@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

@article {pmid42048628,
year = {2026},
author = {Benarroch, E},
title = {What Is the Potential Relevance of Hippocampal Area CA2 in Neurologic Disorders?.},
journal = {Neurology},
volume = {106},
number = {10},
pages = {e218096},
doi = {10.1212/WNL.0000000000218096},
pmid = {42048628},
issn = {1526-632X},
mesh = {Humans ; *CA2 Region, Hippocampal/physiopathology/pathology/physiology ; Animals ; *Nervous System Diseases/physiopathology/pathology ; },
abstract = {The hippocampus has a critical role in the online processing of information; encoding, storage, and retrieval of episodic memory; and novelty detection. These functions have been classically associated with a trisynaptic circuit connecting the entorhinal cortex, the dentate gyrus, area CA3, and area CA1. Until recently, the role of area CA2, located between CA3 and CA1, has been underappreciated. However, increased evidence indicates that, despite its small size,[1] area CA2 has a critical role in in regulating activity throughout the hippocampal circuit and has a unique importance in social recognition memory.[2-8] Area CA2 has widespread connectivity with other hippocampal regions[2] and has unique structural features, electrophysiologic responses, pattens of receptor expression, and subcortical inputs. Pyramidal CA2 neurons are more resistant to excitotoxicity than those in other hippocampal subfields.[9] However, area CA2 is susceptible to accumulation of alpha-synuclein[10,11] and tau.[12] Experimental studies show loss or impaired function of a critical subpopulation of local inhibitory CA2 interneurons in several disorders, including temporal lobe epilepsy,[13] Alzheimer disease (AD), multiple sclerosis, schizophrenia, and autism spectrum disorder.[14].},
}

Humans
*CA2 Region, Hippocampal/physiopathology/pathology/physiology
Animals
*Nervous System Diseases/physiopathology/pathology

@article {pmid42048844,
year = {2026},
author = {Hartmann, T},
title = {Lipid-lowering regimens in Alzheimer's disease dementia: small effects with potential long-term benefit.},
journal = {The journal of prevention of Alzheimer's disease},
volume = {13},
number = {6},
pages = {100576},
doi = {10.1016/j.tjpad.2026.100576},
pmid = {42048844},
issn = {2426-0266},
}

@article {pmid42049166,
year = {2026},
author = {Duchet, B and Subramaniam, S and Greenway, A and He, S and Shackle, N and Pogosyan, A and Denison, T and Sharott, A and Tan, H and Bogacz, R},
title = {Dithering suppresses half-harmonic neural synchronisation to photic stimulation in humans.},
journal = {Brain stimulation},
volume = {},
number = {},
pages = {103111},
doi = {10.1016/j.brs.2026.103111},
pmid = {42049166},
issn = {1876-4754},
abstract = {BACKGROUND: While entraining neural rhythms using brain stimulation has been suggested as a therapeutic mechanism to normalise brain activity in conditions such as depression, chronic pain, or Alzheimer's disease, periodic stimulation can also inadvertently entrain brain rhythms at sub- and superharmonics of the stimulation frequency, which could lead to deleterious effects. Slightly jittering stimulation pulses (called "dithering") was previously proposed on the basis of mathematical modelling to selectively entrain a target neural rhythm while avoiding harmonic entrainment. In this study, we investigated the potential of dithering in humans.

METHODS: We recorded EEG in healthy adults during photic stimulation (light flicker) under periodic, dithered, reduced-strength, and control conditions. Synchronisation was quantified using spectral power and the phase-locking value.

RESULTS: We showed that dithering suppresses half-harmonic synchronisation relative to perfectly periodic flicker, and that dithering affects synchronisation at the stimulation frequency less than at the half-harmonic. This was also the case for a periodic condition with reduced stimulation strength, as predicted by theory. Furthermore, we demonstrated using synthetic data and modelling that the half-harmonic responses observed in participants cannot be explained by the superposition of evoked responses (even when modulated at the half-harmonic frequency), and are better matched by a minimal oscillator model.

CONCLUSION: Our findings are consistent with half-harmonic EEG synchronisation in response to photic stimulation predominantly reflecting half-harmonic entrainment rather than the summation of evoked responses, and with dithering being an effective strategy to suppress subharmonic entrainment without reducing the energy delivered.},
}

@article {pmid42049507,
year = {2026},
author = {Morello, CM and Mnatzaganian, CL and Painter, NA},
title = {Emerging and Off-Label Uses Of Glucagon-Like Peptide-1 Receptor Agonists (GLP1-RA) and Dual GIP/GLP1-RAs.},
journal = {Journal of the American Board of Family Medicine : JABFM},
volume = {39},
number = {1},
pages = {},
doi = {10.3122/jabfm.2025.250158R1},
pmid = {42049507},
issn = {1558-7118},
mesh = {Humans ; *Glucagon-Like Peptide-1 Receptor Agonists ; *Diabetes Mellitus, Type 2/drug therapy ; *Off-Label Use ; *Obesity/drug therapy ; *Gastric Inhibitory Polypeptide/therapeutic use ; *Hypoglycemic Agents/therapeutic use ; },
abstract = {BACKGROUND: Glucagon-like peptide-1 receptor agonists (GLP1-RAs) and the glucagon-dependent insulinotropic polypeptide (GIP)/GLP1-RA are approved for type 2 diabetes (T2D) and obesity given their profound impact on glycemic weight management. Additional indications include reducing cardiovascular disease risk and progression of chronic kidney disease (CKD) in T2D as well as obstructive sleep apnea in patients with obesity. These enhanced effects are likely due to their pleiotropic effects, leading to decreased inflammation and other benefits. This review explored emerging evidence for uses of GLP1-RAs and GIP/GLP1-RA that have been researched but not yet approved. Clinicians may use this information to guide treatment decisions.

REVIEW PROCESS: PubMed and Embase literature searches were conducted using Medical Subject Heading terms. Studies referencing GLP1-RAs and GIP/GLP1-RA were included if they were published in approximately the last decade, included adults, and were either a randomized controlled trial, meta-analysis, or observational study. Of 319 articles reviewed, 27 met inclusion criteria.

EMERGING AND COMPELLING USES: Initial positive impacts have been noted for the following conditions: liver disease/liver transplant, CKD/kidney transplant, Alzheimer's disease, Parkinson's disease, substance use disorders, osteoarthritis, rheumatoid arthritis, psoriasis, COVID-19 virus, asthma, chronic obstructive pulmonary disorder, polycystic ovarian syndrome, and short bowel syndrome.

CONSIDERATIONS: Large randomized controlled trials may lead to approvals of these conditions and are encouraged. Safety and adverse effects of these medications must be assessed when initiating or modifying doses.

CONCLUSION: GLP1-RAs and GIP/GLP1-RA have demonstrated early benefits to several conditions beyond their current approved indications. Clinicians can use this information to determine treatment options for patients, particularly in those with T2D, cardiovascular disease, and/or obesity.},
}

Humans
*Glucagon-Like Peptide-1 Receptor Agonists
*Diabetes Mellitus, Type 2/drug therapy
*Off-Label Use
*Obesity/drug therapy
*Gastric Inhibitory Polypeptide/therapeutic use
*Hypoglycemic Agents/therapeutic use

@article {pmid42049518,
year = {2026},
author = {, and , and , and , and , },
title = {[Clinical practice guideline for integrated PET/MRI in Alzheimer's disease (2026 edition)].},
journal = {Zhonghua yi xue za zhi},
volume = {106},
number = {16},
pages = {1527-1540},
doi = {10.3760/cma.j.cn112137-20251222-03384},
pmid = {42049518},
issn = {0376-2491},
support = {2022YFC2406904//National KeyResearch and Development Program of China/ ; },
mesh = {Humans ; *Alzheimer Disease/diagnostic imaging/diagnosis ; *Positron-Emission Tomography ; *Magnetic Resonance Imaging ; Brain/diagnostic imaging ; },
abstract = {To further standardize the clinical use of integrated PET/MRI brain imaging for Alzheimer's disease (AD) in China, improve early identification and precision diagnosis and management of AD, promote standardized care, and provide evidence-based and consensus recommendations for clinicians and imaging professionals, experts in nuclear medicine, radiology, neurology, and related fields developed this guideline through a consensus process informed by the available research evidence and clinical practice. AD is one of the most common forms of dementia in older adults, with an insidious course; early diagnosis and timely intervention are crucial to improving patient outcomes. Integrated PET/MRI enables the simultaneous, one-stop acquisition of multidimensional information-including cerebral amyloid burden, brain metabolism, and high-resolution anatomical detail-and can be used for early diagnosis, clinical staging, assessment of disease progression, and clinical trial research, making it an important imaging tool for precision care in AD. As integrated PET/MRI systems become increasingly available in China, broader clinical implementation continues to face challenges, including appropriate patient selection and indications, standardization of scanning workflows, image quality control, consistency in image interpretation, and reporting standards. With a focus on clinical feasibility, this guideline provides recommendations across key domains-indications, examination and quality-control procedures, image interpretation, and standardized reporting-with the aim of promoting the standardized use of integrated PET/MRI in AD care and advancing research and translation of relevant imaging biomarkers.},
}

Humans
*Alzheimer Disease/diagnostic imaging/diagnosis
*Positron-Emission Tomography
*Magnetic Resonance Imaging
Brain/diagnostic imaging

@article {pmid42049620,
year = {2026},
author = {Catalán, L and Pepper, A and Pot, AM and Brun, P and Harrison-Dening, K and Oliveira, D},
title = {Nursing staff attitudes towards the prevention of adverse events among hospitalized people with dementia: Qualitative systematic review and evidence synthesis.},
journal = {International psychogeriatrics},
volume = {},
number = {},
pages = {100210},
doi = {10.1016/j.inpsyc.2026.100210},
pmid = {42049620},
issn = {1741-203X},
abstract = {INTRODUCTION: Negative attitudes among nursing staff are linked to adverse events in hospitalized people with dementia, but no qualitative synthesis has thoroughly explored this issue.

AIM: To synthesize existing qualitative evidence regarding the attitudes of nursing staff towards the prevention of adverse events (AE) among hospitalized people with dementia.

METHODS: Literature searches were conducted across PubMed, CINAHL, APA PsycINFO, Web of Science, BVS, Scopus, Cochrane Library, and Google Scholar. All primary qualitative or mixed-methods studies with a qualitative component published in peer-reviewed journals in English, Portuguese, or Spanish were eligible. The search covered all records from each database's start date to July 21. Methodological quality was assessed using the JBI tool. A meta-aggregative approach extracted and synthesized evidence with JBI's SUMARI. Confidence was graded using ConQual.

RESULTS: Eight high-income country studies yielded 122 findings in 18 categories, resulting in four synthesized findings: (1) Perceptions related to the organizational barriers to the provision of safe nursing care for people with dementia; (2) Misconceptions, negative emotions, and perception of lack of preparedness among nursing staff relate to negative attitudes towards prevention AE; (3) Perception of supportive organizational strategies fosters positive attitudes towards prevention AE; (4) Personal and emotional attributes were linked with a positive predisposition towards taking responsibility for safety practices in this context. The confidence in the findings was low.

CONCLUSION: These attitudes reflect organizational conditions and personal beliefs, emotions, and experiences, which influence care practices. Although more studies are needed, hospitals might benefit from fostering empathetic and proactive attitudes among staff to prevent adverse events.},
}

@article {pmid42049746,
year = {2026},
author = {Zhao, YL and Zhang, DD and Gao, PY and Fu, Y and Ge, YJ and Chi, HC and Guo, ZX and Yu, HH and Feng, JF and Tan, L and Cheng, W and Zhang, YR and Yu, JT},
title = {Associations of social isolation and loneliness with neurological disorders, psychiatric disorders, brain structures and behavioural phenotypes among UK Biobank participants.},
journal = {Nature communications},
volume = {},
number = {},
pages = {},
doi = {10.1038/s41467-026-72529-y},
pmid = {42049746},
issn = {2041-1723},
abstract = {Social isolation and loneliness are increasingly recognized as detrimental risk factors for brain health. Here, utilizing data from 383,421 participants in the UK Biobank, we identify significant associations between social isolation, loneliness, and the incidence of 11 neurological and psychiatric disorders, including major depressive disorder (MDD), schizophrenia, bipolar disorder, anxiety disorders, sleep disorders, dementia, Alzheimer's disease, Parkinson's disease, stroke, multiple sclerosis, and epilepsy employing Cox regression models. Furthermore, using Mendelian randomization analysis we find evidence for putative relationships from social isolation and loneliness to MDD, schizophrenia, sleep disorders, and epilepsy. We also observe significant associations between social isolation, loneliness, and worse cognitive and emotional performance, as well as alterations in brain structures. Additionally, mediation analyses indicate that peripheral inflammatory and biochemical markers partially mediated the links from social isolation and loneliness to neurological and psychiatric disorders.},
}

@article {pmid42035843,
year = {2026},
author = {Gao, Q and Sun, J and Hei, B and Zhou, J and Wang, B and Wang, D and Hu, S and Liu, J and Wang, D and Fan, J},
title = {Vitamin E and melatonin synergistically attenuate sleep deprivation-induced Nrf2 dysregulation and hippocampal ferroptosis in Alzheimer's disease mouse models.},
journal = {Experimental neurology},
volume = {},
number = {},
pages = {115781},
doi = {10.1016/j.expneurol.2026.115781},
pmid = {42035843},
issn = {1090-2430},
abstract = {BACKGROUND: Emerging evidence highlights a bidirectional link between Alzheimer's disease (AD) and sleep disturbances. This study investigates whether early chronic sleep deprivation (CSD) exacerbates AD progression by impairing the antioxidant transcription factor Nrf2 and promoting hippocampal ferroptosis.

METHODS: 5xFAD transgenic mice underwent early CSD. Behavioral tests (Morris water maze, novel object recognition, open field) assessed cognition and anxiety. Histological and molecular analyses evaluated neuronal loss, phosphorylated tau (p-tau), oxidative stress markers (Fe[2+], ROS, MDA, GSH), and expression/localization of Nrf2, Keap1, and ferroptosis-related proteins (GPX4, HO-1, ACSL4, SLC7A11). Interventions included Nrf2 knockout, AAV-mediated Nrf2 overexpression, melatonin, vitamin E (Vit.E), their combination, and the ferroptosis inhibitor liproxstatin1(Lip-1). Data were analyzed with t-tests and ANOVA (p < 0.05).

RESULTS: Early CSD accelerated cognitive decline, hippocampal neuronal loss, and p-tau pathology in 5xFAD mice. CSD triggered Nrf2 depletion, suppressed its nuclear translocation, and downregulated GPX4 and HO-1, leading to oxidative stress and ferroptosis. Nrf2 knockout worsened these deficits. While melatonin or Lip-1 attenuated damage, combined melatonin and Vit.E most effectively reactivated Nrf2, inhibited ferroptosis, reduced p-tau, and restored cognitive function.

CONCLUSIONS: Early CSD promotes AD pathogenesis via Nrf2 dysfunction, driving oxidative stress and ferroptosis in the hippocampus. Preemptive intervention targeting sleep and Nrf2 activation-particularly through combined melatonin and vitamin E-represents a promising strategy to delay neurodegeneration in at-risk individuals.},
}

@article {pmid42035853,
year = {2026},
author = {Liu, Y and Liu, Y and Yu, D and Yang, C and Xu, H and Wang, N and Du, J and Li, L and Chen, G and Liu, Z and Tu, Y and Li, Y},
title = {Discovery and mechanistic exploration of natural butyrylcholinesterase inhibitors via integrated virtual screening and multidisciplinary approaches.},
journal = {International journal of biological macromolecules},
volume = {},
number = {},
pages = {152221},
doi = {10.1016/j.ijbiomac.2026.152221},
pmid = {42035853},
issn = {1879-0003},
abstract = {The development of selective butyrylcholinesterase (BChE) inhibitors from natural sources represents a strategic frontier in discovering novel therapeutics for Alzheimer's disease (AD). Employing a rigorous hierarchical virtual screening protocol encompassing high-throughput screening, ensemble molecular docking, and MM/GBSA binding affinity refinement, we systematically interrogated a natural product library containing 60,580 phytochemicals. This computational cascade identified three alkaloid candidates (hirsutine, picrasidine I, and picrasidine T) exhibiting potent BChE inhibition (IC50 < 10 μM) validated through enzymatic assays. Detailed kinetic characterization further established hirsutine and picrasidine I as reversible, mixed-type inhibitors, targeting both the catalytic active site and the peripheral aromatic site (PAS) of BChE. To elucidate the mechanism of interaction, picrasidine I was selected for comprehensive spectroscopic analysis, including molecular fluorescence, time-resolved fluorescence, three-dimensional fluorescence, circular dichroism (CD), and isothermal titration calorimetry (ITC). ITC analysis confirmed a strong affinity between picrasidine I and BChE, yielding a dissociation constant (Kd = 2.97 μM), while fluorescence studies indicated a static quenching mechanism. Molecular dynamics (MD) simulations (50 ns) substantiated the stability of the ligand-protein complex, demonstrated by a backbone RMSD <0.3 nm. Furthermore, ADME predictions suggested favorable blood-brain barrier (BBB) permeability and minimal cytotoxicity in PC-12 neurons. This synergistic computational-experimental paradigm not only successfully identifies new chemotypes as potent BChE inhibitors and unveils their precise molecular mechanism of action, but also provides a practical and highly effective strategy for the rational discovery and development of natural anti-AD agents.},
}

@article {pmid42035900,
year = {2026},
author = {Horakova, H and Mazancova, AF and Vyhnalek, M},
title = {Challenging Memory Tests in Early Alzheimer's Disease: From Research to Clinical Practice.},
journal = {Neuroscience and biobehavioral reviews},
volume = {},
number = {},
pages = {106701},
doi = {10.1016/j.neubiorev.2026.106701},
pmid = {42035900},
issn = {1873-7528},
abstract = {Alzheimer's disease (AD) diagnosis is undergoing rapid change with the advent of disease-modifying therapies, highlighting the need for earlier and more accurate identification of disease-related cognitive changes, particularly in preclinical stages. In response, several challenging memory paradigms have been introduced to more directly target encoding and storage processes affected in early AD. Building on these paradigms, novel experimental methods based on memory binding, cognitive stress testing, and accelerated long-term forgetting have been proposed to target cognitive processes not captured by traditional episodic memory measures. However, their clinical relevance and applicability remain uncertain. This narrative review summarizes current evidence on the clinical utility of these novel methods. It examines construct validity based on associations with AD biomarkers; discriminative validity to distinguish early pathological cognitive decline from normal aging, and to differentiate AD-related impairment from non-AD etiologies; and predictive validity for future cognitive decline and clinical progression. Particular attention is given to their readiness for individual-level interpretation. Although several methods show promise, particularly for detecting subtle cognitive vulnerability in preclinical AD, none currently fulfills the criteria for routine clinical implementation. The strongest evidence is available for the Memory Binding Test and the Loewenstein-Acevedo Scales of Semantic Interference and Learning, followed by the Face-Name Associative Memory Exam. This review discusses key barriers to clinical translation across the reviewed methods, as well as the evolving requirements for validation of neuropsychological tools in the biomarker-driven era, where cognitive testing is increasingly intended for use in preclinical and early prodromal disease stages.},
}

@article {pmid42035914,
year = {2026},
author = {Li, F and Tao, S and Wang, S and Ren, T and Qiu, M and Xu, X},
title = {New Perspectives on oligodendrocytes: Guardians of iron homeostasis and defenders against ferroptosis.},
journal = {Journal of advanced research},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.jare.2026.04.052},
pmid = {42035914},
issn = {2090-1224},
abstract = {BACKGROUND: Oligodendrocytes (OLs) play a pivotal role in preserving iron homeostasis within the central nervous system (CNS), as they harbor the largest cellular iron reservoir essential for myelination. However, this indispensable function places OLs at heightened risk of ferroptosis, a regulated form of cell death characterized by iron-dependent lipid peroxidation. The susceptibility of OLs to ferroptosis has significant implications for CNS health, particularly in the context of neurodegenerative diseases where OL dysfunction exacerbates demyelination and accelerates disease progression.

