@article {pmid41794773,
year = {2026},
author = {Soliman, AR and Fahmy, E and Mahmoud Ahmed, R},
title = {The obesity-brain axis: a comprehensive review of neurological complications and therapeutic interventions in metabolic syndrome.},
journal = {Diabetology & metabolic syndrome},
volume = {18},
number = {1},
pages = {},
pmid = {41794773},
issn = {1758-5996},
abstract = {BACKGROUND: Obesity has emerged as a major global health issue, affecting multiple organ systems. Within the central nervous system obesity causes a series of disruptions that can significantly affect neurological function. Identifying obesity as a modifiable risk factor presents opportunities for preventive and therapeutic strategies that may significantly diminish neurological sequelae.

OBJECTIVE: This narrative review aims to summarize current evidence on how obesity contributes to different neurological diseases and focusing on biological mechanisms linking obesity to these conditions, outlines the characteristic clinical presentations of obesity-related neurological diseases across different age groups and potential therapeutic strategies.

METHODS: This narrative review integrates findings from comprehensive search of PubMed, EMBASE, and Cochrane Library to investigate how obesity and metabolic syndrome relate to a broad spectrum of neurological disorders. After screening 1,950 records, 48 studies were included supplemented by nine manually identified articles.

RESULTS: Obesity triggers a range of biological changes in the nervous system such as increased oxidative stress, persistent low‑grade inflammation, disruption of the blood–brain barrier, and impaired mitochondrial function. Together, these changes raise the risk of several neurological problems, including cognitive decline, Alzheimer’s disease, stroke, faster progression of multiple sclerosis, greater epilepsy‑related complications, transformation of episodic into chronic migraine, idiopathic intracranial hypertension, and various peripheral neuropathies. The impact of body mass index on neurological health differs across diseases and age groups with obesity in midlife representing a high risk. Lifestyle‑based strategies especially Mediterranean or ketogenic dietary patterns, regular physical activity and weight reduction show encouraging potential in reducing these neurological risks.

CONCLUSIONS: Obesity is a modifiable contributor to many neurological disorders. Identifying at‑risk individuals early and adopting healthier daily habits, following tailored diets and managing weight effectively may help lessen the neurological consequences of obesity. Continued research is essential to clarify underlying mechanisms and refine treatment strategies for different patient groups.},
}

@article {pmid41993417,
year = {2026},
author = {Pressman, PS and Basaran, C and Foltz, P and AuYeung, WT and Steele, J and Silbert, L and Hunter, LE},
title = {Dynamic thermodynamic-informational entropic relationship (TIER) models of selective vulnerability to neurodegeneration.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
pmid = {41993417},
issn = {2692-8205},
abstract = {BACKGROUND: Neurodegenerative diseases share selective vulnerability patterns suggesting common physical mechanisms. We apply unified mechanics theory to neural systems, predicting that brain regions accumulate structural damage proportional to computational workload.

METHODS: We simulated a hierarchical neural network implementing relationships between mechanical work (W = F × D), proportional thermodynamic entropy accumulation (Δs ∝ W), and structural failure thresholds. Neural architectures at three hierarchical levels employed Hebbian learning across 2000 simulation sets, tracking thermodynamic entropy generation and dynamic stability. A coupled "siphon" model simulated cortical and subcortical support populations under constant cognitive demand.

RESULTS: Heteromodal integration nodes consistently exhibited elevated work, accelerated entropy accumulation, and dynamic instability across architectures. Support systems reached 50% population loss before cortical systems despite lower absolute work, demonstrating accelerated compensatory failure.

DISCUSSION: These thermodynamic-informational entropic relationship (TIER) models depict mechanisms underlying selective vulnerability across neurodegeneration, reframing neurodegeneration as the physical consequence of evolutionary trade-offs optimizing cognitive performance over longevity.},
}

@article {pmid42050061,
year = {2026},
author = {Chang, SH and Lin, HL and Qian, H and Liu, ZT and Lu, J and Zhong, BL},
title = {Diagnostic accuracy of digital clock drawing test for Alzheimer disease and mild cognitive impairment.},
journal = {NPJ digital medicine},
volume = {},
number = {},
pages = {},
doi = {10.1038/s41746-026-02687-2},
pmid = {42050061},
issn = {2398-6352},
support = {WX23A99//Wuhan Medical Research Project 2023 (Healthy Development)/ ; WX23A99//Wuhan Medical Research Project 2023 (Healthy Development)/ ; 2024020801020405//the 2024 Wuhan Natural Science Foundation Exploration Plan Municipal Medical Institutions Clinical Research Key Project/ ; 2024020801020405//the 2024 Wuhan Natural Science Foundation Exploration Plan Municipal Medical Institutions Clinical Research Key Project/ ; 202305AF150180//Academician Song Weihong Workstation in Yunnan Province/ ; EWEITONG [2021]74//the Young Top Talent Programme in Public Health from the Health Commission of Hubei Province/ ; },
abstract = {Alzheimer's disease (AD) and mild cognitive impairment (MCI) are major public health concerns, requiring accurate and scalable diagnostic tools. The digital clock drawing test (dCDT) captures drawing data and enables extraction of process-related features that may improve diagnostic performance. However, existing evidence remains inconsistent, highlighting the need for a systematic synthesis to support its clinical translation. We searched Web of Science, Embase, PubMed, PsycINFO, IEEE Xplore, CNKI, and Wanfang from inception to January 8, 2026. A bivariate mixed-effects model was used to pool sensitivity and specificity. A total of 13 studies comprising 17 diagnostic tests were included, and risk of bias was notable across studies. For MCI, the standalone dCDT showed pooled sensitivity of 0.765 (95% CI: 0.683-0.832), specificity of 0.752 (95% CI: 0.673-0.817), and pooled area under the summary receiver operating characteristic curve (AUC) of 0.825 (95% CI: 0.790-0.856). When both standalone and augmented dCDT tests were considered for MCI, the pooled sensitivity and specificity were 0.760 and 0.800, respectively, and the pooled AUC increased to 0.845. For AD, the pooled sensitivity, specificity, and AUC of dCDT were 0.820 (95% CI: 0.721-0.889), 0.897 (95% CI: 0.860-0.923), and 0.928 (95% CI: 0.902-0.948), respectively. Exploratory subgroup analyses of standalone dCDT for MCI suggested diagnostic performance appeared higher in studies employing algorithm-based approaches than in those using traditional-scoring approaches. Overall, the available evidence supports dCDT as a promising digital screening tool for cognitive impairment. Further multicenter studies and standardized protocols are needed to enhance its role in early diagnostic and clinical practice.},
}

@article {pmid42050120,
year = {2026},
author = {Esteve, M and Martinez-Gracia, A and Rodríguez-Sala, JJ and Brotons-Mas, JR and Falcó, A},
title = {Retraction Note: A novel approach integrating topological deep learning from EEG Data in Alzheimer's disease.},
journal = {Scientific reports},
volume = {16},
number = {1},
pages = {},
doi = {10.1038/s41598-026-50185-y},
pmid = {42050120},
issn = {2045-2322},
}

@article {pmid42050212,
year = {2026},
author = {Li, XY and Zhang, Y and Ran, Z and Luo, JX and Yu, XQ and Lu, MH},
title = {CD33 Isoform Splicing Dysregulation: A Molecular Determinant of Microglial Dysfunction in Alzheimer's Disease Pathology.},
journal = {Molecular neurobiology},
volume = {63},
number = {1},
pages = {},
pmid = {42050212},
issn = {1559-1182},
support = {Grant No. 2025ZNSFSC1799//Sichuan Science and Technology Program/ ; Grant No. 25MSZX550//Sichuan Provincial Administration of Traditional Chinese Medicine/ ; },
mesh = {*Alzheimer Disease/genetics/pathology/metabolism ; Humans ; *Sialic Acid Binding Ig-like Lectin 3/genetics/metabolism ; *Microglia/metabolism/pathology ; Protein Isoforms/genetics/metabolism ; Animals ; *Alternative Splicing ; *RNA Splicing ; },
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by amyloid-β (Aβ) plaques, neurofibrillary tangles, and chronic neuroinflammation. Genome-wide association studies (GWAS) have identified microglial dysfunction as central to AD pathogenesis, with CD33 emerging as a critical genetic risk factor. This review explores the dual roles of CD33 isoforms, CD33M (pro-pathogenic) and CD33m (protective), in modulating microglial activity, Aβ clearance, and neuroinflammatory responses. We dissect the molecular mechanisms underlying isoform formation, including genetic polymorphisms (e.g., rs3865444, rs12459419) and splicing regulation by hnRNPA/B, PTBP1, and SRSF1. Additionally, we highlight the antagonistic interplay between CD33 and TREM2, emphasizing their convergence on DAP12 signaling and downstream pathways. Emerging therapeutic strategies targeting CD33, such as isoform-specific immunotherapies, small-molecule splicing modulators, and Siglec-glycan interactions, are critically evaluated for their potential to mitigate AD pathology. By integrating recent preclinical and clinical advancements, this review underscores the necessity of precision approaches to harness CD33's therapeutic potential while addressing challenges like blood-brain barrier penetration and species-specific discrepancies.},
}

*Alzheimer Disease/genetics/pathology/metabolism
Humans
*Sialic Acid Binding Ig-like Lectin 3/genetics/metabolism
*Microglia/metabolism/pathology
Protein Isoforms/genetics/metabolism
Animals
*Alternative Splicing
*RNA Splicing

@article {pmid42050268,
year = {2026},
author = {Kern, LM and Fowler, NR and Nothelle, SK},
title = {Family Caregivers and the Need to Navigate Healthcare for People with Alzheimer's Disease and Related Dementias.},
journal = {Journal of general internal medicine},
volume = {},
number = {},
pages = {},
doi = {10.1007/s11606-026-10460-0},
pmid = {42050268},
issn = {1525-1497},
support = {R01AG087243/AG/NIA NIH HHS/United States ; K23AG072037/AG/NIA NIH HHS/United States ; },
}

@article {pmid42050365,
year = {2026},
author = {Dos Reis, S and Tran, P and Mohanty, K and Amill-Rosario, A and Johnson, A and Ryan, K and Alsdurf, H and Oraichi, D and Yun, H},
title = {Reduced risk of dementia with recombinant zoster vaccine in US adults age 65 or older.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {5},
pages = {e71407},
doi = {10.1002/alz.71407},
pmid = {42050365},
issn = {1552-5279},
support = {//GSK/ ; },
mesh = {Humans ; Aged ; Female ; Male ; *Herpes Zoster Vaccine/therapeutic use ; United States/epidemiology ; *Dementia/epidemiology/prevention & control ; Medicare/statistics & numerical data ; Aged, 80 and over ; Incidence ; Alzheimer Disease/epidemiology/prevention & control ; Vaccines, Synthetic ; Herpes Zoster/prevention & control ; Proportional Hazards Models ; Risk Factors ; Vaccination ; },
abstract = {INTRODUCTION: Herpes zoster vaccines may lower the risk of dementia onset. We evaluated new-onset dementia among US Medicare beneficiaries ≥65 years old following recombinant zoster vaccination (RZV).

METHODS: We matched one RZV-exposed to two RZV-unvaccinated on age, sex, and race/ethnicity. Individuals were ≥65 years old on the RZV dose 2 date (RZV-exposed) or preventive care visit date (RZV-unvaccinated), enrolled in Medicare ≥11 months before this date, and had no pre-existing dementia of any type. Weighted Cox proportional hazards models generated hazard ratios (HR) of new-onset dementia, Alzheimer's disease (AD), and vascular dementia (VD).

RESULTS: The incidence per 1000 person-years of new-onset dementia for 15,061/502,845 RZV-exposed and 36,526/1,005,690 RZV-unvaccinated was 10.45 and 15.73, respectively. Time-dependent HRs (95% confidence interval) for ≤3 and >3 years' follow-up were as follows: 0.67 (0.65, 0.68); 0.74 (0.69, 0.79) for dementia; 0.72 (0.69, 0.74); 0.83 (0.74, 0.94) for AD; 0.67 (0.64, 0.70); 0.66 (0.57, 0.78) for VD.

DISCUSSION: Two-dose RZV may lower new-onset dementia, AD, and VD risk.},
}

Humans
Aged
Female
Male
*Herpes Zoster Vaccine/therapeutic use
United States/epidemiology
*Dementia/epidemiology/prevention & control
Medicare/statistics & numerical data
Aged, 80 and over
Incidence
Alzheimer Disease/epidemiology/prevention & control
Vaccines, Synthetic
Herpes Zoster/prevention & control
Proportional Hazards Models
Risk Factors
Vaccination

@article {pmid42050369,
year = {2026},
author = {Tao, Q and Han, J and Ang, TFA and Hou, L and Liu, C and Murabito, JM and Lunetta, KL and Mez, J and Alosco, ML and Stein, TD and Zhang, X and Au, R and Farrer, L and Palmisano, JN and Hamburg, NM and Qiu, WQ},
title = {Peripheral vascular function, including endothelium-dependent measures, and dementia risk: The Framingham Heart Study.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {5},
pages = {e71396},
doi = {10.1002/alz.71396},
pmid = {42050369},
issn = {1552-5279},
support = {N01-HC-25195//National Heart, Lung, and Blood Institute (NHLBI), National Institutes of Health/ ; 75N92025D00012/HL/NHLBI NIH HHS/United States ; NS-17950//National Institute of Neurological Disorders and Stroke (NINDS), National Institutes of Health/ ; AG-008122//National Institute on Aging (NIA), National Institutes of Health/ ; AG-16495//National Institute on Aging (NIA), National Institutes of Health/ ; AG-022476//National Institute on Aging (NIA), National Institutes of Health/ ; //U.S. Department of Veterans Affairs (VA) Merit Award/ ; },
mesh = {Humans ; Female ; Male ; Middle Aged ; Magnetic Resonance Imaging ; Aged ; Biomarkers/blood ; *Brachial Artery/physiopathology/diagnostic imaging ; Brain/pathology/diagnostic imaging ; *Endothelium, Vascular/physiopathology ; *Alzheimer Disease/epidemiology/physiopathology ; Risk Factors ; Hyperemia/physiopathology ; },
abstract = {INTRODUCTION: The relationship between peripheral vascular health, including endothelia, cognitive decline, and Alzheimer's disease (AD) dementia risk is unclear.

METHODS: In this study, 2844 dementia-free Framingham Offspring participants (mean age 60.6 years, 53.2% women) had baseline brachial artery flow-mediated dilation (FMD%) and reactive hyperemia (RH). Participants were then followed for a median of 17 years for incident AD and underwent plasma biomarker testing and brain magnetic resonance imaging.

RESULTS: FMD% (hazard ratio [HR] = 0.83, 95% confidence interval [CI] 0.76 to 0.91, p < 0.001) and RH (HR = 0.89, 95% CI 0.79 to 0.99, p = 0.049) were negatively associated with incident AD dementia after adjusting for confounders. Associations were stronger in individuals with elevated C-reactive protein. Poor vascular function correlated with higher plasma AD biomarkers, smaller brain volumes, greater white matter injury, and increased cerebral microbleeds.

DISCUSSION: Poor FMD% and RH may serve as a prognostic biomarker for cerebrovascular pathology, including endothelial dysfunction in the AD brain.},
}

Humans
Female
Male
Middle Aged
Magnetic Resonance Imaging
Aged
Biomarkers/blood
*Brachial Artery/physiopathology/diagnostic imaging
Brain/pathology/diagnostic imaging
*Endothelium, Vascular/physiopathology
*Alzheimer Disease/epidemiology/physiopathology
Risk Factors
Hyperemia/physiopathology

@article {pmid42050370,
year = {2026},
author = {Aravena, JM and Castro, H and Poblete, R and Saavedra, G and Briceño, R and Torres, W and Vecchi, M and Budinich, M and Fuentes, P and Albala, C and Levy, BR},
title = {Designing a communication strategy to promote Alzheimer's disease prevention: The CULTIVAMENTE campaign.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {5},
pages = {e71448},
doi = {10.1002/alz.71448},
pmid = {42050370},
issn = {1552-5279},
support = {//National Research and Development Agency of Chile/ ; //Yale Social and Behavioral Sciences Research Fund/ ; //Yale University Council on Latin American and Iberian Studies/ ; //Yale MacMillan Center for International and Area Studies/ ; //Yale Center for the Study of Race, Indigeneity, and Transnational Migration/ ; R01AG067533/AG/NIA NIH HHS/United States ; U01AG032284/AG/NIA NIH HHS/United States ; },
mesh = {Humans ; *Alzheimer Disease/prevention & control ; Male ; Female ; Aged ; *Health Promotion/methods ; *Communication ; Health Personnel ; *Health Knowledge, Attitudes, Practice ; Qualitative Research ; Middle Aged ; },
abstract = {INTRODUCTION: Awareness of Alzheimer's disease (AD) prevention remains limited in community settings, contributing to low adoption of evidence-based recommendations. This study aimed to design a context-tailored communication strategy for older adults and health-care providers.

METHODS: A three-phase, multi-method study using a design-thinking framework was conducted in senior centers, including qualitative research, contextual observations, and participatory codesign.

RESULTS: A total of 101 older adults and 54 health-care providers contributed to the development phase. The resulting strategy, CULTIVAMENTE, uses positive aging imagery and nudge-based cues to deliver evidence-based AD prevention messages through posters, brochures, and websites. After implementation, older adults in intervention centers reported increased knowledge of prevention strategies (32.7%-61.4%) and more frequent discussions with health-care providers (9.9%-21.8%). Health-care providers reported high acceptability and use of campaign materials.

DISCUSSION: CULTIVAMENTE is a low-intensity and context-tailored approach that was feasible to implement and supported improvements in AD prevention awareness.},
}

Humans
*Alzheimer Disease/prevention & control
Male
Female
Aged
*Health Promotion/methods
*Communication
Health Personnel
*Health Knowledge, Attitudes, Practice
Qualitative Research
Middle Aged

@article {pmid42050390,
year = {2026},
author = {Xu, Y and Denkinger, MN and Liu, M and Gong, K and Chen, Y and Western, D and Timsina, J and Cheng, Y and Xie, Y and Mu, R and Budde, J and Beach, TG and Serrano, GE and Reiman, EM and Singh, A and Alfradique-Dunham, I and Benzinger, TLS and Schindler, SE and Morris, JC and Holtzman, DM and Perlumtter, JS and Snider, BJ and Campbell, MC and Kotzbauer, PT and Ashton, NJ and Cruchaga, C},
title = {GPND-AI NULISA: A 15-Protein AI classifier for diagnosis and co-pathology profiling across neurodegenerative diseases.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {5},
pages = {e71420},
doi = {10.1002/alz.71420},
pmid = {42050390},
issn = {1552-5279},
support = {R01-AG064614//the National Institutes of Health/ ; U01-AG084514//the National Institutes of Health/ ; P01-NS131131//the National Institutes of Health/ ; R01-AG078964//the National Institutes of Health/ ; R01-AG058501//the National Institutes of Health/ ; R01-AG071706//the National Institutes of Health/ ; P30-AG066444//the National Institutes of Health/ ; R01-AG064877//the National Institutes of Health/ ; P30AG066444//the National Institutes of Health/ ; P01AG03991//the National Institutes of Health/ ; P01AG026276//the National Institutes of Health/ ; },
mesh = {Humans ; *Neurodegenerative Diseases/diagnosis/pathology/classification ; Male ; Female ; Aged ; *Artificial Intelligence ; Proteomics/methods ; Parkinson Disease/diagnosis/pathology ; Alzheimer Disease/diagnosis/pathology ; Lewy Body Disease/diagnosis/pathology ; Biomarkers ; Frontotemporal Dementia/diagnosis/pathology ; Middle Aged ; Aged, 80 and over ; },
abstract = {INTRODUCTION: Accurate clinical diagnosis of neurodegenerative diseases remains challenging, particularly when individuals have mixed pathologies. We implemented the generalizable protein-based neurodegenerative disease artificial intelligence (GPND-AI) classifier using the NUcleic acid-Linked Immuno-Sandwich Assay (NULISA) central nervous system (CNS) panel to classify Alzheimer's disease, Parkinson's disease, frontotemporal dementia, dementia with Lewy bodies, and healthy controls, while disentangling mixed pathologies.

METHODS: Proteomic and clinical information from the Charles F. and Joanne Knight Alzheimer's Disease Research Center (Knight-ADRC) and Movement Disorder Clinic were used to train and test the GPND-AI classifier. External validation was performed in a Banner Sun Health Research Institute cohort and additional Knight-ADRC samples with neuropathologically confirmed diagnoses.

RESULTS: GPND-AI identified 15 proteins that achieve an area under the curve (AUC) of 0.955 and 92.3% accuracy across five diagnostic categories. In validation cohort, predicted co-pathologies significantly correlated with clinical characteristics.

DISCUSSION: GPND-AI identified a 15-protein panel that accurately classifies individuals across the four major neurodegenerative diseases. Validation against neuropathology-confirmed diagnoses supports the utility of proteomics-based approaches for mapping disease-specific and co-existing neurodegenerative processes.},
}

Humans
*Neurodegenerative Diseases/diagnosis/pathology/classification
Male
Female
Aged
*Artificial Intelligence
Proteomics/methods
Parkinson Disease/diagnosis/pathology
Alzheimer Disease/diagnosis/pathology
Lewy Body Disease/diagnosis/pathology
Biomarkers
Frontotemporal Dementia/diagnosis/pathology
Middle Aged
Aged, 80 and over

@article {pmid42050423,
year = {2026},
author = {Hornbecker, M and Suchsland, MZ and MacLeod, T and Koppenhofer, MJ and Selzler, KJ and Ferrell, P and Deckert, A},
title = {The Davos Alzheimer's Collaborative Healthcare System Preparedness US Early Detection of Cognitive Impairment Program in primary care: Methodology.},
journal = {BMC primary care},
volume = {},
number = {},
pages = {},
doi = {10.1186/s12875-026-03312-7},
pmid = {42050423},
issn = {2731-4553},
}

@article {pmid42050540,
year = {2026},
author = {Zhang, H and Xie, L and Meng, F and Cui, J and Ma, B and Wang, Y and Zhang, K and Miao, X},
title = {Shared genetic architecture between Alzheimer's disease and psychiatric disorders revealed by multi-trait genome-wide analyses.},
journal = {BMC medical genomics},
volume = {},
number = {},
pages = {},
doi = {10.1186/s12920-026-02354-1},
pmid = {42050540},
issn = {1755-8794},
}

@article {pmid42050739,
year = {2026},
author = {Chung, SJ and Kang, M and Park, YJ and Oh, K and Koh, SB and Kang, SH},
title = {Impact of appendicular skeletal muscle mass on Alzheimer's disease in relation to age and comorbidities: an 8-year longitudinal follow-up study of a nationwide cohort.},
journal = {Alzheimer's research & therapy},
volume = {},
number = {},
pages = {},
doi = {10.1186/s13195-026-02063-y},
pmid = {42050739},
issn = {1758-9193},
support = {20240088//the 2024 Inje University Research Grant/ ; },
}

@article {pmid42050742,
year = {2026},
author = {Zhang, Y and Tan, Q and Wu, S and Xu, X},
title = {Women's reproductive life patterns, intrinsic capacity, and the risk of all-cause and cause-specific dementia: a prospective cohort study.},
journal = {Alzheimer's research & therapy},
volume = {},
number = {},
pages = {},
doi = {10.1186/s13195-026-02066-9},
pmid = {42050742},
issn = {1758-9193},
support = {21-416//China Medical Board/ ; 72474197//the Natural Science Foundation of China/ ; },
abstract = {BACKGROUND: Few studies comprehensively examined women's life-course reproductive patterns and the risk of dementia. This study aims to examine the association between women's reproductive life sequence and dementia, and to explore the potential role of intrinsic capacity (IC) on such association.

METHODS: This study used data of 153,909 women who were post-menopause and free of dementia at baseline from the UK Biobank. We conducted sequence analysis and cluster analysis to identify women's life-course reproductive sequence and its potential patterns based on self-reported single reproductive factors. Women's IC at baseline comprised four functional domains: psychology, sensory, vitality, and locomotion. Participants were followed from baseline to the onset of dementia, death, or the end of follow-up (September 1, 2023). Fine and Gray's subdistribution hazard models were used to examine the associations between reproductive life sequences, IC, and dementia.

RESULTS: During a median follow-up of 14.5 years, 2,940 dementia (including 1,509 Alzheimer's disease and 577 vascular dementia) cases were documented. Patterns of reproductive life sequences identified were: standard sequence (46.4%), early childbearing and oophorectomy menopause (6.5%), short reproductive span with natural menopause (17.7%), early childbearing and hysterectomy menopause (11.4%), and high parity with long birth span (18.1%). Compared to the standard sequence, short reproductive span with natural menopause (hazard ratio [HR] = 1.30, 95% confidence interval [CI] = 1.18-1.44), early childbearing and hysterectomy menopause (HR = 1.17, 95% CI = 1.04-1.32), and high parity with long birth span (HR = 1.13, 95% CI = 1.03-1.25) were associated with a higher risk of dementia. These associations would be strengthened when combining with IC impairment. For example, women with the combined sequence of short reproductive span with natural menopause and IC impairment had 2.40-fold (1.77-3.24) increased risk of dementia, compared to those with the standard sequence and no IC impairment. The associations between reproductive life patterns and dementia risk were stronger among women with more impairment items of IC.

