reduced Aβ burden in APP/PS1 mice. Proteomic profiling showed that proteins reversed by KXSG were enriched for mitochondrial localization and were closely linked to folate metabolism. DHFR emerged as a key candidate within this network. In cellular assays, KXSG mitigated AD-related mitochondrial impairment while partially normalizing folate-cycle-associated markers and DHFR expression. Notably, methotrexate, a DHFR inhibitor, attenuated the mitochondrial benefits conferred by KXSG.

CONCLUSION: These data support DHFR-associated folate metabolism as an important mechanistic axis through which KXSG promotes mitochondrial function in AD, providing experimental evidence for a folate-mitochondria link underlying its neuroprotective effects.}, } @article {pmid41548697, year = {2026}, author = {Takeda, A and Takeuchi, T and Minakawa, EN and Tanaka, N and Mochizuki, H and Nagai, Y}, title = {Blood extracellular vesicles contribute to the exercise-mediated suppression of brain Aβ pathology in the App[NL-G-F] knockin mouse model of Alzheimer's disease.}, journal = {Neurochemistry international}, volume = {193}, number = {}, pages = {106120}, doi = {10.1016/j.neuint.2026.106120}, pmid = {41548697}, issn = {1872-9754}, mesh = {Animals ; *Alzheimer Disease/pathology/genetics/blood/metabolism ; *Extracellular Vesicles/metabolism/genetics ; *Physical Conditioning, Animal/physiology/methods ; Mice, Transgenic ; *Brain/metabolism/pathology ; *Amyloid beta-Peptides/metabolism/genetics ; Mice ; Disease Models, Animal ; *Amyloid beta-Protein Precursor/genetics ; Gene Knock-In Techniques/methods ; Male ; Mice, Inbred C57BL ; Plaque, Amyloid/pathology/metabolism ; }, abstract = {Epidemiological, clinical, and experimental evidence suggest that physical exercise suppresses the deposition of amyloid β (Aβ) plaques in the brain and reduces the risk of Alzheimer's disease (AD). However, how exercise provides such beneficial effects on AD remains largely unclear. In this study, we show that the exercise-mediated suppression of Aβ deposition requires blood extracellular vesicles (EVs) that are upregulated by exercise. We demonstrated that treadmill exercise induces a transient increase in the secretion of blood EVs in both wild-type mice and the App[NL-G-F] knockin mouse model of AD. Comprehensive analysis of protein contents of the exercise-induced blood EVs demonstrated that molecular chaperones, such as heat shock proteins and cochaperones, are substantially increased, together with substantial changes in proteomic profiles after exercise. Importantly, long-term exercise led to the suppression of Aβ plaque deposition in App[NL-G-F] knockin mice, but this suppressive effect was almost completely diminished by the pharmacological inhibition of EV secretion. These results indicate that the secretion of blood EVs is increased by exercise, which contributes to the suppression of Aβ pathology in the brain. Our study identifies blood EVs as a key mediator of the benefits of exercise throughout the body including the brain, highlighting the therapeutic potential of exercise-induced EVs for the treatment of AD pathology.}, } @article {pmid41548855, year = {2026}, author = {Jiang, A and Ma, Y and Bao, S and Shahbazi, MA and Reis, RL and Kundu, SC and Xiao, B and Shi, X}, title = {Metal-directed nanomedicines for imaging-guided disease treatment.}, journal = {Acta biomaterialia}, volume = {212}, number = {}, pages = {42-66}, doi = {10.1016/j.actbio.2026.01.032}, pmid = {41548855}, issn = {1878-7568}, mesh = {Humans ; *Nanomedicine/methods ; Animals ; *Metals/chemistry ; *Drug Delivery Systems ; *Neoplasms/diagnostic imaging/drug therapy ; }, abstract = {Metal-directed self-assembly, driven by metal-ligand coordination, represents a highly versatile and efficient strategy for constructing drug delivery systems with precisely tunable properties, inherent imaging capabilities, and broad biomedical applications. Stimuli-responsive metal-directed drug delivery systems (MDDSs), guided by advanced imaging techniques, enable precise control over their size and spatial architecture while facilitating site-specific drug release. Moreover, certain metal ions play a dual role, not only orchestrating the self-assembly process but also serving as therapeutic agents and regulatory components for the treatment of various diseases, including cancer, microbial infections, and Alzheimer's disease. This review provides a comprehensive overview of the self-assembly mechanisms underlying diverse MDDSs and their applications in image-guided therapy. Furthermore, we critically examine existing challenges in the field and propose strategic directions to propel the advancement of metal-directed self-assembly in drug delivery. Given the profound implications of this research, further exploration of the critical roles of metal coordination in self-assembly is imperative for the development of next-generation drug delivery platforms. STATEMENT OF SIGNIFICANCE: This review systematically summarize the self-assembly mechanisms of metal-directed drug delivery systems, outlines their applications in image-guided therapy and discusses the current challenges that remain. Furthermore, it elucidates the unique regulatory roles of metal ions in precise drug release and multimodal therapy, providing valuable insights and broad appeal for the development and clinical translation of next-generation smart nanomedicine platforms.}, } @article {pmid41548934, year = {2026}, author = {Neghabi, M and Nategh, P and Stauffer, AM and Hahn, MK and Blakely, RD and Ranji, M}, title = {Elesclomol Diminishes Redox Imbalance in Peripheral Tissues of Mblac1 Knockout Mice.}, journal = {Journal of biophotonics}, volume = {19}, number = {1}, pages = {e70224}, doi = {10.1002/jbio.70224}, pmid = {41548934}, issn = {1864-0648}, support = {EY031533/NH/NIH HHS/United States ; 2154267//National Science Foundation/ ; //Florida Atlantic University I-SENSE Seed Funding to MR/ ; //Florida Department of Health award to RDB/ ; }, mesh = {Animals ; Oxidation-Reduction/drug effects ; Mice ; Female ; Male ; Mice, Knockout ; Liver/metabolism/drug effects ; Kidney/metabolism/drug effects ; Copper/metabolism ; Mitochondria/metabolism/drug effects ; *Cation Transport Proteins/deficiency/genetics/metabolism ; Copper Transporter 1 ; }, abstract = {OBJECTIVE: To determine whether loss of Mblac1, a gene implicated in copper metabolism and Alzheimer's disease, causes systemic mitochondrial redox imbalance and whether treatment with the copper chaperone elesclomol (ES) can restore this balance.

METHODS: We employed 3D cryoimaging to quantify redox ratio (RR) in kidneys and livers of Mblac1 knockout (KO) mice and their wildtype (WT) littermates. Mice of both sexes were administered either vehicle control (C) or ES (10 mg/kg, i.p.).

RESULTS: KO tissues exhibited reduced RR, indicating an oxidized metabolic state. ES treatment recovered 77% of the RR deficit in kidneys and 48% in livers, restoring RR to WT levels.

CONCLUSION: Mblac1 deletion disrupts mitochondrial redox homeostasis in peripheral tissues, while ES partially reverses this imbalance by restoring Cu(I)-dependent metabolism.

SIGNIFICANCE: Optical metabolic imaging reveals Mblac1 as a key regulator of systemic redox balance and supports ES as a potential therapy for Cu-linked metabolic dysfunctions.}, } @article {pmid41549381, year = {2026}, author = {Lee, S and Lee, J and Jeon, J and Lee, H and Choi, B and Hong, J and Lee, SJ}, title = {PLGA Nanoparticle-based Anti-TLR2 scFv Gene Delivery for the Treatment of Alzheimer's Disease.}, journal = {Experimental neurobiology}, volume = {35}, number = {2}, pages = {81-95}, pmid = {41549381}, issn = {1226-2560}, abstract = {In Alzheimer's disease (AD), persistent microglial neuroinflammation and the poor brain exposure and durability of current therapies underscore the need for new, long-acting treatments. We developed a non-viral gene therapy that suppresses microglial Toll-like receptor 2 (TLR2) signaling using poly(lactic-co-glycolic acid) (PLGA) nanoparticles (NPs) loaded with a plasmid encoding the anti-TLR2 single-chain variable fragment (scFv33). Following intra-cisterna magna delivery, PLGA NPs exhibited microglia-biased uptake and enabled brain-wide transgene expression in mice. In 5xFAD mice, a single administration of scFv33 NPs improved recognition memory in the novel object recognition (NOR) assay, outperforming 8 weeks of weekly recombinant scFv33-Fc dosing. Histology showed selective reduction of small hippocampal Aβ plaques and a shift toward a ramified microglial morphology, indicative of reduced activation. In primary neuron-microglia co-culture, scFv33 reduced microglial hypertrophy, restored process complexity, and enhanced Aβ phagocytosis. Together, these data indicate that sustained, local expression of an anti-TLR2 scFv via a clinically translatable PLGA platform recalibrates microglial state and preferentially limits early-stage plaque accumulation, yielding cognitive benefit after a single dose.}, } @article {pmid41549413, year = {2026}, author = {Burns, JM and Alford, S and Coppinger, J and Jiménez-Mausbach, M and Ray, S and Pandey, H and Laird, R}, title = {Early Alzheimer's diagnosis: U.S. primary care physicians and use of blood biomarkers.}, journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association}, volume = {22}, number = {1}, pages = {e70986}, pmid = {41549413}, issn = {1552-5279}, support = {//Novo Nordisk Inc./ ; }, mesh = {Humans ; *Alzheimer Disease/diagnosis/blood ; *Biomarkers/blood ; *Physicians, Primary Care/psychology ; United States ; Early Diagnosis ; Female ; Male ; *Attitude of Health Personnel ; }, abstract = {INTRODUCTION: We aimed to explore primary care physicians' (PCP) attitudes, perceptions, and barriers toward Alzheimer's disease (AD) diagnosis and incorporating blood biomarker (BBM) tests into the diagnostic workflow.

METHODS: Remote 60-min interviews with 20 PCPs were conducted (May 2023). Participants included generalists and geriatricians representing urban, suburban, and rural U.S. practices. Interviews encompassed early AD diagnosis, PCP role, and BBM test implementation.

RESULTS: Most PCPs view investigating cognitive decline as an important part of their role and are somewhat confident in diagnosing AD. Barriers include the complexity and inefficiency of current diagnostic workflows, lack of effective treatments, and stigma. PCPs consider BBM tests accurate and cost-effective but have concerns about reimbursement and diagnostic pathway placement.

DISCUSSION: PCPs are interested in AD diagnosis and receptive toward BBM testing. Education on BBM test use and AD diagnosis may benefit PCPs in the care of individuals with cognitive decline.

HIGHLIGHTS: Early Alzheimer's disease (AD) diagnosis is crucial for initiating treatment Primary care physicians (PCPs) find investigation of cognitive decline important PCPs consider blood biomarker (BBM) tests accurate and cost-effective PCPs seek clarity on reimbursement of BBM tests and their context of use Education on BBM test interpretation and AD diagnosis may benefit primary care.}, } @article {pmid41550171, year = {2024}, author = {Kamaljeet, and Singh, S and Gupta, GD and Aran, KR}, title = {Emerging role of antioxidants in Alzheimer's disease: Insight into physiological, pathological mechanisms and management.}, journal = {Pharmaceutical science advances}, volume = {2}, number = {}, pages = {100021}, pmid = {41550171}, issn = {2773-2169}, abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disease characterized by memory loss, cognitive decline, impairment in activities of daily living, and loss of independent function. Cognitive decline and brain shrinkage, particularly hippocampal atrophy, are associated with the accumulation of tau proteins. They cause inflammation, amyloid plaque deposition, neuronal loss, temporofrontal cortex atrophy, aberrant protein fragment clusters, and twisted fiber bundles. Given the significant role of oxidative processes in neurodegeneration, it is logical to consider the potential of antioxidants in the treatment of AD. Several antioxidants, including glutathione, astaxanthin, ascorbyl palmitate, catalase, and molecular hydrogen, play important roles in AD. Antioxidants interact with free radicals to neutralize them. Several studies have suggested that oxidative stress or damage is involved in the development of AD via different mechanisms and pathways. Thus, new approaches are needed to reduce the extent of oxidative damage that may be therapeutically effective against AD. Although certain antioxidants have exhibited notable benefits in animal models, their efficacy in human clinical trials has been limited, casting doubt regarding the efficacy of antioxidant treatments for AD. Therefore, a more focused and precise strategy that incorporates antioxidants is essential for slowing or stopping AD progression. The integrated role of antioxidants in reducing inflammation must be considered, because the link between inflammation and AD is undeniable. Therefore, the present study aimed to elucidate the role of antioxidants in AD, with the goal of aiding researchers in developing effective and potentially enhanced antioxidant-based therapeutic strategies.}, } @article {pmid41550486, year = {2026}, author = {Gao, H and Yang, S and Zhaorong, O and Wang, Y and Tang, J and Hou, Q and Fang, Z and Shao, N and Cai, B}, title = {Aloe-emodin attenuates Aβ25-35-induced HT22 cell pyroptosis via inhibiting NLRP3 inflammasome pathway.}, journal = {3 Biotech}, volume = {16}, number = {2}, pages = {71}, pmid = {41550486}, issn = {2190-572X}, abstract = {Neuronal death in Alzheimer's disease (AD) is closely associated with NLRP3 inflammasome-mediated pyroptosis. This study aimed to investigate the protective effects of Aloe-emodin (AE) in an AD cellular model and to explore the underlying mechanisms involving the NLRP3 inflammasome pathway. Molecular docking simulations predicted strong binding affinities between AE and key pyroptosis-related proteins (NLRP3, ASC, Caspase-1, GSDMD), with the highest affinity observed for NLRP3. In an Aβ25-35-induced AD cellular model, AE (6 µM) significantly enhanced cell viability and alleviated pyroptotic morphological changes, including cellular swelling and rupture. EdU staining and immunofluorescence analysis further revealed that AE promoted HT22 cell proliferation and reduced Aβ deposition. Moreover, assessments of plasma and mitochondrial membrane integrity, via Hoechst 33,342/PI staining and mitochondrial permeability transition pore (MPTP) assay, respectively, revealed that AE treatment reduced the population of PI-positive cells and suppressed MPTP opening. Western blot, immunofluorescence, and ELISA analyses consistently demonstrated that AE downregulated the expression of pyroptosis-related proteins (NLRP3, ASC, Caspase-1, GSDMD, GSDMD-N) and suppressed the release of inflammatory cytokines (IL-1β, IL-18, IL-6, TNF-α). The inhibitory effect of AE on the pyroptosis pathway was comparable to that of the specific NLRP3 inhibitor MCC950. These results suggest that AE exerts neuroprotective effects in the AD cellular model by inhibiting NLRP3 inflammasome activation, thereby blocking Caspase-1 and GSDMD-N activation, attenuating neuronal pyroptosis, reducing inflammatory responses, and mitigating Aβ-induced pathological damage. Collectively, these findings identify AE as a promising therapeutic candidate for AD.}, } @article {pmid41550591, year = {2026}, author = {Madhi, I and Kim, JH and Shin, HS and So, YH and Jung, EM and Kim, Y}, title = {Ginsenoside Re mitigates Aβ1-42-induced neurotoxicity by promoting autophagy and suppressing NLRP3 inflammasome.}, journal = {Journal of ginseng research}, volume = {50}, number = {1}, pages = {100911}, pmid = {41550591}, issn = {1226-8453}, abstract = {BACKGROUND: Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by β-amyloid (Aβ) accumulation and neuroinflammation. Activation of NOD-like receptor pyrin domain-containing 3 (NLRP3) inflammasome in microglia significantly contributes to AD-associated neuroinflammation and neuronal damage. Ginsenoside Re (G-Re), a major bioactive constituent of Panax ginseng, exhibits anti-inflammatory properties, but its role in modulating inflammasome activation in AD remains unclear.

METHODS: This study evaluated the therapeutic potential of G-Re in mice intracerebroventricularly injected with Aβ1-42 and delineated its molecular mechanisms in complementary cell-based models. We employed behavioral testing, immunohistochemistry, Western blotting, enzyme-linked immunosorbent assays, Annexin V apoptosis assays, and mitochondrial functional assays.

RESULTS: Intraperitoneal administration of G-Re significantly improved cognitive performance, as evidenced by enhanced outcomes in the T-maze and novel object recognition tests. G-Re treatment reduced microglial activation and interleukin-1β (IL-1β) levels in the cortex and hippocampus. In vitro, G-Re protected neurons from conditioned medium derived from Aβ1-42-stimulated microglia, showing neuroprotection comparable to anti-IL-1β treatment. G-Re also inhibited Aβ1-42-induced activation of the NLRP3 inflammasome, as indicated by diminished levels of NLRP3, cleaved caspase-1, cleaved gasdermin D (GSDMD), IL-1β, and IL-18 in brain tissues and cultured microglia. Mechanistically, G-Re reduced mitochondrial reactive oxygen species (mtROS), preserved mitochondrial membrane potential, and activated autophagy via SIRT1/AMPK/mTOR signaling, thereby suppressing inflammasome activation.

CONCLUSION: G-Re ameliorates Aβ1-42-induced neuroinflammation and cognitive impairment by restoring mitochondrial homeostasis, enhancing autophagy, and suppressing NLRP3 inflammasome activation. These findings suggest G-Re as a potential therapeutic intervention for neurodegenerative disorders including AD.}, } @article {pmid41550956, year = {2025}, author = {Piccolino, I and Iannuzzi, F and Lionetti, L and Mazzonello, B and Barreca, V and Banaj, N and Arezzini, V and Piras, F and Bossù, P}, title = {The immunomodulating effect of palmitoylethanolamide on human myeloid dendritic cells and its possible impact on Alzheimer's disease.}, journal = {Frontiers in immunology}, volume = {16}, number = {}, pages = {1664164}, pmid = {41550956}, issn = {1664-3224}, mesh = {Humans ; *Palmitic Acids/pharmacology ; *Ethanolamines/pharmacology ; *Dendritic Cells/drug effects/immunology/metabolism ; *Amides/pharmacology ; *Alzheimer Disease/immunology/drug therapy/metabolism ; *Immunomodulating Agents/pharmacology ; Cells, Cultured ; }, abstract = {Palmitoylethanolamide (PEA) is an endogenous fatty acid amide that has emerged as a promising therapeutic candidate for neurodegenerative disorders, particularly Alzheimer's disease (AD). Recognized for its inherent anti-inflammatory, analgesic, immunomodulatory, and neuroprotective properties, PEA possesses a good potential as a novel treatment addressing neuroinflammation associated with neurodegeneration, even though its precise mechanisms of action remain to be fully understood. Dendritic cells (DCs) are specialized migratory innate immune cells that play a crucial role in initiating and regulating immune responses and inflammation in both the body and the brain. In AD, DCs display a dysfunctional, pro-inflammatory profile, suggesting their involvement in disease pathology and progression. To explore the therapeutic potential of PEA, this study investigated its effects in vitro on human monocyte-derived DCs under both normal and AD-like conditions. The results show that PEA exerts significant immunomodulatory effects, promoting the maturation of DCs in both healthy and disease states. Notably, PEA treatment appears to correct the dysregulated state of DCs observed in AD conditions. This study reveals a novel mechanism by which PEA modulates immune activity through its action on DCs. By restoring normal DC function in neurodegenerative settings, PEA may help reduce inflammation, highlighting its potential as a therapeutic agent for Alzheimer's disease.}, } @article {pmid41550978, year = {2026}, author = {Moien, MAS and Saghravanian, SJ and Fereidoni, M}, title = {Evaluating the impact of intracerebroventricular norepinephrine on spatial memory in rats: Insights into sporadic Alzheimer's pathogenesis.}, journal = {IBRO neuroscience reports}, volume = {20}, number = {}, pages = {84-93}, pmid = {41550978}, issn = {2667-2421}, abstract = {One consequence of stress is the increased release of norepinephrine (NE) in the central nervous system, primarily driven by activation of the sympathetic nervous system. Given the importance of chronic stress in the development and progression of Alzheimer's disease (AD), clarifying the specific contributions of stress-related pathways, including the sympathetic axis and the hypothalamic-pituitary-adrenal (HPA) axis, is critical. In this study, we examined the effects of repeated central NE administration, as a potential contributor to stress-related cognitive impairment, on spatial memory in rats, alone or in combination with a low-dose streptozotocin (STZ) model of sporadic AD. Forty-nine rats were assigned to seven groups: control (no treatment), sham (saline; i.c.v.), low-dose streptozotocin (0.5 mg/kg, i.c.v.), norepinephrine administration at either 1 (adolescent) or 3 (adult) months of age (30 or 50 μg, respectively; i.c.v.), and co-administration of norepinephrine with streptozotocin at 1 or 3 months of age. Spatial memory was assessed using the Morris Water Maze test. Norepinephrine administration during adolescence and adulthood impaired spatial memory similar to streptozotocin in different parameters of the MWM, with adult rats showing the most significant vulnerability (p < 0.001). However, co-administration of both substances did not exacerbate the impairment caused by each alone. The results suggest that norepinephrine may impair cognition through mechanisms distinct from those of STZ-induced deficits. Additionally, they raise questions about the contribution of the sympathetic axis of chronic stress to the progression of sporadic AD.}, } @article {pmid41551731, year = {2025}, author = {Lim, S and Lee, HW and Yoon, S and Han, JW and Chung, JY and Yoon, S}, title = {Sex differences in efficacy/safety of anti-amyloid-beta monoclonal antibodies for the treatment of Alzheimer's disease.}, journal = {Translational and clinical pharmacology}, volume = {33}, number = {4}, pages = {212-223}, pmid = {41551731}, issn = {2289-0882}, abstract = {Alzheimer's disease (AD) is the most common cause of dementia. AD exhibits notable sex-related disparities in prevalence, progression, and treatment response. With the recent approval of anti-amyloid-beta monoclonal antibodies-aducanumab, lecanemab, and donanemab-understanding sex differences in their clinical effects has become increasingly relevant. This review article investigates sex differences in the pharmacokinetics, efficacy, and safety of aducanumab, lecanemab, and donanemab and discusses the possible mechanism underlying the observed differences. Although sex-specific analyses were largely underreported in clinical trials, population pharmacokinetic models identified sex as a covariate affecting clearance and volume of distribution for aducanumab and lecanemab and higher exposure to lecanemab was predicted for females. Subgroup analyses of phase 3 trials revealed that males tended to experience greater benefit from aducanumab and lecanemab, whereas females showed better response to donanemab. The overall incidence of adverse events, including amyloid-related imaging abnormalities, did not show significant differences between sexes. Potential mechanisms underlying these differences include sex-related variations in blood-brain barrier permeability, apolipoprotein E4-associated neuroinflammatory responses, and baseline disease characteristics. These findings underscore the need for future AD clinical trials to incorporate sex-based analyses and to consider sex as a key factor in optimizing treatment strategies.}, } @article {pmid41552781, year = {2022}, author = {Iddi, S and Donohue, MC}, title = {Power and Sample Size for Longitudinal Models in R - The longpower Package and Shiny App.}, journal = {The R journal}, volume = {14}, number = {1}, pages = {264-281}, pmid = {41552781}, issn = {2073-4859}, support = {R01 AG049750/AG/NIA NIH HHS/United States ; U01 AG024904/AG/NIA NIH HHS/United States ; }, abstract = {Longitudinal studies are ubiquitous in medical and clinical research. Sample size computations are critical to ensure that these studies are sufficiently powered to provide reliable and valid inferences. There are several methodologies for calculating sample sizes for longitudinal studies that depend on many considerations including the study design features, outcome type and distribution, and proposed analytical methods. We briefly review the literature and describe sample size formulas for continuous longitudinal data. We then apply the methods using example studies comparing treatment versus control groups in randomized trials assessing treatment effect on clinical outcomes. We also introduce a Shiny app that we developed to assist researchers with obtaining required sample sizes for longitudinal studies by allowing users to enter required pilot estimates. For Alzheimer's studies, the app can estimate required pilot parameters using data from the Alzheimer's Disease Neuroimaging Initiative (ADNI). Illustrative examples are used to demonstrate how the package and app can be used to generate sample size and power curves. The package and app are designed to help researchers easily assess the operating characteristics of study designs for Alzheimer's clinical trials and other research studies with longitudinal continuous outcomes. Data used in preparation of this article were obtained from the Alzheimer's Disease Neuroimaging Initiative (ADNI) database (adni.loni.usc.edu).}, } @article {pmid41552820, year = {2025}, author = {Fakhri, S and Gravandi, MM and Majnooni, MB and Farzaei, MH and Abbaszadeh, F and Rashidi, K and Echeverría, J}, title = {Ferula ammoniacum gum aqueous extract exerts anti-inflammatory and antioxidant mechanisms to combat aluminum chloride-induced Alzheimer's disease in rats: possible involvement of opioid pathways.}, journal = {Frontiers in pharmacology}, volume = {16}, number = {}, pages = {1708643}, pmid = {41552820}, issn = {1663-9812}, abstract = {BACKGROUND: Alzheimer's disease (AD), the most common form of dementia, significantly affects memory and behavior due to dysregulated pathways involving oxidative stress, inflammation, and opioidergic systems. Currently, no effective treatments are available, underscoring the need for novel alternatives. Ferula ammoniacum (D.Don) Spalik, M. Panahi, Piwczyński, and Puchałka [Apiaceae] (FA), an Iranian medicinal plant, is known for its anti-seizure, anti-inflammatory, and analgesic properties, with its gum utilized as a nerve tonic.

PURPOSE: This study investigates the anti-AD effects of F. ammoniacum gum aqueous extract (FAGAE) using an aluminum chloride (AlCl3)-induced Wistar rat model of AD.

MATERIALS AND METHODS: The aqueous extract, prepared by macerating powdered gum in distilled water for 48 h at ambient temperature, was subjected to phytochemical analysis using ultraviolet, infrared, and nuclear magnetic resonance spectroscopy. Thirty rats were assigned to five different groups: one receiving saline, one receiving AlCl3 (100 mg/kg, i.p.), two receiving AlCl3 followed by oral treatment with FAGAE at doses of 50 or 100 mg/kg, and one receiving naloxone (an opioid receptor antagonist) along with AlCl3 and the effective dose of FAGAE. Behavioral changes were evaluated using the open-field, passive avoidance, and elevated plus maze tests. Furthermore, biochemical analyses were conducted to measure the serum nitrite levels, changes in weight, matrix metalloproteinase (MMP) activity, and histopathological changes in brain tissue.

RESULTS AND DISCUSSION: The phytochemical analysis of FAGAE revealed the presence of polysaccharide compounds with tentative arabinogalactan structures. FAGAE decreased step-through latency in the passive avoidance test and modified AlCl3-induced weight changes. FAGAE also significantly increased mobility, grooming, and crossing in the open-field test. Naloxone reversed the anti-AD effects of FAGAE, suggesting a possible role for opioidergic pathways in its therapeutic effects. Zymography results showed that FAGAE reduced MMP-9 activity while increasing MMP-2 activity. Histopathological analysis revealed a preserved number of intact neurons in the hippocampus, whereas reduced serum nitrite levels were observed after FAGAE administration in rats with AD.

CONCLUSION: Behavioral, biochemical, and histopathological impairments induced by AlCl3 were significantly attenuated by FAGAE, possibly through the opioidergic pathway, which combats inflammation and oxidative stress and supports neuronal survival.}, } @article {pmid41553693, year = {2026}, author = {Brandt, PJ and Pototska, O and Stys, PK}, title = {Fluorescence from dual molecular rotors allows sensitive detection of widespread brain pathology in a mouse model of Alzheimer's disease.}, journal = {Photochemical & photobiological sciences : Official journal of the European Photochemistry Association and the European Society for Photobiology}, volume = {25}, number = {2}, pages = {343-354}, pmid = {41553693}, issn = {1474-9092}, mesh = {Animals ; *Alzheimer Disease/pathology ; *Brain/pathology/metabolism ; Mice ; Disease Models, Animal ; *Fluorescent Dyes/chemistry ; Spectrometry, Fluorescence ; *Gentian Violet/chemistry ; Mice, Transgenic ; }, abstract = {Amyloid fibrils formed by the misfolding and aggregation of proteins are a pathological hallmark of many neurodegenerative conditions including Alzheimer's disease (AD). Although recent studies have shown that pre-fibrillar species including low molecular-weight oligomers are more toxic in vitro than mature fibrils, and correlate better with cognitive decline in AD patients, techniques to study this subtle pathology remain limited. Here, we describe the use of the dye pair 9-(dicyanovinyl)julolidine (DCVJ) and crystal violet (CV), two fluorescent molecular rotors, to detect widespread pathology in the 5xFAD mouse model of AD via fluorescence spectroscopy. DCVJ and CV individually displayed a limited ability to detect spectral differences between WT and non-plaque areas of 5xFAD brain samples. However, when used in combination, the two probes discerned subtle but significant differences in a much higher proportion of tissue compared to either dye alone. These spectral differences were eliminated after treatment to disaggregate macromolecular protein assemblies, providing evidence that the dye pair was able to detect subtle pathology present in the parenchyma of the 5xFAD mouse brain. These findings demonstrate that the combined use of DCVJ and CV could be a valuable addition to the tools currently available to study the early stages of protein misfolding, which is essential for advancing therapeutics and diagnostic technologies in many neurodegenerative diseases.}, } @article {pmid41554303, year = {2026}, author = {Çelik, H and Çelik, O and Aydın, Ş and Küçükler, S and Çomaklı, S and Topal, A and Akay, R and Gönüllü, S and Yıldız, MO and Alım, B and Özdemir, S}, title = {Small extracellular vesicles carrying miRNA34 in Alzheimer's disease: effects on oxidative stress, neuroinflammation, cognitive function, and mitochondrial/ferroptosis-related protein regulation.}, journal = {Gene}, volume = {985}, number = {}, pages = {150014}, doi = {10.1016/j.gene.2026.150014}, pmid = {41554303}, issn = {1879-0038}, mesh = {Animals ; *MicroRNAs/genetics/metabolism ; *Alzheimer Disease/genetics/metabolism/therapy ; *Oxidative Stress ; *Extracellular Vesicles/metabolism/genetics ; Mice ; Mitochondria/metabolism ; *Neuroinflammatory Diseases/genetics/metabolism ; Cognition ; Disease Models, Animal ; Male ; }, abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by cognitive decline, oxidative stress, and persistent neuroinflammation. Recent studies have increasingly focused on the regulatory role of microRNAs in AD pathogenesis. In this study, we investigated the therapeutic potential of small extracellular vesicles (sEV) enriched with microRNA34 (miRNA34) to target key pathogenic mechanisms of AD. We hypothesized that miRNA34-loaded sEV could alleviate oxidative damage, inhibit neuroinflammatory responses and ferroptosis, reduce mitochondrial impairment, and ultimately improve cognitive function. We evaluated the effects of miRNA34 administration on oxidative stress markers, pro-inflammatory cytokines, synaptic plasticity indicators, and behavioral outcomes in an in vivo Aβ-induced mouse model of AD. The experimental design included five groups, each consisting of seven mice. The findings demonstrated that miRNA34-loaded sEV treatment significantly reduced oxidative stress and neuroinflammation while enhancing memory and learning performance. Overall, our results indicate that miRNA34-enriched sEV represent a promising and minimally invasive therapeutic strategy capable of modulating AD pathogenesis. This research provides a novel perspective on the potential clinical application of miRNA34 and sEVin neurodegenerative disorders.}, } @article {pmid41555522, year = {2026}, author = {Lahiri, D and Cooper, J and Seixas-Lima, B and Roncero, C and Wellington, C and Cherktow, H}, title = {CAPS Plus: A Clinical Biomarker Scoring System to Predict Aβ Positivity and Facilitate Enrollment in Anti-Amyloid Clinical Trials.}, journal = {The Canadian journal of neurological sciences. Le journal canadien des sciences neurologiques}, volume = {}, number = {}, pages = {1-8}, doi = {10.1017/cjn.2026.10530}, pmid = {41555522}, issn = {0317-1671}, abstract = {BACKGROUND: A critical step toward determining eligibility for experimental and clinical treatment with anti-amyloid therapies in Alzheimer's disease (AD) is to select appropriate subjects having a high likelihood of being Aβ+. We propose a clinical biomarker composite score, named Clinical β-Amyloid Positivity Prediction Score Plus (CAPS Plus), for Aβ+ prediction in people presenting with clinical Alzheimer's syndrome including both prodromal and mild AD.

METHODS: The original CAPS incorporated scores from the neuropsychiatry inventory questionnaire, mini-mental state examination score loss per year and Fazekas score. Plasma p-tau-217, a novel addition to CAPS, was measured using the Simoa HD-X with the AlzPATH p-tau217 Advantage Plus assay. To incorporate p-tau-217 into CAPS Plus, an intra-cohort cut-off (>0.698 pg/ml) for p-tau217 was generated using logistic regression and Yoden's index. CAPS Plus had a maximum score of 5, with those ≥4 indicating a high probability of being Aβ+. The accuracy of CAPS Plus was computed through logistic regression and area under the receiver operating characteristic curve (AUROC) analysis.

RESULTS: Of n = 44 patients, n = 25 (57%) were Aβ+. Plasma p-tau-217 was significantly higher in the Aβ+ subgroup (1.36 vs 0.46 pg/mL, p < 0.0001). The AUROC was 0.89 for a CAPS Plus score of 4 or more, suggesting excellent discrimination and improving the accuracy of the original CAPS (0.86). CAPS Plus has a notably better specificity (89%) than the original CAPS (80%) and p-tau-217 alone (74%).

CONCLUSION: CAPS Plus is potentially a useful screening tool for enrollment in anti-Aβ therapy and clinical trials for AD, specifically addressing people with prodromal and mild AD.}, } @article {pmid41555820, year = {2026}, author = {Smith, PJ and Blumenthal, JA and Ingle, K and Watkins, LL and Avorgbedor, F and Mabe, SK and Kraus, W and Tyson, C and Hinderliter, A and Sherwood, A}, title = {Lifestyle, sleep quality, and cognitive function in resistant hypertension: One-year follow-up from the TRIUMPH trial.}, journal = {Journal of Alzheimer's disease : JAD}, volume = {109}, number = {4}, pages = {1748-1763}, pmid = {41555820}, issn = {1875-8908}, support = {R01 HL122836/HL/NHLBI NIH HHS/United States ; R01 HL130237/HL/NHLBI NIH HHS/United States ; R61 AG080615/AG/NIA NIH HHS/United States ; }, mesh = {Humans ; *Hypertension/psychology/physiopathology/therapy ; Female ; *Sleep Quality ; *Cognition/physiology ; Follow-Up Studies ; Male ; Middle Aged ; *Life Style ; Aged ; Neuropsychological Tests ; Exercise ; }, abstract = {BackgroundTreatment resistant hypertension (TRH) is associated with increased risk of cognitive decline, which may be reduced by healthy lifestyle changes.ObjectiveTo examine the effects of a comprehensive, rehabilitation-based lifestyle hprogram on cognitive function during a one-year follow-up of participants from the TRIUMPH clinical trial.MethodsAmong the 140 TRIUMPH participants originally randomized, 91 (65%) were available for one-year assessments prior to the COVID-19 lockdown. Participants were originally randomized to a Cardiac rehabilitation-based LIFEstyle program (C-LIFE) or to a Standardized Education and Physician Advice (SEPA) condition for 4-months. During their one-year follow-up, participants underwent assessments of sleep quality, body mass index, actigraphy-assessed physical activity levels, and cerebrovascular reactivity using functional near infrared spectroscopy (fNIRS). Cognitive function was assessed using a 45-min test battery incorporating tests of Executive Function/Learning, Memory, and Processing Speed. Regression-based models incorporating reliable change indices were used to assess cognitive change.ResultsParticipants included 91 individuals (mean age = 63.6 [SD = 8.6]), evenly distributed in biological sex and race/ethnicity, and tended to be college-educated. The C-LIFE group had more preserved cognitive functioning compared to SEPA (C-LIFE: z = -0.26 [-0.40, -0.12] versus SEPA: -0.60 [-0.81, -0.39]; d = 0.44, p = 0.008), with reduced PSQI sleep symptoms associating with more preserved cognitive function (B = -0.18, p = 0.050 per 3-points). Treatment did not improve fNIRS markers, although changes in weight and physical activity associated with fNIRS outcomes.ConclusionsLifestyle modification may help preserve cognitive functioning among individuals with resistant hypertension.}, } @article {pmid41555825, year = {2026}, author = {Wang, EJ and Oğuztüzün, Ç and Xu, R and Gao, Z}, title = {Comparative evaluation of large language models in retrieving known and predicting novel drug combinations.}, journal = {Journal of Alzheimer's disease : JAD}, volume = {110}, number = {2}, pages = {619-627}, doi = {10.1177/13872877261415635}, pmid = {41555825}, issn = {1875-8908}, mesh = {*Large Language Models ; Humans ; *Alzheimer Disease/drug therapy ; Drug Combinations ; *Data Mining/methods ; }, abstract = {BackgroundLarge language models (LLMs) are increasingly used in the biomedical field for information retrieval, information extraction and knowledge discovery. However, their potential in retrieving and discovering drug combinations for diseases remains underexplored.ObjectiveThis study aims to evaluate the effectiveness of LLMs in retrieving known drug combinations and to identify novel drug combinations for treating Alzheimer's disease (AD).MethodsWe developed a series of prompts to guide LLMs in retrieving drug combinations. Their performance was evaluated using both FDA-approved combinations and combinations identified through PubMed literature mining. We then assessed the feasibility of identifying novel drug combination candidates for AD. In collaboration with domain experts, we performed pathway enrichment analyses to evaluate their potential mechanisms of action within the context of AD.ResultsIn a comparative evaluation of multiple LLMs, GPT-5 demonstrated the strongest overall performance, achieving an accuracy of 0.95 and a balanced F1 score of 0.95 in identifying FDA-approved drug combinations. Among the top 10 drug-combination candidates for AD treatment suggested by GPT-5, the combination of donepezil and memantine is already FDA-approved. Three other combinations have been tested in AD clinical trials, and three have supporting evidence in the literature. We also identified 10 off-label drug combinations, with pathway enrichment analyses indicating that several target key AD-related biological pathways.ConclusionsLLMs is effective in retrieving drug combinations for a given disease and the performance varies among different language models with best performance for GPT-5. However, the suggestions from LLM models require further validation to be considered reliable.}, } @article {pmid41555828, year = {2026}, author = {Merten, N and Dawes, P and Munro, KJ and Brenowitz, WD}, title = {Hearing impairment and cognitive decline: Alternative explanations to causality.}, journal = {Journal of Alzheimer's disease : JAD}, volume = {110}, number = {1_suppl}, pages = {S25-S29}, pmid = {41555828}, issn = {1875-8908}, support = {R21 AG089427/AG/NIA NIH HHS/United States ; R01 AG079289/AG/NIA NIH HHS/United States ; RF1 AG066837/AG/NIA NIH HHS/United States ; K01 AG062722/AG/NIA NIH HHS/United States ; P01 AG082653/AG/NIA NIH HHS/United States ; }, mesh = {Humans ; *Hearing Loss/epidemiology/complications ; *Cognitive Dysfunction/epidemiology ; Causality ; *Cognition Disorders/epidemiology ; }, abstract = {Despite growing interest in hearing impairment as a potentially modifiable risk factor for dementia, the association is poorly understood. This has implications for whether treating hearing impairment can prevent or delay onset of dementia, as causation is not the only explanation for the association. In this editorial, we highlight how biases in research studies might account for the reported associations. We suggest future research using different study designs and novel biomarkers to help us overcome methodological limitations. This may allow us to determine the strength of the causal pathways linking hearing impairment to dementia, ultimately informing prevention and treatment strategies.}, } @article {pmid41557600, year = {2026}, author = {Fisher, DW and Borisovskaya, A and Lindley, E and Domoto-Reilly, K}, title = {Somatic Symptom Disorder as a Prodrome of Alzheimer Disease and Successful Treatment of Pain and Agitation With Electroconvulsive Therapy: A Case Report.}, journal = {The journal of ECT}, volume = {}, number = {}, pages = {}, pmid = {41557600}, issn = {1533-4112}, support = {P30 AG066509/AG/NIA NIH HHS/United States ; T32 AG052354/AG/NIA NIH HHS/United States ; T32AG052354//National Institute of Aging/ ; }, abstract = {Neuropsychiatric symptoms in dementia can be heterogeneous and hard to treat, though electroconvulsive therapy (ECT) is becoming more widely accepted as a viable treatment option. Here, we describe a patient with Alzheimer disease (AD) who developed Somatic Symptom Disorder as a prodrome to cognitive and functional decline, though atypical, primary affective disorder in AD was also on the differential. This patient further developed debilitating anxiety and agitation that was refractory to multiple behavioral and pharmacological interventions. ECT was able to treat the patient's neuropsychiatric symptoms, resulting in sustained, full remission with minimal transient, cognitive side effects. This case depicts a rare presentation of AD and further adds to the growing body of literature that suggests ECT is safe and effective for treating neuropsychiatric symptoms in dementia.}, } @article {pmid41558720, year = {2026}, author = {Zhou, R and Li, J and Liu, W and Zheng, R and Han, J and Liao, Z and Ning, W and Tang, C}, title = {[Systematic review and mechanistic exploration of "intelligence three-needling" in treatment of Alzheimer's disease].}, journal = {Zhongguo zhen jiu = Chinese acupuncture & moxibustion}, volume = {46}, number = {1}, pages = {153-160}, doi = {10.13703/j.0255-2930.20250723-k0001}, pmid = {41558720}, issn = {0255-2930}, mesh = {*Alzheimer Disease/therapy/metabolism/genetics ; Humans ; *Acupuncture Therapy/methods ; Animals ; Acupuncture Points ; Mice ; }, abstract = {The "intelligence three-needling" therapy, developed by Professor JIN Rui, the eminent acupuncture- moxibustion master in the south of Five Ridges, is effective on cognitive dysfunction in practice. The paper reviews the animal experiment researches of Alzheimer's disease (AD) treated with this therapy, aiming to explain its core mechanism and effect characteristics for AD. The results showed that the "intelligence three-needling" therapy exerts its effect through multiple targets and diverse pathways. It improves cholinergic system function, enhances glucose metabolism in brain regions, reduces oxidative stress damage, suppresses neuroinflammation, regulates the Wnt/β-catenin signaling pathway, promotes autophagy-lysosomal clearance of pathological proteins, activates the transmembrane receptor protein (Notch) pathway to strengthen synaptic plasticity, demonstrates neuroprotective and anti-apoptotic effects, and modulates gut microbiota. In experiments, this therapy demonstrated specific effect in brain regions of 5xFAD mouse models. Compared with the single application at "Benshen" (GB13) or "Shenting" (GV24), the acupoint combination in this therapy displayed the synergistic advantages, regulating more comprehensively adenosine monophosphate activated protein kinase (AMPK)/protein kinase B (Akt)/mammalian target of rapamycin (mTOR) kinase network. This review provides the theoretical basis for optimizing the protocol of acupuncture and moxibustion for AD, and is conducive to promoting the deep integration of traditional acupuncture-moxibustion therapy with modern neuroscience.}, } @article {pmid41559471, year = {2026}, author = {Liu, T and Chen, D and Liu, F and Sun, Y}, title = {ZFP36-mediated ZBP1 degradation inhibits microglia pro-inflammatory and NLRP3 inflammasome activation in Alzheimer's disease.}, journal = {Cell biology and toxicology}, volume = {42}, number = {1}, pages = {25}, pmid = {41559471}, issn = {1573-6822}, mesh = {Animals ; *NLR Family, Pyrin Domain-Containing 3 Protein/metabolism ; *Alzheimer Disease/metabolism/pathology/genetics ; *Microglia/metabolism/pathology ; *Inflammasomes/metabolism ; Amyloid beta-Peptides/metabolism ; *RNA-Binding Proteins/metabolism/genetics ; Hippocampus/metabolism/pathology ; Mice ; Mice, Transgenic ; *DNA-Binding Proteins/metabolism ; *Tristetraprolin/metabolism ; Male ; Peptide Fragments ; Mice, Inbred C57BL ; Proteolysis ; }, abstract = {Alzheimer's disease (AD) is a heterogeneous disease with limited treatment efficacy. Identifying novel molecular targets and mechanisms is therefore crucial for developing therapeutic strategies. Zinc finger protein 36 (ZFP36) has not been reported in AD. This study found that the hippocampus of APP/PS1 mice showed ZFP36 upregulation. Using recombinant adeno-associated virus to overexpress ZFP36 improved the cognitive function of APP/PS1 mice, as assessed by Morris maze and Y maze tests. Furthermore, ZFP36 overexpression reduced Aβ deposition, expression of pro-inflammatory markers, and inhibited NLRP3 inflammasome activation in the hippocampus. These inhibitory effects of ZFP36 overexpression on the aforementioned proteins were also observed in Aβ1-42-treated BV-2 cells. mRNA sequencing identified Z-DNA Binding Protein 1 (ZBP1) as a target of ZFP36. After ZFP36 overexpression, ZBP1 was downregulated in the hippocampus and Aβ1-42-treated BV-2 cells. The interaction between ZFP36 and ZBP1 RNA was verified by RIP-PCR, and ZFP36 was shown to promote the degradation of ZBP1 mRNA. The inhibitory effects of ZFP36 on the NLRP3 inflammasome activation and microglial pro-inflammatory activation was reversed by ZBP1 overexpression. In summary, ZFP36 inhibits microglia pro-inflammatory and NLRP3 inflammasome activation through promoting the degradation of ZBP1 mRNA, thereby ameliorating cognitive deficits of APP/PS1 mice.}, } @article {pmid41560693, year = {2026}, author = {Custodio, B and Montesinos, R and Bayona, W and Rojas Benites, MJ and Camargo, I and Ibañez, M and Huilca, J and Noriega de la Colina, A and Matias-Guiu, JA and Custodio, N}, title = {Perceptions of Peruvian neurologists toward the implementation of anti-amyloid drugs for early Alzheimer's disease in the departments of neurology.}, journal = {Journal of Alzheimer's disease : JAD}, volume = {109}, number = {4}, pages = {1790-1798}, doi = {10.1177/13872877251410959}, pmid = {41560693}, issn = {1875-8908}, mesh = {Humans ; *Alzheimer Disease/drug therapy/diagnosis ; *Neurologists/psychology ; Peru ; Cross-Sectional Studies ; *Attitude of Health Personnel ; Female ; *Antibodies, Monoclonal/therapeutic use ; Male ; Neurology ; Surveys and Questionnaires ; }, abstract = {BackgroundAlzheimer's disease (AD) is a neurodegenerative disease affecting millions globally, with particular severity in low- and middle-income countries due to barriers in timely diagnosis and treatment. To date, two monoclonal anti-amyloids have shown positive results in phase III clinical trials. However, their administration is complex, requiring specialized infrastructure, highly trained professionals, and regular follow-ups, posing major challenges for healthcare systems.ObjectiveThis study explores Peruvian neurologists' perceptions of changes needed to implement monoclonal antibodies in line with clinical guidelines.MethodsA cross-sectional study was conducted in Peru using the key informant (KI) methodology. KI were neurologists from multiple regions across the country. A comprehensive list of tertiary-level hospitals (public healthcare system, social security, and police and armed forces) was compiled, and at least one neurologist from each institution was contacted. The instrument used was adapted from a study conducted in Spain, which included questions focusing on changes in diagnosis, patient care, diagnostic and therapeutic techniques, public and family impact, neurology resources, and dementia research. Data analysis was employed using Stata18, using descriptive statistics and frequency distributions.ResultsTwenty-eight neurologists completed the survey. There was consensus on the significant impact monoclonal antibodies would have on neurology services. Over 85% agreed that more neurologists and nurses would be needed. Additionally, 93% supported using brief diagnostic scales in primary care and increasing follow-up visit frequency.ConclusionsThe introduction of monoclonal antibodies for AD in Peru requires modifications to healthcare institutions, highlighting the urgent need for strategic healthcare planning.}, } @article {pmid41560694, year = {2026}, author = {Wan, Z and Feng, X and Chou, J and Zhou, X and Ma, T and Zhang, T}, title = {Sex- and brain region-specific gene expression in Alzheimer's disease.}, journal = {Journal of Alzheimer's disease : JAD}, volume = {110}, number = {1}, pages = {212-226}, doi = {10.1177/13872877251413797}, pmid = {41560694}, issn = {1875-8908}, support = {R01 AG073823/AG/NIA NIH HHS/United States ; RF1 AG082388/AG/NIA NIH HHS/United States ; }, mesh = {Humans ; *Alzheimer Disease/genetics/metabolism/pathology ; Female ; Male ; *Brain/metabolism/pathology ; *Sex Characteristics ; *Gene Expression ; Gene Expression Profiling ; Gene Expression Regulation ; }, abstract = {BackgroundWomen with Alzheimer's disease (AD) have higher prevalence and more severe dementia syndrome than men with AD, and the brain regions are also affected differently. However, the underlying mechanisms are poorly understood.ObjectiveTo characterize the sex-dependent and region-specific gene expression in AD brain.MethodsA previously published large scale bulk tissue gene expression dataset from postmortem brain samples across 19 cortical regions of normal control and individuals diagnosed with dementia and neuropathology of AD was used for differential gene expression analysis. Functional enrichment analysis was used to identify enriched biological functions or pathways related to selected genes. Protein expression level of a selected gene was validated by western blot.ResultsWe identified 113 dysregulated genes in 11 AD brain regions (9 in men, 7 in women, and 5 shared between men and women). Notably, more dysregulated genes were found in women AD brain (77 genes) than in men (49 genes), and 13 dysregulated genes across these 11 brain regions were shared between women and men. Functional analysis further revealed the distinctive enrichment in categories of cellular component, biological process, and/or molecular function in these dysregulated genes. GPR34 gene expression was upregulated in the men AD brain across three different regions and a significant elevation of GPR34 protein level was confirmed in men AD brain.ConclusionsThese findings provide insight into sex- and brain region-specific gene expression dysregulation, which may indicate novel mechanisms underlying AD pathogenesis and will facilitate the development of personalized diagnosis and treatment strategies for AD.}, } @article {pmid41560713, year = {2026}, author = {Barnwal, M and Baksh, S and Ismail, Z and Shade, DM and Moghekar, A and Ho, SG and Rosenberg, PB and Porsteinsson, AP and Lyketsos, CG and , }, title = {Blood biomarkers for Alzheimer's disease are correlated with measures of agitation and cognition in a randomized trial assessing the effects of escitalopram on agitation.}, journal = {Alzheimer's & dementia (New York, N. Y.)}, volume = {12}, number = {1}, pages = {e70203}, pmid = {41560713}, issn = {2352-8737}, abstract = {INTRODUCTION: Escitalopram for Agitation in Alzheimer's Disease (S-CitAD) is a National Institutes of Health-funded randomized controlled trial that randomized 173 participants with clinically diagnosed Alzheimer's disease (AD) and agitation to escitalopram or placebo for 12 weeks, assessing efficacy and safety. There was no advantage for escitalopram in treating agitation, potentially attributed to including participants at various stages of AD brain pathology, reflected in levels of blood biomarkers. Here, we (1) estimated the fraction of participants meeting blood biomarker criteria for AD pathology, (2) examined associations between baseline blood biomarkers and agitation severity or cognitive functioning, and (3) evaluated whether baseline blood biomarkers predicted treatment response.

METHODS: Eighty-two randomized participants provided blood for biomarker measurement prior to randomization. Plasma amyloid beta (Aβ)42, Aβ40, glial fibrillary acidic protein (GFAP), neurofilament light chain (NfL), and phosphorylated tau (p-tau)217 were measured using standard methods. We examined associations of baseline blood biomarkers and clinical measures at baseline and follow-up with (1) agitation severity (Neuropsychiatric Inventory Clinical Rating of the agitation and aggression domains [NPI-C-A+A]), (2) cognitive status (Mini-Mental State Examination [MMSE]), and (3) escitalopram treatment.

RESULTS: Seventy-seven out of 82 (94%) scored above threshold for p-tau217, supporting the clinical diagnosis of AD. Baseline higher p-tau217 predicted higher NPI-C-A+A scores at weeks 6 (beta = 3.26, p < 0.001) and 12 (beta = 2.86, p = 0.01) after randomization. Baseline higher levels of GFAP (beta = -0.02, p = 0.0002) and p-tau217 (beta = -2.68, p = 0.003) were associated with lower baseline MMSE scores. After adjusting for treatment, higher baseline p-tau217 was associated with greater odds of worsening NPI-C-A+A scores at weeks 6 (odds ratio [OR] = 2.79, p = 0.02) and 12 (OR = 2.55, p = 0.02).

DISCUSSION: In this clinical trial cohort, elevated plasma p-tau217 confirmed AD pathology in 94% of participants and forecast greater agitation severity and worse cognitive functioning, underscoring its practical value for stratifying and monitoring patients in neuropsychiatric intervention studies.

HIGHLIGHTS: We examined whether Alzheimer's disease (AD) blood biomarkers predicted severity of agitation and cognitive impairment and/or treatment response in the 12-week Escitalopram for Agitation in Alzheimer's Disease (S-CitAD) randomized controlled trial.Blood phosphorylated tau (p-tau)217 confirmed the presence of significant AD brain amyloid pathology in 94% of these clinically diagnosed participants.Independent of treatment assignment, higher baseline p-tau217 predicted lower baseline and future Mini-Mental State Examination (MMSE) scores and worse agitation overtime.Independent of treatment assignment, higher baseline levels of glial fibrillary acidic protein were associated with lower baseline and follow-up MMSE scores.}, } @article {pmid41560836, year = {2026}, author = {Zhang, Y and Yin, C and Tian, Y and Li, X and Wang, H and Han, S and Chen, H and Hou, H}, title = {Intranasal delivery of Odorranalectin-modified lipid nanoparticles for multi-targeted therapy of Alzheimer's disease.}, journal = {Materials today. Bio}, volume = {36}, number = {}, pages = {102764}, pmid = {41560836}, issn = {2590-0064}, abstract = {Oxidative stress, neuroinflammation, and β-amyloid (Aβ) deposition act synergistically to drive Alzheimer's disease (AD) progression. Effective treatment, therefore, requires multi-targeted strategies capable of addressing these interconnected pathological mechanisms. Here, an Odorranalectin (OL)-conjugated lipid nanoparticle (siB/QU@L-OL) was engineered for efficient intranasal delivery of β-site APP cleaving enzyme 1 (BACE1) siRNA (siB) and quercetin (QU). siB/QU@L-OL prepared via microfluidics exhibited uniform size distribution, high encapsulation efficiency, and robust stability. Following intranasal administration, OL surface modification enabled binding to L-fucose residues expressed on the olfactory epithelium, reducing mucociliary clearance and facilitating brain transport. In vitro, siB silenced BACE1 expression and inhibited Aβ generation, while QU alleviated Aβ-induced oxidative stress and neuroinflammation, thereby suppressing neuronal apoptosis. In APP/PS1 mice, siB/QU@L-OL restored Aβ homeostasis and redox balance, attenuated neuroinflammation and neuronal loss, and consequently improved cognitive performance. Collectively, this brain-targeted nanoplatform demonstrates strong potential for synergistic intervention in AD.}, } @article {pmid41561733, year = {2026}, author = {Curd, BC and Zubrick, C and Brown, CJC and Sorweid, MK and Dehoney, SB and Anzai, Y and Minoshima, S and Parks, AL and Frost, NA}, title = {Real-world experience with lecanemab therapy for Alzheimer's disease in the Intermountain West.}, journal = {Alzheimer's & dementia (Amsterdam, Netherlands)}, volume = {18}, number = {1}, pages = {e70251}, pmid = {41561733}, issn = {2352-8729}, abstract = {INTRODUCTION: Lecanemab is a monoclonal antibody targeting amyloid plaques that has been approved for the treatment of early symptomatic Alzheimer's disease. Here, we report on the clinical history and outcomes of the first 70 patients at the University of Utah to receive amyloid-removal therapy.

METHODS: This is a retrospective analysis of patients treated with lecanemab over a 26-month period. We extracted patient data from charts and analyzed demographics, health history, and clinical details with outcomes on lecanemab treatment.

RESULTS: In total, we observed 14 cases (20%) of amyloid-related imaging abnormalities (ARIAs), which was significantly associated with apolipoprotein E ε4 homozygosity. Zero cases of ARIAs were symptomatic, and there was no association between distance from clinic and adverse effects.

DISCUSSION: Our study examined the safety and tolerability of centrally managed lecanemab administration across a widely distributed region and suggests that use of distributed infusion sites increases access to disease-modifying treatment without significant increase in risk.

HIGHLIGHTS: Lecanemab therapy can be safely administered to patients across a broadly distributed area through a single clinical center.In our first 70 treated patients, 14 developed amyloid-related imaging abnormalities (ARIAs)-a rate of 20%, which is consistent with clinical trials of lecanemab.No patients experienced symptomatic ARIAs.ARIA incidence was significantly associated with apolipoprotein E genotype, but not other demographic factors, comorbid conditions, or baseline clinical details.}, } @article {pmid41562838, year = {2026}, author = {Wozniczka, CM and Weaver, DF}, title = {β-Alanine Is an Unexploited Neurotransmitter in the Pathogenesis and Treatment of Alzheimer's Disease.}, journal = {NeuroSci}, volume = {7}, number = {1}, pages = {}, pmid = {41562838}, issn = {2673-4087}, support = {KF-2023-1//Krembli Foundation/ ; ASC-2024//Alzheimer's Society Canada/ ; }, abstract = {Alzheimer's disease (AD) remains an unmet medical challenge, as there are no effective therapies that alter the disease's progression. While approaches have targeted molecules like acetylcholine (ACh) and glutamate, these strategies have provided only limited benefits and do not address the complex molecular mechanisms underlying AD development. This review suggests that β-alanine (3-aminopropanoic acid) is an underexplored neurotransmitter that could serve as a potential AD drug target. Existing evidence indicates that β-alanine modulates GABAergic and glutamatergic neurotransmission, thereby affecting neuronal hyperexcitability. Additionally, studies suggest that β-alanine has antioxidant effects, reducing oxidative stress caused by reactive oxygen species (ROS). We propose that β-alanine might bind to Aβ/tau proteins, possibly targeting the six-amino acid sequences EVHHQK/DDKKAK, which are involved in protein aggregation. β-Alanine may also influence the release of pro-inflammatory cytokines from microglia, potentially reducing neuroinflammation. We also hypothesize that β-alanine may help regulate metal dyshomeostasis, which leads to ROS production. Taurine, structurally like β-alanine, appears to influence comparable mechanisms. Although structural similarity doesn't ensure therapeutic effectiveness, this evidence supports considering β-alanine as a treatment for AD. Furthermore, β-alanine and its analogues face challenges, including crossing the blood-brain barrier (BBB) and optimizing structure-activity relationships (SAR). This review includes articles through September 2025, sourced from four databases.}, } @article {pmid41562905, year = {2025}, author = {Fedotcheva, TA and Shimanovsky, NL}, title = {Current State of the Neurotrophin-Based Pharmaceutics in the Treatment of Neurodegenerative Diseases and Neuroinflammation.}, journal = {Medical sciences (Basel, Switzerland)}, volume = {14}, number = {1}, pages = {}, pmid = {41562905}, issn = {2076-3271}, support = {124020900031-0//Ministry of Health of the Russian Federation/ ; }, mesh = {Humans ; *Nerve Growth Factors/therapeutic use ; *Neurodegenerative Diseases/drug therapy ; *Neuroinflammatory Diseases/drug therapy ; Animals ; }, abstract = {BACKGROUND: The regulation of the synthesis of the nerve growth factor and other neurotrophins is one of the dynamically developing areas of pharmacotherapy of neurological and mental disorders. Despite a large number of studies of various ligands of neurotrophin receptors, only a few have reached clinical application and only for ocular diseases. The aim of this narrative review was to systematize the main progress on neurotrophin-based pharmaceutics; to perform a comparative critical analysis of various therapeutic strategies, elucidate the underlying causes of clinical trial failures, and identify the most promising avenues for future development.

METHODS: The literature search was conducted in PubMed, Google Scholar, Medline, and EBSCO, and the ClinicalTrials.gov database was used to track current clinical studies, along with the official websites of pharmaceutical companies. The search covered original studies published up to October 2025, with inclusion restricted to articles published in English. Articles describing specific pharmacological compounds that had reached the clinical trial stage were selected. Foundational biological research was referenced to contextually explain the mechanisms of action of the drugs and their therapeutic implications.

RESULTS: Recombinant neurotrophins and synthetic molecules, the agonists and antagonists of their receptors, and cell-based gene therapy are promising means for the prevention and rehabilitation of ischemic conditions, as well as the treatment of neuropathic pain and neurodegenerative disorders such as Alzheimer's disease and Parkinson's disease. Some of these have undergone clinical trials, yet only neurotrophins for ocular diseases have been implemented in clinical practice: recombinant NGF-cenegermin and recombinant CNTF-Revakinagene taroretcel. The success of these eye drugs is likely attributable to their local administration, improved bioavailability, and low ocular immunoresistance.

CONCLUSIONS: The study identified limitations and future prospects for neurotrophin-based pharmaceuticals. For future clinical trials, attention should be paid to the pharmacogenetic profiles of the patients and the evaluation of the inflammatory status of the disease. Novel plasma biomarkers of the effectiveness are needed as well as TSPO-PET imaging. Drug delivery systems remain insufficient; therefore, efforts should focus on inducing endogenous neurotrophin production and developing highly selective agonists and antagonists of neurotrophin receptors. It is crucial to establish a favorable premorbid background before neurotrophin therapy to minimize immunoresistance.}, } @article {pmid41563466, year = {2026}, author = {Ueffing, M and Lange, C and Schlunck, G and Wolf, J}, title = {[Liquid biopsy proteomics in ophthalmology : A clinical and scientific perspective].}, journal = {Die Ophthalmologie}, volume = {123}, number = {3}, pages = {169-177}, pmid = {41563466}, issn = {2731-7218}, mesh = {Humans ; *Proteomics/methods ; *Aqueous Humor/chemistry/metabolism ; Liquid Biopsy/methods ; *Eye Diseases/diagnosis/pathology/therapy ; *Ophthalmology/trends/methods ; Precision Medicine ; }, abstract = {BACKGROUND: For many patients with age-related macular degeneration, diabetic retinopathy and other partially monogenetic retinal diseases as well as for tumors of the eye that are relatively rare but are usually associated with profound consequences for affected patients, there is still no effective treatment available. Metastatic melanoma, for example, remains poorly predictable with respect to disease progression, response to treatment and outcome. This illustrates the urgent need for a deeper molecular understanding of the disease with the goal to develop novel therapeutic strategies. Liquid biopsies of the aqueous humor represent a promising possibility for molecular analyses in the eyes of patients.

OBJECTIVE: A clinical and scientific perspective with respect to potential fields of applications of liquid biopsy proteomics in ophthalmology is presented.

MATERIAL AND METHODS: A systematic literature search was carried out in PubMed and the personal experiences of the authors are presented.

RESULTS AND CONCLUSION: Aqueous humor proteomics offer a plethora of potential applications in ophthalmology and could become a key factor in personalized ophthalmology. Potential areas of application include the selection of treatment based on the activated biological signalling pathways, the selection of patients for clinical trials as well as the diagnostics, prognosis estimation and monitoring of the response to treatment. In addition, it can be a valuable component of multimodal diagnostics and enable insights into neurodegenerative diseases, such as Alzheimer's or Parkinson's disease.}, } @article {pmid41563682, year = {2026}, author = {Paul, R and Firdous, SM}, title = {Unraveling the molecular mechanisms of aluminium chloride-induced Alzheimer's disease.}, journal = {Biometals : an international journal on the role of metal ions in biology, biochemistry, and medicine}, volume = {39}, number = {2}, pages = {539-564}, pmid = {41563682}, issn = {1572-8773}, mesh = {*Aluminum Chloride ; *Alzheimer Disease/chemically induced/metabolism/pathology ; Humans ; Animals ; Amyloid beta-Peptides/metabolism ; Oxidative Stress/drug effects ; }, abstract = {The most prevalent neurodegenerative illness is Alzheimer's disease (AD). Aluminium chloride (AlCl3) is a heavy metals that produces several neurodegenerative diseases, commonly AD. AlCl3 easily goes through the blood-brain barrier and reaches to brain. In this study, we reviewed literature, highlighting the various molecular mechanisms targeting AlCl3-induced neurodegenerative disorders like AD in numerous in vivo and in vitro models. AlCl3 can cause conformational changes in the beta-sheet of amyloid beta (Aβ) peptide that lead to the aggregation of Aβ in the brain's neuronal cells. AlCl3 can also decrease the expression of protein phosphatase 2A (PP2A), which is essential for evading tau aggregation and neurofibrillary tangles (NFTs) formation. It can increase acetylcholinesterase (AChE) levels in the brain, which can produce cognitive impairment. AlCl3 also produces calcium (Ca[2+]) and iron dyshomeostasis in neuronal cells. It activates various inflammatory mediators such as interleukin-6 (IL-6), interleukin-1β (IL-1β), plasminogen activator inhibitor-1 (PAI-1), and tumour necrosis factor-α (TNF-α). In addition, AlCl3 can increase the production of reactive oxygen species (ROS), which induce telomere degradation, may initiate telomere dysfunction that can initiate neuroinflammation, and induce cellular senescence. AlCl3 may increase the expression of glycogen synthase kinase-3 beta (GSK3β), which produces various cognitive impairments, leading to AD. Various therapeutic techniques like chelation, antioxidant, and drug therapy are used to treat AD, but a better-targeted approach and a deeper understanding of the molecular basis of Alzheimer's due to AlCl3 intoxication are crucial. AlCl3-induced neurotoxicity involves mitochondrial disruption, oxidative stress, neuroinflammation, and DNA impairment, necessitating further research for treatment against aluminium (Al)-induced AD. AlCl3 can cause neurodegenerative diseases like AD, but understanding its molecular mechanisms is challenging due to its interaction with biological systems.}, } @article {pmid41564288, year = {2026}, author = {Chen, ZH and Li, R and Jiang, YH and He, JK and Yan, SS and Zong, GH and Yi, ZX and Ren, XY and Jia, BH}, title = {Predictive Model of Acupuncture Adherence in Alzheimer Disease: Secondary Analysis of Randomized Controlled Trials.}, journal = {JMIR aging}, volume = {9}, number = {}, pages = {e82787}, pmid = {41564288}, issn = {2561-7605}, mesh = {Humans ; *Alzheimer Disease/therapy/psychology ; Male ; Aged ; Female ; *Acupuncture Therapy/statistics & numerical data ; Middle Aged ; Aged, 80 and over ; Randomized Controlled Trials as Topic ; China ; }, abstract = {BACKGROUND: The therapeutic efficacy of acupuncture in treating Alzheimer disease (AD) largely depends on consistent treatment adherence. Therefore, identifying key factors influencing adherence and developing targeted interventions are crucial for enhancing clinical outcomes.

OBJECTIVE: This study aims to develop and validate a predictive model for identifying patients with AD who are likely to maintain good adherence to acupuncture treatment.

METHODS: This secondary analysis included 108 patients with probable AD, aged 50 to 85 years, from 2 independent randomized controlled trials conducted at Guang'anmen Hospital, China Academy of Chinese Medical Sciences. Of all, 66 patients were assigned to the development cohort and 42 to the external validation cohort. Acupuncture adherence was defined as the proportion of completed sessions relative to scheduled sessions, with good adherence defined as ≥80% completion. Baseline data included demographic, clinical, cognitive, functional, psychological, and caregiving variables. Multivariable logistic regression with backward stepwise selection was used to identify significant predictors, and a nomogram was constructed based on the final model. Model performance was assessed using receiver operating characteristic curves, calibration plots, and decision curve analysis, with external validation performed by receiver operating characteristic analysis. Sensitivity analysis was performed using alternative adherence thresholds of 70% and 90%.

RESULTS: A higher number of treatments during the first month was associated with a significant increase in the odds of good adherence (odds ratio [OR] 3.06, 95% CI 1.68-7.01; P=.002), while longer disease duration (OR 0.97, 95% CI 0.94-1.00; P=.049) and receiving care from a part-time caregiver (OR 0.19, 95% CI 0.04-0.72; P=.022) were associated with lower odds of adherence. Sensitivity analyses further supported the stability and reliability of the model.

CONCLUSIONS: This study is the first to develop and validate a predictive model for acupuncture adherence in patients with AD. In clinical research, it can facilitate participant stratification and help identify individuals who may need additional adherence support, thereby reducing bias and enhancing trial quality. In clinical practice, the nomogram enables proactive adherence management by prospectively identifying high-risk patients and guiding targeted strategies to improve adherence and optimize therapeutic outcomes.}, } @article {pmid41564595, year = {2026}, author = {Muzurović, E and Katsiki, N and Volčanšek, Š and Plescia, F and Rizzo, M and Mantzoros, CS}, title = {Emerging incretin- and multi-agonist-based treatments - the continued refinement and continuous expansion of a potent therapeutic armamentarium for cardio-kidney-liver-metabolic diseases and beyond.}, journal = {Metabolism: clinical and experimental}, volume = {177}, number = {}, pages = {156494}, doi = {10.1016/j.metabol.2026.156494}, pmid = {41564595}, issn = {1532-8600}, mesh = {Humans ; *Incretins/therapeutic use ; *Metabolic Diseases/drug therapy ; *Liver Diseases/drug therapy ; *Cardiovascular Diseases/drug therapy ; *Kidney Diseases/drug therapy ; Animals ; Glucagon-Like Peptide-1 Receptor Agonists ; Obesity/drug therapy ; }, abstract = {While the use of glucagon-like peptide-1 (GLP-1) receptor agonists (RAs) has achieved a central position in our therapeutic armamentarium, new and innovative incretin- and multi-agonist-based treatment strategies hold further promise as potential game-changers for obesity and cardio-kidney-liver-metabolic diseases. Molecular pathways of GLP-1, glucose-dependent insulinotropic polypeptide (GIP), amylin, glucagon and peptide YY have been consistently involved in improved outcomes associated with obesity and related disorders. Single, dual, and even triple drug combinations are being researched throughout all phases of clinical trials. The similarities in GLP-1, GIP, and glucagon peptide sequences enable the development of unimolecular multi-receptor activating agonists and/or antagonists. Furthermore, subcutaneously administered peptides are being supplemented with oral analogs currently in development. Both well-designed clinical trials and real-world evidence are fuelling the development of incretin and multi-agonist-based therapies, thereby holding the promise to deliver an increasing double-digit percent weight loss in addition to addressing many obesity-related comorbidities and complications. It is increasingly evident that early initiation of incretin-based therapy across a broad spectrum of cardio-kidney-metabolic disorders improves body weight, dysglycemia, and cardiovascular risk factor management and consequently is expected to reduce cardio-kidney-liver-metabolic and vascular morbidity and mortality and soon most probably those from obesity-related malignancies, Alzheimer's, and other neurocognitive diseases. This review explores new incretin- and multi-agonist-based therapies undergoing clinical trials for chronic weight management, type 2 diabetes mellitus with its complications, chronic kidney disease, metabolic dysfunction-associated steatotic liver disease and obstructive sleep apnea; it also highlights areas of uncertainty regarding the potency, safety, tolerability, and sustainability of incretin-based approaches for obesity and cardio-kidney-liver-metabolic disorders and finally, we discuss future directions.}, } @article {pmid41564814, year = {2026}, author = {Harris, K and Shyer, M and Wang, D and He, E and Cattani, M and Zhang, C and Farrell, CM and Jiang, X and Kim, Y and Schulz, PE}, title = {The influence of bapineuzumab and semagacestat on rapid progressors: A retrospective cohort study.}, journal = {The journal of prevention of Alzheimer's disease}, volume = {13}, number = {3}, pages = {100483}, pmid = {41564814}, issn = {2426-0266}, support = {R01 AG082721/AG/NIA NIH HHS/United States ; R01 AG084637/AG/NIA NIH HHS/United States ; }, mesh = {Humans ; Disease Progression ; Retrospective Studies ; *Antibodies, Monoclonal, Humanized/therapeutic use ; *Alanine/analogs & derivatives/therapeutic use ; *Azepines/therapeutic use ; *Alzheimer Disease/drug therapy/diagnostic imaging ; Biomarkers/cerebrospinal fluid ; Double-Blind Method ; Female ; Male ; Aged ; }, abstract = {BACKGROUND: A subset of Alzheimer's disease patients progresses much more rapidly than average. These rapid progressors exhibit accelerated cognitive and functional decline. Potential differences in Alzheimer's biomarkers for rapid progressors and their responses to disease-modifying treatments remain poorly understood, with previous clinical trials and studies producing limited biomarker data and inconsistent results.

OBJECTIVES: Examine differences in rapid progressor versus non-rapid progressor outcomes in two AD treatment trials (bapineuzumab and semagacestat) and investigate cognitive and biomarker progression in the placebo groups.

DESIGN: Retrospective cohort study.

SETTING: Four randomized, double-blind, phase 3 clinical trials from the Center for Global Clinical Research Data (Semagacestat) and the Yale University Open Data Access Project (Bapineuzumab).

