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

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

RESULTS AND DISCUSSION: The results of pharmacokinetic tests, molecular docking, and 100 ns molecular dynamics experiments confirm that these examined compounds interact favorably with both human acetylcholinesterase and NADPH oxidase enzymes with excellent thermodynamic stability. These results provide further evidence for the potential of the designed compounds to behave as multi-target ligands with AChE inhibition and antioxidant properties that would be effective in the treatment of the complex Alzheimer's disease.},
}

@article {pmid42719334,
year = {2026},
author = {Huang, Q and Xie, Y and Zhang, X and Zuo, Y and Wang, L and Xu, H and Yu, M and Liu, C},
title = {Traditional Chinese medicine ginseng regulates neurotrophic factors to improve neurodegenerative diseases: A potential strategy for Alzheimer's disease treatment.},
journal = {Journal of ginseng research},
volume = {50},
number = {5},
pages = {101078},
pmid = {42719334},
issn = {1226-8453},
abstract = {Alzheimer's disease (AD) is a neurodegenerative disorder characterized by memory impairment and progressive cognitive decline. Its core pathological mechanisms include β-amyloid deposition, abnormal tau phosphorylation, neuroinflammation, and decreased levels of neurotrophic factors. In recent years, the deficiency of neurotrophic factors has been recognized as a key driver of impaired neuronal survival and synaptic dysfunction. Consequently, restoring or enhancing neurotrophic factor signaling has emerged as a major therapeutic target for AD. As a traditional medicinal plant, ginseng exhibits multi-targeted, multi-level neuroprotective effects. Its active components-including ginsenosides, ginseng polysaccharides, and ginseng proteins-have been demonstrated to promote neuronal survival, inhibit apoptosis, and enhance synaptic plasticity by upregulating signaling pathways such as BDNF/TrkB and NGF/TrkA. Additionally, ginseng suppresses inflammatory responses and oxidative stress, thereby indirectly correcting neurotrophic factor imbalances and demonstrating significant neuroprotective potential. This review summarizes recent advances in ginseng's regulation of neurotrophic factor levels and signaling pathways, focusing on its molecular mechanisms for improving neuronal dysfunction and delaying AD progression. It also outlines future research strategies and prospects for clinical translation. In summary, ginseng's neuroprotective effects achieved through regulating the neurotrophic factor network offer a potential natural drug intervention strategy for AD treatment.},
}

@article {pmid42720212,
year = {2026},
author = {Song, B and Wang, W and Liu, S and Jin, X and Qi, Y and Li, M and Yue, D and Liu, Y and Li, X and Yin, L and Feng, L},
title = {Novel Therapeutic Insights Into Alzheimer's Disease: Glymphatic System and Meningeal Lymphatic Vessels.},
journal = {Aging cell},
volume = {25},
number = {9},
pages = {e70699},
doi = {10.1111/acel.70699},
pmid = {42720212},
issn = {1474-9726},
support = {ZR2023QH159//Natural Science Foundation of Shandong Province/ ; ZR2020MH357//Natural Science Foundation of Shandong Province/ ; 82274538//National Natural Science Foundation of China/ ; 2023NS469//Taian City Science and Technology Innovation Development Project/ ; Z20243705//Shandong Province Traditional Chinese Medicine Science and Technology Project/ ; YPM202532//Clinical Research Special Project of Shanghai Yangpu District Health System/ ; 202313011384//Shandong Province Medical Health Science and Technology Development Plan Project/ ; },
mesh = {Humans ; *Alzheimer Disease/therapy/pathology/metabolism ; *Glymphatic System/metabolism/pathology ; *Lymphatic Vessels/metabolism/pathology ; Animals ; *Meninges/pathology/metabolism ; },
abstract = {With the acceleration of global aging, the relationship between Alzheimer's disease (AD) and the glymphatic system (GS) has become a research hotspot in the field of neuroscience in recent years. Traditionally, the central nervous system was thought to lack a lymphatic system; however, research over the past decade has overturned this view. Studies have revealed the existence of GS and meningeal lymphatic vessels (mLVs) in the brain, which clear metabolic waste (such as amyloid-β and tau proteins) through the exchange of cerebrospinal fluid (CSF) and interstitial fluid (ISF). Dysfunction of the GS can lead to abnormal deposition of pathological proteins, which may trigger or exacerbate AD. Currently, the association between the GS and AD treatment mainly focuses on drug development (such as small molecules that promote glymphatic circulation), physical therapies (such as 40 Hz photoacoustic therapy), and surgical interventions (primarily deep cervical lymphatic-vein anastomosis and cranial bone maneuver), all of which are under exploration. With the precision of diagnostic technologies and the targeting of therapeutic methods, future intervention strategies surrounding GS may become a significant breakthrough in overcoming the treatment impasse of AD, bringing new hope to tens of millions of AD patients worldwide.},
}

Humans
*Alzheimer Disease/therapy/pathology/metabolism
*Glymphatic System/metabolism/pathology
*Lymphatic Vessels/metabolism/pathology
Animals
*Meninges/pathology/metabolism

@article {pmid42720565,
year = {2026},
author = {Pereira Da Silva, AM and Haddad Santos, D},
title = {GLP-1 receptor agonism in Alzheimer's disease after EVOKE: From single hypothesis to stratified program.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261485580},
doi = {10.1177/13872877261485580},
pmid = {42720565},
issn = {1875-8908},
abstract = {The phase 3 EVOKE and EVOKE + trials of oral semaglutide in early Alzheimer's disease missed their primary endpoint and every cognitive or functional secondary endpoint. A recent article by Hölscher revisits extension-phase data and reports partial separation at later timepoints, attributing the failure to limited brain penetration. We argue that attrited extension cohorts bear limited inferential weight and that the biomarker substudy, read in full, complicates a clean disease-modification reading. EVOKE does not refute the cardiometabolic hypothesis but reframes the open questions: which pathways, which patients, and which disease stages are most likely to benefit.},
}

@article {pmid42720842,
year = {2026},
author = {Demirdaş, A and Nazıroğlu, M},
title = {Brain-derived neurotrophic factor via TRPM2 inhibition reduces amyloid-beta-mediated increases of apoptosis and mitochondrial oxidative neurotoxicity in neuronal cells.},
journal = {Metabolic brain disease},
volume = {41},
number = {1},
pages = {},
pmid = {42720842},
issn = {1573-7365},
support = {TDK-2021-8386//Süleyman Demirel Üniversitesi/ ; },
mesh = {*Apoptosis/drug effects/physiology ; *TRPM Cation Channels/antagonists & inhibitors/metabolism ; Humans ; *Amyloid beta-Peptides/toxicity/pharmacology ; *Oxidative Stress/drug effects/physiology ; *Neurons/drug effects/metabolism ; *Brain-Derived Neurotrophic Factor/pharmacology ; Cell Line, Tumor ; *Mitochondria/drug effects/metabolism ; Reactive Oxygen Species/metabolism ; Calcium/metabolism ; Membrane Potential, Mitochondrial/drug effects ; },
abstract = {Brain-derived neurotrophic factor (BDNF) has particular importance in the modulation of Alzheimer's disease (AD)-related pathologies such as apoptosis and mitochondrial reactive oxygen species (mROS). The cation channel, transient receptor potential melastatin 2 (TRPM2), stimulation is important for the generation of AD-related pathologies. Antioxidant treatments through the inhibition of TRPM2 play an essential role in the inhibition of Ca[2+] entry, mROS, and apoptosis changes in the SH-SY5Y neuronal cells. However, the effects of antioxidant and antiapoptotic roles of BDNF have not yet been studied in SH-SY5Y treated with amyloid-beta (Aβ). The aim of the present study was to investigate the protective action of BDNF via TRPM2 inhibition on the apoptotic and oxidant values in Aβ-induced SH-SY5Y cells. Five groups of SH-SY5Y cells were established: control, BDNF, Aβ, Aβ + BDNF, and Aβ + TRPM2 channel blockers. The Aβ-induced increases in intracellular Ca[2+] and TRPM2 currents were decreased by BDNF and PARP-1 inhibition. The levels of mROS, intracellular ROS, dysfunction of mitochondrial membrane, SH-SY5Y death, apoptosis, and caspases (caspases-3, -8, and - 9) were increased in the cells treated with Aβ, although glutathione (GSH) and glutathione peroxidase (GSH-Px) were decreased by the treatment. However, the levels of these oxidative and apoptotic markers through the increases in GSH and GSH-Px were reduced in the cells by the incubations of BDNF and TRPM2 channel blockers. Finally, it was shown that BDNF protects neuronal cells against Aβ-induced excessive Ca[2+] entry, oxidative stress, and apoptotic parameters via inhibiting TRPM2. Treatment with BDNF appears to have the capacity to reduce apoptosis and oxidative stress caused by Aβ through inhibiting TRPM2.},
}

*Apoptosis/drug effects/physiology
*TRPM Cation Channels/antagonists & inhibitors/metabolism
Humans
*Amyloid beta-Peptides/toxicity/pharmacology
*Oxidative Stress/drug effects/physiology
*Neurons/drug effects/metabolism
*Brain-Derived Neurotrophic Factor/pharmacology
Cell Line, Tumor
*Mitochondria/drug effects/metabolism
Reactive Oxygen Species/metabolism
Calcium/metabolism
Membrane Potential, Mitochondrial/drug effects

@article {pmid42720909,
year = {2026},
author = {Lista, S and Filippi, L and Emanuele, E and López-Ortiz, S and Cisale, GY and Minoretti, P and Garaci, F and Santos-Lozano, A},
title = {Amyloid-β PET Radioligands in Alzheimer's Disease: From Plaque Detection to Biomarker-Guided Patient Stratification and Therapeutic Monitoring.},
journal = {Molecular diagnosis & therapy},
volume = {},
number = {},
pages = {},
pmid = {42720909},
issn = {1179-2000},
support = {Ricerca Corrente//Ministero della Salute/ ; },
abstract = {Amyloid-β (Aβ) positron emission tomography allows direct in vivo visualization of insoluble fibrillar Aβ deposition and has been used to detect Alzheimer's disease pathology across the clinical continuum, from preclinical stages to overt dementia. Aβ tracers progressed from the prototypical [[11]C]Pittsburgh Compound-B ([[11]C]PiB), which is limited by [[11]C] half-life, to [[18]F]-labeled agents, including [[18]F]Florbetapir, [[18]F]Florbetaben, and [[18]F]Flutemetamol, which allowed centralized production and wide clinical use, with [[18]F]NAV4694 currently in development. In this narrative review, we sought to examine the principal Aβ positron emission tomography radioligands and their methodological framework, including visual reads, the standardized uptake value ratio, and the Centiloid scale, which harmonized quantitative output across tracers, scanners, and protocols and may enable cross-site comparison in multicenter studies and disease-modifying trials. The regulatory approval of lecanemab and donanemab has recently expanded the clinical use of Aβ positron emission tomography. Beyond diagnostic confirmation, the modality can currently confirm eligibility for anti-Aβ therapy, enrich trial populations, monitor target engagement through serial Centiloid measurements, and inform treatment discontinuation at predefined clearance thresholds. However, significant limitations remain, including the imperfect correlation between a high Aβ plaque burden and clinical cognitive decline that constrains its standalone diagnostic utility, tracer-specific variability, restricted accessibility, and the inability of fibril-targeted tracers to image the soluble oligomeric species most directly engaged by anti-Aβ antibodies. Probes for non-fibrillar species and computational tools for assisted interpretation are likely to shape the field in the near future.},
}

@article {pmid42721942,
year = {2026},
author = {Zhang, S and Huang, L and Wang, M and Li, Y and Guo, Q and Wang, Z and Lv, H and Jiang, J},
title = {DIPOG: A dynamic pooling graph neural network with spatial-temporal-frequency awareness for diagnosis of Alzheimer's disease.},
journal = {Medical image analysis},
volume = {115},
number = {},
pages = {104280},
doi = {10.1016/j.media.2026.104280},
pmid = {42721942},
issn = {1361-8423},
abstract = {Resting-state functional magnetic resonance imaging (rsfMRI) discloses the spatiotemporal states of the brain and, through brain network modeling, enables the analysis of time-varying patterns associated with Alzheimer's disease (AD). To extract the spatial-temporal-frequency and dynamic features of brain networks and achieve generalizable AD diagnosis, this paper proposes a dynamic pooling graph neural network with spatial-temporal-frequency awareness. Specifically, a novel autoencoder is proposed to capture the accurate temporal features of rsfMRI through time interval representation learning. To improve the model's ability to fit abnormal spatial-temporal-frequency features associated with AD, a masked self-supervised learning strategy has been designed, and the reconstruction tasks are defined according to the masked brain regions and time periods. Considering the time-varying patterns in rsfMRI, a dynamic pooling method is employed, which utilizes dynamic time warping to merge the features of time steps exhibiting the same pattern, thereby avoiding the loss of time-varying features. A total of 2,857 samples from eight centers were included, and AD classification experiments were conducted. We compared 12 state-of-the-art models, and the results showed that the accuracy of our model was 6.4% higher than that of the best-performing comparison models. Furthermore, we used an explainability method to identify salient brain regions, and demonstrated that these regions were correlated with neuropsychological scale. In addition, AD progression could be reflected by the spatial-temporal-frequency features and time-varying patterns. This study presents a spatiotemporal learning framework that facilitates the individualized and precise diagnosis and treatment of AD.},
}

@article {pmid42722093,
year = {2026},
author = {Dai, C and Yang, Y and Lin, X and Xiang, K and Zhuo, L and Fang, Z and Liu, J and Sun, J},
title = {Betulin supplementation reduces oxidative stress in Alzheimer's disease via the activation of KEAP1/NRF2 pathway.},
journal = {The Journal of nutritional biochemistry},
volume = {},
number = {},
pages = {110504},
doi = {10.1016/j.jnutbio.2026.110504},
pmid = {42722093},
issn = {1873-4847},
abstract = {Betulin (BE) is extracted from pentacyclic triterpenoids of many natural plants and has antioxidation activities. However, the neuroprotective effects and underlying mechanism of Betulin in Alzheimer's disease (AD) have remained limited. Integrate SuperPred, SEA, and Targeted Net databases, as well as KEGG pathway enrichment analysis, to predict and analyze BE-related target genes. Male APP/PS1 mice were treated intragastrically with Betulin for 4 weeks, followed by evaluation of cognitive function and pathological changes, and the levels of ROS, HO‑1, SOD2 and GPX4 were detected. Subsequently, molecular docking and molecular dynamics simulations were utilized to investigate the potential interaction between Betulin and KEAP1 protein, and KEAP1 mutant transfection was used to assess the involvement of KEAP1/NRF2 signaling in the antioxidant response to BE. Finally, KEAP1 and NRF2 protein levels were examined in the animal model. Our results showed that KEGG pathway enrichment analysis revealed that Betulin-related target genes were enriched in pathways associated with AD. Moreover, Betulin significantly alleviated cognitive impairment, neuronal damage, Aβ deposits and Tau phosphorylation in the APP/PS1 mice. Moreover, Betulin significantly increased GSH level, while significantly decreased MDA level. Meanwhile, Betulin significantly decreased ROS level, while significantly increased the levels of HO-1, SOD2, and GPX4 in vitro. Notably, molecular docking and molecular dynamics simulations suggested a potential interaction between Betulin and KEAP1, while KEAP1 mutant transfection attenuated the Betulin-induced increase in NRF2 and antioxidant proteins in vitro. Moreover, Betulin treatment was accompanied by decreased KEAP1 and increased NRF2 protein levels in APP/PS1 mice. These findings indicate that Betulin alleviates oxidative stress and modulates KEAP1/NRF2 signaling in AD models.},
}

@article {pmid42712219,
year = {2026},
author = {Wang, H and Li, L and He, X and Shen, S and Chao, L and You, P and Ji, K and Liu, Y and Hong, Z},
title = {UHPLC-Q/TOF-MS Characterization of Danshen-Chuanxiong and Mechanistic Insights Into Its Protective Effects Against Aβ1-42-Induced Brain Endothelial Injury Through Metabolomics.},
journal = {Journal of separation science},
volume = {49},
number = {9},
pages = {e70527},
doi = {10.1002/jssc.70527},
pmid = {42712219},
issn = {1615-9314},
support = {82173777//National Natural Science Foundation of China/ ; 82504742//National Natural Science Foundation of China/ ; 82473885//National Natural Science Foundation of China/ ; },
mesh = {*Amyloid beta-Peptides/antagonists & inhibitors/metabolism ; Humans ; *Metabolomics ; Chromatography, High Pressure Liquid ; *Endothelial Cells/drug effects/metabolism ; *Drugs, Chinese Herbal/pharmacology/chemistry/metabolism/analysis ; *Peptide Fragments/antagonists & inhibitors ; Salvia miltiorrhiza/chemistry ; *Brain/drug effects/metabolism ; Cell Survival/drug effects ; Mass Spectrometry ; },
abstract = {Danshen-Chuanxiong is a traditional herb pair used for cardiovascular and cerebrovascular disorders, but its chemical basis and potential effects in Alzheimer's disease (AD)-related endothelial injury remain incompletely defined. Here, an integrated analytical workflow combining reversed-phase liquid chromatography (RPLC) and hydrophilic interaction liquid chromatography (HILIC) with quadrupole time-of-flight mass spectrometry (Q-TOF-MS), cellular assays, metabolomics, and network pharmacology was applied in an amyloid-β1-42 (Aβ1-42) oligomer-induced human brain microvascular endothelial cell (hBMEC) injury model. The complementary RPLC/HILIC and positive/negative electrospray-ionization strategy expanded coverage across a broad polarity range. UHPLC-Q/TOF-MS detected 90 compounds, mainly phenolic acids, phthalides, tanshinones, diterpenoids, and other aromatic or terpenoid constituents. The reductions in cell viability and zonula occludens-1 expression following Aβ1-42 exposure confirmed the successful establishment of the cellular injury model, whereas pretreatment with Danshen, Chuanxiong, or their combination increased cell viability and alleviated Aβ1-42-induced cellular injury. Untargeted metabolomics annotated 38 differential metabolites, of which 30 showed a recovery-associated shift toward the control state after Danshen-Chuanxiong treatment; the associated pathways included amino-acid, purine, glutathione, and glycerophospholipid metabolism. Integrative analysis prioritized seven candidate targets of Danshen-Chuanxiong, namely ACHE, VEGFA, NOS2, NOS3, AKR1B1, MDM2, and XDH. These findings provide a separation-MS-based chemical characterization and mechanistic framework for further validation of Danshen-Chuanxiong in AD-related endothelial injury models.},
}

*Amyloid beta-Peptides/antagonists & inhibitors/metabolism
Humans
*Metabolomics
Chromatography, High Pressure Liquid
*Endothelial Cells/drug effects/metabolism
*Drugs, Chinese Herbal/pharmacology/chemistry/metabolism/analysis
*Peptide Fragments/antagonists & inhibitors
Salvia miltiorrhiza/chemistry
*Brain/drug effects/metabolism
Cell Survival/drug effects
Mass Spectrometry

@article {pmid42714032,
year = {2026},
author = {Li, Y and Ye, T and Lu, H and Wang, S and Yu, T and Li, H and Cheng, X},
title = {Effects of Qi-fu-yin on Improving Cognitive Impairment and Reducing Cellular Senescence in the Brains of 5xFAD Mice.},
journal = {Journal of visualized experiments : JoVE},
volume = {},
number = {235},
pages = {},
doi = {10.3791/72118},
pmid = {42714032},
issn = {1940-087X},
mesh = {Animals ; Mice ; *Brain/drug effects/metabolism/pathology ; *Alzheimer Disease/drug therapy/metabolism/pathology ; *Cellular Senescence/drug effects ; *Drugs, Chinese Herbal/pharmacology ; Mice, Transgenic ; Amyloid beta-Peptides/metabolism ; *Cognitive Dysfunction/drug therapy/metabolism/pathology ; Male ; },
abstract = {Although the mechanism of Qi-fu-yin (QFY), a traditional Chinese medicine prescription, remains incompletely understood, it has shown therapeutic potential in Alzheimer's disease (AD). This study aimed to investigate the association between QFY treatment and cognitive impairment in 5xFAD mice. We used grip strength, gait, colony nesting, shuttle box, Morris water maze test, and ELISA to evaluate the levels of Amyloid-β protein 1-42 (Aβ1-42), Aβ1-40, Growth-associated protein 43 (GAP-43), Synaptophysin (SYN), and Postsynaptic density protein 95 (PSD-95) in the brains of 5xFAD mice. Luminex cytokine analysis was used to quantify Senescence-associated secretory phenotype (SASP) levels in the cortex. The amount of Senescence-associated β-galactosidase (SA-β-Gal), Aβ deposition, and dendritic spines in the animals' brains was measured by SA-β-Gal staining, immunohistochemistry, and Golgi-Cox staining, respectively. QFY treatment dramatically reduced cortical Aβ plaque burden and decreased p21 expression in 5xFAD mice, according to immunofluorescence tests. In 5xFAD mice, QFY therapy markedly enhanced learning and memory performance, alleviated aging, and increased the amounts of GAP-43, PSD-95, and SYN proteins in the mice's cortex. Following QFY treatment, there was a significant decrease in Aβ plaque and SA-β-Gal activity in the brain, as well as Aβ1-42 and Aβ1-42/Aβ1-40 levels in the hippocampus. The levels of IL-1α, IL-1β, IL-6, IL-17A, and IFN-γ were considerably reduced in the cortex of the 5xFAD mice. PCA and Pearson correlation analyses demonstrated a strong negative association between SASP cytokines and synaptic protein levels. These findings suggest an association between QFY treatment and improvements in age‑related cognitive decline and cellular senescence phenotypes in 5xFAD mice, alongside mitigated synaptic structural damage. These findings support further investigation of QFY as a potential therapeutic candidate for Alzheimer's disease.},
}

Animals
Mice
*Brain/drug effects/metabolism/pathology
*Alzheimer Disease/drug therapy/metabolism/pathology
*Cellular Senescence/drug effects
*Drugs, Chinese Herbal/pharmacology
Mice, Transgenic
Amyloid beta-Peptides/metabolism
*Cognitive Dysfunction/drug therapy/metabolism/pathology
Male

@article {pmid42714614,
year = {2026},
author = {Schnieder, M},
title = {[Antibody therapy in Alzheimer's disease].},
journal = {Zeitschrift fur Gerontologie und Geriatrie},
volume = {},
number = {},
pages = {},
pmid = {42714614},
issn = {1435-1269},
abstract = {Alzheimer's disease, the leading cause of dementia, is defined by extracellular amyloid‑β (Aβ) plaques, intracellular tau aggregates and neurodegeneration. Lecanemab and donanemab, are the first disease-modifying antibodies available for early Alzheimer's disease. Both reduce Aβ plaques and slow cognitive decline. Lecanemab targets soluble protofibrils and donanemab targets fibrillar Aβ. The primary side effect is amyloid-related imaging abnormalities (ARIA), which can occur as edema (ARIA-E) or hemorrhages (ARIA-H). The risk is higher in APOE4 homozygotes, anticoagulation or cerebrovascular diseases. Therefore, during treatment a regular monitoring with magnetic resonance imaging (MRI) is mandatory.},
}

