@article {pmid41527783,
year = {2026},
author = {Zülke, AE and Beyer, F and Luppa, M and Mildner, T and Frese, T and Gensichen, J and Kaduszkiewicz, H and Czock, D and König, HH and Wiese, B and Hoffmann, W and Thyrian, JR and Villringer, A and Riedel-Heller, SG and Witte, AV},
title = {Evaluating MRI correlates of lifestyle-based dementia risk reduction: Results from the AgeWell.de imaging study.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877251414423},
doi = {10.1177/13872877251414423},
pmid = {41527783},
issn = {1875-8908},
abstract = {BackgroundMultidomain lifestyle interventions can improve dementia risk by risk factor modification. Little is known about possible mechanisms underlying this effect.ObjectiveAnalyze whether changes in a validated dementia risk score were linked to changes in neuroimaging markers in a sample of older adults at increased dementia risk, participating in a multimodal lifestyle intervention.MethodsParticipants of the multi-centric AgeWell.de-trial at the Leipzig study site were examined using 3 Tesla MRI at baseline and 24-months follow-up, assessing markers of hippocampal-limbic atrophy and vascular pathology (hippocampal volume (HCV), entorhinal cortex thickness, free water fraction, peak width of skeletonized mean diffusivity, white matter hyperintensity volume, mean gray matter cerebral blood flow). Dementia risk was assessed using the Lifestyle for Brain Health (LIBRA)-index. Multivariable linear regression analyses assessed effects of changes in LIBRA on neuroimaging markers.ResultsOf 56 participants at baseline, 41 underwent the follow-up assessment (Mage: 68.1 (4.1), % female: 46.3, intervention/control group: 16/25). Lower LIBRA-scores, indicating lower dementia risk, were associated with higher HCV at baseline. LIBRA improved in both groups, with no between-group difference in change. Increases in LIBRA were linked to smaller decline in HCV independently of the intervention. No further effects of lifestyle changes on neuroimaging were detected. Exploratory analyses indicated that detrimental lifestyle changes were linked to decreased cognitive performance in the intervention group.ConclusionsWe found no conclusive evidence for associations between lifestyle changes due to a multidomain lifestyle intervention and structural brain health markers. Larger samples and longer interventions may clarify underlying mechanisms.},
}

@article {pmid41527775,
year = {2026},
author = {Teipel, S and König, A and Brem, AK and Perry, G and Moreira, PI and Cole, J and Ferreira, D and Dyrba, M},
title = {Recommendations for reporting findings from analyses using artificial intelligence and machine learning in the Journal of Alzheimer's Disease.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877251413701},
doi = {10.1177/13872877251413701},
pmid = {41527775},
issn = {1875-8908},
abstract = {We propose five recommendations to make AI-based research studies more suitable for a clinical readership. First, authors should justify the added value of complex and potentially more opaque AI approaches. Second, rigorous description of input data, diagnostic criteria, and preprocessing is essential to avoid biased or clinically irrelevant outcomes. Third, benchmarking against clinically relevant performance thresholds should be established a priori. Fourth, method sections should combine an accessible lay summary with detailed technical supplement. Fifth, model explainability is encouraged to mitigate opacity. These recommendations aim to support AI research that is methodologically robust and interpretable for AD researchers.},
}

@article {pmid41527767,
year = {2026},
author = {Harris, M and Bateman, JR and Shaaban, CE and Becker, J and DeKosky, ST and Lopez, OL and Gogniat, MA and Snitz, B and Kaufer, D},
title = {Certainty-weighted recognition memory: Potential applications for early detection and metacognition.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877251406623},
doi = {10.1177/13872877251406623},
pmid = {41527767},
issn = {1875-8908},
abstract = {BackgroundMemory loss is a core feature of typical Alzheimer's disease (AD) and amnestic mild cognitive impairment (aMCI). Standard memory tests such as word lists assess verbal episodic memory with delayed recall and recognition. However, actual memory fidelity is likely variable, continuous, and has a subjective component.ObjectiveWe investigated dual-processing models of episodic memory (recollection versus familiarity) using confidence ratings in a "judgment of knowing" paradigm (JOK).MethodsThis paradigm was applied to the Consortium to Establish a Registry for Alzheimer's Disease (CERAD) memory test as part of neuropsychological evaluation at University of Pittsburgh Alzheimer's Disease Research Center (ADRC), to generate novel indices of memory function to improve sensitivity to early memory problems and provide a memory awareness metric. On recognition testing, participants rated how sure they were of their yes/no responses to each item. We derived novel variables related to memory and metacognition, including an Accuracy-Certainty Index and the Relative Certainty Index.ResultsIn this sample of 347 participants (185 with AD, 55 with MCI, 111 cognitively unimpaired), CERAD Delayed Recall was the best single variable for discriminating groups, although multiple certainty variables also discriminated groups well.ConclusionsThe addition of certainty indices to a standard verbal memory task increased discriminative power between groups, particularly between cognitively normal controls and MCI or AD.},
}

@article {pmid41527760,
year = {2026},
author = {Yang, Y and Kwak, YT},
title = {Neuropsychiatric signs and symptoms clusters and regional amyloid on [18]F-FC119S PET in Alzheimer's disease.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877251411433},
doi = {10.1177/13872877251411433},
pmid = {41527760},
issn = {1875-8908},
abstract = {BackgroundNeuropsychiatric signs and symptoms (NPS) are highly prevalent in Alzheimer's disease (AD), but whether co-occurring symptom constellations relate to regional amyloid deposition remains unclear.ObjectiveTo identify reproducible NPS clusters in AD and examine their associations with regional amyloid deposition using [18]F-FC119S positron emission tomography (PET).MethodsWe included 143 patients with probable AD and positive amyloid PET. NPS were assessed with the Korean Neuropsychiatric Inventory, and hierarchical cluster analysis (Yule's Q, average linkage) identified symptom clusters. Regional amyloid burden in frontal, temporal, and parietal cortices was quantified by automated SUVRs. Clinical characteristics were compared using t tests, and associations between clusters and regional amyloid patterns were examined with Pearson's χ[2].ResultsFour clusters emerged: Group 1 (delusion, agitation-aggression, disinhibition, aberrant motor behavior); Group 2 (depression, anxiety, irritability); Group 3 (hallucination, euphoria, nighttime behavior, apathy); and Group 4 (eating abnormalities). Group 1 patients were older with worse global status (lower K-MMSE, higher CDR, lower Barthel); Group 2 showed higher GDS15 scores; Group 3 showed selectively lower K-MMSE; Group 4 showed no significant differences. On PET, Group 1 was associated with right frontal and right temporal positivity; Group 2 with left parietal negativity; Group 3 with right frontal positivity plus left parietal negativity; Group 4 showed no significant association.ConclusionsIn amyloid-confirmed, drug-naïve AD, distinct NPS clusters map onto specific regional amyloid patterns and global clinical profiles. These findings support a network-oriented view of NPS pathophysiology and may inform phenotyping and individualized management.},
}

@article {pmid41527759,
year = {2026},
author = {Alkam, T and Tarshizi, E and Van Benschoten, AH},
title = {Flagging high-risk comorbidities in Alzheimer's disease emergency department visits: A machine learning analysis of mortality outcomes.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877251409332},
doi = {10.1177/13872877251409332},
pmid = {41527759},
issn = {1875-8908},
abstract = {BackgroundAlzheimer's disease (AD) patients experience elevated mortality during emergency department (ED) encounters, yet the associated risk factors remain insufficiently characterized.ObjectiveTo identify predictors of mortality among older adults with AD during ED visits and examine differences in comorbidity patterns between those who died and those who survived.MethodsWe analyzed 20,532,351 ED visits for adults aged ≥60 from the 2012-2014 Nationwide Emergency Department Sample (NEDS). Visits were stratified by AD status, ZIP-code income quartile, and mortality outcome (defined as in-ED or in-hospital death following ED presentation). We used logistic regression and machine learning models (random forest, gradient boosting, XGBoost) to predict mortality in a 1:1 matched case-control dataset. SHapley Additive exPlanations (SHAP) were applied to interpret model outputs.ResultsAD patients accounted for 1.76-2.13% of all ED visits, with mortality rates of 2.55-2.68% compared to 1.10-1.76% for non-AD patients. Socioeconomic status and ED charges were not associated with increased mortality. Odds ratio analysis identified rare terminal events as top predictors (e.g., respiratory arrest, OR = 55.5), while SHAP analysis highlighted more prevalent and clinically actionable conditions such as acute respiratory failure and septicemia as major drivers of mortality. All models performed comparably (AUC ≈ 0.85).ConclusionsAD patients face significantly higher mortality during ED encounters. Integrating explainable machine learning with large-scale administrative data may help flag lethal comorbidities in real time and improve outcomes through better ED triage and care prioritization.},
}

@article {pmid41527747,
year = {2026},
author = {Heo, RJ and Negida, A and Barrett, MJ and Chrenka, EA and Bayram, E and Kane, JPM and Werner, AM and Rossom, RC and Wyman-Chick, KA},
title = {Cholinesterase inhibitors for patients with dementia: Patterns of prescribing and disparities in treatment.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877251411418},
doi = {10.1177/13872877251411418},
pmid = {41527747},
issn = {1875-8908},
abstract = {BackgroundCholinesterase inhibitors (ChEIs) are cornerstones of the symptomatic treatment of Alzheimer's disease (AD) and dementia with Lewy bodies (DLB) and are also prescribed for vascular dementia (VaD). Despite their widespread use, patterns of ChEI prescribing are unclear.ObjectiveOur objective was to examine the prevalence, timing, and types of ChEI prescriptions before and after dementia diagnosis.MethodsWe analyzed electronic health record and claims data for patients diagnosed with AD, DLB, or VaD between October 2015 and August 2022 from a large U.S. healthcare system. ChEI claims (donepezil, rivastigmine, galantamine) were identified in the ±3 years surrounding dementia diagnosis. Repeated measures logistic regression was used to estimate the likelihood of ChEI fills by time-period, dementia type, and time x dementia type interaction to determine if change in prescription patterns significantly differed by diagnosis.ResultsAmong 3166 eligible patients, DLB had the highest prevalence of ChEIs both pre-and post-diagnosis compared to patients with AD and VaD. Post-diagnosis, donepezil was the most common, while galantamine use was sparse. After adjusting for demographics, patients with VaD had lower rates of ChEIs relative to AD (OR: 0.34, 95% CI 0.26-0.45). In the fully adjusted model, females (OR: 0.81, 95% CI: 0.71-0.91) and patients from ethnoracially minoritized populations (OR: 0.74, 95% CI: 0.62-0.88) were less likely to fill ChEI prescriptions.ConclusionsDonepezil was the most frequently filled ChEI across dementias. Patients with DLB had the highest prevalence of ChEIs pre- and post-diagnosis. The potential disparities in treatment we identified should be investigated further.},
}

@article {pmid41527744,
year = {2026},
author = {Wang, X and Ye, T and Dai, B and Zhang, J and Zhou, W and , },
title = {Sex-specific patterns in tau spreading throughout the Braak stages in the Alzheimer's disease spectrum.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877251406131},
doi = {10.1177/13872877251406131},
pmid = {41527744},
issn = {1875-8908},
abstract = {BackgroundIncreasing evidence suggests that the trajectory of Alzheimer's disease (AD) pathologies, such as amyloid and tau, differ between the sexes.ObjectiveGiven the higher susceptibility of females to dementia, we aimed to investigate the sex differences in the primary accumulation of tau and its subsequent spread to later cortical brain regions.MethodsWe included 315 participants in this study: 221 cognitively unimpaired individuals with normal amyloid (n = 140, A- CU) or abnormal amyloid (n = 81, A+ CU), and 94 cognitively impaired individuals with abnormal amyloid (A+ CI). Each individual received two to six tau positron emission tomography (PET) scans using the [18F]-Flortaucipir (FTP) tracer. Linear regression analyses were performed to assess sex-specific tau spreading throughout the Braak stages among three clinical groups.ResultsThe median (interquartile range) age of all samples was 73.5 (68 to 78.2) years. In total, 170 participants (54%) were female. In the A+ CU group, females exhibited higher tau-PET SUVR levels in all Braak I, III-IV, and V-VI. We found that the spreading pattern of tau may vary by sex and AD stages. In the A+ CI individuals, there was an observed interaction between the female sex and baseline tau SUVRs in Braak stages III-IV (p < 0.0001 and Bonferroni-corrected p < 0.0023), affecting longitudinal accumulation of tau in later Braak stages V-VI.ConclusionsOur findings found a sex-specific pattern of tau spreading from Braak stages III-IV to V-VI in A+ CI older adults. This disadvantage may indicate that females might experience faster tau spreading and quicker disease progression when the condition develops to more advanced disease stages.},
}

@article {pmid41527739,
year = {2026},
author = {Le, J and Hu, X and Jiang, Y and Wang, Q and Ma, Q and Cui, W},
title = {Insights into phosphoproteomic studies and prospects of phosphoproteins as biomarkers for brain disorders.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877251411546},
doi = {10.1177/13872877251411546},
pmid = {41527739},
issn = {1875-8908},
abstract = {The dysregulation of phosphorylation networks plays a critical role in the pathogenesis of a wide spectrum of brain disorders, including Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, traumatic brain injury, ischemic stroke, drug abuse, major depressive disorder, and schizophrenia. Notably, phosphorylated isoforms of microtubule-associated protein tau and neurofilament heavy polypeptide are already utilized in clinical diagnostics, highlighting the promise of protein phosphorylation signatures as biomarkers for prediction, diagnosis, prognosis, and treatment monitoring. Recent advances in deep phosphoproteomic technologies now facilitate the comprehensive mapping of phosphorylation alterations across diverse biological samples and disease stages. This review summarizes current phosphoproteomic studies aimed at identifying biomarkers for brain disorders and elaborates on the promising application of phosphorylated proteins in this context.},
}

@article {pmid41527736,
year = {2026},
author = {Abedin, MJ and Kastanenka, KV},
title = {The role of astrocytes in Alzheimer's disease: Pathophysiology, biomarkers, and therapeutic potential.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877251411561},
doi = {10.1177/13872877251411561},
pmid = {41527736},
issn = {1875-8908},
abstract = {Astrocytes are glial cells in the brain essential for maintaining neural homeostasis, modulating synaptic activity through gliotransmission, and supporting metabolic processes. As part of Alzheimer's disease (AD) progression, astrocytes undergo significant morphological and functional changes, transitioning to reactive states that can contribute to both neuroprotection and neurodegeneration. This review aims to summarize current knowledge on the roles of astrocytes in AD, focusing on their contributions to amyloid-β (Aβ) and tau pathologies, neuroinflammation, disrupted calcium signaling, and age-related changes. We synthesized findings from published studies investigating astrocytic sodium channels (Nav1.6), key molecular pathways such as apolipoprotein E (ApoE), oxidative stress, and excitatory amino acid transporter 2 (EAAT2), as well as emerging astrocytic biomarkers including GFAP, YKL-40, and MAO-B. Optogenetic studies and other experimental approaches with high spatiotemporal resolution were also considered to understand astrocyte involvement in circuit impairments and sleep deficits in AD. Astrocytes in AD exhibit altered calcium signaling, impaired gliotransmission, and dysregulated sodium channel activity. Reactive astrocytes influence Aβ and tau pathology, contribute to neuroinflammation, and show altered biomarker expression. Molecular dysfunctions, including changes in ApoE, EAAT2, and oxidative stress pathways, exacerbate disease progression. Emerging therapeutic strategies targeting astrocytic pathways, such as siRNA therapy and gene editing, show promise for mitigating these pathological changes. Understanding the complex roles of astrocytes in AD highlights their dual protective and detrimental functions and identifies novel avenues for therapeutic intervention. Targeting astrocytic dysfunction may offer strategies to slow disease progression and improve cognitive outcomes.},
}

@article {pmid41527682,
year = {2026},
author = {Zohud, O and Lone, IM and Midlej, K and Iraqi, FA},
title = {The complexity of dementia development and its comorbidities: The collaborative cross-mouse population for multivarious tasks approach.},
journal = {Animal models and experimental medicine},
volume = {},
number = {},
pages = {},
doi = {10.1002/ame2.70131},
pmid = {41527682},
issn = {2576-2095},
support = {//A core fund from Tel Aviv University/ ; },
abstract = {The rising incidence of dementia and associated neurodegenerative disorders poses a growing public health challenge. These conditions have traditionally been studied as isolated central nervous system disorders; however, emerging evidence suggests that broader systemic factors, including chronic inflammation, immune dysregulation, metabolic dysfunction, and genetic susceptibility, may also play a role. This review examines the interconnection between autoimmune diseases and metabolic syndromes in the pathogenesis and exacerbation of neurodegeneration. Conditions such as rheumatoid arthritis, systemic lupus erythematosus, and type 1 diabetes mellitus have been associated with a heightened risk of developing dementia through chronic immune activation, blood-brain barrier disruption, and neuroinflammatory signaling. Similarly, metabolic disorders such as diabesity promote insulin resistance and oxidative stress, accelerating cognitive decline. The review also discusses glaucoma as a neurodegenerative condition with autoimmune features, underscoring the need for expanded classification and treatment strategies. A key focus is the utilization of the Collaborative Cross (CC) mouse model, which enables the study of gene-environment interactions across genetically diverse backgrounds. Findings from CC mice reveal strain-dependent susceptibility to inflammation, cognitive impairment, and gut-brain axis dysfunction, providing a translational bridge to human variability. This review highlights the importance of integrating precision-based approaches to dementia research that consider systemic influences. Advancing our understanding of these multiorgan interactions holds potential for designing precision-based therapeutic approaches to postpone the onset or reduce the incidence of neurodegenerative conditions.},
}

@article {pmid41527663,
year = {2025},
author = {Barbati, SA and Carota, G and Partsinevelos, K and Di Pietro, L and Privitera, A and Cardaci, V and Graziani, A and Mangione, R and Lazzarino, G and Tavazzi, B and Di Pietro, V and Maiani, E and Bellia, F and Amorini, AM and Lazzarino, G and Baba, SP and Caruso, G},
title = {Preclinical evidence and therapeutic perspectives on carnosine for the treatment of neurodegenerative disorders.},
journal = {AIMS neuroscience},
volume = {12},
number = {4},
pages = {444-513},
doi = {10.3934/Neuroscience.2025025},
pmid = {41527663},
issn = {2373-7972},
abstract = {Carnosine (β-alanyl-L-histidine) is an endogenous dipeptide widely distributed in mammalian tissues, especially skeletal and cardiac muscle cells, and, to a lesser extent, in the brain. While early interest in carnosine was given because of its role in muscle cell metabolism and athletic performance, it has more recently gained attention for its potential application in several chronic diseases. Specifically, brain aging and neurodegenerative disorders have received particular attention, as a marked reduction in carnosine levels has been described in these conditions. Carnosine exerts a wide range of biological activities, including antioxidant, anti-inflammatory, anti-glycation, metal-chelating, and neuroprotective properties. Mechanistically, it acts by inhibiting the production of advanced glycation end products (AGEs), buffering cellular pH, and regulating intracellular nitric oxide signaling and mitochondrial function. Its safety profile, the lack of toxicity, and significant side effects support its application for long-term therapeutic use. In this review, we aim to recapitulate and discuss the effects, dosages, and administration routes of carnosine in preclinical in vivo models, with a particular focus on neurodegenerative disorders where it has been shown to reduce oxidative stress, suppress neuroinflammation, modulate protein aggregation, and preserve cognitive function, all key features of neurodegeneration. Despite promising findings, there are gaps in the knowledge on how carnosine affects synaptic plasticity, neuronal remodeling, and other processes that play a central role in the pathophysiology of neurodegenerative disorders. Additionally, clinical translation remains challenging due to inconsistencies across in vivo studies in terms of dosage, treatment duration, routes of administration, and disease models, which affect reproducibility and cross-study comparability. Therefore, while carnosine emerges as a multifunctional and well-tolerated molecule, further research is needed to clarify its therapeutic relevance in human diseases. In this review, we also address future perspectives and key methodological challenges that must be overcome to effectively translate carnosine's biological potential into clinical practice.},
}

@article {pmid41527522,
year = {2026},
author = {Richardson, TI and Klein, RC and Huang, K and Zhang, J and Mesecar, AD and Dage, JL and Clayton, B and Lamb, BT and Palkowitz, AD},
title = {Next-generation Alzheimer's therapeutics: target assessment and enablement at the Indiana University School of Medicine-Purdue University TREAT-AD Center.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {1},
pages = {e70964},
doi = {10.1002/alz.70964},
pmid = {41527522},
issn = {1552-5279},
support = {U54AG065181/AG/NIA NIH HHS/United States ; },
mesh = {*Alzheimer Disease/drug therapy ; Humans ; *Drug Discovery/methods ; Indiana ; United States ; National Institute on Aging (U.S.) ; Schools, Medical ; },
abstract = {The incidence of Alzheimer's disease (AD) continues to increase, despite decades of effort to develop disease-modifying therapies. In response, the National Institute on Aging (NIA) established the TaRget Enablement to Accelerate Therapy Development for Alzheimer's Disease (TREAT-AD) centers to address the gap between basic research and translational drug discovery. Situated within a robust AD research environment, the Indiana University School of Medicine (IUSM)-Purdue University TREAT-AD Center is one of two National Institutes of Health (NIH)-supported centers funded to accomplish this mission. With a focus on novel biological targets beyond amyloid and tau, our center has assembled the necessary components of a drug discovery engine: project and data management, bioinformatics and computational science, structural biology and biochemistry, assay development and pharmacology, and molecular design and synthesis of small molecules, antibodies, and oligonucleotides. Our objective is to deliver Target Enabling Packages (TEPs) within an open science framework, making data, methods, and research tools broadly accessible through the AD Knowledge Portal. HIGHLIGHTS: The Indiana University School of Medicine (IUSM)-Purdue TREAT-AD Center develops Target Enabling Packages (TEPs) to advance novel targets for the treatment of Alzheimer's disease (AD). The center is overseen by an administrative core and operates through four technical cores - bioinformatics, structural biology, assay development, and medicinal chemistry - within a milestone-driven and open science framework. Multi-omics, systems biology, and machine learning (ML) approaches guide the nomination of high-priority targets beyond amyloid and tau. Cross-core workflows provide structural insights into novel biological targets, validated assays, biomarkers, and molecular probes that enable lead optimization. All data, methods, and tools are openly shared through the AD Knowledge Portal to accelerate global efforts in AD drug discovery.},
}

*Alzheimer Disease/drug therapy
Humans
*Drug Discovery/methods
Indiana
United States
National Institute on Aging (U.S.)
Schools, Medical

@article {pmid41527496,
year = {2026},
author = {Kalita, T and Shakya, A and Ghosh, SK and Singh, UP and Bhat, HR},
title = {Microwave-Assisted Synthesis and In Vitro Anti-Alzheimer Evaluation of Novel 1,3,5-Triazine-Nicotinic Hydrazide Derivatives as Acetylcholinesterase and Butyrylcholinesterase Inhibitors.},
journal = {Journal of biochemical and molecular toxicology},
volume = {40},
number = {1},
pages = {e70685},
doi = {10.1002/jbt.70685},
pmid = {41527496},
issn = {1099-0461},
mesh = {*Cholinesterase Inhibitors/pharmacology/chemical synthesis/chemistry ; *Butyrylcholinesterase/metabolism/chemistry ; *Alzheimer Disease/drug therapy/enzymology ; *Acetylcholinesterase/metabolism/chemistry ; Animals ; Humans ; *Triazines/chemistry/pharmacology/chemical synthesis ; *Microwaves ; Cell Line, Tumor ; Molecular Docking Simulation ; Male ; *Hydrazines/chemistry/pharmacology/chemical synthesis ; Rats ; },
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder posing major global health challenges due to its complex pathophysiology and increasing prevalence among the elderly. In the present work, the molecular hybridization technique was utilized to design and synthesize nicotinic hydrazide-1,3,5-triazine hybrids. Accordingly, this study aimed to design, perform in silico screening, synthesize, and evaluate the in vitro and in vivo anti-AD potential of the proposed compounds. Docking studies revealed that the compounds displayed key interactions with catalytic site and peripheral anionic site residues. Based on binding affinity, ten compounds were synthesized and characterized using different spectroscopic techniques. In vitro AChE and BChE inhibitory assays revealed that the compound 4A36 showed the highest inhibitory ability with log IC50 values of 5.97 μM against AChE and 4.57 μM against BChE. In addition, cytotoxicity screening revealed that 4A36 was non-toxic in SH-SY5Y neuroblastoma cells in the concentration range of 15.625-250 µg/mL. Acute oral toxicity evaluation of the compound revealed no adverse effects up to 175 mg/kg b.w. Further, in vivo studies using the scopolamine-induced model further validated the therapeutic promise of the compound. At a dose of 30 mg/kg b.w., the compound demonstrated significant improvements in learning and memory, reduced MDA levels with concurrent elevation of antioxidant enzymes SOD and Catalase, and reduced AChE activity in hippocampal tissue. Histopathological observations revealed that treatment groups, especially at higher dose (30 mg/kg b.w.), preserved the granular layer of the dentate gyrus and improved neuronal integrity compared to the disease control. These findings indicate that 4A36 at a dose of 30 mg/kg b.w. may be considered as a promising lead compound in AD.},
}

*Cholinesterase Inhibitors/pharmacology/chemical synthesis/chemistry
*Butyrylcholinesterase/metabolism/chemistry
*Alzheimer Disease/drug therapy/enzymology
*Acetylcholinesterase/metabolism/chemistry
Animals
Humans
*Triazines/chemistry/pharmacology/chemical synthesis
*Microwaves
Cell Line, Tumor
Molecular Docking Simulation
Male
*Hydrazines/chemistry/pharmacology/chemical synthesis
Rats

@article {pmid41527485,
year = {2026},
author = {Cheng, Q and Nolz, J and Karr, T and Dorn, N and Readhead, B and Krajmalnik-Brown, R and Mastroeni, D},
title = {Gut proteome and microbiome alterations: Analysis of transverse colon samples from pathologically confirmed Alzheimer's disease patients.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {1},
pages = {e71021},
doi = {10.1002/alz.71021},
pmid = {41527485},
issn = {1552-5279},
support = {U24 NS072026/NS/NINDS NIH HHS/United States ; P30AG19610//the National Institute on Aging/ ; P30AG072980//the National Institute on Aging/ ; 211002//the Arizona Department of Health Services/ ; 4001//the Arizona Biomedical Research Commission/ ; 0011//the Arizona Biomedical Research Commission/ ; 05-901//the Arizona Biomedical Research Commission/ ; and 1001//the Arizona Biomedical Research Commission/ ; //the Michael J. Fox Foundation for Parkinson's Research/ ; //Arizona Alzheimer's Consortium/ ; //Biodesign Center for Health Through Microbiomes/ ; },
mesh = {Humans ; *Alzheimer Disease/pathology/microbiology/metabolism ; *Gastrointestinal Microbiome/physiology ; *Proteome/metabolism ; Female ; Male ; *Colon/microbiology/metabolism/pathology ; Aged ; Proteomics ; Aged, 80 and over ; Amyloid beta-Peptides/metabolism ; },
abstract = {INTRODUCTION: Alzheimer's disease (AD) has been regarded as a brain-first disorder. Emerging evidence suggests that the gut may influence central nervous system pathology, but the mechanisms remain unclear.