PARTICIPANTS: 4,902 patients (2,355 in bapineuzumab trials, 2,647 in semagacestat trials). Rapid progressors were operationally defined as the 10% of patients with the largest changes in cognitive scores from baseline to trial end.

INTERVENTION: Bapineuzumab (monoclonal antibody) and Semagacestat (γ-secretase inhibitor).

MEASUREMENTS: Cognitive assessments (CDR-SB, MMSE, ADAS-Cog, ADCS-ADL) and biological markers (CSF and plasma levels, MRI, FDG PET Scan, and Amyloid PET Scan) at baseline and endpoint.

RESULTS: Rapid progressors showed distinct baseline characteristics in both the bapineuzumab and semagacestat trials: younger age (61.27 vs 63.14 years, p=0.008; and, 72.64 v. 73.64 years, p=0.046), a higher proportion of APOE4 carriers (87.6% vs 41.4%, p<0.001; and, 85.2% vs 49.3%, p = 0.022), and greater cognitive impairment across all measures (p<0.001). Both progression groups demonstrated improvement in specific biomarkers with treatment, though with different patterns. With bapineuzumab according to Conditional Average Treatment Effect analysis, rapid progressors showed biomarker improvement in amyloid CSF, p-Tau CSF, and amyloid PET scan, while non-rapid progressors demonstrated biomarker improvements in p-Tau CSF, amyloid PET, and MRI. With semagacestat, rapid progressors showed improvements in amyloid CSF and plasma while non-rapid progressors showed improvements in amyloid CSF, FDG PET, and MRI.

CONCLUSIONS: This study provides crucial insights for clinical practice and trial design. The distinct response patterns between progression groups suggest that early identification and balancing of RPs between groups could improve clinical trial efficiency. The findings support the development of personalized treatment approaches for rapid progressors, who have aggressive disease progression. These results may significantly modify clinical trial design and patient care in Alzheimer's disease.}, } @article {pmid41565030, year = {2026}, author = {Zhang, X and Ding, W and Guo, C and Chen, X and Chen, B}, title = {Choline serves as the primary active compound of anti-aging tablets and targets PTGS2 to alleviate neuronal damage in Alzheimer's disease by modulating ferroptosis and apoptosis in nerve cells.}, journal = {Behavioural brain research}, volume = {503}, number = {}, pages = {116040}, doi = {10.1016/j.bbr.2026.116040}, pmid = {41565030}, issn = {1872-7549}, mesh = {*Alzheimer Disease/drug therapy/metabolism ; *Cyclooxygenase 2/metabolism/drug effects ; *Ferroptosis/drug effects ; *Apoptosis/drug effects ; Animals ; *Neurons/drug effects/metabolism ; *Choline/pharmacology ; *Neuroprotective Agents/pharmacology ; Tablets ; Humans ; Rats ; Oxidative Stress/drug effects ; }, abstract = {BACKGROUND: Alzheimer's disease (AD), a neurodegenerative disorder characterized by progressive cognitive impairment, involves pathological mechanisms including β-amyloid protein deposition, hyperphosphorylation of Tau proteins, and neuronal damage mediated by ferroptosis. As a traditional Chinese medicine, anti-aging tablets have potential neuroprotective effects, but their active ingredients and mechanisms have not been fully elucidated.

METHODS: We screened active ingredients and AD-related targets in anti-aging tablets using liquid chromatography-mass spectrometry combined with network pharmacology analysis. A protein-protein interaction network was established, and GO/KEGG enrichment analyses were performed. The binding of choline to PTGS2 was verified through molecular thermal shift assay. qPCR was utilized to detect PTGS2 expression. An AD model was constructed, with cellular injury levels evaluated through CCK-8, LDH assays, and WB detection by examining the expression of apoptosis-related biomarkers. The expression of ferroptosis-related proteins (FSP1, SLC7A11, GPX4) was examined through Western blot analysis. MDA and GSH/GSSG analyses determined lipid peroxidation and antioxidant capacity. DCFH-DA detected ROS levels.

RESULTS: The combined use of UPLC-MS/MS with network pharmacology led to the identification and characterization of choline as the key active ingredient in anti-aging tablets. PTGS2 was determined as its primary target. The direct binding of choline to PTGS2 was verified through molecular thermal shift assay. In vitro experiments revealed that choline significantly repressed cell damage in the AD model, as indicated by enhanced cell viability, reduced release of LDH, lowered levels of reactive oxygen species (ROS), and downregulated expression of caspase-3 and Bax. Additional studies uncovered that overexpression of PTGS2 exacerbated ferroptosis-related parameters (upregulation of MDA, decrease in GSH/GSSG ratio, downregulation of FSP1, SLC7A11, and GPX4 expression), whereas Fer-1 treatment reversed these changes.

CONCLUSION: This study revealed that choline targets PTGS2 to depress ferroptosis, thus alleviating AD-related neuronal injury. This study provides a theoretical basis for the pharmacodynamic effects of anti-aging tablets as well as new therapeutic strategies for AD.}, } @article {pmid41565079, year = {2026}, author = {Doshi, PP and Desale, SH and Khutale, AA and Sabarathinam, S and Suresh, S}, title = {Evaluating senescence-targeted approaches in Alzheimer's Disease: What we know and what lies ahead.}, journal = {Ageing research reviews}, volume = {115}, number = {}, pages = {103029}, doi = {10.1016/j.arr.2026.103029}, pmid = {41565079}, issn = {1872-9649}, mesh = {Humans ; *Alzheimer Disease/drug therapy/pathology/metabolism ; Animals ; *Cellular Senescence/drug effects/physiology ; *Senotherapeutics/therapeutic use ; *Aging/pathology/metabolism ; *Brain/pathology/metabolism/drug effects ; }, abstract = {Alzheimer's disease (AD) is a progressive and irreversible neurodegenerative disease, which represents the most prevalent dementia worldwide. Although amyloid-β (Aβ) and tau pathology have been the classic focus of treatment, accumulating evidence indicates that ageing-associated cellular senescence plays a central role in AD pathogenesis. Senescent neurons, astrocytes, microglia and endothelial cells accumulate in the ageing and Alzheimer's brain and adopt a senescence-associated secretory phenotype characterized by sustained release of pro-inflammatory and neurotoxic factors. This chronic inflammatory milieu promotes neurodegeneration, disrupts the synaptic activity and is involved in cognitive deficit. Senolytics, which selectively eliminate senescent cells, have demonstrated benefit in multiple preclinical models of AD, including decreased neuroinflammation, improvement in neuronal function and cognitive performance. Several senolytic agents, such as dasatinib, quercetin, fisetin and navitoclax, hit anti-apoptotic modalities that support the survival of senescent cells. Early-phase human studies suggest the feasibility of senescence-targeted interventions and indicate that senescence-associated molecular changes may compromise blood-brain barrier integrity. Consistently, preclinical studies demonstrate partial restoration of barrier function following senolytic therapy; however, clinical translation remains limited and at an early stage. Major challenges include the identification of senolytic agents with effective central nervous system penetration, the determination of optimal dosing regimens and treatment schedules, generation of robust long-term safety profile in human population, and the development of predictive biomarkers to guide patient selection and clinical study design. As senolytics and senomorphic strategies continue to evolve, they hold promise as complementary approaches to existing anti-amyloid and anti-tau therapies by offering a multi-mechanistic approach toward AD modification. This review synthesizes current evidence on cellular senescence in AD, outlines the mechanistic rationale for senescence-targeted therapies, summarizes available clinical data, while providing future directions for integrating senolytics into AD management.}, } @article {pmid41566034, year = {2026}, author = {Peng, Y and Wang, SS and Lai, KD and Ye, JR and He, WB and Yan, X and Zhang, Z and Chu, SF and Chen, NH}, title = {Protopanaxatriol restores cognitive function in okadaic acid-treated mice via direct inhibition of pathological CDK5 activity.}, journal = {Acta pharmacologica Sinica}, volume = {47}, number = {5}, pages = {1132-1148}, pmid = {41566034}, issn = {1745-7254}, mesh = {Animals ; *Sapogenins/pharmacology/therapeutic use ; *Cyclin-Dependent Kinase 5/metabolism/antagonists & inhibitors ; *Neuroprotective Agents/pharmacology/therapeutic use ; *Okadaic Acid ; Male ; Hippocampus/drug effects/metabolism ; *Cognition/drug effects ; Neurons/drug effects/metabolism ; Mice ; *Alzheimer Disease/drug therapy/chemically induced ; Mice, Inbred C57BL ; tau Proteins/metabolism ; Cognitive Enhancement ; Cells, Cultured ; }, abstract = {Alzheimer's disease (AD), a prevalent neurodegenerative dementia, presents therapeutic challenges due to safety concerns about amyloid-targeting strategies. Traditional Chinese medicine (TCM) may offer alternative avenues for exploration. Ginsenoside Rg1, a key bioactive component of ginseng, has shown neuroprotective potential in okadaic acid (OKA)-induced rat model, its limited brain bioavailability suggests that its metabolite protopanaxatriol (Ppt) may exert these effects. In this study, we investigated the therapeutic effects of Ppt on OKA-induced mice model and the underlying mechanisms. Cultured hippocampal neurons were treated with OKA (0.5 nM) with or without Ppt co-treatment for 24 h. We showed that Ppt (1.25-40 nM) exerted dose-dependent neuroprotection against OKA-induced cytotoxicity, with the maximal protection observed at 10 nM. The suppressed tau aggregation by Ppt was confirmed using a Venus-tau bimolecular fluorescence complementation (BiFC) system. Molecular dynamics simulations and microscale thermophoresis (MST) revealed that Ppt bound to the catalytic domain of CDK5 at Cys83, destabilizing the CDK5/p25 complex. Co-immunoprecipitation (Co-IP) assays with CDK5 mutants (S159T, C83A, F80A and D86A) validated this interaction. In vivo mice were treated with Ppt (10 mg/kg, i.g.) for 25 days. On D8 and D9, the mice were bilaterally microinjected with OKA into the cerebral ventricles. We showed that Ppt administration improved spatial memory deficits in Novel Object Recognition and Barnes Maze tests; these effects were abolished in mice expressing a lentivirus-mediated CDK5[C83A] mutant. Hippocampal transcriptomic profiling in OKA-challenged mice following Ppt intervention revealed that Ppt modulated Drp1-mediated mitochondrial fission/fusion dynamics, mitigating OKA-induced mitochondrial homeostasis disruption. Collectively, these results demonstrate that Ppt attenuates tau pathology by selectively targeting CDK5 at Cys83, thereby reducing pathological kinase activity, rebalancing mitochondrial function, and improving cognitive outcomes in an OKA-induced mice neurodegeneration model. The study underscores the therapeutic potential of Ppt in AD treatment and supports CDK5 modulation as a strategic approach for addressing tau-related neurodegeneration.}, } @article {pmid41567052, year = {2026}, author = {Tziakouri, A and Loser, V and Vicino, A and Baumgartner, T and Di Liberto, G and Pantazou, V and Bernard-Valnet, R and Theaudin, M and Pot, C and Castro-Jimenez, M and Hübsch, CA and Bally, J and Strambo, D and Hirt, L and Caranzano, L and Rouaud, O and Allali, G and Salvioni, P and Sokolov, AA and Pignat, JM and Ryvlin, P and Perrenoud, MP and Rossetti, AO and Novy, J and Beuchat, I and Du Pasquier, R and Michel, P}, title = {[Neurology : what's new in 2025].}, journal = {Revue medicale suisse}, volume = {22}, number = {946}, pages = {161-164}, doi = {10.53738/REVMED.2026.22.946.48114}, pmid = {41567052}, issn = {1660-9379}, mesh = {Humans ; Female ; *Neurology/trends ; Pregnancy ; *Nervous System Diseases/therapy/diagnosis ; }, abstract = {In 2025, several major advances have marked the field of neurology. Anti-FcRN and anti-C5 antibodies have confirmed their long-term efficacy in the treatment of myasthenia gravis. Bruton tyrosine kinase inhibitors have expanded the therapeutic arsenal for multiple sclerosis. An antibody targeting α-synuclein appears to slow motor decline in early-stage Parkinson's disease. The efficacy of late thrombolysis in strokes with radiological mismatch has been confirmed. A blood biomarker facilitates early detection of Alzheimer's disease, and Swiss guidelines specify the modality for the use of anti-amyloid therapies in this disease. Finally, in pregnant women with epilepsy, the recommended dose of folic acid has been reduced.}, } @article {pmid41568664, year = {2026}, author = {Jootar, T and Hongeng, S and Chiangjong, W}, title = {Engineering nanobodies for drug delivery systems in Alzheimer's disease.}, journal = {Artificial cells, nanomedicine, and biotechnology}, volume = {54}, number = {1}, pages = {104-118}, doi = {10.1080/21691401.2026.2617707}, pmid = {41568664}, issn = {2169-141X}, mesh = {*Single-Domain Antibodies/chemistry/immunology/genetics/therapeutic use ; *Alzheimer Disease/drug therapy/metabolism/pathology ; Humans ; Animals ; *Protein Engineering ; *Drug Delivery Systems/methods ; Blood-Brain Barrier/metabolism ; Amyloid beta-Peptides/metabolism ; }, abstract = {Alzheimer's disease (AD) remains a major global health challenge, with current therapies offering only symptomatic relief. A significant constraint in the development of effective treatments is the blood-brain barrier (BBB), as it greatly limits the access of therapeutic drugs targeting amyloid-β (Aβ) aggregation, tau hyperphosphorylation and neuroinflammation. Nanobodies, single-domain antibody fragments derived from camelids, have emerged as versatile tools with unique properties such as small size, high stability and the ability to penetrate the BBB. Engineered formats allow for specific targeting of Aβ and tau, receptor-mediated transcytosis, and conjugation with therapeutic or diagnostic substances. Preclinical studies show that nanobody-based strategies can reduce pathological burden, attenuate neuroinflammation and improve cognitive outcomes in AD models. Manufacturing scale-up, long-term safety and regulatory validation are among the remaining challenges, yet nanobody engineering represents a viable path to disease-modifying medicines. Innovative approaches, including artificial intelligence-driven design, i.e. 4-1BB agonist nanobodies, and clustered regularly interspaced short palindromic repeat-facilitated diversification of nanobody libraries - such as targeted complementarity-determining region 3 mutagenesis followed by functional screening against disease-relevant tau or Aβ conformers - alongside half-life extension strategies, are commencing to surmount these obstacles and enhance the potential of nanobody platforms to develop into clinically viable disease-modifying therapies.}, } @article {pmid41568736, year = {2025}, author = {Liu, W and Li, Y and Qin, W and Wang, X and Li, W and Li, Y and , and Jia, J}, title = {The impact of cholinesterase inhibitors on cognitive trajectories in mild cognitive impairment patients based on amyloid beta status.}, journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association}, volume = {21}, number = {5}, pages = {e70193}, pmid = {41568736}, issn = {1552-5279}, support = {CX23YZ15//Chinese Institutes for Medical Research/ ; U20A20354//Key Project of the National Natural Science Foundation of China/ ; 81530036//Key Project of the National Natural Science Foundation of China/ ; 7244355//Beijing Municipal Natural Science Foundation/ ; 31627803//National Key Scientific Instrument and Equipment Development Project/ ; No.2021ZD0201802//STI2030-Major Projects/ ; Z201100005520016//Beijing Brain Initiative from Beijing Municipal Science & Technology Commission/ ; Z201100005520017//Beijing Brain Initiative from Beijing Municipal Science & Technology Commission/ ; 82401404//National Natural Science Foundation of China/ ; }, mesh = {Humans ; *Cognitive Dysfunction/drug therapy/metabolism ; *Cholinesterase Inhibitors/therapeutic use/adverse effects ; *Amyloid beta-Peptides/metabolism ; Male ; Female ; Disease Progression ; Aged ; *Alzheimer Disease ; *Cognition/drug effects ; Neuropsychological Tests ; Aged, 80 and over ; Kaplan-Meier Estimate ; Proportional Hazards Models ; }, abstract = {INTRODUCTION: This study examines whether cholinesterase inhibitors (ChEIs) influence the progression to Alzheimer's disease (AD) dementia and cognitive trajectories in amnestic mild cognitive impairment (MCI) patients, considering their amyloid beta (Aβ) status.

METHODS: Kaplan-Meier and time-varying Cox models evaluated ChEI use and different Aβ status on MCI-to-AD progression. Linear mixed-effects models assessed cognitive trajectories. Locally estimated scatterplot smoothing regression analyzed cognitive changes before and after ChEI initiation.

RESULTS: Among 558 amnestic MCI participants (168 ChEI users), ChEI users exhibited higher risk of progression to AD dementia (hazard ratio = 1.77, 95% confidence interval: 1.15 to 2.73, p = 0.001). Both ChEI use and Aβ burden independently accelerated MCI progression and cognitive decline. Cognitive trajectories demonstrated decline before ChEI initiation and continued to decline after treatment began.

DISCUSSION: The association between ChEI treatment and accelerated progression to AD dementia and cognitive decline, independent of Aβ status, emphasized the need to reconsider optimal timing for ChEI initiation in MCI.

HIGHLIGHTS: ChEI use in MCI was associated with increased risk of progression to AD dementia. ChEI use in MCI was associated with accelerated longitudinal cognitive decline. Cognitive decline persisted after ChEI initiation rather than reversing. ChEI effects on MCI progression to AD dementia were independent of Aβ status.}, } @article {pmid41569242, year = {2026}, author = {Zuliani, G and Boscolo Bragadin, F and Romagnoli, T and Polastri, M and Cervellati, C and Dario, FDP and Brombo, G and Zuin, M}, title = {Long-Term Effect of Acetylcholinesterase Inhibitors on Behavioral and Psychological Symptoms of Dementia.}, journal = {International journal of geriatric psychiatry}, volume = {41}, number = {1}, pages = {e70195}, pmid = {41569242}, issn = {1099-1166}, support = {P30 AG066515/AG/NIA NIH HHS/United States ; P30 AG062421/AG/NIA NIH HHS/United States ; P30 AG066508/AG/NIA NIH HHS/United States ; P30 AG066519/AG/NIA NIH HHS/United States ; P30 AG072973/AG/NIA NIH HHS/United States ; P30 AG066462/AG/NIA NIH HHS/United States ; P30 AG066530/AG/NIA NIH HHS/United States ; P30 AG066509/AG/NIA NIH HHS/United States ; P30 AG066546/AG/NIA NIH HHS/United States ; P30 AG072958/AG/NIA NIH HHS/United States ; P30 AG072972/AG/NIA NIH HHS/United States ; P30 AG072979/AG/NIA NIH HHS/United States ; P20 AG068082/AG/NIA NIH HHS/United States ; P30 AG072975/AG/NIA NIH HHS/United States ; P30 AG066444/AG/NIA NIH HHS/United States ; P30 AG066507/AG/NIA NIH HHS/United States ; P30 AG072946/AG/NIA NIH HHS/United States ; P30 AG066518/AG/NIA NIH HHS/United States ; P30 AG066511/AG/NIA NIH HHS/United States ; P30 AG086404/AG/NIA NIH HHS/United States ; U24 AG072122/AG/NIA NIH HHS/United States ; P30 AG066512/AG/NIA NIH HHS/United States ; P30 AG072978/AG/NIA NIH HHS/United States ; P30 AG062429/AG/NIA NIH HHS/United States ; P30 AG062422/AG/NIA NIH HHS/United States ; R01 AG079280/AG/NIA NIH HHS/United States ; P30 AG086401/AG/NIA NIH HHS/United States ; P30 AG072977/AG/NIA NIH HHS/United States ; P30 AG062677/AG/NIA NIH HHS/United States ; P30 AG062715/AG/NIA NIH HHS/United States ; P30 AG066506/AG/NIA NIH HHS/United States ; P30 AG066468/AG/NIA NIH HHS/United States ; P30 AG072976/AG/NIA NIH HHS/United States ; P30 AG072947/AG/NIA NIH HHS/United States ; P30 AG072931/AG/NIA NIH HHS/United States ; P30 AG066514/AG/NIA NIH HHS/United States ; P30 AG072959/AG/NIA NIH HHS/United States ; }, mesh = {Humans ; *Cholinesterase Inhibitors/therapeutic use ; Female ; Male ; Aged ; *Dementia/drug therapy/psychology ; Aged, 80 and over ; Behavioral Symptoms/drug therapy ; }, abstract = {OBJECTIVE: Behavioral and psychological symptoms of dementia (BPSD) are critical aspects of the clinical presentation of dementia. There is no universally accepted approach for the managment of BPSD, currently based first on a non-pharmacological and subsequently on a pharmacological approach. We explored the potential effect of long-term treatment with acetylcholinesterase inhibitors (AChEI) on BPSD severity over time.

METHODS: The initial sample included 4032 older patients with mild-moderate dementia (Alzhemier's disease - AD, Lewy body dementia - LBD, or vascular dementias - VaD) from the National Alzheimer's Coordinating Center Uniform Data Set (NACC UDS). After propensity score matching, a cohort of 1408 patients (704 treated with AChEI = AChEI+ and 704 not treated = AChEI-) was generated. The mean age was 73.2 years (females: 50.4%). The mean follow-up duration was 4.3 ± 1.6 years (range: 2.2-8.3 years). Patients were evaluated at baseline, T1 (2 years), T2 (4 years), T3 (6.2 years), and T4 (8.1 years). BPSD severity was assessed by Neuropsychiatric Inventory (NPI-Q).

RESULTS: The baseline mean NPI-Q severity score was 1.33. At T4, the score increased to 1.41 in AChEI- patients (+6% from baseline), while it decreased to 1.26 in AChEI+ (-6%) (all p < 0.01 from T1 to T4). As regards the NPI-Q sub-items, six of them (hallucinations, agitation/aggression, depression/dysphoria, anxiety, disinhibition and irritability/lability) exhibited significant differences over time (all p < 0.01) in favor of the AChEI + group (stabilization or improvement). Similar trends were observed when LOAD, LBD and VaD were considered separately. In contrast, for five domains (delusions, elation/euphoria, motor disturbances, night-time behaviors, and appetite/eating changes) no differences were observed.

CONCLUSIONS: Our study supports the potential role for AChEI in BPSD management, demonstrating a trend toward symptoms stabilization or improvement in patients with mild-moderate dementia. Although the effects were not uniform across all NPI-Q domains, and the limitations of the study, our results reinforces the relevance of AChEI in the comprehensive treatment of dementia.}, } @article {pmid41569280, year = {2026}, author = {Huynh, ALH and Wang, S and Lee, K and Amadoru, S and Wrigley, S and Zisis, G and Ernstrom, K and Raman, R and Aisen, P and Sperling, RA and Masters, CL and Ward, D and Yates, PA}, title = {Prevalence of frailty and its association with cognition in preclinical Alzheimer's disease: a cross-sectional analysis of baseline data from the A4 study.}, journal = {Age and ageing}, volume = {55}, number = {1}, pages = {}, pmid = {41569280}, issn = {1468-2834}, mesh = {Humans ; Female ; Cross-Sectional Studies ; *Alzheimer Disease/epidemiology/psychology/diagnosis/drug therapy ; *Frailty/epidemiology/diagnosis/psychology ; Prevalence ; Male ; Aged ; *Cognition ; Amyloid beta-Peptides/blood ; *Frail Elderly/psychology ; Risk Factors ; Age Factors ; Odds Ratio ; Prodromal Symptoms ; Biomarkers/blood ; Aged, 80 and over ; Neuropsychological Tests ; Geriatric Assessment ; }, abstract = {BACKGROUND: The prevalence and role of frailty in preclinical Alzheimer's disease (AD) is unclear.

METHODS: Cross-sectional analyses of pre-randomization data from the Anti-Amyloid Treatment in Asymptomatic AD (A4) study were analysed to derive two models of a frailty index (FI)-full [FI-Full] and cognitive variables removed [FI-CVR]. The prevalence of frailty (FI > 0.25) according to amyloid status (Aβ+/-), and the association of frailty and cognition (determined by the Preclinical Alzheimer Cognitive Composite (PACC) score) and whether frailty moderates the relationship between amyloid status and cognition was assessed, adjusting for age, sex and education.

RESULTS: Four thousand four hundred eighty-six participants were included (mean age 71.3 ± 4.7 years, 30% participants Aβ+, 59% female). The prevalence of frailty in preclinical AD was 22% (or 44% when cognitive variables were removed from the FI). Using either FI model, in adjusted analyses, Aβ+ participants were more likely to be frail compared to Aβ- [FI-Full-Odds ratio (OR) 1.43 95% confidence interval (CI) 1.20-1.71, P < .001; FI-CVR-OR 1.21 95% CI 1.05-1.40, P < .008]. Frail participants had lower PACC scores compared to non-frail participants, on average (FI-Full-PACC score -0.58 95% CI -0.76 to -0.40, P < .001; FI-CVR-PACC score -0.26 95% CI -0.40 to -0.12, P < .001). Frailty did not influence the relationship between Aβ status and cognition.

CONCLUSIONS: In a cohort screened for a preclinical AD trial, elevated Aβ levels were associated with frailty and frailty was associated with reduced cognitive performance independent of elevated Aβ levels. These associations, and whether or not frailty is associated with longitudinal cognitive decline independent of Aβ status, warrant further study.}, } @article {pmid41570392, year = {2026}, author = {Wischik, CM and Stefanacci, R and Bentham, P and Gauthier, S and Zetterberg, H and Wilcock, GK and Froelich, L and Burns, A and MacSweeney, E and Ballard, C and Yu, JT and Choon, TS and Asvatourian, V and Muehlemann, N and Priel, J and Kook, K and Sullivan, T and Downie, D and Miller, S and Pringle, C and Storey, JMD and Baddeley, T and Harrington, CR and Penny, LK and Arastoo, M and Staff, R and Sandu, AL and Shiells, H and Lo, S and Nazlee, N and Evans, E and Hull, C and Schelter, BO}, title = {Clinical, imaging and blood biomarker outcomes in a Phase 3 clinical trial of tau aggregation inhibitor hydromethylthionine mesylate in mild cognitive impairment and mild to moderate dementia due to Alzheimer's disease.}, journal = {The journal of prevention of Alzheimer's disease}, volume = {13}, number = {3}, pages = {100480}, pmid = {41570392}, issn = {2426-0266}, mesh = {Humans ; *Cognitive Dysfunction/drug therapy/blood/diagnostic imaging ; *Alzheimer Disease/drug therapy/complications/blood ; Male ; Female ; Biomarkers/blood ; *tau Proteins/antagonists & inhibitors/blood ; Aged ; *Phenothiazines/therapeutic use ; Treatment Outcome ; Methylene Blue/analogs & derivatives ; }, abstract = {BACKGROUND: Hydromethylthionine mesylate (HMTM) targets tau pathology and has tau-independent symptomatic activity.

OBJECTIVES: To evaluate the safety and efficacy of HMTM in participants with mild cognitive impairment (MCI) and mild to moderate dementia due to Alzheimer's disease (AD).

SETTING: 82 centres in Canada, European Union, United Kingdom and United States of America.

PARTICIPANTS: A total of 598 amyloid β-PET positive participants were included; 44% (263) met clinical criteria for MCI due to Alzheimer's disease and 56% (335) were diagnosed with mild to moderate dementia due to AD.

INTERVENTION: HMTM 16 mg/day and 8 mg/day were compared with methylthioninium chloride (MTC) 4 mg twice weekly, intended as an inactive urinary colourant to preserve blinding with respect to possible urinary discolouration caused by HMTM.

MEASUREMENTS: HMTM and MTC were compared on cognitive and functional endpoints for the first 52 weeks followed by all receiving HMTM 16 mg/day to 104 weeks in a modified delayed-start trial design. Biomarker outcomes included change in plasma levels of neurofilament light chain (NfL), pTau217 and MRI measures of grey matter atrophy.

RESULTS: It was not possible to demonstrate significant differences on the co-primary clinical endpoints (ADAS-cog11 and ADCS-ADL23) at 52 weeks due to symptomatic activity in the control arm. In participants with MCI, statistically significant differences in cognitive decline (ADAS-cog13) emerged at 78 weeks (p = 0·0291) and 104 weeks (p = 0·0308) between early- and delayed-start HMTM 16 mg/day in analyses specified prior to the 24-month database lock. Statistically significant cognitive improvement over baseline score was sustained for 78 weeks in the early start MCI group, with no significant cognitive or functional decline to 104 weeks. There was a significant reduction in progression of neurodegeneration measured by NfL change (p = 0·0291) at 52 weeks in the whole population, consistent with significant reductions in progression of grey matter atrophy at 52 and 104 weeks, and a reduction in progression of tau pathology (pTau217, p = 0·0165) in MCI. Headache (1·5%) and diarrhoea (1·2%) were the most frequent adverse effects.

CONCLUSIONS: Although HMTM 16 mg/day arrested progression of neurodegeneration and reduced grey matter atrophy at 52 weeks, symptomatic activity in the control arm precluded separation of treatment arms at 52 weeks on primary clinical endpoints. In participants with MCI, significant clinical separation was seen only at 78 and 104 weeks. This effect has been confirmed in a further study. HMTM was well tolerated and has the potential to offer an accessible oral treatment option with a benign safety profile which could be delivered with minimal patient/physician burden.}, } @article {pmid41570699, year = {2026}, author = {Razzaq, R and Ahmed, T and Butt, AM and Jabeen, Z and Khalid, A and Shahid, I and Alzahrani, AR and Rehman, S}, title = {Betanin-encapsulated nanoparticles mitigate neurotoxicity against AlCl3-induced Alzheimer's disease via modulation of AChE/TNF-α/IL-1β expression.}, journal = {Biochemical and biophysical research communications}, volume = {801}, number = {}, pages = {153293}, doi = {10.1016/j.bbrc.2026.153293}, pmid = {41570699}, issn = {1090-2104}, mesh = {Animals ; *Alzheimer Disease/chemically induced/drug therapy/metabolism ; Aluminum Chloride/toxicity ; *Betacyanins/administration & dosage/pharmacology/therapeutic use/chemistry ; Acetylcholinesterase/metabolism/genetics ; Tumor Necrosis Factor-alpha/metabolism/genetics ; *Nanoparticles/chemistry ; Male ; Rats ; Interleukin-1beta/metabolism/genetics ; Oxidative Stress/drug effects ; *Neuroprotective Agents/administration & dosage/pharmacology/therapeutic use ; Hippocampus/drug effects/metabolism ; Rats, Wistar ; Galactose ; }, abstract = {Alzheimer's disease (AD), the most common health problem, is significantly characterized by oxidative stress, neuroinflammation, and cholinergic dysfunction, provoking growing interest in natural antioxidants with improved bioavailability. This study is intended to evaluate the neuroprotective impact and the probable mechanism of betanin and formulated betanin-encapsulated nanoparticles (ChBetNPs) in an AlCl3 and D-galactose-induced rat model Alzheimer's-like neurotoxicity. The rats were treated daily with AlCl3 and D-galactose for 21 days to induce neurotoxicity, followed by two weeks of treatment with low and high doses of betanin and ChBetNPs. After treatment, cognitive performance, oxidative stress markers, acetylcholinesterase (AChE) activity, and hippocampal inflammatory gene expression were assessed. Both low and high doses of ChBetNPs (40 mg/kg/day and 80 mg/kg/day respectively) significantly improved learning and memory performance in AlCl3 + D-galactose-treated rats. Treatment with ChBetNPs also markedly restored antioxidant defenses, as evidenced by increased activities of CAT (∗∗P < 0.01), elevated reduced GSH, and reduced levels of the lipid peroxidation marker MDA. The higher dose of ChBetNPs produced a pronounced protective effect on cholinergic function, reflected by a robust reduction in brain AChE activity (∗∗∗∗P < 0.0001). In addition, both free betanin and ChBetNPs at low and high doses significantly (∗∗P < 0.01) downregulated the hippocampal mRNA expression of AChE, α-synuclein, TNF-α, and IL-1β in hippocampal region of brain as compared with untreated group, indicating attenuation of neuroinflammatory and protein-aggregation-related pathways. In summary, our findings demonstrate that ChBetNPs enhanced learning, memory, and cholinergic neurotransmission, likely by mitigating oxidative stress and the associated NF-κB-mediated inflammatory responses.}, } @article {pmid41570950, year = {2026}, author = {Guo, J and Shi, C and Yu, C and Wang, Y and He, M}, title = {Protein S-sulfhydration: Mechanisms and therapeutic implications in Alzheimer's disease and Parkinson's disease.}, journal = {Free radical biology & medicine}, volume = {246}, number = {}, pages = {431-441}, doi = {10.1016/j.freeradbiomed.2026.01.033}, pmid = {41570950}, issn = {1873-4596}, mesh = {Humans ; *Alzheimer Disease/metabolism/pathology/drug therapy ; *Parkinson Disease/metabolism/pathology/drug therapy ; *Protein Processing, Post-Translational ; *Hydrogen Sulfide/metabolism ; Oxidative Stress ; tau Proteins/metabolism ; Animals ; Phosphorylation ; }, abstract = {BACKGROUND: Alzheimer's disease (AD), Parkinson's disease (PD) and other neurodegenerative diseases have complex pathogenic mechanisms. Traditional theories (e.g., free radical damage/oxidative stress, inflammatory responses) have laid a foundation for understanding these pathological processes. However, single mechanisms cannot fully explain their complexity. In recent years, post-translational modifications (PTMs)-especially redox-related types such as S-sulfhydration-have emerged as key complementary regulators of nervous system homeostasis and disease progression. It is mediated by the endogenous gas signaling molecule hydrogen sulfide (H2S) and has unique regulatory effects.

AIM OF REVIEW: This review systematically summarizes the molecular mechanisms and therapeutic targets of S-sulfhydration in AD and PD. It discusses the potential of S-sulfhydration in disease intervention and treatment. It also looks into H2S-based therapeutic strategies and their clinical application prospects. This review aims to provide a theoretical basis for understanding the role of PTMs in neurological diseases.

This review summarizes clearly: in AD and PD, S-sulfhydration interacts with protein modifications like phosphorylation, S-nitrosylation and succinylation. It regulates key pathogenic proteins such as Tau, Aβ and Parkin. It also takes part in regulating energy metabolism, resisting oxidative stress and inhibiting inflammatory responses. These effects influence neuronal survival and functional homeostasis. This indicates that S-sulfhydration plays an important regulatory role in AD and PD progression. It is part of the complex network of pathological mechanisms. Its modification mechanisms and interaction pathways offer promising complementary molecular targets and intervention strategies for treating AD, PD, and other potential neurodegenerative diseases.}, } @article {pmid41571077, year = {2026}, author = {Abdel-Aal, RA and Meligy, FY and Kamel, G and Ashry, IEM}, title = {Cognitive enhancing effect of Canagliflozin in aluminum-induced rat model of Alzheimer's-like disease: Cross-talk between Amyloid-Β and BDNF/GSK-3β signaling.}, journal = {European journal of pharmacology}, volume = {1015}, number = {}, pages = {178581}, doi = {10.1016/j.ejphar.2026.178581}, pmid = {41571077}, issn = {1879-0712}, mesh = {Animals ; *Glycogen Synthase Kinase 3 beta/metabolism ; *Brain-Derived Neurotrophic Factor/metabolism ; *Alzheimer Disease/chemically induced/drug therapy/psychology/metabolism/pathology ; *Amyloid beta-Peptides/metabolism ; Male ; Signal Transduction/drug effects ; Rats ; Disease Models, Animal ; Aluminum Chloride ; Hippocampus/drug effects/pathology/metabolism ; Cognitive Enhancement ; *Canagliflozin/pharmacology/therapeutic use ; Acetylcholinesterase/metabolism ; Rivastigmine/pharmacology ; Behavior, Animal/drug effects ; *Cognition/drug effects ; Rats, Wistar ; }, abstract = {The strong relationship between Alzheimer's Disease (AD) and diabetes mellitus (DM) is described by the term "type 3 diabetes". Canagliflozin (CAN), a sodium-glucose co-transporter 2 inhibitor (SGLT2i), is an antidiabetic agent under investigation as a potential new treatment for AD due to its acetylcholinesterase (AChE) inhibitory properties. We aimed to examine the effect of CAN on the efficacy of the anti-acetylcholinesterase, rivastigmine (RIV), against aluminum chloride (AlCl3)-induced AD rat model. The efficacy of CAN, RIV, and CAN plus RIV against abnormal behavioral, biochemical, and histological changes in AlCl3-induced AD in rats was examined. Three weeks of treatment with CAN partially reversed the AlCl3-induced behavioral dysfunction, along with significantly elevated levels of brain-derived neurotrophic factor (BDNF) and decreased levels of AChE, glycogen synthase kinase-3β (GSK3β), amyloid beta (Aβ) deposits, and inducible nitric oxide synthase (iNOS) expression. Histological examination revealed that CAN administration significantly increased RIV's efficacy by protecting neurons in rats' hippocampal tissues from AlCl3-induced damage. Interestingly, the RIV + CAN combination exhibited a more pronounced inhibitory effect on Aβ plaque formation, iNOS activity, and neurodegeneration compared to either RIV or CAN alone. However, this combination did not show any additive benefits for behavior, AChE activity, BDNF, or GSK3β concentrations compared with RIV alone. Our research indicates that CAN has potential benefits for AD, as evidenced by improvements in cognitive abilities, cholinergic activity, and neurogenesis in rats with AD. This is attributed to the upregulation of BDNF/GSK3β signaling, reduced neuroinflammation, and Aβ deposition.}, } @article {pmid41571775, year = {2026}, author = {Sathish, R and Muthukumar, R and Kumaran, KM and Murugan, SP}, title = {Intelligent decision-making systems for early detection of alzheimer's disease using wearable technologies and deep learning.}, journal = {Scientific reports}, volume = {16}, number = {1}, pages = {6025}, pmid = {41571775}, issn = {2045-2322}, mesh = {Humans ; *Alzheimer Disease/diagnosis ; *Wearable Electronic Devices ; *Deep Learning ; Early Diagnosis ; Intelligent Systems ; Digital Health ; Algorithms ; *Decision Making ; }, abstract = {Intelligent decision-making systems using wearable electronics and deep learning (DL) might identify Alzheimer's disease (AD) early for treatment. These technologies can continually monitor vital signs and behavioral characteristics to identify early cognitive deterioration in patients. Clinical examinations, neuroimaging, and cognitive testing are the main ways to identify Alzheimer's, but they are difficult, expensive, and frequently miss the illness early on. Such approaches lack the sensitivity and real-time monitoring essential for early intervention. Through wearable technology and sophisticated DL approaches, Early Detection using Deep Learning Algorithm (ED-DLA) tackles these constraints. In real time, wearable sensors capture data on heart rate, sleep habits, and physical activity. DL algorithms evaluate this data to identify early Alzheimer's. Continuous and non-invasive monitoring improves detection sensitivity and accuracy. To evaluate sequential wearable device data, the suggested technique uses an RNN-based image classification model. Temporal patterns are essential for understanding AD development, and the RNN does so well. The slight changes in cognitive and physical activities may indicate early-stage dementia. The suggested AD diagnosis and management system improves early detection accuracy and real-time monitoring, making it more dependable and scalable.}, } @article {pmid41571954, year = {2026}, author = {Ahn, NH and Hong, SC and Hong, CR and Lee, EH and Lee, JH and Choi, SB and Jung, J and Kim, Y and Kim, JS and Park, K and Kim, YK and Kim, Y and Yang, SH}, title = {Fucoxanthin Extracted from the Microalgae Phaeodactylum tricornutum Ameliorates Alzheimer's Pathologies with the Reduction of Aβ-Induced NLRP3 Inflammasome Activation in APP/PS1 Mice.}, journal = {Molecular neurobiology}, volume = {63}, number = {1}, pages = {385}, pmid = {41571954}, issn = {1559-1182}, mesh = {Animals ; *Xanthophylls/pharmacology/therapeutic use/isolation & purification ; *Alzheimer Disease/drug therapy/pathology/metabolism ; *NLR Family, Pyrin Domain-Containing 3 Protein/metabolism ; *Amyloid beta-Peptides/metabolism ; *Inflammasomes/metabolism/drug effects ; *Microalgae/chemistry ; Mice, Transgenic ; *Presenilin-1/metabolism ; Microglia/metabolism/drug effects ; Astrocytes/metabolism/drug effects ; Brain/pathology/metabolism/drug effects ; tau Proteins/metabolism ; *Amyloid beta-Protein Precursor/metabolism ; Male ; }, abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder, one of the most common types of dementia, accompanying severe learning and memory dysfunctions. In AD brains, the misfolded aggregation and deposits of amyloid-β (Aβ) and tau are frequently observed before the cognitive symptom onset; thus, trials for alleviation of these lesions are considered commensurate strategies with AD treatment. Additionally, increasing evidence suggests that misfolded and aggregated proteins induce the activation of microglia and astrocytes by the release of the inflammatory mediators via the activation of the inflammatory signaling cascade, which consequently contributes to AD pathogenesis. Here, we investigated the therapeutic potential of fucoxanthin, a compound derived from the microalgae Phaeodactylum tricornutum, in mitigating AD pathologies. Fucoxanthin was shown to inhibit the aggregation of Aβ and tau, converting their aggregates to monomeric forms. In the brain of APP/PS1 transgenic mice, fucoxanthin administration significantly reduced the levels of Aβ plaques and hyperphosphorylated tau and further ameliorated cognitive impairments by inhibiting the activation of microglia and astrocytes. Notably, fucoxanthin effectively regulated Aβ-induced NLRP3 inflammasome activation in astrocytes, reducing neuroinflammation associated with AD. Thus, our findings showing the multifaceted therapeutic mode of action of fucoxanthin against AD provide that fucoxanthin would have promising roles in the strategies of AD treatment.}, } @article {pmid41572310, year = {2026}, author = {Kashem, M and Haldenby, O and Ahmad, JF and Muhammad, AA and Mostert, CM and Ali, S}, title = {Are diagnostic technologies for alzheimer's disease and dementia cost-effective? A systematic review of economic evaluations.}, journal = {Alzheimer's research & therapy}, volume = {18}, number = {1}, pages = {26}, pmid = {41572310}, issn = {1758-9193}, mesh = {Humans ; *Alzheimer Disease/economics/diagnosis/diagnostic imaging ; *Cost-Benefit Analysis ; *Cost-Effectiveness Analysis ; *Dementia/economics/diagnosis/diagnostic imaging ; *Neuroimaging/economics ; Biomarkers ; }, abstract = {BACKGROUND: Alzheimer's disease (AD) and dementia pose a significant clinical and economic burden globally. Early diagnosis and intervention can potentially delay disease progression. Current diagnostic guidelines recommend considering imaging and biomarker analysis in conjunction with clinical evaluation. Given limited healthcare resources, evidence on the cost-effectiveness of diagnostic technologies is critical to guide allocation of resources.

OBJECTIVE: To systematically review the economic evaluation studies of neuroimaging, biomarkers, and other diagnostic or screening strategies for diagnosing and/or tracking the progression of AD or dementia.

METHODS: A comprehensive search was conducted across Medline, Embase, PsycINFO, CINAHL and EconLit, and to identify relevant studies, with no restrictions on country, language, or publication period. Quality of the studies was evaluated using the Consensus on Health Economic Criteria-Extended (CHEC-Extended) checklist.

RESULTS: Out of 6,804 records, 21 studies met the eligibility criteria. These included evaluations of neuroimaging technologies such as Positron Emission Tomography, Single Photon Emission Computed Tomography, Computed Tomography, and Magnetic Resonance Imaging (n = 10), cerebrospinal fluid and blood biomarkers (n = 7), and alternative diagnostic strategies including screening programs, machine learning-based models, and multidisciplinary care approaches (n = 4). Among the studies evaluating imaging technologies, most (n = 6) did not find them to be cost-effective. In contrast, CSF and blood biomarker studies found these technologies to be cost-effective, with some variability in results. Methodological quality score ranged between 15% and 95%, indicating a mix of low- to high-quality studies. Due to heterogeneity in study designs and reported outcomes, direct comparisons were not feasible.

CONCLUSIONS: While many studies were of high quality, heterogeneity in study objectives, design, and outcomes restricted evidence synthesis. Future research should ensure methodological consistency, transparent cost reporting, and integration of new treatment frameworks to improve the policy relevance and reliability of economic evidence for AD diagnostics.}, } @article {pmid41572662, year = {2026}, author = {Martino-Adami, PV and Jessen, F and Brosseron, F and Bewernick, B and Domschke, K and Luppa, M and Wagner, M and Peters, O and Frölich, L and Riedel-Heller, S and Schramm, E and Ramirez, A and Dafsari, FS}, title = {Exploring blood-based biomarkers in late-life depression: Correlates of psychotherapeutic treatment outcomes.}, journal = {European psychiatry : the journal of the Association of European Psychiatrists}, volume = {69}, number = {1}, pages = {e18}, pmid = {41572662}, issn = {1778-3585}, support = {01KG1716//Bundesministerium für Bildung und Forschung/ ; 01ED2007A//Bundesministerium für Bildung und Forschung/ ; 2030-390661388//Deutsche Forschungsgemeinschaft/ ; }, mesh = {Humans ; *Biomarkers/blood ; Male ; Female ; Aged ; *Major Depressive Disorder/therapy/blood ; Middle Aged ; Treatment Outcome ; *Cognitive Behavioral Therapy ; Aged, 80 and over ; }, abstract = {BACKGROUND: Major depressive disorder is a prevalent and debilitating mental health condition contributing to a growing global burden. Late-life depression (LLD), affecting individuals over 60 years of age, is further associated with elevated risks for cardiovascular diseases, cognitive decline, and dementia. Treatment responses vary widely, potentially due to underlying neurodegeneration and cellular senescence. We aimed to explore blood-based biomarkers related to Alzheimer's disease and senescence-associated secretory phenotype (SASP) proteins, seeking to identify biological underpinnings of LLD and their association with response to psychotherapy.

METHODS: We performed a secondary analysis of the Cognitive Behavioral Therapy for Late-Life Depression (CBTlate) trial in 228 participants aged 60 years and older with a diagnosis of LLD. Depression trajectories were compared using clustering. In participants with available plasma samples, biomarker data were generated post hoc. We assessed associations between biomarkers and depression trajectories, biomarker dynamics, and their ability to predict treatment response.

RESULTS: Two depression trajectories were identified: persistently high stable Geriatric Depression Scale (GDS) scores (hsGDS) and decreasing scores over time (dGDS). The hsGDS group had more severe baseline depression (p = 2.88 × 10[-6]), anxiety (p = 4.39 × 10[-4]), and sleep disorders (p = 1.09 × 10[-3]), and was more likely to have a history of major depression (p = 0.01) and mild cognitive impairment (p = 0.01). Biomarker analysis revealed elevated baseline plasma neurofilament light chain (NfL, p = 2.51 × 10[-2]) and reduced C-X-C Motif Chemokine Ligand 5 (CXCL5, p = 2.83 × 10[-2]) in the hsGDS group. Including CXCL5 in predictive models improved trajectory differentiation (p = 3.94 × 10[-3]).

CONCLUSIONS: Cellular aging biomarkers like CXCL5 may improve understanding of LLD and guide personalized therapeutic interventions.}, } @article {pmid41573059, year = {2025}, author = {Ayla, S and Saygi, HI and Sahin, M and Ciftkaya, E and Kilic, A and Pence, S and Bahadori, F and Dolanbay, EG and Elibol, B}, title = {Urtica dioica can regulate autophagy pathway in the rat hippocampal tissue after STZ-induced neurodegeneration.}, journal = {Northern clinics of Istanbul}, volume = {12}, number = {5}, pages = {531-539}, pmid = {41573059}, issn = {2536-4553}, abstract = {OBJECTIVE: Autophagy plays a crucial role in neuroprotection by helping to clear toxic substances, like misfolded proteins. In neurodegeneration, autophagy is impaired leading to the accumulation of harmful proteins that disrupt neuronal function, promote inflammation, and contribute to the degeneration of brain cells. Therefore, because of its anti-inflammatory and anti-oxidative actions, the effects of Urtica dioica (UD) on the proteins of autophagy signaling pathways was studied in the hippocampus of rats with streptozotocin-(STZ) induced neurodegeneration.

METHODS: Neurodegeneration model of rats was induced by intracerebroventricular injection of STZ (3 mg/kg) to observe both cognitive deficits and autophagic dysfunction. Then, the rats in the treatment group were consumed UD at the dose of 50 mg/kg/day for 4 weeks. At the end of 4 weeks, passive avoidance test was applied for cognitive functions and hippocampal tissue of rats were investigated to determine the changes in the proteins related to autophagy by western blotting and immunofluoresecence.

RESULTS: UD treatment slightly attenuated the STZ-induced memory deficiencies in the rats. In addition, an increase in the autophagy was noted by increasing the expression of Beclin, ATG5, and LC3β proteins in the STZ-UD group compared to the STZ group.

CONCLUSION: In summary, UD may be a candidate molecule as a therapeutic strategy to protect neurons in neurodegeneration through increasing autophagy to reduce toxic protein accumulation.}, } @article {pmid41573383, year = {2025}, author = {Liu, B and Chen, C and Cai, P and Zhang, J and Yang, L and Chen, X and Ma, X and Jiang, X and Zhang, A and Song, L and Jiang, L}, title = {The alterations in brain network functional gradients and dynamic functional connectivity in Alzheimer's disease: a resting-state fMRI study.}, journal = {Frontiers in aging neuroscience}, volume = {17}, number = {}, pages = {1716076}, pmid = {41573383}, issn = {1663-4365}, abstract = {BACKGROUND AND PURPOSE: Alzheimer's disease (AD), the most common form of dementia worldwide, is characterized by progressive cognitive decline. Extensive evidence from dynamic functional connectivity (dFC) studies has demonstrated unstable functional states, reduced network flexibility, and impaired transitions between large-scale neurocognitive networks across the AD continuum. However, how these temporal abnormalities are embedded within the hierarchical spatial organization of brain networks, as captured by functional gradients (FG), and whether combined FG-dFC metrics can provide mechanistically interpretable and potentially sensitive imaging biomarkers, remain to be elucidated.

METHODS: This study enrolled 46 AD patients who were diagnosed according to the Amyloid/Tau/Neurodegeneration (ATN) biological diagnostic framework and 37 age- and sex-matched healthy controls (HC). All participants underwent resting-state fMRI. Functional gradients were derived using connectivity similarity matrices and diffusion embedding (aligned and standardized), while dFC was estimated with a sliding window approach and clustered into four recurrent states. Group differences were assessed with two-sample t-tests with Gaussian Random Field (GRF) correction. Correlation analyses included ATN biomarkers and cognitive scores. A linear support vector machine (SVM) with leave-one-out cross-validation evaluated classification performance based on significant FG features.

RESULTS: Compared to the healthy controls, AD patients exhibited widespread FG alterations between regions of the Default Mode Network (DMN) and the Sensorimotor Network (SMN). In the first gradient DMN, the left precuneus showed reduced gradient scores, whereas the right medial superior frontal gyrus and bilateral angular gyri were increased. In the first gradient of the SMN, the right supplementary motor area increased while bilateral superior temporal gyri decreased. Second-gradient reductions were confined to two regions: the left postcentral gyrus (SMN) and left middle occipital gyrus (visual network, VIS). The right medial superior frontal gyrus first-gradient score correlated negatively with T-Tau (r = -0.50, P = 0.006) and age (r = -0.36, P = 0.02); the right angular gyrus correlated negatively with age (r = -0.29, P = 0.04); the left precuneus correlated positively with age (r = 0.38, P = 0.009). dFC revealed four recurrent states (27.59, 17.67, 28.27, 26.47% of total occurrences). Relative to HC, AD showed higher FT and MDT in states 1-2 and lower scores in state 3, with NT unchanged, alongside state-dependent bidirectional connectivity changes (fronto-insular-sensorimotor increases; DMN-temporal and visuo-auditory decreases). The SVM achieved an AUC of 0.776, sensitivity 78.26%, specificity 67.57%, and accuracy 73.49%, with the right superior temporal gyrus within SMN first-gradient contributing most.

CONCLUSION: AD is characterized by macro-scale hierarchical disorganization centered on the principal functional gradient, accompanied by reduced cross-state flexibility and state-dependent connectivity abnormalities. The combined functional gradient-dynamic functional connectivity (FG-dFC) analysis provides complementary spatiotemporal insights and reveals imaging features associated with T-Tau levels and age, offering new perspectives on the neuropathological mechanisms of AD and potential imaging biomarkers. Moreover, these network topology and dynamic connectivity metrics may prove useful for monitoring disease progression, evaluating treatment effects, and stratifying patients in future clinical and interventional studies.}, } @article {pmid41573517, year = {2025}, author = {Ham, HJ and Park, SS and Lee, YS and Kim, TH and Son, DJ and Kim, JH and Lim, KH and Park, H and Lee, HJ and Yun, J and Han, SB and Choi, MK and Hong, JT}, title = {CHI3L1 monoclonal antibody therapy mitigates cognitive impairment by inhibiting neuroinflammation through ERK and NF-κB pathway in Tg2576 mice.}, journal = {Frontiers in molecular neuroscience}, volume = {18}, number = {}, pages = {1728279}, pmid = {41573517}, issn = {1662-5099}, abstract = {INTRODUCTION: Alzheimer's disease (AD) is neurodegenerative disorder characterized by chronic inflammation in the brain. Chitinase-3-like 1 (CHI3L1), a secreted glycoprotein that is upregulated in a variety of diseases with chronic inflammation, represents a promising target for AD. Here, we studied the inhibitory effect of a novel CHI3L1 monoclonal antibody (H1) on memory impairment and neuroinflammation in Tg2576 transgenic mice.

METHODS AND RESULTS: H1 was shown to cross the blood-brain barrier selectively, as confirmed by fluorescence imaging. Tg2576 mice were administered H1 (2 mg/kg, i.v., weekly for 1 month), and cognitive functions were assessed through behavioral tests. H1 treatment alleviated memory impairment and reduced amyloid deposition and neuroinflammation both in Tg2576 mice and Aβ-induced BV-2 microglial cells. Mechanistically, H1 inhibited the ERK and NF-κB signaling pathways and suppressed M1 microglial marker expression. Global proteomic analysis and gene expression profiling in BV-2 cells and Tg2576 mouse brains revealed a strong association between CHI3L1 and HAX1 expression. H1 therapy significantly reduced HAX1 levels in both in vivo and in vitro models. Moreover, HAX1 induction by Aβ or CHI3L1 was blocked by an NF-κB inhibitor.

DISCUSSION: These findings suggest that CHI3L1 monoclonal antibody therapy may attenuate cognitive decline in AD by modulating neuroinflamma.}, } @article {pmid41574617, year = {2026}, author = {Sharma, P and Goyal, R}, title = {Mitigation of Circadian Disruption-Induced Amyloid Pathology, Neuroinflammation, and Cognitive Disability in C57BL/6J Mice Using Estradiol.}, journal = {ACS chemical neuroscience}, volume = {17}, number = {3}, pages = {537-549}, doi = {10.1021/acschemneuro.5c00650}, pmid = {41574617}, issn = {1948-7193}, mesh = {Animals ; *Estradiol/pharmacology ; Female ; Mice, Inbred C57BL ; Mice ; *Circadian Rhythm/drug effects/physiology ; *Neuroinflammatory Diseases/drug therapy/pathology/metabolism ; Hippocampus/drug effects/metabolism/pathology ; Amyloid beta-Peptides/metabolism ; *Estrogens/pharmacology ; *Cognition Disorders/drug therapy/pathology/metabolism ; *Chronobiology Disorders/drug therapy/pathology ; Suprachiasmatic Nucleus/drug effects/metabolism ; Disease Models, Animal ; }, abstract = {Circadian rhythms (CRs) are intrinsic 24 h cycles that regulate critical physiological processes, including sleep-wake behavior, hormonal signaling, and cognition. Disruption of CRs, often caused by chronic aberrant light exposure, has been linked to neurodegenerative diseases such as Alzheimer's disease (AD), through altered expression of core clock genes and neurotransmitter imbalances. Estrogen is a known neuromodulator that influences both circadian timing and cognitive function, yet the mechanistic interplay between estrogen and circadian dysregulation in neurodegeneration remains underexplored. In this study, we investigated whether estradiol could mitigate neuropathological and circadian disturbances induced by chronic, constant light (LL) exposure in female C57BL/6J mice. Mice were exposed to LL for 6 or 10 weeks (LL6, LL10) to model progressive CR disruption. LL10 significantly delayed locomotor rhythms (p < 0.0001), elevated hippocampal amyloid-β (Aβ) levels (p = 0.0018), and reduced SCN GABA and glutamate levels (p < 0.01), compared to LL6 and light-dark (LD) controls. Both LL6 and LL10 also showed decreased hippocampal nitric oxide and glutathione levels (p < 0.05), indicating oxidative stress. Estradiol treatment (1.5 or 3 μg/kg) restored activity rhythms, reduced Aβ accumulation (p = 0.0019), and normalized SCN neurotransmitter levels (GABA; p = 0.0046; glutamate: p = 0.0003). These effects were abrogated by tamoxifen, suggesting estrogen receptor-mediated signaling. Histological analysis further showed that estradiol attenuated hippocampal inflammation and neuronal damage in LL10-exposed animals. These results demonstrate that estrogen protects against circadian disruption-induced neuropathology and supports its potential as a therapeutic agent in mitigating cognitive decline via ER-dependent pathways.}, } @article {pmid41575410, year = {2026}, author = {Neth, BJ and Graff-Radford, J and Cogswell, PM and Johnson, DR and Botha, H and McCarter, SJ and Jones, DT and Conkins, MM and Hardin, DB and Spence, JJ and Rhegness, CL and Allen, LA and Coburn, RP and Pounders, JD and Burkett, BJ and Pillai, JJ and Day, GS and Graff-Radford, NR and Lachner, C and Messina, SA and Jain, MK and Stricker, NH and Machulda, MM and Fields, JA and Boots, EA and Aduen, PA and Barnard, LR and Remold, MA and Anderlik, AM and Asleson, KM and Martin, LL and Klaassen, JA and Larsen, JJ and Algeciras-Schimnich, A and Bornhorst, JA and Rumilla, AM and Jack, CR and Boeve, BF and Knopman, DS and Petersen, RC and Ramanan, VK}, title = {Establishing an Alzheimer Disease Therapeutics Clinic: Experience From a Year of Evaluations.}, journal = {Mayo Clinic proceedings}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.mayocp.2025.09.019}, pmid = {41575410}, issn = {1942-5546}, abstract = {OBJECTIVE: To describe the establishment and initial experience of a multidisciplinary Alzheimer disease treatment clinic (ADTC), focusing on the evaluation of eligibility for novel disease-modifying therapies, as well as the treatment and monitoring of qualifying patients.

PATIENTS AND METHODS: We completed a retrospective review of cases seen through the Mayo Clinic ADTC between October 2, 2023, and December 31, 2024. Typical evaluations occurred over 4 to 5 days and included multimodal testing, office visits, and a weekly case conference modeled on tumor board meetings.

RESULTS: Patients evaluated in the ADTC (N=232) ranged from 52 to 85 years of age (mean age, 71.2 years). Most patients had mild cognitive impairment (128 of 232 [55%]) or mild dementia (72 of 232 [31%]) syndromes. Overall, 121 patients (52%) were judged eligible for antiamyloid therapy. Eligibility rates were higher among internal (from our institution) referrals compared with external referrals (63% [146 of 232] vs 37% [86 of 232). Reasons for treatment ineligibility were typically multiple but commonly included magnetic resonance imaging features, too severe cognitive/functional impairment, and general health conditions believed likely to increase therapeutic risks. In some cases, the ADTC evaluation uniquely identified treatment risk factors, such as cerebral amyloid angiopathy, that had not been previously discussed with patients. Through shared decision making, approximately 30% of eligible patients (25 of 81) ultimately deferred antiamyloid therapy. In addition, approximately 10% of patients evaluated in the ADTC were amyloid-negative by positron emission tomography, suggesting non-Alzheimer disease diagnoses for their presentations.

CONCLUSION: The ADTC facilitated systematic implementation of antiamyloid therapies for early Alzheimer disease and provided a scalable foundation for integrating future approved treatment options.}, } @article {pmid41575555, year = {2026}, author = {Yu, S and Ye, Z and Zhao, W and Yu, X and Qiu, Y and Lin, K and Lu, T and Ge, L and Sun, J and Hua, R}, title = {Genetic evidence on chemical communication between gut microbiota and neurological and psychiatric disorders: a Mendelian randomization study.}, journal = {European archives of psychiatry and clinical neuroscience}, volume = {276}, number = {4}, pages = {1759-1773}, pmid = {41575555}, issn = {1433-8491}, support = {2019YFC1708601//the National Key Research and Development Program of China/ ; SZ2021ZZ14//the Specific Fund of State Key Laboratory of Dampness Syndrome of Chinese Medicine/ ; YN2018ZD04and2019-140//the Guangdong Provincial Key Laboratory of Research on Emergency in traditional Chinese medicine (TCM)/ ; }, mesh = {Humans ; *Gastrointestinal Microbiome/genetics/physiology ; Mendelian Randomization Analysis ; *Alzheimer Disease/genetics/metabolism/blood/microbiology ; *Autism Spectrum Disorder/genetics/metabolism/microbiology/blood ; *Mental Disorders/genetics/metabolism/microbiology/blood ; *Anxiety Disorders/genetics/metabolism/blood/microbiology ; *Isoleucine/blood ; *Depressive Disorder/genetics/metabolism/microbiology ; *Brain-Gut Axis/physiology ; }, abstract = {BACKGROUND: Accumulating evidence from clinical trials and preclinical studies revealed the importance of the microbiota-gut-brain axis (MGBA) in neurological and psychiatric disorders (NPDs). MGBA remains a blueprint for extended explorations. METHODS: We examine the bidirectional association between 5 NPDs (late-onset Alzheimer’s disease (AD), migraine, autism spectrum disorder (ASD), all anxiety disorder, depression) and gut microbiota (GM) via microbial-derived metabolites, neurotransmitter, and precursors including total branched-chain amino acids (BCAA), isoleucine, leucine, valine, acetate, tryptophan, kynurenine, glutamate, tyrosine, serotonin using two step Mendelian randomization. Five methods were performed, including inverse variance weighted, MR Egger regression, weighted median, weighted mode, and simple mode. The robustness of results was supported by Cochran’s Q test, the MR-Egger regression, the MR pleiotropy residual sum and outlier, and the leave-one-out method. RESULTS: After false discovery rate correction, we found elevated isoleucine in plasma as a risk factor for AD and elevated tyrosine in plasma as a risk factor for anxiety. Conversely, AD has genetically effect on a lower level of total BCAA, isoleucine, leucine, valine, glutamate, and tyrosine in plasma. We also found that Clostridia, Clostridiales, Sutterella, and Ruminococcus torques group were positively correlated with isoleucine. Elevated Sutterella abundance was found strongly positively correlated with ASD. Desulfovibrionales and Desulfovibrionaceae were found strongly positively correlated with AD. Pathways of Clostridia/Clostridiales/Ruminococcus torques group/Sutterella- isoleucine- AD were established with mediating percentages ranging from − 54.265% to 132.908%. CONCLUSION: Our study elucidates how chemical signalling bridges communication between GM and NPDs, paving avenues for microbiota-based treatment.}, } @article {pmid41575675, year = {2026}, author = {Kopalli, SR and Wankhede, N and Rahangdale, SR and Sammeta, S and Aglawe, M and Koppula, S and Taksande, B and Upaganlawar, A and Umekar, M and Kale, M}, title = {Age-driven dysbiosis: gut microbiota in the pathogenesis and treatment of aging disorders.}, journal = {Biogerontology}, volume = {27}, number = {1}, pages = {42}, pmid = {41575675}, issn = {1573-6768}, mesh = {Humans ; *Dysbiosis/microbiology/therapy ; *Aging/physiology ; *Gastrointestinal Microbiome/physiology ; Probiotics/therapeutic use ; Animals ; *Nervous System Diseases/microbiology/therapy ; Fecal Microbiota Transplantation ; }, abstract = {Aging, a complex physiological and molecular process, has undergone significant changes, of which gut microbiome composition has surfaced as an important key in the maintenance of neurological health. Recent studies have revealed the significant impact of age-related gut dysbiosis in the induction of neuroinflammation, metabolic syndrome, disruptions in gut-brain axis, and age-related neurological decline. Although significant studies have revealed the impact of the microbiome-gut-brain axis in individual neurological diseases, an aging-focused holistic synthesis has not yet been adequately developed. This review provides a critical assessment of the involvement of age-related dysbiosis of gut microbiota in the development and progression of neurological disorders such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, multiple sclerosis, and cognitive aging of the elderly, and to focus on age-related microbial patterns and mechanisms of dysbiosis related to neurological aging, including inflammation and immune system dysregulation, metabolic changes, oxidative stress, barrier dysfunction, and gut-brain communication through enteroendocrine, enteric neural, and vagal mechanisms, and to emphasize disease-specific and common microbial patterns of dysbiosis and beneficial and harmful microbial roles in aging diseases. This review assesses some of the latest promising therapies aimed at the microbiota, such as probiotics, prebiotics, dietary therapies, fecal microbiota transplantation, as well as pharmacological therapies, and critically discusses their limitations in terms of interindividual variability and their generalisation and applicability. Focusing on mechanistic, comparative, and translation aspects, this review offers a comprehensive approach to neurological aging due to gut microbiota and identifies gaps for future precision microbiome-based interventions.}, } @article {pmid41576501, year = {2026}, author = {Jayaswamy, PK and Ambrish, T and Sangamesh, VC and Kabekkodu, SP and Kellarai, A and Shetty, J and Shetty, P}, title = {EGFR-Annexin A2 signaling-mediated tauopathy in amyloid-β and aluminum chloride-induced Alzheimer's disease and its modulation by the HDAC inhibitor butyrate.}, journal = {Ecotoxicology and environmental safety}, volume = {310}, number = {}, pages = {119775}, doi = {10.1016/j.ecoenv.2026.119775}, pmid = {41576501}, issn = {1090-2414}, mesh = {Animals ; Aluminum Chloride ; *Amyloid beta-Peptides/toxicity/metabolism ; *ErbB Receptors/metabolism ; *Alzheimer Disease/chemically induced/metabolism/drug therapy ; Signal Transduction/drug effects ; Rats ; Humans ; *Tauopathies/metabolism/chemically induced/drug therapy ; *Annexin A2/metabolism ; tau Proteins/metabolism ; Male ; PC12 Cells ; Neurons/drug effects ; }, abstract = {Alzheimer's disease (AD) is typified by amyloid-β (Aβ) accumulation and tauopathy, culminating in synaptic destabilization, dendritic atrophy, and widespread neurodegeneration. Epidermal growth factor receptor (EGFR), prominently expressed during neurodevelopment, is largely quiescent in adulthood but undergoes pathological reactivation in AD, with its mechanistic contribution remaining elusive. Here, we delineate the EGFR-Annexin A2 (AnxA2) signaling nexus as a pivotal mediator of tau hyperphosphorylation in Aβ1-42-challenged SH-SY5Y and PC12 neuronal cultures and in aluminum chloride (AlCl3)/D-galactose (D-gal)-induced AD rat models. In vitro, Aβ1-42 orchestrated synergistic EGFR-AnxA2 activation, triggering site-specific tau phosphorylation (Thr231/Ser396), synaptic protein depletion, apoptotic cascades, neuroinflammatory signaling, and plasminogen activator inhibitor-1 (PAI-1)-driven fibrinolytic deficits. In vivo, AlCl3/D-gal rats displayed hippocampal EGFR-AnxA2 upregulation, region-specific tauopathy, cognitive impairments in Open Field and Novel Object Recognition paradigms, oxidative perturbations, and elevated TNF-α. Butyrate intervention abrogated EGFR-AnxA2 hyperactivity, attenuated tau pathology, restored PAI-1/tissue plasminogen activator homeostasis, and mitigated oxidative stress and neuroinflammation. Moreover, butyrate preserved synaptic and dendritic architecture, modulated apoptotic effectors by upregulating Bcl-2 and suppressing Bad, and enhanced neuronal viability. In vivo pre-and post-treatment paradigms improved behavioral and molecular outcomes, with prophylactic administration exhibiting superior efficacy. Collectively, these findings establish EGFR-AnxA2 as a central driver of tauopathy and identify prophylactic butyrate as a mechanistically grounded, diet-derived neuroprotective strategy capable of attenuating tau hyperphosphorylation, synaptic loss, and neuroinflammation in AD.}, } @article {pmid41579901, year = {2026}, author = {Tariot, PN and Lopera, FS and Ríos-Romenets, S and Sink, KM and Giraldo-Chica, M and Acosta-Baena, N and Villegas, G and Espinosa, A and Castaño, ML and Muñoz, C and Ospina, P and Bocanegra, Y and Tirado, V and Henao, E and Cardona, E and Luna, E and Lopez, H and Sánchez, G and Collazos, MM and Alvarez, S and Aguillón, D and Hu, N and Clayton, D and Bittner, T and Schneider, A and Dolton, M and Poon, V and Nguyen, J and Thomas, RG and Schneider, LS and Chen, K and Su, Y and Alexander, RC and Quiroz, YT and Cai, Y and Xu, YR and Ostaszewski, B and Selkoe, DJ and Ashton, NJ and Denkinger, MN and Jakimovich, LJ and Doody, RS and Langbaum, JB and Reiman, EM}, title = {Safety and efficacy of crenezumab in cognitively unimpaired carriers of the PSEN1[Glu280Ala] mutation at risk for autosomal-dominant Alzheimer's disease in Colombia (API ADAD Colombia Trial): a phase 2, randomised, double-blind, placebo-controlled trial.}, journal = {The Lancet. Neurology}, volume = {25}, number = {2}, pages = {147-159}, pmid = {41579901}, issn = {1474-4465}, support = {P30 AG019610/AG/NIA NIH HHS/United States ; P30 AG072980/AG/NIA NIH HHS/United States ; R01 AG055444/AG/NIA NIH HHS/United States ; RF1 AG041705/AG/NIA NIH HHS/United States ; }, mesh = {Humans ; *Alzheimer Disease/genetics/drug therapy ; Double-Blind Method ; Male ; *Presenilin-1/genetics ; Female ; Middle Aged ; *Antibodies, Monoclonal, Humanized/therapeutic use/adverse effects ; Colombia ; Adult ; Mutation/genetics ; Heterozygote ; Treatment Outcome ; }, abstract = {BACKGROUND: To have maximal benefit, Alzheimer's disease-modifying treatments might need to be started before the onset of clinical symptoms. Mutations of the PSEN1 gene are inherited as fully penetrant, autosomal-dominant traits, which almost always result in the clinical onset of Alzheimer's disease before the age of 65 years. We aimed to evaluate the efficacy, including possible delayed emergence of cognitive impairment, and safety of crenezumab, an anti-amyloid monoclonal antibody, in cognitively unimpaired carriers of the PSEN1[Glu280Ala] mutation at high imminent risk of developing symptoms due to Alzheimer's disease.

METHODS: This 5-8-year common-close, double-blind, placebo-controlled, single-centre trial screened kindred members aged 30-60 years from the main health-care site in Medellín, Colombia. Participants who were cognitively unimpaired and carried the PSEN1[Glu280Ala] autosomal-dominant mutation were randomly assigned 1:1 to receive placebo or subcutaneous crenezumab (investigators and participants were masked to treatment allocation), with an initial 300 mg dose every 2 weeks that increased to 720 mg every 2 weeks, and a later optional increase to 60 mg/kg intravenously every 4 weeks. Randomisation was stratified by age, education, APOE ɛ4 carrier status, and baseline Clinical Dementia Rating. Mutation non-carriers received placebo and were included in a 1:2 ratio of non-carriers to carriers to maintain genotype masking and include a genetic kindred control. Dual primary outcomes were the annualised rates of change in the Alzheimer's Prevention Initiative (API) preclinical autosomal-dominant Alzheimer's disease (ADAD) composite test total score and Free and Cued Selective Reminding Test-Cueing Index (FCSRT-CI) assessed in randomised participants who received at least one dose of the study drug, according to treatment assignment. Primary endpoints were assessed with a random coefficient regression model with a missing-at-random assumption adjusting for randomisation factors. Safety endpoints for mutation carriers were assessed in randomised participants who received at least one dose of the study drug. This trial is registered with ClinicalTrials.gov (NCT01998841) and is completed.

FINDINGS: 619 Colombian API registrants were prescreened, 315 were assessed for eligibility, and 252 were enrolled (crenezumab-carrier, n=85; placebo-carrier, n=84; placebo-non-carrier, n=83; 160 [63%] women and 92 [37%] men) between Dec 20, 2013, and Feb 27, 2017. 237 (94%) completed the trial, with final data collection on March 22, 2022. The annualised rate of change in the API ADAD composite was -1·10 (SE 0·29) in the crenezumab group and -1·43 (0·29) in the placebo group (between-group difference 0·33 [95% CI -0·48 to 1·13]; p=0·43). The annualised rate of change in FCSRT-CI was -0·03 (0·00) in the crenezumab group and -0·04 (0·00) in the placebo group (between-group difference 0·01 [0·00 to 0·02]; p=0·16). All participants had at least one adverse event; serious adverse events occurred in 23 (27%) of 84 in the crenezumab group and 21 (25%) of 84 in the placebo group. No fatalities occurred.