@article {pmid42714783,
year = {2026},
author = {Verma, E and Mishra, S and Chellammal, HSJ and Khandige, PS and Gasmi, A},
title = {Gut microbiota as a modulator of HDAC: insights into Alzheimer's disease treatment.},
journal = {Pharmacological reports : PR},
volume = {},
number = {},
pages = {},
pmid = {42714783},
issn = {2299-5684},
abstract = {The human gut microbiota (GMB) has a significant impact on physiological function, including gastrointestinal health, immune regulation, and redox homeostasis. It consists of diverse microorganisms that support digestion, nutrient absorption, and intestinal barrier function. Emerging evidence suggests that gut microbiota-derived metabolites may influence the gut-brain axis and regulate epigenetic mechanisms through modulation of histone deacetylases (HDAC). HDAC are key enzymes involved in gene expression, neuronal survival, neuroinflammation, and the pathogenesis of Alzheimer's disease (AD). Gut microbiota-derived metabolites have been reported to modulate HDAC activity and may contribute to neuroprotective and anti-inflammatory effects. Through these mechanisms, the GMB may influence cognitive function and the progression of AD. However, the precise molecular mechanisms involved in these interactions are not yet fully understood and continue to be extensively investigated. Therefore, this review focuses on the correlation between HDAC and the restoration of a healthy GMB as a therapeutic approach for the treatment and prevention of AD. It emphasizes the role of gut-derived metabolites, peptides, and dietary bioactive compounds in regulating HDAC-mediated epigenetic pathways. These interactions may influence gene expression, neurotransmitter biosynthesis, neuroinflammation, and neuroprotective signalling associated with cognitive function. Furthermore, the review delineates the bidirectional interplay among neurotransmitter signalling, GMB composition, and HDAC-mediated epigenetic regulation, along with their potential roles in the pathophysiology of neurodegenerative disorders.},
}

@article {pmid42716045,
year = {2026},
author = {Teunissen, CE and Vermunt, L and Barthélemy, NR and Benzinger, TLS and Graff-Radford, J and Verberk, IMW and Zetterberg, H and Schindler, SE and Jack, CR},
title = {Fluid biomarkers in the evolving care landscape of Alzheimer's disease and related disorders.},
journal = {The Lancet. Neurology},
volume = {25},
number = {10},
pages = {926-938},
doi = {10.1016/S1474-4422(26)00246-2},
pmid = {42716045},
issn = {1474-4465},
mesh = {Humans ; *Biomarkers/cerebrospinal fluid/blood ; *Alzheimer Disease/cerebrospinal fluid/diagnosis/blood ; tau Proteins/cerebrospinal fluid ; Animals ; },
abstract = {Fluid biomarkers for Alzheimer's disease have advanced rapidly during the past several years driven by breakthroughs including development of ultrasensitive and multiplexing technologies and high specificity antibodies. Blood-based biomarkers, such as neurofilament light for frontotemporal dementia and amyotrophic lateral sclerosis, and phosphorylated tau 217 for the diagnosis of Alzheimer's disease, are now being implemented in clinical practice, which is particularly timely because of the increasing clinical availability of amyloid-targeting treatments in Alzheimer's disease. Multiple fluid biomarkers are needed to capture the complexity of disease mechanisms for precise diagnosis and to measure the diverse pathologies that lead to dementia, such as vascular, α-synuclein, and TDP-43 pathologies. Moreover, fluid biomarkers can aid in capturing heterogeneity in treatment course between patients, probably due to copathologies or key intermediates, including microglia and astrocyte dysregulation. Increased focus on biomarker-pathology relationships in experimental models will likely accelerate biomarker development and further the understanding of their precise substrates. Future clinical implementation of biomarkers to capture the full complexity of pathologies will likely be facilitated by the expansion of diagnostic methods, development of point of care technologies, and remote sampling approaches.},
}

Humans
*Biomarkers/cerebrospinal fluid/blood
*Alzheimer Disease/cerebrospinal fluid/diagnosis/blood
tau Proteins/cerebrospinal fluid
Animals

@article {pmid42716046,
year = {2026},
author = {Benzinger, TLS and Cogswell, PM and Arani, A and Chaney, AM and Hutson, K and Glasser, MF and Graff-Radford, J and McConathy, J and Raji, CA and Teunissen, C and Vemuri, P and Zaharchuk, G and Jack, CR},
title = {Neuroimaging in the era of biologically defined Alzheimer's disease and disease-modifying therapy.},
journal = {The Lancet. Neurology},
volume = {25},
number = {10},
pages = {939-951},
doi = {10.1016/S1474-4422(26)00285-1},
pmid = {42716046},
issn = {1474-4465},
mesh = {Humans ; *Alzheimer Disease/diagnostic imaging/therapy/drug therapy ; *Neuroimaging/methods ; *Brain/diagnostic imaging/pathology ; Positron-Emission Tomography/methods ; Magnetic Resonance Imaging/methods ; Biomarkers ; },
abstract = {Disease-modifying therapies and biomarker-based diagnostic frameworks will fundamentally altered the clinical diagnosis and management of Alzheimer's disease. Diagnosis is increasingly anchored in the biological evidence of pathology rather than clinical presentation alone, with implications for treatment eligibility, prognosis, and monitoring. In clinical practice, patients with memory complaints can present with complex mixed pathologies that develop across the lifespan. Brain imaging, particularly MRI and PET, plays a crucial role in visualising these cumulative abnormalities. With Alzheimer's disease-specific therapies now available in many regions of the world, amyloid PET plays a central role in establishing Alzheimer's disease diagnosis, determining eligibility for amyloid-targeting therapies, and quantifying treatment-related amyloid clearance. In settings where available, tau PET informs biological stage, prognosis, and clinical heterogeneity. MRI remains indispensable for differential diagnosis, the assessment of comorbid and vascular pathology, and monitoring for complications, particularly amyloid-related imaging abnormalities. Technological advances-including quantitative imaging, artificial intelligence, accelerated acquisition, and workflow optimisation-are improving reliability, efficiency, and access to these tools. Neuroimaging is now a cornerstone of Alzheimer's disease care and a crucial discriminator tool for characterising brain injury across the lifespan. With emerging fluid biomarkers, neuroimaging supports accurate diagnosis, prognosis, and treatment monitoring.},
}

Humans
*Alzheimer Disease/diagnostic imaging/therapy/drug therapy
*Neuroimaging/methods
*Brain/diagnostic imaging/pathology
Positron-Emission Tomography/methods
Magnetic Resonance Imaging/methods
Biomarkers

@article {pmid42716047,
year = {2026},
author = {Graff-Radford, J and Karliner, L and Barnes, DE and Frisoni, GB and Sperling, R and Villain, N and Benzinger, TLS and Teunissen, C and Jack, CR},
title = {Clinical pathways for cognitively unimpaired individuals with Alzheimer's disease neuropathological change.},
journal = {The Lancet. Neurology},
volume = {25},
number = {10},
pages = {952-964},
doi = {10.1016/S1474-4422(26)00248-6},
pmid = {42716047},
issn = {1474-4465},
mesh = {Humans ; *Alzheimer Disease/pathology/therapy/diagnosis/drug therapy ; Biomarkers ; *Brain/pathology ; },
abstract = {The recent approval of disease-modifying therapies for symptomatic Alzheimer's disease is a major advance for a condition with few therapeutic options. Anti-amyloid monoclonal antibodies have shown clinically meaningful benefits in slowing cognitive decline. Clinical trials in symptomatic Alzheimer's disease suggest that anti-amyloid therapies might provide the greatest benefit in subgroups who have low baseline levels of Alzheimer's disease pathology; ongoing prevention trials are evaluating these therapies in cognitively unimpaired individuals who have biomarker evidence of Alzheimer's disease neuropathological change (ADNC). However, the possibility of biomarker testing and treatment in cognitively unimpaired people raises key questions about ethics and the consequences that follow from a positive test or an uncertain result (ie, the so-called downstream effects on patients and health systems). Furthermore, test accuracy might be questioned when ADNC has a low prevalence in the population being tested and in the case of intermediate-range biomarker concentrations that might not reliably indicate true ADNC or be false positives. If anti-amyloid therapies prove beneficial for cognitively unimpaired people with ADNC and become part of routine practice, several key knowledge gaps must be addressed to support safe, scalable, real-world implementation of Alzheimer's disease treatment.},
}

Humans
*Alzheimer Disease/pathology/therapy/diagnosis/drug therapy
Biomarkers
*Brain/pathology

@article {pmid42716318,
year = {2026},
author = {Bu, X and Yuan, Y and Song, W and Wang, W},
title = {Music intervention as a therapeutic approach to cognitive impairments in APP/PS1 mice.},
journal = {Brain research bulletin},
volume = {245},
number = {},
pages = {112113},
doi = {10.1016/j.brainresbull.2026.112113},
pmid = {42716318},
issn = {1873-2747},
abstract = {Alzheimer's disease (AD) is typified by progressive deterioration in memory and executive capacities. Although music-based interventions represent a promising non-pharmacological strategy for AD, the underlying mechanisms remain insufficiently understood. APP/PS1 transgenic mice were subjected to 30 consecutive days of musical stimulation, with wild-type C57BL/6 J and untreated APP/PS1 mice serving as controls. Neurobehavioral assessments revealed that music intervention substantially improved memory performance in transgenic AD mice. Mechanistically, music attenuated oxidative stress in both serum and hippocampus of APP/PS1 mice, as evidenced by decreased nitric oxide (NO) and malondialdehyde (MDA) levels along with enhanced antioxidant activities of superoxide dismutase (SOD), glutathione peroxidase (GSH-Px), catalase (CAT), and total antioxidant capacity (T-AOC). Peripheral and hippocampal inflammatory responses were also effectively inhibited following musical treatment. Music restored synaptic plasticity-related protein expression, increased postsynaptic density thickness, narrowed synaptic cleft, and elevated dendritic spine density. Additionally, music exposure alleviated Aβ deposition and neuronal loss in APP/PS1 mice. These findings indicate that music-based auditory enrichment exerts neuroprotective effects against AD through synergistically modulating oxidative stress, neuroinflammation, synaptic plasticity, and neuronal survival, providing mechanistic insights into its intervention potential for AD.},
}

@article {pmid42718894,
year = {2026},
author = {Lin, W and Grewal, SS and Byrne, RW},
title = {Two serial MoCA assessments may support biomarker-sparing triage between Parkinson's disease/Lewy body dementia and frontotemporal dementia: a progressive inclusion analysis of 1,129 participants.},
journal = {Frontiers in aging neuroscience},
volume = {18},
number = {},
pages = {1848105},
pmid = {42718894},
issn = {1663-4365},
abstract = {Reliable differentiation of Parkinson's disease/Lewy body dementia (PD/LBD) from frontotemporal dementia (FTD) affects treatment strategy and clinical trial eligibility, yet confirmatory biomarker testing remains costly and unevenly available. Whether routine cognitive trajectories can support testing prioritization has not been systematically quantified. We performed a progressive inclusion analysis of 1,129 National Alzheimer's Coordinating Center participants with PD/LBD (n = 385) or FTD (n = 744) to determine the minimum number of serial Montreal Cognitive Assessment (MoCA) administrations required for diagnostic separation. Random forest classifiers used seven MoCA subdomain slopes from the first k chronological assessments (k = 2 through k = 8), with five-fold stratified cross-validation and 500-iteration bootstrap confidence intervals. In the primary full-cohort analysis, two assessments yielded AUC = 0.785 (95% CI 0.757-0.814; sensitivity = 0.922; specificity = 0.525). The interval-restricted 6-12 month subset yielded AUC = 0.837 (95% CI 0.787-0.885), near the lower edge of published biomarker-panel ranges in an indirect comparison, although its lower confidence bound remained below 0.85. Discrimination persisted after age matching (AUC = 0.794, 95% CI 0.761-0.826; residual age gap = -0.3 years) and age restriction to 55-75 years (AUC = 0.777, 95% CI 0.741-0.814). Age alone yielded lower discrimination (AUC = 0.721, 95% CI 0.691-0.751) than MoCA slopes, while slopes plus age yielded AUC = 0.867 (95% CI 0.845-0.888). Four-assessment performance was AUC = 0.831 (95% CI 0.791-0.873), consistent with an apparent sample-size-limited plateau as eligible N contracted from 391 at k = 4 to 98 at k = 6. These findings support serial MoCA trajectory analysis as an exploratory tool for prioritizing confirmatory diagnostic testing, with age sensitivity, subtype sensitivity, and operating-point performance quantified.},
}

@article {pmid42719214,
year = {2026},
author = {Mittal, D and Solanki, P and Jain, GK and Jhawat, V and Kesharwani, P and Dutt, R and Arora, S and Singh, RP},
title = {Herbal nanoparticles in the treatment of neurodegeneration: from molecular mechanisms to therapeutic translation.},
journal = {3 Biotech},
volume = {16},
number = {10},
pages = {420},
pmid = {42719214},
issn = {2190-572X},
abstract = {UNLABELLED: Neurodegenerative diseases (NDDs), including Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis, are characterized by progressive neuronal loss involving multiple pathological mechanisms, including protein aggregation, oxidative stress, neuroinflammation, and mitochondrial dysfunction. Although conventional therapies provide symptomatic relief, they fail to halt disease progression and are limited by poor blood-brain barrier (BBB) penetration, off-target effects, and systemic toxicity. Likewise, several herbal bioactives, such as curcumin, resveratrol, quercetin, and epigallocatechin gallate, exhibit promising neuroprotective properties but suffer from poor aqueous solubility, low oral bioavailability, rapid metabolism, and inadequate brain delivery. Nanotechnology-based delivery systems have emerged as a promising approach to overcome these pharmacokinetic limitations by enhancing stability, controlled release, BBB transport, and brain accumulation of herbal therapeutics. This review critically summarizes recent advances in herbal nanoformulations, emphasizing disease-specific molecular targets, BBB-targeting strategies, comparative nanocarrier systems, pharmacokinetic optimization, intracellular trafficking, and translational challenges. Unlike previous reviews, it integrates recent evidence on nanotoxicology, manufacturing scalability, quality control, regulatory considerations, and emerging technologies, including biomimetic nanoparticles and extracellular vesicles. Despite encouraging preclinical outcomes, clinical evidence remains limited, and no herbal nanoformulation has yet demonstrated definitive efficacy or received regulatory approval for neurodegenerative diseases. Future clinical translation will require standardized formulations, rigorous safety evaluation, and well-designed clinical trials. Unlike previous reviews that primarily summarize individual nanocarrier systems or herbal therapeutics, the present review provides a comprehensive and critical synthesis of the current evidence by integrating disease-specific molecular mechanisms, herbal bioactives, nanocarrier design strategies, blood-brain barrier transport mechanisms, intracellular trafficking, pharmacokinetic considerations, translational barriers, regulatory challenges, clinical evidence, and emerging technologies. Furthermore, the review identifies major knowledge gaps and future research priorities to facilitate the successful clinical translation of herbal nanoformulations for neurodegenerative disorders.

SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at https://doi.org/10.1007/s13205-026-05048-8.},
}

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

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

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

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

CONCLUSION: Patient heterogeneity, translational gaps, and a lack of mechanistic knowledge continue to pose difficulties despite progress. To enhance AD outcomes, future research should focus on integrated, customized therapies that target the circadian rhythm.},
}

@article {pmid42708376,
year = {2026},
author = {Hosoki, S and Sachdev, PS and Ihara, M},
title = {Arterial spin labeling-derived cerebral blood flow as a translational biomarker and candidate surrogate endpoint for cognitive impairment.},
journal = {Current opinion in psychiatry},
volume = {},
number = {},
pages = {},
doi = {10.1097/YCO.0000000000001112},
pmid = {42708376},
issn = {1473-6578},
abstract = {PURPOSE OF REVIEW: Arterial spin labeling (ASL) MRI noninvasively quantifies cerebral blood flow (CBF), but its role as a mechanistic biomarker and surrogate endpoint in trials of cognitive impairment remains undefined. This review evaluates evidence linking regional CBF to cognition across Alzheimer's disease, mild cognitive impairment (MCI), and cerebral small vessel disease (SVD), with particular emphasis on CADASIL as a mechanistically informative model.

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

SUMMARY: Within the FDA-NIH BEST framework, ASL-CBF appears to meet several criteria consistent with a reasonably likely surrogate endpoint, capturing upstream, potentially reversible hemodynamic dysfunction beyond established structural markers. CADASIL provides an optimal context for qualifications. Larger clinical trials linking treatment-induced CBF changes to clinical benefit, further protocol harmonization, and regulatory engagement are needed to translate ASL-CBF into a validated trial endpoint.},
}

@article {pmid42709250,
year = {2026},
author = {Yang, W and Lu, Y},
title = {Cross-disease protein aggregate interactions in neurodegeneration: from molecular mechanisms to therapeutic strategies.},
journal = {Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology},
volume = {47},
number = {10},
pages = {},
pmid = {42709250},
issn = {1590-3478},
mesh = {Humans ; *Neurodegenerative Diseases/metabolism/therapy/pathology ; *tau Proteins/metabolism ; *Amyloid beta-Peptides/metabolism ; *alpha-Synuclein/metabolism ; Animals ; *DNA-Binding Proteins/metabolism ; *Alzheimer Disease/metabolism ; *Protein Aggregation, Pathological/metabolism/therapy ; },
abstract = {BACKGROUND: Neurodegenerative diseases have traditionally been classified by their predominant protein pathology. However, accumulating evidence reveals extensive molecular cross-talk between distinct pathological proteins, particularly in Alzheimer's disease (AD).

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

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

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

CONCLUSIONS: Recognition of cross-disease protein interactions necessitates a paradigm shift toward multi-target therapeutic strategies and precision medicine approaches accounting for individual co-pathology burden.},
}

Humans
*Neurodegenerative Diseases/metabolism/therapy/pathology
*tau Proteins/metabolism
*Amyloid beta-Peptides/metabolism
*alpha-Synuclein/metabolism
Animals
*DNA-Binding Proteins/metabolism
*Alzheimer Disease/metabolism
*Protein Aggregation, Pathological/metabolism/therapy

@article {pmid42709336,
year = {2026},
author = {Colosimo, C},
title = {The Great Transatlantic Divide: The Case of Experimental Neuropharmacology.},
journal = {Clinical drug investigation},
volume = {},
number = {},
pages = {},
pmid = {42709336},
issn = {1179-1918},
abstract = {Despite substantial agreement between the Food and Drug Administration (FDA) and the European Medicines Agency (EMA) on new drug approval in the past decades, a few new drugs for the treatment of some of the most prevalent and severe neurological disorders, such as Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis, as well as much rarer neurogenetic disorders, were handled differently by the two regulatory agencies. The possible reasons for the differing behaviors of the FDA and EMA are several and wide-ranging, and they will be examined in this opinion-based analysis. How patients' perceptions of the complex approaches to drug approval and commercialization may create disappointment and confusion will also be reappraised.},
}

@article {pmid42709795,
year = {2026},
author = {Du, X and Liu, N and Zhang, T and Yang, C and Luo, H},
title = {Size-tailored nanoparticle-antibody conjugates overcome hepatic sequestration in Alzheimer's disease treatment.},
journal = {Proceedings of the National Academy of Sciences of the United States of America},
volume = {123},
number = {37},
pages = {e2603034123},
doi = {10.1073/pnas.2603034123},
pmid = {42709795},
issn = {1091-6490},
support = {0214187096//Huazhong University of Science and Technology (HUST)/ ; XJ2400008870//Hainan University (HU)/ ; },
mesh = {Animals ; *Alzheimer Disease/drug therapy/therapy/metabolism/immunology ; *Nanoparticles/chemistry ; Amyloid beta-Peptides/metabolism/immunology ; *Liver/metabolism/drug effects ; Silicon Dioxide/chemistry ; Mice ; *Antibodies, Monoclonal/chemistry ; Particle Size ; Mice, Transgenic ; Polyethylene Glycols/chemistry ; Brain/metabolism ; Humans ; *Immunoconjugates/chemistry ; },
abstract = {Antibody-based immunotherapy targeting amyloid-β (Aβ) is a promising approach for Alzheimer's disease (AD). However, its efficacy is limited by rapid hepatic sequestration, complement activation, and liver dysfunction. In this study, we synthesized low-immunogenic 450-nm functionalized mesoporous silica nanoparticles (PEG-MSN-1F12) by conjugating the anti-Aβ42 monoclonal antibody 1F12 to polyethylene glycol-modified mesoporous silica nanoparticles to address these challenges. In APP/PS1 mice, intravenous PEG-MSN-1F12 administration markedly enhanced peripheral Aβ clearance, promoted intestinal excretion, reshaped gut microbiota, and alleviated intestinal inflammation, thus reducing AD-associated hepatic burden. Peripheral Aβ removal further led to decreased brain Aβ deposition, attenuated microglial activation, and improved cognition. These findings highlight that the use of particle size-engineered antibody-nanoparticle conjugates is a safe and effective strategy to overcome hepatic sequestration, augment Aβ clearance, and improve AD outcomes.},
}

Animals
*Alzheimer Disease/drug therapy/therapy/metabolism/immunology
*Nanoparticles/chemistry
Amyloid beta-Peptides/metabolism/immunology
*Liver/metabolism/drug effects
Silicon Dioxide/chemistry
Mice
*Antibodies, Monoclonal/chemistry
Particle Size
Mice, Transgenic
Polyethylene Glycols/chemistry
Brain/metabolism
Humans
*Immunoconjugates/chemistry

@article {pmid42709901,
year = {2026},
author = {},
title = {In brief: Subcutaneous lecanemab (Leqembi Iqlik) for initial treatment of Alzheimer's disease.},
journal = {The Medical letter on drugs and therapeutics},
volume = {68},
number = {1763},
pages = {151},
doi = {10.58347/tml.2026.1763c},
pmid = {42709901},
issn = {1523-2859},
}

@article {pmid42710551,
year = {2026},
author = {Kosa, AC and Lopez-Gutierrez, L and Ando, K and Doeraene, E and Aydin, E and Lasri, H and Wathelet-Depauw, A and Pieters, K and Van Morckhoven, D and Dubois, C and Hupkens, E and Jespers, P and Dewachter, L and Stamatopoulos, B and Brion, JP and Leroy, K},
title = {Effect of tau silencing on tau pathology propagation, a treatment efficient at the earliest stages of the disease?.},
journal = {Neurobiology of disease},
volume = {229},
number = {},
pages = {107598},
doi = {10.1016/j.nbd.2026.107598},
pmid = {42710551},
issn = {1095-953X},
abstract = {Cognitive decline in Alzheimer's disease (AD) correlates more strongly with tau pathology than with amyloid plaques, switching the therapeutic focus towards targeting tau pathology. Tau silencing therapies present an increasing interest as potential therapeutical approaches to treat AD due to their efficiency in reducing pathological tau burden. However, the effects of tau silencing on tau pathology formation and spreading, as well as on cognitive deficits, have not been investigated in AD or AD preclinical models expressing WT tau. In this study, we investigated the effects of Tau siRNA on tau pathology propagation in a mouse model of AD expressing 6 human WT tau isoforms, in which tau pathology formation and spreading has been initiated by intracerebral injection of pathological tau from a human AD brain. Specifically, we examined whether tau silencing affects tau pathology progression when started either simultaneously with the induction of tau pathology or subsequent to the onset of tau lesions, thereby mimicking the clinical scenario in which AD patients are typically diagnosed. Three months after tau pathology was induced, spatial learning and tau pathology were assessed. Cognitive performance was rescued, and tau pathology development was reduced when tau silencing started simultaneously with the induction of tau lesions. Nevertheless, Tau siRNA was ineffective on both cognitive performance and tau pathology propagation when administered after some development of tau pathology. Our results indicate that tau silencing therapy should be administered in early stages of the disease to achieve therapeutic efficacy on the development of tau pathology in AD.},
}

@article {pmid42710608,
year = {2026},
author = {Liu, S and Ren, L and Liu, L and Chen, LL and Zhang, Y and Wang, P and Xie, GJ},
title = {Du-Shu-Wan alleviates Tau protein phosphorylation in Alzheimer's disease by regulating MAPK/JNK signaling pathway.},
journal = {Journal of ethnopharmacology},
volume = {},
number = {},
pages = {122380},
doi = {10.1016/j.jep.2026.122380},
pmid = {42710608},
issn = {1872-7573},
abstract = {Alzheimer's disease (AD) is one of the leading causes of cognitive impairment and dementia among the elderly and has become an urgent public health challenge due to population ageing. Du-Shu-Wan (DSW) is an ancient Chinese herbal medicine that aims to enhance memory and soothe the spirit, and has long been applied for forgetfulness and cognitive decline. At present, there is still no systematic research on the pharmacological basis of DSW and its specific molecular mechanisms for alleviating AD.