CONCLUSION: Our study showed cumulative associations of women's life-course reproductive factors with the risk of dementia in later life, and IC impairment could strengthen such associations. These results suggest the need to prioritize women with high-risk reproductive sequences, with special focus on their IC, in the prevention strategies for dementia.},
}

@article {pmid42050895,
year = {2026},
author = {Tunç, T and Kılınç, N and Demirel, N and Alım, Z},
title = {Design, Synthesis, and Enantioselective Cholinesterase Inhibition of Novel Chiral Anthranilic Diamide Derivatives: In Vitro and In Silico Studies.},
journal = {Chirality},
volume = {38},
number = {5},
pages = {e70104},
doi = {10.1002/chir.70104},
pmid = {42050895},
issn = {1520-636X},
mesh = {*Cholinesterase Inhibitors/chemistry/chemical synthesis/pharmacology ; Stereoisomerism ; Acetylcholinesterase/metabolism/chemistry ; Butyrylcholinesterase/metabolism/chemistry ; *Drug Design ; Molecular Docking Simulation ; *ortho-Aminobenzoates/chemistry/chemical synthesis/pharmacology ; *Diamide/chemistry/pharmacology/chemical synthesis ; Humans ; Animals ; },
abstract = {Acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) enzymes are responsible for the hydrolysis of acetylcholine and play a vital role in Alzheimer's disease (AD) pathology. The observation of decreased AChE activity and a significant increase in BChE activity in the advanced stages of AD makes the identification of novel inhibitors targeting both AChE and BChE enzymes crucial. In this study, novel chiral anthranilic acid-based diamide derivatives (5a-5d, 7a, and 7b) with pure enantiomer structures were synthesized, and their inhibitory potential on AChE and BChE was comprehensively investigated. The structures of the synthesized compounds were confirmed by [1]H NMR, [13]C NMR, IR, and LC-MS analyses. In vitro cholinesterase inhibition studies showed that all compounds exhibited significant inhibitory activity against both enzymes. Specifically, compounds 7a and 7b, containing 2,6-pyridine dicarbonyl, exhibited higher AChE and BChE inhibition compared with the reference drug tacrine, displaying IC50 values at the nanomolar level. Enantioselective analyses showed that S-enantiomers were significantly more effective in AChE inhibition, while enzyme-specific inverse stereoselective preferences emerged in BChE inhibition. Experimental findings were supported by induced coherent molecular docking (IFD), MM-GBSA binding free energy calculations, and 250-ns molecular dynamics simulations. In silico analyses confirmed that 7b exhibited high stability and strong interactions in the AChE active site and 7a in the BChE active pocket. Furthermore, ADME analyses revealed that the compounds possessed favorable pharmacokinetic and drug-like properties. In conclusion, this study demonstrates that chiral anthranilic diamide derivatives are promising novel AChE/BChE inhibitor candidates that act as potent and selective cholinesterase inhibitors.},
}

*Cholinesterase Inhibitors/chemistry/chemical synthesis/pharmacology
Stereoisomerism
Acetylcholinesterase/metabolism/chemistry
Butyrylcholinesterase/metabolism/chemistry
*Drug Design
Molecular Docking Simulation
*ortho-Aminobenzoates/chemistry/chemical synthesis/pharmacology
*Diamide/chemistry/pharmacology/chemical synthesis
Humans
Animals

@article {pmid42051019,
year = {2026},
author = {Hacımüftüoğlu, A and Saraçoğlu, N and Saffour, S and Abad, N and Kesgun, Y and Zegheb, N and Gundeger, E and Yeşilyurt, F and Ateş, MN and Bati-Ayaz, G and Altunlu, Ö and Çınar, B and Yörük, MA and Okkay, U and Özkaraca, M and Ateş, O and Taghizadehghalehjoughi, A and Lafzi, F and Türkez, H},
title = {Multi-Target Neuroprotective Compound Exhibits EAAT2-Modulating and Alzheimer's Pathology-Attenuating Effects in In Vitro and In Vivo Models.},
journal = {ACS chemical neuroscience},
volume = {},
number = {},
pages = {},
doi = {10.1021/acschemneuro.5c00873},
pmid = {42051019},
issn = {1948-7193},
abstract = {Alzheimer's disease (AD) is a debilitating neurodegenerative disorder characterized by cognitive decline and memory loss. Current treatments offer limited efficacy, necessitating the development of innovative multitarget therapeutic strategies. Here, we present N[3],N[5]-bis(2-(5-methoxy-1H-indol-3-yl)ethyl)-2,6-dimethyl-4-(2-nitrophenyl)pyridine-3,5-dicarboxamide (HCM-01), a novel compound developed to target multiple neurodegenerative pathways implicated in AD. In vitro assays included MTT-based cell viability analyses performed in two complementary experimental settings: primary neuronal cultures and astrocyte-based in vitro cell culture models exposed to glutamate. In primary hippocampal neuronal cultures, glutamate exposure induced a statistically significant reduction in cell viability compared with vehicle-treated controls, consistent with glutamate-induced excitotoxicity. Under these conditions, HCM-01 treatment resulted in a statistically significant improvement in neuronal viability, showing a greater protective effect compared with donepezil and memantine. In contrast, in astrocyte-based in vitro cultures, the applied glutamate concentration did not induce overt cytotoxicity, in line with the intrinsic neuroprotective and glutamate-buffering role of astrocytes. Accordingly, astrocytic experiments were designed to assess functional modulation of glutamate-handling mechanisms rather than cell survival. Western blot analysis in C8-D1A astrocytic cells demonstrated increased expression of excitatory amino acid transporter 2 (EAAT2) following HCM-01 treatment compared with control and reference drug-treated groups, suggesting modulation of astrocyte-mediated glutamate homeostasis. In parallel, redox analyses revealed that HCM-01 improved oxidative/antioxidative balance, as evidenced by increased total antioxidant capacity (TAC) and reduced total oxidant status (TOS), supporting an indirect antioxidant contribution to its functional effects. In vivo behavioral assessment of HCM-01 in a streptozotocin (STZ)-induced Alzheimer's model in female Sprague-Dawley rats demonstrated that administration of HCM-01 at doses of 50 mg/kg orally (oral, P.O. and intraperitoneal, I.P.) and 100 mg/kg (P.O.), significantly improved cognitive and memory functions in the passive avoidance (PA), Morris water maze (MWM), and locomotor activity tests. Moreover, histopathological and immunohistochemical analyses of different hippocampal regions revealed reduced neuronal damage, attenuation of tau pathology, antiamyloidogenic effect, and restoration of cholinergic function. Complementary in silico studies, including molecular docking, molecular dynamics simulations (MDS), and free energy calculations, suggested potential interactions of HCM-01 with the allosteric site of EAAT2. Taken together, these findings suggest that HCM-01 exerts neuroprotective effects against glutamate-induced excitotoxicity in primary hippocampal neurons while additionally modulating glutamatergic homeostasis and redox balance through functional mechanisms in astrocyte-based models, supporting its relevance as a multitarget preclinical candidate for early stage AD mechanisms.},
}

@article {pmid42051092,
year = {2026},
author = {Sun, Y and Chan, TW and Liao, W and Li, M and Mao, X and Feng, Y and Rong, J and Zhao, J},
title = {In Silico Design and Evaluation of Diosmin Analogs for Targeting Peroxisome Proliferator-activated Receptor γ (PPAR-γ) Against Alzheimer's Disease.},
journal = {Current neuropharmacology},
volume = {},
number = {},
pages = {},
doi = {10.2174/011570159X453424260218065734},
pmid = {42051092},
issn = {1875-6190},
abstract = {Alzheimer's disease (AD) is a neurodegenerative disorder characterized by progressively declining cognitive abilities and memory impairment. This disease increasingly challenges the quality of life and health of the elderly population, underscoring the need for effective therapeutic strategies. The existing anti-AD medications are designed to improve symptoms but not to cure the disease. Novel drugs are urgently needed to target the specific mechanisms that mediate disease progression. Peroxisome proliferator-activated receptor gamma (PPAR-γ) is a potential target for the development of anti-AD therapies. Through virtual screening of natural PPAR-γ ligands, the flavonoid diosmin was found to bind to PPAR-γ with high potency. This study exploited diosmin as a lead compound to design a panel of diosmin analogs via chemical modifications for better biological efficacy in targeting PPAR-γ. These diosmin analogs were evaluated using in silico approaches, including molecular docking, absorption, distribution, metabolism, and excretion (ADME) predictions, and molecular dynamics (MD) simulations. As a result, molecular docking identified 12 di-osmin analogs with better binding affinity to PPAR-γ compared with diosmin. ADME and MD analyses demonstrated that S1DhP1 exhibited lower binding free energy, better water solubility, and stability than diosmin. Thus, this study provides important information via in silico approaches and hypotheses, suggesting S1DhP1 as a promising PPAR-γ agonist for the treatment of AD that warrants further experimental validation.},
}

@article {pmid42051097,
year = {2026},
author = {Kasthuri, S and Padmavathi, S and Jeevitha, M and Rajangam, J},
title = {Therapeutic Innovations in Parkinson's and Alzheimer's Disease: Molecular Mechanisms and Emerging Strategies.},
journal = {CNS & neurological disorders drug targets},
volume = {},
number = {},
pages = {},
doi = {10.2174/0118715273445849260403045802},
pmid = {42051097},
issn = {1996-3181},
abstract = {Parkinson's Disease (PD) and Alzheimer's Disease (AD) are still significant neurodegenerative disorders that have few disease-modifying therapies. In this review, recent advances are assessed based on the strength of evidence for major molecular targets and the therapeutic approaches that have been developed around those targets. Alpha-synuclein is a key target in PD, as indicated by genetic correlations, pathological distribution, and experimental evidence supporting its involvement in neuronal injury. Initial trials of alpha-synuclein antibodies and vaccines show evidence of target engagement, with yet-to-be-determined clinical outcomes. Interventions targeting gene-based dopamine synthesis restoration using AADC or multi-enzyme vectors have shown consistent biological effects, with clinical variability, and determining optimized delivery and patient selection is necessary. In AD, amyloid-beta- and tau-directed interventions have produced measurable changes in biomarkers, and some agents have demonstrated a slight deceleration of deterioration at an early stage of the disease. The experience with previous BACE inhibitors also demonstrates that excellent mechanistic rationale does not always translate into clinical efficacy in the case of interference with critical physiological processes by target modulation. Regenerative methods, such as stem-cell-based neuronal grafts in PD and neurotrophic factor gene delivery in AD, show potential to repair network function, but still pose issues regarding long-term stability, integration, and the complexity of the procedures. Lifestyle-driven interventions, control of the gut microbiome, and neuromodulation methods also remain of interest and can be included in the list of supportive strategies offered to complement molecular therapies. AI-based analytics and digital tools are helpful in the earlier detection, monitoring, and trial stratification. Taken together, existing evidence suggests that authenticated protein targets, neurotransmitter-targeted remedial strategies, and technology-enabled accuracy methods are the most promising approaches for the development of disease-modifying therapies in PD and AD.},
}

@article {pmid42051098,
year = {2026},
author = {Khan, N and Doshi, G},
title = {Zebrafish (Danio rerio) as a Model for Neurodegenerative Disease Research: Mechanisms, Biomarkers, and Translational Promise.},
journal = {CNS & neurological disorders drug targets},
volume = {},
number = {},
pages = {},
doi = {10.2174/0118715273442688260330060220},
pmid = {42051098},
issn = {1996-3181},
abstract = {Zebrafish (Danio rerio) have gained prominence as a versatile vertebrate model for studying neurodegenerative disorders due to their genetic similarity to humans, rapid development, transparency, and suitability for high-throughput drug screening. The usefulness of zebrafish in modelling human neurological disorders is supported by the similarity of their brains' anatomical and neurochemical characteristics, including comparable divisions of the forebrain, midbrain, and hindbrain, as well as dopaminergic, serotonergic, glutamatergic, and GABAergic pathways. Zebrafish have been used to successfully model several neurodegenerative diseases, including Alzheimer's disease (via tau phosphorylation and amyloid-beta aggregation), Parkinson's disease (via dopaminergic neuronal loss and alpha-synuclein pathology), Huntington's disease (via polyglutamine-expanded huntingtin), and amyotrophic lateral sclerosis (via mutant SOD1 and TDP- 43 transgenes). They have also been used to study multiple sclerosis, spinocerebellar ataxias, and Rett syndrome, enabling mechanistic exploration and preclinical drug discovery. This review crucially depicts how zebrafish models provide an affordable, morally acceptable, and scalable platform for early-stage neurodegeneration research. These models complement, rather than replace, rodent- and human-derived systems. Additionally, we will review how to bridge the gap between therapeutic screening and basic mechanistic findings, highlighting their increasing significance in the neuroscience research continuum.},
}

@article {pmid42051176,
year = {2026},
author = {Blundo, C and Ricci, M},
title = {The caregiver's inventory neuropsychological diagnosis dementia (CINDD) as useful tool in differential diagnosis of dementias.},
journal = {The Clinical neuropsychologist},
volume = {},
number = {},
pages = {1-15},
doi = {10.1080/13854046.2026.2664025},
pmid = {42051176},
issn = {1744-4144},
abstract = {Objective: This study confirms the validity and diagnostic utility of the CINDD (Cargiver's Inventory Neuropsychological Diagnostic Dementia) in assessing cognitive status and behavioral-personality changes through informant-based questions grounded in real-life contexts. We explored the discriminative capacity of the CINDD across various dementia types. Method: We enrolled caregivers of 111 patients at their first diagnostic evaluation. The Clinical population included patients with Alzheimer's Disease (AD), behavioral Fronto-Tempoal Dementia (bvFTD), Dementia with Lewy Body (LBD), non-fluent Primary Progressive Aphasia (nfvPPA), and AD-like Mild Cognitive Impairment (MCI-AD). Patients also underwent a comprehensive neuropsychological assessment including memory, language, visuospatial, and executive function tests. Results: Each CINDD's domain demonstrated meaningful correlations with standard cognitive measures, supporting its construct validity. Notably, the Memory cluster showed strong associations with verbal memory but not with executive or language tasks, while the Language and Perception clusters aligned well with respective cognitive domains. Conversely, Executive and Personality/Behavior clusters did not show significant correlations with any of the neuropsychological measures. The Illusion/Delusion cluster, though targeting neuropsychiatric symptoms, also captured elements of cognitive disorganization seen in conditions like LBD and bvFTD. Diagnostic analyses provided robust cluster-specific cutoffs with acceptable sensitivity and specificity. Particularly, the Memory cluster effectively distinguished memory-dominant dementias (e.g. AD, MCI-AD) from language-predominant variants (e.g. nfvPPA). Conclusion: Finally, given its informant-based structure, the CINDD is especially valuable for assessing individuals with low education, illiteracy, or migrant backgrounds. We recommend its integration with traditional neuropsychological tools to enhance diagnostic accuracy in diverse clinical populations.},
}

@article {pmid42051279,
year = {2026},
author = {Hadinezhad, P and Noroozian, M},
title = {Montreal Cognitive Assessment (MoCA) Scale: Strengths, Limitations, and Implication for Clinical Practice.},
journal = {Iranian journal of psychiatry},
volume = {21},
number = {1},
pages = {140-150},
pmid = {42051279},
issn = {1735-4587},
abstract = {Objective: Mild Cognitive Impairment (MCI) is a transitional state between normal aging and dementia, with high risk of progression. Early detection is essential, and so the Montreal Cognitive Assessment (MoCA) has become a widely used screening tool. Despite its popularity, concerns remain about its psychometric limitations and cultural applicability. This review aims to critically analyze the MoCA, focusing on the validity and limitations of its subtests, and to propose directions for refinement and clinical adaptation. Method : We conducted a structured narrative review (2005-2024) using PubMed, Scopus, and Web of Science databases. Search terms included "Montreal Cognitive Assessment", "MoCA", "validity", "psychometrics", and "cultural adaptation". Studies evaluating psychometric performance, cultural adaptations, and clinical applications of the MoCA were included. Case reports and studies lacking psychometric evaluation were excluded. An item-by-item critical appraisal was performed. Results: The MoCA shows superior sensitivity for MCI detection compared to the Mini-Mental State Examination (MMSE), with strengths in brevity, multidomain coverage, and accessibility. However, limitations include: superficial executive function (EF) assessment, cultural and educational bias, lack of recognition/cueing in memory testing, simplistic binary scoring, and risk of floor/ceiling effects. These may affect diagnostic accuracy across populations. Conclusion: The MoCA remains a valuable tool but should not be used in isolation. Clinicians must consider the cultural/educational context when interpreting results. Refinements such as weighted scoring, cued recall, and culturally adapted items, alongside digital versions, could improve accuracy and fairness. Further empirical validation of these modifications is needed.},
}

@article {pmid42051295,
year = {2026},
author = {Jerez, PA and Rhie, A and Kim, J and Hebbar, P and Nag, S and Antipov, D and Koren, S and Lara, E and Beilina, A and Hansen, NF and Arber, C and Zulueta, J and Crea, PW and Patel, D and Hickey, G and Waltz, B and Malik, L and Skarnes, WC and Reed, X and Genner, R and Daida, K and Pantazis, CB and Grenn, F and Nalls, MA and Billingsley, K and Fossati, V and Wray, S and Ward, M and Ryten, M and Singleton, AB and Cookson, MR and Jain, M and Paten, B and Phillippy, AM and Blauwendraat, C},
title = {The complete genome of the KOLF2.1J reference iPSC line.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.03.06.710144},
pmid = {42051295},
issn = {2692-8205},
abstract = {While induced pluripotent stem cells (iPSCs) have gained popularity in studying neurodegenerative diseases, the heterogeneity of stem cells used across studies impacts cross-study comparison. The iPSC Neurodegenerative Disease Initiative (iNDI) selected the KOLF2.1J cell line and prioritized its use as a reference standard for studying the effects of pathogenic variants on cell biology due to its stability and neutral neurodegenerative disease genetic risk. This cell line, and its derivatives expressing over 100 variants related to Alzheimer's disease, Parkinson's disease, and other neurological diseases, are available for academic and industry access. Current genomic data analyses are limited by the use of a human reference genome that does not capture the complete genetic background of a given iPSC line. While in the future this issue may be partially mitigated by the creation of a comprehensive human pangenome, previous work has shown that generating custom genomes is of value both to characterize the variation present and to serve as a more appropriate genomic reference. Here, we generated and characterized a custom complete genome assembly from KOLF2.1J. Mapping of sequencing reads to a personalized diploid assembly results in more comprehensive mapping compared to traditional linear references (i.e GRCh38). In addition, we provide a comprehensive custom gene annotation along with isoform expression and differential methylation analyses across multiple cell types. The assembly and all additional data is browsable and publicly available. This resource will enable more accurate investigation of the KOLF2.1J cell line and any genomics data generated compared to using traditional generalized references, while also serving as a foundational approach for establishing custom reference assemblies for other high-value iPSC lines.},
}

@article {pmid42051535,
year = {2026},
author = {Lv, S and Kuang, JY and Wang, TW and Zhang, LP and Liu, J and Wang, WD and Yang, MF and Ni, QB and Sun, BL and Sun, JY},
title = {Deciphering the peripheral immune landscape of Alzheimer's disease through integrated multi-omics research and cohort validation.},
journal = {Frontiers in immunology},
volume = {17},
number = {},
pages = {1648591},
pmid = {42051535},
issn = {1664-3224},
mesh = {Humans ; *Alzheimer Disease/immunology/genetics ; Genome-Wide Association Study ; Mendelian Randomization Analysis ; Transcriptome ; Cohort Studies ; Male ; Female ; Aged ; Biomarkers ; Multiomics ; },
abstract = {OBJECTIVE: This study investigated molecular drivers of AD-associated peripheral immune dysregulation to identify pathogenic genes and therapeutic targets for precision diagnosis and intervention.

METHODS: A large-scale GWAS meta-analysis (n = 894,710) was performed, followed by two-sample Mendelian randomization (MR) using multi-tissue cis-eQTL data to identify putative causal genes. Immune response differential genes (IRDGs) were defined from AD peripheral blood transcriptomes and the MSigDB database. A three-step summary-data-based MR framework integrating blood cis-eQTLs and cis-mQTLs was applied to prioritize causal genes and epigenetic regulatory elements. Findings were validated through colocalization analysis, PBMC scRNA-seq and blood-tissue TWAS. Multi-dimensional clinical validation was performed in the ADNI cohort encompassing gene expression, CSF biomarkers, cognitive measures, immune cell profiles, survival analysis, and plasma proteomics, with cross-cohort transcriptomic replication in AddNeuroMed.

RESULTS: Two-sample MR identified eight putative AD pathogenic genes. The three-step SMR and colocalization analysis prioritized five candidate causal genes, whose differential expression in immunocytes was confirmed by scRNA-seq and independently replicated. In the ADNI cohort, PTK2B expression was elevated in AD (ANOVA P = 0.0023), inversely correlated with MMSE (r = -0.164, P = 0.017), and predictive of MCI-to-AD conversion (Cox HR = 1.741, P = 0.050), with independent replication in AddNeuroMed (FDR P = 3.56 × 10[-4]). PLEKHA1 and PTK2B expression were strongly associated with peripheral neutrophil and lymphocyte proportions (P < 10[-7]), and PLEKHA1 correlated with CSF total tau (partial r = 0.102, P = 0.036). The prioritized probe cg19863426 at the PLEKHA1 promoter showed progressive hypermethylation across the CN-MCI-AD continuum (F = 3.45, P = 0.032) and was inversely correlated with PLEKHA1 mRNA (r = -0.33, P = 2.68 × 10[-]¹²).

CONCLUSION: Integrating GWAS, multi-omics Mendelian randomization, single-cell transcriptomics, transcriptome-wide association study, and clinical cohort validation, this study identified peripheral immune causal genes for AD whose blood transcriptomic and epigenetic signatures track with CSF pathology, cognitive decline, and disease progression, supporting their translational potential for early diagnosis and therapeutic development.},
}

Humans
*Alzheimer Disease/immunology/genetics
Genome-Wide Association Study
Mendelian Randomization Analysis
Transcriptome
Cohort Studies
Male
Female
Aged
Biomarkers
Multiomics

@article {pmid42051542,
year = {2026},
author = {Ailani, T and Jauhari, R and Rani, A and Singh, R},
title = {Comment on "AlzStack: Forecasting early-onset Alzheimer's with an explainable AI system using multiple data balancing techniques".},
journal = {Global epidemiology},
volume = {11},
number = {},
pages = {100260},
pmid = {42051542},
issn = {2590-1133},
}

@article {pmid42051551,
year = {2026},
author = {Palmer, JA and Billinger, SA},
title = {APOE4 carriers resistant to cognitive decline show unique relationships between cerebrovascular response to exercise and dual-task cognitive-balance performance.},
journal = {Frontiers in neuroscience},
volume = {20},
number = {},
pages = {1716713},
pmid = {42051551},
issn = {1662-4548},
abstract = {BACKGROUND: Cognitive-motor dual-tasking is an early marker for cognitive impairment, with particular implications for Apolipoprotein E4 (APOE4) carriers who are at higher genetic risk for Alzheimer's disease. While APOE4 carriers typically show accelerated cognitive decline and impaired cerebrovascular function with aging, exceptions to this norm exist and may provide insights into resilience mechanisms. The relationship between cerebrovascular response and cognitive-motor dual-task performance in cognitively-normal APOE4 carriers who maintain preserved function remains unclear.

METHODS: Thirty cognitively-normal older adults (76 ± 4 years, 8 APOE4 carriers, 22 non-carriers) completed clinical balance and cognitive testing under single-task and dual-task conditions. Balance performance was assessed as distance traversed during challenging beam walking. Cognitive performance was assessed as response time during an auditory Stroop test. Transcranial Doppler ultrasound measured cerebrovascular response to moderate-intensity aerobic exercise. We tested group differences in cognitive-balance dual task performance and relationships between cerebrovascular response and dual-task interference (DTI) in balance and cognitive domains, and effects of APOE4 genotype on these relationships.

RESULTS: No differences in cerebrovascular response or dual-task performance were observed between APOE4 carriers and non-carriers. However, APOE4 carriers displayed unique cerebrovascular-behavioral relationships. In APOE4 carriers, higher cerebrovascular response to exercise was associated with less balance DTI (r = 0.839, p = 0.009) and less cognitive DTI (r = 0.832, p = 0.020), while no relationships were observed in non-carriers (p > 0.187).

CONCLUSIONS: Cognitively-normal APOE4 carriers with preserved cognitive-balance dual-task function represent exceptions that may model aging resilience mechanisms. The unique cerebrovascular-behavioral relationships suggest that maintaining cerebrovascular function supports neuromotor and neurocognitive resilience to dual-task challenges in genetically vulnerable populations.},
}

@article {pmid42051575,
year = {2026},
author = {Spencer, C and , and Prashant, NM and Hong, A and Casey, C and Shao, Z and Alvia, M and Argyriou, S and Katsel, P and Auluck, PK and Barnes, LL and Marenco, S and Bennett, DA and Girdhar, K and Voloudakis, G and Haroutunian, V and Bendl, J and Hoffman, GE and Fullard, JF and Lee, D and Roussos, P},
title = {Decoding Pathogenic and Resilient Gene Regulatory Interactions in Alzheimer's Disease.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.02.19.26346666},
pmid = {42051575},
abstract = {The molecular basis of cognitive resilience in Alzheimer's disease (AD), wherein individuals harbor substantial neuropathology yet maintain cognition, remains poorly understood. To systematically decode the regulatory logic underlying divergent cognitive outcomes, we constructed the largest cell-type-resolved gene regulatory network (GRN) atlas of AD to date, profiling 1.7 million nuclei from 687 individuals classified as Controls, cognitively Resilient, or AD dementia across 27 cell types in the human dorsolateral prefrontal cortex. From 223 high-confidence transcription factor regulons, we identify a three-state framework of transcriptional dysregulation: homeostatic erosion of IRF8/STAT1 interferon programs in microglia (State I), compensatory NF-κB suppression via BCL6 in glial populations that distinguishes resilient from demented individuals despite equivalent neuropathological burden (State II), and pathogenic escalation through FLI1/IKZF1 network expansion driving vascular-immune remodeling in AD (State III). NF-κB emerges as the central regulatory hub, with BCL6-mediated repression and FLI1/RELA-driven activation constituting opposing molecular switches that determine cognitive trajectory. These findings, replicated across independent cohorts, reframe resilience as an active regulatory state rather than attenuated disease, and nominate BCL6, IRF8, and FLI1 as priority targets for interventions aimed at extending the compensatory window before dementia onset.},
}

@article {pmid42051629,
year = {2026},
author = {Cullins, MJ and Converse, AK and Rowe, LM and Hoerst, AG and Hibbard, WK and Russell, JA and Connor, NP and Ciucci, MR},
title = {Oropharyngeal dysphagia and amyloid beta pathology in the TgF344-AD rat model of Alzheimer's disease.},
journal = {Frontiers in behavioral neuroscience},
volume = {20},
number = {},
pages = {1812480},
pmid = {42051629},
issn = {1662-5153},
abstract = {INTRODUCTION: Dysphagia is a major consequence of Alzheimer's disease (AD) that is understudied and undertreated. Neuropathology in AD occurs early in the disease progression, but little is known about pathologies underlying functional swallowing changes; this knowledge gap is a barrier to developing effective treatment. We hypothesized that an established AD rat model (TgF344-AD) would demonstrate significant deficits in oromotor/swallowing function versus Wild Type (WT) with corresponding amyloid beta pathology in brain structures critical to swallowing.

METHODS: Nine male TgF344-AD and 6 Wildtype Fisher 344 rats underwent deglutition assessments and PET imaging using the radiotracer [[11]C]PiB to assess brain and brainstem amyloid beta (Aβ) pathology at 11 months of age-a time point corresponding to early-middle stage AD progression. A priori brain regions of interest (ROIs) included those commonly associated with Aβ pathology and more specific swallowing associated structures such as brainstem nuclei and cortical motor areas. Deglutition was assessed using a videofluoroscopic swallow study and a pasta biting task.

RESULTS: Significantly increased levels of Aβ in the AD group were found in regions critical to swallowing motor control including the secondary motor area, thalamus, nucleus ambiguus, and hypoglossal nuclei. The AD group demonstrated significant changes in aerodigestive coordination, including delayed swallow onset, increased apnea duration, and increased frequency of aberrant post-swallow inhale pattern that was correlated with nucleus ambiguus Aβ levels. The AD group also exhibited altered oral processing including reduced bolus size and mastication rate.