INTERPRETATION: Crenezumab therapy administered for 5-8 years did not result in significant benefits on our primary clinical outcomes in cognitively unimpaired participants predisposed to developing ADAD dementia; secondary and exploratory outcomes also showed no significant effect on removal of amyloid plaques or other clinical or biomarker outcomes. Together with the results of other anti-amyloid β trials, robust fibrillar amyloid removal appears necessary for clinical efficacy in people with elevated brain amyloid. This study will further inform the biomarker, cognitive, and clinical trajectory of preclinical ADAD, the risk of clinical progression in amyloid-positive and amyloid-negative mutation carriers, and the size and design of future secondary and primary prevention trials.

FUNDING: US National Institute on Aging (NIA), Banner Alzheimer's Institute, Genentech, F Hoffmann-La Roche.}, } @article {pmid41579987, year = {2026}, author = {Jeon, YN and Baek, JS}, title = {TPGS-coated zein nanoparticles encapsulating Haematococcus pluvialis extract for Alzheimer's disease: An in vitro evaluation towards brain-targeted delivery.}, journal = {International journal of biological macromolecules}, volume = {344}, number = {Pt 2}, pages = {150378}, doi = {10.1016/j.ijbiomac.2026.150378}, pmid = {41579987}, issn = {1879-0003}, mesh = {*Zein/chemistry ; *Alzheimer Disease/drug therapy/metabolism ; Humans ; *Nanoparticles/chemistry ; *Vitamin E/chemistry/analogs & derivatives ; Blood-Brain Barrier/metabolism/drug effects ; Animals ; *Chlorophyta/chemistry ; *Brain/metabolism/drug effects ; Drug Carriers/chemistry ; *Plant Extracts/chemistry/pharmacology ; Xanthophylls/chemistry/pharmacology ; *Drug Delivery Systems ; Mice ; Antioxidants/chemistry/pharmacology ; }, abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by β-amyloid (Aβ) aggregation and limited treatment efficacy due to the restrictive nature of the blood-brain barrier (BBB). To address this, we developed d-α-tocopheryl polyethylene glycol 1000 succinate (TPGS)-coated Zein nanoparticles (Hp-Zein-TPGS NPs) encapsulating Haematococcus pluvialis (Hp) extract as a brain-targeted drug delivery system. Hp-Zein-TPGS NPs exhibited high physical stability over 14 days, sustained astaxanthin release, and potent antioxidant activity. The NPs also demonstrated excellent biocompatibility, showing minimal cytotoxicity in both bEnd.3 and SH-SY5Y cells, along with enhanced cellular uptake in vitro. Based on the reported effects of TPGS on P-glycoprotein (P-gp) inhibition and membrane fluidity, a delivery strategy was designed to facilitate BBB transport. In an in vitro BBB model, Hp-Zein-TPGS NPs exhibited increased transport, and Rhodamine 123 (Rh123) accumulation analysis indicated properties associated with the regulation of P-gp mediated efflux. In addition, Thioflavin T (ThT) fluorescence and morphological analyses confirmed that Hp-Zein-TPGS NPs effectively inhibited Aβ1-42 aggregation and fibril formation, while WST and Annexin V-FITC/PI assays demonstrated that Hp-Zein-TPGS NPs significantly attenuated Aβ1-42-induced neuronal toxicity, indicating their neuroprotective effects. Taken together, these findings suggest that Hp-Zein-TPGS NPs possess favorable stability, biocompatibility, BBB transport potential, and neuroprotective effects, highlighting their promise as a nanocarrier system for brain-targeted therapeutic delivery in AD.}, } @article {pmid41580393, year = {2026}, author = {Feiten, AF and Dahm, K and Schlepckow, K and van Lengerich, B and Suh, JH and Reifschneider, A and Wefers, B and Bartos, LM and Wind-Mark, K and de Weerd, L and Ulas, T and De-Domenico, E and Grundschöttel, P and Paulusch, S and Tast, B and Honda, T and Müller, SA and Becker, M and Khalin, I and Ricci, A and Liesz, A and Brunner, B and Krenner, C and Buschmann, K and Nuscher, B and Spieth, L and Junker, N and Berghoff, SA and Davis, SS and Neher, JJ and Wurst, W and Plesnila, N and Lewcock, JW and Simons, M and Lichtenthaler, SF and Di Paolo, G and Brendel, M and Capell, A and Monroe, KM and Schultze, JL and Haass, C}, title = {TREM2 expression level is critical for microglial state, metabolic capacity and efficacy of TREM2 agonism.}, journal = {Nature communications}, volume = {17}, number = {1}, pages = {}, pmid = {41580393}, issn = {2041-1723}, support = {HA1737/16-1//Deutsche Forschungsgemeinschaft (German Research Foundation)/ ; //Alzheimer Forschung Initiative/ ; //Centres of Excellence in Neurodegeneration/ ; }, mesh = {Animals ; *Microglia/metabolism/drug effects ; *Receptors, Immunologic/agonists/metabolism/genetics ; *Membrane Glycoproteins/agonists/metabolism/genetics ; Mice ; Mice, Transgenic ; Phagocytosis ; Alzheimer Disease/metabolism/genetics/pathology ; Cholesterol/metabolism ; Signal Transduction ; Humans ; Amyloid beta-Protein Precursor/genetics/metabolism ; }, abstract = {Triggering receptor expressed on myeloid cells 2 (TREM2) is a central regulator of microglial activity and loss-of-function coding variants are major risk factors for late onset Alzheimer's disease (LOAD). To better understand the molecular and functional changes associated with TREM2 signalling in microglia, we generated a TREM2 reporter mouse. In APP transgenic animals, bulk RNA-sequencing of isolated microglia sorted based on reporter expression highlighted TREM2 level-related changes in major immunometabolic pathways, and enrichment of genes in oxidative phosphorylation and cholesterol metabolism in microglia with increased TREM2 expression. Metabolic and lipidomic profiling of sorted microglia showed that, independent of Aβ pathology, TREM2 expression correlated with signatures consistent with increased cellular redox, energetics, and cholesterol homoeostasis. In accordance, metabolic activity correlated with phagocytic capacity. Finally, we performed chronic treatment with a TREM2 agonist antibody and identified a window of TREM2 expression where microglia are most responsive, thereby informing clinical applications of TREM2 agonists.}, } @article {pmid41581519, year = {2026}, author = {Vossel, K and Johnson, EL and Cretin, B and Matsumoto, R}, title = {Epileptic activity in Alzheimer's disease: emerging insights and therapeutic implications.}, journal = {The Lancet. Neurology}, volume = {25}, number = {3}, pages = {294-307}, doi = {10.1016/S1474-4422(25)00425-9}, pmid = {41581519}, issn = {1474-4465}, mesh = {Humans ; *Alzheimer Disease/complications/physiopathology/therapy ; *Epilepsy/therapy/diagnosis/complications/drug therapy/physiopathology ; Anticonvulsants/therapeutic use ; }, abstract = {An estimated 60% of patients with Alzheimer's disease develop epilepsy or subclinical epileptiform activity over the course of the disease. New-onset seizures in cognitively healthy adults also increase the risk of developing dementia. Epileptic activity, including both seizures and subclinical epileptiform discharges, can hasten the onset of Alzheimer's disease and accelerate cognitive decline. Studies are investigating whether antiseizure medications could improve cognitive outcomes, particularly in patients with Alzheimer's disease with epileptic activity. Detection of epileptic activity in people with Alzheimer's disease requires high clinical vigilance and neurophysiological monitoring. Evaluation and treatment of late-onset epilepsy or Alzheimer's disease-associated epileptic activity should be informed by clinical advances. Epilepsy management is especially important in patients receiving anti-amyloid monoclonal antibodies, which can increase seizure risk. Recent insights support the concept of an epileptic subtype of Alzheimer's disease, position epileptic activity as a modifiable risk factor in Alzheimer's disease, highlight innovations for earlier identification of epileptic activity, and provide evidence supporting the need for early detection and targeted treatment across the stages of Alzheimer's disease.}, } @article {pmid41582466, year = {2026}, author = {Kim, H and Lee, KH and Han, C and Patkar, AA and Masand, PS and Bahk, WM and Pae, CU}, title = {Brexpiprazole for the Treatment of Agitation Associated with Dementia due to Alzheimer's Disease: Clinical Perspectives.}, journal = {Clinical psychopharmacology and neuroscience : the official scientific journal of the Korean College of Neuropsychopharmacology}, volume = {24}, number = {1}, pages = {15-29}, pmid = {41582466}, issn = {1738-1088}, abstract = {Dementia is a neuropsychiatric disorder that primarily affects the elderly, leading to a widespread decline in cognitive function and significant impairment of occupational, social, and personal functioning. In addition to cognitive deficits, dementia is frequently comorbid with behavioral and psychological symptoms of dementia (BPSD), such as agitation. When present, these secondary symptoms can exacerbate the clinical course of the disease, reduced treatment responsiveness, increased rates of admission to long-term care facilities, extended hospitalization, higher risk of personal injury and a substantial socioeconomic burden. Given these consequences, early management of BPSD-particularly agitation-is critical to mitigating these risks. Although antipsychotics are commonly prescribed to manage agitation, risperidone remains the only agent approved by regulatory authorities for this indication. Recently, however, brexpiprazole, a medication with a pharmacological profile distinct from that of risperidone, received U.S. FDA approval (on May 11, 2023) for the treatment of agitation associated with Alzheimer's disease. Agitation is among the most prevalent BPSD manifestations, with symptoms ranging from verbal to physical aggression. Given its recent approval and unique pharmacodynamic properties, brexpiprazole may have strong potential as a therapeutic option for this population. This paper aims to review the pharmacological mechanisms, clinical evidence, and future perspectives of brexpiprazole as a novel therapeutic option for managing agitation in patients with Alzheimer's disease.}, } @article {pmid41582778, year = {2026}, author = {Mumtaz, and Unnithan, D and Hosseini, H and Ali, J and Khan, MA}, title = {Chitosan nanoparticles for brain targeted nose-to-brain drug delivery in neurodegenerative disease: a comprehensive exploration of advances, limitations and future prospects.}, journal = {Expert opinion on drug delivery}, volume = {23}, number = {5}, pages = {761-779}, doi = {10.1080/17425247.2026.2619090}, pmid = {41582778}, issn = {1744-7593}, mesh = {Humans ; *Chitosan/chemistry ; *Neurodegenerative Diseases/drug therapy/physiopathology ; Animals ; Nanoparticles/chemistry ; Blood-Brain Barrier/metabolism ; Administration, Intranasal ; *Drug Delivery Systems ; Brain/metabolism ; Biological Availability ; Nanoparticle Drug Delivery System ; }, abstract = {INTRODUCTION: Neurodegenerative diseases (NDDs), such as Alzheimer's and Parkinson's and epilepsy, cause irreversible nerve cell degradation, resulting in cognitive and motor decline. The blood-brain barrier (BBB) complicates treatment, limiting drug access and causing low bioavailability. Chitosan nanoparticles (CH-NPs) offer a promising solution for improving drug delivery to the brain due to their biocompatibility and ability to enhance intranasal delivery, potentially increasing therapeutic efficacy.

AREAS OF COVERAGE: The review discusses advancements in chitosan-based nanoparticle drug delivery systems for NDDs, highlighting literature from 2015 to 2025. It indicates that chitosan can improve drug uptake in the brain by up to ten times and emphasizes its potential for targeted central nervous system (CNS) delivery due to its unique properties. Additionally, intranasal delivery is a non-invasive method to bypass the BBB and enhance therapeutic precision.

EXPERT OPINION: CH-NPs effectively deliver therapeutics to the CNS, leveraging their mucoadhesive properties and biocompatibility to cross the BBB via intranasal delivery. This platform enhances drug uptake and retention in the brain, addressing challenges faced by traditional therapies for NDDs. Optimizing nanoparticle biomaterial properties and delivery methods could improve therapeutic precision and clinical outcomes.}, } @article {pmid41582996, year = {2025}, author = {Deng, Y and Yin, H and Lu, Z and Lan, H and Liu, W and Zuo, C and Pan, N and Tian, X and Gong, Q}, title = {LRP1 at the crossroads of Aβ clearance and therapeutic targeting in Alzheimer's disease.}, journal = {Frontiers in aging neuroscience}, volume = {17}, number = {}, pages = {1669405}, pmid = {41582996}, issn = {1663-4365}, abstract = {Alzheimer's disease (AD), characterized by progressive cognitive decline, memory impairment and behavioral disturbances, is the most common form of dementia, and no disease-modifying treatments are available to halt or slow its progression. Amyloid-beta (Aβ) is suggested to play a pivotal role in the pathogenesis of AD, and enhancing the clearance of Aβ from the brain has emerged as a major research direction. As the primary receptor for Aβ clearance at the blood-brain barrier (BBB), low-density lipoprotein receptor-related protein 1 (LRP1) plays a crucial role in regulating Aβ transport and metabolism. Understanding the mechanisms through which LRP1 functions, as well as the factors that influence its activity is essential for enhancing Aβ clearance from the brain and developing targeted therapeutic strategies for Alzheimer's disease. In this review, we introduce the transport of Aβ across the BBB, followed by a discussion of the basic structure and function of LRP1 and its role in AD progression. Then, we summarize factors affecting LRP1 function and current advances in LRP1-targeted therapies. Finally, we explore the potential of LRP1 as a therapeutic target for AD. So, LRP1 may be a central modulator of Aβ dynamics and a clinically actionable target for treatment of Alzheimer's disease.}, } @article {pmid41583006, year = {2025}, author = {Eyamu, J and Ku, B and Kim, K and Lee, KH and Kim, JU}, title = {Aperiodic EEG signatures: unveiling the interplay between APOE ε4 and mild cognitive impairment subtypes.}, journal = {Frontiers in aging neuroscience}, volume = {17}, number = {}, pages = {1675330}, pmid = {41583006}, issn = {1663-4365}, abstract = {BACKGROUND: Mild cognitive impairment (MCI) is a cognitive decline syndrome in the elderly, often a precursor to dementia. It is a heterogeneous condition that can signal degenerative disorders like Alzheimer's or non-degenerative conditions such as vascular issues, depression, or poorly managed diabetes. Early detection of MCI is crucial for timely intervention, and differentiating its phenotypes helps in understanding its causes, progression, and treatment. EEG, which records brain electrical activity, consists of rhythmic and arrhythmic components. Examining these inherently overlapping EEG components calls for quantification, ensuring that an appropriate physiological mechanism is attributed to a given neural response. This study explores the interaction between APOE ε4 (APOE4) and cognitive impairment on non-oscillatory EEG activity.

METHODS: We examined aperiodic EEG activity using a parameterized spectral estimation approach in a sample comprising 751, 142, and 279 cognitively normal (CN), non-amnestic (naMCI), and amnestic (aMCI) MCI patients, respectively. The 5-min EEG was recorded using a prefrontal two-channel EEG device in a resting state, eyes closed. Cognitive decline was assessed using the Seoul Neuropsychological Screening Battery (SNSB) and the Mini-Mental State Examination (MMSE). The analyses were performed using various statistical methods, including independent t-tests and generalized linear models (GLM) with an identity link function. These analyses investigated the main and interaction effects of the APOE4 status and participants' cognitive states.

RESULTS: We found interactions between APOE4 and cognitive states in the aperiodic EEG exponent and the spectral power ratio (SPR). Distinct patterns were observed in the exponent, offset, and SPR between APOE4 non-carriers and carriers across the CN, naMCI, and aMCI. Among the APOE4 carriers, the aMCI individuals exhibited heightened aperiodic activity and a reduced SPR than the naMCI. Furthermore, the CN had a lower SPR compared to the naMCI. However, no differences in the aperiodic component and SPR were observed in the APOE4 non-carriers across the cognitive states.

DISCUSSION: The higher aperiodic component and a reduced SPR observed in aMCI relative to naMCI in APOE4 carriers may indicate an interplay between genetic predisposition, neuropathological changes, and cognitive decline. These aperiodic components, combined with APOE4 status, represent promising neurophysiological markers that may help identify individuals at elevated risk for cognitive decline or progression toward AD.}, } @article {pmid41583320, year = {2025}, author = {Miura, K}, title = {Hematuria as a Diagnostic Clue to Non-cirrhotic Hyperammonemia Due to Corynebacterium urealyticum Urinary Tract Infection: A Case Report.}, journal = {Cureus}, volume = {17}, number = {12}, pages = {e100082}, pmid = {41583320}, issn = {2168-8184}, abstract = {Hyperammonemia is an important cause of altered mental status in older adults; however, non-cirrhotic hyperammonemia in the absence of underlying liver dysfunction is easily overlooked. Hyperammonemia secondary to urinary tract infection (UTI) caused by urease-producing bacteria is relatively rare, and reliable clinical clues for early diagnosis have not been fully established. We report the case of a 95-year-old woman with Alzheimer's disease residing in a nursing facility. She had macroscopic hematuria for two days without any change in consciousness. On the day of admission, she was found unresponsive at breakfast and was transported to the emergency department with impaired consciousness. On arrival, she had renal dysfunction and marked hyperammonemia (168 µg/dL) but normal liver function tests. Her urine was alkaline, turbid, and purulent with gross hematuria, and her mental status improved rapidly after bladder catheterization and fluid resuscitation. Urine culture yielded Corynebacterium urealyticum, and she was diagnosed with non-cirrhotic hyperammonemia secondary to a UTI caused by this urease-producing organism. Including the present case, a review of 33 English- and Japanese-language reports identified gross hematuria in 15 cases, microscopic hematuria alone in 11, and no hematuria in seven; thus, 78.8% of patients demonstrated some degree of hematuria. These findings suggest that, in older patients with preserved liver function who present with impaired consciousness, the presence of hematuria is an important clue to hyperammonemia secondary to a UTI due to urease-producing bacteria. When hematuria is observed, clinicians should consider this entity in the differential diagnosis and promptly assess urine pH, urinary retention, and indwelling urinary catheters to identify ammonia-producing sources and perform timely drainage to prevent delays in diagnosis and treatment.}, } @article {pmid41584821, year = {2026}, author = {Ali, F and Babour, A and Asiry, O and Alghamdi, W and Masmoudi, A and Rajkhan, NW}, title = {Advancing neurological disease treatment: a computational approach for fibroblast growth factor detection.}, journal = {Biomedical engineering letters}, volume = {16}, number = {1}, pages = {167-176}, pmid = {41584821}, issn = {2093-985X}, abstract = {Fibroblast Growth Factor plays a crucial role in neurological health, contributing to neuron protection, injury recovery, and angiogenesis. It is also significantly involved in the onset and progression of neurodegenerative disorders such as Huntington's, Alzheimer's, Parkinson's disease, and stroke, making FGF a vital target for therapeutic interventions. Despite its importance, no computational tool has been developed to predict FGF proteins. In this study, we present the first novel deep learning-based computational approach designed for the prediction of FGF proteins. We constructed two novel, high-quality datasets curated from the UniProt database for training and evaluation. Sequences were transformed into numerical representations using three complementary feature encoding methods including Dipeptide Composition, Dipeptide Deviation from Expected Mean, and Grouped Amino Acid Composition. These features capture both local and global sequence information. Multiple deep learning models were explored, including Convolutional Neural Network, Bidirectional Long Short-Term Memory, Generative Adversarial Network, and Gated Recurrent Unit. Among these, our proposed Convolutional Neural Network-based model outperformed all others, achieving an accuracy of 83.50%, sensitivity of 84.30%, specificity of 82.67%, F1 score of 83.42%, and a Matthews Correlation Coefficient of 0.671. The proposed approach has the potential to advance therapeutic discovery by enabling accurate identification of Fibroblast Growth Factor and improving our understanding of their role in neurological health and disease.}, } @article {pmid41585084, year = {2025}, author = {Matsuzaka, Y and Iyoda, M}, title = {Applications, image analysis, and interpretation of computer vision in medical imaging.}, journal = {Frontiers in radiology}, volume = {5}, number = {}, pages = {1733003}, pmid = {41585084}, issn = {2673-8740}, abstract = {This review summarizes the current advances, applications, and research prospects of computer vision in advancing medical imaging. Computer vision in healthcare has revolutionized medical practice by increasing diagnostic accuracy, improving patient care, and increasing operational efficiency. Likewise, deep learning algorithms have advanced medical image analysis, significantly improved healthcare outcomes and transforming diagnostic processes. Specifically, convolutional neural networks are crucial for modern medical image segmentation, enabling the accurate, efficient analysis of various imaging modalities and helping enhance computer-aided diagnosis and treatment planning. Computer vision algorithms have demonstrated remarkable capabilities in detecting various diseases. Artificial intelligence (AI) systems can identify lung nodules in chest computed tomography scans at a sensitivity comparable to that of experienced radiologists. Computer vision can analyze brain scans to detect problems such as aneurysms and tumors or areas affected by diseases such as Alzheimer's. In summary, computer vision in medical imaging is significantly improving diagnostic accuracy, efficiency, and patient outcomes across a range of medical specialties.}, } @article {pmid41585268, year = {2025}, author = {Srivastav, J and Sharma, S}, title = {Viral and non-viral cellular therapies for neurodegeneration.}, journal = {Frontiers in medicine}, volume = {12}, number = {}, pages = {1718669}, pmid = {41585268}, issn = {2296-858X}, abstract = {Neurodegenerative diseases such as Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), and amyotrophic lateral sclerosis (ALS) are characterized by progressive loss of neurons and still lack curative treatment options. In this review, we describe current and developing therapeutic strategies that include viral vector-based gene delivery, antisense oligonucleotide (ASO) and RNA interference methods, stem cell transplantation, and genome editing technologies. Adeno-associated viruses (AAVs) and lentiviruses have been used for gene delivery in preclinical and clinical studies, while ASOs are under development to reduce expression of pathogenic proteins such as tau, α-synuclein, and mutant huntingtin. Cellular therapies, including mesenchymal stem cell (MSC)-based paracrine support and transplantation of neurons derived from induced pluripotent stem cells (iPSCs), are being evaluated, particularly in PD and AD. We also discuss important gene targets such as APOE4, GBA1, SCNA, and MAPT, and how treatment strategies may differ between monogenic and polygenic forms of these disorders. Lastly, we highlight recent efforts focused on genes like TREM2, PINK1, and progranulin, and examine their role in the future development of gene- and cell-based interventions.}, } @article {pmid41585467, year = {2026}, author = {Yue, J and Wang, X and Ringman, J and Shi, Y}, title = {Graphical modeling of cortical tau pathology topography for its subtyping in Alzheimer's disease.}, journal = {Imaging neuroscience (Cambridge, Mass.)}, volume = {4}, number = {}, pages = {}, pmid = {41585467}, issn = {2837-6056}, abstract = {Hyperphosphorylated tau tangles are essential hallmarks of Alzheimer's disease (AD) and their propagation across brain regions was often considered to follow the classic Braak stages. Recent post-mortem and in vivo tau positron emission tomography (PET) studies, however, revealed the frequent presence of tau pathology heterogeneity. Clustering or event-based methods were proposed previously for the subtyping to tau pathology in AD, but they often lack robustness to varying distributions of disease severity across cohorts. To robustly discover and model tau pathology subtypes in AD, we propose in this work a novel graphical modeling framework that can disentangle the phenotypical differences of tau PET imaging due to disease heterogeneity from the spatiotemporal variations of disease stages. First, we propose a novel Reeb graph representation at the individual level to characterize the topographic patterns of salient tau pathology on cortical surfaces. Next, we use only cross-sectional tau PET data to develop a graphical model at the population level to encode the inter-subject spatiotemporal relationships, which enables us to robustly derive subtypes based on the topographic patterns of tau pathology and hence achieve increased generalization power to new samples with distinct tau pathology severity from the training data. Using synthetic and large-scale tau PET imaging data from the Alzheimer's Disease Neuroimaging Initiative (ADNI) and Anti-Amyloid Treatment in Asymptomatic Alzheimer's (A4) studies, we compare with the state-of-the-art SuStaIn method and demonstrate the improved generalization performance of the proposed method. In addition, we validate both methods on a cohort of autosomal dominant Alzheimer's disease (ADAD) patients with known tau pathology patterns to show that our method has more robust performance in testing data with large deviations from training data. Furthermore, for preclinical patients of the A4 cohort, we demonstrate more significant differences in clinical cognitive measures can be observed across subtypes discovered by our method.}, } @article {pmid41585699, year = {2026}, author = {Ferreira, LAP and Caruso, L and Nadur, NF and Franco, DP and Sousa, GLS and Lacerda, RB and Kümmerle, AE}, title = {Imidazo[1,2‑a]pyridines in Medicinal Chemistry: Recent Advances in Synthesis and Biological Activities.}, journal = {ACS omega}, volume = {11}, number = {2}, pages = {2348-2383}, pmid = {41585699}, issn = {2470-1343}, abstract = {Imidazo-[1,2-a]-pyridines are widely recognized scaffolds present in several marketed drugs, including the anxiolytics alpidem, saripidem, necopidem, and zolpidem, which are some of the most prescribed medications for insomnia. In this review, we analyze publication trends, which reveal exponential growth in research involving this scaffold. We highlight recent synthetic strategies (2017-2025) for the preparation of imidazo-[1,2-a]-pyridine derivatives, such as condensation, multicomponent and tandem reactions, intramolecular cyclizations, and oxidative couplings under green conditions. In addition, we discuss innovative Medicinal Chemistry studies exploring their applications in the treatment of cancer, Alzheimer's disease, tuberculosis, and neglected tropical diseases. Significant advances have been made in identifying derivatives with potent activity against specific biological targets, including kinases, tubulin, HDACs, the cytochrome bc1 complex of Mycobacterium tuberculosis, and key enzymes involved in the pathogenesis of Alzheimer's disease, such as cholinesterases and secretases. Altogether, this review consolidates the vast therapeutic potential of the imidazo-[1,2-a]-pyridine core, emphasizing its synthetic versatility and broad spectrum of biological activities, which firmly establish it as a privileged scaffold for drug discovery.}, } @article {pmid41588024, year = {2026}, author = {Khodaei, F and Namavar, MR and Soutodeh, N and Hadipour, A and Asadi, F and Khoshnoud, MJ and Rashedinia, M}, title = {Mitochondrial protective effects of ellagic acid in a rat model of sporadic Alzheimer's disease induced by STZ.}, journal = {Scientific reports}, volume = {16}, number = {1}, pages = {3498}, pmid = {41588024}, issn = {2045-2322}, support = {9958//Shiraz University of Medical Sciences/ ; }, mesh = {Animals ; *Ellagic Acid/pharmacology ; *Alzheimer Disease/chemically induced/drug therapy/metabolism/pathology ; Streptozocin/toxicity ; *Mitochondria/drug effects/metabolism/pathology ; Rats ; Disease Models, Animal ; Oxidative Stress/drug effects ; Male ; *Neuroprotective Agents/pharmacology ; Hippocampus/drug effects/pathology/metabolism ; Maze Learning/drug effects ; Reactive Oxygen Species/metabolism ; }, abstract = {Alzheimer's disease (AD) is a neurodegenerative disorder primarily affecting the elderly, characterized by mitochondrial dysfunction. Mitochondria play a dual role in AD, serving both as the main source of reactive oxygen species (ROS) generation and as a major target of oxidative damage. This study aimed to investigate the protective mechanisms of ellagic acid (EA) a natural dietary polyphenol on mitochondrial function in an intracerebroventricular (ICV) streptozotocin (STZ)-injected rat model of AD. Rats were randomly assigned to six groups: Control, Sham, STZ (1.5 mg/kg on days 1 and 3), STZ + EA 5 mg/kg, STZ + EA 50 mg/kg, and STZ + EA 100 mg/kg. On day 14, behavioral tests (Shuttle box and Step-down), histopathological evaluations, oxidative stress markers, and mitochondrial indices were assessed in brain tissue. Treatment with EA (100 mg/kg) significantly improved spatial memory, as evidenced by increased latency time in the Morris water maze test (p < 0.001). Furthermore, EA treatment mitigated hippocampal neurodegeneration, increasing neuronal density in the CA1 subfield (p < 0.001) and restoring total hippocampal volume (p < 0.01). At the biochemical level, EA markedly reduced oxidative stress levels (p < 0.001) and enhanced mitochondrial function, restoring cortical ATP levels (p < 0.001) and cytochrome c oxidase activity (p < 0.01) compared to the STZ- group. In conclusion, these findings suggest that EA may have therapeutic potential in mitigating mitochondrial dysfunction and oxidative stress in AD, offering a promising approach for addressing neurodegeneration and energy deficits associated with the disease.}, } @article {pmid41588303, year = {2026}, author = {Zuo, CT and Lu, JY}, title = {[AI-driven PET-MRI multimodal fusion: paradigm shift and clinical translation challenges in precision diagnosis and treatment of neurodegenerative diseases].}, journal = {Zhonghua yi xue za zhi}, volume = {106}, number = {4}, pages = {289-293}, doi = {10.3760/cma.j.cn112137-20250730-01894}, pmid = {41588303}, issn = {0376-2491}, support = {82394434, 82272039, 82021002//National Natural Science Foundation of China/ ; 2022ZD0211606//Science and Technology Innovation 2030-Major Project/ ; }, mesh = {*Neurodegenerative Diseases/diagnostic imaging ; *Magnetic Resonance Imaging ; *Positron-Emission Tomography ; Humans ; Multimodal Imaging ; *Artificial Intelligence ; Precision Medicine ; }, abstract = {Individualized precision diagnosis and treatment of neurodegenerative diseases (Alzheimer's disease, Parkinson's disease, etc.) faces challenges due to overlapping early symptoms and clinical/pathological heterogeneity. PET-MRI multimodal imaging, integrating in vivo molecular pathological information from PET with brain structural/functional information revealed by MRI, has become a crucial cornerstone for precision diagnosis and treatment of neurodegenerative diseases. However, its clinical translation is limited by practical bottlenecks, such as complexities in data integration, and uneven distribution of resources. AI, with its unique strengths in multimodal data fusion, automated quantitative analysis, and cross-modal image synthesis, is gradually reshaping the paradigm of diagnostic and therapeutic landscape of neurodegenerative diseases. This article systematically explores the pivotal role of AI in PET-MRI, covering its contributions to improving diagnostic objectivity, deciphering disease heterogeneity, enabling stratified care pathways. It also critically addresses the multiple challenges hindering the clinical implementation of AI and proposes that future efforts should focus on the development of interpretable AI models, the construction of embedded clinical systems, and the exploitation of inclusive technological solutions to promote the deep integration of AI and PET-MRI, ultimately driving the transformation of neurodegenerative diseases towards a precision medicine paradigm of early prevention, early diagnosis, and early treatment.}, } @article {pmid41588589, year = {2026}, author = {Justin, S and Ali, SA and Masood, M and Abbasi, SW and Farhat, SM and Shakeel, R and Khalid, A and Mahboob, A and Zafar, S and Zahid, S and Ahmed, T}, title = {Evaluation of the Combined Therapeutic Potential of Turmeric and Donepezil on the Cholinergic System in a Mouse Model of AD-like Pathology.}, journal = {Current drug targets}, volume = {}, number = {}, pages = {}, doi = {10.2174/0113894501433829251216060839}, pmid = {41588589}, issn = {1873-5592}, abstract = {INTRODUCTION: The multifactorial pathogenesis of Alzheimer's Disease (AD) makes effective prevention and treatment challenging. Integrative medicine presents a promising approach by complementing conventional treatments with neuroprotective nutraceuticals. This study investigates the individual and combinatorial effects of turmeric, a neuroprotective herb, and donepezil, an acetylcholinesterase (AChE) inhibitor, on cognitive functions in a scopolamine-induced amnesic mouse model.

METHODS: Molecular interactions of curcuminoids and donepezil with AChE were analyzed using AutoDock Vina and AMBER22. In animal model studies, amnesia was induced in BALB/c mice via subcutaneous injections of scopolamine (1mg/kg/day) for a duration of 25 days. From the 11th day onwards, the turmeric rhizome powder (20mg/kg/day) and donepezil (0.5mg/kg/day) were orally administered as monotherapies or in combination. Cognitive functions were assessed through behavior tests.

RESULTS: Molecular docking and dynamics simulations revealed that curcuminoids (curcumin, bisdemethoxycurcumin, and desmethoxycurcumin) inhibited AChE more effectively than donepezil. Animal studies demonstrated significant enhancements in spatial, reference, recognition, and contextual fear memories, with both turmeric and donepezil monotherapies, and their combination therapy. No significant differences were observed between monotherapies, and no additive effect was evident in the combination therapy.

DISCUSSION: Co-administration of turmeric and donepezil did not yield a significant additive effect on cognitive improvement in scopolamine-induced amnesic mice. Turmeric monotherapy showed cognitive improvements comparable to those of donepezil monotherapy, highlighting its potential as a candidate therapy for donepezil-resistant AD.

CONCLUSION: Turmeric monotherapy improved cognitive performance similarly to donepezil monotherapy in scopolamine-induced amnesic mice. These preliminary findings require further research, including dose optimization and clinical trials, to establish their clinical relevance.}, } @article {pmid41588609, year = {2026}, author = {Zhou, S and Hassan, H and Guo, J and Xu, Y and Zhang, P and Yuan, L and Zhou, T and Chen, R}, title = {From gut to brain: formulation and transporter-guided approaches to maximise rutin central nervous system delivery.}, journal = {Nutritional neuroscience}, volume = {}, number = {}, pages = {1-27}, doi = {10.1080/1028415X.2026.2617363}, pmid = {41588609}, issn = {1476-8305}, abstract = {Neurological disorders, including Alzheimer's and Parkinson's disease, are characterised by high morbidity and disability, representing a major global health challenge. A central obstacle in their treatment is the blood-brain barrier, a highly selective interface that limits drug delivery to the central nervous system. Rutin, a naturally occurring flavonoid, exhibits potent antioxidant, anti-inflammatory, and neuroprotective activities, yet its clinical utility remains constrained by poor solubility, low oral bioavailability, and restricted blood-brain barrier permeability. Recent advances in drug delivery and formulation science offer promising solutions. Nanoparticle encapsulation, peptide conjugation, intranasal delivery, and co-administration with absorption enhancers have been shown to improve rutin's solubility, metabolic stability, and central nervous system penetration in preclinical models. Mechanistic studies further reveal that rutin can modulate efflux transporters, regulate tight-junction proteins, and influence microglial activity and cellular metabolism, collectively contributing to enhanced neuroprotection. Experimental evidence highlights its potential to mitigate key neurodegenerative processes, particularly in Alzheimer's disease. This review synthesises current knowledge on rutin's pharmacological effects, limitations in bioavailability, and innovative strategies to improve blood-brain barrier penetration. By integrating mechanistic insights with advances in delivery technologies, this review underscores rutin's translational potential. Priority next steps include optimising delivery systems, establishing long-term safety, and conducting well-designed clinical trials to define efficacy and dosing.}, } @article {pmid41588887, year = {2026}, author = {Edelbach, B and Huang, L and Boling, W}, title = {Vagus Nerve Stimulation in the Management of Neurodegenerative Diseases: A Systematic Review of Advances in Animal Research and Clinical Applications.}, journal = {Current Alzheimer research}, volume = {}, number = {}, pages = {}, doi = {10.2174/0115672050373772251103053036}, pmid = {41588887}, issn = {1875-5828}, abstract = {INTRODUCTION: Vagus Nerve Stimulation (VNS) has been approved by the FDA as a treatment for epilepsy, depression, post-ischemic stroke rehabilitation, and migraine in patients. It is emerging as a potential treatment for neurodegenerative diseases. Herein, we summarize the research on VNS and its application in common neurodegenerative diseases.

METHODS: A literature search was completed in PubMed, ScienceDirect, and Google Scholar using the terms: "neurodegeneration," "neuromodulation," "Vagus Nerve Stimulation," "Parkinson's Disease (PD)," "Alzheimer's Disease (AD)," "dementia," "neuroinflammation," and "cognitive dysfunction." Animal and clinical studies using VNS as a primary intervention in neurodegenerative diseases were included.

RESULTS: The studies of VNS application in Parkinson's and Alzheimer's models were reviewed. In animal studies, VNS was associated with increased locomotion and balance, as well as reduced cognitive impairments. The underlying neuroprotective mechanisms included: increased dopaminergic neurons, reduced α-synuclein concentration in the brain, preservation of the nigrostriatal dopaminergic pathway, increased α7nAChR expression, reduced apoptotic markers, reduced neuroinflammation, and significant reductions in microglial and astrocytic densities. In clinical studies with small patient populations of PD or AD/mild cognitive impairment, VNS was associated with improved gait parameters and enhanced performance in memory-based tasks.

DISCUSSION: Vagus Nerve Stimulation (VNS) shows neuroprotective and anti-inflammatory effects in animal models of Alzheimer's and Parkinson's disease, but clinical results remain inconsistent due to variability in treatment duration, outcome measures, and reliance on subjective assessments. Emerging physiologic biomarkers such as VSEP, EEG, and magnetoencephalography may provide more objective measures of therapeutic response.

CONCLUSIONS: The systematic review highlights the potential of VNS as a therapeutic approach for managing neurodegenerative diseases. The efficacy of VNS in animal models of Parkinson's and Alzheimer's diseases involves both neuroprotection and anti-neuroinflammation, while additional protective mechanisms require further exploration.}, } @article {pmid41588888, year = {2026}, author = {Sahu, A and Khileshwari, and Patle, K and Jain, P and Ajazuddin, }, title = {Advances in Nose-to-Brain Delivery Systems for Effective Alzheimer's Disease Management.}, journal = {Current Alzheimer research}, volume = {}, number = {}, pages = {}, doi = {10.2174/0115672050395356251106100427}, pmid = {41588888}, issn = {1875-5828}, abstract = {Neurodegenerative diseases comprise a heterogeneous group of disorders characterized by the progressive structural and functional deterioration of neurons in the central nervous system. Among them, Alzheimer's disease is the most prevalent worldwide. Despite their distinct clinical manifestations, many neurodegenerative disorders share convergent pathophysiological mechanisms such as protein misfolding and aggregation, oxidative stress, mitochondrial dysfunction, and neuroinflammation, which ultimately drive neuronal loss. These processes lead to profound impairments in cognitive performance, motor coordination, and overall functional capacity, making such diseases exceptionally difficult to diagnose early and manage effectively. Traditional treatment approaches administered orally or parenterally face limitations, including high hepatic metabolism, poor penetration across the blood-brain barrier (BBB), and systemic side effects. This review highlights the potential of the nose-to-brain (N2B) delivery system as an emerging and promising therapeutic strategy. N2B delivery utilizes the olfactory and trigeminal nerve pathways in the nasal cavity to rapidly and precisely deliver drugs to the central nervous system without crossing the blood-brain barrier. Because the system is non-invasive, it offers high bioavailability, reduced systemic exposure, and improved patient compliance. The use of lipid nanocarriers, nanoparticles, dendrimers, and nanogels to enhance the stability of drugs, facilitating efficient targeting and controlled release, is a crucial factor in optimizing N2B drug delivery systems. Various attributes influence drug transport, which are physiological, physicochemical and formulation-dependent characteristics. The main challenges faced by the N2B delivery system are enzymatic degradation and mucociliary clearance. Emerging technologies, such as AI, 3D Printing, and personalized medicine, all hold promise for future inventions in this area. Preclinical and clinical trials demonstrate the efficacy of delivering N2B in treating neurodegenerative diseases; however, its full potential remains to be seen due to regulatory, safety, and scalability concerns. Hence, this review emphasizes the research required to pursue interdisciplinary collaboration and unlock the full potential of N2B delivery, as well as a new approach to transforming neurodegenerative conditions.}, } @article {pmid41588889, year = {2026}, author = {Thakur, A and Chowdhury, KR and Kumar, A and Sharma, VV and Bhatia, R}, title = {Targeting Non-coding RNAs in Neurodegeneration: Advances in Therapeutic RNA Modalities and Next-Gen Delivery Technologies.}, journal = {Current Alzheimer research}, volume = {}, number = {}, pages = {}, doi = {10.2174/0115672050421604251108045622}, pmid = {41588889}, issn = {1875-5828}, abstract = {Non-coding RNA (ncRNA)-based therapies represent an emerging and transformative approach in the treatment of neurodegenerative diseases (NDs), such as Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), and amyotrophic lateral sclerosis (ALS)/Motor Neuron Disease (MND). This review explored the potential for targeting microRNAs (miRNAs), long non-coding RNAs (lncRNAs), and exosomal RNAs, reinforced by promising results from clinical trials demonstrating their capacity to modulate disease pathways. The incorporation of cutting-edge computational methodologies, including RNA structure prediction and gene regulatory network analysis, has been at the forefront in enhancing the efficacy of ncRNA-based treatments. Moreover, chemical methods have improved RNA molecules' stability, accuracy, and directed delivery, enhancing their therapeutic effects. Moreover, cutting-edge RNA editing technologies like Clustered Regularly Interspaced Short Palindromic Repeats/CRISPRassociated protein 13 (CRISPR/Cas13) are advancing our ability to directly manipulate ncRNA expression, offering a powerful avenue for addressing the molecular origins of neurodegeneration. Despite these advances, challenges persist, particularly in ensuring the specificity, delivery efficiency, and long-term efficacy of these treatments. Nanotechnology provides innovative solutions to these obstacles, facilitating more efficient and precise RNA delivery, especially to neuronal tissue. In conclusion, ncRNA-based therapies, while still in nascent stages, represent a hopeful frontier in the fight against NDs. With ongoing research and technological advancements, these therapies could not only halt disease progression but also redefine the future of ND treatment, offering new avenues for patients' care and clinical success.}, } @article {pmid41589492, year = {2026}, author = {Liu, A and Li, J and Gao, W and Li, X and Song, J and Xing, L and Li, H}, title = {Research Progress on Targeted Inhibition of Ferroptosis and Alzheimer's Disease Treatment.}, journal = {Mini reviews in medicinal chemistry}, volume = {26}, number = {2}, pages = {81-88}, pmid = {41589492}, issn = {1875-5607}, mesh = {*Alzheimer Disease/drug therapy/metabolism/pathology ; *Ferroptosis/drug effects ; Humans ; Animals ; Lipid Peroxidation/drug effects ; Iron/metabolism ; Oxidative Stress/drug effects ; }, abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disease characterized by the formation of senile plaques and neurofibrillary fiber tangles. Studies have shown that increased regional iron loading in the brain, dysregulation of iron homeostasis in the body, oxidative stress, and protein and lipid oxidation are all involved in the pathogenesis of AD. Ferroptosis, an irondependent, lipid peroxidation-driven form of regulated cell death, is increasingly implicated in the pathological process of AD, and some new compounds targeting ferroptosis demonstrate therapeutic efficacy in both cellular and animal models of AD. Therefore, this article systematically summarizes recent advances in the role of ferroptosis in AD pathogenesis and highlights progress in targeting ferroptosis for AD treatment, providing insights for future therapeutic and preventive strategies.}, } @article {pmid41589493, year = {2026}, author = {Almawashee, HS and Khalaj-Kondori, M and Hosseinpour Feizi, MA and Safaralizadeh, R}, title = {Correlation of miR-214, miR-204, miR-25, miR-15a Expression with IL-33 and Malondialdehyde in Blood Samples from Patients with Alzheimer's Disease.}, journal = {MicroRNA (Shariqah, United Arab Emirates)}, volume = {}, number = {}, pages = {}, doi = {10.2174/0122115366411857251025004952}, pmid = {41589493}, issn = {2211-5374}, abstract = {INTRODUCTION: Alzheimer's disease (AD) is a late-onset neurodegenerative disease that affects older people. Deregulations of miRNAs play essential roles in AD pathogenesis; as a re-sult, they might be potential biomarkers for AD development, diagnosis, and treatment. This case-control study aimed to assess the expression of miR-214, miR-204, miR-15a, miR-25, and inves-tigate their correlations with the expression of IL-33, plasma level of Malondialdehyde (MDA), and Mini-Mental State Examination (MMSE) score of the AD patients.

METHODS: Blood samples were obtained from 125 participants, including 75 AD patients and 50 healthy controls. Plasma MDA level was assessed using the ZellBio ELISA kit. Total RNA was extracted from blood lymphocytes using RiboExTM (GeneAll), and expression levels of miRNAs and IL-33 were evaluated by qRT-PCR.

RESULTS: Results showed that miR-15a and miR-25, and IL-33 were downregulated in the pa-tients' group, but miR-214 and miR-204 were upregulated. Besides, the plasma level of MDA was significantly higher in the AD patients. A statistically significant negative correlation was observed between miR-15a and IL-33 expression. The MDA level showed a negative correlation with MMSE and a positive correlation with IL-33. Correlations between the miRNAs and MDA or MMSE scores were all non-significant. However, ROC curve analysis revealed that expres-sions of the studied miRNAs, IL-33, and the plasma level of MDA effectively differentiate AD patients from healthy controls.

DISCUSSION: Results showed that expression levels of miR-214, miR-204, miR-25, miR-15a, and IL-33 and MDA plasma levels are deregulated in AD patients, highlighting their potential relation with AD pathogenesis.

CONCLUSION: Expression levels of the studied miRNAs and IL33, and plasma level of MDA might be considered as potential biomarkers for AD development and diagnosis.}, } @article {pmid41589495, year = {2026}, author = {Dewangan, A and Nandy, SK and Das, AK and Sharma, A and Sharma, L}, title = {Enzymatic Biomarkers for Early Diagnosis of Alzheimer's Disease: Uncovering Key Targets and Mechanisms.}, journal = {CNS & neurological disorders drug targets}, volume = {}, number = {}, pages = {}, doi = {10.2174/0118715273418918251112112429}, pmid = {41589495}, issn = {1996-3181}, abstract = {Alzheimer's Disease (AD) is a neuronal illness that disrupts behavior, cognitive, and functional abilities. The development of AD is progressive, continuous, and irreversible, from preclinical illness to mild cognitive or even behavioral disturbance to dementia (a medical brain condition) triggered by AD. Worldwide accepted hypotheses of AD are called the amyloid-cascade and hyperphosphorylated tau-cascade hypotheses, and enzymes are implicated in the pathophysiology of AD directly or indirectly. There is an implication of enzymes in the pathophysiology of AD. Enzymes include proteases (e.g., neprilysin), kinases (e.g., glycogen synthase kinase-3), cholinergic enzymes (e.g., acetylcholinesterase), metalloproteinases (e.g., matrix metalloproteinases), and oxidative stress-related enzymes (e.g., superoxide dismutase). However, during abnormal or early Alzheimer's Disease (AD) conditions, the activity and expression of these enzymes are altered in biological samples such as blood, urine, and cerebrospinal fluid (CSF) in patients with early AD when examined. These alterations in enzyme activity in early AD demonstrate the potential of these enzymes as biomarkers. Early detection of AD in its early stages is crucial for effective control and treatment of the disease. Existing diagnostic techniques rely mainly on neuroimaging and medical evaluation. Through this technique, we can only diagnose the advanced or late stage of AD. Therefore, there is a crucial need to establish valid biomarkers that might assist in the early detection of AD. Enzymatic targets have come to light as a promising alternative for the development of selective and sensitive diagnostic assays. This review aims to investigate the potential of enzymes as an enzymatic target for early AD diagnosis, emphasizing their diagnostic use and fundamental mechanisms. Here, we summarize the role or implication of 25 enzymes in the pathophysiology of AD in the early stage.}, } @article {pmid41590318, year = {2026}, author = {Rajkumar, M and Tian, F and Javed, B and Prajapati, BG and Deepak, P and Girigoswami, K and Karmegam, N}, title = {Smart Biosensing Nanomaterials for Alzheimer's Disease: Advances in Design and Drug Delivery Strategies to Overcome the Blood-Brain Barrier.}, journal = {Biosensors}, volume = {16}, number = {1}, pages = {}, pmid = {41590318}, issn = {2079-6374}, mesh = {*Alzheimer Disease/drug therapy ; *Blood-Brain Barrier ; Humans ; *Drug Delivery Systems ; *Biosensing Techniques ; *Nanostructures ; Nanoparticles ; Animals ; }, abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder marked by persistent memory impairment and complex molecular and cellular pathological changes in the brain. Current treatments, including acetylcholinesterase inhibitors and memantine, only help with symptoms for a short time and do not stop the disease from getting worse. This is mainly because these drugs do not reach the brain well and are quickly removed from the body. The blood-brain barrier (BBB) restricts the entry of most drugs into the central nervous system; therefore, new methods of drug delivery are needed. Nanotechnology-based drug delivery systems (NTDDS) are widely studied as a potential approach to address existing therapeutic limitations. Smart biosensing nanoparticles composed of polymers, lipids, and metals can be engineered to enhance drug stability, improve drug availability, and target specific brain regions. These smart nanoparticles can cross the BBB via receptor-mediated transcytosis and other transport routes, making them a promising option for treating AD. Additionally, multifunctional nanocarriers enable controlled drug release and offer theranostic capabilities, supporting real-time tracking of AD treatment responses to facilitate more precise and personalized interventions. Despite these advantages, challenges related to long-term safety, manufacturing scalability, and regulatory approval remain. This review discusses current AD therapies, drug-delivery strategies, recent advances in nanoparticle platforms, and prospects for translating nanomedicine into effective, disease-modifying treatments for AD.}, } @article {pmid41591092, year = {2026}, author = {Angelopoulou, E and Papageorgiou, S and Papatriantafyllou, J}, title = {Reframing Dementia Prevention Strategies Aligned with the WHO Global Action Plan: A Structured Narrative Review Focusing on Mild Behavioral Impairment.}, journal = {Neurology international}, volume = {18}, number = {1}, pages = {}, pmid = {41591092}, issn = {2035-8385}, abstract = {Background/Objectives: Dementia represents a growing public health challenge. The WHO Global Action Plan on the Public Health Response to Dementia emphasizes early detection, risk reduction, and innovation as key priorities. Mild Behavioral Impairment (MBI), defined as the emergence of persistent neuropsychiatric symptoms in older individuals, represents a potential marker of early neurodegeneration and possible window for early intervention. This review explores the role of MBI in dementia prevention, mapping current evidence within the WHO Global Action Plan framework. Methods: A comprehensive search was performed in PubMed, Scopus, and the official WHO website, during 1 September 2025-10 November 2025, without time restrictions. Eligible sources included original clinical studies, reviews, and policy documents addressing MBI, dementia prevention, and public health. Data were thematically synthesized according to the seven objectives of WHO: (1) dementia as a public health priority, (2) dementia awareness and friendliness, (3) dementia risk reduction, (4) dementia diagnosis, treatment, care and support, (5) support for dementia carers, (6) information systems for dementia, and (7) dementia research and innovation. Results: Accumulating evidence indicates that MBI assessment can capture early behavioral manifestations of neurodegenerative and other forms of dementia, correlating with fluid, neuroimaging and genetic biomarkers. Integrating MBI screening through the easy-to-administer MBI Checklist (MBI-C) into clinical and community-based care, including telemedicine pathways and research, may enhance early identification and personalized interventions, enrich the pool for clinical trials, and facilitate research in biomarker and therapy. MBI-related research further supports its integration in remote digital monitoring and population-based prevention. Conclusions: Embedding MBI-informed screening and interventions into national dementia strategies aligns with WHO objectives for early, equitable and scalable prevention and brain health.}, } @article {pmid41591137, year = {2025}, author = {Khalid, MZ and Iqbal, N and Ali, B and Rahman, JSU and Iqbal, S and Almudaimeegh, L and Hamd, ZY and Gareeballah, A}, title = {Detection and Classification of Alzheimer's Disease Using Deep and Machine Learning.}, journal = {Tomography (Ann Arbor, Mich.)}, volume = {12}, number = {1}, pages = {}, pmid = {41591137}, issn = {2379-139X}, support = {RSP 25850//Princess Nourah bint Abdulrahman University/ ; }, mesh = {Humans ; *Alzheimer Disease/diagnostic imaging/classification ; *Magnetic Resonance Imaging/methods ; Random Forest ; *Machine Learning ; *Deep Learning ; Convolutional Neural Networks ; Classification Algorithms ; Female ; Support Vector Machine ; *Image Interpretation, Computer-Assisted/methods ; Male ; Aged ; Decision Trees ; Brain/diagnostic imaging ; Predictive Learning Models ; }, abstract = {BACKGROUND/OBJECTIVES: Alzheimer's disease is the leading cause of dementia, marked by progressive cognitive decline and a severe socioeconomic burden. Early and accurate diagnosis is crucial to enhancing patient outcomes, yet traditional clinical and imaging assessments are often limited in sensitivity, particularly at early stages. This study presents a dual-modal framework that integrates symptom-based clinical data with magnetic resonance imaging (MRI) using machine learning (ML) and deep learning (DL) models, enhanced by explainable AI (XAI).

METHODS: Four ML classifiers-K-Nearest Neighbors (KNN), Support Vector Machine (SVM), Decision Tree (DT), and Random Forest (RF)-were trained on demographic and clinical features. For stage-wise classification, five DL models-CNN, EfficientNetB3, DenseNet-121, ResNet-50, and MobileNetV2-were applied to MRI scans. Interpretability was incorporated through SHAP and Grad-CAM visualizations.

RESULTS: Random Forest achieves the highest accuracy of 97% on clinical data, while CNN achieves the best overall performance of 94% in MRI-based staging. SHAP and Grad-CAM were used to find clinically relevant characteristics and brain areas, including hippocampal atrophy and ventricular enlargement.

CONCLUSIONS: Integrating clinical and imaging data and interpretable AI improves the accuracy and reliability of AD staging. The proposed model offers a valid and clear diagnostic route, which can assist clinicians in making timely diagnoses and adjusting individual treatment.}, } @article {pmid41591746, year = {2026}, author = {Cummings, JL and Chumki, SR and Chang, D and Zhang, Z and Brubaker, M and Hefting, N and Such, P and Wang, D and Grossberg, GT}, title = {Efficacy of Brexpiprazole in Participants with Agitation Associated with Dementia Due to Alzheimer's Disease: Pooled Analysis of Randomized Controlled Trials.}, journal = {Clinical drug investigation}, volume = {46}, number = {3}, pages = {281-292}, pmid = {41591746}, issn = {1179-1918}, mesh = {Humans ; *Quinolones/therapeutic use/administration & dosage ; *Thiophenes/therapeutic use/administration & dosage ; *Alzheimer Disease/complications/drug therapy/psychology ; *Psychomotor Agitation/drug therapy/etiology ; Double-Blind Method ; Female ; Randomized Controlled Trials as Topic ; Male ; Aged ; Treatment Outcome ; Aged, 80 and over ; *Aberrant Motor Behavior in Dementia/drug therapy ; }, abstract = {OBJECTIVE: This analysis aimed to evaluate the efficacy of brexpiprazole 2 or 3 mg/day for the treatment of agitation associated with dementia due to Alzheimer's disease, on the basis of pooled clinical trial data.

METHODS: Data were pooled from two similarly designed, phase 3, 12-week, multicenter, randomized, double-blind, placebo-controlled trials of fixed-dose brexpiprazole in participants in care facilities or community-based settings who had agitation associated with dementia due to Alzheimer's disease. Efficacy outcomes included Cohen-Mansfield Agitation Inventory (CMAI) total score (which measures the frequency of 29 different agitation symptoms), Clinical Global Impression-Severity of illness (CGI-S) score, CMAI factor scores (aggressive behaviors, physically nonaggressive behaviors, and verbally agitated behaviors), and response rates. A sensitivity analysis included a third trial with flexible dosing.

RESULTS: In total, 621 participants were randomized (brexpiprazole, 368; placebo, 253), and completion rates were 320/368 (87.0%) and 225/253 (88.9%), respectively. Mean (SD) baseline CMAI total scores were: brexpiprazole 76.9 (17.2) points and placebo 75.5 (18.0) points. Over 12 weeks, CMAI total scores improved by least squares mean (SE) - 22.8 (0.8) points for brexpiprazole and - 18.3 (1.0) points for placebo, with a least squares mean difference between treatment arms of - 4.50 points (95% CI - 6.90 to - 2.10; p < 0.001; Cohen's d 0.30). CGI-S, CMAI factor, and response analyses also showed greater improvement with brexpiprazole versus placebo. The sensitivity analysis was supportive.

CONCLUSIONS: Brexpiprazole 2 or 3 mg/day reduced agitation symptoms compared with placebo over 12 weeks in this large, pooled sample of participants with dementia due to Alzheimer's disease.

STUDY REGISTRATION: ClinicalTrials.gov identifiers: NCT01862640, NCT03548584, and NCT01922258.}, } @article {pmid41592400, year = {2026}, author = {Gönüllü, S and Aydın, Ş and Çelik, H and Çelik, O and Küçükler, S and Topal, A and Akay, R and Yıldız, MO and Alım, B and Çulha, MH and Özdemir, S}, title = {In vitro investigation of miR-206-3p-loaded extracellular vesicles as modulators of Aβ-induced neurodegeneration.}, journal = {Biochemical and biophysical research communications}, volume = {802}, number = {}, pages = {153306}, doi = {10.1016/j.bbrc.2026.153306}, pmid = {41592400}, issn = {1090-2104}, mesh = {Humans ; *MicroRNAs/genetics/administration & dosage/metabolism ; *Amyloid beta-Peptides/metabolism/toxicity ; *Extracellular Vesicles/metabolism/genetics ; Cell Line, Tumor ; Oxidative Stress/drug effects ; Mitochondria/metabolism ; *Alzheimer Disease/pathology/genetics/metabolism ; }, abstract = {In this study, we investigated the therapeutic potential of miR-206-3p delivered via small extracellular vesicles (sEVs) in an in vitro Alzheimer's disease model using SH-SY5Y human neuroblastoma cells treated with amyloid beta (Aβ). The sEV-miR-206-3p complexes were successfully loaded with miR-206-3p (∼0.001 copies per particle) without disrupting vesicle integrity or inducing cytotoxicity at the optimized concentration of 5 μg/mL. Aβ treatment significantly increased oxidative stress markers (ROS, MDA, LDH) and decreased antioxidant enzyme activity (SOD), while GPX1 showed an opposite trend. Furthermore, Aβ elevated proinflammatory gene expression (ICAM1, TNF-α) and reduced neuroprotective BDNF levels, induced mitochondrial dysfunction (increased Cyt-c, PINK1, DNM1L; decreased TFAM), impaired synaptic proteins (CPLX2, ROR1), and promoted tau phosphorylation and Aβ accumulation. Treatment with sEV-miR-206-3p effectively mitigated these alterations, reducing oxidative stress, suppressing neuroinflammatory responses, restoring mitochondrial function and synaptic protein levels, and attenuating tau and Aβ pathology. These findings demonstrate that miR-206-3p-loaded sEVs protect neuroblastoma cells from Aβ-induced neurodegenerative processes, highlighting their potential as a novel drug delivery system for neuroprotection.}, } @article {pmid41592521, year = {2026}, author = {Wang, J and Su, O and Meng, Z and Lu, L and Qi, Y and Zhang, Z and Li, Z and Dong, X and Lian, H and Mu, Y}, title = {Layered double hydroxide-induced modulation of oxidative stress in disease therapy.}, journal = {Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie}, volume = {195}, number = {}, pages = {119063}, doi = {10.1016/j.biopha.2026.119063}, pmid = {41592521}, issn = {1950-6007}, mesh = {*Oxidative Stress/drug effects ; Humans ; *Hydroxides/pharmacology/chemistry/therapeutic use ; Animals ; *Antioxidants/pharmacology/chemistry/therapeutic use ; }, abstract = {Oxidative stress plays a crucial role in the development of various diseases, including diabetes, cardiovascular diseases, cancer, and rheumatic disorders. It disrupts the redox balance and initiates a series of pathological changes. As two-dimensional inorganic solids with an open structure and anion-exchange properties, layered double hydroxides (LDHs) offer significant advantages in the biomedical field, such as drug carriers, antioxidant catalysts. This article outlines application of LDHs in the treatment of cancer, rheumatic diseases, bone disorders, diabetes, Alzheimer's disease, and other conditions. More importantly, this paper elaborates on the challenges faced by the application of LDHs, including the biological activity to be explored, the performance to be optimized, and their in vivo functions and molecular mechanisms to be clarified. The solution strategies have also been discussed, which pointed out the direction for promoting the clinical transformation and application of LDHs in the future.}, } @article {pmid41592930, year = {2026}, author = {Fu, Z and Yang, Y and Chung, MK and Cheng, F}, title = {Artificial Intelligence to Guide Repurposing of Drugs.}, journal = {Annual review of medicine}, volume = {77}, number = {1}, pages = {381-398}, pmid = {41592930}, issn = {1545-326X}, support = {R21 AG083003/AG/NIA NIH HHS/United States ; R01 AG082118/AG/NIA NIH HHS/United States ; RF1 AG082211/AG/NIA NIH HHS/United States ; RF1 NS133812/NS/NINDS NIH HHS/United States ; U01 AG073323/AG/NIA NIH HHS/United States ; R01 AG066707/AG/NIA NIH HHS/United States ; P01 HL158502/HL/NHLBI NIH HHS/United States ; R01 AG076448/AG/NIA NIH HHS/United States ; }, mesh = {Humans ; *Drug Repositioning/methods ; *Artificial Intelligence ; Precision Medicine/methods ; Multiomics ; Machine Learning ; }, abstract = {With the pharmacokinetics, dosing, safety, and manufacturing of approved or investigational drugs already well-characterized, drug repurposing and repositioning offer emerging strategies to rapidly develop effective treatments for various challenging diseases. However, the growing mass of genetic and multiomics data has not been effectively explored by the drug repurposing community due to a lack of accurate approaches. This review aims to be an authoritative, critical, and accessible review and discussion of general interest to the drug repurposing community concerning the use of artificial intelligence (AI) and machine learning (ML) tools. Emerging questions include what is achievable with AI in this domain and what its impact will be, what AI and ML embrace, and how we, as geneticists, pharmacologists, and computational scientists, can contribute to the discovery of new, inexpensive, and affordable repurposable medicines. The fast growth of genetics and multiomics data (genomics, transcriptomics, proteomics, metabolomics, and radiomics) and electronic health records in diverse populations contributes to answering questions, including how to rapidly identify effective repurposable medicines, what a clinically meaningful effect size in trials is, and what the potential implications for precision medicine are. This review discusses AI and ML for drug repurposing in the context of genetics, multiomics, real-world data collection, and crowdsourcing of knowledge. We conclude by considering questions on how AI and ML methodologies can unite the diverse aspects of translational medicine for emerging treatment development in human-challenging diseases.}, } @article {pmid41593034, year = {2026}, author = {Fulop, T and Cohen, AA and Frost, EH and Lévesque, S and Khalil, A and Rodrigues, S and Desroches, M and Alami, M and Berrougui, H and Ramassamy, C and Hirokawa, K and Witkowski, JM and Laurent, B}, title = {Unmasking the hidden catalyst: How infections trigger Alzheimer's disease.}, journal = {Journal of Alzheimer's disease : JAD}, volume = {110}, number = {2}, pages = {519-536}, pmid = {41593034}, issn = {1875-8908}, mesh = {Humans ; *Alzheimer Disease/etiology/pathology/metabolism ; Amyloid beta-Peptides/metabolism ; Animals ; tau Proteins/metabolism ; *Infections/complications ; Neuroinflammatory Diseases ; }, abstract = {For years, the understanding of Alzheimer's disease (AD) has been shaped by the amyloid hypothesis, which suggests that pathological markers like amyloid-β (Aβ) and phosphorylated tau are the primary drivers of the disease. This hypothesis has guided the development of major treatment strategies, including monoclonal antibodies targeting Aβ. However, most of these treatments have failed to produce clinically significant results, highlighting the urgent need for a new therapeutic approach. It is now evident that AD is a complex, multifactorial disease that develops over decades, ultimately leading to Aβ and tau accumulation. Therefore, addressing the underlying causes of these depositions is crucial. One well-supported yet underrecognized theory is the infection hypothesis, which links infections to AD pathology. Despite substantial scientific evidence, this perspective has faced significant resistance. In this review, we describe how chronic infections contribute to AD by triggering neuroinflammation and Aβ accumulation. We also explore the barriers to accepting the infection hypothesis and the steps necessary for its integration into drug development and early-stage treatment strategies. Persisting with an amyloid-centric approach will only exacerbate the societal burden. Embracing the infection hypothesis could transform AD research, diagnosis, and treatment, bringing new hope to millions.}, } @article {pmid41593242, year = {2026}, author = {Hobson, R and Levy, SHS and Singal, CMS and Flaherty, D and Xiao, H and Ciener, B and Reddy, H and Zabinyakov, N and Kim, CY and Teich, AF and Shneider, NA and Bradshaw, EM and Elyaman, W}, title = {Clonal CD8[+] T cells populate the leptomeninges and coordinate with immune cells in human degenerative brain diseases.}, journal = {Nature immunology}, volume = {27}, number = {2}, pages = {323-335}, pmid = {41593242}, issn = {1529-2916}, support = {PF-IMP-870699//Parkinson's Foundation (Parkinson's Foundation, Inc.)/ ; P30 AG066462/AG/NIA NIH HHS/United States ; UL1 TR001873/TR/NCATS NIH HHS/United States ; RF1 NS142171/NS/NINDS NIH HHS/United States ; R01 AG067581/AG/NIA NIH HHS/United States ; P30 CA013696/CA/NCI NIH HHS/United States ; }, mesh = {Humans ; *CD8-Positive T-Lymphocytes/immunology/metabolism ; *Meninges/immunology/pathology ; Brain/immunology/pathology ; Microglia/immunology/metabolism ; *Alzheimer Disease/immunology/pathology ; Female ; Receptors, Antigen, T-Cell/genetics ; *Neurodegenerative Diseases/immunology ; *Parkinson Disease/immunology ; Aged ; *Amyotrophic Lateral Sclerosis/immunology ; Male ; Memory T Cells/immunology ; Animals ; }, abstract = {Meningeal immune cells monitor the central nervous system (CNS) and influence neuroinflammation in mice, but the human leptomeningeal immune landscape and the changes that occur in this immunological niche in neurodegeneration remain underexplored. Here we performed single-cell RNA and T cell receptor (TCR) sequencing of 99,625 high-quality immune cells from 57 leptomeninges and brain samples from donors with Alzheimer's disease (AD), amyotrophic lateral sclerosis and Parkinson's disease and found that although the leptomeninges are home to highly clonally expanded CD8 tissue-resident memory (TRM) T cells, the maximal level of clonal expansion was decreased in AD in comparison to non-neurodegenerative controls. Intra-patient paired tissue analysis further revealed that brain and leptomeningeal TCR repertoires share significant similarities, but tissue-specific clones emerge in AD. Finally, in AD, the degree of CD8 TRM clonal expansion was positively correlated with microglial TGFB2, suggesting that brain and leptomeningeal immune cells coordinate their activities in AD. In addition to identifying key inflammatory dynamics in the human degenerating CNS, this study establishes a foundational resource for future studies that could inform treatment for AD and other neuroinflammatory diseases.}, } @article {pmid41593813, year = {2026}, author = {Beusink, M and de Rijke, TJ and Schaaij-Visser, TBM and Berkhout, M and Kroon, L and Smeitink, M and van der Landen, SM and Kaijser, KKM and Saaltink, DJ and van der Rhee, E and Rebers, S and de Boer, C and Rhodius-Meester, HFM and van der Flier, WM and Visser, LNC}, title = {Evaluation and lessons learned regarding Public Involvement: a panel advising on an Alzheimer's disease and related dementia cohort study.}, journal = {Research involvement and engagement}, volume = {12}, number = {1}, pages = {}, pmid = {41593813}, issn = {2056-7529}, support = {ZonMw projectnumber 10510022110004//the Memorabel Dementia Fellowship 2021/ ; }, abstract = {BACKGROUND: Public involvement (PI) in research is increasingly requested, yet systematic evaluation is limited. This study evaluates whether a panel advising an Alzheimer’s Disease and Related Dementia’s (ADRD) Cohort Study fulfills PI quality criteria and leads to perceived Cohort Study improvement and describe lessons learned. METHODS: A panel of 49 members of the public advised the Cohort Study through questionnaires and meetings. Panelists and Cohort Study researchers completed questionnaires based on PI quality criteria as formulated in the Patient Engagement Quality Guidance Framework, specifically developed to capture insights on the quality of PI. Findings were supplemented by reflections of the panel organizers and three panelists. Additionally, we outlined the panel’s aim and design to provide a practical example of PI in ADRD research. RESULTS: Of 49 panelists, 43 consented for use of their data for evaluation purposes (72% female (31/43), mean age 62 years, 82% (35/43) in good health). Response rates to the evaluation questionnaire were 37% for panelists (16/43) and 67% for researchers (4/6). Most panelists reported that the panel’s purpose (95%; 15/16) and communication were (very) clear (94%; 15/16), certainly adequate resources to provide input (75%; 12/16), and sufficient transparency (87%; 14/16). All felt respected and found it easy to participate in online panel questionnaires. However, 56% (9/16) found attending in-person meetings challenging due to time or travel. Researchers reported positive impact on Cohort Study quality, e.g., improved participant information letter, yet also highlighted the required time and effort to involve a panel and suggested to improve management of panelists’ expectations. Among the lessons learned are the value of offering multiple ways to participate, and the need for more communication between all parties involved. CONCLUSIONS: Engaging a PI panel was perceived to improve an ADRD Cohort Study and fulfilled most quality criteria from the Patient Engagement Quality Guidance Framework. However, results must be interpreted with caution due to potential consent bias.}, } @article {pmid41593839, year = {2026}, author = {Grese, Z and Naidu, A and Silverglate, BD and Grossberg, GT}, title = {The impact of the ketogenic diet on Alzheimer's disease progression.}, journal = {Expert review of neurotherapeutics}, volume = {26}, number = {3}, pages = {265-277}, doi = {10.1080/14737175.2026.2621502}, pmid = {41593839}, issn = {1744-8360}, mesh = {Humans ; *Diet, Ketogenic ; *Alzheimer Disease/diet therapy ; Disease Progression ; Quality of Life ; }, abstract = {INTRODUCTION: The ketogenic diet as a potential treatment for Alzheimer's disease (AD) has been investigated in several controlled trials. This topic is significant because of the limited nature of current interventions for AD, and the increasing recognition that lifestyle interventions may be important for reducing the risk of AD. The ketogenic diet is one of the few lifestyle interventions that has the potential to be beneficial after diagnosis.

AREAS COVERED: In this narrative review, the authors discuss the biological plausibility of how a ketogenic diet may improve amyloid burden and reduce neuroinflammation by providing an alternative energy source. They review relevant meta-analyses, systematic reviews, and controlled trials to investigate this diet in people diagnosed with AD. To this end, the authors used PubMed to search for appropriate systematic reviews and human trials, and closely examined the bibliographies of these papers to find trials potentially missed in their initial search.

EXPERT OPINION: More research is needed before a ketogenic diet could be broadly recommended in patients diagnosed with AD. However, to the extent a treatment effect has been demonstrated, it is comparable to some pharmaceutical interventions in AD. Challenges that remain include demonstrating improvement in quality of life, improving adherence, and standardizing ketogenic therapies.}, } @article {pmid41594629, year = {2026}, author = {Zedde, M and Losa, M and Grisafi, E and Lucia, DD and Gandoglia, I and Del Sette, M and Pardini, M and Roccatagliata, L and Pascarella, R and Piazza, F}, title = {Spontaneous and Drug-Induced Amyloid-Related Imaging Abnormalities: Overlaps, Divergences, and Clinical Implications Across a Continuum Between Alzheimer's Disease and Cerebral Amyloid Angiopathy.}, journal = {Biomolecules}, volume = {16}, number = {1}, pages = {}, pmid = {41594629}, issn = {2218-273X}, mesh = {Humans ; *Cerebral Amyloid Angiopathy/diagnostic imaging/chemically induced/pathology ; *Alzheimer Disease/diagnostic imaging/pathology ; *Amyloid/metabolism ; }, abstract = {BACKGROUND: Amyloid-related imaging abnormalities (ARIA) have gained significance in the context of anti-amyloid therapies (AATs), exhibiting clinical and radiological manifestations that overlap with Cerebral Amyloid Angiopathy-related inflammation (CAA-ri). This review aims to elucidate the similarities and differences between spontaneous (sARIA) and drug-induced ARIA (dARIA).

METHODS: We conducted a narrative review comparing sARIA and dARIA, focusing on their underlying mechanisms, clinical presentations, and implications for diagnosis and treatment.

RESULTS: Both sARIA and dARIA are characterized by similar pathophysiological mechanisms involving amyloid deposits and neuroinflammation. Notably, ARIA can manifest as ARIA-E (edema) or ARIA-H (hemorrhage), with varying incidence rates in clinical trials. The review highlights that while sARIA occurs independently from treatment, dARIA is associated with AAT and can lead to significant symptomatic presentations.

