@article {pmid41663779,
year = {2026},
author = {Roy, KK and Kumari, R and Upadhyay, AK and Mohanty, S},
title = {Tailoring treatments: pharmacogenomics in the management of neurodegenerative diseases.},
journal = {Acta neurologica Belgica},
volume = {},
number = {},
pages = {},
pmid = {41663779},
issn = {2240-2993},
abstract = {Neurodegenerative diseases like Alzheimer's, Parkinson's, Huntington's, and amyotrophic lateral sclerosis are growing more common worldwide, yet treatment is still poor. Conventional therapies can have unforeseen side effects, produce poor medication reactions, and take longer to work. This persistent treatment gap highlights the need for novel approaches to these disorders' complex distinctions. Pharmacogenomics, which examines how genetic differences affect drug response, is a promising new subject and an urgent solution. Pharmacogenomics tailors medicine selection and administration to each patient's genetic profile, addressing the main causes of poor treatment response and preventable side effects. This research has enabled precision medicine that can improve neurodegenerative disease therapy and reduce harm. In this in-depth research, we examine neurodegenerative disease management issues, pharmacogenomics breakthroughs, and how incorporating genetics to clinical practice can improve outcomes. We examine the latest evidence that genetics affect drug breakdown, efficacy, and toxicity. We also discuss the challenges and opportunities of applying this knowledge. Pharmacogenomic approaches must be widely applied to make medicines for these awful disorders safer, more effective, and really suited to patient needs, according to our compilation.},
}

@article {pmid41663727,
year = {2026},
author = {Pusparani, Y and Lin, CY and Jan, YK and Liau, BY and Lin, FY and Furqon, EN and Talal, M and Pravin, SC and Tsai, ZR and Lung, CW},
title = {Evaluation of deep learning models for segmentation of hippocampus volumes from MRI images in Alzheimer's disease.},
journal = {Scientific reports},
volume = {},
number = {},
pages = {},
doi = {10.1038/s41598-026-38220-4},
pmid = {41663727},
issn = {2045-2322},
support = {NSTC 114-2923-E-468-001-MY3//National Science and Technology Council of Taiwan/ ; },
}

@article {pmid41663665,
year = {2026},
author = {Kang, IK and Lee, S and Moon, TK and Han, AR and Yu, DB and Jung, M and Kwak, C and Seo, JK and Rhee, HW and Kim, SW and Woo, HN and Mun, JY and Lee, H},
title = {Proximity labeling unveils potential roles of the Miro2-CISD1 network in mitochondrial dynamics and neuronal differentiation.},
journal = {Communications biology},
volume = {9},
number = {1},
pages = {195},
pmid = {41663665},
issn = {2399-3642},
mesh = {*Mitochondrial Dynamics ; Animals ; *Neurogenesis ; *Neural Stem Cells/metabolism/cytology ; *Cell Differentiation ; Humans ; *rho GTP-Binding Proteins/metabolism/genetics ; Mitochondria/metabolism ; *Neurons/metabolism/cytology ; Hippocampus/cytology/metabolism ; Mice ; *Mitochondrial Proteins/metabolism/genetics ; },
abstract = {Adult hippocampal neurogenesis, crucial for maintaining neural homeostasis, is integral to neurodegeneration. We previously identified Miro2 as a key regulator of mitochondrial dynamics and survival in hippocampal neural stem cells with potential relevance to Alzheimer's disease. Here, using TurboID-based proximity labeling, we explore Miro2's interaction networks and identify sixty-six unique interactors specific to hippocampal neural stem cells. Functional enrichment analysis reveals that these proteins are crucial for mitochondrial organization, transport, and neurodegeneration. CISD1 emerges as a significant interaction partner. Knockdown of Miro2 and CISD1 impairs mitochondrial trafficking in adult hippocampal stem cells, disrupted stem cell differentiation with increased cytotoxicity. Rescue experiments partially reverse cell death, and both Miro2 and CISD1 show increased expression and interaction during differentiation. These findings suggest the Miro2-CISD1 axis as a critical regulator of mitochondrial remodeling and neurogenesis, providing a framework for future studies on how mitochondrial dynamics contribute to neurodegenerative disease mechanisms.},
}

*Mitochondrial Dynamics
Animals
*Neurogenesis
*Neural Stem Cells/metabolism/cytology
*Cell Differentiation
Humans
*rho GTP-Binding Proteins/metabolism/genetics
Mitochondria/metabolism
*Neurons/metabolism/cytology
Hippocampus/cytology/metabolism
Mice
*Mitochondrial Proteins/metabolism/genetics

@article {pmid41663048,
year = {2026},
author = {Zhou, J and Lee, DA and Talebi, Y and Wu, G and Wu, H},
title = {Risk of Dementia in Type 2 Diabetes Patients with Open-Angle Glaucoma: Insights from a Nationwide Real-World Cohort Study.},
journal = {American journal of ophthalmology},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.ajo.2026.02.003},
pmid = {41663048},
issn = {1879-1891},
abstract = {PURPOSE: To evaluate whether open-angle glaucoma (OAG) serves as a risk marker for subsequent dementia in patients with type 2 diabetes mellitus (T2DM), a population at elevated risk for both conditions.

DESIGN: Retrospective cohort study using longitudinal electronic health record (EHR) data.

PARTICIPANTS: A total of 1,580,368 adults with T2DM from the Merative™ Explorys® Therapeutic Dataset (2010-2022), including 12,405 patients diagnosed with OAG.

METHODS: OAG was treated as a time-dependent exposure in Cox proportional hazards models to account for variable onset timing relative to T2DM diagnosis. The primary outcome was the first recorded diagnosis of all-cause or subtype-specific dementia. Models were adjusted for demographic, clinical, behavioral, and ocular covariates. Kaplan-Meier and subtype-specific time-dependent Cox analyses were performed to evaluate crude and adjusted associations.

MAIN OUTCOME MEASURES: Hazard ratios for incident all-cause and subtype-specific dementia.

RESULTS: Compared to T2DM patients without OAG, those with OAG had significantly reduced dementia-free survival (log-rank p < 0.001). After covariate adjustment, OAG was associated with a 13% increased risk of all-cause dementia (HR = 1.13, 95% CI: 1.09-1.17). Subtype-specific analysis revealed elevated risks for vascular (HR = 1.37, 95% CI: 1.08-1.74) and frontotemporal dementia (HR = 1.39, 95% CI: 1.06-1.82), but no evidence of increased risk for Alzheimer's disease (HR = 0.63, 95% CI: 0.52-0.76). Stroke and depression were also strong independent risk factors.

CONCLUSIONS: In patients with T2DM, OAG was associated with an increased risk of non-Alzheimer's dementia, particularly vascular and frontotemporal types. These findings support the hypothesis of shared neurovascular mechanisms and highlight the potential of ophthalmic assessments for early dementia risk stratification in high-risk populations.},
}

@article {pmid41663025,
year = {2026},
author = {El-Sheekh, MM and Ramadan, NE and Elshikh, FM and R Youssef, F and Salem, JW and Sharaf, MT and Elmor, SH and Ali, SS},
title = {Smart alginate-based biomaterials for neurodegenerative disease therapy: Innovations in delivery, regeneration, and clinical translation.},
journal = {International journal of biological macromolecules},
volume = {},
number = {},
pages = {150688},
doi = {10.1016/j.ijbiomac.2026.150688},
pmid = {41663025},
issn = {1879-0003},
abstract = {Neurodegenerative diseases and central nervous system (CNS) injuries remain among the most challenging disorders to treat due to their complex pathophysiology, limited regenerative capacity, and the presence of the blood-brain barrier (BBB), which severely restricts therapeutic delivery. Despite extensive research efforts, most current interventions are palliative and fail to modify disease progression. Biomaterial-based strategies have emerged as promising adjuncts to conventional therapies, with alginate-based systems attracting increasing attention due to their biocompatibility, mild aqueous processing, and tunable physicochemical properties. This review critically examines the role of alginate-based biomaterials in CNS drug delivery, tissue engineering, and regenerative medicine, with particular emphasis on their ability to address key translational barriers, including BBB penetration, immune compatibility, and localized, sustained therapeutic release. We discuss how alginate can be engineered into nanoparticles, hydrogels, microspheres, and three-dimensional scaffolds to engage distinct transport mechanisms-such as receptor-mediated transcytosis, adsorptive-mediated uptake, and nose-to-brain delivery-while preserving the stability of labile bioactive cargos. Quantitative design parameters relevant to CNS applications, including stiffness ranges, degradation kinetics, and porosity, are highlighted to support rational material selection. Importantly, this review distinguishes between the structural and delivery functions of alginate as a carrier material and the biological effects mediated by encapsulated therapeutic agents, avoiding overstatement of alginate's intrinsic bioactivity. Disease-specific applications in Alzheimer's disease, Parkinson's disease, spinal cord injury, and brain tumors are discussed in a balanced manner, with clear differentiation between preclinical findings and clinically validated evidence. Current limitations related to mechanical robustness, batch-to-batch variability, and regulatory scalability are critically evaluated, alongside emerging solutions such as surface functionalization, hybrid biomaterials, and advanced fabrication strategies. Overall, this review provides a realistic and integrative framework for understanding the opportunities and constraints of alginate-based systems in CNS therapy, emphasizing that while alginate offers significant preclinical promise, substantial translational challenges remain before widespread clinical adoption can be achieved.},
}

@article {pmid41662806,
year = {2026},
author = {Zhang, H and Zhang, H and Zhao, M and Luo, W and Chen, S and Wang, P and Liu, X and Xu, S},
title = {Da-Bu-Yin-Wan rescues cognitive deficits in aging and Alzheimer's disease models by Wnt/β-catenin-dependent restoration of lysosomal acidification.},
journal = {Phytomedicine : international journal of phytotherapy and phytopharmacology},
volume = {153},
number = {},
pages = {157916},
doi = {10.1016/j.phymed.2026.157916},
pmid = {41662806},
issn = {1618-095X},
abstract = {BACKGROUND: Lysosomal acidification deficits are increasingly recognized as a convergent pathological mechanism driving both age-related cognitive decline (ARCD) and early Alzheimer's disease (AD) progression, creating a self-reinforcing cycle of cellular aging and Aβ dyshomeostasis. Despite demonstrated neuroprotective effects of Da-Bu-Yin-Wan (DBYW) in Parkinson's disease models, its therapeutic potential for lysosomal dysfunction in ARCD and AD remains an uncharted area of investigation.

PURPOSE: This present work aimed to elucidate the mechanistic basis by which DBYW mitigates both ARCD and AD pathology through functionally rescuing impaired lysosomal acidification.

METHODS: Cell-based D-galactose and Aβ-induced in BV2 cells to study lysosomal acidification. Molecular analyses combined immunofluorescence localization studies with quantitative immunoblotting of lysosomal and Wnt signaling proteins. In vivo, DBYW treatment effects were systematically evaluated in both D-gal-induced and APP/PS1 transgenic models using cognitive behavioral followed by immunohistochemical and biochemical assessment of brain tissues lysosomal parameters and Wnt signaling activity.

RESULTS: DBYW attenuated the mechanistic basis of ARCD and AD pathology by functionally rescuing impaired lysosomal acidification. Overexpression of β-catenin could modulate D-galactose or Aβ-induced dysregulation of the Wnt/β-catenin pathway and restore lysosomes with abnormal acidification, while DBYW could regulate lysosomal function by promoting Wnt/β-catenin signaling. In addition, in D-gal-induced aging and AD model mice, DBYW treatment activated Wnt/β-catenin signaling to restore lysosomal acidification, while spatial memory deficits in ARCD and AD models were improved, and pathology in mouse attenuation and APP/PS1 mouse brain tissue was inhibited.

CONCLUSION: DBYW shows a potential dual efficacy in improving cognitive decline in ARCD and AD models. It makes DBYW a promising disease-modifying intervention targeting the shared lysosomal pathophysiology of aging-associated neurodegeneration.},
}

@article {pmid41662789,
year = {2026},
author = {Mayeli, M and Matuskey, D and , },
title = {Social determinants of brain structure and cognition.},
journal = {Social science & medicine (1982)},
volume = {394},
number = {},
pages = {119045},
doi = {10.1016/j.socscimed.2026.119045},
pmid = {41662789},
issn = {1873-5347},
abstract = {BACKGROUND: Socioeconomic disadvantage is recognized as a risk factor for cognitive decline, yet its associated neural pathways remain unclear. We investigated whether neighborhood disadvantage, measured by the Area Deprivation Index (ADI), was associated with cognitive performance in older adults and patients with mild cognitive impairment (MCI) and Alzheimer's disease (AD), and whether structural brain differences explained this relationship.

METHODS: Participants included 822 older adults (478 cognitively unimpaired [CU], 271 with MCI, and 73 with AD). Associations between ADI, cognition, and brain structure were examined using regression models adjusting for age and sex. Mediation analyses tested whether total brain volume accounted for ADI-cognition relationships.

RESULTS: Higher ADI was associated with poorer cognitive performance across all domains in CU individuals (National ADI: memory β = -0.008, p < 0.001; executive function β = -0.005, p < 0.001; language β = -0.005, p < 0.001; visuospatial β = -0.004, p < 0.001) and across multiple domains in MCI (memory β = -0.007, p = 0.002; executive β = -0.007, p < 0.001). ADI was also associated with smaller total cerebral, gray, and white matter volumes in CU (State ADI and gray matter β = -2.37, FDR-p = 0.006) and greater white matter hyperintensity burden (β = 0.152, FDR-p = 0.009). Associations were weaker in MCI and absent in AD. Mediation analyses showed that total brain volume significantly mediated the effect of ADI on language performance (ACME p = 0.024; proportion mediated = 19.7 %, p = 0.036).

CONCLUSIONS: Neighborhood disadvantage is linked to widespread cognitive vulnerability and structural brain differences. However, brain volume explains only a small portion of these associations, suggesting that environmental and contextual factors shape cognitive performance through pathways that extend beyond structural neurodegeneration.},
}

@article {pmid41662521,
year = {2026},
author = {Boskovic, P and Shalita, R and Gao, W and Vernon, H and Deng, YL and Colonna, M and Majzner, RG and Amit, I and Kipnis, J},
title = {Engineering chimeric antigen receptor CD4 T cells for Alzheimer's disease.},
journal = {Proceedings of the National Academy of Sciences of the United States of America},
volume = {123},
number = {7},
pages = {e2530977123},
doi = {10.1073/pnas.2530977123},
pmid = {41662521},
issn = {1091-6490},
support = {R01AG078667//HHS | NIH | National Institute on Aging (NIA)/ ; R61AG090394//HHS | NIH | National Institute on Aging (NIA)/ ; no number//Carol and Gene Ludwig Family Foundation/ ; no number//Cure Alzheimer's Fund (CAF)/ ; no number//Fred and Ginger Haberle Charitable Fund at East Texas Communities Foundation/ ; },
mesh = {*Alzheimer Disease/therapy/immunology/pathology ; *CD4-Positive T-Lymphocytes/immunology/metabolism/transplantation ; Animals ; *Receptors, Chimeric Antigen/genetics/immunology/metabolism ; Mice ; Humans ; Amyloid beta-Peptides/metabolism/immunology ; *Immunotherapy, Adoptive/methods ; Disease Models, Animal ; Brain/pathology/immunology/metabolism ; },
abstract = {Alzheimer's disease (AD) is the prevailing cause of age-associated dementia worldwide. Current standard of care relies on antibody-based immunotherapy. However, antibody-based approaches carry risks for patients, and their effects on cognition are marginal. Increasing evidence suggests that T cells contribute to AD onset and progression. Unlike the cytotoxic effects of CD8[+] cells, CD4[+] T cells capable of regulating inflammation show promise in reducing pathology and improving cognitive outcomes in mouse models of AD and in aging. Here, we sought to exploit the beneficial properties of CD4[+] T cells while circumventing the need for TCR and peptide-MHC antigen discovery, thereby providing a potential universal therapeutic approach. To achieve this, we engineered CD4[+] T cells with chimeric antigen receptors (CARs) targeting fibrillar forms of aggregated amyloid-β. Our findings demonstrate that optimized CAR-T cells can alter amyloid deposition in the dura and reduce parenchymal pathology in the brain. Furthermore, we observed that CAR-T treatment promotes the expansion and recruitment of endogenous CD4[+] T cells into the brain parenchyma and leptomeninges. In summary, we established the feasibility of amyloid plaque-specific CAR-T cells as a potential therapeutic avenue for AD. These findings highlight the potential of CD4[+] CAR-T therapy not only to modify amyloid pathology but also to reshape the immune landscape of the CNS, paving the way for future development of cellular immunotherapies for neurodegenerative disease.},
}

*Alzheimer Disease/therapy/immunology/pathology
*CD4-Positive T-Lymphocytes/immunology/metabolism/transplantation
Animals
*Receptors, Chimeric Antigen/genetics/immunology/metabolism
Mice
Humans
Amyloid beta-Peptides/metabolism/immunology
*Immunotherapy, Adoptive/methods
Disease Models, Animal
Brain/pathology/immunology/metabolism