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

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

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

CONCLUSIONS: According to this study, DSW may enhance cognitive function in AD rats, an effect that is associated with reduced JNK pathway activity and reduced tau protein hyperphosphorylation at Ser422.},
}

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

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

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

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

CONCLUSIONS: Our study demonstrates BSYZ promotes hippocampal neurogenesis to ameliorate cognitive impairment by activating ST8Sia II/IV-PSA-NCAM pathway. These findings provide mechanistic evidence supporting the therapeutic potential of BSYZ for AD treatment.},
}

@article {pmid42711466,
year = {2026},
author = {Mimica, N and Dumitrescu, L and Gregorič Kramberger, M and Hort, J and Kovács, T and Popadić, K and Popescu, BO and Rakuša, M and Rejdak, K and Turčáni, P},
title = {Expert opinion on Alzheimer's disease diagnostics and management in Central Eastern European countries representing 88 million population.},
journal = {Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology},
volume = {47},
number = {10},
pages = {},
pmid = {42711466},
issn = {1590-3478},
mesh = {Humans ; *Alzheimer Disease/diagnosis/therapy/epidemiology ; Europe, Eastern/epidemiology ; *Disease Management ; },
abstract = {The expert panel from Croatia, Czech Republic, Hungary, Poland, Romania, Slovakia and Slovenia discussed the current situation of various topics related to the diagnostics, general management and treatment of Alzheimer's disease (AD) in these Central Eastern European (CEE) countries, representing around 88 million population. The aim was to estimate AD prevalence, confirm the presence of AD patients/caregivers' associations and AD registries, and establish the availability and reimbursement of costs for AD diagnostic biomarkers and treatment. The panel acknowledged similarities and differences among CEE countries and issued recommendations for cross specialty collaboration between experts in neurology, psychiatry and general practitioners for the early AD diagnosis. They also agreed that CEE countries should provide comprehensive education and training and encourage collaboration between health experts. The panel suggested that CEE countries should involve various stakeholders, policymakers, implement routine screening, combine advanced diagnostic tools and use telemedicine and remote monitoring technologies, invest in research to develop AI-based analyses, new AD diagnostic and monitoring methods, digital tools and wearables. The focus is to address the stigma, reimburse costs of diagnostic tests and therapy, and reduce the modifiable risk factors for AD.},
}

Humans
*Alzheimer Disease/diagnosis/therapy/epidemiology
Europe, Eastern/epidemiology
*Disease Management

@article {pmid42711740,
year = {2026},
author = {Papait, A and Natale, F and Silini, AR and Nifo Sarrapochiello, I and Orecchini, E and Sollazzo, R and Rinaudo, M and Farigu, S and Garofalo, N and Mantini, G and Giuffrè, GM and Romele, P and Ragozzino, E and Dellaria, A and Giacò, L and Marra, C and Ripoli, C and Grassi, C and Parolini, O and Fusco, S},
title = {Human amniotic mesenchymal stromal cell-derived extracellular vesicles reprogram microglia and prevent neurodegeneration in experimental models of Alzheimer's disease.},
journal = {Translational neurodegeneration},
volume = {15},
number = {1},
pages = {},
pmid = {42711740},
issn = {2047-9158},
mesh = {*Alzheimer Disease/pathology/metabolism ; *Extracellular Vesicles/transplantation/metabolism ; Animals ; Humans ; *Microglia/metabolism/pathology ; Female ; Mice ; *Mesenchymal Stem Cells/metabolism ; Disease Models, Animal ; Mice, Transgenic ; *Amnion/cytology ; Hippocampus/metabolism ; Administration, Intranasal ; },
abstract = {BACKGROUND: Alzheimer's disease (AD) is the most prevalent neurodegenerative disorder and disproportionately affects women, with neuroinflammation emerging as a key driver of disease onset and progression. Beyond amyloid-β (Aβ) and hyperphosphorylated tau protein accumulation, chronic activation of microglia and astrocytes amplifies synaptic dysfunction and neuronal loss. Mesenchymal stromal cell-derived extracellular vesicles (MSC-EVs) represent a promising translational strategy due to their capacity to modulate inflammation and promote neuroprotection. Here, we investigated whether intranasal administration of extracellular vesicles derived from human amniotic membrane MSCs (hAMSC-EVs) could counteract cognitive decline, neuroinflammation, and synaptic alterations in experimental and human cellular models of AD.

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

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

CONCLUSIONS: hAMSC-EVs exert robust anti-inflammatory and neuroprotective effects in both murine and human AD models, improving cognition, modulating glial activation, and restoring synaptic integrity. These findings highlight the translational potential of intranasal hAMSC-EVs as an adjuvant therapeutic strategy targeting neuroinflammation and neurodegeneration in AD.},
}

*Alzheimer Disease/pathology/metabolism
*Extracellular Vesicles/transplantation/metabolism
Animals
Humans
*Microglia/metabolism/pathology
Female
Mice
*Mesenchymal Stem Cells/metabolism
Disease Models, Animal
Mice, Transgenic
*Amnion/cytology
Hippocampus/metabolism
Administration, Intranasal

@article {pmid42711950,
year = {2026},
author = {Hwang, J and Pietras, A and Naasan, G and Elahi, FM and Gandy, S},
title = {Rapid plaque clearance with anti-amyloid therapy for Alzheimer's disease: in consideration of donanemab treatment duration from real-world cases.},
journal = {Neurocase},
volume = {},
number = {},
pages = {1-4},
doi = {10.1080/13554794.2026.2730462},
pmid = {42711950},
issn = {1465-3656},
abstract = {To assess the possibility that individualized duration of donanemab treatment might enable early pausing of therapy, and to explore the possible utility of plasma P-tau[217] as a biomarker for treatment response monitoring in real-time, two unrelated patients with early-stage Alzheimer's disease were treated with donanemab at the Icahn School of Medicine at Mount Sinai. Clinical progress was monitored via medical chart review, including serial brain MRI, amyloid PET scans, and blood-based biomarker assays (Quanterix Simoa® and Fujirebio Lumipulse®). Both patients achieved complete amyloid clearance as judged by amyloid PET prior to their 6th and 9th infusions, which were significantly earlier than the 12-month mark typically recommended for follow-up amyloid assessment. In agreement with the amyloid PET, concurrently measured plasma P-tau[217] levels fell within a low range. Treatment was discontinued for both patients. These patients highlight the possibility of individualized treatment durations for anti-amyloid therapy with donanemab, guided by biomarker response. Early cessation following rapid plaque clearance could reduce healthcare costs and minimize exposure to the risk of amyloid-related imaging abnormalities and the generation of neutralizing antibodies. Plasma P-tau[217] warrants further investigation as a reliable, cost-effective surrogate for PET scans to monitor real-time treatment response and guide the timing of discontinuation.},
}

@article {pmid42700810,
year = {2026},
author = {Han, Z and Liu, W and Fu, W and Wang, K and Tan, Z and Zhang, D and Yang, F and Dong, W and Sang, Z},
title = {Imidazo[1,2-a]pyridine-based HDAC6 inhibitor a17 for the treatment of Alzheimer's disease.},
journal = {European journal of pharmacology},
volume = {1034},
number = {},
pages = {179320},
doi = {10.1016/j.ejphar.2026.179320},
pmid = {42700810},
issn = {1879-0712},
abstract = {Alzheimer's disease (AD) is a prevalent, chronic, and progressive neurodegenerative disorder that predominantly affects the elderly population, and no effective pharmacological treatments are currently available. Histone deacetylase 6 (HDAC6) is overexpressed in the hippocampus of AD patients, and its inhibition has been shown to clear amyloid-β (Aβ) deposits, promote tau protein degradation, ameliorate mitochondrial transport deficits, and restore α-tubulin acetylation. Thus, selective HDAC6 inhibition represents a promising therapeutic strategy for AD, yet the underlying mechanisms by which HDAC6 inhibitors ameliorate cognitive impairment in AD remain elusive. In our previous study, a series of novel imidazo [1,2-a]pyridine-based HDAC6 inhibitors were developed, among which compound a17 exhibited potent HDAC6 inhibitory activity with an IC50 value of 7.51 nM, warranting further investigation into its anti-AD effects. Herein, we demonstrated that a17 exerted robust neuroprotective effects against L-Glutamate (L-Glu-)/Aβ25-35-induced HT22 cell injury. Additionally, a17 displayed favorable blood-brain barrier (BBB) permeability in vitro and drug-likeness properties. In vivo studies revealed that a17 significantly attenuated AD-like phenotypes in an Aluminium chloride (AlCl3)-induced zebrafish AD model, a mechanism potentially associated with the differential regulation of ODC1, Serpine1, and PAG-1. Furthermore, a17 markedly improved scopolamine-induced memory deficits in mice. Collectively, these findings indicate that an HDAC6 inhibitor, a17, was found to attenuate AD-associated pathological and behavioral markers by regulating the expression of ODC1, Serpine1, or PAG-1. Accordingly, a17 merit consideration for a pharmacological treatment of choice for AD.},
}

@article {pmid42701177,
year = {2026},
author = {Riedlinger, D and Karamercan, MA and Dündar, ZD and Janssens, K and Adam, VN and Bjørnsen, LP and Fabbri, A and Laribi, S and Möckel, M and Polyzogopoulou, E and Somodi, S and Koc, M and Colak, T and Slagman, A and , },
title = {Non-traumatic chief complaints in older patients in European emergency departments and associated outcomes during the Covid-19 pandemic - a secondary analysis of the cross sectional EGERS study.},
journal = {BMC geriatrics},
volume = {26},
number = {1},
pages = {},
pmid = {42701177},
issn = {1471-2318},
mesh = {Humans ; Cross-Sectional Studies ; Female ; Europe/epidemiology ; *Emergency Service, Hospital/statistics & numerical data ; Male ; Aged, 80 and over ; *COVID-19/epidemiology ; Aged ; Prospective Studies ; Hospital Mortality ; Emergency Room Visits ; Hospitalization/statistics & numerical data ; Pandemics ; },
abstract = {BACKGROUND: The scope of medical conditions addressed in Emergency Departments (ED) increases with growing numbers of older patients among the ED patient population. More information on their chief complaints and related treatment outcomes is essential to ensure high-quality ED care. The objective of this study was to describe the pattern of chief complaints of older ED patients and evaluate the associations between these complaints and outcomes such as mortality and hospital admission.

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

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

CONCLUSION: Older patients frequently require hospital admission. As chief complaints do not reflect underlying condition or severity, structured evaluation, staff training and geriatric specific care pathways may improve care and reduce adverse clinical outcomes.},
}

Humans
Cross-Sectional Studies
Female
Europe/epidemiology
*Emergency Service, Hospital/statistics & numerical data
Male
Aged, 80 and over
*COVID-19/epidemiology
Aged
Prospective Studies
Hospital Mortality
Emergency Room Visits
Hospitalization/statistics & numerical data
Pandemics

@article {pmid42701205,
year = {2026},
author = {Gabb, VG and Harding, S and Lemke, T and Alderman, S and Woodward, N and Clayton, J and McNair, A and Barrett-Muir, W and Richardson, A and Dooley, J and Rudd, S and Coulthard, E and Turner, N},
title = {Outcomes reported in interventional studies for mild cognitive impairment: a scoping umbrella review to inform core outcome set development.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {9},
pages = {e71800},
pmid = {42701205},
issn = {1552-5279},
support = {NIHR204135//National Institute for Health Research (NIHR)/ ; },
mesh = {Humans ; *Cognitive Dysfunction/therapy ; *Outcome Assessment, Health Care ; Treatment Outcome ; },
abstract = {There is currently no consensus on the most important treatment outcomes in patients with mild cognitive impairment (MCI). As part of developing a core outcome set for MCI, we conducted a pragmatic scoping umbrella review to summarize outcomes reported in previous studies. Six electronic databases were searched from inception to August 2023. Systematic and scoping reviews in English with ≥70% of studies describing at least one quantitative outcome of interventions involving adults with MCI were eligible. Verbatim outcomes were extracted from eligible papers within selected reviews. From 170 papers covering 153 studies from 42 reviews, 143 unique outcomes were identified. Global cognition was the only outcome reported by more than 50% of studies. Two-thirds of outcomes were reported by no more than three studies. Heterogeneous outcome reporting limits evidence synthesis and treatment evaluation. A core outcome set for MCI is warranted to standardize outcome reporting and offer stronger evidence for decision-making.},
}

Humans
*Cognitive Dysfunction/therapy
*Outcome Assessment, Health Care
Treatment Outcome

@article {pmid42702949,
year = {2026},
author = {Moro, V and Vianello, G and Gambina, G and Gobbetto, V and Gasparini, M and Beccherle, M},
title = {The clinical implications of anosognosia in Alzheimer's disease.},
journal = {Expert review of neurotherapeutics},
volume = {},
number = {},
pages = {1-13},
doi = {10.1080/14737175.2026.2726416},
pmid = {42702949},
issn = {1744-8360},
abstract = {INTRODUCTION: Assessing awareness of patients with Alzheimer's disease (AD) is essential for diagnosis and treatment. Anosognosia, defined as impaired awareness of cognitive and functional deficits, is associated with poorer prognosis, reduced decision-making capacity, increased risk of accidents, and earlier institutionalization.

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

EXPERT OPINION: Taking care of unaware AD patients represents a challenge, and anosognosia is often underestimated in clinical practice. Evidence suggests that awareness deficits may emerge even in the earliest stages of AD, affecting patients' autonomy and capacity to make informed decisions. A two-step assessment process is recommended, consisting of an initial screening followed by a comprehensive evaluation carried out by specialized neuropsychologists. Targeted caregiver training is also essential to address the challenges associated with impaired awareness.},
}

@article {pmid42704398,
year = {2026},
author = {Zhu, Z and Jiang, X and Huang, R and Guo, X and Wang, Y and Liu, T and Wang, J and Huang, J and Huang, W and Zhang, D and Li, Q and Chen, S and Yang, Z and Liu, Q and Wei, Z},
title = {Deferiprone Modulates Ferroptosis to Protect Macrophages and Liver during Neospora caninum Infection.},
journal = {Acta parasitologica},
volume = {71},
number = {5},
pages = {},
pmid = {42704398},
issn = {1896-1851},
support = {32002309//the National Natural Science Foundation of China/ ; 2022A1515010960//Guangdong Basic and Applied Basic Research Foundation/ ; NJTG20240253//Guangdong Provincial Department of Agriculture and Rural Affairs - Guangdong Agricultural Technical Service "Light Cavalry" Project 2024/ ; SWU-KQ24021//Central University Basic Scientific Research Program of Southwest University/ ; },
mesh = {Animals ; *Ferroptosis/drug effects ; *Neospora/drug effects/physiology ; *Deferiprone/pharmacology/administration & dosage ; *Coccidiosis/drug therapy/parasitology ; *Liver/parasitology/drug effects ; Mice ; *Macrophages/drug effects/parasitology ; Mice, Inbred C57BL ; Iron/metabolism ; Reactive Oxygen Species/metabolism ; Oxidative Stress/drug effects ; Female ; },
abstract = {BACKGROUND: Neospora caninum (N. caninum), an obligate intracellular apicomplexan parasite, infects nucleated cells across diverse mammalian hosts, resulting in severe clinical outcomes, including reproductive failure (abortion, stillbirth) and neurological impairment. Ferroptosis, an iron-dependent, non-apoptotic cell death pathway characterized by excessive lipid peroxidation, is closely associated with disrupted iron metabolism and oxidative stress. Deferiprone (DFP), a clinically approved iron chelator, is widely used in the treatment of iron overload disorders such as β-thalassemia, Alzheimer's disease, and superficial hemosiderosis. While ferroptosis has been implicated in various disease states, its role in N. caninum infection remains unknown.

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

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

CONCLUSIONS: In summary, these results establish ferroptosis as a critical pathogenic mechanism in N. caninum infection and highlight DFP's dual role in mitigating oxidative injury while possibly impairing host metabolic responses. Our findings provide novel insights into iron-targeted therapeutic strategies for combating intracellular parasitic infections, paving the way for future investigations into optimizing host-directed antiparasitic interventions.},
}

Animals
*Ferroptosis/drug effects
*Neospora/drug effects/physiology
*Deferiprone/pharmacology/administration & dosage
*Coccidiosis/drug therapy/parasitology
*Liver/parasitology/drug effects
Mice
*Macrophages/drug effects/parasitology
Mice, Inbred C57BL
Iron/metabolism
Reactive Oxygen Species/metabolism
Oxidative Stress/drug effects
Female

@article {pmid42705162,
year = {2026},
author = {Guarneri, L and Beh, C and de Campo, L and Whitten, AE and Moir, M and Hung, A and Clulow, AJ and Conn, CE and van 't Hag, L},
title = {Nanoscale localisation of memantine governs structural modulation and loading in bicontinuous cubic phase systems.},
journal = {Journal of colloid and interface science},
volume = {726},
number = {},
pages = {141405},
doi = {10.1016/j.jcis.2026.141405},
pmid = {42705162},
issn = {1095-7103},
abstract = {Memantine is a primary pharmacological treatment for moderate-to-severe Alzheimer's disease but its efficacy and brain delivery remain limited. Lipid bicontinuous cubic phases and their nanoparticle dispersions (cubosomes) offer platforms for enhancing central nervous system drug delivery, yet the rigid adamantane scaffold of memantine can destabilise lipid organisation. This study resolves how an amphiphilic, adamantane-containing drug interacts with non-lamellar lipid bilayers using monoolein-based bulk cubic mesophases and cubosomes formulated with biomimetic lipid compositions and multiple stabilisers. SAXS revealed that lipid composition primarily governed mesophase structure, while memantine induced only modest structural changes in bulk cubic phases. Following memantine incorporation, cubosomes retained cubic symmetry and colloidal stability across stabilisers, although they were more susceptible than bulk phases to additive-induced disorder, with cryo-TEM showing transitions toward less ordered, lower curvature sponge-like structures. Bulk mesophases exhibited 3-5-fold higher apparent drug retention than nanoparticle dispersions. Under excess hydration, however, even bulk phases released memantine rapidly, losing ∼65% of the drug within 24 h. SANS and molecular dynamics simulations revealed a mobile state of memantine with predominantly interfacial localisation rather than stable burial within the hydrophobic tails, providing a mechanistic explanation for its mesophase-dependent structural effects and its limited retention. These findings show that the adamantane scaffold alone is insufficient to ensure efficient incorporation into cubic phases. Localisation, accommodation, and retention are governed by the balance between hydrophobic anchoring and the hydration demands of attached functionalities, establishing a mechanistic framework for predicting the behaviour of amphiphilic adamantane-containing therapeutics in non-lamellar lipid nanocarriers.},
}

@article {pmid42705844,
year = {2026},
author = {Zhou, Q and Yang, MX and Zhang, QQ and Li, YQ and Wang, ZQ},
title = {Efficacy and Durability of Repetitive Transcranial Magnetic Stimulation on Cognitive Function in Patients With Mild-to-Moderate Alzheimer's Disease: A Systematic Review and Meta-Analysis.},
journal = {Psychogeriatrics : the official journal of the Japanese Psychogeriatric Society},
volume = {26},
number = {5},
pages = {e70199},
pmid = {42705844},
issn = {1479-8301},
support = {2022ZD0208506//STI 2030-Major Projects/ ; 82201628//National Natural Sciencen Foundation of China/ ; U24A20274//National Natural Sciencen Foundation of China/ ; S23042//SiChuan Province Medical Research Project Program/ ; 513//2024 Annual Specialized Research Project on Traditional Chinese Medicine of SiChuan Provincial Administration of Traditional Chinese Medicine/ ; },
mesh = {Humans ; *Alzheimer Disease/therapy/psychology ; *Transcranial Magnetic Stimulation/methods ; *Cognition/physiology ; Treatment Outcome ; Cognitive Enhancement ; Randomized Controlled Trials as Topic ; Aged ; },
abstract = {Repetitive transcranial magnetic stimulation (rTMS) is a non-invasive brain stimulation technique that has shown potential for improving cognitive function in Alzheimer's disease (AD), though findings remain inconsistent. This meta-analysis evaluated the efficacy and durability of rTMS in patients with mild to moderate AD and explored potential moderating factors. Randomised controlled trials (RCTs) comparing active rTMS with sham stimulation were identified through systematic searches of major databases. Effect sizes were calculated using Hedges' g, with random-effects models applied. Risk of bias was assessed using the Cochrane RoB 2 tool. Five RCTs (N = 143) were included in the primary analysis. rTMS showed a small-to-moderate improvement in MMSE scores (g = 0.41, 95% CI [0.06, 0.75], p = 0.021, I[2] = 6.5%). Excluding two studies with methodological concerns yielded a similar effect (g = 0.46), though with wider confidence intervals. Sensitivity analysis including studies with change scores confirmed the robustness of results (g = 0.48). Given the limited number of studies (k < 10), formal publication bias tests and trim-and-fill adjustment were not applied, in line with current methodological guidance. Notably, all five studies employed excitatory stimulation protocols (high-frequency rTMS or iTBS), with four of five targeting the left dorsolateral prefrontal cortex (DLPFC), suggesting that excitatory stimulation of key cognitive network hubs represents the most consistent evidence base to date. Meta-regression identified treatment duration as a significant moderator (β = -0.193, p = 0.034), suggesting shorter, more intensive protocols may be more effective. Follow-up analyses indicated a nonsignificant trend towards sustained benefits (g = 0.25), while time-trend analysis demonstrated a stable overall effect (g = 0.38). In conclusion, rTMS provides modest cognitive benefits in mild to moderate AD, with excitatory protocols targeting the left DLPFC showing the most consistent efficacy and treatment duration influencing outcomes. However, evidence remains limited, highlighting the need for larger, standardised, multi-centre trials with long-term follow-up.},
}

Humans
*Alzheimer Disease/therapy/psychology
*Transcranial Magnetic Stimulation/methods
*Cognition/physiology
Treatment Outcome
Cognitive Enhancement
Randomized Controlled Trials as Topic
Aged

@article {pmid42706500,
year = {2026},
author = {Ding, J and Miao, J and Zhang, L and Liu, Q and Zhang, Y and Li, J and Li, Y},
title = {Cognitive safety of statin use in the elderly: Evidence from a nationally representative sample.},
journal = {Journal of internal medicine},
volume = {},
number = {},
pages = {},
doi = {10.1111/joim.70159},
pmid = {42706500},
issn = {1365-2796},
support = {SCYG2025-1//Sichuan Hospital Management and Development Research Center/ ; YF25-Y15//Sichuan Medical and Health Rule of Law Research Center-Chinese Society of Health Law Joint Project/ ; scsyxh202502//Hospital Pharmaceutical Research Funding Project of 'Yue·Stealth' of Sichuan Province Pharmaceutical Association/ ; 26MSZX599//Special Science and Technology Research Project of the Sichuan Province Administration of Traditional Chinese Medicine/ ; 26MSZX601//Special Science and Technology Research Project of the Sichuan Province Administration of Traditional Chinese Medicine/ ; CSXL-26209//Foundation of the Sichuan Research Center of Applied Psychology/ ; MZSJ202602//Mianyang Key Laboratory of Anesthesia and Neuroregulation/ ; 17PJ332//Sichuan Province Health Commission Project/ ; },
abstract = {OBJECTIVE: To systematically evaluate the association between current statin use and global cognitive impairment in US older adults and examine potential variations across treatment intensity, duration, and specific cognitive domains to guide clinical cardiometabolic management.