CONCLUSION: The TgF344-AD rat model of Alzheimer's exhibits robust changes in oral processing and respiratory-swallow coordination that parallel clinical AD dysphagia. At this early-middle stage timepoint, Aβ pathology is primarily impacting cerebral swallowing networks as well as the nucleus ambiguus and hypoglossal nuclei in the brainstem. Our finding of increased Aβ in the nucleus ambiguus warrants further study as this motor nucleus plays a role in swallowing, respiration, and vocalization-all factors that are known to be impacted by AD in the clinical population.},
}

@article {pmid42051919,
year = {2026},
author = {Pavithra, P and Bradshaw Bernacchi, JK and Ahmed, S and McDermott, G and McCarron, M and McCallion, P and McGlinchey, E and Lopez Valdes, A},
title = {EEG hyperscanning in intellectual disability: a scoping review with implications for cognitive stimulation therapy.},
journal = {Frontiers in neuroergonomics},
volume = {7},
number = {},
pages = {1757738},
pmid = {42051919},
issn = {2673-6195},
abstract = {Electroencephalography (EEG) hyperscanning has emerged as a valuable method for examining social dynamics during group-based activities and may serve as a promising outcome measure in group interventions. Cognitive stimulation therapy (CST) is one such interventions shown to improve cognition and quality of life in people with dementia and has recently been adapted for individuals with intellectual disability (ID). However, the potential for obtaining objective neural markers of CST benefit via EEG and hyperscanning is yet to be explored. This scoping review aims to identify existing evidence and gaps related to the use of EEG within CST research for adults with ID by examining three relevant areas: (1) the use of individual EEG and hyperscanning to evaluate cognitive and social outcomes in CST; (2) the evidence base for individual and group-based CST in people with ID; and (3) the use of EEG to evaluate cognitive and social outcomes for people with ID. Following the PRISMA-ScR guidelines, studies were searched in CINAHL, MEDLINE, PsychInfo, and EMBASE. Our search focused on adult participants with ID and studies that used EEG for the purpose of evaluating cognitive or social outcomes. Currently, there are no studies that use EEG to evaluate CST in adults with ID. Following screening and eligibility assessment, no studies met the inclusion criteria for EEG and CST. Five studies were included for CST and ID, and 14 articles met criteria for EEG and ID. In total, 19 articles were included in the final review. The evidence base suggests that EEG has been successfully used to investigate neural mechanism in ID and Down Syndrome related Alzheimer's disease. Existing CST research in ID remains largely feasibility-focused but some preliminary findings show cognitive benefits, enhanced enjoyment, and social connectedness. Our review shows that there is a large gap when it comes to any objective metrics for CST in general. Given that there is evidence of EEG studies including populations with ID, we propose that this gap can be filled by EEG hyperscanning which offers a non-invasive, objective approach to evaluate cognitive and social outcomes in people with ID in future CST research.},
}

@article {pmid42052139,
year = {2026},
author = {Liu, W and Wang, Y and Shi, Y and Huang, L and Tan, C and Tan, L and Xu, W and , },
title = {Dynamic trajectories of neuropsychiatric symptoms predict Alzheimer's disease risk and clinical phenotypes.},
journal = {General psychiatry},
volume = {39},
number = {},
pages = {e70018},
pmid = {42052139},
issn = {2517-729X},
abstract = {BACKGROUND: Neuropsychiatric symptoms (NPS) may serve as early predictors of Alzheimer's disease (AD). However, NPS evolve over time, and most existing studies have relied on single or sparse assessments that do not capture clinically meaningful longitudinal patterns.

AIMS: To examine whether distinct trajectories of NPS are associated with the risk of incident AD, neurodegeneration and cognitive decline.

METHODS: NPS were assessed using the neuropsychiatric inventory questionnaire. We first characterised and compared the retrospective trajectories of NPS between 290 incident AD dementia cases and 74 healthy controls who remained free of dementia during 8 years of follow-up. Latent class growth modelling was then applied to identify NPS trajectories over the first 3 years among 982 people without dementia at baseline. Cox regression and linear mixed-effects models were used to investigate the associations between NPS trajectories and incident AD risk, cognitive decline, brain atrophy and changes in brain metabolism during early (baseline to year 3) and later (years 3-8) follow-up periods. Interaction between NPS trajectories and APOE ε4 was examined. Causal mediation analyses were conducted to assess whether neurodegeneration mediated the associations between NPS trajectories and cognitive function.

RESULTS: Compared to individuals who remained free of dementia, people who developed AD showed progressively increasing NPS levels prior to AD diagnosis (p < 0.005). Three NPS trajectories were identified: consistently no symptoms (71.8%, as reference), increasing trajectory (18.6%) and remitting trajectory (9.6%). The increasing trajectory was significantly associated with a higher risk of AD during both the early (hazard ratio [HR] = 1.720, p < 0.001) and late (HR = 2.130, p = 0.026) follow-up periods. The remitting trajectory was associated with an elevated risk of AD only in the early follow-up (HR = 1.980, p < 0.001). The increasing trajectory was also linked to faster brain atrophy (β = -139.662, p < 0.001 for the hippocampus, β = -108.642, p = 0.007 for the entorhinal cortex and β = -305.059, p = 0.003 for the middle temporal regions), greater declines in brain metabolism (β = -0.013, p = 0.007) and accelerated cognitive deterioration (β = -0.162 for the memory, β = -0.154 for the executive function, all p < 0.001) during the late follow-up period. These associations were stronger among APOE ε4 carriers. Brain volume loss and metabolism decline partially mediated the relationships of increasing NPS and cognitive impairment.

CONCLUSIONS: NPS trajectories can predict AD risk, neurodegeneration and cognitive decline, especially among APOE ε4 carriers. Progressive neurodegenerative changes may underlie these associations.},
}

@article {pmid42052145,
year = {2026},
author = {Tariot, PN and Chumki, SR and Wang, D and Such, P and Palma, AM and Zhang, Z and Montano, CB},
title = {Brexpiprazole for Agitation in Patients with Alzheimer's Dementia with and without Co-Occurring Psychosis: Post Hoc Analysis of Short- and Long-Term Trials.},
journal = {Neuropsychiatric disease and treatment},
volume = {22},
number = {},
pages = {586701},
pmid = {42052145},
issn = {1176-6328},
abstract = {PURPOSE: Patients with Alzheimer's dementia may experience co-occurring agitation and psychosis symptoms. This exploratory post hoc analysis aimed to analyze the efficacy and safety of brexpiprazole for agitation in patients with Alzheimer's dementia with and without co-occurring psychosis.

PARTICIPANTS AND METHODS: Data were pooled from two Phase 3, 12-week, randomized, double-blind, placebo-controlled, fixed-dose trials of brexpiprazole versus placebo in participants with Alzheimer's dementia and agitation, conducted in Europe, Russia, and the US (ClinicalTrials.gov identifiers: NCT01862640, NCT03548584). Post hoc, participants were stratified into subgroups with or without co-occurring psychosis at baseline, defined as a score ≥4 on the Neuropsychiatric Inventory Delusions domain, Hallucinations domain, or both. Efficacy was assessed by the Cohen-Mansfield Agitation Inventory Total score. Safety was assessed by treatment-emergent adverse events (TEAEs).

RESULTS: 142/607 participants (23.4%) had co-occurring psychosis at baseline. Brexpiprazole 2 or 3 mg/day was associated with greater improvement in agitation compared with placebo in participants with co-occurring psychosis (least squares mean difference at Week 12, -9.18 [95% confidence interval -15.2 to -3.12]; P=0.004; Cohen's d=0.52) and in participants without co-occurring psychosis (-4.22 [-6.91 to -1.54]; P=0.002; Cohen's d=0.29). In participants with co-occurring psychosis, for brexpiprazole and placebo respectively, 52.9% and 40.0% had TEAEs, and 3.4% and 9.1% discontinued due to TEAEs. No deaths occurred among participants with co-occurring psychosis. In participants without co-occurring psychosis, for brexpiprazole and placebo respectively, 49.3% and 38.2% had TEAEs, and 5.5% and 2.6% discontinued due to TEAEs. Two participants without co-occurring psychosis died; neither death was considered related to brexpiprazole treatment.

CONCLUSION: In this post hoc analysis, brexpiprazole improved agitation and was generally well tolerated in patients with Alzheimer's dementia with and without co-occurring psychosis. These exploratory data suggest that brexpiprazole may be of value to patients with Alzheimer's dementia who present with agitation and psychosis in clinical practice.},
}

@article {pmid42052379,
year = {2026},
author = {Yan, X and Liang, C and Zhou, Y and Hong, G and Li, C and Wang, K and Huang, Y and Xiao, X},
title = {Plasma chaperone-mediated autophagy associated protein HSPA8 combined with white matter hyperintensities serves as the predictive marker of early-stage Alzheimer's disease.},
journal = {Frontiers in aging neuroscience},
volume = {18},
number = {},
pages = {1753692},
pmid = {42052379},
issn = {1663-4365},
abstract = {BACKGROUND: The relationship between plasma chaperone-related autophagy proteins and white matter hyperintensity (WMH) in Alzheimer's disease (AD) remains unclear.

METHODS: We employed 4D-DIA proteomics to identify plasma protein changes, and evaluated the clinical relevance of the chaperone-mediated autophagy (CMA)-related protein HSPA8. Additionally, using ITK-SNAP software to assess WMH volume's role in AD. We analyzed the ROC curves for both HSPA8 and WMH in the AD spectrum. Among which, using One-Anova, Kruskal-Wallis, and multivariable logistic analyses to detect the population data. Moreover, the impact of age on WMH volume changes between the AD group and the CN group will be assessed using sensitivity analysis and testing the age-diagnosis interaction.

RESULTS: Significant factors in the AD population included age, MMSE score, MoCA score, and WMH volumes. The OR for age in MCI and for WMH volume in AD patients were significant. The expression of HSPA8 was decline in the AD disease spectrum, but it had no statistical difference. Importantly, HSPA8 protein had the highest AUC value for distinguishing between cognitively normal (CN)/mild cognitive impairment (MCI) and MCI/AD groups. Meanwhile, WMH was significant in the AD disease spectrum. And the influence of age on WMH is comparable in cognitively normal elderly individuals and those with AD. Combining HSPA8 with WMH improved the AUC value, which was further enhanced by including age and gender.

CONCLUSION: We found that the level of CMA-related protein HSPA8 is decline in the AD disease continuum, and WMH volume may help differentiate the AD spectrum. Moreover, Age is the primary factor influencing WMH changes in both CN and AD groups, with AD status having no significant effect on WMH levels or their progression. Thus, age should be carefully considered when evaluating elevated WMH in AD patients. It is noteworthy that the integration of HSPA8 and WMH may function as a potential early biomarker for AD, thereby enhancing the accuracy of its early diagnosis. Including age and gender increases the diagnostic model's AUC value, indicating HSPA8 and WMH are crucial for early AD diagnosis.},
}

@article {pmid42052380,
year = {2026},
author = {Yuan, J and Liu, Y and Jin, J and Li, S and Zhang, Y},
title = {Early detection of Alzheimer's disease via multimodal MRI and machine learning.},
journal = {Frontiers in aging neuroscience},
volume = {18},
number = {},
pages = {1794982},
pmid = {42052380},
issn = {1663-4365},
abstract = {OBJECTIVE: This study aimed to identify effective biomarkers associated with early-stage Alzheimer's disease (AD) by integrating multimodal neuroimaging features with machine learning (ML), addressing clinical challenges posed by global population aging.

MATERIALS AND METHODS: Multimodal neuroimaging-including resting-state functional MRI (rs-fMRI), structural MRI (sMRI), and diffusion tensor imaging (DTI)-was combined with ML techniques. A total of 234 subjects [cognitively normal (CN), mild cognitive impairment (MCI), and AD] were selected from the AD Neuroimaging Initiative (ADNI) database. Brain functional, structural, and microstructural features were extracted, and nine ML models, including support vector machine (SVM), random forest (RF), and Naive Bayes, were trained and evaluated across three binary classification tasks: AD-CN, MCI-CN, and AD-MCI.

RESULTS: The SVM model achieved the highest performance for AD-CN (AUC = 0.901) and MCI-CN (AUC = 0.839), while RF performed best for AD-MCI classification (AUC = 0.809). Functional analyses revealed significant abnormalities in key regions, including the anterior cingulate cortex, hippocampus, and middle frontal gyrus in AD patients. Structural analyses confirmed that hippocampal subfield atrophy was strongly associated with cognitive decline. Diffusion metrics, particularly the DTI-ALPS index, reflected microstructural white matter damage effectively.

CONCLUSION: Integrating multimodal neuroimaging with ML enhances diagnostic accuracy for AD and MCI and identifies potential neuroimaging biomarkers, providing objective evidence to support early clinical intervention.},
}

@article {pmid42052506,
year = {2026},
author = {Butters, E and Collins-Jones, L and Mesquita, RC and Acharya, D and McKiernan, E and Laurell, AAS and Low, A and Srinivasan, S and O'Brien, JT and Su, L and Bale, G},
title = {Brain network analysis in Alzheimer's disease and mild cognitive impairment using high-density diffuse optical tomography.},
journal = {Imaging neuroscience (Cambridge, Mass.)},
volume = {4},
number = {},
pages = {},
pmid = {42052506},
issn = {2837-6056},
abstract = {Dementia is associated with altered resting-state connectivity, measures of which could aid in its early detection and monitoring. High-density diffuse optical tomography (HD-DOT) is well suited to detect these alterations at scale due to its numerous practical advantages, but it has not yet been applied to dementia. In this study, we investigated resting-state functional connectivity across the prefrontal cortex in individuals with mild cognitive impairment (MCI, n = 22), Alzheimer's disease (AD, n = 21), and in healthy controls (n = 22). A graph theoretical approach was taken to characterise both global and local patterns of prefrontal connectivity over a 5-minute resting period. We found that individuals with MCI exhibited denser and stronger networks with shorter path lengths, which normalised in AD, accompanied by a redistribution of network hubs that were less stable. These results perhaps reflect the recruitment of additional connections in the early stages of pathology to maintain short-term network stability, which is ultimately associated with less efficient and more fragmented network organisation in later stages. Following the demonstration of HD-DOT's capacity to detect differences between healthy ageing and AD-type cognitive impairment, this work opens up new possibilities for the use of optical imaging in the study of this clinical population and HD-DOT's potential for scalable clinical use.},
}

@article {pmid42052655,
year = {2026},
author = {Zhao, R and Guo, M and Yang, F and Yan, Y and Tian, D and Deng, L and Wang, Q and Xie, M},
title = {A microglia membrane biomimetic platinum-based MOF-loaded quercetin nanodrug delivery system for the treatment of Alzheimer's disease.},
journal = {Journal of materials chemistry. B},
volume = {},
number = {},
pages = {},
doi = {10.1039/d6tb00201c},
pmid = {42052655},
issn = {2050-7518},
abstract = {The aberrant deposition of β-amyloid (Aβ) is a central pathological hallmark of Alzheimer's disease (AD), triggering oxidative stress, metal ion dyshomeostasis, and excessive microglial activation in a self-perpetuating pathological cascade. To address these interconnected processes, a platinum-based metal-organic framework (Pt-MOF) with intrinsic antioxidant enzyme-mimetic activity was constructed and loaded with quercetin (Qu) to regulate microglial dysfunction. To enhance blood-brain barrier (BBB) penetration and inflammation-targeting capability, Pt-MOF/Qu was further camouflaged with microglial cell membranes (BV2), yielding Pt-MOF/Qu/BV2 nanoparticles. In vitro studies demonstrated that Pt-MOF/Qu/BV2 efficiently scavenged reactive oxygen species and effectively chelated Cu[2+] ions via surface functional groups, thereby inhibiting Aβ aggregation and promoting the disassembly of preformed Aβ aggregates. In addition, the Pt-MOF enabled efficient loading and controlled release of Qu, which significantly restored mitochondrial membrane potential and alleviated microglial over-activation. The BV2 membrane coating markedly improved the biocompatibility and BBB translocation efficiency of the nanoplatform. Furthermore, Pt-MOF/Qu/BV2 significantly reduced reactive oxygen species (ROS) in vivo and Aβ brain plaque accumulation in the head region, alleviated neurotoxicity and improved the behavioral phenotype in the C. elegans AD model. Overall, this biomimetic multifunctional MOF-based nanoplatform represents a promising multi-target therapeutic strategy for AD.},
}

@article {pmid42052757,
year = {2026},
author = {Svobodova, I and Bendova, Z and Novotny, J},
title = {Astrocytes and Their Role in the Development and Progression of Alzheimer's Disease: Gatekeepers of Neurodegeneration.},
journal = {Journal of integrative neuroscience},
volume = {25},
number = {4},
pages = {49765},
doi = {10.31083/JIN49765},
pmid = {42052757},
issn = {0219-6352},
support = {23-07184S//Czech Grant Foundation/ ; },
mesh = {*Alzheimer Disease/metabolism/pathology ; Humans ; *Astrocytes/metabolism ; Animals ; Disease Progression ; },
abstract = {Astrocytes are increasingly recognized as central players in the pathogenesis of Alzheimer's disease (AD), exhibiting both neuroprotective and neurotoxic functions, which complicates their role in disease progression. Under physiological conditions, astrocytes support neuronal homeostasis, facilitate synaptic function, and promote the clearance of Amyloid-β (Aβ), thereby contributing to neuroprotection. In the context of AD, however, reactive astrocytes can adopt detrimental phenotypes, releasing pro-inflammatory cytokines, generating oxidative stress, and disrupting neuronal networks, thereby exacerbating neurodegeneration. Consequently, the shift from a protective to a neurotoxic phenotype may not only drive neuronal loss but also accelerate AD progression. The dual roles of astrocytes and the dynamic changes in their functions-protecting neurons under normal conditions while promoting pathology when dysregulated-underscore their complex contribution to AD pathophysiology. Elucidating the mechanisms underlying astrocyte-mediated neuroprotection and neurotoxicity is essential for developing targeted therapeutic strategies aimed at modulating astrocyte activity to slow or prevent disease progression. This review aims to present and critically discuss recent advances and ongoing controversies concerning the involvement of astrocytes in AD.},
}

*Alzheimer Disease/metabolism/pathology
Humans
*Astrocytes/metabolism
Animals
Disease Progression

@article {pmid42052761,
year = {2026},
author = {Guo, Y and Zhang, Z and Chen, B and Liu, H and Wei, F and Liu, X and Guo, Z},
title = {Functional Connectivity Alterations in the Cholinergic Neural Circuits of Patients With Alzheimer's Disease: A Donepezil Intervention Study Using Resting-State Functional Magnetic Resonance Imaging.},
journal = {Journal of integrative neuroscience},
volume = {25},
number = {4},
pages = {50039},
doi = {10.31083/JIN50039},
pmid = {42052761},
issn = {0219-6352},
support = {2017KY109//General Project of the Department of Science and Technology of Zhejiang Province/ ; 2020358406//General Project of the Department of Science and Technology of Zhejiang Province/ ; 2018KY031//General Project of the Department of Science and Technology of Zhejiang Province/ ; 2024KY873//General Project of the Department of Science and Technology of Zhejiang Province/ ; [2024]90662//National Leading Medical Specialty Development Project-Department of Geriatrics, Tongde Hospital of Zhejiang Province/ ; [2024]10//Zhejiang Provincial Alliance of Traditional Chinese Medicine Advantage Specialty for Geriatric Diseases/ ; },
mesh = {Humans ; *Donepezil/pharmacology/administration & dosage ; *Alzheimer Disease/drug therapy/diagnostic imaging/physiopathology ; Male ; Female ; Magnetic Resonance Imaging ; Aged ; *Cholinesterase Inhibitors/pharmacology/administration & dosage ; *Nerve Net/diagnostic imaging/drug effects/physiopathology ; Middle Aged ; *Connectome ; *Basal Forebrain/diagnostic imaging/drug effects/physiopathology ; Longitudinal Studies ; *Nootropic Agents/pharmacology/administration & dosage ; Cerebellum/diagnostic imaging/physiopathology/drug effects ; Aged, 80 and over ; },
abstract = {BACKGROUND: Although donepezil alleviates Alzheimer's disease (AD) symptoms by raising acetylcholine levels, its impact on cholinergic pathways remains unclear. In this longitudinal, resting-state functional magnetic resonance imaging (rs-fMRI) study, we investigated donepezil-induced changes in cholinergic pathway networks in AD.

METHODS: AD patients and healthy controls (HCs) were enrolled. AD patients received 24 weeks of donepezil treatment. Cognitive and emotional symptoms were assessed using the Mini-Mental State Examination (MMSE), Cornell Scale for Depression in Dementia (CSDD), and Neuropsychiatric Inventory (NPI) pre- and post-treatment. rs-fMRI was used to examine basal forebrain (BF) functional connectivity.

RESULTS: Sixteen AD patients and 16 HCs completed the study. Post-treatment MMSE scores improved, and NPI and CSDD scores decreased. Reduced BF functional connectivity in the left cerebellar lobule VI, post-treatment, was revealed by rs-fMRI. Compared with HCs, post-treatment AD patients showed lower BF functional connectivity in the right postcentral gyrus (PoG); pre-treatment patients exhibited higher BF functional connectivity in the left cerebellar lobule VI. Right PoG functional connectivity was negatively correlated with disease duration pre-treatment and positively correlated with MMSE post-treatment.

CONCLUSIONS: Donepezil improved clinical symptoms in AD by modulating the BF-PoG cholinergic pathway.},
}

Humans
*Donepezil/pharmacology/administration & dosage
*Alzheimer Disease/drug therapy/diagnostic imaging/physiopathology
Male
Female
Magnetic Resonance Imaging
Aged
*Cholinesterase Inhibitors/pharmacology/administration & dosage
*Nerve Net/diagnostic imaging/drug effects/physiopathology
Middle Aged
*Connectome
*Basal Forebrain/diagnostic imaging/drug effects/physiopathology
Longitudinal Studies
*Nootropic Agents/pharmacology/administration & dosage
Cerebellum/diagnostic imaging/physiopathology/drug effects
Aged, 80 and over

@article {pmid42052762,
year = {2026},
author = {Balakrishnan, J and Kannan, S and Shanmugam, K and Sugasini, D},
title = {Targeting Lipid Metabolism in Alzheimer's Disease: Emerging Insights and Future Directions.},
journal = {Journal of integrative neuroscience},
volume = {25},
number = {4},
pages = {48436},
doi = {10.31083/JIN48436},
pmid = {42052762},
issn = {0219-6352},
mesh = {Humans ; *Alzheimer Disease/metabolism/genetics/drug therapy ; *Lipid Metabolism/physiology ; Animals ; Lipidomics ; },
abstract = {Alzheimer's disease (AD) is a multifactorial neurodegenerative disease that is conventionally characterized by amyloid-β and tau pathology. There is growing evidence, however, that lipid metabolic disturbances are part of the biology of the disease, and not a secondary phenomenon. Lipid signaling controls membrane organization, amyloid precursor protein, tau phosphorylation, mitochondrial energetics, neuroinflammatory signaling, and synaptic stability. The accumulating genetic evidence, including risk variants in the APOE (apolipoprotein E), ABCA1 (ATP-binding cassette subfamily A member 1), ABCA7 (ATP-binding cassette subfamily A member 7), and TREM2 (Triggering receptor expressed on myeloid cells 2) genes, further makes lipid transport and lipid-sensing pathways central to late-onset AD vulnerability. Recent developments in lipidomics based on mass spectrometry have revealed concerted changes in phospholipids, sphingolipids, sterols, and oxidized lipid derivatives in brain tissue and peripheral biofluids. Instead of single abnormalities, directional metabolic imbalance is indicated by pathway changes, including decreased sphingomyelin-to-ceramide ratios and decreased polyunsaturated phospholipids. Co-analysis of lipidomic, genomic, and proteomic data has shown the existence of metabolically different subgroups, which aids genotype stratified risk evaluation and the lipid responder phenotype concept. Protein-centered therapies are complemented by therapeutic strategies that focus on lipid homeostasis, such as the regulation of cholesterol efflux, sphingolipid metabolism, pro-resolving lipid mediators, and metabolic reprogramming. There is also emerging evidence that implicates peroxisomal dysfunction and compromised glymphatic clearance in interfering with lipid balance. Although this field of research has come a long way, the issues of proving causality, standardizing lipidomic techniques, and converting pathway signatures into clinically useful resources persist. Restructuring AD as a lipid network instability disorder offers a systems level model of earlier diagnosis and targeted treatment.},
}

Humans
*Alzheimer Disease/metabolism/genetics/drug therapy
*Lipid Metabolism/physiology
Animals
Lipidomics

@article {pmid42052769,
year = {2026},
author = {Wang, Z and Pan, Y and Shu, M and Zou, L},
title = {The Lysosomal-Associated Protein Transmembrane Family and Neurological Disorders: Therapeutic Potential and Future Research Directions.},
journal = {Journal of integrative neuroscience},
volume = {25},
number = {4},
pages = {47903},
doi = {10.31083/JIN47903},
pmid = {42052769},
issn = {0219-6352},
support = {82201590//National Natural Science Foundation of China/ ; 2022CFB721//Natural Science Foundation of Hubei Province/ ; ZNJC202536//The Translational Medicine, the Interdisciplinary Research Joint Fund of Zhongnan Hospital of Wuhan University/ ; CXPY202535//Science and Technology Innovation Cultivation Fund of Zhongnan Hospital of Wuhan University/ ; },
mesh = {Humans ; *Nervous System Diseases/metabolism/therapy ; Animals ; *Membrane Proteins/metabolism ; Lysosomes/metabolism ; *Oncogene Proteins/metabolism ; },
abstract = {Lysosomal-associated protein transmembrane (LAPTM) family members-including LAPTM4A, LAPTM4B, and LAPTM5-are key regulators of lysosomal integrity, autophagy-lysosome flux, lipid metabolism, and immune responses. Dysregulation of LAPTM proteins contributes to neurological disorders such as Alzheimer's disease, Parkinson's disease, ischemic stroke, and gliomas, affecting neuronal survival, glial homeostasis, neuroinflammation, and tumor progression. In this review, we summarize recent insights into the structural features and molecular mechanisms of LAPTM proteins in the nervous system and highlight their therapeutic potential in promoting protein aggregate clearance, mitigating oxidative stress, regulating microglial polarization, and enhancing tumor immunotherapy. Future research integrating gene therapy, small-molecule modulators, multi-omics profiling, and advanced delivery platforms may enable translation of LAPTM-targeted interventions into clinical practice, offering new avenues for diagnosis, prognosis, and treatment of neurological diseases.},
}

Humans
*Nervous System Diseases/metabolism/therapy
Animals
*Membrane Proteins/metabolism
Lysosomes/metabolism
*Oncogene Proteins/metabolism

@article {pmid42052844,
year = {2026},
author = {Chen, W and Wang, J and Li, Q and Zhang, L and Wu, X and Luo, S and Xie, Y and Guo, P},
title = {Keap1-Nrf2 Signaling Pathway-Mediated Antioxidant Defense in Neurodegenerative Diseases: Mechanisms and Traditional Chinese Medicine Therapeutic Strategies.},
journal = {Frontiers in bioscience (Landmark edition)},
volume = {31},
number = {4},
pages = {45233},
doi = {10.31083/FBL45233},
pmid = {42052844},
issn = {2768-6698},
support = {81660671//National Natural Science Foundation of China/ ; 202101AZ070001-172//Yunnan Provincial Science and Technology Department-Applied Basic Research Joint Special Funds of Chinese Medicine/ ; 202105AG070014//Yunnan Provincial Key Laboratory of Formula Granules/ ; zyzdxk-2023192//High-level Discipline Construction Project of Dai Medicine, National Administration of Traditional Chinese Medicine/ ; 2024SS24045//Yunnan Key Laboratory for Dai and Yi Medicines/ ; },
mesh = {Humans ; *NF-E2-Related Factor 2/metabolism ; *Signal Transduction/drug effects ; *Kelch-Like ECH-Associated Protein 1/metabolism ; *Neurodegenerative Diseases/metabolism/drug therapy ; *Medicine, Chinese Traditional/methods ; *Antioxidants/metabolism/therapeutic use ; Oxidative Stress/drug effects ; Animals ; Drugs, Chinese Herbal/therapeutic use ; },
abstract = {Neurodegenerative diseases (NDs) are incurable, progressively disabling disorders marked by sustained neuronal degeneration and loss. Their molecular basis involves intricate regulatory networks, while current therapeutic strategies remain inadequate. Oxidative stress (OS) constitutes a major driver in the initiation and progression of age-related pathologies. Kelch-like enoyl-CoA hydratase-associated protein-1 (Keap1)-Nuclear factor Erythroid 2-related factor 2 (Nrf2) signaling pathway, an essential antioxidant system, exerts protective effects by limiting OS-mediated cellular injury. Extensive evidence demonstrates a close association between Nrf2 signaling and the pathological processes of NDs, including Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), and amyotrophic lateral sclerosis (ALS). Traditional Chinese medicine, characterized by multi-target and multi-pathway regulatory actions of its bioactive constituents, offers distinctive therapeutic potential for NDs. This review provides an integrated analysis of current advances of Nrf2 involvement in NDs and evaluates therapeutic strategies based on traditional Chinese medicine and its active components, with the aim of guiding future clinical translation.},
}