CONCLUSIONS: Understanding the continuum between sARIA and dARIA is crucial for improving diagnostic criteria, risk stratification, and therapeutic approaches. The proposed unified framework emphasizes the need for consensus in managing these conditions and advancing future research in amyloid-related diseases.}, } @article {pmid41594643, year = {2026}, author = {Pawar, Y and Kopranovic, A and C S, R and Meyer-Almes, FJ}, title = {Epigenetic Dysregulation in Neurodegeneration: The Role of Histone Deacetylases and Emerging Inhibitor Strategies.}, journal = {Biomolecules}, volume = {16}, number = {1}, pages = {}, pmid = {41594643}, issn = {2218-273X}, support = {none//Darmstadt University of Applied Sciences/ ; }, mesh = {Humans ; *Histone Deacetylase Inhibitors/pharmacology/therapeutic use/chemistry ; *Epigenesis, Genetic/drug effects ; *Histone Deacetylases/metabolism/genetics ; *Neurodegenerative Diseases/drug therapy/genetics/metabolism ; Animals ; }, abstract = {Neurodegenerative diseases such as Alzheimer's disease (AD), Parkinson's disease (PD), and Huntington's disease (HD) are characterized by complex pathologies with progressive neurodegeneration, protein misfolding, oxidative stress, and persistent inflammation. Recent findings indicate the pivotal involvement of epigenetic disruption, particularly aberrant histone deacetylase (HDAC) activity, in disease initiation and progression. In the current review, we systematically discuss the mechanistic function of HDACs across all classes (I, IIa, IIb, III, and IV) in neurodegenerative disease mechanisms, such as their involvement in the modulation of gene expression, mitochondrial function, proteostasis, and neuronal survival. We discuss the therapeutic potential, as well as limitations, of HDAC inhibitors (HDACis), such as pan-inhibitors and isoenzyme-selective inhibitors, and new multi-target-directed ligands with HDAC inhibition combined with acetylcholinesterase modulation, PDE modulation, MAO-B inhibition, or NMDAR modulation. Particular emphasis is placed on the development of HDAC6-selective inhibitors with enhanced brain permeability and reduced toxicity, which have shown promising preclinical efficacy in ameliorating hallmark pathologies of AD, PD, and HD. In addition, s-triazine-based scaffolds have recently emerged as promising chemotypes in HDAC inhibitor design, offering favorable pharmacokinetic profiles, metabolic stability, and the potential for dual-target modulation relevant to neurodegeneration. The review also explores the future of HDAC-targeted therapies, including PROTAC degraders, dual-inhibitor scaffolds, and sustainable, BBB-penetrant molecules. Collectively, this review underscores the importance of HDAC modulation as a multifaceted strategy in the treatment of neurodegenerative diseases and highlights the need for continued innovation in epigenetic drug design.}, } @article {pmid41594819, year = {2026}, author = {Motoi, Y and Sanjo, N}, title = {Switching from Oral Cholinesterase Inhibitors to a Transdermal Donepezil Patch Attenuated Gastrointestinal Symptoms and Allowed Treatment Continuation in Three Patients with Alzheimer's Disease in Clinical Settings.}, journal = {Brain sciences}, volume = {16}, number = {1}, pages = {}, pmid = {41594819}, issn = {2076-3425}, abstract = {Background: Cholinesterase inhibitors (ChEIs) are commonly prescribed for the treatment of Alzheimer's disease (AD) and achieve long-term benefits for cognition and survival in real-world settings. However, the discontinuation rate is high due to their side effects, with gastrointestinal (GI) symptoms hampering long-term prescriptions. The risk of side effects associated with rivastigmine was previously shown to be lower with transdermal delivery than with oral capsules; however, this has yet to be examined in detail for donepezil, the most widely used ChEI. The daily application of a donepezil transdermal patch was officially approved in Japan in 2023. The incidence of side effects was lower with the donepezil transdermal patch than with oral donepezil in healthy volunteers, but has not yet been assessed in clinical settings. Results: We herein report three AD patients in two different memory clinics who developed GI symptoms with oral ChEIs that were attenuated by switching to the donepezil transdermal patch. Conclusions: The donepezil transdermal patch may improve tolerability and adherence in patients who develop gastrointestinal adverse effects with oral donepezil.}, } @article {pmid41594924, year = {2026}, author = {Bao, Y and Miao, G and He, N and Bao, X and Shi, Z and Hu, C and Liu, X and Wang, B and Sun, C}, title = {Melatonin as a Guardian of Mitochondria: Mechanisms and Therapeutic Potential in Neurodegenerative Diseases.}, journal = {Biology}, volume = {15}, number = {2}, pages = {}, pmid = {41594924}, issn = {2079-7737}, abstract = {Mitochondrial dysfunction is a key early pathological process in neurodegenerative diseases (NDs), leading to oxidative stress, impaired energy metabolism, and neuronal apoptosis prior to the onset of clinical symptoms. Although mitochondria represent important therapeutic targets, effective interventions targeting mitochondrial function remain limited. This review summarizes current evidence regarding the mechanisms by which melatonin protects mitochondria and evaluates its therapeutic relevance, with a primary focus on Alzheimer's disease, Parkinson's disease, and Huntington's disease-the major protagonists of NDs-while briefly covering other NDs such as amyotrophic lateral sclerosis, multiple sclerosis, and prion diseases. Melatonin selectively accumulates in neuronal mitochondria and exerts neuroprotection through multiple pathways: (1) direct scavenging of reactive oxygen species (ROS); (2) transcriptional activation of antioxidant defenses via the SIRT3 and Nrf2 pathways; (3) regulation of mitochondrial dynamics through DRP1 and OPA1; and (4) promotion of PINK1- and Parkin-mediated mitophagy. Additionally, melatonin exhibits context-dependent pleiotropy: under conditions of mild mitochondrial stress, it restores mitochondrial homeostasis; under conditions of severe mitochondrial damage, it promotes pro-survival autophagy by inhibiting the PI3K/AKT/mTOR pathway, thereby conferring stage-specific therapeutic advantages. Overall, melatonin offers a sophisticated mitochondria-targeting strategy for the treatment of NDs. However, successful clinical translation requires clarification of receptor-dependent signaling pathways, development of standardized dosing strategies, and validation in large-scale randomized controlled trials.}, } @article {pmid41595571, year = {2025}, author = {Lee, MS and Son, SJ and Kim, J and Go, S and Hong, CH and Roh, HW and Chang, J}, title = {Exploratory Analysis of Autophagy-Lysosomal Pathway Proteins in Dermal Fibroblasts as Potential Peripheral Biomarkers for Alzheimer's Disease: A Pilot Study.}, journal = {Biomedicines}, volume = {14}, number = {1}, pages = {}, pmid = {41595571}, issn = {2227-9059}, support = {RS-2024-00338983//National Research Foundation of Korea/ ; RS-2019-NR040055//National Research Foundation of Korea/ ; }, abstract = {Background/Objectives: Alzheimer's disease (AD) is characterized by accumulation of abnormal intracellular substances and autophagy-lysosomal pathway (ALP) dysfunction. While current diagnostic methods rely on cerebrospinal fluid biomarkers and neuroimaging, minimally invasive peripheral biomarkers are needed. Dermal fibroblasts could serve as accessible reporters of AD-related molecular changes. This exploratory pilot study investigated whether ALP-associated proteins in patient-derived fibroblasts could serve as potential peripheral biomarkers for AD diagnosis. Methods: We analyzed dermal fibroblasts from 9 AD patients (amyloid Positron emission tomography (PET)-positive) and 9 age-matched controls (amyloid PET-negative). Comprehensive immunoblot analysis assessed expression profiles of 16 AD- and ALP-associated proteins. Autophagic flux and lysosomal function were evaluated using bafilomycin A1 treatment and LysoTracker staining. Diagnostic performance was assessed through receiver operating characteristic (ROC) curve analysis and multivariable logistic regression. Results: AD fibroblasts showed significantly reduced Beta-site APP cleaving enzyme 1 (BACE1) (p = 0.022) and elevated Tax1-binding protein 1 (TAX1BP1) (p = 0.035) expression. BCL2-associated athanogene proteins 2 (BAG2) and OPTN demonstrated consistent directional changes across patients. Preliminary ROC analysis showed promising performance for protein combinations, with BAG2 + OPTN achieving Area under the curve (AUC) = 0.963 (sensitivity 77.8%, specificity 88.9%). Integration with Apolipoprotein E4 (APOE4) status further enhanced diagnostic accuracy (APOE4 + BACE1: AUC = 0.914). Notably, baseline autophagic flux and lysosomal acidification were preserved, suggesting pathway-specific rather than systemic ALP dysfunction. Conclusions: This exploratory study provides preliminary evidence that dermal fibroblast-derived ALP proteins show disease-associated alterations in AD and may represent potential peripheral biomarkers. However, given the small sample size (n = 18) and lack of independent validation, these findings require confirmation in larger multi-center cohorts before clinical translation.}, } @article {pmid41595595, year = {2025}, author = {Beretti, F and Malenchini, M and Gatti, M and Maraldi, T}, title = {Oxidative Stress as a Central Mechanistic Bridge Between Alzheimer's and Vascular Pathologies in Mixed Dementia: Emerging Evidence and Therapeutic Perspectives.}, journal = {Biomedicines}, volume = {14}, number = {1}, pages = {}, pmid = {41595595}, issn = {2227-9059}, abstract = {Mixed dementia (MD), characterized by overlapping features of Alzheimer's disease (AD) and vascular dementia (VaD), represents the most prevalent form of late-life cognitive decline. Increasing evidence identifies oxidative stress as a unifying molecular mechanism driving both neurodegenerative and vascular pathologies in MD. Reactive oxygen species (ROS) contribute to amyloid-β aggregation, tau hyperphosphorylation, endothelial dysfunction, and blood-brain barrier disruption, creating a self-perpetuating cycle of neuronal and vascular injury. Mechanistic models demonstrate how chronic hypoperfusion and mitochondrial dysfunction exacerbate ROS generation and neuroinflammation, while impaired Nrf2-mediated antioxidant defense further amplifies damage. Therapeutically, classical antioxidants show inconsistent efficacy, shifting focus toward mitochondrial protection, Nrf2 activation, and lifestyle-based oxidative load reduction. Therefore, we sought to outline therapeutic approaches capable of broadly targeting these mechanisms, through focused narrative analysis of recent studies employing delivery systems for antioxidant proteins and/or redox-regulating miRNAs. In particular, experimental interventions using mesenchymal stem cell-derived extracellular vesicles (MSC-EVs) demonstrate neuroprotective and anti-inflammatory effects via the Nrf2 pathway, suggesting promising avenues for multimodal treatment. Integrating oxidative, vascular, and neurodegenerative paradigms is essential for advancing diagnostic precision and developing targeted interventions capable of addressing the complex pathophysiology of mixed dementia.}, } @article {pmid41596255, year = {2026}, author = {Wang, Z and Ba, S and Li, M and Wei, Y and Wang, Y and Mao, J and Xiang, Y and Qin, D and Zeng, C}, title = {Targeting the Gut Microbiota: Mechanistic Investigation of Polyphenol Modulation of the Gut-Brain Axis in Alzheimer's Disease.}, journal = {International journal of molecular sciences}, volume = {27}, number = {2}, pages = {}, pmid = {41596255}, issn = {1422-0067}, support = {82560898//National Natural Science Foundation of China/ ; 82060831//National Natural Science Foundation of China/ ; }, mesh = {Humans ; *Alzheimer Disease/drug therapy/microbiology/metabolism ; *Polyphenols/pharmacology/therapeutic use ; *Gastrointestinal Microbiome/drug effects ; Animals ; *Brain/drug effects/metabolism ; *Brain-Gut Axis/drug effects ; Dysbiosis ; }, abstract = {Alzheimer's disease (AD) represents an increasingly severe global health challenge. Recently, the role of the gut-brain axis in AD pathogenesis has garnered significant attention. Dysbiosis of the gut microbiota can exacerbate core pathologies such as neuroinflammation, amyloid beta (Aβ) deposition, and tau hyperphosphorylation through neural, endocrine, and immune pathways. Polyphenolic compounds have emerged as a focal point in neuroprotective research owing to their pronounced anti-inflammatory and antioxidant properties. Notably, polyphenols exert effects not only by directly influencing the central nervous system (CNS) but also through indirectly modulating the composition and function of the gut microbiota, thereby impacting bidirectional gut-brain communication. This dual mechanism offers a potential avenue for their application in the prevention and treatment of AD. This review aims to compile recent research on the relationship between polyphenols and the gut microbiota. We assessed the literature from PubMed, Google Scholar, and Web of Science databases, published from the establishment of the database to 24 November 2025. The keywords used include "Polyphenols", "Gut-brain axis", "Gut microbiota", "Alzheimer's disease", "Epigallocatechin gallate", "Quercetin", "Curcumin", "Ferulic acid", "Resveratrol", "Anthocyanin", "Myricetin", "Chlorogenic acid", etc. This review discusses the various mechanisms by which polyphenols influence AD through modulating the gut microbiota. Polyphenols and gut microbiota exhibit critical bidirectional interactions. On one hand, the bioavailability and activity of polyphenols are highly dependent on metabolic conversion by gut microbiota. On the other hand, polyphenols selectively promote the proliferation of beneficial bacteria such as bifidobacteria and lactobacilli like prebiotics, while inhibiting the growth of pathogenic bacteria. This reshapes the intestinal microecology, enhances barrier function, and regulates beneficial metabolites. Utilizing a nanotechnology-based drug delivery system, the pharmacokinetic stability and brain targeting efficacy of polyphenols can be significantly enhanced, providing innovative opportunities for the targeted prevention and management of AD.}, } @article {pmid41596530, year = {2026}, author = {Higgins, M and Wasef, V and Kwakowsky, A}, title = {FDA-Approved Passive Immunization Treatments Against Aβ in Alzheimer's Disease: Where Are We Now?.}, journal = {International journal of molecular sciences}, volume = {27}, number = {2}, pages = {}, pmid = {41596530}, issn = {1422-0067}, mesh = {Humans ; *Alzheimer Disease/therapy/immunology/metabolism ; *Amyloid beta-Peptides/immunology/metabolism ; *Immunization, Passive/methods ; Apolipoprotein E4/genetics ; Animals ; Antibodies, Monoclonal/therapeutic use ; United States ; Blood-Brain Barrier/metabolism ; United States Food and Drug Administration ; Drug Approval ; Biomarkers ; }, abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder marked by decreased amyloid-beta (Aβ) clearance, enhanced Aβ aggregation, an increased risk of amyloid-related imaging abnormalities (ARIA), and blood-brain barrier (BBB) dysfunction. The APOE4 allele, being the leading genetic risk factor for AD, contributes strongly to these symptoms. This review covers the relationship between APOE4 status and the efficacy of FDA-approved monoclonal antibody (mAb) therapies, namely aducanumab, lecanemab, and donanemab. Across several clinical trials, APOE4 carriers exhibited higher rates of ARIA-E and ARIA-H compared to non-carriers. While the therapies did often meet biomarker endpoints (i.e., reduced amyloid), benefits were only observed in early and mild AD, and cognitive benefits were often marginal. Going forward, experimental apoE4-targeted immunotherapies may ease the burden of APOE4-related pathology. The field is shifting towards a more integrated approach, focusing on earlier interventions, biomarker-driven precision treatment, and improved drug delivery systems, such as subcutaneous injections, receptor-mediated transport, and antibodies with enhanced BBB penetration. As it stands, high treatment costs, limited accessibility, and strict eligibility criteria all stand as barriers to treatment. By integrating the APOE4 genotype into treatment planning and focusing on disease-stage-specific approaches, a safer and more effective means of treating AD could be achieved.}, } @article {pmid41596649, year = {2026}, author = {Al-Ghraiybah, NF and Alkhalifa, AE and Itokazu, Y and Farr, TO and Perez, NC and Ali, H and Kaddoumi, A}, title = {Apolipoprotein E4 in Alzheimer's Disease: Role in Pathology, Lipid Metabolism, and Drug Treatment.}, journal = {International journal of molecular sciences}, volume = {27}, number = {2}, pages = {}, pmid = {41596649}, issn = {1422-0067}, mesh = {Humans ; *Alzheimer Disease/metabolism/pathology/drug therapy/genetics ; *Lipid Metabolism ; *Apolipoprotein E4/metabolism/genetics ; Blood-Brain Barrier/metabolism/pathology ; Animals ; Amyloid beta-Peptides/metabolism ; }, abstract = {Alzheimer's Disease (AD) is a neurodegenerative disorder characterized by cognitive decline and memory loss. Among the genetic risk factors linked to AD, the Apolipoprotein E4 (ApoE4) remains the strongest. It is well known that carrying the ApoE4 isoform is associated with advanced AD pathology, blood-brain barrier (BBB) disruption, and changes in lipid metabolism. In this review, we provide an overview of the role of centrally and peripherally produced ApoE in AD. After this introduction, we focus on new findings regarding ApoE4's effects on AD pathology and BBB function. We then discuss ApoE's role in lipid metabolism in AD, highlighting examples of lipid changes caused by carrying the ApoE4 isoform. Next, the review explores the implications of ApoE4 isoforms for current treatments-whether they involve anti-amyloid therapy or other pharmacological agents used for AD-emphasizing the importance of personalized medicine approaches for patients with this high-risk allele. This review aims to provide an updated overview of ApoE4's effects on AD pathology and treatment. By integrating recent discoveries, it underscores the critical need to consider ApoE4 status in both research and clinical settings to enhance therapeutic strategies and outcomes for individuals with AD.}, } @article {pmid41596702, year = {2026}, author = {Shaikh, A and Ahmad, F and Murthy, J and Teoh, SL and Yahaya, MF}, title = {Early Molecular Biomarkers in an Amyloid-β-Induced Rat Model of Alzheimer's Disease: Effects of Kelulut Honey.}, journal = {International journal of molecular sciences}, volume = {27}, number = {2}, pages = {}, pmid = {41596702}, issn = {1422-0067}, support = {GUP-2021-038//UKM Research University Grant/ ; }, mesh = {Animals ; *Alzheimer Disease/metabolism/blood/chemically induced ; *Amyloid beta-Peptides/metabolism ; *Biomarkers/metabolism/blood ; Disease Models, Animal ; Rats ; Hippocampus/metabolism/pathology ; tau Proteins/metabolism ; Male ; Peptide Fragments/metabolism ; *Honey ; Chemokine CCL2/metabolism/blood ; Superoxide Dismutase-1/metabolism/blood ; Phosphorylation ; Oxidative Stress ; Humans ; Transcription Factor RelA/metabolism ; }, abstract = {Alzheimer's disease (AD) is the leading cause of dementia worldwide, characterized by progressive neurodegeneration and cognitive decline. Early diagnosis remains critical for enabling timely intervention. However, detecting the earliest pathological changes is challenging due to the limited availability of reliable biomarkers that reflect early disease pathology in experimental models. This study evaluated molecular markers associated with AD-related processes in a rat model inoculated with human amyloid β (Aβ)1-42 peptides. We assessed the levels of biomarkers: Aβ1-42, Aβ42, phosphorylated tau, monocyte chemoattractant protein-1 (MCP-1), nuclear factor kappa B (NF-κB p65) and superoxide dismutase 1 (SOD1) in hippocampal tissue and serum using enzyme-linked immunosorbent assay. A treatment group receiving Kelulut honey was included to evaluate biomarker responsiveness. Results showed significant elevation in hippocampal Aβ1-42 and phosphorylated tau in diseased rats, with changes in inflammatory markers MCP-1 and NF-κB p65, whereas no significant change was observed in oxidative stress marker SOD1. Serum levels of Aβ1-42 and MCP-1 did not differ significantly between groups, indicating limited peripheral sensitivity after a month of disease induction. These findings suggest that amyloid-, tau-, and inflammation-related markers in hippocampal tissue may be informative for early pathological changes in this acute model, while serum markers showed limited sensitivity.}, } @article {pmid41597254, year = {2026}, author = {Brustovetsky, T and Khanna, R and Brustovetsky, N}, title = {Collapsin Response Mediator Protein 2 (CRMP2) Modulates Induction of the Mitochondrial Permeability Transition Pore in a Knock-In Mouse Model of Alzheimer's Disease.}, journal = {Cells}, volume = {15}, number = {2}, pages = {}, pmid = {41597254}, issn = {2073-4409}, support = {R01 NS098772/GF/NIH HHS/United States ; }, mesh = {Animals ; *Alzheimer Disease/metabolism/pathology ; *Mitochondrial Permeability Transition Pore/metabolism ; *Nerve Tissue Proteins/metabolism ; *Intercellular Signaling Peptides and Proteins/metabolism ; Disease Models, Animal ; Phosphorylation/drug effects ; Mitochondria/metabolism/drug effects ; *Mitochondrial Membrane Transport Proteins/metabolism ; Mice ; Neurons/metabolism ; Mice, Transgenic ; Gene Knock-In Techniques ; Mitochondrial ADP, ATP Translocases/metabolism ; Humans ; }, abstract = {Hyperphosphorylated collapsin response mediator protein 2 (CRMP2) is elevated in the cerebral cortex of an APP-SAA knock-in mouse model of Alzheimer's disease and binds the adenine nucleotide translocase (ANT) in a phosphorylation-dependent manner. We propose that, in Alzheimer's disease (AD) mitochondria, dissociation of hyperphosphorylated CRMP2 from ANT promotes opening of the permeability transition pore (PTP). We showed that purified ANT, when reconstituted into giant liposomes, forms large calcium-dependent channels resembling the PTP, which are effectively blocked by recombinant, unphosphorylated CRMP2. In synaptic mitochondria isolated from the cortices of APP-SAA knock-in mice and control B6J hAbeta mice, we observed an increased susceptibility to permeability transition pore (PTP) induction in AD mitochondria, accompanied by reduced viability of cultured cortical neurons. Pre-treatment of AD mice with the CRMP2-binding small molecule (S)-lacosamide ((S)-LCM), which prevents CRMP2 hyperphosphorylation and restores its interaction with ANT, attenuated PTP induction and improved neuronal viability. Interestingly, direct application of (S)-LCM to isolated mitochondria failed to suppress PTP induction, indicating that its protective effect requires upstream cellular mechanisms. These findings support a phosphorylation-dependent role for CRMP2 in regulating PTP induction in AD mitochondria and highlight (S)-LCM as a promising therapeutic candidate for mitigating mitochondrial dysfunction and enhancing neuronal viability in AD.}, } @article {pmid41598278, year = {2026}, author = {Burgos-Puentes, S and Avendaño-Estrada, A and Sablón-Carrazana, M and Ramírez-Hernández, E and Granados-Juárez, A and Ramírez-Rodríguez, GB and Meraz-Ríos, M and Martínez-Coria, H and Ávila-Rodríguez, MA}, title = {Animal Models of Alzheimer's Disease Evaluated with [[11]C]Pittsburg Compound B.}, journal = {Life (Basel, Switzerland)}, volume = {16}, number = {1}, pages = {}, pmid = {41598278}, issn = {2075-1729}, support = {PRONACES 322512//CONAHCYT/ ; PAPPIT-IT201623//DGAPA-UNAM/ ; }, abstract = {Several animal models of Alzheimer's disease have been developed and tested for diagnostic and treatment purposes. [[11]C]PIB is the gold-standard radiotracer for the detection of Aβ plaque deposits, a hallmark of the disease. This study aimed to evaluate the in vivo detection of Aβ plaques using [[11]C]PIB microPET imaging across different animal models of Alzheimer's disease. The study included 3xTg-AD transgenic mice, TgF344-AD transgenic rats and Aβ injection-based rat model. The results showed an age-related increase in [[11]C]PIB uptake in 3xTg-AD mice, particularly in the midbrain and thalamus. In TgF344-AD rats, differences were also observed compared to WT controls, with the highest values observed in the hippocampus and cortex. In the injection-based model, inoculated rats showed greater uptake in the injection site than SHAM animals. Across all microPET studies, [[11]C]PIB uptake was consistently higher in females than in their male counterparts. These findings support the value of transgenic and Aβ injection-based models in preclinical research on Aβ plaque deposition and highlight the importance of considering species, model type, sex, and age in experimental design.}, } @article {pmid41599176, year = {2026}, author = {Santos, P and Sá Filho, AS and Aprigliano, V and Duarte, AG and Ribeiro, NA and Lombardo, KM and Fajemiroye, JO and Buchholz, AP and Vaz, VR and Chiappa, GR}, title = {Liraglutide and Exenatide in Alzheimer's Disease and Mild Cognitive Impairment: A Systematic Review and Meta-Analysis of Cognitive Outcomes.}, journal = {Pharmaceutics}, volume = {18}, number = {1}, pages = {}, pmid = {41599176}, issn = {1999-4923}, abstract = {Background/Objective: Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) exhibit neuroprotective properties in preclinical models of Alzheimer's disease (AD), reducing amyloid accumulation, neuroinflammation, and insulin resistance within the brain. However, clinical evidence regarding their cognitive effects in AD and mild cognitive impairment (MCI) remains inconclusive. To evaluate the effects of GLP-1 RAs on cognitive outcomes in patients with AD or MCI due to AD. Methods: A systematic review was conducted according to PRISMA 2020 and registered in PROSPERO (CRD420251143171). Although the original registry was broad, the identification of a small set of homogeneous randomized controlled trials (RCTs) during screening, prior to data extraction, allowed for a random-effects meta-analysis of cognitive outcomes. RCTs enrolling adults with clinically or biomarker-confirmed AD or MCI were included. Interventions comprised liraglutide or exenatide compared with placebo. Standardized mean differences (SMD) in global cognitive scores were pooled using a random-effects model (restricted maximum likelihood [REML] estimator with Hartung-Knapp adjustment). Results: Three randomized trials (n = 278 participants; 51% women; mean age 68 ± 7 years) met inclusion criteria. Treatment duration ranged from 26 weeks to 18 months. Pooled analysis revealed no significant effect of GLP-1 RAs on global cognition compared with placebo -0.21 (95% CI -0.81 to 0.38; I[2] = 47%; τ[2] = 3.77). Sensitivity analyses restricted to liraglutide or studies ≥ 12 months yielded similar results. Conclusions: Current randomized evidence does not support cognitive improvement with GLP-1 RAs in AD or MCI.}, } @article {pmid41599177, year = {2026}, author = {Li, F and Wu, L and Feng, X and Li, Y and Fan, H}, title = {Extracellular Vesicles in Alzheimer's Disease: Dual Roles in Pathogenesis, Promising Avenues for Diagnosis and Therapy.}, journal = {Pharmaceutics}, volume = {18}, number = {1}, pages = {}, pmid = {41599177}, issn = {1999-4923}, support = {LQ24H160003//Zhejiang Provincial Natural Science Foundation/ ; 2023KY299//Medical Scientific Research Foundation of Zhejiang Province/ ; 2024KY351//Medical Scientific Research Foundation of Zhejiang Province/ ; 2023J365//Ningbo Natural science foundation/ ; 2021A-012-G//Young Innovative Talent Project of Yongjiang Talent Introduction Programme of Ningbo Municipal Government/ ; 2023RC004//Bei'An Talent Programme of Jiangbei District of Ningbo/ ; }, abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by the accumulation of amyloid-β (Aβ) plaques, neurofibrillary tau tangles, chronic neuroinflammation, and synaptic loss, leading to cognitive decline. Extracellular vesicles (EVs)-lipid bilayer nanoparticles secreted by nearly all cell types-have emerged as critical mediators of intercellular communication, playing a complex dual role in both the pathogenesis and potential treatment of AD. This review generally delineates two opposite roles of EVs in pathogenesis and potential treatment of AD. On one hand, EVs derived from neurons, astrocytes, microglia and oligodendrocytes can propagate toxic proteins (Aβ, tau) and inflammatory signals, thereby accelerating disease progression. On the other hand, EVs-especially those from mesenchymal stem cells (MSCs)-exert neuroprotective effects by facilitating toxic protein clearance, modulating immune responses, preserving synaptic integrity, and alleviating oxidative stress. The cargo-carrying function of EVs gives them considerable diagnostic value. The associated cargos such as proteins and microRNAs (miRNAs) in the EVs may serve as minimally invasive biomarkers for early detection and monitoring of AD. Therapeutically, engineered EVs, including those incorporating CRISPR/Cas9-based genetic modification, are being developed as sophisticated delivery platforms for targeting core AD pathologies. Furthermore, this review highlights emerging technologies such as microfluidic chips and focused ultrasound (FUS), discussing their potential to enhance the translational prospects of EV-based early diagnostic and treatment for AD.}, } @article {pmid41599190, year = {2026}, author = {El-Dakroury, WA and Salim, SA and Said, AR and Asaad, GF and Abdelhameed, MF and Shabana, ME and Ibrahim, MM and Abualmajd, SG and Mosaad, HH and Salama, AA and Asran, SE and Amer, ML and Doghish, AS and El-Tokhy, FS}, title = {Novel Repurposing of Empagliflozin-Loaded Buccal Composite (Chitosan/Silk Fibroin/Poly(lactic acid)) Nanofibers for Alzheimer's Disease Management via Modulation of Aβ-AGER-p-tau Pathway.}, journal = {Pharmaceutics}, volume = {18}, number = {1}, pages = {}, pmid = {41599190}, issn = {1999-4923}, abstract = {Background/Objectives: Empagliflozin (EMPA) was repurposed for Alzheimer's disease (AD) treatment via buccal delivery, exploiting novel nanofibers (NFs) integrating chitosan (Cs), silk fibroin (Fb), and poly(lactic acid) (PLA). Methods: EMPA-loaded Cs/Fb/PLA NFs were electrospun in different formulations to optimize the formulation parameters. The optimized formulation was then investigated for its enhanced in vivo effect. Results: Optimized nanofiber diameters ranged from 459 ± 173 to 668 ± 148 nm, possessing bead-free morphology confirmed by SEM and satisfactory mechanical properties. EMPA was successfully well-dispersed in the polymer matrix as evidenced by FTIR, XRD, and drug content. The optimized NFs displayed a hydrophilic surface (contact angle < 90°), and biphasic drug release with sustained EMPA liberation (84.98% over 24 h). In vivo, buccal EMPA-Cs/Fb/PLA NFs in an AlCl3-induced AD rat model significantly reduced brain-amyloid-β, phosphorylated tau, IL-1β, and AGER expression by 2.88-, 2.64-, 2.87-, and 2.50-fold, respectively, compared to positive controls, and improved locomotor activity (1.86-fold) and cognitive performance (T-maze) (4.17-fold). Compared to pure EMPA, the nanofiber formulation achieved further reductions in amyloid-β (1.78-fold), p-tau (1.42-fold), IL-1β (1.89-fold), and AGER (1.38-fold), with efficacy comparable to memantine. Histopathological examination revealed preservation of the hippocampal neuronal structure. Conclusions: The findings suggest EMPA-loaded Cs/Fb/PLA NFs as a promising non-invasive, sustained-release buccal delivery platform for AD therapy, offering multimodal neuroprotection through modulation of the Aβ-AGER-p-tau axis.}, } @article {pmid41599225, year = {2026}, author = {Bernatoniene, J and Kopustinskiene, DM and Casale, R and Medoro, A and Davinelli, S and Saso, L and Petrikonis, K}, title = {Nrf2 Modulation by Natural Compounds in Aging, Neurodegeneration, and Neuropathic Pain.}, journal = {Pharmaceutics}, volume = {18}, number = {1}, pages = {}, pmid = {41599225}, issn = {1999-4923}, support = {S-A-UEI-23-7//Research Council of Lithuania (LMTLT)/ ; }, abstract = {This review summarizes the role of nuclear factor erythroid 2-related factor 2 (Nrf2) as a common link between aging, neurodegeneration, and neuropathic pain. Aging is characterized by oxidative stress and constant inflammation, which coincides with reduced Nrf2 activity and weaker antioxidant responses, increasing vulnerability to diseases. In neurodegenerative disorders-including Alzheimer's, Parkinson's, Huntington's disease, and amyotrophic lateral sclerosis-evidence indicates that impaired Nrf2 signaling contributes to oxidative damage, neuroinflammation, and mitochondrial dysfunction. Furthermore, in neuropathic pain, similar mechanisms are involved, and Nrf2 could play a role as a potential analgesic target because of its role in regulating cellular defense pathways. We also review natural Nrf2 modulators (e.g., flavonoids, other polyphenols, terpenoids, alkaloids), discussing their benefits alongside common translational limitations such as poor solubility, low oral bioavailability, rapid metabolism, and potential safety issues, including possible pro-oxidant effects and chemoresistance. We also outline future directions that should prioritize improving delivery systems, addressing NRF2/KEAP1 gene variations, evaluating combinations with standard therapies, exploring preventive applications, and defining dosing, treatment duration, and long-term safety. Overall, current evidence indicates that Nrf2 modulation is a practical, cross-cutting approach relevant to healthy aging and disease management.}, } @article {pmid41599308, year = {2026}, author = {Ptak, A and Warchoł, M and Morańska, E and Laurain-Mattar, D and Spina, R and Dupire, F and Waligórski, P and Simlat, M}, title = {Amaryllidaceae Alkaloids and Phenolic Acids Identification in Leucojum aestivum L. Plant Cultures Exposed to Different Temperature Conditions.}, journal = {Molecules (Basel, Switzerland)}, volume = {31}, number = {2}, pages = {}, pmid = {41599308}, issn = {1420-3049}, support = {00078.DDD.6509.00124.2022.06//Agency for Restructuring and Modernization of Agriculture/ ; }, mesh = {*Amaryllidaceae Alkaloids/chemistry/metabolism ; Temperature ; *Hydroxybenzoates/metabolism/chemistry ; *Amaryllidaceae/chemistry/metabolism ; }, abstract = {Amaryllidaceae alkaloids are of notable pharmacological relevance. For instance, galanthamine is used in the treatment of Alzheimer's disease, while other alkaloids (lycorine, crinine, etc.) derived from Amaryllidaceae plants are also of great interest because they exhibit antitumour, antiviral, antibacterial, antifungal, antimalarial, analgesic and cytotoxic properties. Phenolic acids comprise a group of natural bioactive substances that have commercial value in the cosmetic, food and medicinal industries due to their antioxidant, anticancer, anti-inflammatory and cardioprotective potential. In the present study, the effect of temperature (15, 20, 25 and 30 °C) on Amaryllidaceae alkaloid and phenolic acid biosynthesis in Leucojum aestivum in vitro plant cultures was investigated. The highest diversity of alkaloids (i.e., galanthamine, crinan-3-ol, demethylmaritidine, crinine, 11-hydroxyvitattine, lycorine, epiisohaemanthamine, chlidanthine) was noted in plants cultured at 30 °C. By contrast, ismine and tazettine were only present in plants cultured at 15 °C. Temperatures of 20 °C and 30 °C were found to stimulate galanthamine accumulation. The highest lycorine content was noted in plants grown at temperatures of 15 and 30 °C, and it was negatively correlated with the expression of the gene that encodes the cytochrome P450 96T (CYP96T) enzyme which catalyses a key step in the biosynthesis of different types of Amaryllidaceae alkaloids. This observation may reflect temperature-induced shifts in metabolic flux among different branches of Amaryllidaceae alkaloid biosynthesis. The observed stimulating effect of a 15 °C temperature on the chlorogenic, caffeic, p-coumaric, sinapic, ferulic and isoferulic acid content was in line with the highest expression of a gene that encodes the tyrosine decarboxylase (TYDC) enzyme, which is involved in plant stress response mechanisms. At 30 °C, however, the highest content of the caffeic, vanillic, p-coumaric and isoferulic acids was noted.}, } @article {pmid41599628, year = {2025}, author = {Titze-de-Almeida, R and Oliveira Gomes, GM and Santos, TCD and Titze-de-Almeida, SS}, title = {C16-siRNAs in Focus: Development of ALN-APP, a Promising RNAi-Based Therapeutic for Alzheimer's Disease.}, journal = {Pharmaceuticals (Basel, Switzerland)}, volume = {19}, number = {1}, pages = {}, pmid = {41599628}, issn = {1424-8247}, abstract = {This review examines a small interfering RNA (siRNA) designed for intrathecal (IT) injection, which reduces the formation of amyloid beta precursor protein (APP), a critical factor in the pathology of Alzheimer's disease (AD). The siRNA, designated ALN-APP, incorporates a 16-carbon chain (C16-siRNA) to enhance its delivery to the central nervous system (CNS) while leveraging advancements in specificity and duration of action based on previously approved drugs by the Food and Drug Administration. The development of ALN-APP involved a comprehensive analysis of the optimal carbon chain length and its conjugation position to the siRNA. Preclinical studies conducted on male Sprague Dawley rats, mice, and non-human primates (NHPs) demonstrated the efficacy of ALN-APP. In rats, an IT injection of C16-siRNAs at a concentration of 30 mg/mL, delivering a dose of 0.9 mg, resulted in cranial distribution via cerebrospinal fluid and led to a 75% reduction in copper-zinc superoxide dismutase 1 (SOD1) mRNA levels. These effects were dose-dependent and persisted for three months across multiple brain regions. Furthermore, studies in NHPs indicated that soluble APP levels were reduced to below 25%, sustained for two months. In the cerebrovascular amyloid Nos2[-/-] (CVN) mouse model of AD, administration of 120 µg of siRNA via the intracerebroventricular route produced reductions in APP expression, with mRNA levels remaining suppressed for 60 days in the ventral cortex. Indeed, ALN-APP controlled neuropathology in 5xFAD mice by significantly reducing amyloid levels and brain neuroinflammation, with improved behaviors in the elevated plus maze. Following these promising results in animal models, ALN-APP advanced to a Phase 1 trial, designated ALN-APP-001, which assessed its safety and efficacy in 12 participants with early-onset Alzheimer's disease (EOAD). Initial findings revealed a 55% reduction in soluble APPα and a 69% reduction in APPβ by day 15. These exploratory findings require further validation with larger cohorts and proper statistical analysis. In a subsequent cohort of 36 patients, administration of the 75 mg dose via IT injection led to mean reductions of 61.3% in soluble APPα (sAPPα) and 73.5% in soluble APPβ (sAPPβ) after one month. These silencing effects persisted for six months and were associated with important decreases in Aβ42 and Aβ40 levels. These results highlight the potential of ALN-APPs to address Alzheimer's pathology while maintaining a favorable safety profile. Whether ALN-APP succeeds in further clinical trials, key challenges include ensuring accessibility and affordability due to treatment costs, the need for specialized intrathecal administration, and establishing infrastructure for large-scale production of siRNAs. In conclusion, advancements in ALN-APP represent a promising strategy to reduce beta-amyloid formation in AD, with substantial biomarker reductions suggesting potential disease-modifying effects. Continued development may pave the way for innovative treatments for neurodegenerative diseases.}, } @article {pmid41599761, year = {2026}, author = {Yang, L and Yin, Y and Liu, X and Guo, B}, title = {Aptamer-Based Delivery of Genes and Drugs Across the Blood-Brain Barrier.}, journal = {Pharmaceuticals (Basel, Switzerland)}, volume = {19}, number = {1}, pages = {}, pmid = {41599761}, issn = {1424-8247}, support = {1R01CA293945-01/NH/NIH HHS/United States ; RP260101//Cancer Prevention and Research Institute of Texas/ ; }, abstract = {The blood-brain barrier (BBB) restricts therapeutic delivery to the central nervous system (CNS), hindering the treatment of neurological disorders, such as Alzheimer's disease, Parkinson's disease, brain cancers, and stroke. Aptamers, short single-stranded DNA or RNA oligonucleotides that can fold into unique 3D shapes and bind to specific target molecules, offer high affinity and specificity, low immunogenicity, and promising BBB penetration via receptor-mediated transcytosis targeting receptors such as the transferrin receptor (TfR) and low-density lipoprotein receptor-related protein 1 (LRP1). This review examines aptamer design through the Systematic Evolution of Ligands by Exponential Enrichment (SELEX) and its variants, mechanisms of BBB crossing, and applications in CNS disorders. Recent advances, including in silico optimization, in vivo SELEX, BBB chip-based MPS-SELEX, and nanoparticle-aptamer hybrids, have identified brain-penetrating aptamers and enhanced the brain delivery efficiency. This review highlights the potential of aptamers to transform CNS-targeted therapies.}, } @article {pmid41599763, year = {2026}, author = {Md Roslan, AH and Tengku Muhazan Shah, TMH and Mohd Saffian, S and John, LJ and Che Ramli, MD and Nassir, CMNCM and Mahadi, MK and Hein, ZM}, title = {Neuroprotective Potential of SGLT2 Inhibitors in Animal Models of Alzheimer's Disease and Type 2 Diabetes Mellitus: A Systematic Review.}, journal = {Pharmaceuticals (Basel, Switzerland)}, volume = {19}, number = {1}, pages = {}, pmid = {41599763}, issn = {1424-8247}, support = {GUP-2024-100//National University of Malaysia/ ; }, abstract = {Background: Alzheimer's disease (AD) features progressive cognitive decline and amyloid-beta (Aβ) accumulation. Insulin resistance in type 2 diabetes mellitus (T2DM) is increasingly recognised as a mechanistic link between metabolic dysfunction and neurodegeneration. Although sodium-glucose cotransporter-2 inhibitors (SGLT2is) have established glycaemic and cardioprotective benefits, their neuroprotective role remains less well defined. Objectives: This systematic review examines animal studies on the neuroprotective effects of SGLT2i in T2DM and AD models. Methods: A literature search was conducted across the Web of Science, Scopus, and PubMed databases, covering January 2014 to November 2024. Heterogeneity was assessed with I[2], and data were pooled using fixed-effects models, reported as standardised mean differences with 95% confidence intervals. We focus on spatial memory performance as measured by the Morris Water Maze (MWM) test, including escape latency and time spent in the target quadrant, as the primary endpoints. The secondary endpoints of Aβ accumulation, oxidative stress, and inflammatory markers were also analysed and summarised. Results: Twelve studies met the inclusion criteria for this review. A meta-analysis showed that SGLT2i treatment significantly improved spatial memory by reducing the escape latency in both T2DM and AD models. In addition, SGLT2i yielded a significant improvement in spatial memory, as indicated by an increased target quadrant time for both T2DM and AD. Furthermore, SGLT2i reduced Aβ accumulation in the hippocampus and cortex, which met the secondary endpoint; the treatment also lessened oxidative stress and inflammatory markers in animal brains. Conclusions: Our findings indicate that SGLT2is confer consistent neuroprotective benefits in experimental T2DM and AD models.}, } @article {pmid41601569, year = {2025}, author = {Gan, Y and Sun, J and Yang, D and Fang, C and Zhou, Z and Yin, J}, title = {Exploration and validation of biomarkers for Alzheimer's disease based on GEO database.}, journal = {IBRO neuroscience reports}, volume = {19}, number = {}, pages = {1157-1165}, pmid = {41601569}, issn = {2667-2421}, abstract = {OBJECTIVES: The purpose of this study is to leverage bioinformatics techniques to identify differentially expressed genes in Alzheimer's disease (AD), explore potential biomarkers for its early diagnosis, and provide new insights for the early diagnosis and treatment of AD.

METHODS: Two Alzheimer's disease-associated datasets, GSE66351 and GSE153712, were obtained from the Gene Expression Omnibus (GEO) database. Differential methylation analysis was conducted on the raw data utilizing the R programming language. Key genes were discerned by integrating LASSO regression, Pearson correlation analysis, and protein-protein interaction network analysis (PPI). Furthermore, the functional roles of these genes were investigated via Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway and Gene Ontology (GO) enrichment analyses. To assess their causal association with AD, a Mendelian randomization analysis was performed.

RESULTS: In two AD datasets, we identified a total of 387 overlapping differential methylation sites, which mapped to 297 genes. The GO enrichment analysis indicated that these genes are involved in a range of biological processes, such as signal transduction, cell cycle regulation, as well as the function of neuronal cell bodies and synapses. Furthermore, KEGG pathway analysis uncovered that these genes play crucial roles in the PI3K-Akt and TGF-beta signaling pathways. By utilizing a combination of LASSO, Pearson correlation analysis, and PPI network interaction analysis, we have identified five pivotal genes: EBF1, IGF1, EGR2, PRDM16, and RBL2. Finally, Mendelian randomization analysis demonstrated that the IVW analysis for cg00000029 (RBL2) yielded statistically significant results with an odds ratio (OR) of 1.201, and a 95 % confidence interval (CI) ranging from 1.089 to 1.325, corresponding to a p -value of 0.000249.

CONCLUSIONS: This study not only confirmed the known genes linked to AD but, more significantly, revealed the potential connection between the RBL2 gene and AD. Furthermore, it verified a causal link between RBL2 and the risk of AD onset. This finding suggests that the RBL2 gene could serve as a promising biomarker for the early diagnosis of AD, thereby offering novel avenues for future research and clinical interventions.}, } @article {pmid41601601, year = {2025}, author = {Yang, E and Al-Ghraiybah, NF and Alkhalifa, AE and Woodie, LN and Swinford, SP and King, J and Greene, MW and Kaddoumi, A}, title = {Dose-dependent evaluation of chronic oleocanthal on metabolic phenotypes and organ toxicity in 5xFAD mice.}, journal = {Pharmacological research. Natural products}, volume = {8}, number = {}, pages = {}, pmid = {41601601}, issn = {2950-1997}, support = {R21 NS101506/NS/NINDS NIH HHS/United States ; R43 AG061952/AG/NIA NIH HHS/United States ; }, abstract = {In Alzheimer's disease (AD), alterations in the basal metabolic rate (BMR) and energy expenditure, known as metabolic phenotyping, are present early in the disease, which progresses as the disease advances. The Mediterranean diet, including extra-virgin olive oil (EVOO), has been known to reduce AD risk. Oleocanthal (OC) is a major phenolic compound in EVOO. Previous research showed that OC reduced brain amyloid-β, tau hyperphosphorylation, neuroinflammation, and improved blood-brain barrier and memory functions in AD mouse models. In this work, we aimed to investigate the dose-dependent impact of chronic oral OC treatment on modulating metabolic phenotypes affected by AD and its toxicity in 5xFAD mice, an AD mouse model. 5xFAD mice were treated with OC for 3 months, starting at the ages of one (prevention mode, before the pathology hallmarks appear) and 6 months (treatment mode, after the pathology hallmarks appear). Findings demonstrated OC altered metabolic phenotypes in the 5-20 mg/kg dose range in both groups. Furthermore, OC proved not toxic except at 20 mg/kg, where hepatic toxicity is observed. In conclusion, these findings highlight the OC effect in rectifying metabolic phenotypes in AD. However, it limits the dose range in mice to 5 and 10 mg/kg despite exhibiting a favorable response in metabolic parameters due to observed hepatotoxicity with the 20 mg/kg.}, } @article {pmid41601969, year = {2025}, author = {Ntsapi, C and Weyers, M and Chinheya, R and Jim, T and Matsabisa, M}, title = {Exploring cannabinoid modulation on autophagy mechanisms in Alzheimer's disease: a review.}, journal = {Frontiers in pharmacology}, volume = {16}, number = {}, pages = {1748368}, pmid = {41601969}, issn = {1663-9812}, abstract = {Alzheimer's disease (AD) is a neurodegenerative disorder characterized by the accumulation of toxic protein aggregates in the brain, leading to brain cell death and cognitive impairment. Central to AD pathogenesis is the autophagy pathway, a crucial cellular self-digestion process. Cannabinoids, the fundamental phytochemical compounds derived from the Cannabis sativa plant, have been demonstrated to exhibit neuroprotective qualities when used as a treatment at microdoses. However, the impact of multi-cannabinoid treatments on autophagy induction and subsequent cell survival in AD in vitro models remains uncertain. This review seeks to explore the potential of a multi-cannabinoid treatment strategy in enhancing neuronal cell survival through autophagy activation within an AD in vitro model. The proposed approach involves a combination of cannabinoids in their potential to upregulate autophagy mechanisms, potentially supporting neuronal cell resilience. By unravelling the mechanistic link between autophagy, cannabinoid treatment, and neuronal viability, this review aims to elucidate how cannabinoids influence neuronal function and survival at a cellular and molecular level. By offering insights into the exploitation of the endocannabinoid system, this review contributes to the development of novel cannabinoid-based treatment avenues for AD. This pursuit aligns with the broader objective of addressing the debilitating effects of AD on the quality of life for those affected.}, } @article {pmid41602161, year = {2025}, author = {Greco, D and Čočková, Z and Das, D and Mali, AS and Novotný, J and Olsen, MJ and Telenský, P}, title = {Small molecule FTO inhibitor MO-I-500 protects differentiated SH-SY5Y neuronal cells from oxidative stress.}, journal = {Frontiers in molecular neuroscience}, volume = {18}, number = {}, pages = {1736173}, pmid = {41602161}, issn = {1662-5099}, abstract = {INTRODUCTION: Oxidative stress is a central driver of brain aging, impairing cellular function and increasing susceptibility to neurodegenerative diseases. Recent studies suggest that the RNA demethylase FTO regulates N6-methyladenosine (m6A) RNA modification, a key pathway in modulating oxidative stress in the brain. However, the precise mechanisms underlying FTO's role remain unclear. This study examines the neuroprotective potential of MO-I-500, a small-molecule FTO inhibitor, against oxidative stress induced by tert-butyl hydroperoxide (TBHP) in neuron-like SH-SY5Y cells differentiated with retinoic acid and BDNF (dSH-SY5Y).

METHODS: dSH-SY5Y cells were treated with MO-I-500 alone for 72 h or with TBHP alone for 24 h. Alternatively, cells were pretreated with 1 μM MO-I-500 for 48 h, followed by co-treatment with MO-I-500 and 25 or 50 μM TBHP for an additional 24 h, for a total treatment duration of 72 h. Cellular metabolism was assessed using a Seahorse XF MitoStress assay, and oxidative stress markers, including ROS and superoxide levels, were quantified with DCFDA and MitoSOX probes. ATP content was measured using a bioluminescence assay.

RESULTS: FTO inhibition by MO-I-500 induced a metabolic shift toward an energy-efficient state, enhancing cellular resilience to oxidative stress. Pretreatment significantly reduced TBHP-induced oxidative damage, lowering intracellular ROS levels and preserving ATP content.

CONCLUSION: Together with our previous findings demonstrating the protective effects of MO-I-500 in astrocytes and recent studies supporting the importance of astrocyte function in neurodegeneration, these results suggest a dual protective role of MO-I-500 in neurons and astrocytes. This dual action positions MO-I-500 as a promising therapeutic strategy to mitigate oxidative damage and reduce the risk of neurodegenerative diseases, including Alzheimer's disease.}, } @article {pmid41602207, year = {2025}, author = {Tarnanas, I and Seixas, A and Wyss, M and Vlamos, P and Çöltekin, A}, title = {Merging multimodal digital biomarkers into "Digital Neuro Fingerprints" for precision neurology in dementias: the promise of the right treatment for the right patient at the right time in the age of AI.}, journal = {Frontiers in digital health}, volume = {7}, number = {}, pages = {1727707}, pmid = {41602207}, issn = {2673-253X}, abstract = {Digital biomarkers are revolutionizing medicine in ways that were unimaginable a few years ago. Consequently, precision medicine approaches now realistically can promise personalization, i.e., the right treatments for the right patients at the right time, including earlier, targeted interventions which lead to a major paradigm shift in how medicine is practiced from reactive to preventive action. Although the scientific evidence is clear on the power of digital biomarkers, there is an unmet need for translating these findings into actionable insights in clinical practice. In this paper, we focus on Alzheimer's disease and related dementias (ADRD), and how digital biomarkers could empower clinical decision making in its preclinical stages. We argue that a new all-encompassing score is needed, akin to a BrainHealth Index linked to the established and validated risk stratifications frameworks and is directed at the prevention of ADRD. Specifically, we propose the new concept "Digital Neuro Fingerprint (DNF)", built with simultaneous collection of multimodal digital biomarkers (speech, gait, eye movements etc.) from smartphone based augmented reality or virtual reality while an individual is immersed in activities of daily living. Fusing the captured multimodal digital biomarkers, data is automatically analyzed with custom combinations of machine- and deep-learning approaches and enhanced with explainable artificial intelligence (XAI) and uncertainty quantifications. We argue that DNF is useful for capturing ADRD progression and should supersede the biomarkers that are invasive and expensive to obtain, offering a sensitive and highly specific score that measures meaningful aspects of health for the patients in high-frequency intervals.}, } @article {pmid41603335, year = {2026}, author = {Byeon, JH and Lee, D and Shin, EJ and Park, EM and Yoon, EJ and Kim, H and Ham, H and Yeo, J and Yoo, H and Youn, JH and Kang, SH and Lee, JY}, title = {Validation of a web-based cognitive test for early detection of Alzheimer's disease.}, journal = {Journal of Alzheimer's disease : JAD}, volume = {110}, number = {2}, pages = {639-648}, doi = {10.1177/13872877261415925}, pmid = {41603335}, issn = {1875-8908}, mesh = {Humans ; *Alzheimer Disease/diagnosis/psychology ; Aged ; Female ; Male ; *Neuropsychological Tests ; Aged, 80 and over ; *Internet ; Middle Aged ; *Cognitive Dysfunction/diagnosis/psychology ; Early Diagnosis ; Sensitivity and Specificity ; }, abstract = {BackgroundEarly detection of Alzheimer's disease (AD) is critical for effective disease management and treatment. Web-based assessment tools offer advantages by enabling broader accessibility and reducing reliance on specialized clinical infrastructure.ObjectiveThis study aimed to validate a self-administered, web-based cognitive assessment tool for AD screening.MethodsA total of 106 older adults aged 55 to 84 years were recruited and clinically classified as cognitively unimpaired (CU, n = 35), amnestic mild cognitive impairment (aMCI, n = 37), or AD (n = 34). Participants completed Cogscreen, a 10-min web-based cognitive test comprising verbal cued memory and digit symbol substitution tasks.ResultsBoth the verbal cued memory and digit symbol substitution tasks showed significant score differences among CU, aMCI, and AD (p < 0.001). The Cogscreen composite score yielded area under the curve (AUC) values of 0.876 for aMCI (cut-off = 0.64, sensitivity = 0.865, specificity = 0.657) and 0.994 for AD (cut-off = -0.59, sensitivity = 0.971, specificity = 0.971), and outperformed the Mini-Mental State Examination (MMSE) in diagnosing aMCI (AUC = 0.638, p = 0.001). The composite score significantly correlated with the Consortium to Establish a Registry for Alzheimer's Disease assessment packet total score (r = 0.765, p < 0.001) and MMSE score (r = 0.722, p < 0.001).ConclusionsCogscreen is a rapid, self-administered cognitive screening tool for detecting aMCI and AD. It outperforms the MMSE in identifying early cognitive decline and holds potential for detecting even subtler cognitive changes in the future.}, } @article {pmid41603338, year = {2026}, author = {Ho, BL and Liu, CF and Huang, YB and Huang, LC and Yang, YH}, title = {Treatment persistence with acetylcholinesterase inhibitors in Alzheimer's disease: Real-world evidence from a retrospective cohort study.}, journal = {Journal of Alzheimer's disease : JAD}, volume = {110}, number = {1}, pages = {443-451}, doi = {10.1177/13872877251415021}, pmid = {41603338}, issn = {1875-8908}, mesh = {Humans ; *Cholinesterase Inhibitors/therapeutic use/administration & dosage ; *Alzheimer Disease/drug therapy ; Retrospective Studies ; Female ; *Rivastigmine/therapeutic use/administration & dosage ; *Donepezil/therapeutic use/administration & dosage ; Male ; Aged ; Aged, 80 and over ; Cohort Studies ; }, abstract = {BackgroundAlzheimer's disease (AD) is the leading cause of dementia worldwide, yet long-term persistence with acetylcholinesterase inhibitors remains suboptimal in routine practice.ObjectiveTo compare real-world treatment persistence among patients with mild to moderate AD receiving oral donepezil, rivastigmine capsules, or transdermal rivastigmine patches, and to identify factors influencing discontinuation.MethodsIn this retrospective cohort study, 1062 patients aged ≥65 years with newly diagnosed AD were identified from a hospital registry between 2015 and 2019 and followed through 2021. Treatment persistence was evaluated by duration and 1-year continuation rates. Discontinuation was defined as a prescription gap exceeding 90 days. Multivariable Cox proportional hazards models were used to identify predictors of discontinuation.ResultsPatients receiving donepezil had significantly longer mean treatment duration (3.03 years) and higher 1-year continuation rates (66.2%) than those receiving rivastigmine capsules (1.81 years, 39.9%) or patches (1.43 years, 45.5%). Both rivastigmine formulations were independently associated with greater discontinuation risk (adjusted hazard ratio [aHR] 1.44 and 1.76, respectively; p < 0.001). Participation in a national dementia care program was the strongest protective factor, associated with a 69% lower discontinuation risk (aHR 0.31; p < 0.001). Higher baseline CASI scores, younger age, and milder cognitive impairment predicted greater persistence, whereas adverse events markedly increased discontinuation.ConclusionsDonepezil demonstrated superior real-world persistence compared with rivastigmine. Structured dementia care programs substantially enhanced treatment continuity, underscoring the importance of both pharmacologic choice and system-level support in sustaining long-term therapy in AD.}, } @article {pmid41603342, year = {2026}, author = {Sha, L and Wu, M and Sun, S and Xie, Y and Liu, Y and Li, Z and Liu, R and Guo, W and Yan, S and Xu, B and Kang, L}, title = {Subcutaneous transplantation of mesenchymal stem cell spheroids ameliorates cognitive deficits in Alzheimer's disease.}, journal = {Journal of Alzheimer's disease : JAD}, volume = {110}, number = {2}, pages = {782-794}, doi = {10.1177/13872877261418164}, pmid = {41603342}, issn = {1875-8908}, mesh = {Animals ; *Alzheimer Disease/therapy/diagnostic imaging/pathology/genetics ; *Mesenchymal Stem Cell Transplantation/methods ; *Spheroids, Cellular/transplantation ; Mice, Transgenic ; Mice ; Disease Models, Animal ; Brain/metabolism/diagnostic imaging/pathology ; *Cognitive Dysfunction/therapy/diagnostic imaging ; Magnetic Resonance Imaging ; *Mesenchymal Stem Cells ; Plaque, Amyloid/pathology ; Presenilin-1/genetics ; }, abstract = {BackgroundMesenchymal stem cell (MSC)-based therapy has emerged as a promising alternative treatment for Alzheimer's disease (AD) but is limited by low cell survival rates and complex handling.ObjectiveThe present study explored the therapeutic potential of subcutaneous transplantation of MSC spheroids in a mouse AD model.MethodsWe prepared uniform size MSC spheroids with good stemness properties, and performed three consecutive subcutaneous treatments with MSC spheroids on early-stage AD APP/PS1 mice (6 months old), with each injection administered one month apart. Following treatment, behavioral experiments were conducted to evaluate learning and cognitive functions. Additionally, positron emission tomography (PET) and functional magnetic resonance imaging (fMRI) were utilized to assess cerebral glucose metabolism and neuronal functional connectivity. Subsequently, brain tissue sections were prepared and stained to evaluate amyloid plaque deposition, levels of inflammation, and other pathological changes.ResultsAPP/PS1 mice treated with MSC spheroids demonstrated better performance in cognitive behavioral tests compared to the AD model group. Imaging studies showed that brain glucose metabolism was higher in the MSC spheroids-treated group than in the AD model group, with enhanced functional brain connectivity. Moreover, pathological analysis revealed that MSC spheroids treatment resulted in a reduced amyloid-β plaque burden and attenuated inflammatory phenotypes in AD mice. MSC spheroids also protected neurons from apoptosis and restored synaptic plasticity.ConclusionsOur study suggests that subcutaneous transplantation of MSC spheroids reduced key pathological changes in AD by improving brain glucose metabolism and alleviating inflammation.}, } @article {pmid41603392, year = {2026}, author = {Prevot, E and Shand, C and , and Oxtoby, N}, title = {How reproducible are data-driven subtypes of Alzheimer's disease atrophy?.}, journal = {Journal of Alzheimer's disease : JAD}, volume = {110}, number = {1}, pages = {426-442}, pmid = {41603392}, issn = {1875-8908}, mesh = {Humans ; *Alzheimer Disease/classification/diagnostic imaging/pathology ; Magnetic Resonance Imaging ; Atrophy/pathology ; Female ; Reproducibility of Results ; *Brain/pathology/diagnostic imaging ; Male ; Cohort Studies ; Aged ; Disease Progression ; Algorithms ; Aged, 80 and over ; Databases, Factual ; }, abstract = {BackgroundAlzheimer's disease (AD) exhibits substantial clinical and biological heterogeneity, complicating efforts in treatment and intervention development. While new computational methods offer insights into AD subtyping and disease staging, the reproducibility of these subtypes across datasets remains understudied, particularly concerning the robustness of subtype definitions when validated on diverse databases.ObjectiveThis study evaluates the robustness of the AD progression subtypes identified by the Subtype and Stage Inference (SuStaIn) algorithm on a larger and more diverse cohort.MethodsWe extracted T1-weighted MRI data for 5444 subjects from ANMerge, OASIS, and ADNI datasets, forming four independent cohorts. Each cohort was analyzed with SuStaIn under two conditions: one using the full cohort, including cognitively normal controls, and another excluding controls to test subtype robustness.ResultsResults confirm the three primary atrophy subtypes identified in earlier studies: Typical, Cortical, and Subcortical, as well as the emergence of rare and atypical AD variants such as posterior cortical atrophy. Notably, each subtype displayed varying robustness to the inclusion of controls, with certain subtypes, like the Subcortical subtype, more influenced by cohort composition.ConclusionsThis investigation underscores SuStaIn's reliability for defining stable AD subtypes and suggests its utility in clinical stratification for trials and diagnosis. However, our findings also highlight the need for improved dataset ethnic and demographic diversity, particularly in terms of ethnic representation, to enhance generalizability and support broader clinical application.}, } @article {pmid41603883, year = {2026}, author = {Burn, O and Molloy, K and Kanekiyo, M and Parker, C and Rothwell, S and Pan, JJ and Trueman, D and Ritchie, C}, title = {Estimating the long-term health outcomes of treatment with lecanemab in early Alzheimer's disease: a modelling study.}, journal = {Journal of medical economics}, volume = {29}, number = {1}, pages = {250-262}, doi = {10.1080/13696998.2025.2600875}, pmid = {41603883}, issn = {1941-837X}, mesh = {Humans ; *Alzheimer Disease/drug therapy/mortality ; Markov Chains ; Female ; Aged ; Male ; Severity of Illness Index ; Cognitive Dysfunction/drug therapy ; Disease Progression ; Aged, 80 and over ; }, abstract = {AIMS: To assess the long-term effects of lecanemab plus standard of care (SoC) compared with SoC alone in a cohort of patients with early Alzheimer's disease (AD; mild cognitive impairment [MCI] due to AD, or mild AD dementia) using different modeling approaches and data from Clarity AD (NCT0388745538).

METHODS: A Markov model was employed using health states based on disease severity, long-term institutionalization, and death, with disease severity defined using the Clinical Dementia Rating - Sum of Boxes (CDR-SB) classification for MCI due to AD, and Mild, Moderate, and Severe AD. State transitions during the first 18 months of treatment were estimated using either patient count data (Approach 1) or multistate survival analysis (Approach 2). Transition probabilities beyond 18 months for the lifetime of the cohort were informed by longitudinal natural history data for the SoC arm with a hazard ratio for time-to-worsening health state applied to estimate outcomes in the lecanemab arm.

RESULTS: Over a lifetime horizon, the model predicted a delayed time to Mild, Moderate, and Severe AD for patients treated with lecanemab compared to SoC by 1.31, 1.85, and 2.04 years, respectively when using Approach 1. Patients treated with lecanemab experienced a survival benefit of 1.36 years, comprised of an additional 1.85 years in early AD and 0.49 years less in moderate and severe AD, compared to patients treated with SoC alone. The model also predicted that compared to SoC, lecanemab increased the time in community care and reduced time spent in institutional care. Results were similar when using Approach 2.

LIMITATIONS: Long-term disease progression was informed by constant annual transition probabilities derived from the published literature.

CONCLUSIONS: Patients treated with lecanemab experience delayed progression to Moderate and Severe AD, resulting in additional life-years (LYs) and reduced time in institutional care.}, } @article {pmid41603981, year = {2026}, author = {Raswanthiya, SP and Fernandes, OP and Mathew, MP and Balgote, PJ and Sivaraman, J}, title = {Decoding BDNF in neurodevelopmental, neurodegenerative, and neurological disorders: mechanisms and therapeutic perspectives.}, journal = {Molecular biology reports}, volume = {53}, number = {1}, pages = {330}, pmid = {41603981}, issn = {1573-4978}, mesh = {Humans ; *Brain-Derived Neurotrophic Factor/metabolism/genetics ; *Neurodegenerative Diseases/metabolism/genetics ; Animals ; Signal Transduction ; *Nervous System Diseases/metabolism/genetics ; Neurodevelopment ; *Neurodevelopmental Disorders/metabolism/genetics ; Receptor, trkB/metabolism ; }, abstract = {Brain-Derived Neurotrophic Factor (BDNF) is an essential neurotrophin involved in neuronal survival, synaptic plasticity, and neurogenesis, critical for normal brain function as well as the pathology of neurological and psychiatric disorders. It primarily functions by activating TrkB receptors, which subsequently modulate intracellular signalling pathways such as PI3K-Akt, Ras-MAPK, and PLC-γ1. The expression of BDNF is precisely controlled by genetic, epigenetic, and transcriptional mechanisms, with environmental and activity-dependent factors providing further modulation. However, it is worth noting that BDNF dysregulation has been linked to major diseases such as depression, schizophrenia, autism spectrum disorder, epilepsy, Alzheimer’s disease (AD), and Parkinson’s disease (PD), and depression, with growing evidence supporting its use as a biomarker for disease monitoring and treatment. This review provides a comprehensive overview of BDNF synthesis, regulation, and signalling mechanisms, highlighting its context-dependent roles in both health and disease. It also examines the role of BDNF in cerebellar development, specifically its effects on granule cells, Purkinje cells, and interneurons govern neuronal survival, migration, and synaptic refinement, and its disruption may predispose to neuropsychiatric vulnerability. While BDNF modulation correlates with clinical outcomes, it remains unclear whether BDNF upregulation directly contributes to therapeutic efficacy or is merely an associated response. BDNF shows promise as a diagnostic biomarker and therapeutic target, merging mechanistic and clinical insights, but requires further research for full potential in precision medicine.}, } @article {pmid41604898, year = {2026}, author = {Ni, H and Xiong, Y and Liu, M and Liu, J and Liu, M and Zhang, L and Zhao, Y and Yi, L and Zhou, R and He, Q and Li, Y and Du, Q and Liu, L and Huang, Y and Ning, W and Zhou, H and Dong, Y}, title = {Sinomenine inhibits oxidative stress to attenuate Alzheimer's disease pathology via α7 nicotinic acetylcholine receptor.}, journal = {Phytomedicine : international journal of phytotherapy and phytopharmacology}, volume = {152}, number = {}, pages = {157779}, doi = {10.1016/j.phymed.2026.157779}, pmid = {41604898}, issn = {1618-095X}, mesh = {Animals ; *alpha7 Nicotinic Acetylcholine Receptor/metabolism ; *Alzheimer Disease/drug therapy/pathology/metabolism ; *Oxidative Stress/drug effects ; *Morphinans/pharmacology ; Humans ; NF-E2-Related Factor 2/metabolism ; Mice, Transgenic ; *Neuroprotective Agents/pharmacology ; Mice ; Signal Transduction/drug effects ; Amyloid beta-Peptides/metabolism ; Kelch-Like ECH-Associated Protein 1/metabolism ; Male ; Cell Line, Tumor ; Disease Models, Animal ; }, abstract = {BACKGROUND: The pathological mechanism of Alzheimer's disease (AD) is complex. The binding of Aβ to α7 nicotinic acetylcholine receptor (α7nAChR) contributes to neuronal damage. Sinomenine (SIN) is an alkaloid extracted from the traditional Chinese medicine Qingfengteng (Sinomenium acutum). The anti-inflammatory, antioxidant, and immunomodulatory effects of SIN were confirmed to be closely associated with the α7nAChR.

PURPOSE: This study aimed to investigate whether α7nAChR serves as a pharmacological target of SIN against AD, and to evaluate the neuroprotective effects of SIN both in vivo and in vitro, focusing on the α7nAChR/Nrf2/Keap1 signaling pathway.

METHODS: In this study, the effects of SIN in both APP/PS1 transgenic mice and SH-SY5Y cells subjected to Aβ1-42-induced injury were assessed. The selective antagonist α-bungarotoxin ‌(α-BTX), the agonist nicotine (Nic) of α7nAChR, and α7nAChR siRNA were employed. The cognitive function, Aβ deposition, synaptic plasticity markers, the tau protein phosphorylation, mitochondrial membrane potential, oxidative stress and the α7nAChR/Nrf2/Keap1 signaling pathway were analyzed in vivo and/or in vitro.

RESULTS: SIN significantly enhanced learning and memory abilities in APP/PS1 mice, reduced Aβ plaque deposition and synaptic dysfunction, and inhibited hyperphosphorylation of tau protein and oxidative stress in the brain. In Aβ1-42-induced neuronal injury model, SIN alleviated apoptosis, increased BDNF and ACh levels, inhibited mitochondrial damage, stabilized calcium homeostasis, and suppressed oxidative stress. Meanwhile, SIN disrupted Nrf2-Keap1 binding to promote the Nrf2/HO-1 signaling pathway. Nevertheless, SIN effects above were inhibited by α-BTX. The knockdown of α7nAChR in vitro significantly promoted Nrf2/HO-1 pathway and BDNF expression.