METHODS: We conducted a proteomic and microbial analysis of transverse colon samples from clinically and pathologically confirmed AD and control cases.

RESULTS: In the AD gut samples, antimicrobial humoral response and oxidative stress response were downregulated, while catabolic processes and insulin signaling were upregulated. Several complement (e.g., C5) and synaptic (e.g., synaptophysin) proteins were downregulated. Amyloid beta 42 was detected at higher levels. Christensenellaceae, Desulfovibrio, and Candida tropicalis amplicon sequence variants were higher in abundance, while Streptococcus, Lachnospiraceae, Blautia, and Nakaseomyces were lower. In general, bacterial composition correlated with AD clinical variables such as plaque and tangle burden.

DISCUSSION: These findings underscore the gut's possible involvement in AD pathogenesis and provide new insights into potential biomarkers and therapeutic targets.

HIGHLIGHTS: This study provides the first in-depth analysis of the proteome and microbiome in AD transverse colon tissues. Multiple immune and oxidative stress response pathways were downregulated in AD, while metabolic pathways were upregulated. Synaptic protein, complement protein, and Aβ42 levels were significantly different between AD and controls. Transverse colon microbial composition was associated with AD clinical variables.},
}

Humans
*Alzheimer Disease/pathology/microbiology/metabolism
*Gastrointestinal Microbiome/physiology
*Proteome/metabolism
Female
Male
*Colon/microbiology/metabolism/pathology
Aged
Proteomics
Aged, 80 and over
Amyloid beta-Peptides/metabolism

@article {pmid41527161,
year = {2026},
author = {Cheng, CM and Tsai, MJ and Tseng, CC and Lin, YS and Lin, YS and Chen, LY and Liu, MN and Fuh, JL},
title = {Pharmacological management of agitation in dementia: An evidence-based review with expert consensus.},
journal = {Journal of the Chinese Medical Association : JCMA},
volume = {},
number = {},
pages = {},
doi = {10.1097/JCMA.0000000000001342},
pmid = {41527161},
issn = {1728-7731},
abstract = {Agitation is a frequently occurring and challenging neuropsychiatric symptom of Alzheimer's disease (AD) that substantially affects quality of life, caregiver burden, and healthcare utilization. Non-pharmacological interventions, especially trigger identification, environmental adjustments, and supportive activities, remain the first-line approach for treating agitation. Pharmacological treatment should be considered only when non-drug measures are insufficient or when agitation causes severe distress or safety risks. This consensus integrates evidence up to June 2025, the Taiwan Ministry of Health and Welfare approvals, and Taipei Veterans General Hospital expert opinion. Among the approved agents, brexpiprazole demonstrated the strongest evidence and most favorable safety profile. Risperidone and aripiprazole are effective, but require careful monitoring for cerebrovascular and extrapyramidal risks. Selected antidepressants, particularly citalopram and agomelatine, should be considered when safety is prioritized. Anticonvulsants, acetylcholinesterase inhibitors, and memantine have limited efficacy and should be reserved for refractory cases. Long-term or routine pharmacological use is not supported by current evidence. Future research should focus on identifying responsive patient subgroups, optimizing dosing strategies, and integrating medications into individualized, multidisciplinary care plans.},
}

@article {pmid41527104,
year = {2026},
author = {Chen, H and Li, N and Liu, N and Zhu, H and Ma, C and Ye, Y and Shi, X and Luo, G and Dong, X and Tan, T and Wei, X and Yin, H},
title = {Correction: Photobiomodulation modulates mitochondrial energy metabolism and ameliorates neurological damage in an APP/PS1 mouse model of Alzheimer's disease.},
journal = {Alzheimer's research & therapy},
volume = {18},
number = {1},
pages = {7},
pmid = {41527104},
issn = {1758-9193},
}

@article {pmid41527082,
year = {2026},
author = {Du, Y and Wu, L and Mao, Y and Chen, S and Gao, X},
title = {IL-27, a metabolic regulator secreted by astrocytes in response to GLP-1RA OHP2, modulates microglial reprogramming in Alzheimer's disease by regulating cGAS lactylation.},
journal = {Journal of neuroinflammation},
volume = {},
number = {},
pages = {},
doi = {10.1186/s12974-025-03683-1},
pmid = {41527082},
issn = {1742-2094},
support = {82473834//National Natural Science Foundation of China,China/ ; 82373780//National Natural Science Foundation of China,China/ ; CPU2022PZQ10//"Double First-Class" University Project/ ; },
}

@article {pmid41527012,
year = {2026},
author = {Weber, C and Wind, D and Petzsch, P and Supprian, T and Dilthey, A and Christl, J and Finzer, P},
title = {Dysbiotic shift in the oral microbiota of patients with Alzheimer's disease compared to their healthy life partners-a combinatorial approach and a paired study design.},
journal = {Alzheimer's research & therapy},
volume = {},
number = {},
pages = {},
doi = {10.1186/s13195-025-01941-1},
pmid = {41527012},
issn = {1758-9193},
abstract = {BACKGROUND: The oral microbiota has been associated with Alzheimer's disease (AD). However, earlier studies provided conflicting results using varying sampling methods, sequencing techniques, and statistics, as well as independent subjects.

METHODS: To robustly identify disease-associated microbial features, we recruited patients and their healthy life partners from the same households sharing a more similar microbiota compared to independent individuals increasing statistical power via paired design and combined three different sequencing methods - including metagenomics-and several bioinformatic pipelines. We recruited 26 AD-patients and their life partners. Salivary and supragingival samples were collected and a clinical examination of the mouth was performed.

RESULTS: Both groups showed comparable oral health. By focusing primarily on recurrently identified species across the different datasets we were able to identify a Core dysbiosis. This Core dysbiosis surprisingly spares the most central of oral diseases pathogens, namely Porphyromonas gingivalis. However, it includes numerous other species commonly associated with oral pathologies such as Prevotella nigrescens, Streptococcus anginosus, Dialister invisus, Anaeroglobus geminatus, Olsenella uli and Mogibacterium timidum. In contrast, more host-compatible species such as Prevotella melaninogenica or Streptococcus parasanguinis are identified in controls.

CONCLUSIONS: This is the first study using a combined sequencing approach and a paired study design to identify robust features of the oral microbiota of AD-patients. Although promising, the results should nevertheless be interpreted with caution, as the cross-sectional study design limits the possibilities of interpretation, and larger, longitudinal data are necessary for causal conclusions. However, this combined approach on multiple processing levels to identify intra-partnership differences still offers the possibility to better identify disease-associated microbial features potentially involved in AD-pathogenesis.

TRIAL REGISTRATION: This study was prospectively registered at the German Clinical Trials Register (DRKS00023456) at the 30th of November 2020.},
}

@article {pmid41526986,
year = {2026},
author = {Fu, X and Cai, H and Quan, S and Zhang, W and Geng, Y and Tian, Q and Ren, Z and Xu, Y and An, C and Li, J and Chu, C and Wang, W and Pang, Y and Wang, Q and Lu, L and Wang, Q and Li, Y and Li, F and Nie, S and Jia, L},
title = {Systemic complement factors in aging, Alzheimer's disease and other dementias: a longitudinal study over 10 years.},
journal = {Molecular neurodegeneration},
volume = {},
number = {},
pages = {},
doi = {10.1186/s13024-026-00927-3},
pmid = {41526986},
issn = {1750-1326},
support = {81870825, 82071194//National Natural Science Foundation of China/ ; Z201100005520016//Beijing Brain Initiative from Beijing Municipal Science & Technology Commission/ ; 7202061//Beijing Municipal Natural Science Foundation/ ; 2022-2-2017//Capital's Funds for Health Improvement and Research/ ; 2022ZD0211600, 2022ZD0211605//STI2030-Major Projects/ ; },
abstract = {BACKGROUND: Complement dysregulation is increasingly recognized in Alzheimer's disease (AD). However, the temporal profile of complement alterations preceding AD onset and their distinction from age-related immune changes remain poorly defined. Clarifying these dynamics could provide insights into AD pathogenesis and identify systemic factors that predict disease onset and progression.

METHODS: We conducted a study involving two cohorts: a longitudinal cohort (n = 235; all cognitively normal at baseline) and a cross-sectional cohort (n = 323; including 53 with AD, 54 with vascular dementia, 51 with Parkinson's disease dementia, 56 with behavioral variant frontotemporal dementia, and 52 with dementia with Lewy bodies). Plasma levels of 14 complement factors were assessed every 2 years over a 10-year follow-up period in the longitudinal cohort and once in the cross-sectional cohort.

RESULTS: In the longitudinal cohort, aging was accompanied by gradual reductions in C4, C4b, Factor I, and Properdin and by increases in Factor D. These changes were more pronounced in individuals who subsequently developed AD. Importantly, this pattern of complement alterations was detectable during the preclinical and clinical phases of AD but was not observed in other dementias. In the cross-sectional cohort, the same complement profile was specific to AD and distinguished it from other dementia subtypes.

CONCLUSIONS: The results of this study indicate an AD-specific peripheral complement signature associated with disease development, highlighting complement factors as critical immune mediators that link aging and AD. This signature implicates complement factors as promising systemic markers for early detection and potential therapeutic targeting in preclinical AD.},
}

@article {pmid41526743,
year = {2026},
author = {},
title = {CDK3 drives neuron loss in Alzheimer's disease.},
journal = {Nature aging},
volume = {},
number = {},
pages = {},
pmid = {41526743},
issn = {2662-8465},
}

@article {pmid41526727,
year = {2026},
author = {Mei, Y and Zheng, L and He, M and Wang, L and Zhou, Y and Zhang, T and Lee, TH and Chen, D},
title = {Zipper-interacting Protein Kinase Modulates Gene Expression Linked to Synaptic and Neuronal Processes after Traumatic Brain Injury.},
journal = {Molecular neurobiology},
volume = {63},
number = {1},
pages = {358},
pmid = {41526727},
issn = {1559-1182},
support = {82001128//National Natural Science Foundation of China/ ; 82571556//National Natural Science Foundation of China/ ; 82571601//National Natural Science Foundation of China/ ; 2023Y9007//Joint Funds for the Innovation of Science and Technology, Fujian Province/ ; 2024Y9094//Joint Funds for the Innovation of Science and Technology, Fujian Province/ ; 2024J01485//Natural Science Foundation of Fujian Province/ ; },
mesh = {Animals ; *Brain Injuries, Traumatic/genetics/pathology/enzymology ; *Neurons/metabolism/pathology ; *Synapses/metabolism/genetics ; Mice, Inbred C57BL ; *Gene Expression Regulation ; Male ; Mice ; *Protein Serine-Threonine Kinases/metabolism/genetics ; Signal Transduction/genetics ; },
abstract = {Traumatic brain injury (TBI) is one of the leading causes of disability and death worldwide. Zipper-interacting protein kinase (ZIPK) is a serine/threonine kinase, whose main function is to regulate cell death, inflammation and smooth muscle contraction. ZIPK dysregulation has been implicated in a range of neurological disorders, including ischemic stroke, Alzheimer's disease, and TBI. Downregulation of ZIPK expression level or pharmacological inhibition of ZIPK kinase activity alleviates neuronal injury. ZIPK has a nuclear localization signal sequence and transcriptional regulatory activity. However, whether ZIPK affects gene expression in the brain after TBI remains unknown. In this study, transcriptome sequencing analysis was employed to compare the differences in gene expression in the peri-injury tissues between wild-type and ZIPK heterozygous mice after TBI. Our results indicated that ZIPK regulates a variety of genes and signaling pathways, including pathways related to synaptic function, learning and memory, vascular function, and DNA replication, after TBI. Gene set enrichment analysis highlighted the important role of ZIPK in synapses during TBI. In addition, quantitative real-time PCR analysis validated changes in the expression of multiple genes related to synaptic function, including Drd1, Grin2a, Grin2b, Dlg4, Fn1, and Pecam1, which were identified by gene correlation analysis and protein-protein interaction analysis. Immunofluorescence staining revealed that partial deletion of ZIPK alleviates synaptic protein loss induced by TBI. In conclusion, our data suggest a role for ZIPK in the regulatory network in the brain, especially in relation to synaptic damage, after TBI, providing a new therapeutic strategy for this condition.},
}

Animals
*Brain Injuries, Traumatic/genetics/pathology/enzymology
*Neurons/metabolism/pathology
*Synapses/metabolism/genetics
Mice, Inbred C57BL
*Gene Expression Regulation
Male
Mice
*Protein Serine-Threonine Kinases/metabolism/genetics
Signal Transduction/genetics

@article {pmid41526725,
year = {2026},
author = {Li, R and Berlowitz, D and Mez, J and Silver, B and Wang, X and Hu, W and Goodwin, R and Keating, H and Liu, W and Lin, H and Yu, H},
title = {Early prediction of Alzheimer's disease using longitudinal electronic health records of US military veterans.},
journal = {Communications medicine},
volume = {6},
number = {1},
pages = {23},
pmid = {41526725},
issn = {2730-664X},
abstract = {BACKGROUND: Early prediction of Alzheimer's disease is important for timely intervention and treatment. We examine whether machine learning on longitudinal electronic health record notes can improve early prediction of Alzheimer's disease.

METHODS: From Veterans Health Administration records (2000 to 2022), we studied 61,537 individuals diagnosed with Alzheimer's disease and 234,105 without, aged 45-103 years, 98.4% were male. From clinical notes, we quantified the frequency of subjective cognitive decline and Alzheimer's disease-related keywords, and applied statistical machine learning models to assess their ability to predict future diagnosis.

RESULTS: Here we show that Alzheimer's-related keywords (e.g., "concentration," "speaking"), occur more often in notes of individuals who later develop Alzheimer's disease than in controls. In the 15 years preceding diagnosis, cases demonstrate an exponential increase in keyword mentions (from 9.4 to 57.7 per year), whereas controls show a slower, linear increase (8.2 to 20.3). These trends are consistent across demographic subgroups. Random forest models using these keywords for prediction achieve an area under receiver operating characteristic curve from 0.577 at ten years before diagnosis to 0.861 one day before diagnosis, consistently outperforming models using only structured data.

CONCLUSIONS: Signs and symptoms of early Alzheimer's disease are reported in clinical notes many years before a clinical diagnosis is made and the frequency of these signs and symptoms, approximated by keywords, increases the closer one is to the diagnosis. A simple keyword-based approach can capture these signals and can help identify individuals at high risk of future Alzheimer's disease.},
}

@article {pmid41526711,
year = {2026},
author = {Sheng, J and Yang, Z and Wang, Y and Zhang, Q and Xin, Y and Song, Y and Wang, L},
title = {Metabolism fluctuation coupling can track the progression of dementia and describe MST1 gene-related pathology.},
journal = {Communications medicine},
volume = {6},
number = {1},
pages = {24},
pmid = {41526711},
issn = {2730-664X},
support = {62271177//National Natural Science Foundation of China (National Science Foundation of China)/ ; LZ24F01007//Natural Science Foundation of Zhejiang Province (Zhejiang Provincial Natural Science Foundation)/ ; },
abstract = {BACKGROUND: Cognitive resilience refers to an individual's capacity to cope with brain aging and pathology and to delay cognitive decline, whereas existing techniques such as functional magnetic resonance imaging capture only macroscopic features without linking them to neurophysiological mechanisms. Recent studies have shown that overexpression of the MST1 gene exacerbates Alzheimer's disease phenotypes by affecting neuronal activity and metabolism; however, its association with cognitive trajectories and imaging biomarkers remains to be further investigated.

METHODS: Multimodal imaging data using information from 116 individuals with mild cognitive impairment was obtained from the ADNI database and participants from the HABS database. The correlation coefficient between glucose metabolism and neuronal low-frequency fluctuations was calculated, and residuals were derived from regression models of correlation coefficient with amyloid protein. Unsupervised clustering was then applied, and mediation analysis was conducted to investigate the mediating role of limbic orbital frontal cortex residuals in the association between MST1 gene expression and cognitive trajectories.

RESULTS: Clustering identifies five groups with distinct cognitive trajectories: the high and low cognitive resilience groups exhibit slower dementia progression with lower MST1 expression, whereas the high and low cognitive vulnerability groups show faster dementia progression with higher MST1 expression. No significant differences are observed in glucose metabolism or amyloid protein levels across groups, while the limbic orbital frontal cortex residuals partially mediate the effect of MST1 gene expression on cognitive trajectories.

CONCLUSIONS: Residual biomarkers can track dementia progression and characterize MST1-related pathology, providing imaging markers for assessing cognitive resilience and monitoring disease at the molecular level.},
}

@article {pmid41526632,
year = {2026},
author = {Salajková, Z and Ciasca, G and Di Lorenzo, F and Ghoreishi, M and Reale, R and Gambarota, MG and Zhang, J and Zhang, Y and Ricco, V and Ruocco, G and Leonetti, M},
title = {Non-invasive screening of alzheimer's disease via label-free tri-spectral retinal imaging.},
journal = {Scientific reports},
volume = {},
number = {},
pages = {},
doi = {10.1038/s41598-026-35383-y},
pmid = {41526632},
issn = {2045-2322},
support = {No. 855923/ERC_/European Research Council/International ; No. 855923/ERC_/European Research Council/International ; CUP J33C22001130001//NextGenerationEU PNRR MUR- M4C2-Action/ ; No. 101098989//European Innovation Council/ ; CUP: 2022CFP7RF//MUR PRIN 2022/ ; CUP: 2022CFP7RF//MUR PRIN 2022/ ; },
abstract = {Alzheimer's disease (AD) is the most prevalent form of dementia, yet its early detection remains challenging due to the invasiveness, cost, and limited accessibility of current diagnostics. Increasing evidence suggests that retinal changes mirror cerebral pathology in AD, making the eye a promising site for non-invasive biomarker discovery. Here, we present a technique employing a custom-built tri-spectral retinal imaging module, designed to be integrated with existing fundus imaging systems, that captures retinal reflectance across three optimized spectral bands to quantify spectral alterations linked to AD. We validate the system in a case-control study of 38 mild AD patients and 28 age-matched controls, revealing spatially resolved differences in a fundus map derived from the blue-to-green ratiometric channel (p < 0.001). Our analysis identifies specifically the fovea-to-optic disc region as the most discriminative for AD, with an AUC of 0.74. Building on this, we developed a biologically informed machine-learning classification model incorporating spectral, clinical, and demographic data. On an independent validation test, the model achieved an AUC of 0.91, matching or slightly outperforming the most advanced spectral retinal measurements, yet using a simpler, more stable, and cost-effective setup that further facilitates clinical translation. The demonstrated technology, thanks to its non-invasiveness and its integrability with both existing medical technologies and advanced quantitative statistical methods, holds the potential to drive a significant leap forward in the early detection of AD, opening a window for timely intervention and thus profoundly impacting patient care.},
}

@article {pmid41526594,
year = {2026},
author = {Fisher, DW and Fisher, JR and Urfer, SR and Tran, NA and Kerr, KF and , and Darvas, M},
title = {Higher burden of neuropsychiatric symptom-like behaviors associated with canine cognitive dysfunction compared to normal aging in the Dog Aging Project.},
journal = {GeroScience},
volume = {},
number = {},
pages = {},
pmid = {41526594},
issn = {2509-2723},
abstract = {Non-cognitive, neuropsychiatric symptoms (NPS) are nearly universal in Alzheimer's disease (AD), but investigation of their underlying biology is complicated by comparative medicine approaches that incompletely capture spontaneous disease, primarily using transgenic rodent models. The aged companion dog, which spontaneously develops an AD-like disease called canine cognitive dysfunction (CCD), may help fill this translational gap. Using data from the Dog Aging Project with > 10,000 aged dogs (> 8 years old), we identify numerous behaviors in dogs "at-risk" for and with CCD that mirror NPS in humans. Compared to dogs without CCD, our analysis shows that dogs with CCD are less physically active, exhibit fewer previously trained behaviors, demonstrate fewer motivated behaviors, have more daytime sleep, demonstrate more separation anxiety, have altered anxious responses to novelty, have changes in aggressive behaviors, and exhibit lower appetite. Using k-means clustering, we did not find evidence for behavioral sub-phenotypes. Overall, our analysis of a large number of aged dogs suggests clinically significant NPS are associated with CCD and that the companion dog may serve as an important comparative medicine approach to understand these debilitating symptoms across species.},
}

@article {pmid41526552,
year = {2026},
author = {Wang, W and Zhu, H and Jiang, Q and Shi, Y and Wang, X},
title = {FOXO: a key target in regulating aging and age-related diseases.},
journal = {Biogerontology},
volume = {27},
number = {1},
pages = {38},
pmid = {41526552},
issn = {1573-6768},
support = {202301BA070001-046 and 202401BA070001-090//the Special Basic Cooperative Research Programs of Yunnan Provincial Undergraduate Universities' Association/ ; },
mesh = {Humans ; *Aging/metabolism/genetics ; Animals ; *Forkhead Transcription Factors/metabolism ; Oxidative Stress ; Autophagy ; *Neurodegenerative Diseases/metabolism ; Signal Transduction ; },
abstract = {FOXOs constitute a class of evolutionarily conserved transcription factors that play pivotal roles in diverse cellular processes, including glucose and lipid metabolism, energy homeostasis, oxidative stress response, and autophagy. They are recognized as central regulators of longevity. This review details the mechanisms linking FOXO to aging. FOXO activity is regulated via nucleocytoplasmic shuttling, a process controlled by phosphorylation and dephosphorylation through the insulin/insulin-like growth factor (IIS) signaling pathway. This shuttling influences the expression of aging-related genes, thereby modulating aging-related phenotypes in tissues such as muscle and liver. Furthermore, FOXO can also regulate the autophagy pathway through multiple mechanisms: On one hand, it transcriptionally activates core autophagy genes such as Ulk2 and Becn1; on the other hand, it enhances autophagic activity by modulating miRNAs or epigenetic modifications, thereby promoting the elimination of damaged cellular components, and ultimately delaying organismal aging. Moreover, as a key sensor of oxidative stress, FOXO is activated by reactive oxygen species (ROS), thereby inducing the expression of antioxidant enzymes that mitigate oxidative damage and delay cellular aging. This review provides an in-depth exploration of the dual roles of FOXO in various aging-related diseases. This includes neurodegenerative diseases (such as Huntington's disease, Parkinson's disease, and Alzheimer's disease), metabolic disorders (such as type 2 diabetes), and various cancers. Meanwhile, this review also discusses drugs targeting the FOXO pathway in recent years (such as canagliflozin, metformin, resveratrol, and berberine). These FOXO-targeting compounds demonstrate great potential in improving metabolic disorders and delaying the onset of aging phenotypes.},
}

Humans
*Aging/metabolism/genetics
Animals
*Forkhead Transcription Factors/metabolism
Oxidative Stress
Autophagy
*Neurodegenerative Diseases/metabolism
Signal Transduction

@article {pmid41526199,
year = {2026},
author = {Iwamoto, S and Hatta, D and Fujii, M and Yamamoto, D and Ohta, R and Okita, K and Shirotani, K and Iwata, N},
title = {Cell type- and neuronal differentiation-dependent MME 5'UTR splice variants with distinct translational outputs in human cells.},
journal = {Journal of biochemistry},
volume = {},
number = {},
pages = {},
doi = {10.1093/jb/mvag002},
pmid = {41526199},
issn = {1756-2651},
abstract = {Neprilysin (NEP) is a major enzyme that degrades amyloid β-peptide (Aβ) in the brain. Deficient NEP activity causes Aβ to accumulate, leading to amyloid pathology in Alzheimer's disease. Transcripts from the MME gene encoding NEP comprise seven splice variants (v1, v1bis, v2a, v2b, and v3-5) with different structures in the 5'-untranslated region. We analyzed the expression levels of MME variants in neuronal and non-neuronal cells using real-time PCR and investigated their translational outputs using cells co-transfected with cDNAs of each MME variant and green fluorescent protein. v1 and v1bis were constitutively expressed as major components in both cell types, whereas v2b was preferentially expressed in non-neuronal cells. The translational outputs of v1 and v2b were similar to each other and much higher than those of the other variants. Retinoic acid-induced neuronal differentiation altered the compositional ratios of MME variants and transiently enhanced their translational outputs, which declined in a variant-specific manner with further differentiation. We demonstrated that MME variants show cell type-dependent expression and distinct translational outputs that are sensitive to retinoic acid. Further studies are required to elucidate the molecular mechanisms underlying the post-translational roles of MME variants, such as subcellular localization and local translation.},
}

@article {pmid41525887,
year = {2026},
author = {Draper, D and George, AE and Veenendaal, T and van Dijk, S and Soltani, E and Sanzà, P and Verweij, FJ and Klumperman, J and Farías, GG},
title = {HOPS disruption impairs APP trafficking and processing, promoting exosomal secretion of APP-CTFs.},
journal = {Neurobiology of disease},
volume = {},
number = {},
pages = {107269},
doi = {10.1016/j.nbd.2026.107269},
pmid = {41525887},
issn = {1095-953X},
abstract = {Amyloid precursor protein (APP) is a key player in various neuronal functions but also the source for toxic Aβ that accumulates in the brain of Alzheimer patients. APP trafficking and processing depend on the endo-lysosomal system, but the molecular mechanisms that coordinate these processes remain not fully understood. Here, we studied the HOPS complex, a central regulator of endo-lysosomal maturation. We show that HOPS disruption impairs retromer-mediated recycling of APP to the TGN, resulting in the accumulation of APP in late endosomes. In neurons, this accumulation is spatially restricted to somatodendritic endosomes. These APP-containing endosomes are catalytically inactive and lack the γ-secretase subunit PSEN2. However, they do contain BACE1, which contributes to the build-up of toxic APP C-terminal fragments (APP-CTFs). Notably, loss of HOPS function enhances secretion of APP-CTFs by exosomes, suggesting a potential mechanism for disease propagation. Together, our findings establish a mechanistic link between HOPS loss-of-function and aberrant APP processing, with implications for neurodegeneration.},
}

@article {pmid41525885,
year = {2026},
author = {Nagarajan, V and Libowitz, CL and Ackley, BD and Wolfe, MS},
title = {A C. elegans model of familial Alzheimer's disease shows age-dependent synaptic degeneration independent of amyloid β-peptide.},
journal = {Neurobiology of disease},
volume = {},
number = {},
pages = {107267},
doi = {10.1016/j.nbd.2026.107267},
pmid = {41525885},
issn = {1095-953X},
abstract = {The membrane-embedded γ-secretase complex is involved in the intramembrane cleavage of ~150 substrates. Cleavage of amyloid precursor protein (APP)-derived substrate C99 generates 38-43-residue secreted amyloid β-peptides (Aβ), with the aggregation-prone 42-residue form (Aβ42) particularly implicated in the pathogenesis of Alzheimer's Disease (AD). However, whether Aβ42 is the primary driver of neurodegeneration in AD remains unclear. Dominant mutations in APP or presenilin-the catalytic component of γ-secretase-cause early-onset familial AD (FAD) and reduce one or more steps in the multi-step processive proteolysis of C99 to Aβ peptides, apparently through stabilization of γ-secretase enzyme-substrate (E-S) complexes. To investigate mechanisms of neurodegeneration in FAD, we developed new C. elegans models co-expressing wild-type or FAD-mutant C99 substrate and presenilin-1 (PSEN1) variants in neurons, allowing intramembrane processing of C99 to Aβ in vivo. We demonstrate that while FAD-mutation of either C99 or PSEN1 leads to age-dependent synaptic loss, proteolytically inactive PSEN1 did not. Designed mutations that allow stable E-S complex formation without Aβ42 or Aβ production likewise result in synaptic degeneration. Moreover, replacement of C99 with variants of a Notch1-based substrate revealed that disrupted processing of another γ-secretase substrate can similarly lead to synaptic degeneration. These results support a model in which synaptic loss can be triggered by toxic, stalled γ-secretase E-S complexes in the absence of Aβ production and not by simple loss of proteolytic function. This new C. elegans system provides a powerful platform to study the role of dysfunctional γ-secretase substrate processing in FAD pathogenesis.},
}

@article {pmid41525820,
year = {2026},
author = {Mateo, D and Souza, MCO and Carrión, N and Heredia, L and Cabrera, C and Marquès, M and Forcadell, E and Pino, M and Zaragoza, J and Domingo, JL and Barbosa, F and Torrente, M},
title = {Elevated fecal silver, lithium, and platinum in cognitive impairment: A pilot exploration of microbiota-metal interactions.},
journal = {Neurotoxicology},
volume = {},
number = {},
pages = {103390},
doi = {10.1016/j.neuro.2026.103390},
pmid = {41525820},
issn = {1872-9711},
abstract = {BACKGROUND: Gut microbiota (GMB) and metal exposure have both been implicated in cognitive impairment (CI), including amnestic mild cognitive impairment (aMCI) and Alzheimer's disease (AD). However, studies integrating these areas remain scarce.