@article {pmid41662056,
year = {2025},
author = {Mondragón Bohórquez, SP and Gutiérrez-López, C},
title = {Scope of anti-stigma programs against Alzheimer's disease: A scoping review.},
journal = {PLOS mental health},
volume = {2},
number = {8},
pages = {e0000406},
doi = {10.1371/journal.pmen.0000406},
pmid = {41662056},
issn = {2837-8156},
abstract = {This study identifies and reports evidence related to key guidelines for intervention programs aimed at reducing social stigma associated with Alzheimer's Disease. This scoping review followed the methodology of the Joanna Briggs Institute. The databases searched included: SCOPUS, PubMED, Science Direct, Taylor and Francis, Google Scholar, JBI, Prospero, and Cochrane Library. The STROBE statement was used to organize and draft the protocol. Of the 2275 initial studies, 22 articles were identified for the analysis of emerging categories: social stigma assessment, measurement, and intervention strategies. Of the 2275 initial studies, 22 articles were analysed for the purpose of identifying emerging categories: social stigma assessment, measurement and intervention strategies. Programmes against stigma addressed the following aspects: clinical and epidemiological knowledge and information; emotions, care and impact on patients' lives; general information on the disease; dementia-friendly communities; a multimedia campaign on stigmatising beliefs; digital platforms; support in the arts; knowledge and clinical aspects; bilingual presentations adapted to the culture; and awareness and knowledge about Alzheimer's disease. The most common strategies were: patient and intergenerational contact, life stories [vignettes], theatre, music, art, adapting content for culture, curriculum work, discussion groups and health education. The evidence suggests that the content of educational programs and interventions should focus on promoting understanding of the disease, working with groups or peers with the same condition, and generating intergenerational contact, affectionate bonds, and emotional expression to reduce social stigma.},
}

@article {pmid41661849,
year = {2025},
author = {Braun, LD and Allen, HR and Beyl, RA and Keller, JN},
title = {A case-controlled study investigating gender differences in Face Name Hobby Recall (FNHR) performance in healthy community-dwelling older adults.},
journal = {PLOS mental health},
volume = {2},
number = {3},
pages = {e0000244},
doi = {10.1371/journal.pmen.0000244},
pmid = {41661849},
issn = {2837-8156},
abstract = {Difficulties remembering the faces and the names of individuals are two of the most common memory complaints among older adults (OA's), with impaired performance on face-name recall tests implicated to be one of the earliest changes during the transition to Alzheimer's disease. Studies in children, young-, and middle-aged adults have identified that females generally perform better on face-name association tests than males, although little is known in terms of female versus male performance in OA's. Studies in these same age groups have identified the existence of a "gender bias" whereby face-name recall is improved when facial images are from the same sex as the individual being evaluated. In the current study we employed a case-controlled study design to evaluate 115 OA males and 115 OA females in terms of their performance on the Face Name Hobby Recall (FNHR) test. OA females were observed to have significantly higher levels of both immediate and delayed recall on the FHNR test as compared to males. Improved FNHR test performance by females persisted for up to 12-months in the subset of 21 males and 21 females in the study for whom longitudinal data was available. The rates of learning for names and hobbies did not significantly differ between OA males and females. OA males and females did not exhibit improved FNHR test performance for facial images of their same sex, although OA males did show improved FHNR test performance with female faces as compared to male faces. Data from the current study have implications for future studies that examine the causes and consequences of perturbations in face-name recall in the context of aging and dementia-related research.},
}

@article {pmid41661585,
year = {2026},
author = {Chin, NA and Erickson, CM and Widera, E},
title = {Importance of Function for Alzheimer Diagnosis and Management-More Than Memory.},
journal = {JAMA internal medicine},
volume = {},
number = {},
pages = {},
doi = {10.1001/jamainternmed.2025.7621},
pmid = {41661585},
issn = {2168-6114},
}

@article {pmid41661364,
year = {2026},
author = {Li, L and Kong, J and Fan, R and Yuan, Y and Zhu, L},
title = {Correction: Role of tRNA-Derived Fragments and Their Modifications in the Pathogenesis and Treatment of Alzheimer's Disease.},
journal = {Molecular neurobiology},
volume = {63},
number = {1},
pages = {429},
doi = {10.1007/s12035-026-05713-2},
pmid = {41661364},
issn = {1559-1182},
}

@article {pmid41661222,
year = {2026},
author = {Daly, T and Imbimbo, BP},
title = {Tau Phosphorylation as an Adaptive Physiological Response: Implications for the Therapy of Tauopathies.},
journal = {FASEB journal : official publication of the Federation of American Societies for Experimental Biology},
volume = {40},
number = {4},
pages = {e71538},
doi = {10.1096/fj.202503803R},
pmid = {41661222},
issn = {1530-6860},
support = {//N/A./ ; },
mesh = {Humans ; *tau Proteins/metabolism ; *Tauopathies/metabolism/therapy ; Phosphorylation ; Animals ; *Adaptation, Physiological ; Alzheimer Disease/metabolism ; },
abstract = {Recent evidence demonstrates that tau phosphorylation, traditionally viewed as a hallmark of neurodegeneration, also occurs in completely reversible physiological contexts such as mammalian hibernation and human neonatal development. These findings challenge the classical protein-centric "proteinopathy" model of Alzheimer's disease (AD) and other tauopathies. Instead, we propose that phosphorylated tau (p-tau) functions as an adaptive molecular response to metabolic or neuronal activity shifts, and that tauopathies such as AD represent a failure of broader mechanisms that normally restore tau protein homeostasis. Therapeutic strategies should focus on restoring tau protein homeostasis and functionality rather than simply removing phosphorylated species. To achieve this, we discuss one possible therapeutic strategy: dismantling aggregated tau species.},
}

Humans
*tau Proteins/metabolism
*Tauopathies/metabolism/therapy
Phosphorylation
Animals
*Adaptation, Physiological
Alzheimer Disease/metabolism

@article {pmid41661194,
year = {2026},
author = {Talucci, I and Leske, T and Klafki, HW and Hassan, MM and Steiert, A and Morgado, B and Bothe, S and van Werven, L and Liepold, T and Walter, J and Schindelin, H and Wiltfang, J and Wirths, O and Jahn, O and Maric, HM},
title = {Aggregation-dependent epitope sequence and modification fingerprints of anti-Aβ antibodies.},
journal = {eLife},
volume = {14},
number = {},
pages = {},
doi = {10.7554/eLife.106156},
pmid = {41661194},
issn = {2050-084X},
support = {AFN419//Interdisziplinäres Zentrum für Klinische Forschung, Universitätsklinikum Würzburg/ ; MA6957/1-1//Deutsche Forschungsgemeinschaft/ ; IT//Graduate School of Life Sciences, Julius-Maximilians-Universität Würzburg/ ; WI3472/11-1//Deutsche Forschungsgemeinschaft/ ; RTG2824/OW//Deutsche Forschungsgemeinschaft/ ; WA1477/6-6//Deutsche Forschungsgemeinschaft/ ; RTG2824/MMH1//Deutsche Forschungsgemeinschaft/ ; },
mesh = {*Amyloid beta-Peptides/immunology/chemistry/metabolism/genetics ; Humans ; *Epitopes/immunology/chemistry ; *Antibodies, Monoclonal/metabolism ; Alzheimer Disease/drug therapy ; Antibodies, Monoclonal, Humanized/metabolism ; Protein Processing, Post-Translational ; Protein Binding ; },
abstract = {A hallmark of Alzheimer's disease (AD), the most common form of dementia, is the progressive accumulation of amyloid-beta (Aβ) peptides across distinct brain regions. Anti-Aβ antibodies (Aβ-Abs) targeting specific Aβ variants are essential tools for AD research, diagnostics, and therapy. The monoclonal antibodies Aducanumab, Lecanemab, and Donanemab have recently been approved as the first disease-modifying treatments for early AD, highlighting the clinical importance of their exact binding profiles. In this study, we systematically characterized the binding and modification requirements of 20 Aβ-Abs, including biosimilars of Aducanumab, Lecanemab, and Donanemab, across monomeric, oligomeric, and aggregated Aβ forms. Array-based analysis of 20,000 modified Aβ peptides defined binding epitopes at single-residue resolution and revealed the impact of sequence variation, including familial AD mutations, as well as diverse post-translational modifications (PTMs). Notably, genetic variants, such as H6R, impaired binding of therapeutic Aβ-Abs like Aducanumab. Donanemab showed strong preference for pyroglutamate-modified AβpE3-17, while Lecanemab and Aducanumab exhibited aggregation- and sequence-context-dependent binding requirements. Comparison of peptide binding profiles with binding of full-length and aggregated Aβ via immunoprecipitation-mass spectrometry, capillary immunoassays, Western blotting, and immunohistochemistry on AD brain tissue revealed distinct aggregation-dependent binding behaviours. The valency- and context-dependence of Aducanumab binding, together with its preference for Ser8-phosphorylated Aβ, supports a dimerization-mediated binding mechanism. For Lecanemab, our data suggest that additional structural contributions beyond the minimal N-terminal epitope are required for binding to aggregated Aβ, which remain to be fully resolved. Together, this work provides the most comprehensive dataset to date on aggregation-dependent sequence and modification selectivity of Aβ-Abs. By integrating mutational, PTM, and aggregation contexts in a unified experimental framework, we establish a resource that enables rational selection of antibodies for research and diagnostic applications and offers mechanistic insights that may inform the design and optimization of future therapeutic antibodies in AD.},
}

*Amyloid beta-Peptides/immunology/chemistry/metabolism/genetics
Humans
*Epitopes/immunology/chemistry
*Antibodies, Monoclonal/metabolism
Alzheimer Disease/drug therapy
Antibodies, Monoclonal, Humanized/metabolism
Protein Processing, Post-Translational
Protein Binding

@article {pmid41661182,
year = {2026},
author = {Teng, S and Ma, J and Wang, X and Jiang, P and Li, Y},
title = {The clinical significance of miR-484 in depression of older people with Alzheimer's disease and its potential role on depressive behavior.},
journal = {Psychiatric genetics},
volume = {},
number = {},
pages = {},
doi = {10.1097/YPG.0000000000000411},
pmid = {41661182},
issn = {1473-5873},
abstract = {OBJECTIVE: MicroRNAs exhibit remarkable potential as biomarkers due to their multiple advantages in Alzheimer's disease (AD). This study aimed to explore the significance of miR-484 in AD.

METHODS: The study included 216 participants [70 healthy controls (HCs), 77 AD with nondepression, 69 AD with depression (AD-D)]. PCR measured serum and tissue miR-484 levels. Receiver operator characteristic curves evaluated miR-484 diagnostic potential for AD/AD-D. Logistic regression identified AD-D risk factors. Bioinformatics predicted miR-484 targets and functional pathways. Dual-luciferase assay validated the interaction between miR-484 and platelet derived growth factor subunit A (PDGFA). Chronic restraint stress (CRS) induced depression animal model by Kunming mice (20 each group × 6 groups). The effect of miR-484/PDGFA axis on depression-like behaviors was evaluated through behavioral tests (sucrose preference, forced swim, and open field).

RESULTS: Serum miR-484 was downregulated in AD and further decreased in AD-D compared with HCs. MiR-484 downregulation diagnosed AD-D from AD. MiR-484 expression was correlated with amyloid β-protein 1-42 (r = 0.682), total tau (r = -0.575), Mini-Mental State Examination score (r = 0.593), and Hamilton depression rating scale score (r = -0.709). MiR-484 was a risk factor for depression in AD. In the depression mouse model, miR-484 overexpression ameliorated depression-like behaviors (sucrose preference, forced swim immobility time, locomotor activity) by regulating PDGFA.

CONCLUSION: Downregulated miR-484 expression, correlating with cognitive function and depression degree, showed a diagnostic value on AD and AD-D. MiR-484 attenuated the CRS-induced depression-like behavior by regulating PDGFA.},
}

@article {pmid41661021,
year = {2026},
author = {Pervushina, EV and Kutlubaev, MA and Kuznetsova, DR and Karimova, GI and Kachemaeva, OV and Mkhitaryan, EA},
title = {[Combination of amyotrophic lateral sclerosis with Alzheimer's disease].},
journal = {Zhurnal nevrologii i psikhiatrii imeni S.S. Korsakova},
volume = {126},
number = {1},
pages = {132-136},
doi = {10.17116/jnevro2026126011132},
pmid = {41661021},
issn = {1997-7298},
mesh = {Humans ; *Amyotrophic Lateral Sclerosis/complications/diagnosis ; *Alzheimer Disease/complications/diagnosis ; Male ; Aged ; Female ; Middle Aged ; },
abstract = {The combination of amyotrophic lateral sclerosis (ALS) with Alzheimer's disease is rare. Currently, it is unclear whether such comorbidity is an accidental coincidence or a manifestation of a specific pathological process. A case of simultaneous occurrence of classic symptoms of the bulbar form of ALS and Alzheimer's disease is presented. The possible mechanisms of the combination of two diseases are analyzed.},
}

Humans
*Amyotrophic Lateral Sclerosis/complications/diagnosis
*Alzheimer Disease/complications/diagnosis
Male
Aged
Female
Middle Aged

@article {pmid41661003,
year = {2026},
author = {Sayfitdinkhuzhaev, ZF and Zhukova, NG and Nasyrova, RF and Gaponova, OV and Zhukova, IA and Masenko, AY and Baydanova, AN},
title = {[Pathophysiological and neurobiological basis for the development of depression in patients with Parkinson's disease].},
journal = {Zhurnal nevrologii i psikhiatrii imeni S.S. Korsakova},
volume = {126},
number = {1},
pages = {7-12},
doi = {10.17116/jnevro20261260117},
pmid = {41661003},
issn = {1997-7298},
mesh = {Humans ; *Parkinson Disease/physiopathology/complications/psychology ; *Depression/etiology/physiopathology ; Serotonin/deficiency/metabolism ; Dopamine/deficiency/metabolism ; Substantia Nigra/physiopathology/metabolism ; Locus Coeruleus/physiopathology/metabolism ; Raphe Nuclei/physiopathology/metabolism ; Norepinephrine/deficiency/metabolism ; },
abstract = {Parkinson's disease (PD) is one of the most common neurodegenerative diseases, second only to Alzheimer's disease. PD is characterized by multisystemic lesions and steady progression of the pathological process, which inevitably leads to the occurrence of various symptoms. PD symptoms are divided into motor and non-motor. It is generally accepted that non-motor symptoms precede motor ones and appear several decades before motor symptoms. The most common non-motor symptom of PD is depression, which significantly reduces patients' quality of life. The review addresses recent studies of the pathophysiology of depression in PD patients. The analysis showed the involvement of the substantia nigra, the raphe nuclei, and the locus ceruleus in the development of depression in PD patients. The molecular basis of their dysfunction is a deficiency of dopamine, serotonin, and norepinephrine. A detailed study of the neurobiological mechanisms of the development and progression of depression will create highly effective and pathogenetically based therapeutic areas.},
}

Humans
*Parkinson Disease/physiopathology/complications/psychology
*Depression/etiology/physiopathology
Serotonin/deficiency/metabolism
Dopamine/deficiency/metabolism
Substantia Nigra/physiopathology/metabolism
Locus Coeruleus/physiopathology/metabolism
Raphe Nuclei/physiopathology/metabolism
Norepinephrine/deficiency/metabolism