AIM OF REVIEW: This review aims to systematically elucidate the mechanisms by which mature OLs balance their dual roles as guardians of iron homeostasis and defenders against ferroptosis. Furthermore, it aims to underscore the ramifications of impaired OL iron regulation in prominent neurodegenerative conditions and to investigate potential therapeutic interventions aimed at bolstering OL resilience.

Mature OLs employ a sophisticated, multi-layered defense system to maintain iron homeostasis and prevent ferroptosis, encompassing precise metabolic regulation of iron uptake and storage, alongside a specialized antioxidant network centered on selenoprotein synthesis. Disruption of this delicate balance renders OLs vulnerable in diseases such as multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS), Parkinson's disease (PD) and Alzheimer's disease (AD), leading to a vicious cycle of OL death, iron dysregulation, and demyelination. Targeting OL iron homeostasis and anti-ferroptotic pathways through iron modulation, antioxidant reinforcement, or direct ferroptosis inhibition represents a promising strategy to promote remyelination and mitigating neurodegeneration.},
}

@article {pmid42035925,
year = {2026},
author = {Siew, JJ and Chern, Y},
title = {Galectins as stress-integrating regulators of neuroimmune signaling and proteinopathy in the central nervous system.},
journal = {Neurobiology of disease},
volume = {},
number = {},
pages = {107410},
doi = {10.1016/j.nbd.2026.107410},
pmid = {42035925},
issn = {1095-953X},
abstract = {Galectins are β-galactoside-binding lectins that play increasingly mechanistic functions in central nervous system (CNS) physiology and disease. Over the past decade, a rapidly expanding literature has identified galectins as regulators of microglial activation, misfolded protein pathology, vesicle damage sensing, autophagy, synaptic plasticity, myelination, vascular repair, and neuroimmune communication. Galectins operate across intracellular and extracellular compartments to integrate cellular stress and innate immune signaling. Here, we review CNS studies of galectin-1, galectin-3, galectin-4, galectin-8, and galectin-9, focusing primarily on work published from 2019 onward while incorporating selected earlier studies to establish foundational concepts. Across experimental models and human studies, galectins orchestrate microglial state transitions, regulate aggregation and propagation of amyloid-β, tau, α-synuclein, and mutant huntingtin, and function as intracellular sensors of vesicle and lysosomal damage. Multiple studies further establish galectins as biomarkers and therapeutic targets across Alzheimer's disease, Parkinson's disease, Huntington's disease, multiple sclerosis, stroke, traumatic brain injury, spinal cord injury, retinal degeneration, and chronic pain. Importantly, this review highlights a stage- and context-dependent paradox in which the same galectin axis can amplify neuroinflammation and proteopathic spread in some settings yet support recovery or tissue protection in others. Together, these findings position galectins as central regulators that convert intracellular stress into coordinated neuroimmune programs shaping proteinopathy, circuit dysfunction, and tissue remodeling.},
}

@article {pmid42036434,
year = {2026},
author = {Mohammadi, F and Koohi, MK and Adeli, S and Hassan, J and Amini, A and Azadbakht, AR and Zayerzadeh, E and Babaei, JF},
title = {Effects of co-administered melatonin and methylphenidate on cognitive impairment and histopathological alterations in an AlCl3-induced neurotoxicity model of alzheimer's disease in BALB/C mice.},
journal = {Scientific reports},
volume = {},
number = {},
pages = {},
doi = {10.1038/s41598-026-43776-2},
pmid = {42036434},
issn = {2045-2322},
}

@article {pmid42036736,
year = {2026},
author = {Chang, JH and Jang, YJ and Yoon, SC and An, JH and Choi, JS and Jeon, HJ},
title = {Digital Psychiatry with Virtual Reality and Augmented Reality: Recent Advances and Limitations.},
journal = {Clinical psychopharmacology and neuroscience : the official scientific journal of the Korean College of Neuropsychopharmacology},
volume = {24},
number = {2},
pages = {240-251},
doi = {10.9758/cpn.25.1382},
pmid = {42036736},
issn = {1738-1088},
abstract = {Digital psychiatry has rapidly expanded with the integration of immersive technologies such as virtual reality (VR) and augmented reality (AR). These modalities allow for controlled, engaging, and ecologically valid interventions across a wide range of psychiatric disorders. In this review, a narrative synthesis was conducted based on systematic reviews, meta-analyses, and randomized controlled trials identified through PubMed, Google Scholar, complemented by seminal earlier works. VR-based therapies demonstrated robust efficacy for anxiety disorders and phobias, with meta-analytic evidence supporting large effect sizes. For post-traumatic stress disorder virtual reality exposure therapy was superior to waitlist control and comparable to established psychotherapies, although AR exposure therapy remains underexplored. In autism spectrum disorder, VR and AR interventions significantly enhanced cognitive, social, and communication skills. AR applications have additionally been validated for cognitive assessment in Alzheimer's disease, and VR/AR-supported rehabilitation showed promise in attention deficit hyperactivity disorder and neurodevelopmental disorders. Despite encouraging findings, challenges remain, including small sample sizes, short follow-up periods, heterogeneity of protocols, and risks such as cybersickness or fatigue. VR and AR represent innovative tools with growing empirical support across psychiatric practice, extending from diagnostic assessment to therapeutic and rehabilitative interventions. Standardized protocols, large-scale trials, and long-term outcome studies are needed to integrate these technologies into routine clinical care.},
}

@article {pmid42036745,
year = {2026},
author = {Cho, YJ and Yoon, S and Kim, Y and Song, HM and Nam, YJ and Lee, SH and Lee, S and Shin, D and Lee, SM and Moon, SY and Kim, EJ and Cho, SH and Kim, BC and Choi, SH and Seo, SW and Kim, JC and Park, YJ and Kang, HY and Lee, SR and Hong, S and Son, SJ and Hong, CH and Roh, HW},
title = {Cellular Senescence of Patient-derived Fibroblasts Reveals the Mid-old Stage as a Critical Window for Transcriptomic Signatures Linked to Alzheimer's Disease Biomarkers and Classification.},
journal = {Clinical psychopharmacology and neuroscience : the official scientific journal of the Korean College of Neuropsychopharmacology},
volume = {24},
number = {2},
pages = {353-367},
doi = {10.9758/cpn.25.1360},
pmid = {42036745},
issn = {1738-1088},
abstract = {OBJECTIVE: Alzheimer's disease (AD) is strongly associated with aging, yet the interactions remain unclear. This study modeled replicative senescence in patient-derived fibroblasts to compare gene expression between AD dementia and controls across senescence stages and to evaluate whether stage-specific alterations reflect disease characteristics with diagnostic implications.

METHODS: Dermal fibroblasts from 13 AD dementia patients and 13 healthy controls were repeatedly passaged to induce replicative senescence and classified into young (passage 7), mid-old (passage 18), and old stages (passage 25-28). Transcriptomic profiling was performed by RNA sequencing, followed by stepwise gene extraction, machine learning-based classification, and correlation analyses with AD biomarkers.

RESULTS: Fibroblasts were successfully driven into replicative senescence, validated by SA-β-gal staining, increased expression of CDKN1A and CDKN2A, and transcriptomic age acceleration. From transcriptome data, 605 senescence-associated genes were identified, enriched in extracellular matrix remodeling, chromatin organization, and immune-related pathways. Machine learning classifiers trained on these genes achieved the highest accuracy at the mid-old stage above 0.9, markedly outperforming the young and old stages. In addition, among the most consistently selected mid-old genes, H2AC18, H1-2, and LTBP1 showed significant correlations with cortical amyloid burden and plasma pTau217, linking cellular transcriptomic changes to established AD biomarkers.

CONCLUSION: In summary, replicative senescence models of patient-derived fibroblasts revealed that transcriptomic differences between AD dementia and controls peak at the mid-old stage. This transitional window represents the most informative point for capturing disease-related alterations with strong biomarker relevance.},
}

@article {pmid42036797,
year = {2026},
author = {Bonta, KM and Li, JS and Tun, SM and Fredericks, CA},
title = {Sleep duration and amyloid status moderate the association between mood symptoms and amygdalar tau in preclinical Alzheimer's disease.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {4},
pages = {e71447},
doi = {10.1002/alz.71447},
pmid = {42036797},
issn = {1552-5279},
support = {K23AG059919/NH/NIH HHS/United States ; 2019-AACSF-644153/ALZ/Alzheimer's Association/United States ; //The McCance Foundation/ ; },
mesh = {Humans ; *Alzheimer Disease/metabolism/diagnostic imaging/psychology ; Male ; Female ; *tau Proteins/metabolism ; Positron-Emission Tomography ; Aged ; *Amygdala/metabolism/diagnostic imaging ; *Anxiety/metabolism ; *Sleep/physiology ; *Depression/metabolism ; Longitudinal Studies ; *Amyloid beta-Peptides/metabolism ; Aged, 80 and over ; Prodromal Symptoms ; Sleep Duration ; },
abstract = {INTRODUCTION: Anxiety and depressive symptoms are common in Alzheimer's disease (AD), yet their relationships with amyloid, tau, and sleep remain unclear. We examined whether amyloid status and sleep duration moderate the relationships between anxiety and depressive symptoms and amygdalar tau burden in cognitively unimpaired older adults at risk for AD.

METHODS: Participants (n = 393) from the Anti-Amyloid Treatment in Asymptomatic Alzheimer's Disease (A4) and the Longitudinal Evaluation of Amyloid Risk and Neurodegeneration (LEARN) studies underwent tau and amyloid positron emission tomography imaging. Anxiety and depressive symptoms were evaluated using the State-Trait Anxiety Inventory and Geriatric Depression Scale. Sleep duration was self-reported.

RESULTS: Positive amyloid status moderated the relationship between depressive symptoms and amygdalar tau. Sleep duration moderated the relationship between anxiety and amygdalar tau, such that greater anxiety symptoms were associated with higher tau levels at shorter sleep durations.

DISCUSSION: Findings suggest biological and behavioral factors jointly influence neuropsychiatric symptom-tau relationships in preclinical AD, supporting an interactive model of early disease vulnerability.},
}

Humans
*Alzheimer Disease/metabolism/diagnostic imaging/psychology
Male
Female
*tau Proteins/metabolism
Positron-Emission Tomography
Aged
*Amygdala/metabolism/diagnostic imaging
*Anxiety/metabolism
*Sleep/physiology
*Depression/metabolism
Longitudinal Studies
*Amyloid beta-Peptides/metabolism
Aged, 80 and over
Prodromal Symptoms
Sleep Duration

@article {pmid42036812,
year = {2026},
author = {Yelton, B and Workman, L and Schaurer, L and Riccardi, N and McCollum, Q and Belza, B and Ory, MG and Thorpe, RJ and Wheeler, SB and Trinh-Shevrin, C and Kreps, GL and Langa, KM and Friedman, DB},
title = {Guiding Approaches to Studying Alzheimer's Disease: A Scoping Review of Community Engagement, Health Communication, and Implementation Science Research.},
journal = {The Gerontologist},
volume = {},
number = {},
pages = {},
doi = {10.1093/geront/gnag056},
pmid = {42036812},
issn = {1758-5341},
abstract = {BACKGROUND AND OBJECTIVES: Alzheimer's disease and related dementias (ADRD) are a leading cause of death, affecting up to 57 million globally. Up to 45% of dementia cases could be prevented or delayed by addressing non-medical drivers of health (NMDoH). Community engagement, health communication, and implementation science are core areas of public health and important to consider when researching ADRD. However, these fields are often siloed, limiting efficacy of ADRD prevention and intervention. This scoping review maps how researchers have incorporated models and theoretical frameworks from these fields specific to ADRD outcomes and with attention to NMDoH.

RESEARCH DESIGN AND METHODS: We searched five social science databases, and articles were included if they were empirical, written in English language, published 2010 forward, focused on ADRD or cognitive health, guided by or developed a framework, theory, or model, and addressed community engagement, health communication, or implementation science.

RESULTS: We retrieved 2,428 articles which were reviewed in multiple stages by five co-authors, resulting in a final sample of 32 articles. Most articles utilized published frameworks, models, or theories, while five were guided by author-developed approaches. Nine articles integrated two core areas, and only one article integrated all three.

DISCUSSION AND IMPLICATIONS: Increased integration of core areas and systematic application of theoretical frameworks are necessary to improve ADRD research with attention to NMDoH. Findings have the potential to inform training and mentorship opportunities for early-career researchers on best practices in interdisciplinary ADRD research, thereby improving community and population health outcomes.},
}

@article {pmid42036938,
year = {2026},
author = {Chu, W and Recchia, D and Islam, S and Sison, C and Sinvani, L},
title = {A multicomponent unit-based approach for hospital care of older adults with behavioral and psychological symptoms of dementia.},
journal = {Journal of hospital medicine},
volume = {},
number = {},
pages = {},
doi = {10.1002/jhm.70336},
pmid = {42036938},
issn = {1553-5606},
support = {//National Institute of Nursing/ ; },
abstract = {BACKGROUND: Persons with Alzheimer's disease and related dementias (ADRD) are more frequently hospitalized and often experience behavioral and psychological symptoms of dementia (BPSD). This study describes a dementia-focused medical unit that aims to improve the management of BPSD in hospitalized patients with ADRD.

OBJECTIVES: The objective of the present paper is to: (1) describe the dementia-focused medical unit; (2) describe the population admitted to the dementia-focused medical unit; (3) present management strategies of BPSD prior to and post unit transfer; and (4) describe patient (e.g., mobility, goals-of-care, mortality) and hospital metrics (e.g. LOS, 30-day hospital readmission) for the unit. The remainder of the abstract is the same.

METHODS: A 10-bed dementia-focused medical unit was created in a large academic center in New York. The unit consisted of geographic cohorting, dementia care education for staff (e.g., de-escalation, redirection), and environmental modifications (e.g., common area). An interprofessional team conducted daily rounds that focused on the 4Ms (mobility, mentation, matters most, and medication management), and early discharge planning.

RESULTS: A total of 165 hospitalized patients were admitted to the dementia-focused medical unit between July 1, 2024, and October 28, 2024. The mean age of patients was 84.7 years old (SD = 9.0); 67.9% (n = 112) had a documented history of dementia, of which 96.4% (n = 108) had at least moderate dementia (FAST stage 6A+). A comparison of BPSD management before and after transfer demonstrated a significant reduction in constant observation (30.9% vs. 0.0%, p < .001), benzodiazepines (13.3% vs. 6.7%, p = .035), and "as-needed" antipsychotics (29.7% vs. 20.0%, p = .009). While as-needed antipsychotics decreased, there was an increase in scheduled antipsychotics (18.2% vs. 28.5%, p < .001), indicating a shift from reactive to proactive medication management.

CONCLUSION: There is an urgent need to improve the management of BPSD in hospitalized older adults with ADRD. Dementia-focused medical units are an innovative strategy that requires further investigation.},
}

@article {pmid42037294,
year = {2026},
author = {Lyon, TR and Weintraub, J},
title = {An Empirical Evaluation of a Non-Directive Storytelling Program for Spiritual Well-Being and Quality of Life in Dementia.},
journal = {Clinical gerontologist},
volume = {},
number = {},
pages = {1-13},
doi = {10.1080/07317115.2026.2663004},
pmid = {42037294},
issn = {1545-2301},
abstract = {OBJECTIVES: People living with dementia (PLWD) often experience disruptions to meaning, identity, and spiritual well-being that are insufficiently addressed by existing psychosocial interventions. This study reports findings from a pilot evaluation examining the feasibility, acceptability, and descriptive quality-of-life outcomes of a non-directive nondenominational storytelling program designed to support personal identity, social connection, and spiritual well-being.

METHODS: A convergent mixed-methods pilot evaluation was conducted with six participants over 20 weeks. Quality of life (QoL) was assessed across three time points using the Quality of Life in Alzheimer's Disease scale (QOL-AD). Semi-structured interviews were analyzed using reflexive thematic analysis, with findings integrated across methods.

RESULTS: QOL-AD scores increased modestly from baseline to mid-program and returned to near-baseline levels at program completion, reflecting overall stability in group-level QoL alongside increasing individual variability across time. Qualitative analysis yielded two overarching themes, Finding Meaning Through Storytelling and Belonging as Healing, describing how narrative engagement and relational safety supported meaning making, identity continuity, and spiritually resonant well-being.

CONCLUSIONS: Findings provide early evidence that non-directive, narrative-based group programs are feasible, acceptable, and clinically relevant forms of spiritually integrative psychosocial support.