Humans
*NF-E2-Related Factor 2/metabolism
*Signal Transduction/drug effects
*Kelch-Like ECH-Associated Protein 1/metabolism
*Neurodegenerative Diseases/metabolism/drug therapy
*Medicine, Chinese Traditional/methods
*Antioxidants/metabolism/therapeutic use
Oxidative Stress/drug effects
Animals
Drugs, Chinese Herbal/therapeutic use

@article {pmid42052872,
year = {2026},
author = {Tosun, D},
title = {APOE shifts the tipping point: addressing pathological heterogeneity in Alzheimer's disease trials.},
journal = {Brain : a journal of neurology},
volume = {},
number = {},
pages = {},
doi = {10.1093/brain/awag151},
pmid = {42052872},
issn = {1460-2156},
}

@article {pmid42052893,
year = {2026},
author = {Geithus, S and Flønes, IH and Alves, G and Tysnes, OB and van de Berg, WDJ and Pihlstrøm, L and Nido, GS and Tzoulis, C},
title = {Comparative transcriptomics reveal molecular convergence and divergence in parkinsonian disorders.},
journal = {Brain : a journal of neurology},
volume = {},
number = {},
pages = {},
doi = {10.1093/brain/awag153},
pmid = {42052893},
issn = {1460-2156},
abstract = {Neurodegenerative parkinsonisms are phenotypically diverse disorders including Parkinson's disease, dementia with Lewy bodies, multiple system atrophy, progressive supranuclear palsy, and corticobasal degeneration. These currently incurable diseases are characterized by overlapping but also distinct clinicopathological and molecular features, and largely unknown pathogenesis. Transcriptomic studies have offered insights, but are limited by small sample sizes, technical variability, and limited reproducibility. Here, we present a large comparative bulk transcriptomic analysis of parkinsonian syndromes, comprising n = 977 post-mortem prefrontal cortex samples from pathologically-confirmed Parkinson's disease (n = 448), dementia with Lewy bodies (n = 80), multiple system atrophy (n = 35), progressive supranuclear palsy (n = 42), corticobasal degeneration (n = 17), Alzheimer's disease (n= 72), and neurologically healthy controls (n = 283). Accounting for key covariates including age, sex, RNA integrity (RIN), brain bank origin, and cell type composition, we identify convergent and divergent gene expression and pathway profiles across parkinsonisms and Alzheimer's disease. All diseases showed neuronal transcript loss and enrichment of glial signatures, consistent with neurodegeneration. Across the parkinsonian spectrum, we identified consistent downregulation of pathways related to protein homeostasis, mitochondrial energy metabolism, RNA processing, and DNA repair, highlighting core processes associated with neurodegeneration. Lewy body diseases (Parkinson's disease, dementia with Lewy bodies) and tauopathies (progressive supranuclear palsy and corticobasal degeneration) formed distinct similarity clusters, while multiple system atrophy occupied an intermediate position, possibly reflecting its glial pathology. To facilitate further research and discovery, we provide an open-access interactive web resource (https://parkdb.decode-pd.org) enabling researchers to query, visualize, and compare differential gene and pathway expression across disorders. This study establishes the most comprehensive comparative transcriptomic map of neurodegenerative parkinsonisms to date, identifies shared and distinct molecular mechanisms in α-synucleinopathies and tauopathies, and provides a resource for hypothesis generation and therapeutic target discovery.},
}

@article {pmid42053112,
year = {2026},
author = {Dharshan, SS and Madesh, S and Ramamurthy, K and Radhakrishnan, J and Salamuthu, K and Almutairi, MH and Almutairi, BO and Namasivayam, SKR and Kumaradoss, KM and Arockiaraj, J},
title = {Combating Cadmium-Induced Neurotoxicity, Oxidative Stress, and Inflammatory Pathways Using DOPA-31, a Dioxopiperidinamide Derivative in an In Vivo Zebrafish Model.},
journal = {Journal of biochemical and molecular toxicology},
volume = {40},
number = {5},
pages = {e70872},
doi = {10.1002/jbt.70872},
pmid = {42053112},
issn = {1099-0461},
mesh = {Animals ; Zebrafish ; *Oxidative Stress/drug effects ; *Cadmium/toxicity ; Disease Models, Animal ; *Neuroprotective Agents/pharmacology ; *Inflammation/chemically induced/metabolism/drug therapy ; *Neurotoxicity Syndromes/metabolism/drug therapy/pathology ; Antioxidants/pharmacology ; },
abstract = {Cadmium (Cd), a prevalent environmental toxin and pollutant capable of causing neurodegenerative diseases (NDs) like Alzheimer's and Parkinson's, primarily through oxidative stress, calcium imbalance, and neuroinflammation-induced mechanisms. Cd exposure increases the level of reactive oxygen species (ROS) and disrupts neurotransmitters by lowering antioxidants, leading to neuron death. Cd exposure in zebrafish results in neurodegeneration, with motor, mental, and behavioral impairments. The efficacy of the DOPA-31 intervention at varying concentrations was evaluated through the behavioral tests, biochemical assays for antioxidant enzyme activities (SOD, CAT, GSH, MDA), and histopathological analysis. Additionally, the alterations in expression levels of inflammation (tnf-α, il-1β) and neuroprotective (bdnf, syn2a) genes were also assessed. The Cd exposure exhibited the major deficits in the key behavioral parameters (motor, anxiety, and cognitive impairment). It disrupted antioxidant enzyme activity, increased lipid peroxidation, and elevated acetyl cholinesterase (AChE) activity, leading to cholinergic dysfunction. Histopathology showed extensive neuronal damage and amyloid-like protein aggregation. DOPA-31 at a 20 µM concentration, substantially exhibited antioxidant and AChE activity by reducing oxidative stress and improving motor and cognitive functions. Molecular analysis of DOPA-31 treatment showed significant downregulation of pro-inflammatory markers and upregulation of neuroprotective factors. In addition, DOPA-31 restored behavioral changes by potentially mitigating neuronal damage and protein aggregation caused by the Cd-induced neurotoxicity. This research investigation suggests the novel drug candidate DOPA-31 as a preliminary treatment for Neurodegenerative Disorder (NDD)-like features and warrants further exploration in higher animal models to assess clinical relevance.},
}

Animals
Zebrafish
*Oxidative Stress/drug effects
*Cadmium/toxicity
Disease Models, Animal
*Neuroprotective Agents/pharmacology
*Inflammation/chemically induced/metabolism/drug therapy
*Neurotoxicity Syndromes/metabolism/drug therapy/pathology
Antioxidants/pharmacology

@article {pmid42053135,
year = {2026},
author = {Arslan, B and Gobom, J and Simrén, J and Fahlén, H and Andreasson, U and Andrea Lessa Benedet, and Kvartsberg, H and Zetterberg, H},
title = {Real-world performance of Lumipulse G plasma p-tau217: a six-month experience of a specialized clinical neurochemistry laboratory.},
journal = {Clinical chemistry and laboratory medicine},
volume = {},
number = {},
pages = {},
pmid = {42053135},
issn = {1437-4331},
abstract = {OBJECTIVES: Plasma p-tau217 is a leading blood-based biomarker for Alzheimer's disease (AD), offering high diagnostic accuracy and potential utility for treatment eligibility and monitoring. However, real-world data on concordance between cerebrospinal fluid (CSF) Aβ42/40 and plasma p-tau217 in routine clinical laboratory settings remain limited.

METHODS: We retrospectively evaluated all plasma p-tau217 tests performed in the Clinical Neurochemistry Laboratory at Sahlgrenska University Hospital between August 2025 and March 2026. De-identified plasma p-tau217, additional blood biomarkers, and available CSF results were extracted from the laboratory information system. Concordance between plasma p-tau217 and CSF Aβ42/40 was evaluated by calculating positive and negative percent agreement, with CSF Aβ42/40 used as the reference standard. In addition, diagnostic accuracy for brain amyloid positivity was assessed using two predefined clinical cutoffs for plasma p-tau217 (<0.22 vs. >0.34 ng/L). Internal analytical performance was monitored over a six-month period using commercial quality control materials, with additional evaluation of lot-to-lot consistency for plasma p-tau217.

RESULTS: Among 1,352 plasma p-tau217 measurements, paired CSF Aβ42/40 data were available for 121 individuals. Based on plasma p-tau217 probability categories, 541 samples (40.0 %) were classified as low probability, 228 (16.9 %) as intermediate probability, and 583 (43.1 %) as high probability for amyloid pathology. Using CSF Aβ42/40 as the reference standard, plasma p-tau217 demonstrated a positive percent agreement of 84.5 % (95 % CI: 72.6-92.7 %) and a negative percent agreement of 87.5 % (95 % CI: 73.2-95.8 %). Internal quality control analyses showed good within-batch precision, with coefficients of variation below 7.3 %. Batch-dependent bias was observed in QC measurements, most notably for one batch (+14.4-18.4 %); however, subsequent QC investigations indicated that this deviation originated from the QC material rather than from assay-related performance. Lot-to-lot consistency assessment did not reveal systematic reagent lot-dependent effects during the study period.

CONCLUSIONS: Lumipulse plasma p-tau217 demonstrated stable analytical performance and consistent concordance with CSF Aβ42/40 in routine clinical practice. The observed agreement supports the feasibility of plasma p-tau217 as a supportive tool in the clinical evaluation of AD, while underscoring the need for continued quality control monitoring and prospective evaluation of assay performance.},
}

@article {pmid42053356,
year = {2026},
author = {Pandey, P and Kruger, M and Sharma, A and Swanepoel, W and Rodrigo, H and Beukes, E and Manchaiah, V},
title = {Effects of Hearing Devices for Adults With Mild-to-Severe Hearing Loss: A Systematic Review and Meta-Analysis of Randomized Controlled Trials.},
journal = {Journal of speech, language, and hearing research : JSLHR},
volume = {},
number = {},
pages = {1-24},
doi = {10.1044/2026_JSLHR-25-00737},
pmid = {42053356},
issn = {1558-9102},
abstract = {OBJECTIVES: The aim of this study was to evaluate the effect of hearing devices for adults with mild-to-severe hearing losses. Specifically, we assessed the magnitude of change across outcome domains, identified measurement tools used, and reported adverse effects associated with device use.

DESIGN: We conducted a systematic review and meta-analysis following Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Searches were performed in PubMed, CINAHL, and Embase. Included studies were randomized controlled trials (RCTs) involving adults (≥ 18 years of age) with mild-to-severe hearing loss, comparing any air-conduction hearing device to passive or active controls. Effect sizes were calculated as Hedges's g, and random-effects models estimated pooled effects.

RESULTS: Thirty-three RCTs (N = 4,471 participants) met the inclusion criteria, although pooled estimates could be derived from only a subset of trials due to limited reporting. Hearing aids demonstrated moderate-to-large benefits on hearing-related self-report outcomes compared with no-intervention or waitlist controls; however, pooled meta-analytic estimates could not be generated for this comparison because of insufficient data across trials. Compared with placebo, hearing aids yielded a small pooled effect (g ≈ 0.37), driven largely by trials including participants with comorbid Alzheimer's disease. Personal sound amplification products (PSAPs) showed a pooled medium effect compared with no intervention (g ≈ 0.42), with benefits primarily observed for hearing-specific self-report outcomes and selected behavioral measures. In head-to-head comparisons, hearing aids showed a large pooled advantage over other hearing devices, including smartphone hearing aid applications (SHAAs) and extended-wear hearing aids (EWHAs; g ≈ 0.88), based on data from two trials. Across the included studies, most outcomes were self-reported (≈ 81%) and behavioral (≈ 45%), with very limited assessment of cognitive or neurophysiological domains. Nine studies reported adverse events, with only one device-related incident. Heterogeneity was high (I[2] > 80%), but no publication bias was detected.

CONCLUSIONS: Hearing aids provide substantial benefit for hearing-related self-reported outcomes in comparison to PSAPs, SHAAs, EWHAs, and placebo. However, high heterogeneity prevents reliable conclusions based on pooled estimates. There also remains limited evidence on cognitive, neurophysiological, and long-term behavioral outcomes, underscoring the need for more rigorous, domain-diverse RCTs in this field.

SUPPLEMENTAL MATERIAL: https://doi.org/10.23641/asha.32086299.},
}

@article {pmid42053514,
year = {2026},
author = {},
title = {RETRACTION: The 12-15-Lipoxygenase is a Modulator of Alzheimer's-Related Tau Pathology In Vivo.},
journal = {Aging cell},
volume = {25},
number = {5},
pages = {e70524},
doi = {10.1111/acel.70524},
pmid = {42053514},
issn = {1474-9726},
abstract = {P. F. Giannopoulos, Y. B. Joshi, J. Chu, and D. Praticò, "The 12-15-Lipoxygenase is a Modulator of Alzheimer's-Related Tau Pathology In Vivo," Aging Cell 12, no. 6 (2013): 1082-1090, https://doi.org/10.1111/acel.12136. The above article, published online on 17 July 2013 in Wiley Online Library (wileyonlinelibrary.com), has been retracted by agreement between the journal Editor-in-Chief, Monty Montano; The Anatomical Society; and John Wiley & Sons Ltd. The retraction has been agreed upon following an investigation into concerns raised by the corresponding author, D. Praticò. This identified image duplication of the tau1 bands in Figures 3A and 5A. As a result, the data and the conclusions are considered unreliable. D. Praticò and Y. B. Joshi agreed to the decision to retract. P. F. Giannopoulos and J. Chu were informed of the decision to retract but remained unresponsive.},
}

@article {pmid42053612,
year = {2026},
author = {Shen, X and Ding, L and Li, X and Gu, L and Yang, J},
title = {Diagnosis of Alzheimer's disease based on particle swarm optimization EEG signal channel selection and gated recurrent unit.},
journal = {Computer methods in biomechanics and biomedical engineering},
volume = {},
number = {},
pages = {1-16},
doi = {10.1080/10255842.2026.2661797},
pmid = {42053612},
issn = {1476-8259},
abstract = {Electroencephalogram (EEG) reflect changes in the electrophysiological activity of the brain and can be used in the diagnosis of Alzheimer's disease (AD). Each EEG channel provides real-time information about the brain, while different EEG channels contain different information about the brain. Using all EEG channel data for AD diagnosis contains redundancy data, leading to increased computation and reduced data analysis accuracy. In this paper, a diagnostic method for AD based on Particle Swarm Optimization (PSO) EEG channel selection and Gated Recurrent Unit (GRU) is proposed. Using EEG energy as the fitness function and PSO to select EEG channels, the redundant information in EEG data is reduced and the accuracy of EEG data analysis is improved. GRU is a special kind of recurrent neural network (RNN) structure. It uses EEG data extracted by the principal component analysis (PCA) feature based on singular value decomposition (SVD) as input to the model. And it has a good advantage in analyzing the time series of EEG. The results show that the classification accuracy of the method in this paper reaches 0.9487, which is higher than the performance of other proposed methods. Compared to the results of using all EEG channel data analysis, the classification accuracy of this method was improved by 0.0757. It shows that the method proposed in this paper can improve the classification accuracy of EEG in AD classification tasks and can be applied to related classification tasks.},
}

@article {pmid42053700,
year = {2026},
author = {Lin, C and Qi, L and Gao, X and Hu, L and Qian, B and Deng, Y and Zhou, C and Wang, C and Liu, G and Ding, Q and Lin, Z and Zhu, X and Zhang, M},
title = {Therapeutic Mechanisms of Stem Cell-Derived Exosomes for Neurological Disorders: An Overview.},
journal = {Molecular neurobiology},
volume = {63},
number = {1},
pages = {},
pmid = {42053700},
issn = {1559-1182},
support = {82271747//the National Natural Science Foundation of China/ ; 82505180//the National Natural Science Foundation of China/ ; ZY2023013//Wenzhou Major Scientific and Technological Innovation Project/ ; 2025C02081//he Zhejiang Provincial Key Research and Development Program/ ; 2025M783998//the China Postdoctoral Science Foundation/ ; },
mesh = {*Exosomes/metabolism/transplantation ; Humans ; Animals ; *Nervous System Diseases/therapy ; *Stem Cells/metabolism ; *Stem Cell Transplantation/methods ; },
abstract = {The current management of neurological disorders remains largely symptomatic. In recent years, stem cell-derived exosomes have emerged as a promising alternative therapeutic strategy. This narrative review synthesizes evidence from preclinical studies investigating the mechanisms and efficacy of exosome-based therapy for neurological conditions. The included studies encompass animal models and in vitro systems. Accumulating preclinical evidence consistently supports the therapeutic potential of stem cell-derived exosomes across several neurological disorders. In Alzheimer's disease models, stem cell-derived exosomes reduce β-amyloid plaque deposition and attenuate neuroinflammation. For Parkinson's disease, they exert neuroprotective effects on dopaminergic neurons. They also inhibit α-synuclein aggregation. In ischemic stroke and spinal cord injury, stem cell-derived exosomes promote functional recovery through multiple mechanisms. These include suppressing ferroptosis, promoting angiogenesis, and stimulating axonal regeneration. Improved delivery strategies, such as intranasal administration and hydrogel encapsulation, have further enhanced brain targeting and treatment durability. Despite these promising preclinical findings, several challenges remain. A primary issue is the lack of standardized preparation protocols. Significant uncertainties also exist regarding long-term safety. Furthermore, pathways for clinical translation are still unclear. Future research should prioritize elucidating the underlying mechanisms of exosome therapy. The refinement of targeted delivery systems is equally important. Finally, advancing rigorously designed clinical trials is crucial to facilitate the translation of these therapies into clinical practice.},
}

*Exosomes/metabolism/transplantation
Humans
Animals
*Nervous System Diseases/therapy
*Stem Cells/metabolism
*Stem Cell Transplantation/methods

@article {pmid42053826,
year = {2026},
author = {Pradhan, D and Upadhyay, RK},
title = {Unravelling the spatiotemporal dynamics of amyloid- β -induced astrocyte-neuron network model in Alzheimer's disease.},
journal = {Journal of mathematical biology},
volume = {92},
number = {5},
pages = {},
pmid = {42053826},
issn = {1432-1416},
support = {CRG/2023/000583//Science and Engineering Research Board, IN/ ; },
mesh = {*Alzheimer Disease/physiopathology/metabolism/etiology/pathology ; *Astrocytes/physiology/metabolism ; Humans ; *Neurons/physiology/metabolism ; *Models, Neurological ; *Amyloid beta-Peptides/metabolism/physiology ; Computer Simulation ; Calcium Signaling/physiology ; Mathematical Concepts ; Nerve Net/physiopathology ; Animals ; Synapses/physiology ; },
abstract = {Recent research highlights that calcium dysfunction, emerging from impaired neuron-astrocyte interactions plays a crucial role in the pathogenesis of Alzheimer's disease (AD). In our current study, we investigate this through a computational model of bidirectional coupling between a neuron and an astrocyte within a tripartite synapse framework. Individually, neuron is designed to exhibit neuronal firing dynamics, while the astrocyte captures amyloid- β -mediated calcium signaling. In particular, we consider the spatiotemporal version of the model across three scenarios: (i) no diffusion; (ii) diffusion in either neurons or astrocytes; and (iii) diffusion in both. Without diffusion, bifurcation analysis reveals that astrocytic feedback can trigger neuronal firing via a supercritical Andronov-Hopf bifurcation, emphasizing astrocytic regulation of excitability. With diffusion only in neurons, complex Ginzburg-Landau analysis (CGLE) reveals spiral and antispiral wave patterns. When only astrocytic diffusion is present, regular and distorted hexagonal patterns emerge. The third scenario yields Turing-like structures. We further extend the model to a spatial network to explore collective dynamics and synchronization behaviors, where stronger coupling leads to partially synchronized neuronal activity. These findings demonstrate how astrocyte-neuron crosstalk and diffusion-driven instabilities contribute to emergent wave-like activity, shedding light on spatial mechanisms in AD progression.},
}

*Alzheimer Disease/physiopathology/metabolism/etiology/pathology
*Astrocytes/physiology/metabolism
Humans
*Neurons/physiology/metabolism
*Models, Neurological
*Amyloid beta-Peptides/metabolism/physiology
Computer Simulation
Calcium Signaling/physiology
Mathematical Concepts
Nerve Net/physiopathology
Animals
Synapses/physiology

@article {pmid42054026,
year = {2026},
author = {Jang, H and Lee, SM and Kim, HJ and Jung, NY and Zetterberg, H and Blennow, K and Apostolova, LG and Moon, SY and Kim, EJ and , },
title = {Plasma Biomarkers and Clinical Outcomes in Early-Onset Dementia.},
journal = {JAMA network open},
volume = {9},
number = {4},
pages = {e269687},
doi = {10.1001/jamanetworkopen.2026.9687},
pmid = {42054026},
issn = {2574-3805},
mesh = {Humans ; *Biomarkers/blood ; Female ; Male ; tau Proteins/blood ; Middle Aged ; Prospective Studies ; Neurofilament Proteins/blood ; *Alzheimer Disease/blood ; *Frontotemporal Dementia/blood ; Longitudinal Studies ; Glial Fibrillary Acidic Protein/blood ; Republic of Korea ; Aged ; Age of Onset ; },
abstract = {IMPORTANCE: Clinical utility and dynamics of plasma biomarkers in early-onset dementia remain underexplored.

OBJECTIVE: To investigate plasma biomarker trajectories and their associations with clinical outcomes in early-onset Alzheimer disease (EOAD) and frontotemporal dementia (FTD).

This multicenter, prospective cohort study analyzed participants in phase 1 of the Longitudinal Study of Early-onset Dementia and Family Members (LEAF), which was conducted from April 2021 through December 2023 in 34 centers across South Korea. Patients with β-amyloid-positive EOAD and FTD were included and underwent annual blood sampling and clinical assessment, within a follow-up period of approximately 2 years. Data were analyzed between June 2025 and March 2026.

EXPOSURE: Levels of plasma phosphorylated tau 217 (p-tau217), glial fibrillary acidic protein (GFAP), and neurofilament light chain (NfL) biomarkers were analyzed using assays.

MAIN OUTCOMES AND MEASURES: (1) Associations of baseline biomarkers with clinical outcomes (assessed with the Mini-Mental State Examination [MMSE] and the Clinical Dementia Rating-Sum of Boxes [CDR-SB] for the EOAD group, or the frontotemporal lobar degeneration [FTLD]-modified CDR-SB for the FTD group), (2) biomarker trajectories, and (3) association of biomarker level changes and clinical outcomes.

RESULTS: A total of 322 participants with p-tau217, GFAP, and NfL analyses were stratified into the EOAD or FTD group based on their diagnosis. The EOAD group (n = 245) had a mean (SD) age of 61.8 (5.4) years and included 163 females (66.5%), while the FTD group (n = 77) had a mean (SD) age of 65.1 (7.3) years and included 45 females (62.3%). In the EOAD group, higher log2-transformed baseline p-tau217, GFAP, and NfL were each associated with faster decline in the MMSE score (association estimate [SE], -0.390 [0.127], P = .002; -0.775 [0.164], P < .001; and -0.679 [0.182], P < .001, respectively) and the CDR-SB score (estimate [SE], 0.401 [0.099], P < .001; 0.535 [0.126], P < .001; and 0.693 [0.122], P < .001, respectively). In the FTD group, GFAP and NfL were associated with MMSE decline (estimate [SE], -2.118 [0.566], P < .001 and -2.360 [0.428], P < .001, respectively), whereas p-tau217 was not (estimate [SE], 0.071 [0.418], P = .87). No biomarker was associated with FTLD-modified CDR-SB score change. Longitudinally, all mean (SD) biomarker levels increased in the EOAD group (p-tau217: 0.253 [0.077] pg/mL, P = .001; GFAP: 0.173 [0.040] pg/mL, P < .001; NfL: 0.149 [0.045] pg/mL, P = .001), whereas in the FTD group, only NfL level showed an upward pattern (0.251 [0.127] pg/mL, P = .05). Annualized biomarker changes were associated with worsening clinical outcomes in the EOAD group, but not in the FTD group. GFAP and NfL level increases were associated with MMSE score decline (estimate [SE], -0.005 [0.002], P = .007 and -0.010 [0.003], P = .001, respectively), while p-tau217 level increases were associated with CDR-SB score worsening (estimate [SE], 0.072 [0.024], P = .003) in the EOAD group.

CONCLUSIONS AND RELEVANCE: In this cohort study of patients with EOAD and FTD, baseline p-tau217, GFAP, and NfL were consistently associated with clinical outcomes in the EOAD group, whereas GFAP and NfL were associated with cognition only in the FTD group. These findings demonstrate distinct characteristics of plasma biomarkers in EOAD and FTD, supporting their potential utility for risk stratification.},
}

Humans
*Biomarkers/blood
Female
Male
tau Proteins/blood
Middle Aged
Prospective Studies
Neurofilament Proteins/blood
*Alzheimer Disease/blood
*Frontotemporal Dementia/blood
Longitudinal Studies
Glial Fibrillary Acidic Protein/blood
Republic of Korea
Aged
Age of Onset

@article {pmid42054328,
year = {2026},
author = {Emelin, AY and Lobzin, VY},
title = {[Early signs of cognitive impairment: Definitions and diagnostic criteria].},
journal = {Zhurnal nevrologii i psikhiatrii imeni S.S. Korsakova},
volume = {126},
number = {4. Vyp. 2},
pages = {23-28},
doi = {10.17116/jnevro202612604223},
pmid = {42054328},
issn = {1997-7298},
mesh = {Humans ; *Cognitive Dysfunction/diagnosis ; Neuropsychological Tests ; Early Diagnosis ; },
abstract = {OBJECTIVE: To conduct a comparative analysis of existing approaches to determining the early stages of cognitive impairment, and based on the results, to propose a universal practical approach to their coding and develop diagnostic criteria.

MATERIAL AND METHODS: A comparative analysis of available literature data was performed, including Russian and international sources in the PubMed and eLibrary databases addressing the issues of determining, diagnosing, preventing, and treating the predementia stages of cognitive deficits.

RESULTS: The article discusses various options for identifying the predementia stages of cognitive impairment. Based on the analysis, it is proposed to use the universal term-the early signs of cognitive impairment-in everyday practice to encode the stage of cognitive impairment preceding the moderate cognitive impairment (MCI). The following diagnostic criteria are proposed: the symptoms of decreased memory, attention, and general mental activity presented independently or identified during an interview; the symptoms are repeated at least once a week and are not associated with any obvious reasons and external factors; extended neuropsychological examination can reveal deviations from the reference indicators; the presence of risk factors for the development of cognitive impairment; the duration of symptoms is at least 6 months; concern about their condition due to a feeling of a worse cognitive activity in comparison with other people of the same age; no MCI criteria are met.