OBJECTIVE: This pilot study aimed to investigate whether exposure to metals modulates the relationship between GMB composition and clinical outcomes in individuals with CI.

METHODS: Stool samples were collected from aMCI (n = 12), AD (n = 18), and cognitively healthy controls (HC, n = 30). Participants were categorized into CI (n = 30) and HC (n = 30). Gut microbial diversity was assessed using shotgun sequencing, and 25 metals were quantified by inductively coupled plasma mass spectrometry (ICP-MS). Cognitive, neuropsychological, neuropsychiatric, and functional assessments were also conducted.

RESULTS: No significant differences were observed between groups in microbial richness, alpha-diversity (Shannon index), or beta-diversity (Bray-Curtis). Likewise, microbial diversity measures were not associated with cognitive outcomes. In contrast, aMCI and AD participants exhibited significantly higher fecal concentrations of silver (Ag), lithium (Li), and platinum (Pt) compared to HC (all p < 0.001).

CONCLUSION: This multidimensional pilot study integrating microbiota profiling, metal exposure assessment, and cognitive evaluation, revealed elevated fecal excretion of Ag, Li, and Pt in participants with cognitive impairment, suggesting potential interactions between trace metals and neurodegenerative processes. While no significant differences in overall microbial diversity were observed between groups, these findings emphasize the need for larger, longitudinal investigations to elucidate the complex relationships among gut microbiota, metal homeostasis, and cognitive decline.},
}

@article {pmid41525811,
year = {2026},
author = {Pradhan, LK and Das, SK},
title = {Zebrafish neural regeneration: mechanistic insights into human nervous system repair.},
journal = {Neuroscience},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.neuroscience.2026.01.009},
pmid = {41525811},
issn = {1873-7544},
abstract = {The zebrafish (Danio rerio) is a powerful vertebrate model for studying neurodegenerative diseases and regenerative medicine due to its genetic similarity to humans and its unique ability to regenerate the central nervous system (CNS). This review synthesizes key findings on zebrafish neural regeneration across the retina, spinal cord, and brain, emphasizing translational relevance. Zebrafish effectively model disorders such as Alzheimer's, Parkinson's, amyotrophic lateral sclerosis, stroke, epilepsy, autism spectrum disorders, and CNS injuries. Unlike mammals, they restore damaged axons and recover function through a permissive extracellular matrix, transient inflammation, and glial plasticity. In the retina, Müller glia reprograms after injury to generate progenitors that replace lost neurons, regulated by Wnt/β-catenin, Shh, EGF, Hippo/YAP, and ROCK signaling. In the spinal cord, ependymo-radial glia forms a laminin- and fibronectin-rich "glial bridge," guided by FGF and CTGF signaling, supporting axon regrowth. In the brain, GFAP- and Olig2-positive radial glia drive neurogenesis within ventricular niches, integrating new neurons while maintaining circuit integrity. Regeneration involves transient Notch suppression, context-specific Wnt and FGF activation, and immune modulation without fibrosis. Advances in single-cell RNA sequencing, CRISPR-Cas9, lineage tracing, and multi-omics have identified injury-induced progenitor states, regulators (ascl1a, lin28, sox2, stat3), and epigenetic programs enabling regeneration. Emerging research on bioelectric signaling, microbiota-brain interactions, and lipid mediators further expands systemic understanding. Overall, zebrafish provide a unified model for decoding vertebrate CNS regeneration and guiding therapeutic strategies to restore neural repair in humans.},
}

@article {pmid41525748,
year = {2026},
author = {Lu, W and Gong, Q and Chen, Y and Qiu, S and An, J},
title = {Hippocampus-centered structural covariance network reorganization in Alzheimer's disease: An individualized graph-based biomarker validated by machine learning.},
journal = {Neural networks : the official journal of the International Neural Network Society},
volume = {198},
number = {},
pages = {108542},
doi = {10.1016/j.neunet.2026.108542},
pmid = {41525748},
issn = {1879-2782},
abstract = {Alzheimer's disease (AD) is characterized by progressive brain network disintegration, yet quantifying this process at an individual level remains challenging. This study explores the potential of an individualized differential structural covariance network (IDSCN) as a graph theory-based biomarker to capture disease-specific network reorganization. We found that throughout the AD spectrum, significant progressive atrophy occurred in multiple brain regions, especially the hippocampus. At the same time, the brain underwent a profound structural covariant reorganization, and this reorganization was significantly centered on the hippocampus. Graph theory analysis revealed a significant enhancement in nodal strength and nodal efficiency across widespread brain regions, with the hippocampus, amygdala, middle temporal gyrus, and entorhinal cortex emerging as core hubs of pathological impact. Importantly, betweenness centrality selectively increased only in the bilateral hippocampus, highlighting their critical role as bridges in the pathological propagation network. Machine learning validation confirmed that this individualized network biomarker performs excellently in distinguishing AD patients from cognitively normal individuals, demonstrates comparable efficacy to traditional morphological models in capturing early disease-related changes, and shows potential in differentiating between mild cognitive impairment converters and non-converters. Our study establishes the hippocampus-centered IDSCN as an effective, individualized graph theory-based biomarker, providing new insights into the network pathophysiology of AD and holding significant potential for early diagnosis and prognostic stratification.},
}

@article {pmid41525648,
year = {2026},
author = {Yao, Y and Zhang, H and Tang, X and Li, J and Xu, J and Yang, J and Meng, Y},
title = {Rich-Neighborhood Contrastive Learning Framework for Drug Repositioning via Structural and Semantic Neighbor Fusion.},
journal = {IEEE journal of biomedical and health informatics},
volume = {PP},
number = {},
pages = {},
doi = {10.1109/JBHI.2026.3651355},
pmid = {41525648},
issn = {2168-2208},
abstract = {Drug repositioning accelerates therapeutic discovery by identifying new indications for approved drugs, substantially reducing the time and cost associated with drug development. However, graph collaborative filtering (GCF)-based methods for predicting drug-disease associations are limited by data sparsity and structural noise, impeding the modeling of latent high-order and semantic relationships. We hypothesize that jointly leveraging complementary information from structural and semantic neighborhoods can alleviate data sparsity and improve predictive performance. To this end, we propose a unified framework, Rich-Neighborhood Contrastive Learning for Drug Repositioning (RCL-DR), which integrates both structural and semantic neighborhood modeling into a LightGCN-based collaborative filtering backbone and optimizes semantic prototypes via an Expectation-Maximization (EM) algorithm. Experiments on three public datasets using 10 × 10- fold cross-validation demonstrate that RCL-DR outperforms representative baselines, achieving an area under the receiver operating characteristic curve (AUROC) of 0.9419 and an area under the precision-recall curve (AUPR) of 0.5126, representing absolute improvements of 0.0345 and 0.0138, respectively. Furthermore, RCL-DR identifies promising drug candidates for Alzheimer's disease (e.g., buspirone) and Parkinson's disease (e.g., trihexyphenidyl) by predicting previously unknown drug-disease associations on the Fdataset and validating them against authoritative databases. In summary, RCL-DR provides a unified contrastive learning framework for robust drug repositioning and precision pharmacology.},
}

@article {pmid41525500,
year = {2025},
author = {Oomens, JE and Harrison, TM and Dage, JL and Russ, KA and Zetterberg, H and Jagust, WJ and Foroud, TM and Biber, S and Mormino, EC and Johnson, SC},
title = {Biomarkers.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 2},
number = {},
pages = {e104199},
doi = {10.1002/alz70856_104199},
pmid = {41525500},
issn = {1552-5279},
mesh = {Humans ; *Alzheimer Disease/blood/diagnostic imaging ; *Biomarkers/blood ; Female ; Male ; *tau Proteins/blood ; Aged ; Neuroimaging ; Amyloid beta-Peptides ; Aged, 80 and over ; Brain/diagnostic imaging ; },
abstract = {BACKGROUND: Data accessibility and interoperability across the U.S. Alzheimer's Disease Research Centers (ADRCs) provides necessary resources and data access to enable novel hypothesis testing without additional data collection and will allow end users to rapidly advance our understanding of multiple pathologies or multiple chronic conditions on disease progression within Alzheimer's disease and related diseases. The aim of the current study was to integrate plasma data from the National Centralized Repository for Alzheimer's Disease and Related Dementia's (NCRAD) with ADRC neuroimaging data from the SCAN initiative and National Alzheimer's Coordinating Center Uniform Data Set (NACC UDS) demographic data, all publicly available through the NACC Data Platform and Data Front Door. We provide sample descriptives and present the results of initial data explorations.

METHOD: The NACC and NCRAD data request procedures were completed to gain access to the data. We focused on the subset of participants for whom Quanterix Simoa HD-X Alzpath plasma pTau217 data was available (NCRAD). Amyloid pathology was defined based on centiloid values (cut-off >= 20; SCAN initiative). Demographic information was available for all participants (NACC UDS). We integrated data using the NACC identifier and visit age where available. We used Spearman correlations to assess the association between plasma pTau217 and centiloid values and we used ROC analyses to assess amyloid classification performance.

RESULT: Plasma pTau217 data was available for 927 participants (sample descriptives in Table 1). Figure 1 shows the distribution of plasma pTau217 levels across diagnostic groups. In the subset of participants for whom amyloid PET was available (n = 170, Table 1), the Spearman correlation between plasma pTau217 levels and centiloid values was 0.59. Quanterix pTau217 accurately classified amyloid status with a ROC AUC of .92 (95%CI 0.89-0.97; accuracy 85%; Figure 2). Tau PET was available for 135 participants with plasma pTau217 data and 114 participants with both plasma pTau217 and amyloid PET data.

CONCLUSION: Combining the SCAN PET and NCRAD plasma results in a promising resource, already with 36% demographic diversity. Sample sizes will increase through ongoing efforts as part of the SCAN initiative and the ADRC Consortium for Clarity in ADRD Research Through Imaging (CLARiTI).},
}

Humans
*Alzheimer Disease/blood/diagnostic imaging
*Biomarkers/blood
Female
Male
*tau Proteins/blood
Aged
Neuroimaging
Amyloid beta-Peptides
Aged, 80 and over
Brain/diagnostic imaging

@article {pmid41525410,
year = {2026},
author = {Custodio, N and Malaga, M and Bustamante-Paytan, D and Huilca-Flores, J and Agüero, K and Verastegui, G and Bartolo, P and Bendezu, D and Yauri, Z and Montesinos, R},
title = {Clinical characterization of probable Dementia with Lewy Bodies based on the initial clinical presentation in a Latin American Low- and Middle- Income Country.},
journal = {Neuro-degenerative diseases},
volume = {},
number = {},
pages = {1-21},
doi = {10.1159/000550415},
pmid = {41525410},
issn = {1660-2862},
abstract = {BACKGROUND: Dementia with Lewy Bodies (DLB) is a distinct form of dementia characterized by the accumulation of alpha-synuclein in the brain. Early presentations are often heterogeneous, and the impact of this variability on disease progression remains poorly understood. This study explored the initial clinical presentation of DLB among Peruvian patients and its influence on the clinical course.

METHODS: We conducted a retrospective study of patients diagnosed with DLB and Alzheimer's disease (AD) using standard clinical criteria. Cognitive function was assessed using MMSE, INECO Frontal Screening (IFS), and Uniform Data Set (UDS). We classified DLB patients based on their initial symptoms (hallucinations or parkinsonism) and compared their clinical and neuropsychological characteristics. Statistical analyses (ANOVA, chi-squared, Wilcoxon tests, and multivariate linear regression) were used to evaluate group differences and examine how initial symptoms influenced disease progression and cognitive decline.

RESULTS: Forty-six patients with probable DLB between June 2018 and May 2023 were included. The median time from symptom onset to diagnosis was five years. Cognitive symptoms were the most frequent initial presentation, followed by motor and behavioral signs. No significant clinical or neuropsychological differences were found between presentation subgroups at evaluation. Compared to AD patients, those with DLB scored higher on cognitive measures (MMSE, RUDAS) and behavioral symptoms (NPI). Neuropsychological testing revealed DLB patients had more pronounced deficits in visuospatial and executive functions than those with AD.

CONCLUSIONS: In our cohort, patients in the cognitive-onset group reached the threshold for dementia more rapidly. However, the initial presenting symptoms did not result in worse severity across specific cognitive or behavioral domains.},
}

@article {pmid41525398,
year = {2026},
author = {Huan, SY and Otgaar, H and Howe, ML and Liu, YR and Xu, HZ and Wang, J and Yu, J},
title = {A meta-analysis of false memory in healthy and pathological cognitive aging.},
journal = {Psychology and aging},
volume = {},
number = {},
pages = {},
doi = {10.1037/pag0000966},
pmid = {41525398},
issn = {1939-1498},
support = {//National Natural Science Foundation of China/ ; //Fonds Wetenschappelijk Onderzoek/ ; //Ministry of Education in China/ ; },
abstract = {Although there is a consensus about age-related impairments in true memory, the relationship between aging and false memory remains less clear. Both the fuzzy-trace theory and the activation-monitoring theory postulate possible effects of cognitive aging on the processes of encoding, consolidation, and retrieval. Yet, quantitative analyses of cognitive aging, both healthy (younger vs. older adults) and pathological (older adults vs. mild cognitive impairment/Alzheimer's disease), on false memory have not been conducted. We meta-analyzed 150 articles with 414 independent effect sizes and found a robust aging effect of false memory, with older adults showing higher levels of false memory than younger adults in both spontaneous (Hedges's g = 0.538, 95% CI [0.432, 0.644]) and suggestion-induced false memory (Hedges's g = 0.460, 95% CI [0.255, 0.665]). Mild cognitive impairment/Alzheimer's disease patients showed significantly higher levels of spontaneous (Hedges's g = 0.486, 95% CI [0.053, 0.919]) but not suggestion-induced false memory (Hedges's g = 0.608, 95% CI [-0.286, 1.502]) than healthy older adults. For the study and test phase, moderator analyses indicated that experimental material, modality, true memory, paradigm, type of test, and the retention interval significantly influenced aging effect on false memory. For general moderators, participants' age and education level were also significant. Our results underscore the importance of integrating the fuzzy-trace theory and activation-monitoring theory to account for age differences in false memory across types. Both healthy and pathological cognitive aging increase susceptibility to false memory, and the decline in verbatim memory and monitoring functions, combined with hyperactivation during encoding, may account for aging effect in false memory. (PsycInfo Database Record (c) 2026 APA, all rights reserved).},
}

@article {pmid41525217,
year = {2026},
author = {Lin, TI and Wang, WL},
title = {Grouped multi-trajectory modeling using finite mixtures of multivariate contaminated normal linear mixed model.},
journal = {Statistical methods in medical research},
volume = {},
number = {},
pages = {9622802251404054},
doi = {10.1177/09622802251404054},
pmid = {41525217},
issn = {1477-0334},
abstract = {There has been growing interest across various research domains in the modeling and clustering of multivariate longitudinal trajectories obtained from internally near-homogeneous subgroups. One prominent motivation for such work arises from the Alzheimer's Disease Neuroimaging Initiative (ADNI) cohort study, which involves multiple clinical measurements, exhibiting complex features such as diverse progression patterns, multimodality, and the presence of atypical observations. To tackle the challenges associated with modeling and clustering such grouped longitudinal data, we propose a finite mixture of multivariate contaminated normal linear mixed model (FM-MCNLMM) and its extended version, referred to as the EFM-MCNLMM, which allows the mixing weights to potentially depend on concomitant covariates. We develop alternating expectation conditional maximization algorithms to carry out maximum likelihood estimation for the two models. The utility and effectiveness of the proposed methodology are demonstrated through simulations and analysis of the ADNI data.},
}

@article {pmid41525163,
year = {2025},
author = {Hua, N and Minaeva, O and Parsons, D and Moncaster, JA and Demb, E and Goldstein, LE},
title = {Biomarkers.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 2},
number = {},
pages = {e107226},
doi = {10.1002/alz70856_107226},
pmid = {41525163},
issn = {1552-5279},
mesh = {Animals ; Mice, Transgenic ; *Alzheimer Disease/pathology/diagnostic imaging ; Mice ; Disease Models, Animal ; Biomarkers ; *Brain Injuries, Traumatic/diagnostic imaging/pathology/complications ; *Hippocampus/pathology/diagnostic imaging ; Diffusion Magnetic Resonance Imaging ; Magnetic Resonance Imaging ; Male ; },
abstract = {BACKGROUND: Traumatic brain injury (TBI) is a risk factor for the earlier onset of Alzheimer's disease (AD), and the more severe the injury, the greater the risk of developing AD. Given the prevalence of AD in modern society, the possibility that TBI may predispose individuals to develop AD has significant social and economic implications. Therefore, it is important to understand how TBI triggers accelerated AD progression. In this study, we explored how neurotrauma accelerates hippocampal degeneration in a transgenic mouse model of AD using high-resolution ex vivo diffusion-MRI.

METHOD: Unanesthetized 3xTg-AD mice (n = 4) were pretreated with a non-sedating dose of the analgesic buprenorphine and then subjected to left-lateral closed-head impact injury (Figure 1) at 10-12 weeks of age. At 6-months post-TBI, the mice were sacrificed via transcardial perfusion. The harvested brains were submerged in 10% formalin for 24 hours and then stored in Gadavist-doped PBS (1:400 dilution) until MRI. MRI data were acquired using a 9.4T Bruker scanner and a cryoprobe. Key parameters were TR=300ms, TE=27.7ms, b=3000 (48 directions), and 5000s/mm[2] (80 directions), FOV=14.30x10.66x7.02mm[3], Matrix=220x164x108, resolution=65mm[3]. Diffusion MRI was analyzed in DSI Studio and NODDI toolbox. T1-weighted (T1W) images (resolution=32.5 µm[3]) were also acquired (FLASH) for structural reference. Age-, gender-matched 3xTg-AD mice (n = 4) without TBI were used as controls.

RESULT: Figure 2 shows a representative T1W image and corresponding diffusion-derived hippocampal maps from a TBI mouse. Compared to the contralateral side, the ipsilateral radiatum of CA1 and CA3 showed decreased quantitative anisotropy (QA) values and increased orientation dispersion index (ODI), the ipsilateral stratum pyramidale showed decreased QA and axial diffusivity (AxD), and the ipsilateral alveus showed decreased AxD. Statistical analysis revealed that the average fractional anisotropy (FA) values in radiatum were lower (CA3, significant; CA1, trend) in the ipsilateral hippocampus compared to the contralateral side of TBI mice or the bilateral sides of control mice (Figure 3).

CONCLUSION: Our results demonstrate that the hippocampal CA1/CA3 subregions are more vulnerable to neurotrauma. This finding may help clarify the mechanisms underlying trauma-accelerated AD and suggest that advanced diffusion-MRI is a potential tool for the early diagnosis of trauma patients at risk of developing AD.},
}

Animals
Mice, Transgenic
*Alzheimer Disease/pathology/diagnostic imaging
Mice
Disease Models, Animal
Biomarkers
*Brain Injuries, Traumatic/diagnostic imaging/pathology/complications
*Hippocampus/pathology/diagnostic imaging
Diffusion Magnetic Resonance Imaging
Magnetic Resonance Imaging
Male

@article {pmid41525055,
year = {2026},
author = {Russell, JK and Schlachetzki, Z and Ances, BM and Rafii, MS and , },
title = {Concordance of Biological and Clinical Staging of Alzheimer Disease Pathology in Down Syndrome.},
journal = {JAMA neurology},
volume = {},
number = {},
pages = {},
doi = {10.1001/jamaneurol.2025.5261},
pmid = {41525055},
issn = {2168-6157},
}

@article {pmid41525005,
year = {2026},
author = {Mir, PA and Kumar, N and Bhutia, GT and Chaudhary, P and Kaur, G and Gupta, SK},
title = {The aging gut-glia-immune axis in alzheimer's disease: microbiome-derived mediators of neuroinflammation and therapeutic innovation.},
journal = {GeroScience},
volume = {},
number = {},
pages = {},
pmid = {41525005},
issn = {2509-2723},
abstract = {Alzheimer's disease (AD), the most common cause of dementia in the aging population, is marked by amyloid-beta (Aβ) plaques, tau tangles, and progressive neuronal degeneration, placing heavy clinical and socioeconomic burdens on healthcare worldwide. Aging remains the strongest risk factor, with chronic low-grade inflammation, oxidative stress, mitochondrial dysfunction, and impaired proteostasis creating a vulnerable brain environment that accelerates AD onset and progression. Recent evidence highlights the gut-glia-immune axis as a critical pathway linking age-related microbiome changes to glial dysfunction. Microbial metabolites, such as short-chain fatty acids and tryptophan derivatives, regulate microglial maturation, astrocytic activity, and neuroimmune signaling. However, age-associated dysbiosis disrupts glial homeostasis, amplifies neuroinflammation, and impairs amyloid clearance, thereby worsening neurodegeneration. Preclinical models including germ-free mice and fecal microbiota transplantation along with clinical studies of elderly AD patients, provide compelling evidence of microbiome-driven modulation of disease. From a therapeutic perspective, microbiome-targeted interventions including probiotics, prebiotics, synbiotics, and microbiota-directed small molecules offer promising strategies to restore glial balance, reduce inflammation, and protect cognitive function. This review highlights the therapeutic potential of probiotics, synbiotics, and fecal microbiota transplantation for mitigating neuroinflammation and cognitive decline in Alzheimer's disease. However, given the multifactorial nature of neurodegenerative disorders, these strategies are unlikely to be universally effective and must be tailored to individual patient profiles.},
}

@article {pmid41524953,
year = {2026},
author = {O'Mara, A and Mody, BP and Mammi, M and Simjian, T and Ghattas, K and Kaliki, S and Le, NPM and Liew, A and Migliore, M and Mekary, RA},
title = {The effect of GLP-1 receptor agonists on cognition in nondiabetic patients with mild cognitive impairment or alzheimer's disease: a meta-analysis of randomized controlled trials.},
journal = {Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology},
volume = {47},
number = {1},
pages = {149},
pmid = {41524953},
issn = {1590-3478},
mesh = {Humans ; *Alzheimer Disease/drug therapy ; *Cognitive Dysfunction/drug therapy ; *Glucagon-Like Peptide-1 Receptor Agonists ; Randomized Controlled Trials as Topic ; *Cognition/drug effects ; },
abstract = {BACKGROUND: Currently, the cognitive impact of Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) remains unclear in non-diabetic patients with Alzheimer's disease (AD) and mild cognitive impairment (MCI), despite their widespread use for type 2 diabetes. This meta-analysis summarized cognitive outcomes from randomized controlled trials (RCTs) of GLP-1 RAs in non-diabetic patients with AD or MCI.

METHODS: PubMed, Cochrane Library, and Embase were searched for studies through October 27, 2024. Pooled standardized mean differences (SMD) and 95% confidence intervals (CI) were calculated using random-effects models. Sensitivity analyses addressed variations in cognitive assessment methodologies. Between-study heterogeneity was evaluated using the I² index.

RESULTS: Four RCTs comprising 112 patients (61 placebo, 51 treatment) were included. For cognitive tests where higher scores indicate better outcomes, no significant difference was observed between GLP-1 RA and placebo groups (pooled SMD: -0.10, 95% CI: -0.53, 0.34; I² = 23.9%). Sensitivity analyses yielded consistent results. Analysis of the Alzheimer's Disease Assessment Scale-Cognitive subscale from two studies, where lower scores indicate better outcomes, similarly showed no significant treatment effect (SMD: 0.07, 95% CI: -0.47, 0.62; I² = 0%).