CLINICAL IMPLICATIONS: This storytelling-based group program offers a scalable approach clinicians can implement to support QoL and spiritual well-being in PLWD without requiring religious content or specialized spiritual training.},
}

@article {pmid42037619,
year = {2026},
author = {Yang, JC},
title = {From Limb to Brain: Lymphedema as a Systemic Disease with Metabolic, Immunological, and Neurodegenerative Consequences and the Disease-Modifying Potential of Lymphaticovenous Anastomosis-An Integrative Analysis.},
journal = {Seminars in plastic surgery},
volume = {40},
number = {1},
pages = {97-102},
pmid = {42037619},
issn = {1535-2188},
abstract = {Lymphedema has traditionally been viewed as a localized disorder characterized by regional fluid accumulation and tissue swelling. However, emerging evidence challenges this paradigm, revealing that lower limb lymphedema induces significant systemic pathophysiological changes. This review synthesizes recent findings demonstrating that lymphedema triggers widespread oxidative stress, chronic inflammation, dysregulated gene expression in circulating monocytes, and contralateral limb muscle edema-even in the absence of clinical lymphedema in the unaffected limb. Furthermore, we examine the potential association between lymphedema and increased Alzheimer's disease (AD) risk through shared mechanisms involving oxidative stress and neuroinflammation. Lymphaticovenous anastomosis (LVA), a minimally invasive supermicrosurgical technique, has emerged as an effective intervention that not only reduces limb volume but also reverses many of these systemic alterations. Studies utilizing advanced imaging techniques, including magnetic resonance volumetry and diffusion tensor imaging, combined with comprehensive biomarker analyses, have documented post-LVA improvements in antioxidant capacity, reduction in oxidative stress markers, normalization of inflammatory cytokines, recovery of dysregulated gene expression patterns, and decreased muscle edema bilaterally. Additionally, preliminary data suggest LVA may reduce AD biomarkers, including tau protein and amyloid-beta levels, while increasing neuroprotective factors such as brain-derived neurotrophic factor. These findings fundamentally redefine lymphedema as a systemic condition with far-reaching metabolic and potentially neurodegenerative consequences, positioning LVA as a therapeutic intervention with benefits extending beyond local symptom control to systemic disease modification.},
}

@article {pmid42037680,
year = {2026},
author = {Sirajo, MU and Obie, R and Mukhtar, AI and Abdullahi, NM and Taniyohwo, EM and Oyem, JC and Badamasi, IM},
title = {Targeting VDR-RXR heterodimerization in neurodegenerative diseases: a hypothetical framework for combined vitamin D3 and vitamin A therapy.},
journal = {Frontiers in neurology},
volume = {17},
number = {},
pages = {1754364},
pmid = {42037680},
issn = {1664-2295},
abstract = {Neurodegenerative diseases such as Alzheimer's and Parkinson's disease are characterized by progressive neuronal loss, oxidative stress, and limited treatment options. While vitamin D3 has demonstrated neuroprotective potential, we hypothesize that its co-administration with vitamin A may enhance therapeutic effects via synergistic interactions between their nuclear receptors (the vitamin D Receptor (VDR) and Retinoid X Receptor (RXR)). The interaction leads to the formation of a heterodimer, which regulates genes involved in neuronal survival, inflammation, and oxidative balance. A comprehensive literature review was conducted to evaluate the mechanisms underlying Vitamin D3's neuroprotection and Vitamin A's modulatory role through RXR activation, focusing on studies exploring the VDR-RXR heterodimer in Alzheimer's and Parkinson's disease models. Evidence indicates that vitamin D3 mitigates neurodegeneration by upregulating neuroprotective genes, reducing oxidative stress, and modulating calcium homeostasis, with these effects amplified by RXR activation. The VDR-RXR heterodimer interaction appears critical for enhancing transcriptional activity, promoting neuronal resilience, while potentially slowing neurodegeneration progression. We propose that combined vitamin D3 and vitamin A supplementation could offer a promising therapeutic strategy by synergistically optimizing VDR-RXR signaling, thereby improving neuroprotection. This hypothesis requires validation through an integrated approach that includes molecular, cellular, behavioral, and translational neuroimaging methods to investigate neuroprotective effects associated with VDR-RXR co-activation.},
}

@article {pmid42037682,
year = {2026},
author = {Zhao, Y and Zeng, M and Zhang, S and Peng, D},
title = {Frailty status and the risk of dementia, Alzheimer's disease: a meta-analysis of observational studies.},
journal = {Frontiers in neurology},
volume = {17},
number = {},
pages = {1798080},
pmid = {42037682},
issn = {1664-2295},
abstract = {BACKGROUND: Frailty and dementia are critical geriatric syndromes that pose a substantial global public health burden. While the association between frailty and increased dementia risk is widely recognized, the magnitude of this association, its consistency across populations, and the influence of frailty subtypes remain inadequately synthesized and quantified.

OBJECTIVE: To address this gap, we conducted a systematic review and meta-analysis to precisely estimate the association between frailty and the risk of incident all-cause dementia and Alzheimer's disease (AD), and to explore sources of heterogeneity through comprehensive subgroup analyses.

METHODS: We systematically searched PubMed, Embase, and the Cochrane Library for cohort studies published from inception to March 8, 2025. Data from eligible studies were pooled using random-effects models to calculate summary odds ratios (ORs) with 95% confidence intervals (CIs). Pre-specified subgroup analyses were performed based on geographic region, study design, and frailty subtype. Heterogeneity was assessed using the I[2] statistic.

RESULTS: Thirteen cohort studies comprising 835,992 participants were included. The meta-analysis showed that frailty was associated with significantly higher odds of all-cause dementia (pooled OR = 1.76, 95% CI: 1.48-2.10). For Alzheimer's disease, the pooled estimate suggested increased odds but did not reach statistical significance (OR = 1.91, 95% CI: 0.86-4.20), and the evidence was limited by the small number of contributing studies (k = 4) and substantial heterogeneity.

CONCLUSION: This study provides robust, quantitative evidence that frailty is a major independent risk factor for dementia, with the strength of association varying by population and frailty domain. These findings underscore the imperative of integrating standardized, multi-domain frailty assessments into clinical practice to identify high-risk individuals and inform targeted, personalized prevention strategies for dementia.

https://www.crd.york.ac.uk/prospero/, CRD420251008804.},
}

@article {pmid42037699,
year = {2026},
author = {Wu, J and Jiang, H and Wang, R and Lv, X and Tang, F and Chai, X and Zhu, Y and Cheng, Z and Wu, Y and Tang, Q},
title = {Differential associations of NFL and GFAP with neuropsychiatric symptoms by amyloid status across the Alzheimer's disease continuum.},
journal = {Frontiers in neurology},
volume = {17},
number = {},
pages = {1782816},
pmid = {42037699},
issn = {1664-2295},
abstract = {BACKGROUND: Neuropsychiatric symptoms (NPS) are key clinical manifestations across the Alzheimer's disease (AD) continuum and predict worse clinical outcomes, yet their biological correlates remain incompletely understood. It remains unclear whether biomarkers of neuroaxonal injury and astrocytic activation, namely neurofilament light chain (NFL) and glial fibrillary acidic protein (GFAP), are associated with NPS independently of amyloid-β (Aβ) pathology or through downstream structural brain changes.

METHODS: We conducted a cross-sectional study of 478 individuals from the First Affiliated Hospital of the University of Science and Technology of China, spanning the cognitive spectrum from cognitively unimpaired (CU) to mild cognitive impairment (MCI), AD dementia, and non-AD dementia. NPS were assessed using the Neuropsychiatric Inventory Questionnaire (NPIQ). We measured core AD biomarkers (Aβ42/40, pTau181, and pTau217) and serum NFL and GFAP using single-molecule array (Simoa) assays. Aβ status was determined by amyloid PET or CSF Aβ42/Aβ40 ratio, and cortical thickness was derived from 3D T1-weighted MRI.

RESULTS: NPS burden was substantially higher in both AD dementia and non-AD dementia than in CU or MCI, highlighting the transdiagnostic nature of NPS in dementia syndromes. Associations between serum biomarkers and NPS differed by Aβ status. In Aβ - individuals, serum NFL was associated with global NPIQ burden and multiple symptom domains, whereas in Aβ + individuals, serum GFAP was associated with global NPIQ burden and several symptom domains. Formal interaction analyses confirmed significant effect modification by Aβ status for serum NFL, but not for serum GFAP. Sensitivity analyses excluding extreme NFL values yielded unchanged results.

CONCLUSION: These findings support an Aβ-dependent dissociation in biomarker correlates of NPS, with stronger NFL-related associations in Aβ - individuals and stronger GFAP-related associations in Aβ + individuals. Our results suggest that biologically distinct pathways may underlie neuropsychiatric manifestations across the cognitive continuum and support biomarker-informed subtyping of NPS in aging and dementia.},
}

@article {pmid42037712,
year = {2026},
author = {Wiechmann, D and Kerz, E and Albrecht, M and Qiao, Y and Pinho, J and Reetz, K and Costa, AS},
title = {Detecting CSF-validated Alzheimer's disease from spontaneous speech in German: an interpretable end-to-end machine-learning framework.},
journal = {Frontiers in neurology},
volume = {17},
number = {},
pages = {1780783},
pmid = {42037712},
issn = {1664-2295},
abstract = {BACKGROUND: Speech and language impairments, long recognized as early symptoms of Alzheimer's disease (AD), can now be quantified with unprecedented precision due to recent advances in natural language processing (NLP) and artificial intelligence (AI). Despite growing interest in AI-enabled speech biomarkers, few studies have linked spontaneous speech to biologically verified AD, and most have focused on English-language data or acoustic features with limited linguistic interpretability. Here, we present the first end-to-end machine-learning framework for automatic AD detection from German speech, using clinical-biological criteria validated by cerebrospinal fluid (CSF) biomarkers.

METHODS: 44 participants were included: 22 biomarker-defined AD cases from a prospective observational study (German Clinical Trials Register, DRKS00030633) and 22 socio-demographically matched cognitively healthy controls (CHC). Connected speech was elicited using the standardized Cookie Theft picture description task. Recordings were transcribed with a state-of-the-art automatic speech recognition (ASR) system. From these transcripts, 32 theory-driven linguistic biomarkers were computed with an advanced NLP tool, falling into three categories: information-theoretic, lexical richness, and syntactic. AD-versus-CHC classification used five supervised models (logistic regression, support vector machine with a radial basis function kernel, random forest, gradient boosting, XGBoost) under stratified five-fold cross-validation, with stability-based recursive feature elimination performed within training folds. Model interpretability was assessed using SHapley Additive exPlanations (SHAP).

RESULTS: Recursive feature elimination retained seven of 32 candidate speech biomarkers as consistently informative across folds. Trained on this subset, all classifiers showed strong discrimination between biomarker-defined AD and CHC. Logistic regression, SVM, random forest, and gradient boosting achieved ~91% mean accuracy with F1 ≈ 0.90 and sensitivity ≈ 0.90, while XGBoost was slightly lower (~89% accuracy). SHAP analyses indicated that model decisions were primarily driven by information-theoretic and structural markers: lower compressibility, reduced lexical density, shorter clauses and sentences, and weaker predictive sequencing indexed by higher-order n-gram statistics.

CONCLUSION: Clinically meaningful linguistic biomarkers can be robustly derived from spontaneous speech, even in small, well-characterized clinical samples. Theory-driven features and stability-focused modeling show that information-theoretic and structural properties of connected speech capture core Alzheimer-related impairments with robust classification performance. These findings support AI-enabled speech analysis as a non-invasive, scalable complement to established biological biomarkers of Alzheimer's disease.},
}

@article {pmid42037717,
year = {2026},
author = {Zhang, X and Yang, C},
title = {Research progress in neuroimaging of sporadic early-onset Alzheimer's disease.},
journal = {Frontiers in neurology},
volume = {17},
number = {},
pages = {1788814},
pmid = {42037717},
issn = {1664-2295},
abstract = {Early-onset Alzheimer's disease (EOAD) is defined as Alzheimer's disease (AD) with an age at onset younger than 65 years, accounting for approximately 5% of all AD cases. More than 90% of EOAD cases do not carry autosomal dominant pathogenic mutations. Although its prevalence is lower than that of late-onset Alzheimer's disease (LOAD), EOAD follows a more aggressive clinical course. A subset of EOAD patients present with non-amnestic variant phenotypes, including logopenic variant of primary progressive aphasia (lvPPA), frontal variant Alzheimer's disease (fvAD), posterior cortical atrophy (PCA), and corticobasal syndrome (CBS). However, the neuroimaging characteristics of EOAD and their differences from those of LOAD remain poorly elucidated to date. Therefore, this review systematically summarizes the recent research progress in neuroimaging of EOAD, including structural, functional, and metabolic imaging modalities. We also discuss the potential pathogenesis of EOAD, with the aim to provide evidence-based reference for the development of EOAD-specific imaging assessment systems and the optimization of disease efficacy monitoring protocols in future research.},
}

@article {pmid42038088,
year = {2026},
author = {Permoda-Pachuta, A and Obszanski, P and Grad, Z and Futyma-Jędrzejewska, M and Ziemecki, P and Dominiak, M},
title = {Depression as an early symptom and risk factor of dementia - a narrative review.},
journal = {Frontiers in psychiatry},
volume = {17},
number = {},
pages = {1786179},
pmid = {42038088},
issn = {1664-0640},
abstract = {Depression is a common psychiatric disorder, while dementia represents a growing global health challenge, particularly in aging populations. Although substantial progress has been made in pharmacotherapy, neurodegenerative processes can only be partially slowed, and disease progression cannot be completely halted. Neurodegenerative diseases therefore remain largely incurable, underscoring the importance of early recognition and intervention. This raises an important clinical and conceptual question: does depression represent an early manifestation of dementia, act as a risk factor for its development or both? Understanding these relationships is essential for accurate diagnosis, appropriate treatment, and timely implementation of preventive strategies. This article presents a narrative review of the literature examining the complex relationship between depression and dementia, with a focus on clinical presentation, diagnostic challenges, and neurobiological mechanisms. Neuroimaging techniques such as MRI and PET, and in selected contexts SPECT, support the differential diagnosis of depression and dementia, although limitations in sensitivity and specificity persist. Inflammation has been extensively investigated as a shared pathological mechanism underlying both conditions. Emerging evidence also suggests that anti-amyloid therapies may be associated with improvements in depressive symptoms in selected patient populations, further highlighting overlapping pathophysiological pathways between depression and dementia. Improved understanding of the interplay between depression and dementia may facilitate earlier diagnosis, reduce diagnostic uncertainty, and support the development of more effective preventive and therapeutic strategies.},
}

@article {pmid42038337,
year = {2026},
author = {Hong, R and Han, J and Dong, F and Kalsoom, UE and Cao, C and Zhou, A and Wu, Q and Qu, X},
title = {Cynanchum bungei Decne-derived extracellular vesicles alleviate cognitive impairment and pathological damage in Alzheimer's disease.},
journal = {Frontiers in cellular neuroscience},
volume = {20},
number = {},
pages = {1798965},
pmid = {42038337},
issn = {1662-5102},
abstract = {INTRODUCTION: Cynanchum bungei Decne (CB) is known for its therapeutic benefits for neurodegenerative conditions as anti-inflammatory, antioxidant, and barrier significantly limits their potential advantages. Given the ability of crossing the barrier with minimal toxicity, extracellular vesicles derived from CB (CB-EVs) were utilized as an innovative approach to mitigate Alzheimer's disease (AD).

METHODS: CB-EVs were isolated using gradient ultracentrifugation and identified via TEM imaging, nanoparticle tracking analysis, marker identification, and in vivo imaging system. Ten-month-old triple transgenic AD (3xTg-AD) mice received intravenous administration of CB-EVs at doses of 10 or 20 mg/kg every 3 days for the cognitive and pathological assessments. The human APP Swedish mutation transgenic SH-SY5Y cells were constructed as Aβ-induced neural damage model, and different concentrations of CB-EVs were added into medium to analyze its roles on cell viability, transcriptome changes, oxidative stress, and mitochondrial damage.

RESULTS: CB-EVs exhibited standard morphological and molecular traits, accumulating in the cerebral cortex and hippocampus. Two months of CB-EVs treatment alleviated cognitive impairments, diminished Aβ plaque, reduced Tau protein hyperphosphorylation, and lessened neuronal loss in 3xTg-AD mice. In transgenic SH-SY5Y cells, CB-EVs improved cell viability, enhanced superoxide dismutase activity, downregulated oxidative stress related NUPR1 and CHOP expression, decreased reactive oxygen species, lipid peroxidation, and malondialdehyde levels, reduced mitochondrial damage.

CONCLUSION: These results demonstrated that CB-EVs could protect neurons from oxidative stress, attenuate cognitive impairment and pathological damage in AD.},
}

@article {pmid42038539,
year = {2026},
author = {K, V and Jaisankar, N},
title = {Design of a deep learning prediction model for Alzheimer's and Parkinson's Disease using MRI images.},
journal = {Frontiers in artificial intelligence},
volume = {9},
number = {},
pages = {1777236},
pmid = {42038539},
issn = {2624-8212},
abstract = {INTRODUCTION: Alzheimer's disease (AD) and Parkinson's disease (PD) are types of neurodegenerative diseases that affect the body and get worse over time. The cause of AD mainly involves the buildup of protein which are abnormal, issues with the immune reaction, death of neurons. Different from this, the death of the neurons that make dopamine leads to PD and causes both motor and non-motor problems. MRI images are used to provide an early and correct diagnosis to enable timely treatment planning and management of the disease.

METHODS: In this paper, a design of an AI-based deep learning framework is proposed for the classification of neurodegenerative disease based on the brain MRI data. The pipeline that we propose begins with data preparation including data augmentation using InceptionGAN for augmentation of the dataset and fixing of class imbalance issues. A composite method of feature extraction using ConvNeXt and MaxViT along with the Cross-Fusion Attention model, worked well to capture local and global spatial features. Bayesian Optimization and Genetic Algorithm are used to optimize hyperparameters for improving the performance of the model.

RESULTS: The Hybrid Deep Neural Network (HDNN) is the last classifier with an accuracy of 97.4%. Based on performance accuracy, F1-score, the model is strong and reliable. We used Gradient-weighted Class Activation Mapping++ to explain how regions of interest in the brain influence our model's decisions.

DISCUSSION: This study offers an interpretable and high-performing deep learning framework for the early and precise prediction of neurodegenerative disorders utilizing MRI imaging, thereby enhancing clinical decision-making and patient care.},
}

@article {pmid42038662,
year = {2026},
author = {Paes, BP and da Silva, JCRB and de Carvalho, PM and Ferreira, AGF},
title = {Long-term clinical progression of Sneddon syndrome associated with antiphospholipid syndrome.},
journal = {Dementia & neuropsychologia},
volume = {20},
number = {},
pages = {e2025450},
pmid = {42038662},
issn = {1980-5764},
abstract = {Sneddon syndrome (SS) is a rare neurocutaneous disorder characterized by livedo racemosa and recurrent cerebrovascular events, frequently associated with antiphospholipid syndrome (APS). We report a 10-year follow-up of a 62-year-old man diagnosed with SS and APS. Initial presentation included seizures and ischemic lesions on brain magnetic resonance imaging (MRI). Over the years, he developed progressive livedo racemosa, progression of ischemic brain lesions, and cognitive decline. This case illustrates the natural course of SS, despite adequate therapy.},
}

@article {pmid42038691,
year = {2026},
author = {Wiranto, Y and Setiawan, D and Watts, A and Ashourvan, A},
title = {Development of Alzheimer's disease risk score for future integrated primary care: a white-box approach.},
journal = {Frontiers in aging neuroscience},
volume = {18},
number = {},
pages = {1759273},
pmid = {42038691},
issn = {1663-4365},
abstract = {INTRODUCTION: Receiving timely Alzheimer's disease (AD) diagnosis is often delayed due to long waitlists for specialists. Our study aimed to bridge the gap between the timeliness and complexity of diagnosing AD by developing a scoring system with interpretable machine learning using variables that are obtainable at integrated primary care settings.

METHODS: We trained the model using 666 participants with normal cognition or mild cognitive impairment at baseline visit from the Alzheimer's Disease Neuroimaging Initiative (ADNI) and externally validated the scorecard using 4,876 participants from the National Alzheimer's Coordinating Center (NACC). We integrated cognitive measures, daily functioning measured with Functional Assessment Questionnaire (FAQ), and demographics into FasterRisk algorithm.

RESULTS: Combinations of 4 separate measures were selected to generate 10 scorecards, showing strong performance (area under the curve [AUC] = 0.868-0.892) in ADNI and remaining robust when externally validated in NACC (AUC = 0.795). The features were Category Animal ≤ 20 (2 points), Trail Making Test B ≤ 143 (-3 points), Logical Memory Delayed ≤ 3 (4 points), Logical Memory Delayed ≤ 8 (3 points), and FAQ ≤ 2 (-5 points). The probable AD risk increased correspondingly with higher total points: 7.4% (-8), 25.3% (-4), 50% (-1), 74.7% (2), and >90% (>6). We refer to this model as the (F)unctioning, (LA)nguage, (M)emory, and (E)xecutive functioning or FLAME scorecard.