@article {pmid41660967,
year = {2026},
author = {Elugbadebo, O and Farombi, T and Arulogun, O and Nichols, M and Ogunronbi, M and Olawuyi, C and Simbine, AC and Mkubila, A and Adeleye, O and Olujobi, D and Olorunsogbon, OF and Ojo, O and Adeniyi, S and Moses, A and Oguike, W and Olajire, K and Towolawi, B and Oyinlola, O and Mandy, I and Ogunde, G and Bakor, N and Asibey, SO and Laryea, R and Akinyemi, JO and Rheem, N and Dinku, T and Andrea, D and Njamnshi, K and Akinwande, K and Ogbole, GI and Damasceno, A and Bello, A and Wahab, K and Musyimi, C and Ndetei, D and Nwani, P and Mutiso, V and Njamnshi, WY and Obiako, R and Olowoyo, P and Zewde, YZ and Ayele, BA and Okubadejo, N and Osaigbovo, G and Okereke, C and Sarfo, F and Akpalu, A and Kamada, L and Ogundele, AT and Njamnshi, AK and Iwuozo, E and Adoukonou, T and Paddick, SM and Nwazor, EO and Osemwegie, N and Adebusoye, LA and Olowookere, OO and Ikanga, J and Guerchet, M and Griswold, AJ and Seshadri, S and Caban-Holt, A and Baiyewu, O and Vance, J and Owolabi, M and Byrd, G and Walker, R and Cucarro, M and Kalaria, R and Ogunniyi, A and Pericak-Vance, M and Akinyemi, R},
title = {Recruiting and retaining persons with suspected Alzheimer's disease and related dementias for genetic studies in selected African countries: Lived realities of researchers.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261416066},
doi = {10.1177/13872877261416066},
pmid = {41660967},
issn = {1875-8908},
abstract = {BackgroundGenomic research in dementia in Africa is of utmost importance based on recent reports from studies on African-Americans that the African ancestral gene is associated with a lower risk effect for developing AD. However, dementia-related genetic studies are still evolving in sub-Saharan Africa, with unique challenges influencing participant recruitment.ObjectiveThis study sought to identify key challenges of recruitment and retention how they were mitigated in the READD-ADSP Africa and 'Origins of AD in African ancestry' genetic studies.MethodsA qualitative narrative research design using in-depth interviews explored the challenges of recruiting participants and how these were managed by the nineteen stakeholders involved in the recruitment process from nine African countries participating in the African Dementia Consortium. An inductive thematic analysis was applied to code and analyze the data systematically.ResultsNineteen stakeholders from nine African countries, participating in READD-ADSP and 'Origins' studies were interviewed. Similar challenges were observed across most African countries, including the non-existing national dementia registry. Other challenges include language diversity, myths around blood collection, family dynamics, stigma, logistics, unmet expectations concerning incentives, fewer older controls and data privacy. Leveraging previous research programs, existing community engagement activities and client-doctor relationships were strategies used in addressing these challenges.ConclusionsThere are some unique challenges with recruiting and retaining participants in genetic studies in Africa. Strengthening community engagement and advocacy for genomic research, alongside a well-populated dementia registry in the African Dementia Consortium, could overcome these challenges and improve participant recruitment in genetic studies.},
}

@article {pmid41660965,
year = {2026},
author = {Libon, DJ and Swenson, R and Tobyne, S and Emrani, S and Salciunas, L and Brown, AJ and Ginsberg, T and Kling, M and Overbeck, K and Powell, L and White, C and Okoli-Umeweni, A and Janson, C and Scheinthal, S},
title = {Digital neuropsychological assessment-Part 2: Relations with cardiovascular risk and informant ratings of neurocognitive decline, functional disabilities, and psychiatric symptoms.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261418287},
doi = {10.1177/13872877261418287},
pmid = {41660965},
issn = {1875-8908},
abstract = {BackgroundThe Digital Assessment of Cognition (DAC) is a brief, 7-minute iPad administered-scored neuropsychological protocol.ObjectiveThe current research sought to investigate relationships between DAC test results and family ratings for neurocognitive decline; instrumental activities of daily living (IADL) impairment; psychiatric symptoms, and physician-determined cardiovascular risks.Methods179 memory clinic patients were assessed. Family members rated the severity of neurocognitive impairment, IADL decline, and psychiatric symptoms using the Everyday Cognition Scales (ECog); the Functional Assessment Questionnaire (FAQ); the Instrumental Activities of Daily Living-Compensation Scale (IADL-C); and the Neuropsychiatric Inventory (NPI), respectively. An index measuring cardiovascular risk was extracted from medical records.ResultsPartial correlations controlled for age, education, and sex found that greater functional disability and elevated cardiovascular risks were associated with lower DAC memory and executive index scores. Lower DAC memory scores were seen in relation to family ratings suggesting impaired Ecog Episodic Memory difficulty; relatively intact ECog Executive/Attention ability; and impaired IADL-C Memory/Self-Management difficulty. By contrast, lower DAC executive performance was seen in relation to family ratings suggesting impaired Ecog Executive/Planning difficulty and IADL-C Social Skills difficulty. Lower DAC-executive index scores were also associated with greater informant rated apathy.ConclusionsThe relations between DAC index scores and total informant FAQ and IADL-scores; Ecog and IADL-C subscales; and selected NPI-defined psychiatric problems suggest that the DAC is both sensitive to gross IADL decline, and specific to differing ECog and IADL-C and psychiatric problems. Combining digital assessment with family IADL ratings could help with clinical decision-making.},
}

@article {pmid41660964,
year = {2026},
author = {Aiello, EN and Luca, G and Moreschi, A and Curti, B and Cazzini, F and Cerri, A and Saba, S and Patisso, V and Maranzano, A and Silani, V and Ticozzi, N and Poletti, B and Verde, F},
title = {The yes-no reversal phenomenon: Prevalence and correlates in mild cognitive impairment and dementia due to neurodegenerative, chronic cerebrovascular, and mixed etiologies.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261418686},
doi = {10.1177/13872877261418686},
pmid = {41660964},
issn = {1875-8908},
abstract = {BackgroundThe yes-no reversal (YNR) phenomenon consists in a patient saying "yes" when meaning "no", or vice-versa.ObjectiveTo investigate the prevalence of the YNR phenomenon in mild cognitive impairment (MCI) and dementia across different neurodegenerative, chronic cerebrovascular, or mixed etiologies, and to explore its demographic and clinical correlates.MethodsInformants of N = 267 patients with MCI or dementia due to possible/probable Alzheimer's disease (AD; N = 164), frontotemporal lobar degeneration (N = 25), Lewy body disease (N = 18), mixed-i.e., AD and chronic cerebrovascular-etiologies (N = 37), Aβ-negative degenerative etiologies (N = 6), and chronic cerebrovascular disease (N = 17) were inquired on the occurrence of YNRs in everyday-life conversations. YNR+ and YNR- patients were compared on demographics (i.e., age, sex, education), disease duration (in months), disease severity (i.e., MCI versus dementia), etiology and total and subscale-/item-level Mini-Mental State Examination (MMSE) scores. A multiple logistic model was also run on the presence/absence of YNRs by addressing, as predictors, variables that yielded significance at an univariable level.ResultsThe YNR phenomenon was recorded in 23 patients (8.61%), all of them being demented (i.e., no MCI patient showed YNRs). YNR+ patients were younger and scored lower on Immediate recall and Language subscores of the MMSE. The prevalence of YNRs was higher in non-AD- (∼18%) versus AD-related (∼5%) etiologies. The effects of disease severity and etiology were confirmed by the multiple logistic model, while the others were not.ConclusionsThe YNR phenomenon is a clinical sign possibly associated with dementia due to non-AD etiologies.},
}

@article {pmid41660958,
year = {2026},
author = {Kadamangudi, S and Sanchez-Sanchez, L and Limon, A and Taglialatela, G},
title = {Regional correlates of tau pathology and synaptic function in primary age-related tauopathy.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261416524},
doi = {10.1177/13872877261416524},
pmid = {41660958},
issn = {1875-8908},
abstract = {BackgroundEmerging studies implicate the microtubule-associated protein tau as a key modulator of neuronal excitability and synaptic dysfunction in human tauopathies. How distinct tau forms influence synaptic excitability across brain regions with differing susceptibility to tau accumulation remains unclear. Primary age-related tauopathy (PART), defined by hippocampal-restricted tau pathology in the absence of amyloid-β, offers a tractable model to investigate tau-specific effects on synaptic physiology.ObjectiveTo determine how regionally enriched tau species in PART relate to synaptic excitation-inhibition balance and to identify molecular pathways linking tau oligomers to synaptic dysfunction.MethodsAutopsy-derived hippocampal and superior middle temporal gyrus tissues from neuropathologically validated PART specimens were analyzed. Tau species, including monomers, oligomers, and paired helical filaments (PHFs), were quantified by western blot. Synaptic function was assessed by microtransplantation of synaptosomal membranes into Xenopus laevis oocytes, followed by electrophysiological recordings of glutamatergic (kainate-evoked AMPAR) and GABAergic (GABAAR) currents to calculate the synaptic excitation-to-inhibition (sE/I) ratio. Proteomic and enrichment analyses of brain-derived tau oligomer (BDTO) interactomes from PART hippocampi were performed.ResultsPART specimens showed hippocampal accumulation of aggregation-prone tau assemblies (oligomeric and PHF-tau) that were negatively correlated with sE/I. Proteins within the BDTO interactome linked to reduced sE/I were enriched for pathways related to vesicle-mediated transport, synaptic endocytosis, and neurotransmitter receptor regulation.ConclusionsIn PART, oligomeric and fibrillar tau are associated with shift toward synaptic inhibition, predominantly within the hippocampus. Proteomic correlates implicate vesicle trafficking pathways as mediators of tau oligomer-associated alterations in synaptic function, providing mechanistic insight into early-stage tauopathy.},
}

@article {pmid41660956,
year = {2026},
author = {Cotelli, MS and Bracca, V and Fasolato, D and Geviti, A and Antonella, A and Cagnin, A and Borroni, B},
title = {Repetitive behaviors in syndromes associated with frontotemporal lobar degeneration.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261418302},
doi = {10.1177/13872877261418302},
pmid = {41660956},
issn = {1875-8908},
abstract = {BackgroundRepetitive behaviors (RB) are purposeless movements, speech, or routines performed without self-awareness or conscious intent.ObjectiveThe present study aims to investigate the prevalence and longitudinal changes of RB and to assess these symptoms in a large cohort of patients with frontotemporal lobar degeneration (FTLD)-associated syndromes using a newly developed caregiver-based questionnaire.MethodsThis was a longitudinal cohort study conducted in tertiary frontotemporal dementia research clinics. A total of 210 FTLD patients were included, 68 of whom had follow-up evaluation. RB were assessed through structured caregiver interviews. Compulsive/impulsive behaviors, stereotypies, and ritualistic behaviors were recorded. Univariate and multiple generalized linear models and generalized linear mixed models were used to estimate predictors and longitudinal changes associated with RB.ResultsRB were reported in 71% of patients, showing a progressive increase from the prodromal to moderate dementia stages. Notably, 30% of patients presented RB since the disease onset phase, especially in the form of compulsive/impulsive behaviors. Predictors included male gender, the behavioral variant of frontotemporal dementia and the semantic variant of primary progressive aphasia phenotypes, and higher scores on Frontal Behavioral Inventory scale, part B. A significant increase in total RB was observed in patients reassessed at 8 to 22 months follow-up from baseline (p = 0.0001), especially in the form of stereotypies and ritualistic behaviors.ConclusionsThe questionnaire developed in this study effectively captures the prevalence and progression of RB. It could contribute to the standardization of the behavioral assessment in FTLD clinical trials and, consequently, to a deeper understanding of these syndromes.},
}

@article {pmid41660954,
year = {2026},
author = {Libon, DJ and Drabick, D and Swenson, R and Tobyne, S and Emrani, S and Bezdicek, O and Salciunas, L and Brown, AJ and Ginsberg, T and Kling, M and Overbeck, K and Powell, L and White, C and Okoli-Umeweni, A and Janson, C and Scheinthal, S},
title = {Digital neuropsychological assessment-part 1: Defining mild cognitive impairment subtypes.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261418280},
doi = {10.1177/13872877261418280},
pmid = {41660954},
issn = {1875-8908},
abstract = {BackgroundIn prior research, the Digital Assessment of Cognition (DAC), a brief digitally administered neuropsychological protocol that assesses verbal episodic memory, verbal working memory, and language, has been used to classify a small sample of memory clinic patients (n = 77) into four meaningful clinical groups.ObjectiveThe current research sought to extend these findings with a considerably larger sample.MethodsThe DAC was administered to 179 ambulatory care/memory clinic patients (45.30% female; 91.10% Caucasian). A comprehensive analysis of DAC core outcome measures and behavior reflecting process/errors was undertaken. Traditional paper/pencil assessment was also obtained. Using Jak, Bondi criteria (2009), paper/pencil test results classified patients into five groups: cognitively unimpaired (CU; n = 74), subtle cognitive impairment (SCI; n = 21), amnestic mild cognitive impairment (aMCI; n = 21), combined dysexecutive/mixed MCI (dys/mxMCI; n = 22), and mild dementia (n = 41).ResultsThe aMCI group presented with many of the classic features consistent with amnesia, i.e., rapid forgetting, reduced free recall clustering, and profligate responding to recognition foils. Latency for correct recognition responding was slower for aMCI compared to the CU group and appears to be associated with a neurocognitive network measuring both memory and language-related operations. SCI and dys/mxMCI groups tended to produce more perseverations on working memory test trials; and produced lower scores on DAC executive outcome measures that assessed auditory span and semantic fluency.ConclusionsThese findings support the criterion and construct validity of the DAC. When brought to scale the DAC could be an effective tool to assess for emergent MCI and dementia syndromes.},
}

@article {pmid41660940,
year = {2026},
author = {Dorfsman, DA and Cai, D and Hamilton-Nelson, KL and Adams, LD and Mena, PR and Rodriguez, VC and Sanchez, JJ and Valladares, GS and Lopez, M and Whitehead, PL and Prough, MB and Manrique, P and Martinez, A and Mas, SM and Scaramutti, C and Acosta, H and Silva-Vergara, C and McInerney, K and Griswold, AJ and Feliciano-Astacio, BE and Cuccaro, ML and Kunkle, BW and Reitz, C and Tosto, G and Bush, WS and Haines, JL and Akinyemi, JO and Akinyemi, RO and Ogunniyi, A and Byrd, GS and Vance, JM and Celis, K and Seixas, A and Pericak-Vance, MA and Rajabli, F},
title = {Educational attainment is associated with reduced functional decline in Puerto Ricans with elevated pTau181.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261415933},
doi = {10.1177/13872877261415933},
pmid = {41660940},
issn = {1875-8908},
abstract = {BackgroundEducation promotes cognitive reserve (CR), potentially buffering Alzheimer's disease pathology (ADP). However, the education-CR relationship may differ by population and genetic background.ObjectiveTo examine education, APOE ε4, and functional scores in a Puerto Rican (PR) cohort with varying plasma pTau181, an ADP biomarker.MethodsA subset of 514 PR older adults with "high" (>mean+1SD) or "low" pTau181 ( 0) and (2) severity among impaired participants, adjusting for age and sex.ResultsHigh EA was associated with better CDR-FUNC than low EA within the high pTau181 group (n = 80; MedianLow_EA = 7, MedianHigh_EA = 0; p = 0.011). The hurdle model similarly showed that each additional year of education reduced the odds of any functional impairment in the high-pTau181 group (OR = 0.89, 95% CI [0.79-0.99]). No significant education × APOE ε4 interaction was observed, though a negative trend suggested that increasing education attenuated ε4-related impairment.ConclusionsGreater education is linked to functional preservation in PR older adults, particularly in those with elevated ADP, suggesting potential CR-mediated resilience. APOE ε4 may worsen outcomes with decreasing education, suggesting both educational and genetic factors should inform strategies to mitigate cognitive decline globally.},
}

@article {pmid41660761,
year = {2026},
author = {D'Sa, A and Crutzen, R and Bödenler, M and Diaz, A and Hanke, S and Hilberger, H and Thunborg, C and Mangialasche, F and Bruinsma, J},
title = {Socioeconomic differences in dementia risk, lifestyle, and relevant determinants of behavior.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877251414376},
doi = {10.1177/13872877251414376},
pmid = {41660761},
issn = {1875-8908},
abstract = {BackgroundA healthy lifestyle supports cognitive aging while reducing dementia risk. Multidomain interventions promote healthy behavior, but are often unsuccessful in reaching those with a low socio-economic position (SEP), who face additional challenges with changing behavior.ObjectiveThis cross-sectional study explores differences between SEP-groups in dementia risk, lifestyle, and the socio-cognitive determinants of behavior.Methods3,341 Dutch adults (aged 40-79) were divided into low, medium, or high SEP groups. Using Chi-squared tests and ANOVA, SEP-related differences were explored for dementia risk, lifestyle behaviors, and health conditions. SEP-related differences in socio-cognitive determinants were examined using a modified version of Confidence Interval-Based Estimation of Relevance (CIBER).ResultsParticipants in the low SEP group had a significantly higher prevalence of all health conditions and engaged in more unhealthy behaviors, translating into a significantly higher dementia risk score. Many had misperceptions about the room for lifestyle improvement, but those in the low SEP group were slightly more aware of not adhering to lifestyle recommendations. Additionally, they perceived less self-confidence towards engaging in sports, considered healthy food as more expensive, perceived alcohol less pleasurable, experienced habits as less influential on alcohol intake, and had less confidence in their ability to quit smoking while pleasure and habits were strongly associated with smoking.ConclusionsAdults with a low SEP are at higher risk for dementia and have more potential for lifestyle-based risk reduction. Tailored, co-designed interventions that also consider the broader environment are needed to enhance perceived behavioral control, support behavior change, and reduce inequalities in dementia.},
}