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

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

CONCLUSION: Current statin use was not significantly associated with global cognitive impairment in older adults. Although cross-sectional observational neutrality precludes inferring long-term safety, indicated statin therapy should not be routinely withheld over cognitive concerns, with prescribing remaining firmly guided by established atherosclerotic cardiovascular disease risk guidelines.},
}

@article {pmid42706972,
year = {2026},
author = {Yu, X and Yi, Y and Liu, X and Zhao, C and Li, C and Shang, Y and He, K and Zhai, Y},
title = {Scutellaria Barbata Flavonoids Mitigate Alzheimer's Disease-related Aβ25-35 Toxicity in N2a Cells through CREB Phosphorylation.},
journal = {Current medicinal chemistry},
volume = {},
number = {},
pages = {},
doi = {10.2174/0109298673438931260822121059},
pmid = {42706972},
issn = {1875-533X},
abstract = {BACKGROUND: Mouse neuroblastoma cells (N2a) are spontaneously derived from mice and possess the characteristics of neural stem cells. The proliferation, differentiation, and protrusion growth of N2a cells in vitro are consistent with those in vivo. Flavonoids isolated from the aerial parts of Scutellaria barbata (SBFs) can improve learning and memory deficits and protect against neuronal injury in many in vivo AD-- like models. N2a cells exposed to Aβ25-35 for Alzheimer's disease-related toxicity were subsequently used to observe the ameliorative effects of SBFs, and the effective mechanism through which SBFs promote the phosphorylation of CREB was further studied by using BI-D1870, an indirect inhibitor, and Rolipram, an activator of CREB phosphorylation.

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

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

CONCLUSION: SBFs protected against N2a cell damage induced by toxic Aβ25-35, and the effective mechanism by which SBFs promote the phosphorylation of CREB at the Ser133 site was confirmed through the application of the indirect CREB phosphorylation inhibitor BI-D1870 and the activator Rolipram. These findings suggest that SBFs may be helpful in the treatment of AD by intervening in CREB phosphorylation.},
}

@article {pmid42706977,
year = {2026},
author = {Saxena, B and Sisodiya, N and Khabiya, R and Pandit, A and Rajput, MS and Gupta, R},
title = {AI-Driven Precision Medicine in Alzheimer's Disease: Drug Repurposing, Digital Therapeutics and Clinical Decision Support.},
journal = {Current pharmaceutical design},
volume = {},
number = {},
pages = {},
doi = {10.2174/0113816128478269260818075055},
pmid = {42706977},
issn = {1873-4286},
abstract = {Alzheimer's Disease (AD) is a neurodegenerative disease that causes significant clinical, social, and economic burden worldwide. Despite improvements in understanding its multifaceted pathogenesis, current treatments are mostly symptomatic and ineffective across varied patient populations. To overcome these constraints, AI-driven precision medicine allows tailored risk assessment, treatment selection, and disease monitoring. This review covers AI's role in AD precision medicine, focusing on drug repurposing, digital therapies and clinical decision support systems. Machine and deep learning models are used to predict medication response, integrate heterogeneous data sources such as genomics, transcriptomics, neuroimaging and electronic health records, and uncover pharmacogenomic treatment success factors. The paper covers AIenabled precision pharmacology, including tailored dosing algorithms, adaptive therapeutic monitoring, and adverse drug reaction prediction. Bioinformatics-based target identification, network pharmacology, graphbased AI models, virtual screening, and real-world and clinical data validation are emphasized in AI-driven medication repurposing. AI-powered digital treatments like personalized cognitive training platforms, wearable- derived digital biomarkers, virtual and mixed reality interventions, adherence monitoring, and digital twins for therapy optimization have been discussed. AI-based clinical decision support systems are also thoroughly assessed for clinical value, accuracy, and explainability in disease subtyping, trajectory prediction, and risk stratification in preclinical and prodromal AD. Despite these promises, data heterogeneity, algorithmic bias, legal barriers, and privacy concerns exist. Federated learning enables safe multi-center collaboration and hybrid AI-human approaches, and it represents the future. AI's ability to alter AD care opens the door to precision medicine paradigms that use repurposed medications, digital tools and intelligent decision-making to improve patient outcomes.},
}

@article {pmid42707167,
year = {2026},
author = {Zhao, K and Dai, S and Zhang, Y and Liu, G and Gu, P and Lin, C and Thompson, PM and Leow, A and Huang, H and He, L and Zhan, L and Tang, H},
title = {Interpretable multimodal learning for integrating neuroimaging and genetic data in Alzheimer's disease.},
journal = {Frontiers in radiology},
volume = {6},
number = {},
pages = {1912277},
pmid = {42707167},
issn = {2673-8740},
abstract = {INTRODUCTION: Early detection of Alzheimer's disease (AD) requires models that combine brain structure changes with genetic risk, but existing methods struggle to align these different data types.

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

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

DISCUSSION: These results show that interpretable multimodal AI can integrate imaging and genetics to reveal disease mechanisms, providing a foundation for clinical tools that enable earlier risk assessment and inform precision treatment in Alzheimer's disease.},
}

@article {pmid42694564,
year = {2026},
author = {Lu, P and Liu, M and Zhang, L and Fan, JJ and Sun, Y},
title = {Synergistic Regulation of Alzheimer's Disease and Intestinal Microbiota Metabolism Mediated by the Gut-Brain Axis: A Comprehensive Analysis from a Multidisciplinary Perspective.},
journal = {International journal of medical sciences},
volume = {23},
number = {9},
pages = {2939-2962},
pmid = {42694564},
issn = {1449-1907},
mesh = {Humans ; *Alzheimer Disease/microbiology/metabolism/immunology/therapy ; *Gastrointestinal Microbiome/immunology/physiology ; *Brain/metabolism/immunology ; Animals ; Multiomics ; *Brain-Gut Axis/immunology/physiology ; *Dysbiosis/microbiology/immunology ; },
abstract = {Alzheimer's disease (AD), as a neurodegenerative disease with the interaction of multiple factors, has a close association between its pathological process and the metabolic imbalance of the gut microbiota mediated by the gut-brain axis. This review systematically summarizes the molecular mechanisms by which the gut microbiota regulates the functions of the central nervous system bidirectionally through molecular pathways such as metabolites (e.g., short-chain fatty acids, tryptophan-kynurenine metabolites), immunomodulatory mediators (e.g., cytokines, chemokines), and bioactive substances (e.g., γ-aminobutyric acid, 5-hydroxytryptophan) via the gut-brain axis. It synthesizes current evidence suggesting the imbalance of microbiota homeostasis may be closely associated with the core pathologies of AD (including β-amyloid deposition and tau protein hyperphosphorylation) through mechanisms such as the activation of the C/EBPβ-AEP signaling pathway, induction of chronic neuroinflammation, oxidative stress cascade reactions, and metabolic network remodeling. These findings, primarily derived from preclinical models and correlational human studies, indicate potential mechanisms but require further causal validation and rigorous clinical translation, including the downregulation of butyrate synthesis pathways and their associated epigenetic and immunomodulatory consequences (as mechanistically dissected in Section 5.2). Multi-omics integration (metagenomics, metabolomics, spatial transcriptomics) has delineated characteristic microbial and metabolic alterations in AD, while computational approaches are beginning to elucidate the complex networks underlying these associations (see Sections 6 and 7 for details).Intervention strategies based on microbiota regulation (such as microbiota-targeted dietary interventions and postbiotics) are emerging as promising approaches, although their clinical applications remain in early stages. Preliminary evidence suggests that fecal microbiota transplantation may improve cognitive outcomes in AD patients with comorbid conditions; however, rigorous randomized controlled trials are essential to validate its efficacy and safety. Critically, translating these mechanistic insights into clinical practice requires overcoming three translational bottlenecks: inferring causality from correlational multi-omics data, resolving species/strain-level functional heterogeneity masked by genus-level taxonomy, and establishing standardized safety protocols for live biotherapeutic products. Addressing these challenges defines the near-term roadmap for precision medicine in AD. However, current research still faces challenges such as the heterogeneity of cross-omics data, the lack of technical standardization, and insufficient interdisciplinary cooperation mechanisms. In the future, it is necessary to promote the early molecular diagnosis and personalized targeted treatment of AD through longitudinal multi-omics dynamic monitoring, modeling of the microbiota-host interaction network, and optimization of the ethical-translational medicine framework.},
}

Humans
*Alzheimer Disease/microbiology/metabolism/immunology/therapy
*Gastrointestinal Microbiome/immunology/physiology
*Brain/metabolism/immunology
Animals
Multiomics
*Brain-Gut Axis/immunology/physiology
*Dysbiosis/microbiology/immunology

@article {pmid42695408,
year = {2026},
author = {Li, Y and Fan, H and Han, X and Ni, M and Hou, X and Xia, H and Shi, Y and Zhang, L and Sun, J},
title = {Effect of MALT1 inhibition by MI‑2 on the microglial phenotype switch, inflammatory cytokine secretion, neuronal loss and oxidative stress in Alzheimer's disease.},
journal = {International journal of molecular medicine},
volume = {58},
number = {5},
pages = {},
doi = {10.3892/ijmm.2026.5973},
pmid = {42695408},
issn = {1791-244X},
mesh = {*Microglia/metabolism/drug effects/pathology ; *Oxidative Stress/drug effects ; *Mucosa-Associated Lymphoid Tissue Lymphoma Translocation 1 Protein/antagonists & inhibitors/metabolism ; *Alzheimer Disease/metabolism/pathology/drug therapy ; Humans ; *Neurons/metabolism/pathology/drug effects ; Animals ; *Cytokines/metabolism ; Mice ; Phenotype ; Reactive Oxygen Species/metabolism ; NF-kappa B/metabolism ; Cell Line ; Amyloid beta-Peptides ; Cell Survival/drug effects ; },
abstract = {Mucosa‑associated lymphoid tissue lymphoma translocation protein 1 (MALT1) is a key paracaspase enzyme regulating immune responses, inflammation and oxidative stress. The present study aimed to investigate the effect of MALT1 inhibition on neuroinflammation, neuronal loss and oxidative stress in Alzheimer's disease (AD). A co‑culture system involving microglia and neuron cells under β‑amyloid (Aβ) intervention was used to establish AD cellular models using human microglia HMC3 cells and neuroblastoma SH‑SY5Y cells and mouse microglia BV‑2 and hippocampal neuron HT‑22 cells. The inhibition of MALT1 proteolytic activity was achieved by MALT1 inhibitor 2 (MI‑2) treatment, and the NF‑κB pathway was activated by phorbol 12‑myristate 13‑acetate (PMA) treatment in HMC3 and BV‑2 cells. Western blotting, ELISA, Cell Counting Kit‑8, EdU staining, reactive oxygen species (ROS) detection and reduced glutathione (GSH) assays were performed to evaluate molecular changes, inflammatory responses, neuronal viability and oxidative stress. MALT1 expression was upregulated following Aβ treatment in HMC3 and BV‑2 cells. MALT1 inhibition by MI‑2 suppressed the microglial M1 phenotype but enhanced the M2 phenotype, reduced the levels of the proinflammatory cytokines TNF‑α and IL‑1β and inactivated the NF‑κB pathway in HMC3 and BV‑2 cells. Moreover, microglial MALT1 inhibition elevated cell viability (verified by Cell Counting Kit‑8 and EdU assays), increased the level of reduced glutathione and decreased the levels of reactive oxygen species in SH‑SY5Y and HT‑22 cells. NF‑κB activation by PMA attenuated the effects of MALT1 inhibition on the microglial phenotype switch and proinflammatory cytokine secretion in HMC3 and BV‑2 cells, as well as cell viability and oxidative stress in SH‑SY5Y and HT‑22 cells. The present study reveals that MALT1 inhibition may suppress microglial M1 phenotype, neuroinflammation, neuronal loss and oxidative stress by inactivating the NF‑κB pathway in AD.},
}

*Microglia/metabolism/drug effects/pathology
*Oxidative Stress/drug effects
*Mucosa-Associated Lymphoid Tissue Lymphoma Translocation 1 Protein/antagonists & inhibitors/metabolism
*Alzheimer Disease/metabolism/pathology/drug therapy
Humans
*Neurons/metabolism/pathology/drug effects
Animals
*Cytokines/metabolism
Mice
Phenotype
Reactive Oxygen Species/metabolism
NF-kappa B/metabolism
Cell Line
Amyloid beta-Peptides
Cell Survival/drug effects

@article {pmid42697072,
year = {2026},
author = {Wu, Q and Li, L and Lei, Y and Zhou, T and Tang, H and Zhang, B and Lu, Y and Salvatore, M and Zhang, D and Tong, J and Wang, T and Chen, S and Li, H and Xu, Z and Huang, Y and Hu, Y and Hong, N and Zhou, Y and Lin, F and O'Brien, KS and Chen, Y and Li, R and Xu, H and Wang, F and Bian, J and Wolk, DA and Chen, Y},
title = {Discovering repurposable drugs for Alzheimer's disease and related dementias: target trial emulation using decentralised real-world data.},
journal = {EBioMedicine},
volume = {132},
number = {},
pages = {106466},
doi = {10.1016/j.ebiom.2026.106466},
pmid = {42697072},
issn = {2352-3964},
abstract = {BACKGROUND: Alzheimer's disease and related dementias (ADRD) affect nearly 6.9 million Americans, with the number expected to triple by 2050, while disease-modifying therapies remain unavailable. Drug repurposing, which identifies new indications for already approved medications, offers a more efficient and cost-effective pathway to accelerate development of effective therapies for ADRD. The aim of this study is to identify potential drug repurposing signals by systematically screening routinely prescribed drugs for associations with progression from mild cognitive impairment (MCI) to ADRD.

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

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

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

FUNDING: National Institutes of Health.},
}

@article {pmid42697176,
year = {2026},
author = {Bellelli, G and Brignoli, O and Canevelli, M and Cherubini, A and Clegg, A and Dubois, B and Ferrara, MC and Fratiglioni, L and Frisoni, GB and Grande, G and Jessen, F and Kennelly, SP and Magni, A and Marelli, M and Marengoni, A and Velilla, NM and Shenkin, SD and Suárez-Calvet, M and Timmons, S and Padovani, A},
title = {Integrating frailty into decision-making for disease-modifying therapies in Alzheimer's disease: a proposed expert-opinion based approach.},
journal = {The journal of prevention of Alzheimer's disease},
volume = {13},
number = {9},
pages = {100666},
doi = {10.1016/j.tjpad.2026.100666},
pmid = {42697176},
issn = {2426-0266},
abstract = {The introduction of disease-modifying therapies for Alzheimer's disease (AD-DMTs) is reshaping clinical practice, raising critical questions about patient selection, diagnostic pathways, treatment appropriateness, and equity of access. Frailty, a multidimensional condition of reduced physiological reserve and increased vulnerability to stressors, is common in older adults with AD, yet has not been systematically assessed in AD-DMTs trials, limiting the generalizability of trial findings to real-world populations. In this review, we examine the role of frailty in the emerging era of AD-DMTs, summarizing evidence on its prevalence and prognostic relevance, approaches to its assessment, and its potential impact on treatment safety and effectiveness. We propose that regular frailty assessment should inform decision-making in both clinical trials and clinical practice, while frailty-informed management-including medication review and multidomain interventions-may support more appropriate, individualized care.},
}

@article {pmid42697335,
year = {2026},
author = {Li, X and Wan, R and Wu, Y and Zhao, Y and Chen, X and Li, Y and Yang, R and Zhang, D and Li, Q and Luo, C},
title = {Targeting the mitochondrial functional network: Decoding upstream pathological mechanisms and novel therapeutic paradigms for Alzheimer's disease.},
journal = {Ageing research reviews},
volume = {},
number = {},
pages = {103359},
doi = {10.1016/j.arr.2026.103359},
pmid = {42697335},
issn = {1872-9649},
abstract = {Alzheimer's disease (AD) is the most prevalent neurodegenerative disorder worldwide. Conventional downstream interventions targeting β-amyloid (Aβ) and tau proteins have repeatedly failed in clinical practice, and mitochondrial functional decline has been identified as the core upstream driver of AD pathogenesis. Focusing on the mitochondrial functional network as the core target, this paper systematically dissects the key molecular mechanisms of mitochondrial dysfunction during AD progression, including oxidative phosphorylation impairment, mitochondrial DNA (mtDNA) mutations and genetic defects, excessive reactive oxygen species (ROS) production, mitochondrial dynamics imbalance, mitophagy dysfunction, calcium homeostasis dysregulation, mitochondrial transport defects, and the bidirectional regulatory pathway of tau pathology, and elucidates the pathological network featured by cascade amplification and reciprocal regulation among these abnormal mechanisms. It also comprehensively summarizes mitochondria-targeted intervention strategies for AD, analyzes the research limitations in this field such as model heterogeneity, lack of specific biomarkers and inefficient drug delivery, and prospects future research directions by integrating cutting-edge technologies including cell reprogramming and artificial intelligence (AI). This study provides a novel interpretation of the aging-related pathogenic mechanisms of AD from a mitochondrial perspective, lays a theoretical foundation for the development of precise and efficient mitochondria-targeted therapeutic strategies for AD, and offers a new paradigm for breaking through the bottlenecks of clinical diagnosis and treatment of AD.},
}

@article {pmid42697346,
year = {2026},
author = {Cai, J and Luo, J and Cai, Y and Xu, Y and Ran, R and Xiao, M and Ye, Q and Zheng, W and Li, S},
title = {Artemether alleviates Aβ1-42-induced neuronal cell damage via PGC-1α-mediated mitochondrial homeostasis in Alzheimer's disease.},
journal = {Cellular signalling},
volume = {149},
number = {},
pages = {112879},
doi = {10.1016/j.cellsig.2026.112879},
pmid = {42697346},
issn = {1873-3913},
abstract = {BACKGROUND: Alzheimer's disease (AD) is the most common neurodegenerative disorder worldwide and the leading cause of dementia. Mitochondrial dysfunction is a key pathogenic event that drives neuronal damage and disease progression. Thus, protecting against mitochondrial damage in neuronal cells has become a critical therapeutic target for AD prevention and treatment. Our previous research has shown that artemether can protect PC12 cells from oxidative stress damage induced by Aβ and oxygen-glucose deprivation, but its underlying regulatory mechanisms remain elusive. Therefore, it is essential to elucidate the role and mechanism of artemether in Aβ-induced mitochondrial damage.

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

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

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

CONCLUSION: Our findings indicate that neuronal mitochondrial dysfunction serves as a central driver in AD pathogenesis, and activating the PGC1α/ERRα/TFAM axis through artemether offers an effective and feasible strategy for the prevention and treatment of AD.},
}

@article {pmid42697379,
year = {2026},
author = {Mohammad, SI and Vasudevan, A and Oriquat, G and Gajjar, TB and Hanumanthayya, M and Shukla, SK and Tailor, NK and Baig, MR and Fadaam, O and Abdul, AS},
title = {Extracellular Vesicles in Neurodegenerative Diseases: A New Frontier in Diagnosis and Therapy.},
journal = {Behavioural brain research},
volume = {},
number = {},
pages = {116455},
doi = {10.1016/j.bbr.2026.116455},
pmid = {42697379},
issn = {1872-7549},
abstract = {Neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and Huntington's disease are among the progressive disorders of the nervous system that are characterized by the gradual destruction of neurons, the accumulation of misfolded proteins, and the limited effective therapeutic options. In recent years, numerous lines of evidence have emphasized the important role of extracellular vesicles (EVs) in the formation and progression of these diseases. These vesicles are membrane-bound nanoscale structures that are secreted by almost all cell types and play a role in cell-cell communication through the transfer of molecules such as proteins, lipids, and nucleic acids. In neurodegenerative disorders, EVs can facilitate the transport and dissemination of disease-related proteins, including amyloid-β, tau, α-synuclein, mutant huntingtin, SOD1, and TDP-43, thus contributing to the spread of pathological processes in different parts of the nervous system. On the other hand, the ability of these vesicles to cross the blood-brain barrier and reflect molecular changes occurring in the central nervous system makes them valuable candidates for the development of minimally invasive biomarkers. This review reviews the biogenesis, classification, isolation methods, and molecular content of EVs, and analyzes their role in the pathogenesis, diagnosis, and treatment of the most important neurodegenerative diseases. Also, the importance of EV-associated proteins, RNAs, and lipids as emerging diagnostic biomarkers, as well as the therapeutic potential of natural and engineered vesicles as drug delivery systems and regulators of neuroinflammation and neurodegenerative processes, is discussed.},
}

@article {pmid42697496,
year = {2026},
author = {Zhang, J and Chen, X and Hu, Z and Zhang, J and Wu, T and Zhou, J and Song, B and Xu, Y and Yang, H and Zhu, X},
title = {Breaking the autophagy-oxidative stress vicious cycle in Alzheimer's disease: Lactiflorin unlocks P62 dual phosphorylation via ULK1 targeting.},
journal = {Journal of ethnopharmacology},
volume = {374},
number = {Pt 1},
pages = {122367},
doi = {10.1016/j.jep.2026.122367},
pmid = {42697496},
issn = {1872-7573},
abstract = {The dried root of Paeonia lactiflora Pall. has a long history of medicinal use in traditional Chinese medicine. Classical materia medica and traditional practice describe Paeonia-related medicinal materials for headache, dizziness, restlessness, and other neurological or behavioral manifestations, particularly in disorders traditionally associated with blood or yin deficiency and liver-yang hyperactivity. Modern pharmacological studies have further demonstrated neuroprotective and antioxidant effects of Paeonia lactiflora and its bioactive monoterpene glycosides. Lactiflorin (LAC) is a naturally occurring monoterpene glycoside reported as a constituent of Paeonia lactiflora and exhibits antioxidant and cytoprotective properties; however, its therapeutic potential and underlying mechanisms in Alzheimer's disease (AD) remain unclear. This study therefore investigated the protective effects of LAC against AD and explored its underlying mechanisms.