CONCLUSION: There was no evidence that GLP-1 RAs improved cognitive outcomes compared to placebo in non-diabetic patients with AD or MCI. Further research is needed to clarify their neuroprotective potential and explore alternative therapeutic strategies for cognitive decline.},
}

Humans
*Alzheimer Disease/drug therapy
*Cognitive Dysfunction/drug therapy
*Glucagon-Like Peptide-1 Receptor Agonists
Randomized Controlled Trials as Topic
*Cognition/drug effects

@article {pmid41524819,
year = {2026},
author = {Prata, O and Cherubini, V and Ranaldi, V and Baldinelli, S and Fiori, C and Rosettani, P and Biagiotti, A and Belcecchi, S and Silvestrini, M and Toraldo, A and Luzzi, S},
title = {Homocysteine levels do not impact cognitive profile in frontotemporal dementia.},
journal = {Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology},
volume = {47},
number = {1},
pages = {148},
pmid = {41524819},
issn = {1590-3478},
mesh = {Humans ; *Homocysteine/blood ; Male ; Female ; *Frontotemporal Dementia/blood/psychology/complications ; Cross-Sectional Studies ; Middle Aged ; Aged ; Neuropsychological Tests ; *Cognition/physiology ; },
abstract = {BACKGROUND: This study aimed at investigating whether high plasma homocysteine (Hcy) levels affect specific cognitive functions in individuals with Frontotemporal Dementia (FTD). While Hcy is a well-established risk factor for cerebrovascular disorders and Alzheimer's Disease, its role in other neurodegenerative dementias remains unclear. Furthermore, it is not known whether elevated Hcy levels contribute to a generalized cognitive decline or selectively impair specific cognitive domains. This uncertainty may stem from previous studies predominantly relying on global cognitive assessments rather than detailed domain-specific measures.

METHODS: In a cross-sectional design, 173 patients with a diagnosis of FTD underwent a comprehensive neuropsychological evaluation assessing key cognitive domains, including memory, language, visuoperception, visuospatial abilities, executive functioning, constructional praxis, and ideomotor praxis. The influence of plasma Hcy levels and other potential risk factors (e.g., cholesterol levels, smoking habits, triglycerides, and the presence of the apolipoprotein E ε4 allele) was analysed.

RESULTS: A Generalized Linear Model analysis revealed no significant association between elevated Hcy levels and cognitive performance across domains in the FTD cohort.

CONCLUSIONS: Hcy levels were not significantly associated with cognitive performance in a large sample of individuals with FTD. If replicated, these findings could challenge the hypothesis that Hcy constitutes a risk factor for FTD.},
}

Humans
*Homocysteine/blood
Male
Female
*Frontotemporal Dementia/blood/psychology/complications
Cross-Sectional Studies
Middle Aged
Aged
Neuropsychological Tests
*Cognition/physiology

@article {pmid41524814,
year = {2026},
author = {Tripathi, P and Shah, J},
title = {Valacyclovir Mitigates Amyloid Plaque Deposition, P-Tau Aggregation, and Neuroinflammation in Streptozotocin induced Alzheimer's Disease Rat Model.},
journal = {Molecular neurobiology},
volume = {63},
number = {1},
pages = {356},
pmid = {41524814},
issn = {1559-1182},
support = {GSBTM/MD/PROJECTS/SSA/4887/2016-17//Gujarat State Biotechnology Mission, Government of Gujarat, India./ ; },
mesh = {Animals ; *Alzheimer Disease/drug therapy/chemically induced/metabolism/pathology ; *tau Proteins/metabolism ; Streptozocin ; Male ; *Valacyclovir/pharmacology/therapeutic use ; Disease Models, Animal ; *Plaque, Amyloid/drug therapy/metabolism/pathology ; *Neuroinflammatory Diseases/drug therapy/metabolism/pathology ; Rats ; Amyloid beta-Peptides/metabolism ; Rats, Wistar ; *Protein Aggregates/drug effects ; Neuroprotective Agents/pharmacology/therapeutic use ; Oxidative Stress/drug effects ; },
abstract = {Alzheimer's Disease (AD), a leading cause of dementia, is a known neurodegenerative disorder. Affecting millions of people worldwide, AD pathogenesis involves diverse risk factors such as lifestyle, environmental, and metabolic conditions that accelerate sporadic AD. Very recently, backed with substantial evidence, herpes simplex virus-1 (HSV-1) has been recognized as a potential causative factor that may play a pivotal role in sporadic AD. Latent virus is estimated to activate key underlying pathways, preferably Aβ and p-tau, to cause AD. Additionally, Antivirals such as Valacyclovir have emerged to impart a potential neuroprotective role in AD. Present research aimed to explore the neuroprotective role and mechanism of Valacyclovir in the streptozotocin-induced Alzheimer's disease model in rats. A single dose of 3 mg/kg ICV (intracerebroventricular) Streptozotocin (STZ) was administered to induce AD in rats. Two doses of Valacyclovir, i.e., 100 mg/kg and 150 mg/kg were evaluated with Donepezil 5 mg/kg as standard. Post 21 days of treatment, Valacyclovir demonstrated dose-dependent improvement in neurobehavioral parameters. Further, AD-specific parameters i.e. Aβ1-40 and Aβ1-42, p-tau, and BACE-1 were significantly (p < 0.001) reduced with parallel reduction in inflammatory (p < 0.001) and oxidative stress markers. Additionally, Valacyclovir also increased the levels of amyloid clearance enzymes i.e., neprilysin (NEP) (p < 0.001) and insulin-degrading enzyme (IDE) (p < 0.001). Results suggest promising neuroprotective action of valacyclovir via reducing Aβ-amyloid protein, p-Tau, BACE-1, as well as demonstrating anti-inflammatory and antioxidant activity.},
}

Animals
*Alzheimer Disease/drug therapy/chemically induced/metabolism/pathology
*tau Proteins/metabolism
Streptozocin
Male
*Valacyclovir/pharmacology/therapeutic use
Disease Models, Animal
*Plaque, Amyloid/drug therapy/metabolism/pathology
*Neuroinflammatory Diseases/drug therapy/metabolism/pathology
Rats
Amyloid beta-Peptides/metabolism
Rats, Wistar
*Protein Aggregates/drug effects
Neuroprotective Agents/pharmacology/therapeutic use
Oxidative Stress/drug effects

@article {pmid41524809,
year = {2026},
author = {Singh, G and Aran, KR},
title = {Rethinking on bile acid-brain axis: decoding neurotoxic and neuroprotective landscape in aging and Alzheimer's disease.},
journal = {Biogerontology},
volume = {27},
number = {1},
pages = {37},
pmid = {41524809},
issn = {1573-6768},
mesh = {Humans ; *Alzheimer Disease/metabolism/drug therapy/pathology ; *Bile Acids and Salts/metabolism ; *Aging/metabolism ; *Brain/metabolism/pathology ; Animals ; Gastrointestinal Microbiome ; Neuroprotective Agents ; Neuroprotection ; },
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative condition in which aging serves as the predominant risk factor. Emerging research underscores the importance of bile acids (BAs), traditionally recognized for their role in digestion, as key signaling mediators involved in both systemic metabolism and neural communication. Disruption of bile acid (BA) metabolism during aging arises from altered hepatic synthesis, gut microbial imbalance, and defective receptor signaling. These changes have been implicated in several neurodegenerative processes, including Aβ accumulation, tau protein abnormalities, mitochondrial impairment, and disturbances in immune regulation. Aging induces a shift in BA composition toward more cytotoxic species, contributing to blood-brain barrier disruption and enhanced neuronal damage. Multi-omics analyses have identified distinct BA signatures in plasma and cerebrospinal fluid of individuals with mild cognitive impairment and AD. These alterations show strong correlations with brain atrophy and progressive cognitive decline. Experimental and early clinical findings suggest potential neuroprotective effects of hydrophilic BAs such as ursodeoxycholic acid and tauroursodeoxycholic acid, along with therapeutic opportunities through modulation of BA receptors and microbiome-driven BA regulation. In the current era of AD research, the gut-liver-brain BA axis emerges as a novel mechanistic framework linking systemic metabolic aging to neurodegeneration. This review examines the molecular pathways through which BA dysregulation influences aging and AD, emphasizing its therapeutic relevance and supporting the development of biomarker-based and precision medicine approaches for neurodegenerative disorders.},
}

Humans
*Alzheimer Disease/metabolism/drug therapy/pathology
*Bile Acids and Salts/metabolism
*Aging/metabolism
*Brain/metabolism/pathology
Animals
Gastrointestinal Microbiome
Neuroprotective Agents
Neuroprotection

@article {pmid41524705,
year = {2026},
author = {Wang, X and Yang, J and Zhang, J and Yu, G and Zhu, J and Nie, Y},
title = {Polyphenol consumption and neurodegeneration risk: a systematic meta-analysis of randomized controlled trials bridging nutrition and cognitive health.},
journal = {Food & function},
volume = {},
number = {},
pages = {},
doi = {10.1039/d5fo05135e},
pmid = {41524705},
issn = {2042-650X},
abstract = {Given the potential of polyphenols to mitigate neurodegenerative diseases (NDDs), this meta-analysis investigated whether clinical evidence supports the use of polyphenols for neuroprotection and as nutritional strategies in NDDs. We analyzed different polyphenol types across seven NDDs, 13 studies involving 849 participants were included. Prespecified outcomes comprised global cognition (Mini-Mental State Examination, MMSE), domain-specific cognition (Alzheimer's Disease Cooperative Study-Cognitive Subscale, ADCS-Cog), activities of daily living (Alzheimer's Disease Cooperative Study-Activities of Daily Living, ADCS-ADL), neuropsychiatric symptoms (Neuropsychiatric Inventory, NPI), and selected biomarkers (plasma amyloid-β40 and brain-derived neurotrophic factor, BDNF). Reporting followed PRISMA 2020 guidelines, methods conformed to the Cochrane Handbook, and certainty of evidence was assessed using GRADE. Overall, polyphenol supplementation was associated with improved global cognition (pooled MD in MMSE = 2.06; 95% CI 0.62-3.49). In subgroup analyses, flavonoids were associated with a modest but significant improvement in MMSE scores, whereas stilbenes produced a significant benefit in daily functioning (ADCS-ADL) without clear gains in MMSE or ADCS-Cog and no consistent effects on NPI. Anthocyanidins, phenolic acids, and lignans did not significantly affect cognitive outcomes (MMSE or ADCS-Cog), and polyphenol subclasses did not yield robust or consistent changes in NPI or biomarker endpoints (Aβ40 and BDNF). Specific polyphenol subclasses therefore appear to confer selective cognitive and functional benefits, with stilbenes primarily supporting functional outcomes and flavonoids potentially enhancing global cognition.},
}

@article {pmid41524585,
year = {2026},
author = {Hu, G and Li, W and Lei, X and Yao, Y and Ye, S},
title = {Aloe-emodin attenuated Aβ-induced tau phosphorylation by autophagy-NLRP3 inflammasome pathway.},
journal = {Neuroreport},
volume = {},
number = {},
pages = {},
doi = {10.1097/WNR.0000000000002246},
pmid = {41524585},
issn = {1473-558X},
support = {82205235//the National Natural Science Foundation of China/ ; 2022AH050502//The Key Project Foundation of Natural Science Research of Anhui University of Chinese Medicine/ ; 2022rcyb028//The Talent Support Program of Anhui University of Traditional Chinese Medicine/ ; YQYB2024028//Anhui Province 2024 Action Project for Training Young and Middle aged Teachers in Universities/ ; },
abstract = {OBJECTIVE: Anthraquinone derivative aloe-emodin, extracted from Chinese herbs has been confirmed with various pharmacological effects, including anti-inflammatory and neuroprotective properties, particularly in Alzheimer's disease, but the exact mechanism of action remains unclear.

METHODS: In this study, the PC12 cells were induced by amyloid β-protein (Aβ) to establish an in vitro model of Alzheimer's disease. The 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyltetrazolium bromide, 5-ethynyl-2'-deoxyuridine staining, transmission electron microscopy, real-time quantitative PCR, western blot, ELISA, coimmunoprecipitation (Co-IP), and immunofluorescence were employed to evaluate effect of aloe-emodin on the survival and expression of related genes and proteins in PC12 cells induced by Aβ.

RESULTS: We found that 5 μM aloe-emodin significantly enhanced cell survival and proliferation. It also increased the mRNA and protein expression of Beclin-1 and LC3II, while decreasing the mRNA expression of P62, PI3K, AKT, mechanistic target of rapamycin (mTOR), NOD-like receptor protein 3 (NLRP3), and caspase-1, as well as the protein expression of P62, NLRP3, cleaved-caspase-1, p-PI3K, p-AKT, p-mTOR, interleukin-18 (IL-18), and IL-1β. Additionally, aloe-emodin reduced the intensity of p-tau fluorescence. The Co-IP results demonstrated a direct interaction between NLRP3 and LC3. Interestingly, aloe-emodin exhibited effects comparable to those of RAPA, an mTOR inhibitor.

CONCLUSION: These findings demonstrate that aloe-emodin offers neuroprotective benefits by reducing NLRP3-mediated inflammation and promoting autophagy, thereby providing a novel perspective on the treatment of Alzheimer's disease.},
}

@article {pmid41524357,
year = {2025},
author = {Guzanova, EV and Zorkova, AV and Sorokina, TA and Goncharov, VV and Voronina, DS and Beschastnova, IA},
title = {[Frequency of nutritional deficiency in patients with Alzheimer's disease and Parkinson's disease].},
journal = {Zhurnal nevrologii i psikhiatrii imeni S.S. Korsakova},
volume = {125},
number = {12},
pages = {113-119},
doi = {10.17116/jnevro2025125121113},
pmid = {41524357},
issn = {1997-7298},
mesh = {Humans ; Aged ; *Parkinson Disease/complications ; *Alzheimer Disease/complications ; Male ; Female ; Middle Aged ; Aged, 80 and over ; *Malnutrition/epidemiology/etiology/diagnosis/diet therapy ; Nutritional Status ; Nutrition Assessment ; Incidence ; Body Mass Index ; },
abstract = {OBJECTIVE: To determine the incidence of nutritional deficiencies in patients with Alzheimer's disease (AD) and Parkinson's disease (PD) and, if identified, to correct them.

MATERIAL AND METHODS: 111 patients with neurodegenerative diseases AD and PD aged 50 to 89 years) were examined. Patients were examined twice: at the initial visit and 2 months later. During the first visit, a neurological examination and neuropsychological assessment were performed, and anxiety and depression levels were determined. Nutritional status was assessed using the Mini Nutritional Assessment (MNA) questionnaire, and body mass index (BMI) was calculated. For laboratory confirmation of malnutrition, hemoglobin, albumin, lipid profile, urea, and creatinine levels were assessed. All patients at risk of malnutrition were given dietary recommendations. The patient's family discussed adherence to a dietary regimen and maintaining a nutritious diet. To treat malnutrition, patients were also recommended to receive enteral nutrition supplements at a rate of 30-35 kcal/kg of body weight for outpatients (a total of at least 400 kcal/day) and 1 g of protein/kg of body weight/day. For this purpose, Fresubin protein was used, individually adjusted from 2 to 6 measuring spoons (12-36 g of protein). In the presence of dysphagia, depending on the severity of the swallowing disorder, a diet with a modified consistency was prescribed: Fresubin Cream 2 kcal, Fresubin Yogurt, Fresubin Condensed Level 2, and Fresubin Condensed Level 1. At the second visit (2 months later), treatment effectiveness was assessed.

RESULTS: Among the examined patients, AD was diagnosed in 66 (59.5%) patients, and PD in 45. (40.5%). malnutrition/risk of malnutrition was detected in 31 (28%) patients. In the group of patients with AD who had malnutrition/risk of malnutrition, 15 (62.5%) patients had malnutrition, 9 (37.5%) had the risk of malnutrition. Among patients with PD, 3 (42.9%) patients were diagnosed with malnutrition, 4 (57.1%) had the risk of malnutrition. Patients with AD who had moderate and severe dementia had significantly more often malnutrition and risk of malnutrition (p<0.05). Patients with PD at a more severe stage of the disease and, accordingly, with more pronounced movement disorders, had significantly more often malnutrition and the risk of malnutrition (p<0.05). A moderate correlation was obtained between dysphagia, oral apraxia, tooth loss, chewing disorder and malnutrition and the risk of malnutrition in patients with AD and PD (r=0.3, p<0.001). The value of laboratory parameters, such as increased creatinine, decreased albumin and hemoglobin, statistically significantly correlated with malnutrition and the risk of malnutrition (p<0.05). The study found a statistically significant association between depression, affective disorders, and malnutrition and the risk of malnutrition in patients with AD and PD (p<0.05). When examining patients malnutrition and the risk of malnutrition at the second visit, BMI increased in all patients.

CONCLUSION: Malnutrition and the risk of malnutrition occur in more than a quarter of patients with AD and PD. The risk of malnutrition increases in moderate and severe stages of the disease. Malnutrition is more common in AD compared to PD. Malnutrition and the risk of malnutrition were significantly associated with the presence of depression, affective disorders, as well as with chewing disorders, tooth loss, dysphagia, and oral apraxia. Early recognition of the risks of malnutrition is important for the timely correction of modifiable factors for the development of malnutrition, including the organization of adequate nutrition for the patient, dental prosthetics, Adjustment of the treatment regimen for the underlying disease, treatment of depressive episodes, and affective disorders. If a diagnosis of malnutrition is made, it is necessary to calculate and replenish the patient's energy and fluid needs, including the inclusion of additional enteral nutrition in the comprehensive treatment strategy.},
}

Humans
Aged
*Parkinson Disease/complications
*Alzheimer Disease/complications
Male
Female
Middle Aged
Aged, 80 and over
*Malnutrition/epidemiology/etiology/diagnosis/diet therapy
Nutritional Status
Nutrition Assessment
Incidence
Body Mass Index

@article {pmid41524345,
year = {2025},
author = {Yusupov, FA and Abdykadyrov, MS},
title = {[Neurogenesis in neurodegeneration: multifactorial regulation, mechanisms of impairment, and therapeutic strategies].},
journal = {Zhurnal nevrologii i psikhiatrii imeni S.S. Korsakova},
volume = {125},
number = {12},
pages = {14-21},
doi = {10.17116/jnevro202512512114},
pmid = {41524345},
issn = {1997-7298},
mesh = {Humans ; *Neurogenesis/physiology ; *Alzheimer Disease/physiopathology/metabolism/therapy ; *Neurodegenerative Diseases/physiopathology/therapy ; *Parkinson Disease/physiopathology/therapy/metabolism ; Animals ; },
abstract = {OBJECTIVE: To systematize current data on neurogenesis and its role in the pathogenesis of neurodegenerative conditions, such as Alzheimer's disease and Parkinson's disease, with a focus on molecular mechanisms of regulation, the nature of disorders in neurodegeneration, and the evaluation of therapeutic approaches aimed at stimulating neurogenesis.

MATERIAL AND METHODS: Research papers published in scientific databases, mainly Scopus, PubMed, and Google Scholar, over the past 5 years were used for this review. Special attention was paid to studies on neurogenesis and its role in the pathogenesis of neurodegenerative diseases. The review included studies that met the following criteria: publications from the past five years reporting current neurogenesis data, using clearly identified experimental and clinical techniques, published in peer-reviewed international journals with a high impact factor, and providing reliable statistics to support the results.

UNLABELLED: Studies with a limited sample size and insufficient statistical significance, those lacking a transparent methodology or exhibiting a low level of data reproducibility, reviews without a clear focus on neurogenesis or its connection to neurodegenerative diseases, and studies providing insufficient information on the applied technologies and analysis methods were excluded.

RESULTS: Modern research has significantly expanded the understanding of neurogenesis and its role in neurodegenerative diseases. Neurogenesis has been confirmed to occur in specific areas of the adult brain, including the hippocampus, where it is involved in cognitive processes such as learning, memory consolidation, spatial adaptation, cognitive flexibility, and regulation of affective behavior. However, the extent and functional significance of neurogenesis in different brain regions remain a matter of debate. The effect of neurodegenerative diseases on neurogenesis varies: in Alzheimer's disease, studies in animal models demonstrate its impairment; however, data on humans are inconsistent: a decrease in neurogenesis is observed in the early stages of the disease, but in some cases, its increase is reported, likely as a compensatory mechanism. Factors influencing neurogenesis in Alzheimer's disease include β-amyloid and tau protein accumulation, neuroinflammation, mitochondrial dysfunction, and oxidative stress. Parkinson's disease is associated with a decrease in neurogenesis in the subventricular zone and hippocampus due to the degeneration of dopaminergic neurons and the accumulation of α-synuclein; however, deep brain stimulation is able to enhance neuronal proliferation. Therapeutic strategies include pharmacological approaches aimed at stimulating neurogenesis, such as the use of neurotrophic factors, acetylcholinesterase inhibitors, selective serotonin reuptake inhibitors, Wnt and EGFR signaling pathway modulators, uric acid, and MFG-E8, as well as non-pharmacological methods, including physical activity, enriched environment, cognitive training, electrical stimulation, and music therapy.

CONCLUSION: Neurodegenerative diseases are a significant problem in modern healthcare, requiring an in-depth study of the mechanisms of neurogenesis and its role in pathogenesis. Despite conflicting evidence on neurogenesis in adult humans, animal model studies and cellular technologies demonstrate prospects for its therapeutic stimulation. Pharmacological and non-pharmacological methods, including the use of neurotrophic factors, electrical stimulation, and cognitive training, as well as cellular and gene therapy, are the basis of new intervention strategies. However, the issues of controlling the differentiation and integration of new neurons, as well as the ethical aspects associated with the use of stem cells, remain unresolved. Further interdisciplinary research aimed at studying the regulatory mechanisms of neurogenesis and its therapeutic potential may lead to the development of effective treatment strategies that can slow or even reverse the progression of neurodegenerative diseases. It highlights the need to integrate advanced technologies and approaches in modern neuroscience and clinical practice.},
}

Humans
*Neurogenesis/physiology
*Alzheimer Disease/physiopathology/metabolism/therapy
*Neurodegenerative Diseases/physiopathology/therapy
*Parkinson Disease/physiopathology/therapy/metabolism
Animals

@article {pmid41524344,
year = {2025},
author = {Bogolepova, AN and Kovalenko, EA and Gileva, EA and Makhnovich, EV and Gasilova, AD and Skvortsov, DI},
title = {[A new look at blood biomarkers in Alzheimer's patients].},
journal = {Zhurnal nevrologii i psikhiatrii imeni S.S. Korsakova},
volume = {125},
number = {12},
pages = {7-13},
doi = {10.17116/jnevro20251251217},
pmid = {41524344},
issn = {1997-7298},
mesh = {Humans ; *Alzheimer Disease/blood/diagnosis ; *Biomarkers/blood ; Amyloid beta-Peptides/blood ; tau Proteins/blood ; Peptide Fragments/blood ; },
abstract = {Alzheimer's disease (AD), as one of the leading causes of dementia in the world, is a neurodegenerative disease with a long pre-symptomatic period and the development of slowly progressive cognitive impairment. The rising number of patients diagnosed with AD and the socio-economic impacts of this condition necessitate the proactive identification and implementation of effective disease control methods in clinical practice. One of the key areas is the improvement of methods for the early diagnosis of AD, thus enabling therapeutic intervention at pre-dementia stages and further prevention of irreversible progressive degeneration of neuronal structures. Diagnosis of AD is based on a combination of clinical and neuroimaging data, as well as analysis of the spectrum of biological markers in cerebrospinal fluid. However, the use of this laboratory method in clinical practice is limited due to the low accessibility and invasive nature of the sampling procedure. Therefore, the study of blood biomarkers is a promising area for the diagnosis of the disease. The presented literature review addresses data on traditional blood biomarkers of AD diagnosis from the modern point of view for the pathogenesis of AD, and also summarizes the results of studies conducted to date on less studied blood biomarkers in AD, which have possible diagnostic potential for the development of cost-effective and affordable biomarkers for preclinical diagnosis.},
}

Humans
*Alzheimer Disease/blood/diagnosis
*Biomarkers/blood
Amyloid beta-Peptides/blood
tau Proteins/blood
Peptide Fragments/blood

@article {pmid41523616,
year = {2025},
author = {Sharif, N and Bibi, A and Sadiq, R and Ullah, I and Rauf, A and Arshad, MT and Bashir, S and Zamir, H and Gull, S and Anwar, T and Laryea, E},
title = {Computational Identification of Potent Multitarget Natural Ligands for Alzheimer's Disease Therapeutics.},
journal = {Scientifica},
volume = {2025},
number = {},
pages = {1132636},
pmid = {41523616},
issn = {2090-908X},
abstract = {Alzheimer's disease (AD), a complex neurodegenerative disorder, urgently necessitates a multitarget therapeutic approach. This study presents a novel in silico framework targeting a unique combination of four AD-relevant proteins-sortilin, clusterin, tau, and amyloid-beta (Aβ)-not previously explored together in multitarget docking studies. The study leveraged a comprehensive computational strategy integrating ADME (absorption, distribution, metabolism, excretion) and ProTox-3.0 analyses with AutoDock Vina molecular docking, binding, and bond interaction via SiteMap/CASTp and PLIP, respectively. Fifteen novel natural ligands and three established AD reference drugs (donepezil, memantine, and rivastigmine) were assessed against four key AD proteins: sortilin, clusterin, Aβ peptide, and tau. Pharmacokinetic and toxicity predictions revealed favorable drug-likeness for many ligands, 4-tert-amylphenol, allicin, apigenin, and resveratrol, which exhibited high gastrointestinal absorption but varied in blood-brain barrier (BBB) permeation, solubility, and drug-likeness. Ligands, such as apigenin, cyanidin, and galantamine, demonstrated favorable oral bioavailability and lead-likeness. Nevertheless, predicted toxicity profiles revealed potential hepatotoxicity concerns for ligands like 4-tert-amylphenol and berberine. Comparison with reference drugs highlighted the importance of optimizing ADME properties and minimizing toxicity. Molecular docking results consistently highlighted ginkgolide with multitarget binding to sortilin (-16.29 kcal/mol), clusterin (-13.98 kcal/mol), and tau (-10.63 kcal/mol). Critical interactions were identified, including binding to the aggregation domain of tau via HIS329. Other promising natural ligands, including ginsenosides, berberine, and apigenin, also exhibited strong multitarget interactions. Ginsenosides were a notable lead, demonstrating key molecular contacts with ILE141 on sortilin and directly targeting the Aβ core at ALA4. Apigenin also showed strong binding to the tau repeat domain at ILE328. Notably, memantine displayed significant binding to both sortilin and Aβ, forming a hydrogen bond with the amyloidogenic ILE5 residue. The study identified several potent multitarget binding capabilities compounds, offering compelling avenues for developing novel, more effective therapeutics for AD.},
}

@article {pmid41523330,
year = {2025},
author = {Raphael, DL},
title = {Neuropsychiatric symptoms in mild cognitive impairment and early Alzheimer's disease: Clinical pattern and diagnostic implications.},
journal = {AIMS neuroscience},
volume = {12},
number = {4},
pages = {676-705},
pmid = {41523330},
issn = {2373-7972},
abstract = {BACKGROUND: Alzheimer's disease (AD) and mild cognitive impairment (MCI) are widely recognized for their hallmark cognitive deficits, typically characterized by progressive cognitive deterioration. However, neuropsychiatric symptoms (NPS), including depression, apathy, anxiety, irritability, and sleep disturbances, are increasingly prevalent in the early stages of these conditions and significantly influence the disease trajectory and patient outcomes. Importantly, neuropsychiatric symptoms often precede overt memory loss by several years, with subtle mood and behavioral disturbances serving as early pre-diagnostic markers of an underlying Alzheimer's pathology. Their presence complicates the diagnosis, accelerates the disease progression, and intensifies the caregiver burden. However, distinguishing NPS arising from neurodegeneration and primary psychiatric disorders remains a profound diagnostic challenge, thus delaying timely intervention and obscuring early disease recognition.