@article {pmid41660277,
year = {2026},
author = {Fang, Y and Han, Z and Yang, S and Chen, J and Li, R and Zhang, Z and Song, J and Wang, D and Ban, Y},
title = {Ferroptosis and Alzheimer's disease: unraveling the molecular mechanisms and therapeutic opportunities.},
journal = {Frontiers in cell and developmental biology},
volume = {14},
number = {},
pages = {1758041},
pmid = {41660277},
issn = {2296-634X},
abstract = {Ferroptosis is a novel form of regulated cell death. Compared with other types of cell death, it shows great differences in structure and biochemistry. This type of cell death is receiving increasing attention. For example, studies have found that it plays a key role in the development of neurodegenerative diseases underlying brain atrophy, such as Alzheimer's disease (AD). AD is a chronic and worsening neurodegenerative disease. It poses a serious threat to the health and quality of life of the elderly. The pathology of AD is mainly the presence of extracellular beta-amyloid (Aβ) plaques and intracellular tau-based nerve fiber entanglement (NFTs). Although there are a large number of studies and interventions for AD, so far, no clinical drugs have been found that can stop the pathological progression of AD or cure it. Currently, treatment strategies for this disease only focus on alleviating clinical symptoms and do not achieve slowing disease progression or curing it. Ferroptosis is gradually considered to play a key role in the occurrence and development of AD. Research based on the AD model confirms that neuronal ferroptosis can be inhibited through pharmacology to reverse cognitive disorders. In this review, we first describe the key molecular mechanisms of ferroptosis, and then discuss how these mechanisms operate and develop in AD. Then, we give a detailed introduction to the latest treatments for AD, including iron chelators, antioxidants, and specific ferroptosis inhibitors. What is noteworthy is that this article emphasizes the analysis of the mechanisms of iron metabolism disorders, as well as the introduction of new drugs for the prevention, rather than the alleviation of AD.},
}

@article {pmid41660275,
year = {2026},
author = {Sabbir, MG and Mansouri, B and Ramjiawan, B},
title = {Loss of CAMKK2 and iron-transport proteins-transferrin and its receptor-in the Alzheimer's disease hippocampus: link to tau pathology.},
journal = {Frontiers in cell and developmental biology},
volume = {14},
number = {},
pages = {1716718},
pmid = {41660275},
issn = {2296-634X},
abstract = {INTRODUCTION: Calcium and iron are essential bioelements regulating neuronal function and survival. Dysregulation of calcium signaling and iron homeostasis is implicated in Alzheimer's disease (AD), contributing to oxidative stress, synaptic dysfunction, and neurodegeneration. Previously, using in vitro cell-based models and transgenic mice, we demonstrated that CAMKK2, a calcium/calmodulin-dependent protein kinase, regulates iron transport via transferrin (TF) and transferrin receptor (TFRC). While excessive iron deposition is a hallmark of AD brains, the mechanisms underlying its dysregulation remain poorly understood. In a prior study of postmortem temporal cortex tissues, we showed that CAMKK2/TF/TFRC protein levels were significantly reduced in AD compared to cognitively normal (CN) individuals, and that increased iron accumulation in AD correlated with reduced TF/TFRC levels. This follow-up study aimed to assess CAMKK2/TF/TFRC protein levels in hippocampal tissues - an early site of AD pathology - and examine their relationship with tau (MAPT) aggregation in AD, Parkinson's disease (PD), and frontotemporal dementia (FTD).

METHODS: Postmortem hippocampal tissues from 29 CN individuals and patients diagnosed with AD/FTD/PD (N = 73/7/9 respectively) were analyzed. CAMKK2/TF/TFRC/MAPT levels were quantified using Western blotting. Correlation analyses evaluated associations among these proteins and with age, sex, and postmortem interval (PMI). Isoelectric focusing (IEF) was used to assess post-translational modifications of CAMKK2 and TF.

RESULTS: CAMKK2 and TF levels were significantly reduced in AD, FTD, and PD hippocampi compared to CN controls. TFRC reduction was specific to late onset AD, suggesting a later event. MAPT levels were significantly elevated in AD, with high molecular weight smears indicating tau aggregation. CAMKK2 and MAPT were positively correlated in CN but not in AD, indicating disease-specific disruption. TF and CAMKK2 were also positively correlated in CN but attenuated in AD. No significant changes in CAMKK2 or TF charge states were detected.

DISCUSSION: CAMKK2 downregulation and impaired iron transport appear to be shared features across multiple neurodegenerative diseases, but their decoupling from tau pathology seems specific to AD. These findings position CAMKK2 as a molecular gatekeeper linking calcium signaling, iron metabolism, and tau aggregation. Future studies should focus on elucidating the mechanisms underlying CAMKK2 downregulation to better understand its role in AD pathogenesis.},
}

@article {pmid41660266,
year = {2026},
author = {Rai, A and Damisah, EC and Hill, RA and Tong, L and Grutzendler, J},
title = {TREM2 and APOE are dispensable for microglial clearance of dying neurons revealed by in vivo imaging.},
journal = {iScience},
volume = {29},
number = {2},
pages = {114559},
pmid = {41660266},
issn = {2589-0042},
abstract = {TREM2 and APOE are major Alzheimer's disease (AD) risk genes that may influence microglial pathophysiology by affecting their ability to phagocytose cellular debris and protein aggregates. Here, we investigated the impact of TREM2 and APOE on the removal of dying neurons in the live brain by combining a targeted photochemical method for programmed cell death with high-resolution two-photon imaging in adult mice. We show that deletion of either Trem2 or Apoe does not affect the dynamics of microglia engagement with dying neurons or their efficiency in phagocytosing corpses. Notably, microglia encapsulating amyloid deposits phagocytosed nearby dying cells without disengaging from plaques or moving their cell bodies; however, in the absence of TREM2, microglial cell bodies readily migrated toward dying cells, subsequently disengaging from plaques. These findings indicate TREM2 and APOE variants likely confer AD risk through mechanisms independent of impaired neuronal corpse phagocytosis.},
}

@article {pmid41660240,
year = {2026},
author = {Balzano, E and Twayana, S and Kosiyatrakul, ST and Logsdon, GA and Thakur, BL and Eichler, EE and Bohl, B and Koch, P and Sidoli, S and Kumari, A and Munson, KM and Hoekzema, K and Aladjem, MI and Schildkraut, CL},
title = {Impact of Tau overexpression on DNA replication dynamics in centromeres of human neural progenitor cells.},
journal = {iScience},
volume = {29},
number = {2},
pages = {114707},
pmid = {41660240},
issn = {2589-0042},
abstract = {Aging somatic cells are characterized by specific chromosome aneuploidy, particularly involving chromosome Y (ChrY) and chromosome 21 (Chr21), which are associated with Alzheimer's disease (AD) pathology. This study investigates the role of DNA replication within centromeric regions of these chromosomes using human neural progenitor cells engineered to overexpress either wild-type (wt) or pseudo-hyper-phosphorylated (php) Tau protein. We developed a method to analyze replication dynamics in centromeric DNA. Our findings reveal that replication origins and fork pausing events are mainly located within α-satellite sequences of ChrY and Chr21, where wt and php Tau distinctly modulate origin activation and initiation. Mass spectrometry analysis on immunoprecipitated Tau identified nuclear interactors of Tau, particularly in its php form, which might directly influence the chromatin architecture and gene expression. These studies provide critical insights into the molecular mechanisms of aneuploidy in tauopathies.},
}

@article {pmid41660209,
year = {2026},
author = {Sheng, C and Zheng, W and Yang, H and Chen, X},
title = {Editorial: The role of neuropsychiatry in neurodegenerative disorders.},
journal = {Frontiers in psychiatry},
volume = {17},
number = {},
pages = {1781963},
doi = {10.3389/fpsyt.2026.1781963},
pmid = {41660209},
issn = {1664-0640},
}

@article {pmid41660149,
year = {2025},
author = {Prasher, P and Sharma, M},
title = {O-glycosylation as a potential biomarker in Alzheimer's disease.},
journal = {EXCLI journal},
volume = {24},
number = {},
pages = {1347-1351},
pmid = {41660149},
issn = {1611-2156},
}

@article {pmid41659709,
year = {2025},
author = {Farah, AI and Itoh, SG and Okumura, H},
title = {Molecular dynamics simulations of amyloid-β(29-42) aggregation in bulk water and at the air-water interface.},
journal = {Biophysics and physicobiology},
volume = {22},
number = {4},
pages = {e220033},
pmid = {41659709},
issn = {2189-4779},
abstract = {Oligomers of amyloid-β (Aβ) peptides are related to Alzheimer's disease, and their formation is accelerated at hydrophilic-hydrophobic interfaces. We performed all-atom molecular dynamics simulations of Aβ(29-42) peptides in bulk water and at an air-water interface. In bulk water, the fragments formed stable aggregates, and the secondary structures were hardly changed. At the interface, the peptides were more easily separated from each other due to the low free-energy barrier and changed their secondary structures more frequently. This conformational flexibility is likely to promote amyloid fibril growth, suggesting a key role of interfacial environments in early aggregation processes.},
}

@article {pmid41659668,
year = {2026},
author = {Carroll, T and Pfendler, D and Alhaj Arhayem, H and Thoma, R and Müller-Eigner, A and Straut, A and Johnson, GVW and Nehrke, K},
title = {Tunable Tau Expression in C. elegans Neurons Reveals that Early-AD Tau Phosphorylation Selectively Impacts Behavior and Mitochondrial Quality Control.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.01.26.701793},
pmid = {41659668},
issn = {2692-8205},
abstract = {UNLABELLED: Tau protein accumulates myriad post-translational modifications as Alzheimer's disease (AD) progresses, and early-disease tau modifications such as phosphorylation at threonine 231 (T231) likely play a key role in AD pathogenesis. Here, a series of "tunable tau" strains was developed in C. elegans to test the relative impact of tau pseudo-phosphorylation of T231 (T231E) compared to protein expression level as a driver of phenotypic penetrance and severity. Multiple copies of a cassette coding for pan-neuronal wildtype tau or T231E were inserted at a genomic safe harbor loci to create a repertoire of strains expressing tau from low to high levels. In stereotypical behavioral assays of locomotory activity, T231E selectively impacted phenotypic severity compared to wild-type human tau controls, which further tracked with age and tau expression level. However, deficits in associative memory were non-selective between tau and T231E. Moreover, genetic, pharmacologic, and molecular approaches indicated that mitophagy modulation could suppress T231E phenotypes. Additionally, a robust mitochondrial unfolded protein response (UPRmt) occurred in T231E, and loss of atfs-1 , a transcription factor central to the UPRmt suppressed T231E toxicity. These results demonstrate that phenotypic severity is invariably associated with tau dosage, while early-AD relevant modifications can be causative drivers of selective deficits. Consistent with recent findings, enhancing mitophagy or suppressing potentially maladaptive consequences of persistent UPRmt induction can be beneficial. This provides a solid foundation for further interrogation into mitochondrial quality control disruption as a potential root cause for AD pathogenesis.

HIGHLIGHTS: Matched sets of pan-neuronal, multi-copy tau strains enhance experimental controlPhosphomimetic tau elicits selective behavioral and neuronal dysfunctionPhosphomimetic tau triggers a unique mitochondrial unfolded responseTau depletion and mitochondrial interventions rescue observed deficits.},
}

@article {pmid41659659,
year = {2026},
author = {Bhandiwad, AA and Kronman, FN and Liwang, J and Gao, P and Ding, SL and Xu, X and Ng, L and Kim, Y and Mollenkopf, T},
title = {A curvilinear coordinate flatmap for visualizing hippocampal structure and development.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.01.29.702633},
pmid = {41659659},
issn = {2692-8205},
abstract = {The hippocampal formation is a highly curved and topographically complex forebrain structure. This complex geometry presents persistent challenges for analyzing subregional, laminar, and connectivity patterns. Here, we present a computational workflow that generates curvilinear-coordinate flatmaps from Common Coordinate Framework (CCF) registered hippocampal and retrohippocampal regions by solving the Laplacian equation to derive geodesic streamlines. This transformation unfolds the hippocampus into a planar slab, bounded by the meningeal and ventricular surfaces, with the depth defined along the radial axis. We apply this transform to image volumes, single neuron reconstructions, and point data, including spatial transcriptomic and rabies tracing datasets, revealing topographic variations in the dorsoventral and radial axes that are obscured in the CCF coordinate space. As proof of principle, we use flatmaps to show connectivity loss in a mouse model of Alzheimer's disease and track postnatal development of microglial distribution in the hippocampus. This work provides an efficient and accessible resource for visualizing hippocampal organization across development and disease, offering new opportunities to interrogate the structure and function of this important brain region.},
}

@article {pmid41659651,
year = {2026},
author = {Peck, MR and Chapman, JE and Hill, T and Quinn, K and Ikiz, ED and Lopez, A and Hascup, ER and Bae, C and Hascup, KN},
title = {D-Methionine Improves Spatial Navigation and Attenuates Oxidative Stress and Amyloid Pathology in a Sex-Specific Manner.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.01.27.702104},
pmid = {41659651},
issn = {2692-8205},
abstract = {BACKGROUND: Oxidative stress and maladaptive neuroimmune activation contribute to cognitive decline in Alzheimer's disease (AD) and represent therapeutic targets beyond amyloid-centered approaches.

OBJECTIVE: To determine whether oral D-methionine (D-Met), a redox-active amino acid, reduces amyloid pathology and lipid peroxidation and confers disease-modifying benefits in AD mouse models.

METHODS: Male and female APP/PS1 and APP [NL-F] mice with advanced AD pathology received oral D-Met or vehicle. Behavioral assessments included locomotor activity and hippocampal-dependent spatial learning and memory. Amyloid burden, lipid peroxidation, peripheral metabolic and inflammatory markers, and hippocampal microglial phenotypes were evaluated using biochemical and histological analyses.

RESULTS: D-Met did not alter locomotor or exploratory behavior but improved spatial memory recall in both sexes of APP/PS1 mice and in female APP [NL-F] mice. APP [NL-F] males exhibited improved learning during Morris water maze (MWM) acquisition. Amyloid pathology was modestly and region-specifically reduced, including decreased hippocampal plaque size in male APP [NL-F] mice, reduced cortical plaque size in female APP/PS1 mice, and lower soluble amyloid-β (Aβ) 42 in male APP/PS1 mice. Lipid peroxidation, assessed by malondialdehyde, was reduced only in female APP [NL-F] mice. D-Met induced pronounced sex-dependent peripheral effects, increasing adiposity and pro-inflammatory adipose signaling in males, while reducing perigonadal white adipose tissue (pgWAT) IL-6 expression in female APP [NL-F] mice. In the hippocampus, D-Met remodeled microglial signatures, with female APP [NL-F] mice showing reduced Iba1 and disease-associated microglial (DAM) markers and increased Axl expression.