CONCLUSION: Early objective diagnosis of the initial stages of cognitive impairment is challenging even for trained, problem-oriented specialists; therefore, it is necessary to standardize and universalize the diagnostic criteria available at all stages of medical care. A comprehensive assessment of the symptoms, the circumstances of their occurrence, and their persistence and recurrence is necessary. Objective evidence of impairment should be standardized using a universal set of neuropsychological methods.},
}

Humans
*Cognitive Dysfunction/diagnosis
Neuropsychological Tests
Early Diagnosis

@article {pmid42054329,
year = {2026},
author = {Vorobev, SV and Emelin, AY and Yanishevskiy, SN and Tantasheva, AM},
title = {[Alzheimer's disease: Diagnostic criteria and their evolution].},
journal = {Zhurnal nevrologii i psikhiatrii imeni S.S. Korsakova},
volume = {126},
number = {4. Vyp. 2},
pages = {29-39},
doi = {10.17116/jnevro202612604229},
pmid = {42054329},
issn = {1997-7298},
mesh = {Humans ; *Alzheimer Disease/diagnosis/history/pathology ; Brain/pathology ; History, 19th Century ; History, 20th Century ; },
abstract = {Studies of diseases associated with cognitive impairment have been undertaken since ancient times, at the dawn of medical science. Initially, the main focus was on the connection between higher cortical function disorders and age-related changes. This approach has been used for many centuries. In the 19[th] century, as neurology, anatomy, morphology, and other disciplines developed, it became clear that dementia is associated with specific changes in brain structure. At the beginning of the 20[th] century, Alzheimer's disease was recognized as a distinct nosological entity, with descriptions of its classical clinical manifestations, extracellular amyloid inclusions, and intracellular neurofibrillary tangles. Such a clinical and morphological approach prevailed over the next few decades. However, it was not until the 1980[s] that sufficiently clear criteria for the disease were established. The main priority was dementia in Alzheimer's disease. In addition, the definitive diagnosis was possible only on the basis of pathomorphological examination of brain tissue samples. Clearly, this situation cannot meet the current needs of both clinicians and the scientific community, especially given the diagnostic trend toward early verification of the pathological process. Therefore, research in this direction continued, and at the beginning of the 21[st] century, several diagnostic criteria were proposed based on methods for detecting Alzheimer's disease at predementia stages. There is a gradual shift in priority from clinical evaluation to laboratory and neuroimaging biomarkers. It allows us to consider Alzheimer's disease a biological process characterized by specific biochemical changes in the brain manifested long before the onset of distinct symptoms.},
}

Humans
*Alzheimer Disease/diagnosis/history/pathology
Brain/pathology
History, 19th Century
History, 20th Century

@article {pmid42054330,
year = {2026},
author = {Syromyatnikov, NN and Preobrazhenskaya, IS},
title = {[Alzheimer's disease and bilingualism].},
journal = {Zhurnal nevrologii i psikhiatrii imeni S.S. Korsakova},
volume = {126},
number = {4. Vyp. 2},
pages = {40-46},
doi = {10.17116/jnevro202612604240},
pmid = {42054330},
issn = {1997-7298},
mesh = {Humans ; *Multilingualism ; *Alzheimer Disease/physiopathology/psychology ; Cognitive Reserve ; Cognitive Dysfunction ; Disease Progression ; },
abstract = {This article examines the relationship between cognitive impairment and neurodegeneration in patients with Alzheimer's disease, with particular attention to the presence or absence of bilingualism. The concepts of cognitive and cerebral reserve are explored, along with findings from studies evaluating the effects of bilingualism on cognitive reserve and on the preservation of brain function during neurodegeneration. Bilingualism is identified as a multifaceted phenomenon encompassing various components of language experience, such as proficiency level, functional language use, language of education, age of second-language acquisition, societal status of languages, and language switching. These factors complicate research on how bilingualism influences the progression of cognitive impairment in neurodegenerative settings. The article discusses the methodological challenges inherent in bilingualism research and considers the potential influence of learning additional languages on the development of cerebral structures and neuronal connections, as shaped by language experience. The review details findings from studies investigating the impact of bilingualism on the onset and progression of Alzheimer's disease. Overall, the evidence suggests that the relationship between bilingualism and Alzheimer's disease is complex and multifactorial. Current data indicate that bilingualism is likely a significant contributor to cognitive reserve, although interpretation of research findings is frequently complicated by methodological limitations.},
}

Humans
*Multilingualism
*Alzheimer Disease/physiopathology/psychology
Cognitive Reserve
Cognitive Dysfunction
Disease Progression

@article {pmid42054332,
year = {2026},
author = {Kolmakova, KA and Lobzin, VY and Emelin, AY},
title = {[Sleep disorders in Alzheimer's disease].},
journal = {Zhurnal nevrologii i psikhiatrii imeni S.S. Korsakova},
volume = {126},
number = {4. Vyp. 2},
pages = {56-62},
doi = {10.17116/jnevro202612604256},
pmid = {42054332},
issn = {1997-7298},
mesh = {Humans ; *Alzheimer Disease/complications/physiopathology ; *Sleep Wake Disorders/therapy/etiology/physiopathology ; Memantine/therapeutic use ; Cognitive Behavioral Therapy ; Polysomnography ; },
abstract = {This article investigates the progression of sleep disturbances in Alzheimer's disease (AD) and the mechanisms by which these disturbances may accelerate neurodegeneration. Key electrophysiological patterns identified through polysomnography in patients with AD and sleep disorders are analyzed. Therapeutic interventions are reviewed, with non-pharmacological and pharmacological approaches considered separately. The roles of cognitive behavioural therapy, relaxation techniques, and optimization of sleep conditions are emphasized. Current pharmacological treatment options are discussed, highlighting the need for careful drug selection due to the high risk of adverse effects and the potential dangers of certain medications, such as benzodiazepines and cyclopyrroles, in elderly patients with cognitive impairment. The use of memantine as a foundational therapy is given particular attention, as it may improve both cognitive function and sleep quality.},
}

Humans
*Alzheimer Disease/complications/physiopathology
*Sleep Wake Disorders/therapy/etiology/physiopathology
Memantine/therapeutic use
Cognitive Behavioral Therapy
Polysomnography

@article {pmid42054333,
year = {2026},
author = {Bogolepova, AN and Burd, SG and Lebedeva, AV and Rubleva, YV and Kovalenko, EA and Machnovich, EV and Osinovskaya, NA and Pantina, NV and Kovaleva, II and Bokitko, TA and Alexeeva, GA},
title = {[Myoclonus in Alzheimer's disease].},
journal = {Zhurnal nevrologii i psikhiatrii imeni S.S. Korsakova},
volume = {126},
number = {4. Vyp. 2},
pages = {63-69},
doi = {10.17116/jnevro202612604263},
pmid = {42054333},
issn = {1997-7298},
mesh = {Humans ; *Alzheimer Disease/complications/diagnosis ; *Myoclonus/diagnosis/etiology ; Electroencephalography ; Diagnosis, Differential ; Male ; Aged ; Female ; },
abstract = {Neurodegenerative diseases are often presented with myoclonus, sudden, short-term, involuntary muscle contractions («flinching»). According to the literature, myoclonus in Alzheimer's disease (AD) can occur up to 40-50% in cases of disease with early onset and in atypical forms. Importantly, epileptic myoclonus may indicate a risk of seizures with loss of consciousness, convulsions, and epileptiform activity, which may lead to more rapid progression of cognitive deficits. Diagnosis of myoclonus is essential for timely treatment and improving the quality of life of AD patients. The paper describes the main features of myoclonus in AD, the possibility of using additional examination methods, in particular video-electroencephalographic (video-EEG) monitoring for differential diagnosis and etiology clarification, and also presents a clinical case of a patient with AD and epileptic and non-epileptic myoclonus.},
}

Humans
*Alzheimer Disease/complications/diagnosis
*Myoclonus/diagnosis/etiology
Electroencephalography
Diagnosis, Differential
Male
Aged
Female

@article {pmid42054337,
year = {2026},
author = {Selezneva, ND and Roshchina, IF and Gavrilova, SI},
title = {[Efficacy of choline alfoscerate treatment for subjective cognitive impairment in first-degree relatives of patients with Alzheimer's disease: Results of a comparative 5-year study].},
journal = {Zhurnal nevrologii i psikhiatrii imeni S.S. Korsakova},
volume = {126},
number = {4. Vyp. 2},
pages = {92-99},
doi = {10.17116/jnevro202612604292},
pmid = {42054337},
issn = {1997-7298},
mesh = {Humans ; Male ; Female ; *Alzheimer Disease/drug therapy/genetics ; Middle Aged ; *Glycerylphosphorylcholine/therapeutic use ; *Cognitive Dysfunction/drug therapy ; Aged ; Treatment Outcome ; Neuropsychological Tests ; Prospective Studies ; Follow-Up Studies ; Family ; },
abstract = {OBJECTIVE: To evaluate the five-year change of cognitive functioning in first-degree relatives of patients with Alzheimer's disease (AD) with signs of subjective cognitive impairment (SCI) treated with choline alfoscerate and untreated.

MATERIAL AND METHODS: The study included 122 subjects: 56 (45.9%) in the treatment group and 66 (54.1%) in the control group. Relatives from the treatment group received 4 courses of three-month oral choline alfoscerate therapy (400 mg 3 times a day) every 1.5 years. The study used prospective clinical, psychometric, neuropsychological, and statistical methods. Evaluation included 9 assessment visits using a battery of 10 cognitive scales and tests: in the treatment group, before and after each course of therapy, with a follow-up assessment 3 months after the end of therapy. Assessment visits in the control group were conducted using a similar methodology at the same time points.

RESULTS: On the Clinical Global Impression (CGI-I) scale, varying improvement was observed in the treatment group after each course of therapy and at follow-up examination. By the end of treatment, 96.8% of the subjects reported a marked and moderate improvement. In the control group, after 57 months, deterioration in cognitive functioning was identified at the 39[th], 57[th], and 60[th] months. SCI was converted to mild cognitive impairment syndrome (MCI) in 9.1, 15.2, and 16.7% of cases, respectively. In the treatment group, all psychometric scales and tests showed a significant improvement compared to all baseline mean group indicators after each course of therapy, and at follow-up examination in 4 out of 10 tests. In the control group, significant deterioration in scores on all scales and tests was observed from Month 39 of follow-up.

CONCLUSION: Repeated courses every three months of oral choline alfoscerate therapy for five years led in the vast majority of observations to improved cognitive functioning in persons from the treatment group at increased risk for developing AD, while untreated relatives had decreasing cognitive functioning, including a 16.7% rate of transformation of SCI into MCI.},
}

Humans
Male
Female
*Alzheimer Disease/drug therapy/genetics
Middle Aged
*Glycerylphosphorylcholine/therapeutic use
*Cognitive Dysfunction/drug therapy
Aged
Treatment Outcome
Neuropsychological Tests
Prospective Studies
Follow-Up Studies
Family

@article {pmid42054438,
year = {2026},
author = {Demuro, S and Russo, D and Penna, I and Grabska, S and Grabski, H and Dalle Vedove, A and Valeri, A and Sauvey, C and Ottonello, G and Summa, M and Bertozzi, SM and Ortega, J and Bertorelli, R and Storici, P and Girotto, S and Cruciani, G and Di Martino, RMC and Abagyan, R and Cavalli, A},
title = {A Polypharmacology-Driven Approach to Alzheimer's Disease and Tauopathies: Rational Design, Synthesis and Characterization of Amino-Pyrazole-Based Multikinase (GSK-3β/FYN-α/DYRK1A) Inhibitors.},
journal = {Journal of medicinal chemistry},
volume = {},
number = {},
pages = {},
doi = {10.1021/acs.jmedchem.5c01810},
pmid = {42054438},
issn = {1520-4804},
abstract = {Accumulation of microtubule-associated protein tau is a neurotoxic hallmark in Alzheimer's disease (AD) and related tauopathies. To date, no small molecule disease-modifying therapy exists, underscoring an urgent unmet need. In this context, the multitarget-directed ligand (MTDL) approach offers a viable polypharmacological option for modulating key pathways/targets involved in tau pathology. Leveraging the interconnected roles of GSK-3β, FYN, and DYRK1A in tau hyperphosphorylation, we conducted a computational and X-ray crystallography-driven SAR exploration around our previously disclosed GSK-3β/FYN/DYRK1A inhibitor ARN25068 (1). Modification of the thieno[3,2-d]pyrimidine central core of 1 led to the discovery of quite well-balanced GSK-3β/FYN/DYRK1A triple-targeting analogs (27, 28 (ARN25699) and 31 (ARN26646)). Among these, 28 displayed a favorable ADME profile, acceptable pharmacokinetic properties, and efficacy in an in vitro tau phosphorylation assay, outperforming three single-target inhibitors tested individually or in combination. These compounds represent promising MTDL leads poised to advance therapeutic innovation in AD and related tauopathies.},
}

@article {pmid42054495,
year = {2026},
author = {Western, D and Yang, C and Timsina, J and Liu, M and Wang, C and Campbell, MC and Kotzbauer, P and Perlmutter, JS and Schindler, SE and Morris, JC and Holtzman, DM and Alvarez, I and Pastor, P and Wyss-Coray, T and Marquié, M and Cano, A and Sung, YJ and de Rojas, I and Ruiz, A and Budde, J and Fernandez, MV and Tarawneh, R and Ibanez, L and Cruchaga, C},
title = {Low overlap of plasma and CSF protein quantitative trait loci affects protein discovery for neurological disease.},
journal = {Science translational medicine},
volume = {18},
number = {847},
pages = {eadz2016},
doi = {10.1126/scitranslmed.adz2016},
pmid = {42054495},
issn = {1946-6242},
mesh = {Humans ; *Quantitative Trait Loci/genetics ; *Nervous System Diseases/genetics/blood/cerebrospinal fluid ; *Blood Proteins/metabolism/genetics ; *Cerebrospinal Fluid Proteins/metabolism/genetics ; Alzheimer Disease/genetics/cerebrospinal fluid/blood ; },
abstract = {Plasma protein quantitative trait loci (pQTLs) have been integrated with genetic studies to prioritize proteins implicated in numerous human diseases. However, limited interaction between plasma and the central nervous system decreases the fluid's relevance for neurological disease. We compared the pQTL landscapes between plasma and cerebrospinal fluid (CSF), detecting widespread differences across fluids that translate to the identification and prioritization of proteins and pathways implicated in neurological disorders. Of almost 5000 CSF and plasma pQTLs, fewer than 30% were present in both fluids, demonstrating the importance of cross-context analyses to understand genetic regulation of protein abundance. We identified 427 associations between proteins and risk of 14 neurological traits, including 249 associations that were not found in previous studies. Only 69 of the associations were consistently detected in both fluids, demonstrating the information gained through the analysis of multiple bodily contexts. We further demonstrated that CSF proteogenomics captures more substantial disease overlap (for example, between Alzheimer's disease and dementia with Lewy bodies) and captures trait-relevant biology missed in plasma, including cell death and immune response signatures in Alzheimer's and multiple sclerosis. Through this work, we demonstrated the importance of analyzing less accessible but more trait-relevant contexts to fully understand human disease.},
}

Humans
*Quantitative Trait Loci/genetics
*Nervous System Diseases/genetics/blood/cerebrospinal fluid
*Blood Proteins/metabolism/genetics
*Cerebrospinal Fluid Proteins/metabolism/genetics
Alzheimer Disease/genetics/cerebrospinal fluid/blood

@article {pmid42054665,
year = {2026},
author = {Liu, J and Wang, X and Shieu, B and Garcia, DD and Vondenberger, A and Xu, J and Zhang, Y and Monjur, M and Wang, W and Nirjon, S and Svatek, R and Gonzales, M and Patel, N and Song, L},
title = {An Internet of Things-Based Audio and Radio Connected System Supporting Older Adults With Physical and Cognitive Health Challenges: Qualitative Stakeholder-Informed Design Study.},
journal = {JMIR formative research},
volume = {10},
number = {},
pages = {e76341},
doi = {10.2196/76341},
pmid = {42054665},
issn = {2561-326X},
mesh = {Humans ; Qualitative Research ; Aged ; Male ; Female ; *Internet of Things ; Caregivers/psychology ; Aged, 80 and over ; Stakeholder Participation ; Chronic Disease/therapy/psychology ; Middle Aged ; Alzheimer Disease ; },
abstract = {BACKGROUND: Older adults managing chronic illnesses, such as cancer and Alzheimer disease and related dementias (ADRD), often experience significant physical or cognitive impairments that hinder daily activities and increase caregiver burden. Smart Internet of Things (IoT) technologies offer promising solutions by enabling passive monitoring, timely reminders, and personalized support at home. However, these technologies must be carefully tailored to accommodate users' individualized needs and preferences.

OBJECTIVE: This formative qualitative study aimed to explore stakeholder perspectives, including patients, caregivers, health care providers, and technical experts, on the use of smart home-based IoT systems to support chronic illness management. The goal was to inform the early development of the audio and radio connected (AURA) system, an IoT prototype integrating Wi-Fi sensing, wearable trackers, and voice-assistive features.

METHODS: Semistructured interviews were conducted with 6 patients who underwent postostomy creation for colorectal or bladder cancer treatment and 5 patients with ADRD and their caregivers. Input from additional stakeholders, including 2 health care providers, 2 community health workers, and 2 computer scientists, was also included in the report. Stakeholders reviewed a demonstration video depicting the conceptual features of the AURA system. Interviews explored stakeholders' needs and preferences for using such systems. Thematic analysis was guided by the extended Unified Theory of Acceptance and Use of Technology 2 (UTAUT2) framework, with 5 adapted constructs: performance expectancy, effort expectancy, social influence, facilitating conditions, and hedonic motivation and habit.

RESULTS: Stakeholders identified distinct yet complementary needs across populations. Patients with cancer emphasized physical health monitoring, integration with health care systems, and customization; ADRD stakeholders prioritized routine support, emotional engagement, and simplicity; caregivers and clinicians emerged as key influencers of adoption. Barriers included privacy concerns, technology literacy, and fatigue, while facilitators included perceived caregiving support, streamlined interfaces, and electronic health record integration. Patients with cancer focused on motivational cues for physical activity, while emotional engagement and habit were more prominent for ADRD users.

CONCLUSIONS: Stakeholder insights underscore the importance of designing adaptable, user-centered IoT systems that reflect the varied capabilities and care needs of older adults with chronic illnesses. These findings informed the design of the AURA prototype and highlighted theoretical considerations for technology acceptance in health care. Future work will test AURA in real-world settings to evaluate usability, acceptability, and clinical relevance.},
}

Humans
Qualitative Research
Aged
Male
Female
*Internet of Things
Caregivers/psychology
Aged, 80 and over
Stakeholder Participation
Chronic Disease/therapy/psychology
Middle Aged
Alzheimer Disease

@article {pmid42054703,
year = {2026},
author = {Bouldin, ED and Cheney, A and Pugh, MJ and Morales, K and Delgado, RE},
title = {Home- and Community-Based Service Use and Preferences Among Post-9/11 Veterans With or at High Risk of Alzheimer Disease and Related Dementia and Their Caregivers: Protocol for a Mixed Methods Observational Study.},
journal = {JMIR research protocols},
volume = {15},
number = {},
pages = {e83629},
doi = {10.2196/83629},
pmid = {42054703},
issn = {1929-0748},
mesh = {Humans ; *Caregivers/psychology/statistics & numerical data ; *Veterans/psychology/statistics & numerical data ; *Alzheimer Disease/therapy/psychology ; United States ; Aged ; Male ; Female ; *Home Care Services/statistics & numerical data ; *Community Health Services/statistics & numerical data ; *Dementia ; Observational Studies as Topic ; United States Department of Veterans Affairs ; },
abstract = {BACKGROUND: Veterans have an increased risk of developing Alzheimer disease and related dementia (ADRD) due to military exposures such as traumatic brain injury. There is a lack of information on home- and community-based services (HCBS) use among Veterans who served in the post-9/11 era and their caregivers.

OBJECTIVE: This study aims to (1) quantify HCBS use among post-9/11 Veterans with or at higher risk of ADRD, (2) identify facilitators, barriers, and preferences for HCBS among Veterans and family caregivers, and (3) prioritize HCBS interventions with input from Veterans and family caregivers.

METHODS: This study will include post-9/11 Veterans aged 65 years or younger with early-onset Alzheimer disease or frontotemporal dementia (current ADRD), and Veterans at elevated ADRD risk due to traumatic brain injury or cognitive dysfunction. Veterans' family caregivers will also be recruited. Secondary data will come from the Department of Veterans Affairs (VA), the Department of Defense, and a previous neurotrauma study. Using VA data augmented with Centers for Medicare and Medicaid Services data, we will characterize HCBS utilization. To address aim 1, we will calculate the crude and adjusted cumulative frequency of HCBS use and the proportion of Veterans using a service among Veterans with ADRD, and those at higher and lower risk for ADRD. We will compare groups using t tests for continuous measures (number of services) and chi-square tests for categorical measures (any service use). To address aim 2, we will interview Veterans and caregivers to identify facilitators and barriers to HCBS use. We will use descriptive content analysis, including rich descriptions, coding, and theme identification. Finally, to address aim 3, we will use a modified Delphi approach to identify and rank HCBS modifications that would increase use. Using the ranking data, we will consider items to have consensus on high importance if 70% or more respond "important" or "very important." Participants for primary data collection will be recruited from prior studies, VA health systems data, VA clinics, and Veteran- and caregiver-serving organizations.

RESULTS: This study was reviewed by the institutional review boards of the University of Utah, Salt Lake City Veterans Affairs, and UT Health at San Antonio and classified as exempt. The 46,053 Veterans in the preliminary aim 1 cohort (903 with early-onset Alzheimer disease/frontotemporal dementia and 45,150 at-risk Veterans matched on age and index year) averaged 55 years old at the index date and were mostly male (38,842/46,053, 84%) and non-Hispanic White (28,016/46,053, 61%).

CONCLUSIONS: This study will quantify current HCBS use and identify barriers and needs of Veterans with or at higher risk of ADRD and their caregivers. It will identify HCBS modifications that have consensus for needed changes, which will be shared with health system leaders.},
}

Humans
*Caregivers/psychology/statistics & numerical data
*Veterans/psychology/statistics & numerical data
*Alzheimer Disease/therapy/psychology
United States
Aged
Male
Female
*Home Care Services/statistics & numerical data
*Community Health Services/statistics & numerical data
*Dementia
Observational Studies as Topic
United States Department of Veterans Affairs

@article {pmid42054746,
year = {2026},
author = {Biscetti, L and Gambuzza, ME and Princiotto, M and Sabbatinelli, J and Olivieri, F and Fiorillo, M and Chinigò, C and Muglia, L and Cozza, A and Beccacece, A and Gembillo, G and Bruschetta, G and Villalta Savedra, E and Lattanzio, F and Corsonello, A and Soraci, L},
title = {From necroptosis to neuroinflammation: Unraveling mechanisms and therapeutic targets in age-related cognitive decline.},
journal = {Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie},
volume = {199},
number = {},
pages = {119326},
doi = {10.1016/j.biopha.2026.119326},
pmid = {42054746},
issn = {1950-6007},
abstract = {Aging is the major risk factor for several chronic conditions, including cognitive decline and dementia. It is accompanied by profound immune alterations characterized by a progressive decline in immune competence, a process known as immunosenescence. The resulting dysregulation of immune function leads to the overproduction of proinflammatory cytokines and fuels a persistent, low-grade inflammatory state termed inflammaging. This chronic inflammation contributes to dysfunction across the central and peripheral nervous systems, promoting neuronal damage and accelerating neurodegenerative processes such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and other age-related cognitive disorders. Within this framework, prolonged activation of inflammatory pathways can trigger regulated forms of cell death. Among these, necroptosis has recently emerged as a potential mediator linking inflammaging to neurodegeneration. Its core molecular effectors, including the receptor-interacting protein kinases RIPK1 and RIPK3 and the mixed-lineage kinase domain-like protein (MLKL), are increasingly expressed in aged neural tissues, promoting the release of damage-associated molecular patterns (DAMPs) that amplify glial activation, oxidative stress, and blood-brain barrier disruption. Growing evidence suggests that necroptotic signaling may be upregulated in the aging brain and in neurodegenerative disorders, where it could contribute to neuronal loss and cognitive impairment. This review discusses the potential role of necroptosis in the continuum between inflammation and neurodegeneration, highlighting emerging diagnostic and therapeutic perspectives. Epigenetic and circulating biomarkers, such as phosphorylated MLKL and specific microRNAs, may support early detection, while pharmacological and nutraceutical strategies targeting necroptosis show promising neuroprotective effects in preclinical studies.},
}

@article {pmid42054867,
year = {2026},
author = {Coles, M and Rosa Porto, R and Chesworth, R and Steiner-Lim, GZ and Karl, T},
title = {Combining cannabidiol and delta-9-tetrahydrocannabinol at a 50:3 ratio - a new therapeutic strategy for APPSwe/PS1ΔE9 transgenic mice?.},
journal = {Neurobiology of aging},
volume = {164},
number = {},
pages = {79-90},
doi = {10.1016/j.neurobiolaging.2026.04.003},
pmid = {42054867},
issn = {1558-1497},
abstract = {Preclinical evidence suggests that cannabidiol (CBD) can ameliorate Alzheimer's disease (AD)-related pathologies, including amyloid-β aggregation and tau hyperphosphorylation, and can reverse and prevent cognitive decline in AD rodent models. Interestingly, low-dose delta-9-tetrahydrocannabinol (THC) can improve cognition in aged mice, and 1:1 CBD+THC appears to exhibit a greater therapeutic profile in AD mouse models than either phytocannabinoid alone. Here, the potential of chronic treatment with 50 mg/kg bodyweight CBD combined with 3 mg/kg THC to reverse the behavioural deficits of adult APPSwe/PS1ΔE9 (APP/PS1) AD transgenic mice was evaluated. 14-month-old male and female transgenic mice and their wild type-like littermates were used. They were treated via daily intraperitoneal injection with CBD+THC treatment (or vehicle) for 3 weeks prior to and throughout behavioural assessment. CBD+THC significantly improved the initial localisation of the reward zone during a spatial memory probe trial in APP/PS1 mice and restored the increased acoustic startle response of APP/PS1 females. APP/PS1 mice had deficient object recognition memory and impaired spatial learning, neither of which were restored following combined cannabinoid treatment. Interestingly, CBD+THC impaired social recognition of APP/PS1 males. Treatment reduced sensorimotor gating in females. In males, treatment decreased risk assessment behaviour, and reduced acoustic startle. CBD+THC treatment had mild therapeutic properties but also off-target effects, suggesting that CBD+THC might be less preferable than CBD alone in a mouse model of advanced AD. Further research into alternate cannabinoid dosage and dose ratios is required to elucidate the potential of cannabinoid combination therapies for AD more comprehensively.},
}

@article {pmid42055092,
year = {2026},
author = {Høilund-Carlsen, PF and Alavi, A and Andalib, S and Castellani, RJ and Costa, T and de Girolamo, G and Espay, AJ and Neve, RL and Perry, G and Revheim, ME and Robakis, NK and Sensi, SL and Vissel, B and Barrio, JR},
title = {Serious Side Effects of Alzheimer's Immunotherapy Demand Scrutiny.},
journal = {Ageing research reviews},
volume = {},
number = {},
pages = {103151},
doi = {10.1016/j.arr.2026.103151},
pmid = {42055092},
issn = {1872-9649},
abstract = {Monoclonal antibodies targeting amyloid-β, i.e., lecanemab and donanemab, have recently been approved for treating early Alzheimer's disease (AD). Though these antibodies are by many considered milestones in AD therapy, clinical approvals have been inconsistent due to ongoing debates over their clinical benefit and safety. The reported cognitive decline slowing is modest and often below the thresholds for clinically significant differences on outcome scales. Moreover, these therapies are linked to adverse effects, including infusion reactions, headaches, and nausea, as well as more serious issues like amyloid-related imaging abnormalities (ARIAs), the long-term impact of which remains unclear. In this Viewpoint article, we highlight three safety concerns: ARIAs, accelerated brain volume loss, and therapy-related deaths. ARIAs occur much more frequently in treated AD patients than in placebo groups, yet their functional consequences remain poorly understood. Evidence also suggests that treatment with anti-amyloid antibodies may lead to more brain tissue loss than placebo treatments, though this has received limited attention in trials and regulatory evaluations. Finally, reliable data on therapy-related mortality is scarce due to insufficient access to detailed clinical and neuropathological information. These issues underscore significant uncertainties in assessing the risk-benefit profile of anti-amyloid therapies. A more systematic investigation-including routine brain volume monitoring, functional PET imaging, and independent death evaluations-is crucial for a comprehensive understanding of both benefits and risks in regulatory and clinical decisions.},
}