OBJECTIVE: This structured narrative review examines the diagnostic complexities, clinical impact, and current management of NPS in early-stage Alzheimer's disease (AD) and Mild Cognitive Impairment (MCI), alongside the biological underpinnings, clinical relevance, diagnostic challenges, and treatment perspectives. We argue that understanding and managing NPS is essential to improve the clinical outcomes, reduce the caregiver burden, and guide therapeutic innovation.

METHODS: A structured narrative review of peer-reviewed studies published between 2012 and 2025 was conducted using PubMed, MEDLINE, Scopus, PsycINFO, Google Scholar, and CINAHL. The included studies investigated NPS prevalence, neurobiological correlations, and management strategies in individuals with AD or MCI.

FINDINGS: NPS affects up to 80% of individuals with early AD or MCI, often preceding cognitive decline. The current management strategies heavily rely on non-pharmacological interventions such as caregiver support, behavioral activation, and structured routines, while pharmacological options remain limited by modest efficacy and safety concerns.

DISCUSSION: Advancing knowledge of NPS and their association with cognitive decline is critical to establish more precise diagnostic criteria and to inform personalized therapeutic approaches. Future research should emphasize biomarker-driven diagnostics and the development of novel, targeted interventions that simultaneously address cognitive and neuropsychiatric domains to optimize outcomes for patients and caregivers. This study contributes to the field by reframing NPS as potential early biomarkers in the trajectory of MCI and dementia progression.},
}

@article {pmid41523281,
year = {2026},
author = {Jin, Z and Song, Y and Abdelmoaty, AAA and Lin, F and Li, J and Chen, X},
title = {Anti-Neuroinflammation Activity of Essential Oils and Fatty Acids.},
journal = {Food science & nutrition},
volume = {14},
number = {1},
pages = {e71422},
pmid = {41523281},
issn = {2048-7177},
abstract = {Neuroinflammation plays a pivotal role in the pathogenesis of neurodegenerative disorders, including Alzheimer's disease (AD) and Parkinson's disease (PD). Current pharmacological interventions, such as NSAIDs and corticosteroids, are limited by systemic toxicity and insufficient efficacy in targeting chronic neuroinflammatory processes. Emerging evidence highlights the therapeutic potential of plant-derived essential oils and fatty acids in modulating neuroinflammatory pathways through multi-target mechanisms. Essential oils enriched with terpenoids (e.g., carnosic acid, eugenol) attenuate microglial activation and cytokine production by suppressing NF-κB and MAPK signaling, while polyunsaturated fatty acids (PUFAs), particularly omega-3, enhance blood-brain barrier integrity and promote the resolution of oxidative stress via Nrf2-mediated antioxidant defenses. Preclinical studies demonstrate that these compounds reduce Aβ plaque burden, protect dopaminergic neurons, and ameliorate cognitive deficits in animal models of AD and PD. This review provides a comprehensive evaluation of the multifaceted roles of essential oils and fatty acids in combating neuroinflammation and their potential as therapeutic agents. Furthermore, this sets a foundation for further research into translating these natural products into clinical applications in modulating neuroinflammation and related disorders.},
}

@article {pmid41523267,
year = {2026},
author = {Sadybekov, AV and Duro, MV and Wang, S and Ebright, B and Dikeman, D and Hugo, C and Kerman, BE and Ma, QL and Nazarova, AL and Sadybekov, AA and Asante, I and Louie, SG and Katritch, V and Yassine, HN},
title = {Development of potent, selective cPLA2 inhibitors for targeting neuroinflammation in Alzheimer's disease and other neurodegenerative disorders.},
journal = {NPJ drug discovery},
volume = {3},
number = {1},
pages = {2},
pmid = {41523267},
issn = {3005-1452},
abstract = {Chronic neuroinflammation plays a key role in the progression of Alzheimer's disease (AD), and the cytosolic calcium-dependent phospholipase A2 (cPLA2) enzyme is a critical mediator of inflammatory lipid signaling pathways. Here we investigate the therapeutic potential of novel cPLA2 inhibitors in modulating neuroinflammation in AD. By leveraging the giga-scale V-SYNTHES2 virtual screening in on-demand chemical space and conducting two rounds of optimization for potency and selectivity, we have identified BRI-50460, achieving an IC50 of 0.88 nM in cellular assays that measure cPLA2-mediated arachidonic acid release. In vivo studies revealed favorable brain-to-plasma ratios, highlighting the ability of BRI-50460 to penetrate the central nervous system, modulating neuroinflammatory pathways, and restoring lipid homeostasis. In astrocytes and neurons derived from human induced pluripotent stem cells, BRI-50460 mitigates the effects of amyloid beta 42 oligomers on cPLA2 activation, tau hyperphosphorylation, and synaptic loss. Our results support that small molecule inhibitors of cPLA2 can modulate the downstream inflammatory signaling, offering a promising therapeutic strategy for neurodegenerative diseases.},
}

@article {pmid41523211,
year = {2026},
author = {Merenstein, JL and Song, AW and Johnson, KG and Whitson, HE and Madden, DJ},
title = {Higher spatial resolution diffusion-weighted imaging improves characterization of white matter disconnection in Alzheimer's disease.},
journal = {Imaging neuroscience (Cambridge, Mass.)},
volume = {4},
number = {},
pages = {},
pmid = {41523211},
issn = {2837-6056},
abstract = {In addition to the accumulation of neuropathologies (i.e., amyloid beta, neurofibrillary tangles), Alzheimer's disease (AD) is associated with the degradation of white matter (WM) structural pathways that connect distributed brain regions. However, previous studies of AD-related decreases in WM structural connectivity have primarily used standard spatial resolution diffusion-weighted imaging (DWI) acquisitions, which cannot adequately resolve WM connections in fine-grained regions with crossing fibers or high curvature. To better assess more subtle WM tissue degradation in AD, this DWI study compared measures of structural connectivity derived from a high-resolution multi-shot multiplexed sensitivity encoding (MUSE) acquisition (1 mm isotropic voxels; 1 µl volume) and a standard resolution acquisition (1.5 mm isotropic voxels; 3.375 µl volume), using a sample of 24 participants with AD and 24 demographically matched healthy controls. Graph theoretical measures of within-network connectivity, between-network connectivity, and system segregation were obtained from a standard network partition. As expected, results indicated larger AD-related decreases in between-network than within-network connectivity, leading to increased network segregation for both DWI acquisitions. However, the high-resolution MUSE DWI acquisition achieved higher sensitivity and specificity to AD-related differences in structural connectivity than the standard resolution DWI protocol, consistent with prior findings from rodents and healthy adults across the lifespan. Together, these findings suggest that this clinically feasible, high-resolution MUSE DWI methodology may detect more subtle AD-related differences in WM connectivity than standard resolution DWI acquisitions.},
}

@article {pmid41523195,
year = {2026},
author = {Um, YH and Wang, SM and Kang, DW and Kim, S and Kim, S and Kim, D and Choe, YS and Kim, REY and Lim, HK},
title = {Cerebellar subregional structural changes across the Alzheimer's disease continuum: a longitudinal analysis of cognitive and behavioural correlates.},
journal = {Brain communications},
volume = {8},
number = {1},
pages = {fcaf500},
pmid = {41523195},
issn = {2632-1297},
abstract = {Although traditionally viewed as relatively spared in Alzheimer's disease (Ad), the cerebellum is increasingly recognized for its contribution to cognitive and behavioural dysfunction. However, longitudinal data delineating subregional cerebellar involvement across the Ad continuum remain limited. In this study, we investigated longitudinal cerebellar atrophy and its clinical correlates in 259 older adults classified via amyloid PET into four biomarker-defined groups: cognitively normal controls, preclinical Ad, Ad-related mild cognitive impairment and Ad dementia. Structural MRI data were analysed using the Spatially Unbiased Infratentorial Template (SUIT), and longitudinal changes in 28 cerebellar subregions were assessed via generalized estimating equations, controlling for demographic and biological covariates. Across longitudinal analyses, cerebellar structural alterations in preclinical Ad were closely associated with both cognitive and behavioural measure changes. Reductions in lobule VI and Crus I/II were correlated with episodic memory decline, emphasizing the cerebellum's contributions to early cognitive deterioration. The same regions were involved in associations with apathy and behavioural dysregulation, suggesting the cerebellar contribution to emerging neuropsychiatric symptoms through disruption of motivational and executive circuits. In addition, stage-dependent cortico-cerebellar coupling was noted, with coordinated volume loss between cerebellar lobule VI and temporo-orbitofrontal cortices in the preclinical stage, but selective posterior cerebellar-posterior cingulate synchrony in dementia, indicating progressive network reorganization and eventual decoupling along the disease continuum. This study provides the first biomarker-defined longitudinal mapping of cerebellar subregional atrophy in Ad. The findings demonstrate that cerebellar degeneration is not confined to advanced stages but emerges early and dynamically interacts with cortical networks, influencing both cognitive decline and neuropsychiatric symptoms. The distinct atrophy patterns and cortico-cerebellar decoupling underscore the cerebellum's potential as a disease-stage-specific biomarker and therapeutic target in Ad.},
}

@article {pmid41523193,
year = {2026},
author = {Requena-Komuro, MC and Jiang, J and Benhamou, E and Sivasathiaseelan, H and Johnson, JCS and Chokesuwattanaskul, A and Nelson, A and Hardy, CJD and Warren, JD},
title = {Subjective time perception in dementia: a behavioural and neuroanatomical analysis.},
journal = {Brain communications},
volume = {8},
number = {1},
pages = {fcaf496},
pmid = {41523193},
issn = {2632-1297},
abstract = {Subjective time perception-the modulation of elapsed clock time by sensory, homeostatic and psychological factors-is fundamental to how we experience the world. People with Alzheimer's disease and frontotemporal dementia often exhibit clinically relevant symptoms of altered temporal awareness but these are poorly understood. Here we addressed this issue in a cross-sectional, case-control study of 60 patients representing all major Alzheimer (n = 24) and frontotemporal (n = 36) syndromes [mean age 68.8 (range 48-77 years); 28% female] and 24 cognitively well age-matched controls [age 69.4 (6.5) years; 50% female]. Subjective duration perception was assessed using an auditory temporal bisection paradigm, in which the task was to compare sound stimulus durations with learned (2 and 5 s) reference intervals. We varied sound emotional valence and semantic identity (behavioural salience) to create four stimulus conditions: pleasant environmental (running water), unpleasant environmental (machine noise), pleasant human (laughter) and unpleasant human (crying) sounds. Psychometric functions were constructed to assess sound duration estimation (bisection point) and sensitivity (Weber's ratio), and participant groups were compared using linear mixed regression models. Neuroanatomical associations of altered subjective time perception (sound duration estimation) were assessed using voxel-based morphometry of patients' brain MRI images. All participants perceived environmental sounds as lasting longer than human sounds, unpleasant environmental sounds as longer than pleasant environmental sounds and pleasant human sounds as longer than unpleasant human sounds (all P < 0.05). In dementia syndromes, the effect of sound semantic category was accentuated: patients with nonfluent variant primary progressive aphasia overestimated environmental sound duration, while patients with logopenic aphasia underestimated the duration of human sounds, relative to controls (P < 0.05). In addition, patients with typical Alzheimer's disease and behavioural variant frontotemporal dementia discriminated sound duration changes less sensitively than controls, while patients with semantic variant primary progressive aphasia discriminated sound duration more sensitively than other syndromic groups (P < 0.05). Neuroanatomical correlates of auditory duration perception were identified for different sound categories, in distributed cortical areas previously implicated in the pathogenesis of these diseases (all significant at P < 0.05, after correction for multiple voxel-wise comparisons in pre-specified regions of interest): precuneus (environmental sounds), supramarginal gyrus (pleasant human sounds) and insula (unpleasant human sounds). Our findings show that canonical dementia syndromes have clinical and neuroanatomical signatures of altered subjective time perception, linked to clinically relevant properties of sensory stimuli and the core pathophysiology of frontotemporal dementia and Alzheimer's disease. The findings suggest a novel paradigm for characterizing these diseases, with diagnostic and management implications.},
}

@article {pmid41523185,
year = {2026},
author = {Pérez-Millan, A and Falgàs, N and Bosch, B and Borrego-Écija, S and Antonell, A and Fernández-Villullas, G and Esteller-Gauxax, D and Tort-Merino, A and Bargalló, N and Balasa, M and Lladó, A and Aguillon, D and Chrem, P and Day, GS and Devenney, E and Huey, ED and Ikeuchi, T and Jucker, M and Kasuga, K and Vöglein, J and Roh, JH and Vitali, P and Sosa Ortiz, AL and Llibre-Guerra, JJ and Gordon, BA and McDade, E and Bateman, RJ and Sánchez-Valle, R and , },
title = {Cortical asymmetry in autosomal dominant Alzheimer's disease progression.},
journal = {Brain communications},
volume = {8},
number = {1},
pages = {fcaf488},
pmid = {41523185},
issn = {2632-1297},
abstract = {The cortical asymmetry index evaluates the cortical thickness asymmetry between hemispheres. We investigated cortical asymmetry index in asymptomatic and symptomatic mutation carriers of autosomal dominant Alzheimer's disease to explore the brain asymmetry within the Alzheimer's disease continuum. Sixty baseline T1-weighted MRI scans were obtained from the Clinic Barcelona cohort. Baseline and longitudinal MRI data from 564 participants within the dominantly inherited Alzheimer network observational study were used as an independent, confirmatory cohort. Cerebrospinal fluid and plasma neurofilament light chain levels were included when available. Cortical thickness was calculated using Freesurfer and cortical asymmetry index was calculated via an open-source pipeline. Cross-sectional analyses examined cortical asymmetry index differences based on clinical classification and APOE ε4 status, adjusting for age, sex and estimated years from onset, while correlations were assessed with age, estimated years from onset, mini-mental state examination scores, and neurofilament light. Longitudinal cortical asymmetry index evolution was modelled using generalized additive models in the dominantly inherited Alzheimer network observational study cohort, incorporating age, sex, and the interaction between group and estimated years from onset. The cortical asymmetry index successfully distinguished asymptomatic mutation carrier and symptomatic mutation carriers from healthy controls in the Clinic Barcelona cohort and symptomatic mutation carriers from controls in dominantly inherited Alzheimer network observational study. Higher cortical asymmetry index in mutation carriers (asymptomatic mutation carrier and symptomatic mutation carriers combined) and in symptomatic mutation carriers were associated with higher plasma neurofilament light levels, a closer proximity to symptom onset, and lower mini-mental state examination in the Clinic Barcelona cohort. In the dominantly inherited Alzheimer network observational study cohort, mutation carriers exhibited increased cortical asymmetry index compared to controls and correlated with elevated neurofilament light (plasma and Cerebrospinal fluid), lower mini-mental state examination, and a closer proximity to symptom onset. APOE3/3 carriers showed greater asymmetry than other APOE genotypes and significant cortical asymmetry index differences between asymptomatic mutation carrier and symptomatic mutation carriers. Longitudinally, cortical asymmetry index increased over time significantly in symptomatic mutation carriers. These findings underscore brain asymmetry as a potential biomarker for early Alzheimer's disease progression in autosomal dominant Alzheimer's disease, with implications for detection and monitoring tracking disease-related neuroanatomical changes.},
}

@article {pmid41523182,
year = {2026},
author = {Llorente-Saguer, I and Oxtoby, NP},
title = {Enhanced monitoring of Alzheimer's disease brain atrophy using composite value ratios of volumes.},
journal = {Brain communications},
volume = {8},
number = {1},
pages = {fcaf497},
pmid = {41523182},
issn = {2632-1297},
abstract = {Brain atrophy is a natural consequence of ageing but can be accelerated by neurodegenerative diseases such as Alzheimer's disease. We apply an existing algorithm to identify new biomarkers that better track volumetric changes over time, i.e. atrophy. These new biomarkers are the volumetric ratio of two composite regions of interest, identified by an algorithm optimized to enhance the monitoring of Alzheimer's disease progression. The algorithm prioritizes biomarkers with less noisy trajectories (quantified by lower sample size estimates for clinical trials) and that capture disease signal by showing a greater rate of change in amyloid-positive versus amyloid-negative individuals, ensuring the biomarker effectively reflects Alzheimer's pathology. Data from 1381 individuals from the Alzheimer's Disease Neuroimaging Initiative database having multiple MRI scans were analysed. The new biomarkers outperformed traditional volumetric measures (whole brain, hippocampus and ventricles) across all metrics. This improvement was particularly pronounced in cognitively impaired individuals, where atrophy is more severe. Among the traditional measures, ventricular volume had the best performance. Results suggest that ratios of regional brain volumes could enhance disease progression tracking, as has been shown in other modalities like fluid biomarker ratios and standardized uptake value ratios from positron emission tomography.},
}

@article {pmid41523152,
year = {2026},
author = {Safaeipour, C and Sherzai, D and Zikria, B},
title = {Exercise and Brain Health: Expert Review.},
journal = {American journal of lifestyle medicine},
volume = {},
number = {},
pages = {15598276251415530},
pmid = {41523152},
issn = {1559-8284},
abstract = {Preserving brain health is essential to maintaining quality of life and cognitive function with age. Exercise plays an essential role. Aerobic exercise such as running and cycling can enhance brain plasticity through increasing gray matter volume in the cerebellum and temporal lobe, as well as the density of connections in the brain's frontal and motor areas via upregulating brain-derived neurotrophic factor (BDNF) and serotonin systems. Anaerobic exercise, such as weightlifting, primarily increases gray matter volume in the basal ganglia and increases the density of connections in the posterior lobe of the cerebellum. In midlife, aerobic exercise can increase white matter integrity and cortical thickness in primary motor and somatosensory areas, while in older age it improves specific markers of cognitive function, such as episodic memory. With regards to neurodegenerative diseases, aerobic exercise has been linked to improved memory performance and reduced hippocampal atrophy in Alzheimer's disease. In Parkinson disease, aerobic exercise has shown to reduce brain atrophy, improve motor function and cognitive control, while anaerobic exercise improves motor performance and information processing. Overall, both aerobic and anaerobic exercises are integral and complementary to preserving brain health through effects on cognitive function and brain structure.},
}

@article {pmid41522705,
year = {2026},
author = {Mohanty, SK and Nayak, Y},
title = {Impact of Momordica charantia phytocompounds against ache associated with neurodegenerative diseases: in-silico approaches.},
journal = {In silico pharmacology},
volume = {14},
number = {1},
pages = {17},
pmid = {41522705},
issn = {2193-9616},
abstract = {The bioactive phyto-components of M. charantia L. demonstrate significant therapeutic potential against the acetylcholinesterase (AChE) enzyme, which is associated with neurodegenerative diseases such as Alzheimer's. In this study, computational tools were used to screen the essential bioactive compounds of M. charantia L. against AChE. Docking results revealed that among the 19 phytocompounds analysed, Ajmalacine, Alkaloid AQC2, Alkaloid SP-K, Steroid U, and Quinine exhibited high binding affinities towards AChE. Ligand-protein binding interactions indicated that these selected compounds showed excellent interaction with AChE, with binding scores ranging from - 11.0 to - 9.1 kcal/mol. Additionally, drug-likeness scores suggest that Quinine and Steroid U are suitable as drug-like molecules. The findings of the present study indicate that Quinine and Steroid U have potential as therapeutic agents in the development of anti-AChE drugs for neurodegenerative diseases such as Alzheimer's. Specifically targeting the acetylcholinesterase (AChE) enzyme, a key biomarker in Alzheimer's disease, the identification of Quinine and Steroid U as potential, drug-like AChE inhibitors suggest an unexplored therapeutic potential of M. charantia beyond its traditional medicinal uses. The work uniquely combines ligand-protein interaction analysis and drug-likeness profiling to propose new lead candidates for anti-AChE drug development. However, these findings are preliminary and based solely on molecular docking and ADMET predictions. Further validation through ligand-protein interactions analyses is warranted to confirm the stability and realistic binding affinity of these complexes in dynamic environments. The bioactive phyto-components of M. charantia L. demonstrate significant therapeutic potential against the acetylcholinesterase (AChE) enzyme, which is associated with neurodegenerative diseases such as Alzheimer's. In this study, computational tools were used to screen the essential bioactive compounds of M. charantia L. against AChE. Docking results revealed that among the 19 phytocompounds analysed, Ajmalacine, Alkaloid AQC2, Alkaloid SP-K, Steroid U, and quinine exhibited high binding affinities towards AChE. Ligand-protein binding interactions indicated that these selected compounds showed excellent interaction with AChE, with binding scores ranging from - 11.0 to - 9.1 kcal/mol. additionally, drug-likeness scores suggest that quinine and Steroid U are suitable as drug-like molecules. The findings of the present study indicates that quinine and Steroid U have potential as therapeutic agents in the development of anti-AChE drugs for neurodegenerative diseases such as Alzheimer's. However, the present findings are preliminary and based solely on docking and ADMET predictions; future studies involving molecular dynamics simulations and binding free-energy calculations are warranted to validate the stability and realistic binding affinity of these complexes.},
}

@article {pmid41522596,
year = {2025},
author = {Vishnumukkala, T and Chiroma, SM and Jagadeesan, S and Gopalakrishna, PK and Sura, S and Nor, NHM and Moklas, MAM},
title = {Hippocampal Beta-Amyloid Accumulation In Aluminium Chloride and D-Galactose-Induced Rats: Establishing a Nontransgenic Alzheimer's Model.},
journal = {Journal of pharmacy & bioallied sciences},
volume = {17},
number = {4},
pages = {217-219},
pmid = {41522596},
issn = {0976-4879},
abstract = {BACKGROUND: Alzheimer's disease (AD) is characterized by tau protein aggregation and beta-amyloid (Aβ) plaques leading to progressive cognitive decline. Nontransgenic models using aluminium chloride (AlCl3) and D-galactose (D-gal) have been established to mimic AD pathology, but beta-amyloid deposition in hippocampal regions remains underexplored.

OBJECTIVE: To investigate beta-amyloid accumulation in the hippocampal CA2 region using a nontransgenic rat model of AD made by combined AlCl3 and D-gal administration.

METHODS: Twelve adults male Wistar rats were divided into control (n = 6) and model groups (n = 6). The control group received normal saline orally and water intraperitoneally. The model group received D-gal (60 mg/kg b.w., i.p.) and AlCl3 (200 mg/kg b.w., oral) daily for 10 weeks. Beta-amyloid expression in hippocampal CA2 region was assessed using immunohistochemistry.

RESULTS: Immunohistochemical analysis revealed marked beta-amyloid immunoreactivity in the model group, with dense extracellular and intracellular deposits distributed throughout the CA2 subfield. The control group showed minimal beta-amyloid staining without plaques, confirming the specificity of the observed pathology.

CONCLUSION: Combined AlCl3 and D-gal administration successfully induced significant beta-amyloid accumulation in the hippocampal CA2 region, validating this nontransgenic model for investigating AD pathogenesis. This model provides a valuable platform for studying sporadic AD mechanisms and evaluating potential therapeutic interventions.},
}

@article {pmid41522468,
year = {2026},
author = {Kim, JS and Yi, D and Byun, MS and Ahn, H and Jung, G and Choi, H and Lee, JY and Kang, KM and Sohn, CH and Lee, YS and Kim, YK and Sohn, BK and Lee, DY},
title = {Plasma GFAP as a mediator and moderator of Aβ, tau, and neurodegeneration in Alzheimer's disease.},
journal = {NPJ dementia},
volume = {2},
number = {1},
pages = {3},
pmid = {41522468},
issn = {3005-1940},
abstract = {Astrogliosis is increasingly recognized as a critical component of Alzheimer's disease (AD) pathology, but its precise mechanistic contribution to the interplay among amyloid-β (Aβ), tau, and neurodegeneration remains unclear. Glial fibrillary acidic protein (GFAP), a widely used biomarker of astrocytic activation, shows strong associations with both Aβ and tau pathologies; however, its causal and modulatory involvement in disease progression has yet to be fully delineated. In this study, we investigated whether plasma GFAP functions as a mediator and/or moderator of the relationships linking Aβ deposition, tau accumulation, and neurodegenerative changes in AD. Ninety-two older adults from the KBASE cohort underwent multimodal imaging including Aβ-PET, tau-PET, FDG-PET, and MRI-based hippocampal volumetry, along with blood sampling for plasma GFAP assessment. Elevated plasma GFAP levels were associated with increased Aβ and tau burden, reduced cerebral glucose metabolism, and smaller hippocampal volume, as well as poorer cognitive performance. Mediation analyses demonstrated that GFAP significantly explained the relationships between Aβ and tau, and between tau and metabolic dysfunction. Moderation analyses further revealed that GFAP strengthened the Aβ-tau association, while mitigating tau-related metabolic decline. Overall, these results support a dual role of GFAP as both a conduit and regulator of disease progression.},
}

@article {pmid41522467,
year = {2026},
author = {Williams, DM and Heikkinen, S and Hiltunen, M and , and Davies, NM and Anderson, EL},
title = {The proportion of Alzheimer's disease attributable to apolipoprotein E.},
journal = {NPJ dementia},
volume = {2},
number = {1},
pages = {1},
pmid = {41522467},
issn = {3005-1940},
abstract = {Variation in the APOE gene strongly affects Alzheimer's disease (AD) risk. However, the proportion of AD burden attributable to this variation requires clarification, which would help to elucidate the scope of strategies targeting apolipoprotein E (APOE) for AD prevention and treatment. We estimated the extents to which clinically diagnosed AD, AD neuropathology and all-cause dementia are attributable to the common APOE alleles in four large studies. First, we used data on 171,105 and 289,150 participants aged ≥60 years from UK Biobank (UKB) and FinnGen, respectively. AD and all-cause dementia were ascertained from linked electronic health records in these cohorts. Second, we examined amyloid-β positivity from amyloid positron emission tomography scans of 4415 participants of the A4 Study. Third, we analysed data from the Alzheimer's Disease Genetics Consortium (ADGC), where neuropathologically confirmed AD cases were compared to pathology-negative, cognitively intact controls (N = 5007). In each analysis, we estimated outcome risk among carriers of APOE risk alleles ε3 and ε4, relative to individuals with an ε2/ε2 genotype, and calculated attributable fractions to show the proportions of the outcomes due to ε3 and ε4. For AD, fractions ranged from 71.5% (95% confidence interval: 54.9%, 81.7%) in FinnGen to 92.7% in the ADGC (82.4, 96.5%). In A4, 85.4% (17.5, 94.5%) of cerebral amyloidosis was attributable to ε3 and ε4. The proportions of all-cause dementia attributable to ε3 and ε4 in UKB and Fin-Gen were 44.4% (95% CI: 18.2%, 62.2%) and 45.6% (30.6%, 56.9%), respectively. Without strong underlying risks from APOE ε3 and ε4, almost all AD and half of all dementia would not occur. Intervening on APOE should be prioritised to facilitate dementia prevention.},
}

@article {pmid41522465,
year = {2026},
author = {Moon, HE and Lee, YS and Roh, S and Allick, C and Galvin, JE and Stone, ST},
title = {Self-efficacy as a mediator between dementia knowledge and screening intention among American Indian adults.},
journal = {Innovation in aging},
volume = {10},
number = {1},
pages = {igaf131},
pmid = {41522465},
issn = {2399-5300},
abstract = {BACKGROUND AND OBJECTIVES: While early detection of Alzheimer's disease and related dementias (ADRD) can help delay progression and improve outcomes, limited research is available on dementia-related health behavior, such as screening intention among American Indian/Alaska Native communities. Guided by the Theory of Reasoned Action, the Theory of Planned Behavior, and the Health Belief Model, this study examines whether self-efficacy mediates the association between dementia knowledge and intention to seek ADRD screening among American Indian adults.