CONCLUSION: Short-term D-Met acts as a metabolic and redox modulator with modest amyloid-lowering effects mediated by improved microglial function. Therapeutic efficacy is strongly sex- and model-dependent, with the greatest benefit observed in female APP [NL-F] mice.},
}

@article {pmid41659639,
year = {2026},
author = {Khoshkhoo, S and Bae, M and Wang, Y and Tillett, A and Ramirez, RB and Finander, B and Egan, ED and Marx, L and Patel, D and Zhou, Z and Chahine, Y and Chhouk, B and Zoullas, SM and Lai, A and Coras, R and Bielle, F and Navarro, V and Mathon, B and Valiante, TA and Chameh, HM and Gao, AF and Krings, T and Gooley, S and Hildebrand, MS and Bulluss, K and Clark, J and Morokoff, AP and King, JA and Todaro, M and Kwan, P and O'Brien, TJ and Berkovic, SF and Scheffer, IE and Perucca, P and Lapinskas, E and Rolston, JD and Cosgrove, GR and Sarkis, RA and D'Gama, AM and Alexadrescu, S and Yang, E and Poduri, A and Richardson, RM and Erson-Omay, EZ and DeLanerolle, N and Spencer, DD and Brown, KS and Miller, MB and Roberts, AE and Santos, LN and Kontaridis, MI and Bien, CG and Blacklow, SC and Kahle, KT and Blümcke, I and Huang, AY and Lee, EA and Walsh, CA},
title = {Activating Ras-MAPK pathway variants drive hippocampal clonal competition in human epilepsy.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.01.26.701822},
pmid = {41659639},
issn = {2692-8205},
abstract = {Mesial (a.k.a., medial) temporal lobe epilepsy (MTLE) is the most common focal epilepsy [1,2] and, in drug-resistant cases, is treated by surgical removal of the anterior temporal lobe, which often shows neuronal loss and gliosis consistent with hippocampal sclerosis (HS) [2] . MTLE with HS has minimal contribution from germline genetic variation [3] , and is associated with prior precipitating insults such as prolonged childhood seizures and head trauma [4-6] . Somatic variants in Ras-MAPK pathway genes were recently reported in a few MTLE surgical specimens [7,8] , but their prevalence, clinical relevance, and underlying biological mechanisms remain unknown. Targeted duplex sequencing of hippocampal DNA from 462 surgical resections revealed significant enrichment of deleterious somatic variants in MTLE versus controls, with >40% of MTLE specimens harboring activating Ras-MAPK variants in PTPN11 , NF1 , BRAF , KRAS , and twelve genes not previously associated with focal epilepsy. Eight Ras-MAPK genes showed positive clonal selection in MTLE. Increased somatic variant burden predicted worse surgical outcome. Somatic Ras-MAPK variants at ultra-low (<0.5%) variant allele fractions were associated with older seizure onset and HS pathology, supporting a late prenatal or postnatal origin. Ras-MAPK variants in MTLE were enriched in cells derived from hippocampal progenitors-neurons, astrocytes, oligodendrocytes-in line with the known neuronal hyperexcitability and seizures induced by Ras-MAPK overactivation [9,10] ; in contrast, Alzheimer disease hippocampi exhibited microglial enrichment of Ras-MAPK variants, consistent with prior reports [11] . Single-nucleus RNA sequencing showed increased expression of Ras-MAPK genes in neurons and upregulation of pathways mediating neurogenesis and neural development in MTLE. Functional validation of novel, recurrent PTPN11 variants confirmed gain-of-function, while cellular modeling in induced pluripotent stem cells demonstrated proliferative/survival advantages for mutant cells in mosaic culture. Overall, our data suggest that somatic Ras-MAPK variants and acquired risk factors may converge on clonal competition in the hippocampus to modulate epilepsy risk.},
}

@article {pmid41659595,
year = {2026},
author = {Chaggar, P and Vogel, JW and Thompson, TB and Aldea, R and Strandberg, O and Stomrud, E and Palqmvist, S and Ossenkoppele, R and Jbabdi, S and Magon, S and Klein, G and , and Mattson-Carlgren, N and Hansson, O and Goriely, A},
title = {Dynamical A β -Tau-Neurodegeneration Model Predicts Alzheimer's Disease Mechanisms and Biomarker Progression.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.01.27.701320},
pmid = {41659595},
issn = {2692-8205},
abstract = {UNLABELLED: Alzheimer's disease is characterised by the pathological interaction of two proteins, amyloid-beta (Aβ) and tau, which collectively drive neurodegeneration and cognitive decline. The progression of Aβ, tau, and neurodegeneration biomarkers is captured by the ATN framework, which is a powerful tool for disease classification. However, since the ATN framework is mainly descriptive, it cannot quantify or predict relationships between biomarkers over time. We address this limitation by introducing a dynamical ATN (dATN) model that mechanistically simulates the spatiotemporal progression of Aβ, tau, and neurodegeneration. The dATN model integrates mechanisms of prion-like protein aggregation of Aβ and tau, network-based tau propagation, Aβ-driven catalysis of tau progression, and tau-driven neurodegeneration. We calibrated the model using multimodal longitudinal imaging data from both the ADNI and BioFINDER-2 cohorts and show that it accurately fits longitudinal regional Aβ, tau, and neurodegeneration data. Using the dATN model, we show that Aβ-induced effects predict Braak-like cortical tau progression, that the spatial colocalisation of Aβ and tau is a crucial biomarker of disease acceleration, and that tau-driven atrophy strongly correlates with observed neurodegeneration. Furthermore, by integrating the disease progression model with pharmacokinetic-pharmacodynamic simulations, we present a powerful tool that facilitates regional evaluation of therapeutic strategies targeting Aβ, identification of critical intervention windows, and prediction of heterogeneous treatment effects across brain regions. This framework unifies mechanistic understanding with clinical imaging biomarkers, offering a quantitative approach for forecasting disease progression, testing mechanistic hypotheses, and optimising personalised treatment strategies in AD.

ONE SENTENCE SUMMARY: Colocalisation of A β and tau predicts regional tau progression and optimal A β -targeted intervention windows, while tau predicts neurodegeneration.},
}

@article {pmid41659563,
year = {2026},
author = {Gelber, A and Romero, H and Burrows, D and Whittaker, DS and Carlin, D and Mukamel, EA and Desplats, P},
title = {Spatial transcriptomics reveals brain-wide circadian disruption in an Alzheimer's disease model.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.01.26.701799},
pmid = {41659563},
issn = {2692-8205},
abstract = {Diurnal rhythms in brain transcription align neural, immune, and metabolic processes with the light-dark cycle and are profoundly disrupted in Alzheimer's disease (AD). However, the regional organization of diurnal transcription in the healthy and diseased brain remains poorly defined. Using large-scale spatial transcriptomics, we mapped 24-hour rhythmic transcription across cortical and subcortical regions of the mouse brain. We identified marked regional differences in rhythmicity, including distinct oscillatory signatures across cortical areas and along the rostro-caudal axis. In the APP23 mouse model of AD, pathology-vulnerable brain regions exhibited early, region-specific disruption of diurnal transcription prior to substantial amyloid plaque deposition. These findings reveal a spatially organized architecture of brain diurnal rhythms and identify early rhythmic dysregulation as a feature of Alzheimer's disease pathogenesis.},
}

@article {pmid41659516,
year = {2026},
author = {Rifat, JM and Engala, S and Bozdag, S},
title = {scAURA: Alignment- and Uniformity-based Graph Debiased Contrastive Representation Architecture for Self-Supervised Clustering of Single-Cell Transcriptomics.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.01.25.701579},
pmid = {41659516},
issn = {2692-8205},
abstract = {UNLABELLED: Single-cell RNA sequencing (scRNA-seq) allows transcriptomic profiling at single-cell resolution, providing valuable insights into cellular diversity across tissues, developmental stages, and diseases. However, accurately identifying cell types remains challenging due to the high dimensionality, sparsity, and noise inherent in scRNA-seq data. To address these challenges in cell type identification in scRNA-seq data, we introduce scAURA (single c ell A lignment- and U niformity-based Graph Debiased Contrastive R epresentation A rchitecture), a unified framework that integrates graph debiased contrastive learning with self-supervised clustering. We evaluated scAURA on 18 real single-cell datasets collected from six sequencing platforms spanning diverse tissue and cell types in human and mouse. scAURA outperformed all state-of-the-art (SOTA) methods in nine and eight datasets in Adjusted Rand Index (ARI) and Normalized Mutual Information (NMI), respectively. On average, scAURA obtained average ranks of 2.28 (ARI) and 2.39 (NMI) across all 13 SOTA methods, demonstrating its consistent superiority across datasets. scAURA also exhibited strong robustness to dropout noise by maintaining stable clustering performance even under increasing sparsity levels. Furthermore, in an external single-cell Alzheimer's disease dataset, scAURA accurately clustered different cell types, identified novel cell type-specific marker genes, and inferred their potential transcriptional regulators. The source code and datasets are available at https://github.com/bozdaglab/scAURA .

CONTACT: Serdar.Bozdag@unt.edu.},
}

@article {pmid41659508,
year = {2026},
author = {Georgescauld, F and Okekenwa, S and Boyd, T and Donahue, C and Quittot, N and Dickson, JR and Fan, Z and Brady, S and Blackstone, C and Hyman, B and Song, Y},
title = {Dynamic conformational ensembles of soluble Tau encode neuronal toxicity prior to aggregation.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.01.26.701882},
pmid = {41659508},
issn = {2692-8205},
abstract = {UNLABELLED: Tau aggregation is a defining feature of Alzheimer's disease and related tauopathies, yet the conformational states of Tau in neurons prior to aggregation remain poorly understood. Existing structural models are derived largely from fibrillar assemblies and provide limited insight into the dynamic, soluble Tau species that initiate pathology. Here, we combine hydrogen-deuterium exchange mass spectrometry with super-resolution imaging and neuronal models to define the conformational ensemble of soluble Tau under physiological and disease-relevant conditions. We show that soluble Tau populates distinct, dynamic conformations characterized by regional stabilization and long-range intramolecular interactions that are invisible to fibril-based structures. Disease-associated perturbations selectively remodel these conformational ensembles, exposing aggregation-prone regions and altering Tau subcellular organization in neurons. Notably, these Tau species inhibit axonal transport, which is essential for neuronal health, linking specific ensemble states to neuronal toxicity. These findings establish soluble Tau conformation as a dynamic, regulatable state that precedes aggregation and encodes disease relevance. By defining the structural logic of Tau before fibril formation, this work provides a framework for understanding early tauopathy mechanisms and for targeting Tau pathology at its earliest stages.

SUMMARY: Tau pathology is a hallmark of Alzheimer's disease (AD) and related dementias (ADRDs). Although Tau is often described as intrinsically disordered, it is a dynamic protein with distinct but poorly defined conformations. Here we conduct a systematic time-resolved structure-function analysis of normal and pathologic Tau, including hyperphosphorylated, mutant Tau, and posttranslational-modification-mimetic Tau. To characterize dynamic conformational changes of Tau, we combined state-of-the-art hydrogen deuterium exchange mass spectrometry with structured illumination microscopy, demonstrating a novel Tau-MT binding mode: "dynamic oscillation". To correlate Tau structure with neuronal function, we evaluated axonal transport as a sensitive readout of neuronal health. Many toxic Tau forms share a common signature of increased exposure of the N-terminal phosphate activating domain (PAD) in vitro and in vivo . Aberrant exposure of PAD correlates with Tau pathology and axonal transport defects. Tau phosphorylation at S262 alone is sufficient to alter Tau-microtubule interactions beyond R1-R4 motifs, globally changing Tau conformation, disrupting "dynamic oscillation" on MTs, and inhibiting axonal transport. Frontotemporal dementia-associated P301L-Tau remains associated with microtubules but also inhibits axonal transport. Our results reveal a well-defined conformation of soluble WT Tau in neurons and its highly dynamic interaction with microtubules, altered by AD/ADRD-Tau forms. Our multidisciplinary approach comprising biochemical manipulations, innovative MS tools, advanced microscopy, cellular assays, and mouse and human data pair Tau conformations with distinct neuronal functions and pathologies in health and disease.},
}

@article {pmid41659445,
year = {2026},
author = {Korukonda, A and Blankenship, HE and Kam, K and Kour, D and Espinosa-Garcia, C and Jang, WE and Srivastava, U and Mulvey, B and Tish, MM and Witztum, R and Ramelow, CC and Pate, BS and Liles, LC and Lu, L and Atallah, J and Guo, E and Martinowich, K and Sharpe, AL and Varga, AW and Rangaraju, S and Beckstead, MJ and Weinshenker, D},
title = {Pathogenic tau in the mouse locus coeruleus produces noradrenergic hyperactivity and neuropsychiatric phenotypes reminiscent of early Alzheimer's disease.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.01.30.702923},
pmid = {41659445},
issn = {2692-8205},
abstract = {Alzheimer's disease (AD), though defined as a cognitive disorder, often presents neuropsychiatric symptoms such as anxiety, depression, agitation and sleep disruptions years before the onset of frank memory impairment. An early pathological feature is the accumulation of hyperphosphorylated "pretangle" tau (pTau) in the locus coeruleus (LC), the brain's primary source of norepinephrine (NE). While clinical studies link LC pTau burden to behavioral abnormalities, causal mechanisms remain unclear. We developed a translationally-relevant mouse model that recapitulates the 'LC-first' phenomenon using cell type-specific viral expression of pathogenic P364S mutant human tau in LC neurons. Three months post-infusion, pTau accumulation induced anxiety-and compulsive-like behaviors and reduced sleep spindles without altering overall sleep architecture. Consistent with the behavioral phenotypes, electrophysiological recordings revealed significant increases in spontaneous and evoked firing of LC neurons, accompanied by robust astrocytic reactivity with no apparent cell death. Transcriptomic analysis identified upregulation of Hcn2 and downregulation of Clic6 , suggesting changes in neuronal excitability. To further define molecular mechanisms, we developed a cell type-specific proteomics approach, which showed synaptic and metabolic alterations associated with LC-specific tau pathology. Early anxiety-like behaviors observed at 3 months diminished at later timepoints (6-9 months) and were replaced by anxiolytic characteristics. These findings demonstrate that pTau triggers phenotypes reflective of LC-NE hyperactivity in the early stages of AD pathogenesis, laying the foundation for the development of LC-based disease-modifying therapies to address neuropsychiatric manifestations.},
}

@article {pmid41659441,
year = {2026},
author = {Kwon, HC and Eiden, A and Li, J and MacKinnon, M and Garfinkel, JB and Hooper, SM and Liu, Y and Nelson, MT and Koretsky, A and Mughal, A},
title = {Electro-Calcium uncoupling precedes neurodegeneration in Alzheimer's disease.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.01.26.701803},
pmid = {41659441},
issn = {2692-8205},
abstract = {Alzheimer's disease (AD) is categorized as a neurodegenerative disease, but there is a growing recognition of the vascular components in AD pathophysiology. Reduction in cerebral perfusion is routinely observed in AD patients and preclinical models prior to overt clinical symptoms. However, there is a limited mechanistic understanding of the early neurovascular deficits in AD, and how these may ultimately contribute to pathology. Here, we investigated the mechanisms of early neurovascular dysfunction in AD by using 3-month-old 5xFAD mice, a familial mouse model of AD. Functional hyperemia-the increase in cerebral blood flow (CBF) in response to neuronal activity-is driven by inward rectifier K [+] (K ir 2.1)-mediated hyperpolarizing (electrical) signals and Ca [2+] -dependent nitric oxide production within the capillary endothelial cells (cECs). Electrical and Ca [2+] signals are tightly coupled through cECs membrane potential, referred to as Electro-Calcium (E-Ca) coupling. We hypothesize that E-Ca uncoupling contributes to impaired functional hyperemia in 5xFAD mice and that these neurovascular deficits precede the neurodegeneration and cognitive decline. At three months of age, 5xFAD mice did not exhibit any impairment in spatial learning and memory, or neuronal density. However, whisker stimulation-induced functional hyperemia was significantly reduced in 5xFAD mice compared to controls. Functional hyperemia exhibited a bimodal response in controls-consisting of fast and slow phases-with the slow phase being significantly reduced in 5xFAD mice. To identify mechanisms underlying these deficits, we measured cortical neuronal and endothelial Ca [2+] activity using in-vivo imaging. Neuronal Ca [2+] activity was comparable between controls and 5xFAD mice, while cECs Ca [2+] activity was significantly reduced in 5xFAD mice. Moreover, K ir 2.1 channel blocker, barium (100 μM) significantly suppressed cECs Ca [2+] activity in controls, but not in 5xFAD mice, consistent with crippled E-Ca coupling. Despite these vascular functional impairments, capillary density was preserved in 5xFAD mice. TRPV4 channels are one of the major Ca [2+] entry pathways in cECs and potentiate E-Ca coupling. cECs TRPV4 current density was significantly reduced in 5xFAD mice while K ir 2.1 current density was unchanged, indicating that impaired TRPV4 function underlies the E-Ca uncoupling. In summary, early E-Ca uncoupling leads to impaired functional hyperemia in 5xFAD mice and may contribute to later neuronal and cognitive decline.},
}

@article {pmid41659428,
year = {2026},
author = {Mao, Y and Pan, B and Liu, X and , },
title = {Global brain activity links subcortical degeneration to cortical tau progressively across Braak regions over early Alzheimer's disease stages.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.01.23.701360},
pmid = {41659428},
issn = {2692-8205},
abstract = {Alzheimer's disease (AD) is characterized by early tau pathology in subcortical neuromodulatory nuclei, followed by progressive cortical tau accumulation; however, the mechanisms linking subcortical dysfunction to cortical tau pathology remain unclear. Using multimodal neuroimaging data from the ADNI cohort, we examined how infra-slow (< 0.1 Hz) global brain (i.e., gBOLD) activity is related to the volume of the nucleus basalis of Meynert (NbM) and cortical tau accumulations in the early stages of AD. NbM degeneration was associated with reduced gBOLD activity and spatially co-localized tau accumulation, appearing in early Braak regions during the preclinical stage, i.e., cognitively unimpaired participants with abnormal CSF markers, and extending to more advanced Braak areas during the prodromal stage, i.e., mild cognitive impairment (MCI) subjects. Our findings suggest that infra-slow gBOLD activity serves as a functional neural mediator linking subcortical degeneration to cortical tau pathology, highlighting a potential functional pathway linking subcortical and cortical pathology in early AD.},
}

@article {pmid41659356,
year = {2026},
author = {Fausto, BA and Akbulut, E and Sheikh, M and Grass, D and Aquino, N and Garza-Martinez, L and Hercules-Tawe, F and Ghaly, S and Codrington, A and Gamil, A and Arshad, I and Napoleon, D and Perna, R and Paruzel, V and Gluck, MA and Fitzgerald-Bocarsly, P},
title = {Lower CD8+ T-cell senescence partially mediates the neuroprotection of higher aerobic fitness.},
journal = {Alzheimer's & dementia (New York, N. Y.)},
volume = {12},
number = {1},
pages = {e70202},
pmid = {41659356},
issn = {2352-8737},
abstract = {INTRODUCTION: Immunosenescence - age-related changes in immunity - may exacerbate the pathologic processes of Alzheimer's disease (AD), a condition that disproportionately affects African Americans. Fortunately, a higher level of aerobic fitness is linked to both reduced immunosenescence and lower AD risk. However, it remains unclear whether higher aerobic fitness and decreased AD is mediated by lower proportions of T-cell senescence. In a cohort of older African Americans, we aimed to (1) examine the relationship between aerobic fitness and generalization (a cognitive indicator of AD risk) and (2) investigate whether T-cell senescence mediated this relationship.