INTERPRETATION: Our findings highlight the potential to predict AD development using obtainable information, allowing for implementation into integrated primary care workflows to initiate early intervention. While our scope centers on AD, this established foundation paves the way for other types of dementia.},
}

@article {pmid42038694,
year = {2026},
author = {Mjaaseth, UN and Hsu, MF and Arballo, J and Haj, FG and Patel, V},
title = {Dysregulated glucose metabolism in the visual cortex of human subjects with mild cognitive impairment and Alzheimer's disease.},
journal = {Frontiers in aging neuroscience},
volume = {18},
number = {},
pages = {1710075},
pmid = {42038694},
issn = {1663-4365},
abstract = {INTRODUCTION: Alzheimer's disease (AD) is characterized by progressive neurodegeneration and impaired glucose metabolism. While most studies focus on heavily affected brain regions such as the hippocampus and prefrontal cortex, the visual cortex remains relatively preserved in early AD and provides an opportunity to examine metabolic alterations that precede widespread pathology.

METHODS: Postmortem human visual cortex samples were obtained from control, mild cognitive impairment (MCI), and AD subjects without non-AD neuropathologic conditions. Untargeted metabolomics was performed using liquid chromatography-mass spectrometry, and expression of key metabolic, inflammatory, and AD-related genes was measured by quantitative PCR. Data analysis was conducted using MetaboAnalyst and R.

RESULTS: Metabolomic profiling revealed progressive disruptions in glucose metabolism, and mitochondrial function across MCI and AD subjects. Gene expression analyses showed reduced levels of glycolytic enzymes (HK1, PFKM, PKM1), mitochondrial regulators (PDHA1, NDUFC1), and the neuronal glucose transporter SLC2A3. Insulin signaling was altered, with decreased IDE and increased INSR and PTPN1 gene expression. Inflammatory markers including TNF, IL1B, and GFAP were elevated in AD. Sex-stratified analyses revealed both shared and distinct metabolic signatures, particularly within glucose and mitochondrial pathways. Several metabolic gene changes correlated negatively with Braak stage, highlighting a progressive decline in energy metabolism alongside tau pathology.

DISCUSSION: These findings demonstrate early and progressive metabolic dysfunction in the visual cortex of MCI and AD subjects. Even in a region with limited structural pathology, profound alterations in energy metabolism were observed, underscoring its central role in AD pathogenesis and highlighting improving neuronal metabolic function as a promising target for therapeutic intervention.},
}

@article {pmid42038695,
year = {2026},
author = {Wang, X and Tian, L},
title = {The therapeutic efficacy of transcranial direct current stimulation in managing Alzheimer's disease: a systematic review and meta-analysis.},
journal = {Frontiers in aging neuroscience},
volume = {18},
number = {},
pages = {1726469},
pmid = {42038695},
issn = {1663-4365},
abstract = {OBJECTIVE: The present study aimed to investigate the therapeutic efficacy of transcranial direct current stimulation (tDCS) for Alzheimer's disease (AD) and identify potential influential factors.

METHODS: A comprehensive literature search was conducted in PubMed, Embase, Web of Science, and the Cochrane Library up to April 2025. Eligible studies were randomized controlled trials (RCTs) in which tDCS was the sole differential intervention between study arms. The pooled effects of tDCS on patients' global cognition, language, memory, executive function, and emotion were evaluated. Subgroup analyses were also performed to identify potential influential factors.

RESULTS: A total of 23 studies involving 24 trials and 823 mild to moderate AD patients were included. Our meta-analysis showed that tDCS significantly improved global cognition in AD patients (standardized mean difference [SMD] = 0.66; 95% confidence interval [CI], 0.38-0.95; p < 0.01), but had no significant effects on language or emotion. Subgroup analyses further revealed that significant memory improvement was observed in patients who received ≤ 10 sessions of tDCS and those with >6 years of education. Additionally, executive function was improved in patients who received stimulation on the left dorsolateral prefrontal cortex and in tDCS groups with ≤ 10 sessions. Moreover, improved executive function was observed in patients with 6-10 years of education, but not in other subgroups.

CONCLUSION: tDCS treatment leads to improvements in global cognition, memory, and executive function in AD patients, but not in language or psychomotor symptoms. However, due to the relatively high heterogeneity of the included data, further well-designed studies are warranted before tDCS can be established as a standard therapeutic approach for AD.},
}

@article {pmid42038702,
year = {2026},
author = {Zhao, S and Shi, H and Guan, C and Zeng, Q and Zhang, C and Wan, Y},
title = {Research on Alzheimer's disease MRI image classification based on spatial attention mechanism.},
journal = {Frontiers in aging neuroscience},
volume = {18},
number = {},
pages = {1657578},
pmid = {42038702},
issn = {1663-4365},
abstract = {INTRODUCTION: Early diagnosis of Alzheimer's Disease (AD) is crucial for improving patient quality of life and treatment outcomes. However, accurately classifying MRI scans of AD remains challenging due to the subtle and spatially complex nature of lesion regions. This study proposes a novel bidirectional spatial attention mechanism to enhance the focus on key pathological features in AD MRI images, aiming to improve classification accuracy and support earlier intervention.

METHODS: To enhance model performance, we introduced a customized bidirectional spatial attention module (ATT) integrated into a Swin-Tiny Transformer backbone. Unlike conventional attention methods, the ATT module generates spatial attention maps by adaptively pooling features along both vertical and horizontal orientations, allowing refined adjustment of attention weights across different image regions. Furthermore, to address issues of limited sample size and class imbalance, we employed data augmentation and expansion strategies, enriching the diversity of training data. The model was trained and evaluated on the augmented OASIS1 dataset.

RESULTS: The improved Swin-Tiny+ATT model demonstrated significant performance gains across all key metrics on the augmented dataset. Compared to the baseline Swin Transformer, accuracy improved from 84.83% to 87.96%, recall from 89.82% to 91.92%, precision from 85.27% to 91.98%, and the F1 score from 87.26% to 91.89%. These results confirm that the ATT module effectively enhances the model's ability to capture complex spatial features and identify critical lesion regions.

DISCUSSION: The proposed Swin-Tiny+ATT model exhibits strong potential for improving MRI-based classification of Alzheimer's Disease. The bidirectional spatial attention mechanism successfully directs the model's focus to relevant anatomical regions, contributing to higher precision and recall. Combined with data augmentation strategies, the approach mitigates class imbalance and enhances generalization. This work provides a promising deep learning framework to support early and accurate diagnosis of AD, with implications for clinical decision-making and personalized treatment planning.},
}

@article {pmid42039100,
year = {2026},
author = {Gendra, JC and Lopez-Sola, E and Castaldo, F and Lleal-Custey, È and Sanchez-Todo, R and Vohryzek, J and Salvador, R and Andrzejak, RG and Ruffini, G and , },
title = {Restoring oscillatory dynamics in Alzheimer's disease: A laminar whole-brain model of serotonergic psychedelic effects.},
journal = {Network neuroscience (Cambridge, Mass.)},
volume = {10},
number = {2},
pages = {303-328},
pmid = {42039100},
issn = {2472-1751},
abstract = {Classical serotonergic psychedelics show promise in addressing neurodegenerative disorders such as Alzheimer's disease by modulating pathological brain dynamics. However, the precise neurobiological mechanisms underlying their effects remain elusive. This study introduces a personalized whole-brain model built upon a laminar neural mass framework to elucidate these effects. Using multimodal neuroimaging data from 30 subjects diagnosed with mild to moderate Alzheimer's disease, we simulate the impact of serotonin 2A receptor activation, characteristic of psychedelics, on cortical dynamics. By modulating the excitability of layer 5 pyramidal neurons, our models reproduce hallmark changes in EEG power spectra observed under psychedelics, including alpha power suppression and gamma power enhancement. These spectral shifts are shown to correlate strongly with the regional distribution of serotonin 2A receptors. Furthermore, simulated EEG reveals increased complexity and entropy, suggesting restored network function. These findings underscore the potential of serotonergic psychedelics to reestablish healthy oscillatory dynamics in the prodromal and early phases of Alzheimer's disease and offer mechanistic insights into their potential therapeutic effects in neurodegenerative disorders.},
}

@article {pmid42039150,
year = {2026},
author = {Ouro, A and Ben-Dor, GA and Debasa-Mouce, M and Gulkarov, S and De Leon, J and Castro-Mosquera, M and Sobrino, T and Bougea, A and Reiss, AB},
title = {Monoclonal antibodies and small molecules: on the cutting edge of Alzheimer's disease therapy.},
journal = {Frontiers in cell and developmental biology},
volume = {14},
number = {},
pages = {1766762},
pmid = {42039150},
issn = {2296-634X},
abstract = {Alzheimer's disease (AD) remains a major global health challenge, with prevalence projected to increase dramatically in the coming decades and no effective treatments available. Current therapies offer only symptomatic relief, reinforcing the need for disease-modifying strategies targeting underlying pathogenic mechanisms. Advances in understanding amyloid-β (Aβ) and tau pathology have propelled the development of targeted interventions, particularly monoclonal antibodies (mAbs) and small-molecule therapeutics. Recent anti-Aβ antibodies, such as aducanumab, lecanemab, and donanemab, have demonstrated significant biological activity and reductions in amyloid burden, leading to regulatory approvals that represent important proof-of-concept milestones. However, these therapies face ongoing controversies related to modest clinical efficacy, accessibility, cost, and safety concerns. In parallel, small-molecule development has expanded beyond failed secretase inhibitors toward more refined mechanisms, including tau aggregation inhibition, kinase modulation, mitochondrial stabilization, and anti-inflammatory pathways. These compounds offer advantages in oral administration, blood-brain barrier penetration, and multi-target engagement. Together, mAbs and small molecules represent complementary therapeutic strategies addressing different aspects of AD pathophysiology. Their integration with emerging biomarkers, genetic profiling, and early diagnostic frameworks is driving a transition toward personalized and stage-specific treatment approaches. This review synthesizes current mechanistic insights, clinical evidence, and translational challenges of both modalities, highlighting how their convergence may shape the next-generation of AD therapeutics.},
}

@article {pmid42039220,
year = {2026},
author = {Ghasemi, Y},
title = {Distant Origins of Local Pathologies: Rethinking the Systemic Roots of Alzheimer's Disease and Beyond.},
journal = {Iranian journal of medical sciences},
volume = {51},
number = {3},
pages = {157-159},
pmid = {42039220},
issn = {1735-3688},
}

@article {pmid42039285,
year = {2026},
author = {Chen, Y and Sun, X and Xi, Y and Luo, Z and Lai, H and Zhu, D and Zhang, Y and Xu, F and Li, J and Zhou, J and Ding, Y and Zhang, H},
title = {Pathology-directed drug delivery strategies: How to overcome blood-brain barrier for the treatment of brain diseases.},
journal = {Acta pharmaceutica Sinica. B},
volume = {16},
number = {4},
pages = {2250-2281},
pmid = {42039285},
issn = {2211-3835},
abstract = {Despite the different degrees of blood-brain barrier (BBB) damage in diverse brain diseases, it remains a formidable barrier that restricts most drugs from penetrating the brain. A comprehensive understanding and elucidation of the disease-specific changes of BBB in various brain pathologies are essential for directing the customized brain-targeted drug delivery systems, potentially improving cerebral delivery efficiency and therapeutic efficacy. Hence, this review compared anatomical and physiological changes of BBB under healthy and pathological states and discussed the effects of these changes on cerebral delivery efficiency. Thereafter, a particular emphasis was placed on the pathology-directed drug delivery strategies tailored to different brain diseases, including Alzheimer's disease, Parkinson's disease, multiple sclerosis, stroke, and brain tumors. By combining insights from cutting-edge studies and emerging technologies, we proposed forward-looking suggestions on future directions to brain-targeted drug delivery, thereby improving the therapeutic efficacy and accelerating the translation from preclinical attempts into clinical practice.},
}

@article {pmid42039377,
year = {2026},
author = {Dhinagar, NJ and Jagad, C and Senthilkumar, P and Thomopoulos, SI and Khan, MH and Liew, SL and , and Banaj, N and Boric, MR and Boyd, LA and Brodtmann, A and Cassidy, JM and Conforto, AB and Cramer, SC and Dula, AN and Geranmayeh, F and Gregory, CM and Hordacre, B and Jaywant, A and Kautz, SA and Leech, KA and Lotze, M and Mataró, M and Piras, F and Rosario, ER and Sanossian, N and Schambra, HM and Schweighofer, N and Seo, NJ and Soekadar, SR and Thielman, GT and Winstein, C and Wittenberg, GF and Wong, KA and Thompson, PM},
title = {CALM-VLM: CALIBRATION AND SELECTIVE PREDICTION IN VISION-LANGUAGE MODELS FOR RELIABLE BRAIN MRI CLASSIFICATION.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.04.10.717865},
pmid = {42039377},
issn = {2692-8205},
abstract = {Recent advances in vision-language models (VLMs) have demonstrated strong multimodal capabilities for medical image analysis. However, their confidence in diagnostic predictions is often unclear, limiting adoption in clinical settings. We introduce CALM-VLM (CAL ibration M echanism for Vision-Language Models), which integrates confidence calibration and selective prediction into a generative 3D VLM. To create CALM-VLM, we fine-tuned the Med3DVLM architecture for Alzheimer's disease (AD) and stroke classification as initial test cases. To improve reliability, we incorporated temperature scaling on the VLM's generative outputs. The calibrated model then selectively abstained from predictions when uncertain; this also improved its diagnostic accuracy. Experiments across multi-site MRI datasets, from 10 countries worldwide, show that CALM-VLM improved confidence relative to uncalibrated VLMs. Coverage-adjusted test receiver-operator characteristic curve-area under the curve (ROC-AUC) increased by 5% to 13% for both diagnostic tasks across independent test sets. Our calibrated VLM achieved a test ROC-AUC of 0.951 for AD classification and 0.905 for stroke classification. These findings highlight the importance of calibrated, uncertainty-aware VLMs for trustworthy neuroimaging AI.},
}

@article {pmid42039396,
year = {2026},
author = {Strain, JF and Barthélemy, NR and Jha, R and Guo, O and Parihar, M and Chan, K and Adeyemo, B and Millar, PR and Womack, K and Gordon, B and Schindler, S and Morris, JC and Benzinger, T and Ances, BM and Phuah, CL},
title = {History of Traumatic Brain Injury with Loss of Consciousness and APOE ε4 Carriers Synergistically Increase Late-Life Amyloid PET Burden.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.04.14.717801},
pmid = {42039396},
issn = {2692-8205},
abstract = {BACKGROUND: Traumatic brain injury with loss of consciousness (TBI-LOC) is an established risk factor for dementia, yet the pathways linking remote TBI to Alzheimer's disease (AD) biology remain incompletely defined. APOE ε4 is the strongest genetic predictor of amyloid accumulation in late-onset AD, it may moderate the long-term consequences of head injury. This study investigates whether history TBI-LOC independently contributes or synergistically interacts with APOE ε4 to amplify late-life amyloid and tau burden.

METHODS: 429 participants completed the Ohio State University TBI screening tool and an amyloid PET scan (centiloids). A subcohort (n=352) also underwent tau PET. TBI history was classified by recency (<10 vs >10 years) and severity (no TBI, dazing/confusion [TBI-DZ], TBI-LOC). Analyses were stratified by degree of clinical impairment as assessed by Clinical Dementia Rating (CDR=0 vs CDR>0). Logistic and linear regression models examined associations between TBI and amyloid, adjusting for age, sex, education, and APOE ε4, including an APOE*TBI-LOC status interaction term, while Fisher's exact tests evaluated TBI recency and biomarker positivity.

RESULTS: In CDR=0 participants (n=365), 119 reported a history of TBI, comprising 56 TBI-DZ and 63 TBI-LOC. TBI-LOC but not TBI-DZ, correlated with elevated amyloid PET levels (p<0.001; [4.6-17]). Furthermore, an interaction between APOE ε4 and TBI-LOC indicated that TBI-LOC augmented the amyloid-related risk associated with the APOE ε4 allele (p=0.003; [4.3-21]). The interaction persisted when stratified by TBI recency with only remote TBI-LOC (occurring more than 10 years prior) associated with increased amyloid PET (p=0.003 [5.2-25]). No association between TBI and tau was identified in a subset with tau PET, and no TBI-amyloid correlations were observed among symptomatic participants (CDR>0; n=64) suggesting a ceiling effect of pathology once clinical dementia is present.