RESEARCH DESIGN AND METHODS: Using a community-based participatory research approach, a cross-sectional survey was conducted with 248 American Indian adults (18 years and over) from a partner tribal community in the Northern Plains region in 2024. Measures included dementia knowledge, self-efficacy, screening intention, perceived susceptibility, stigma, and demographic factors. Mediation was tested using the Baron and Kenny framework and Sobel-Goodman tests.

RESULTS: Dementia knowledge significantly predicted both ADRD screening intention and self-efficacy. Self-efficacy also significantly predicted screening intention and partially mediated the relationship between knowledge and intention. Approximately 32% of the effect of dementia knowledge on screening intention was mediated by self-efficacy.

DISCUSSION AND IMPLICATIONS: Findings underscore self-efficacy as a critical mechanism through which dementia knowledge translates into ADRD screening intention in American Indian communities. Interventions to promote early ADRD detection could enhance both knowledge and individual confidence. Future research should include more diverse groups within American Indian communities to identify common and unique dynamics among knowledge, self-efficacy, and screening intention, informing effective intervention strategies to reduce stigma and confidence in seeking timely ADRD screening.},
}

@article {pmid41522370,
year = {2026},
author = {Foley, KE and Weekman, EM and Wilcock, DM},
title = {Acute anti-Aβ antibody exposure induces microglial changes and significantly alters chemokine signaling.},
journal = {Alzheimer's & dementia (New York, N. Y.)},
volume = {12},
number = {1},
pages = {e70201},
pmid = {41522370},
issn = {2352-8737},
abstract = {INTRODUCTION: While the anti-amyloid-lowering immunotherapies provide the first disease-targeting therapies for the treatment of Alzheimer's disease, there remain harmful adverse events causing hesitation among patients, families, physicians, and regulatory bodies. Though these drugs have been repeatedly proven to lower brain amyloid plaque burden, the specific cellular mechanisms and pathways by which the immunotherapy impacts the brain remain unclear.

METHODS: This study aimed to transcriptionally profile the brain's immediate immune response to anti-amyloid beta (anti-Aβ) antibodies. To evaluate acute cellular priorities, we intracranially injected anti-Aβ antibody (3D6) or an isotype-matched control immunoglobulin G (IgG) antibody and performed single-cell sequencing analysis after 3 days.

RESULTS: We found reduced numbers of a motile microglia cluster and homeostatic microglia in the 3D6 antibody-injected cortex compared to the IgG-injected cortex. It was also found that chemokine/cytokine signaling was enriched across homeostatic-proinflammatory microglia, interferon-responding microglia, and disease-associated microglia 2 (DAM2) following 3D6 antibody injection. We explored "CCL" signaling, which suggested a change in outgoing signaling coordinated by all microglia types targeting homeostatic microglia, surprisingly not targeting DAM1 or DAM2. We then analyzed enriched signaling pathways clustered by k-means river plots and identified pathways enriched and dampened with acute 3D6 treatment.

DISCUSSION: Together these data supply evidence for significant involvement of microglia in the anti-Aβ response in the brain after just 3 days. Most interestingly, there are changes in cytokine/chemokine signaling across microglia subtypes, specifically with communication in CCL pathways targeting homeostatic microglia and T cells. These acute signaling changes provide novel insights and generate unique hypotheses on the brain's immediate immune reaction to anti-Aβ antibody.

HIGHLIGHTS: Intracranially injected anti-amyloid beta (anti-Aβ) antibody promotes an immediate microglial response.3D6 exposure resulted in fewer homeostatic and motile microglia subtypes.Acute 3D6 enriches for chemokine/cytokine signaling pathways.},
}

@article {pmid41522369,
year = {2026},
author = {Bain, A and Tomeo, C and André, C and Garnier-Crussard, A and de Flores, R and Dautricourt, S},
title = {Locus coeruleus alterations in dementia with Lewy bodies: A systematic review.},
journal = {Alzheimer's & dementia (New York, N. Y.)},
volume = {12},
number = {1},
pages = {e70199},
pmid = {41522369},
issn = {2352-8737},
abstract = {INTRODUCTION: The locus coeruleus (LC) is a small nucleus located deep within the brainstem, serving as the brain's main source of noradrenergic neurons. Through its extensive projections, it plays a critical role in regulating cognitive processes and arousal. Although LC degeneration has been well documented in Alzheimer's disease and Parkinson's disease, its specific involvement in the pathophysiology of dementia with Lewy bodies (DLB) remains poorly understood.

METHODS: This systematic review, conducted in accordance with the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) guidelines, explores the role of LC in the pathogenesis of DLB by synthesizing findings from human neuropathological and neuroimaging research and animal models of α-synucleinopathy.

RESULTS: Although studies directly examining the LC in DLB remain limited, particularly in human living patients, available evidence points to early and severe LC alterations in DLB and suggests that LC dysfunction may contribute to key clinical symptoms such as impaired arousal and anxiety.

DISCUSSION: A better understanding of the mechanisms driving LC dysfunction and neurodegeneration in DLB could facilitate the development of novel biomarkers and, ultimately, symptomatic therapies.

HIGHLIGHTS: Locus coeruleus (LC) alterations are among the earliest changes in dementia with Lewy bodies (DLB).Accumulation of α-synuclein in the LC disrupts noradrenergic function.LC neurodegeneration may contribute to cognitive and neuropsychiatric symptoms.Neuromelanin-sensitive magnetic resonance imaging (NM-MRI) reveals LC signal loss from the prodromal stage of DLB.LC dysfunction emerges as a potential biomarker and therapeutic target in DLB.},
}

@article {pmid41522368,
year = {2026},
author = {Scheltens, P and Atri, A and Feldman, HH and Zetterberg, H and Sano, M and Johannsen, P and Colombo, TL and Bardtrum, L and Jeppesen, R and Hansen, CT and Cummings, JL},
title = {Baseline characteristics from evoke and evoke+: Two phase 3 randomized placebo-controlled trials of semaglutide in participants with early-stage symptomatic Alzheimer's disease.},
journal = {Alzheimer's & dementia (New York, N. Y.)},
volume = {12},
number = {1},
pages = {e70200},
pmid = {41522368},
issn = {2352-8737},
abstract = {INTRODUCTION: The glucagon-like peptide-1 receptor agonist semaglutide may impact neuroinflammation and reduce neurodegeneration. We present baseline characteristics of participants enrolled in the evoke (NCT04777396) and evoke+ (NCT04777409) trials, referred to as "evoke (+)" hereafter.

METHODS: Evoke (+) are two ongoing global, multicenter, randomized, double-blind, parallel-group, placebo-controlled phase 3 trials investigating semaglutide in participants with early-stage symptomatic Alzheimer's disease (AD) with confirmed amyloid positivity (by positron emission tomography or cerebrospinal fluid testing). Inclusion criteria are the same for both trials, except that by design, evoke+ also includes participants with significant small vessel pathology. Both trials include a 12-week screening phase before randomization (1:1) to receive oral semaglutide titrated to 14 mg or placebo for 156 weeks. Baseline data were summarized and analyzed descriptively. Additionally, data were pooled and assessed by five main geographical regions.

RESULTS: Evoke (+) recruited 9996 participants from 566 sites in 40 countries. The mean (standard deviation) age of participants was 71.8 (7.1) and 72.6 (7.1) years in evoke and evoke+, respectively; more participants were female than male (female: 53.0% and 51.9%, respectively) and most had a Clinical Dementia Rating (CDR) global score of 0.5 (72.8% and 71.4%; CDR global score of 1: 26.5% and 27.6%). Both trial populations had similar demographics, and clinical and cognitive baseline characteristics, except that 2.8% of participants in evoke+ had magnetic resonance imaging-documented significant small vessel pathology as per protocol inclusion criteria. Regional-level data demonstrated some differences in AD treatment characteristics, including cholinesterase inhibitor use of 41.7% in North America versus 61.6% in Asia.

DISCUSSION: Evoke (+) are the only large-scale, phase 3 trials investigating the longer-term efficacy and safety of semaglutide in early AD as a potential disease-modifying treatment. The baseline characteristics from evoke (+) reflect a varied, global population with early-stage symptomatic AD. Primary readouts are expected in the second half of 2025.

HIGHLIGHTS: evoke and evoke+ are the only large-scale randomized controlled trials (RCTs) investigating the longer-term efficacy and safety of semaglutide in early AD.Baseline characteristics reflect a varied, global population.The trials' primary readouts are expected in the second half of 2025.},
}

@article {pmid41522285,
year = {2026},
author = {Liu, Z and Soria, D and Lai, DJ and Zhang, J and Shergill, S and Ang, CS},
title = {The use of fully immersive virtual reality for screening neurodegenerative diseases: A systematic review of behavioral and diagnostic outcomes.},
journal = {Alzheimer's & dementia (Amsterdam, Netherlands)},
volume = {18},
number = {1},
pages = {e70244},
pmid = {41522285},
issn = {2352-8729},
abstract = {UNLABELLED: Early detection of Alzheimer's disease (AD), Parkinson's disease (PD), and mild cognitive impairment (MCI) is crucial for timely intervention. Traditional cognitive screening tools lack ecological validity and sensitivity. Virtual reality (VR) provides realistic, controlled environments for assessing multidimensional cognition. This systematic review evaluated the diagnostic accuracy, feasibility, and applicability of immersive VR assessments for neurodegenerative screening. We searched PubMed, PsycINFO, and Embase for studies published June 2005 to April 2024. Eligible studies used head-mounted displays in adults with MCI, early AD/PD, or dementia. Ten studies (n = 472) met criteria. Tasks targeted spatial memory, executive function, attention, and navigation. Several reported strong discriminations (area under the curve up to 0.89) and, when combined with machine learning, accuracies of 87% to 100%. Immersive VR shows promise as an ecologically valid, engaging, and scalable screening approach; however, standardization of tasks and outcomes, real-world validation, and robust longitudinal evidence are needed to support clinical adoption.

HIGHLIGHTS: This review systematically describes the application of fully immersive virtual reality (VR) in the early screening of neurodegenerative diseases, with a focus on studies using head-mounted devices to simulate real-life tasks.Task types such as spatial memory, daily living simulations, and executive function assessments have demonstrated high sensitivity and specificity in diagnosing mild cognitive impairment (MCI) and early-stage Alzheimer's disease (AD).Approximately one third of studies combined machine learning techniques to analyze multimodal behavioral data (e.g., path deviations, task duration, and language responses), significantly improving diagnostic accuracy.This study highlights methodological heterogeneity, small sample sizes, and the lack of longitudinal studies as current research limitations, and calls for future standardized, multicenter, and long-term follow-up studies to validate the predictive validity and real-world applicability of VR tools.},
}

@article {pmid41522283,
year = {2026},
author = {Cook Maher, A and Rose, S and DuBois, KN and Kanaan, NM and Koeppe, R and Bross, J and Flynn, E and Murphey, YL and Persad, CC and Giordani, B},
title = {Motor, not cognitive, performance relates to amyloid status in normal older adults.},
journal = {Alzheimer's & dementia (Amsterdam, Netherlands)},
volume = {18},
number = {1},
pages = {e70237},
pmid = {41522283},
issn = {2352-8729},
abstract = {INTRODUCTION: The National Insitutes of Health Toolbox (NIHTB) measures may be useful for Alzheimer's disease (AD) risk detection. This study investigates whether cognitively normal older adults with and without elevated brain amyloid, an early AD biomarker, differed on NIHTB cognitive and motor subtests and whether inclusion of pTau-217 enhanced this differentiation. Motor measures were of interest based on past research reporting linkages to early AD pathology.

METHODS: Data from 112 consensus-diagnosed cognitively normal older adults who completed amyloid-PET imaging, blood draw for pTau217 analysis, and NIHTB Cognition and Motor batteries were analyzed using linear regression.

RESULTS: Amyloid positivity significantly predicted performance on only NIHTB Standing Balance (F(2,86) = 9.90, p < 0.001). Inclusion of pTau217 enhanced prediction of Standing Balance (F(4,84) = 5.88, p < 0.001) and Walking Endurance (F(4,88) = 9.70, p < 0.001) and Dominant-hand Grip Strength (F(2,92) = 51.59, p < 0.001).

DISCUSSION: For AD-related detection research, findings support inclusion of NIHTB motor measures, which may prove more sensitive early in the disease course before overt cognitive change.

HIGHLIGHTS: The National Institutes of Health ToolBox motor performance may signal early Alzheimer's disease (AD) risk, even before memory change.Balance performance may be sensitive to early cumulative AD-neuropathology loading.Motor measures should be included in early AD-risk detection batteries.},
}

@article {pmid41522259,
year = {2026},
author = {Wen, Z and Biros, G},
title = {LNODE: Uncovering the Latent Dynamics of A β in Alzheimer's Disease.},
journal = {Medical image computing and computer-assisted intervention : MICCAI ... International Conference on Medical Image Computing and Computer-Assisted Intervention},
volume = {15974},
number = {},
pages = {313-322},
pmid = {41522259},
abstract = {A β Positron Emission Tomography (PET) is often used to manage Alzheimer's disease (AD). To better understand A β progression, we introduce and evaluate a mathematical model that couples A β at parcellated gray matter regions. We term this model LNODE for "latent network ordinary differential equations". At each region, we track normal A β , abnormal A β , and m latent states that intend to capture unobservable mechanisms coupled to A β progression. LNODE is parameterized by subject-specific parameters and cohort parameters. We jointly invert for these parameters by fitting the model to A β -PET data from 585 subjects from the ADNI dataset. Although underparameterized, our model achieves population R 2 ≥ 98 % compared to R 2 ≤ 60 % when fitting without latent states. Furthermore, these preliminary results suggest the existence of different subtypes of A β progression.},
}

@article {pmid41522078,
year = {2026},
author = {Wang, K and Shao, B and Ye, LF and Wen, JZ and Chen, Y and Fang, C and Luo, X},
title = {Effects of acupuncture on brain functional networks in patients with mild cognitive impairment and Alzheimer's disease: a systematic review and activation likelihood estimation meta-analysis of neuroimaging studies.},
journal = {Quantitative imaging in medicine and surgery},
volume = {16},
number = {1},
pages = {29},
pmid = {41522078},
issn = {2223-4292},
abstract = {BACKGROUND: The increasing prevalence of Alzheimer's disease (AD) and mild cognitive impairment (MCI) presents a significant societal and familial burden. Acupuncture has shown promise in modulating brain function; however, systematic evidence on its effects on brain functional networks in individuals with AD and MCI remains limited. This study aimed to quantitatively synthesize neuroimaging findings using activation likelihood estimation (ALE) meta-analyses.

METHODS: We systematically searched PubMed, PsycINFO, Google Scholar, SinoMed, and China National Knowledge Infrastructure (CNKI) for neuroimaging studies on acupuncture in AD and MCI. Activation coordinates were analyzed using GingerALE software. Separate ALE meta-analyses were conducted for AD and MCI with family-wise error (FWE) correction (P<0.05) and a cluster-forming threshold of P<0.001 (5,000 permutations), achieving >80% post hoc power. Contrast analyses used P<0.01, a minimum cluster size of 200 mm[3] (10,000 permutations), and 95% confidence intervals from permutation distributions.

RESULTS: Thirteen studies (702 participants: 105 with AD, 312 with MCI, and 285 controls) with 303 activation foci (153 increased and 150 decreased) were included in the analysis. In patients with AD, acupuncture enhanced activation in the right superior frontal gyrus (BA10), left cerebellar regions, and right inferior occipital gyrus (BA19), while reducing activation in the right middle frontal gyrus (BA6). In an individual with MCI, increased activation was found in the right superior and middle temporal gyri (BA38 and BA21), parahippocampal gyrus (BA28), bilateral posterior cerebellar lobes, and left superior parietal lobe (BA7), which was accompanied by decreased activity in the right superior frontal gyrus (BA6) and cerebellar regions. Combined analyses revealed convergent activation in the bilateral cerebellar tonsils, parahippocampal gyrus, right middle temporal gyrus, left superior parietal lobe, and right superior frontal gyrus, indicating shared modulatory effects across both disorders.

CONCLUSIONS: Acupuncture consistently activates the frontal, temporal, parietal, and cerebellar regions linked to cognitive and sensorimotor functions. Stronger effects in individuals with MCI suggest greater neuroplastic responsiveness. These findings provide quantitative evidence supporting acupuncture as a potential adjunctive therapy for cognitive impairment in neurodegenerative diseases.},
}

@article {pmid41522038,
year = {2026},
author = {Li, J and Xu, L and Liu, F and Wang, J and Shao, X and Lin, J and Chen, C and Zeng, M and Cheng, X and Liu, S},
title = {Deep medullar veins: predictors of clinical progression in Alzheimer's disease.},
journal = {Quantitative imaging in medicine and surgery},
volume = {16},
number = {1},
pages = {27},
pmid = {41522038},
issn = {2223-4292},
abstract = {BACKGROUND: Early detection of Alzheimer's disease (AD) remains challenging due to limited biomarkers. This retrospective longitudinal study evaluated whether alterations in the deep medullary veins (DMVs) predict cognitive decline.

METHODS: We analyzed 170 participants from the Open Access Series of Imaging Studies-3 (OASIS-3) database [95 cognitive normal (CN), 36 mild cognitive impairment (MCI), and 39 AD]. DMVs were scored on susceptibility-weighted imaging (SWI). Cox proportional hazard models assessed the association between DMVs and longitudinal cognitive decline. Mediation analysis tested whether amyloid-β (Aβ) partially mediates the effect of DMVs on cognition.

RESULTS: DMVs scores increased across groups {7 [6, 8] in CN, 13 [8.25, 15] in MCI, and 14 [13, 15] in AD; P<0.001}.
DMVs score correlated with age (r=0.371, P<0.001), Mini-Mental State Examination (MMSE) (r=-0.494, P<0.001), cortical volume (r=-0.371, P<0.001), and Aβ burden (r=0.498, P<0.001). A higher DMVs score was associated with an increased risk of cognitive progression in AD [hazard ratio (HR) =1.13, 95% confidence interval (CI): 1.02-1.24, P=0.014], demonstrating good classification performance [area under the curve (AUC) =0.800, P<0.001]. Mediation analysis showed Aβ burden partially mediated the DMVs effect on MMSE (indirect effect β=-0.154, 95% CI: -0.337 to -0.017).

CONCLUSIONS: DMVs alterations increase with AD severity, correlate with Aβ deposition, and predict cognitive decline, suggesting DMVs score as a promising imaging biomarker for early identification of individuals at risk of AD progression.},
}

@article {pmid41521688,
year = {2026},
author = {Wang, X and Zhang, Q and Zhang, X and Liu, J and Zhang, J and Liu, C and Cui, Y and Song, Q and Hou, Y and Wang, Y and Cao, M and Wang, P},
title = {Synaptic Vesicle Glycoprotein 2A Suppresses Amyloidogenesis Beyond Its Synaptic Role: A Novel Mechanism Disrupting BACE1 Binding and Altering APP Localization.},
journal = {Aging cell},
volume = {25},
number = {2},
pages = {e70379},
doi = {10.1111/acel.70379},
pmid = {41521688},
issn = {1474-9726},
support = {82030064//State Key Program of the National Natural Science Foundation of China/ ; 81871714//National Natural Science Foundation of China/ ; L246009//Beijing Natural Science Foundation/ ; HZ2021PYLJ023//HUIZHI Talent Leadership Development Program of Xuanwu Hospital/ ; },
mesh = {Animals ; *Amyloid Precursor Protein Secretases/metabolism ; Mice ; *Membrane Glycoproteins/metabolism/genetics ; *Aspartic Acid Endopeptidases/metabolism ; *Amyloid beta-Protein Precursor/metabolism ; Humans ; *Nerve Tissue Proteins/metabolism/genetics ; Protein Binding ; *Synapses/metabolism ; Alzheimer Disease/metabolism/pathology/genetics ; Mice, Transgenic ; },
abstract = {Synaptic vesicle glycoprotein 2A (SV2A), a transmembrane protein widely localized to synaptic vesicles, serves as a key indicator of synaptic loss in Alzheimer's disease (AD). In this study, adeno-associated virus (AAV) was injected by brain stereotactic injection technique to construct SV2A-overexpressing APP/PS1 mice, then the effects of SV2A on amyloid precursor protein (APP) degradation and its molecular mechanism were further explored in vivo or in vitro. Our results demonstrated that SV2A overexpression significantly reduced Aβ plaque deposition in brain tissue of APP/PS1 mice. Mechanistically, SV2A was identified as a novel APP-binding protein that attenuated the amyloidogenic processing of APP by inhibiting its interaction with β-site APP cleaving enzyme 1 (BACE1). Furthermore, SV2A overexpression altered the subcellular distribution of APP, shifting its localization away from the endosomal-lysosomal compartments. Collectively, our findings unveil SV2A as a critical regulator of APP metabolism and propose it as a promising therapeutic target for intervening in the early pathological progression of AD.},
}

Animals
*Amyloid Precursor Protein Secretases/metabolism
Mice
*Membrane Glycoproteins/metabolism/genetics
*Aspartic Acid Endopeptidases/metabolism
*Amyloid beta-Protein Precursor/metabolism
Humans
*Nerve Tissue Proteins/metabolism/genetics
Protein Binding
*Synapses/metabolism
Alzheimer Disease/metabolism/pathology/genetics
Mice, Transgenic

@article {pmid41521630,
year = {2026},
author = {K, A and B, SK and Reddy, SG and Kugabalasooriar, S},
title = {Innovations in Nanobot and Microbot Propulsion for Targeted CNS Drug Delivery Across the Blood-Brain Barrier.},
journal = {Critical reviews in analytical chemistry},
volume = {},
number = {},
pages = {1-30},
doi = {10.1080/10408347.2025.2612631},
pmid = {41521630},
issn = {1547-6510},
abstract = {The transport of therapeutic molecules to the brain is one of the largest challenges of contemporary medicine because of the restrictive nature of the blood-brain barrier (BBB), which blocks the penetration of almost all biological therapeutics and most small-molecule drugs. This is a major limitation to the treatment of such neurological diseases as Parkinson's disease (PD), glioblastoma, and Alzheimer's disease. To beat these obstacles, there must be advanced delivery systems that can be precise, be released under control, and move without being invasive. Over the past decade, there have been innovations in micro and nanorobotic technologies, which provide a groundbreaking model that incorporates innovations in materials science, analytical chemistry, and biomedical engineering. Such engineered nanorobots are magnetically controlled, polymeric, or biologically derived nanorobots, which can be magnetically, acoustically, optically, or chemically controlled, and can cross the BBB with greater specificity. It has also been possible to follow the behavior of nanorobots at a direct visualization level in biological systems due to the development of analytical tools, especially imaging, real-time monitoring, and in situ sensing, which allows the behavior of nanorobots to be evaluated rigorously in terms of motions, shape transformation, and drug release profiles. The present review gives a detailed description of the propulsion-based nanorobotic drug delivery systems to the central nervous system (CNS), including structural components, modes of actuation, and protocols of analysis. The review explains that the combined effects of physicochemical features, external stimuli, and interactions between biointerfaces influence permeability via the BBB and accuracy of therapeutic response.},
}

@article {pmid41521425,
year = {2026},
author = {Batarseh, N and Abdulla, FA},
title = {Mediterranean-DASH Intervention for Neurodegenerative Delay (MIND) diet and brain health: a systematic review.},
journal = {Nutritional neuroscience},
volume = {},
number = {},
pages = {1-26},
doi = {10.1080/1028415X.2025.2610643},
pmid = {41521425},
issn = {1476-8305},
abstract = {INTRODUCTION: By 2050, the global population aged 60+ is expected to reach two billion. As the population ages, the prevalence of neurodegenerative disorders will increase, while depression and anxiety will continue to be major causes of disability. A diet rich in antioxidants can positively impact cognitive function and protect against psychological disorders.

OBJECTIVE: to summarize the evidence of the impact of the MIND diet in reducing risks or slowing neurodegenerative and psychological diseases.

METHODOLOGY: The data were collected by searching electronic databases, including PubMed and Science Direct, until September 2023. The search terms included 'Alzheimer's, Anxiety, Brain Health, Cognitive Decline, Dementia, Depression, Parkinson's, MIND diet, and psychological disorders.' Peer-reviewed studies conducted on individuals aged 18 or older were included. 135 papers were identified and reviewed. 26 full-text, relevant original articles were included.