METHODS: A total of 231 older African American participants from the Aging & Brain Health Alliance (M age = 70.74 years, SD = 6.40; M education = 14.02 years, SD = 2.25; M MoCA = 23.16, SD = 2.63) responded to demographic, health, and lifestyle questionnaires; completed a cognitive battery including a generalization task (stimulus differentiation and transfer task); underwent anthropometric and physical performance measures; and provided a blood sample for T-cell senescence characterization. Peripheral blood mononuclear cells were isolated and analyzed for senescence-associated beta-galactosidase activity as a measure of proportions of cytotoxic CD8+ T-cell senescence. Aerobic fitness (VO2peak) was estimated from the six-minute walk test. Covariates included age, sex, education, and waist-to-hip ratio.

RESULTS: Higher aerobic fitness was significantly associated with fewer generalization errors. Furthermore, higher aerobic fitness was associated with lower CD8+ T-cell senescence (β = -0.15, p = 0.02), which was associated with fewer generalization errors (β = -0.17, p = 0.01). Overall, 15% of the effect of higher aerobic fitness on fewer generalization errors was mediated by lower CD8+ T-cell senescence.

DISCUSSION: One pathway by which higher aerobic fitness is associated with lower AD risk in older African Americans is through lower proportions of CD8+ T-cell senescence. These results highlight the immune and cognitive function benefits of a physically active lifestyle, particularly in a demographic that faces a higher risk for AD.},
}

@article {pmid41659355,
year = {2026},
author = {Alshahrani, M and Burley, CV and Guan, Z and Brain, J and Dunne, J and Sabatini, S and Tang, EY and Myers, B and Sohrabi, HR and Naheed, A and Tully, PJ and Burton, E and Harrison, F and Siervo, M and Stephan, BC},
title = {Informing depression-specific dementia risk models: An evidence-based analysis of moderators of the depression-dementia association.},
journal = {Alzheimer's & dementia (New York, N. Y.)},
volume = {12},
number = {1},
pages = {e70218},
pmid = {41659355},
issn = {2352-8737},
abstract = {Depression is a major modifiable risk factor for dementia, yet most prediction models treat it as a homogeneous exposure, despite evidence that risk varies among people with depression. This study aimed to identify key modifiers of the depression-dementia association to inform the development of tailored prediction models. A narrative synthesis was conducted, incorporating (1) an umbrella review of nine meta-analyses examining the depression-dementia association; (2) a systematic review of depression-related medication use on dementia risk; and (3) findings from three Lancet Commission reports on dementia (2017, 2020, and 2024). Seven key modifiers were identified that influenced the reliability and direction of risk estimates: demographic factors, assessment methods, depression severity, follow-up duration, depression timing and trajectory, the outcome predicted (e.g., all-cause vs dementia subtypes), and antidepressant use. Late-life and severe depression conferred the highest risk, with associations being stronger for vascular dementia than for Alzheimer's disease. Clinical diagnoses yielded higher risk estimates compared to symptomatic rating scales. Duration of follow-up was associated with contradictory directional effects. Antidepressant use was associated with increased dementia risk. However, class-specific analyses were inconclusive due to extreme heterogeneity. The Lancet Commission emphasized late-life and mid-life depression as key modifiable risk factors. Multiple clinical, methodological, and temporal factors influence dementia risk estimates in individuals with depression. The findings support developing depression-specific dementia risk models that prioritize high-risk subgroups. Recommendations include distinguishing between symptom-based and clinical diagnostic approaches, addressing heterogeneity in timing and severity, modeling reverse causation, and validating models across diverse populations.},
}

@article {pmid41659250,
year = {2026},
author = {Farias Quipildor, GE and Belfiore, R and Althobaiti, K and Najarzadeh, Z and Glabe, C and Readhead, BP and Gandy, S and Salton, SRJ and Ehrlich, ME},
title = {Differential downstream signaling in microglia lacking Alzheimer's-related TREM2 or its adaptor TYROBP/DAP12.},
journal = {Molecular neurodegeneration advances},
volume = {2},
number = {1},
pages = {8},
pmid = {41659250},
issn = {3059-4944},
abstract = {UNLABELLED: Microglia, the primary immune cell in the brain, have multiple activation phenotypes involved in broad functions within the brain, playing roles in neurotoxicity/neuroprotection, release of inflammatory and anti-inflammatory cytokines, and in cell survival, proliferation, and phagocytosis. TREM2 and TYROBP form a transmembrane complex in microglia that modulates intracellular signaling networks, and these proteins are essential regulators of the transition from homeostatic to activated microglia. Recent findings support a TREM2-independent molecular signature that is involved in the early transition of homeostatic to disease-associated microglia (DAM), with the next sequential step of DAM activation from stage 1 to stage 2 being TREM2-dependent. However, the underlying mechanisms determining how TREM2 or TYROBP regulate these downstream phenotypes are largely unknown. We isolated primary microglia from C57BL/6 wild-type (WT) controls, Trem2 knock-out (KO), and Tyrobp KO mice at post-natal day 0-3. Cells were treated with Alzheimer's disease (AD)-relevant stimuli, such as amyloid beta (Aβ) oligomers or fibrils, or 'neuroinflammatory-like' stimuli, such as lipopolysaccharide (LPS). We explored protein and gene expression in the presence or absence of inhibitors of the TREM2/TYROBP downstream signaling pathway. We also performed a high-throughput Olink proteomic analysis of conditioned media from WT, Trem2 KO, and Tyrobp KO stimulated with either LPS or Aβ oligomers or fibrils. Our results show that the absence of either TREM2 or TYROBP is associated with increased basal levels of phosphorylated ERK in primary microglia compared to WT controls. In addition, Trem2 KO and Tyrobp KO cells show a less ramified cell morphology at baseline, as compared to WT microglia. Moreover, stimulating primary microglia with either Aβ oligomers or LPS leads to differential protein and gene expression in cells lacking TREM2 or TYROBP. The dysregulated downstream signal transduction and morphology in the absence of TREM2 or TYROBP suggest their essential roles not only in microglial homeostasis but also in their activation in response to different stimuli.

SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s44477-025-00012-x.},
}

@article {pmid41659206,
year = {2026},
author = {Liu, T and Rong, Z and Li, J and Wu, H and Wei, J},
title = {Three-dimensional interactive network: Mitochondrial-metabolic-calcium homeostasis driving Alzheimer's disease.},
journal = {Genes & diseases},
volume = {13},
number = {3},
pages = {101846},
pmid = {41659206},
issn = {2352-3042},
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by cognitive decline and neuronal loss, with its pathogenesis tightly linked to a "pathological triad"-mitochondrial dysfunction, metabolic dysregulation, and calcium homeostasis imbalance. This triad forms a mutually reinforcing network that amplifies AD pathology, yet its precise causal relationships and clinical relevance remain incompletely understood. Here, we critically synthesize evidence from human studies, animal models, and in vitro systems to dissect how these dysfunctions interact in vivo: mitochondrial structural damage and bioenergetic failure (e.g., reduced cytochrome c oxidase activity) impair ATP production, triggering metabolic reprogramming (e.g., astrocytic Warburg-like glycolysis, lactate shuttle dysfunction) and disrupting calcium buffering via mitochondrial calcium uniporter (MCU) dysregulation. Conversely, metabolic stress (e.g., hyperglycemia-induced mitochondrial overload) and calcium overload (e.g., NMDA receptor hyperactivation) exacerbate mitochondrial damage through reactive oxygen species (ROS) bursts and mitochondrial permeability transition pore (mPTP) opening. These processes are further amplified by amyloid β-protein (Aβ) and tau pathology: Aβ oligomers directly inhibit mitochondrial respiration and activate calcium channels, while hyperphosphorylated tau disrupts mitochondrial trafficking and exacerbates metabolic enzyme dysfunction. We evaluate the clinical translatability of preclinical findings, highlighting inconsistencies (e.g., conflicting results of CoQ10 trials) and gaps (e.g., human-specific metabolic signatures). Finally, we propose a framework prioritizing multi-target therapies that disrupt the triad's vicious cycle, emphasizing the need for biomarkers to stratify patients based on triad dysregulation patterns.},
}

@article {pmid41659073,
year = {2026},
author = {Pinilla Manriquez, V and Laho, EM and Marvin, SA and Usman, Y and Properzi, MJ and Palmgren, KA and Rao, Y and Yau, WW and Reynolds, G and Johnson, KA and Buckley, R and Rentz, D and Amariglio, R and Redline, S and Purcell, S and Sperling, RA and Djonlagic, I and Chhatwal, JP and Schultz, SA},
title = {REM Sleep is Associated with Cognition and Biomarkers Longitudinally in Older Adults Across the Alzheimer Disease Continuum.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.01.22.26344642},
pmid = {41659073},
abstract = {UNLABELLED: Sleep disturbances represent a potentially modifiable risk factor for Alzheimer disease (AD). The extent to which changes in rapid eye movement (REM) sleep are related to the accumulation of AD pathology and brain tissue loss is not well understood. In the current study, ninety-four individuals 74 clinically unimpaired [CU] and 20 clinically impaired [CI]) underwent polysomnography (PSG), cognitive assessments, and neuroimaging. Cross-sectional and longitudinal models examined the associations between PSG outcomes of interest (percentage of sleep period spent in REM [%REM] and REM latency) and pre-clinical Alzheimer's cognitive composite-5 (PACC5) scores, entorhinal tau-positron emission tomography (PET; 18F-flortaucipir), cerebral amyloid-PET (11C-Pittsburgh Compound B; PiB), AD signature cortical thickness, and hippocampal volume, after adjusting for covariates. Across CU and CI individuals, less time spent in REM sleep and prolonged REM latency were associated with poorer cognition after adjusting for age, sex, and years of education. Additionally, these factors were associated with a greater AD pathologic burden after adjusting for age and sex. Longitudinal data, spanning up to 16 years, demonstrated that the rate of change in cognition and AD biomarkers in the time preceding PSG assessment was also strongly associated with REM characteristics. Our findings highlight the potentially bidirectional relationship between the accumulation of AD pathology and the disruption of REM sleep. Future studies are needed to better understand the longitudinal relationship between sleep characteristics, AD progression, and cognitive decline, and to assess the potential of sleep-focused interventions to alter the course of AD clinical, cognitive, and pathological progression.

ONE SENTENCE SUMMARY: Cognitive and biomarker data are associated with REM sleep characteristics in unimpaired and impaired individuals cross-sectionally and over time.},
}

@article {pmid41659060,
year = {2026},
author = {Zhou, W and Wang, Y and Wu, Y and Li, X and Liu, H and Wang, H and Zhang, Z and Huang, H},
title = {AI-driven multimodal precision diagnosis and progression prediction of Alzheimer's disease: Data fusion mechanisms, clinical applications, and research trends (2017-2024).},
journal = {Digital health},
volume = {12},
number = {},
pages = {20552076251412649},
pmid = {41659060},
issn = {2055-2076},
abstract = {AIMS: This study combines bibliometric and structured analyses to comprehensively examine the development, methodological characteristics, and application trends of multimodal artificial intelligence (AI) in Alzheimer's disease (AD) diagnosis.

MATERIALS AND METHODS: Literature from January 1, 2017 to December 31, 2024, was retrieved from the Web of Science Core Collection. Retrospective bibliometric and visual analyses were conducted using VOSviewer, CiteSpace, and the Bibliometrix R package.

RESULTS: A total of 234 papers were identified, showing a continuous increase in publication volume, with the United States and China as dominant contributors. The analysis focused on data modalities, fusion architectures, and clinical applications. Data trends highlight the fusion of imaging data with genetics, biomarkers, and clinical data. Methodologically, five fusion approaches were categorized, with intermediate fusion being the most widely used strategy for its ability to balance heterogeneous data integration. In application, multimodal AI demonstrated clear advantages in early diagnosis, disease classification, and progression prediction.

CONCLUSION: Research on multimodal AI for AD has gained global attention and remains a key direction for diagnostic innovation. By synthesizing bibliometric insights with structured analyses of modalities and fusion strategies, this study offers a systematic understanding of current progress and provides valuable guidance for future methodological and translational research.},
}

@article {pmid41659035,
year = {2026},
author = {Hu, C and Zeng, X and Zhang, L and Sehrawat, A and Powell, M and Song, E and Walker, ELS and Watterson, A and Zhu, W and Karikari, TK and Xia, Z},
title = {Plasmaphosphorylated tau as biomarkers for multiple sclerosis diagnosis, subtyping, and prognosis.},
journal = {Brain communications},
volume = {8},
number = {1},
pages = {fcaf510},
pmid = {41659035},
issn = {2632-1297},
abstract = {Blood-based biomarkers are crucial for individualized management of multiple sclerosis (MS). Blood neurofilament light chain (NfL) and glial fibrillary acidic protein (GFAP) have shown promising clinical utility in MS, but they are insufficient to guide clinical management. Plasma tau proteins remain underexplored despite the growing evidence of shared pathology in Alzheimer's disease and MS. We aimed to: (i) assess the utility of plasma tau biomarkers [phosphorylated tau 181 (p-tau181), p-tau217 and total tau (t-tau)] in MS diagnosis, subtyping and prognosis; and (ii) compare their performance with NfL and GFAP. From a clinic-based prospective cohort, we evaluated 160 people with MS [pwMS; 117 with relapsing-remitting MS, 43 with progressive MS (PMS)] and 20 non-MS controls, all with baseline plasma samples. We measured baseline plasma concentrations of p-tau181, p-tau217, t-tau, NfL and GFAP using ultrasensitive immunoassays. We collected demographics, clinical information, and longitudinal multi-modal outcomes (Patient Determined Disease Steps, normalized age-related MS severity score, walking speed, manual dexterity, cognitive performance, retinal nerve fibre layer thickness, total brain volume and grey matter volume) over a median follow-up of 3.0 years (interquartile range, 3.5). Adjusting for demographic and clinical covariates, we evaluated associations between biomarkers and MS diagnosis, subtypes, and prognosis. We examined the enhanced value of tau markers, in addition to NfL and GFAP, for subtype distinction and outcome prediction. Participants were enrolled between 2017 and 2023. Assays were performed in August 2023. Analyses were conducted in December 2024. Participants (n = 180) had a median age of 51 years and were predominantly women (68%) and non-Hispanic white (91%). Compared with controls, pwMS had higher levels of p-tau217 (1.0 versus 0.7 pg/ml; P = 0.04) and NfL (14.1 versus 9.0 pg/ml; P < 0.01). Among pwMS, higher p-tau181 (adjusted odds ratio (aOR) [95% confidence interval (CI)] = 2.3 [1.4, 4.1]) and p-tau217 (aOR [95% CI] = 3.0 [1.8, 5.7]) were associated with PMS. These markers improved MS subtype classification accuracy beyond clinical features, NfL and GFAP. Higher baseline p-tau181 and p-tau217 predicted worse disability, functional outcomes and imaging outcomes independent of other biomarkers. Plasma p-tau181 and p-tau217 are promising biomarkers for MS subtype classification and disability prediction, providing complementary information to NfL and GFAP. Further studies to validate their potential clinical utility in guiding MS management are warranted.},
}

@article {pmid41658423,
year = {2026},
author = {Nistor, P and Espin-Garcia, O and Merali, Z and Ali, S},
title = {Predicting Dementia Risk: Progress, Pitfalls, and Priorities.},
journal = {International journal of public health},
volume = {71},
number = {},
pages = {1609520},
pmid = {41658423},
issn = {1661-8564},
}

@article {pmid41658395,
year = {2026},
author = {Kaur, B and Zhang, L and Nada, H and Calvo-Barreiro, L and Gabr, MT},
title = {Discovery of a CHI3L1-targeted small molecule modulating neuroinflammation in Alzheimer's disease via DNA-encoded library (DEL) screening.},
journal = {RSC medicinal chemistry},
volume = {},
number = {},
pages = {},
pmid = {41658395},
issn = {2632-8682},
abstract = {Chitinase-3-like protein 1 (CHI3L1, also known as YKL-40) has emerged as a central effector of astrocyte-mediated neuroinflammation and a promising biomarker for Alzheimer's disease (AD). However, small molecule CHI3L1 inhibitors that modulate neuroinflammation are limited. Here, we report the discovery of a CHI3L1-targeted small molecule, DEL-C1, identified through DNA-encoded library (DEL) screening and validated using orthogonal biophysical, computational, and cellular approaches. DEL-C1 demonstrated direct CHI3L1 binding in microscale thermophoresis (MST) and surface plasmon resonance (SPR) assays, with reversible and concentration-dependent association. Molecular docking and 100 ns molecular dynamics simulations revealed a stable binding mode within the CHI3L1 substrate groove, anchored by Tyr206 and flanked by Trp99 and Trp352, supporting a thermodynamically favorable interaction. In vitro ADME profiling indicated a balanced physicochemical profile, permeability, and metabolic stability, consistent with CNS drug-like properties. Functionally, DEL-C1 reversed CHI3L1-induced astrocyte dysfunction by restoring Aβ uptake, lysosomal acidification, and proteolytic activity, while reducing CHI3L1 and IL-6 secretion. DEL-C1 also suppressed CHI3L1-driven NF-κB transcriptional activation, highlighting its anti-inflammatory potential. Collectively, this study establishes DEL-C1 as a promising small molecule modulator of CHI3L1 and a chemical tool to interrogate astrocyte-driven neuroinflammation in AD.},
}