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

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

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

CONCLUSIONS: LAC alleviated Aβ deposition, oxidative injury, and cognitive dysfunction by engaging ULK1, suggesting its potential as a promising natural compound for AD treatment.},
}

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

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

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

CONCLUSION: Escitalopram may have an impact on the severity of symptoms of depression/dysphoria in AD. No new symptoms of hallucinations in the escitalopram group throughout the 12 week trial suggest a possible direction for future research into selective serotonin reuptake inhibitors (SSRIs) and the treatment and/or delaying of psychotic symptoms in AD. As this was an exploratory analysis involving multiple comparisons, findings may be spurious.},
}

@article {pmid42699154,
year = {2026},
author = {Rouault, M and Kindler, DR and Ni, R and Liberale, L and Seiler, R and Ielacqua, GD and Nitsch, R and Pryce, C and Camici, GG and Kulic, L and Klohs, J},
title = {Coagulation factor XII deficiency alleviates vascular dysfunction and cognitive impairment in a mouse model of cerebral β-amyloidosis and cerebral amyloid angiopathy.},
journal = {Aging brain},
volume = {10},
number = {},
pages = {100167},
pmid = {42699154},
issn = {2589-9589},
abstract = {Amyloid-β (Aβ) can activate the factor XII (FXII)-driven contact system, which exerts several downstream effects on Alzheimer's disease (AD) pathology associated with cognitive impairment. Here, using genetically modified FXII deficient mice crossed with arcAβ mice, we show that genetic deletion of FXII ameliorates β-amyloidosis-mediated susceptibility to arterial thrombus formation, blood-brain barrier leakage, and cerebral microbleed load. Furthermore, we show that genetic deletion of FXII improves cognitive deficits, without affecting Aβ deposition. Thus, the FXII-driven contact system constitutes an important pathway contributing to vascular dysfunction and cognitive impairment in AD, independent of Aβ neuropathology, with important implications for the diagnosis and treatment of the disease.},
}

@article {pmid42699553,
year = {2026},
author = {Laginha, I and Schmitz, M and da Silva Correia, Â and Saleem, T and da Silva Correia, S and Zafar, S and Younas, N and Canaslan, S and Göbel, S and Root, E and Breitbarth, M and Fischer, AL and Dittmar, K and Žakova, D and Hermann, P and Zerr, I},
title = {Prion protein (PrP) profiles in blood and CSF: insights into pre-symptomatic and symptomatic prion disease.},
journal = {Brain communications},
volume = {8},
number = {5},
pages = {fcag321},
pmid = {42699553},
issn = {2632-1297},
abstract = {The conversion of native prion protein (PrP) into its misfolded isoform, scrapie (PrP[Sc]) and its intracellular accumulation represent central events in the pathogenesis of prion diseases. Reduction of native PrP in the central nervous system (CNS) has emerged as a promising strategy for treatment and prevention of prion diseases in humans. To facilitate translation into clinical practice, it is essential to identify at-risk individuals through biomarker development and to elucidate PrP behaviour across prion disease subtypes and biological fluids. Measurements of PrP in accessible biofluids, such as plasma and cerebrospinal fluid (CSF), may provide a pharmacodynamic readout and enable monitoring for PrP-targeted therapies. This study systematically quantifies PrP in plasma and CSF of individuals with sporadic and genetic prion diseases, healthy controls (HC), patients with non-neurodegenerative neurological conditions (ND) and Alzheimer's disease (AD). We analysed 136 plasma and 84 CSF samples, including HC, AD, sporadic Creutzfeldt-Jakob disease (sCJD), as well as symptomatic patients and asymptomatic carriers of the mutations D178N, E200K and P102L. Quantification of PrP was performed using a BetaPrion Human ELISA. Statistical analyses assessed differences between diagnostic groups, associations with demographic factors and PRNP codon 129 polymorphism, and diagnostic accuracy via ROC curves. Plasma PrP was significantly reduced in patients with sCJD (P = 0.043), in symptomatic patients with the E200K (P = 0.0078) and in both symptomatic and asymptomatic D178N carriers (P = 0.0002) compared to HC. Furthermore, symptomatic and asymptomatic D178N carriers had significantly lower plasma PrP levels than patients with AD (P = 0.0025 and P = 0.0041, respectively). In CSF, PrP concentrations were notably lower in D178N symptomatic patients (P = 0.0026) versus non-neurodegenerative (ND) controls. Plasma PrP levels showed no association with age, sex or disease onset and were lower in genetic prion disease patients with the methionine/valine (MV) genotype at PRNP codon 129. The diagnostic accuracy for PrP quantification in plasma as a biomarker discriminated D178N asymptomatic carriers [area under the curve (AUC) = 0.96] and D178N symptomatic patients (AUC = 0.90) from HC with excellent accuracy. In CSF, PrP quantification discriminated D178N symptomatic patients from ND with good accuracy (AUC = 0.64). Taken together, this study defines a characteristic profile of persistently low plasma and CSF PrP in D178N symptomatic and asymptomatic mutation carriers. Low plasma levels in sCJD and E200K, in contrast to P102L, are puzzling. Mutation-specific patterns of PrP need to be considered for monitoring purposes in clinical trials.},
}

@article {pmid42700283,
year = {2026},
author = {Atiq, A and Choe, K and Kang, MH and Park, HY and Atiq, U and Ahmad, W and Ali, W and Park, TJ and Kim, MO},
title = {Neuroprotective Effect of Isorhapontigenin (ISO) Against LPS-Induced Neurodegenerative Condition via TLR4/RAGE-Mediated p-NF-kB Activation.},
journal = {Molecular neurobiology},
volume = {63},
number = {1},
pages = {},
pmid = {42700283},
issn = {1559-1182},
mesh = {Animals ; *Toll-Like Receptor 4/metabolism ; *Neuroprotective Agents/pharmacology/therapeutic use ; Lipopolysaccharides ; *NF-kappa B/metabolism ; *Stilbenes/pharmacology/therapeutic use ; Signal Transduction/drug effects ; *Receptor for Advanced Glycation End Products/metabolism ; Oxidative Stress/drug effects ; Male ; Mice ; *Neurodegenerative Diseases/metabolism/drug therapy/chemically induced/pathology ; Microglia/metabolism/drug effects ; Glycogen Synthase Kinase 3 beta/metabolism ; Mice, Inbred C57BL ; },
abstract = {Alzheimer's disease (AD) is a complex neurodegenerative disorder characterized by persistent neuroinflammation, oxidative imbalance, cognitive decline, Aβ buildup, tau phosphorylation, and synaptic dysfunction. Despite progress in understanding AD's development, effective treatments are still limited. Isorhapontigenin (ISO), a methoxylated stilbenoid similar to resveratrol, shows neuroprotective, anti-inflammatory, and antioxidative effects. In this study, we explored ISO's therapeutic potential in a mouse model of AD-like pathology induced by LPS, focusing on TLR4/RAGE-triggered NF-κB signaling pathway and related neuroinflammatory responses, oxidative stress, GSK3β signaling, tau pathology, Aβ accumulation, glial activation, and synaptic health. Western blot and immunofluorescence techniques were used to measure the levels of TLR4/RAGE signaling components, glial markers (GFAP and Iba-1), p-NF-κB signaling pathway activation, proinflammatory cytokines (TNF-α, COX-2, and IL-1β), oxidative stress indicators (Nrf2 and HO-1), neurodegeneration markers (p-GSK3β, p-tau, and Aβ), and synaptic proteins (PSD-95, SNAP-23, and SYP). Nissl staining helped assess neuronal density and structure. BV2 microglial cells were treated similarly in vitro, followed by viability tests and Apotox-Glo™ triplex assays, along with protein expression analysis. The levels of TLR4, RAGE, GFAP, and Iba-1 increased in the LPS-treated group, along with proinflammatory mediators, ROS, LPO, and neurodegenerative markers. Yet, ISO treatment significantly reduced their expression. Moreover, LPS lowered Nrf2 and HO-1 levels, reduced p-GSK3β, and decreased synaptic proteins, indicating oxidative damage and synaptic failure. ISO reversed these changes by restoring p-GSK3β, activating Nrf2/HO-1, and boosting synaptic protein levels, followed by behavioral improvement as evidenced by reduced escape latency and increased spontaneous alternations in the Morris water maze (MWM) and Y-maze tests. Additionally, ISO preserved neuronal and synaptic integrity and provided consistent neuroprotection in BV2 cells. Overall, these results demonstrate that ISO reduces LPS-induced AD-like pathology by activating TLR4/RAGE-driven p-NF-κB, decreasing neuroinflammation, enhancing Nrf2/HO-1 activity, inhibiting GSK3β, lowering Aβ and p-Tau accumulation, preserving synaptic health, and prominent improvement in spatial memory, emphasizing its potential as an AD treatment.},
}

Animals
*Toll-Like Receptor 4/metabolism
*Neuroprotective Agents/pharmacology/therapeutic use
Lipopolysaccharides
*NF-kappa B/metabolism
*Stilbenes/pharmacology/therapeutic use
Signal Transduction/drug effects
*Receptor for Advanced Glycation End Products/metabolism
Oxidative Stress/drug effects
Male
Mice
*Neurodegenerative Diseases/metabolism/drug therapy/chemically induced/pathology
Microglia/metabolism/drug effects
Glycogen Synthase Kinase 3 beta/metabolism
Mice, Inbred C57BL

@article {pmid42700644,
year = {2026},
author = {Cote, I and Valfort, AC and Sanders, RK and Burris, SL and Hayes, ME and Arya, R and Maram, L and Elgendy, B and Yue, F and Burris, TP},
title = {BE2012 a novel, REV-ERB antagonist that promotes regenerative myogenesis in vivo with substantially improved pharmacokinetics relative to SR8278.},
journal = {The Journal of pharmacology and experimental therapeutics},
volume = {393},
number = {9},
pages = {105011},
doi = {10.1016/j.jpet.2026.105011},
pmid = {42700644},
issn = {1521-0103},
abstract = {Pharmacological inhibition of REV-ERBs has emerged as a potential therapeutic strategy for several diseases with unmet medical needs. Indeed, chronic treatment with SR8278, a synthetic REV-ERB antagonist, has mitigated pathology in various preclinical models of human musculoskeletal and neurological diseases, including Duchenne muscular dystrophy, epilepsy, Alzheimer disease, Parkinson disease, and frontotemporal dementia. However, SR8278, the first and most widely used REV-ERB antagonist, has poor pharmacokinetic properties, which limits its utility. The REV-ERBs (α and β) are widely expressed nuclear receptors that function as ligand-dependent transcriptional repressors, and the therapeutic potential for inhibition of these receptors remains unclear because of the lack of adequate pharmacological tools. Here, we report BE2012, a significantly improved REV-ERB antagonist with >22-fold longer half-life than SR8278. In a cell-based reporter assay, BE2012 exhibited greater potency toward REV-ERBα (EC50 = 0.38 μM) and REV-ERBβ (EC50 = 0.57 μM) compared with SR8278. Notably, in primary myoblast differentiation assays, BE2012 outperformed SR8278 in increasing the proportion of MyoG[+] cells as well as differentiation and fusion indices. In a cardiotoxin-induced muscle injury model, both BE2012 and SR8278 led to increased myofiber cross-sectional area (22%-34% higher than controls). Lastly, transcriptomic profiling revealed remarkable overlap of differentially expressed genes between the 2 compounds, with oxidative phosphorylation and mitochondrial protein complex emerging as the most significantly enriched pathways for both ligands, which have been shown to accelerate regenerative myogenesis. These results establish BE2012 as a refined REV-ERB antagonist for in vivo applications and a valuable tool for deeper exploration of the therapeutic potential of inhibiting REV-ERB activity. SIGNIFICANCE STATEMENT: This study establishes BE2012 as a novel REV-ERBα/β antagonist with a 22-fold longer half-life and improved potency compared with SR8278, the only available REV-ERB antagonist whose poor bioavailability has limited its utility for in vivo use. In an acute muscle injury model in mice, BE2012 promoted regenerative myogenesis and induced a broad transcriptomic reprogramming that was highly concordant with that of SR8278, suggesting it could serve as a new gold-standard REV-ERB antagonist tool compound in the field.},
}

@article {pmid42693696,
year = {2026},
author = {Catakli, D and Ozen-Basoglu, O and Tuncgovde, EB and Ozsarlak-Sozer, G},
title = {The Crosstalk Between Diabetes and Alzheimer's Disease: A Molecular Perspective.},
journal = {Basic & clinical pharmacology & toxicology},
volume = {139},
number = {4},
pages = {e70294},
pmid = {42693696},
issn = {1742-7843},
mesh = {Humans ; *Alzheimer Disease/drug therapy/metabolism/physiopathology/epidemiology ; *Diabetes Mellitus, Type 2/drug therapy/metabolism/epidemiology/physiopathology/complications ; Animals ; Insulin Resistance ; Signal Transduction/drug effects ; Brain/metabolism/drug effects ; Oxidative Stress ; Amyloid beta-Peptides/metabolism ; Hypoglycemic Agents/pharmacology/therapeutic use ; Insulin/metabolism ; },
abstract = {The global prevalence of type 2 diabetes mellitus (T2DM) and Alzheimer's disease (AD) is increasing significantly in an age-dependent manner. Growing evidence supports the conceptualization of AD as 'type 3 diabetes,' a term proposed to describe a metabolic disease primarily driven by impaired insulin signalling and insulin resistance within the brain. This review explores the shared molecular mechanisms underlying both T2DM and AD, including chronic neuroinflammation, oxidative stress, mitochondrial dysfunction and impaired glucose metabolism. Specifically, the crosstalk involves the phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt) pathway, where insulin resistance leads to increased glycogen synthase kinase 3β (GSK-3β) activity, promoting tau hyperphosphorylation and amyloid-β (Aβ) accumulation. Furthermore, the article examines the roles of the NOD-like receptor protein 3 (NLRP3) inflammasome, O-linked β-N-acetylglucosamine modification (O-GlcNAcylation), and the gut-brain axis as critical mediators linking metabolic dysfunction to neurodegeneration. Unlike previous reviews that predominantly address individual pathways in isolation, this review provides an integrated molecular framework that connects insulin resistance to neurodegeneration through converging signalling cascades and highlights emerging therapeutic targets including the NLRP3 inflammasome and O-GlcNAcylation as potential mechanistic bridges between T2DM and AD. Finally, the therapeutic potential of various antidiabetic agents such as glucagon-like peptide-1 (GLP-1) receptor agonists, sodium-glucose cotransporter-2 (SGLT-2) inhibitors and thiazolidinediones is discussed, as these drugs offer promising opportunities for the treatment and prevention of AD by targeting these common molecular pathways.},
}

Humans
*Alzheimer Disease/drug therapy/metabolism/physiopathology/epidemiology
*Diabetes Mellitus, Type 2/drug therapy/metabolism/epidemiology/physiopathology/complications
Animals
Insulin Resistance
Signal Transduction/drug effects
Brain/metabolism/drug effects
Oxidative Stress
Amyloid beta-Peptides/metabolism
Hypoglycemic Agents/pharmacology/therapeutic use
Insulin/metabolism

@article {pmid42693831,
year = {2026},
author = {Lin, LY and Wu, JS and Jeng, WJ and Tsai, CH and Liu, SY and Huang, TW and Yuliani, FS and Lin, SH},
title = {Dementia Risk After Glaucoma Surgery and Medical Therapy: A Multicentre Real-World Cohort Study.},
journal = {International journal of geriatric psychiatry},
volume = {41},
number = {9},
pages = {e70252},
pmid = {42693831},
issn = {1099-1166},
mesh = {Humans ; Female ; Aged ; *Dementia/epidemiology/etiology ; *Glaucoma/surgery/drug therapy/therapy ; Male ; Middle Aged ; Risk Factors ; Aged, 80 and over ; Vision Disorders/epidemiology ; Alzheimer Disease/epidemiology ; Cohort Studies ; },
abstract = {BACKGROUND AND PURPOSE: Glaucoma, a neurodegenerative optic neuropathy and leading cause of irreversible vision loss, shares vascular and neurodegenerative mechanisms with dementia. The 2024 Lancet Commission newly identified visual impairment as a modifiable dementia risk factor. As glaucoma management ranges from long-term medical therapy to laser/surgical intervention, it remains uncertain whether treatment modality influences long-term systemic outcomes such as dementia. This study compares dementia risk in patients receiving glaucoma surgery versus medical therapy.

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

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

CONCLUSIONS: Patients who underwent glaucoma surgery were associated with a lower subsequent risk of all-cause dementia and vascular dementia, with a non-significant trend for Alzheimer's disease, compared with those receiving medical therapy. These findings suggest that surgical management is associated with more favourable long-term cognitive outcomes beyond ocular benefits, which may provide additional context for treatment-escalation decisions in suitable patients.},
}

Humans
Female
Aged
*Dementia/epidemiology/etiology
*Glaucoma/surgery/drug therapy/therapy
Male
Middle Aged
Risk Factors
Aged, 80 and over
Vision Disorders/epidemiology
Alzheimer Disease/epidemiology
Cohort Studies

@article {pmid42693863,
year = {2026},
author = {Chauhan, SB and Bhardwaj, A and Jain, C and Singh, I},
title = {Nano-Magnetism for Precision Neuroscience: Biohybrid Magnetoelectric Nanocarriers as Next-Generation Neural Drug Delivery Platforms.},
journal = {CNS & neurological disorders drug targets},
volume = {},
number = {},
pages = {},
doi = {10.2174/0118715273397455251030094458},
pmid = {42693863},
issn = {1996-3181},
abstract = {Neuroscience is making tremendous progress toward precision medicine, with nanotechnology playing a critical role in overcoming hurdles to successful brain medication delivery. Nano magnetism, namely biohybrid magnetoelectric nanocarriers (MENs), has emerged as a potential method for targeted and non-invasive medication delivery in neurological illnesses. These nanocarriers possess magnetoelectric properties, enabling stimulus-responsive drug release that is externally controlled. This allows for precise targeting across the blood-brain barrier (BBB), with exceptional spatial and temporal resolution. MENs can deliver neurotherapeutics deep into brain regions by combining magnetic guidance with electrical stimulation, thereby improving treatment outcomes for conditions such as Alzheimer's, Parkinson's, epilepsy, and glioblastoma. Furthermore, their biohybrid nature, which is accomplished by functionalizing nanocarriers with biocompatible coatings, peptides, or membranes produced from neural cells, increases biostability, decreases immune response, and improves neuron targeting. This review investigates the underlying concepts of magnetoelectric nanocarriers, production processes, and interactions with brain tissue. It dives deeper into recent advances in precision neural drug delivery, including the effect of external magnetic and electric fields on regulated drug release, neurostimulation, and neuromodulation. While MENs have tremendous promise, long-term biocompatibility, precise control systems, and regulatory restrictions continue to impede clinical translation. Future research should concentrate on enhancing nanocarrier design, increasing targeting efficiency, and undertaking large-scale preclinical and clinical trials. Magnetoelectric nanocarriers have the potential to transform non-invasive neurotherapeutics by bridging the gap between nano magnetism and neuroscience, resulting in safer and more successful treatment paradigms for complex brain illnesses.},
}

@article {pmid42694488,
year = {2026},
author = {Wang, M and Qian, Y and Huang, E and Chu, C and Gao, T and Chen, S and Zhao, N and Luo, C and Liu, Y and Zheng, X and Hu, H and Han, B and Chen, M and Mao, W and Li, W},
title = {Identification of interleukin-11 as a comorbid risk factor for prostate cancer and Alzheimer's disease using integrated bioinformatics and machine learning.},
journal = {Frontiers in immunology},
volume = {17},
number = {},
pages = {1911726},
pmid = {42694488},
issn = {1664-3224},
mesh = {Male ; *Interleukin-11/genetics/metabolism ; Humans ; *Alzheimer Disease/epidemiology/genetics/immunology/metabolism ; *Prostatic Neoplasms/epidemiology/genetics/metabolism/immunology ; *Machine Learning ; Animals ; Mice ; Risk Factors ; Computational Biology/methods ; Comorbidity ; Gene Expression Profiling ; Cell Line, Tumor ; Transcriptome ; Gene Expression Regulation, Neoplastic ; Mice, Inbred C57BL ; },
abstract = {BACKGROUND: Prostate cancer (PCa) and Alzheimer's disease (AD) are age-related disorders with a complex epidemiological association and limited therapeutic options. Identifying shared molecular drivers may reveal new treatment targets.

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

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

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

CONCLUSION: IL11 acts as a shared risk factor related to PCa progression and cognitive decline in AD, representing a convergent molecular pathway and a potential therapeutic target for both age-related diseases.},
}

Male
*Interleukin-11/genetics/metabolism
Humans
*Alzheimer Disease/epidemiology/genetics/immunology/metabolism
*Prostatic Neoplasms/epidemiology/genetics/metabolism/immunology
*Machine Learning
Animals
Mice
Risk Factors
Computational Biology/methods
Comorbidity
Gene Expression Profiling
Cell Line, Tumor
Transcriptome
Gene Expression Regulation, Neoplastic
Mice, Inbred C57BL

@article {pmid42693052,
year = {2026},
author = {Yu, YZ and Zhu, YH and Yang, XK and Wang, SS and Sun, JQ and Qiu, Y and Zhao, W and Yao, LM and Li, WR},
title = {[Danggui Shaoyao San promotes ketone body production and utilization to improve brain energy metabolism and prevent Alzheimer's disease].},
journal = {Zhongguo Zhong yao za zhi = Zhongguo zhongyao zazhi = China journal of Chinese materia medica},
volume = {51},
number = {15},
pages = {4377-4386},
doi = {10.19540/j.cnki.cjcmm.20260505.801},
pmid = {42693052},
issn = {1001-5302},
mesh = {Animals ; Male ; *Ketone Bodies/metabolism/biosynthesis ; *Alzheimer Disease/metabolism/prevention & control/genetics/drug therapy ; *Drugs, Chinese Herbal/administration & dosage ; *Energy Metabolism/drug effects ; *Brain/metabolism/drug effects ; Mice ; Mice, Inbred C57BL ; Humans ; },
abstract = {This study focuses on the mechanism by which Danggui Shaoyao San(DSS) regulates hepatic fatty acid metabolism to promote ketone body production, transport, and utilization, thereby alleviating brain energy metabolism disorders in APP/PS1 mice and enhancing their cognitive abilities. Six SPF-grade 3-month-old male C57BL/6J mice served as the control group. Thirty 3-month-old male APP/PS1 mice were randomly allocated into a model group, a low-dose DSS(DSS-L, 3.2 g·kg~(-1)) group, a medium-dose DSS(DSS-M, 6.4 g·kg~(-1)) group, a high-dose DSS(DSS-H, 12.8 g·kg~(-1)) group, and a ketogenic diet(KD) group. The control and model groups received 8 weeks of normal saline gavage, while the DSS-L, DSS-M, and DSS-H groups received corresponding concentrations of DSS via gavage for 8 weeks. The KD group was fed the ketogenic diet for 8 weeks. After 8 weeks of treatment, the Morris water maze test, novel object recognition test, Y-maze test, and open field test were carried out to evaluate the cognitive function, memory processing, spatial memory, and spontaneous activity and exploratory behavior, respectively. A Roche meter was used to measure the fasting blood glucose level. The β-hydroxybutyrate(BHB) and lactate levels in the liver and brain tissue were quantified by the microplate assay. The adenosine triphosphate(ATP) and adenosine diphosphate(ADP) levels were detected by chemiluminescence. ELISA was employed to measure the serum level of insulin and brain tissue levels of mitochondrial complexes Ⅰ-Ⅳ, citrate synthase(CS), isocitrate dehydrogenase(ICD), and α-ketoglutarate dehydrogenase(α-KG). Immunofluorescence assay was employed to detect the expression of monocarboxylate transporter 2(MCT2) in the hippocampus. Western blot was used to determine the expression levels of 3-hydroxy-3-methylglutaryl-coenzyme A synthase 2(HMGCS2) in the liver, as well as 3-oxoglutarate-CoA transferase(OXCT1) and 3-hydroxybutyrate dehydrogenase(BDH1) in the brain. The results showed that compared with the control group, the model group exhibited reduced time and distance in the target quadrant in the Morris water maze, weakened novel object recognition, decreased Y-maze alternation percentage, and reduced distance and average speed in the open field(P<0.01, P<0.001). Furthermore, the model group exhibited raised levels of fasting blood glucose, insulin in the serum, and lactic acid in the brain, declined level of BHB in the liver(P<0.05, P<0.01), reduced levels of mitochondrial respiratory chain complexes Ⅰ-Ⅳ, CS, ICD, α-KG, ADP and ATP in the brain tissue(P<0.01, P<0.001), down-regulated expression of HMGCS2 in the liver, OXCT1 in the cortex and hippocampus, and BDH1 in the hippocampus(P<0.05, P<0.01). Compared with the model group, the DSS groups and the KD group showed increases in time in the target quadrant, levels of BHB in the liver and brain, mitochondrial complexes Ⅰ and Ⅳ, CS, α-KG, and ATP, and expression of BDH1 in the hippocampus and OXCT1 in the cortex, and reduced levels of fasting blood glucose, insulin in the serum, and lactate in the brain(P<0.05, P<0.01). All the DSS groups exhibited increased average speed in the open field test(P<0.05, P<0.01). The distance in the target quadrant, levels of mitochondrial complexes Ⅱ and Ⅲ, ICD, and ADP, and expression of BDH1 in the cortex increased in the DSS-M, DSS-H, and KD groups(P<0.05, P<0.01). The novel object recognition index and HMGCS2 expression in the liver raised in the DSS-L, DSS-H, and KD groups(P<0.05, P<0.01). The total distance traveled in the open field test increased in the DSS-L, DSS-M, and KD groups(P<0.05, P<0.01). The percentage of alternation in the Y-maze test and MCT2 expression level in the DG region increased in the KD group(P<0.05). In addition, the OXCT1 expression level in the hippocampus was up-regulated in the DSS-H and KD groups(P<0.05, P<0.01). DSS can promote the generation of ketone bodies in the liver and the transport and utilization of ketone bodies in the brain tissue, thereby alleviating the brain energy crisis and cognitive impairment of APP/PS1 mice.},
}