RESULTS: The study analyzed a sample of 37 to 16,058 participants, ages 20-97. Among the identified studies, 6 RCTs, 11 cross-sectional studies, and 9 longitudinal studies were analyzed. The results indicate that adherence to the MIND diet slows cognitive decline and positively influences cognitive function and verbal memory in later life, reducing the risk of developing Parkinsonism, non-motor symptoms, depressive symptoms, and lowering stress levels.

CONCLUSION: Our systematic review implies that the MIND diet can enhance cognitive health and is highly beneficial for mitigating risks of dementia, physiological diseases, anxiety, and depression due to its superior antioxidant and anti-inflammatory activities. However, further research is required to evaluate its long-term effects on health.},
}

@article {pmid41521149,
year = {2026},
author = {Russell, JK and Schlachetzki, Z and Conley, AC and Boyd, BD and Newhouse, PA and Aisen, PS and Rafii, MS and , },
title = {Relationship of cholinergic basal forebrain atrophy with the time course of Alzheimer's disease pathology and cognitive decline in adults with Down syndrome: a longitudinal cohort study.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {1},
pages = {e71028},
pmid = {41521149},
issn = {1552-5279},
support = {U01AG051406/AG/NIA NIH HHS/United States ; U01AG051412/AG/NIA NIH HHS/United States ; U19AG068054/AG/NIA NIH HHS/United States ; //National Institute for Child Health and Human Development/ ; //Investigation of Co-occurring conditions across the Lifespan to Understand Down syndrome/ ; P50 AG008702/AG/NIA NIH HHS/United States ; P30 AG062421/AG/NIA NIH HHS/United States ; P50 AG016573/AG/NIA NIH HHS/United States ; P50 AG005133/AG/NIA NIH HHS/United States ; P50 AG005681/AG/NIA NIH HHS/United States ; P30 AG062715/AG/NIA NIH HHS/United States ; P30 AG066519/AG/NIA NIH HHS/United States ; P30 AG066468/AG/NIA NIH HHS/United States ; P30 AG072973/AG/NIA NIH HHS/United States ; P50 HD105353/HD/NICHD NIH HHS/United States ; UL1 TR001873/TR/NCATS NIH HHS/United States ; UL1 TR002373/TR/NCATS NIH HHS/United States ; UL1 TR001414/TR/NCATS NIH HHS/United States ; UL1 TR001857/TR/NCATS NIH HHS/United States ; UL1 TR002345/TR/NCATS NIH HHS/United States ; UL1 TR002366/TR/NCATS NIH HHS/United States ; U24 AG21886//National Centralized Repository for Alzheimer Disease and Related Dementias/ ; //NIHR Cambridge Biomedical Research Centre/ ; //Windsor Research Unit, CPFT, Fulbourn Hospital Cambridge/ ; },
mesh = {Humans ; *Down Syndrome/pathology/diagnostic imaging/complications ; Male ; Female ; *Basal Forebrain/pathology/diagnostic imaging/metabolism ; Atrophy/pathology ; *Alzheimer Disease/pathology/diagnostic imaging/complications ; Longitudinal Studies ; Adult ; Positron-Emission Tomography ; Hippocampus/pathology/diagnostic imaging ; Middle Aged ; *Cognitive Dysfunction/diagnostic imaging/pathology ; tau Proteins/metabolism ; Neuropsychological Tests ; Disease Progression ; },
abstract = {INTRODUCTION: Adults with Down syndrome (DS) display increased Alzheimer's disease (AD) risk. The cholinergic system declines early in the AD continuum and relates to cognitive and functional decline. We aimed to identify the timeline of cholinergic decline in relation to hippocampal atrophy within the AT(N) framework in DS.

METHODS: Three-hundred fifty-eight adults with DS were assessed for longitudinal changes in cholinergic basal forebrain and hippocampal volume, amyloid positron emission tomography (PET), tau PET, and cognitive performance.

RESULTS: Amyloid PET increased at 36.5 years old, while tau accumulation, cholinergic basal forebrain (ChBF), and hippocampal volumetric changes occurred in the participants' 40s. Cognitive decline on the modified cued recall test initiated at 41.7 years old. ChBF and hippocampal volumes negatively associated with AD pathology and positively associated with cognitive performance, with ChBF effects moderated by hippocampal volume.

DISCUSSION: The timeline presented will inform the design of clinical trials targeting the cholinergic system or utilizing volumetric measures as biomarkers of efficacy or cognition.

HIGHLIGHTS: The first longitudinal assessment of cholinergic basal forebrain and hippocampal volume in DSAD. The AT(N) framework utilized sporadic AD is consistent in DSAD. Cholinergic basal forebrain volume is an alternate measure of neurodegeneration in the AT(N) framework. Cholinergic effects on total recall on the mCRT are moderated by the hippocampus.},
}

Humans
*Down Syndrome/pathology/diagnostic imaging/complications
Male
Female
*Basal Forebrain/pathology/diagnostic imaging/metabolism
Atrophy/pathology
*Alzheimer Disease/pathology/diagnostic imaging/complications
Longitudinal Studies
Adult
Positron-Emission Tomography
Hippocampus/pathology/diagnostic imaging
Middle Aged
*Cognitive Dysfunction/diagnostic imaging/pathology
tau Proteins/metabolism
Neuropsychological Tests
Disease Progression

@article {pmid41521126,
year = {2026},
author = {Sankhe, K and Ruthirakuhan, M and Andreazza, AC and Brawman-Mintzer, O and Craft, S and Herrmann, N and Ismail, Z and Lerner, AJ and Levey, AI and Mintzer, J and Padala, PR and Perin, J and Porsteinsson, AP and Rosenberg, PB and Shade, D and Tumati, S and van Dyck, CH and Lanctôt, KL},
title = {Peripheral biomarkers associated with apathy and predicting response to methylphenidate: Secondary analysis of the Apathy in Dementia Methylphenidate Trial 2 (ADMET2) study.},
journal = {International psychogeriatrics},
volume = {},
number = {},
pages = {100181},
doi = {10.1016/j.inpsyc.2025.100181},
pmid = {41521126},
issn = {1741-203X},
abstract = {BACKGROUND: In Apathy in Dementia Methylphenidate Trial 2 (ADMET2), apathy in Alzheimer's disease improved with methylphenidate (MPH) in a randomized, placebo-controlled trial, though response varied. Here we evaluated serum biomarkers for their association with apathy and with treatment response.

METHODS: All ADMET2 participants with available blood samples were included. Markers of inflammation [interleukin (IL)-6, IL-10, Tumor Necrosis Factor (TNF)], oxidative stress [lipid hydroperoxide (LPH), 4-hydroxynonenal (4-HNE), 8-isoprostane (8-ISO)] and neuronal injury [neurofilament light (NfL), S100B] were assessed and values log-transformed. Neuropsychiatric Inventory-apathy (NPI-A) measured apathy. Least Absolute Shrinkage and Selection Operator (LASSO) regression was performed for feature selection of baseline markers predicting NPI-A at Month-6 (M6). Univariate analyses examined individual biomarker effects and multivariable models evaluated their combined effects. Treatment interactions, baseline and change in biomarker levels in treatment responders (≥4 change in NPI-A) and remitters (M6 NPI-A=0) were explored.

RESULTS: In the ADMET2 biomarker subset (n = 44, MPH:21, age:75 years, MMSE:20.2), higher baseline TNF was associated with higher M6 NPI-A [B(SE)= 6.86 (1.71), p = .0003], and multivariable models found lower baseline TNF [B(SE)= 8.28(1.61), p < .001] and higher baseline S100B [B(SE)= -6.41(1.95), p = .002] were associated with lower M6 NPI-A. Exploratory analyses suggested that higher baseline NfL significantly interacted with treatment to predict lower M6 NPI-A [B(SE)= -8.36(4.21), p = .05], only when adjusting for cognition. MPH remitters had lower baseline TNF [B(SE)= -0.27(0.10), p = .02], higher baseline NfL [B(SE)= 0.33(0.14), p = .03], and a greater decrease in IL-6 [B(SE)= -0.44 (0.17), p = .02].

CONCLUSIONS: Inflammatory and neuronal injury biomarkers may have prognostic value and may potentially inform treatment response and remission outcomes in apathy. Apathy in Dementia Methylphenidate Trial 2 (ADMET2), NCT02346201, https://clinicaltrials.gov/study/NCT02346201.},
}

@article {pmid41521074,
year = {2026},
author = {Ham, HJ and Lee, JA},
title = {Stress Granules as a Central Hub Linking Organelle Stress, Aging, and Neurodegeneration.},
journal = {BMB reports},
volume = {},
number = {},
pages = {},
pmid = {41521074},
issn = {1976-670X},
abstract = {Stress granules (SGs) are dynamic cytoplasmic assemblies composed of RNAs and proteins that form in response to cellular stress, serving to halt translation and protect cellular integrity. In neurons, SGs mediate adaptive, pro-survival responses to acute stress; however, their dysregulation has been increasingly associated with both aging and neurodegenerative diseases. Aging neurons frequently exhibit changes in SG dynamics - with an increased propensity to form SGs while displaying reduced efficiency in their clearance - resulting in persistent granules that can facilitate the accumulation of pathological protein aggregates (e.g., TDP-43 or tau). Aberrant SG formation and defective clearance mechanisms are implicated in the pathogenesis of key neurodegenerative disorders, including amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), Alzheimer's disease (AD), and Parkinson's disease (PD). Recent findings have shown that SGs interface with organelles such as lysosomes, mitochondria, and the endoplasmic reticulum, utilizing autophagic and other protein quality-control mechanisms for clearance. As these clearance pathways progressively decline with age, SGs can transition from promoting cellular adaptation to contributing to cellular dysfunction. In this mini-review, we examine how aging influences SG biology, detail the role of SGs in neurodegenerative diseases, and discuss emerging mechanistic insights and therapeutic strategies aimed at modulating SG dynamics in the context of brain aging.},
}

@article {pmid41521046,
year = {2026},
author = {Desforges, S},
title = {[Supporting neurodegenerative disorders at home: The role and challenges of the gerontology care assistant].},
journal = {Soins; la revue de reference infirmiere},
volume = {71},
number = {902},
pages = {40-44},
doi = {10.1016/j.soin.2025.11.009},
pmid = {41521046},
issn = {0038-0814},
mesh = {Humans ; *Neurodegenerative Diseases/nursing/therapy ; *Home Care Services/organization & administration ; Aged ; },
abstract = {Aging often leads to a decline in cognitive abilities and independence, making it difficult to remain at home and increasing isolation. Gerontology care assistants, trained and integrated into specialized Alzheimer's teams, offer personalized support combining cognitive stimulation, relational support, and motor assistance. This multidisciplinary approach ensures coordinated care, preventing loss of independence and improving the quality of life for patients and their loved ones.},
}

Humans
*Neurodegenerative Diseases/nursing/therapy
*Home Care Services/organization & administration
Aged

@article {pmid41520885,
year = {2026},
author = {Moon, S and Kwon, H and Cho, E and Lee, S and Park, SJ and Moon, M and Ryu, JH and Jang, DS and Bae, HJ and Kim, DH},
title = {Swertisin improves Alzheimer's disease-like pathology in 5XFAD male mice through regulation in plasmin activity.},
journal = {Neurochemistry international},
volume = {},
number = {},
pages = {106118},
doi = {10.1016/j.neuint.2026.106118},
pmid = {41520885},
issn = {1872-9754},
abstract = {Abnormal accumulation of amyloid β (Aβ), which may result from excessive production or impaired clearance, is one of the pathomechanisms of Alzheimer's disease (AD). Plasmin is one of the important proteases involved in the Aβ clearance system. In this study, we investigated whether swertisin can regulate plasmin activity and reduce Aβ pathology. First, we examined whether swertisin regulated plasmin activity, mature brain-derived neurotrophic factor (mBDNF) levels, and plasminogen activator inhibitor-1 (PAI-1) activity in vitro. Next, we assessed the effect of swertisin on memory impairments in an Aβ-injected AD-like mouse model and in 5XFAD mice. To evaluate the involvement of plasmin in the effect of swertisin in the Aβ-injected AD-like mouse model, we used 6-aminocaproic acid (6-AA), a plasmin inhibitor. Additionally, we measured plasmin activity and mBDNF levels in the hippocampus of Aβ-injected AD-like mice and 5XFAD mice. Swertisin increased plasmin activity and mBDNF levels in hippocampal slices from both normal and 5XFAD mice. Moreover, swertisin ameliorated Aβ-induced synaptic long-term potentiation (LTP) deficits in hippocampal slices. Swertisin also mitigated memory impairments induced by ventricular injection of Aβ, and this effect was blocked by 6-AA. Furthermore, swertisin improved learning and memory in 5XFAD mice while reducing Aβ deposition and neuroinflammation. This study demonstrates that swertisin ameliorates AD-like pathology by regulating plasmin activity. Plasmin activated by swertisin may cleave Aβ aggregates and increase mBDNF levels, thereby protecting the brain from Aβ toxicity. Swertisin may represent an effective therapeutic strategy for AD patients.},
}

@article {pmid41520868,
year = {2026},
author = {Bajinka, O and Jallow, L and Ozdemir, G},
title = {A multi-target therapeutic framework for Alzheimer's disease: an integrative mechanistic review.},
journal = {Neuroscience},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.neuroscience.2026.01.010},
pmid = {41520868},
issn = {1873-7544},
abstract = {BACKGROUND: Alzheimer's disease (AD) is increasingly recognized as a multifactorial network disorder in which amyloid and tau pathology interact with mitochondrial dysfunction, neuroinflammation, metabolic impairment, vascular dysregulation, and synaptic failure. This review provides an integrative, systems-level synthesis of these mechanisms with emphasis on diagnostic and therapeutic implications.

METHODS: A structured narrative review was conducted using PubMed, Scopus, Web of Science, and Embase (2010-2025). Eligible studies included clinical trials, biomarker validation studies, cohort analyses, and mechanistic investigations. Evidence was synthesized by mechanistic domain with focus on cross-system interactions and translational relevance.

FINDINGS: Convergent data indicate that soluble Aβ species, tau propagation, glial dysregulation, insulin resistance, mitochondrial bioenergetic failure, lipid imbalance, and BBB dysfunction form a self-reinforcing neurodegenerative network. Diagnostic advances-including plasma p-tau181/217, Aβ42/40 ratio, GFAP, sTREM2, neuronal exosomes, and multimodal machine-learning models-enable earlier staging and refinement of therapeutic selection. Therapeutic development is shifting from linear amyloid removal to multi-target strategies incorporating anti-tau agents, glial-modulating compounds, metabolic and microbiome interventions, medical nutrition, and multidomain lifestyle programs. Across trials, combined strategies targeting interacting mechanisms demonstrate stronger biomarker and cognitive effects than single-axis approaches.

CONCLUSIONS: AD management requires a systems-oriented therapeutic architecture in which interventions are selected based on mechanistic dominance, biomarker stage, and potential synergy. We outline a multi-target strategy integrating amyloid/tau modulation, neuroimmune regulation, metabolic-vascular stabilization, and synaptic support. Future work should prioritize biomarker-guided stratification, treatment sequencing, and prevention-oriented combination designs.},
}

@article {pmid41520719,
year = {2026},
author = {Polerà, N and Juli, G and Agapito, G and Procopio, A and Lucibello, M and Nardi, M and Bonacci, S and Milano, M and Cannataro, M and Lim, D and Altomare, E and Arbitrio, M},
title = {Upregulation of ACHE and BACE2 genes by Oleacein in Alzheimer's Disease and Neuroblastoma.},
journal = {Chemico-biological interactions},
volume = {},
number = {},
pages = {111909},
doi = {10.1016/j.cbi.2026.111909},
pmid = {41520719},
issn = {1872-7786},
abstract = {Alzheimer's disease (AD) and neuroblastoma are distinct conditions that affect the nervous system. However, they share some molecular similarities, particularly concerning the amyloid precursor protein (APP) and related pathways. While previous studies have demonstrated a correlation between neurodegenerative diseases and various tumors, the causality and direction of their relationship remain unclear. Oleacein, one of the most abundant polyphenols in Extra Vergin Olive Oil (EVOO) may exert neuroprotective and/or antitumor effects. In this study, we explored the effects of the polyphenol oleacein, obtained by a simple and efficient sustainable semi-synthesis starting from natural oleuropein, on AD-related genes in SHSY5Y, a human neuroblastoma cell line, and in 3Tg-iAstro cells, immortalized astrocytes from the hippocampus of 3xTg-AD mice, to identify potential shared biological pathways.},
}

@article {pmid41520543,
year = {2025},
author = {Xue, R and Wang, F and Zhang, B and Wu, J and Zhang, N and Sun, C},
title = {Carrier-free nanoassembly with dual antioxidant and anti-inflammatory activities camouflaged by melanoma cell membrane for tau-targeted therapy of Alzheimer's disease.},
journal = {Biomaterials},
volume = {329},
number = {},
pages = {123970},
doi = {10.1016/j.biomaterials.2025.123970},
pmid = {41520543},
issn = {1878-5905},
abstract = {Targeting phosphorylated tau (p-tau) across the blood-brain barrier (BBB) represents a critical prerequisite for attenuating tau pathology and disease progression in Alzheimer's disease (AD) by alleviating oxidative stress and neuroinflammation. To address this challenge, we developed a novel carrier-free selenium-based nanoassembly stabilized by hydroxyl-rich fingolimod (FTY720), a sphingosine analogue. Following camouflaging with melanoma cell membranes and further functionalizing with T807, the resulting nanocomposite (FSMT) demonstrated robust capacity for BBB crossing and target p-tau both in vitro and in vivo. Additionally, FTY720 and nano-selenium exert remarkable antioxidant and anti-inflammatory effects by modulating the GSK-3β and NF-κB signaling pathways, respectively, thereby attenuating tau hyperphosphorylation and preventing neuronal cell death. In an okadaic acid-induced AD mouse model, the FSMT treatment not only significantly ameliorated oxidative stress and neuroinflammation, but also improved spatial learning and memory impairments. The reduction in abnormal tau aggregation following treatment was confirmed by PET-CT imaging. Overall, this p-tau-targeted biomimetic nanocomposite demonstrated excellent biocompatibility and therapeutic efficacy, presenting a translatable strategy for treating AD and other neurological disorders through analogous mechanisms.},
}

@article {pmid41520466,
year = {2026},
author = {Rapaka, D and Saniotis, A and Thatayaone, M and Bitra, VR},
title = {Neuroendocrine signaling as a pathological seed for the female bias of Alzheimer's disease and the concept of estrobolome.},
journal = {Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie},
volume = {195},
number = {},
pages = {118999},
doi = {10.1016/j.biopha.2026.118999},
pmid = {41520466},
issn = {1950-6007},
abstract = {The prevalence of Alzheimer's disease (AD) is anticipated to escalate with the global increase in life expectancy. Although sex-based differences in AD have been previously documented, doubts persist regarding the relationship between sex and pathophysiological pathways. Sex hormones may contribute to these disparities, with a heightened risk of AD-related dementia associated with oophorectomy before menopause. We cannot ascertain if estrogens alone are solely accountable for this accelerated pathological progression of the disease. Estrogens are regulated by the gut microbiota. Thus, the gut-estrogen-brain axis appears to be implicated as a potential new influencer in the pathophysiology of AD, as the female microbiome differs from the male gut microbiome. This suggests it could be a risk factor for the higher prevalence of AD in women. This review speculates on the possible mechanisms for AD prevalence in women, including both anatomical and neuroendocrinological perspectives.},
}

@article {pmid41520445,
year = {2026},
author = {Tiburcio, MA and Silva, BPN and Garcia, MLDC and Pereira, LMB and Grigoli, MM and Cominetti, MR and Carlos, RM},
title = {Insulin modulates Aβ1-42 aggregation toward non-toxic forms: A comparative study with cis-[Ru(phen)2(3,4Apy)2][2].},
journal = {Journal of inorganic biochemistry},
volume = {277},
number = {},
pages = {113225},
doi = {10.1016/j.jinorgbio.2026.113225},
pmid = {41520445},
issn = {1873-3344},
abstract = {Intranasal insulin therapy for Alzheimer's disease (AD) has received increasing attention due to its potential to modulate amyloid-β (Aβ) aggregation, a hallmark of AD pathology. Molecular dynamics simulations suggest that insulin binds across U-shaped Aβ1-42oligomers, disrupting β-strand alignment via its A-chain. In contrast, the Ru(II) complex cis-[Ru(phen)2(3,4Apy)2][2+](Ru3,4Apy; phen = 1,10-phenanthroline; 3,4Apy = 3,4-aminopyridine) primarily interacts with fibril surfaces. Although both target the central hydrophobic core motif, they bind to distinct regions of Aβ1-42. Their co-aggregation with Aβ1-42 may thus influence aggregation and cytotoxicity differently, providing insight into the molecular mechanisms underlying insulin's mitigation of Aβ-induced cytotoxicity. We monitored Aβ1-42 aggregation using Tyr10 intrinsic fluorescence, circular dichroism, atomic force microscopy, and SH-SY5Y cell viability assays in the presence of insulin, Ru3,4Apy, or both. Ru3,4Apy reduced β-sheet formation but did not prevent Aβ1-42-induced cytotoxicity. In contrast, insulin limited conformational flexibility, prevented Tyr10 burial, suppressed β-sheet formation, and promoted amorphous, non-toxic aggregates. Notable, in the Aβ1-42/Ru3,4Apy/Insulin mixture, aggregation followed a non-toxic pathway bypassing the buried-core β-sheet typical of mature fibrils. These findings emphasize the specificity of Aβ1-42/Insulin interactions and suggest targeting defined binding sites as a promising AD therapeutic strategy.},
}

@article {pmid41520153,
year = {2026},
author = {Avila-Rieger, JF and Huber, B and Tom, SE and Robinson, WR and Hill-Jarrett, TG and Farina, MP and Hohman, TJ and Schupf, N and Brickman, AM and Mayeux, RP and Manly, JJ},
title = {Associations of Lifetime Cumulative Estrogen Exposure with Lifecourse Social Exposures, Cognitive Decline, and Dementia Risk Among Postmenopausal White, Black, and Latina Women.},
journal = {The journals of gerontology. Series B, Psychological sciences and social sciences},
volume = {},
number = {},
pages = {},
doi = {10.1093/geronb/gbag001},
pmid = {41520153},
issn = {1758-5368},
abstract = {OBJECTIVES: Greater lifetime exposure to estrogen may protect women from cognitive decline and dementia later in life. Gender-related social factors also influence women's cognitive outcomes; however, little is known about how these biological and social influences work together. We examined the extent to which cumulative estrogen exposure and lifecourse social exposures jointly influence late-life memory trajectories and dementia risk among a community-based sample of White, Black, and Latina women.

METHODS: Participants were 3,688 postmenopausal women in the Washington Heights-Inwood Columbia Aging Project. Lifetime cumulative estrogen exposure was estimated based on age at menarche and menopause, breastfeeding duration, and hormone replacement therapy (HRT) use. Lifecourse social factors included birth cohort, childhood SES, educational and occupational attainment, and later-life income. Multiple-group growth models and Cox regression models were estimated across racial and ethnic groups.

RESULTS: Greater lifetime estrogen exposure was independently associated with higher baseline memory performance among Black and Latinx women, slower memory decline among White women, and lower dementia risk among Latinx women. Later birth year and higher lifecourse SES were associated with greater lifetime estrogen exposure, with associations varying in magnitude across racial and ethnic groups. Associations between lifecourse SES and each cognitive outcome were partially mediated by estrogen exposure indicators.

DISCUSSION: Cumulative estrogen exposure is socially patterned. We found that lifecourse social factors and estrogen exposure synergistically contribute to women's late-life cognitive health outcomes. Understanding how sex-linked biology and gender-related social forces intertwine is essential for developing interventions to decrease dementia risk among women.},
}

@article {pmid41520099,
year = {2026},
author = {Mao, C and Wang, W and Huang, X and Wu, M and Wang, Y and Wang, T and Qiu, Y and Chu, S and Jin, W and Jiang, Y and Bao, J and You, Y and Li, Y and Dong, L and Feng, F and Huo, L and Qiu, L and Gao, J},
title = {Real world clinical practice of lecanemab at PUMCH dementia cohort: focus on dynamic imaging and biomarker evolution.},
journal = {Alzheimer's research & therapy},
volume = {},
number = {},
pages = {},
doi = {10.1186/s13195-025-01943-z},
pmid = {41520099},
issn = {1758-9193},
support = {2021-I2M-1-020//CAMS Innovation fund for medical sciences (CIFMS)/ ; 2022-PUMCH-A-254//National High Level Hospital Clinical Research Funding/ ; 2020YFA0804500, 2020YFA0804501//National Key Research and Development Program of China/ ; },
abstract = {BACKGROUND: Lecanemab is an anti-Aβ antibody approved in China for mild cognitive impairment (MCI) and mild dementia. Real-world application requires comprehensive assessment beyond MMSE scores, considering factors like ARIA risk. This single-center, real-world study aims to evaluate its efficacy in an expanded population, observe biomarker changes, and assess its safety profile in clinical practice.

METHODS: We recruited adults aged 40-90 with early AD from the PUMCH Dementia Cohort. A total of 42 patients received lecanemab treatment, of whom 29 completed the 6-month treatment evaluation. Participants had confirmed amyloid and tau pathology and met clinical criteria (CDR ≤ 1, CDR-SB ≤ 8and MMSE ≥ 18). Comprehensive assessments included neuropsychological testing, CSF and plasma biomarkers (Lumipulse G1200), multi-sequence 3T MRI (volumetric and ALPS index analysis), and amyloid/tau PET imaging (Centiloid quantification). All were monitored for adverse reactions. Matched control groups (matched for sex, age, APOE genotype, disease severity, and baseline therapy) were established for comparison of longitudinally changes in cognitive function, daily living ability and structure MRI.

RESULTS: Treatment was effective even for patients with lower MMSE scores but still classified as having mild dementia by CDR. A significant median Centiloid reduction of 30.9 was observed, with a 24.1% amyloid PET negativity rate after six months. While scores on cognitive and functional scales (CDR-SB, ADL) significantly worsened, indicating disease progression, the rate of progression was significantly slower compared to the control group. Structural MRI showed significant volume reduction in multiple brain regions and increased ventricular volume post-treatment, with no statistically significant change in the ALPS value. The rate of brain volume reduction is faster than that in the control group. Plasma biomarker dynamics (Aβ42, GFAP) indicated effective disease-modifying therapy. Greater Centiloid reduction was linked to more brain volume loss, higher baseline Centiloid levels, higher plasma Aβ42 increase and older age of onset. APOE ɛ4 homozygotes showed less Centiloid reduction. A favorable safety profile was observed, with a 7.1% incidence of asymptomatic, mild ARIA.