@article {pmid41658393,
year = {2025},
author = {Gohar, N and Saeed, A and Abbas, M and Ayaz, S and Zulfiqar, I and Masaud, SM and Nadeem, H},
title = {Novel isoxazolone derivatives as acetylcholinesterase inhibitors: design, synthesis, in silico and in vitro evaluation.},
journal = {RSC medicinal chemistry},
volume = {},
number = {},
pages = {},
pmid = {41658393},
issn = {2632-8682},
abstract = {Acetylcholinesterase (AChE) plays a pivotal role in Alzheimer's disease by accelerating acetylcholine breakdown, leading to cognitive decline. In this study, a series of novel isoxazolone derivatives were synthesized and structurally characterized using spectroscopic methods. The compounds were evaluated for their AChE inhibitory activity, where several candidates demonstrated stronger inhibition than the standard drug Donepezil. Molecular docking supported these findings, highlighting favorable interactions within the enzyme's active site. Selected compounds also exhibited promising antioxidant properties in the DPPH assay. A developed QSAR model provided insights into structural features contributing to bioactivity. In silico ADMET profiling indicated drug-like behavior, and molecular dynamics simulations confirmed the stability of the top ligand-enzyme complexes. Collectively, the results underscore the potential of isoxazolone-based scaffolds as multifunctional agents for managing Alzheimer's disease. Further biological evaluation is recommended to explore their therapeutic applicability.},
}

@article {pmid41658109,
year = {2026},
author = {Zingales, SK and Gibson, M and Tapia-Hernandez, J and Jenkins, K and Munzing, M and Dickerson, G and Speikers, S and Frazer, DJ and Padgett, CW and Wentzel, MT},
title = {Multicomponent Green Synthesis Involving Aryl Aldehydes and Trapped Enols: Dimerization over Cyclization.},
journal = {ACS omega},
volume = {11},
number = {4},
pages = {5112-5121},
pmid = {41658109},
issn = {2470-1343},
abstract = {This report serves two main purposes: (1) to correct the literature in the area of multicomponent synthesis involving aryl aldehydes and trapped enols 4-hydroxycoumarin 1 or 4-hydroxy-6-methyl-2-pyrone 2 and (2) to fully characterize the dimerization products bis-coumarins 3 and bis-pyrones 4. There have been many reports of cyclizations occurring with these species and various catalysts; however, many products have been mis-characterized and are, in fact, dimers. We successfully synthesized these dimers using a green, one-pot reaction in water that avoids hazardous organic solvents, uses a catalytic amount of acid, does not require chromatography for purification, and has strong green chemistry metrics. Our simplified procedure resulted in high yields of dimers ranging from 24 to 96% including the first report of a meta-substituted bis-pyrone 4i. Herein, we report a green method for their synthesis, along with their photophysical properties, full characterization, and potential as AChE inhibitors for anti-Alzheimer's therapy.},
}

@article {pmid41658012,
year = {2026},
author = {Xu, J and He, Y and Li, Z and Zhou, W and Huang, C and Lu, L and Bajpai, AK and Li, M},
title = {Identification of CTHRC1 as a novel candidate for neurodevelopmental disorders.},
journal = {Frontiers in aging neuroscience},
volume = {18},
number = {},
pages = {1737003},
pmid = {41658012},
issn = {1663-4365},
abstract = {BACKGROUND: Cognitive dysfunction affects over 50 million individuals worldwide, with Alzheimer's disease (AD) representing two-thirds of cases. We identified CTHRC1 (Collagen Triple Helix Repeat Containing 1) as a novel candidate associated with cognitive function and neurodegeneration.

METHODS: Human proteomic analysis revealed CTHRC1 as highly upregulated in AD patients (~5-fold increase, adj. p = 0.05), with corresponding elevation in 5xFAD mice. Single-cell RNA sequencing showed predominant astrocyte and oligodendrocyte progenitor expression. Using BXD mice, systems genetics analysis revealed associations between hippocampal CTHRC1 expression and 22 cognition-related phenotypes. PheWAS, ePheWAS, and GWAS analyses confirmed links to nervous system and AD-related traits.

RESULTS: eQTL mapping identified CTHRC1 as cis-regulated in hippocampus, and correlating with protein transport, transcription, and neurodegeneration pathways. Network analysis revealed 17 direct interactors, including key neurodegeneration genes (BACE1, NEFL, IRS1, VDAC1, SNCAIP) connecting CTHRC1 to core AD pathways (APP, MAPT, APOE, PSEN1/2). CTHRC1 overexpression in SH-SY5Y cells promoted tau degradation and modulated network partner expression.

CONCLUSION: CTHRC1 represents a central hub in cognitive function networks, suggesting therapeutic potential for neurodegenerative disorders.},
}

@article {pmid41658010,
year = {2026},
author = {Rajczyk, JI and Burke, JF and Xu, WY and Wing, JJ},
title = {Broadband Availability and Alzheimer's Disease and Related Dementias Prevalence in Central Appalachia.},
journal = {Journal of social service research},
volume = {},
number = {},
pages = {},
pmid = {41658010},
issn = {0148-8376},
abstract = {Geographical differences in Alzheimer's disease and related dementias (ADRD) prevalence may be driven by under-diagnosis due to insufficient healthcare access. Telehealth may improve ADRD detection in remote regions but relies on broadband service availability. We evaluated the influence of county-level broadband availability on Appalachian and rural variation of ADRD prevalence in six US Central Appalachian states and hypothesized that accounting for broadband access may accentuate Appalachian/non-Appalachian and rural/urban differences. An ecologic analysis evaluated county-level ADRD prevalence among the Medicare fee-for-service population across 591 Central Appalachian counties from 2015 to 2018. ADRD prevalence by Appalachian/non-Appalachian and rural/urban county-designation was estimated using negative binomial regression sequentially adjusting for age/education, diagnostic access, broadband presence/usage, poverty, and internet access/device ownership. Appalachian counties had lower ADRD prevalence than non-Appalachian counties in rural compared to urban counties (βAppXRural = -0.028; 95% Confidence Interval (CI): -0.052, -0.005). This variation attenuated with adjustment for broadband access (βAppXRural = -0.014; 95% CI: -0.038, 0.009). Broadband presence (β= -0.020; 95% CI: -0.032, -0.008) and a higher proportion of households with broadband in a county (β= -0.405; 95% CI: -0.534, -0.277) were negatively associated with ADRD prevalence after adjustment for poverty. Future research should implement alternative study designs to investigate mechanisms linking broadband access to ADRD prevalence.},
}

@article {pmid41657697,
year = {2026},
author = {Gaugler, JE and Johnson, E and Denno, B and Baumgart, M and McGuire, LC},
title = {National and state-level variations in caregiving for persons living with dementia in the US.},
journal = {Frontiers in public health},
volume = {14},
number = {},
pages = {1751603},
pmid = {41657697},
issn = {2296-2565},
mesh = {Humans ; *Caregivers/statistics & numerical data ; *Dementia/nursing ; Cross-Sectional Studies ; Female ; Male ; United States ; Middle Aged ; Aged ; Behavioral Risk Factor Surveillance System ; Adult ; Aged, 80 and over ; },
abstract = {PURPOSE: The objective of this study was to examine variations between dementia caregivers, caregivers of people without dementia, and non-caregivers across a range of sociodemographic and health variables nationally in 47 states and within five specific states representing a region of the U. S. (New York, Arizona, Minnesota, Idaho, Maine).

METHODS: This cross-sectional, observational study utilized 2021-2022 data from the Centers for Disease Control and Prevention (CDC) Behavioral Risk Factor Surveillance System (BRFSS). Bivariate and cross-tabulation analyses were conducted to examine empirical variation.

RESULTS: Although national results remain fairly consistent with prior research on dementia caregivers, heterogeneity emerges when comparing national results with dementia caregiving data across the five selected states.

CONCLUSION: The availability of local data resources on dementia caregiving could help to provide more accurate/relevant estimates of ADRD caregiving prevalence and better deliver home and community-based services where they are most needed.},
}

Humans
*Caregivers/statistics & numerical data
*Dementia/nursing
Cross-Sectional Studies
Female
Male
United States
Middle Aged
Aged
Behavioral Risk Factor Surveillance System
Adult
Aged, 80 and over

@article {pmid41657477,
year = {2026},
author = {Rahi, A and Jafari, E and Azizian, R and Mohammadi, MR and Razmfarsa, A and Shakeri Hosseinabad, S and Hamidi, M},
title = {Exploring the Gut-Brain Connection: The Role of Microbiota in Alzheimer's Disease Pathogenesis.},
journal = {Dementia and neurocognitive disorders},
volume = {25},
number = {1},
pages = {1-12},
pmid = {41657477},
issn = {2384-0757},
abstract = {Alzheimer's disease (AD), the primary cause of dementia accounting for 60% to 70% of cases globally, results in a gradual decline in cognitive abilities, affecting memory, executive function, and daily activities. Recent research highlights the essential involvement of the microbiota-gut-brain axis in AD pathogenesis, characterized by complex bidirectional signaling that modulates neuroinflammation, neurogenesis, neurotransmission, and immune functions. This manuscript extends the discussion beyond the gut alone by emphasizing the significance of the oral-gut microbiota axis as a dynamic and relatively under-investigated factor in AD progression. Microbial populations in both the oral cavity and gastrointestinal tract produce key neurotransmitters, such as gamma-aminobutyric acid, noradrenaline, and dopamine, as well as neuroactive metabolites like short-chain fatty acids, which together impact brain physiology. Disturbances in gut and oral microbial balance can compromise barrier integrity, promoting systemic inflammation and neuroinflammation, and facilitating amyloid-β plaque formation and tau-related changes typical of AD. This review introduces a novel probiotic, prebiotics, synbiotics, and postbiotics (PPSP) therapeutic model designed to modulate both oral and gut microbiota, aiming to restore homeostasis, regulate neuroimmune interactions, and counteract cognitive impairment. We comprehensively assess emerging clinical and translational findings supporting the effectiveness of microbiota-targeted therapies in the scope of this dual-axis framework, addressing both their potential to alter disease course and recognized limitations. By underscoring the importance of the integrated oral-gut microbiota axis alongside targeted PPSP interventions, this manuscript puts forth a paradigm-shifting conceptual strategy that may redefine approaches to AD management and improve cognitive outcomes.},
}

@article {pmid41657474,
year = {2026},
author = {Kim, GH and Pyun, JM and Kang, D and Kang, SH and Koh, SH and Kim, JS and Moon, SY and Moon, WJ and Park, YH and Shim, Y and Yang, DW and Youn, YC and Jung, YH and Cho, H and Choi, H and Lim, JS and Park, KH and Choi, SH},
title = {A Protocol of Korean JOint RegistrY for ALZheimer's Treatment and Diagnostics (JOY-ALZ).},
journal = {Dementia and neurocognitive disorders},
volume = {25},
number = {1},
pages = {25-41},
pmid = {41657474},
issn = {2384-0757},
abstract = {BACKGROUND AND PURPOSE: To assess the long-term effectiveness, safety, and economic viability of recently approved Alzheimer's disease (AD) therapies, as well as to evaluate the real-world application of novel diagnostics among AD patients with diverse comorbidities, comprehensive real-world data (RWD) analysis is essential. The Korean JOint RegistrY for ALZheimer's Treatment and Diagnostics (JOY-ALZ) endeavors to create a registry of RWD derived from clinical practice on new diagnostic methods and therapeutic agents for AD introduced in Korea since 2021.

METHODS: Participants must fulfill all the following: 1) be at least 19 years old; 2) be actively receiving, scheduled to initiate, or undergoing evaluation for any AD disease-modifying treatment; 3) have completed amyloid positron emission tomography or cerebrospinal fluid AD immunoassay (a positive result is not essential for participation); 4) have a clinical classification of cognitively unimpaired, mild cognitive impairment, or probable AD dementia. Data generated during routine care is segmented into a minimum dataset, extended dataset, and research-only dataset requiring extra consent. Assessments encompass clinical, cognitive, functional, neurobehavioral, neuroimaging, and biomarker evaluations, in addition to systematic monitoring of new AD treatments and their safety. Data are collected and monitored at baseline, at semiannual intervals during the initial 2 years, and then annually up to 2034. To date, 46 medical centers will participate in JOY-ALZ.

CONCLUSIONS: JOY-ALZ is expected to promote understanding of the long-term clinical outcomes, safety, and cost-effectiveness of recently introduced diagnostics and treatments for AD, thereby supporting the progress of precision medicine in AD care and diagnosis.

TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT06889818.},
}

@article {pmid41657473,
year = {2026},
author = {Lee, J and Jung, S and Lee, AY},
title = {Predicting Brain Amyloid PET Positivity Using the Amyloid Beta Composite (ABC) Index in Patients With Cognitive Impairment.},
journal = {Dementia and neurocognitive disorders},
volume = {25},
number = {1},
pages = {79-89},
pmid = {41657473},
issn = {2384-0757},
abstract = {BACKGROUND AND PURPOSE: Amyloid positron emission tomography (PET) is a crucial diagnostic tool for Alzheimer's disease (AD), but its application is constrained by cost and accessibility. This study aimed to create a practical composite index to predict cerebral amyloid positivity in patients with cognitive impairment.

METHODS: We included patients with mild cognitive impairment or early-stage AD who underwent amyloid PET. Various combinations of clinical and imaging variables were assessed through receiver operating characteristic analysis to identify the optimal model for predicting amyloid positivity. The Amyloid Beta Composite (ABC) index, a risk scoring model, was developed using logistic regression and a weighted scoring system. We evaluated the ABC index's performance based on accuracy, sensitivity, and specificity, and conducted internal validation using a chronological split-sample from the same cohort.

RESULTS: We analyzed a total of 223 patients. The best-performing model incorporated five variables: Mini-Mental State Examination (MMSE), secondary memory recall from the modified MMSE, Clinical Dementia Rating-Sum of Boxes, medial temporal lobe atrophy, and apolipoprotein E genotype. This model demonstrated excellent performance in the development group (area under the curve [AUC], 0.88; 95% confidence interval, 0.82-0.94). In the validation group, the ABC index achieved an AUC of 0.74, with an accuracy of 0.70, sensitivity of 0.63, and specificity of 0.78.

CONCLUSIONS: The ABC index, utilizing commonly accessible clinical data, serves as a simple and practical screening tool for predicting cerebral amyloid deposition. It may aid in patient selection for amyloid PET, anti-amyloid therapies, and clinical trials, thereby reducing unnecessary imaging.},
}

@article {pmid41657418,
year = {2026},
author = {Geiger, PC and Pennington, JS and Kueck, PJ and John, CS and Mayfield, HD and Kemna, RE and Burns, J and Vidoni, E and Honea, R and Li, Y and Mahnken, J and Morris, JK},
title = {Heat therapy in individuals at risk for Alzheimer's disease-methods for a randomized controlled trial.},
journal = {Frontiers in neurology},
volume = {17},
number = {},
pages = {1736108},
pmid = {41657418},
issn = {1664-2295},
abstract = {UNLABELLED: Heat therapy (HT) has been shown to improve peripheral blood glucose regulation in some populations, yet its effects on brain glucose metabolism remain largely unexplored. The chronic benefits of HT may arise in part from upregulation of heat-shock proteins (HSPs). These proteins play a crucial role in the stress response and modulate diverse processes such as proteostasis and cell signaling pathways, including that of insulin signaling. Understanding the impact of HT on both peripheral and central glucose metabolism, including the effects of varying temperatures, is essential for elucidating potential mechanisms underlying its brain benefits. The Feasibility of Improving Glycemia to prevent Alzheimer's Disease (FIGHT-AD) study is a randomized controlled trial that aims to investigate changes in blood and brain glucose regulation following 10 weeks of HT. Specifically, we will examine the peripheral biomarker responses to warm and hot HT and assess how these responses relate to brain metabolic changes in both treatment groups. This trial will be the first to quantify the effect of HT on cerebral glucose metabolism in individuals at metabolic risk for Alzheimer's Disease (AD). The FIGHT-AD trial will provide critical data to inform the design of future clinical trials targeting metabolic and brain health through HT.

