@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},
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.},
}

*Alzheimer Disease/microbiology/genetics
*Mendelian Randomization Analysis
Humans
*Gastrointestinal Microbiome
Genome-Wide Association Study

@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 {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 {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.},
}

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

@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.},
}

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

@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.},
}

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

@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.},
}

*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

@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.},
}

Humans
*RNA Editing/genetics
*Adenosine Deaminase/metabolism/genetics
*Central Nervous System Diseases/genetics/therapy/pathology/metabolism
Animals
*RNA-Binding Proteins/metabolism/genetics

@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.},
}

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

@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 {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.},
}

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

@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 {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 {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 {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.},
}

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

@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 {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.},
}

Humans
*Cognitive Dysfunction/therapy
*Acupuncture Therapy/methods/instrumentation
*Needles
*Gold/therapeutic use
Aged
Female
Male
Middle Aged
Treatment Outcome
Biomarkers/blood

@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},
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.},
}

Humans
*Alzheimer Disease/drug therapy
Female
Phenotype
Aged
Male
Retrospective Studies
Biomarkers
Aged, 80 and over
*Patient Selection
Middle Aged
*Eligibility Determination

@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 {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.},
}

Humans
*Alzheimer Disease/metabolism/drug therapy
Animals
*Energy Metabolism/physiology/drug effects
*Brain/metabolism
*Mitochondria/metabolism
Glucose/metabolism

@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.},
}

Humans
*Alzheimer Disease/drug therapy/diagnosis/enzymology/metabolism
*Butyrylcholinesterase/metabolism/drug effects
*Cholinesterase Inhibitors/pharmacology/therapeutic use
Animals
*Acetylcholinesterase/metabolism/drug effects

@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.},
}

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

@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.},
}

Humans
*Alzheimer Disease/drug therapy/metabolism
*Histone Deacetylase Inhibitors/pharmacology/therapeutic use
Animals
*Histone Deacetylases/metabolism
Epigenesis, Genetic/drug effects
*Neuroprotective Agents/pharmacology

@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.},
}

Humans
*Alzheimer Disease/metabolism/pathology
*Energy Metabolism/physiology
*Mitochondria/metabolism
*tau Proteins/metabolism
Animals

@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.},
}

Humans
*Alzheimer Disease/metabolism
*Energy Metabolism/physiology
Animals
*Lipid Metabolism/physiology
*Brain/metabolism
Mitochondria/metabolism

@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},
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.},
}

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

@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 {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.},
}

Humans
*Alzheimer Disease/diagnosis/therapy/epidemiology
Mexico/epidemiology
Biomarkers/blood
tau Proteins
Disease Progression

@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},
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.},
}

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

@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 {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.},
}

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

@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},
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},
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 {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.},
}

Humans
*Medicine, Chinese Traditional/methods
*Aging/drug effects
Animals
*Nervous System Diseases/drug therapy
*Drugs, Chinese Herbal/therapeutic use
Oxidative Stress/drug effects

@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.},
}

Humans
*Alzheimer Disease/pathology/metabolism
*Autophagy/physiology
*Neuroglia/pathology/metabolism
Animals
*Lysosomes/metabolism/pathology
*Inflammation/pathology/metabolism
Signal Transduction

@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 {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 {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 {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.},
}

*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

@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.},
}

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

@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.},
}

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

@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.},
}

Humans
*Software
Male
*Sex Characteristics
*Alzheimer Disease/genetics/metabolism
Female
*Computational Biology/methods
Genomics/methods
Single-Cell Analysis

@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.},
}

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

@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 {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},
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},
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},
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},
mesh = {Humans ; *Alzheimer Disease/drug therapy ; *Antibodies, Monoclonal/therapeutic use ; Evidence-Based Medicine ; Cognitive Dysfunction/drug therapy ; },
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.},
}

Humans
*Alzheimer Disease/drug therapy
*Antibodies, Monoclonal/therapeutic use
Evidence-Based Medicine
Cognitive Dysfunction/drug therapy

@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},
mesh = {Humans ; *Stroke/complications ; *Stroke Rehabilitation/methods ; *Cognitive Dysfunction/prevention & control/etiology ; *Dementia/prevention & control/etiology ; Bayes Theorem ; *Exercise Therapy/methods ; Randomized Controlled Trials as Topic ; Clinical Trials, Phase III as Topic ; Resistance Training/methods ; Brain ; Multicenter Studies as Topic ; Biomarkers/blood ; Cognition ; Neuroimaging ; },
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.},
}

Humans
*Stroke/complications
*Stroke Rehabilitation/methods
*Cognitive Dysfunction/prevention & control/etiology
*Dementia/prevention & control/etiology
Bayes Theorem
*Exercise Therapy/methods
Randomized Controlled Trials as Topic
Clinical Trials, Phase III as Topic
Resistance Training/methods
Brain
Multicenter Studies as Topic
Biomarkers/blood
Cognition
Neuroimaging