CONCLUSIONS: This study confirms the clinical efficacy, biomarker changes, and safety profile of lecanemab treatment over a 6-month period, demonstrating its positive therapeutic value and a favorable safety profile in the Chinese population with AD.},
}

@article {pmid41519615,
year = {2026},
author = {Wang, Y and Li, M and Chen, T and Li, Y and Wang, Q and Zhang, X and Wang, N and Yang, L and Guo, L and Nie, W},
title = {Preeclampsia as a reversible risk factor for Alzheimer's disease: A prospective MRI study on morphological changes of the cerebral cortex and impairment of cognitive functions.},
journal = {The journal of prevention of Alzheimer's disease},
volume = {},
number = {},
pages = {100475},
doi = {10.1016/j.tjpad.2025.100475},
pmid = {41519615},
issn = {2426-0266},
abstract = {PURPOSE: To investigate the cross-sectional and longitudinal alterations in cortical thickness and surface area and Cognitive Impairment among patients with preeclampsia.

METHODS: The thickness and surface area of the cerebral cortex were systematically segmented from MRI using the automated cortical segmentation software FreeSurfer, and the corresponding values for each brain region were accurately quantified. Data collection includes the clinical characteristics, serological markers of proteins associated with cognitive function, and cognitive assessments.

RESULTS: Compared with healthy pregnancies, the cortical thicknesses of the right caudal anterior cingulate (R-CACg), right posterior cingulate (R-PoCg), right rostral anterior cingulate (R-RoACg), and right superior frontal (R-SF) in the preeclampsia group exhibited significant alterations. Notably, the change in the R-SF was specific to preeclampsia and was not associated with normal physiological pregnancies. Mediation analysis further confirmed that elevated prepregnancy BMI was directly associated with reduced Symbol Digit Modalities Test scores and indirectly contributed to cognitive decline through an increase in MAP. The cortical thickness of left pars opercularis was identified as a key component in this underlying mechanism. No statistically significant changes in cortical surface area were observed in patients with preeclampsia. Follow-up studies have indicated that cortical thickness alterations in brain regions associated with preeclampsia demonstrate signs of recovery. Among cognitive-related test indicators, only the Auditory Word Learning Test exhibited a statistically significant improvement.

CONCLUSION: The cortical thickness alterations in the R-CACg, R-PoCg, R-RoACg, and R-SF of patients with preeclampsia may represent the structural basis for cognitive impairment. Longitudinal studies have confirmed the neuroplasticity of cortical thickness changes and the potential for recovery from preeclampsia-related memory deficits.},
}

@article {pmid41519344,
year = {2026},
author = {Li, H and Kim, H and Kim, M and Lee, JY},
title = {Revealing the conformational landscape of tau P → L mutants in R23 tau macromolecule: A pathway to targeted therapeutic design.},
journal = {International journal of biological macromolecules},
volume = {},
number = {},
pages = {150033},
doi = {10.1016/j.ijbiomac.2025.150033},
pmid = {41519344},
issn = {1879-0003},
abstract = {Misfolding of the microtubule-associated protein tau is central to the pathology of several neurodegenerative disorders, including Alzheimer's disease, Pick's disease, and progressive supranuclear palsy. Although proline-to-leucine (P → L) substitutions in tau are known to accelerate aggregation, the molecular mechanisms underlying this effect-and potential strategies to counter it-remain incompletely understood. Here, we use replica-exchange molecular dynamics (REMD) to investigate how single (P301L, P332L) and double (P2L) P → L mutations in tau's R23 fragment reshape its conformational landscape. Our simulations reveal that single mutations substantially elevate β-sheet content (by up to 17% compared to wild-type) and increase aggregation propensity. Paradoxically, the double mutant reduces β-sheet formation and enhances α-helical structure, effectively curtailing aggregation. Contact map and hydrogen-bond analysis confirm that introducing the second P → L substitution reorganizes intrachain interactions in a way that mitigates misfolding. These findings advance our fundamental understanding of tau aggregation and suggest a counter-intuitive therapeutic concept: engineering an additional mutation may stabilize tau more effectively than merely suppressing a pathogenic mutation. We propose integrative next steps-virtual screens, AI clustering, and ssNMR-to guide translation.},
}

@article {pmid41519279,
year = {2026},
author = {Cai, M and Wang, S and Liu, M and Lai, B and Chen, C and Ding, J and Wang, X},
title = {Elevated FKBP5 expression associates with epilepsy-related molecular changes and promotes neuronal hyperexcitability.},
journal = {Brain research},
volume = {},
number = {},
pages = {150157},
doi = {10.1016/j.brainres.2026.150157},
pmid = {41519279},
issn = {1872-6240},
abstract = {OBJECTIVE: Epilepsy is one of the neurological disorders, characterized by recurrent, spontaneous seizures arising from neuronal hyperexcitability and hypersynchrony in the brain. The mechanisms of epilepsy are intricate and remain elusive. FKBP5 has emerged as a significant protein implicated in neurological disorders such as Alzheimer's disease (AD) and Parkinson's disease (PD). This study aims to investigate the role of FKBP5 in a kainic acid (KA)-induced intrahippocampal epilepsy model and assessed how FKBP5 gain-of-function and FKBP51 inhibition influence neurotransmitter dynamics and neuronal excitability.

METHODS: We examined the expression of FKBP5 in the hippocampus of the kainic acid (KA)-induced epilepsy model. To explore the impact of FKBP5 on neuronal activity, we overexpressed FKBP5 in primary cortical neurons and astrocytes, assessing extracellular glutamate levels in neuron-astrocytes co-cultures with or without the FKBP51-selective inhibitor SAFit2 (250 nM). Intrinsic excitability, voltage-gated Na[+] currents, and network activity were evaluated using whole-cell patch-clamp recordings and high-density microelectrode arrays (HD-MEAs).

RESULTS: We observed an elevated level of FKBP5 in the hippocampus of a kainic acid (KA)-induced chronic epilepsy mouse model, whereas cortical FKBP5 did not show clear changes across the examined post-insult time points.. Moreover, FKBP5 overexpression induced a remarkable increase in the extracellular glutamate level in co-cultured primary cortical neurons and astrocytes. Intriguingly, FKBP5 overexpression modifies the electrophysiological properties of primary neurons, resulting in increased intrinsic excitability and enhanced Na[+] currents. Additionally, the network activity exhibits hyperexcitability with FKBP5 overexpression. Notably, SAFit2 treatment was also associated with elevated extracellular glutamate in the co-culture system, while intracellular FKBP5 and EAAT2 protein levels showed no significant group differences in the current dataset.

CONCLUSION: These findings suggested that FKBP5 played a significant role in regulating neuronal excitability and extracellular glutamate homeostasis. However, due to discrete sampling and the lack of continuous seizure monitoring, the present in vivo data do not establish a definitive causal contribution of FKBP5 to epileptogenesis, warranting future studies integrating longitudinal EEG and cell-type-specific manipulations.},
}

@article {pmid41519243,
year = {2026},
author = {Sharma, K and Shahid, M and Patel, R and Islam, A},
title = {Insights into Mechanism of Ionic Liquids for Protein Stability: Future Implications for Neurodegeneration Treatment.},
journal = {Ageing research reviews},
volume = {},
number = {},
pages = {103024},
doi = {10.1016/j.arr.2026.103024},
pmid = {41519243},
issn = {1872-9649},
abstract = {Neurodegenerative diseases are characterized by a gradual loss of neurons, cellular dysfunction, loss of intricate synaptic networks and brain damage, which are going to be the second leading cause of death in future. These proteinopathies are marked by abnormal amyloid fibril deposition, aberrant aggregation of misfolded proteins via polymerization, where protein aggregates serve as key pathological hallmarks in Alzheimer's, Parkinson's, and multiple system atrophy disorders. These toxic aggregates accumulate in the brain and disrupt neuronal function targeting motor neurons, spinal cord, and ultimately leading to respiratory failure and death. As population age, the prevalence of these neuronal disorders rises significantly, emphasizing to approach effective treatment for risk reduction. In the pursuit of developing effective anti-amyloidogenesis therapeutic agents, ionic liquids (ILs) continue to receive least attention. ILs have emerged as promising substitute for conventional solvents, owing to their unique physicochemical properties that facilitate protein refolding, mitigate denaturation, amyloidogenesis, and prevent aggregation. This review critically addresses intricate IL-protein interactions, dictated by anions-cations composition of ILs, their polarity, hydrophobicity, kosmotropicity, chaotropicity, amphiphillicity, and network, which modulate protein behavior and support structural and functional integrity. This article also underscores the need for precision in IL selection, ensuring their properties align with the desired structural outcome. We showcase ILs as a promising therapeutic avenue for neurodegenerative diseases, demonstrating their potential to modulate pathological protein aggregation and enhance protein homeostasis. Lastly, this review of outstanding research works, account for current lacunae that will guide future perspectives for the rational designing of IL for protein stabilization and offers new strategies for addressing underlying mechanism of ageing disorders.},
}

@article {pmid41519200,
year = {2026},
author = {Fazeli, E and Jan, A and Huber, AK and Jensen, AMG and Fazeli, E and Klein, J and Merchant, K and Andersen, OM},
title = {A luminescent reporter assay to quantify SORL1 ectodomain shedding and Retromer-dependent endosome recycling activity.},
journal = {The Journal of biological chemistry},
volume = {},
number = {},
pages = {111136},
doi = {10.1016/j.jbc.2026.111136},
pmid = {41519200},
issn = {1083-351X},
abstract = {Growing evidence suggests that defects in endosomal recycling are a causal mechanism for Alzheimer's disease (AD). Sortilin-like receptor (SORL1) is an endosomal sorting receptor that acts together with the Retromer complex to facilitate shuttling of cargo from endosomes back to the trans-Golgi network or to the cell surface. Accumulating data indicate that SORL1 dysfunction contributes to AD pathogenesis. SORL1 is trafficked from the endosome to the cell surface in a Retromer-dependent process where it undergoes enzymatic cleavage, resulting in shedding of the SORL1 ectodomain (also known as soluble SORL1). We capitalized on this physiological process to develop and validate a cell-based luminescent reporter assay incorporating enhanced Gaussia Luciferase (eGLuc) to quantify soluble SORL1 in the conditioned media as a marker of endosomal recycling function. The shedding of eGLuc-SORL1 provided a reliable luminescent readout correlating with cellular SORL1 expression under conditions of stable and transient transfection in mammalian cell cultures. Using this system, we demonstrated a robust dependence of SORL1 shedding on Retromer levels. Pharmacological treatments and manipulations that either inhibited or enhanced Retromer activity produced corresponding changes in eGLuc-SORL1 shedding. Furthermore, the assay demonstrated a reduction in SORL1 shedding in cells expressing pathogenic variants associated with AD, supporting its application in evaluating variant pathogenicity. Given its simplicity and cost-effectiveness, this assay is well-suited for high-throughput screening of small-molecule drug candidates that modulate SORL1 trafficking and endosomal recycling. In a broader context, it provides a valuable tool for investigating the biological significance of AD-associated SORL1 variants.},
}

@article {pmid41519166,
year = {2026},
author = {Zhao, P and Cao, Z and Rozpędek-Kamińska, W},
title = {Receptor Tyrosine Kinases in Alzheimer's Disease: Mechanistic Insights and Therapeutic Implications.},
journal = {Neurochemistry international},
volume = {},
number = {},
pages = {106117},
doi = {10.1016/j.neuint.2026.106117},
pmid = {41519166},
issn = {1872-9754},
abstract = {Alzheimer's disease (AD) is a complex neurodegenerative disorder whose pathogenesis remains incompletely understood. It is considered one of the most costly, fatal, and socially burdensome diseases of the twenty-first century. Previous studies have shown that receptor tyrosine kinases (RTKs) play an important role in the pathological progression of AD. RTKs regulate amyloid-beta (Aβ) deposition and Tau hyperphosphorylation, thereby influencing neuronal survival, synaptic plasticity, and spatial cognitive function in patients with AD. From a therapeutic perspective, RTK-targeted interventions offer new avenues for AD treatment. Inhibiting specific RTKs can reduce Aβ production and pathological Tau phosphorylation, thereby slowing disease progression. Conversely, activating selected neuroprotective RTKs can promote neuronal survival, restore synaptic function, and ameliorate cognitive impairment. Several small-molecule inhibitors and monoclonal antibodies targeting RTKs have already demonstrated promising therapeutic potential in preclinical studies. Overall, this review systematically summarizes the clinical features and mechanisms of AD, as well as the current applications and future challenges of RTK-based research in neurodegenerative diseases, providing theoretical guidance for the development and repurposing of novel multi-pathway RTK-directed therapies.},
}

@article {pmid41518900,
year = {2025},
author = {Loraine, A and Farr, SA and Niehoff, ML and Larrea, IG and Ganev, Y and Samanta, J and Rahman, K and Crider, AM and Sandoval, K and Witt, KA},
title = {Dual sigma receptor 1 and 2 modulator improves memory behavior in mouse model of age-related cognitive decline.},
journal = {The Journal of pharmacology and experimental therapeutics},
volume = {393},
number = {2},
pages = {103795},
doi = {10.1016/j.jpet.2025.103795},
pmid = {41518900},
issn = {1521-0103},
abstract = {Sigma-1 (S1R) and sigma-2 (S2R) receptors are promising targets for treating Alzheimer disease (AD), playing important roles in cognitive function, with potential to mitigate neuropathology. The dual S1R/S2R receptor modulator (+/-)-cis-1-n-Butyl-8-methoxy-1,2,3a,4,5,9b-hexahydrobenz[e]indole hydrochloride (BBZI) was evaluated in the senescence-accelerated mouse prone 8 model of cognitive decline and AD as to behavior and hippocampal expression effects. Chronic BBZI treatment (0, 0.001, 0.01, 0.1, 1.0, or 10 mg/kg, i.p. daily, 27-days) was evaluated using a behavioral battery including open field activity (day-15), elevated plus maze (day-16), Y-maze (day-22), T-maze foot-shock avoidance (days 20 and 27), and novel object recognition (days 23 and 24). No changes were observed in open field, elevated plus maze, Y-maze, or novel object recognition tests at any dose of BBZI as compared with vehicle. BBZI enhanced T-maze foot-shock memory retention at 0.1 (P < .05, Bonferroni) and 1.0 mg/kg (P < .001, Bonferroni) compared with vehicle (day-27). In a separate cohort, a single-injection of BBZI (0, 0.001, 0.01, 0.1 & 1.0 μg, i.c.v.) with testing 7-days later showed a significant effect in the T-maze foot-shock test (P = .011) and enhanced memory retention behavior at 0.01 μg compared with vehicle (P < .05, Bonferroni). Poly(A) RNA sequencing evaluation of hippocampal tissue 24-hours after intracerebroventricular administered BBZI (1.0 μg/μL) versus vehicle showed unique gene expression changes, with notable effects relevant to mitochondrial energetics and synaptic function. Gene enrichment analysis identified affiliations with pathways involved in neurodegenerative disease. This data supports dual S1R/S2R receptor modulation as a promising strategy for AD treatment and identifies potential gene pathways involved. SIGNIFICANCE STATEMENT: Dual sigma receptor 1 and 2 modulator BBZI improved memory behavior in senescence-accelerated mouse prone 8 mice. Evaluation of senescence-accelerated mouse prone 8 hippocampal tissue 24 hours after BBZI (1.0 μg/μL i.c.v.) versus vehicle administration identified gene changes related to mitochondrial energetics and synaptic function. BBZI to mitigates cognitive decline behavior, impacting hippocampal genes critical for brain function.},
}

@article {pmid41518895,
year = {2026},
author = {Das, A and P, N and Chowdhury, D and Das, A and Manna, R and Bodakhe, SH},
title = {Chronic stress, gut dysbiosis, and cholesterol metabolism: Implications for Alzheimer's disease.},
journal = {Journal of neuroimmunology},
volume = {413},
number = {},
pages = {578853},
doi = {10.1016/j.jneuroim.2026.578853},
pmid = {41518895},
issn = {1872-8421},
abstract = {Alzheimer's disease is a degenerative neurological condition that gradually worsens and is the predominant type of dementia evident in millions of individuals globally. The intricate origin and development of this condition includes multiple genetic and environmental risk factors, alterations in gene expression, and activation of detrimental pathways. Chronic stress can adversely affect brain structure and function, leading to diminished cognitive ability, impaired decision-making, and poor mood regulation. The gut-brain axis, influenced by dietary and early life variables, significantly affects the control of stress responses. The human microbiota forms a symbiotic interaction with the host, impacting protective cell barriers, metabolic processes, and immune functions in the intestines. Chronic stress and high-cholesterol diets can alter gut microbiota composition, influencing behaviour, immune responses, and intestinal function. Oxysterols affect gut health and inflammation through the alteration of tight junctions and the stimulation of proinflammatory bacterial proliferation. This review provides a thorough explanation of the structure and function of the dietary stress system, its relationship with the central nervous system (CNS) and endocrine axis, and evidence connecting stress to the core processes of stress-related illnesses impacting AD. A thorough comprehension of the complex interplay among chronic stress, gut dysbiosis, and Alzheimer's disease progression could provide novel insights for the formulation of targeted therapeutic interventions.},
}

@article {pmid41518808,
year = {2026},
author = {Qu, J and Jiang, X and Ma, Y and Sheng, X and Pi, C and Wang, Y and Xu, Q and Li, R and Wang, P and Qian, D and Wang, J and Yi, Z and Yi, J and Wen, L and Liu, S},
title = {Unveiling the gut-brain axis: How chronic exposure to arsenic-induced microglial pyroptosis drives Alzheimer's disease-like pathology.},
journal = {Journal of hazardous materials},
volume = {503},
number = {},
pages = {141087},
doi = {10.1016/j.jhazmat.2026.141087},
pmid = {41518808},
issn = {1873-3336},
abstract = {Arsenic, a pervasive environmental contaminant in groundwater, poses a severe global threat to public health. Chronic arsenic exposure has been linked to neurological impairment, however, its specific pathogenic mechanism and whether the gut-brain axis plays a key role remain unclear. This study investigated the role of gut microbiota and its metabolite indoxyl sulfate (IS) in mediating chronic exposure to arsenic-induced cognitive impairment and Alzheimer's disease (AD)-like pathology, with a specific focus on microglial pyroptosis. We found that chronic arsenic exposure induced cognitive dysfunction and intestinal barrier injury, disrupted gut microbiota composition, promoted IS accumulation in serum and brain, and activated the AhR/NF-κB/NLRP3 signaling pathway, triggering microglial pyroptosis and elevating AD-like pathological markers in mice. Meanwhile, fecal microbiota transplantation (FMT) from arsenic-exposed mice recapitulated cognitive impairment, elevated IS levels, and neuroinflammation in recipient mice. Furthermore, arsenic upregulated hepatic IS-synthesis genes (CYP2E1, Sult1d1) and downregulated renal IS-excretion gene (ABCG2). In vitro, arsenic and IS co-exposure promoted M1 polarization and enhanced pyroptosis by activating the AhR/NF-κB/NLRP3 signaling pathway, while suppressing phagocytosis-related proteins (TREM2, SYK and CD36). Furthermore, SiAhR treatment could alleviated microglial inflammatory injury and enhancing the microglia's phagocytic capacity induced by arsenic and IS co-exposure in BV2 cells through inhibiting the AhR/NF-κB/NLRP3-mediated pyroptosis signaling pathway. In conclusion, chronic arsenic exposure induced cognitive impairment and AD-like pathological via the gut microbiota-AhR-pyroptosis cascade, where in IS accumulation served a key mediator. These findings provide new insights into preventing arsenic-related cognitive damage.},
}

@article {pmid41518717,
year = {2026},
author = {Gramkow, MH and Gleerup, HSC and Simonsen, AH and Waldemar, G and Frederiksen, KS},
title = {Digital biomarkers in early Alzheimer's disease from wearable or portable technology: A scoping review.},
journal = {Journal of the neurological sciences},
volume = {481},
number = {},
pages = {125734},
doi = {10.1016/j.jns.2026.125734},
pmid = {41518717},
issn = {1878-5883},
abstract = {BACKGROUND: The pursuit of accurate biomarkers for early detection and disease monitoring of Alzheimer's disease (AD) has driven a growing interest in digital biomarkers. We aimed to map the research landscape of digital biomarkers in early AD obtained with wearable or portable digital health technologies (DHTs).

METHODS: In our scoping review, we included original research on portable or wearable DHTs where digital biomarkers were measured in populations of early AD (mild cognitive impairment (MCI) or mild dementia). We searched MEDLINE, Web of Science and EMBASE with a wide search strategy with independent review and data extraction by two review team members. We charted data in tabular/graphical form.

RESULTS: After deduplication and screening of 8893 records, we included 109 studies describing a wide array of wearable or portable DHTs that obtained digital biomarkers. The study population consisted of 3019 individuals with MCI due to AD (54 % female, weighted mean age 73 years), and 1942 individuals with mild AD (55 % female, weighted mean age 73 years). The most studied biomarkers were rest/activity (39 %), speech (17 %), and gait (14 %), with most studies focusing on one domain. Few studies reported outcomes associated with diagnosis (16 %) and prognosis (3 %).

CONCLUSION: We identified a growing evidence base investigating digital biomarkers in early AD. There is a paucity of studies examining diagnostic and prognostic properties, representing a knowledge gap. This overview may help to guide future research efforts to bridge the gap between the development and clinical implementation of digital biomarkers in early Alzheimer's disease.},
}

@article {pmid41518671,
year = {2025},
author = {Vieira, HC and Zanini, D and Loureiro, BB and Barreto, FJN},
title = {The impact of loneliness on the development of alzheimer's disease in women: a systematic review.},
journal = {Trends in psychiatry and psychotherapy},
volume = {},
number = {},
pages = {},
doi = {10.47626/2237-6089-2025-1088},
pmid = {41518671},
issn = {2238-0019},
abstract = {INTRODUCTION: Alzheimer's disease (AD) is the leading cause of dementia in the elderly and involves pathophysiological events which results in progressive cognitive impairment and functional disabilities. Loneliness is a unique condition in which an individual perceives themselves as socially isolated, even when they are among other people. It is also a worldwide public health challenge associated with higher mortality, and risk of cardiovascular and psychiatric diseases. The aim of this study is to investigate the impacts of loneliness on the development of AD in women.

METHODS: Systematic Review registered in PROSPERO (CDCRD42024521068) and adherent to PRISMA and Cochrane guidelines. In November 2025, systematic searches conducted by independent reviewers were carried out in international databases. The methodological quality of the included studies was assessed using the Newcastle-Ottawa Scale and the Downs and Black Checklist.

RESULTS: A significant association is suggested between loneliness and the development of AD. Possible causal mechanisms were identified, namely chronic stress associated with loneliness, lack of social and emotional support, and reduced cognitive and social activity. The organization of studies allows for an analysis of the incidence of AD, the progression of cognitive decline, and the relationship with neurobiological changes associated with loneliness.

CONCLUSION: Despite being a complex and barely understood relationship, Loneliness may play a relevant role in the development of AD among women. Psychosocial factors must be considered in the context of aging and women's mental health, emphasizing its role in increasing the risk and progression of the disease.},
}

@article {pmid41518572,
year = {2026},
author = {Zhang, Z and Zhang, M and Cao, Z and Zhao, H and Li, X and Luo, P},
title = {Fibrillarin: bridging ribosome biogenesis and apoptosis in cellular stress and disease.},
journal = {Apoptosis : an international journal on programmed cell death},
volume = {31},
number = {1},
pages = {11},
pmid = {41518572},
issn = {1573-675X},
support = {82171363//National Natural Science Foundation of China/ ; },
mesh = {Humans ; *Apoptosis/genetics ; *Ribosomes/metabolism/genetics ; *Neoplasms/genetics/metabolism/pathology ; *Stress, Physiological ; Animals ; Tumor Suppressor Protein p53/metabolism/genetics ; *Neurodegenerative Diseases/genetics/metabolism/pathology ; Cell Nucleolus/metabolism ; Signal Transduction ; Chromosomal Proteins, Non-Histone ; },
abstract = {Nucleolar stress has emerged as a critical regulatory mechanism linking ribosome biogenesis defects to apoptotic cell death in various pathological conditions. Fibrillarin (FBL), the catalytic component of box C/D small nucleolar ribonucleoproteins, participates in multiple forms of programmed cell death through both p53-dependent and p53-independent pathways across diverse disease contexts including cancer and neurodegeneration. In malignancies including breast cancer, colorectal cancer, and hepatocellular carcinoma, FBL overexpression promotes apoptosis resistance, whereas in Alzheimer's disease and ALS/FTD, FBL dysfunction contributes to pathological neuronal death. Dysregulation of FBL can lead to excessive apoptosis or apoptosis resistance depending on cellular context and disease state. Various cellular stressors trigger aberrant FBL function, disrupting rRNA processing and ribosome assembly, which then activates nucleolar stress responses that culminate in cell death through ribosomal protein-MDM2-p53 axis activation or selective translational control of survival factors in a context-dependent manner. Therefore, targeting FBL-mediated apoptotic pathways is considered an important avenue for the treatment of various cancers and neurodegenerative diseases. In this review, we summarize the major and recent findings focusing on the mechanisms of FBL-regulated apoptosis in disease pathogenesis and provide a systematic overview of current therapeutic strategies targeting nucleolar stress pathways, including RNA polymerase I inhibitors and precision medicine approaches based on p53 status, which may provide important therapeutic targets that merit further investigation.},
}

Humans
*Apoptosis/genetics
*Ribosomes/metabolism/genetics
*Neoplasms/genetics/metabolism/pathology
*Stress, Physiological
Animals
Tumor Suppressor Protein p53/metabolism/genetics
*Neurodegenerative Diseases/genetics/metabolism/pathology
Cell Nucleolus/metabolism
Signal Transduction
Chromosomal Proteins, Non-Histone

@article {pmid41518543,
year = {2026},
author = {Sheng, D and Wang, S and Xiao, Z and Liu, W and Xiao, B and Zhou, L},
title = {Evaluating causal links between retinal thickness, Alzheimer's disease, and circulating total-tau: evidence from Mendelian randomization and colocalization analysis.},
journal = {European archives of psychiatry and clinical neuroscience},
volume = {},
number = {},
pages = {},
pmid = {41518543},
issn = {1433-8491},
support = {81601139//National Natural Science Foundation of China/ ; 2024JJ5576//Natural Science Foundation of Hunan Province/ ; },
}