CONCLUSIONS: History of remote TBI-LOC is linked to elevated amyloid PET levels in later life, particularly among APOE ε4 carriers with a CDR=0. The robust findings for amyloid, contrasted with null tau results and the reduced association in symptomatic cases underscore the importance of considering TBI history when screening for preclinical AD and assessing early-stage risk.},
}

@article {pmid42039405,
year = {2026},
author = {Trushin, S and Nguyen, TKO and Ostroot, M and Galkin, A and Nambara, T and Lu, W and Kanekiyo, T and Johnson, G and Trushina, E},
title = {Discovery and Preclinical Validation of a Clinically Optimized Mitochondrial Complex I Modulator for Alzheimer's Disease.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.04.10.717554},
pmid = {42039405},
issn = {2692-8205},
abstract = {Alzheimer's disease (AD) is characterized by diminished capacity to mount adaptive cellular stress responses required to maintain energy homeostasis and proteostasis. An emerging therapeutic strategy is to restore adaptive stress responses by inducing mild energetic stress through inhibition of mitochondrial complex I (mtCI). However, pharmacological inhibition of the respiratory chain has remained challenging, as it can induce bioenergetic failure rather than beneficial signaling. Here, we describe C273, a brain-penetrant small molecule that delivers controlled, weak attenuation of mtCI activity to therapeutically restore endogenous adaptive stress pathways. This work establishes a first-in-class mechanism in which calibrated activation of multifaceted adaptive mechanisms enhances cellular resilience, rather than impairing mitochondrial function. Structure-activity relationship optimization yielded a compound with high potency against Aβ-induced cellular toxicity, strong selectivity for mtCI, and favorable drug-like properties. C273 demonstrated excellent oral bioavailability, metabolic stability in mouse, rat, and human microsomes, minimal CYP liabilities, and a clean ancillary pharmacology profile in the Eurofins CEREP44 panel. In vivo , C273 readily crosses the blood-brain barrier and activates AMP-activated protein kinase (AMPK), initiating a coordinated hormetic response characterized by enhanced antioxidant defenses, suppression of inflammatory signaling, induction of autophagy, and increased mitochondrial biogenesis and turnover. Genetic deletion of AMPKα1/α2 abolished these responses, establishing AMPK as a critical mediator of C273 activity. Pharmacological competition experiments further confirmed the target, as pretreatment with non-toxic concentrations of rotenone blocked C273 interaction with the quinone-binding site of mtCI and eliminated its neuroprotective effects. Repeated oral administration of C273 (20-80 mg/kg/day) to wild-type mice for one month produced no detectable cardiac or hepatic toxicity, indicating a favorable in vivo safety margin. Importantly, C273 activated these mechanisms and reduced Aβ and p-Tau levels in induced pluripotent stem cell-derived cerebral organoids from patients with sporadic AD. Collectively, these results establish controlled mtCI modulation as a therapeutic strategy and position C273 as a promising disease-modifying candidate for AD.},
}

@article {pmid42039430,
year = {2026},
author = {Sharma, AL and Sariyer, IK and Naik, UP and Tyagi, M},
title = {HIV and Cocaine exposure promote Tau phosphorylation through RSK-1 in a GSK3β-independent manner.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.04.14.718541},
pmid = {42039430},
issn = {2692-8205},
abstract = {UNLABELLED: HIV and cocaine are known to disrupt neuronal signaling and contribute to neurocognitive dysfunction, yet the underlying molecular mechanisms are not clear. In this study, we delineate the underlying molecular mechanism by which HIV and/or cocaine enhance Tau phosphorylation (p-Tau S396), a marker of Tau-mediated neuropathies. Furthermore, we elucidate how these two independent neuropathogenic factors, cocaine and HIV, exploit distinct yet convergent signaling pathways to drive this pathological event. We demonstrate that HIV robustly activates and upregulates RSK1, which functions upstream of AKT and promotes Tau phosphorylation through an AKT-independent mechanism while simultaneously inactivating GSK3β via serine-9 phosphorylation (p-GSK3β S9). However, cocaine not only activates RSK1 but also strongly stimulates AKT1, resulting in sustained GSK3β inhibition and persistent Tau phosphorylation. Notably, Tau phosphorylation persists even under conditions of GSK3β inactivation in both HIV and cocaine exposure, revealing a previously unrecognized GSK3β-independent mechanism of Tau modification. Collectively, these findings identify RSK1 as the primary mediator of Tau phosphorylation upon HIV and/or cocaine exposure, and uncover a novel RSK1-driven, GSK3β-independent pathway contributing to Tauopathy. Through a combination of immunofluorescence, immunoblotting, genetic knockout, and overexpression approaches, we establish RSK1 as a central signaling hub linking the AKT-GSK3β pathway to Tau phosphorylation. We demonstrate that RSK1 operates as a critical upstream regulator of AKT and GSK3β signaling, playing dual roles, both activating AKT and suppressing GSK3β, thereby uncovering a novel layer of pathways that regulates Tau phosphorylation. The reproducibility of these main signaling pathways across SH-SY5Y neurons, mixed cell 3D spheroids, and human brain organoids underscores the robustness and biological relevance of this mechanism. Collectively, these findings reveal mechanistic convergence of HIV and cocaine on RSK1-dependent signaling and provide critical insight into how diverse neuropathic / neuropathological factors remodel neuronal signaling to drive Tau-associated dysfunction. These findings provide novel mechanistic insight into the molecular underpinnings of neuro-HIV and substance abuse associated Tauopathy. By identifying RSK1 as a master regulator and demonstrating that Tau phosphorylation can bypass GSK3β inhibition, our study advances understanding of signaling complexity and highlights new opportunities for therapeutic intervention. Targeting RSK1 may represent a promising strategy to mitigate Tau pathology, induced due to insoluble aggregates of phosphorylated Tau, a common factor promoting cognitive decline not only in individuals with Alzheimer's disease but also in those exposed to cocaine or/and infected with HIV.

SIGNIFICANCES: This study demonstrates that exposure to HIV and/or cocaine induces Tau phosphorylation at serine 396 (S396), a well-established marker of Tau pathology, and delineates how these two independent neuropathogenic factors engage distinct yet convergent signaling pathways to drive this pathogenic event. We show that HIV exposure drives robust RSK1 activation, positioning it upstream of AKT to promote Tau phosphorylation via an AKT-independent mechanism, while concurrently suppressing GSK3β activity through serine-9 phosphorylation. In contrast, cocaine, while only moderately activating RSK1, primarily enhances AKT signaling, leading to sustained GSK3β inhibition and increased Tau phosphorylation. Notably, Tau phosphorylation persists even under conditions of GSK3β inactivation in both settings, revealing a previously unrecognized, RSK1-centered, GSK3β-independent pathway of Tau modification. Overall, our findings demonstrate that Tau phosphorylation in the context of HIV infection and cocaine exposure is a complex, multi-layered regulatory process involving multiple signaling nodes. Importantly, we identify RSK1 as a central integrative hub linking viral and substance-induced signaling to downstream Tau pathology. This work advances our understanding of the molecular mechanisms underlying neuroHIV and substance abuse-associated neurodegeneration. Furthermore, it highlights RSK1 as a novel and promising therapeutic target for mitigating Tauopathy in both cocaine-using and non-using people with HIV (PWH).

HIGHLIGHTED POINTS: RSK1 acts as a central regulator of Tau phosphorylation, capable of driving this process through a GSK3β-independent mechanism.HIV promotes Tau phosphorylation primarily via robust upregulation and activation of RSK1, operating largely independent of AKT1, while concurrently inducing GSK3β inactivation.Drugs of abuse, such as cocaine induces Tau phosphorylation through dual activation of AKT1 and RSK1, alongside sustained inactivation of GSK3β.Tau phosphorylation persists despite GSK3β inhibition, revealing a complex AKT1-RSK1 signaling axis and underscoring the dominant role of GSK3β-independent mechanisms in Tau pathology following HIV and cocaine exposure.HIV and cocaine engage distinct yet convergent signaling pathways that disrupt neuronal homeostasis and drive tauopathy, providing mechanistic insight into neuroHIV and substance abuse-associated neurodegeneration.RSK1 functions as a key upstream modulator of AKT and GSK3β pathways, positively regulating AKT signaling while negatively regulating GSK3β activity.RSK1 emerges as a potential therapeutic target, offering new opportunities for intervention in HIV-associated neurocognitive disorders (HAND) and drug-induced neurodegeneration.Established and characterized H80 cells as a novel neuronal cell model and demonstrated their suitability for studying neuron-specific signaling pathways, including Tau phosphorylation.The conserved and widespread nature of the signaling cascade driving Tau phosphorylation in response to HIV and/or cocaine exposure was validated across multiple model systems, including both 2D neuronal cell cultures and 3D systems such as human brain organoids and spheroids.

STRENGTH OF THE STUDY: This original study provides novel mechanistic insight into how HIV and cocaine, two independent neuropathological factors, converge and diverge on intracellular signaling pathways to regulate Tau phosphorylation. By integrating immunofluorescence, immunoblotting, genetic knockout, and overexpression approaches, we identified RSK1 as a master regulator of Tau phosphorylation. Importantly, we discovered that HIV robustly upregulates and activates RSK1 to promote Tau phosphorylation through an AKT-independent route while simultaneously inactivating GSK3β. On the other hand, cocaine exerts a moderate effect on RSK1 but strongly stimulates AKT to induce GSK3β inactivation and drive Tau phosphorylation. A key strength of this work is the discovery that Tau phosphorylation persists despite GSK3β inactivation, revealing a complex, GSK3β-independent mechanism, involving RSK1 in Tau pathology. Moreover, our study, for the first time, identify RSK1 as an upstream regulator of AKT-GSK3β signaling cascade, enhancing AKT signaling while simultaneously inhibiting GSK3β activity, thereby underscoring the critical role of RSK1 in Tau phosphorylation and associated illnesses, such as HAND and Alzheimer's disease. Together, these findings not only advance our understanding of the molecular underpinnings of neuroHIV and substance abuse associated tauopathy but also highlight RSK1 as a promising therapeutic target for not only HIV and cocaine induced neurotoxicity but also other neurodegenerative diseases, such as Alzheimer's disease. Another key strength of this study is the establishment and characterization of H80 cells as a novel neuronal model, demonstrating their suitability for investigating neuron-specific signaling pathways, including Tau phosphorylation. The combination of comparative signaling analysis, genetic perturbations, and integrative mechanistic modeling makes this study both conceptually and technically novel, besides broadly relevant to the fields of neurovirology, addiction neuroscience, neurodegeneration, and cognitive impairments.},
}

@article {pmid42039451,
year = {2026},
author = {Kwon, S and Lee, S and Siegel, JS and Chiulli, N and Freedberg, M and Hebscher, M and Hendrikse, J and Hermiller, MS and Ji, GJ and Tambini, A and Ye, E and Cohen-Zimerman, S and Corbetta, M and Grafman, J and Voss, JL and Siddiqi, SH},
title = {Non-invasive Neuromodulation Targeting Approach by Mapping Stimulations and Lesions That Modify Visual Memory.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.04.10.717784},
pmid = {42039451},
issn = {2692-8205},
abstract = {UNLABELLED: Therapeutic brain stimulation is believed to target specific networks, but targeting approaches for memory remain debated. For other symptoms, neuromodulation targets have been localized by mapping connectivity of lesions and stimulation sites to specific symptoms. This approach has yielded networks for global memory, but it remains unclear whether it applies to specific types of memory. Here, we mapped connectivity of stimulation sites, lesions, and atrophy patterns associated with different memory types. We included 544 individuals across three datasets: transcranial magnetic stimulation (N =262), penetrating head trauma (N =169), and ischemic stroke (N =113). We identified a network preferentially connected to lesions and stimulation sites specifically associated with changes in visual memory. Of note, the direction of this effect was inverted depending on whether lesions or stimulation occurred at younger age or an older age, consistent with prior results. This age effect was replicated in an independent dataset of patients with preclinical Alzheimer's disease (N=1240). To examine neuromodulation targets, we computed electrical field models for potential TMS sites that overlap with the networks derived from each stimulation or lesion dataset; the resulting targets intersected with established targets that demonstrated efficacy for treating memory impairment - precuneus, cortical-hippocampal network, and dorsolateral prefrontal cortex - with peak intersection at medial posterior parietal lobe, angular gyrus, and left anterior middle frontal gyrus, respectively. Future head-to-head clinical trials are needed to systematically compare these proposed neuromodulation targets against each other.

ONE SENTENCE SUMMARY: Neuromodulation targets for visual memory diverge by age at the time of injury or stimulation.},
}

@article {pmid42039455,
year = {2026},
author = {Chong Chie, JAKH and Persohn, SA and Simcox, OR and Salama, P and Territo, PR and , },
title = {Multidomain Analysis of Clinical Cognitive Assessments and Imaging Data in Alzheimer's Disease Accurately Predicts Disease Stage and Grade Independent of Amyloid and Tau.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.04.12.717232},
pmid = {42039455},
issn = {2692-8205},
abstract = {Background Individual clinical cognitive assessments (CCA) for Alzheimer's disease (AD) provide broad disease stratification but are limited in sensitivity and specificity, requiring integration of multiple CCA for optimal disease staging. Recent work from our lab suggests that neuro-metabolic and vascular dysregulation (MVD) occurs early in AD, prior to clinical symptoms, and may provide higher sensitivity and specificity than CCA alone. In this study, we combined three widely accepted CCA with MVD readouts and developed a multimodal ensemble machine learning approach across the AD spectrum to predict disease stage and grade. Methods AD subjects (N=372) across the disease spectrum with imaging (PET:18F-FDG, MRI:T1w, T2 FLAIR, ASL) and CCAs (ADAS-Cog, CDR, MoCA) data were analyzed from ADNI. Imaging data were registered to MNI152+, z-scored relative to cognitively normal controls, and processed for MVD. A clinical-set-enrichment analysis (CSEA) was developed to link regional brain changes with CCA scores, map changes to functional categories, project them into a 3D Cartesian space, and model trajectories, thus revealing at-risk and resilient regions. In addition, an ensemble machine-learning approach was utilized for disease stage classification, and a disease grading scheme across the AD spectrum was developed to further stratify within disease stages. Findings Regional data followed an MVD pattern across AD stages stratified by CSEA scores. Females showed greater stage separation along the CCA axis within each region, indicating faster disease progression. Moreover, progression in at-risk brain regions (e.g., mid- and inf-temporal gyri, amygdala) was associated with longer disease path lengths, whereas progression in resilient brain regions (supramarginal gyrus) was not. Moreover, our classification and grading approach can predict AD stage and grade independent of amyloid-beta and tau with high precision and accuracy. Interpretation A framework was developed to evaluate MVD and CCA variations across the AD spectrum, thereby distinguishing at-risk and resilient brain regions. Distinct disease trajectories were identified, and a new data-driven grading scheme was proposed to highlight the potential for precision medicine and therapeutic evaluation. Funding NIH T32AG071444.},
}

@article {pmid42039466,
year = {2026},
author = {Caligiore, D and Torsello, S and , },
title = {Explainable machine learning identifies candidate shared neuroanatomical features in Alzheimer's and Parkinson's via importance inversion transfer.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.04.10.717735},
pmid = {42039466},
issn = {2692-8205},
abstract = {Despite significant neurobiological and pathological overlaps, Alzheimer's and Parkinson's diseases-the primary threats to healthy aging-are still managed as distinct clinical entities. Standard machine learning exacerbates this diagnostic fragmentation by prioritizing divergent markers over shared traits, thereby obscuring the invariant foundations of neurodegeneration. This study introduces Importance Inversion Transfer, an explainable machine learning framework designed to identify neuroanatomical invariants across the neurodegenerative spectrum. Prioritizing structural stability over discriminative utility isolates a shared pathological core consisting of ten regional volumetric anchors, validated through an inductive protocol with high diagnostic fidelity (AUC = 0.894). The identified morphological continuum between healthy aging and neurodegeneration delineates shared structural substrates consistent with-though not demonstrative of-a potential common early-phase vulnerability. Aligned with the Neurodegenerative Elderly Syndrome hypothesis, this evidence establishes a possible paradigm for early, system-level diagnosis.},
}

@article {pmid42039494,
year = {2026},
author = {Duarte-Abritta, B and Abulafia, C and Fiorentini, L and Tafet, G and Brusco, LI and Tsuchiyagaito, A and Mathew, SJ and Villarreal, MF and Guinjoan, SM},
title = {Distinct Multimodal Imaging Correlates of Depression in Middle-Aged Adults With and Without a Family History of Alzheimer's Disease.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.04.13.717731},
pmid = {42039494},
issn = {2692-8205},
abstract = {BACKGROUND: Depression is associated with risk for late-onset Alzheimer's disease (LOAD), but its underlying pathogenesis in at-risk individuals remains unclear. We examined multimodal imaging correlates of depressive symptoms in cognitively normal middle-aged offspring of patients with LOAD (O-LOAD) compared with control individuals without LOAD history up to a 4 [th] degree of kinship (HC).

METHODS: Participants (n=58; 52±3 years; 74% female) underwent assessment with the Beck Depression Inventory-II (BDI), structural MRI, resting-state fMRI, FDG-PET, and PiB-PET. Resting-state fMRI data were available for 28 O-LOAD and 24 HC; PET data for 24 O-LOAD and 22 HC. General linear models tested associations between imaging measures and BDI, including group interactions.

RESULTS: In O-LOAD, higher BDI scores were associated with reduced cortical thickness in the left postcentral gyrus. Resting-state fMRI revealed significant group-by-BDI interactions involving cingulate and orbitofrontal networks. In O-LOAD, greater depressive symptom severity was associated with reduced cingulate connectivity across distributed corticolimbic, prefrontal, insular, occipital, and cerebellar regions (β range -0.10 to -0.18). In HC, depressive symptoms were associated with reduced right orbitofrontal and somatosensory-medial orbitofrontal connectivity (β=-0.13), with divergent patterns of cingulate connectivity. FDG-PET showed no significant associations with depressive symptoms. PiB-PET demonstrated regionally specific associations between amyloid signal and BDI in HC, involving an inverse pattern in anterior and posterior insular cortices.

CONCLUSIONS: Depressive symptoms in middle-aged individuals at familial risk for LOAD are associated with distinct structural and functional alterations, involving circuitry subserving salience and reward, and suggesting early network-level mechanisms linking affective symptoms with vulnerability to neurodegeneration.},
}

@article {pmid42039513,
year = {2026},
author = {Zhou, X and Ai, M and Adeli, E and Zhang, Y and Liu, YM and Vankee-Lin, F},
title = {Resting-state fMRI foundation models enable robust and generalizable latent neural target discovery in cognitive aging interventions.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2025.12.30.697042},
pmid = {42039513},
issn = {2692-8205},
abstract = {UNLABELLED: The benefits of interventions targeting cognitive aging vary substantially across individuals, largely owing to heterogeneity in aging-related comorbidities. It is necessary to robustly identify neural patterns underlying intervention response and test their generalizability across heterogeneous cohorts. Resting-state functional MRI (rsfMRI) offers a potential pathway, but relying on predefined summary features with conventional methods has limited capacity to capture both within-individual longitudinal variation and between-individual differences, particularly in small and heterogeneous studies. Recent rsfMRI foundation models pretrained on large observational cohorts present a promising alternative by learning transferable spatiotemporal representations from time-series signals. Yet their validity and generalizability in local intervention settings remain unclear. Here, we systematically evaluated rsfMRI foundation models using data from two independent randomized controlled trials of older adults with mild cognitive impairment, testing whether these models can robustly extract longitudinal brain representations that predict post-intervention changes in episodic memory across trials. Foundation models outperformed conventional machine learning and deep learning approaches across both trials. Clinically informed adaptation using an external Alzheimer's disease cohort further improved performance and robustness to confounders (i.e., head motion, site, and intervention arm), with accuracy up to 82%. Multivariate decomposition of foundation model embeddings identified latent neural patterns associated with episodic memory change with cross-study consistency at baseline that became more spatially distributed at post-intervention. These findings show that rsfMRI foundation models can enable robust and generalizable identification of latent neural patterns linking longitudinal brain dynamics to individual intervention response, laying the foundation for precision-driven neural target discovery in cognitive aging research.