CONCLUSION: SIN exerts neuroprotective effect in APP/PS1 transgenic mice and Aβ1-42-induced neuronal injury by inhibiting oxidative stress via α7nAChR/Nrf2/Keap1 pathway. This study provides evidence for α7nAChR as a new target and the clinical application potential of SIN in AD treatment.}, } @article {pmid41605321, year = {2026}, author = {Zhang, H and Xu, Q and Ye, M and Wu, X and Ren, Z and Qin, L and Tang, Z and Wang, G and Xiang, Q and Liu, L}, title = {Inclisiran attenuates Alzheimer's disease-like changes by suppressing microvascular endothelial ferroptosis to preserve blood-brain barrier integrity.}, journal = {Free radical biology & medicine}, volume = {246}, number = {}, pages = {547-561}, doi = {10.1016/j.freeradbiomed.2026.01.045}, pmid = {41605321}, issn = {1873-4596}, mesh = {Animals ; *Blood-Brain Barrier/drug effects/metabolism/pathology ; *Ferroptosis/drug effects ; *Alzheimer Disease/drug therapy/pathology/metabolism/genetics ; Humans ; Mice ; *Endothelial Cells/drug effects/metabolism/pathology ; *Proprotein Convertase 9/genetics/metabolism ; Amyloid beta-Peptides/metabolism/genetics ; Disease Models, Animal ; Microvessels/drug effects/pathology/metabolism ; RNA, Small Interfering/genetics ; Male ; }, abstract = {The integrity of blood-brain barrier (BBB) plays a pivotal role in the pathogenesis of Alzheimer's disease (AD) by regulating Aβ clearance and neurotoxic compound exclusion. Hyperlipidemia exacerbates AD by impairing the BBB function. Inclisiran, a PCSK9-targeting siRNA, reduces cholesterol levels; however, its neuroprotective effects remain unclear. Here, we report the novel discovery that Inclisiran attenuates AD-like changes through the PCSK9-ferroptosis axis in brain microvascular endothelial cells (BMECs). First, integrated bioinformatics analysis and experimental validation of cortical tissues from patients with AD and healthy controls revealed a coordinated upregulation of PCSK9 and β-amyloid (Aβ), accompanied by increased iron deposition and significant activation of the ferroptosis pathway. Interestingly, these changes are located in the BMECs of the blood-brain barrier rather than in the brain parenchyma. Second, in hyperlipidemic ApoE[-/-] mouse models, integrated application of cerebral microvessel isolation, molecular biology techniques, immunofluorescence co-localization analysis, and behavioral tests demonstrated that Inclisiran significantly reduced AD-like changes by attenuating BBB dysfunction based on the suppression of PCSK9-mediated ferroptosis in BMECs. Third, in vitro studies employing the HCMEC/D3 BBB model with integrated assessments of lipid peroxidation, mitochondrial function, and transwell-based barrier integrity demonstrated that Inclisiran significantly reduced ferroptosis and restored BBB integrity via PCSK9 suppression. Our findings not only establish a novel PCSK9-ferroptosis-BBB regulatory axis in AD pathogenesis but also posit the clinically approved lipid-lowering drug, Inclisiran, as a promising therapeutic candidate for AD, providing new targets and mechanisms for the prevention and treatment of AD.}, } @article {pmid41605825, year = {2026}, author = {Rodriguez, AD and DuBose, JR and Rozga, A and Zimring, CM and Mynatt, ED and Clifford, GD and Vickers, KL and Goldstein, FC and Giannotto, EL and Thelin, J and Levey, AI}, title = {Rationale and design of a multidomain lifestyle program for mild cognitive impairment.}, journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association}, volume = {22}, number = {1}, pages = {e71068}, pmid = {41605825}, issn = {1552-5279}, support = {//The James M. Cox Foundation/ ; //Cox Enterprises, Inc./ ; }, mesh = {*Cognitive Dysfunction/therapy/psychology ; Humans ; *Life Style ; Quality of Life ; Cognitive Training ; }, abstract = {The development of non-pharmacological treatment approaches is supported by evidence that addressing key modifiable risk factors may prevent or delay up to 45% of dementia cases. The Charlie and Harriet Shaffer Cognitive Empowerment Program (CEP) was developed to address current gaps in access to, and evidence for, interventions that reduce lifestyle risk factors and improve quality of life in individuals with mild cognitive impairment (MCI). Co-designed with patients and families, clinicians, researchers, and industry professionals, the CEP is situated in a conceptual framework that guides assessments and interventions/supports to holistically address the experience of living with MCI. CEP comprises four cores (Therapeutic Programs, Technology, Built Environment, and Innovation Accelerator) that map to the conceptual framework. We contend that our approach provides an opportunity to contribute to the evidence base for multidomain lifestyle programs and gain a deeper understanding of MCI and how individuals can be empowered to manage it. HIGHLIGHTS: The cognitive empowerment program (CEP) is a multidomain lifestyle program that was developed using a co-design process and a conceptual framework that holistically addresses the experience of living with mild cognitive impairment (MCI). CEP provides comprehensive assessment and intervention/support through four cores that map to the conceptual framework: therapeutic programs, technology, built environment and research innovation. CEP's unique approach provides an opportunity to build the evidence base for multidomain lifestyle interventions and to develop and refine lifestyle biomarkers that can be used for early detection of MCI, tracking of disease progression, and objective measurement of the impact of lifestyle interventions.}, } @article {pmid41606687, year = {2026}, author = {Wang, Y and Mohammadi, B and Hartmann, C and Hartmann, K and Thies, E and Matamoros-Angles, A and Fang, C and Harris, DA and Tatzelt, J and Altmeppen, HC and Sepulveda-Falla, D and Strittmatter, SM and Glatzel, M and Krasemann, S}, title = {Presymptomatic pharmacological inhibition of mGluR5 improves survival in a mouse model of prion diseases.}, journal = {Acta neuropathologica communications}, volume = {14}, number = {1}, pages = {}, pmid = {41606687}, issn = {2051-5960}, support = {P30 AG066508/AG/NIA NIH HHS/United States ; R01 AG034924/AG/NIA NIH HHS/United States ; }, mesh = {Animals ; *Receptor, Metabotropic Glutamate 5/antagonists & inhibitors/metabolism ; Disease Models, Animal ; *Prion Diseases/drug therapy/pathology/metabolism ; Mice ; Mice, Transgenic ; Male ; Pyridines/pharmacology ; Mice, Inbred C57BL ; }, abstract = {Toxic signaling of oligomeric protein species via binding to the cellular prion protein (PrPC) is implicated in various neurodegenerative diseases, including Alzheimer’s (AD) and Parkinson’s disease (PD). Metabotropic glutamate receptor 5 (mGluR5) has been identified as a PrPC signaling partner, and pharmacological inhibition of mGluR5 was shown to improve cognitive performance and rescue long-term-potentiation (LTP) impairment in both in vitro and in vivo models of AD and PD. Prion diseases are another group of fatal neurodegenerative disorders that are characterized by templated misfolding of endogenous PrPC itself into the disease-driving counterpart PrPSc. Besides its role in the self-propagating misfolding cascade and aggregation, PrPSc also acts as a toxic PrPC ligand in aberrant signaling through mGluR5. Therefore, targeting metabotropic glutamate receptors has been proposed as a therapeutic strategy for the intervention of prion disease. In this study, we investigated the impact of long-term oral administration of two different selective mGluR5 inhibitors, the negative allosteric inhibitor CTEP and a Silent Allosteric mGluR5 Modulator (SAM), in a mouse model of prion disease. Our findings demonstrate that treatment initiated during the preclinical phase significantly prolonged the survival of mice, whereas treatment starting after the onset of symptoms was no longer effective. Early treatment also delayed the formation of spongiosis, a pathological hallmark of prion diseases, but did not alter PrPRes levels. Preclinical dysregulation of mGluR5 could be shown in the mouse and a non-human primate model for prion diseases. Interestingly, in primary neurons, subacute treatment with CTEP blocked Aβ-induced, but not PrPSc-associated synaptotoxicity. Thus, modes of action might differ markedly from those observed in models of Alzheimer’s disease. Together, although our data show that targeting mGluR5 may be an efficient therapy, however, since treatment needs to be started early during prion disease progression, the narrow therapeutic window limits its therapeutic application in human prion diseases.}, } @article {pmid41607405, year = {2025}, author = {Crivelli, SM and Quadri, Z and van Kruining, D and Martinez-Martinez, P and Bieberich, E and Chatton, JY}, title = {Editorial: The role of glial cells in the pathophysiology and treatment of Alzheimer's disease.}, journal = {Frontiers in neuroscience}, volume = {19}, number = {}, pages = {1749170}, doi = {10.3389/fnins.2025.1749170}, pmid = {41607405}, issn = {1662-4548}, } @article {pmid41607407, year = {2025}, author = {Reading, CL and Yan, J and Testa, MA and Simonson, DC and Javaid, H and Schmunk, L and Martin-Herranz, DE and Brooke, R and Gordevicius, J and Zhang, J and Yuan, H and Ahlem, C and Wang, L and Markham, P and Osman, N and O'Quinn, S and Palumbo, J}, title = {Correction: An exploratory analysis of bezisterim treatment associated with decreased biological age acceleration, and improved clinical measure and biomarker changes in mild-to-moderate probable Alzheimer's disease.}, journal = {Frontiers in neuroscience}, volume = {19}, number = {}, pages = {1758523}, doi = {10.3389/fnins.2025.1758523}, pmid = {41607407}, issn = {1662-4548}, abstract = {[This corrects the article DOI: 10.3389/fnins.2025.1516746.].}, } @article {pmid41607671, year = {2025}, author = {Tommet, D and Foldi, NS and Lamar, M and Wang, C and Rabin, L and Grandoit, E and Choi, SE and Jutten, RJ and Lee, M and Nakano, C and Gibbons, LE and Scollard, P and Mungas, D and Jones, RN and , and Crane, PK}, title = {Six month repeat cognitive testing to identify people with MCI at greatest AD dementia risk.}, journal = {medRxiv : the preprint server for health sciences}, volume = {}, number = {}, pages = {}, doi = {10.64898/2025.12.30.25343228}, pmid = {41607671}, support = {P30 AG066509/AG/NIA NIH HHS/United States ; }, abstract = {INTRODUCTION: People with mild cognitive impairment (MCI) are candidates for early intervention, but not all progress to Alzheimer's disease (AD) dementia. Identifying a subgroup at highest risk may improve treatment targeting.

METHODS: We analyzed data from participants with MCI enrolled in the Alzheimer's Disease Neuroimaging Initiative (ADNI). Cognitive domains included memory, executive functioning, language, and visuospatial abilities. We evaluated baseline performance and 6-month change scores, using proportional hazards models to estimate associations with time to conversion to AD dementia.

RESULTS: The strength of association varied by domain, but in general both baseline performance and 6-month change were associated with conversion. The strongest effects observed for memory and language. Observed associations were largely independent of established risk biomarkers, including APOE genotype, structural MRI measures, and CSF biomarkers.

DISCUSSION: 6-month change scores on cognitive tests may help identify a high-risk subgroup of persons with MCI likely to progress to AD dementia.

RESEARCH IN CONTEXT: Systematic review. The authors reviewed the literature using traditional (e.g. PubMed) sources. There is a modest literature on change scores in the context of the AD clinical spectrum, but few investigations have evaluated whether short-term changes may be able to identify a high-risk subgroup of people with MCI. The authors have published a systematic review of this literature (Jutten et al. 2020) and appropriately refer to relevant citations here.Interpretation: Our findings suggest that short-term changes in cognition may be useful as part of a strategy to identify subsets of people with MCI who are at highest risk of conversion. Findings were clearest for memory and language. Domain-specific changes appeared to be independent from other biomarkers used to identify people at highest risk. Domain-specific changes did not appear to be better than changes in global cognition as measured by the MMSE or the CDR-sum of boxes.Future directions: Short-term changes in cognition may be useful to help identify a subgroup of people with MCI at highest risk of conversion to AD dementia. Future work could consider time frames shorter than the 6-month data we had available, better characterizing changes with more than 2 time points, or developing strategies that combine changes in cognition with other biomarkers to identify a subgroup of people with MCI to target for treatment.}, } @article {pmid41608511, year = {2025}, author = {Xu, Y and Gao, J and Wang, M and Zhang, H}, title = {Exercise-mimicking effects of betaine in chronic disease prevention and management.}, journal = {Frontiers in nutrition}, volume = {12}, number = {}, pages = {1762908}, pmid = {41608511}, issn = {2296-861X}, abstract = {Betaine, a natural compound found in beets, wheat germ, shellfish, and mammalian tissues, plays a crucial role in preventing and treating various chronic diseases. As the global population ages, chronic diseases are posing the primary threat to the health of the elderly, significantly increasing the medical pressure on families and society. Chronic diseases associated with aging involve complex molecular mechanisms and, therefore, developing multipronged interventions is crucial for their prevention and treatment. Although exercise is a primary intervention for preventing and treating chronic diseases, many elderly individuals have motor disabilities. Therefore, researchers are exploring natural products that mimic the therapeutic effects of exercise in individuals who are unable to exercise. Betaine has exhibited significant preventive and therapeutic effects in studies on chronic diseases and is known as an exercise mimetic. A deeper understanding of betaine may help elucidate crucial molecular mechanisms underlying its effects and offer theoretical insights for developing exercise-mimicking foods, supplements, and drugs, which are expected to benefit the human health.}, } @article {pmid41609034, year = {2026}, author = {Gashtrodkhani, AA and Shirkouhi, SG and Khatami, SS and Kamari, F and Ghaedi, S and Blaabjerg, M and Andalib, S}, title = {Neuroplasticity and Alzheimer's Disease.}, journal = {Journal of integrative neuroscience}, volume = {25}, number = {1}, pages = {48051}, doi = {10.31083/JIN48051}, pmid = {41609034}, issn = {0219-6352}, mesh = {*Alzheimer Disease/physiopathology/therapy/metabolism ; *Neuronal Plasticity/physiology ; Humans ; Animals ; *Cognitive Dysfunction/physiopathology/etiology ; *Nerve Growth Factors/metabolism ; }, abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disease that leads to a decline in cognitive function, including memory. The exact causes of AD are not fully understood, and to date no treatments are available that can stop the progression of this neurocognitive disorder. AD is associated with progressive loss of neurons, synaptic connectivity, and disruption of neuroplasticity in the brain. Neuroplasticity is the nervous system's ability to adapt and recover in response to experiences, injuries, or a pathological change. Synaptic dysfunction and impairment of neuroplasticity are important elements of AD progression and cognitive decline. Studies have demonstrated that enhancement of neuroplasticity effectively improves cognition and memory, preventing the progression of AD. In this narrative review, we discuss the role of various pathophysiological explanations regarding the impairment of neuroplasticity in the pathogenesis of AD. We also highlight neuromodulation approaches, such as exercise, neurotrophic factor mimetics, pharmacological drugs, light therapy, and diet therapy that can promote neuroplasticity and have the potential for use in the prevention and treatment of AD.}, } @article {pmid41609117, year = {2026}, author = {Wu, CK and Dailey, JM and Donahue, JE}, title = {Behavioral Variant in Alzheimer's Disease.}, journal = {Acta neurologica Taiwanica}, volume = {35}, number = {1}, pages = {14-24}, doi = {10.4103/ant.ANT-D-25-00098}, pmid = {41609117}, issn = {1028-768X}, mesh = {Aged ; Female ; Humans ; Male ; *Alzheimer Disease/psychology/diagnosis/complications ; Middle Aged ; }, abstract = {In this review, the authors report on the development and discovery of atypical variants in Alzheimer's disease (AD). The behavioral variant of AD is emphasized and described in detail, in addition to its comparison with other variants. Furthermore, the newly developed diagnostic criteria and diagnostic approach are explained and applied for clinical practice in neurology. Principles of management and treatment for behavioral variants are highlighted. Three cases are reported to illustrate different courses of pathophysiology in behavioral variants in AD.}, } @article {pmid41609790, year = {2026}, author = {Haußmann, A}, title = {[New treatments for Alzheimer disease : A challenge for radiology].}, journal = {Radiologie (Heidelberg, Germany)}, volume = {66}, number = {4}, pages = {249-257}, pmid = {41609790}, issn = {2731-7056}, mesh = {Humans ; *Alzheimer Disease/diagnostic imaging/drug therapy ; *Magnetic Resonance Imaging ; *Antibodies, Monoclonal/therapeutic use ; Diagnosis, Differential ; }, abstract = {Alzheimer's disease is one of the most common causes of dementia in older adults. Since 2024, monoclonal antibody therapy has been available, which can slow disease progression at certain stages. During therapy, magnetic resonance imaging changes called amyloid-related imaging abnormalities (ARIA)-edema (ARIA-E) and hemorrhage (ARIA-H)-must be monitored at specific points during treatment; depending on severity, therapy may need to be paused. Cerebral amyloid angiopathy (CAA) and its inflammatory form (CAA-I) should be considered in the differential diagnosis.}, } @article {pmid41609875, year = {2026}, author = {Shahabinejad, E and Shakoeizadeh, A and Karimabad, MN and Asadi, F and Heydari, M and Salandari-Rabori, M}, title = {Utilizing nanotechnology to diagnose and treat central nervous system disorders.}, journal = {Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology}, volume = {47}, number = {2}, pages = {209}, pmid = {41609875}, issn = {1590-3478}, mesh = {Humans ; *Central Nervous System Diseases/diagnosis/therapy/drug therapy ; *Nanotechnology/methods ; Animals ; *Drug Delivery Systems/methods ; }, abstract = {The CNS presents a unique challenge to therapeutic intervention due to its sophisticated organization, the protective blood-brain barrier (BBB), and the low regenerative potential of neural tissue. Over the last few decades, nanotechnology has emerged as a revolutionary technology capable of transforming the diagnosis and treatment of CNS diseases, thereby offering new hope to patients with previously incurable neurodegenerative diseases. This review highlights the therapeutic and diagnostic potential of newer types of nanomaterials-i.e., nanoliposomes (NLs), metallic nanoparticles (MNPs), and carbon nanotubes (CNTs)-which have been found to cross the blood-brain barrier (BBB) and deliver drugs with enhanced specificity and efficacy. Nanoparticle-based therapies have revolutionized drug delivery, gene therapy, in vivo imaging, and molecular profiling for CNS diseases. However, despite such advancements, hurdles remain, particularly in terms of biocompatibility, long-term safety, and site-specific activity within complex biological systems. Herein, we summarize recent advances in the construction of smart nanocarriers and multi-functional platforms for overcoming physiological and pharmacological challenges in CNS therapy. Finally, we emphasize the urgent need for interdisciplinary studies to unlock the full clinical potential of nanotechnology in neurology and answer outstanding questions regarding toxicity, immune responses, and scalability for human application.}, } @article {pmid41610646, year = {2026}, author = {Kumar, S and Srivastava, S and Tan, CS and Abohashrh, M and Malviya, R}, title = {Correlation between oral disease and neurodegenerative disorders: Role of biological proteins for the modulation of oral-brain axis and gut-brain axis.}, journal = {Colloids and surfaces. B, Biointerfaces}, volume = {262}, number = {}, pages = {115480}, doi = {10.1016/j.colsurfb.2026.115480}, pmid = {41610646}, issn = {1873-4367}, mesh = {Humans ; *Brain/metabolism ; *Neurodegenerative Diseases/metabolism ; Animals ; *Mouth Diseases/metabolism ; *Proteins/metabolism ; Biomarkers/metabolism ; Alzheimer Disease/metabolism ; }, abstract = {Biological proteins play a crucial role at the intersection of oral health and neuroscience, offering promising opportunities for improved diagnosis, prevention, and treatment. This review highlights the molecular, inflammatory, and biochemical pathways linking oral diseases, particularly periodontal disease and microbial dysbiosis, with neurodegenerative disorders such as Alzheimer's and Parkinson's disease. Key inflammatory, neuroprotective, and tissue-repair proteins play a crucial role in maintaining both oral integrity and neural function. Advances in proteomics and molecular imaging have clarified how protein misfolding, aggregation, and immune responses drive neuroinflammation and cognitive decline. Emerging therapies include protein-based biomaterials, such as hydrogels, nanocarriers, and protein-polymer hybrids, for delivering neuroprotective and regenerative agents through oral and nasal routes. Early diagnosis is being transformed by salivary proteomics and transcriptomics, enabling non-invasive detection of neurodegenerative biomarkers. Host-defense peptides and antimicrobial proteins also show promise in controlling oral infections that may exacerbate brain inflammation. Integrating oral biology, biomaterials science, and neuroscience is accelerating clinical translation through the development of innovative scaffolds and smart delivery systems. Despite challenges in biomarker validation and clinical application, advances in artificial intelligence, bioinformatics, and protein engineering are driving the future of personalized regenerative and preventive medicine. Overall, biological proteins provide a critical molecular link between oral and neural health, paving the way for novel non-invasive diagnostic and therapeutic strategies.}, } @article {pmid41611033, year = {2026}, author = {Zeng, X and Peng, D and Shen, Y and Tang, L and Ran, T and Pan, Z and Liu, H}, title = {Bletilla striata polysaccharide alleviates Alzheimer's disease in Caenorhabditis elegans by modulating autophagy via the insulin/AMPK pathway.}, journal = {Free radical biology & medicine}, volume = {247}, number = {}, pages = {27-38}, doi = {10.1016/j.freeradbiomed.2026.01.051}, pmid = {41611033}, issn = {1873-4596}, mesh = {Animals ; Caenorhabditis elegans/drug effects/genetics/metabolism ; *Alzheimer Disease/drug therapy/pathology/metabolism/genetics ; Autophagy/drug effects ; *Polysaccharides/pharmacology ; Signal Transduction/drug effects ; *Insulin/metabolism/genetics ; Caenorhabditis elegans Proteins/genetics/metabolism ; *AMP-Activated Protein Kinases/metabolism/genetics ; Amyloid beta-Peptides/metabolism/genetics ; Oxidative Stress/drug effects ; *Orchidaceae/chemistry ; Disease Models, Animal ; Humans ; }, abstract = {Alzheimer's disease (AD) is a common neurodegenerative disorder characterized by the abnormal aggregation of amyloid-β (Aβ). Bletilla striata polysaccharide (BSP), the primary active component of the traditional Chinese medicine Bletilla striata, exhibits various pharmacological effects including hemostatic, antioxidant, anti-inflammatory, and immunomodulatory activities. This study aimed to systematically investigate the protective effects and molecular mechanisms of BSP in Caenorhabditis elegans AD model. We found that BSP effectively alleviated the paralysis phenotype in AD worms, with optimal efficacy observed at a concentration of 100 μg/mL. Furthermore, BSP significantly extended the lifespan of both wild type and AD worms, reduced lipofuscin deposition and egg-laying capacity, improved neuromuscular function, learning ability, and stress resistance, and lowered the level of oxidative stress in vivo. Additionally, BSP treatment markedly suppressed Aβ aggregation in AD worms. Transcriptomic analysis revealed that BSP significantly regulates the autophagy pathway. In combination with genetic experiments, we further elucidated that BSP coordinates the insulin and AMPK signaling pathways to modulate autophagy, thereby reducing abnormal autophagosome accumulation and restoring autophagic homeostasis. Notably, the neuroprotective effects of BSP were completely abolished in mutants of key insulin signaling pathway genes (daf-2, age-1, akt-1, akt-2, daf-16) and the AMPK homologous gene aak-2, indicating that its efficacy is associated with the insulin/AMPK-autophagy regulatory axis. This study reveals the mechanism by which BSP ameliorates AD pathology through multi-target and multi-pathway regulation of autophagy, providing a new theoretical basis for its development as a candidate therapeutic agent for AD and further highlighting the potential medical value of Bletilla striata in combating AD.}, } @article {pmid41611624, year = {2026}, author = {Donohue, MC and Hussen, K and Langford, O and Gallardo, R and Jimenez-Maggiora, G and Aisen, PS and , }, title = {Alzheimer's clinical research data via R packages: The alzverse.}, journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association}, volume = {22}, number = {2}, pages = {e71152}, pmid = {41611624}, issn = {1552-5279}, support = {R01 AG063689/AG/NIA NIH HHS/United States ; //Servier/ ; //Genentech, Inc./ ; //ADNI/ ; //AbbVie/ ; //Transition Therapeutics/ ; /EB/NIBIB NIH HHS/United States ; //Foundation for the National Institutes of Health/ ; //NIA/ ; //Eisai Inc./ ; //Biogen/ ; //BristolMyers Squibb Company/ ; //Johnson & Johnson Pharmaceutical Research & Development LLC./ ; //Yugilbar Foundation/ ; //CIHR/Canada ; //Alzheimer's Disease Neuroimaging Initiative/ ; //Statewide California Electronic Library Consortium/ ; //Albert Einstein College of Medicine and the Foundation for Neurologic Diseases/ ; //Lumosity/ ; U24AG057437/GF/NIH HHS/United States ; //Piramal Imaging/ ; //Epstein Family Foundation/ ; //Takeda Pharmaceutical Company/ ; //Araclon Biotech/ ; //Alzheimer's Association; Alzheimer's Drug Discovery Foundation/ ; //Novartis Pharmaceuticals Corporation/ ; //Meso Scale Diagnostics, LLC./ ; //CereSpir, Inc./ ; //Northern California Institute for Research and Education/ ; //BioClinica, Inc./ ; //GHR Foundation/ ; //GE Healthcare/ ; U19AG024904/GF/NIH HHS/United States ; //Cogstate/ ; //Davis Alzheimer Prevention Program/ ; /NH/NIH HHS/United States ; //Pfizer Inc./ ; //Elan Pharmaceuticals, Inc./ ; //Avid Radiopharmaceuticals/ ; //Women's Hospital/ ; //Eli Lilly and Company/ ; //IXICO Ltd./ ; //NeuroRx Research/ ; //Merck & Co., Inc./ ; //SCELC/ ; //Neurotrack Technologies/ ; //Fujirebio/ ; //Lundbeck/ ; }, mesh = {Humans ; *Alzheimer Disease/diagnostic imaging ; *Biomedical Research ; Reproducibility of Results ; Neuroimaging ; *Software ; }, abstract = {INTRODUCTION: Sharing clinical research data is essential for advancing Alzheimer's disease (AD) research, yet challenges in accessibility, standardization, documentation, usability, and reproducibility persist.

METHODS: We developed R data packages to streamline access to curated datasets from key AD studies. A4LEARN includes data from the Anti-Amyloid Treatment in Asymptomatic Alzheimer's (A4) randomized trial and its companion observational study, the Longitudinal Evaluation of Amyloid Risk and Neurodegeneration (LEARN). ADNIMERGE2 contains curated data from the Alzheimer's Disease Neuroimaging Initiative (ADNI), a longitudinal biomarker and imaging study.

RESULTS: These packages bundle data, documentation, and reproducible analysis vignettes into portable, analysis-ready formats that can be installed and used within R. We also introduce the alzverse package, which applies a common data standard to integrate study-specific packages and facilitate meta-analyses.

DISCUSSION: By promoting collaboration, transparency, and reproducibility, R data packages provide a scalable framework to accelerate AD clinical research.

HIGHLIGHTS: R packages enable access to curated Alzheimer's clinical study datasets. A4LEARN and ADNIMERGE2 provide portable, analysis-ready data resources. R packages integrate data, documentation, and reproducible analysis vignettes. alzverse unifies study packages via common standards to support meta-analyses. Tools promote transparency, collaboration, and reproducibility in Alzheimer's disease (AD) research.}, } @article {pmid41611638, year = {2026}, author = {Tang, C and Yang, J and Lei, X and Zhang, M and Chen, Y and Peng, X and He, D}, title = {Association between brain volume and depression in Alzheimer's disease: Neuroimaging insights.}, journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association}, volume = {22}, number = {2}, pages = {e71120}, pmid = {41611638}, issn = {1552-5279}, support = {R01AG021910//Washington University, St.Louis/ ; P30AG072979/AG/NIA NIH HHS/United States ; P30 AG066444/AG/NIA NIH HHS/United States ; P30AG062429/AG/NIA NIH HHS/United States ; R01AG058724//Cure Alzheimer's Fund/ ; P50AG005142//University of Southern California/ ; 200775//Cure Alzheimer's Fund/ ; UL1TR000448//Washington University, St.Louis/ ; //Avid Radiopharmaceuticals/Eli Lilly/ ; P50AG005133//University of Pittsburgh/ ; R01AG043434//Washington University, St.Louis/ ; P30AG072972/AG/NIA NIH HHS/United States ; P30 AG066518/AG/NIA NIH HHS/United States ; P30AG062422/AG/NIA NIH HHS/United States ; P20AG068024/AG/NIA NIH HHS/United States ; R01AG061788//Indiana University/ ; P50AG005136//University of Washington/ ; P20//University of Alabama, Birmingham/ ; P30AG072976/AG/NIA NIH HHS/United States ; R01EB009352//Washington University, St.Louis/ ; U01AG057195//Indiana University/ ; R56AG045571//North western University/ ; P50AG008702//Columbia/ ; R01AG069453//Arizona Alzheimer's Center/ ; P20AG068082//Vanderbilt University/ ; P30AG072973/AG/NIA NIH HHS/United States ; P30AG019610//Arizona Alzheimer's Center/ ; P30AG066518/AG/NIA NIH HHS/United States ; U19NS120384//Cure Alzheimer's Fund/ ; P30AG053760//University of Michigan ADRC/ ; P30AG066507//Johns Hopkins/ ; P30AG072947/AG/NIA NIH HHS/United States ; P30AG066515/AG/NIA NIH HHS/United States ; 1I01RX001534//Cure Alzheimer's Fund/ ; P30AG072947//WakeForest/ ; P30AG066509/AG/NIA NIH HHS/United States ; P30AG079280/AG/NIA NIH HHS/United States ; P30AG066512-01S2//New York University/ ; P30AG062428//Clevel and ADRC/ ; P30AG062677/AG/NIA NIH HHS/United States ; P50AG033514//University of Wisconsin/ ; R01AG067781//North western University/ ; R01AG056531//New York University/ ; P01 AG003991/AG/NIA NIH HHS/United States ; P30AG072946/AG/NIA NIH HHS/United States ; P30AG072959/AG/NIA NIH HHS/United States ; P01 AG026276/AG/NIA NIH HHS/United States ; P30AG072931//University of Michigan ADRC/ ; R01AG055005//Rooney Family Research Fund/ ; P30AG062429//University of California, San Diego/ ; R01AG056258//North western University/ ; R01AG073235//Cure Alzheimer's Fund/ ; R01AG062276//Yale/ ; P30 AG062422/AG/NIA NIH HHS/United States ; R01NS075075//North western University/ ; P30AG066511/AG/NIA NIH HHS/United States ; IRX001381//Cure Alzheimer's Fund/ ; U24RR021382//Washington University, St.Louis/ ; P30AG066444/AG/NIA NIH HHS/United States ; P30AG066468/AG/NIA NIH HHS/United States ; P30AG008017//Oregon Health and Science University/ ; P20AG068077/AG/NIA NIH HHS/United States ; P30AG010161//Rush University/ ; P30AG072977/AG/NIA NIH HHS/United States ; R35AG072262//Cure Alzheimer's Fund/ ; P20AG068053/AG/NIA NIH HHS/United States ; P01AG03991//Washington University, St.Louis/ ; P30AG072975/AG/NIA NIH HHS/United States ; P50AG016573//University of California, Irvine/ ; R56AG074321//Oregon Health and Science University/ ; W81XWH2110743//Cure Alzheimer's Fund/ ; P30AG066511//Emory University/ ; P30AG066508/AG/NIA NIH HHS/United States ; P30AG066462/AG/NIA NIH HHS/United States ; P30AG072976//Indiana University/ ; P30AG066530/AG/NIA NIH HHS/United States ; P30AG035982//University of Kansas/ ; P30AG066506/AG/NIA NIH HHS/United States ; P50AG047270//Yale/ ; U24AG072122//National Institute on Aging and National Institutes of Health/ ; P30AG066512/AG/NIA NIH HHS/United States ; P20AG068077//University of New Mexico/ ; P30AG066546/AG/NIA NIH HHS/United States ; P20AG068053//Las Vegas/ ; R01DC008552//North western University/ ; P30 AG066509/AG/NIA NIH HHS/United States ; P30AG062421/AG/NIA NIH HHS/United States ; P30AG072958//Duke/UNCADRC/ ; P30AG066519/AG/NIA NIH HHS/United States ; P30AG066514/AG/NIA NIH HHS/United States ; P30AG072958/AG/NIA NIH HHS/United States ; P30AG072980//Arizona Alzheimer's Center/ ; P50AG047366//Stanford/ ; P30AG10133//Indiana University/ ; U19AG073153//North western University/ ; P30AG072978/AG/NIA NIH HHS/United States ; P50AG047266//1Florida/ ; R01AG054110//Mount Sinai/ ; U19AG063911//Indiana University/ ; P30NS098577//Washington University, St.Louis/ ; //and the State of Arizona which provided additional funding supporting our center/ ; P01AG026276//Washington University, St.Louis/ ; S10OD026738-01//Cure Alzheimer's Fund/ ; 2021ZD0201801//STI2023-Major Projects/ ; P20AG068082/AG/NIA NIH HHS/United States ; P30 AG072976/AG/NIA NIH HHS/United States ; R01AG053509//Mount Sinai/ ; P30AG013846//Boston University/ ; P30AG066514//Mount Sinai/ ; R01AG053993//Indiana University/ ; P30AG066507/AG/NIA NIH HHS/United States ; P30AG066515//Stanford/ ; R01AG19771//Indiana University/ ; R01AG045571//North western University/ ; P30AG013854//North western University/ ; P50AG016574//Mayo Clinic/ ; P30AG10129//University of California, Davis/ ; //Clevel and Clinic/ ; P30AG062422//University of California, San Francisco/ ; P20MH071616//Washington University, St.Louis/ ; P30AG066506-03//1Florida/ ; P30AG072972//University of California, Davis/ ; P30AG072931/AG/NIA NIH HHS/United States ; P30AG062715/AG/NIA NIH HHS/United States ; //Key and Dominant Discipline Construction Project of the Health Commission of Guizhou Province in 2023, China/ ; //and the Indiana University Department of Radiology and Imaging Sciences/ ; R01AG068338//Cure Alzheimer's Fund/ ; P30AG028283-15S1//University of Kentucky/ ; R01AG077444//North western University/ ; R01AG056031//New York University/ ; P30AG066444//Washington University, St.Louis/ ; R01AG052560//Yale/ ; 2019NF4100087335//University of Pennsylvania-State of PA project/ ; }, mesh = {Humans ; *Alzheimer Disease/diagnostic imaging/pathology/complications/psychology ; Female ; Male ; *Brain/pathology/diagnostic imaging ; *Depression/diagnostic imaging/pathology ; Neuroimaging ; Magnetic Resonance Imaging ; Aged ; Atrophy/pathology ; Aged, 80 and over ; Organ Size ; Cognitive Dysfunction/pathology ; Hippocampus/pathology ; Neuropsychological Tests ; }, abstract = {INTRODUCTION: Alzheimer's disease (AD) often co-occurs with depression, affecting cognitive function and quality of life. Understanding the neurobiological links between brain abnormalities and depressive symptoms is essential for effective treatment.

METHODS: We analyzed 2,722 participants from the National Alzheimer's Coordinating Center, including 886 AD patients and 1,836 cognitively normal controls. Neuroimaging assessed brain volumes, while depressive symptoms were measured using the Geriatric Depression Scale. Multiple linear regression and mediation analyses evaluated associations between brain structure, cognitive function, and depression.

RESULTS: AD patients had significantly higher rates of depressive symptoms (35.3% vs. 14.7%; p < 0.001) and cognitive impairments (mean Mini-Mental State Examination [MMSE]: 23.1 vs. 28.9; p < 0.001). Hippocampal atrophy mediated the relationship between depression and AD (indirect effect = -0.107; p < 0.001).

CONCLUSION: Hippocampal atrophy significantly mediates the relationship between depression and AD, suggesting targeted interventions may enhance patient outcomes.}, } @article {pmid41612173, year = {2026}, author = {Yu, L and Zhao, M and Zhang, W and Lv, Z and Zhao, K and Li, H and Qi, Y and Peng, X and Zheng, Z and Zhang, W}, title = {Precise Aβ clearance and antioxidant therapy in Alzheimer's disease via photoacoustic imaging-guided palladium hydride nanosheet-mediated photothermal treatment.}, journal = {BMC neuroscience}, volume = {27}, number = {1}, pages = {8}, pmid = {41612173}, issn = {1471-2202}, mesh = {Animals ; *Alzheimer Disease/therapy/metabolism/drug therapy/diagnostic imaging ; *Palladium/administration & dosage ; *Amyloid beta-Peptides/metabolism ; *Photothermal Therapy/methods ; *Antioxidants/administration & dosage/pharmacology ; Hydrogen/administration & dosage ; *Nanostructures/administration & dosage ; Photoacoustic Techniques/methods ; Blood-Brain Barrier/metabolism/drug effects ; Mice ; Mice, Transgenic ; Male ; Brain/metabolism/drug effects ; }, abstract = {Inflammation and oxidative stress are critical pathological hallmarks of Alzheimer’s disease (AD). Hydrogen therapy shows promise due to its selective hydroxyl radical (∙OH) scavenging capacity, yet conventional hydrogen delivery fails to effectively accumulate in the brain due to low solubility and rapid diffusion. Here, we report ultra-small palladium hydride (PdH) nanosheets as a dual-functional nanomedicine for AD treatment. The PdH nanosheets exhibit high hydrogen-releasing efficiency via autocatalysis, enabling in situ ∙OH scavenging in the brain. Concurrently, their near-infrared (NIR) photothermal effect, degrading amyloid-β (Aβ) aggregates and transiently enhancing blood-brain barrier (BBB) permeability for improved drug delivery. In AD mice, intravenous PdH treatment combined with NIR irradiation significantly reduced escape latency in the Morris water maze, paralleling reductions in brain Aβ plaques and ROS levels. This study establishes a synergistic strategy of nanoscale hydrogen delivery and photothermal therapy, addressing the dual challenges of BBB penetration and multi-pathology intervention in AD.}, } @article {pmid41613446, year = {2025}, author = {Sun, Y and Sun, J and Feng, Y and Zhang, Y and Li, J and Wang, F and Loznik, M and Tian, Y and Zhang, H and Herrmann, A and Liu, K and Zhang, C}, title = {Significant downregulation of Alzheimer's amyloid-β levels enabled by engineered DNA nanomaterials.}, journal = {Fundamental research}, volume = {5}, number = {5}, pages = {2241-2247}, pmid = {41613446}, issn = {2667-3258}, abstract = {Although there are no effective therapies to block or reverse Alzheimer's disease (AD) progression at present, a promising therapeutic strategy is to reduce levels of amyloid-β (Aβ) proteins, which drive the formation of amyloid plaque, a primary hallmark in AD brains. Herein, we report that amphiphilic lipid-DNA molecules (LD) were designed by incorporating a long alkyl chain into the nucleotide base. It significantly down-regulated Alzheimer's Aβ levels in vivo and in vitro. In contrast to small-molecule chemical drugs and antibody therapies, the assembled DNA nanoparticles allowed them to effectively cross the blood-brain barrier (BBB) and accumulate in the brain, increasing the therapeutic effects. Notably, lipid-DNA downregulated the levels of Aβ peptides significantly in vitro. AD mice model experiments demonstrated that the LD-treated groups exhibited a rapid cognition behavioral improvement, which was associated with brain engagement of LD and reduced Aβ levels. Thus, the molecularly engineered DNA nanomaterials effectively regulated Aβ peptides. This work might provide a promising DNA engineering strategy for AD treatment.}, } @article {pmid41613657, year = {2025}, author = {Arai, H and Yamamoto, H and Akiba, Y and Aiba, S and Arai, R}, title = {Amyloid Positron Emission Tomography Imaging at the Onset of Amyloid-Related Abnormalities With Edema in an Alzheimer's Disease Patient.}, journal = {Cureus}, volume = {17}, number = {12}, pages = {e100276}, pmid = {41613657}, issn = {2168-8184}, abstract = {Amyloid-related imaging abnormalities with edema (ARIA-E) are known adverse events of anti-amyloid monoclonal antibody therapy for Alzheimer's disease (AD), but to our knowledge, amyloid positron emission tomography (PET) captured exactly at the moment of ARIA-E onset has not previously been reported. We report an 85-year-old woman with AD who received anti-amyloid antibody therapy for approximately one year. As part of routine post-treatment evaluation, a second amyloid PET scan obtained 16 days after her final infusion unexpectedly revealed asymptomatic ARIA-E when followed immediately by magnetic resonance imaging (MRI). Compared with the baseline, the follow-up PET showed a marked overall reduction in cortical amyloid burden, including near-complete loss of tracer uptake in the region corresponding to ARIA-E, while the adjacent white matter exhibited reduced, non-specific uptake likely related to edema. This unique, same-day PET-MRI pairing at the moment of ARIA-E detection highlights dynamic regional changes in amyloid signal during treatment and emphasizes the value of continued neuroimaging surveillance even in asymptomatic patients.}, } @article {pmid41613766, year = {2026}, author = {McMackin, R and Price, S and Slator, GR and Hardiman, O and Kelly, JA}, title = {JAK4D, a first-in-class thyrotropin-releasing hormone analogue, reverses scopolamine-induced memory deficits.}, journal = {Brain communications}, volume = {8}, number = {1}, pages = {fcag006}, pmid = {41613766}, issn = {2632-1297}, abstract = {There is a pressing unmet clinical and health economic need for effective drugs to treat cognitive impairment that occurs in neurodegenerative diseases. JAK4D is a first-in-class thyrotropin releasing hormone (TRH) analogue that overcomes the pharmacological limitations of thyrotropin releasing hormone and enables delivery of the long-recognized multifactorial neurotherapeutic actions of thyrotropin releasing hormone without inducing endocrine side effects. JAK4D is demonstrated to be neuroprotective and significantly reduce excitotoxic-induced hippocampal-dependent memory deficits in rat. In the present study, we used the scopolamine challenge test coupled with the novel object recognition test to evaluate the effect of JAK4D on scopolamine-induced recognition memory deficits in the male, Lister-Hooded rat. Scopolamine administration has been shown by others to mimic cholinergic and brain network disruption in neurodegenerative diseases. Although the scopolamine challenge test does not fully replicate the pathophysiology of neurodegenerative disease, such as Alzheimer's disease, it is a well-recognized acute pharmacological model for assessing the ability of pharmacological interventions to counteract memory deficits relevant to neurodegenerative diseases. In this model of cholinergic dysfunction, we also assessed the effects of thyrotropin releasing hormone, taltirelin (a degradation-stabilized thyrotropin releasing hormone analogue) and the acetylcholinesterase inhibitor, donepezil, as a positive reference compound. The discrimination (d2) index was used as the primary measure to assess the effect of treatment on scopolamine-induced performance deficit in the novel object recognition test. d2 is a standard well-recognized measure of discrimination between a novel and familiar object in the novel object recognition test, which advantageously takes into account individual differences in exploration levels. Across all investigations, JAK4D (1 mg/kg i.p.) significantly reversed scopolamine-induced recognition memory impairment (P = 0.0274, P = 0.0002, P < 0.0001). The degree of reversal of scopolamine-induced memory deficits by JAK4D (1 mg/kg i.p.) was indistinguishable from that observed for donepezil (0.1 mg/kg p.o.) (P = 0.026). Subcutaneously administered JAK4D (0.3-10.0 mg/kg) also significantly reversed this deficit (P = 0.0432-0.0021). Furthermore, similar pro-cognitive effects were exerted by thyrotropin releasing hormone (5 mg/kg i.p., P = 0.0055) and taltirelin (10 mg/kg p.o., P = 0.0002). Together, these results underscore the relevance of the central thyrotropin releasing hormone signalling system for the treatment of memory impairment. Data from the current study provide further evidence in support of the potential of JAK4D as a novel therapeutic for cognitive deficits in neurodegenerative diseases.}, } @article {pmid41614554, year = {2026}, author = {Büyükgök, D and Ince Guliyev, E and Bilgiç, B}, title = {Apathy in dementia: pharmacological and nonpharmacological treatment strategies.}, journal = {Current opinion in psychiatry}, volume = {39}, number = {2}, pages = {160-167}, doi = {10.1097/YCO.0000000000001054}, pmid = {41614554}, issn = {1473-6578}, mesh = {Humans ; *Apathy/drug effects ; *Methylphenidate/therapeutic use ; *Central Nervous System Stimulants/therapeutic use ; *Dementia/therapy/psychology/drug therapy ; *Alzheimer Disease/therapy/drug therapy/psychology ; Cholinesterase Inhibitors/therapeutic use ; }, abstract = {PURPOSE OF REVIEW: Apathy is one of the most prevalent and disabling symptoms of neurodegenerative disorders, yet targeted treatments remain poorly defined. In recent years, growing interest in its conceptualization and management has led to an increasing number of randomized controlled trials (RCTs) and meta-analyses addressing both pharmacological and nonpharmacological interventions.

RECENT FINDINGS: Among pharmacological approaches, methylphenidate presented with early reductions in apathy with an acceptable safety profile in multiple RCTs, including a large 6-month trial. However, the sustainability of effect has not been fully achieved. Other stimulants, bupropion, and conventional Alzheimer's medications such as cholinesterase inhibitors and memantine show inconsistent or limited effects. Antidepressants and antipsychotics are not recommended for apathy, although selected agents may benefit comorbid conditions. As for the nonpharmacological interventions, evidence supports the benefits of physical exercise and the emerging promise of neuromodulation. Technology-based interventions are feasible but show variable efficacy.

SUMMARY: Methylphenidate currently represents the most studied pharmacological agent for apathy in Alzheimer's disease (AD). However, optimal management is likely to combine pharmacological and psychosocial strategies tailored to the patient context. Future studies should include pragmatic trials with apathy as a primary endpoint, long-term follow-up, and expansion beyond AD.}, } @article {pmid41614916, year = {2026}, author = {Zhao, X and Yin, J and Du, B and Fan, W and Chen, Y and Yang, Y and Fang, F and Guan, J}, title = {Behavioral, Histopathological, and Biochemical Implications of Aloe Emodin in Copper-Aβ-Induced Alzheimer's Disease-like Model Rats.}, journal = {Current issues in molecular biology}, volume = {48}, number = {1}, pages = {}, pmid = {41614916}, issn = {1467-3045}, support = {82074001//National Natural Science Foundation of China/ ; zyyzdxk-2023265//the State Administration of Traditional Chinese Medicine High-level TCM key discipline Con-struction Project/ ; }, abstract = {Simultaneously inhibiting beta-amyloid protein (Aβ) aggregation and reducing metal ion overload in the brain is a promising strategy for treating Alzheimer's disease (AD). Aloe emodin (AE) is one of the major components of the traditional Chinese medicine rhubarb. Based on its reported pharmacological effects and its structural affinity for metal ions, this study aims to explore the potential of AE in improving AD pathology. Through the injection of Aβ or copper-Aβ complex in the bilateral hippocampus of rats, we constructed two kinds of nontransgenic animal models. Behavioral tests were used to evaluate cognitive impairment, and the effects of AE on neuronal damage and Aβ deposition were measured via Nissl staining and immunohistochemistry. Furthermore, we detected copper content in the serum and brain tissues as well as some biochemical indexes of Aβ cascade pathology in the brain tissues of model rats to explore the mechanism of action. AE treatment decreased copper accumulation and regulated Aβ metabolism in the brain of model rats, thereby improving Aβ deposition, memory impairment, hippocampal nerve cell damage, and related biochemical indicators. AE ameliorated the AD pathology of the model rats by targeting copper-induced Aβ toxicity, revealing a mechanism of action by which AE may exhibit good clinical efficacy in treating AD.}, } @article {pmid41615932, year = {2026}, author = {Hedaya, RJ}, title = {Iterative Dual-AI Consultation for Error Detection in Clinical Medicine: A Case Study Demonstrating Convergent Validity Through Cross-Validation of Large Language Models.}, journal = {Alternative therapies in health and medicine}, volume = {32}, number = {1}, pages = {}, pmid = {41615932}, issn = {1078-6791}, abstract = {BACKGROUND: Large language models have demonstrated remarkable promise in medical data analysis, but serious concerns about reliability and error propagation persist. This study reports a novel approach of using iterative consultation between two independent AI systems to analyze complex clinical neuroimaging data.

METHODS: A 63-year-old woman with a family history of Alzheimer's disease and Parkinsonism underwent brain MRI volumetry showing apparent 10-13% increases in gray matter volume following intensive multimodal interventions (Functional Medicine and HYLANE™ treatment). Despite clinical improvement, objective cognitive testing declined during the same period. Two AI systems (Claude and Perplexity) independently analyzed neuroimaging reports, cognitive testing, and clinical data over 5-7 iterative cycles, systematically challenging each other's interpretations.

RESULTS: Initial analyses diverged substantially (45-60 percentage-point difference in probability estimates). Through autonomous error detection and cross-validation, systems converged to a consensus (<10 percentage-point difference). Critical autonomous discoveries included: (1) 3.5% increase in total intracranial volume (physiologically impossible, indicating measurement artifact), (2) 11-month temporal gap between cognitive testing and MRI, and (3) literature review revealing hyperbaric oxygen therapy produces maximum 1-2% volumetric changes. Final consensus: modest real improvements (2-4%) embedded within measurement artifact (3-5%).

CONCLUSIONS: Dual-AI iterative consultation achieved autonomous error detection, literature integration, and convergent validity without requiring human identification of critical flaws. This approach may enhance reliability in complex clinical decision-making while maintaining appropriate physician oversight.

KEYWORDS: artificial intelligence, clinical decision support, neuroimaging, automated volumetry, large language models, convergent validity, error detection.}, } @article {pmid41616387, year = {2026}, author = {Upadhayay, S}, title = {Unrevealing role of TLRs/NLRP receptors in halting Alzheimer's neuroinflammation: Current progress and existing therapies.}, journal = {International immunopharmacology}, volume = {173}, number = {}, pages = {116285}, doi = {10.1016/j.intimp.2026.116285}, pmid = {41616387}, issn = {1878-1705}, mesh = {Humans ; *Alzheimer Disease/drug therapy/immunology/metabolism ; *Toll-Like Receptors/metabolism/antagonists & inhibitors/immunology ; Animals ; Inflammasomes/metabolism ; *Neuroinflammatory Diseases/drug therapy/metabolism/immunology ; *NLR Proteins/metabolism/antagonists & inhibitors ; Signal Transduction/drug effects ; *Neuroprotective Agents/therapeutic use/pharmacology ; }, abstract = {Alzheimer's disease (AD) is a multifactorial condition caused by genetic, environmental, metabolic, and immunological factors. These pathological alterations trigger oxidative stress, excitotoxicity, and neuroinflammation, leading to the degeneration of cholinergic neurons in the brain. Several studies have found that persistent neuroinflammation plays a key role in AD progression; still, no curative medicine is available to halt the disease progression. For this reason, exploring new target-based therapy is necessary for AD treatment. The current review aims to understand the inflammatory processes associated with the activation of toll-like receptors (TLRs) and Inflammasomes (NLRPs) in AD progression. Additionally, the impact of TLR and NLRP inhibitors on improving the condition of AD patients. As multiple studies have confirmed, TLR/NLRP activation stimulates the infiltration of inflammatory cytokines, which enhances AD severity. Similarly, various studies have shown that inhibition of the TLR/NLRP signaling axis reduces oxidative stress, inflammatory cytokines, and apoptosis, thereby demonstrating a neuroprotective effect. This review examines the roles of TLR and NLRP pathways in AD progression, focusing on preclinical and clinical evidence supporting the neuroprotective benefits of targeting these pathways in AD. This review extensively examined the molecular mechanisms of TLR/NLRP inhibitors, highlighting recent discoveries that could be used to initiate clinical trials in patients with Alzheimer's.}, } @article {pmid41616931, year = {2026}, author = {Licciardo, D and Matti, C and Benelli, A and Isella, V and Appollonio, I and Santarnecchi, E}, title = {Gray matter atrophy and structural connectivity in Posterior Cortical Atrophy: A voxel-based meta-analysis.}, journal = {Neuroscience and biobehavioral reviews}, volume = {183}, number = {}, pages = {106554}, doi = {10.1016/j.neubiorev.2026.106554}, pmid = {41616931}, issn = {1873-7528}, mesh = {Humans ; Atrophy/pathology ; *Gray Matter/pathology/diagnostic imaging ; *Cerebral Cortex/pathology/diagnostic imaging ; Neural Pathways/pathology/diagnostic imaging ; }, abstract = {Posterior Cortical Atrophy (PCA) is a neurodegenerative syndrome most commonly associated with Alzheimer's disease, characterized by progressive visuospatial and visuoperceptual decline. Although voxel-based morphometry studies have described gray matter loss in PCA, a comprehensive and updated coordinate-based meta-analysis is still missing, and associated structural connectivity alterations remain unclear. We conducted a systematic review and meta-analysis of whole-brain voxel-based morphometry studies comparing patients with PCA and healthy controls (PROSPERO ID: CRD420251010673). Analyses were performed using Seed-based d Mapping with Permutation of Subject Images (SDM-PSI) with family-wise error correction, and meta-regressions assessed the impact of demographic and clinical variables. To investigate structural connectivity, deterministic tractography was carried out on a normative diffusion MRI template, using meta-analytic gray matter clusters as seeds. Eighteen studies were included (339 PCA; 577 healthy controls). The meta-analysis revealed consistent bilateral gray matter atrophy in the lateral occipital cortex, inferior parietal lobule, precuneus, and ventral occipitotemporal regions. Meta-regression highlighted an interaction between age and disease duration, associated with atrophy in the left superior temporal gyrus and right thalamus. Tractography demonstrated that affected clusters were embedded within major long-range pathways, including the superior and inferior longitudinal fasciculi, vertical occipital fasciculi, and parietal aslant tract. Regression-derived clusters additionally mapped onto the arcuate fasciculus, frontal aslant tract, and superior thalamic radiations. This is the first systematic review and voxel-based meta-analysis of PCA conducted after the establishment of consensus diagnostic criteria, providing a statistically robust characterization of gray and white matter alterations and identifying potential imaging biomarkers for diagnosis and treatment.}, } @article {pmid41616952, year = {2026}, author = {Denver, P and Duffy, A and Kennedy, RT and Gault, VA and McClean, PL}, title = {Therapeutic efficacy of synthetic analogues of gut hormones in a mouse model of Alzheimer's disease.}, journal = {Neuroscience}, volume = {600}, number = {}, pages = {63-81}, doi = {10.1016/j.neuroscience.2026.01.038}, pmid = {41616952}, issn = {1873-7544}, mesh = {Animals ; *Alzheimer Disease/drug therapy/pathology/metabolism/genetics ; Disease Models, Animal ; Mice, Transgenic ; Mice ; Amyloid beta-Protein Precursor/genetics/metabolism ; *Gastrointestinal Hormones/pharmacology ; Male ; Liraglutide/pharmacology ; Brain/drug effects/pathology/metabolism ; Amyloid beta-Peptides/metabolism ; Synapses/drug effects/pathology ; Maze Learning/drug effects ; Gastric Inhibitory Polypeptide/pharmacology ; Neurogenesis/drug effects ; }, abstract = {Alzheimer's disease (AD) is a neurodegenerative condition characterised by amyloid-β pathology, neuroinflammation, synaptic dysfunction and cognitive decline. Few pharmacological interventions are available, offering only symptomatic relief, and approval for a number of anti-amyloid biologics is limited, with concerns about safety, cost and efficacy. Here we investigated the effects of 8-10 weeks treatment with liraglutide, NAcGIP[Lys(37)PAL] and Xenin-25[Lys(13)PAL], long-lasting analogues of gut hormones glucagon-like peptide-1 (GLP-1), glucose-dependent insulinotropic peptide (GIP) and xenin-25, respectively, in the APP/PS1 mouse model of AD. Cognitive function was measured in novel object recognition (NOR) and Morris water maze (MWM) tasks and amyloid burden, gliosis, synapse density and neurogenesis were assessed in brains of APP/PS1 and wild-type mice. AD-associated gene expression analysis was performed to identify potential pathways targeted by treatment. Liraglutide and NAcGIP[Lys(37)PAL] improved cognitive performance in APP/PS1 mice and, along with Xenin-25[Lys(13)PAL], reduced amyloid-β burden in the brain. Liraglutide ameliorated gliosis and all three treatments restored synaptophysin levels. Additionally, Xenin-25[Lys(13)PAL] increased neurogenesis in the dentate gyrus. Numerous AD-associated genes were altered in the brain following treatments. Notably, Serpina3c was upregulated in brains of APP/PS1 mice treated with liraglutide, NAcGIP[Lys(37)PAL] and Xenin-25[Lys(13)PAL], while Map2, Adam9, Lrp8, Casp3, Abca1 and App were downregulated. These results underscore the neuroprotective effects of liraglutide and suggest that NAcGIP[Lys(37)PAL] and Xenin-25[Lys(13)PAL] possess neuroprotective properties. Further investigation of the precise nature of these effects may support development of multi-target therapeutics based on combinations of gut hormone analogues.}, } @article {pmid41617942, year = {2026}, author = {Ran, Z and Yang, LL and Zhou, LY and Wen, T and Wang, WJ and Chen, L}, title = {Research trends and hotspots of nanomaterials in Alzheimer's disease: bibliometric analysis.}, journal = {Discover nano}, volume = {21}, number = {1}, pages = {20}, pmid = {41617942}, issn = {2731-9229}, support = {82204761//National Natural Science Foundation of China/ ; 2024SZY120//the Deyang Science and Technology Bureau/ ; }, abstract = {INTRODUCTION: Alzheimer's disease (AD) is a progressive neurodegenerative disorder with limited clinical treatment options. Nanoparticle technology offers promising new strategies for innovative diagnosis and therapy of AD. However, the rapid development of this field has not been accompanied by a systematic bibliometric analysis. This study applies bibliometric methods to comprehensively evaluate the development trends and prospects of nanoparticle applications in AD research.

MATERIALS AND METHODS: Publications related to nanomaterials in AD were retrieved from the Web of Science Core Collection. Visualization and analysis were conducted using VOSviewer, CiteSpace, and the Bibliometrix package in R to identify research hotspots in the field.

RESULTS: A total of 2837 publications were included, involving 92 countries/regions, 2953 institutions, and 13,294 authors. China, the Chinese Academy of Sciences, and Xiao-Gang Qu were the most productive country, institution, and author, respectively. The Journal of Controlled Release was the most influential. Among them, Saraiva et al. (J Control Release 235:34-47, 2016) ranked first with 1069 citations, and their research highlights the great potential of nanoparticle drug delivery technology to cross the blood-brain barrier. Emerging keyword trends indicate a shift in research focus toward nasal delivery, extracellular vesicles, graphene quantum dots for diagnostics, and nanostructured lipid carriers for therapy.

CONCLUSION: Nanomaterial-based AD research is expanding rapidly. Current focus involves developing targeted nanoparticle systems to overcome the blood-brain barrier, mitigate Aβ pathology, and enable early diagnosis. Future work should prioritize mechanistic studies and clinical trials to translate potential into practical applications.}, } @article {pmid41618017, year = {2026}, author = {Beccherle, M and Amato, S and Facci, E and Stefanescu, G and Bertagnoli, S and Francesco, VD and Fontana, G and Gambina, G and Moro, V}, title = {Patterns of cognitive and motor decline in Alzheimer's Disease (AD) and ageing in healthy populations.}, journal = {Aging clinical and experimental research}, volume = {38}, number = {1}, pages = {74}, pmid = {41618017}, issn = {1720-8319}, mesh = {Humans ; *Alzheimer Disease/physiopathology/psychology ; Aged ; Female ; *Aging/physiology/psychology ; Male ; Aged, 80 and over ; *Cognition/physiology ; Psychomotor Performance ; Nutritional Status ; Quality of Life ; }, abstract = {BACKGROUND: Various patterns may apply to an individual’s health-span, with quality of life deriving from a balance between physical conditions, motor and cognitive abilities (i.e. psychomotor capabilities). METHODS: In this study, the Italian version of the Éxamen Geronto-Psychomoteur was administered to a sample of Alzheimer’s Disease (AD) patients (n = 94) and a group of healthy older adults (n = 333) to compare the patterns of psychomotor decline in pathological and physiological ageing. Three domains were considered to integrate bodily and cognitive dimensions: cognitive functions, motor abilities, and muscular tone alterations (physical constraints). Potential correlations with general cognitive functioning, autonomy in daily life, mood and nutritional status were also investigated. RESULTS: A correlation between cognitive, motor and physical dimensions is confirmed, and the results show that the patterns relating to healthy and pathological ageing are not only quantitatively but also qualitatively different. Besides the cognitive functions, the deterioration in AD also affects the physical components, precociously. Specifically, hypertonia may be present since the initial phases of illness. In healthy subjects, body representations decline early, while verbal memory, temporal and space representation resist over time. Malnutrition correlates with hypertonia in AD and with a reduction in daily life abilities in healthy people. CONCLUSIONS: The results highlight the importance of adopting an integrated psychomotor approach in the screening, diagnosis and treatment of ageing and AD to investigate early motor and bodily indicators, which are often not fully considered in clinical practice.}, } @article {pmid41618453, year = {2026}, author = {Swain, A and Soni, ND and Gaspar, RB and Davis, JG and Liu, F and Juul, H and Nanga, RPR and Baur, JA and Reddy, R}, title = {In vivo imaging of glutamate uncovers the neuroprotective effects of nicotinamide riboside on excitotoxicity in an Alzheimer's mouse model.}, journal = {Alzheimer's research & therapy}, volume = {18}, number = {1}, pages = {37}, pmid = {41618453}, issn = {1758-9193}, support = {P41 EB029460/EB/NIBIB NIH HHS/United States ; R01 AG063869/AG/NIA NIH HHS/United States ; R01 DK098656/DK/NIDDK NIH HHS/United States ; }, mesh = {Animals ; *Alzheimer Disease/diagnostic imaging/metabolism/drug therapy/pathology ; *Glutamic Acid/metabolism ; *Niacinamide/analogs & derivatives/pharmacology ; *Neuroprotective Agents/pharmacology ; Mice, Transgenic ; Mice ; Disease Models, Animal ; Magnetic Resonance Imaging/methods ; Glial Fibrillary Acidic Protein/metabolism ; Pyridinium Compounds ; *Brain/drug effects/metabolism/diagnostic imaging ; Male ; Female ; }, abstract = {BACKGROUND: Nicotinamide adenine dinucleotide (NAD+) precursors, such as nicotinamide riboside (NR), have gained interest as potential therapeutics for alleviating Alzheimer’s disease (AD) pathology. Chemical exchange saturation transfer (CEST) magnetic resonance imaging (MRI) can provide insights into the effects of NR on AD by virtue of its sensitivity to monitoring the metabolic status of tissue in vivo. METHODS: This study used glutamate-weighted CEST (GluCEST) MRI to monitor glutamate-associated metabolic changes following NR treatment in the 5xFAD mouse model of AD. Drinking water was supplemented with NR or provided as is to animals over the course of expected disease progression prior to imaging experiments. Following imaging, an immunohistochemical assay to monitor the expression of glial fibrillary acidic protein (GFAP) and ionized calcium-binding adaptor molecule 1 (Iba1) was performed to assess the extent of neuroinflammatory glial responses. A two-way ANCOVA with interaction was performed for statistical analysis of both CEST and IHC data. RESULTS: Results from GluCEST revealed significantly higher glutamate levels in the hippocampal dentate gyrus of AD mice compared to WT, with a significant reduction following treatment. GFAP staining mirrored this trend, implicating reactive astrogliosis as a mechanism for elevated glutamate. Similar patterns were observed in the cerebral peduncles, a white matter bundle, in which GFAP and Iba1 supported GluCEST findings and suggested neuroinflammation in axonal tracts. Our findings are in concordance with studies reporting elevated glutamate associated with reactive gliosis and morphological changes disrupting glutamate imbalance. Interestingly, NR restores glutamate homeostasis and alleviates neuroinflammatory processes, thus rescuing tissue from excitotoxic insults. CONCLUSION: Overall, this study demonstrates the potential of NR to mitigate glutamate-driven excitotoxicity in AD pathology, and highlights GluCEST as a sensitive in vivo, clinically translatable biomarker for neuroinflammation and excitotoxicity.}, } @article {pmid41618467, year = {2026}, author = {Ziaei, A and Kargar, M and Shirvani-Farsani, Z and MehrabMohseni, M}, title = {Emerging roles of circular RNAs and enhancer RNAs: new insights into the development and management of neurodegenerative disorders.}, journal = {Biomarker research}, volume = {14}, number = {1}, pages = {25}, pmid = {41618467}, issn = {2050-7771}, abstract = {Neurodegenerative disorders involve the gradual breakdown of neurons, leading to problems with thinking, movement, and mental health. More evidence is emerging about the important roles of non-coding RNAs (ncRNAs). CircRNAs are a type of ncRNA formed through back-splicing and are widely present in the mammalian brain. They play crucial roles in brain development and mainly regulate gene expression and post-transcriptional processes by acting as molecular sponges for miRNAs and RBPs. eRNAs are another class of ncRNAs. They are produced from enhancer regions of the genome and act as vital regulatory elements in gene expression. There is increasing evidence that abnormal levels of circRNAs and eRNAs can be found in many human diseases, including neurodegenerative conditions. This suggests they could have important clinical uses in these illnesses. The unique stability and disease-specific expression patterns of circRNAs and eRNAs in biofluids like blood and cerebrospinal fluid make them strong candidates for noninvasive biomarkers in neurodegenerative disorders, such as Alzheimer's disease, Parkinson's disease, Huntington's disease, and multiple sclerosis. Additionally, their roles in crucial pathological pathways open new opportunities for treatment. This includes strategies that target RNA, such as antisense oligonucleotides or miRNA sponges, to influence gene expression networks. This review gathers recent findings to propose that circRNAs and eRNAs might introduce a new layer of regulation in neurodegeneration, providing exciting possibilities for real-world applications.}, } @article {pmid41618768, year = {2026}, author = {Golden, JC and Murphy, KS and Tampi, RR}, title = {From schizophrenia to dementia: Is Cobenfy a potential treatment for behavioral and psychological symptoms of dementia?.}, journal = {The Journal of international medical research}, volume = {54}, number = {1}, pages = {3000605261417092}, pmid = {41618768}, issn = {1473-2300}, mesh = {Humans ; *Dementia/drug therapy/psychology ; *Schizophrenia/drug therapy/physiopathology ; *Nortropanes/therapeutic use ; *Benzilates/therapeutic use ; *Thiadiazoles/therapeutic use ; Drug Combinations ; *Antipsychotic Agents/therapeutic use ; Alzheimer Disease/drug therapy/psychology ; }, abstract = {Behavioral and psychological symptoms of dementia significantly impact patient outcomes, caregiver burden, and healthcare costs. Current pharmacologic treatments are limited by efficacy and safety concerns. Cobenfy, a novel combination of xanomeline and trospium chloride, has shown efficacy in schizophrenia and presents a promising alternative for treating behavioral and psychological symptoms of dementia. This editorial explores the potential role of Cobenfy in the management of behavioral and psychological symptoms of dementia. To date, no trials of Cobenfy for behavioral and psychological symptoms of dementia have been completed; however, multiple trials are underway to investigate this medication for psychosis and agitation in Alzheimer's disease. Cobenfy may offer a safer pharmacologic option for behavioral and psychological symptoms of dementia compared with existing treatments. Further research in older adult populations is warranted.}, } @article {pmid41619339, year = {2026}, author = {Shaaban, D and Seerley, A and Crew, L and Kaylor, C and McElroy, S and Guter, E and Pounder, J and Panter, AG}, title = {The impact of formic acid treatment on brain tissues for prion inactivation.}, journal = {Acta histochemica}, volume = {128}, number = {2}, pages = {152324}, pmid = {41619339}, issn = {1618-0372}, support = {P20 GM152335/GM/NIGMS NIH HHS/United States ; S10 OD038298/OD/NIH HHS/United States ; }, mesh = {Animals ; *Formates/pharmacology ; *Brain/pathology/drug effects/metabolism ; Mice ; *Prions/metabolism/drug effects ; Disease Models, Animal ; Wasting Disease, Chronic/pathology ; Prion Diseases ; }, abstract = {There are significant risks in clinical, diagnostic, and research settings to those who investigate prion diseases, due to the difficult nature of inactivating prion proteins with standard decontamination methods. Formic acid treatment has been shown to be effective for decontaminating infectious prions and commonly used in biosafety practice to prevent occupational exposure. However, the impact of formic acid protocols on the morphology of tissue samples has not been adequately documented. The goal of this study is to examine morphologic effects of formic acid treatment on central nervous system tissue, using mouse model brain hemisphere tissues that exhibit varying degrees of neurodegeneration as a model. This study included normal, non-diseased wild-type tissues and a 5xFAD model, which recapitulates aspects of Alzheimer's Disease (AD). A model exhibiting Chronic Wasting Disease (CWD), a prion disease of deer and elk, was also used to analyze the effects of formic acid on tissues with spongiform changes. Tissues from both formic acid and untreated control treatment groups were embedded in paraffin, sectioned, stained, and imaged microscopically. Anatomical regions were analyzed and evaluated quantitatively to determine the width, area, and structural integrity of the tissue between treatment groups. Our findings demonstrated that while formic acid has been previously reported to effectively inactivate prions, it compromised the morphology of mouse brain tissues. Furthermore, the effects of formic acid were not distributed equally between regions of the brain. Age did not play a role in the morphologic changes seen in the formic acid treatment group. Interestingly, the presence of neurodegeneration in the tissues did not appear to exacerbate the effects of morphological changes post-formic acid treatment. These results emphasize the need to explore alternative prion inactivation methods that ensure the safety and reliability of handling prion-infected tissues without compromising the integrity of tissues.}, } @article {pmid41619409, year = {2026}, author = {Vogelgsang, J and Beck, C and Patrick, R and Vahia, I and Weisenbach, S}, title = {Preclinical amyloid pathology is associated with anxiety but not depression in cognitively normal older adults: Evidence for differential neuropsychiatric pathways.}, journal = {The journal of prevention of Alzheimer's disease}, volume = {13}, number = {4}, pages = {100497}, pmid = {41619409}, issn = {2426-0266}, mesh = {Humans ; *Anxiety/metabolism ; *Depression/psychology ; Aged ; Female ; Positron-Emission Tomography ; Male ; *Alzheimer Disease/psychology/diagnostic imaging ; Aged, 80 and over ; Cognition ; *Amyloid beta-Peptides/metabolism ; *Amyloid/metabolism ; }, abstract = {INTRODUCTION: Neuropsychiatric symptoms may represent early Alzheimer's disease (AD) manifestations, but their relationship with amyloid pathology in cognitively unimpaired individuals remains unclear.

METHODS: We analyzed 4,492 cognitively unimpaired adults (aged 65-85) from the Anti-Amyloid Treatment in Asymptomatic Alzheimer's Study. Participants completed amyloid-PET imaging and assessments of anxiety, depression, memory complaints, and AD concerns.

RESULTS: 1,231 participants (27.4%) were amyloid-positive. While anxiety and depression scores remained within normal ranges, amyloid-positive participants reported higher memory complaints (p = 0.008) and AD concerns (p < 0.001) before status disclosure. Regression analyses showed amyloid burden associated with anxiety (β = 0.04, standardized, p = 0.003) but not depression (p = 0.68). Mediation analyses revealed anxiety was directly associated with amyloid, while depression was mediated through subjective cognitive concerns.