Animals
Male
*Ketone Bodies/metabolism/biosynthesis
*Alzheimer Disease/metabolism/prevention & control/genetics/drug therapy
*Drugs, Chinese Herbal/administration & dosage
*Energy Metabolism/drug effects
*Brain/metabolism/drug effects
Mice
Mice, Inbred C57BL
Humans

@article {pmid42693185,
year = {2026},
author = {Dalakas, MC and Lünemann, JD},
title = {Role of complement and complement-targeted therapeutics in neurological diseases.},
journal = {Nature reviews. Neurology},
volume = {},
number = {},
pages = {},
pmid = {42693185},
issn = {1759-4766},
abstract = {Complement comprises a group of plasma and membrane proteins that provide an effective bridging function for innate and adaptive humoral immunity. Understanding complement pathophysiology is fundamental given that inappropriate complement function in host defence can lead to infectious diseases and inefficient disposal of altered, damaged or senescent cells can lead to or enhance autoimmune neurological processes. Although the rising number of approved drugs targeting complement pathways remains primarily focused on diseases with complement-fixing pathogenic antibodies (such as myasthenia gravis and neuromyelitis optica spectrum disorder), a robust pipeline of emerging treatments holds promise for expanding complement-targeted therapies to a broader spectrum of autoimmune neurological diseases, such as multiple sclerosis and even neurodegenerative diseases such as Alzheimer disease or amyotrophic lateral sclerosis. This Review presents insights into complement biology as it relates to the development or initiation of autoimmune and possibly degenerative diseases affecting the central and peripheral nervous systems or muscle. The effects, merits, risks and challenges of marketed drugs or biologic agents in ongoing phase I-III clinical trials engineered to inhibit proximal or distal components of the complement cascade are also discussed. Anti-complement therapeutics are destined to change the treatment of autoimmune neurologic conditions in which the therapeutic landscape is now becoming crowded with biologic agents targeting other key autoimmunity factors.},
}

@article {pmid42689394,
year = {2026},
author = {Liu, Y and Wu, J},
title = {Low-dose N-methyl-D-aspartate protects against amyloid-β-induced neurotoxicity by suppressing the MLK3-MKK7-JNK3 pathway and activating the PI3K-PDK1-Akt pathway.},
journal = {Neuroreport},
volume = {},
number = {},
pages = {},
doi = {10.1097/WNR.0000000000002310},
pmid = {42689394},
issn = {1473-558X},
abstract = {OBJECTIVE: Oligomeric amyloid-β (Aβ) peptide-induced neuronal apoptosis is a key process in Alzheimer's disease pathogenesis. Low-dose N-methyl-D-aspartate (NMDA) has been shown to promote cell survival both in vitro and in vivo, but its effect on Aβ neurotoxicity remains largely unknown. This study aimed to investigate whether low-dose NMDA protects against Aβ-induced neurotoxicity and to elucidate the underlying molecular mechanisms.

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

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

CONCLUSION: Low-dose NMDA exerts neuroprotective effects against Aβ-induced neurotoxicity. These effects are mediated by the dual modulation of the pro-survival PI3K-PDK1-Akt pathway and the pro-apoptotic MLK3-MKK7-JNK3 pathway.},
}

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

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

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

CONCLUSIONS: Marked changes in brain Aβ levels and cognitive performance were not associated with either p-AMPK or autophagy marker levels, suggesting that additional mechanisms contribute to the neuroprotective effects of TRE in AD. Markers of autophagy initiation and AMPK activity responded similarly to AD modeling and TRE treatment and were positively correlated in the hippocampus, suggesting a role for AMPK in the regulation of TRE-induced hippocampal autophagy.},
}

Animals
*Alzheimer Disease/drug therapy/chemically induced/metabolism/pathology
*Neuroprotective Agents/pharmacology
*Trehalose/pharmacology
Mice
*AMP-Activated Protein Kinases/metabolism
Disease Models, Animal
Signal Transduction/drug effects
Male
Mice, Inbred C57BL
Autophagy/drug effects
Amyloid beta-Peptides/metabolism
Brain/drug effects/metabolism/pathology
Hippocampus/drug effects/metabolism
Cognition/drug effects
Pyrazoles
Pyrimidines

@article {pmid42690003,
year = {2026},
author = {Sonkodi, B},
title = {Alzheimer's Disease, Piezo2 Channelopathy, Piezo1 Channelopathy, and the Body-Wide Piezo2 System.},
journal = {Frontiers in bioscience (Landmark edition)},
volume = {31},
number = {8},
pages = {52555},
doi = {10.31083/FBL52555},
pmid = {42690003},
issn = {2768-6698},
support = {23-2026/ HUSS_PUBL_FUND//Hungarian University of Sports Science/ ; },
mesh = {*Alzheimer Disease/metabolism/genetics/physiopathology ; *Ion Channels/metabolism/genetics ; Humans ; Animals ; *Channelopathies/metabolism/genetics ; Mice ; Phosphatidylinositol 4,5-Diphosphate/metabolism ; },
abstract = {Alzheimer's disease initiates pathophysiology in the 10 to 20 years prior to detectable clinical symptoms. A recent genetic analysis implicated the critical role of Piezo2 in Alzheimer's disease pathophysiology. A recent genetic study, involving PIEZO1 manipulation, showed that phosphatidylinositol 4,5-bisphosphate (PIP2) rectified brain capillary endothelial Piezo1 channelopathy in a mouse model of Alzheimer's disease. However, the present opinion paper posits that the initiating microdamage is in the prefrontal cortex, further upstream of pathophysiology, namely an irreversible Piezo2 channelopathy of glutamatergic terminals that is proposed to finely regulate oxytocin release resulting from stressful ultradian events, leading to impaired ultradian rhythm. The involvement of Piezo2 in the defensive arousal response reveals an underlying body-wide Piezo2 system of which the proposed prefrontal Piezo2 channelopathy is possibly a critical locus. PIP2 is emerging as a potential treatment method for Piezo channelopathy in Alzheimer's disease. However, the challenge of its more precise administration to target affected regions of the brain still remains.},
}

*Alzheimer Disease/metabolism/genetics/physiopathology
*Ion Channels/metabolism/genetics
Humans
Animals
*Channelopathies/metabolism/genetics
Mice
Phosphatidylinositol 4,5-Diphosphate/metabolism

@article {pmid42691219,
year = {2026},
author = {Iqbal, T and Tabassum, S and Imran, M and Tang, S and Xiao, P and Wei, T and Hailaiti, D and Fan, P and Lu, W and Li, H and Huang, J},
title = {The Glymphatic and Meningeal Lymphatic Systems: Gatekeepers of Brain Health in Aging and Neurodegeneration.},
journal = {Aging and disease},
volume = {},
number = {},
pages = {},
doi = {10.14336/AD.2026.0009},
pmid = {42691219},
issn = {2152-5250},
abstract = {The discovery of the glymphatic system and of meningeal lymphatic vessels has substantially revised our understanding of how the central nervous system clears waste and maintains neuroimmune homeostasis. Acting in series, these two pathways remove interstitial solutes, metabolic by-products, and neurotoxic proteins such as tau and amyloid-β from the brain parenchyma and deliver them to the peripheral lymphatic system. Converging experimental and clinical evidence indicates that both pathways decline with age, and that impaired clearance contributes to the onset and progression of Alzheimer's disease, Parkinson's disease, and stroke, although the direction of causality in these associations is not yet fully resolved. In this review, we summarize current knowledge of the anatomy and physiology of the glymphatic and meningeal lymphatic systems; examine the molecular and cellular mechanisms by which their function deteriorates with age; appraise the imaging modalities and fluid biomarkers used to assess them; and evaluate the therapeutic strategies being developed to restore them. A clearer understanding of this clearance pathways may open new avenues for the treatment of age-related neurodegenerative disease.},
}

@article {pmid42691804,
year = {2026},
author = {Sato, S and Sasabuchi, Y and Yamana, H and Kohro, T and Yasunaga, H},
title = {Treatment Duration of Cholinesterase Inhibitor Formulations in Alzheimer's Disease.},
journal = {Journal of the American Medical Directors Association},
volume = {27},
number = {11},
pages = {106481},
doi = {10.1016/j.jamda.2026.106481},
pmid = {42691804},
issn = {1538-9375},
abstract = {OBJECTIVES: To examine treatment duration of oral and transdermal cholinesterase inhibitor formulations in older adults with severe Alzheimer's disease (AD) in routine clinical practice.

DESIGN: Retrospective population-based cohort study.

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

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

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

CONCLUSIONS AND IMPLICATIONS: In older adults with severe AD, oral cholinesterase inhibitor formulations were continued substantially longer than transdermal patches. Given the limited evidence supporting prolonged cholinesterase inhibitor use in severe AD, these findings raise concerns regarding long-term prescribing practices in advanced dementia care.},
}

@article {pmid42680930,
year = {2026},
author = {Ballard, C and Doherty, P and Ismail, Z and Corbett, A and Cummings, JL},
title = {Symptomatic treatment for Alzheimer disease: current evidence and future directions.},
journal = {Nature reviews. Neurology},
volume = {},
number = {},
pages = {},
pmid = {42680930},
issn = {1759-4766},
abstract = {Symptomatic treatment remains central to the clinical management of Alzheimer disease (AD), even as disease-targeted therapies emerge. This Review synthesizes current evidence for pharmacological and non-pharmacological symptomatic therapies targeting cognition, function and neuropsychiatric symptoms in AD. Non-pharmacological interventions, including cognitive training, physical exercise, cognitive stimulation therapy and multimodal lifestyle programmes, show small-to-moderate benefits, particularly in mild cognitive impairment, although implementation challenges persist. Established pharmacological treatments, notably cholinesterase inhibitors and memantine, deliver modest but significant benefits, with biomarker-stratified analyses suggesting the greatest benefit in individuals with confirmed AD pathology. Advances in muscarinic agonists, multitarget agents, neurotrophic modulators and repurposed drugs highlight emerging opportunities for broader symptomatic benefit. Neuropsychiatric symptoms remain highly prevalent and burdensome; personalized psychosocial interventions demonstrate meaningful reductions in agitation and depression, whereas atypical antipsychotics offer only modest efficacy with substantial safety concerns. Newer agents, including brexpiprazole for agitation and pimavanserin for psychosis, show promise but require careful interpretation of effect size and safety. Future progress will depend on biomarker-informed patient selection, integration of circuit-level measures, rational combination strategies spanning pharmacological and non-pharmacological modalities, and adoption of patient-centred outcomes. Symptomatic therapies will remain essential for improving quality of life in people with AD, even as disease-targeted therapies reshape disease trajectories.},
}

@article {pmid42682011,
year = {2026},
author = {Yang, Q and Chen, Z and Zhu, J and Chai, T and Tang, F and Fan, M and Li, Y and Chen, S and Liu, Y and Zheng, M},
title = {Brain-Targeting siRNA Delivery to Tackle Alzheimer's Disease.},
journal = {Wiley interdisciplinary reviews. Nanomedicine and nanobiotechnology},
volume = {18},
number = {5},
pages = {e70076},
pmid = {42682011},
issn = {1939-0041},
support = {25IRTSTHN032//Program of Technology Innovation Team of the Colleges and Universities of Henan Province/ ; SBGJ202503048//the Henan Provincial Medical Science and Technology Research Program, Joint Provincial-Ministerial Project, the Henan Provincial Health Commission/ ; 2025M780051//the China Postdoctoral Science Foundation/ ; 32601935//National Natural Science Foundation of China/ ; },
mesh = {Humans ; *Alzheimer Disease/therapy ; *RNA, Small Interfering/therapeutic use/administration & dosage/metabolism ; *Brain/metabolism ; Animals ; },
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder that places an increasing burden on patients, caregivers, and healthcare systems worldwide. Current disease-modifying therapies (DMTs) are limited by high costs, complex administration, and reliance on advanced biomarker infrastructure, highlighting the shortcomings of existing treatment paradigms. These limitations have sparked growing interest in gene- and nucleic acid-based interventions as upstream strategies to modify AD pathogenesis. Among these, small interfering RNA (siRNA) is especially compelling because it can be rationally programmed, directed at multiple molecular pathways, and paired with rapidly evolving delivery technologies. However, the clinical translation of siRNA therapies for AD is still constrained by challenges in brain-targeted delivery, safety, and sustained efficacy. In this review, we summarize current concepts in AD pathology, highlight recent clinical and translational advances, and critically assess emerging brain-targeted siRNA delivery platforms and their key bottlenecks. Within a precision-medicine framework, brain-targeted siRNA offers the possibility of aligning patient selection, molecular targets, and delivery strategies with biomarker-defined AD endotypes. We discuss both the therapeutic promise and the realistic limitations of siRNA-based approaches for AD, outline priorities for future development, and identify key gaps that must be addressed to enable meaningful clinical implementation.},
}

Humans
*Alzheimer Disease/therapy
*RNA, Small Interfering/therapeutic use/administration & dosage/metabolism
*Brain/metabolism
Animals

@article {pmid42682321,
year = {2026},
author = {Chen, L and Sun, H and Fang, MJ and Cheng, N and Xu, Y},
title = {Proteome-wide genetic study identified therapeutic targets for early-onset and late-onset Alzheimer's disease.},
journal = {International journal of surgery (London, England)},
volume = {112},
number = {6},
pages = {12666-12678},
pmid = {42682321},
issn = {1743-9159},
abstract = {BACKGROUNDS: Given the distinct pathogenic mechanisms of early-onset Alzheimer's disease (EOAD) and late-onset Alzheimer's disease (LOAD), identifying disease-specific therapeutic targets for each subtype is particularly critical.

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

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

CONCLUSIONS: This study pinpointed APOE, NECTIN2, and PVR as shared therapeutic targets for EOAD and LOAD, and EPHB4 and BTN1A1 singled out as a priority target for LOAD.},
}

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

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

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

DISCUSSION: These findings demonstrate that curcumin and turmeric residue exert neuroprotective effects against AD-related pathological alterations by regulating metabolic disturbances and restoring metabolite homeostasis. The integration of chemical profiling, AFAI-MSI, and metabolomics provides new insights into the therapeutic potential and metabolic mechanisms of turmeric-derived resources in Alzheimer's disease.},
}

@article {pmid42682864,
year = {2026},
author = {Li, L and Ding, G and Zhang, L and Luo, H and Boyd, E and Li, Q and Kaur, J and Bohara, M and Chopp, M and Zhang, ZG and Jiang, Q},
title = {Imaging the therapeutic effects of cerebral endothelial cell derived exosome treatment of a preclinical model of Alzheimer's disease.},
journal = {Frontiers in aging neuroscience},
volume = {18},
number = {},
pages = {1788077},
pmid = {42682864},
issn = {1663-4365},
support = {R03 AG098231/AG/NIA NIH HHS/United States ; RF1 AG057494/AG/NIA NIH HHS/United States ; RF1 AG094722/AG/NIA NIH HHS/United States ; R01 NS108463/NS/NINDS NIH HHS/United States ; R01 AG068072/AG/NIA NIH HHS/United States ; R01 DK136843/DK/NIDDK NIH HHS/United States ; },
abstract = {BACKGROUND: Alzheimer's disease (AD) is characterized by the excessive accumulation of select proteins in the brain, associated with altered vascular function, glymphatic transport, cerebrospinal fluid (CSF) dynamics, and cerebral microstructure. Exosomes derived from cerebral endothelial cells (CEC-Exo) have been demonstrated to reduce vascular dysfunction, which may beneficially impact perivascular glymphatic clearance, and potentially, protein aggregates and the corresponding microstructural disruption.

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

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

CONCLUSION: CEC-Exo treatment preserved glymphatic transport, CSF motion, and microstructural integrity in the AD brain, accompanied by a reduced cognitive decline. With a global therapeutic impact, the CEC-Exo therapy provides a novel strategy on the treatment of AD. Our data support the value of dMRIlow-b as a clinically feasible imaging tool for assessing alterations in CSF dynamics that mediate perivascular glymphatic clearance.},
}

@article {pmid42683384,
year = {2026},
author = {Liu, J and Xu, C and Wang, Y and Zhang, J and Hui, R and Lv, W and Xu, A and Dang, Y and Su, S and Zhao, H and Gao, Y and Zhang, J},
title = {From amyloid PET to plasma biomarkers: A multimodal imaging framework for early diagnosis and staging of Alzheimer's disease.},
journal = {Alzheimer's & dementia (Amsterdam, Netherlands)},
volume = {18},
number = {3},
pages = {e70463},
pmid = {42683384},
issn = {2352-8729},
abstract = {INTRODUCTION: Alzheimer's disease (AD) is biologically defined by amyloid beta and tau pathology. Available biomarkers enable early diagnosis but differ in targets, accessibility, and utility. This review synthesizes evidence for plasma biomarkers, magnetic resonance imaging (MRI), and positron emission tomography (PET) to develop a pragmatic, stage-aware framework for early diagnosis and staging.

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

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

DISCUSSION: The preferred pathway is sequential: clinical evaluation and MRI establish context, validated plasma tests guide referral, and PET resolves uncertainty or refines staging when results may change management. This resource-aware integration improves diagnostic specificity and treatment decisions. Prospective implementation studies are needed to validate thresholds and equitable performance across diverse settings.},
}

@article {pmid42683436,
year = {2026},
author = {Guth, MAS},
title = {The highest clinical trial failure rate for any disease in modern medicine: How both amyloid- and non-amyloid-targeting therapies failed to alter disease course in Alzheimer's disease.},
journal = {Free neuropathology},
volume = {7},
number = {},
pages = {22},
pmid = {42683436},
issn = {2699-4445},
abstract = {Background: Alzheimer's disease drug development has produced a 99.6 percent failure rate for disease-modifying compounds (244 compounds tested 2002-2012, one regulatory approval; Cummings et al., 2014; Cummings, 2018)-the most sustained and costly therapeutic failure in the history of modern medicine. The field's standard explanation is that the biology is intractable. The present analysis offers a different and more instructive diagnosis: the failure was not primarily scientific. It was institutional. Objective: To characterize the structural and institutional forces that sustained investment in repeatedly ineffective mechanisms of action across 567 Phase 2 and Phase 3 Alzheimer's trials from 2010 to 2026, and to determine whether peer-reviewed alternative pathogenic frameworks were available at the time each major Go/No Go decision was made. Methods: Trials were identified from ClinicalTrials.gov using the following criteria: primary diagnosis of Alzheimer's disease or mild cognitive impairment attributed to Alzheimer's disease; Phase 2 or Phase 3; status of terminated or completed; primary completion date between January 1, 2010 and May 4, 2026. After exclusion of 70 trials not classifiable by mechanism of action, a final analytic dataset of 497 trials was classified by primary mechanism using the Common Alzheimer's Disease Research Ontology (CADRO). A temporal alignment analysis was conducted for the 12 largest trials by enrollment (N ≥ 1,300), mapping each trial's initiation date against the publication dates of peer-reviewed alternative mechanistic frameworks available at the time of trial launch. Results: Amyloid-targeting approaches accounted for approximately 31 percent of the 497 classified trials, nearly all of which failed to demonstrate clinical efficacy. Among the 12 largest trials, 11 targeted amyloid pathology and 10 were terminated for futility or lack of efficacy. All 12 trials were initiated after the publication in high-impact journals of peer-reviewed alternative frameworks, including the TREM2 neuroinflammation pathway, the antimicrobial protection hypothesis, the periodontitis-associated bacterial pathogenesis hypothesis, and the GLP-1 metabolic pathways. The post-2022 period revealed that genuinely novel non-amyloid mechanisms-TREM2 agonism, GLP-1 receptor stimulation, filamin A modulation, and progranulin/sortilin restoration-also failed to produce clinical benefit at scale despite confirmed target engagement. Three establishment forces are identified as operative causes: regulatory path dependency, institutional entrenchment within grant and editorial review panels, and shareholder-driven sunk-cost pressures. Conclusion: The 567-trial record constitutes a structural verdict on a model of drug development that was never designed to solve a problem of this complexity. The uniformity of negative results across all mechanism categories-amyloid, tau, neuroinflammation, metabolic, and synaptic-points toward deeper problems of disease definition, intervention timing, and endpoint validity that institutional and financial pressures have prevented the field from confronting. The Dominantly Inherited Alzheimer Network (DIAN) biomarker data demonstrates that pathology precedes symptoms by 15-25 years; the 2025 DIAN Trials Unit (DIAN-TU) extension provides the first evidence that treatment before symptom onset may delay dementia. Prevention trials in asymptomatic at-risk populations represent the only strategy the accumulated trial record has not yet refuted.},
}

@article {pmid42684813,
year = {2026},
author = {Unger, RH and Rohatgi, S and Ferraciolli, SF and Kako, B and Omid-Fard, N and Imbett, REM and Dowling, T and Zhu, S and Romero, JM and Ford, JN},
title = {Real-World Challenges in the MRI Detection and Classification of Amyloid-Related Imaging Abnormalities.},
journal = {AJR. American journal of roentgenology},
volume = {},
number = {},
pages = {},
doi = {10.2214/AJR.26.35478},
pmid = {42684813},
issn = {1546-3141},
abstract = {Anti-amyloid monoclonal antibody therapies (AATs) are increasingly used for the treatment of early symptomatic Alzheimer disease. Safe implementation of AATs relies on accurate assessment for exclusionary findings on baseline brain MRI and reliable longitudinal detection of amyloid-related imaging abnormalities (ARIA), including ARIA-H (hemosiderin or hemorrhage) and ARIA-E (edema or effusion). In routine clinical practice, MRI findings encountered during baseline screening and ARIA surveillance sometimes fall into borderline or ambiguous categories that do not clearly conform to trial-defined criteria. For example, subtle or artifactual FLAIR signal abnormality, equivocal microhemorrhage counts, and overlapping features of ARIA-E and ARIA-H can create uncertainty with direct implications for treatment management. Given limited practical guidance addressing these and other gray zones, this imaging-focused review synthesizes common interpretive challenges encountered in a high-volume AAT program and offers practical management-oriented recommendations. Key issues addressed include recognizing technical factors that affect interpretation of susceptibility-weighted and FLAIR images, managing variability in lesion detection across serial examinations, and accurately reporting the temporal evolution of ARIA-related findings. As AAT use expands, recognition of the presented pitfalls can improve diagnostic confidence and help avoid misclassification of findings that may influence therapeutic decisions.},
}