SIGNIFICANCE STATEMENT: Interventions for cognitive aging show highly variable outcomes across individuals, limiting their clinical effectiveness. This study introduces a foundation model-based approach to identify latent neural patterns underlying individual differences in intervention response using resting-state fMRI. By leveraging pretrained models and domain-adaptive fine-tuning, we demonstrate robust and generalizable prediction of cognitive improvement across independent trials. Our findings suggest that latent brain representations, rather than predefined features, provide a scalable pathway toward precision-driven intervention strategies for aging populations.},
}

@article {pmid42039533,
year = {2026},
author = {Lucciola, R and Herdy, JR and Vajaphattana, Y and Karbacher, L and Sabedot, TS and Cuoco, MS and Traxler, L and Kang, A and Reynolds, M and Jones, JR and Schafer, ST and Mertens, J and Gage, FH},
title = {RUNX1 and YY1 modulate neuronal fate and energy metabolism in Alzheimer's disease.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.04.13.716801},
pmid = {42039533},
issn = {2692-8205},
abstract = {Loss of neuronal identity and metabolic dysfunction are features of Alzheimer's disease (AD), yet the upstream-acting molecular drivers remain incompletely understood. By integrating multi-omics data from patient-derived induced neurons (iNs) and AD post-mortem human brains, we discovered that AD neurons express two master transcription factors (TFs), RUNX1 and YY1. While these TFs are primarily expressed during development where they play fundamental roles in cell fate determination and cellular bioenergetics, respectively, they can be reactivated in adult neurons in response to stress. To understand their functional role in AD neurons, we overexpressed RUNX1 or YY1 in aged iNs and found that the expression of each TF was sufficient to recapitulate two AD-associated features. Specifically, RUNX1 overexpression caused loss of neuronal fate, whereas YY1 overexpression regulated gene regulatory programs associated with metabolic dysfunction. Conversely, downregulation of either TF, in AD iNs, reinstated gene regulatory programs associated with a healthy mature neuronal phenotype. Together, these findings identify two transcriptional master regulators of the AD neuronal phenotype and establish a mechanistic foundation for further studying their role in the pathogenesis of AD and as putative therapeutical targets for the treatment of AD and age-associated neurodegeneration.},
}

@article {pmid42039545,
year = {2026},
author = {Mercado, C and Amaro, A and Martinez-Pinto, J and Vidal, R and Jury-Garfe, N and Lasagna-Reeves, CA},
title = {TREM2 deficiency causes region-specific brain effects in a mouse model of cerebral amyloid angiopathy.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.04.17.719285},
pmid = {42039545},
issn = {2692-8205},
abstract = {Cerebral amyloid angiopathy (CAA), a major vascular contributor to cognitive decline, is present in 85-95% of Alzheimer's disease (AD) patients. Despite its high prevalence, the mechanisms by which CAA contributes to neurodegeneration remain poorly understood. Triggering receptor expressed on myeloid cells 2 (TREM2), an innate immune receptor expressed exclusively by microglia, regulates activation, phagocytosis, and amyloid clearance, thereby shaping neuroinflammation. Loss-of-function mutations in TREM2 markedly increase AD risk, but its role in CAA pathology remains unknown. To investigate this, we crossed the Familial Danish Dementia (Tg-FDD) mouse model, which accumulates robust vascular amyloid, with TREM2 knockout (TREM2KO) mice to generate Tg-FDD/TREM2KO animals. Histological and transcriptomic analyses revealed region-specific effects of TREM2 deficiency. In the cortex, TREM2 loss markedly reduced vascular amyloid deposition, accompanied by decreased tau pathology. In contrast, in the cerebellum, TREM2 deletion exacerbated vascular amyloid accumulation, promoted astrogliosis, and enhanced tau pathology. Transcriptomic profiling further identified distinct neuroinflammatory signatures between cortex and cerebellum, particularly in cytokine signaling, matrix remodeling, and lipid metabolism. Together, these findings demonstrate that TREM2 deficiency leads to region-specific effects on CAA, revealing extensive regional variability in vascular amyloid pathology and underscoring the importance of considering these differences when developing TREM2-based therapies.},
}

@article {pmid42039567,
year = {2026},
author = {Radeen, KR and Hao, C and Wei, Z and Fan, X},
title = {β-Amyloid and Glutathione Dysregulation Cooperatively Drive Lipid Peroxidation and Ferroptosis in Neuron-Like Cells.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.04.15.718809},
pmid = {42039567},
issn = {2692-8205},
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by β-amyloid (Aβ) accumulation and oxidative stress, with aging being its greatest risk factor. Age-related decline in antioxidant defenses, particularly glutathione (GSH), may increase neuronal vulnerability to Aβ-mediated toxicity; however, the mechanisms linking redox dysregulation to neuronal death remain incompletely understood. In this study, we investigated how impaired GSH homeostasis influences neuronal susceptibility to Aβ-associated injury. Human SH-SY5Y neuron-like cells were engineered to express either wild-type APP 695 or the familial AD-associated APP Swe/Ind mutant, and intracellular GSH depletion was induced using both pharmacological and genetic approaches. GSH depletion markedly sensitized APP Swe/Ind -expressing cells to cell death, accompanied by increased plasma membrane lipid peroxidation, elevated malondialdehyde (MDA) and 4-hydroxynonenal (4-HNE) levels, and enhanced lactate dehydrogenase (LDH) release. This cell death was not prevented by the pan-caspase inhibitor Z-VAD-FMK but was effectively rescued by the ferroptosis inhibitors ferrostatin-1 (Fer-1) and liproxstatin-1 (Lip-1), indicating a ferroptotic mechanism. Similar ferroptotic responses were observed when Aβ oligomers were combined with intracellular GSH depletion. Mechanistically, Aβ and GSH depletion synergistically increased transferrin receptor-1 expression and intracellular iron levels while markedly suppressing glutathione peroxidase 4 (GPX4), a central regulator of ferroptosis. Importantly, inhibition of autophagy with bafilomycin A1 restored GPX4 expression and rescued cells from ferroptotic death, suggesting that autophagy-mediated GPX4 degradation contributes to this process. Collectively, our findings demonstrate that GSH dysregulation synergizes with Aβ to induce lipid peroxidation and ferroptosis in neuron-like cells. These results identify impaired redox homeostasis as a critical driver of neuronal vulnerability in AD and suggest that preserving GSH levels or targeting ferroptotic pathways may offer promising therapeutic strategies for neurodegeneration.},
}

@article {pmid42039599,
year = {2026},
author = {Larimi, MG and Thurber, KR and Tycko, R},
title = {Polymorphic structures of rapidly twisting 40-residue amyloid-β fibrils.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.04.10.717728},
pmid = {42039599},
issn = {2692-8205},
abstract = {Fibrils formed by 40- and 42-residue amyloid-β peptides (Aβ40 and Aβ42) are polymorphic, containing molecular structures that vary with growth conditions in ways that are not fully understood. Here we use cryogenic electron microscopy to characterize the structure of rapidly twisting Aβ40 fibrils, for which the distance between apparent width minima in electron microscope images ("cross-over distances") is approximately 25 nm. From samples grown under a single set of growth conditions, we obtain high-resolution structures for three different rapidly twisting polymorphs. Although their cross-over distances are similar, the three rapidly twisting polymorphs differ in twist handedness, symmetry, molecular conformations, and intermolecular contacts. Two of the rapidly twisting polymorphs resemble slowly twisting Aβ40 polymorphs that have been described previously, including polymorphs extracted from brain tissue of Alzheimer's disease patients or created by seeded growth from amyloid in brain tissue, but with shorter conformationally ordered segments and other specific conformational differences. These results contribute to our understanding of amyloid polymorphism, connections between morphology and molecular structure, and relationships between brain-derived and in vitro -grown fibrils.},
}

@article {pmid42039605,
year = {2026},
author = {Wu, Y and Tolman, M and Dai, Y and Walsh, S and Agha, H and Lefton, KB and An, H and Manno, R and Haydon, PG and Papouin, T},
title = {Astrocytes mediate the pro-cognitive value of α7nAChRs and of α7nAChR-targeting therapeutics.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.04.16.719027},
pmid = {42039605},
issn = {2692-8205},
abstract = {The α7-nicotinic acetylcholine receptor (α7nAChR) has driven extensive research over the past three decades for its pro-cognitive potential. It is the leading druggable target for the cognitive deficits associated with schizophrenia and has motivated major pharmaceutical and clinical efforts to ameliorate similar impairments in other neurological disorders, such as Alzheimer's disease (AD). Yet, a systematic evaluation of the role played by α7nAChR in cognition, and its mechanistic underpinnings, is still lacking. Here we report that α7nAChRs on principal and inhibitory forebrain neurons are largely inconsequential to mouse behavior, including in domains that are most sensitive to schizophrenia-related cognitive impairments. By contrast, loss of α7nAChR from astrocytes produces profound behavioral alterations that are cognitive domain-specific, are time-of-day dependent, coincide with reduced levels of the N-methyl D-aspartate receptor (NMDAR) co-agonist D-serine, and are fully restored by D-serine supplementation. Further, an α7nAChR partial agonist previously evaluated in Phase III trials for cognitive enhancement in schizophrenia and AD fails to augment behavior in mice lacking astrocytic α7nAChRs. Together, these findings identify astrocytes and D-serine/NMDAR signaling as a central mechanism through which α7nAChR, a major drug target, promotes cognitive behavior.},
}

@article {pmid42039626,
year = {2026},
author = {Martínez-Flores, R and Martín-Sobrino, I and Falgàs, N and Grau-Rivera, O and Suárez-Calvet, M and Cristi-Montero, C and Ibañez, A and Supèr, H},
title = {Cognitive Vergence and Pupillary Responses as Functional Oculomotor Signatures to Differentiate AT(N) Biological Profiles.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.04.14.718456},
pmid = {42039626},
issn = {2692-8205},
abstract = {BACKGROUND: The AT(N) biological framework classifies Alzheimer's disease (AD) pathology using CSF biomarkers, with the A+T+ profile defining biological AD and the A-T+ profile representing a biologically distinct entity consistent with suspected non-Alzheimer's pathophysiology, such as primary age-related tauopathy. Functional assessment capable of differentiating these profiles non-invasively remains limited. This study investigates whether cognitive vergence and pupillary temporal dynamics during a visual oddball task can distinguish A-T+ from A+T+ biological profiles in individuals with mild cognitive impairment (MCI).

METHODS: Thirty-eight participants with MCI (12 A-T+, 26 A+T+) classified by CSF biomarkers completed a visual oddball task (80% distractors, 20% targets) under continuous eye-tracking. Linear mixed-effects models examined profile × condition interactions on full time series and six trial-level temporal features. Participant-level differentiation was assessed using binomial logistic regression, adjusting for age, sex, and MMSE.

RESULTS: Both profiles showed comparable overall oculomotor response magnitudes but diverged markedly in temporal organization. Significant profile × condition interactions emerged for cognitive vergence global slope, time to peak, and pupillary time to peak. Logistic regression confirmed that timing features discriminated biological profiles at the participant level, with differentiation reversing direction between distractor and target conditions. A-T+ participants also maintained superior target detection accuracy (89.3% vs. 82.4%, p = 0.001).

CONCLUSION: Cognitive Vergence and pupillary temporal dynamics during an oddball task provide condition-dependent functional oculomotor signatures that systematically differentiate AT(N) biological profiles in MCI, suggesting that oculomotor assessment may offer an accessible, non-invasive complement to CSF-based profile characterization.},
}

@article {pmid42039664,
year = {2026},
author = {Tyler, AL and Garceau, D and Kotredes, KP and Haber, A and Spruce, C and Pandey, RS and Preuss, C and Sasner, M and Carter, GW},
title = {Humanized Klotho haplotypes cause widespread transcriptomic changes in mouse brain.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.04.15.718745},
pmid = {42039664},
issn = {2692-8205},
abstract = {Klotho KL is an aging factor that has been associated with Alzheimer's Disease (AD) risk. Two common alleles circulate in human populations: the major allele FC and the minor allele VS, which is defined by two SNPs that cause two amino acid substitutions (F352V and C370S) in KL 's second exon. To investigate the possibility that human KL variants influence brain aging and cognition, we developed a novel mouse model with humanized KL alleles. We used RNA-Seq to measure the whole brain transcriptome in four-and 12-month-old male and female C57Bl/6J mice carrying either the FC or the VS KL allele. We found that FC and VS carriers had widespread differences in gene expression in the brain at 12 months old, but not at four months old. The largest differences were in genes annotated to mitochondrial, ribosomal, and synaptic functions. Differential exon usage analysis identified differential splicing of synaptic genes, further supporting a role for KL on neuronal function. A more focused analysis of differential expression identified variation in glutamate receptors and amyloid precursor (APP) processing in particular, thereby linking human KL haplotypes to biological processes integral to AD pathogenesis. These results provide evidence that the human FC and VS KL haplotypes affect the function of the KL protein product in a manner that has widespread effects on gene expression in the brain and supports the hypothesis that these haplotypes may influence AD risk and pathogenesis.},
}

@article {pmid42039828,
year = {2026},
author = {Li, Z and Xie, C and Pan, C},
title = {The oral-gut-brain axis: how periodontitis influence depression.},
journal = {Frontiers in microbiology},
volume = {17},
number = {},
pages = {1778744},
pmid = {42039828},
issn = {1664-302X},
abstract = {Depression has a high global prevalence and is a common mental-emotional disorder that severely jeopardizes human health. However, current treatment options remain limited, necessitating the exploration of novel pathological mechanisms and intervention targets. Recent studies indicate that periodontitis, as a prevalent chronic oral infectious disease, not only causes local microbial dysbiosis and inflammatory responses but may also influence central nervous system function through the "oral-gut-brain axis," thereby contributing to the pathogenesis and progression of neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, and multiple sclerosis, as well as neuropsychiatric disorders like depression. This review systematically examines the impact of periodontitis on oral microbiota and its subsequent translocation and colonization in the gut microbiota through pathways including swallowing and bloodstream circulation, ultimately leading to structural and functional dysregulation of the gut microbiota. The interaction between oral and gut microbiota can influence the brain through the "gut-brain axis," including disturbances in neurotransmitter metabolism, activation of systemic immune responses, and direct or indirect effects of bacterial metabolites (such as short-chain fatty acids, lipopolysaccharides, etc.) on the blood-brain barrier and neural function. This suggests that periodontal health management may serve as a novel strategy for the prevention and treatment of depression. This article further summarizes the potential of oral interventions for periodontitis (such as mechanical debridement and local/systemic antimicrobial therapy), microbiota modulation methods (such as probiotics, prebiotics, and fecal microbiota transplantation), and multidisciplinary collaborative comprehensive treatment strategies in improving microbial homeostasis and alleviating depressive symptoms. Finally, this paper points out the current research limitations in mechanistic details, causal relationships, and clinical translation, while envisioning the feasibility and prospects of developing personalized treatment strategies by targeting the "oral-gut-brain axis" in the future.},
}

@article {pmid42039925,
year = {2026},
author = {Lennon, MJ and Xu, Y and Thalamuthu, A and Mather, K and Sachdev, PS},
title = {Druggable genome-wide Mendelian randomization analysis identifies potential treatment targets in vascular dementia.},
journal = {Alzheimer's & dementia (New York, N. Y.)},
volume = {12},
number = {},
pages = {e70258},
pmid = {42039925},
issn = {2352-8737},
abstract = {BACKGROUND: There are currently no US Food and Drug Administration-approved treatments for vascular dementia (VaD). Genome-wide approaches have successfully identified druggable targets and treatments for various disorders. In this study, we performed druggable genome-wide two-sample Mendelian randomization (2SMR) analysis to identify possible treatment targets for VaD.

METHODS: 2SMR analyses were used to estimate the causal effects of druggable gene expression on VaD risk. The exposure variables were significant cis-expression quantitative trait loci (eQTLs) and cis-protein quantitative trait loci (pQTLs) in the cerebrospinal fluid (CSF), brain, and plasma. The main outcome variable was genetic VaD risk, based on the Mega Vascular Cognitive Impairment and Dementia Consortium genome-wide association study. 2SMR analysis examined the causal relationship between eQTLs/pQTLs and imaging markers of VaD. A phenome-wide 2SMR analysis explored the relationships between significant druggable genes and phenotype summary statistics derived from the UK Biobank. False discovery rate (FDR) P value corrections were applied to all analyses.

RESULTS: A total of 12,224 druggable genes were identified from the Drug-Gene Interaction Database (DGIdb) and associated papers. Of these, the 2SMR analysis identified four FDR-significant genes in the pQTL analysis, with none identified among the eQTLs. In the CSF, TOMM40 had a significant (P = 3.67E-36) effect on VaD outcomes as well as cerebral small vessel disease (cSVD), white matter hyperintensities (WMH; P = 0.0001) and fractional anisotropy (FA; P = 0.0028). In the brain, apolipoprotein E (APOE; P = 1.90E-54) was associated with VaD and three cSVD markers: WMH (P = 1.61E-06), FA (P = 0.0018), and mean diffusivity (P = 0.0244). ERAP1 (P = 0.0163), and SAA1-4 (P = 0.0163) showed weaker associations with VaD, did not show colocalization, and were not associated with cSVD imaging markers.

DISCUSSION: This study identified four potential drug targets for VaD, using a 2SMR analysis approach. Two genes, APOE and TOMM40, are well understood to be associated with both Alzheimer's disease and VaD, whereas the other two, ERAP1 and SAA1-4, are novel targets involved in immune system regulation and inflammation.},
}

@article {pmid42039926,
year = {2026},
author = {Johnson, PE and Vandermause, R},
title = {Spiritual practices for dementia care of Black persons: An integrative review.},
journal = {Alzheimer's & dementia (New York, N. Y.)},
volume = {12},
number = {},
pages = {e70255},
pmid = {42039926},
issn = {2352-8737},
abstract = {It is crucial to identify practices that effectively meet the unique spiritual needs of Black persons living with dementia. Currently, ≈ 7 million individuals in the United States are affected by dementia, a figure that is expected to rise alarmingly to nearly 13 million by 2050. National statistics indicate that Black persons are twice as likely to be diagnosed with Alzheimer's disease and related dementias as Whites. Health care often focuses on physical health at the expense of addressing the person's holistic needs, including emotional and spiritual well-being. This review focuses on literature related to spiritual practices for dementia care in a specific population, Black persons living with dementia. The Whittemore and Knafl framework was used for this integrative review. Findings are summarized through the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Nine studies met the inclusion criteria. Three main thematic categories were found: (1) Transformative faith-based programs to address the spiritual needs of Black persons living with dementia, (2) spiritual practices adapted to support caregiving experiences, and (3) spiritual practices tailored to both caregivers and the Black persons living with dementia. While caring for caregivers is important, it is equally crucial to focus on the unique challenges faced by individuals living with dementia. Most of the programs highlighted in this review aim to improve caregiving experiences. There is a lack of literature dedicated to developing practices specifically for individuals diagnosed with the disease. A notable gap exists in targeted practices that meet the unique spiritual needs of Black persons living with dementia. Future research should focus on developing spiritual interventions that address these essential needs.},
}

@article {pmid42040178,
year = {2026},
author = {Huang, Y and Li, Q and Chen, A and Li, Y and Chuang, YN and Hu, X and Guo, SJ and He, X and Pang, Y and Zhou, J and Wu, Y and Guo, Y and Bian, J},
title = {Feasibility of identifying factors related to Alzheimer's disease and related dementia in real-world data.},
journal = {JAMIA open},
volume = {9},
number = {2},
pages = {ooag060},
pmid = {42040178},
issn = {2574-2531},
abstract = {OBJECTIVE: This study aimed to provide a comprehensive understanding of factors associated with Alzheimer's disease (AD) and AD-related dementias (AD/ADRD), which could aid in studies to develop new treatments for AD/ADRD patients and identify high-risk populations for prevention.

SCOPE AND METHOD: In our study, we summarized the risk factors for AD/ADRD by reviewing existing meta-analyses and review articles on risk and preventive factors for AD/ADRD. From this literature review and the identified AD/ADRD factors, we examined the accessibility of these risk and preventive factors in both structured and unstructured Electronic Health Records (EHRs) data.

RESULTS: In total, we extracted 401 factors in 10 categories from the identified studies. To share our findings, we created an interactive knowledge graph of these risk factors and the relationships among them to assist in the design of future AD/ADRD studies that aim to use large collections of real-world data (RWD) to generate real-world evidence (RWE).