DISCUSSION: Preclinical amyloid pathology directly associates with subclinical anxiety but only indirectly with depression through subjective stress, suggesting distinct neuropsychiatric pathways in early AD that could inform detection strategies.}, } @article {pmid41620006, year = {2026}, author = {Ma, S and Wang, Q and Yang, W and Zhang, S and Liu, F and Guan, F and Liu, H and Li, D}, title = {4,4'-dimethoxychalcone exerts neuroprotective effects in Alzheimer's disease mice by activating the Keap1/Nrf2 signaling pathway.}, journal = {European journal of pharmacology}, volume = {1016}, number = {}, pages = {178617}, doi = {10.1016/j.ejphar.2026.178617}, pmid = {41620006}, issn = {1879-0712}, mesh = {Animals ; *Kelch-Like ECH-Associated Protein 1/metabolism ; *NF-E2-Related Factor 2/metabolism ; *Alzheimer Disease/drug therapy/metabolism/pathology/psychology ; *Neuroprotective Agents/pharmacology/therapeutic use ; Signal Transduction/drug effects ; *Chalcones/pharmacology/therapeutic use ; Mice ; Male ; Oxidative Stress/drug effects ; Disease Models, Animal ; Amyloid beta-Peptides/metabolism ; Cell Line ; Neurogenesis/drug effects ; }, abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disease with no effective therapies. 4,4'-Dimethoxychalcone (DMC) is a natural chalcone extracted from Angelica keiskei (Miq.) Koidz and Angelica sinensis (Oliv.) Diels, which could promote autophagy and prolong lifespan. However, the neuroprotective effects and mechanisms of DMC on AD mice have not been reported. In this study, we proved that DMC treatment significantly mitigated cognitive impairment and depressive behavior, ameliorated blood-brain barrier permeability and amyloid β pathology, and inhibited p-Tau expression in 5 × FAD mice. Also, DMC suppressed glial cell activation, enhanced neurogenesis, and decreased oxidative stress in vivo and in vitro by activating the Kelch-like ECH-associated protein1 (Keap1)/nuclear factor-erythrocyte 2-associated factor 2 (Nrf2) signaling pathway. However, Brusatol, an inhibitor of the Keap1/Nrf2 signalling, partly attenuated the neuroprotective effects of DMC on lipopolysaccharide-induced HT22 cells injury and 5 × FAD mice. In conclusion, DMC exhibited neuroprotective effects on 5 × FAD mice via the activation of Keap1/Nrf2 signalling pathway. Thus, DMC may be a promising therapeutic drug for AD.}, } @article {pmid41620439, year = {2026}, author = {Gong, Q and Fu, X and Feng, D and Rao, S and Pütz, B and Müller-Myhsok, B and Wei, L and Shen, C and Zhang, Y and Xu, L and Chen, W and Yang, K and Chen, D and Lv, X and Yan, Z and Luo, D and Wei, P and Jiang, H and Chen, W}, title = {Randomized, double-blind, sham-controlled pilot trial of theta-band transcranial alternating current stimulation during cognitive training in mild Alzheimer's disease.}, journal = {Translational psychiatry}, volume = {16}, number = {1}, pages = {57}, pmid = {41620439}, issn = {2158-3188}, support = {82071181//National Natural Science Foundation of China (National Science Foundation of China)/ ; 82101581//National Natural Science Foundation of China (National Science Foundation of China)/ ; 82371453//National Natural Science Foundation of China (National Science Foundation of China)/ ; }, mesh = {Humans ; Double-Blind Method ; *Transcranial Direct Current Stimulation/methods ; Pilot Projects ; Male ; *Alzheimer Disease/therapy/physiopathology ; Female ; *Cognitive Training ; Aged ; *Theta Rhythm/physiology ; Cognitive Enhancement ; Treatment Outcome ; Electroencephalography ; Memory, Short-Term ; Neuropsychological Tests ; Cognition ; }, abstract = {Cognitive deficits are a hallmark of Alzheimer's disease (AD), and effective treatments remain elusive. Transcranial alternating current stimulation (tACS), a non-invasive technique, has shown potential in improving cognitive function across various populations, but further research is needed to investigate its efficacy in AD. In a randomized, double-blind, sham-controlled pilot trial, 36 mild AD patients received active or sham theta-tACS (8 Hz, 1.6 mA, 20-min daily) during n-back task for two weeks, followed by a 10-week follow-up. Cognitive assessments and resting-state EEG were analyzed at baseline, after-treatment, and follow-up. The results showed that the active group demonstrated significant cognitive improvements after treatment (MMSE: t (15) =-3.273, p = 0.005, Cohen's d = 0.82), particularly in short-term memory (MMSE-recall: Z = -2.11, p = 0.035, r = 0.53), with maintained benefits after 10 weeks. In contrast, the sham group exhibited long-term cognitive decline (MMSE: t (4) = 3.586, p = 0.023, Cohen's d = -1.60). EEG analysis revealed reduced gamma power (t (23) = 2.689, p = 0.013, Cohen's d = 1.077) and theta connectivity in active group, particularly in the frontotemporal regions (F4/F7: t (23) = 2.467, p = 0.021, Cohen's d = 0.988; F4/T3: t (23) = 2.465, p = 0.022, Cohen's d = 0.987), which was correlated with cognitive improvements (R = -0.57, p = 0.043). In conclusion, tACS combining cognitive training may offer cognitive benefits in mild AD by modulating neural activity, though further studies are needed to clarify its mechanisms.}, } @article {pmid41620763, year = {2026}, author = {Luque, M and Matic, M and Heras-Garvin, A and Amo-Aparicio, J and Luk, KC and Haindl, MT and Khalil, M and Skouras, DB and Dinarello, CA and Stefanova, N}, title = {Clinically advanced NLRP3 inhibitor modulates microglial transcriptome and alleviates α-synuclein-induced progression of parkinsonism.}, journal = {Journal of neuroinflammation}, volume = {23}, number = {1}, pages = {}, pmid = {41620763}, issn = {1742-2094}, support = {MJFF-022681//Michael J. Fox Foundation for Parkinson's Research/ ; }, mesh = {Animals ; *NLR Family, Pyrin Domain-Containing 3 Protein/antagonists & inhibitors/metabolism ; *Microglia/drug effects/metabolism ; *alpha-Synuclein/toxicity ; Mice ; *Transcriptome/drug effects ; Mice, Transgenic ; *Parkinsonian Disorders/metabolism/drug therapy/pathology ; Disease Progression ; Humans ; Male ; Mice, Inbred C57BL ; Disease Models, Animal ; }, abstract = {BACKGROUND: Parkinson’s disease (PD), the second most common neurodegenerative disorder after Alzheimer’s disease, and the rare disorder multiple system atrophy (MSA), are both characterized by intracellular accumulation of α-synuclein fibrils and early, sustained microglial reactivity in parallel to the neurodegeneration. Activation of the NLRP3 inflammasome in disease-associated reactive microglia is increasingly recognized as a key pathogenic driver and a promising therapeutic target in synucleinopathies. Dapansutrile (OLT1177®) is a selective, orally bioavailable NLRP3 inhibitor with a favorable safety profile in clinical trials for non-neurological indications. Here, we evaluated the therapeutic potential of dapansutrile in preclinical models of PD and MSA and explored the predictive and translational value of its effects. METHODS: Two established mouse models of synucleinopathy with nigral neurodegeneration were employed: the α-synuclein preformed fibril (PFF) propagation model and the transgenic PLP-α-syn model expressing human wild-type α-synuclein in oligodendrocytes. Pharmacokinetic analyses assessed plasma and brain exposure after oral administration. The efficacy of six-month dapansutrile treatment was examined in both preventive (post-PFF injection) and therapeutic (PLP-α-syn mice) paradigms, using behavioral, histopathological, and molecular readouts. Transcriptomic profiling of striatal and midbrain microglia identified differentially expressed genes (DEGs) associated with treatment and compared them with post-mortem transcriptomic signatures of disease-associated microglia in PD patients. Plasma IL-18 and neurofilament light chain (NfL) levels were evaluated as translational biomarkers. RESULTS: Chronic oral dapansutrile treatment at clinically relevant doses improved motor performance, reduced α-synuclein inclusions, attenuated gliosis, and mitigated nigral neurodegeneration in both models. Microglial transcriptomic analyses revealed that dapansutrile reversed key transcriptional signatures characteristic of PD-associated reactive microglia. Moreover, plasma IL-18 and NfL levels correlated with neuropathological and functional outcomes, supporting their potential as biomarkers of target engagement and treatment efficacy. CONCLUSIONS: These data identify chronic NLRP3 activation as a shared and targetable mechanism in PD and MSA and highlight dapansutrile as a CNS-penetrant, clinically advanced candidate for disease modification in α-synucleinopathies. The observed transcriptomic reprogramming of microglia and the parallel changes in blood biomarkers provide a strong translational bridge to clinical development.}, } @article {pmid41621181, year = {2026}, author = {Spinelli, R and Sanchis, I and de Orellana, M and Humpola, MV and Rietmann, Á and Siano, ÁS}, title = {A nature-inspired peptide from the Boana cordobae frog as a potent and reversible AChE inhibitor with anti-amyloid and neuroprotective activities.}, journal = {Bioorganic chemistry}, volume = {171}, number = {}, pages = {109566}, doi = {10.1016/j.bioorg.2026.109566}, pmid = {41621181}, issn = {1090-2120}, mesh = {Animals ; *Cholinesterase Inhibitors/pharmacology/chemistry/isolation & purification/chemical synthesis ; *Neuroprotective Agents/pharmacology/chemistry/isolation & purification ; *Acetylcholinesterase/metabolism ; Humans ; *Amyloid beta-Peptides/antagonists & inhibitors/metabolism ; *Peptides/pharmacology/chemistry/isolation & purification ; Anura/metabolism ; Structure-Activity Relationship ; Dose-Response Relationship, Drug ; Monoamine Oxidase/metabolism ; Electrophorus ; Molecular Structure ; }, abstract = {Alzheimer's disease (AD) is a multifactorial and progressive neurodegenerative disorder for which no effective treatment currently exists. The development of multitarget-directed ligands (MTDLs) capable of simultaneously modulating several pathological pathways represents a rational strategy to address its complex etiology. In this study, we report the isolation, chemical synthesis, and functional characterization of BcI-4, a short cationic peptide identified from the skin secretion of the Argentinean frog Boana cordobae. The peptide exhibited potent and reversible inhibitory activity against acetylcholinesterase (AChE), with IC50 values of 1.10 and 0.9 μM for recombinant human and Electrophorus electricus AChE, respectively, acting through a non-competitive mechanism involving the peripheral anionic site (PAS). BcI-4 also inhibited AChE-induced β-amyloid (Aβ) aggregation, showed modest monoamine oxidase B (MAO-B) inhibition, and displayed both antioxidant and metal-chelating activities, including inhibition of lipid peroxidation. The peptide retained the multifuctional pharmacological profile previously observed for the crude extract of B. cordobae, with significantly enhanced potency and selectivity toward AChE. Moreover, BcI-4 was non-toxic in vitro (hemolysis and HeLa cell assays) and in vivo (Artemia salina test) even at the highest concentrations tested. Altogether, these findings position BcI-4 as a nature-inspired multitarget peptide with neuroprotective potential, combining reversible AChE inhibition, anti-amyloid, antioxidant, and MAO-B modulatory activities. BcI-4 represents a promising lead compound for the development of peptide-based therapeutics against AD.}, } @article {pmid41621469, year = {2026}, author = {Miller, D and Jordan, L and Lambert, S and Goodwin, AM and Sinvani, L and Perrin, A and Cheung, YK and Davidson, KW and Butler, MJ}, title = {Protocol for a single-arm, multi-component behavior change technique (BCT) intervention to develop a walking habit among caregivers for persons with Alzheimer disease and related dementias (ADRD).}, journal = {Contemporary clinical trials}, volume = {162}, number = {}, pages = {108248}, pmid = {41621469}, issn = {1559-2030}, support = {P30 AG063786/AG/NIA NIH HHS/United States ; }, mesh = {Humans ; *Caregivers/psychology ; *Alzheimer Disease ; *Walking ; *Behavior Therapy/methods ; *Dementia ; Habits ; Female ; Male ; Health Behavior ; Fitness Trackers ; Aged ; Exercise ; }, abstract = {Even low to moderate physical activity is critical in improving and maintaining physical health and well-being. Caregivers of people living with Alzheimer disease and related dementias (ADRD) are a burdened population and, as such, can experience challenges with managing even modest increases in physical activity while caring for others. While some interventions have been proposed to increase physical activity, many fail to consider the unique needs of caregivers of people with ADRD. The purpose of this 12-week decentralized behavioral trial is to test the efficacy of a multi-component, personalized text-message delivered BCT intervention to encourage the formation of a daily walking habit among caregivers of persons with ADRD assessed by Fitbit activity trackers via the key mechanism of behavior change (MoBC) of behavioral automaticity. Formation of a daily walking habit will be defined as attainment of walking 1000 or more additional steps during the same one-hour period on 7 consecutive days as set up in a personalized walking plan. We will also evaluate the association of habit formation attainment with changes in behavioral automaticity, association between longitudinal behavioral automaticity and habit formation attainment over time, and the heterogeneity of treatment effects between participants. Results will advance science about behavioral habit formation among caregivers for persons with ADRD and determine whether behavioral automaticity acts as the primary MoBC for the effect on this BCT intervention on daily habitual walking. This trial is registered on www.ClinicalTrials.gov (https://clinicaltrials.gov/study/NCT06803797); NCT #: NCT06803797.}, } @article {pmid41621577, year = {2026}, author = {Guo, H and Peng, X and Zhang, X and Ruganzu, JB and Wu, X and Zhao, M and Yang, P and Ji, S and Yang, W}, title = {Insulin-like growth factor-1 enhances β-amyloid protein clearance in HMC3 microglia via low-density lipoprotein receptor-related protein 1-mediated pathway.}, journal = {Experimental cell research}, volume = {457}, number = {1}, pages = {114920}, doi = {10.1016/j.yexcr.2026.114920}, pmid = {41621577}, issn = {1090-2422}, mesh = {*Amyloid beta-Peptides/metabolism ; *Microglia/metabolism/drug effects ; *Insulin-Like Growth Factor I/pharmacology/metabolism ; Humans ; *Low Density Lipoprotein Receptor-Related Protein-1/metabolism/genetics ; Signal Transduction/drug effects ; *Peptide Fragments/metabolism ; Phosphatidylinositol 3-Kinases/metabolism ; Lysosomes/metabolism ; Proto-Oncogene Proteins c-akt/metabolism ; Animals ; *Receptors, LDL/metabolism/genetics ; Cell Line ; Alzheimer Disease/metabolism/pathology ; }, abstract = {β-amyloid protein (Aβ) deposition occurs years before cognitive symptoms appear and is considered one of the main causes underlying the pathogenic events that occur in Alzheimer's disease (AD). Mounting evidence suggests that the imbalance of Aβ production and clearance leads to the accumulation of Aβ and the subsequent formation of toxic Aβ aggregates. Aβ is internalized by microglia and transported to lysosomes for degradation, which is one of the main ways by which Aβ may be cleared from the brain. Insulin-like growth factor-1 (IGF-1) promotes clearance of Aβ in the brain by enhancing Aβ carrier proteins. Our previous study demonstrated that low-density lipoprotein receptor-related protein 1 (LRP1) mediates the internalization of Aβ1-42 and lysosomal trafficking in primary cortical neurons. However, whether IGF-1 enhances the clearance of Aβ in microglia through the LRP1-mediated pathway and its underlying mechanisms is incompletely understood. Here, we reported that knockdown of LRP1 expression significantly decreased the internalization of Aβ1-42 in HMC3 cells. Furthermore, pretreatment with IGF-1 significantly increased intracellular Aβ1-42, indicating IGF-1 enhances HMC3 cells uptake of extracellular Aβ1-42. Interestingly, the intracellular Aβ1-42 in LRP1-knockdown HMC3 cells was reduced after preincubation with IGF-1. Thus, it was indicated that LRP1 is essential for IGF-1-enhanced internalization of Aβ1-42 in HMC3 cells. Moreover, IGF-1 significantly inhibited the downregulation of PI3K, phospho-PI3K, Akt, and phospho-Akt induced by Aβ1-42. Importantly, treatment with LY294002, a PI3K inhibitor, significantly reduced the intracellular Aβ1-42 levels and decreased the expression of LRP1. These findings indicated that IGF-1 enhances the internalization of Aβ in a LRP1-dependent manner by activating the PI3K/Akt signaling pathway. Finally, we identified that IGF-1 promotes lysosomal proteolysis of Aβ1-42 by increasing cathepsin B (CTSB) and cathepsin D (CTSD) expression. Consequently, these results demonstrated that IGF-1 promotes the internalization and lysosomal degradation of Aβ by microglia, which is an effective approach to lowering brain Aβ levels, and it might be a promising therapeutic target for AD.}, } @article {pmid41622469, year = {2026}, author = {Xu, X and Khan, A and Xia, X and Zahid, A and Forsberg, E and Lu, W and Jiang, C and Cheng, X}, title = {Photonic biosensing and optogenetic technologies: Emerging therapeutic strategies in neurodegenerative diseases.}, journal = {Neural regeneration research}, volume = {}, number = {}, pages = {}, doi = {10.4103/NRR.NRR-D-25-00711}, pmid = {41622469}, issn = {1673-5374}, abstract = {The rising burden of neurodegenerative diseases has exposed critical gaps in the development of diagnostic and therapeutic tools, particularly regarding their limited sensitivity, poor spatiotemporal resolution, and lack of treatment specificity. These shortcomings highlight the need for technologies that enable early disease detection, real-time monitoring of regenerative processes, and precise therapeutic interventions. This review focuses on recent advances in photonic biosensing and optogenetics, examining how these technologies are reshaping neural regeneration research and assessing their potential for clinical translation. Photonic biosensing platforms, including chemiluminescence, plasmonics, and fluorescencebased methods, now achieve ultrasensitive, multiplexed biomarker detection. These technologies can identify pathological biomarkers such as amyloid-beta, tau, and alphasynuclein at sub-picomolar concentrations, revealing molecular signatures years before symptom onset. Optogenetics provides unprecedented control over neural activity through light-sensitive proteins, offering millisecond temporal precision and cell-type specificity. Studies demonstrate that targeted optogenetic modulation can enhance synaptic plasticity, promote axonal regeneration, and restore functional connectivity. Preclinical models show memory restoration in Alzheimer's disease through hippocampal circuit reactivation, motor recovery in Parkinson's disease via basal ganglia stimulation, and movement restoration after spinal cord injury. Most notably, optogenetic therapy has achieved partial vision restoration in a blind patient with retinitis pigmentosa, marking a significant clinical milestone in humans. Three fundamental paradigm shifts characterize current progress in neural regeneration research. First, the field is transitioning from single-biomarker detection strategies to integrated multiparameter sensing platforms capable of simultaneously quantifying diverse molecular signatures, enabling a comprehensive assessment of disease states and regenerative processes. Second, static endpoint measurements are evolving toward dynamic real-time monitoring capabilities that capture temporal changes in cellular and molecular events during neural repair. Third, broad-spectrum pharmacological interventions are giving way to cell-type-specific neuromodulation strategies that selectively target distinct neuronal populations within affected circuits. Clinical translation faces substantial challenges that require systematic resolution. Biomarker standardization across diverse patient populations and validation through multicenter studies remain incomplete. Device miniaturization and optimization for chronic biocompatibility are essential for long-term implantation. Long-term safety assessments of optogenetic constructs, particularly regarding immune responses and potential genotoxicity, require rigorous clinical evaluation. Regulatory frameworks for these novel therapeutic modalities need further development. Despite these hurdles, continued technological innovation and interdisciplinary collaboration position photonic biosensing and optogenetics to deliver more precise diagnostic and therapeutic solutions for neurodegenerative diseases, potentially improving patient neurological outcomes and quality of life in the coming decade.}, } @article {pmid41622474, year = {2026}, author = {Cui, Z and Li, G and Wei, S and Cheng, Q and Yu, Q and Zong, S and Zhang, P and Chen, H and Yu, S and Wu, S and Li, M and Lu, Z}, title = {Blood-based biomarkers and early diagnosis of Alzheimer's disease.}, journal = {Neural regeneration research}, volume = {}, number = {}, pages = {}, doi = {10.4103/NRR.NRR-D-25-00759}, pmid = {41622474}, issn = {1673-5374}, abstract = {Alzheimer's disease is a common neurodegenerative disease characterized by progressive memory loss, cognitive decline, and behavioral changes. Blood-based biomarkers have recently gained significant attention due to their accessibility and cost-effectiveness. This review highlights the latest progress in multiple key areas of bloodbased biomarkers for Alzheimer's disease. For early diagnosis, blood-based biomarkers such as amyloid-β and phosphorylated tau can identify Alzheimer's disease even before clinical symptoms emerge. Dynamic changes in blood-based biomarkers, including p-tau217 and neurofilament light chain, reflect disease progression and correlate with cognitive decline, enabling continuous monitoring of Alzheimer's disease progression. Additionally, bloodbased biomarkers such as p-tau181 and glial fibrillary acidic protein aid in differential diagnosis by distinguishing Alzheimer's disease from other dementias such as frontotemporal dementia. Blood-based biomarkers related to nerve repair have opened up new avenues for tracking nerve regeneration and therapeutic response, especially brain-derived neurotrophic factor. Furthermore, advanced detection technologies such as single-molecule array and immunoprecipitation-mass spectrometry have significantly improved the sensitivity and specificity of bloodbased biomarkers, facilitating their clinical translation. In summary, blood-based biomarkers hold strong potential to improve early diagnosis, monitor progression, differential diagnosis, and evaluate therapies in Alzheimer's disease. This review provides a comprehensive and updated evaluation of the translational potential of bloodbased biomarkers, emphasizing their practical utility in clinical settings and offering insights into future directions for large-scale application. This review emphasizes the need to prioritize the allocation of scientific resources, expedite the transition of blood-based biomarkers to clinical implementation, and ultimately achieve precise treatment of Alzheimer's disease using these biomarkers.}, } @article {pmid41622475, year = {2026}, author = {Guo, J and Lu, X and Qiu, L and Xue, W and Fu, H and Wang, K and Wang, Y}, title = {Analysis of the dual role of amyloid-beta in Alzheimer's disease through multi-omics integration.}, journal = {Neural regeneration research}, volume = {}, number = {}, pages = {}, doi = {10.4103/NRR.NRR-D-25-00872}, pmid = {41622475}, issn = {1673-5374}, abstract = {Accumulation of amyloid-beta is highly important in the development of Alzheimer's disease. Given the limitations of the amyloid cascade hypothesis and the repeated clinical failures of anti-amyloid-beta therapies, researchers are increasingly exploring the infection hypothesis. This review explores the dual behaviors of amyloid-beta in Alzheimer's disease, with a particular focus on its protective role against infection by microorganisms and its complicated connections with innate immune system. This new opinion holds that amyloid-beta can play an antimicrobial peptide role. During microbial invasion, its original role is to protect neural tissue, but prolonged accumulation leads to chronic deposition and involvement in pathological processes. Evidence from in vitro experiments, animal models, and clinical studies indicates that amyloid-beta may possess antiviral and antibacterial properties, particularly against infections such as (herps simplex virus) HSV, (human immunodeficiency virus) HIV, and Porphyromonas gingivalis. However, excessive accumulation of amyloid beta triggers a neuroinflammatory cascade that impairs neuronal regeneration and cognitive function. Despite substantial research into Alzheimer's disease, current treatments have not yielded significant clinical benefits. Although monoclonal antibodies such as Aducanumab, Lecanemab, and Donanemab have been approved for marketing, their strict indications and high costs pose challenges for widespread promotion. The infection hypothesis of amyloid-beta has spurred clinical trials investigating vaccines targeting specific pathogens to assess their potential in preventing or treating Alzheimer's disease. This highlights the need for further exploring the multifaceted role of amyloid-beta in Alzheimer's disease. In addition, microbial infections can also trigger or regulate genetic and epigenetic factors, accelerating amyloid beta deposition. Among them, the apolipoprotein E epsilon 4 allele is the strongest genetic risk factor for Alzheimer's disease, as it exacerbates the accumulation of amyloid beta and promotes neuroinflammation. Strategies targeting epigenetic regulation may provide novel approaches to inhibit Alzheimer's disease pathology. This review also integrates various technologies such as genomics, proteomics, and metabolomics. This provides a broader system-level understanding of the risk gene loci, protein interaction networks, and metabolic changes associated with amyloid beta under the influence of microbial infections. Such techniques may lead to the identification of new molecular targets, the development of individualized treatment strategies, and the creation of early biomarkers for use in clinical research. In conclusion, this review suggests that amyloid-beta is not merely a pathological by-product but an environmentally responsive molecule with dual functions. A deeper understanding of the dynamic regulation of amyloid-beta, considering infection status and disease stage, can provide new directions for treatment strategies aimed at the prevention and treatment of Alzheimer's disease.}, } @article {pmid41622480, year = {2026}, author = {Martinez, B and Peplow, PV}, title = {Treatment of animal models of Alzheimer's disease with extracellular vesicles or exosomes and involvement of microRNAs.}, journal = {Neural regeneration research}, volume = {}, number = {}, pages = {}, doi = {10.4103/NRR.NRR-D-25-01116}, pmid = {41622480}, issn = {1673-5374}, abstract = {Alzheimer's disease is a complex and devastating neurodegenerative disorder that accounts for roughly 80% of all dementia cases. It is primarily marked by the accumulation of senile amyloid-β plaques and neurofibrillary tangles composed of hyperphosphorylated tau protein. These pathological features are accompanied by chronic neuroinflammation and glial cell dysfunction, which collectively contribute to the progressive loss of synapses and neurons. As a result, individuals with Alzheimer's disease experience gradual memory loss and cognitive decline. Currently, the global patient population is nearing 50 million, a number expected to increase dramatically over the coming decades. Conventional treatments focus on symptom management through acetylcholinesterase inhibitors, such as donepezil, galantamine, and rivastigmine, and the N-methyl-D-aspartate receptor antagonist memantine. However, the past few years have seen the approval of newer agents such as sodium oligomannate, aducanumab, and lecanemab, which show some promise in slowing disease progression. Unfortunately, most patients are not diagnosed until moderate or advanced stages when irreversible brain damage has occurred. This highlights an urgent need for early diagnosis and biomarkers together with therapeutic strategies aimed at early-stage intervention and identifying novel drug targets that address prodromal and established forms of the disease. This article is a literature review of extracellular vesicles/exosomes treatment in animal models of Alzheimer's disease involving microRNAs. In the in vivo animal studies of Alzheimer's disease reviewed, extracellular vesicles and exosomes from various sources improved memory and cognitive decline, lowered inflammation and amyloid deposition, and increased neuron survival in the brain. Loading extracellular vesicles and exosomes with microRNA mimics (e.g., miR-22, -29b, -124, -132, -138-5p, -342-5p, -711, and -7670-3p) or antagomirs (e.g., miR-206-antagomir) improved outcomes in animal models of Alzheimer's disease. Supporting results were found in the in vitro cell studies reviewed.}, } @article {pmid41623423, year = {2025}, author = {Tang, B and Tao, M}, title = {Research progress on 40 Hz sensory stimulation for the treatment of Alzheimer's disease.}, journal = {Frontiers in aging neuroscience}, volume = {17}, number = {}, pages = {1710041}, pmid = {41623423}, issn = {1663-4365}, abstract = {Alzheimer's disease (AD) is a prevalent neurodegenerative disorder characterized by β-amyloid (Aβ) deposition, tau protein hyperphosphorylation, and synaptic dysfunction. In recent years, 40 Hz sensory stimulation-including visual, auditory, and multimodal modalities-has emerged as a novel, non-invasive intervention demonstrating potential efficacy in both animal models and preliminary clinical studies. Preclinical evidence indicates that such stimulation can markedly reduce cerebral Aβ burden (by approximately 37%-53%), inhibit tau protein phosphorylation, enhance neuronal network synchrony and synaptic plasticity, and improve learning and memory performance. Limited human trials suggest that 40 Hz sensory stimulation is safe and well tolerated in patients with mild cognitive impairment (MCI) and early-stage AD, with a slowing trend in cognitive scale score decline following intervention. This review summarizes the mechanisms of action, experimental evidence from animal models, and advances in clinical application of 40 Hz sensory stimulation in AD prevention and treatment. It further explores the potential for multimodal combination therapies integrating sensory stimulation with cognitive training, pharmacological interventions, and lifestyle modifications, and addresses challenges such as optimal timing of intervention and the influence of ambient electromagnetic fields in real-world settings. Current evidence supports 40 Hz sensory stimulation as a feasible, multi-target, and safe adjunctive intervention; however, its efficacy and applicability must be verified through multicenter, randomized controlled trials with long-term follow-up.}, } @article {pmid41624205, year = {2025}, author = {Wang, Y and Liu, C and Zheng, X and Wang, Z and Wang, Y and Geng, Y and Yang, J and Wei, K and Chen, X}, title = {Modified Sanjia Powder ameliorates cognitive impairment and exerts neuroprotective effects in 5 × FAD mice: insights from quantitative proteomics.}, journal = {Frontiers in nutrition}, volume = {12}, number = {}, pages = {1699142}, pmid = {41624205}, issn = {2296-861X}, abstract = {BACKGROUND: Modified Sanjia Powder (MSP) is a traditional Chinese herbal formulation with potential use as a dietary supplement, which has shown neuroprotective properties against Alzheimer's disease (AD). However, its mechanisms of action, particularly those related to metabolic pathways, remain poorly understood. Given the emerging role of lipid metabolism and associated oxidative stress in AD pathogenesis, this study aimed to investigate the therapeutic effects of MSP on cognitive impairment and explore its molecular mechanisms, with emphasis on nutritionally relevant pathways, in the 5 × FAD mouse model of AD using quantitative proteomics.

METHODS: Cognitive, pathological, and molecular functions were evaluated following MSP treatment. Cognitive performance was assessed using behavioral tests including the Y-maze, novel object recognition (NOR), and Morris Water Maze. Brain tissues from control, 5 × FAD, and MSP-treated mice were analyzed by data-independent acquisition mass spectrometry to identify differentially expressed proteins (DEPs). Key findings were validated using Western blotting, immunohistochemistry, and cytokine assays.

RESULTS: MSP treatment significantly improved cognitive function in 5 × FAD mice across multiple behavioral tests. It reduced Aβ plaque deposition, attenuated tau hyperphosphorylation, inhibited microglial activation, and decreased levels of pro-inflammatory cytokines (IL-1β, TNF-α, and IL-6). Proteomic analysis identified 460 DEPs, with significant enrichment in pathways related to fatty acid biosynthesis, lipid metabolism, and oxidative stress. Notably, among these DEPs, ACSL4-a key regulator of lipid metabolism and oxidative stress-was upregulated in 5 × FAD mice but markedly downregulated after MSP treatment. Importantly, MSP's modulation of lipid metabolism appeared selective for the ACSL4 pathway, without broadly affecting other lipid metabolic pathways that influence cytokine release. MSP also reduced levels of reactive oxygen species (ROS) and lipid peroxidation markers (MDA and 4-HNE).

CONCLUSION: MSP confers neuroprotection in AD by modulating ACSL4-mediated lipid metabolism and oxidative stress, leading to improved cognitive function and reduced neuroinflammation in the 5 × FAD mouse model. These results position MSP as a promising therapeutic candidate for AD and demonstrate the value of quantitative proteomics in elucidating the mechanisms of traditional Chinese medicines.}, } @article {pmid41624730, year = {2026}, author = {Qiao, F and Guo, Y and Dong, Y and Song, K and Yan, B and Zhou, J}, title = {Unlocking a Novel Therapeutic Modality: Low-Intensity Transcranial Ultrasound as a Key to CNS Treatment - A Bibliometric and Systematic Review.}, journal = {Journal of central nervous system disease}, volume = {18}, number = {}, pages = {11795735261415705}, pmid = {41624730}, issn = {1179-5735}, abstract = {OBJECTIVES: Over the past decade, low-intensity transcranial ultrasound stimulation (LITUS) has emerged as a promising non-invasive neuromodulation technique for central nervous system (CNS) disorders. This study aims to chart the current research landscape, uncover key trends and challenges, and offer a reference for future investigations.

METHODS: Following PRISMA guidelines, we sourced data from 3 databases and included 454 literature. We conducted bibliometric analyses using R, VOSviewer, and CiteSpace to explore publication trends, journal/region contributions, keyword co-occurrence networks, research clusters, and emerging frontiers.

RESULTS: The United States, China, and South Korea were the most influential countries in the field, while Brain Stimulation was the leading journal. Keyword analysis revealed 7 research clusters, and burst-detection highlighted frontiers such as safety, thalamic stimulation, and frequency. The literature review shows that LITUS is an emerging field with therapeutic promise, but faces challenges in areas like safety and ultrasound parameter standardization.

CONCLUSION: As the first comprehensive bibliometric and systematic review of LITUS in CNS disorders treatment, this work presents a global picture of publication trends, hotspots, and obstacles-providing valuable guidance for future research and clinical translation of LITUS.}, } @article {pmid41625339, year = {2025}, author = {Knudsen, E and Tadje, J and Coggins, C and Venketaraman, V}, title = {Glutathione and neurodegenerative diseases: immunopharmacological implications.}, journal = {Frontiers in pharmacology}, volume = {16}, number = {}, pages = {1737199}, pmid = {41625339}, issn = {1663-9812}, abstract = {Neurodegenerative diseases are characterized by progressive neuronal dysfunction, often accompanied by chronic inflammatory states and redox imbalance within the central nervous system (CNS). Glutathione (GSH), a key regulator of oxidative stress and cellular immunity, has a critical role in modulating the functional states of CNS-resident and infiltrating immune cell subsets. This review aims to synthesize emerging evidence on how GSH depletion contributes to impaired immune and antioxidant activity in neurodegenerative diseases, such as Parkinson's Disease (PD), Alzheimer's Disease (AD), and multiple sclerosis (MS). By exploring how redox signaling via GSH influences inflammatory immune phenotypes across different disease states, we will isolate possible therapeutic interventions for treatment of these conditions. By characterizing GSH's function and designating it as a special regulator of immune cell behavior, this review highlights its potential as both a therapeutic agent and biomarker for patients with neurodegenerative conditions.}, } @article {pmid41626292, year = {2026}, author = {Ashford, MT and Tank, R and Kabeto, MU and Nosheny, RL and Weiner, MW and Weir, DR and Langa, KM}, title = {Exclusions affect representativeness of Alzheimer's disease trial participants.}, journal = {Alzheimer's & dementia (New York, N. Y.)}, volume = {12}, number = {1}, pages = {e70191}, pmid = {41626292}, issn = {2352-8737}, support = {F32 AG072730/AG/NIA NIH HHS/United States ; K01 AG088464/AG/NIA NIH HHS/United States ; }, abstract = {BACKGROUND: This study assessed how medical exclusion criteria of a prevention Alzheimer's disease trial impact potential eligibility and sample characteristics.

METHODS: Medical exclusion criteria from the Anti-Amyloid Treatment in Asymptomatic Alzheimer's Disease (A4) trial were applied to N = 3695 participants from the population-based Health Retirement Study (HRS) with linked Medicare data. We determined the proportion of hypothetical eligibility. Multivariate Poisson regression was used to estimate associations between sociodemographic characteristics and eligibility.

RESULTS: Of the participants, 74.2% (N = 2742) were deemed ineligible. Accounting for all sociodemographic characteristics, older age, female gender, fewer years of education, lower net worth, and body mass index of 30+ was associated with a higher odds of being deemed ineligible. Ethnocultural identity and living arrangement were not associated with eligibility.

CONCLUSIONS: Our results suggest that certain sociodemographic factors may limit eligibility for a prevention Alzheimer's disease trial due to the presence of exclusionary medical conditions. This highlights the need to make trials more inclusive.

HIGHLIGHTS: A total of 2742 participants (74.2%) were deemed ineligible for the Anti-Amyloid Treatment in Asymptomatic Alzheimer's Disease (A4) trial based on the medical exclusion criteria.The most common medical exclusion in this sample was for cardiovascular conditions.Ineligibility was associated with age, education, net worth, and body mass index.}, } @article {pmid41626761, year = {2026}, author = {Chen, H and Zhang, H and Yang, M and Xie, Q and Zhu, L}, title = {Association between apolipoprotein E gene polymorphisms and serum lipid indicators and Alzheimer's disease risk.}, journal = {Journal of Alzheimer's disease : JAD}, volume = {110}, number = {2}, pages = {696-704}, doi = {10.1177/13872877261416064}, pmid = {41626761}, issn = {1875-8908}, mesh = {Humans ; *Alzheimer Disease/genetics/blood ; Female ; Male ; *Apolipoproteins E/genetics ; Aged ; *Lipids/blood ; *Genetic Predisposition to Disease/genetics ; Amyloid beta-Peptides/blood ; *Polymorphism, Genetic/genetics ; Genotype ; Biomarkers/blood ; tau Proteins/blood ; Triglycerides/blood ; Aged, 80 and over ; Peptide Fragments/blood ; Apolipoprotein E4/genetics ; ROC Curve ; Risk Factors ; }, abstract = {BackgroundApolipoprotein E (APOE) polymorphisms, particularly the APOE4 genotype, are established genetic risk factors for Alzheimer's disease (AD). However, the clinical utility of combining APOE genotypes with serum lipids and blood-based AD biomarkers remains incompletely defined.ObjectiveTo investigate the association between APOE gene polymorphisms, serological indicators, and the occurrence of AD.MethodsBlood samples of 109 patients with AD and 85 non-AD participants were used to detect APOE genotypes. Serum levels of total cholesterol (TC), triglyceride (TG), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), amyloid-β 1-42 (Aβ1-42), and p-tau-181 were measured. Receiver operating characteristic analysis was performed in an independent validation set of 82 cases.ResultsThe frequency of the APOE4 genotype was significantly higher in the AD group compared with the non-AD group, whereas APOE2 and APOE3 genotypes showed no significant differences. TC, HDL-C, and LDL-C levels were significantly elevated in the AD group compared with the non-AD group, while TG, Aβ1-42, and p-tau-181 levels did not differ significantly. Among patients with AD carrying the APOE4 genotype, TC and LDL-C levels were significantly higher than those in non-AD APOE4 carriers. Further, within the AD group, APOE4 carriers had a significantly higher proportion of elevated TC and LDL-C levels than non-APOE4 carriers. Validation experiments revealed that the combination of APOE4 genotype with elevated TC and LDL-C demonstrated greater diagnostic efficacy for AD.ConclusionsAPOE4 genotype combined with elevated TC and LDL-C levels strongly correlate with AD onset and may be valuable auxiliary biomarkers for AD diagnosis and treatment.}, } @article {pmid41626944, year = {2026}, author = {Zhou, S and Xu, L and Dong, J and Zhang, X and Gao, W and Luo, H and Fang, X}, title = {Advances in Immune Cell Interactions and Natural Compounds Therapeutic Strategies in Alzheimer's Disease.}, journal = {Phytotherapy research : PTR}, volume = {40}, number = {4}, pages = {1837-1861}, doi = {10.1002/ptr.70249}, pmid = {41626944}, issn = {1099-1573}, support = {82304913//National Natural Science Foundation of China/ ; 82204785//National Natural Science Foundation of China/ ; 82474141//National Natural Science Foundation of China/ ; YDZJ202501ZYTS803//Department of Science and Technology of Jilin Province/ ; YDZJ202401110ZYTS//Department of Science and Technology of Jilin Province/ ; 20240601005RC//Department of Science and Technology of Jilin Province/ ; 20230401074YY//Department of Science and Technology of Jilin Province/ ; YDZJ202401442ZYTS//Department of Science and Technology of Jilin Province/ ; 202104011055YY//Department of Science and Technology of Jilin Province/ ; 20220204001YY//Department of Science and Technology of Jilin Province/ ; }, mesh = {*Alzheimer Disease/drug therapy/immunology ; Humans ; Microglia/drug effects/immunology ; Animals ; *Biological Products/therapeutic use/pharmacology ; Amyloid beta-Peptides/metabolism ; Blood-Brain Barrier ; }, abstract = {As the global population ages, the incidence of Alzheimer's disease (AD) increases, burdening patients, families, and society. In recent years, microglia have been shown to interact with T cells, astrocytes, and other immune cells to form a complex immune microenvironment, which plays a damaging or protective role on neurons during the pathological process of AD. Herein, we review the interactions between microglia and other immune cells in the pathogenesis of AD and explore the potential of natural compounds as multi-targeted therapeutic strategies: (1) Balancing glial cell polarization status and ameliorating neuroinflammation by inhibiting core neuroinflammatory pathways such as NF-κB (nuclear factor kappa-B), MAPK, and NLRP3 inflammasome; (2) modulating the gut flora-brain axis function to inhibit central inflammation indirectly; (3) multi-targeted interventions for core AD pathology, including amyloid-beta (Aβ) clearance, tau phosphorylation, and synaptic plasticity. However, natural compounds still face clinical translation bottlenecks such as low bioavailability and poor blood-brain barrier permeability. Current studies have shown that nanocarrier systems and combination therapy strategies hold promise for addressing existing bottlenecks. However, systematic validation is still required for their clinical translation. This review systematically summarizes progress in the treatment of AD by regulating microglia and other immune cell interactions using natural compounds.}, } @article {pmid41627306, year = {2026}, author = {Cronin, M and Jennings, AA and Caufield, U and Coonan, I and Cornally, N and Daly, B and Dockeray, L and Hartigan, I and Lawlor, B and McCarthy, G and Ni Chorcorain, AM and O'Dowd, S and Nolan-Palmer, J and Perry, M and Quinlan, D and Timmons, S and Foley, T}, title = {Co-designing a structured referral template to enhance dementia diagnosis: a modified e-Delphi study.}, journal = {Age and ageing}, volume = {55}, number = {2}, pages = {}, pmid = {41627306}, issn = {1468-2834}, support = {APA-2022-027//Applied Partnership Award from the Health Research Board/ ; }, mesh = {Humans ; Delphi Technique ; *Referral and Consultation/organization & administration ; *Dementia/diagnosis/psychology/therapy ; Consensus ; Predictive Value of Tests ; Clinical Relevance ; }, abstract = {BACKGROUND: Dementia care is a health and social care priority, with rising prevalence driven by ageing populations worldwide. Timely and accurate diagnosis improves quality of life, enables access to support and is becoming even more critical due to the emergence of disease-modifying therapies for Alzheimer's disease. Complex referral pathways can contribute to diagnostic delays and under-diagnosis. A structured, evidence-based referral template could enhance diagnostic efficiency and care quality.

METHODS: This study was conducted in two phases. First, a two-round e-Delphi survey was used to achieve consensus on items for inclusion in a dementia referral template. In the second phase, a modified Nominal Group Technique was employed with a multidisciplinary panel and Public and Patient Involvement (PPI) contributors to discuss, refine and prioritise items, ensuring clinical relevance and practical applicability.

RESULTS: The consensus process refined and prioritised 76 potential referral items into a final set of 11 essential components. The resulting concise template balances clinical relevance with usability, potentially supporting more efficient referral and triage. Items achieving the highest consensus included cognitive screening scores, rapid deterioration, problems with daily activities and patient safety concerns.

CONCLUSION: The findings demonstrate the value of structured consensus methods in developing a practical, evidence-based referral template, tailored to optimise dementia diagnostic pathways. This is particularly important in the current evolving therapeutic landscape, to ensure that people with suspected dementia receive timely diagnosis and access to appropriate care and treatment options.}, } @article {pmid41627667, year = {2026}, author = {Jia, YJ and Ge, YJ and Li, B and Yang, Y and Chen, H and Liu, J and Guo, JH and Yu, JT and Ye, KQ and Wang, JZ and Song, W and Wang, YJ}, title = {Advances in Alzheimer's disease: mechanistic insights and therapeutic targets.}, journal = {Science China. Life sciences}, volume = {}, number = {}, pages = {}, pmid = {41627667}, issn = {1869-1889}, abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder marked by cognitive decline, memory loss, and behavioral disturbances, eventually leading to dementia and severely diminishing quality of life. With the global population aging, AD has become an unprecedented challenge for society and families. Recent advances in the development of amyloid-beta (Aβ)-targeting monoclonal anti-bodies, like lecanemab and donanemab, provided hope for slowing or even halting disease progression. However, these treatments have not yet achieved the ultimate goal of reversing cognitive deterioration and restoring normal function. The complexity of AD stems from multiple contributing factors, with Aβ deposition and tau protein tangles being central to its pathology, while genetic predispositions, aging, and systemic factors further drive disease progression. Addressing AD by targeting a single factor has proven insufficient, highlighting the need for a comprehensive understanding of its multifaceted mechanisms. This review explores the latest advances in AD mechanistic research and therapeutic development, focusing on key areas such as amyloid precursor protein (APP) metabolism, Aβ dynamics, Aβ antibody immunotherapy, tau protein dysfunction, genetic influences, aging mechanisms, and systemic factors. By critically examining these aspects, we aim to provide insights that support more holistic approaches to AD diagnosis and treatment, ultimately laying the groundwork for innovative strategies to combat this debilitating disease.}, } @article {pmid41628818, year = {2026}, author = {Munir, S and Chauhdary, Z and Khan, IA and Ahmad, M and Khurshid, M and Ashfaq, UA}, title = {Discovery of a novel IMS48 as a dual inhibitor of acetylcholinesterase and butyrylcholinesterase: In vitro and in vivo study for Alzheimer therapy.}, journal = {Neuropharmacology}, volume = {289}, number = {}, pages = {110856}, doi = {10.1016/j.neuropharm.2026.110856}, pmid = {41628818}, issn = {1873-7064}, mesh = {Animals ; *Cholinesterase Inhibitors/pharmacology/therapeutic use ; *Alzheimer Disease/drug therapy ; *Butyrylcholinesterase/metabolism ; Male ; Rats ; *Acetylcholinesterase/metabolism ; *Benzimidazoles/pharmacology/therapeutic use ; Brain/drug effects/pathology/metabolism ; Donepezil/pharmacology ; Aluminum Chloride ; Oxidative Stress/drug effects ; Humans ; Neuroprotective Agents/pharmacology ; }, abstract = {Current medications for Alzheimer's disease (AD) provide symptomatic relief only and fail to prevent neurodegeneration, necessitating the development of new therapeutic agents. This study aimed to evaluate benzimidazole (BIM) analogs as potential inhibitors for AD. In vitro screening identified 1-benzyl-3-(2-((3-chlorophenyl)amino)-2-oxoethyl)-1H-benzo[d]imidazole-3-ium chloride (IMS48) as a potent inhibitor of both acetylcholinesterase (AChE) and butyrylcholinesterase (BChE), with IC50 values of 0.31 ± 0.04 μM and 1.85 ± 0.05 μM, respectively, outperforming the standard drug donepezil. In the in vivo study, rats were administered D-gal (300 mg/kg) and AlCl3 (150 mg/kg) orally for three weeks to induce AD-like symptoms. Concurrently, IMS48 was administered at doses of 0.75 mg/kg and 1.5 mg/kg for 21 days. Donepezil (DON) was used as a positive control to evaluate the therapeutic efficacy of the IMS8 compound. IMS48 treatment significantly reversed behavioral alterations and improved learning ability. Histopathological analysis demonstrated that IMS48 effectively inhibited neuronal death and neurofibrillary tangles in the brain tissue. Furthermore, IMS48 restored the altered antioxidant enzyme levels (p < 0.001), reducing malondialdehyde (MDA) concentration and enhancing superoxide dismutase (SOD), glutathione (GSH), and catalase (CAT) concentrations. IMS48 also downregulated the gene expression of AChE (1.56 ± 0.10-fold and 1.71 ± 1.76-fold), APP (1.96 ± 0.17-fold and 3.39 ± 0.139-fold), BACE1 (1.92 ± 0.10-fold and 2.59 ± 0.04-fold), TNFα (2.16 ± 0.21-fold and 3.35 ± 0.17-fold), IL-1α (1.86 ± 0.236-fold and 2.56 ± 0.15-fold), and IL-1β (1.58 ± 1.82-fold and 2.32 ± 0.13-fold), associated with AD pathology and neuroinflammation. Overall, these findings highlight the neuroprotective potential of IMS48 in enhancing cognitive function and mitigating neurodegeneration in AD.}, } @article {pmid41628871, year = {2026}, author = {Wei, M and Zhang, Q and Zhao, Z and Chen, L and Tan, R}, title = {Saffron (Crocus sativus L.): A multi-target phytochemical with potential therapeutic relevance for autism spectrum disorder - A review of pharmacological mechanisms and future perspectives.}, journal = {Journal of ethnopharmacology}, volume = {361}, number = {}, pages = {121299}, doi = {10.1016/j.jep.2026.121299}, pmid = {41628871}, issn = {1872-7573}, mesh = {*Crocus/chemistry ; Humans ; Animals ; *Phytochemicals/pharmacology/therapeutic use/isolation & purification ; *Autism Spectrum Disorder/drug therapy/metabolism ; *Plant Extracts/pharmacology/therapeutic use ; }, abstract = {Saffron (Crocus sativus L.) has a long history of use in traditional medicine practices across Persia/the Middle East, India, and the Mediterranean region. Traditionally, it has been regarded for its potential to regulate mood, support cognition, and promote sleep. This paper explores saffron's potential applications and mechanisms of action in autism spectrum disorder (ASD) and related comorbidities (such as anxiety, sleep disorders, and cognitive impairments) from an ethnopharmacological perspective. It integrates pharmacological evidence from saffron's primary constituents-crocins, crocetin, picrocrocin, and safranal-emphasizing the convergence of traditional medicinal knowledge with modern scientific evidence.

AIM OF THE STUDY: This review aims to systematically evaluate the therapeutic potential of saffron (Crocus sativus L.) and its bioactive constituents (crocins, crocetin, picrocrocin, safranal) in ASD, its comorbid conditions, and related neurodegenerative diseases. The goal is to synthesize current evidence on saffron's mechanisms of action and translational prospects for ASD management.

MATERIALS AND METHODS: A comprehensive literature search was conducted across PubMed, Web of Science and Science Direct databases up to May 2025. Search terms included combinations of keywords such as "saffron," "crocetin," "autism," "anxiety," "depression," "Alzheimer's disease," and "Parkinson's," to identify relevant preclinical and clinical studies on saffron's neuroprotective effects and therapeutic applications.

RESULTS: Saffron exhibits pleiotropic neuroprotective effects by modulating multiple key pathways involved in ASD and neurodegeneration, including inhibition of neuroinflammatory signaling pathways such as NF-κB/NLRP3, activation of antioxidant responses via the Nrf2/ARE pathway, and restoring balance between GABAergic and glutamatergic neurotransmission. These mechanisms support saffron's potential to reestablish neurodevelopmental homeostasis and alleviate core ASD symptoms, along with associated comorbidities such as anxiety and cognitive impairments.

CONCLUSION: Saffron is a promising natural multi-target agent with significant translational potential for ASD and related disorders. Its ability to modulate neuroinflammatory, oxidative, and neurotransmission pathways underscores its potential as an adjunctive or alternative therapy. Future research should focus on elucidating precise mechanisms, conducting rigorous clinical validations, and optimizing formulations to facilitate evidence-based integration of saffron into ASD treatment strategies.}, } @article {pmid41628899, year = {2026}, author = {Huan, T and Intrator, O and Simning, A and Boockvar, K and Grabowski, DC and Cai, S}, title = {Psychotherapy and Problematic Behavior Reduction in Long-Stay Nursing Home Residents With Alzheimer's Disease and Related Dementias.}, journal = {Journal of the American Medical Directors Association}, volume = {27}, number = {4}, pages = {106106}, doi = {10.1016/j.jamda.2025.106106}, pmid = {41628899}, issn = {1538-9375}, mesh = {Humans ; *Nursing Home Residents/psychology ; Female ; Retrospective Studies ; Male ; United States ; *Nursing Homes ; *Alzheimer Disease/therapy/psychology ; *Psychotherapy ; Aged, 80 and over ; Aged ; *Problem Behavior/psychology ; *Dementia/therapy/psychology ; }, abstract = {OBJECTIVES: To examine the association between receipt of psychotherapy and behavior reduction among long-stay nursing home residents with Alzheimer's disease and related dementias (ADRD).

DESIGN: Retrospective cohort study using Minimum Data Set assessments linked to Medicare: Master Beneficiary Summary File, Part B Carrier, and Part D Event file (2017-2018).

SETTING AND PARTICIPANTS: All US Medicare- or Medicaid-certified nursing homes. Traditional Medicare beneficiaries enrolled in Medicare Parts B and D, aged ≥65 with ADRD and any problematic behaviors (physical, verbal, or other), stratified to residents with both ADRD and co-occurring psychiatric disorders, and ADRD only.

METHODS: The unit of analysis was 2 consecutive quarters with indication of a problematic behavior in the first. Outcomes were reductions in any, physical, verbal, or other behaviors. The treatment was receipt of psychotherapy in both quarters vs neither. Covariates included predisposing, enabling, and need factors. Propensity score weighting balanced resident characteristics, and generalized estimating equation logistic models were applied.

RESULTS: The cohort included 175,165 resident-quarter observations from 99,584 unique long-stay residents with ADRD and problematic behaviors. Psychotherapy was received in 9% of observations, most often in short (73%), quarterly (59%), or monthly (35%) sessions delivered by psychologists (56%) or social workers (34%). After weighting, psychotherapy was associated with greater likelihood of behavior reduction (ADRD + psychiatric disorders: 17%, P < .01; ADRD only: 33%, P < .05). In ADRD-only residents, psychotherapy was associated with 36% reduction in physical behaviors and 28% in verbal behaviors. In those with ADRD + psychiatric disorders, reductions were seen in physical (31%) and other behaviors (18%).

CONCLUSIONS AND IMPLICATIONS: Fewer than 10% of nursing home residents with ADRD and problematic behaviors received psychotherapy, yet its receipt was significantly associated with behavior reduction. Findings underscore the need to expand access to psychotherapy in nursing homes and to further investigate the psychotherapy characteristics that contribute to effectiveness.}, } @article {pmid41630733, year = {2025}, author = {Aliffia, D and Wihadmadyatami, H and Raihan, MZZ and Kustiati, U and Sanjaya, WBT and Aviana, AP and Nugrahaningsih, DAA and Widayati, WT and Karnati, S and Kusindarta, DL}, title = {C3H mouse model of Alzheimer's disease: Blood markers, proteomic biomarkers, cognitive ability, and histopathology.}, journal = {Open veterinary journal}, volume = {15}, number = {11}, pages = {5718-5726}, pmid = {41630733}, issn = {2218-6050}, mesh = {Animals ; *Alzheimer Disease/pathology/chemically induced/physiopathology/blood ; Male ; *Disease Models, Animal ; Biomarkers/blood ; Trimethyltin Compounds ; Mice ; Mice, Inbred C3H ; *Cognition ; Proteomics ; Brain/pathology ; }, abstract = {BACKGROUND: Alzheimer's disease (AD) is a neurodegenerative condition, and the number of cases of AD is projected to increase each year. Developing an AD animal model has a major impact on studying the pathology of the disease and on developing therapies and treatments.

AIM: This study aimed to create an AD animal model using C3H mice by administering trimethyltin (TMT) via intraperitoneal injection. Hematological analysis, pathology, protein biomarkers, and behavioral assessments supported the findings.

METHODS: In this experiment, two groups were included: a non-treated group (normal mouse) and a treatment group (AD animal model). Each group consisted of four male C3H mice aged 8 weeks. The treatment group was intraperitoneally injected with 2.5 mg/kg of body weight TMT. Hematological analyses were conducted to assess the blood routine, while pathological changes in brain structure, particularly in the hippocampus, were examined using hematoxylin and eosin staining as well as Nissl staining. Additionally, proteomic profiling was used to analyze protein biomarkers associated with AD via liquid chromatography-high-resolution mass spectrometry. Behavioral analysis was conducted using the radial arm maze.

RESULTS: Hematological analysis revealed an increase in hematocrit, mean corpuscular volume, leucocytes, and neutrophil levels, whereas other parameters remained within the normal range. Histopathological analysis revealed neuronal loss and structural alterations in the pyramidal cell layers of the CA1 and CA3, the presence of inflammation, and neurofibrillary tangles. Proteomic analysis identified several protein biomarkers related to AD in the AD animal model, including amyloid beta, tau protein, apolipoprotein E, and Triggering Receptor Expressed on Myeloid cells. Behavioral analysis demonstrated significant cognitive and memory declines in AD animal models compared with non-treated animals.

CONCLUSION: The intraperitoneal administration of TMT in C3H mice effectively induces pathological changes in the brain that are related to AD. The observed pathological and behavioral changes in this AD animal model resemble those found in human cases of the disease. This model can serve as a valuable platform for studying the etiology, pathogenesis, and pathophysiology of AD, as well as testing new therapies.}, } @article {pmid41630792, year = {2026}, author = {Sato, K and Niimi, Y and Kurihara, M and Ihara, R and Iwata, A and Iwatsubo, T}, title = {Utility of APOE testing for reducing ARIA under probabilistic stopping rates to treat with anti-amyloid therapy for ε4-homozygote patients: A simulation study.}, journal = {JAR life}, volume = {15}, number = {}, pages = {100059}, pmid = {41630792}, issn = {2534-773X}, abstract = {BACKGROUND: APOE ε4/ε4 genotype increases the risk of Amyloid-Related Imaging Abnormalities (ARIA) from anti-amyloid antibody treatment (AAT). While guidelines recommend testing, its practical utility depends on the resulting probability (p) that treatment is actually withheld for ε4-homozygotes, which varies significantly across clinical settings.

OBJECTIVES: To quantify the Number Needed to Test (NNT) to prevent one ARIA event as a function of p of withholding AAT in ε4/ε4 patients.

DESIGN: A Bayesian simulation study using a Beta-Binomial model to analyze genotype-stratified contingency tables.

SETTING: Data were derived from two published, phase 3 clinical trials: Clarity-AD (lecanemab) and TRAILBLAZER-ALZ 2 (donanemab).

PARTICIPANTS: Aggregate data from source trials.

INTERVENTION: Simulation of varying treatment discontinuation probability p from 0 (none) to 1 (universal for ε4-homozygotes).

MEASUREMENTS: NNT to prevent one ARIA event (any ARIA-E, any ARIA-H, and symptomatic ARIA-E) and the fractional reduction in total ARIA events as a function of p.

RESULTS: NNTs increased (worsened) significantly as p decreased. Under the most conservative policy (p = 1), the median NNT to prevent one any ARIA-E event was 20-30 (lecanemab) and 15-25 (donanemab), yet this only reduced total ARIA events by 10-30%. The NNT to prevent one symptomatic ARIA-E (lecanemab) was substantially higher, at 70-90 (at p = 1).

CONCLUSIONS: The direct safety impact of APOE testing for ARIA mitigation is limited, even under universal discontinuation policies. Its primary value lies in supporting shared decision-making and operational planning rather than as a standalone safety lever.}, } @article {pmid41631871, year = {2026}, author = {Sun, M and Lin, J and Li, S}, title = {Extracellular tau oligomers exert neurocytotoxicity by triggering mitochondrial dysfunction.}, journal = {Journal of Alzheimer's disease : JAD}, volume = {110}, number = {1}, pages = {409-425}, doi = {10.1177/13872877251414979}, pmid = {41631871}, issn = {1875-8908}, mesh = {Humans ; *tau Proteins/metabolism/toxicity ; *Mitochondria/metabolism/drug effects/pathology/ultrastructure ; Apoptosis/drug effects/physiology ; Cell Line, Tumor ; Membrane Potential, Mitochondrial/drug effects/physiology ; Reactive Oxygen Species/metabolism ; Calcium/metabolism ; *Neurons/metabolism/drug effects ; Cell Survival/drug effects/physiology ; Autophagy/drug effects ; }, abstract = {BackgroundAbnormal tau aggregation is implicated in the development of neurodegenerative diseases such as Alzheimer's disease (AD). The presence of tau in the extracellular space and the spread of tau between nerve cells is associated with its toxicity. At present, researchers are trying to treat AD by limiting, blocking or removing extracellular tau.ObjectiveTo investigate the molecular mechanism underlying the cytotoxicity of extracellular tau oligomers.MethodsThe morphology of tau oligomers was observed by transmission electron microscopy. The neurocytotoxicity of tau oligomers was examined using CCK-8 assay. The localization of tau oligomers in cells was observed by laser confocal microscopy. The influence of tau oligomers on apoptosis was detected by Hoechst 33342/PI double-staining, Annexin V/PI double-staining and flow cytometry. JC-1 staining, DCFH-DA staining and Fluo-4 AM staining were used to evaluate the effect of tau oligomers on mitochondria. Western blot analysis was used to investigate the mechanism underlying the effects of tau oligomers on apoptosis and autophagy.ResultsAfter treatment with tau oligomers, the viability of SH-SY5Y cells decreased, and a typical apoptotic morphology was observed. Tau oligomers can enter cells, decrease the mitochondrial membrane potential, increase reactive oxygen species levels and drive calcium levels up to disrupt calcium homeostasis. The cytotoxicity of tau oligomers is closely related to the induction of mitochondrial apoptosis and blockade of mitophagy.ConclusionsThis study provides a molecular mechanism for understanding the cytotoxicity of extracellular tau oligomers and provides a therapeutic target for the development of effective treatment strategies for tau-related diseases.}, } @article {pmid41633894, year = {2026}, author = {Kim, DH and Jo, HY and Oh, YJ and Lim, JR and Chae, CW and Jung, YH and Han, HJ and Lee, HJ}, title = {Folate receptor 1 activation suppresses high glucose-induced amyloidogenesis in neurons via STAT3/Nrf2 pathway-dependent mitigation of mitochondrial oxidative stress.}, journal = {Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie}, volume = {196}, number = {}, pages = {119074}, doi = {10.1016/j.biopha.2026.119074}, pmid = {41633894}, issn = {1950-6007}, mesh = {*NF-E2-Related Factor 2/metabolism ; *Glucose/toxicity ; *Oxidative Stress/drug effects/physiology ; *STAT3 Transcription Factor/metabolism ; Animals ; *Neurons/metabolism/drug effects/pathology ; *Mitochondria/metabolism/drug effects ; Signal Transduction/drug effects ; *Folate Receptor 1/metabolism ; Amyloid Precursor Protein Secretases/metabolism ; Folic Acid/pharmacology ; Amyloid beta-Peptides/metabolism ; Reactive Oxygen Species/metabolism ; Cells, Cultured ; Aspartic Acid Endopeptidases/metabolism ; Amyloid beta-Protein Precursor/metabolism ; }, abstract = {Diabetes is a major risk factor for diabetic encephalopathy (DE), which is closely associated with sporadic Alzheimer's disease. Folic acid (FA) receptor signaling can suppress generation of neuropathogenic amyloid-beta (Aβ) induced by high extracellular glucose, suggesting that enhanced activation of this pathway could be a therapeutic strategy against DE-associated dementia, but the precise molecular signaling mechanisms are unclear. We report that high glucose levels increased the expression of amyloid precursor protein (APP) and β-secretase (BACE1) in cultured neurons and concomitantly induced amyloidogenesis, while FA treatment suppressed high glucose-stimulated expression of APP and BACE1, Aβ release, and accumulation of mitochondrial reactive oxygen species. Expression of nuclear factor erythroid 2-related factor 2 (Nrf2) was minimal under high glucose conditions, but was significantly upregulated together with downstream antioxidant enzymes following FA co-treatment. High glucose stimulation also increased folate receptor 1 (FOLR1) mRNA expression, suggesting a compensatory protective response. While treatment with 5-methyltetrahydrofolate (5-MTHF), the activated form of folate, did not significantly alter high glucose-induced upregulation of APP and BACE1, knockdown of FOLR1 mRNA reduced high glucose-stimulated Nrf2 expression and further augmented APP and BACE1 expression under high glucose conditions. Treatment with the STAT3 inhibitor 5'15-DPP also abolished high glucose-stimulated Nrf2 expression and increased APP and BACE1 expression levels. These findings indicate that FA/FOLR1 activation suppresses high glucose-induced amyloidogenesis by mitigating mitochondrial oxidative stress via STAT3/Nrf2 pathway signaling. In conclusion, present study suggests that the FA/FOLR1/STAT3/Nrf2 pathway is an effective therapeutic target for DE.}, } @article {pmid41634017, year = {2026}, author = {Li, Y and Wang, H and Zhang, D and Wang, S and Li, Z and Li, J and Tai, S and Tong, D and Wang, B and Lu, D and Yuan, S and Sun, W and Yang, B and Bai, C and Wang, Q and Ding, J and Wang, Z and Gao, Y and Yu, H and Cui, K and Liu, C and Mao, J and Yao, Y and Liu, F and Wan, Y and Yuan, J and Liu, X and Zheng, J}, title = {Gut microbiota-dependent 24-hydroxycholesterol metabolism contributes to capsaicin-induced amelioration of Alzheimer's disease-like pathology in mice.}, journal = {Nature communications}, volume = {17}, number = {1}, pages = {}, pmid = {41634017}, issn = {2041-1723}, support = {82160558//National Natural Science Foundation of China (National Science Foundation of China)/ ; }, mesh = {Animals ; *Capsaicin/pharmacology/administration & dosage ; *Alzheimer Disease/metabolism/pathology/microbiology/drug therapy ; Male ; *Hydroxycholesterols/metabolism/blood ; Humans ; Mice ; *Gastrointestinal Microbiome/drug effects/physiology ; Liver X Receptors/metabolism ; Disease Models, Animal ; Amyloid beta-Peptides/blood/metabolism ; Brain/metabolism/drug effects/pathology ; Microglia/drug effects/metabolism ; Female ; }, abstract = {Dietary capsaicin intake appears to affect the pathogenesis of Alzheimer's disease (AD), while the underlying mechanisms remain unclear. Here, we found in human cohorts that moderate-to-high level of dietary capsaicin intake was associated with improved cognitive performance. Similarly, long-term oral capsaicin administration in male 5×FAD mice ameliorated AD-like pathologies and reshaped gut microbial composition. Gut microbiota transfer from capsaicin-treated mice produced similar effects of capsaicin intake. Moreover, capsaicin elevated the level of host 24(S)-hydroxycholesterol (24-HC), relating to the increase of gut Oscillibacter genus abundance. The 24-HC elevation enhanced microglial phagocytic activity in the brain, and inhibited proinflammatory factors production via liver x receptor β (LXRβ)-mediated transcriptional regulation. Finally, we observed elevation of 24-HC in plasma in AD patients with higher level of dietary capsaicin intake, which correlated with cognitive scores and plasma Aβ and p-tau biomarkers. These findings suggest the potential of capsaicin or capsaicin-rich diets in the prevention or treatment of AD and related diseases.}, } @article {pmid41634843, year = {2026}, author = {Bellelli, F and Delrieu, J and van Kan, GA and Peluso, A and Soriano, G and Vellas, B and Angioni, D and Sourdet, S}, title = {Are pre-frail and frail amyloid positive individuals eligible to Lecanemab? A cross-sectional analysis from the Cogfrail real-world cohort.}, journal = {Alzheimer's research & therapy}, volume = {18}, number = {1}, pages = {}, pmid = {41634843}, issn = {1758-9193}, mesh = {Humans ; Female ; Male ; Aged ; Cross-Sectional Studies ; *Amyloid beta-Peptides/cerebrospinal fluid ; Aged, 80 and over ; *Frail Elderly ; *Frailty/cerebrospinal fluid ; France ; *Alzheimer Disease/drug therapy/cerebrospinal fluid ; Cohort Studies ; United States ; Peptide Fragments/cerebrospinal fluid ; }, abstract = {BACKGROUND: Following the positive outcomes of the Clarity-AD trial, Lecanemab received marketing authorization from the European Medicines Agency (EMA) and is expected to become available across Europe. However, the trial did not specifically evaluate frailty, making it difficult to estimate the potential effects of Lecanemab among frail individuals. This study aimed to apply Lecanemab eligibility criteria-based on both the Clarity-AD trial and the Appropriate Use Recommendations (AUR) from the United States and France-to a real-world population of pre-frail and frail older adults with confirmed positive amyloid status, and to evaluate differences in frailty status between eligible and non-eligible patients.

METHODS: Eligibility criteria from the Clarity-AD trial, the American and the French AUR, were applied to all participants with confirmed amyloid positivity (n = 120), assessed through amyloid-PET (visual reading) or cerebrospinal fluid (CSF) analysis (Aβ42 levels or Aβ42/Aβ40 ratio). Frailty was defined using the Fried phenotype.

RESULTS: The median age of the sample was 82.0 years (IQR: 79-85); 65% (n = 78) were women, and 36.7% (n = 44) were frail. Overall, 20.0% (n = 24) met the Clarity-AD eligibility criteria, while 50.8% (n = 61) and 47.5% (n = 57) were potentially eligible according to the American and French AURs, respectively. Only 9.1% (n = 4) of frail individuals met the Clarity-AD criteria, compared to 26.3% (n = 20) of pre-frail participants (p = 0.042). In contrast, 50.0% (n = 22) and 45.5% (n = 20) of frail individuals were potentially eligible according to the American and French AURs, respectively.

CONCLUSION: Although less than one in five participants would have been eligible for the Clarity-AD trial, approximately half the cohort would be potentially treatable with Lecanemab under real-world recommendations. While a considerable proportion of frail patients may have access to Lecanemab treatment in real-life, the low proportion of potentially eligible frail individuals for Clarity-AD in our cohort indirectly suggests that frailty may have been underrepresented in the trial, raising concerns about the generalizability of its findings to this population. Caution is warranted when targeting amyloid burden without previously addressing the underlying frailty.

TRIAL REGISTRATION: NCT03129269.}, } @article {pmid41635245, year = {2026}, author = {Wiatrak, B and Szeląg, A}, title = {Alzheimer's disease: Time to reassess research and clinical priorities.}, journal = {Advances in clinical and experimental medicine : official organ Wroclaw Medical University}, volume = {35}, number = {3}, pages = {397-401}, doi = {10.17219/acem/217199}, pmid = {41635245}, issn = {1899-5276}, mesh = {Humans ; *Alzheimer Disease/therapy/diagnosis ; Biomarkers ; Precision Medicine ; *Biomedical Research ; Electroencephalography ; }, abstract = {Alzheimer's disease (AD) remains one of the most pressing challenges in contemporary neurology, with growing evidence highlighting the limitations of the amyloid hypothesis and monomodal therapies. This editorial advocates for a shift toward multidimensional research and therapeutic frameworks that integrate molecular, electrophysiological, neuroimaging, and behavioral data. Emphasis is placed on the potential of microRNA-based biomarkers, electroencephalography (EEG) analysis, and non-invasive methods to improve early diagnosis. Emerging multimodal treatment strategies - including immunotherapy, neurostimulation, and nutraceuticals - are discussed alongside ethical and regulatory challenges in implementing novel interventions. The authors propose an integrated, patient-centered model that combines precision medicine with preventive approaches rooted in lifestyle, digital biomarkers, and AI-powered personalization. A paradigm shift toward systemic, translational, and ethically grounded strategies is urgently needed to meet the growing burden of AD.}, } @article {pmid41635250, year = {2026}, author = {Xu, Z and Xu, W and He, J and Qian, J and Wang, H and Li, C and Zhou, X}, title = {β-Asarone Attenuates Neuroinflammation of Alzheimer's Disease by Activating Autophagy and Suppressing NLRP3 Inflammasome Assembly.}, journal = {CNS neuroscience & therapeutics}, volume = {32}, number = {2}, pages = {e70771}, pmid = {41635250}, issn = {1755-5949}, support = {LJHSQY26H280002//Central Zhejiang Science and Technology Innovation CorridorJoint Fund of Zhejiang Provincial Natural Science Foundation of China/ ; 2025CC02//Inhua Traditional Chinese medicine science and technology project/ ; 2025ZL061//Zhejiang Province Traditional Chinese medicine science and technology project/ ; 2024-3-094//Jinhua major key science and technology plan project/ ; }, mesh = {Animals ; Allylbenzene Derivatives ; *Anisoles/pharmacology/therapeutic use ; *Autophagy/drug effects/physiology ; *NLR Family, Pyrin Domain-Containing 3 Protein/metabolism/antagonists & inhibitors ; *Alzheimer Disease/drug therapy/metabolism/pathology ; Mice ; Mice, Transgenic ; *Inflammasomes/metabolism/antagonists & inhibitors/drug effects ; *Neuroinflammatory Diseases/drug therapy/metabolism ; Male ; Mice, Inbred C57BL ; Maze Learning/drug effects ; }, abstract = {AIM: Alzheimer's Disease (AD) is a neurodegenerative condition with poorly understood mechanisms and few effective treatments. β-asarone has shown potential in AD management, though its molecular actions require further clarification. This study investigates the mechanisms through which β-asarone exerts its effects using both animal and cellular models.

METHODS: In vivo, the 3×Tg-AD mice were administered β-asarone for 8 weeks. Learning and memory abilities were assessed via the Morris water maze and step-down tests. Histomorphological examination, immunofluorescence, immunohistochemistry, ELISA, transmission electron microscopy, and Western blotting were employed to detect pathological changes, neuroinflammation, and protein expression of relevant signaling pathway molecules. In vitro, Aβ was used to culture BV-2 cells to mimic the brain microenvironment in Alzheimer's disease; changes in neuroinflammation, autophagy, and NLRP3 inflammasome-related proteins were observed after treatment with β-asarone.

RESULTS: The administration of β-asarone resulted in enhanced cognitive performance in 3×Tg-AD mice, alongside a reduction in microglial apoptosis induced by Aβ. Additionally, β-asarone diminished the accumulation of Aβ and phosphorylated Tau, ultimately supporting neuronal survival. In both the hippocampal tissue and BV-2 cell models, treatment with β-asarone led to a downregulation of neuroinflammatory markers and modulation of autophagy-related proteins (Beclin-1, P62, ATG5, LC3-II/I), while concurrently suppressing components of the NLRP3 inflammasome (NLRP3, ASC, Caspase-1, cleaved Caspase-1). Notably, the autophagy inhibitor 3-MA counteracted the inhibitory effects of β-asarone on NLRP3 activation.

CONCLUSION: β-Asarone attenuates AD-related neuroinflammation by activating autophagy to inhibit NLRP3 inflammasome assembly.}, } @article {pmid41636819, year = {2026}, author = {Fu, H and Feng, J and Zhang, X and Tian, L and Sun, S and Bo, H and He, C and Wang, X}, title = {Memantine mitigates radiation-induced cognitive impairment by modulating AKT/GSK3β signaling.}, journal = {Radiation and environmental biophysics}, volume = {65}, number = {1}, pages = {257-269}, pmid = {41636819}, issn = {1432-2099}, support = {NO.HYZHXM02004//State Key Laboratory of Space Medicine Fundamentals and Application, China Astronaut Research and Training Center/ ; xcxjh20230610//Foundation of the Graduate Innovation Center, Nanjing University of Aeronautics and Astronautics/ ; }, mesh = {Animals ; *Memantine/pharmacology/therapeutic use ; *Glycogen Synthase Kinase 3 beta/metabolism ; *Signal Transduction/drug effects/radiation effects ; *Proto-Oncogene Proteins c-akt/metabolism ; Male ; Mice ; *Cognitive Dysfunction/drug therapy/etiology/metabolism ; Mice, Inbred ICR ; }, abstract = {Memantine hydrochloride (MH), primarily employed in the clinical treatment of Alzheimer’s disease (AD), has been reported to exert beneficial effects on radiation-induced cognitive impairment; however, its underlying mechanisms have not been fully elucidated. In this study, a mouse model of radiation-induced injury was established. ICR(Institute of Cancer Research) mice were divided into six groups: control, 8 Gy irradiation, prophylactic 20 mg/kg + 8 Gy, prophylactic 40 mg/kg + 8 Gy, post-irradiation 8 Gy + 20 mg/kg, and post-irradiation 8 Gy + 40 mg/kg. Behavioral assessments indicated that ionizing radiation induced spatial cognitive deficits, which were ameliorated by MH administration. Morphological analyses revealed neuronal damage, synaptic injury, and demyelination in the hippocampal dentate gyrus (DG) region, which were markedly attenuated following MH treatment. Western blot analysis demonstrated that radiation upregulated dopamine D2 receptor (D2R) and β-arrestin 2 expression, suppressed PP2A expression, promoted AKT dephosphorylation, and led to GSK3β overactivation, along with increased expression of MBP and PLP1—potential mechanisms underlying radiation-induced cognitive impairment. MH administration downregulated D2R and β-arrestin 2, enhanced PP2A-AKT interaction, reduced GSK3β activity, and upregulated MBP and PLP1 expression. Notably, prophylactic administration conferred greater neuroprotection than post-irradiation treatment. These findings provide preliminary insight into the protective mechanisms of MH against radiation-induced cognitive impairment and offer a basis for future studies in radiation neuroprotection.}, } @article {pmid41636955, year = {2026}, author = {Hu, F and Tang, NLS and Wang, H and Zheng, H}, title = {Resolving Heterogeneity in the Diagnosis of Alzheimer's Disease and its Progression Using Multimodal Data.}, journal = {Journal of molecular neuroscience : MN}, volume = {76}, number = {1}, pages = {24}, pmid = {41636955}, issn = {1559-1166}, support = {No.2018SHZDZX01//Shanghai Municipal Science and Technology Major Project/ ; }, mesh = {Humans ; *Alzheimer Disease/diagnosis/genetics/classification/diagnostic imaging ; Clustering Algorithms ; *Cognitive Dysfunction/diagnosis/genetics/diagnostic imaging ; Disease Progression ; Biomarkers/cerebrospinal fluid ; Magnetic Resonance Imaging ; Male ; Female ; Aged ; }, abstract = {Alzheimer’s disease (AD) is a complex and diverse illness that makes early detection extremely difficult. Most existing research utilizes data to identify biomarkers and more homogeneous subgroups to improve the detection, prediction of progression, and prognosis of AD. However, AD still suffers from a lack of appropriate biomarkers for early symptom detection and blurred boundaries between different subgroups. Here, an unsupervised clustering method known as similarity network fusion (SNF) was employed to analyze multimodal data from 972 subjects, including 370 with cognitively normal (CN), 565 with mild cognitive impairment (MCI), and 37 patients with AD. First, we constructed a similarity network for subjects using cognitive scores, genetics, and magnetic resonance imaging (MRI) related data, respectively. Then the SNF fusion method was employed to integrate the data, and spectral clustering was used to find subgroups sharing similarities across modalities. Our results indicated that the approach accurately diagnosed both current and prospective AD (~ 90%). Notably, we successfully identified two MCI subtypes with biological and clinical significance, validated by longitudinal studies of cognitive, clinical, fluid biomarkers and MRI-related features, dementia diagnosis, and pseudo-trajectory analysis. We also observed many dysregulated processes and signaling pathways between MCI subtypes, such as the GnRH signaling pathway, VEGF signaling pathway, and insulin signaling pathway. Overall, our research offers a distinctive viewpoint on the diversity of AD, and the more specific subtypes of MCI help create customized treatment plans.}, } @article {pmid41639038, year = {2026}, author = {Haskell, AK and Kulas, JA and Carter, WE and Javens-Wolfe, J and Hinkel, RD and Moussaif, M and Smiley, JS and Lazaro, O and Robertson, S and Palkowitz, AD and Lamb, BT and Richardson, TI and Dage, JL and Chu, S and Johnson, T and Stancato, LF and Syed, AQ}, title = {Generation and characterization of iPSC-derived microglia for in vitro modeling of stimuli-specific neuroimmune responses.}, journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association}, volume = {22}, number = {2}, pages = {e71117}, pmid = {41639038}, issn = {1552-5279}, support = {//Center for Medical Genomics at Indiana University School of Medicine/ ; U54 AG065181/AG/NIA NIH HHS/United States ; U54 AG090792/AG/NIA NIH HHS/United States ; U01AG088021/AG/NIA NIH HHS/United States ; U54AG090792/AG/NIA NIH HHS/United States ; U54AG065181/AG/NIA NIH HHS/United States ; //Indiana University Grand Challenges Precision Health Initiative/ ; U01 AG088021/AG/NIA NIH HHS/United States ; }, mesh = {*Microglia/immunology/metabolism/cytology ; Humans ; *Induced Pluripotent Stem Cells/cytology ; Phagocytosis ; Cell Differentiation ; Receptors, Immunologic/metabolism/immunology ; Membrane Glycoproteins/metabolism/immunology ; Myelin Sheath/metabolism ; Cells, Cultured ; }, abstract = {INTRODUCTION: Microglia are macrophage-like brain resident immune cells known to express numerous Alzheimer's disease risk genes. Here we generated a human induced pluripotent stem cell (iPSC) derived microglia cell culture model for use in neuroimmune modeling and therapeutic testing.