@article {pmid42055093,
year = {2026},
author = {Nakum, B and Vejpara, D and Faldu, K and Soni, R and Shah, J},
title = {Tiny Titans, Big Promise: Nanotechnology and microRNA in the Fight Against Alzheimer's Disease.},
journal = {Ageing research reviews},
volume = {},
number = {},
pages = {103149},
doi = {10.1016/j.arr.2026.103149},
pmid = {42055093},
issn = {1872-9649},
abstract = {Alzheimer's disease (AD) remains the most common neurodegenerative disorder. It is driven by complex molecular dysfunctions that includes amyloid aggregation, tau pathology, and neuroinflammation. It leads to cognitive deficits and memory loss in elderly people. Current treatments offer limited symptomatic relief. Hence, there is urgent need for innovative therapeutics and diagnostic approaches. Among emerging therapeutic targets, microRNAs (miRNAs) have pivotal role in regulating genes linked to amyloid precursor protein (APP), tau phosphorylation, and inflammatory cascades. This review explores the synergistic as well as individual potentials of nanotechnology and microRNAs (miRNAs) in AD. Nanotechnology aids in targeted drug delivery, enhanced imaging and theranostic capabilities; whereas miRNAs are key regulators of gene expression. Beyond pathogenesis, circulating and cerebrospinal miRNAs serve as minimally invasive biomarkers capable of distinguishing AD from mild cognitive impairment, offering early diagnostic potential. However, therapeutic translation faces challenges of instability, poor bioavailability, and limited blood-brain barrier (BBB) permeability. Here, combination of nanotechnology with miRNA is a compelling solution. Engineered nano-based system enhance miRNA stability, protect them from enzymatic degradation, and enable targeted delivery. This review highlights the synergistic use of nanotechnology and miRNA for AD diagnostics and therapeutics as a multifaceted strategy. Together, these advances promise a path toward early diagnosis and personalized treatment options for AD.},
}

@article {pmid42055109,
year = {2026},
author = {Zhu, Y and Zhang, H and Zhang, Z and Song, G and Fu, J and Wang, H},
title = {The role of ultrasound in addressing neurodegenerative diseases: A review of mechanisms, applications, and challenges.},
journal = {Neuroscience},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.neuroscience.2026.04.024},
pmid = {42055109},
issn = {1873-7544},
abstract = {With the aging of the global population, neurodegenerative diseases have become a major public health challenge. Currently, there are many limitations in the traditional treatment of neurodegenerative diseases, such as medicine, deep brain stimulation, transcranial magnetic stimulation, and transcranial direct current stimulation, including the inability to penetrate the blood-brain barrier (BBB) accurately and challenges in achieving precise and quantitative control during the treatment process. Ultrasound is an emerging neural modulation technology that stands out for its non-invasive nature, precise targeting, and unique ability to penetrate the BBB, demonstrating tremendous application potential. In this review, we summarized the common types of neurodegenerative diseases, including Alzheimer's disease (AD), Parkinson's disease (PD), and Amyotrophic lateral sclerosis (ALS), and the limitations of traditional treatments. It delves into the physical principles, classification, mechanisms, and unique advantages of ultrasound therapy in neuromodulation. It provides a detailed account of the current status of application of ultrasound in neurodegenerative diseases, and represents the advantages and challenges currently faced by ultrasound therapy, which offers insights into future research directions and technological improvements.},
}

@article {pmid42055146,
year = {2026},
author = {Lin, C and Xu, Z and Yan, J and Liu, B and Li, F},
title = {Icariin Promotes Lysosomal Degradation of Amyloid-β Precursor Protein via Enhanced Endosome-Lysosome Trafficking to Reduce Amyloid-β Accumulation and Improve Cognitive Function in Alzheimer's Disease Models.},
journal = {Brain research bulletin},
volume = {},
number = {},
pages = {111906},
doi = {10.1016/j.brainresbull.2026.111906},
pmid = {42055146},
issn = {1873-2747},
abstract = {Alzheimer's disease (AD) represents a devastating global public health crisis, characterized by progressive cognitive decline and memory impairment, with its prevalence and associated disability rates rising exponentially amid global population aging. The pathological hallmarks of AD include the accumulation of amyloid-beta (Aβ) plaques and hyperphosphorylated tau protein tangles, which primarily arise from the aberrant processing of amyloid-β precursor protein (AβPP). Currently, approved therapeutic strategies for AD only provide symptomatic relief, and there is a critical unmet need for effective disease-modifying treatments-particularly those targeting the transport and degradation mechanisms of AβPP, which remain poorly understood and under-explored. This study aims to elucidate the effects of icariin on AβPP subcellular localization and degradation via the lysosomal pathway in both APP/PS1 transgenic mouse model and human-APP695-overexpressing cell line. Combining behavioral assessments with biochemical analyses and confocal microscopy, this study demonstrates that prolonged icariin treatment significantly enhances cognitive function, reduces levels of AβPP, BACE1, and Aβ, and promotes the lysosomal degradation of AβPP by facilitating its transport from early endosomes to lysosomes. The findings reveal that icariin effectively mitigates Aβ generation and cognitive deficits by shortening the residence time of AβPP in early endosomes, thereby filling a key knowledge gap in AβPP metabolism and uncovering a novel regulatory mechanism. These results not only establish icariin as a promising candidate for AD intervention but also propose a new therapeutic avenue targeting AβPP degradation mechanisms, with substantial implications for both basic research and clinical applications in AD treatment. Future investigations should focus on evaluating the translational potential of icariin and characterizing its pharmacological profile to optimize clinical efficacy and safety, addressing the urgent need for disease-modifying therapies for this devastating neurodegenerative disorder.},
}

@article {pmid42055188,
year = {2026},
author = {Aziz, S and Penheiro, R and Morrison, C and Zhukovsky, P and Anderson, JAE and , },
title = {Longitudinal Surface-Based Morphometry Changes in the Hippocampus in Dementia.},
journal = {Neuropsychologia},
volume = {},
number = {},
pages = {109470},
doi = {10.1016/j.neuropsychologia.2026.109470},
pmid = {42055188},
issn = {1873-3514},
abstract = {The hippocampus is central to Alzheimer's disease (AD), characterized by atrophy and cognitive decline. While volume loss is well-documented, surface-based morphometric (SBM) features-curvature, gyrification, and thickness-remain less explored. Using T1-weighted MRI data from the Alzheimer's Disease Neuroimaging Initiative (3,144 timepoints; CN: 450, MCI: 284, AD: 204), hippocampal subfields were analyzed with HippUnfold. Linear mixed effects models examined volume and SBM changes, tracking cognitive trajectories in stable (n = 710) and progressing (n = 228) individuals. Focusing on CA1 as a representative subfield, baseline volume differed significantly across diagnostic groups, with all clinical groups showing reduced volume relative to cognitively normal individuals, consistent with disease severity. In contrast, surface-based morphometry (SBM) measures showed minimal baseline group differences, with only the CN to MCI/AD group exhibiting a significant negative main effect across SBM metrics. Longitudinal analyses revealed that disease-related changes were primarily captured by time-dependent interactions. In particular, the MCI to AD group demonstrated the most robust longitudinal changes, showing the largest magnitude of volume loss and accompanying SBM alterations over follow-up. Individuals progressing from CN to MCI/AD exhibited similar, though slightly smaller, longitudinal SBM changes, indicating early surface remodeling prior to overt clinical progression. In contrast, Stable AD showed significant longitudinal effects only for volume loss, and Stable MCI displayed minimal or nonsignificant SBM and volumetric changes. Analyses linking longitudinal morphometric change to cognitive domains was differentially associated with rates of cognitive decline across domains and disease stages, with SBM changes linked to slower language decline in early stages and to accelerated memory and visuospatial decline during progression from MCI to AD. While hippocampal volume loss remains a robust marker of AD, it does not fully capture longitudinal morphometric changes associated with disease progression. In particular, SBM measures showed their strongest and most consistent longitudinal effects in individuals progressing from MCI to AD, where changes in surface geometry accompanied accelerated volume loss. These findings suggest that SBM features are most sensitive to morphometric reorganization during active disease progression and provide complementary information beyond volume alone.},
}

@article {pmid42055309,
year = {2026},
author = {Khasanov, S and Tolibov, M and Daminova, N},
title = {Bridging the gaps in Alzheimer's disease biomarker research: From multi-omics integration to point-of-care diagnostics: A comprehensive review.},
journal = {Clinica chimica acta; international journal of clinical chemistry},
volume = {},
number = {},
pages = {121046},
doi = {10.1016/j.cca.2026.121046},
pmid = {42055309},
issn = {1873-3492},
abstract = {Alzheimer's disease (AD) is the most prevalent neurodegenerative disorder, yet its early and definitive diagnosis remains a formidable clinical challenge. Over the past decade, substantial progress has been made in the identification and validation of AD biomarkers across cerebrospinal fluid (CSF), blood, and emerging non-invasive biofluids. The core CSF biomarkers-amyloid-β (Aβ42), total tau (t-tau), and phosphorylated tau (p-tau)-have been integrated into revised diagnostic criteria, while blood-based biomarkers such as plasma p-tau217 and the Aβ42/Aβ40 ratio are approaching clinical readiness. Simultaneously, electrochemical biosensor technologies have demonstrated remarkable detection sensitivity at the femtomolar level, and multi-omics approaches combining metabolomics, lipidomics, proteomics, and epigenomics are revealing new molecular signatures of early AD. Despite these advances, several critical research questions remain unanswered, including how to optimally combine biomarkers across biofluids, how to translate biosensor technology from the laboratory to the clinic, how to integrate multi-omics data into practical diagnostic frameworks, how to validate non-invasive biofluid markers at clinical scale, and how to harmonize blood-based assays for global implementation. This review systematically examines the current state of AD biomarker science, identifies key unresolved challenges, evaluates the most promising existing approaches, and proposes specific methodological strategies to advance the field from discovery to clinical practice.},
}

@article {pmid42055333,
year = {2026},
author = {Gigant, B and Khodja, LA and Campanacci, V and Lippens, G},
title = {A coherent structural picture of the interaction of Tau with tubulin provides a link to its aggregation.},
journal = {The Journal of biological chemistry},
volume = {},
number = {},
pages = {113086},
doi = {10.1016/j.jbc.2026.113086},
pmid = {42055333},
issn = {1083-351X},
abstract = {Tauopathies are a group of neurodegenerative diseases characterized by the presence of insoluble filaments of the Tau protein in the brain. In physiological conditions, Tau is involved in the regulation of microtubule dynamics. The study of its interaction with different tubulin assemblies, using various experimental approaches, leads to a seemingly disparate picture. Here, we propose to integrate this information into a model of how Tau participates in microtubule assembly and stabilization. Related to its intrinsically disordered nature, the binding of Tau to microtubules involves both specific interactions, along protofilaments, and non-specific ones, with the C-terminal region of tubulin subunits. In addition, the recent determination of a Tau:tubulin structure provides a model for a functional dimer of Tau targeting a microtubule aperture between protofilaments. Therefore, Tau regulates microtubule dynamics by modulating both longitudinal and lateral contacts. Finally, we discuss a possible connection of this dimer of Tau with its oligomerization, whether physiological or pathological.},
}

@article {pmid42055490,
year = {2026},
author = {Banerjee, C and Singh, RK and Mehan, S},
title = {Raloxifene Beyond Osteoporosis: Unlocking Neurorestoration Through Remyelination, Inflammatory Regulation, and Neuroimmune Modulation in CNS Pathologies.},
journal = {International immunopharmacology},
volume = {181},
number = {},
pages = {116668},
doi = {10.1016/j.intimp.2026.116668},
pmid = {42055490},
issn = {1878-1705},
abstract = {Raloxifene, a selective estrogen receptor modulator (SERM), has emerged as a promising candidate for repurposing in neurodegenerative and neuropsychiatric disorders. Traditionally approved for osteoporosis and breast cancer prevention, its tissue-selective estrogen receptor modulation underpins its potential therapeutic applications. This review critically examines the pharmacological, preclinical, and clinical evidence supporting raloxifene's neuroprotective and neuropsychiatric effects, as well as its mechanisms of action, safety profile, and clinical limitations. Raloxifene exerts neuroprotective effects by targeting estrogen receptors, including ERα, ERβ, and GPER, modulating genomic and non-genomic pathways. These pathways regulate oxidative stress, mitochondrial stability, neuroinflammation, and apoptosis-core features of neurological disorders such as Alzheimer's (AD), Parkinson's (PD), Multiple sclerosis (MS), and Amyotrophic lateral sclerosis (ALS). Preclinical studies demonstrate raloxifene's ability to reduce amyloid-β aggregation in AD, protect dopaminergic neurons in PD, mitigate demyelination in MS, and decrease protein aggregation in ALS. Additionally, raloxifene exhibits positive effects on memory, attention, and negative symptoms in schizophrenia, alongside antidepressant and anxiolytic properties. Although promising, raloxifene's clinical translation faces challenges. Existing trials are limited by small sample sizes, heterogeneous designs, and a lack of long-term data. Most studies focus on postmenopausal women, leaving gaps regarding effects in men, premenopausal women, and younger populations. Furthermore, discrepancies between preclinical and clinical dosing complicate its therapeutic optimization. Future research should explore sex-specific effects, optimize CNS-targeted dosing strategies, and employ biomarkers for neuroprotection and inflammation. Long-term trials are essential to evaluate its disease-modifying potential. Raloxifene represents a promising repurposing candidate for CNS disorders, however, its therapeutic role remains to be established through robust clinical validation.},
}

@article {pmid42055498,
year = {2026},
author = {Zheng, W and Zhou, Y and Lu, M and Wang, Y},
title = {Associations of obstructive sleep apnea with A/T/N biomarkers, neuroimaging abnormalities, neurodegenerative progression, and CPAP-related changes in Alzheimer's disease.},
journal = {Sleep medicine},
volume = {144},
number = {},
pages = {108975},
doi = {10.1016/j.sleep.2026.108975},
pmid = {42055498},
issn = {1878-5506},
abstract = {BACKGROUND: Obstructive sleep apnea (OSA) has been increasingly linked to cognitive impairment and dementia, yet its relationship with core Alzheimer's disease (AD) pathology, multimodal brain injury, longitudinal neurodegenerative progression, and potential treatment responsiveness remains incompletely understood.

METHODS: Cross-sectional analyses compared amyloid/tau/neurodegeneration (A/T/N) biomarkers and multimodal neuroimaging measures between groups, including cerebrospinal fluid (CSF) biomarker quantification, amyloid positron emission tomography (PET), structural MRI, white matter imaging, the diffusion tensor imaging analysis along the perivascular space (DTI-ALPS) index, and choroid plexus volume, the latter two used as indirect imaging markers reflecting potential alterations in glymphatic-related fluid transport and waste-clearance pathways. Among OSA participants who initiated continuous positive airway pressure (CPAP) therapy, changes over the approximately 6-month follow-up period were compared according to adherence status.

RESULTS: Compared with patients without OSA, those with OSA showed a more adverse A/T/N biomarker profile, including lower CSF Aβ42 (528.19 ± 147.83 vs 612.37 ± 158.46 pg/mL), lower CSF Aβ42/40 ratio (0.064 ± 0.013 vs 0.071 ± 0.014), higher amyloid PET SUVR (1.38 ± 0.21 vs 1.24 ± 0.18), higher CSF p-tau181 (74.92 ± 26.15 vs 63.48 ± 21.37 pg/mL), higher plasma NfL (31.79 ± 13.27 vs 24.68 ± 10.42 pg/mL), and higher plasma GFAP (233.47 ± 104.26 vs 196.54 ± 82.71 pg/mL). Neuroimaging analyses further showed smaller hippocampal volume, greater white matter injury, a lower DTI-ALPS index (1.27 ± 0.18 vs 1.43 ± 0.19), and a larger choroid plexus volume (3291.73 ± 768.61 vs 2814.56 ± 712.48 mm[3]) in the OSA group. Longitudinally, OSA was associated with faster annual increases in NfL (2.37 vs 0.72 pg/mL/year) and GFAP (15.19 vs 4.54 pg/mL/year), as well as faster hippocampal atrophy over time. Among treated participants, CPAP adherence was associated with improved cognition (MoCA: +0.59; ADAS-Cog: -1.48) and reductions in IL-6 (-0.95 pg/mL), GFAP (-14.67 pg/mL), and NfL (-2.33 pg/mL).

CONCLUSIONS: In patients with AD, OSA was associated with a more adverse A/T/N biomarker profile, broader neuroimaging abnormalities, including altered DTI-ALPS index and choroid plexus volume as indirect imaging markers of potential glymphatic-related dysfunction, and faster neurodegenerative progression. CPAP adherence was associated with more favorable short-term trajectories, suggesting that OSA may be a clinically relevant and potentially modifiable contributor to disease burden in AD.},
}

@article {pmid42055632,
year = {2026},
author = {Alhadidy, MM and Hinton, TV and Ernst, KN and Yang, Y},
title = {Amyloid extraction from neurodegenerative disease tissues for structural studies.},
journal = {Methods in enzymology},
volume = {729},
number = {},
pages = {1-33},
doi = {10.1016/bs.mie.2026.01.032},
pmid = {42055632},
issn = {1557-7988},
mesh = {Humans ; Cryoelectron Microscopy/methods ; *Neurodegenerative Diseases/metabolism/pathology ; *Brain/metabolism/pathology ; *Amyloid beta-Peptides/isolation & purification/chemistry/ultrastructure ; alpha-Synuclein/isolation & purification/chemistry ; tau Proteins/isolation & purification/chemistry ; DNA-Binding Proteins/isolation & purification/chemistry ; },
abstract = {Amyloid aggregates are hallmarks of neurodegenerative diseases including Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), and frontotemporal dementia (FTD). Yet structural analysis of these brain-extracted filaments requires specialized extraction protocols that minimize structural perturbation while removing tissue matrix components. This chapter focuses on amyloid-β (Aβ) filaments, the primary component of senile plaques in AD, and presents three complementary methods for isolating these filaments from human brain tissues suitable for cryo-electron microscopy analysis. These methods have enabled high-resolution structural studies reaching 2.0-3.5 Å resolution and revealed distinct conformational polymorphs in AD and other neurodegenerative diseases. Method selection depends on tissue type, target filaments, and downstream analysis requirements, with comprehensive guidance provided for optimal protocol choice and implementation. The protocols demonstrate broad applicability beyond Aβ extraction, with successful adaptations provided for tau, α-synuclein, and TDP-43 extraction. Understanding these filamentous structures extracted with minimal perturbation is essential for developing targeted therapeutics and advancing structure-based drug design approaches for AD, PD, ALS, FTD, and other neurodegenerative diseases.},
}

Humans
Cryoelectron Microscopy/methods
*Neurodegenerative Diseases/metabolism/pathology
*Brain/metabolism/pathology
*Amyloid beta-Peptides/isolation & purification/chemistry/ultrastructure
alpha-Synuclein/isolation & purification/chemistry
tau Proteins/isolation & purification/chemistry
DNA-Binding Proteins/isolation & purification/chemistry

@article {pmid42055633,
year = {2026},
author = {Zhao, Q and Liu, K and Li, D and Liu, C},
title = {Cryo-EM methods to study binding between amyloid fibrils and chemical compounds.},
journal = {Methods in enzymology},
volume = {729},
number = {},
pages = {107-144},
doi = {10.1016/bs.mie.2026.01.029},
pmid = {42055633},
issn = {1557-7988},
mesh = {*Cryoelectron Microscopy/methods ; *Amyloid/chemistry/metabolism/ultrastructure ; *alpha-Synuclein/chemistry/metabolism/ultrastructure ; Humans ; Protein Binding ; Binding Sites ; Ligands ; Molecular Docking Simulation/methods ; Amyloid beta-Peptides/chemistry/metabolism ; },
abstract = {Amyloid fibrils formed by amyloid proteins such as α-synuclein (α-syn), Amyloid-β (Aβ) and Tau are central to the pathology of neurodegenerative diseases like Parkinson's disease (PD) and Alzheimer's disease (AD). Structural elucidation of fibril-ligand interactions is essential for the rational design of imaging probes and therapeutic inhibitors targeting these pathological aggregates. Here, we present a comprehensive cryo-electron microscopy (cryo-EM)-based workflow for modeling small-molecule binding to amyloid fibrils, with a focus on α-syn-ligand complexes. The protocol integrates optimized fibril sample preparation, helical reconstruction, and iterative 2D/3D classification to yield high-resolution density maps suitable for atomic modeling. Ligands are incorporated by generating coordinates from SMILES strings and restraint files from Phenix eLBOW, followed by manual docking and real-space refinement. Using CCA-α-syn complex as a case study, we demonstrate precise ligand placement into specific fibril binding sites (the C-pocket, N-pocket, and a back-surface groove of the fibril core distinct from typical globular protein pockets). Subsequent structural refinement preserved key interaction features, including π-π stacking and side-chain hydrogen bonding. Validation metrics confirm the stereochemical integrity and good model-to-map fit of the final fibril-ligand complex structures. Overall, this workflow enables accurate modeling of ligand engagement with amyloids even at ∼3-4 Å resolution and provides a scalable framework for structure-guided ligand discovery in neurodegenerative disease research.},
}

*Cryoelectron Microscopy/methods
*Amyloid/chemistry/metabolism/ultrastructure
*alpha-Synuclein/chemistry/metabolism/ultrastructure
Humans
Protein Binding
Binding Sites
Ligands
Molecular Docking Simulation/methods
Amyloid beta-Peptides/chemistry/metabolism

@article {pmid42055635,
year = {2026},
author = {Gelenter, MD and Li, T and Anfinrud, P and Bax, A},
title = {Opportunities and challenges in the use of pressure-jump NMR to study Aβ and protein oligomerization.},
journal = {Methods in enzymology},
volume = {729},
number = {},
pages = {179-230},
doi = {10.1016/bs.mie.2026.01.036},
pmid = {42055635},
issn = {1557-7988},
mesh = {*Amyloid beta-Peptides/chemistry/metabolism ; Humans ; *Nuclear Magnetic Resonance, Biomolecular/methods/instrumentation ; Protein Multimerization ; *Peptide Fragments/chemistry ; Hydrostatic Pressure ; Alzheimer Disease/metabolism ; },
abstract = {Extracellular plaques comprised of amyloid-β (Aβ) are a defining hallmark of Alzheimer's disease. However, it remains debated whether these insoluble fibrils or the soluble oligomers that precede them are the toxic species responsible for pathology. Aβ oligomers are difficult to study by conventional biophysical techniques because of their transient nature and heterogeneous size. While Aβ40 oligomers are invisible to solution nuclear magnetic resonance (NMR) spectroscopy due to their slow tumbling, the intrinsically disordered monomeric form is readily detected by solution NMR. Under appropriate conditions, oligomers rapidly form at atmospheric pressure and can be dissociated by the application of ∼2.5 kbar hydrostatic pressure. By incorporating pressure jumps within NMR experiments, features of the NMR-invisible oligomers can be probed indirectly by detecting the NMR-visible monomer. This chapter discusses operation of a home-built pressure-jump apparatus and its application to measuring oligomeric relaxation times, chemical shifts, and [1]H-[1]H NOE transfers. Aβ40 oligomers have particularly short [15]N T2 relaxation times and long T1 relaxation times, especially for residues V18-A21 and I31-L34, indicating that these oligomers contain highly ordered regions that tumble slowly in solution. [1]H-[1]H NOEs further reveal that Aβ40 oligomers contain hydrogen bonds between V18 and M35, between F20 and G33, and between E22 and I31. Zn[2+] ions accelerate oligomer formation and promote homogeneous, rigid assemblies with reduced internal motion. Some of the technology development was carried out using Amelotin, an intrinsically disordered protein that also forms pressure-sensitive oligomers but is less prone to irreversible fibril formation and more amenable to large-scale perdeuterated expression.},
}

*Amyloid beta-Peptides/chemistry/metabolism
Humans
*Nuclear Magnetic Resonance, Biomolecular/methods/instrumentation
Protein Multimerization
*Peptide Fragments/chemistry
Hydrostatic Pressure
Alzheimer Disease/metabolism

@article {pmid42055636,
year = {2026},
author = {Kengwerere, MK and Wang, T and Qiang, W},
title = {Characterizations of the β-amyloid (Aβ)-membrane interaction intermediates.},
journal = {Methods in enzymology},
volume = {729},
number = {},
pages = {231-258},
doi = {10.1016/bs.mie.2026.01.028},
pmid = {42055636},
issn = {1557-7988},
mesh = {*Amyloid beta-Peptides/chemistry/metabolism ; Humans ; Alzheimer Disease/metabolism/pathology ; *Cell Membrane/metabolism/chemistry ; Nuclear Magnetic Resonance, Biomolecular/methods ; Magnetic Resonance Spectroscopy/methods ; Molecular Dynamics Simulation ; },
abstract = {Non-specific membrane disruption induced by the amyloidogenic aggregation of β-amyloid (Aβ) peptides is considered an underlying molecular mechanism of Alzheimer's disease (AD). Therefore, elucidating the membrane interruptive intermediate states of Aβ aggregates is a crucial step towards the understanding of molecular basis of AD pathology. However, such intermediate states are heterogeneous, low-abundant, and insoluble, bringing challenges for the application of high-resolution techniques. The solid-state nuclear magnetic resonance (ssNMR) spectroscopy remains the most feasible technique to characterize the structural features and molecular dynamics of the Aβ-membrane intermediate systems. Despite the capability, specific quantitative and sensitivity-enhanced ssNMR approaches, as well as membrane biophysical and/or cell-based biophysical assays, should be combined to maximize the biological relevance of the intermediate structural characterizations. In this methodology chapter, we will review the experimental and data analysis protocols that have been established in our laboratory.},
}

*Amyloid beta-Peptides/chemistry/metabolism
Humans
Alzheimer Disease/metabolism/pathology
*Cell Membrane/metabolism/chemistry
Nuclear Magnetic Resonance, Biomolecular/methods
Magnetic Resonance Spectroscopy/methods
Molecular Dynamics Simulation

@article {pmid42055638,
year = {2026},
author = {Shahbaz, A and Weetman, SL and Chitty, C and Xue, WF},
title = {Methods for characterizing the individual filament structures of amyloid peptide assemblies using atomic force microscopy.},
journal = {Methods in enzymology},
volume = {729},
number = {},
pages = {281-308},
doi = {10.1016/bs.mie.2026.01.026},
pmid = {42055638},
issn = {1557-7988},
mesh = {*Microscopy, Atomic Force/methods ; Humans ; *Amyloid beta-Peptides/chemistry/ultrastructure ; *Amyloid/chemistry/ultrastructure ; },
abstract = {A wide range of distinctive helical filamentous amyloid structures self-assembled from monomeric peptide or protein building blocks are found both in nature and in human disease states. Amyloid nano-fibrils are also being developed and synthetically made as novel peptide-based nanomaterials. In humans, accumulation of a range of amyloid structures, for example those formed from the amyloid-beta peptides in Alzheimer's disease, play a crucial role in the pathology of neurodegenerative and metabolic diseases. The diverse range of amyloid structures found is a manifestation of the amyloid structural polymorphism phenomenon. This is where different filament structures are assembled even from the same peptide or protein precursors. Due to the structural diversity of amyloid fibrils that can be found even in the same sample or the same disease state, an experimental method that allows structural analysis of individual amyloid filaments is required to understand the relationships between the polymorphic structures and the biological and physicochemical properties they elicit. Here, a method with a detailed protocol to analyze the structures of individual amyloid filament assemblies by topological Atomic Force Microscopy (AFM) imaging and Contact-Point Reconstruction AFM (CPR-AFM) image analysis is described. This approach to resolve the 3D shapes of amyloid polymorphs, one individual fibril at a time, allows mapping of the polymorphic landscapes of amyloid assemblies. It serves as an inexpensive, fast and effective experimental tool for individual filament level structural analysis, and offers new, exciting opportunities in elucidating population distributions of heterogeneous amyloid samples, rare amyloid structures within the populations, and structural variations between or within individual filaments. These are all key parts to experimental developments in therapeutic discovery and novel bio-nanomaterials applications.},
}