DISCUSSION AND CONCLUSION: Most factors, including conditions, medications, biomarkers, and procedures, are accessible from structured EHRs. For those not accessible from structured EHRs, clinical narratives serve as promising sources of information. However, evaluating genomic factors using RWD remains to be a challenge, possibly due to the fact that genetic testing for AD/ADRD is still uncommon and poorly documented in both structured and unstructured EHRs. Considering the continuously and rapidly evolving research on AD/ADRD, automated literature mining via natural language processing (NLP) methods offers a way to automatically update our knowledge graph.},
}

@article {pmid42040334,
year = {2026},
author = {, },
title = {Retraction: Early detection and classification of Alzheimer's disease through data fusion of MRI and DTI images using the YOLOv11 neural network.},
journal = {Frontiers in neuroscience},
volume = {20},
number = {},
pages = {1845919},
doi = {10.3389/fnins.2026.1845919},
pmid = {42040334},
issn = {1662-4548},
abstract = {[This retracts the article DOI: 10.3389/fnins.2025.1554015.].},
}

@article {pmid42040345,
year = {2026},
author = {Li, S and Luo, Y and Shi, S and Ding, Y},
title = {Functional and genetic divergence of aging-related TOMM40 polymorphisms in Alzheimer's disease: an integrative bioinformatics and systematic review with meta-analysis and trial sequential analysis.},
journal = {Frontiers in neuroscience},
volume = {20},
number = {},
pages = {1772368},
pmid = {42040345},
issn = {1662-4548},
abstract = {BACKGROUND: The etiology of late-onset Alzheimer's disease (AD) is only partly understood. Because TOMM40 is located within the APOE-TOMM40-APOC1 locus, its independent role remains unclear. This study aimed to assess the association of six TOMM40 polymorphisms with AD risk across five genetic models while integrating genome-wide, regulatory, and functional genomic evidence to clarify their potential biological roles.

METHODS: A comprehensive literature search was conducted across five electronic databases. RevMan 5.1 was used for meta-analysis, including subgroup, meta-regression, and sensitivity analyses. To provide biological context, genome-wide data from IGAP/NIAGADS, AD-specific functional annotations from AGORA, and regulatory eQTL/sQTL evidence from GTEx were incorporated, with pathway enrichment using Enrichr.

RESULTS: Thirteen articles were included in the meta-analysis. rs2075650 showed a significantly increased AD risk across all genetic models, while rs157580 consistently demonstrated a protective effect. rs157581 was also associated with elevated risk, whereas rs8106922, rs11556505, and rs1160985 showed no significant associations. Bioinformatic analysis showed that rs2075650 and rs157581 reside within the APOE-linked LD block and affect TOMM40 splicing, whereas rs157580 demonstrated an LD-independent regulatory pattern, influencing the expression of genes involved in lipid- and amyloid-related pathways.

CONCLUSION: rs2075650, rs157580, and rs157581 show significant associations with AD risk. rs2075650 and rs157581 confer elevated risk, while rs157580 is protective. Integrated genomic evidence indicates that the risk variants act via TOMM40 splicing within the APOE locus, whereas the protective variant modulates expression of lipid- and amyloid-related genes, suggesting distinct mechanisms.},
}

@article {pmid42040397,
year = {2026},
author = {Maia, ME and Carvalho, M and Sousa Gomes, C and Arruda, M and Antunes de Magalhães, AJ and Farias, D},
title = {Plant-Derived Peptides with Neuroprotective Activity: Advances and Perspectives in the Prevention of Neurodegenerative Diseases.},
journal = {ACS omega},
volume = {11},
number = {15},
pages = {22458-22478},
pmid = {42040397},
issn = {2470-1343},
abstract = {Neurodegenerative diseases, such as Alzheimer's, Parkinson's, Huntington's, and amyotrophic lateral sclerosis, represent an increasing global public health challenge, driven by population aging and the lack of effective curative therapies. In this context, plant-derived peptides have emerged as promising bioactive compounds due to their multitarget neuroprotective properties and favorable safety profiles. This review provides a comprehensive overview of plant peptides with reported activity against neurodegeneration, highlighting their natural sources, biological activities, and mechanisms of action. Evidence from in vitro and in vivo models indicates that these peptides act through multiple complementary pathways, including attenuation of oxidative stress, modulation of neuroinflammation, regulation of apoptosis, preservation of mitochondrial function, and inhibition of toxic protein aggregation. Additionally, several peptides have been shown to enhance synaptic plasticity, modulate neurotransmission, and regulate ion channel activity, suggesting beneficial effects on neuronal communication and cognitive function. Some studies explored structural modifications, such as the introduction of specific residues or glycosylation, which have resulted in greater stability and enhanced efficacy against oxidative insults. Overall, plant-derived peptides demonstrate consistent neuroprotective effects and low toxicity; however, challenges related to the blood-brain barrier, bioavailability, and the understanding of molecular mechanisms must still be overcome to enable their clinical application.},
}

@article {pmid42040541,
year = {2026},
author = {Zhang, C and Xiu, Y and Ying, W and Xiao, Y},
title = {Trends in rehabilitation needs for neurological disorders in China, 1990-2021: a cross-sectional analysis of the Global Burden of Disease Study 2021.},
journal = {Frontiers in medicine},
volume = {13},
number = {},
pages = {1688298},
pmid = {42040541},
issn = {2296-858X},
abstract = {BACKGROUND: Neurological disorders are a leading cause of long-term disability, generating substantial rehabilitation needs. China's rapid population aging and evolving epidemiological profile underscore the urgency of quantifying these needs.

METHOD: Using data from the Global Burden of Disease Study 2021, we assessed rehabilitation needs for 10 neurological disorders in China from 1990 to 2021. Prevalence and years lived with disability (YLDs) were analyzed by age, sex, and cause, benchmarked against global trends. Temporal trends were quantified by estimated annual percentage change (EAPC), and Bayesian age-period-cohort modeling was applied to forecast to 2050.

RESULTS: From 1990 to 2021, China's age-standardized prevalence and YLDs rates increased significantly, with EAPCs of 0.42 (95% CI 0.38 to 0.45) and 0.40 (95% CI 0.36 to 0.43), both exceeding global averages. The largest absolute burdens in 2021 were from stroke, Alzheimer's disease, and Parkinson's disease. Parkinson's disease (EAPC = 1.85, 95% CI 1.78 to 1.92), multiple sclerosis (1.42, 95% CI 1.36 to 1.48), and motor neuron disease (1.11, 95% CI 1.05 to 1.17) showed the steepest proportional rises. Women bore higher late-life burdens, while men had greater trauma-related disability. Rehabilitation needs were concentrated in older adults, with substantial geographic and service-access inequities reported in prior national surveys. Forecasts to 2050 indicate sustained growth, with neurodegenerative disorders comprising an increasing share of total rehabilitation demand.

CONCLUSION: The scale and pace of growth in China's neurological rehabilitation needs reflect demographic aging, improved survival, and persistent service gaps. Meeting this challenge will require decentralizing rehabilitation, integrating disease-specific pathways into universal health coverage, and prioritizing underserved rural and older populations.},
}

@article {pmid42040755,
year = {2026},
author = {Bigjahan, B and Cavallari, M and Barisano, G},
title = {MRI evaluation of cerebral perivascular spaces predicts amyloid-related imaging abnormalities risk in preclinical Alzheimer's disease.},
journal = {Frontiers in dementia},
volume = {5},
number = {},
pages = {1719740},
pmid = {42040755},
issn = {2813-3919},
abstract = {BACKGROUND AND PURPOSE: Amyloid-related imaging abnormalities (ARIA) are radiographic findings observed in the natural course of Alzheimer's disease and have been reported at higher rates in patients receiving anti-amyloid monoclonal antibody therapy. Identifying novel radiographic factors predicting ARIA risk may help prevent its occurrence, improve patient stratification, and provide insight on the underlying biological mechanisms. It remains unclear whether cerebral perivascular spaces (PVS) along with other quantitative radiographic markers of cerebral small vessel disease may help predict the risk of incident ARIA in patients diagnosed with preclinical Alzheimer's disease.

METHODS: Participants from the A4 study were included. PVS and white matter hyperintensities (WMH) were segmented with robust fully-automated methods on T1-weighted and FLAIR images, respectively. Number of microhemorrhages and subcortical infarcts were previously recorded by expert radiologists. Baseline measurements of these markers were used in Cox proportional-hazards models to predict ARIA risk controlling for relevant demographic, clinical, and radiographic factors.

RESULTS: Among 6,028 brain MRI from 1,088 participants (median age: 71-y.o.; 59.4% women), 356 ARIA were diagnosed (median study follow-up: 5.4 years). The volume fraction of PVS and WMH, and the number of microhemorrhages at baseline predicted higher ARIA risk (adjusted hazard ratio ranges: 1.32-1.55; adjusted p-values all <0.05). Importantly, the effect of PVS on ARIA with microhemorrhages risk was observed in individuals considered at low risk of ARIA according to current guidelines, i.e., APOE-ε4 non-carriers, low WMH burden, or no microhemorrhages.

CONCLUSIONS: These results support the use of quantitative measurements of PVS in addition to WMH and microhemorrhages to assist clinicians in estimating an individual's risk of ARIA.},
}

@article {pmid42040886,
year = {2026},
author = {Fawad, A and van der Landen, SM and Tideman, P and van der Putten-Toorenburg, A and Butterbrod, E and Smith, R and van Westen, D and Calling, S and Midlöv, P and Mattsson-Carlgren, N and Borgström Bolmsjö, B and Stomrud, E and Nilsson, MH and Hansson, O and Sikkes, SAM and Palmqvist, S},
title = {Clinical staging in Swedish primary care using the Amsterdam Instrumental Activities of Daily Living Questionnaire.},
journal = {Alzheimer's & dementia (Amsterdam, Netherlands)},
volume = {18},
number = {},
pages = {e70344},
pmid = {42040886},
issn = {2352-8729},
abstract = {INTRODUCTION: We assessed the accuracy of the Amsterdam Instrumental Activities of Daily Living Questionnaire (A-IADL-Q) for clinical staging in Swedish primary care.

METHODS: Participants from the Swedish BioFINDER Primary Care study were included. Discriminative performance of the A-IADL-Q was evaluated using receiver operating curves. Multinomial and linear regression models assessed associations among A-IADL-Q scores, clinical stage, demographics, cognition, and comorbidities.

RESULTS: Among 623 patients, 148 (23.8%) had subjective cognitive decline (SCD), 274 (43.9%) mild cognitive impairment (MCI), and 201 (32.3%) dementia with a mean (standard deviation) age of 76.7 (7.3). The area under the curve (95% confidence interval) for discriminating between SCD versus MCI/dementia was 0.89 (0.86-0.91) and for SCD/MCI versus dementia 0.89 (0.87-0.92). Age (β = -0.25), Mini-Mental State Examination (β = 0.91) and Montreal Cognitive Assessment (β = 0.57), but no other demographics and comorbidities, were associated with the A-IADL-Q.

DISCUSSION: The A-IADL-Q may help primary care physicians determine clinical stage and shows promise for use to adequately refer patients to secondary or tertiary care.},
}

@article {pmid42040899,
year = {2026},
author = {Yin, D and Wang, J and Li, C and Wang, X and Wang, Y and Xie, Q and Tian, N and Chen, Z and Sun, X and Wang, Y and Hou, T and Cong, L and Zhou, L and Du, Y and Song, L and Qiu, C},
title = {Deep medullary vein abnormalities associated with cognitive function and Alzheimer's disease plasma biomarkers in dementia-free older adults: A population-based study.},
journal = {Alzheimer's & dementia (Amsterdam, Netherlands)},
volume = {18},
number = {2},
pages = {e70320},
pmid = {42040899},
issn = {2352-8729},
abstract = {INTRODUCTION: We investigated the associations of deep medullary vein (DMV) score with cognitive phenotypes and blood biomarkers for Alzheimer's disease among older adults.

METHODS: This population-based cross-sectional study used data from 1206 participants in the Multimodal Interventions to Delay Dementia and Disability in Rural China (MIND-China) magnetic resonance imaging (MRI) substudy; of these, plasma amyloid-β (Aβ), total tau, neurofilament light chain, phosphorylated tau 217 (p-tau217), and glial fibrillary acidic protein were measured in subsamples (n = 901∼1133).

RESULTS: A higher DMV score was significantly associated with increased likelihoods of mild cognitive impairment (MCI) and amnestic MCI, and lower z-scores of verbal fluency, memory, attention, executive function, and global cognition (all p < 0.05); such associations were significant only in males. In the biomarker subsamples, a higher DMV score was significantly associated with a lower plasma Aβ42/40 ratio (p < 0.05), but not with the other examined biomarkers.

DISCUSSION: Discontinuous DMVs might be a biomarker for MCI and poor cognitive function in older men, and the role of Alzheimer's pathology deserves further exploration.},
}

@article {pmid42040951,
year = {2026},
author = {Benzinger, T and Powles, ST and Hoagey, D and Flores, S and Friedrichsen, K and Wu, S and Rajamanickam, J and Joseph-Mathurin, N and Keefe, S and Nagy, S and McKay, N and Wisch, J and Sabaredzovic, E and Chen, G and Simmons, A and Jones, L and Soda, AK and Powles, J and Doering, S and Jana, N and Massoumzadeh, P and Baker, B and Cruchaga, C and Schindler, S and Ibanez, L and Morris, J and An, H and Liu, J and Tu, Z and Brier, M},
title = {[11C]CS1P1 PET links T-cell-associated immune activation with endothelial and astrocytic responses.},
journal = {Research square},
volume = {},
number = {},
pages = {},
doi = {10.21203/rs.3.rs-9237372/v1},
pmid = {42040951},
issn = {2693-5015},
abstract = {Neuroimmune signaling across the peripheral-vascular-glial axis is increasingly recognized as a driver of both age‑related brain vulnerability and the earliest stages of neurodegenerative disease, including Alzheimer disease. Evaluating this axis in vivo remains challenging due to limited neuroinflammatory imaging biomarkers. We utilized [11C]CS1P1 positron emission tomography (PET) to quantify sphingosine-1-phosphate receptor 1 (S1PR1) availability alongside plasma proteomics in 42 cognitively normal individuals (age 21-82). Through differential abundance analysis and structural equation modeling (SEM), we identified a multi-compartment neuroimmune cascade linking peripheral T-cell activation (CD40LG), vascular endothelial disruption (ICAM1/TEK), central S1PR1 upregulation, and reactive astrogliosis (GFAP). Mediation analysis estimated this S1PR1 axis accounts for 25.5% of the total effect of CD40LG on GFAP. This cascade appears coupled to the astrocytic immune response and is exacerbated by underlying amyloid-beta pathology. These findings suggest [11C]CS1P1 may serve as an in vivo tool for evaluating peripheral-to-central immune crosstalk.},
}

@article {pmid42041135,
year = {2026},
author = {Lee, B and Flood, B and Potter, E and Wang, T},
title = {Identification of Secondary Nucleation Inhibitors of Amyloid-β Aggregation by Cellular Selection of a SICLOPPS Library.},
journal = {Chembiochem : a European journal of chemical biology},
volume = {27},
number = {8},
pages = {e202500908},
doi = {10.1002/cbic.202500908},
pmid = {42041135},
issn = {1439-7633},
support = {R21AG088715/AG/NIA NIH HHS/United States ; },
mesh = {*Amyloid beta-Peptides/metabolism/antagonists & inhibitors/chemistry ; Humans ; *Peptide Library ; Protein Aggregates/drug effects ; *Peptides, Cyclic/chemistry/pharmacology/metabolism ; *Peptide Fragments/metabolism/antagonists & inhibitors/chemistry ; },
abstract = {Alzheimer's disease is characterized by the accumulation of amyloid beta (Aβ) aggregates. Soluble oligomers Aβ oligomeric intermediates (AβOs) generated during aggregation are hypothesized to be a neurotoxic species. Many cyclic peptides have been developed to inhibit Aβ aggregation but primarily target Aβ monomers and fibrils; few cyclic peptides selectively recognize AβOs. We selected a library of >10[7] cyclic peptides generated by the widely used split-intein mediated circular ligation of peptides and proteins (SICLOPPS) strategy for binders of AβOs. These selections identified cyclo-CRLISFF, which significantly delayed Aβ42 aggregation in vitro but displayed a mechanism inconsistent with inhibitors selectively targeting AβOs. To resolve this discrepancy, we tested whether intermediates formed during SICLOPPS cyclic peptide generation might also possess AβO binding activity. Our experiments showed that the CRLISFF sequence was active as an intein-bound intermediate which selectively targeted AβOs by inhibiting the secondary nucleation step of the Aβ42 aggregation cascade. This intermediate has not been previously examined in studies employing SICLOPPS and may present a convoluting factor when using this technology to generate cyclic peptide libraries. The CRLISFF motif also retained activity when transplanted onto an unrelated protein scaffold, suggesting that SICLOPPS sequences may be compatible with peptide grafting strategies used to create protein-based binders.},
}

*Amyloid beta-Peptides/metabolism/antagonists & inhibitors/chemistry
Humans
*Peptide Library
Protein Aggregates/drug effects
*Peptides, Cyclic/chemistry/pharmacology/metabolism
*Peptide Fragments/metabolism/antagonists & inhibitors/chemistry

@article {pmid42041187,
year = {2026},
author = {Wesson, J and Cross, AJ and Watson, K and Jokanovic, N and Schneider, C and Mirzaei, A and Lo, JCM and Sawan, M},
title = {Priorities for medication management information resources for people with dementia and carers: a community-driven approach using a modified Delphi method.},
journal = {Age and ageing},
volume = {55},
number = {4},
pages = {},
doi = {10.1093/ageing/afag108},
pmid = {42041187},
issn = {1468-2834},
mesh = {Humans ; Delphi Technique ; *Dementia/drug therapy/diagnosis/psychology ; *Caregivers/psychology/education ; Consensus ; Community-Based Participatory Research ; Female ; Male ; *Health Priorities ; Health Literacy ; *Medication Therapy Management ; Medication Errors/prevention & control ; Aged ; Health Knowledge, Attitudes, Practice ; },
abstract = {BACKGROUND: Managing medications safely can be challenging for people with dementia and carers living in the community and medication errors can be a source of preventable harm. Resources to support people in medication management must address their information needs and prioritise these alongside those of broader stakeholders.

OBJECTIVE: We aimed to generate content statements for inclusion in tailored medication management literacy resources for people with dementia and carers.

DESIGN AND METHODS: Using a community-based participatory research approach, we established a Medication Management Guidance Partnership: collaboration between the research team, research advisory group, and partner organisations. A mixed-method approach generated 49 statements (Phase 1) then we conducted an online modified Delphi process to gain consensus (Rounds 1 and 2) and prioritise statement order (Round 3) for inclusion in resources (Phase 2). Primary criterion for consensus required ≥80% of participants rating statements as important (≥7 on 9-point Likert-type scale). Secondary criteria assessed response variability, and statements were required to meet all criteria for inclusion.

RESULTS: People with dementia (n = 5), carers (n = 5), healthcare professionals and/or national consumer organisation representatives (n = 13) reached consensus on 44 statements across six information domains. 'Information about decision-making' was ranked highest, followed by 'general question prompts', 'information about common medications', 'addressing complexities,' 'getting guidance in different languages' and 'additional supports.'