@article {pmid42686946,
year = {2026},
author = {Trushin, S and Nguyen, TKO and Ostroot, M and Nesbitt, JJ and Kovalenko, T and Galkin, A and Nambara, T and Lu, W and Kanekiyo, T and Johnson, G and Trushina, E},
title = {Discovery and preclinical validation of a translationally optimized mitochondrial complex I modulator for Alzheimer's disease.},
journal = {npj drug discovery},
volume = {3},
number = {1},
pages = {},
pmid = {42686946},
issn = {3005-1452},
support = {23AARF-1027342/ALZ/Alzheimer's Association/United States ; U19 AG069701/AG/NIA NIH HHS/United States ; R01AG 55549//NIH/ ; },
abstract = {Alzheimer's disease (AD) is characterized by progressive metabolic failure, impaired mitochondrial function, and diminished adaptive stress responses, highlighting the need for disease-modifying therapies that restore cellular resilience rather than target downstream pathology. Here, we report the discovery and preclinical validation of C273, a translationally optimized, brain-penetrant mitochondrial complex I (mtCI) modulator developed through medicinal chemistry optimization of our first-generation compounds. C273 retained nanomolar neuroprotective activity against Aβ-induced toxicity while exhibiting favorable drug-like properties, including high oral bioavailability, efficient brain penetration, microsomal stability, minimal CYP and off-target pharmacology liabilities, and selective mild modulation of mtCI. Mechanistic studies demonstrated that C273 activated AMP-activated protein kinase (AMPK) and coordinated antioxidant, autophagic, anti-inflammatory, and mitochondrial quality-control pathways in cultured cells and mouse brain. These responses were absent in AMPKα1/α2-deficient cells, establishing AMPK as an essential mediator, while rotenone pretreatment abolished C273-mediated neuroprotection, supporting engagement of the mtCI quinone-binding site. Repeated administration to wild-type mice for 30 days produced no detectable cardiac or hepatic toxicity. Importantly, C273 activated the same neuroprotective pathways and reduced Aβ and p-Tau levels in induced pluripotent stem cell-derived cerebral organoids from patients with sporadic AD. Together, these findings establish mild modulation of mtCI as a therapeutic strategy to restore metabolic resilience and identify C273 as a promising disease-modifying candidate for AD treatment.},
}

@article {pmid42687900,
year = {2026},
author = {McClarty, B and Monteiro, R and Dong, H},
title = {Histone Deacetylase Inhibitors Improve Memory Function and Decrease Neuropathology in APP/PS1 Mice.},
journal = {Research square},
volume = {},
number = {},
pages = {},
doi = {10.21203/rs.3.rs-10816126/v1},
pmid = {42687900},
issn = {2693-5015},
abstract = {Although histone deacetylase (HDAC) inhibitors have shown therapeutic potential in aging and Alzheimer's disease (AD), direct comparisons of nonselective and selective HDAC inhibitors across aging and AD models are lacking. We compared the effects of the broad-spectrum HDAC inhibitor valproic acid (VPA) and the selective class I HDAC inhibitors entinostat (MS-275) and tacedinaline (CI-994) in 3-, 12-, and 18-month-old wild-type and APP/PS1 mice. Mice received 30 days of treatment, followed by a series of behavioral tests assessing different memory domains. Brain tissue was then analyzed for molecular and pathological changes. Both MS-275 and CI-994 improved recognition memory and short-term working memory in 12- and 18-month-old APP/PS1 mice, whereas only CI-994 restored long-term spatial reference memory. CI-994 increased hippocampal synapse-related gene expression and H3K9 acetylation at their promoters, consistent with improved hippocampus-dependent memory. In contrast, MS-275 enhanced synapse-related gene expression and H3K9 acetylation, in the prefrontal cortex (PFC), corresponding to improvements in recognition and working memory. MS-275 also significantly reduced amyloid plaque burden in the hippocampus and PFC, whereas both MS-275 and CI-994 decreased microglial density in APP/PS1 mice. These findings demonstrate distinct spatial and functional effects of selective HDAC inhibition in AD. CI-994 primarily targets hippocampal synaptic plasticity to improve long-term spatial memory, whereas MS-275 preferentially modulates PFC synaptic function and reduces amyloid pathology, leading to improved recognition and working memory. Together, these results identify region-specific HDAC mechanisms that differentially regulate cognitive function and AD pathology, supporting selective HDAC inhibition as a promising therapeutic strategy for AD.},
}

@article {pmid42687965,
year = {2026},
author = {Zeidan, HM and Shah, GH and Zeidan, IH and Samawi, HM and Jones, JA},
title = {Association between Internet Use for Health Information and Self-reported Alzheimer's Disease Diagnosis among Older Adults in the United States: Racial and Gender Disparities.},
journal = {Research square},
volume = {},
number = {},
pages = {},
doi = {10.21203/rs.3.rs-10570409/v1},
pmid = {42687965},
issn = {2693-5015},
abstract = {UNLABELLED: Background Alzheimer's disease (AD) disproportionately affects racial and ethnic minority populations, reflecting broader inequities in access to diagnosis, treatment, and long-term care. As digital health technologies become increasingly widespread, understanding whether internet use for health information is associated with Alzheimer's disease diagnosis may inform strategies to address disparities in aging populations.

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

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

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

CONCLUSION: These findings suggest that digital health engagement is associated with Alzheimer's disease diagnosis among older adults and underscore the importance of equitable and culturally responsive access to digital health resources to address persistent disparities in cognitive aging.},
}

@article {pmid42687999,
year = {2026},
author = {Hai, H and Li, M and Hu, X and Peng, J and He, Z},
title = {Targeting cellular senescence with Traditional Chinese Medicine: advances in neurodegenerative disorder treatment.},
journal = {Frontiers in neurology},
volume = {17},
number = {},
pages = {1875385},
pmid = {42687999},
issn = {1664-2295},
mesh = {Humans ; *Cellular Senescence/drug effects/physiology ; *Neurodegenerative Diseases/drug therapy/metabolism ; *Medicine, Chinese Traditional/methods ; Animals ; *Drugs, Chinese Herbal/therapeutic use/pharmacology ; Signal Transduction/drug effects ; },
abstract = {Neurodegenerative diseases (NDDs), including Alzheimer's disease (AD), Parkinson's disease (PD), and Huntington's disease (HD), represent formidable health challenges, particularly within aging populations. Cellular senescence, marked by irreversible cell cycle arrest and the secretion of pro-inflammatory cytokines, has emerged as a crucial factor in the pathogenesis of these disorders. The accumulation of senescent cells in the nervous system exacerbates neuroinflammation, impairs neuronal function, and accelerates tissue degeneration, all of which are key features of NDDs. In this context, bioactive components derived from Traditional Chinese Medicine (TCM) have attracted significant attention for their potential to modulate cellular senescence and alleviate neurodegeneration. This review examines the shared molecular signaling pathways linking cellular senescence to NDDs, explores the mechanisms by which TCM-derived compounds-such as ginsenosides, ginkgo biloba extract, and curcumin-intervene in senescence-related processes, and discusses the translational potential of these natural compounds for clinical application.},
}

Humans
*Cellular Senescence/drug effects/physiology
*Neurodegenerative Diseases/drug therapy/metabolism
*Medicine, Chinese Traditional/methods
Animals
*Drugs, Chinese Herbal/therapeutic use/pharmacology
Signal Transduction/drug effects

@article {pmid42688139,
year = {2026},
author = {Zupan, M and Prelog, PR and Kramberger, MG and Frol, S},
title = {Anti-amyloid treatment in Alzheimer disease: updated implications for patients with cerebral amyloid angiopathy and other cerebrovascular conditions.},
journal = {Frontiers in neurology},
volume = {17},
number = {},
pages = {1889769},
pmid = {42688139},
issn = {1664-2295},
mesh = {Humans ; *Cerebral Amyloid Angiopathy/drug therapy/complications ; *Alzheimer Disease/drug therapy/complications ; *Cerebrovascular Disorders/drug therapy ; *Antibodies, Monoclonal/therapeutic use ; },
abstract = {Anti-amyloid treatment (AAT) with monoclonal antibodies represents a major therapeutic advance in early Alzheimer disease (AD), but its introduction has important and underappreciated implications for vascular neurology. Because many patients with AD also have cerebral amyloid angiopathy and other cerebrovascular pathology, AAT influences stroke diagnosis, acute reperfusion therapy, and long-term antithrombotic management. Clinical trials of lecanemab and donanemab enrolled highly selected patients with minimal baseline cerebrovascular pathology, limiting generalizability to real-world populations with prevalent vascular comorbidity. Amyloid-related imaging abnormalities, particularly vasogenic edema and microhemorrhages, constitute a central safety concern and may clinically mimic acute ischemic stroke, complicating emergency decision-making and increasing the risk of inappropriate intravenous thrombolysis (IVT). Emerging reports of intracerebral hemorrhage following IVT in treated patients underscore the need for revised acute stroke pathways and support consideration of mechanical thrombectomy when otherwise indicated, although AAT-specific safety data are lacking. Beyond the hyperacute phase of stroke, concomitant use of anticoagulants or dual antiplatelet therapy raises unresolved questions regarding hemorrhagic risk, particularly in patients with atrial fibrillation or those requiring complex antithrombotic regimens. Alternative strategies, including left atrial appendage closure, may be considered in selected patients, although evidence in AAT recipients remains limited. As AAT enters routine practice, multidisciplinary collaboration, dedicated imaging protocols, and prospective safety registries will be essential to integrate disease-modifying AD treatment with safe and effective cerebrovascular care.},
}

Humans
*Cerebral Amyloid Angiopathy/drug therapy/complications
*Alzheimer Disease/drug therapy/complications
*Cerebrovascular Disorders/drug therapy
*Antibodies, Monoclonal/therapeutic use

@article {pmid42688663,
year = {2026},
author = {Svintozelskiy, PV and Wahlert, AJ and Harrod, C and Kay, DG and Grady, KP and Grossberg, GT},
title = {Nicotinic Acetylcholine Receptor Modulation Distinguishes Clinical Benefits of Galantamine in Alzheimer's Disease.},
journal = {Sage open aging},
volume = {12},
number = {},
pages = {30495334261485634},
pmid = {42688663},
issn = {3049-5334},
abstract = {Alzheimer's disease (AD) is the leading cause of dementia and represents a public health challenge in aging populations. Acetylcholinesterase inhibitors (AChEIs) remain first-line symptomatic therapy for mild to moderate AD, with real-world effectiveness largely influenced by tolerability, adherence, and treatment persistence. Galantamine and its inactive prodrug benzgalantamine are differentiated within the class by a dual mechanism that combines reversible acetylcholinesterase inhibition with positive allosteric modulation of nicotinic acetylcholine receptors. This narrative review synthesizes preclinical and clinical evidence examining galantamine-based therapy, with a focus on aspects related to nicotinic acetylcholine receptors: behavioral symptoms and sleep-related effects. Across randomized, observational, and longitudinal studies, galantamine has been associated with improvement or stabilization in behavioral domains including aberrant motor behavior, agitation/aggression, anxiety, apathy, delusions, disinhibition, and hallucinations. However, like other members of the AChEI class, gastrointestinal tolerability issues may affect treatment persistence. Benzgalantamine was developed to address gastrointestinal tolerability, with the aim of improving adherence and long-term treatment continuity.},
}

@article {pmid42675112,
year = {2026},
author = {Maas, C and Fang, L and Mathey, E and Jacob, C and Stremel, T and Viering, T and Fliedner, R and Schnieder, M and von Arnim, CAF},
title = {A comprehensive German claims data analysis of care pathways, risk factors and comorbidities among acetylcholinesterase inhibitor initiators in Alzheimer's disease.},
journal = {Scientific reports},
volume = {16},
number = {1},
pages = {},
pmid = {42675112},
issn = {2045-2322},
mesh = {Humans ; *Alzheimer Disease/drug therapy/epidemiology/diagnosis ; Germany/epidemiology ; Female ; *Cholinesterase Inhibitors/therapeutic use ; Risk Factors ; Retrospective Studies ; Male ; Comorbidity ; Aged ; Aged, 80 and over ; },
abstract = {Early stages of Alzheimer's Disease (AD), commonly referred to as early AD (eAD), represent a critical phase for timely diagnosis and intervention. However, significant gaps remain in understanding real-world care of individuals initiating first-line treatment such as acetylcholinesterase inhibitors (AChE-I) in Germany. A retrospective study was conducted using the German InGef claims database with a pragmatic proxy approach, identifying de novo AChE-I initiators as individuals suspected of having eAD. Two cohorts were defined: a pre-cohort (2022) capturing eight-years prior to AChE-I initiation, and a post-cohort (2017), analyzing five-years following initiation. Patients were matched 1:1 to controls without AD based on demographic characteristics. Outcomes included comorbidities, risk factors, diagnostics, prescriptions, and survival. The study identified 1,994 (pre-cohort) and 2,051 (post-cohort) AChE-I initiators, and respective controls. Mobility disorders increased significantly (+ 55%) over the eight years preceding treatment. Eight years pre-initiation, 81.9% of initiators exhibited at least one modifiable risk factor compared to 76.2% in controls (p < 0.001). Advanced diagnostic procedures were underutilized (MRI: 39.0%, cerebrospinal fluid analysis: 9.2%, in year -1). Only 78.6% received an AD-specific diagnosis within the first year post-initiation. Extensive use of psycholeptics and psychoanaleptics was observed, with a notable decline in dementia-specific medications post-initiation. Post-initiation, initiators showed higher comorbidity burden (e.g., urinary incontinence: 40.2% vs. 10.7% by year 5) and higher observed, unadjusted mortality (53.3% vs. 21.7%, p < 0.001). This study highlights patterns suggestive of gaps in the management of AChE-I initiators in Germany, including underutilization of guideline-based diagnostics, high comorbidity burden, and higher observed mortality. Improved management strategies and the development of more precise diagnostic coding that reflects disease stages could help to address these issues.},
}

Humans
*Alzheimer Disease/drug therapy/epidemiology/diagnosis
Germany/epidemiology
Female
*Cholinesterase Inhibitors/therapeutic use
Risk Factors
Retrospective Studies
Male
Comorbidity
Aged
Aged, 80 and over

@article {pmid42675683,
year = {2026},
author = {Wu, HY and Wang, XS and Yang, M and Cai, J},
title = {The global research of artificial intelligence on Alzheimer disease: A 25-year bibliometric analysis.},
journal = {Medicine},
volume = {105},
number = {35},
pages = {e50370},
pmid = {42675683},
issn = {1536-5964},
mesh = {*Alzheimer Disease/diagnosis ; *Bibliometrics ; Humans ; *Artificial Intelligence/trends ; *Biomedical Research ; },
abstract = {BACKGROUND: With the increasing global prevalence of Alzheimer disease (AD), there has been heightened attention on the onset and progression of AD. Studies indicate that artificial intelligence (AI) has demonstrated potential in the early prediction and diagnosis of AD. However, current research still falls short in terms of data diversity and the application of personalized models.

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

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

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

CONCLUSIONS: AI is accelerating AD research through DL and multimodal imaging, driving progress in early diagnosis and biomarker discovery. However, challenges remain, including limited data diversity and a lack of model interpretability. Future efforts should focus on developing robust, generalizable, and clinically interpretable models by integrating diverse and longitudinal data to enable personalized diagnosis and treatment.},
}

*Alzheimer Disease/diagnosis
*Bibliometrics
Humans
*Artificial Intelligence/trends
*Biomedical Research

@article {pmid42676462,
year = {2026},
author = {Noh, MY and Sung, W and Kim, H and Son, B and Kim, YE and Choi, YY and Holtzman, DM and Kim, SH},
title = {Lecanemab in symptomatic PSEN1 p.Met233Val early-onset Alzheimer's disease: Neuroimaging safety, regional amyloid-PET dynamics, and longitudinal plasma biomarkers.},
journal = {Alzheimer's & dementia (Amsterdam, Netherlands)},
volume = {18},
number = {3},
pages = {e70468},
pmid = {42676462},
issn = {2352-8729},
abstract = {INTRODUCTION: The presenilin 1 (PSEN1) p.Met233Val variant is a Dominantly Inherited Alzheimer Network-Trials Unit (DIAN-TU)-eligible autosomal-dominant Alzheimer's disease (ADAD) variant for which lecanemab response data are unavailable.

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

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

DISCUSSION: Lecanemab demonstrated neuroimaging safety and evidence of biological target engagement in this symptomatic PSEN1 p.Met233Val ADAD carrier. These longitudinal neuroimaging and plasma biomarker findings may help inform interpretation of treatment responses in genetically defined ADAD.},
}

@article {pmid42676482,
year = {2026},
author = {Ren, X and Jin, X and Li, L and Li, F},
title = {Direct toll-like receptor 4 inhibition in Alzheimer's disease models: a focused scoping review of inflammatory, amyloid-handling, and functional outcomes.},
journal = {Frontiers in aging neuroscience},
volume = {18},
number = {},
pages = {1889254},
pmid = {42676482},
issn = {1663-4365},
abstract = {OBJECTIVE: This focused scoping review evaluated whether direct toll-like receptor 4 (TLR4) inhibition, antagonism, or genetic suppression in Alzheimer's disease (AD)-related models was associated with concordant inflammatory, amyloid-β (Aβ)-handling, and functional outcomes.

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

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

CONCLUSION: Toll-like receptor 4 suppression relatively consistently attenuated inflammatory readouts, whereas amyloid-related and functional outcomes remained heterogeneous, supporting an exploratory, hypothesis-generating model of context-dependent inflammatory-amyloid-functional dissociation rather than a uniform therapeutic benefit.},
}

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

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

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

CONCLUSION: These findings demonstrate that APS alleviates cognitive deficits and AD-like pathology, partially through remodeling gut microbiota and modulating the gut-brain axis. APS represents a promising natural compound-based therapeutic candidate for managing cognitive decline associated with Alzheimer's disease.},
}

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

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

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

CONCLUSION: The findings demonstrate that AlCl3 exposure impairs cholinergic function, induces oxidative damage, and leads to cognitive dysfunction, whereas LTN treatment effectively mitigates these effects, suggesting potential neuroprotective benefits against aluminum-induced neurotoxicity.},
}

Animals
*Glutamates/pharmacology
Aluminum Chloride/toxicity
Male
Rats, Wistar
Rats
*Cognitive Dysfunction/chemically induced/drug therapy
Lipid Peroxidation/drug effects
Aluminum Compounds
Disease Models, Animal
*Alzheimer Disease/chemically induced/drug therapy
Brain/drug effects/metabolism
*Neurotoxicity Syndromes/drug therapy/etiology
Glutathione/metabolism
Oxidative Stress/drug effects
Chlorides
Acetylcholinesterase/metabolism
Maze Learning/drug effects
Neuroprotective Agents/pharmacology

@article {pmid42678603,
year = {2026},
author = {Hey, JA and Abushakra, S and Power, A and Watson, D and Porsteinsson, A and Sabbagh, M and MacSweeney, E and Cohen, S and Boada, M and Doraiswamy, PM and Elahi, FM and Rissman, RA and Liang, E and Flint, S and Hristova, E and Kesslak, P and McLaine, R and Albayrak, A and Schaefer, JF and Yu, JY and Tolar, L and Tolar, M},
title = {Plasma Biomarker Effects of Oral Valiltramiprosate/ALZ-801 in Early Alzheimer's Disease from Phase 3 and Phase 2 Trials: Analysis of Core Biomarkers and Correlations with Clinical and Neuroimaging Outcomes.},
journal = {Drugs},
volume = {},
number = {},
pages = {},
pmid = {42678603},
issn = {1179-1950},
abstract = {BACKGROUND: Alzheimer's disease (AD) is a progressive neurodegenerative disorder with few treatment options, especially for APOE4/4 homozygotes who carry high genetic risk. Valiltramiprosate/ALZ-801 is an oral small-molecule inhibitor of amyloid-beta oligomer formation in late-stage development as a disease-modifying therapy for AD. A recent Phase 3 trial did not meet its primary clinical endpoint in the overall population, but demonstrated significant benefits in cognition, function, and brain volumetric MRI (vMRI) in the prespecified subgroup with mild cognitive impairment (MCI). Here, we report plasma p-tau217, p-tau217/Aβ42, and neurofilament light chain (NfL) results from the Phase 3 trial, along with 4-year fluid biomarker data from the Phase 2 study in APOE4 carriers with early AD.

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

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

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

CLINICAL TRIAL REGISTRY: NCT04770220 and NCT04693520.},
}

@article {pmid42678693,
year = {2026},
author = {Zhang, Q and Zhou, Q and Yang, M and Zou, S and Li, Y and Wang, Z},
title = {Non-pharmacological interventions for sleep improvement in Alzheimer's disease: A systematic review and meta-analysis.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261480066},
doi = {10.1177/13872877261480066},
pmid = {42678693},
issn = {1875-8908},
abstract = {BackgroundSleep disturbances are common in Alzheimer's disease (AD) and may worsen neuropsychiatric symptoms, caregiver burden, quality of life, and disease progression. Non-pharmacological strategies are increasingly used because long-term hypnotic or antipsychotic treatment may be limited by safety concerns, but their effects on subjective and objective sleep outcomes remain uncertain.ObjectiveTo evaluate the efficacy of non-pharmacological interventions for improving sleep in patients with AD.MethodsFollowing PRISMA guidelines, we searched PubMed, Embase, the Cochrane Library, Web of Science, and CINAHL through June 6, 2025, for randomized controlled trials of non-pharmacological interventions in AD. The primary outcome was the Pittsburgh Sleep Quality Index (PSQI); secondary outcomes were actigraphy-derived sleep efficiency, total sleep time, wake after sleep onset, number of awakenings, and time in bed. Standardized mean differences were pooled using fixed- or random-effects models. Subgroup, sensitivity, publication-bias, and meta-regression analyses were performed where appropriate.ResultsFourteen randomized controlled trials comprising 937 participants were included. Non-pharmacological interventions significantly reduced PSQI scores (SMD = -0.46, 95% CI -0.70 to -0.21). Neuromodulation-based interventions showed potentially favorable effects on PSQI, and caregiver-delivered programs such as NITE-AD modestly reduced nocturnal awakenings. No significant effects were observed for sleep efficiency, total sleep time, wake after sleep onset, or time in bed.ConclusionsNon-pharmacological interventions may modestly improve subjective sleep quality in AD, but objective sleep benefits remain limited. Larger, multicenter trials with standardized protocols, longer follow-up, harmonized subjective and objective outcomes, and AD-related biomarker assessment are needed.},
}

@article {pmid42678698,
year = {2026},
author = {Luster, CB and Nowinski, CJ and Abdolmohammadi, B and Feigel, ED and Mastrodicasa, MJ and Finegan, B and Goldstein, L and Katz, DI and Cantu, RC and Dwyer, B and Tripodis, Y and Stein, TD and Alosco, ML and McKee, AC and Mez, J and Daneshvar, DH},
title = {Neurodegenerative Disease Death Certification Among National Football League Players With Dementia.},
journal = {JAMA network open},
volume = {9},
number = {9},
pages = {e2631614},
pmid = {42678698},
issn = {2574-3805},
mesh = {Humans ; Male ; *Dementia/mortality ; *Death Certificates ; *Football/statistics & numerical data ; *Neurodegenerative Diseases/mortality ; Aged ; Retrospective Studies ; Middle Aged ; United States/epidemiology ; *Athletes/statistics & numerical data ; Cohort Studies ; },
abstract = {IMPORTANCE: Researchers frequently use death certificate data to evaluate occupational risks among National Football League (NFL) players, demonstrating elevated neurodegenerative mortality risk. Robust epidemiologic data suggest deaths attributable to neurodegenerative disease (NDD) are frequently underreported on death certificates, leading to substantial underascertainment of neurodegenerative mortality. Better characterization of the factors underlying neurodegenerative death certification is critical to addressing underreporting of NDDs, informing disease surveillance and resource allocation.

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

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

EXPOSURE: NFL career.