*Microscopy, Atomic Force/methods
Humans
*Amyloid beta-Peptides/chemistry/ultrastructure
*Amyloid/chemistry/ultrastructure

@article {pmid42055642,
year = {2026},
author = {Portugal Barron, D and Guo, Z},
title = {Application of EPR spectroscopy in the structural studies of Aβ oligomers and fibrils.},
journal = {Methods in enzymology},
volume = {729},
number = {},
pages = {361-388},
doi = {10.1016/bs.mie.2026.01.030},
pmid = {42055642},
issn = {1557-7988},
mesh = {Electron Spin Resonance Spectroscopy/methods ; *Amyloid beta-Peptides/chemistry/metabolism ; Humans ; Alzheimer Disease/metabolism/pathology ; Spin Labels ; *Amyloid/chemistry ; Protein Multimerization ; },
abstract = {Electron paramagnetic resonance (EPR) spectroscopy, in combination with site-directed spin labeling, is a powerful tool to elucidate the structures of Aβ oligomers and fibrils central to Alzheimer's disease pathology. This chapter describes general strategies of spin labeling, sample preparation, and data analysis for EPR studies of Aβ aggregation. The parallel in-register β-sheet structure commonly found in many amyloid fibrils gives rise to a characteristic single-line EPR spectrum. Quantitative analysis of the single-line spectrum reveals site-specific structural information in both Aβ fibrils and oligomers. In addition to structural studies, EPR methods for mechanistic studies such as co-aggregation and oligomer-to-fibril conversion are also discussed. This chapter underscores the important role of EPR in providing structural and mechanistic insights into Aβ aggregation with implications for a better molecular understanding of Alzheimer's disease.},
}

Electron Spin Resonance Spectroscopy/methods
*Amyloid beta-Peptides/chemistry/metabolism
Humans
Alzheimer Disease/metabolism/pathology
Spin Labels
*Amyloid/chemistry
Protein Multimerization

@article {pmid41826653,
year = {2026},
author = {Alqarni, A and Abd-Elghany, AA and Bedewi, MA and Alqarni, AM and Alanazi, HG and Hussein, MA and El-Adl, NI and Salah, A},
title = {Naringenin-loaded nanoparticles ameliorate scopolamine-induced neurotoxicity.},
journal = {Scientific reports},
volume = {16},
number = {1},
pages = {},
pmid = {41826653},
issn = {2045-2322},
support = {PSAU/2025/01/32590//Prince Sattam bin Abdulaziz University/ ; },
abstract = {UNLABELLED: Background Naringenin has shown attractive neuroprotective effects; however, it is characterized by low oral bioavailability. Naringenin-loaded nanoparticles (Nar-NPs) were prepared for enhanced delivery, and their effects in scopolamine-induced cholinergic hypofunction model were tested, either alone or in combination with donepezil. Methods Nar-NPs were developed via solvent evaporation with Span-80/Tween-80 and then characterized for morphological characteristics (TEM), hydrodynamic size/PDI, and zeta potential (DLS/ELS). Encapsulation efficiency (EE%), drug loading (DL%), and stability in simulated physiological buffer were also determined. Three different batches were used to evaluate the reproducibility of the formulation. Male mice were injected with scopolamine (3 mg/kg, i.p.) and orally administered Nar-NPs (37.75 mg/kg) or Nar-NPs combined with donepezil (10 mg/kg). Results were evaluated as Morris Water Maze, oxidative stress and inflammatory markers, lipid profile, qRT-PCR, and histopathology. Molecular docking analyses examined possible bonds of naringenin interaction with GABRA5α and GSK-3β as hypothesis-generating results. Results Nar-NPs were spherical in shape (~ 95 nm), of monodisperse size (PDI < 0.2) and negatively charged (ζ ≈ -28.5mV). The formulation showed high encapsulation efficiency (EE% = 89.2 ± 3.1%), demonstrated good colloidal stability in phosphate buffer (pH 7.4) over 24 h, and exhibited a sustained drug release profile as well with sustained release profile (Korsmeyer-Peppas, n ≈ 0.56). The batch-to-batch reproducibility of ζ was high (− 28.47, -28.71, − 28.52mV; mean = − 28.57 ± 0.13mV; CV% ≈ 0.44%). In vivo, Nar-NP attenuated scopolamine-induced deficits as evidenced by the amelioration of acquisition and probe trial performance, normalization in levels of antioxidant defenses, reduction in neuroinflammatory mediators, and reinforcement of hippocampal architecture. The combination with donepezil produced effects greater than either monotherapy alone, suggesting potential additive or synergistic interaction. Docking indicated reasonable binding to GABRA5α and GSK-3β, but this is exploratory and needs validation ex vivo/in vivo for the mechanism of action. Conclusions Nar-NPs are a predictable, stable, and bioavailable formulation with multidomain neuroprotective potential in a cholinergic impairment model. Since the reversible model we use mimics acute cholinergic dysfunction with associated oxidative and inflammatory sequelae rather than the progressive proteinopathies (amyloid-β accumulation, tau hyperphosphorylation) and chronic neurodegeneration seen in Alzheimer’s disease, the current findings ought to be interpreted as an example of symptom-relevant rather than disease-modifying neuroprotection. As such, the multi-domain therapeutic potential implied by our molecular and histopathological endpoints must be tested stringently in chronic, pathology-induced models (e.g., transgenic APP/PS1 or 3xTg-AD mice) for determining translational relevance to Alzheimer’s disease.

SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1038/s41598-026-44225-w.},
}

@article {pmid42044955,
year = {2026},
author = {Zhuang, Z and Li, CY and Li, WH and Wang, YQ and Wang, Y and Hou, YS and Wang, ZW and Xu, MM and Lyu, QY and Xie, JY},
title = {Development of a community home-based dual-supplier cooperation care model for people with dementia based on an intelligent decision-assistance system: protocol of a 1-year randomised controlled trial in China.},
journal = {BMJ open},
volume = {16},
number = {4},
pages = {e092678},
doi = {10.1136/bmjopen-2024-092678},
pmid = {42044955},
issn = {2044-6055},
mesh = {Humans ; *Dementia/therapy ; China ; *Caregivers ; *Home Care Services/organization & administration ; Quality of Life ; Aged ; Independent Living ; *Artificial Intelligence ; Randomized Controlled Trials as Topic ; Male ; Female ; },
abstract = {INTRODUCTION: Dementia imposes significant care and financial burdens on families and countries globally. While high-quality home-based care is crucial, the current supply chain of care-relying on family caregivers and community healthcare workers-remains fragmented and lacks effective integration. Furthermore, although artificial intelligence (AI) holds promise, existing applications predominantly focus on diagnosis or monitoring rather than holistic care delivery and quality of life (QoL). This study aims to evaluate the effectiveness of the community home-based dual-supplier cooperation (CHDSC) care model in older people with dementia.

METHODS AND ANALYSIS: A 1-year, assessor-blinded, parallel-group, superiority randomised controlled trial with 1:1 allocation will be conducted. A total of 200 pairs (community-dwelling people with dementia aged ≥65 years and their primary family caregivers) will be recruited from four community health centres in Guangzhou, China, and randomly assigned to either the CHDSC care model intervention or usual care. The intervention comprises monthly home visits following a structured six-step cycle (problem assessment, personalised recommendation generation, case seminar, training, task execution with progressive handover and reassessment), delivered collaboratively by community healthcare workers and family caregivers and guided by an intelligent decision-assistance system. The primary outcome is the QoL of patients assessed using the Quality of Life in Alzheimer's Disease scale. Secondary outcomes include caregiver burden, quality of home-based care, behavioural and psychological symptoms, cognitive function, ability to perform activities of daily living, adverse event rate and unplanned readmission rate. A comprehensive process evaluation embedded in the randomised controlled trial will be taken.

ETHICS AND DISSEMINATION: Ethics approval was obtained from the Institutional Review Board of Jinan University. Written informed consent will be obtained from all participants. The study findings will be disseminated through publication in a peer-reviewed journal and presented at conferences.

TRIAL REGISTRATION NUMBER: ChiCTR2300075393: Implementation and effectiveness evaluation of a home-based dual-supplier cooperation care model for community-dwelling patients with dementia based on intelligent decision assistance system.},
}

Humans
*Dementia/therapy
China
*Caregivers
*Home Care Services/organization & administration
Quality of Life
Aged
Independent Living
*Artificial Intelligence
Randomized Controlled Trials as Topic
Male
Female

@article {pmid42045164,
year = {2026},
author = {Pozzi-Ruiz, V and Giner de Gracia, A and Glauser, L and Romani, M and Gunter-Rahman, F and González-Ramón, A and Haj-Yahya, M and Kolla, R and Burns, AM and Lashuel, HA and Auwerx, J and Gräff, J and Sanchez-Mut, JV},
title = {The PM20D1-OLE pathway induces microglia rewiring to ameliorate Alzheimer disease.},
journal = {Cell death & disease},
volume = {},
number = {},
pages = {},
doi = {10.1038/s41419-026-08791-1},
pmid = {42045164},
issn = {2041-4889},
support = {PID2022-143263OB-I00//Ministry of Economy and Competitiveness | Agencia Estatal de Investigación (Spanish Agencia Estatal de Investigación)/ ; PRE2020-093825//Ministry of Economy and Competitiveness | Agencia Estatal de Investigación (Spanish Agencia Estatal de Investigación)/ ; PRE2020-093389//Ministry of Economy and Competitiveness | Agencia Estatal de Investigación (Spanish Agencia Estatal de Investigación)/ ; ERC-AdG-787702//EC | EU Framework Programme for Research and Innovation H2020 | H2020 Priority Excellent Science | H2020 European Research Council (H2020 Excellent Science - European Research Council)/ ; SNSF 31003A_179435//Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung (Swiss National Science Foundation)/ ; },
abstract = {There is increasing evidence of microglia participation in Alzheimer's disease (AD), which incentives their modulation to intercept the disease. Here, we describe a new mechanism by which the recently AD-associated Peptidase M20 Domain Containing 1 (PM20D1) instructs microglia to tackle AD. We show that the PM20D1-derived N-oleoyl-Leucine (OLE) improves AD pathologies in two animal models of AD. OLE induces microglia association with amyloid beta (Aβ) plaques, reduce their size, number and toxicity, and leads to enhanced neuroprotection and cognition. Furthermore, OLE also increases Aβ chemotaxis and clearance in microglia cultures and enhances cell viability in neurons subjected to AD-related stressors. Finally, we also find evidence for a PM20D1- and OLE-mediated microglia association with amyloid plaques and neuroprotection in human AD brains. In sum, our results provide further insight into the protective role of PM20D1 in AD and support the use of OLE as a microglia-modifying treatment for AD.},
}

@article {pmid42045207,
year = {2026},
author = {Shi, L and Liu, YL and Dai, MN and Ma, YX and Wu, JN and Guo, L and Luo, L and Fu, HH and Huang, CY and Zhang, JY and Kou, YN and Luo, HR and Wu, GS},
title = {D-pinitol extends the lifespan of Caenorhabditis elegans through integrated antioxidant defense, proteostasis, and autophagy signaling.},
journal = {npj aging},
volume = {},
number = {},
pages = {},
doi = {10.1038/s41514-026-00381-x},
pmid = {42045207},
issn = {2731-6068},
support = {2023YFC3603300//Key Technologies Research and Development Program/ ; 2024SSY07161//Jiangxi Province Key Laboratory of Aging and Disease/ ; 20232BCJ22024//Project for Academic and Technical Leaders of Major Disciplines in Jiangxi Province/ ; 20232ACB206015//Natural Science Foundation of Jiangxi Province/ ; },
abstract = {Aging is driven in part by progressive deterioration of proteostasis and antioxidant defense, leading to cellular dysfunction and age-associated disease. The naturally occurring methylated inositol D-pinitol (DP) was reported to present metabolic, antioxidant, and anti-inflammatory effects, as well as to extend the lifespan of D. melanogaster and C. elegans through the insulin/IGF-1 signaling pathway. But the mechanism of DP on delay aging remains poorly understand. Here, we showed that 200 μM of DP increased mean lifespan of C. elegans by 28.6%, as well as healthspan phenotypes including preserved locomotor function and delayed lipofuscin accumulation. DP also attenuated proteotoxicity and delays functional decline in C. elegans models of Parkinson's, Huntington's, and Alzheimer's diseases. Moreover, DP suppressed cellular senescence in multiple mammalian cell types. Genetic and reporter analyses show that DP activates conserved stress-response regulators Nrf2/SKN-1 and HSF-1 through the p38 MAPK signaling cascade to improve resistance to oxidative and thermal stress. DP further enhanced HLH-30-dependent autophagy and mitophagy activities, which are essential for lifespan extension. Together, these findings identify DP as a conserved modulator of proteostasis, redox homeostasis, and autophagy, positioning it as a promising, low-toxicity candidate for promoting healthy aging and mitigating age-related neurodegenerative pathology.},
}

@article {pmid42045407,
year = {2026},
author = {McLoughlin, J and Sayfullaeva, J and Kiliç, E and Carmody, C and Grochowska, N and Potapov, K and Potapov, D and Clarkson, A and Peppercorn, K and Tate, W and Kwakowsky, A},
title = {Estren prevents beta-amyloid-induced basal forebrain cholinergic loss and long-term spatial memory deficits in aged female mice.},
journal = {Scientific reports},
volume = {},
number = {},
pages = {},
doi = {10.1038/s41598-026-49638-1},
pmid = {42045407},
issn = {2045-2322},
support = {110089.01//Otago Medical School, University of Otago/ ; },
}

@article {pmid42045435,
year = {2026},
author = {Kochunov, P and Gao, S and Salminen, LE and Jahanshad, N and Nir, TM and Thompson, PM and Du, X and Adhikari, BM and Kochunov, A and Cassidy, R and Ma, Y and Chiappelli, J and Ament, S and Pan, Y and Chen, S and Shuldiner, AR and Mitchell, BD and Soares, LJ and Hong, LE},
title = {Alzheimer's disease-like brain pattern biomarker: capturing risks and predicting disease onset.},
journal = {Molecular psychiatry},
volume = {},
number = {},
pages = {},
pmid = {42045435},
issn = {1476-5578},
support = {RF1NS114628//U.S. Department of Health & Human Services | NIH | National Institute of Neurological Disorders and Stroke (NINDS)/ ; R01NS114628//U.S. Department of Health & Human Services | NIH | National Institute of Neurological Disorders and Stroke (NINDS)/ ; RF1NS114628//U.S. Department of Health & Human Services | NIH | National Institute of Neurological Disorders and Stroke (NINDS)/ ; R01NS114628//U.S. Department of Health & Human Services | NIH | National Institute of Neurological Disorders and Stroke (NINDS)/ ; RF1NS114628//U.S. Department of Health & Human Services | NIH | National Institute of Neurological Disorders and Stroke (NINDS)/ ; R01NS114628//U.S. Department of Health & Human Services | NIH | National Institute of Neurological Disorders and Stroke (NINDS)/ ; S10OD023696//U.S. Department of Health & Human Services | NIH | NIH Office of the Director (OD)/ ; R01EB015611//U.S. Department of Health & Human Services | NIH | National Institute of Biomedical Imaging and Bioengineering (NIBIB)/ ; U01MH108148//U.S. Department of Health & Human Services | NIH | National Institute of Mental Health (NIMH)/ ; R01MH117601//U.S. Department of Health & Human Services | NIH | National Institute of Mental Health (NIMH)/ ; R01MH112180//U.S. Department of Health & Human Services | NIH | National Institute of Mental Health (NIMH)/ ; R01MH133812//U.S. Department of Health & Human Services | NIH | National Institute of Mental Health (NIMH)/ ; R01MH116948//U.S. Department of Health & Human Services | NIH | National Institute of Mental Health (NIMH)/ ; U01MH108148//U.S. Department of Health & Human Services | NIH | National Institute of Mental Health (NIMH)/ ; R01ES033961//U.S. Department of Health & Human Services | NIH | National Institute of Environmental Health Sciences (NIEHS)/ ; },
abstract = {Preventing Alzheimer's disease (AD) requires early-warning biomarkers. We developed a Regional Vulnerability Index (RVI) that quantifies individual brain similarity to AD patients' expected brain deficit patterns. We calculated regional effect sizes to establish brain deficit patterns in amyloid-positive AD cases compared to amyloid-negative healthy controls. RVI-AD was calculated as a linear index of individual similarity to this established brain pattern in AD. We demonstrated RVI-AD elevation associated with risk factors in 335 participants (mean age: 49 ± 13 years) in the Amish Connectome Project, followed by an independent sample consisting of 26,010 participants (mean age: 64 ± 7 years) from the UK Biobank. Genetic and cardiovascular risks were evaluated using APOE-e4 genotype and Framingham Cardiovascular Risk Scores (FCVRS), respectively. Additionally, we assessed the risk of converting from MCI to dementia in N = 1932 participants (mean age: ~74) from the Alzheimer's Disease Neuroimaging Initiative (ADNI). Healthy participants with the APOE-e4 allele had significantly elevated RVI-AD indices (p = 0.03 and 2·10[-5], for ACP and UKBB samples respectively). FCVRS significantly contributed to higher RVI-AD in an interaction with APOE-e4-specific manner (p = 2·10[-4] and 7·10[-6] for ACP and UKBB samples respectively). In ADNI cohort, RVI-AD significantly predicted conversion from MCI to dementia in the next decade, particularly in the first three years (AUC = 70-74%, OR = 2.16, 95% CI = 1.8-2.6, p < 10[-16]). In healthy individuals, the RVI-AD detected the insidious impact of APOE-ε4 and cardiovascular risks in otherwise normally aging cohorts. Elevated RVI-AD also predicted conversion to dementia within ten years in the older, high-risk cohort. Further development of this brain-pattern similarity-based approach may yield a noninvasive, clinically accessible biomarker to aid early detection of the subtle to more imminent effects of AD risks.},
}

@article {pmid42045900,
year = {2026},
author = {Román-Domínguez, A and Mas-Bargues, C and Pérez, V and Medina, M and Ávila, J and Borrás, C and Viña, J},
title = {Peripheral blood biomarkers RCAN1, Clusterin, RAGE, and malondialdehyde for early diagnosis and progression of Alzheimer's disease.},
journal = {BMC medicine},
volume = {},
number = {},
pages = {},
doi = {10.1186/s12916-026-04882-0},
pmid = {42045900},
issn = {1741-7015},
support = {OP ERDF of Comunitat Valenciana 2014-2020//European Regional Development Fund/ ; OP ERDF of Comunitat Valenciana 2014-2020//European Regional Development Fund/ ; OP ERDF of Comunitat Valenciana 2014-2020//European Regional Development Fund/ ; OP ERDF of Comunitat Valenciana 2014-2020//European Regional Development Fund/ ; OP ERDF of Comunitat Valenciana 2014-2020//European Regional Development Fund/ ; OP ERDF of Comunitat Valenciana 2014-2020//European Regional Development Fund/ ; PID2020-113839RB-I00//Ministerio de Ciencia, Innovación y Universidades/ ; CIAICO/2022/190//Conselleria de Educación, Cultura y Universidades, Spain/ ; PI-2023-004//VLC-Bioclinic/ ; AP2024VLC-08//VLC-Biomed/ ; CB16/10/00435//Centro de Investigación Biomédica en Red Fragilidad y Envejecimiento Saludable/ ; },
}

@article {pmid42045931,
year = {2026},
author = {Ismail, M and Kanth, PD and Hussein, S},
title = {Estimating long-term care needs in data-scarce settings: a diagnostic model with evidence from MENA.},
journal = {Population health metrics},
volume = {},
number = {},
pages = {},
doi = {10.1186/s12963-026-00477-2},
pmid = {42045931},
issn = {1478-7954},
abstract = {BACKGROUND: Rapid population ageing, high burdens of non-communicable diseases (NCDs), and limited formal care systems are converging in the Middle East and North Africa (MENA) region, generating an urgent need for evidence-based long-term care (LTC) planning. However, the absence of individual-level data on care dependency hampers assessment and policy design.

METHODS: We developed a population-based LTC Needs Index to estimate care dependency in data-scarce contexts. The Index integrates demographic ageing, prevalence of disability, and transition probabilities from five major NCDs (cardiovascular disease, diabetes, cancer, Alzheimer's disease, and Parkinson's disease) using standardized national and international data sources. Cross-country comparability was ensured through normalization and weighting procedures, and the model's robustness was tested using Bayesian, bootstrap, and deterministic sensitivity analyses.

RESULTS: The LTC Needs Index reveals substantial heterogeneity in care dependency across eight MENA countries, ranging from approximately 3% of the total population in Oman to 22.8% in Saudi Arabia. Projections for 2024-2030 show a consistent upward trend in LTC needs, primarily driven by demographic ageing. Disability emerged as the dominant factor, accounting for 67-94% of total index values, with diabetes and cardiovascular diseases contributing most strongly in Gulf states. Sensitivity analyses confirmed the index's stability under varying assumptions.

CONCLUSIONS: The LTC Needs Index offers a scalable, validated diagnostic model for estimating population-level LTC needs in data-limited settings. It highlights the need for differentiated LTC strategies reflecting the varying contributions of disability and NCDs across countries. To advance equity and precision in planning, countries should invest in nationally representative survey data on ageing, disability, and care dependency to capture intra-country inequalities. The Index provides a transferable framework applicable to other data-scarce regions seeking to strengthen long-term care systems and policy preparedness for population ageing.},
}

@article {pmid42045954,
year = {2026},
author = {Li, Z and Li, X and Qu, Z and Su, R and Yin, B and Yin, L},
title = {An interpretable deep learning diagnostic framework for early Alzheimer's disease based on EEG microstate spectra and multi-branch CNN.},
journal = {Journal of neuroengineering and rehabilitation},
volume = {},
number = {},
pages = {},
doi = {10.1186/s12984-026-01980-1},
pmid = {42045954},
issn = {1743-0003},
support = {236Z2004G//S&T Program of Hebei/ ; 23372006D//S&T Program of Hebei/ ; UY202201//the Medical-Industrial Crossover Special Incubation Project of Yanshan University and The First Hospital of Qinhuangdao/ ; QN2024061//Science Research Project of Hebei Education Department/ ; H2025107031//Hebei Natural Science Foundation/ ; },
}

@article {pmid42046023,
year = {2026},
author = {Zhou, R and Sun, X and Chen, S and Zhao, S and Zhao, C and Qu, J and Zeng, W and Li, C and Zhang, X and Li, Z and Wang, Y and Zhang, T and Xu, X and Jia, J and Liang, Y},
title = {Amyloid-beta statuses prediction with free water MR imaging features in Alzheimer's disease using machine learning models.},
journal = {BMC medical imaging},
volume = {},
number = {},
pages = {},
doi = {10.1186/s12880-026-02380-6},
pmid = {42046023},
issn = {1471-2342},
support = {62401072//the National Natural Science Foundation of China/ ; 62171300//the National Natural Science Foundation of China/ ; 31600933//the National Natural Science Foundation of China/ ; 2023YFF1203502//National Key Research and Development Program of China/ ; 2023YFC3605403//National Key Research and Development Program of China/ ; },
}

@article {pmid42046086,
year = {2026},
author = {Guedjdal, S and Leghay, C and Derisbourg, M and Eddarkaoui, S and Lecerf, S and Vermon, F and Caillierez, R and Begard, S and Regost, C and Laloux, C and da Costa, PJ and Carvalho, K and Chiappetta, G and Verdier, Y and Buée-Scherrer, V and Deramecourt, V and Schraen, S and Blum, D and Martin, F and Buée, L and Hamdane, M},
title = {N-terminally acetylated Met11-Tau: a new pathological truncated Tau species with functional relevance in Alzheimer's disease.},
journal = {Translational neurodegeneration},
volume = {15},
number = {1},
pages = {},
pmid = {42046086},
issn = {2047-9158},
support = {ALZ201912009641//Fondation pour la Recherche Médicale/ ; LabEx DISTALZ ANR-11-LABX-01//Agence Nationale de la Recherche/ ; RiboTAUxic ANR-21-CE12-0028-01//Agence Nationale de la Recherche/ ; AAP PFA 2024 - Dossier #6469//Association France Alzheimer/ ; MAT-PI-14188-A-01//Inserm Transfert/ ; MAT-PI-18399-A-03//Inserm Transfert/ ; Start-AIRR 2016-06656//Conseil Régional Hauts-de-France/ ; },
mesh = {Animals ; *Alzheimer Disease/metabolism/pathology/genetics ; *tau Proteins/metabolism/genetics/immunology ; Mice, Transgenic ; Humans ; Mice ; Acetylation ; Brain/metabolism/pathology ; Male ; Disease Models, Animal ; Female ; Antibodies, Monoclonal ; },
abstract = {BACKGROUND: Tauopathies are a group of neurodegenerative diseases, including Alzheimer's disease (AD), characterized by progressive accumulation of pathological Tau proteins. Among the diverse Tau species, truncated variants are emerging as key contributors, yet their identity remains elusive, particularly for the N-terminal truncated ones. The present study identifies and characterizes a novel N-terminally truncated and N-alpha-acetylated form of the Tau protein, named AcMet11-Tau.

METHODS: We identified AcMet11-Tau by further analyses of previous proteomic data (capillary liquid chromatography-tandem mass spectrometry). We developed a monoclonal antibody, termed 2H2D11, by hybridoma method. The specificity of 2H2D11 was validated by ELISA, Western blot and immunohistochemistry. Expression of AcMet11-Tau in transgenic mouse model of Tau pathology and postmortem brain tissues was analyzed by ELISA and/or immunohistochemistry. Overexpression of AcMet11-Tau in the mouse brain was achieved by stereotaxic injections of lentiviral vectors carrying the coding sequence in the hippocampus. To neutralize AcMet11-Tau, transgenic mice received repeated intraperitoneal immunizations with either 2H2D11 or control antibody. The effects on Tau pathology were assessed by immunohistochemistry, qPCR, and behavioral assays.

RESULTS: Using 2H2D11, the newly developed antibody specifically targeting the AcMet11-Tau variant, we demonstrated that this species accumulated early in degenerating neurons in both transgenic mouse models of AD-related Tau pathology and post-mortem brain tissues from AD patients. Importantly, in vivo functional experiments revealed that expression of this truncated Tau species exacerbated Tau pathology in the transgenic mice, whereas targeted immunotherapeutic with the specific 2H2D11 antibody significantly reduced pathological Tau accumulation and prevented associated memory impairments.