METHODS: We generated iPSC lines using episomal reprogramming for subsequent stepwise differentiation of iPSC-derived microglia (iMG) without commercial kits. We characterized the responses of this model to immunogenic stimuli and recombinant TREM2 antibodies.

RESULTS: The iMG expressed several key microglia signature genes and are morphologically and transcriptionally dynamic. iMG rapidly phagocytosed myelin debris and strongly changed expression of lipid homeostasis genes. iMG expressed TREM2 and increased TREM2 levels in response to IL-4. Recombinant TREM2 antibody treatment impaired iMG myelin phagocytosis and upregulated chemokines.

DISCUSSION: We validated our iMG model system for the evaluation of biological responses of human microglia-like cells to stimuli and pharmacological agents for their transcriptional and functional impacts.}, } @article {pmid41639293, year = {2026}, author = {Amr, Y and Gad, W and Leiva, V and Martin-Barreiro, C and Abdelkader, T}, title = {Comparative analysis of supervised and ensemble models with unsupervised exploration for alzheimer's disease prediction.}, journal = {Scientific reports}, volume = {16}, number = {1}, pages = {}, pmid = {41639293}, issn = {2045-2322}, mesh = {*Alzheimer Disease/diagnosis ; Humans ; Random Forest ; Boosting Machine Learning Algorithms ; Prediction Algorithms ; Predictive Learning Models ; Classification Algorithms ; Support Vector Machine ; Clustering Algorithms ; Ensemble Learning ; ROC Curve ; Data Analytics ; Logistic Models ; }, abstract = {Alzheimer's disease is a progressive neurodegenerative disorder characterized by memory loss and cognitive decline, with no known cure. Early detection of dementia, a primary manifestation of Alzheimer's disease, is critical to enable timely intervention and treatment planning. This study introduces ensemble learning models for predicting Alzheimer's disease and presents a comparative analysis between traditional machine learning and advanced ensemble models. The evaluation is conducted using the "Open Access Series of Imaging Studies" 2 (OASIS-2) dataset. Traditional models, including logistic regression, decision tree, support vector machine, and random forest, are benchmarked against ensemble models such as adaptive boosting, extreme gradient boosting, and a hyperparameter-tuned majority voting ensemble models. Performance is assessed using accuracy, precision, and the area under the receiver operating characteristic curve. Results show that ensemble models, particularly the optimized majority voting classifier, consistently outperform traditional methods. To complement the supervised comparison, exploratory unsupervised methods were applied using multiple correspondence analysis and k-means clustering to uncover latent structures in the dataset. By categorizing all variables, these unsupervised methods highlight patterns of clinical and demographic similarity. Unlike prior studies that focus solely on predictive accuracy, this work integrates supervised classification, ensemble learning, and unsupervised exploratory analysis within a unified framework. This combined approach enables both robust performance comparison and deeper insights into latent data structures relevant to Alzheimer's disease. All computational experiments were conducted using the Python programming language.}, } @article {pmid41639575, year = {2026}, author = {Zetterberg, H and Bendlin, BB}, title = {Biofluid biomarkers in Alzheimer's disease and other neurodegenerative dementias.}, journal = {Nature}, volume = {650}, number = {8100}, pages = {49-59}, pmid = {41639575}, issn = {1476-4687}, support = {R01 AG062285/AG/NIA NIH HHS/United States ; P30 AG062715/AG/NIA NIH HHS/United States ; R01 AG037639/AG/NIA NIH HHS/United States ; R01 AG054059/AG/NIA NIH HHS/United States ; R01 AG070883/AG/NIA NIH HHS/United States ; RF1 AG057784/AG/NIA NIH HHS/United States ; R01 AG057912/AG/NIA NIH HHS/United States ; R01 AG070973/AG/NIA NIH HHS/United States ; }, mesh = {Animals ; Humans ; alpha-Synuclein/blood/cerebrospinal fluid ; *Alzheimer Disease/blood/cerebrospinal fluid/diagnosis ; Amyloid beta-Peptides/cerebrospinal fluid/metabolism ; *Biomarkers/cerebrospinal fluid/blood/analysis/metabolism ; Brain/pathology/metabolism ; Dementia/pathology/metabolism/diagnosis/blood ; DNA-Binding Proteins/cerebrospinal fluid/metabolism ; *Neurodegenerative Diseases/pathology/metabolism/diagnosis ; tau Proteins/cerebrospinal fluid/metabolism ; }, abstract = {Biofluid-based biomarkers have transformed neurodegenerative disease research and care, providing insights into the molecular underpinnings of Alzheimer's disease (AD) and other neurodegenerative dementias. This Review provides an update on recent developments in biofluid-based biomarkers for amyloid-β (Aβ) pathology, tau pathology, neurodegeneration, glial reactivity, α-synuclein pathology, TAR DNA-binding protein 43 (TDP-43) pathology, synaptic pathophysiology and cerebrovascular disease-pathologies and processes that are all relevant to neurodegenerative dementias. Complementing longstanding cerebrospinal assays, improved technologies now facilitate the detection of molecules linked to neurodegenerative brain changes at very low concentrations in the blood. This promises to complement the clinical evaluation of suspected neurodegenerative disease in healthcare with molecular phenotyping biomarkers that will help to link the clinical symptoms to ongoing pathophysiological processes in the brain and improve how patients are referred to specialty clinics for initiation and monitoring of molecularly targeted treatments. Clinically relevant breakthroughs such as the use of anti-Aβ monoclonal antibodies to address Aβ pathology in AD serve as important proof-of-concept examples of how the field is advancing toward molecularly informed prevention and treatment. This Review provides an overview of the most established biofluid-based biomarkers currently in use and offers practical guidance on their interpretation and implementation in clinical settings.}, } @article {pmid41639713, year = {2026}, author = {You, C and Wu, S and Zhang, Y and Li, Q and Cui, Y and Wu, Y}, title = {Exploration of borneol essential oil function in the treatment of Alzheimer's disease based on network pharmacology and experimental validation.}, journal = {BMC complementary medicine and therapies}, volume = {26}, number = {1}, pages = {}, pmid = {41639713}, issn = {2662-7671}, mesh = {Animals ; *Camphanes/pharmacology/chemistry ; *Alzheimer Disease/drug therapy ; *Oils, Volatile/pharmacology/chemistry ; Mice ; Network Pharmacology ; Molecular Docking Simulation ; Mice, Transgenic ; Male ; Cinnamomum camphora/chemistry ; Disease Models, Animal ; Gas Chromatography-Mass Spectrometry ; }, abstract = {BACKGROUND: Borneol essential oil was obtained by distillation with steam from the branches and leaves of Cinnamomum camphora chvar. Borneol alleviates learning and memory impairments, but it is not known whether and how it exerts an effect on Alzheimer’s Disease (AD). To explore the possible mechanisms of borneol essential oil in AD via network pharmacology and molecular docking. METHODS: Gas chromatography–time-of-flight mass spectrometry (GC-TOFMS) was used to characterize the volatile constituents of borneol essential oil, followed by network pharmacology analysis to elucidate the core targets and key signaling pathways underlying its potential therapeutic effects on Alzheimer’s disease. Molecular docking was used to find out the active components of the essential oil of borneol. Behavioral tests, enzyme-linked immunosorbent assay (ELISA), western blotting (WB), and immunohistochemistry (IHC) were run in an amyloid precursor protein/presenilin 1 (APP/PS1) transgenic mouse AD model. The impact of borneol essential oil on improving AD symptoms and its mechanisms, mainly focusing on the anti-inflammatory ones, was explored. RESULTS: Five core targets of the essential oil—ESR1, MAPK3, PGR, ERBB2, and MAPK1—were treated with AD. The NF-κB pathway was the main signaling pathway and guaiol was the main active ingredient. And also borneol essential oil alleviated the cognitive deficit, motor deficit, and pathological phenomena in APP/PS1 model mice. Mechanically, they were correlated with downregulation of the extracellular signal-regulated kinase (ERK)/nuclear factor kappa B (NF-κB) signaling pathway, suggesting anti-inflammatory effects that may contribute to the modulation of AD-related pathology. CONCLUSION: Borneol essential oil alleviated neuroinflammatory responses and ameliorated AD-like pathological features in APP/PS1 mice through modulation of the ERK/NF-κB pathway.}, } @article {pmid41640724, year = {2026}, author = {Hayashi, M and Morimoto, Y and Mikuzuki, L}, title = {Comparison of electroencephalogram waveforms in older patients with/without dementia after administration of midazolam: a prospective, observational comparative study.}, journal = {Journal of dental anesthesia and pain medicine}, volume = {26}, number = {1}, pages = {41-51}, pmid = {41640724}, issn = {2383-9309}, abstract = {BACKGROUND: Sedation with midazolam in older patients with severe dementia can cause reactions that differ from those encountered in healthy individuals. We hypothesized that one reason for this is that electroencephalogram (EEG) responses to midazolam in patients with severe dementia may differ from those encountered in healthy individuals. In this study, we aimed to examine the effects of midazolam on EEG findings in older patients with severe dementia and compare them with those observed in older adults without dementia.

METHODS: We included 25 patients aged ≥ 60 years, and allocated them to either the dementia (13 patients) or non-dementia (12 patients) group. Participants with a Mini-Mental State Examination score of ≤ 23, Functional Assessment Staging of Alzheimer's disease stage 6 or 7, and/or Clinical Dementia Rating of being "severe" were considered to have severe dementia. EEG electrodes were attached to patients' frontal pole (Fp2). Midazolam was administered until a modified Observer's Assessment of Alertness/Sedation (OAA/S) score of 2 was attained. Chi-square test, Mann-Whitney U test, and Wilcoxon signed-rank test were performed to assess between-group differences. Differences were considered statistically significant at P < 0.05.

RESULTS: The power of the delta wave at baseline and immediately before treatment was higher in patients with dementia than that in the patients without dementia. Conversely, the power of the alpha wave was lower in the dementia group in the sedated state of the OAA/S 2. Regarding the changes within each group, the theta and beta waves in the dementia group decreased after midazolam administration.

CONCLUSION: Regarding EEG waveforms in the frontal pole, administration of midazolam significantly decreased the power of the fast wave (alpha wave) and increased the power of the slow wave (delta wave) in older patients with severe dementia compared with that in older patients without cognitive decline.}, } @article {pmid41640856, year = {2026}, author = {Badalova, A and Stott, J and Leff, AP}, title = {Proper name anomia in people with Alzheimer's disease: implications for diagnosis and treatment-a systematic review.}, journal = {NPJ dementia}, volume = {2}, number = {1}, pages = {11}, pmid = {41640856}, issn = {3005-1940}, abstract = {Proper name anomia (PNA) is a common experience that can become unpleasantly amplified in people with Alzheimer's disease (AD). In this systematic review, we discuss the key cognitive stages where naming can fail: facial recognition, person-specific semantics, and proper-name retrieval. We examine claims that PNA is an early indicator of AD and review studies that have attempted to treat PNA in individuals with AD. Twenty-two eligible studies were included. The main findings are that individuals with AD frequently experience difficulties in recalling proper names at any point in the disease process, with the distribution of functional breakdown between the three key cognitive stages involved in successful naming being: facial recognition (19%), person-specific semantics (30%), and proper-name retrieval (40%). PNA can be an early manifestation of AD. Effective behavioural treatments are available for those whose naming difficulties occur at the retrieval stage, including trial-by-trial practice using vanishing cues and spaced retrieval. We also provide clinical recommendations regarding the diagnosis and treatment of PNA.}, } @article {pmid41640998, year = {2025}, author = {Kawabata, S}, title = {Therapeutic and preventive strategies based on the maladaptive plasticity hypothesis for Alzheimer's disease.}, journal = {Frontiers in aging neuroscience}, volume = {17}, number = {}, pages = {1726144}, pmid = {41640998}, issn = {1663-4365}, abstract = {Alzheimer's disease (AD), the most common form of dementia, is characterized by two hallmark pathologies, amyloid plaques (APs) and neurofibrillary tangles (NFTs). Amyloid-β and tau, key components of APs and NFTs, respectively, are widely considered primary drivers of neurodegeneration in AD. In contrast, an alternative view proposes that network failure, arising from amyloid-β precursor protein-driven excessive/aberrant and maladaptive synaptic plasticity, underlies AD pathophysiology. Synaptic plasticity is indispensable for cognitive functions such as learning and memory; however, when dysregulated, it may lead to cognitive decline and accelerate the trajectory toward AD. This paper, based on this hypothesis, examines strategies to mitigate maladaptive plasticity while preserving adaptive plasticity, and proposes the potential of novel approaches for the prevention and treatment of mild cognitive impairment and AD, encompassing both activity-based interventions and pharmacological treatments. This hypothesis-driven framework offers a coherent perspective linking molecular, circuit, and cognitive levels of dysfunction in AD, and may guide more integrative, multi-level approaches to future preventive and therapeutic strategies, a direction increasingly emphasized in current experimental and clinical AD research.}, } @article {pmid41641000, year = {2025}, author = {Khan, SA and Raza, K and Tiwari, P and El-Tanani, M and Rabbani, SA and Parvez, S}, title = {Mechanisms to medicines: navigating drug repurposing strategies in Alzheimer's disease.}, journal = {Frontiers in aging neuroscience}, volume = {17}, number = {}, pages = {1676065}, pmid = {41641000}, issn = {1663-4365}, abstract = {Alzheimer's disease (AD) represents a continuously advancing neurodegenerative condition distinguished by the unremitting deterioration of cognitive abilities and memory impairment, which significantly hampers daily functioning of life. In the absence of disease modifying treatments, it continues to pose a significant global challenge. Though symptomatic treatment exists, the inherent complexity involved with AD pathogenesis related to Aβ plaques, neurofibrillary tangles, neuroinflammation, oxidative stress, etc. poses a tremendous challenge to developing drugs. With the incidence of AD increasing yearly globally, research into already existing pharmacological agents has the potential to uncover a brighter future for breakthroughs in treatment strategy. A primary strategy to accelerate the development of AD therapies is drug repurposing: determining a new use for an existing known medication. Following innovative approaches like high-throughput screening, AI-based techniques, a number of classes of drugs originally designed for other diseases are now being tested to modulate the complex pathology mechanisms in AD. This review focuses on the therapeutic promise of drug repurposing as adjunctive to the much-needed renaissance in AD therapies. The review continues to focus on some promising repurposed drug candidates, methodologies applied, and the evaluation of the present status of drugs in the clinic. Apart from the information regarding mechanisms involved in AD, this review also complements case studies, challenges, and limitations along with the various drug repurposing strategies for AD. By understanding and harnessing the potential of existing pharmacological agents, we can expand therapeutic options and improve patient outcomes.}, } @article {pmid41641094, year = {2026}, author = {Wang, J and Braunstein, JB and Wolz, R and Harper, L and Locascio, T and McPherson, HE and Mohs, R and Pontecorvo, MJ and Burnham, SC}, title = {Interchangeability of blood-based biomarkers and PET to identify Alzheimer's disease pathology.}, journal = {Alzheimer's & dementia (Amsterdam, Netherlands)}, volume = {18}, number = {1}, pages = {e70196}, pmid = {41641094}, issn = {2352-8729}, abstract = {INTRODUCTION: Establishing interchangeability between blood biomarkers and amyloid-positron emission tomography (PET) could help identify patients who would benefit from novel amyloid-targeting therapies for Alzheimer's disease.

METHODS: Adult participants from the Global Alzheimer's Platform Foundation's Bio-Hermes study with clinical diagnosis of mild cognitive impairment/mild dementia and available amyloid-PET evaluations and Aβ42/40-based PrecivityAD[®] (by C2N Diagnostics) and/or phosphorylated tau at threonine 217 (p-Tau217 (research use Meso Scale Discovery, Lilly) were included. Interchangeability between plasma-based tests (per pre-established thresholds) and amyloid-PET stratifications was evaluated.

RESULTS: PrecivityAD (N = 537) and p-Tau217 (N = 531) plasma-based tests had high agreement with florbetapir-PET (overall percent agreement: 80.7% and 90.1%, respectively) and accurately selected patients identified as florbetapir-PET-positive (positive predictive value: 86.0% and 88.0%, respectively). Further, they were non-inferior to quantitative florbetapir-PET (at 37 Centiloids) for identifying positive florbetapir-PET visual reads.

DISCUSSION: Results support the hypothesis that blood biomarkers may be interchangeable with amyloid-PET criteria for selecting patients who may benefit from treatment with novel amyloid-targeting therapies.

HIGHLIGHTS: Interchangeability of plasma-based tests and amyloid-PET stratifications was demonstrated.Non-inferiority of plasma-based biomarkers to amyloid-PET for identifying patients with AD pathology was observed.High agreement between plasma-based test stratification and florbetapir-PET expert visual read was observed.}, } @article {pmid41641155, year = {2025}, author = {Sánchez-Juan, P and Baz, P and Arrieta, E and Novick, D and Díaz-Cerezo, S and Cotton, S and Walker, C and Trueba Saiz, Á and Núñez, M}, title = {The diagnostic pathway of Alzheimer's disease in real-world clinical practice in Spain: results from the Adelphi Dementia Disease Specific Programme™.}, journal = {Frontiers in neurology}, volume = {16}, number = {}, pages = {1702805}, pmid = {41641155}, issn = {1664-2295}, abstract = {INTRODUCTION: There are challenges associated with the timely diagnosis of people with mild cognitive impairment (MCI) and Alzheimer's disease (AD), especially with the future introduction of amyloid-targeting therapies. This study evaluates the current diagnostic journey for MCI and dementia due to AD in Spain.

METHODS: This study used data from the Adelphi Real World Dementia Disease Specific Programme (DSP[TM]), a cross-sectional survey with retrospective data collection. The survey involved primary care physicians (PCPs) and hospital specialists with experience in managing and treating AD, along with their consulting patients, between January and July 2023 in Spain. Analyses were descriptive.

RESULTS: Physicians (N = 94; 44.7% PCPs, 38.3% neurologists) reported data for 723 patients. Most patients (78.9%) first consulted a PCP. The median (inter-quartile range) time since symptom onset to first consultation was 21.6 (6.1-48.2) weeks and, in those patients who were not diagnosed immediately, the time from first consultation to diagnosis was 13.0 (6.0-21.9) weeks if diagnosed by a PCP, or 28.9 (17.1-52.1) weeks if diagnosed by a specialist. The diagnosing physician was a specialist or a PCP for 83.2% and 16.8% of patients, respectively. In addition, the most used advanced diagnostic techniques were computed tomography scans and magnetic resonance imaging (57.2% and 43.3% of patients, respectively). CSF determination of AD biomarkers was conducted in 12.4% of patients and AD-specific blood biomarkers in 2.9%. Treatment was mostly initiated by neurologists.

CONCLUSION: The diagnostic process for people with MCI and AD could be accelerated by increased awareness of the disease, shorter referral times, and better access to specialized diagnostic services. This study shows limited use of AD-specific biomarker testing in Spain.}, } @article {pmid41641384, year = {2026}, author = {Lai, X}, title = {Intrinsic mechanical vibrations as a missing dimension in amyloid-β clearance: a mechanochemical hypothesis for Alzheimer's disease.}, journal = {Frontiers in aging neuroscience}, volume = {18}, number = {}, pages = {1749562}, pmid = {41641384}, issn = {1663-4365}, abstract = {Alzheimer's disease is widely viewed as a disorder of disturbed amyloid-β (Aβ) homeostasis, yet it remains unclear why Aβ shifts from routine turnover to progressive retention and plaque growth in mid-life. This article advances a mechanochemical hypothesis: that age-related reductions in low-intensity mechanical vibrations in the head and neck-arising from everyday self-vocalization (speech, singing, humming) and physiological, non-hypoxic upper-airway motion during stable sleep-contribute to a gradual narrowing of the Aβ clearance bottleneck. Gentle vibrations transmitted through bone and soft tissue could, in principle, enhance interstitial mixing, reduce local supersaturation and nucleation, increase encounter rates at blood-brain barrier and meningeal-lymphatic interfaces, and augment perivascular and glymphatic transport. A sustained decline in this "intrinsic mechanical vibration" (IMV) dose in mid-life might therefore favor Aβ retention without any change in production. We bring together indirect lines of evidence that are compatible with this view, including sleep and glymphatic studies, neuromodulatory stimulation paradigms, music and singing interventions, and hearing-loss epidemiology, and we discuss domains that at first appear inconsistent, such as voice-heavy occupations and obstructive sleep apnea. We then outline a testable cascade that links behavioral and sleep changes in mid-life to reduced mechanical drive and impaired clearance, and we propose concrete experiments spanning human laboratory studies, clinical trials, animal models, and prospective cohorts. Whether ultimately supported or refuted, this IMV-clearance framework highlights mechanical forces as a potentially modifiable dimension of Alzheimer's disease risk and treatment response, alongside sleep, vascular health, and cognitive engagement.}, } @article {pmid41641469, year = {2026}, author = {Ye, Q and Gao, W and Feng, J and Li, X and Li, J and Yang, F and Li, L and Zi, M and Wu, X and Gao, H and Li, H}, title = {Spatial heterogeneity in microglia-complement crosstalk: Implications for synaptic pruning in Alzheimer's disease.}, journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association}, volume = {22}, number = {2}, pages = {e71185}, pmid = {41641469}, issn = {1552-5279}, support = {82105035//National Natural Science Foundation of China/ ; LH2023H064//Nature Science Foundation of Heilongjiang Province/ ; 2024065//Research Project of the Health Commission of Jiangsu Province/ ; HABZ202325//Huai'an Basic Research Project/ ; HABL202222//Huai'an Science and Technology Bureau/ ; ZHY2024-304//Research Project of the Traditional Chinese Medicine Administration of Heilongjiang Province/ ; }, mesh = {*Alzheimer Disease/pathology/immunology/physiopathology/metabolism ; Humans ; *Microglia/metabolism/physiology ; Animals ; *Neuronal Plasticity/physiology ; *Complement System Proteins/metabolism ; *Synapses ; Brain/pathology ; }, abstract = {Alzheimer's disease (AD) is a neurodegenerative disorder characterized by synaptic loss, as a key pathological feature in its early stages. Recent studies have highlighted the central role of microglia-complement interactions in synaptic pruning. This interaction exhibits significant spatial heterogeneity in AD, with activation patterns and functional manifestations varying across different brain regions and stages of disease. Therefore, this article systematically reviews the synergistic mechanisms of microglia and the complement system in physiological synaptic pruning. Additionally, the dynamic evolution of the complement-immune network during disease progression is analyzed, and the amplifying effect of genetic factors on the spatial heterogeneity of synaptic pruning is explored. Furthermore, current treatment strategies from both Western medicine and traditional Chinese medicine are discussed, emphasizing the potential value of combining these approaches for intervening in synaptic loss in AD.}, } @article {pmid41641771, year = {2026}, author = {Ruan, Q and Zhang, C and Wu, P and Huang, K and Xiong, X and Qiu, Z and Song, X and Wu, H and Guo, J}, title = {Restoration of intracellular osmotic pressure balance induced by protein nanoparticles: A potential target for developing Alzheimer's disease treatment strategies.}, journal = {Neural regeneration research}, volume = {}, number = {}, pages = {}, doi = {10.4103/NRR.NRR-D-25-00763}, pmid = {41641771}, issn = {1673-5374}, abstract = {The progressive accumulation of amyloid-β and glutamate in synapses is a characteristic feature of early-stage Alzheimer's disease. This study investigated the influence of transmembrane osmotic pressure on Alzheimer's disease pathogenesis using a fluorescence resonance energy transfer-based optical probe for intermediate filament tension. Cotreatment with amyloid-β and glutamate at predicted cerebrospinal fluid levels induced Alzheimer's disease-like neuronal injury. Probe-transfected cells were used to monitor intermediate filament tension, whereas cytoplasmic osmolality was measured using a freezing point osmometer under individual and combined treatment with amyloid-β and glutamate. The results showed that the combined treatment of 50 nM amyloid-β and 0.3 mM glutamate significantly elevated intermediate filament tension and osmotic pressure. Cellular experiments indicated that this increase resulted from the formation of intracellular protein nanoparticles through nucleotide-binding oligomerization domain-like receptor protein 3 inflammasome formation and cytoskeletal depolymerization. Oligomers of 50 nm amyloid-β induced an outward membrane current, whereas 0.3 mM glutamate increased both amyloid-β-induced current and calcium signals. The increase in protein nanoparticle levels and Ca2+ signals promoted voltage-dependent nonselective cation and anion influx, resulting in upregulated osmotic pressure, which was closely associated with the sensitization of ion channels elicited by calmodulin and protein kinase C activation. The attenuation of intracellular protein nanoparticles and desensitization of ion channels by drug combinations effectively alleviated transmembrane osmotic pressure and Alzheimer's disease-like neuronal injury. Behavioral assays performed using Caenorhabditis elegans Alzheimer's disease models further confirmed the efficacy of drug combinations. Therefore, protein nanoparticle-induced osmotic pressure plays a pivotal role in Alzheimer's disease pathogenesis, particularly in response to amyloid-β and glutamate cotreatment. Restoring intracellular osmotic pressure seems to be a potential target for developing new effective therapeutic strategies for Alzheimer's disease.}, } @article {pmid41641880, year = {2026}, author = {Wieland, LS and Ludeman, E and Chi, Y and Feinberg, TM and Chen, IH and Chen, KH and Zhu, Y and Wolverson, E and Amri, H}, title = {Ginkgo biloba for cognitive impairment and dementia.}, journal = {The Cochrane database of systematic reviews}, volume = {2}, number = {2}, pages = {CD013661}, pmid = {41641880}, issn = {1469-493X}, mesh = {*Ginkgo biloba/adverse effects ; Humans ; Randomized Controlled Trials as Topic ; *Cognitive Dysfunction/drug therapy ; *Phytotherapy/methods/adverse effects ; *Dementia/drug therapy ; *Plant Extracts/therapeutic use/adverse effects ; Ginkgo Extract ; }, abstract = {BACKGROUND: Dementia is a neurocognitive disorder that interferes with cognition and independent functioning. Common dementia subtypes include Alzheimer's disease, vascular dementia, and mixed type. Mild cognitive impairment (MCI) is a risk factor for dementia, and subjective cognitive complaints may be the earliest manifestation. Although cholinesterase inhibitors may help reduce some cognitive and behavioral symptoms, there is no established treatment that cures or slows dementia progression. Ginkgo biloba (ginkgo) is a popular herbal preparation that is used to improve brain and circulatory health, and neuroprotective effects are biologically plausible.

OBJECTIVES: To assess the benefits and harms of Ginkgo biloba for the treatment of people with cognitive impairment or dementia.

SEARCH METHODS: We searched the Cochrane Dementia and Cognitive Improvement Group's register, MEDLINE, Embase, four other databases, and two trials registries on 8 December 2022. The search was updated in MEDLINE, Embase, CENTRAL, and the trials registers on 18 November 2024.

SELECTION CRITERIA: We included randomized controlled trials (RCTs) comparing ginkgo with placebo, usual treatment, or other treatments for cognitive problems in people with cognitive complaints or diagnoses of MCI or dementia.

DATA COLLECTION AND ANALYSIS: Two review authors independently selected trials, extracted data, and assessed studies for risk of bias. Key outcomes were global clinical status, global cognitive function, activities of daily living (ADLs), adverse events (AEs), and serious adverse events (SAEs) at six months. When clinically appropriate, we pooled data using a random-effects model and expressed treatment effects as mean differences (MDs), standardized mean differences (SMDs), or risk ratios (RRs), each with its 95% confidence interval (CI). We used GRADE methods to assess the certainty of the evidence for each estimate.

MAIN RESULTS: We included 82 studies with 10,613 participants; 72 studies with 9783 participants provided extractable data. Four studies were at low risk of bias in all domains. Below we present data for the comparison of ginkgo versus placebo in people with different clinical conditions. Subjective cognitive impairment Three studies (597 participants) compared ginkgo with placebo for people with subjective cognitive complaints. Based on one study that lasted six months, it is uncertain whether ginkgo has any effect on global clinical status measured on a five-point Likert scale (MD 0.00, 95% CI -0.33 to 0.33; P = 1.00; 1 study, 197 participants; very low-certainty evidence). There were no data on cognition or ADLs. One study reported no difference in minor side effects between treatment groups and did not mention SAEs. A larger study lasting three months found that the risk of AEs may be higher with ginkgo versus placebo. It provided very uncertain evidence on the risk of SAEs. Multiple sclerosis and cognitive impairment Two studies (164 participants) tested ginkgo versus placebo over three months in people with multiple sclerosis and cognitive problems. Ginkgo probably has little or no effect on cognition measured on the Perceived Deficits Questionnaire (MD -0.09, 95% CI -0.41 to 0.22; P = 0.55, I² = 0%; 2 studies, 152 participants; moderate-certainty evidence). There were no data on global clinical status or ADLs. The studies suggested no important difference in numbers of AEs between groups, and there was no indication of SAEs due to ginkgo. Mild cognitive impairment Twelve studies (1913 participants) tested ginkgo against placebo in people with MCI. At six months, moderate-certainty evidence suggests that ginkgo probably has little to no effect on global clinical status measured on the Clinical Dementia Rating Scale (MD -0.03, 95% CI -0.06 to 0.01; 3 studies, 631 participants; I² = 0%), cognition measured on the Alzheimer's Disease Assessment Scale - cognition (MD -0.07, 95% CI -0.67 to 0.51; I² = 0%; 2 studies, 508 participants), and ADLs measured on the Instrumental ADL scale (MD -0.05, 95% CI -0.29 to 0.19; 1 study, 350 participants). There may be little or no difference between ginkgo and placebo at up to 12 months in the risk of AEs (RR 0.98, 95% CI 0.77 to 1.24; I² = 58%; 7 studies, 991 participants, 379 events; low-certainty evidence), and there is little or no difference in the risk of SAEs (RR 0.95, 95% CI 0.82 to 1.09; I² = 0%; 3 studies, 714 participants, 327 events; high-certainty evidence). Dementia Thirteen studies (3288 participants) compared ginkgo with placebo for dementia. At six months, low-certainty evidence suggests that people taking ginkgo may have better global clinical status on a six-point Likert scale (lower is better; MD -0.06, 95% CI -1.00 to -0.20; I² = 88%; 5 studies, 1359 participants), better cognition measured by decreases on a short cognitive performance test (Syndrom-Kurztest; MD -1.86, 95% CI -3.48 to -0.24; I² = 96%; 9 studies, 2801 participants), and slightly better ADLs measured on the ADL International Scale (MD -0.19, 95% CI -0.35 to -0.03; I² = 91%; 8 studies, 2571 participants). There is probably little or no difference between ginkgo and placebo in the risk of AEs at up to 12 months (RR 0.95, 95% CI 0.90 to 1.00; I² = 0%; 9 studies, 2746 participants, 1480 events; moderate-certainty evidence). There may be little or no difference in risk of SAEs at six months (RR 0.88, 95% CI 0.58 to 1.33; I² = 0%; 6 studies, 2463 participants, 89 events; low-certainty evidence).

AUTHORS' CONCLUSIONS: In people with cognitive complaints, we are unsure whether ginkgo improves global clinical status at six months, and it may be associated with an increased risk of AEs at three months. Ginkgo probably has no benefit at three months for cognition in multiple sclerosis; numeric data on AEs were unavailable, but studies did not suggest concerns. In people with MCI, ginkgo probably has little or no effect at six months on global status, cognition, or ADLS. There may be little or no difference in AEs, and there is little or no difference in SAEs, at up to 12 months. In people with dementia, there may be small to moderate benefits at six months for global status, cognition, and ADLs. There is probably little or no difference in AEs at up to 12 months, and there may be no difference in SAEs.}, } @article {pmid41641965, year = {2026}, author = {Brenowitz, WD and Ehrlich, JR and Deal, JA and Yaffe, K}, title = {Introduction to Supplement Issue: Sensory loss in Alzheimer's disease and related dementias.}, journal = {Journal of Alzheimer's disease : JAD}, volume = {110}, number = {1_suppl}, pages = {S3-S5}, pmid = {41641965}, issn = {1875-8908}, support = {R61 AG089063/AG/NIA NIH HHS/United States ; }, mesh = {Humans ; *Alzheimer Disease/complications ; *Dementia/complications ; *Sensation Disorders/etiology ; }, abstract = {Sensory impairments (e.g., decreased function in hearing, vision, olfaction, and other senses) may be risk factors for or early markers of Alzheimer's disease (AD) and related dementias (ADRD). Sensory impairments are common and have a large impact on wellbeing. Furthermore, they are clinically detectable and, often, treatable, and could be leveraged to identify and prevent AD/ADRD. This Supplement Issue brings together original research articles, reviews, and thought papers regarding the links between sensory impairments and cognitive health. Together, this work highlights the significant opportunities to use sensory information and remediation for earlier diagnosis, treatment, and prevention of dementia.}, } @article {pmid41642425, year = {2026}, author = {Li, Z and Wang, X and Li, M and Zhang, G and Zhang, Y and Wang, X and Zhang, C}, title = {Exploring the relationship between Alzheimer's disease and colorectal/breast cancers using SEER database, Mendelian randomization, and transcriptomic data.}, journal = {Discover oncology}, volume = {17}, number = {1}, pages = {}, pmid = {41642425}, issn = {2730-6011}, support = {2024JH2/102600293//Liaoning province livelihood science and technology joint plan/ ; }, abstract = {BACKGROUND: Alzheimer's disease (AD) and cancer are among the most prevalent age-related diseases. Despite previous research into their potential relationship, the nature of their association remains poorly understood. This study aims to examine the clinical characteristics of AD and various cancers using data from the Surveillance, Epidemiology, and End Results (SEER) database, investigate the causal relationship between AD and cancers through Mendelian randomization (MR) analysis, and identify potential shared underlying mechanisms through transcriptomic profiling.

METHODS: Clinical data from AD patients were retrieved from the Surveillance, Epidemiology, and End Results (SEER) database, and survival analysis was conducted using Kaplan-Meier curves. For the two-sample Mendelian randomization (MR) analysis, data were obtained from genome-wide association study (GWAS) databases. Multiple MR approaches, including inverse-variance weighted, MR-Egger, and weighted median methods, were applied, along with assessments of heterogeneity and sensitivity to ensure the robustness and reliability of the results. Transcriptomic data for AD, colorectal cancer (CRC), and breast cancer (BC) were downloaded from the Gene Expression Omnibus (GEO) database. Differentially expressed genes (DEGs) were identified through differential expression analysis, followed by functional enrichment analysis using Gene Ontology (GO) and the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis.

RESULTS: A total of 42,768 cancer patients who died from AD were included from the SEER database. Survival analysis revealed a more favorable prognosis (p < 0.01) in patients younger than 65 years. Asian or Pacific Islander patients exhibited better survival outcomes compared with White patients. Regarding tumor sites, patients with uterine corpus cancer had the best prognosis, while lung cancer patients had the poorest outcomes. Patients who received surgery, radiotherapy, or chemotherapy showed significantly improved survival compared to those who received no cancer treatment. Higher household income and being married were also associated with better prognosis, although no significant difference was observed by gender. MR analysis demonstrated a significant positive causal relationship between AD and CRC, and a weak inverse relationship between AD and BC, suggesting that increased genetic susceptibility to AD is associated with elevated CRC risk and reduced BC risk. Intersection analysis of DEGs revealed that shared DEGs between AD and BC were enriched in GO terms related to amino acid transport regulation, organic acid transport regulation, positive regulation of vesicle docking, and myo-inositol transmembrane import. Shared DEGs between AD and CRC were enriched in presynaptic actin cytoskeleton organization, proteasome ubiquitin-independent protein catabolic process, negative regulation of cellular amide metabolic process, and adenylate cyclase binding. KEGG enrichment analysis indicated that AD and BC may share the synaptic vesicle cycle pathway.

CONCLUSION: Our study reveals significant subgroup heterogeneity among cancer patients who died from AD. MR analysis demonstrates that AD increases the risk of CRC while showing weak evidence for a decreased risk of BC. These associations may be mediated by mechanisms involving amino acid transport regulation, myo-inositol transmembrane import, and synaptic vesicle cycling. These findings offer new perspectives on the AD-cancer relationship and may guide future investigations into shared mechanisms.}, } @article {pmid41642483, year = {2026}, author = {Alhajeri, MM and Abukhaled, Y and Alkhanjari, RR and Bassiouni, W and Al-Ali, H and Baig, A and Sembaij, SH and Al Muhairi, FA and Dimassi, Z and Hamdan, H and Abd-Elrahman, KS}, title = {Neuroglial Function and Hormonal Modulation in Neurodegenerative Diseases: The Influence of Sex Hormones.}, journal = {Cellular and molecular neurobiology}, volume = {46}, number = {1}, pages = {43}, pmid = {41642483}, issn = {1573-6830}, mesh = {Humans ; *Neurodegenerative Diseases/metabolism/pathology ; Animals ; *Neuroglia/metabolism/pathology ; *Gonadal Steroid Hormones/metabolism ; }, abstract = {Astrocytes, microglia, and oligodendrocytes, key neuroglial cell types, are essential for central nervous system (CNS) homeostasis, immune regulation, and neuronal support. In neurodegenerative diseases such as Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), and amyotrophic lateral sclerosis (ALS), glial dysfunction contributes to pathogenesis via chronic inflammation, synaptic disruption, oxidative stress, and impaired myelination. Growing evidence highlights the regulatory influence of sex hormones on glial function. These hormones modulate inflammatory tone, synaptic remodeling, and remyelination, potentially contributing to sex-based differences in disease incidence, progression, and treatment response. This review synthesizes current understanding of glial involvement in neurodegeneration and examines how gonadal hormones interact with astrocytes, microglia, and oligodendrocytes. By integrating glial biology with neuroendocrinology, we propose that hormone-glia interactions represent promising, personalized targets for sex-informed therapies in CNS disorders.}, } @article {pmid41642798, year = {2026}, author = {Justo-Henriques, SI and Silva, RCG and Carvalho, JO and Pérez-Sáez, E and de São João, RMV and Ribeiro, O}, title = {Differential response to cognitive stimulation in moderate versus moderately severe Alzheimer's disease.}, journal = {Canadian journal of experimental psychology = Revue canadienne de psychologie experimentale}, volume = {80}, number = {2}, pages = {143-157}, doi = {10.1037/cep0000395}, pmid = {41642798}, issn = {1878-7290}, mesh = {Humans ; *Alzheimer Disease/therapy/rehabilitation/physiopathology/complications ; Female ; Male ; Aged ; Severity of Illness Index ; Aged, 80 and over ; Cognitive Training ; Treatment Effect Heterogeneity ; *Executive Function/physiology ; Cognitive Enhancement ; }, abstract = {Alzheimer's disease (AD) is characterized by impairments across several neurocognitive domains, particularly memory and executive function. The study explored the effectiveness of an individual cognitive stimulation (iCS) program on cognitive outcomes in older adults with moderate to moderately severe AD. A multicentre randomized controlled trial was conducted with 80 Portuguese older adults (Mage: 83.0 ± 7.1 years) with AD. Participants were randomly assigned to either iCS (n = 39; 49%) or treatment as usual (n = 41; 51%). Alzheimer's Disease Severity (ADS) categorized two groups based on Mini-Mental State Examination score: 10-14 in the ADS moderately severe group and 15-20 in the ADS moderate group. In participants with moderate AD, iCS led to significant improvements in memory-related outcomes (particularly Memory Assessment Test) and a trend toward improvement in global cognition. In contrast, no significant effects were observed in participants with moderately severe AD. Meta-analytic comparisons and meta-regression confirmed a significant difference in intervention effectiveness between severity levels. iCS was significantly more effective in individuals with moderate AD than in those with moderately severe AD. This difference in responsiveness between severity levels was statistically confirmed (Q = 11.29, p < .001). iCS was effective in enhancing memory in individuals with moderate AD, with additional indications of global cognitive benefit. However, no meaningful effects were observed in participants with moderately severe impairment, suggesting diminished responsiveness to iCS as disease severity increases. (PsycInfo Database Record (c) 2026 APA, all rights reserved).}, } @article {pmid41643605, year = {2026}, author = {Kim, WS and Choi, J and Kim, SS and Kim, JH and Han, YE and Kwak, MJ and Oh, SJ and Lee, B and Cho, IH and Choi, CW and Hong, GS and Kim, MS}, title = {Vitisin B, extracted from Vitis vinifera, enhances memory function and neuroprotective effects in scopolamine-induced memory-impaired mice.}, journal = {Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie}, volume = {196}, number = {}, pages = {119019}, doi = {10.1016/j.biopha.2026.119019}, pmid = {41643605}, issn = {1950-6007}, mesh = {Animals ; Scopolamine ; *Vitis/chemistry ; *Neuroprotective Agents/pharmacology/therapeutic use/isolation & purification ; *Memory Disorders/drug therapy/chemically induced ; Humans ; Male ; Mice ; *Memory/drug effects ; Alzheimer Disease/drug therapy ; Cell Line, Tumor ; Maze Learning/drug effects ; *Benzofurans/pharmacology/isolation & purification ; Hippocampus/drug effects/metabolism ; Cell Survival/drug effects ; Disease Models, Animal ; Brain-Derived Neurotrophic Factor/metabolism ; Neuronal Plasticity/drug effects ; Plant Extracts/pharmacology ; }, abstract = {Alzheimer's disease (AD) is characterized by progressive cognitive decline and memory dysfunction, with prominent roles in cholinergic deficits and synaptic plasticity impairments. Vitisin B, a resveratrol tetramer derived from Vitis vinifera, exhibits potent antioxidant and neuroprotective properties. However, its potential to influence cognitive function in AD models remains inadequately explored. In this study, we first tested vitisin B in an in vitro model using SH-SY5Y cells exposed to scopolamine-induced cytotoxicity, where vitisin B significantly enhanced cell viability and promoted cell survival. We evaluated its therapeutic potential in vivo using both systemic administration and direct delivery into the third ventricle of the brain in a scopolamine-induced AD mouse model. Across both administration routes, vitisin B exerted a broad pro-cognitive effect, restoring multiple domains of learning and memory disrupted by scopolamine. Vitisin B recovered spatial working memory in the Y-maze, normalized exploratory activity in the open field, improved recognition memory in the novel object recognition (NOR) test, and enhanced long-term memory retention in the passive avoidance assay. This treatment restored cognitive function, alleviated cholinergic deficits, increased hippocampal brain-derived neurotrophic factor (BDNF) levels, and enhanced synaptic plasticity. These results suggest that vitisin B exerts reliable cognitive and neuroprotective effects through both systemic and cerebral administration, highlighting its potential as a promising therapeutic compound for restoring cholinergic function and enhancing hippocampal synaptic plasticity in AD.}, } @article {pmid41645328, year = {2026}, author = {Xiao, J and Liu, Y and Peng, M and Ma, J and Lei, S and Chen, Y and Liu, S and Zhao, X and Lu, D and Sun, Q}, title = {ISX9 activates the Wnt/β-catenin signaling pathway and exerts neuroprotective effects in Alzheimer's disease.}, journal = {Alzheimer's research & therapy}, volume = {18}, number = {1}, pages = {}, pmid = {41645328}, issn = {1758-9193}, support = {82470591//National Natural Science Foundation of China/ ; 82273485//National Natural Science Foundation of China/ ; JCYJ20240813142838050//Shenzhen Basic Research Program/ ; 2022A1515010598 and 2024A1515012466//Natural Science Foundation of Guangdong Province/ ; }, mesh = {Animals ; *Alzheimer Disease/drug therapy/metabolism/pathology ; Mice, Transgenic ; *Wnt Signaling Pathway/drug effects ; *Neuroprotective Agents/pharmacology/therapeutic use ; Mice ; Hippocampus/drug effects/metabolism ; Disease Models, Animal ; beta Catenin/metabolism ; Humans ; Neurons/drug effects/metabolism ; Male ; Amyloid beta-Peptides/metabolism ; *Heterocyclic Compounds, 3-Ring/pharmacology ; }, abstract = {BACKGROUND: Defective Wnt/β-catenin signaling is closely associated with the pathogenesis of Alzheimer's disease (AD), thus validating this pathway as a therapeutic target for AD. ISX9 is a potent agonist of the Wnt/β-catenin pathway. However, it remains unknown whether ISX9 exerts anti-AD effects by enhancing the Wnt/β-catenin signaling pathway. We therefore explored the neuroprotective potential of ISX9 using both hippocampal neuron-derived HT22 cells and 5×FAD transgenic mouse model of AD.

METHODS: In HT22 cells, we employed the SuperTOPFlash reporter gene, Co-IP and Western blot assays to investigate the mechanism by which ISX9 activates the Wnt signaling pathway. The effects of ISX9 on the biological behavior of HT22 cells were further evaluated through MTT, BrdU and IF staining. To study the therapeutic effect of ISX9 on AD, six-month-old 5×FAD transgenic mice were randomly divided into four groups: WT, WT/ISX9, AD and AD/ISX9. The mice were intraperitoneally injected with ISX9 or vehicle at an interval of one day for 2 months. Behavioral tests were conducted to evaluate the cognitive and learning abilities of mice, while the expression levels of Aβ peptides, Tau-related proteins, neuroinflammatory factors, blood-brain barrier (BBB)-related proteins and the components of Wnt/β-catenin signaling were investigated.

RESULTS: Our results demonstrated that ISX9 potently activated Wnt/β-catenin signaling by promoting the association of LRP6 with AXIN1, and increased the viability and proliferation of hippocampal cells. At the behavioral level, ISX9 improved learning and memory abilities in 5×FAD mice, and ameliorated hippocampal neuronal damage. Furthermore, ISX9 treatment effectively reduced the expression of Aβ peptides, total Tau, and phosphorylated Tau (S404) proteins in the AD mice. Mechanistically, ISX9 exhibited its neuroprotective effects, activating the Wnt/β-catenin signaling pathway via potentiating the interaction of LRP6 with AXIN1, upregulating the expression of BBB-related proteins and downregulating neuroinflammatory factors in AD mice.

CONCLUSION: Our findings indicate that ISX9 potently activates the Wnt/β-catenin signaling pathway and confers cognitive protection in hippocampal cells and AD mice. This compound may serve as a promising therapeutic agent for the treatment of AD.}, } @article {pmid41645578, year = {2026}, author = {İlhan, A and Güneş, F and Ertürk, A and Anıl, B and Gülçin, İ and Koca, M}, title = {Acetylcholinesterase and Carbonic Anhydrase Inhibition Profiles of New 5-HMF Chalcones and Their Ester Derivatives.}, journal = {Archiv der Pharmazie}, volume = {359}, number = {2}, pages = {e70198}, doi = {10.1002/ardp.70198}, pmid = {41645578}, issn = {1521-4184}, support = {TBTK-0097-8209//Türkiye Bilimsel ve Teknolojik Araştırma Kurumu/ ; }, mesh = {*Cholinesterase Inhibitors/pharmacology/chemical synthesis/chemistry ; *Carbonic Anhydrase Inhibitors/pharmacology/chemical synthesis/chemistry ; *Acetylcholinesterase/metabolism/drug effects ; Molecular Docking Simulation ; Structure-Activity Relationship ; *Chalcones/pharmacology/chemical synthesis/chemistry ; Carbonic Anhydrase I/antagonists & inhibitors/metabolism ; Carbonic Anhydrase II/antagonists & inhibitors/metabolism ; Molecular Structure ; Esters/pharmacology/chemistry/chemical synthesis ; Humans ; Animals ; }, abstract = {Acetylcholinesterase (AChE) is one of the most important therapeutic targets in the treatment of neurological disorders such as Alzheimer's disease. In recent years, studies on the use of carbonic anhydrase (CA) inhibitors in the treatment of Alzheimer's disease have attracted considerable attention. In this study, novel benzene/5-HMF-chalcone hybrids and their benzoate esters were synthesized. Furthermore, the AChE, carbonic anhydrases I and II (CA I and II) inhibition potentials of the compounds were evaluated through in vitro enzyme inhibition assays and molecular docking studies to identify new potential drug candidate molecules. According to the inhibition results, the Ki values of the synthesized compounds were found to be in the range of 1.51-2.91 nM against AChE, 26.15-68.66 nM against CA I, and 27.91-107.04 nM against CA II. Molecular docking studies revealed that the compounds bind to both the catalytic active site (CAS) and the peripheral anionic site (PAS) of AChE, with Glide scores ranging from -5.76 to -8.50 kcal/mol. In contrast, the molecules interacted with the active site of CA I/II by coordinating with the catalytic Zn[2+] ion. All compounds complied with Lipinski's Rule of Five, indicating favorable drug-like properties. These results suggest that 5-HMF-chalcone hybrids and their benzoate derivatives could serve as promising scaffolds for the development of new anti-Alzheimer's agents. These findings suggest that 5-HMF-chalcone hybrids and their benzoate derivatives may be useful in establishing the structural basis of new anti-Alzheimer's agents.}, } @article {pmid41645728, year = {2026}, author = {Lodhi, MS and Maisam, M and Khan, MT and Bibi, A and Wei, D and Mou, K}, title = {Targeted Nanodelivery of WGX50 and Curcumin via Gold Nanoparticles for Alzheimer's Therapy.}, journal = {Journal of cellular and molecular medicine}, volume = {30}, number = {3}, pages = {e71045}, pmid = {41645728}, issn = {1582-4934}, mesh = {*Curcumin/chemistry/pharmacology/administration & dosage ; Animals ; *Alzheimer Disease/drug therapy/pathology/metabolism ; *Gold/chemistry ; *Metal Nanoparticles/chemistry ; Rats ; MicroRNAs/genetics ; Humans ; Male ; Disease Models, Animal ; Drug Delivery Systems ; Amyloid beta-Peptides/metabolism ; }, abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder, posing a global health challenge. It affects millions of people, causing cognitive decline and a heavy burden on healthcare systems. Neuroinflammation is a key pathological feature of AD, often associated with the dysregulation of microRNAs such as hsa-miR-146a-5p. WGX50 (N-[2-(3,4-Dimethoxy-phenyl)-ethyl]-3-phenyl-acrylamide), a small molecule derived from Zanthoxylum bungeanum Maxim, has antioxidant and anti-inflammatory activities. While WGX50 demonstrates potent inhibition of neuroinflammation, its poor blood-brain barrier permeability may be improved using targeted delivery strategies. The current study aimed to design a novel nanoconjugate of WGX50 and curcumin with gold nanoparticles (AuNPs) to observe its therapeutic effects in a rat model. All nanoconjugates were synthesised as targeted (Cys-capped AuNPs with WGX50-insulin and curcumin-insulin) and non-targeted (without insulin). Immunohistochemical analysis revealed that both non-targeted (WGX50-NT) and targeted (WGX50-T) therapies have a significant effect in the rat model, with WGX50-T showing a more pronounced effect. The histopathology results of WGX50 and WGX50-T showed an approximate 80%-90% reduction in Aβ plaque deposition. The treatment with both curcumins targeted (C-T) and non-targeted (C-NT) formulations led to a significant reduction in Aβ levels in AD rats. Fluorescence microscopy confirmed that targeted delivery was more effective, potentially leading to better therapeutic outcomes. The expression levels of hsa-miR-146a-5p showed differential expression levels with targeted treatments correlating with lower expression levels, suggesting a role in modulating neuroinflammation and immune responses. Overall, these findings highlight the potential of targeted drug delivery systems in enhancing the efficacy of AD treatments.}, } @article {pmid41645766, year = {2026}, author = {Li, W and Guo, Y and Wang, X and Yang, C and Zhu, J and Cao, Z}, title = {Design, synthesis and biological evaluation of donepezil-safinamide hybrids as dual AChE and MAO-B inhibitor for Alzheimer's disease treatment.}, journal = {Journal of enzyme inhibition and medicinal chemistry}, volume = {41}, number = {1}, pages = {2622769}, pmid = {41645766}, issn = {1475-6374}, mesh = {*Alzheimer Disease/drug therapy ; Drug Design ; *Donepezil/chemistry/pharmacology ; *Benzylamines/chemistry/pharmacology ; Alanine/analogs & derivatives/pharmacology/analogs & derivatives ; *Monoamine Oxidase Inhibitors/chemistry/pharmacology ; *Cholinesterase Inhibitors/chemistry/pharmacology ; Molecular Dynamics Simulation ; Molecular Docking Simulation ; Animals ; Mice ; Blood-Brain Barrier ; Molecular Structure ; Structure-Activity Relationship ; Male ; Mice, Inbred C57BL ; Humans ; }, abstract = {Alzheimer's disease (AD) still lacks therapies that definitively halt its progression. Dual AChE/MAO-B inhibitors offer a promising strategy to address both symptoms and pathology. Here, we designed and synthesised a series of donepezil-safinamide hybrids. The optimised compound 28c was identified as a potent inhibitor of AChE (IC50 = 1.70 μM) and MAO-B (IC50 = 0.18 μM). Mechanistic studies indicated that 28c acts as a reversible mixed-type inhibitor of AChE and a competitive reversible inhibitor of MAO-B. Molecular docking and molecular dynamic simulations revealed that 28c could strongly and stably bind to MAO-B and AChE mainly through van der Waals interactions. Moreover, compound 28c demonstrated effective blood-brain barrier penetration, exhibited suitable stability in mouse plasma and brain homogenate, and showed a favourable safety profile both in vitro and in vivo. Furthermore, 28c could attenuate AD-related symptoms and exert hippocampal neuroprotection effect in vivo, highlighting its promise as an anti-AD candidate.}, } @article {pmid41645816, year = {2026}, author = {Liu, W and Rao, X and Sun, W and Chen, X and Yu, L and Zhang, J}, title = {Radiofrequency electromagnetic fields in Alzheimer's therapy: emerging evidence and future prospects.}, journal = {Electromagnetic biology and medicine}, volume = {}, number = {}, pages = {1-18}, doi = {10.1080/15368378.2026.2627962}, pmid = {41645816}, issn = {1536-8386}, abstract = {Alzheimer's disease (AD) is a neurodegenerative disorder and the most common cause of dementia in humans. The accumulation of abnormal protein aggregates, including extracellular amyloid plaques and intracellular neurofibrillary tangles, is considered a key pathological hallmark of AD. Currently, the primary approach for treating AD is pharmacological treatment, which is only symptomatic and unable to cure or reverse the progression of AD. Increasing evidence suggests that radiofrequency electromagnetic fields (RF-EMFs) may attenuate the progression of AD and improve memory function. This article reviews the studies related to the application of RF-EMFs in the field of AD, including investigations at the cellular and molecular levels, in animal models, and in clinical applications. The therapeutic potential of RF-EMFs as an intervention for AD is discussed in the present review, along with current challenges and future research directions.}, } @article {pmid41648171, year = {2026}, author = {Kumar, V and Franco, VMS and Ferry, FS and Xie, Y and Hutson, AN and Zhang, YJ and Daniels, SD and Nguyen, DL and Spera, LK and Snyder, EM and Knauss, A and Sudhakar, SL and Duan, GY and Paul, EM and Tabuchi, M}, title = {Neuronal microscale biophysical instability mediates macroscale network dynamics shaping pathological manifestations.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {41648171}, issn = {2692-8205}, support = {R00 NS101065/NS/NINDS NIH HHS/United States ; R35 GM142490/GM/NIGMS NIH HHS/United States ; }, abstract = {UNLABELLED: Subtle changes in membrane excitability may contribute to neurological disease, but disease-relevant dynamical signatures that generalize across models remain poorly defined. Here, we quantified variability in action potential initiation in Drosophila neurons expressing tauopathy- or epilepsy-associated mutations and in human iPSC-derived neurons from patients with Alzheimer's disease or epilepsy. Across these models, disease-associated neurons exhibited increased instability in spike timing relative to controls. In Drosophila neurons, this phenotype was accompanied by increased variability in voltage-gated sodium currents during non-stationary inactivation, identifying a candidate biophysical contributor to altered spike initiation. Antiepileptic drugs reduced sodium-current variability and stabilized spike initiation in fly neurons, and similarly improved spike-timing instability in patient-derived human neurons. In the fly models, neuronal instability was also associated with altered circuit- and brain-state readouts. Together, these findings identify unstable spike initiation as a conserved electrophysiological phenotype across distinct neurological disease models and suggest that sodium-channel-dependent variability may contribute to this phenotype. Rather than establishing a complete multiscale causal framework, our study defines a tractable cellular and dynamical entry point for investigating how subtle perturbations in intrinsic excitability may scale toward circuit dysfunction and disease-relevant phenotypes.

SIGNIFICANCE STATEMENT: Linking microscale neuronal changes to macroscale disease phenotypes remains a key challenge in neuroscience biophysics. Here, we show that neurons from Drosophila models of tauopathy and epilepsy and human iPSC-derived neurons from patients with Alzheimer's disease and epilepsy share increased biophysical instability in their local neural activities. In fly neurons, this phenotype is associated with increased variability in voltage-gated sodium currents and is reduced by antiepileptic treatment. These findings define unstable local spike variability as a conserved dynamical signature across distinct disease models and nominate sodium-current variability as a mechanistically testable, pharmacologically reversible contributor to pathological excitability.}, } @article {pmid41648425, year = {2026}, author = {Nada, H and Yuan, S and Gaamouch, FE and Cho, S and Gabr, MT}, title = {Small Molecule Agonists of TREM2 Reprogram Microglia and Protect Synapses in Human Alzheimer's Models.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, doi = {10.64898/2026.01.19.700278}, pmid = {41648425}, issn = {2692-8205}, abstract = {Triggering receptor expressed on myeloid cells-2 (TREM2) is a key immune receptor in the central nervous system that regulates microglial phagocytosis, survival, and neuroinflammatory responses. TRME2 variants have been established as genetic risk factors for Alzheimer's disease (AD). However, the therapeutic development of TREM2 modulators has been limited to antibody-based approaches that face limitations in blood-brain barrier penetration and manufacturing scalability. Furthermore, there are no FDA approved TREM2 therapeutics available to date marking an unmet therapeutic gap. Herein, we report the identification of the first TREM2 small molecule submicromolar binders as a result of optimizing compound 4a to yield S9 with TREM2 binding affinity of 0.95 µM. S9 demonstrated robust TREM2 agonism in cellular assays where it induced proximal Syk phosphorylation, activated downstream NFAT transcriptional signaling, enhanced APOE internalization and microglial phagocytic capacity. Pharmacokinetic profiling of the optimized hits revealed S9 to exhibit improved drug-likeness compared to 4a with 7-fold enhanced aqueous solubility, superior metabolic stability, reduced intrinsic clearance and a 9-fold improved hERG safety margin. Functional validation in human iPSC-derived microglia confirmed that S9 suppresses amyloid-beta (Aβ)-induced IL-1β secretion through a TREM2-dependent mechanism. In human neuron-microglia co-culture models exposed to amyloid stress, S9 treatment preserved synaptic integrity as measured by PSD95 expression that indicates promising neuroprotective activity. Together, these findings establish S9 as a first-TREM2 submicromolar small molecule TREM2 agonist which is orally bioavailable with favorable pharmacokinetic properties and promising therapeutic potential for the treatment of Alzheimer's disease.}, } @article {pmid41650025, year = {2026}, author = {Hou, XH and Zhang, W and Kang, K and Jin, Y and Ren, P and Wang, L and Li, Z and Li, Y and You, J and Zhang, B and Ma, Q and , and Xie, F and Yu, JT and Feng, JF and Cheng, W}, title = {Proteomics reveals three molecular subtypes of Alzheimer's disease with distinct progression patterns.}, journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association}, volume = {22}, number = {2}, pages = {e71106}, pmid = {41650025}, issn = {1552-5279}, support = {2023YFC3605400//National Key R&D Program of China/ ; 2018YFC1312904//National Key R&D Program of China/ ; 2019YFA0709502//National Key R&D Program of China/ ; 2025ZD0546300//Noncommunicable Chronic Diseases-National Science and Technology Major Project/ ; 82472055//National Natural Science Foundation of China/ ; 62433008//National Natural Science Foundation of China/ ; 82071201//National Natural Science Foundation of China/ ; 81971032//National Natural Science Foundation of China/ ; 92249305//National Natural Science Foundation of China/ ; 25TQ010//Shanghai Pilot Program for Basic Research-Fudan University 21TQ1400100/ ; 23JS1410100//Shanghai Science and Technology Commission Program/ ; 2022ZD0211600//Science and Technology Innovation 2030 Major Projects/ ; 2022QD002//Research Start-Up Fund of Huashan Hospital/ ; 3030277001//Excellence 2025 Talent Cultivation Program at Fudan University/ ; 2019074//Shanghai Talent Development Funding for the Project/ ; 2018SHZDZX01//Shanghai Municipal Science and Technology Major Project/ ; B18015//111 Project/ ; }, mesh = {Humans ; *Alzheimer Disease/classification/cerebrospinal fluid/pathology ; Disease Progression ; *Proteomics ; Female ; Male ; Aged ; tau Proteins/cerebrospinal fluid ; Biomarkers/cerebrospinal fluid ; Longitudinal Studies ; Atrophy ; }, abstract = {INTRODUCTION: Alzheimer's disease (AD) shows marked molecular heterogeneity. Defining biological subtypes may refine diagnosis and treatment.

METHODS: We analyzed cerebrospinal fluid (CSF) proteomics and longitudinal data from 550 participants in the Alzheimer's Disease Neuroimaging Initiative with up to 16.5 years of follow-up. We profiled 6361 proteins, applied machine learning to identify biological subtypes, and validated them in three independent cohorts.

RESULTS: Three AD subtypes were identified. Subtype 1, enriched in RNA metabolism pathways, showed the mildest atrophy and slowest cognitive decline. Subtype 2, characterized by axonogenesis-related pathways, exhibited the greatest CSF tau elevations, moderate atrophy, and intermediate decline. Subtype 3, associated with catabolic processes, showed the most severe atrophy and fastest progression. These patterns were consistently replicated across validation cohorts.

DISCUSSION: These findings demonstrate robust, biologically distinct AD subtypes linked to divergent molecular pathways, clinical features, and progression rates. Such refined stratification supports precision diagnostics and targeted therapeutic strategies.}, } @article {pmid41651301, year = {2026}, author = {Zeying, W and Houyu, L and Zhongbin, Y and Yu, T and Qi, H and Kun, H and Qihang, H and Yingnan, Z and Zhi, L and Xiaojing, L and Xueming, Z and Qiang, M and Jingye, Z and Caixia, S and Liran, H and Jing, J and Yan, S}, title = {D-ribose-induced cytotoxicity in K562 cells: RBKS-dependent disruption of copper homeostasis and mitochondrial function.}, journal = {Free radical biology & medicine}, volume = {247}, number = {}, pages = {240-250}, doi = {10.1016/j.freeradbiomed.2026.01.062}, pmid = {41651301}, issn = {1873-4596}, mesh = {Humans ; K562 Cells ; *Ribose/pharmacology/metabolism ; *Copper/metabolism ; *Mitochondria/metabolism/drug effects ; Homeostasis ; Cell Proliferation/drug effects ; Oxidative Stress/drug effects ; *Phosphotransferases (Alcohol Group Acceptor)/metabolism/genetics ; Apoptosis ; }, abstract = {BACKGROUND: D-ribose, a highly reducing pentose sugar, can be phosphorylated by ribokinase (RBKS) to form ribose-5-phosphate (R-5-P). Elevated urinary D-ribose levels have been reported in patients with type 2 diabetes mellitus (T2DM) and Alzheimer's disease, implicating its potential role in disease pathogenesis. Previous investigations into D-ribose cytotoxicity have primarily focused on its non-enzymatic glycation activity, while alternative mechanisms remain underexplored. Since hemoglobin is a major in vivo target of glycation, this study utilized K562 cells-which retain inducible hemoglobin expression-to explore additional cytotoxic mechanisms of D-ribose.

METHODS AND RESULTS: CCK-8 assays demonstrated that D-ribose inhibited K562 cell proliferation in a concentration- and time-dependent manner, and this inhibitory effect was significantly enhanced in both hemin-induced differentiated and RBKS knockout K562 cells. Conversely, RBKS overexpression promoted proliferation and alleviated oxidative stress in K562 cells. Transcriptomic analysis revealed that differentially expressed genes in D-ribose-treated cells were enriched in mineral absorption and oxidative phosphorylation pathways (KEGG), as well as in biological processes related to copper ion homeostasis (GO). RT-qPCR confirmed that both D-ribose treatment and RBKS knockout downregulated key copper homeostasis genes (e.g., SLC31A1, MT1F, ATOX1) and mitochondrial respiratory chain genes (e.g., COX17, COX11, MTATP8, MTND6), and were accompanied by a significant reduction in intracellular free copper levels.

CONCLUSIONS: These findings reveal a novel cytotoxic mechanism mediated by the RBKS-copper-oxidative phosphorylation axis in D-ribose-treated K562 cells, providing key insights into the intracellular role of D-ribose.}, } @article {pmid41651379, year = {2026}, author = {Huang, X and Sun, YY and Qin, YR and Chen, H and Pan, TT and Zhao, SS and Cai, Q and Zhang, XS and Nie, XD and Feng, L and Hu, H and Tang, Y and Zhang, PZ and Zhong, ZY and Li, J and Lu, L and Meng, FH and Ma, QH}, title = {ApoE-directed CpG nano-immunoadjuvant ameliorates Alzheimer's-like pathology in mice.}, journal = {Journal of controlled release : official journal of the Controlled Release Society}, volume = {392}, number = {}, pages = {114687}, doi = {10.1016/j.jconrel.2026.114687}, pmid = {41651379}, issn = {1873-4995}, mesh = {Animals ; *Alzheimer Disease/pathology/drug therapy/metabolism/immunology ; *Oligodeoxyribonucleotides/administration & dosage/therapeutic use/chemistry ; Mice, Transgenic ; Amyloid beta-Peptides/metabolism ; Brain/metabolism/pathology/drug effects ; Toll-Like Receptor 9/agonists/metabolism ; *Apolipoproteins E/immunology ; Microglia/drug effects/metabolism ; *Adjuvants, Immunologic/administration & dosage/therapeutic use ; Humans ; Blood-Brain Barrier/metabolism/drug effects ; Nanoparticles/administration & dosage ; Toll-Like Receptor Agonists ; Mice, Inbred C57BL ; Disease Models, Animal ; Mice ; Male ; Neuroprotective Agents/administration & dosage ; Neurons/drug effects/metabolism ; Presenilin-1/genetics ; }, abstract = {Toll-like receptor 9 (TLR9), expressed in both microglia and neurons of the CNS, represents a promising therapeutic target for Alzheimer's disease (AD). While either microglial or neuronal TLR9 activation exerts neuroprotective effects that ameliorate AD pathology and preserve cognitive function, CpG oligodeoxynucleotides (ODNs), the synthetic agonists, cannot cross the blood-brain barrier (BBB). To overcome this, we developed tNCpG, an apolipoprotein E (ApoE)-functionalized polymersome nanocarrier for brain-targeted delivery of CpG ODNs. APP/PS1 transgenic mice, which overexpress human mutant APP/PS1 and are widely used in AD mouse models for preclinical studies, were administered tNCpG intravenously biweekly for 3 months, starting at 4 months of age. tNCpG achieved efficient brain delivery while specifically targeting microglia and neurons. tNCpG treatment enhanced microglial recruitment to and phagocytosis of Aβ plaques, suppressed Aβ production while promoting its degradation, and improved BBB integrity and Aβ efflux. Collectively, these effects significantly reduced cerebral Aβ burden, neuroinflammation, and neurodegeneration, leading to the rescue of cognitive deficits. Our study establishes targeted TLR9 activation via tNCpG as a disease-modifying therapeutic strategy for AD.}, } @article {pmid41652334, year = {2026}, author = {Allison, GO and McCage, S and Brandt, S and Presciutti, M and Walker, K and Cornelius, T and Parker, RA and Dams-O'Connor, K and Dickerson, B and Ritchie, C and Vranceanu, AM and Bannon, SM}, title = {"We can do this. That I learned.": A nonrandomized open pilot of Resilient Together for Dementia, a post-diagnosis dyadic intervention.}, journal = {BMC geriatrics}, volume = {26}, number = {1}, pages = {}, pmid = {41652334}, issn = {1471-2318}, support = {K23 AG075188/AG/NIA NIH HHS/United States ; 1K23AG075188-01A1/AG/NIA NIH HHS/United States ; 1K24AT011760-01/AT/NCCIH NIH HHS/United States ; R01NR019982-01/NR/NINR NIH HHS/United States ; }, mesh = {Humans ; Pilot Projects ; Female ; Male ; *Dementia/psychology/therapy/diagnosis ; Aged ; Feasibility Studies ; *Resilience, Psychological ; Aged, 80 and over ; Quality of Life/psychology ; *Stress, Psychological/psychology/prevention & control ; }, abstract = {BACKGROUND AND OBJECTIVES: Alzheimer's disease and related dementias (ADRDs) are prevalent conditions that are stressful and elevate emotional distress in couples after diagnosis. Without treatment, emotional distress may become chronic and negatively affect couples' quality of life. We report results from an NIH Stage 1A open pilot of Resilient Together for Dementia (RT-ADRD), a novel, dyadic, skills-based intervention aimed at preventing chronic emotional distress in couples early after diagnosis. We describe results from our mixed-methods single arm feasibility study, including preliminary feasibility and acceptability of the intervention, and qualitative feedback from exit interviews. We also present exploratory analyses for change in outcomes and mechanisms of action.

METHODS: Six couples (N = 12 individuals) were recruited within six months of ADRD diagnosis by their diagnosing providers. Participants completed baseline assessments, participated in weekly RT-ADRD sessions together, then completed post-intervention assessments and one 60-min exit interview together.

RESULTS: RT-ADRD exceeded all a-priori feasibility and acceptability benchmarks (> 70%). Feedback from exit interviews suggested that participants had favorable impressions of the program and found the skills useful and relevant. Participants also offered perspectives on barriers and facilitators of engagement and program enhancement. In exploratory analyses, persons living with dementia exhibited significant reductions in perceived stress at post-intervention (p < .05; Cohens d > 0.8). Both persons living with dementia and their care partners exhibited statistically significant improvements in positive dyadic interactions measured by the Dyadic Relationship Scale (ps < .05); Cohens ds > 0.8).