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

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

CONCLUSIONS AND RELEVANCE: This cohort study found that only 30.7% of brain donors with clinician-adjudicated dementia had neurodegenerative death certification. These results add to growing evidence of frequent NDD underascertainment where more severe disease is associated with neurodegenerative death certification, offering insight into factors that must be considered when using death certificate data to assess NDD burden. Factors such as worsened executive functioning and cognitive symptoms, greater functional impairment, and more severe neuropathology may be associated with an increased likelihood of neurodegenerative death certification among NFL players.},
}

Humans
Male
*Dementia/mortality
*Death Certificates
*Football/statistics & numerical data
*Neurodegenerative Diseases/mortality
Aged
Retrospective Studies
Middle Aged
United States/epidemiology
*Athletes/statistics & numerical data
Cohort Studies

@article {pmid42679930,
year = {2026},
author = {Kılınç, S and Yılmaz, ŞG and Bozkurt, AS and Balcı, SO},
title = {Bovine lactoferrin can reduce Aβ /TAU accumulation in two major pathological Alzheimer's Disease rat models.},
journal = {Behavioural brain research},
volume = {},
number = {},
pages = {116453},
doi = {10.1016/j.bbr.2026.116453},
pmid = {42679930},
issn = {1872-7549},
abstract = {INTRODUCTION: Alzheimer's disease (AD) is a neurodegenerative disease characterized by progressive cognitive decline. Bovine lactoferrin (bLf) is an iron-binding protein with immunomodulatory effects both in the intestine and throughout the body. In this study, the potential therapeutic effects of bLf were evaluated using two different rat models that mimic key aspects of AD pathology.

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

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

CONCLUSION: These findings were consistent across both models. Overall, bLf holds promise as a therapeutic candidate capable of simultaneously targeting two key pathological features of AD.},
}

@article {pmid42680070,
year = {2026},
author = {Wang, J and Luo, L and Zhang, J and Yu, L and Cui, L},
title = {The gut microbiota and gut-brain axis in Alzheimer's disease: From pathogenesis to treatment.},
journal = {Ageing research reviews},
volume = {122},
number = {},
pages = {103345},
doi = {10.1016/j.arr.2026.103345},
pmid = {42680070},
issn = {1872-9649},
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder whose pathological course involves amyloid-β (Aβ) deposition, tau abnormalities, neuroinflammation, and neurovascular dysfunction. Interest in the microbiota-gut-brain axis does not arise because gut dysbiosis has been established as an independent initiating cause of sporadic AD, but because this axis connects modifiable peripheral factors-including diet, medication, ageing, and intestinal physiology-with barrier homeostasis, immunometabolic state, neural afferent signaling, and the brain's response to pathology. Human studies have detected microbiota differences in biomarker-positive preclinical AD and suggest that barrier abnormalities may be associated with subsequent cognitive change; patient-derived microbiota transfer, APOE-dependent tau models, and immune-vagal circuit studies further support phenotype modifiability under defined experimental conditions. This review therefore integrates barrier, immune, metabolic, and neural pathways and emphasizes that diverse microbial alterations may converge on a limited set of measurable functional nodes that could be more informative than individual genera for mechanistic validation, risk stratification, and treatment monitoring. Although clinical intervention evidence remains at an early stage, the peripheral accessibility and modifiability of the microbiota provide a rationale for investigating it as an adjunctive target alongside standard AD therapy. Future work should concurrently evaluate the microbiome, metabolites, both barriers, and immune and neural readouts in longitudinal cohorts and stratified randomized trials to determine which patients, disease stages, and intervention modalities are most likely to benefit.},
}

@article {pmid42680110,
year = {2026},
author = {Nie, T and Li, J and Tan, S and Chen, S and Yang, D and Nepovimova, E and Wu, Q and Kuca, K},
title = {T-2 toxin disrupts Alzheimer's-relevant App/Tau homeostasis via circadian-p53-senescence crosstalk: Evidence from human neuroblastoma cells.},
journal = {Neurotoxicology},
volume = {117},
number = {},
pages = {103559},
doi = {10.1016/j.neuro.2026.103559},
pmid = {42680110},
issn = {1872-9711},
abstract = {Environmental mycotoxins are pervasive exposures, yet how they perturb Alzheimer's disease (AD)-relevant proteostasis remains unclear. We treated SH-SY5Y cells with low-dose T-2 toxin (6 nM) for 24 h, and profiled AD-relevant protein changes alongside transcriptomic, circadian, and senescence-related readouts. We report that T‑2 toxin remodels APP and Tau homeostasis, featuring an early decrease in full‑length APP and a delayed, sustained increase in Tau phosphorylation and total Tau, accompanied by dynamic cytokine release. RNA‑seq at 12 h revealed a p53‑centered stress response and enrichment of circadian‑related pathways. Cosinor analysis indicated that CLOCK rhythmicity is preserved but reparameterized following T-2 toxin exposure, with a marked phase shift and an elevated mesor. Pharmacological disruption of CLOCK attenuated p53 induction and Tau elevation, whereas inhibition of p53 partially restored APP and reduced Tau changes while reshaping CLOCK abundance and localization, consistent with CLOCK-p53 cross‑regulation. T‑2 toxin also induced a time‑dependent senescence‑like phenotype that was attenuated by CLOCK and/or p53 inhibition. Post‑treatment with senolytic drugs dasatinib and quercetin reduced SA‑β‑gal burden, dampened p53 signaling, and improved the APP/Tau profile. Together, these data link T‑2 toxin exposure to AD‑relevant proteostasis remodeling through a CLOCK-p53-senescence axis and suggest circadian and senescence‑targeting strategies as complementary intervention points.},
}

@article {pmid42671334,
year = {2026},
author = {Zhang, W and Wang, S and Gou, X},
title = {Research progress on terpenoids alleviating Alzheimer's disease through the Keap1/Nrf2/ARE pathway by exerting antioxidant effects and promoting mitophagy.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261480043},
doi = {10.1177/13872877261480043},
pmid = {42671334},
issn = {1875-8908},
abstract = {The exact initiating causes of Alzheimer's disease (AD) remain inconclusive. Meanwhile, the causal sequence and interactions within its pathological network are still poorly understood, which limits the efficacy of single treatment strategies and impedes drug development. Oxidative stress, identified as a central intersection point within this network, drives the deposition of amyloid-β protein, excessive tau phosphorylation, neuroinflammation, and mitochondrial damage, creating a self-perpetuating cycle. Consequently, oxidative stress has become a focal point for multi-target interventions. This review systematically investigates the evidence of terpenoids in cellular and animal models, elucidating their protective effects via a dual antioxidant mechanism. Firstly, terpenoids activate the Keap1/Nrf2/ARE pathway, leading to the upregulation of antioxidant genes and reduced free radical generation. Secondly, they enhance PINK1/Parkin-mediated mitophagy, facilitating the clearance of damaged organelles and preventing the release of reactive oxygen species. The review also delves into the positive feedback regulatory network involving molecules like Nrf2 and key proteins of mitophagy, such as p62/SQSTM1, offering a detailed mechanistic insight into the synergistic effects of terpenoids. This study underscores the significance of natural terpenoids, with their unique regulatory role in oxidative stress, as a promising candidate library for Alzheimer's drug development due to their diverse structures, clear mechanisms, and high safety profile. Additionally, it establishes a theoretical and experimental basis for the development of novel intervention strategies targeting multiple pathways with a single drug.},
}

@article {pmid42671540,
year = {2026},
author = {Vernooij, MW and Oliveira, TG and Wiest, R and Fox, NC and Frisoni, GB and Barkhof, F},
title = {SWI versus T2*GRE for ARIA-H monitoring: a pragmatic perspective on adoption in clinical practice.},
journal = {Neuroradiology},
volume = {},
number = {},
pages = {},
pmid = {42671540},
issn = {1432-1920},
abstract = {Although radiological severity thresholds for amyloid-related imaging abnormalities with hemosiderin deposition (ARIA-H) were developed using 2-dimensional acquisitions of T2*-weighted gradient-recalled echo (T2*GRE) MRI in pivotal anti-amyloid trials, adoption of well established 3D susceptibility-weighted imaging (SWI) in ARIA-H monitoring in clinical practice represents a reasonable long-term direction for clinical practice. SWI provides documented higher sensitivity and comparable or superior inter-rater reliability compared with conventional T2*GRE for detecting cerebral microbleeds and cortical superficial siderosis, the two key imaging manifestations of ARIA-H. Moreover, SWI is already incorporated into most contemporary dementia MRI protocols, offering important practical and logistical advantages. Available preliminary evidence suggests that the downstream clinical impact of detecting a few additional microbleeds or areas of siderosis may remain modest for most patients. Earlier and more reliable detection could potentially enhance safety by identifying individuals at higher risk of ARIA-H before treatment initiation. The critical requirements are transparency regarding sequence choice and consistency within individual patients over time.},
}

@article {pmid42673747,
year = {2026},
author = {Pyne, IT and Roy, AJ and Boraschi, S and Hajgude, SS and Hall, RA},
title = {Panoramic characterization of proposed ligands for GPR3: oleoylethanolamide as a pharmacological chaperone.},
journal = {Molecular pharmacology},
volume = {108},
number = {8},
pages = {100146},
doi = {10.1016/j.molpha.2026.100146},
pmid = {42673747},
issn = {1521-0111},
abstract = {G protein-coupled receptor 3 (GPR3) is a constitutively active G protein-coupled receptor known to regulate β-amyloid deposition in the brain and metabolism in brown adipose tissue. Although multiple compounds have been proposed to activate GPR3 signaling, it is still considered an orphan receptor. Recently, structural evidence revealed a hydrophobic tunnel in GPR3, suggesting that a lipid may be an endogenous agonist for GPR3. We sought to characterize the reported agonists for GPR3 to determine which might be authentic agonists and found that only the synthetic ligand, diphenyleneiodonium chloride, and the endogenous lipids, oleoylethanolamide (OEA) and oleamide, stimulated cAMP generation in a GPR3-dependent manner. Although treatment of cells with diphenyleneiodonium chloride stimulated rapid cAMP generation, we observed gradual increases in GPR3 activation over multiple hours after OEA treatment. Additionally, we found that chronic stimulation with OEA caused an increase in GPR3 cell surface expression. Coupled with the slow activation kinetics of OEA-stimulated GPR3 signaling, these findings suggest that OEA does not behave strictly as a classical agonist for GPR3. Indeed, we found that the OEA-mediated increase in GPR3 on the cell surface can be blocked by inhibiting receptor forward trafficking through the endoplasmic reticulum and Golgi, which positions OEA as a pharmacological chaperone that increases GPR3 signaling by promoting receptor trafficking to the cell surface. These findings suggest a novel mechanism for the regulation of the constitutively active receptor GPR3, whereby the amount of receptor at the plasma membrane, and therefore, the receptor's signaling activity, can be regulated by lipid binding in the endoplasmic reticulum/Golgi. SIGNIFICANCE STATEMENT: This study proposes a novel mechanism for the regulation of the activity of the G protein-coupled receptor, G protein-coupled receptor 3. This study found that the endogenous lipid oleoylethanolamide functions as a pharmacological chaperone by promoting the accumulation of G protein-coupled receptor 3 at the plasma membrane through increased forward trafficking, thereby inducing increased receptor signaling activity.},
}

@article {pmid42668333,
year = {2026},
author = {Kalra, P and Chaturvedi, D and Kumar, A and Grewal, AK and Khan, H and Singh, V and Singh, TG and Singh, T and Ahmad, SF and Attia, SM},
title = {AMBMP Hydrochloride Reverses STZ-Induced Alzheimer-Type Dementia Associated with Wnt/β-catenin/TLR4 Signaling.},
journal = {Neuromolecular medicine},
volume = {28},
number = {1},
pages = {},
pmid = {42668333},
issn = {1559-1174},
support = {ORF-2026-748//King Saud University/ ; },
mesh = {Animals ; *Alzheimer Disease/drug therapy/chemically induced ; *Toll-Like Receptor 4/physiology/agonists ; Streptozocin/toxicity ; Male ; Mice ; *Wnt Signaling Pathway/drug effects ; *Neuroprotective Agents/therapeutic use/pharmacology ; Oxidative Stress/drug effects ; Donepezil/therapeutic use/pharmacology ; Disease Models, Animal ; Maze Learning/drug effects ; beta Catenin/physiology ; Acetylcholinesterase/metabolism ; Palmitic Acid/pharmacology ; },
abstract = {Alzheimer's disease (AD) is a debilitating neurodegenerative disorder with progressive cognitive decline and neuronal loss. This study investigated the neuroprotective effects of AMBMP Hydrochloride, a Wnt/β-catenin agonist, in a streptozotocin (STZ)-induced mice model of AD, elucidating the interplay between dysregulated Wnt/β-catenin signaling and Toll-Like Receptor 4 (TLR4)-mediated inflammation, with Palmitic acid used as a TLR4 pathway modulator. Mice received bilateral intracerebroventricular (i.c.v.) injections of STZ (3 mg/kg) on Day 1 and Day 3, followed by administration of Donepezil (3 mg/kg)/ AMBMP Hydrochloride (5 mg/kg and 10 mg/kg)/Palmitic acid (TLR4 agonist, 20 mg/kg) via the intraperitoneal (i.p.) route from Day 4 to Day 22. STZ-treated mice exhibited significant cognitive dysfunction, characterized by impaired performance in the Morris Water Maze (MWM) task along with increase in acetylcholinesterase (AChE) activity, oxidative stress (thiobarbituric acid reactive substances; TBARS), neuroinflammation [tumor necrosis factor alpha (TNF-α)/Interleukin-6 (IL-6)/Interleukin-1 beta (IL-1β) and nuclear factor kappa B (NF-κB)] and decreased reduced glutathione (GSH) levels. However, AMBMP Hydrochloride significantly improved behavioral and biochemical alterations possibly through modulation of Wnt/β-catenin signaling and attenuation of TLR4-mediated inflammation. Interestingly, Palmitic acid co-treatment was found to counteract these protective effects, further pointing to a role of TLR4 in the pharmacological effect of AMBMP Hydrochloride. In summary, we confirmed that AMBMP Hydrochloride exhibits potent neuroprotective effects associated with modulating Wnt/β-catenin/TLR4 signaling, offering a promising therapeutic approach against Alzheimer-Type Dementia. Future studies should delve deeper into the molecular mechanisms and translational promise of AMBMP hydrochloride, paving the way for its development as a potential candidate for AD management.},
}

Animals
*Alzheimer Disease/drug therapy/chemically induced
*Toll-Like Receptor 4/physiology/agonists
Streptozocin/toxicity
Male
Mice
*Wnt Signaling Pathway/drug effects
*Neuroprotective Agents/therapeutic use/pharmacology
Oxidative Stress/drug effects
Donepezil/therapeutic use/pharmacology
Disease Models, Animal
Maze Learning/drug effects
beta Catenin/physiology
Acetylcholinesterase/metabolism
Palmitic Acid/pharmacology

@article {pmid42668348,
year = {2026},
author = {Han, Z and Chen, H and Yao, Y and Bo, X and Ni, X and Liu, H and Bai, M and Li, T and Bao, L and Zhang, D and Dong, W},
title = {Promoting Effect of (+)-Borneol on Alzheimer's Disease Treatment in APP Transgenic Zebrafish and Its Blood-Brain Barrier Permeation Mechanism.},
journal = {Molecular neurobiology},
volume = {63},
number = {1},
pages = {},
pmid = {42668348},
issn = {1559-1182},
mesh = {Animals ; *Blood-Brain Barrier/drug effects/metabolism/pathology ; Zebrafish/genetics ; Animals, Genetically Modified ; *Alzheimer Disease/drug therapy/genetics/pathology/metabolism ; *Camphanes/pharmacology/therapeutic use ; *Amyloid beta-Protein Precursor/genetics/metabolism ; Brain/pathology/metabolism/drug effects ; },
abstract = {(+)-Borneol (Bor) has been shown to enhance drug penetration across the blood-brain barrier (BBB); yet its mechanisms of action and adjuvant effects on Alzheimer's disease (AD) drugs remain insufficiently investigated. This study systematically explored the adjuvant effects of Bor and its underlying mechanisms by employing AB wild-type zebrafish and APP transgenic zebrafish models. Results demonstrated that Bor at concentrations of 0.05 mM or lower exhibited no toxicity toward AB wild-type zebrafish, whereas 0.01 and 0.05 mM Bor significantly increased the expression of green fluorescent protein (GFP) in the zebrafish brain. Genetic analyses revealed that Bor downregulated genes encoding tight junction proteins and P-glycoprotein (P-gp). Drug treatment experiments showed that Bor enhanced the efficacy of AD therapeutic agents, including Zhenbaopill (ZBP, a traditional medicinal preparation) and the synthetic drug 8e. Specifically, Bor ameliorated AD-related behavioral impairments, inhibited cerebral apoptosis, restored the expression of AD-associated genes, normalized the activities of acetylcholine (ACh)-related enzymes, and downregulated both the mRNA and protein levels of Claudin 5. In summary, Bor enhances BBB permeability by regulating the expression of genes encoding BBB-related proteins, thereby increasing the brain concentration and bioavailability of AD drugs with anticholinesterase activity. An appropriate dose of Bor may thus contribute to enhancing the therapeutic efficacy of AD drugs.},
}

Animals
*Blood-Brain Barrier/drug effects/metabolism/pathology
Zebrafish/genetics
Animals, Genetically Modified
*Alzheimer Disease/drug therapy/genetics/pathology/metabolism
*Camphanes/pharmacology/therapeutic use
*Amyloid beta-Protein Precursor/genetics/metabolism
Brain/pathology/metabolism/drug effects

@article {pmid42668476,
year = {2026},
author = {Wu, B and Wu, J and Zhu, L and Li, A and Fu, Y and Lei, Z and Wu, D and Peng, W and Xie, L},
title = {Intranasal L-DOPA/TPP-engineered extracellular vesicles deliver icariin to ameliorate mitochondrial dysfunction with associated sphingolipid remodeling in Alzheimer's disease models.},
journal = {Materials today. Bio},
volume = {40},
number = {},
pages = {103563},
pmid = {42668476},
issn = {2590-0064},
abstract = {Alzheimer's disease (AD) is associated with mitochondrial dysfunction, oxidative stress, and disrupted lipid homeostasis, but the therapeutic translation of mitochondrial-protective agents remains limited by inefficient brain delivery, insufficient neuronal selectivity, and poor subcellular precision. Here, we developed an intranasal extracellular vesicle formulation (L-DOPA/TPP-EV-ICA) by loading icariin (ICA) into mesenchymal stem cell-derived extracellular vesicles and post-inserting DSPE-PEG-Levodopa and TPP-PEG-PE to enhance nasal environment, neuronal association, and mitochondria-associated intracellular enrichment. The engineered vesicles retained EV-like morphology, showed measurable ICA encapsulation, and maintained colloidal stability under the tested storage and simulated nasal conditions. In a human nasal epithelial Transwell model, L-DOPA/TPP-EV-ICA showed greater neuronal uptake than unmodified EVs without detectable disruption of epithelial barrier integrity and exhibited preferential colocalization with mitochondria-associated structures after cellular internalization. In Aβ-injured neuronal cells, L-DOPA/TPP-EV-ICA treatment reduced mitochondrial oxidative stress and mPTP opening, improved membrane potential, and enhanced ATP production and redox-related parameters. Following intranasal administration, the engineered formulation generated stronger and more persistent brain-associated fluorescence and showed preferential association with NeuN-positive cells. In APP/PS1 mice, treatment improved cognitive performance, and attenuated histopathological and mitochondrial abnormalities. Integrated proteomic, metabolomic analyses, and protein-level analyses further identified treatment-associated alterations in sphingolipid-related pathways. These findings support L-DOPA/TPP-EV-ICA as a promising preclinical intranasal EV platform for improving mitochondrial function and modulating sphingolipid-associated alterations in AD-related models.},
}

@article {pmid42668611,
year = {2026},
author = {Gao, F and Luo, G and Liu, B and Qiu, X and Bai, J and Wang, R},
title = {Comparative effectiveness of multiple interventions for Alzheimer's disease on ABC syndromes and QoL: A Bayesian network meta-analysis.},
journal = {iScience},
volume = {29},
number = {9},
pages = {117250},
pmid = {42668611},
issn = {2589-0042},
abstract = {Evidence comparing directly pharmacological and non-pharmacological treatments for Alzheimer's disease (AD) is scarce. The ABC symptoms-activities of daily living (ADLs) (A), behavioral and psychological symptoms (BPSs) (B), cognitive function (C), and quality of life (QoL)-are critical for diagnosing and assessing treatment effects in AD. This study aims to evaluate five interventions for AD: pharmacological therapy (PT), photobiomodulation (PBM), cognitive therapy (CT), exercise therapy (ET), and repetitive transcranial magnetic stimulation (rTMS) using a Bayesian network meta-analysis approach. Among 6,450 records screened, 91 randomized controlled trials (RCTs) involving 12,242 participants met the inclusion criteria. PBM and rTMS showed significant benefits for cognitive function in AD patients. PT and CT showed notable effectiveness in enhancing activities of daily living. For QoL, CT and ET were identified as more favorable outcomes. Collectively, each intervention exerts unique merits targeting ABC symptoms and QoL, implying combined pharmacological and non-pharmacological regimens could optimize therapeutic gains for AD management.},
}

@article {pmid42669137,
year = {2026},
author = {Xu, B and Li, X and Dong, S and Zhang, Z and Jin, D and Li, G and Wang, J},
title = {Modulating the Gut-Microbiota-Brain Axis in Alzheimer's Disease: Therapeutic Potential of Nutritional and Metabolic Factors.},
journal = {CNS neuroscience & therapeutics},
volume = {32},
number = {9},
pages = {e71117},
pmid = {42669137},
issn = {1755-5949},
mesh = {Humans ; *Alzheimer Disease/metabolism/diet therapy/microbiology/therapy ; *Gastrointestinal Microbiome/physiology ; Animals ; *Brain/metabolism ; *Brain-Gut Axis/physiology ; Fecal Microbiota Transplantation/methods ; },
abstract = {BACKGROUND: Alzheimer's disease (AD) is a progressive neurodegenerative disorder and the leading cause of dementia among the elderly, characterized by a gradual decline in memory and cognitive function. The growing body of evidence highlighting the interaction between the gut microbiota and the central nervous system has positioned the gut microbiota as a key area of research in AD pathogenesis.

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

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

CONCLUSIONS: Nutritional interventions targeting the gut-microbiota-brain axis represent a promising approach for the comprehensive prevention and management of AD. Further mechanistic and clinical studies are warranted to translate these findings into effective therapeutic strategies.},
}

Humans
*Alzheimer Disease/metabolism/diet therapy/microbiology/therapy
*Gastrointestinal Microbiome/physiology
Animals
*Brain/metabolism
*Brain-Gut Axis/physiology
Fecal Microbiota Transplantation/methods

@article {pmid42669176,
year = {2026},
author = {Forsyth, F and Diaz, A and Andersson, V and Haraldsen, IH and Gove, D},
title = {Ethical considerations of fluid biomarker use in alzheimer's disease - a rapid review.},
journal = {Aging & mental health},
volume = {},
number = {},
pages = {1-14},
doi = {10.1080/13607863.2026.2719938},
pmid = {42669176},
issn = {1364-6915},
abstract = {OBJECTIVE: Alzheimer's disease (AD) care has been reshaped by the integration of fluid biomarkers. This review addressed the question "What are the ethical considerations of fluid biomarker use in eligibility assessments for treatment in AD and mild cognitive impairment?"

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

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

CONCLUSIONS: Multiple ethical concerns surround the use of fluid biomarkers in AD treatment decisions, and there is limited empirical evidence to substantiate claims about benefits and harms. Uncertainty in biomarker performance, particularly in underrepresented groups, raises risks to non-maleficence, autonomy, and justice and complicates clinical decision making.},
}