CONCLUSION: Our 'menu' of statements about medication management priorities, endorsed by end-users, can be used to guide development of resources to improve medication management and potentially reduce medication-related harm in this population.},
}

Humans
Delphi Technique
*Dementia/drug therapy/diagnosis/psychology
*Caregivers/psychology/education
Consensus
Community-Based Participatory Research
Female
Male
*Health Priorities
Health Literacy
*Medication Therapy Management
Medication Errors/prevention & control
Aged
Health Knowledge, Attitudes, Practice

@article {pmid42041219,
year = {2024},
author = {Xie, P and Sun, C and Li, Y and Deng, Y and Xie, C},
title = {Clinical Study on Mesenchymal Stem Cell Factors Therapy for Alzheimer's Disease.},
journal = {Nigerian journal of clinical practice},
volume = {27},
number = {10},
pages = {1216-1220},
doi = {10.4103/njcp.njcp_561_24},
pmid = {42041219},
issn = {1119-3077},
abstract = {BACKGROUND: Alzheimer's disease (AD), characterized by cognitive decline, lacked effective cures. Mesenchymal stem cell (MSC) factors (MSCFs) offered a new approach by promoting brain tissue repair and modulating immune responses, presenting a promising alternative to AD treatment with minimal risks.

AIM: This study aimed to investigate the effects of MSCF on AD and to compare the effects with traditional MSC treatments.

METHODS: Sixty patients were divided into control and observation groups, with 30 cases in each group. The control group were injected intravenously with 10 mL of MSCs (5.0 × 10 9 L -1) plus 100 mL normal saline (once every 5 days for six consecutive treatments). The observation group received intramuscular injections of 0.5 mL (1 mL for the first dose) of MSCF (every other day for 15 consecutive treatments). Amyloid-β 42 (Aβ42) and Tau protein concentrations in cerebrospinal fluid were determined by ELISA pretreatment and at 1, 3, and 6 months' post-treatment. The Clinical Dementia Rating of AD patients was recorded at these intervals to evaluate treatment efficacy.

RESULTS: Aβ42 levels increased, and Tau protein levels decreased in both groups. The CDR score dropped post treatment. The total effective rate and clinical cure rate were 86.67% and 6.70% in the control group and 100% and 40% in the observation group, respectively. MSCF and MSCs uniquely impact AD.

CONCLUSION: MSCs contributed to damaged nerve cell repair, new nerve cell differentiation, and the participation of some dormant nerve cells in physiological activity. MSCF offered a small-dose, rapid, and safe treatment with simple operation.},
}

@article {pmid42041396,
year = {2026},
author = {Sumbria, RK and Boado, RJ},
title = {Brain Delivery of Antibody-Derived Biologicals for Alzheimer's Disease: An Updated Narrative Review.},
journal = {Antibodies (Basel, Switzerland)},
volume = {15},
number = {2},
pages = {},
doi = {10.3390/antib15020037},
pmid = {42041396},
issn = {2073-4468},
abstract = {Antibodies directed against β-amyloid (Aβ) have been developed for the treatment of Alzheimer's disease (AD). However, the in vivo central efficacy is reduced by the poor penetration of antibodies across the blood-brain barrier (BBB). In addition, these antibodies have been associated with adverse effects like amyloid-related imaging abnormalities. Thus, the development of new antibody-based therapies for AD with improved transport across the BBB may improve efficacy and reduce adverse effects. Antibodies targeting the BBB transferrin receptor (TfR) are able to cross the BBB through receptor-mediated transcytosis, producing a global distribution throughout the brain. Along the same line, bispecific antibodies directed to both the BBB TfR and Aβ showed enhanced brain uptake and pharmacological effects with diminished adverse side effects in experimental animal models of AD and in clinical trials. A generation of brain-penetrating fusion proteins targeting the BBB-TfR has been shown to represent novel treatments for AD, and this includes erythropoietin, tumor necrosis factor alpha inhibitors, neprilysin, somatostatin, oligonucleotides, and an antibody activating TREM2. The aim of this article is to review the progress made in the delivery of antibody-derived biologicals to the brain for AD, targeting the BBB-TfR.},
}

@article {pmid42041411,
year = {2026},
author = {Nagpal, D and Singh, A and Link, J and Mehta, AS and Kumar, A and Budhraja, V},
title = {Recent Advances in Graphene-Based Field-Effect Transistor Biosensors for Disease Biomarker Detection and Clinical Prospects.},
journal = {Biosensors},
volume = {16},
number = {4},
pages = {},
doi = {10.3390/bios16040190},
pmid = {42041411},
issn = {2079-6374},
mesh = {*Biosensing Techniques ; Humans ; *Graphite/chemistry ; *Biomarkers/analysis ; *Transistors, Electronic ; Neoplasms/diagnosis ; },
abstract = {Field-effect transistor (FET) biosensors using graphene have become one of the most promising biosensing platforms for the early diagnosis of diseases with features such as high sensitivity, label-free detection and application compatibility with point-of-care systems. Herein, we critically discuss recent advances in graphene FET (GFET) biosensor development toward clinically relevant biomarkers associated with representative diseases including cancer, neurodegenerative disease, infectious disease, and inflammatory conditions. Recent progress was reviewed to evaluate GFET architectures, surface functionalization methods, and detection quality. The biomarkers explored were clusterin in Alzheimer's disease, thrombin in coagulopathy, estrogen receptor α (ER-α) in breast cancer, Carcinoembryonic antigen in lung cancer, microRNAs for malignant tumors, exosomes derived from HepG2 for the hepatocellular carcinoma (HCC) cell line, interleukin-6 (IL-6) for chronic obstructive pulmonary disease (COPD), Polyclonal antibodies and antigens (P24) for HIV and prostate-specific antigen for prostate cancer. The developed devices demonstrate ultralow detection limits at femtomolar to attomolar concentrations with the aid of designed antibodies, aptamers and nanomaterials. Herein, this review presents the sensing mechanisms and biomedical application of various GFET platforms, focusing on their emerging potential as next-generation platforms for rapid, non-invasive and point-of-care diagnostics.},
}

*Biosensing Techniques
Humans
*Graphite/chemistry
*Biomarkers/analysis
*Transistors, Electronic
Neoplasms/diagnosis

@article {pmid42041525,
year = {2026},
author = {Bertoni, G and Ristori, S and Monti, D},
title = {Immunosenescence and Inflammaging as Drivers of Neurodegeneration: Cellular Mechanisms, Neuroimmune Crosstalk, and Therapeutic Implications.},
journal = {Cells},
volume = {15},
number = {8},
pages = {},
doi = {10.3390/cells15080657},
pmid = {42041525},
issn = {2073-4409},
support = {DM 1557 11.10.2022//Next Generation EU/ ; },
mesh = {Humans ; *Immunosenescence/immunology ; *Neurodegenerative Diseases/immunology/pathology/therapy ; *Inflammation/immunology/pathology ; Animals ; *Aging/immunology ; *Neuroimmunomodulation ; },
abstract = {Aging is accompanied by profound alterations in immune function, termed immunosenescence, and by a chronic, low-grade inflammatory state known as inflammaging. These processes are increasingly recognized as central drivers of age-related neurodegenerative diseases, including Alzheimer's Disease, Parkinson's Disease, Amyotrophic Lateral Sclerosis and Multiple Sclerosis. In the central nervous system, senescent microglia and astrocytes lose their homeostatic and neuroprotective functions, while systemic immune aging and blood-brain barrier dysfunction further amplify neuroinflammation and impair protein aggregate clearance. This sustained pro-inflammatory environment promotes synaptic dysfunction, neuronal loss and cognitive decline. Here, we synthesize current knowledge of the mechanistic links among immunosenescence, inflammaging, and neurodegeneration, highlighting innate and adaptive immune dysregulation, mitochondrial impairment, and failed resolution pathways. We further discuss emerging therapeutic strategies, including senolytics, immunoceuticals, microbiome-based interventions and advanced drug delivery systems, aimed at restoring immune homeostasis and enhancing brain resilience. By integrating mechanistic and translational insights, this review provides a framework for developing novel interventions to target immune aging in neurodegenerative diseases.},
}

Humans
*Immunosenescence/immunology
*Neurodegenerative Diseases/immunology/pathology/therapy
*Inflammation/immunology/pathology
Animals
*Aging/immunology
*Neuroimmunomodulation

@article {pmid42041537,
year = {2026},
author = {Panuccio, A and Yurtsever, ZN and Cutuli, D and Giacovazzo, G and Decandia, D and Tortolani, D and Landolfo, E and Oddi, S and Maccarrone, M and Petrosini, L and Coccurello, R},
title = {Sustained Palmitoylethanolamide Infusion Restores Incentive Motivation and Synaptic Plasticity in the Tg2576 Mouse Model of Alzheimer's Disease.},
journal = {Cells},
volume = {15},
number = {8},
pages = {},
doi = {10.3390/cells15080669},
pmid = {42041537},
issn = {2073-4409},
support = {RF-2018-12365391//Italian Ministry of Health/ ; PNRR-MAD-2022-12376730//European Union -Next Generation EU/ ; },
mesh = {Animals ; *Alzheimer Disease/drug therapy/physiopathology/pathology ; *Palmitic Acids/pharmacology/administration & dosage/therapeutic use ; *Ethanolamines/pharmacology/administration & dosage ; *Amides/pharmacology ; Disease Models, Animal ; *Neuronal Plasticity/drug effects ; Mice ; *Motivation/drug effects ; Mice, Transgenic ; Brain-Derived Neurotrophic Factor/metabolism ; PPAR alpha/metabolism ; Male ; Mice, Inbred C57BL ; Prefrontal Cortex/drug effects/metabolism ; },
abstract = {Alzheimer's disease (AD) is increasingly recognized as a disorder not only of cognition but also of motivation and emotional regulation. Apathy and anhedonia often precede memory deficits, implicating early dysfunction in reward-related circuits. This study investigated whether chronic infusion of palmitoylethanolamide (PEA), a lipid-derived PPARα agonist, could restore motivational behavior and dendritic plasticity in the Tg2576 mouse model of AD. The motivational behavior of mice that received sustained-release PEA pellets for 6 months was assessed by using the conditioned place preference (CPP) paradigm. Morphological and molecular analyses were conducted in the entorhinal cortex (EC), dentate gyrus (DG), and prefrontal cortex (PFC). In Tg2576 mice, PEA significantly rescued CPP performance, increased basal dendritic spines in WT mice in the EC, and both basal and apical dendritic expression in EC and DG from Tg2576 mice, and upregulated the expression of both PPAR-α and brain-derived neurotrophic factor (BDNF) in the PFC. Interestingly, the BDNF increase occurred even in the absence of baseline deficits, suggesting a trophic-enhancement effect. These findings suggest that the PEA-PPARα-BDNF axis may be a potential mechanism for restoring motivation and synaptic integrity in an AD-like mouse model. Lipid-based neuromodulation may therefore offer novel therapeutic routes for addressing non-cognitive symptoms and affective circuitopathy in neurodegenerative diseases.},
}

Animals
*Alzheimer Disease/drug therapy/physiopathology/pathology
*Palmitic Acids/pharmacology/administration & dosage/therapeutic use
*Ethanolamines/pharmacology/administration & dosage
*Amides/pharmacology
Disease Models, Animal
*Neuronal Plasticity/drug effects
Mice
*Motivation/drug effects
Mice, Transgenic
Brain-Derived Neurotrophic Factor/metabolism
PPAR alpha/metabolism
Male
Mice, Inbred C57BL
Prefrontal Cortex/drug effects/metabolism

@article {pmid42041540,
year = {2026},
author = {Uranga, RM and Allani, SK},
title = {From Lipids to Mitochondria: Shared Metabolic Alterations in Obesity and Alzheimer's Disease.},
journal = {Cells},
volume = {15},
number = {8},
pages = {},
doi = {10.3390/cells15080672},
pmid = {42041540},
issn = {2073-4409},
mesh = {Humans ; *Alzheimer Disease/metabolism/pathology ; *Obesity/metabolism ; *Mitochondria/metabolism ; *Lipid Metabolism ; Animals ; Adipose Tissue/metabolism ; Brain/metabolism ; },
abstract = {The increasing prevalence of obesity and Alzheimer's disease (AD) in the aging population underscores an urgent need to understand the common cellular and metabolic mechanisms they share. Accumulated evidence suggests that overlapping metabolic disturbances contribute to the pathogenesis of these two conditions. In this review, we highlight key underlying interconnecting metabolic pathways: (1) adipose-brain crosstalk mediated by adipokines and adipose tissue-derived extracellular vesicles that can modulate neuronal function and amyloid pathology, (2) dysregulated lipid metabolism affecting cholesterol, sphingolipids, and phospholipids and thereby promoting inflammation, amyloid precursor protein processing, and tau hyperphosphorylation, (3) impaired glycolysis and insulin resistance, which accelerate both obesity and neurodegenerative processes, (4) mitochondrial dysfunction marked by disrupted tricarboxylic acid cycle enzymes and electron transport chain complexes, leading to elevated reactive oxygen species and driving both obesity and AD pathology, and (5) gut microbiota dysbiosis, which can trigger inflammation as well as amyloid and tau aggregation. Together, these mechanisms show that metabolic alterations appear early, preceding clinical disease, and that understanding these underlying connections can provide strategies to protect metabolic health and prevent disease progression.},
}

Humans
*Alzheimer Disease/metabolism/pathology
*Obesity/metabolism
*Mitochondria/metabolism
*Lipid Metabolism
Animals
Adipose Tissue/metabolism
Brain/metabolism

@article {pmid42041558,
year = {2026},
author = {Delbaz, A and St John, JA},
title = {Outer Membrane Vesicles as Systems-Level Drivers of Neuroinflammation, Metabolic Dysfunction, and Proteinopathy in Alzheimer's Disease.},
journal = {Cells},
volume = {15},
number = {8},
pages = {},
doi = {10.3390/cells15080690},
pmid = {42041558},
issn = {2073-4409},
mesh = {Humans ; *Alzheimer Disease/metabolism/pathology ; *Neuroinflammatory Diseases/metabolism/pathology ; Animals ; *Bacterial Outer Membrane/metabolism ; Brain/metabolism/pathology ; },
abstract = {Alzheimer's disease is a complex neurodegenerative condition characterized by progressive cognitive decline, neuroinflammation, metabolic dysregulation, and abnormal protein deposition. While genetic factors and amyloid-beta-focused hypotheses have been extensively investigated, they fail to fully account for the prolonged prodromal phase or the early susceptibility of olfactory and limbic regions. Emerging evidence suggests chronic peripheral and mucosal infections may influence disease risk; however, mechanisms by which microbial activity outside the central nervous system contributes to persistent neuropathology remain poorly understood. This review explores the emerging concept that bacterial outer membrane vesicles act as mobile, lipid-rich vectors linking peripheral microbial reservoirs to neuroimmune and metabolic dysfunction in the aging brain. We discuss evidence suggesting vesicles originating from oral, olfactory, and upper airway niches can access the central nervous system via vascular routes and direct neural pathways, including olfactory and trigeminal nerves, where they influence glial and endothelial cell function. We also propose the Accumulative Vesicle Load Hypothesis, which describes how cumulative lifetime exposure to bacterial vesicles shapes disease onset, anatomical vulnerability, and progression, and incorporates components of other hypotheses proposed for Alzheimer's disease. This offers a system-level perspective for early diagnosis and upstream therapeutic strategies, including minimally invasive vesicle profiling in nasal fluid, saliva, blood, and cerebrospinal fluid. This work is a conceptual review that summarizes current evidence in a hierarchically organized manner and proposes a testable model; it does not assert causality where direct human evidence is currently limited.},
}

Humans
*Alzheimer Disease/metabolism/pathology
*Neuroinflammatory Diseases/metabolism/pathology
Animals
*Bacterial Outer Membrane/metabolism
Brain/metabolism/pathology

@article {pmid42041560,
year = {2026},
author = {Lee, BK and Yoo, JR and Jung, YS},
title = {Platelet-Derived Granules and Extracellular Vesicles in Neurodegenerative Diseases: Neurovascular Mechanisms and Clinical Implications.},
journal = {Cells},
volume = {15},
number = {8},
pages = {},
doi = {10.3390/cells15080692},
pmid = {42041560},
issn = {2073-4409},
support = {GRRCAjou2023-B01//GRRC program of Gyeonggi province, Republic of Korea/ ; },
mesh = {Humans ; *Extracellular Vesicles/metabolism ; *Blood Platelets/metabolism ; *Neurodegenerative Diseases/metabolism/pathology ; Animals ; *Cytoplasmic Granules/metabolism ; Alzheimer Disease/pathology/metabolism ; Platelet Activation ; Cell Communication ; },
abstract = {Platelets are increasingly recognized as multifunctional regulators that extend beyond hemostasis to actively engage in immunological regulation and neurovascular homeostasis. Platelets employ specialized secretory mechanisms, including granule-dependent release and extracellular vesicle (EV) shedding, to convey diverse bioactive mediators to vascular, immune, and neural cells. Growing evidence indicates that platelet-derived granules and EVs significantly influence the neurovascular unit, regulate inflammatory signaling, and modify neuronal function in both health and disease. In neurodegenerative disorders, particularly Alzheimer's disease (AD), accumulating evidence suggests that platelet activation may be increased in neurodegenerative conditions, including AD, although the extent and causality of this activation remain under investigation. This review delineates the secretory apparatus of platelets and their mechanistic functions in intercellular communication, underscores platelet contributions to AD and other neurological disorders, and explores novel clinical prospects for biomarker development and therapeutic targeting based on platelet-derived EVs.},
}

Humans
*Extracellular Vesicles/metabolism
*Blood Platelets/metabolism
*Neurodegenerative Diseases/metabolism/pathology
Animals
*Cytoplasmic Granules/metabolism
Alzheimer Disease/pathology/metabolism
Platelet Activation
Cell Communication

@article {pmid42041587,
year = {2026},
author = {Elias, A and Stern, S},
title = {Gene Editing Strategies for Neurological and Mental Disorders: Advances in Delivery, Methodology, and Clinical Translation.},
journal = {Cells},
volume = {15},
number = {8},
pages = {},
doi = {10.3390/cells15080720},
pmid = {42041587},
issn = {2073-4409},
mesh = {Humans ; *Gene Editing/methods ; *Nervous System Diseases/therapy/genetics ; *Mental Disorders/therapy/genetics ; *Genetic Therapy/methods ; Animals ; CRISPR-Cas Systems/genetics ; *Gene Transfer Techniques ; *Translational Research, Biomedical ; },
abstract = {Neurological and mental disorders are among the main causes of disability worldwide, affecting over three billion people and increasing the socioeconomic burden. Advances in molecular genetics and genome engineering have led to gene-targeted therapies that address root causes rather than just symptoms. This review covers current genome-editing tools, including CRISPR/Cas, base editing, and prime editing. The focus is on the benefits of gene editing in the central nervous system, where post-mitotic neurons allow lasting effects after a single treatment. It also discusses emerging delivery platforms such as viral vectors, nanoparticles, and exosome systems, as well as methods to bypass the blood-brain barrier. Recent clinical progress in spinal muscular atrophy, Parkinson's disease, Huntington's disease, and Alzheimer's disease is highlighted, with promising preclinical results for autism, bipolar disorder, epilepsy, and other neurogenetic conditions. The review concludes with regulatory issues, market trends, and ongoing clinical trials, underscoring the potential of gene therapies to transform disease management and provide long-term solutions.},
}

Humans
*Gene Editing/methods
*Nervous System Diseases/therapy/genetics
*Mental Disorders/therapy/genetics
*Genetic Therapy/methods
Animals
CRISPR-Cas Systems/genetics
*Gene Transfer Techniques
*Translational Research, Biomedical