CONCLUSION: These findings position this newly identified Tau variant as a marker of neurofibrillary degeneration and a Tau species that contributes to disease-associated pathological processes, supporting its potential as a therapeutic target in Tau-related disorders, notably AD.},
}

Animals
*Alzheimer Disease/metabolism/pathology/genetics
*tau Proteins/metabolism/genetics/immunology
Mice, Transgenic
Humans
Mice
Acetylation
Brain/metabolism/pathology
Male
Disease Models, Animal
Female
Antibodies, Monoclonal

@article {pmid42046101,
year = {2026},
author = {Andrews, D and Golchi, S and Collins, DL and , },
title = {A digital twin methodology using retrospective patient data for sample size reduction in Alzheimer's disease clinical trials.},
journal = {Alzheimer's research & therapy},
volume = {},
number = {},
pages = {},
doi = {10.1186/s13195-026-02024-5},
pmid = {42046101},
issn = {1758-9193},
support = {FRN 165921/CAPMC/CIHR/Canada ; RGPIN-2015-03633//Natural Sciences and Engineering Research Council of Canada/ ; },
}

@article {pmid42046390,
year = {2026},
author = {Lyu, X and Mundada, NS and Brown, CA and Sadeghpour, N and McGrew, E and Xie, L and Li, Y and Wuestefeld, A and Duong, MT and Cook, P and Gee, J and Nasrallah, IM and Chen-Plotkin, AS and Shaw, LM and Mechanic-Hamilton, D and Wisse, LEM and Yushkevich, PA and Das, SR and Wolk, DA},
title = {Medial temporal lobe Tau-Neurodegeneration mismatch from structural imaging and plasma biomarkers.},
journal = {Brain : a journal of neurology},
volume = {},
number = {},
pages = {},
doi = {10.1093/brain/awag105},
pmid = {42046390},
issn = {1460-2156},
abstract = {While tau pathology is closely associated with neurodegeneration in Alzheimer's disease (AD), our prior work using multi-modality imaging revealed that mismatch between tau (T) and neurodegeneration (N) may reflect contributions from non-AD processes. The medial temporal lobe (MTL), an early site of AD pathology, is also a common target of co-pathologies such as limbic-predominant age-related TDP-43 encephalopathy neuropathologic change (LATE-NC), often following an anterior-posterior atrophy gradient. Given the susceptibility of MTL to co-pathologies, here we explored T-N mismatch specifically within MTL using plasma ptau217 and MTL morphometry for identifying vulnerabilities and resilience in cognitively impaired or unimpaired AD patients. We parcellated the MTL into 100 spatially contiguous segments and calculated their T-N mismatch using plasma ptau217 as a measure for T and thickness as a marker of N. Based on these mismatch profiles, we clustered 447 amyloid-positive individuals from ADNI cohort into data-driven T-N phenotypes. We characterized the T-N phenotypes by examining their cross-sectional and longitudinal atrophy both within the MTL and across the whole brain, as well as cognitive trajectories. This framework was replicated in an independent cohort and finally translated to a real-world clinical sample of 50 patients undergoing anti-amyloid therapy. Clustering identified three T-N phenotypes with different MTL T-N mismatch profiles, atrophy patterns, and cognitive outcomes, despite comparable AD severity. The "canonical" group, characterized by low T-N residuals (N ∼ T), showed AD-like neurodegeneration patterns. The "vulnerable" group, characterized by disproportionately greater neurodegeneration than tau (N > T), showed atrophy primarily in the anterior MTL that extended into temporal-limbic regions, both in cross-sectional and longitudinal analyses. This group also exhibited neurodegeneration that preceded estimated tau onset and experienced faster cognitive decline across multiple domains, aligning with the typical characteristics of mixed LATE-NC with AD. In contrast, the "resilient" group (N < T) showed minimal atrophy and preserved cognitive function. These phenotypes were reproducible in an independent research cohort. Importantly, in a feasibility study applying the model developed from ADNI to a clinical cohort of patients receiving lecanemab, we identified vulnerable individuals with LATE-like atrophy patterns. This highlights its potential utility for identifying individuals with co-pathology in clinical settings. Our findings demonstrate that T-N mismatch within MTL using MRI and plasma biomarkers can reveal AD groups with varying vulnerability/resilience, with the vulnerable group displaying structural and cognitive outcomes suggestive of LATE-NC. This approach offers a cost-effective strategy for clinical trial stratification and precision medicine for AD therapeutics.},
}

@article {pmid42046563,
year = {2026},
author = {Mohl, GA and Dixon, G and Marzette, E and McKetney, J and Samelson, AJ and Serras, CP and Jin, J and Ariqat, N and Keys, A and Chavira, C and Li, A and Boggess, SC and Swaney, DL and Kampmann, M},
title = {Multi-omic phenotyping of MAPT V337M neurons reveals early changes in axonogenesis and tau phosphorylation.},
journal = {NPJ dementia},
volume = {2},
number = {1},
pages = {24},
pmid = {42046563},
issn = {3005-1940},
abstract = {Tau aggregation is a hallmark of several neurodegenerative diseases, including Alzheimer's disease and frontotemporal dementia. There are disease-causing variants of the tau-encoding gene, MAPT, and the presence of tau aggregates is highly correlated with disease progression. However, the molecular mechanisms linking pathological tau to neuronal dysfunction are not well understood. This is in part due to an incomplete understanding of the normal functions of tau in development and aging, and how the associated molecular and cellular processes change in the context of causal disease variants of tau. To address these questions in an unbiased manner, we conducted multi-omic characterization of iPSC-derived neurons harboring the MAPT V337M mutation or MAPT knockdown. RNA-seq, ATAC-seq, and phosphoproteomics revealed that both the V337M mutation and tau knockdown perturbed levels of transcripts and phosphorylation of proteins related to axonogenesis or axon morphology. When we directly measured axonogenesis, we found that both MAPT V337M and MAPT knockdown caused decreased axon length. Surprisingly, we found that neurons with V337M tau had much lower tau phosphorylation than neurons with WT tau. CRISPR-based screens uncovered regulators of tau phosphorylation in neurons and found that factors involved in axonogenesis modified tau phosphorylation in both MAPT WT and MAPT V337M neurons. Intriguingly, the p38 MAPK pathway specifically modified tau phosphorylation in MAPT V337M neurons. We propose that V337M tau perturbs tau phosphorylation and axon morphology pathways that are relevant to the normal function of tau in development, which could contribute to previously reported cognitive changes in preclinical MAPT variant carriers.},
}

@article {pmid42046874,
year = {2026},
author = {Kong, L and Yang, Y and Zhou, W and Hu, S},
title = {Sporadic Alzheimer's disease with bipolar-like features: a case report and a brief review of the current research status.},
journal = {Journal of Zhejiang University. Science. B},
volume = {27},
number = {4},
pages = {416-425},
doi = {10.1631/jzus.B2500307},
pmid = {42046874},
issn = {1862-1783},
mesh = {*Alzheimer Disease/pathology/diagnosis ; Humans ; Amyloid beta-Peptides/metabolism ; Female ; tau Proteins/metabolism ; Aged ; Male ; Oxidative Stress ; Brain/pathology ; },
abstract = {Alzheimer's disease (AD) is among the main causes of cognitive impairment, memory loss, and dementia, particularly in old adults. It has been listed as one of the most expensive, lethal, and burdening diseases of the 21st century and develops with the process of aging worldwide (Scheltens et al., 2021). Currently, it is widely acknowledged that the typical pathogenesis of AD involves the deposition of amyloid-β (Aβ) and Tau proteins in the cerebral parenchyma and vasculature, intraneuronal neurofibrillary tangles, and the gradual degeneration of synapses (Scheltens et al., 2016; Rostagno, 2022). According to several hypotheses, abnormalities and dysfunctions in vascular structure, mitochondrial metabolism, oxidative stress, glucose utilization, and neuroinflammation are considered fundamental for AD pathology (Scheltens et al., 2016).},
}

*Alzheimer Disease/pathology/diagnosis
Humans
Amyloid beta-Peptides/metabolism
Female
tau Proteins/metabolism
Aged
Male
Oxidative Stress
Brain/pathology

@article {pmid42047177,
year = {2026},
author = {Peressott, S and Garcia Garrido, M and Dzialecka, P and Hoi Law, RM and Portillo-Lara, R and Geary, B and Faillace, E and Merlo-Nikpay Aslie, S and Wojewska, M and Otero-Jimenez, M and Genta, M and Tan, L and Duff, K and Alegre-Abarrategui, J and Green, R and Grossmann, N},
title = {Temporal Interference Stimulation Enhances Neural Regeneration.},
journal = {Advanced science (Weinheim, Baden-Wurttemberg, Germany)},
volume = {},
number = {},
pages = {e24341},
doi = {10.1002/advs.202524341},
pmid = {42047177},
issn = {2198-3844},
support = {771985/ERC_/European Research Council/International ; UKEP/W004844/1//Engineering and Physical Sciences Research Council/ ; //UK Dementia Research Institute/ ; //National Institute for Health and Care Research/ ; //Imperial Biomedical Research Centre/ ; },
abstract = {Neural regeneration therapies aim to treat neurodegeneration by promoting the proliferation and maturation of exogenous or endogenous neural progenitor cells (NPCs). However, their efficacy has been limited. Deep brain stimulation (DBS) via implanted electrodes has been shown to promote neurogenesis in vitro and in vivo. Still, its invasiveness precludes deployment in research and widespread clinical use. Temporal interference (TI) has emerged as a strategy for non-invasive, high-precision DBS using multiple kHz-range electric fields to target the deep brain. Here, we validate the potential of TI stimulation for neural regeneration augmentation in the central nervous system (CNS). First, we showed that TI stimulation modulated at the theta-band frequency enhances the maturation of embryonic neural progenitor cells in vitro. We then demonstrate that theta-band TI stimulation targeting the hippocampus enhances endogenous hippocampal neurogenesis in an in vivo mouse model of Alzheimer's disease-like amyloidosis. By uncovering frequency-specific control of stem cell fate, we propose a clinically relevant regeneration strategy that avoids pharmacological or genetic manipulation. Our results enable focal, non-invasive augmentation of deep-brain neural regeneration via electrical stimulation.},
}

@article {pmid42047293,
year = {2026},
author = {Elias, MN and Thompson, HJ and Kross, EK and Temkin, NR and Khan, BA and Zee, PC and Munro, CL},
title = {Sleep and Cognitive Health Interventions to Prevent Cognitive Decline in Older Adult Survivors of Critical Illness: Randomized Clinical Trial Protocol.},
journal = {Nursing research},
volume = {},
number = {},
pages = {},
doi = {10.1097/NNR.0000000000000912},
pmid = {42047293},
issn = {1538-9847},
abstract = {BACKGROUND: Older adults frequently experience acute and long-term cognitive impairment following critical illness hospitalization in an intensive care unit (ICU). Delirium affects up to 80% of ICU patients and is linked to cognitive dysfunction and increased risk of cognitive decline associated with Alzheimer's disease and related dementias (ADRD). Sleep and circadian rhythm disturbances are present in about 75-80% of ICU patients and may exacerbate delirium and undermine cognitive interventions. Nonpharmacological interventions such as earplugs, eye masks, and computerized cognitive training show promise in reducing delirium and improving sleep but have not been rigorously tested - separately or combined - in older adult ICU survivors. Moreover, prior studies have not leveraged chronotherapeutic timing to align cognitive training with individual circadian rhythms.

OBJECTIVES: We propose a multi-modal combination of sleep promotion intervention [SLEEP], and computerized cognitive training program timed daily according to individual chronotype [COG], to improve cognitive function in hospitalized older adult ICU survivors. The primary aim is to test the feasibility, acceptability, and preliminary separate and combined effects of SLEEP and COG [SLEEP, COG, SLEEP+COG] versus an active control condition [AC] in improving cognitive function after the intervention period. The secondary aims are to explore: (1) circadian rhythm parameters of continuous body temperature to determine the optimal window for chronotherapeutic timing of cognitive interventions; (2) if the effects of each intervention on cognitive function are mediated by sleep and activity; (3) if biopsychosocial and clinical factors moderate the effects of each intervention on cognitive function; and (4) the effects of each intervention on cognitive function at 1, 6, and 12 months.

METHODS: After discharge from ICU, English- or Spanish-speaking older adult ICU survivors (n=100) are randomly assigned to 7 days of (1) SLEEP, (2) COG, (3) SLEEP+COG, or (4) AC. Cognitive function, delirium severity, sleep and circadian rhythms, patient-reported symptoms, and data regarding biopsychosocial and clinical factors are collected.

RESULTS: Results are pending study completion.

DISCUSSION: We aim to target sleep and circadian rhythm disturbances, mitigate ICU delirium, and reduce cognitive decline associated with ADRD. If hypotheses are supported, this combination of low-cost, non-pharmacological interventions could be integrated into standard care to accelerate cognitive recovery during hospitalization.},
}

@article {pmid42047294,
year = {2026},
author = {Chong Chie, JAK and Persohn, SA and Pandey, RS and Simcox, OR and Carter, G and Salama, P and Territo, PR and , },
title = {Multiscale metabolic covariance networks uncover stage-specific biomarker signatures across the Alzheimer's disease continuum.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {4},
pages = {e71218},
doi = {10.1002/alz.71218},
pmid = {42047294},
issn = {1552-5279},
support = {U01 AG024904/NH/NIH HHS/United States ; T32AG071444/NH/NIH HHS/United States ; W81XWH-12-2-0012//Department of Defense/ ; /AG/NIA NIH HHS/United States ; /EB/NIBIB NIH HHS/United States ; },
mesh = {Humans ; *Alzheimer Disease/metabolism/diagnostic imaging ; Female ; Male ; *Biomarkers/metabolism ; Aged ; Retrospective Studies ; Disease Progression ; *Brain/metabolism/diagnostic imaging ; *Connectome ; Aged, 80 and over ; Magnetic Resonance Imaging ; },
abstract = {INTRODUCTION: Functional connectomics studies leverage the power of interregional brain relationships using graph theory of glycolytic metabolism to establish neural connections and their roles in cognition and disease and to monitor therapeutic responses.

METHODS: Using a retrospective clinical population (N = 431) from ADNI, we evaluated disease changes using metabolic covariance analysis. In addition, we developed a novel region set enrichment analysis (RSEA) to detect brain functional changes based on metabolic variations. Results were aligned with transcriptomic signatures and clinical cognitive assessments (CCAs).

RESULTS: Our findings highlight sexual dimorphic changes across the disease spectrum, which suggest brain network reorganization occurs as compensatory mechanisms due to pathological disruptions. RSEA indicated functional changes in motor, memory, language, and cognitive functions related to disease progression, and these changes were supported by transcriptomic signatures.

DISCUSSION: Together, metabolic covariance analysis, regional connectomics, and RSEA allow for AD progression tracking and functional alteration identification based on metabolic readouts, consistent with CCA.},
}

Humans
*Alzheimer Disease/metabolism/diagnostic imaging
Female
Male
*Biomarkers/metabolism
Aged
Retrospective Studies
Disease Progression
*Brain/metabolism/diagnostic imaging
*Connectome
Aged, 80 and over
Magnetic Resonance Imaging

@article {pmid42047299,
year = {2026},
author = {Phares, S and Kremer, I and Wall, JK and Wood, J and Baumgart, M and Dickson, S and Fickie, M and Hubbard, T and Jannati, A and Monane, M and Rivet, C and Hirsch, G},
title = {System changes to empower primary care in Alzheimer's disease detection and care.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {4},
pages = {e71276},
doi = {10.1002/alz.71276},
pmid = {42047299},
issn = {1552-5279},
mesh = {Humans ; *Alzheimer Disease/diagnosis/therapy ; *Primary Health Care ; United States ; Delivery of Health Care ; },
abstract = {Despite advances in disease-modifying treatments, significant barriers in the evaluation and clinical management of people with early Alzheimer's disease (AD) remain. These barriers have been documented in scientific literature and increasingly call for primary care to play a larger role in the detection, diagnosis, treatment, and monitoring of AD. Drawing upon the work of a multistakeholder consortium, this article identifies systemic and structural barriers that hinder primary care professionals in the United States from playing a larger role. We propose solutions to these barriers and call for evolution of the U.S. healthcare system to ensure it is prepared to adapt to the rapidly progressing scientific and societal landscape and meet the growing needs of people affected by the early stages of AD.},
}

Humans
*Alzheimer Disease/diagnosis/therapy
*Primary Health Care
United States
Delivery of Health Care

@article {pmid42047375,
year = {2026},
author = {Guo, C and Liu, M and An, Z and Li, S and Cui, M and Nie, J and Sun, Y and Bai, Z},
title = {Integrating Acridinium Ester with a Soluble Macromolecular Amplification Carrier for Ultrasensitive Detection of Aβ1-42 in Plasma.},
journal = {Analytical chemistry},
volume = {},
number = {},
pages = {},
doi = {10.1021/acs.analchem.6c00193},
pmid = {42047375},
issn = {1520-6882},
abstract = {The research presents the development of a novel ultrasensitive immunoassay for the detection of amyloid-β 1-42 (Aβ1-42) in plasma, a key biomarker for Alzheimer's disease, through the integration of a soluble signal amplification platform (Ficoll400-SA) with an acridinium ester (AE) direct chemiluminescence system. The synthesis of Ficoll400-SA was optimized to maximize the loading of AE molecules by adjusting cross-linker activation ratios and AE labeling density, achieving an approximately 35-fold enhancement of signal intensity relative to conventional streptavidin-AE conjugates. The immunoassay protocol was further refined to improve sensitivity and specificity, resulting in a limit of detection (LoD) of 0.15 pg·mL[-1] and a lower limit of quantitation (LLoQ) of 0.31 pg·mL[-1]. The assay exhibited excellent specificity, with negligible cross-reactivity (<0.5%) to other amyloid isoforms, high precision indicated by coefficients of variation below 8%, and robust reagent stability under both accelerated and onboard conditions. Analysis of clinical samples demonstrated strong correlation (Spearman's ρ = 0.983) and minimal bias compared to a commercial reference method, confirming the assay's reliability. Collectively, this study successfully expanded the application of the Ficoll400-SA signal amplification carrier from enzymatic chemiluminescence assays to the AE direct chemiluminescence platform. Moreover, these findings validate the Ficoll400-SA platform as a versatile, highly sensitive, and automatable approach for detecting low-abundance biomarkers, with significant potential to advance the early diagnosis of Alzheimer's disease and biomarker research.},
}

@article {pmid42047469,
year = {2026},
author = {Chung, J and Jessup, RE and Yang, J},
title = {Charge-Based Discrimination of Amyloids Using an Amyloid-Targeting Chemiluminescent Probe.},
journal = {Chembiochem : a European journal of chemical biology},
volume = {27},
number = {8},
pages = {e202600008},
doi = {10.1002/cbic.202600008},
pmid = {42047469},
issn = {1439-7633},
mesh = {Animals ; *alpha-Synuclein/metabolism/analysis/chemistry ; Humans ; *Amyloid beta-Peptides/metabolism/analysis/chemistry ; Mice ; tau Proteins/metabolism/analysis ; *Fluorescent Dyes/chemistry/chemical synthesis ; Luminescent Measurements ; Biomarkers/analysis ; Protein Aggregates ; Optical Imaging ; *Amyloid/metabolism/analysis ; Luminescence ; },
abstract = {Fluorescent probes have been widely developed for detecting amyloid biomarkers associated with neurodegenerative diseases (NDs). The requirement for external light for excitation, however, limits their utility for research and in vivo applications. Chemiluminescent probes, which use chemical reactions to generate emissive excited states rather than externally applied light, may offer a promising alternative to overcome some limitations for optical imaging of amyloid biomarkers. Here, we designed and synthesized a chemiluminescent amyloid-binding probe (CLIP-1) and evaluated its capability to label three amyloid biomarkers for NDs-amyloid β (Aβ), α-synuclein (α-syn), and tau protein aggregates. We found that CLIP-1 exhibits markedly enhanced chemiluminescence (CL) in aqueous solution when activated by ambient oxygen in the presence of aggregated Aβ, whereas little to no emission is observed in the absence of aggregates or in the presence of monomeric Aβ. Additionally, CLIP-1 displayed a different wavelength of emission when bound to tau aggregates compared to Aβ or α-syn aggregates, which we attribute to differences in the relative overall charge of the amyloids at neutral pH. Imaging of brain slices confirmed enhanced CL of CLIP-1 in an Alzheimer's disease mouse model, highlighting the potential for amyloid-targeting chemiluminescent probes as new tools for aiding in diagnosis of amyloid-associated neurodegenerative diseases.},
}

Animals
*alpha-Synuclein/metabolism/analysis/chemistry
Humans
*Amyloid beta-Peptides/metabolism/analysis/chemistry
Mice
tau Proteins/metabolism/analysis
*Fluorescent Dyes/chemistry/chemical synthesis
Luminescent Measurements
Biomarkers/analysis
Protein Aggregates
Optical Imaging
*Amyloid/metabolism/analysis
Luminescence

@article {pmid42047539,
year = {2026},
author = {Eruysal, E and Ravdin, L and Iadecola, C and Ishii, M},
title = {Associations of circulating resistin with Alzheimer's disease biomarkers and cognitive function in the preclinical stage of Alzheimer's disease.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261442230},
doi = {10.1177/13872877261442230},
pmid = {42047539},
issn = {1875-8908},
abstract = {BackgroundResistin is a circulating protein linked to systemic metabolic disorders and inflammation, both of which can contribute to the pathogenesis of Alzheimer's disease (AD). However, the role of resistin during the preclinical stage of AD and its associations with amyloid-β and tau pathology have not been established.ObjectiveTo measure plasma resistin concentrations in cognitively normal older adults and examine its association with cerebrospinal fluid (CSF) AD biomarkers and neuropsychological measures.Methods155 (64 men and 91 women) cognitively normal (Clinical Dementia Rating 0) volunteers met all study criteria with 55 (29 men and 26 women) categorized as preclinical AD based on established CSF criteria. Plasma resistin concentrations were measured by immunoassay.ResultsSince plasma resistin concentrations were higher in men compared to women, all analyses were sex stratified. In men, plasma resistin concentrations were significantly higher in preclinical AD compared to biomarker negative controls and were associated with CSF concentrations of tau and p-tau181; however, after correcting for multiple comparisons, there were no significant associations with any AD biomarkers. Furthermore, plasma resistin concentrations were significantly associated with semantic fluency but not with episodic memory or executive function. In women, plasma resistin concentrations were similar between preclinical AD and controls, and there were no significant associations with CSF AD biomarkers and cognitive measures.ConclusionsThese findings raise the possibility that, in men, alterations in peripheral resistin signaling occur during the earliest stages of AD and could represent an early link between systemic metabolic and inflammation dysregulation in AD.},
}

@article {pmid42047940,
year = {2026},
author = {He, DL and Wu, Z and Jia, RJ and Wu, TY and Qiu, YM and Fan, YG},
title = {AS1842856 Reduces β-Amyloid Burden via Inhibiting PLA2G4A-Mediated Lysosomal Dysfunction in APP/PS1 Mice.},
journal = {CNS neuroscience & therapeutics},
volume = {32},
number = {4},
pages = {e70910},
doi = {10.1002/cns.70910},
pmid = {42047940},
issn = {1755-5949},
support = {82301626//National Natural Science Foundation of China/ ; },
mesh = {Animals ; *Lysosomes/drug effects/metabolism ; Mice, Transgenic ; Amyloid beta-Protein Precursor/genetics ; Mice ; *Group IV Phospholipases A2/metabolism/antagonists & inhibitors ; *Amyloid beta-Peptides/metabolism ; Presenilin-1/genetics ; *Alzheimer Disease/drug therapy/metabolism/genetics/pathology ; Disease Models, Animal ; Male ; Humans ; Mice, Inbred C57BL ; Cell Line, Tumor ; },
abstract = {AIMS: Both cytosolic phospholipase A2 (PLA2G4A)-induced lysosomal membrane disruption and glycogen synthase kinase-3α/β (GSK3α/β)-mediated lysosomal dysfunction have been implicated in neurodegeneration, with a potential regulatory relationship between these two pathways. We recently identified AS1842856 (AS) as a suppressor of GSK3α/β. This study was therefore designed to investigate whether AS mitigates Alzheimer's disease (AD) progression by targeting PLA2G4A to restore lysosomal homeostasis.

METHODS: The therapeutic potential of AS was investigated in APP/PS1 mice by analyzing cognitive function, β-amyloid (Aβ) load, and lysosomal integrity, with its mechanism of action further explored in N2a-sw cells.

RESULTS: AS treatment reduced GSK3α/β expression in both APP/PS1 mice and N2a-sw cells. This suppression led to decreased PLA2G4A levels, restoration of lysosomal membrane integrity, and enhanced lysosomal degradation of Aβ. Consequently, AS administration alleviated Aβ burden and improved cognitive function in APP/PS1 mice. Moreover, AS was found to inhibit NF-κB-mediated PLA2G4A expression. Knockdown experiments further revealed that reduced GSK3β-but not GSK3α-reproduced the suppressive effect on PLA2G4A.

CONCLUSION: Our study identified the GSK3β/NF-κB/PLA2G4A signaling axis as a novel therapeutic target in AD, and AS could inhibit this axis to mitigate Aβ pathology by promoting lysosomal degradation of Aβ.},
}

Animals
*Lysosomes/drug effects/metabolism
Mice, Transgenic
Amyloid beta-Protein Precursor/genetics
Mice
*Group IV Phospholipases A2/metabolism/antagonists & inhibitors
*Amyloid beta-Peptides/metabolism
Presenilin-1/genetics
*Alzheimer Disease/drug therapy/metabolism/genetics/pathology
Disease Models, Animal
Male
Humans
Mice, Inbred C57BL
Cell Line, Tumor

@article {pmid42048351,
year = {2026},
author = {Bham, K and Anandakrishnan, M and Wu, CH and Ross, KE},
title = {A network-centric approach reveals novel pathways impacted by Prader-Willi Syndrome.},
journal = {PloS one},
volume = {21},
number = {4},
pages = {e0347773},
doi = {10.1371/journal.pone.0347773},
pmid = {42048351},
issn = {1932-6203},
mesh = {*Prader-Willi Syndrome/genetics/metabolism ; Humans ; RNA, Small Nucleolar/genetics ; *Protein Interaction Maps ; *Gene Regulatory Networks ; },
abstract = {Prader-Willi Syndrome (PWS), a rare multi-system disorder characterized by insatiable appetite, growth abnormalities, and cognitive delay, results from genetic defects in a paternally expressed region of chromosome 15, q11.2-q13. This region contains several protein-coding genes and several genes encoding small nucleolar RNA (snoRNAs), including the SNORD116 gene cluster, but their exact role in PWS remains unclear. Since snoRNAs have wide-ranging effects on protein expression and proteins interact in a complex network, the genetic aberrations causing PWS are likely to cause far-reaching indirect effects on protein expression and activity. Here, we mapped PWS gene expression data onto a human protein-protein interaction (PPI) network and used graph learning techniques to 1) identify the most impacted proteins and 2) suggest novel disease mechanisms. We adapted GeneEMBED, a network-based method originally developed to model genetic variants associated with Alzheimer's Disease. Specifically, we integrated PWS or control expression data with the PPI network, calculated node embeddings, and identified proteins with large differences between PWS and control embeddings. These candidate proteins were subjected to functional enrichment analysis to discover altered biological processes in PWS. Candidate proteins were highly enriched for glycosylated proteins. Analysis of candidate glycosylation enzymes suggested abnormalities in mucin-type O-glycosylation, fucosylation, and glycosaminoglycan synthesis. Defects in these glycosylation pathways have been linked to several PWS phenotypes, including obesity, cognitive delay, and production of secondary sex hormones. Homeobox proteins, master regulators of transcription during development, were also overrepresented among the candidate proteins. In particular, we identified homeobox proteins that drive development of GABAergic and dopaminergic neurons. These neuronal pathways regulate appetite and other behaviors that are abnormal in individuals with PWS. Our results were highly reproducible across PWS model systems. This work offers new avenues for further research in PWS and provides a promising approach that can be applied to other complex diseases.},
}

*Prader-Willi Syndrome/genetics/metabolism
Humans
RNA, Small Nucleolar/genetics
*Protein Interaction Maps
*Gene Regulatory Networks