CONCLUSIONS: RT-ADRD shows promise as a feasible and acceptable dyadic intervention delivered early after diagnosis. Results support a future NIH Stage 1B trial of RT-ADRD to establish definitive feasibility markers of both intervention and control before formal efficacy testing.

TRIAL REGISTRATION: This open pilot was registered on ClinicalTrials.gov (NCT06421545) on 05/20/2024.}, } @article {pmid41652415, year = {2026}, author = {Tang, F and Li, Y and Bai, X and Zhu, Z and Dong, H and Chen, J and Ye, B and Yuan, M and Wu, Q and Fu, W and Zhang, Y and Wang, C}, title = {BMAL1-GPX3 axis in the choroid plexus mitigates Aβ pathology in an amyloid mouse model.}, journal = {Journal of neuroinflammation}, volume = {23}, number = {1}, pages = {}, pmid = {41652415}, issn = {1742-2094}, support = {2024NSCQ-MSX0951//Natural Science Foundation of Chongqing Municipal Bureau of Science and Technology/ ; 2023NSCQ-MSX3605//Natural Science Foundation of Chongqing Municipal Bureau of Science and Technology/ ; KJQN202400476//Scientific and Technological Research Program of Chongqing Municipal Education Commission/ ; KZD-JI202400406//Scientific and Technological Research Program of Chongqing Municipal Education Commission/ ; 82271470//National Natural Science Foundation of China/ ; STI2030-Major Projects 2021ZD0202400//National Key Research and Development Program of China/ ; LG-GG-202401-ADA010100//Lingang Laboratory AD Special Project/ ; }, mesh = {Animals ; *Choroid Plexus/metabolism/pathology ; *ARNTL Transcription Factors/metabolism/genetics ; Mice ; *Amyloid beta-Peptides/metabolism ; *Glutathione Peroxidase/metabolism/genetics ; Mice, Transgenic ; Disease Models, Animal ; *Alzheimer Disease/pathology/metabolism/genetics ; Humans ; Astrocytes/metabolism/pathology ; }, abstract = {Alzheimer’s disease (AD) is the most common neurodegenerative disorder, with circadian rhythm disturbances strongly linked to its pathogenesis. The choroid plexus (ChP) is a circadian-regulated structure in the brain ventricles, but the role of the core clock gene brain and muscle ARNT-like protein 1 (BMAL1) in ChP in relation to AD pathology remains unclear. Here, we report that knockdown of Bmal1 in ChP epithelial cells of 5xFAD mice alleviates amyloid-β (Aβ) pathology, primarily by improving the function of astrocytes and border-associated macrophages (BAMs), with the latter potentially mediated by the upregulation of the secreted protein glutathione peroxidase 3 (GPX3), which reduces lipid peroxidation in BAMs. Collectively, our findings establish the ChP-driven BMAL1-GPX3 axis as a new Aβ clearance mechanism, with GPX3 representing a promising therapeutic target. These findings provide new mechanistic insights into AD and suggest innovative treatment approaches.}, } @article {pmid41653394, year = {2026}, author = {Okuyama, C and Oishi, N and Ishizu, K and Hasegawa, H and Ito, M and Fujita, Y and Kusano, K and Okina, T and Kagawa, S and Watanabe, H and Higashi, T and Yamauchi, H and Ono, M}, title = {A new amyloid PET evaluation method using separated gray-matter histogram based on three-component model.}, journal = {Annals of nuclear medicine}, volume = {40}, number = {5}, pages = {564-574}, pmid = {41653394}, issn = {1864-6433}, support = {KAKENHI (JSPS Grant Number JP21K07635).//Japan Society for the Promotion of Science/ ; }, mesh = {Humans ; *Gray Matter/diagnostic imaging/metabolism ; *Image Processing, Computer-Assisted/methods ; *Amyloid/metabolism ; Male ; Female ; Retrospective Studies ; Aged ; *Positron Emission Tomography Computed Tomography ; Middle Aged ; *Positron-Emission Tomography ; }, abstract = {OBJECTIVE: We have constructed a three-component model underlying amyloid PET accumulation and developed a new gray matter histogram evaluation method based on this model. This study aims to validate the utility of the new method compared with conventional visual and SUVR-based quantitative evaluation. METHODS: A retrospective analysis was performed on amyloid PET/CT data from 63 participants (25 healthy volunteers, 38 patients with dementia or cognitive impairment) of previous study using 18F-FPYBF-2. Subjects were visually classified into three groups: negative, borderline, and positive, and quantitatively evaluated using composed standardized uptake value (comSUVR) with a reference to cerebellar cortex. Histograms were generated for the whole-brain, gray matter (GM-histogram), and white matter (WM-histogram) based on probability-tissue maps. The GM-histogram was further decomposed into two Gaussian components: G1 and G2 using statistical software. Parameters of whole-brain histogram: skewness, mode-to-mean ratio (MMR), and parameters of GM-histogram: GM-kurtosis, µG2 (mean of G2), and πG2 (proportion of G2), were compared among visual groups and the correlation with comSUVR was evaluated. RESULTS: The GM-histogram was sharply unimodal in visually negative group but showed a wide shape to bimodal patterns in visually positive cases. Visually border group showed significantly higher πG2 than negative group, and positive group showed significantly higher µG2 than border group. GM-kurtosis and µG2 showed stronger negative (p < 0.0001, R2 = 0.7539) and positive (p < 0.0001, R2 = 0.8589) correlations with ComSUVR, respectively than the correlations between whole-brain histogram parameters and ComSUVR. CONCLUSION: Our proposed GM-histogram provides a visually comprehensive morphology and quantitative indicators that match conventional visual and SUVR-based assessments and may potentially detect even subtle amyloid accumulation. This method is considered promising as a complementary tool for early diagnosis and treatment monitoring of Alzheimer’s disease.}, } @article {pmid41653511, year = {2026}, author = {Nie, RZ and Luo, HM and Wang, H and Yang, YR and Wang, YZ and Zhang, SZ and Feng, K and Li, YL and Chen, FY and Duan, CX and Chen, JY and Ma, T and Li, PF}, title = {The inhibitory mechanisms of PGG, a natural polyphenol enriched with gallate moieties, against Aβ42 amyloid aggregation: A unified experimental and molecular dynamics simulation study.}, journal = {Bioorganic & medicinal chemistry}, volume = {136}, number = {}, pages = {118584}, doi = {10.1016/j.bmc.2026.118584}, pmid = {41653511}, issn = {1464-3391}, mesh = {*Amyloid beta-Peptides/antagonists & inhibitors/metabolism/chemistry ; *Molecular Dynamics Simulation ; *Peptide Fragments/antagonists & inhibitors/metabolism/chemistry ; *Hydrolyzable Tannins/chemistry/pharmacology ; Humans ; *Polyphenols/chemistry/pharmacology ; *Gallic Acid/chemistry/pharmacology ; Protein Aggregates/drug effects ; Molecular Structure ; Structure-Activity Relationship ; }, abstract = {Alzheimer's disease currently affects over 44 million individuals worldwide. Inhibiting Aβ aggregation and preventing the formation of toxic Aβ oligomers were regarded as promising therapeutic approaches. Experimental studies demonstrated that 1,2,3,4,6-Penta-O-galloyl-β-d-glucopyranose (PGG), a natural polyphenol enriched with gallate moieties, significantly inhibited Aβ42 oligomerization and amyloid formation both in vitro and in vivo, underscoring its potential as a promising lead compound for AD therapy. Nevertheless, the detailed molecular mechanisms remained mostly unknown. Herein, we employed relevant biophysical methods to investigate the inhibitory effects of PGG and its analogs on Aβ42 amyloid aggregation, particularly on oligomer formation, providing direct evidence for the influence of gallate moiety number on its inhibitory activity against Aβ42 amyloid aggregation. Moreover, we further conducted 1500 ns all-atom MD simulations to explore how PGG inhibited Aβ amyloid aggregation. The simulations revealed that PGG promoted the adoption of a more loosely packed conformation of the Aβ42 dimer, and completely prevented the helix-to-β-sheet conformational change. Moreover, the binding of PGG molecules to the Aβ42 dimer resulted in the disruption of the inter-peptide interactions, and dramatically weakened the intra-peptide contacts. We observed that, apart from the usual hydrogen bonds and hydrophobic interactions, both π-π and cation-π interactions were also detected between specific residues of the Aβ42 dimer and the gallate moieties of PGG. We believed that these results might provide novel insights into the mechanisms underlying the inhibitory effects of PGG on Aβ42 amyloid aggregation and further support its potential for AD prevention and treatment.}, } @article {pmid41653883, year = {2026}, author = {Vanderlip, CR and Gillen, DL and Grill, JD and Stark, CEL}, title = {Digital memory assessments and plasma pTau217 enable efficient preclinical Alzheimer's trials.}, journal = {The journal of prevention of Alzheimer's disease}, volume = {13}, number = {4}, pages = {100503}, pmid = {41653883}, issn = {2426-0266}, mesh = {Humans ; *Alzheimer Disease/blood/diagnosis ; Aged ; *tau Proteins/blood ; Female ; Male ; Aged, 80 and over ; Disease Progression ; Biomarkers/blood ; *Memory/physiology ; Prodromal Symptoms ; Neuropsychological Tests ; }, abstract = {BACKGROUND: Preclinical Alzheimer's disease (AD) trials enroll cognitively unimpaired, amyloid-positive older adults; however, most remain clinically stable over typical trial durations. Limited near-term decline reduces statistical power and drives large sample sizes and high costs. Scalable enrichment strategies capable of identifying individuals most likely to decline are critically needed.

OBJECTIVES: To determine whether a brief digital memory assessment (DMA) and plasma phosphorylated tau 217 (pTau217), individually or combined, identify preclinical AD participants at elevated risk for cognitive and biological progression, and whether such enrichment reduces clinical trial sample-size requirements.

DESIGN: Analysis of data from the Anti-Amyloid Treatment in Asymptomatic Alzheimer's Disease (A4) Study, a multicenter randomized clinical trial with 240 weeks of follow-up.

SETTING: Secondary-prevention trial conducted across sites in the United States, Canada, Australia, and Japan.

PARTICIPANTS: A total of 1,169 cognitively unimpaired adults aged 65-85 years who were amyloid-positive and completed both a baseline DMA and plasma pTau217 measurement.

MEASUREMENTS: Primary outcome was change in the Preclinical Alzheimer Cognitive Composite (PACC) over 240 weeks. Secondary outcomes included Clinical Dementia Rating-Sum of Boxes, Mini-Mental State Examination, Cognitive Function Instrument, and annualized change in amyloid PET, plasma pTau217, and tau PET.

RESULTS: Participants with both elevated pTau217 and low DMA exhibited the greatest cognitive decline and reached the 240-week PACC decline of the overall cohort 83 weeks earlier. Participants with neither marker showed minimal decline. Dual enrichment reduced sample-size estimates for a clinical trial from 3,252 to 818 participants per arm (75 % reduction). These individuals also demonstrated faster increases in plasma pTau217 and neocortical tau PET.

CONCLUSIONS: A brief DMA combined with plasma pTau217 identifies a subset of cognitively unimpaired, amyloid-positive older adults at highest risk for cognitive and biomarker progression. This dual-marker enrichment strategy enables smaller, shorter, and more cost-efficient preclinical AD trials and supports more targeted evaluation of preventive therapies.}, } @article {pmid41654149, year = {2026}, author = {Yuan, J and Zhang, S and Han, D and Dong, X}, title = {Agrin at the crossroads of aging: A pleiotropic regulator in age-related diseases.}, journal = {Pharmacological research}, volume = {225}, number = {}, pages = {108131}, doi = {10.1016/j.phrs.2026.108131}, pmid = {41654149}, issn = {1096-1186}, mesh = {Humans ; *Agrin/metabolism ; Animals ; *Aging/metabolism ; Signal Transduction ; }, abstract = {Aging is a significant risk factor for numerous age-related diseases, and elucidating its key molecular mechanisms is crucial for disease prevention and treatment. Agrin, initially identified for its role in neuromuscular junction development, is an extracellular matrix protein. Recent studies have revealed its broad functions in maintaining tissue homeostasis and facilitating cellular signal transduction. During aging, alterations in the expression and function of Agrin may participate in the regulation of tissue repair, inflammatory responses, and intercellular communication, thereby influencing the onset and progression of various age-related diseases. This review systematically examines the central role of Agrin in age-related diseases such as Alzheimer's disease, ischemic stroke, myocardial infarction, osteoarthritis, and type 2 diabetes. Accumulating evidence indicates that Agrin exhibits a distinct ''double-edged sword'' characteristic across different disease stages or tissue contexts-exerting protective effects in some scenarios while promoting pathological progression in others. We summarize current findings on the involvement of Agrin in disease mechanisms, including the regulation of amyloid deposition, blood-brain barrier integrity, synaptic function, inflammatory responses, and tissue repair. Furthermore, we discuss potential Agrin-targeted therapeutic strategies. We propose that Agrin represents a critical molecular node linking aging mechanisms with multiple age-related diseases. A deeper understanding of its context-dependent functional switching and the development of precise targeting approaches hold substantial promise for the prevention and treatment of age-related pathologies.}, } @article {pmid41654915, year = {2026}, author = {Hofling, U and Jakobsson, J and Erngren, I and Ekman, O and Freyhult, E and Sreenivasan, AP and Siljebo, J and Libard, S and Kilander, L and Löwenmark, M and Ingelsson, M and Kultima, K and Virhammar, J}, title = {Targeted CSF metabolomics and conformal prediction improve diagnostic accuracy of normal pressure hydrocephalus.}, journal = {Fluids and barriers of the CNS}, volume = {23}, number = {1}, pages = {}, pmid = {41654915}, issn = {2045-8118}, mesh = {Humans ; *Hydrocephalus, Normal Pressure/cerebrospinal fluid/diagnosis ; *Metabolomics/methods ; Female ; Biomarkers/cerebrospinal fluid ; Male ; Aged ; Alzheimer Disease/cerebrospinal fluid/diagnosis ; Cognitive Dysfunction/cerebrospinal fluid/diagnosis ; Frontotemporal Dementia/cerebrospinal fluid/diagnosis ; Aged, 80 and over ; Machine Learning ; }, abstract = {BACKGROUND AND OBJECTIVES: Idiopathic normal pressure hydrocephalus (iNPH) is a progressive but treatable neurological disorder. Yet, diagnosis is often confounded by overlapping symptoms and biomarker profiles with Alzheimer’s disease (AD), mild cognitive impairment (MCI), and frontotemporal dementia (FTD). We aimed to determine whether cerebrospinal fluid (CSF) metabolomic profiling, combined with uncertainty-aware machine learning using conformal prediction (CP), could improve diagnostic differentiation of iNPH. METHODS: CSF samples were collected from 120 patients with iNPH, 44 healthy controls, and 152 individuals with AD, MCI, or FTD. Targeted metabolomics of 59 metabolites was performed using liquid chromatography–high-resolution mass spectrometry. Group differences were assessed using age- and sex-adjusted regression models. Multivariate classification with partial least squares discriminant analysis (PLS-DA) incorporated metabolites, demographics, and conventional biomarkers (amyloid-β42, tau, phosphorylated tau). CP was applied to address individual-level diagnostic uncertainty. RESULTS: Eight metabolites (proline, threonine, histidine, tyrosine, tryptophan, isobutyrylcarnitine, citric acid, and dehydroascorbic acid) were consistently reduced in iNPH (q < 0.05), independent of ventricular volume and cortical tau or amyloid-β pathology. An integrated PLS-DA model combining metabolomic, demographic, and AD-biomarker data achieved excellent discrimination (AUC = 0.97). CP provided calibrated case-level confidence, identifying clear-cut and uncertain cases while maintaining high accuracy (94% for iNPH, 97% for not-iNPH). DISCUSSION: iNPH exhibits a distinct CSF metabolomic signature reflecting altered amino acid metabolism, mitochondrial function, and oxidative stress. Integrating metabolomic data with established biomarkers enhances diagnostic accuracy, while CP adds individualized uncertainty estimates to improve diagnostic confidence and guide treatment decisions.}, } @article {pmid41654970, year = {2026}, author = {Lu, W and Kawatani, K and Ren, Y and Nambara, T and Jia, L and Jeevaratnam, S and Lee, E and Martinez, PR and Izhar, T and Wang, N and Raulin, AC and Wszolek, ZK and Bu, G and Kanekiyo, T and Li, Y}, title = {CI-994 is a dual modulator of class I HDACs and Wnt/β-catenin signaling for the treatment of Alzheimer's disease.}, journal = {Alzheimer's research & therapy}, volume = {18}, number = {1}, pages = {}, pmid = {41654970}, issn = {1758-9193}, support = {R01 AG078615/AG/NIA NIH HHS/United States ; R21 AG065653/AG/NIA NIH HHS/United States ; R21AG065653, R01AG078615, 24A07//NIH, Florida Department of Health Ed and Ethel Moore Alzheimer's Disease Research Program/ ; }, mesh = {Humans ; *Alzheimer Disease/drug therapy/metabolism ; *Wnt Signaling Pathway/drug effects ; HEK293 Cells ; *Histone Deacetylase Inhibitors/pharmacology/therapeutic use ; *Phenylenediamines/pharmacology/therapeutic use ; *Histone Deacetylases/metabolism ; beta Catenin/metabolism ; Neurons/drug effects/metabolism ; tau Proteins/metabolism ; Induced Pluripotent Stem Cells/drug effects ; Cell Line, Tumor ; Benzamides ; }, abstract = {BACKGROUND: Growing evidence supports that epigenetic dysregulation through histone deacetylases (HDACs) plays a critical role in synaptic dysfunction and memory loss in Alzheimer’s disease (AD), and that HDACs have been highlighted as an attractive class of targets for AD therapy. Moreover, restoring Wnt/β-catenin signaling, which is greatly suppressed in AD brains, is a promising therapeutic strategy. CI-994 is an orally active class I HDAC inhibitor that has undergone several phase II/III clinical trials on cancer treatment. Importantly, CI-994 can cross the blood–brain barrier and is a cognitive enhancer. METHODS: Wnt activity was initially examined by Wnt reporter activity assay in Wnt3A-expression HEK293 cells, and profiling HDAC inhibition was performed against 10 individual HDACs. Activities of CI-994 on class I HDACs and Wnt/β-catenin signaling were further tested in HEK293 cells, LRP6-expressing HT1080 cells and neuronal SH-SY5Y cells. The therapeutic effects of CI-994 were examined in patient-specific iPSC-derived neurons and cerebral organoids carrying APOE ε4/ε4 genotype or MAPT p.P301L mutation. RESULTS: We herein report that CI-994 is not only a potent class I HDAC inhibitor but also an activator of Wnt/β-catenin signaling. Mechanistically, activation of Wnt/β-catenin signaling by CI-994 is associated with stabilizing Wnt co-receptor LRP6 protein and modulating HDAC activity. Importantly, CI-994 significantly increases histone acetylation, activates Wnt/β-catenin signaling, and decreases tau phosphorylation in patient-specific iPSC-derived cerebral organoids carrying APOE ε4/ε4 genotype or MAPT p.P301L mutation. Moreover, studies with the specific Wnt inhibitor LGK974 demonstrate that activation of Wnt/β-catenin signaling contributes to CI-994-induced the inhibition of tau phosphorylation in the iPSC-derived cerebral organoids. Additionally, CI-994 increases synaptic protein levels, enhances spontaneous synaptic firing and network formation and decreases tau phosphorylation in iPSC-derived neurons. Finally, RNA sequencing, combined with RT-qPCR validation, of the iPSC-derived cerebral organoids reveals that CI-994 significantly regulates genes associated with synapse plasticity and cognitive function including NEUROD1, CACNA1G, NRGN, NRTN, SLC7A10 and OMG. CONCLUSION: Our findings suggest that CI-994 can be repurposed as a novel therapeutic agent for AD therapy.}, } @article {pmid41656099, year = {2026}, author = {Ma, YN and Huang, X and Xia, Y and Song, P and Hu, X}, title = {Protein persulfidation: The missing link in Alzheimer's disease defense mechanisms.}, journal = {Drug discoveries & therapeutics}, volume = {20}, number = {1}, pages = {1-6}, doi = {10.5582/ddt.2026.01004}, pmid = {41656099}, issn = {1881-784X}, mesh = {*Alzheimer Disease/metabolism/drug therapy ; Humans ; *Hydrogen Sulfide/metabolism ; Animals ; Signal Transduction ; tau Proteins/metabolism ; Glycogen Synthase Kinase 3 beta/metabolism ; Cystathionine gamma-Lyase/deficiency/metabolism ; Brain/metabolism ; Phosphorylation ; }, abstract = {Despite decades of research dominated by the amyloid-beta hypothesis, clinical treatment of Alzheimer's disease (AD) has yet to achieve a decisive breakthrough. This editorial advances an alternative pathological paradigm: the collapse of endogenous hydrogen sulfide (H2S) signaling represents a central failure point in the brain's intrinsic defense mechanisms against AD. We dissect the molecular cascade triggered by cystathionine γ-lyase (CSE) deficiency, focusing on how reduced persulfidation of glycogen synthase kinase 3β (GSK3β) directly promotes Tau hyperphosphorylation and subsequent neuronal injury. A critical message of this commentary is the need to dispel the oversimplified notion that sulfide supplementation alone can confer neuroprotection. Because H2S works within a narrow therapeutic window and has complex hormetic effects, untargeted dietary or environmental exposure cannot match the spatiotemporal precision of endogenous signaling. Instead, it may increase the risk of toxicity. By integrating analyses of transsulfuration metabolism, mitochondrial function, and nutritional status, we propose a precision medicine framework centered on brain-targeted delivery technologies and metabolic correction strategies to selectively restore compromised H2S signaling networks. This conceptual shift marks a new direction in AD research, shifting the focus from clearing toxic protein aggregates to restoring endogenous neuronal resilience.}, } @article {pmid41657418, year = {2026}, author = {Geiger, PC and Pennington, JS and Kueck, PJ and John, CS and Mayfield, HD and Kemna, RE and Burns, J and Vidoni, E and Honea, R and Li, Y and Mahnken, J and Morris, JK}, title = {Heat therapy in individuals at risk for Alzheimer's disease-methods for a randomized controlled trial.}, journal = {Frontiers in neurology}, volume = {17}, number = {}, pages = {1736108}, pmid = {41657418}, issn = {1664-2295}, support = {R01 AG081304/AG/NIA NIH HHS/United States ; T32 AG078114/AG/NIA NIH HHS/United States ; }, abstract = {UNLABELLED: Heat therapy (HT) has been shown to improve peripheral blood glucose regulation in some populations, yet its effects on brain glucose metabolism remain largely unexplored. The chronic benefits of HT may arise in part from upregulation of heat-shock proteins (HSPs). These proteins play a crucial role in the stress response and modulate diverse processes such as proteostasis and cell signaling pathways, including that of insulin signaling. Understanding the impact of HT on both peripheral and central glucose metabolism, including the effects of varying temperatures, is essential for elucidating potential mechanisms underlying its brain benefits. The Feasibility of Improving Glycemia to prevent Alzheimer's Disease (FIGHT-AD) study is a randomized controlled trial that aims to investigate changes in blood and brain glucose regulation following 10 weeks of HT. Specifically, we will examine the peripheral biomarker responses to warm and hot HT and assess how these responses relate to brain metabolic changes in both treatment groups. This trial will be the first to quantify the effect of HT on cerebral glucose metabolism in individuals at metabolic risk for Alzheimer's Disease (AD). The FIGHT-AD trial will provide critical data to inform the design of future clinical trials targeting metabolic and brain health through HT.

CLINICAL TRIAL REGISTRATION: clinicaltrials.gov, identifier NCT06023407.}, } @article {pmid41657474, year = {2026}, author = {Kim, GH and Pyun, JM and Kang, D and Kang, SH and Koh, SH and Kim, JS and Moon, SY and Moon, WJ and Park, YH and Shim, Y and Yang, DW and Youn, YC and Jung, YH and Cho, H and Choi, H and Lim, JS and Park, KH and Choi, SH}, title = {A Protocol of Korean JOint RegistrY for ALZheimer's Treatment and Diagnostics (JOY-ALZ).}, journal = {Dementia and neurocognitive disorders}, volume = {25}, number = {1}, pages = {25-41}, pmid = {41657474}, issn = {2384-0757}, abstract = {BACKGROUND AND PURPOSE: To assess the long-term effectiveness, safety, and economic viability of recently approved Alzheimer's disease (AD) therapies, as well as to evaluate the real-world application of novel diagnostics among AD patients with diverse comorbidities, comprehensive real-world data (RWD) analysis is essential. The Korean JOint RegistrY for ALZheimer's Treatment and Diagnostics (JOY-ALZ) endeavors to create a registry of RWD derived from clinical practice on new diagnostic methods and therapeutic agents for AD introduced in Korea since 2021.

METHODS: Participants must fulfill all the following: 1) be at least 19 years old; 2) be actively receiving, scheduled to initiate, or undergoing evaluation for any AD disease-modifying treatment; 3) have completed amyloid positron emission tomography or cerebrospinal fluid AD immunoassay (a positive result is not essential for participation); 4) have a clinical classification of cognitively unimpaired, mild cognitive impairment, or probable AD dementia. Data generated during routine care is segmented into a minimum dataset, extended dataset, and research-only dataset requiring extra consent. Assessments encompass clinical, cognitive, functional, neurobehavioral, neuroimaging, and biomarker evaluations, in addition to systematic monitoring of new AD treatments and their safety. Data are collected and monitored at baseline, at semiannual intervals during the initial 2 years, and then annually up to 2034. To date, 46 medical centers will participate in JOY-ALZ.

CONCLUSIONS: JOY-ALZ is expected to promote understanding of the long-term clinical outcomes, safety, and cost-effectiveness of recently introduced diagnostics and treatments for AD, thereby supporting the progress of precision medicine in AD care and diagnosis.

TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT06889818.}, } @article {pmid41659595, year = {2026}, author = {Chaggar, P and Vogel, JW and Thompson, TB and Aldea, R and Strandberg, O and Stomrud, E and Palqmvist, S and Ossenkoppele, R and Jbabdi, S and Magon, S and Klein, G and Mattson-Carlgren, N and Hansson, O and Goriely, A}, title = {Dynamical A β -Tau-Neurodegeneration Model Predicts Alzheimer's Disease Mechanisms and Biomarker Progression.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {41659595}, issn = {2692-8205}, support = {/WT_/Wellcome Trust/United Kingdom ; R01 AG083740/AG/NIA NIH HHS/United States ; U01 AG024904/AG/NIA NIH HHS/United States ; U54 MH091657/MH/NIMH NIH HHS/United States ; }, abstract = {Alzheimer's disease is characterised by the pathological interaction of two proteins, amyloid-beta (Aβ) and tau, which collectively drive neurodegeneration and cognitive decline. The progression of Aβ, tau, and neurodegeneration biomarkers is captured by the ATN framework, which is a powerful tool for disease classification. However, since the ATN framework is mainly descriptive, it cannot quantify or predict relationships between biomarkers over time. We address this limitation by introducing a dynamical ATN (dATN) model that mechanistically simulates the spatiotemporal progression of Aβ, tau, and neurodegeneration. The dATN model integrates mechanisms of prion-like protein aggregation of Aβ and tau, network-based tau propagation, Aβ-driven catalysis of tau progression, and tau-driven neurodegeneration. We calibrated the model using multimodal longitudinal imaging data from both the ADNI and BioFINDER-2 cohorts and show that it accurately fits longitudinal regional Aβ, tau, and neurodegeneration data. Using the dATN model, we show that Aβ-induced effects predict Braak-like cortical tau progression, that the spatial colocalisation of Aβ and tau is a crucial biomarker of disease acceleration, and that tau-driven atrophy strongly correlates with observed neurodegeneration. Furthermore, by integrating the disease progression model with pharmacokinetic-pharmacodynamic simulations, we present a powerful tool that facilitates regional evaluation of therapeutic strategies targeting Aβ, identification of critical intervention windows, and prediction of heterogeneous treatment effects across brain regions. This framework unifies mechanistic understanding with clinical imaging biomarkers, offering a quantitative approach for forecasting disease progression, testing mechanistic hypotheses, and optimising personalised treatment strategies in AD.}, } @article {pmid41660277, year = {2026}, author = {Fang, Y and Han, Z and Yang, S and Chen, J and Li, R and Zhang, Z and Song, J and Wang, D and Ban, Y}, title = {Ferroptosis and Alzheimer's disease: unraveling the molecular mechanisms and therapeutic opportunities.}, journal = {Frontiers in cell and developmental biology}, volume = {14}, number = {}, pages = {1758041}, pmid = {41660277}, issn = {2296-634X}, abstract = {Ferroptosis is a novel form of regulated cell death. Compared with other types of cell death, it shows great differences in structure and biochemistry. This type of cell death is receiving increasing attention. For example, studies have found that it plays a key role in the development of neurodegenerative diseases underlying brain atrophy, such as Alzheimer's disease (AD). AD is a chronic and worsening neurodegenerative disease. It poses a serious threat to the health and quality of life of the elderly. The pathology of AD is mainly the presence of extracellular beta-amyloid (Aβ) plaques and intracellular tau-based nerve fiber entanglement (NFTs). Although there are a large number of studies and interventions for AD, so far, no clinical drugs have been found that can stop the pathological progression of AD or cure it. Currently, treatment strategies for this disease only focus on alleviating clinical symptoms and do not achieve slowing disease progression or curing it. Ferroptosis is gradually considered to play a key role in the occurrence and development of AD. Research based on the AD model confirms that neuronal ferroptosis can be inhibited through pharmacology to reverse cognitive disorders. In this review, we first describe the key molecular mechanisms of ferroptosis, and then discuss how these mechanisms operate and develop in AD. Then, we give a detailed introduction to the latest treatments for AD, including iron chelators, antioxidants, and specific ferroptosis inhibitors. What is noteworthy is that this article emphasizes the analysis of the mechanisms of iron metabolism disorders, as well as the introduction of new drugs for the prevention, rather than the alleviation of AD.}, } @article {pmid41661364, year = {2026}, author = {Li, L and Kong, J and Fan, R and Yuan, Y and Zhu, L}, title = {Correction: Role of tRNA-Derived Fragments and Their Modifications in the Pathogenesis and Treatment of Alzheimer's Disease.}, journal = {Molecular neurobiology}, volume = {63}, number = {1}, pages = {429}, doi = {10.1007/s12035-026-05713-2}, pmid = {41661364}, issn = {1559-1182}, } @article {pmid41661788, year = {2024}, author = {McCormick, L and Bodla, AP and Rubin, RT}, title = {Very early onset dementias: Importance of differentiating from schizophrenia spectrum disorders.}, journal = {PLOS mental health}, volume = {1}, number = {3}, pages = {e0000107}, pmid = {41661788}, issn = {2837-8156}, abstract = {Very early onset dementias and other neurodegenerative diseases often present with prominent behavioral disturbances and can be initially misdiagnosed as schizophrenia spectrum disorders. Differentiating a primary psychiatric condition from a neurodegenerative cause is important, because there are considerable differences in prognosis, treatment, and the services required for effective management. To illustrate the implications of misdiagnosis, we provide case examples of very early onset dementias, most of which were initially diagnosed as schizophrenia or other psychotic disorder, owing to their unusually young age of onset and initial behavioral presentations. We suggest how a clinician can differentiate schizophrenia from rarer, early onset neurodegenerative causes of altered behavior and mentation, including behavioral variant frontotemporal dementia (bvFTD), Wilson's disease, adult metachromatic leukodystrophy (MLD), Creuzfeldt-Jakob disease (CJD), and very early-onset Alzheimer's disease. Schizophrenia with prominent obsessive-compulsive (OC) symptoms is briefly discussed, given that OC symptoms can be a major feature of dementias with prominent behavioral components.}, } @article {pmid41662521, year = {2026}, author = {Boskovic, P and Shalita, R and Gao, W and Vernon, H and Deng, YL and Colonna, M and Majzner, RG and Amit, I and Kipnis, J}, title = {Engineering chimeric antigen receptor CD4 T cells for Alzheimer's disease.}, journal = {Proceedings of the National Academy of Sciences of the United States of America}, volume = {123}, number = {7}, pages = {e2530977123}, pmid = {41662521}, issn = {1091-6490}, support = {R01AG078667//HHS | NIH | National Institute on Aging (NIA)/ ; R61AG090394//HHS | NIH | National Institute on Aging (NIA)/ ; no number//Carol and Gene Ludwig Family Foundation/ ; no number//Cure Alzheimer's Fund (CAF)/ ; no number//Fred and Ginger Haberle Charitable Fund at East Texas Communities Foundation/ ; }, mesh = {*Alzheimer Disease/therapy/immunology/pathology ; Animals ; *CD4-Positive T-Lymphocytes/immunology/transplantation/metabolism ; *Receptors, Chimeric Antigen/immunology/genetics/metabolism ; Mice ; Humans ; Amyloid beta-Peptides/immunology/metabolism ; Brain/immunology/pathology ; *Immunotherapy, Adoptive/methods ; Disease Models, Animal ; }, abstract = {Alzheimer's disease (AD) is the prevailing cause of age-associated dementia worldwide. Current standard of care relies on antibody-based immunotherapy. However, antibody-based approaches carry risks for patients, and their effects on cognition are marginal. Increasing evidence suggests that T cells contribute to AD onset and progression. Unlike the cytotoxic effects of CD8[+] cells, CD4[+] T cells capable of regulating inflammation show promise in reducing pathology and improving cognitive outcomes in mouse models of AD and in aging. Here, we sought to exploit the beneficial properties of CD4[+] T cells while circumventing the need for TCR and peptide-MHC antigen discovery, thereby providing a potential universal therapeutic approach. To achieve this, we engineered CD4[+] T cells with chimeric antigen receptors (CARs) targeting fibrillar forms of aggregated amyloid-β. Our findings demonstrate that optimized CAR-T cells can alter amyloid deposition in the dura and reduce parenchymal pathology in the brain. Furthermore, we observed that CAR-T treatment promotes the expansion and recruitment of endogenous CD4[+] T cells into the brain parenchyma and leptomeninges. In summary, we established the feasibility of amyloid plaque-specific CAR-T cells as a potential therapeutic avenue for AD. These findings highlight the potential of CD4[+] CAR-T therapy not only to modify amyloid pathology but also to reshape the immune landscape of the CNS, paving the way for future development of cellular immunotherapies for neurodegenerative disease.}, } @article {pmid41662806, year = {2026}, author = {Zhang, H and Zhang, H and Zhao, M and Luo, W and Chen, S and Wang, P and Liu, X and Xu, S}, title = {Da-Bu-Yin-Wan rescues cognitive deficits in aging and Alzheimer's disease models by Wnt/β-catenin-dependent restoration of lysosomal acidification.}, journal = {Phytomedicine : international journal of phytotherapy and phytopharmacology}, volume = {153}, number = {}, pages = {157916}, doi = {10.1016/j.phymed.2026.157916}, pmid = {41662806}, issn = {1618-095X}, mesh = {Animals ; *Alzheimer Disease/drug therapy/metabolism ; *Lysosomes/metabolism/drug effects ; *Wnt Signaling Pathway/drug effects ; *Aging/drug effects ; Disease Models, Animal ; Mice ; Mice, Transgenic ; *Cognitive Dysfunction/drug therapy ; beta Catenin/metabolism ; *Drugs, Chinese Herbal/pharmacology ; Male ; Brain/drug effects/metabolism ; *Neuroprotective Agents/pharmacology ; Mice, Inbred C57BL ; Galactose ; Amyloid beta-Peptides/metabolism ; }, abstract = {BACKGROUND: Lysosomal acidification deficits are increasingly recognized as a convergent pathological mechanism driving both age-related cognitive decline (ARCD) and early Alzheimer's disease (AD) progression, creating a self-reinforcing cycle of cellular aging and Aβ dyshomeostasis. Despite demonstrated neuroprotective effects of Da-Bu-Yin-Wan (DBYW) in Parkinson's disease models, its therapeutic potential for lysosomal dysfunction in ARCD and AD remains an uncharted area of investigation.

PURPOSE: This present work aimed to elucidate the mechanistic basis by which DBYW mitigates both ARCD and AD pathology through functionally rescuing impaired lysosomal acidification.

METHODS: Cell-based D-galactose and Aβ-induced in BV2 cells to study lysosomal acidification. Molecular analyses combined immunofluorescence localization studies with quantitative immunoblotting of lysosomal and Wnt signaling proteins. In vivo, DBYW treatment effects were systematically evaluated in both D-gal-induced and APP/PS1 transgenic models using cognitive behavioral followed by immunohistochemical and biochemical assessment of brain tissues lysosomal parameters and Wnt signaling activity.

RESULTS: DBYW attenuated the mechanistic basis of ARCD and AD pathology by functionally rescuing impaired lysosomal acidification. Overexpression of β-catenin could modulate D-galactose or Aβ-induced dysregulation of the Wnt/β-catenin pathway and restore lysosomes with abnormal acidification, while DBYW could regulate lysosomal function by promoting Wnt/β-catenin signaling. In addition, in D-gal-induced aging and AD model mice, DBYW treatment activated Wnt/β-catenin signaling to restore lysosomal acidification, while spatial memory deficits in ARCD and AD models were improved, and pathology in mouse attenuation and APP/PS1 mouse brain tissue was inhibited.

CONCLUSION: DBYW shows a potential dual efficacy in improving cognitive decline in ARCD and AD models. It makes DBYW a promising disease-modifying intervention targeting the shared lysosomal pathophysiology of aging-associated neurodegeneration.}, } @article {pmid41663779, year = {2026}, author = {Roy, KK and Kumari, R and Upadhyay, AK and Mohanty, S}, title = {Tailoring treatments: pharmacogenomics in the management of neurodegenerative diseases.}, journal = {Acta neurologica Belgica}, volume = {}, number = {}, pages = {}, pmid = {41663779}, issn = {2240-2993}, abstract = {Neurodegenerative diseases like Alzheimer's, Parkinson's, Huntington's, and amyotrophic lateral sclerosis are growing more common worldwide, yet treatment is still poor. Conventional therapies can have unforeseen side effects, produce poor medication reactions, and take longer to work. This persistent treatment gap highlights the need for novel approaches to these disorders' complex distinctions. Pharmacogenomics, which examines how genetic differences affect drug response, is a promising new subject and an urgent solution. Pharmacogenomics tailors medicine selection and administration to each patient's genetic profile, addressing the main causes of poor treatment response and preventable side effects. This research has enabled precision medicine that can improve neurodegenerative disease therapy and reduce harm. In this in-depth research, we examine neurodegenerative disease management issues, pharmacogenomics breakthroughs, and how incorporating genetics to clinical practice can improve outcomes. We examine the latest evidence that genetics affect drug breakdown, efficacy, and toxicity. We also discuss the challenges and opportunities of applying this knowledge. Pharmacogenomic approaches must be widely applied to make medicines for these awful disorders safer, more effective, and really suited to patient needs, according to our compilation.}, } @article {pmid41664331, year = {2026}, author = {Siddiqui, S and Tufail, P and Khan, F and Khalid, MF and Khalid, F}, title = {Protocatechuic Acid Alleviates Neurodemyelination by Modulating PKCα-p38/MAPK Pathways in an LPC-Induced Model of Neurodegeneration.}, journal = {Current protein & peptide science}, volume = {}, number = {}, pages = {}, doi = {10.2174/0113892037385148251207081917}, pmid = {41664331}, issn = {1875-5550}, abstract = {INTRODUCTION: Neuroinflammation, axonal damage, and alterations in extracellular matrix (ECM) protein expression are hallmarks of neurodegenerative diseases. Therapies that enhance recovery from brain injury are of significant clinical value. Therefore, this study investigated the antiinflammatory properties of protocatechuic acid (PCA).

METHODS: Neuroglial cocultures were prepared from P0-P1 rats. Demyelination was induced using LPC (0.003%). The effects of PCA (10 and 25 μg) on neurite outgrowth were assessed using morphometry software. Expression of COX-2, NF-κβ, PKC-α, and p38/MAPK was examined through immunostaining, SDS-PAGE, and Western blotting. Expression intensities were quantified using ImageJ software. Sustained repetitive neuronal firing was evaluated using the patch-clamp technique.

RESULTS: PCA increased neurite outgrowth in LPC-treated cultures after 72 hours in vitro. LPCinduced upregulation of ECM proteins TN-C, LN, and CSPGs was significantly reduced by PCA treatment compared with LPC controls. Similarly, PCA decreased the expression intensities of the pro-inflammatory markers NF-κβ and COX-2 relative to LPC controls. Furthermore, PCA reversed the sustained neuronal firing pattern observed in untreated LPC-exposed neurons.

DISCUSSION: Purified bioactive compounds commonly present in everyday foods show therapeutic potential for Parkinson's and Alzheimer's diseases due to their lower toxicity compared with conventional drugs. Artificial intelligence tools, such as AlphaFold and RoseTTAFold, further support drug development by predicting PCA binding modes with PKCα and P38/MAPK, thereby contributing to the design of personalized therapeutics and advancing neuroscience research.

CONCLUSION: PCA alleviated neuroinflammation by reducing phosphorylation of PKCα and p38/MAPK.}, } @article {pmid41664517, year = {2026}, author = {Silva Fernandes, A and Barbosa de Souza, Á and Benvindo de Souza, M and Madureira Almeida, L and Luiz Franco, O and Luiz Cardoso Bailão, EF and Borges, LL and Sérgio Nakao de Aguiar, A}, title = {DNA damage induced by fungicides triadimefon, triadimenol, and their mixture in human lymphocytes: cytogenotoxicity and computational analysis of metabolic pathways.}, journal = {Drug and chemical toxicology}, volume = {}, number = {}, pages = {1-9}, doi = {10.1080/01480545.2026.2626753}, pmid = {41664517}, issn = {1525-6014}, abstract = {Triadimefon (TF) and triadimenol (TN) are triazole fungicides widely used to prevent fungal infections in cereals, fruits, and other economically important crops. Their harmful effects on non-target organisms have been reported. This study investigated the cytogenotoxic effects of TF and TN, isolated and combined, at environmentally relevant concentrations (TF: 0.006, 0.012, and 0.024 mg/mL; TN: 1.5, 3.0, and 6.0 mg/mL; and 0.012 mg/mL TF + 3.0 mg/mL TN) on human lymphocytes using the trypan blue exclusion test and the comet assay. Additionally, in silico tools, BioTransformer and DIGEP-Pred, were employed to elucidate metabolic pathways more effectively for detoxifying these xenobiotics and to evaluate their putative effects on gene transcription, respectively. Exposure to TF and TN, either alone or in combination, did not affect lymphocyte viability at the tested concentrations. However, both compounds induced an increase in the percentage of DNA strand breaks after treatment. The in silico predictions suggested that the interaction with the cytochrome P450 isoforms (CYP1A2, CYP2A6, CYP2C9, and CYP2D6) differed for each compound analyzed. Gene expression prediction indicated that TF and TN may up-regulate genes involved with hormonal alterations, Alzheimer's disease risk, and cancer progression (SF1, SPON1, ADGRF5, and RORB). While they may down-regulate a gene involved with changes in heart rhythm and neurotoxicity (HCN1). In conclusion, our findings reinforced that the triazole fungicides TF and TN, while effective in agriculture, may pose risks to genomic stability in humans, highlighting the importance of biomonitoring studies in exposed populations.}, } @article {pmid41664707, year = {2026}, author = {Xiang, Q and Shi, RL and Huang, YX and Liu, LN and Tao, JS and Li, XH and Li, XD}, title = {Oligodendrocyte: Development, Plasticity, Biological Functions, Diseases, and Therapeutic Targets.}, journal = {MedComm}, volume = {7}, number = {2}, pages = {e70618}, pmid = {41664707}, issn = {2688-2663}, abstract = {In the past few years, the incidence rate of central nervous system (CNS) diseases is still growing. Meanwhile, the molecular mechanism on the pathogenesis of neurological diseases remains elusive. Oligodendrocyte progenitor cells (OPCs) are distributed in the whole CNS and represent a population of migrating and proliferating adult progenitor oligodendrocytes that can be differentiated into oligodendrocytes (OLs). The main function of OLs is to produce myelin, the membrane wrapping tightly around the axon, which are associated with the myelination and remyelination. During regeneration, the new OLs from OPCs can regenerate lost myelin, which prevents axonal degeneration and restores its plasticity and function. Considering these energy-consuming processes, the high metabolic turnover OLs are susceptible to neurotoxic factors and its excitatory toxicity. Thus, the pathogenesis of OPC and OL are proven in neurological diseases, such as multiple sclerosis, Alzheimer's disease, major psychiatric diseases, and epilepsy. The current study reviewed the development, plasticity as well as application of OPCs and OLs researches on CNS diseases. Additionally, the effective methods and bioengineering technologies as well as biomaterials relevant to regenerative medicine are also discussed, which could provide the novel insight into the therapeutic treatment of those diseases, exploring new pathological clues, identifying the key molecules and targets as well as the potential biomarkers.}, } @article {pmid41665706, year = {2026}, author = {Giacomini, PS and Voss, P and Devonshire, V and Schneider, R and Macaron, G and Hussein, S and Blanchette, F and de Villers-Sidani, É}, title = {Eye tracking as a digital biomarker in neurodegenerative diseases.}, journal = {Journal of neurology}, volume = {273}, number = {2}, pages = {133}, pmid = {41665706}, issn = {1432-1459}, mesh = {Humans ; *Neurodegenerative Diseases/diagnosis/physiopathology ; Biomarkers ; *Eye-Tracking Technology ; }, abstract = {Oculomotor abnormalities are a common finding in neurodegenerative diseases due to degeneration of neural pathways and brain regions involved in controlling eye movements. Pathological changes to the dorsolateral prefrontal cortex, basal ganglia, superior colliculus and cerebellum produce subtle changes in eye-movement metrics that may not be detected by clinical examination. The present review addresses the potential use of eye-movement biomarkers in neurodegenerative conditions such as multiple sclerosis, Parkinson's disease, Alzheimer's disease and other dementias, and amyotrophic lateral sclerosis. Eye-movement metrics such as saccades, anti-saccades, fixation and smooth pursuit are prognostic of disease progression, can differentiate pathologic subtypes as an aid to diagnosis, and enable clinicians to evaluate early worsening of motor and cognitive function. The cost of medical technologies limits their optimal use and accessibility in clinical practice. The shortage of subspecialist neurologists further limits access to care. New eye-tracking technologies incorporated into widely-accessible digital devices such as smart phones and tablets now permit detailed assessments with minimal equipment requirements, providing an important non-invasive and potentially cost-effective method for patient evaluation in routine clinical practice and as an aid to treatment decision-making. Digital biomarkers can be readily employed by healthcare professionals such as family physicians, nurses and pharmacists to bridge the care gaps, potentially providing them with powerful tools that can be broadly adopted to improve the delivery of care to patients with neurodegenerative conditions.}, } @article {pmid41665751, year = {2025}, author = {Voronova, AD and Karsuntseva, EK and Shishkina, VS and Chadin, AV and Fursa, GA and Gurin, PI and Kuznetsova, TV and Reshetov, IV and Shport, SV and Stepanova, OV and Chekhonin, VP}, title = {Clinical Trials of Cell Products for the Treatment of Alzheimer's Disease (Review).}, journal = {Bulletin of experimental biology and medicine}, volume = {180}, number = {1}, pages = {112-118}, pmid = {41665751}, issn = {1573-8221}, mesh = {Humans ; *Alzheimer Disease/therapy/pathology ; Clinical Trials as Topic ; *Cell- and Tissue-Based Therapy/methods ; Animals ; Brain/pathology ; }, abstract = {Existing approaches to the treatment of Alzheimer's disease are ineffective because they do not stop neurodegenerative processes in the brain and do not promote the regeneration of the nervous tissue. Cell therapy is a promising strategy for the treatment of this disease. This review discusses clinical studies of cell-based therapies for Alzheimer's disease, evaluates their therapeutic potential, and proposes strategies for developing safe, accessible, and effective cell products.}, } @article {pmid41666058, year = {2026}, author = {Zhang, H and Wang, D and Yang, J and Zhao, Y and Liu, Y and Zhu, R and Wang, L and Song, R and Zhang, W}, title = {Unsupervised Disentanglement of Brain Heterogeneity for Identifying Subtypes of Alzheimer's Disease.}, journal = {IEEE transactions on bio-medical engineering}, volume = {PP}, number = {}, pages = {}, doi = {10.1109/TBME.2026.3663181}, pmid = {41666058}, issn = {1558-2531}, abstract = {Neuroanatomical heterogeneity in Alzheimer's disease (AD) hinders precision diagnosis and treatment, as distinct brain phenotypes may correspond to different disease subtypes. However, MRI-based subtype classifications are often confounded by co-occurring pathologies and non-AD factors, such as genetic predisposition and environmental influences, limiting their clinical interpretability. We propose 3D-DisAD, an unsupervised deep learning framework that disentangles AD-specific neuroanatomical variations from unrelated influences and clusters patients into subtypes with homogeneous brain phenotypes. The framework comprises two synergistic networks: (1) Contrastive Disentanglement Network, which separates AD-specific variations from those shared by AD patients and healthy controls; and (2) Transformation Generation Network, which refines these disease-specific variations by transforming healthy brain representations into realistic, pathology-consistent anatomies via diffusion-based generative modeling. Evaluated on four public datasets, 3D-DisAD reveals strong correlations between the disentangled AD-specific variations and diverse clinical and biological profiles, validating their relevance. Using these variations, we identify four AD subtypes with significant differences in biomarkers, cognitive trajectories, and genetic signatures, and uncover distinct longitudinal progression patterns that suggest potential windows for early intervention. By disentangling AD-specific variations, our method enables more precise patient stratification and personalized treatments, particularly in the early stage of AD. Code is available at: https://github.com/cnuzh/3D-DisAD.}, } @article {pmid41666126, year = {2026}, author = {Yue, J and Jones, B and Tran, KH and Deen, M and Holicek, V and Cheng, WH and Michalik, M and Power, S and Wellington, CL and Watson, NV and Vocadlo, DJ}, title = {Pharmacological inhibition of O-GlcNAcase reduces pS129-α-synuclein positive aggregates in the substantia nigra of mThy1-hSNCA mice.}, journal = {Journal of Parkinson's disease}, volume = {16}, number = {2}, pages = {217-232}, doi = {10.1177/1877718X251410291}, pmid = {41666126}, issn = {1877-718X}, mesh = {Animals ; *alpha-Synuclein/metabolism/drug effects ; *Substantia Nigra/drug effects/metabolism/pathology ; Mice, Transgenic ; Mice ; Disease Models, Animal ; *beta-N-Acetylhexosaminidases/antagonists & inhibitors ; Humans ; *Parkinson Disease/metabolism/drug therapy ; *Protein Aggregation, Pathological/drug therapy/metabolism ; *Benzothiazoles/pharmacology ; *Pyrans/pharmacology ; Male ; *Enzyme Inhibitors/pharmacology/administration & dosage ; Thiazoles ; }, abstract = {BackgroundThe aggregation and spread of α-synuclein within brain are associated with the loss of dopaminergic neurons and the formation of Lewy bodies as seen in Parkinson's disease. Blocking the initiation of α-synuclein aggregation, or the spread of such aggregates, may offer disease-modifying approaches to slow disease progression. Previous studies have demonstrated that modification of aggregation prone proteins, including α-synuclein, with O-linked β-N-acetylglucosamine (O-GlcNAc) reduces their aggregation. Small molecule inhibitors of the enzyme O-GlcNAcase (OGA), which removes O-GlcNAc from proteins, confers neuroprotective benefits in various preclinical disease models of Alzheimer's and Parkinson's diseases.ObjectiveThis study investigates the effects of long-term pharmacological enhancement of O-GlcNAcylation in a transgenic mouse model of Parkinson's disease overexpressing human α-synuclein.MethodsThiamet-G was orally administered to mThy1-hSNCA and wild-type (WT) mice for ten months. Behavioral assessments were conducted to examine changes in locomotion and cognition. Histological analyses were performed to analyze α-synuclein aggregates and dopaminergic neurons in brain sections. Immunoblot and ELISA analyses were performed to analyze O-GlcNAc and soluble α-synuclein using brain lysates, respectively.ResultsThiamet-G increased the level of O-GlcNAc in the brain of both mThy1-hSNCA and WT mice. The levels of total α-synuclein in the brain were unaltered. However, Thiamet-G strongly attenuated the deposition of pS129-immunoreactive α-synuclein aggregates within the substantia nigra, prior to observable neurodegeneration. Thiamet-G also protected against locomotor decline.ConclusionsThese results support OGA inhibition as a therapeutic approach to block the pathological formation of toxic α-synuclein as a disease-modifying treatment against Parkinson's disease.}, } @article {pmid41666521, year = {2026}, author = {Qin, Z and Wang, Z and Gao, C and Yong, X and Hua, Y and Zhou, Y and Xie, J}, title = {Ultrasound-mediated blood-brain barrier opening for targeted neurological drug delivery.}, journal = {Biomaterials advances}, volume = {183}, number = {}, pages = {214754}, doi = {10.1016/j.bioadv.2026.214754}, pmid = {41666521}, issn = {2772-9508}, mesh = {Humans ; Animals ; Ultrasonics ; *Ultrasonic Waves ; *Blood-Brain Barrier/drug effects ; *Drug Delivery Systems/methods ; Nanoparticles/chemistry ; *Central Nervous System Agents/chemistry/pharmacology ; Microbubbles ; }, abstract = {Neurological disorders represent a devastating global health crisis, and the blood-brain barrier (BBB) remains a major obstacle for their treatment. Conventional strategies for BBB opening, including direct intracranial injection, osmotic disruption, receptor-mediated transcytosis, and nanoparticle carriers, often suffers from surgical invasiveness, systemic toxicity, poor biodistribution, and off-target effects. Ultrasound-mediated drug delivery has emerged as a revolutionary non-invasive technology for transient and targeted BBB opening, enabling enhanced penetration of therapeutic agents into the central nervous system. This review comprehensively summarizes the mechanisms underlying ultrasound-based delivery with focus on current delivery platforms including microbubble (MB)-assisted, nanoparticle-based, and MB-nanoparticle composite strategies. Furthermore, we highlight recent advances in the application of focused ultrasound (FUS) combined with MBs for the treatment of Alzheimer's disease, Parkinson's disease, and glioma. Finally, we discuss emerging technologies such as sonodynamic therapy and ultrasound-controlled magnetic nanorobots, while also addressing current challenges in this field. This review underscores the transformative potential of ultrasound-mediated drug delivery as a versatile platform for precision neurology. It also prospects future directions for advancing multidisciplinary research and clinical translation.}, } @article {pmid41666775, year = {2026}, author = {Chaudhari, S and Shinde, A and Salunke, M and Bairagi, S and Dhage, A and Patel, P and Rathod, V and Pathare, S and Altwaijry, N and Khan, MS}, title = {Investigating the anti-Alzheimer potential of biogenic compounds from Zinc15 database as NMDA antagonist: An in-silico approach.}, journal = {Journal of molecular graphics & modelling}, volume = {144}, number = {}, pages = {109277}, doi = {10.1016/j.jmgm.2026.109277}, pmid = {41666775}, issn = {1873-4243}, mesh = {*Receptors, N-Methyl-D-Aspartate/antagonists & inhibitors/chemistry ; *Alzheimer Disease/drug therapy ; Molecular Dynamics Simulation ; Humans ; *Biological Products/chemistry/pharmacology ; Molecular Docking Simulation ; Ligands ; Protein Binding ; Binding Sites ; }, abstract = {Alzheimer's disease is an unavoidable neurological disorder in which the death of brain cells brings on memory loss, cognitive decline, and eventual dementia. There is no recognized treatment for Alzheimer's illness. By the year 2050, it is expected that the global population will witness approximately 100 million cases of Alzheimer's disease (AD). Despite recognizing AD as a formidable illness for over a century, no effective cure has been discovered thus far. Synaptic dysfunction could result from disturbed synaptic calcium handling caused by excessive activation of glutamate receptors, particularly the N-methyl-D-aspartate receptors (NMDARs). Glutamate serves as the brain's primary excitatory neurotransmitter, acting on ionotropic and metabotropic glutamate receptors. In recent years, several pharmacologically active substances derived from plants, animals, and microbes have shown promise in treating AD by focusing on various pathogenic processes. Initially, we used virtual screening to assess natural product-like compounds against NMDA receptors. In this research study, we have screened a natural compound database derived from zinc15. The best candidate was then validated through molecular dynamics simulation (MDS). The results revealed that out of 4221 compounds tested, only 165 showed superior binding interactions compared to native ligands, making them inhibitors for protein. Further analysis using ADMET indicates favorable drug-like properties, particularly for CNS drug-likeness. The MDS results, including RMSD, RMSF, Rg, and residue interactions, indicated a strong and stable association between top molecules and target protein. This confirms that top molecules can effectively remain within the binding pockets of the target proteins, forming stable protein-ligand complexes.}, } @article {pmid41667280, year = {2026}, author = {Skyles, T and Bouchal, SM and Giarratana, A and Wengler, J and Hart, I and Greig, E and Singh, H and Huang, SS and Martinez, F and Nguyen, B and Shin, CH and Yang, M and Parent, E and Robb, WH and Franceschi, AM and Burkett, B and Johnson, D and Koran, ME}, title = {PET Imaging in Alzheimer Disease in the Era of Antiamyloid Therapy in the United States: Clinical Utility, Quantification, and Policy Landscape.}, journal = {Journal of nuclear medicine technology}, volume = {54}, number = {1}, pages = {10-17}, pmid = {41667280}, issn = {1535-5675}, mesh = {Humans ; *Positron-Emission Tomography/methods ; *Alzheimer Disease/diagnostic imaging/therapy/metabolism/drug therapy ; United States ; Immunotherapy ; tau Proteins/metabolism ; }, abstract = {Alzheimer disease (AD) is increasingly diagnosed using molecular imaging biomarkers. PET imaging provides the opportunity to visualize amyloid and tau aggregates and in vivo neurodegenerative changes. These techniques provide exciting new avenues toward diagnosis, disease staging, and therapeutic monitoring of AD. Methods: This review details recent advances in amyloid PET, tau PET, and [18]F-FDG PET as they relate to the diagnosis, staging, and treatment of AD. The increasing roles of PET in the biologically based diagnosis of AD and antiamyloid immunotherapy response monitoring are addressed. Results: Amyloid PET enables improved detection of amyloid-β plaques within the brain. Amyloid PET is increasingly vital for confirming AD diagnoses given the emergence of antiamyloid immunotherapies, which require biomarker-verified amyloid positivity to initiate treatment. Tau PET provides a direct measure of neurofibrillary tangle pathology and is useful for disease staging, the interpretation of atypical clinical presentations, and treatment decision-making. [18]F-FDG PET plays a vital role in distinguishing AD from other dementia subtypes. Expanded reimbursement policies for amyloid and tau PET have increased accessibility to these modalities. Finally, quantitative methods facilitate interscan reproducibility and permit therapeutic monitoring. Conclusion: Molecular neuroimaging is poised to play a central role in the biologic definition, diagnosis, staging, and management of AD. Integrating amyloid, tau, and FDG PET with clinical assessments and fluid biomarkers provides earlier and more accurate diagnoses, opening the door to personalized treatment.}, } @article {pmid41667282, year = {2026}, author = {Grabher, BJ}, title = {Centiloids in Amyloid PET: A Practical Guide to Quantitation Interpretation.}, journal = {Journal of nuclear medicine technology}, volume = {54}, number = {1}, pages = {42-46}, doi = {10.2967/jnmt.125.271823}, pmid = {41667282}, issn = {1535-5675}, mesh = {*Positron-Emission Tomography/methods ; Humans ; *Amyloid/metabolism ; Alzheimer Disease/diagnostic imaging/metabolism ; *Image Processing, Computer-Assisted/methods ; *Image Interpretation, Computer-Assisted/methods ; }, abstract = {The approval of disease-modifying antiamyloid therapies has expanded the clinical role of amyloid PET beyond diagnostic confirmation to include baseline characterization and longitudinal monitoring of treatment response. Although visual interpretation remains the clinical standard for amyloid PET, it may be limited in borderline cases and when assessing subtle changes in amyloid burden over time. Quantitative amyloid PET provides objective measures that complement visual assessment, with z scores, SUV ratios, and Centiloid scaling offering increasing clinical utility. The Centiloid scale standardizes amyloid PET quantification across tracers, scanners, and institutions by anchoring measurements to biologically defined reference points, enabling consistent interpretation and comparison. This article describes the principles of amyloid PET quantification, explains the origin and interpretation of Centiloids, and discusses their role in therapy monitoring and clinical decision-making. Understanding quantitative amyloid PET and its limitations is essential for nuclear medicine professionals in the evolving landscape of Alzheimer disease imaging.}, } @article {pmid41667287, year = {2026}, author = {Casper, A and Bolin, J}, title = {Alzheimer Disease and the Utility of PET.}, journal = {Journal of nuclear medicine technology}, volume = {54}, number = {1}, pages = {32-38}, doi = {10.2967/jnmt.125.271758}, pmid = {41667287}, issn = {1535-5675}, mesh = {Humans ; *Positron-Emission Tomography/methods ; *Alzheimer Disease/diagnostic imaging/metabolism ; Amyloid beta-Peptides/metabolism ; Animals ; tau Proteins/metabolism ; }, abstract = {Alzheimer disease (AD) is the most common cause of dementia and one of the leading causes of death in adults age 65 y or older in the United States. AD presents with symptoms of cognitive impairment that worsen with disease progression, ultimately affecting an individual's functional abilities, independence, and overall health. Historically, treatment has relied on the mitigation of the adverse effects of the disease; however, the recent development of antiamyloid monoclonal antibodies allows for the targeting of pathologic factors that drive the progression of disease. Nuclear medicine has established itself as a useful tool in the evaluation of AD through the use of PET tracers, which target pathologic biomarkers such as amyloid-β and tau proteins, as well as metabolic processes reflective of neurodegenerative damage. Amyloid-β PET imaging and quantification have recently gained interest for their ability to more effectively diagnose AD and identify patients eligible for treatment with new antiamyloid therapies.}, } @article {pmid41667430, year = {2026}, author = {Rossini, PM and Pappalettera, C}, title = {Should all MCI with Alzheimer's biological diagnosis receive anti-amyloid therapy?.}, journal = {Cell death & disease}, volume = {17}, number = {1}, pages = {212}, pmid = {41667430}, issn = {2041-4889}, mesh = {Humans ; *Alzheimer Disease/drug therapy/diagnosis ; *Cognitive Dysfunction/drug therapy/diagnosis ; Biomarkers/metabolism ; *Amyloid beta-Peptides/metabolism/antagonists & inhibitors ; }, abstract = {Our perspective addresses one of the most pressing and timely debates in contemporary neurology and health policy: whether the recent approval of anti-amyloid monoclonal antibodies for Alzheimer's disease should extend to all individuals with mild cognitive impairment (MCI; a large population of tens of millions of individuals worldwide mainly represented in Countries with aged population) who test positive for amyloid biomarkers, despite wide variability in prognosis and therapeutic response and the epidemiological demonstration that only about half of them manifest symptoms of dementia. The manuscript highlights three central themes. First, while epidemiological and meta-analytic data confirm that MCI significantly increases the risk of dementia, more than half of affected individuals-many of whom are biomarker-positive for amyloid/tau-do not progress to dementia even over long- term follow-up. Second, recently approved anti-amyloid therapies, although representing a landmark in disease-modifying treatments, carry high costs, non-negligible risks (particularly amyloid-related imaging abnormalities), and uncertain long-term real-world benefits. Third, indiscriminate prescription of these agents risks exposing large numbers of subjects to unnecessary harm while placing unsustainable burdens on healthcare systems. We argue that the field should urgently move to identify and validate accurate and sustainable instruments for risk-stratified treatment pathways, integrating genetic, clinical, neuropsychological, neuroimaging, and fluid biomarker data including risk and resilience factors to refine prognostication. In addition, we call on the scientific community, journals, and policymakers to foster dialog that bridges neurology, geriatrics, bioethics, health economics, and patient advocacy, so that clinical innovation is matched by ethical responsibility and equitable implementation.}, } @article {pmid41668484, year = {2026}, author = {Wang, Q}, title = {[Current status and future perspectives on age-related hearing loss and cognitive impairment].}, journal = {Lin chuang er bi yan hou tou jing wai ke za zhi = Journal of clinical otorhinolaryngology head and neck surgery}, volume = {40}, number = {3}, pages = {220-225}, doi = {10.13201/j.issn.2096-7993.2026.03.002}, pmid = {41668484}, issn = {2096-7993}, mesh = {Humans ; *Presbycusis ; *Cognitive Dysfunction ; Quality of Life ; Aging ; *Hearing Loss ; Aged ; Alzheimer Disease ; Cognition Disorders ; }, abstract = {Objective:Age-related hearing loss（ARHL） is one of the most common sensory degenerative disorders in the elderly, characterized by high prevalence, insidious onset, and progressive deterioration. Recent studies indicate that ARHL not only impairs communication and quality of life in older adults, but is also significantly associated with the development of cognitive impairment and Alzheimer's disease. However, its underlying pathogenesis remains incompletely understood, and the relationship between clinical phenotypes of ARHL and cognitive decline has yet to be clearly defined. ARHL occupies a pivotal position in geriatric health management and in the prevention of neurodegenerative diseases, yet it has not been systematically conceptualized or mechanistically examined. In this review, we summarize the current research progress on ARHL and cognitive impairment, analyze possible mechanisms linking the two conditions, evaluate the potential cognitive protective effects of hearing interventions, and propose priority directions for future research and clinical practice. With advances in multidisciplinary collaboration and technological innovation, the prevention and treatment of ARHL are expected to enter a new era of greater precision and efficiency, offering novel opportunities to reduce the risk of cognitive impairment and improve overall health in older populations.}, } @article {pmid41668529, year = {2026}, author = {Wang, W and Chen, Y and Xiong, Z and Wang, Z and Ye, W and Li, X}, title = {Donepezil Research in Cognitive Impairment: A Bibliometric and Scientometric Analysis of Global Trends and Pharmacological Perspectives.}, journal = {Brain and behavior}, volume = {16}, number = {2}, pages = {e71251}, pmid = {41668529}, issn = {2162-3279}, support = {//Neurosurgery First-class Discipline Funding Project of the Second Affiliated Hospital of Harbin Medical University/ ; }, mesh = {*Donepezil/therapeutic use/pharmacology ; Humans ; *Bibliometrics ; *Cognitive Dysfunction/drug therapy ; *Nootropic Agents/therapeutic use ; Alzheimer Disease/drug therapy ; *Cholinesterase Inhibitors/therapeutic use ; }, abstract = {BACKGROUND: Cognitive impairment (CI) greatly affects global health and quality of life. Donepezil, a widely used treatment for CI, particularly in Alzheimer's disease, has been extensively studied; however, a comprehensive bibliometric analysis summarizing global research trends remains limited.

METHODS: Relevant English-language articles and reviews published between 2000 and 2025 were retrieved from the Web of Science Core Collection. CiteSpace and VOSviewer were employed to analyze publication trends, collaborative networks, journal distribution, co-citation patterns, and keyword co-occurrence.

RESULTS: A total of 1907 publications were identified. The United States led in both output and citation impact, with the University of Toronto emerging as the most influential institution. The U.S. Department of Health and Human Services provided the greatest funding support. The Journal of Alzheimer's Disease was the primary publishing outlet, and Etsuro Mori was the most prolific and influential author. Keyword analysis revealed "Donepezil," "Alzheimer's disease," and "Mild cognitive impairment" as dominant terms. Recent hotspots-such as "acetylcholinesterase," "oxidative stress," "neuroinflammation," "tau protein," and "mechanism"-reflect a shift toward mechanistic and preclinical research.

CONCLUSION: Research on donepezil for CI has shown consistent growth, evolving from clinical application toward mechanistic exploration and disease modification. Future studies are expected to focus on individualized therapy, combination strategies, and underexplored CI subtypes, aiming to enhance the therapeutic potential and clinical value of donepezil.}, } @article {pmid41668547, year = {2026}, author = {Zhang, Y and Wang, J and Yuan, J and Li, S and Sun, Y}, title = {FA-2-b-β modulates HMGB1/NF-κB/NLRP3 signaling to alleviate neuroinflammation in Alzheimer's disease.}, journal = {Journal of Alzheimer's disease : JAD}, volume = {110}, number = {2}, pages = {882-894}, pmid = {41668547}, issn = {1875-8908}, mesh = {Animals ; *NLR Family, Pyrin Domain-Containing 3 Protein/metabolism/drug effects ; *HMGB1 Protein/metabolism/drug effects ; *Alzheimer Disease/metabolism/drug therapy ; *NF-kappa B/metabolism/drug effects ; *Signal Transduction/drug effects ; *Neuroinflammatory Diseases/metabolism/drug therapy ; Pyroptosis/drug effects ; Humans ; Amyloid beta-Peptides ; Male ; Mice ; *Neuroprotective Agents/pharmacology ; Rats ; *Drugs, Chinese Herbal/pharmacology ; Disease Models, Animal ; }, abstract = {BackgroundFA-2-b-β, an extract derived from traditional Chinese medicine (TCM), has been suggested as a potential neuroprotective agent.ObjectiveThis study aimed to elucidate its role in modulating HMGB1-mediated inflammation and pyroptosis in Alzheimer's disease (AD), with a particular emphasis on the interaction between FA-2-b-β and HMGB1.MethodsAD cell and animal models were used to examine the effect of FA-2-b-β on HMGB1/NF-κB/NLRP3 signaling pathway. Protein expression levels were detected by western blotting, and enzyme-linked immunosorbent assay (ELISA), respectively. Immunofluorescence staining was performed to determine the cellular localization of key proteins. The role of HMGB1 in amyloid-β (Aβ)-induced neuroinflammation and pyroptosis was examined through siRNA-mediated HMGB1 knockdown. Behavioral tests were conducted in AD animal models to evaluate cognitive improvements following FA-2-b-β treatment.ResultsIn cellular models, FA-2-b-β significantly suppressed Aβ-induced overexpression HMGB1 and inhibited the activation of NF-κB, which consequently led to a reduction in the formation of the NLRP3 inflammasome. This suppression resulted in decreased of activation caspase-1 and lower levels of IL-1β and IL-18, thereby alleviating pyroptosis and neuroinflammation. The knockdown of HMGB1 further corroborated its role in mediating Aβ-induced inflammatory responses. In AD animal models, treatment with FA-2-b-β attenuated neuroinflammation, preserved neuronal integrity, and enhanced cognitive function.ConclusionsFA-2-b-β exhibits a capacity to modulate the HMGB1/NF-κB/NLRP3 signaling pathway, thereby mitigating neuroinflammation and pyroptosis, highlighting its potential as a therapeutic intervention for AD.}, } @article {pmid41668551, year = {2026}, author = {Gao, C and Li, Y and Zhou, B and Liu, Y and Hao, MQ and Sun, H and Jin, Z and Li, LL and Yang, XF and Guo, XL and Yin, Y}, title = {The application of exosomes derived by mesenchymal stem cell from different tissues in the management of Alzheimer's disease.}, journal = {Nanomedicine (London, England)}, volume = {21}, number = {6}, pages = {839-851}, pmid = {41668551}, issn = {1748-6963}, mesh = {Humans ; *Exosomes/transplantation/metabolism ; *Alzheimer Disease/therapy/pathology/metabolism ; *Mesenchymal Stem Cells/cytology/metabolism ; Animals ; Amyloid beta-Peptides/metabolism ; Mesenchymal Stem Cell Transplantation ; Blood-Brain Barrier/metabolism ; }, abstract = {With the intensifying global trend of population aging, the treatment of Alzheimer's disease (AD) faces significant challenges. Current therapeutic approaches can only temporarily alleviate symptoms without halting or reversing disease progression. Numerous studies on mesenchymal stem cell-derived exosomes (MSC-Exos) suggest that, compared to stem cell therapy, MSC-Exos offer considerable advantages in the treatment of AD. This review examines the various mechanisms by which exosomes produced from MSCs function as therapeutic agents for AD. Additionally, it provides a concise overview of the research conducted on MSC-Exos for AD, categorized by tissue source. The text also provides an account of the ongoing clinical trials involving MSC-Exos and examines their benefits, drawbacks, and potential avenues for future research.}, } @article {pmid41668753, year = {2026}, author = {Giff, AE and Wruble Clark, M and Bhattacharyya, S and Sage, PT and Madore, B and Guenette, JP and Miyawaki, EK}, title = {Deep cervical lymph node analysis in central nervous system inflammatory disease.}, journal = {Frontiers in immunology}, volume = {17}, number = {}, pages = {1747114}, pmid = {41668753}, issn = {1664-3224}, mesh = {Humans ; *Lymph Nodes/immunology/pathology ; Animals ; *Neuroinflammatory Diseases/immunology/pathology ; Glymphatic System/immunology ; Meninges/i