CLINICAL TRIAL REGISTRATION: clinicaltrials.gov, identifier NCT06023407.},
}

@article {pmid41657416,
year = {2026},
author = {Drakopoulos, M and Lyons, CE and Sikora, H and Abbott, S and Volpe, N and Mirza, RG},
title = {Quantitative ophthalmic posterior segment optical coherence tomography angiography and neurologic conditions: a review.},
journal = {Frontiers in neurology},
volume = {17},
number = {},
pages = {1746695},
pmid = {41657416},
issn = {1664-2295},
abstract = {OBJECTIVES: To investigate the potential of quantitative ophthalmic posterior segment optical coherence tomography angiography (OCTA) imaging metrics to serve as biomarkers for systemic involvement in five neurologic diseases (multiple sclerosis, neuromyelitis optica spectrum disorder, myelin oligodendrocyte glycoprotein antibody-associated disease, Alzheimer disease, and Parkinson disease) by reviewing the reported correlations between such OCTA metrics and clinically relevant features of systemic involvement in these diseases.

METHODS: This article is a literature review of the PubMed database for articles reporting OCTA metrics in any of the included neurologic diseases. Articles correlating quantitative retinal, optic nerve head, or choriocapillaris OCTA metrics to clinically relevant features of systemic involvement, specifically serum, cerebrospinal fluid (CSF), or other established biomarkers; genotype; systemic symptom and severity scores; stage; non-ocular organ involvement; brain or other non-ocular imaging findings; and systemic medication use were included.

RESULTS: OCTA parameters have been significantly correlated to established biomarkers, severity scores, non-ocular organ involvement and imaging findings, and systemic medication use in multiple sclerosis. OCTA parameters have been significantly correlated to established biomarkers, severity scores, and non-ocular organ involvement and imaging findings in neuromyelitis optica spectrum disorder. OCTA parameters have been significantly correlated to severity scores in myelin oligodendrocyte glycoprotein antibody-associated disease. OCTA parameters have been significantly correlated to established biomarkers, genotype, severity scores, disease stage, and non-ocular organ involvement and imaging findings in Alzheimer disease. OCTA parameters have been significantly correlated to severity scores, disease stage, and non-ocular organ involvement in Parkinson disease.

CONCLUSION: Our findings suggest that ophthalmic posterior segment OCTA might improve our understanding of the pathophysiology of systemic neurologic conditions, including those that do not traditionally affect the eye, and might identify biomarkers useful in the diagnosis, prognosis, and management of these conditions, justifying further investigation.},
}

@article {pmid41657222,
year = {2026},
author = {Selber-Hnatiw, S and Trajanoska, K and Pelletier, J and Su, CY and McClelland, P and Taliun, D and Yoshiji, S and Mooser, V and Bhérer, C and Zhou, S},
title = {Phenome-Wide Mendelian Randomization Identifying Circulating Proteins for Cardiovascular Traits in Populations of African Ancestry.},
journal = {Circulation. Genomic and precision medicine},
volume = {},
number = {},
pages = {e005159},
doi = {10.1161/CIRCGEN.125.005159},
pmid = {41657222},
issn = {2574-8300},
abstract = {BACKGROUND: Circulating proteins represent robust drug targets with therapeutic potential. Many discoveries have focused on European-ancestry populations, disregarding minuscule yet substantial proteomic differences that may contribute to disease and alter drug generalizability in other ancestry groups.

METHODS: Using 2-sample Mendelian randomization and colocalization, we analyzed the effects of 1562 circulating proteins on 145 cardiometabolic-centric outcomes to identify robust protein-phenotype associations in African-ancestry populations and reveal African-ancestry associations with heterogeneous effects. We further replicated these findings using the proteomic data available from the UK Biobank Pharma Proteomics Project and tested the effect of protein quantity in association with select phenotypes. Population branch statistics were also constructed to examine whether protein-genetic instruments under natural selection could lead to significant protein-outcome associations specific to the African ancestry.

RESULTS: We identified 115 robust protein target-outcome associations in African-ancestry populations. Among these, 51 demonstrated heterogeneous effects between African- and European-ancestry populations. We further replicated 4 cross-platform African-ancestry associations in the UK Biobank Pharma Proteomics Project and also revealed 4 significant, direct associations between protein levels and phenotypes. Ultimately, based on our prioritization criteria, we found that CD36 (glycoprotein IIIb), APOC1 (apolipoprotein C1), GSTA1 (glutathione S-transferase alpha 1), and FOLH1 (folate hydrolase 1) were shown to influence lipids and heart diseases, and were uniquely represented in African-ancestry populations. In addition, using population branch statistics, we showed that 47.5% of the 115 significant protein-outcome associations were possibly driven by cis-acting protein quantitative trait loci under natural selection.

CONCLUSIONS: Multiple lines of evidence were used to interrogate proteomic determinants of cardiometabolic diseases and traits in African-ancestry populations. We highlighted actionable circulating protein targets that could represent potential drug targets for cardiovascular diseases specific to populations with African ancestry.},
}

@article {pmid41657128,
year = {2026},
author = {van der Veere, PJ and van Harten, AC and van Maurik, IS and Teunissen, CE and Barkhof, F and Vos, SJB and Froelich, L and Kornhuber, J and Wiltfang, J and Maier, W and Peters, O and Rüther, E and Frisoni, GB and Spiru, L and Freund-Levi, Y and Wallin, ÅK and Hampel, H and Tsolaki, M and Kłoszewska, I and Mecocci, P and Vellas, B and Lovestone, S and Galluzzi, S and Herukka, SK and Santana, I and Baldeiras, I and de Mendonca, A and Silva, D and Chetelat, G and Poisnel, G and Visser, PJ and Johnson, SC and Stormrud, E and Hansson, O and Palmqvist, S and Piñol-Ripoll, G and , and Berkhof, J and van der Flier, WM},
title = {Revising the ABIDE MCI to dementia prediction model for automated cerebrospinal fluid assays.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {2},
pages = {e71192},
doi = {10.1002/alz.71192},
pmid = {41657128},
issn = {1552-5279},
support = {/AG/NIA NIH HHS/United States ; U24 AG072122/GF/NIH HHS/United States ; P30 AG062429/GF/NIH HHS/United States ; 73305095007//Personalized Medicine Approach for Alzheimer's Disease/ ; LSHM20106//Health∼Holland, Topsector Life Sciences & Health/ ; ZEN24-1069572/ALZ/Alzheimer's Association/United States ; //GHR Foundation/ ; ADG-101096455/ERC_/European Research Council/International ; 2023-00356//Swedish Research Council/ ; 2021-02219//Swedish Research Council/ ; 2018-02052//Swedish Research Council/ ; 2022-0231//Knut and Alice Wallenberg foundation/ ; 101053962//European Union's Horizon Europe/ ; //Strategic Research Area MultiPark (Multidisciplinary Research in Parkinson's disease) at Lund University/ ; AF-1011949//Swedish Alzheimer Foundation/ ; AF-994075//Swedish Alzheimer Foundation/ ; AF-994229//Swedish Alzheimer Foundation/ ; AF-981132//Swedish Alzheimer Foundation/ ; FO2024-0284//Swedish Brain Foundation/ ; FO2022-0204//Swedish Brain Foundation/ ; FO2021-0293//Swedish Brain Foundation/ ; FRS-0004//Rönström's Foundation/ ; FRS-0011//Rönström's Foundation/ ; 115372//Innovative Medicines Initiative Joint/ ; FP7/2007-2013//European Union's Seventh Framework Programme/ ; U01 AG024904/AG/NIA NIH HHS/United States ; W81XWH-12-2-0012//Department of Defense/ ; /EB/NIBIB NIH HHS/United States ; //AbbVie/ ; //Alzheimer's Drug Discovery Foundation/ ; //Araclon Biotech/ ; //BioClinica, Inc./ ; //Biogen/ ; //Bristol-Myers Squibb Company/ ; //CereSpir, Inc./ ; //Cogstate/ ; //Elan Pharmaceuticals, Inc./ ; //Eli Lilly and Company/ ; //F. Hoffmann-La Roche Ltd and its affiliated company Genentech, Inc./ ; //Fujirebio/ ; //GE Healthcare/ ; //IXICO Ltd./ ; //Janssen Alzheimer Immunotherapy Research & Development, LLC./ ; //Johnson & Johnson Pharmaceutical Research & Development LLC./ ; //Lumosity/ ; //Lundbeck/ ; //Merck & Co., Inc./ ; //Meso Scale Diagnostics, LLC./ ; //NeuroRx Research/ ; //Neurotrack Technologies/ ; //Novartis Pharmaceuticals Corporation/ ; //Pfizer Inc./ ; //Piramal Imaging/ ; //Servier/ ; //Takeda Pharmaceutical Company/ ; //Transition Therapeutics/ ; P30 AG062429/AG/NIA NIH HHS/United States ; P30 AG066468/AG/NIA NIH HHS/United States ; P30 AG062421/AG/NIA NIH HHS/United States ; P30 AG066509/AG/NIA NIH HHS/United States ; P30 AG066514/AG/NIA NIH HHS/United States ; P30 AG066530/AG/NIA NIH HHS/United States ; P30 AG066507/AG/NIA NIH HHS/United States ; P30 AG066444/AG/NIA NIH HHS/United States ; P30 AG066518/AG/NIA NIH HHS/United States ; P30 AG066512/AG/NIA NIH HHS/United States ; P30 AG066462/AG/NIA NIH HHS/United States ; P30 AG072979/AG/NIA NIH HHS/United States ; P30 AG072972/AG/NIA NIH HHS/United States ; P30 AG072976/AG/NIA NIH HHS/United States ; P30 AG072975/AG/NIA NIH HHS/United States ; P30 AG072978/AG/NIA NIH HHS/United States ; P30 AG072977/AG/NIA NIH HHS/United States ; P30 AG066519/AG/NIA NIH HHS/United States ; P30 AG062677/AG/NIA NIH HHS/United States ; P30 AG079280//NACC/ ; P30 AG062422/AG/NIA NIH HHS/United States ; P30 AG066511/AG/NIA NIH HHS/United States ; P30 AG072946/AG/NIA NIH HHS/United States ; P30 AG062715/AG/NIA NIH HHS/United States ; P30 AG072973/AG/NIA NIH HHS/United States ; P30 AG066506/AG/NIA NIH HHS/United States ; P30 AG066508/AG/NIA NIH HHS/United States ; P30 AG066515/AG/NIA NIH HHS/United States ; P30 AG072947/AG/NIA NIH HHS/United States ; P30 AG072931/AG/NIA NIH HHS/United States ; P30 AG066546/AG/NIA NIH HHS/United States ; P30 AG086401/AG/NIA NIH HHS/United States ; P30 AG086404/AG/NIA NIH HHS/United States ; P20 AG068082/AG/NIA NIH HHS/United States ; P30 AG072958/AG/NIA NIH HHS/United States ; P30 AG072959/AG/NIA NIH HHS/United States ; /CAPMC/CIHR/Canada ; },
mesh = {Humans ; *Cognitive Dysfunction/cerebrospinal fluid/diagnosis ; *Dementia/cerebrospinal fluid/diagnosis ; Male ; Female ; Aged ; Disease Progression ; Biomarkers/cerebrospinal fluid ; *Amyloid beta-Peptides/cerebrospinal fluid ; Cohort Studies ; Aged, 80 and over ; },
abstract = {INTRODUCTION: Automated cerebrospinal fluid (CSF) biomarker assays have largely replaced manual immunoassays for measuring amyloid pathology in CSF. We refitted and validated the ABIDE model, predicting progression from mild cognitive impairment (MCI) to dementia, with CSF measurements from the automated Elecsys platform.

METHODS: We included 2413 MCI participants (998 [41%] amyloid-positive) from seven observational cohorts. Elecsys was used in 958 (40%) participants. The parameters of the previous ABIDE Cox model were re-estimated. Model discrimination and calibration were evaluated with leave-one-cohort-out cross-validation.

RESULTS: During follow-up, 1034 (42%; 585 [58%] amyloid-positive) participants developed dementia. Discrimination was good with Harrell's C of 0.70 (95% confidence interval [CI]: 0.66-0.73). Calibration was good in the total population and amyloid-positive subgroup, with substantial predicted progression risks for all amyloid-positive participants.

DISCUSSION: We refitted the ABIDE model, predicting MCI to dementia progression, with automated CSF measurements. The model was well calibrated in amyloid-positive patients and may support clinical discussions regarding ATTs.},
}

Humans
*Cognitive Dysfunction/cerebrospinal fluid/diagnosis
*Dementia/cerebrospinal fluid/diagnosis
Male
Female
Aged
Disease Progression
Biomarkers/cerebrospinal fluid
*Amyloid beta-Peptides/cerebrospinal fluid
Cohort Studies
Aged, 80 and over

@article {pmid41656841,
year = {2025},
author = {Zhang, X and Pan, M},
title = {[Changes and forecast of the disease burden of senile dementias among Chinese residents from 1992 to 2021].},
journal = {Zhong nan da xue xue bao. Yi xue ban = Journal of Central South University. Medical sciences},
volume = {50},
number = {11},
pages = {2071-2081},
doi = {10.11817/j.issn.1672-7347.2025.250464},
pmid = {41656841},
issn = {1672-7347},
mesh = {Humans ; China/epidemiology ; Aged ; *Alzheimer Disease/epidemiology/mortality ; Male ; Female ; Incidence ; Middle Aged ; Aged, 80 and over ; Disability-Adjusted Life Years ; *Cost of Illness ; Forecasting ; *Dementia/epidemiology ; Global Burden of Disease ; Bayes Theorem ; East Asian People ; },
abstract = {OBJECTIVES: The China Alzheimer's Disease Report 2024 reveals that the number of deaths in China due to Alzheimer's disease (AD) and other types of dementia reached 320 715, accounting for 19.8% of global dementia-related deaths. The socioeconomic burden is increasingly prominent and poses a serious threat to the health of Chinese residents. This study aims to analyze the changes in the disease burden of dementias among Chinese residents from 1992 to 2021 and to predict future trends, so as to provide a reference for dementia prevention and control.

METHODS: Based on data from the Global Burden of Disease (GBD) Study 2021, Joinpoint regression models were used to analyze the incidence and age-standardized incidence rate, deaths and age-standardized mortality rate, disability-adjusted life year (DALY) and age-standardized DALY rate of senile dementia among Chinese residents aged 60 years and above from 1992 to 2021. Age-period-cohort models were used to analyze incidence and mortality under different effects. Bayesian age-period-cohort models were applied to predict the age-standardized incidence rate of dementias among Chinese residents from 2022 to 2031.

RESULTS: From 1992 to 2021, the disease burden of senile dementia among Chinese residents increased year by year. The age-standardized incidence rate and age-standardized DALY rate showed fluctuating upward trends, while the age-standardized mortality rate declined. The average annual percent change (AAPC) of the age-standardized incidence rate, age-standardized mortality rate, and age-standardized DALY rate were 0.57%, -0.07%, and 0.09%, respectively (all P<0.05). From 2019 to 2021, the numbers of incident cases, deaths, and DALY of dementia among Chinese residents aged 60 years and above increased significantly, with higher values in females than in males. The age-period-cohort model indicated that incidence and mortality risks increased with age, with a marked increase after 70 years of age; incidence risk showed a "wave-like" pattern of increase-decrease-increase over periods, while mortality risk showed a trend of decrease followed by increase; incidence risk fluctuated upward across birth cohorts, whereas mortality risk fluctuated downward. Predictions from the Bayesian age-period-cohort model indicate that from 2022 to 2031, the age-standardized incidence rate of dementia in China may continue to increase, reaching 1 616.87 per 100 000 in the total population, 1 304.71 per 100 000 in males, and 1 809.09 per 100 000 in females by 2031.

CONCLUSIONS: From 1992 to 2021, the disease burden of senile dementia in China has increased year by year, with a particularly heavy burden among older women. Senile dementia remains a major public health problem, and its disease burden may continue to increase in the future. It is recommended to promote early screening to promote early screening among high-risk populations and to enhance public awareness through extensive health education to reduce incidence risk and comprehensively improve the effectiveness of senile dementia prevention and control.},
}

Humans
China/epidemiology
Aged
*Alzheimer Disease/epidemiology/mortality
Male
Female
Incidence
Middle Aged
Aged, 80 and over
Disability-Adjusted Life Years
*Cost of Illness
Forecasting
*Dementia/epidemiology
Global Burden of Disease
Bayes Theorem
East Asian People

@article {pmid41656821,
year = {2025},
author = {Wu, T and Wen, X and Zhang, J and Zhang, Y and Fu, M and Yi, G},
title = {Tear fluid participates in systemic immunity.},
journal = {Zhong nan da xue xue bao. Yi xue ban = Journal of Central South University. Medical sciences},
volume = {50},
number = {10},
pages = {1930-1939},
doi = {10.11817/j.issn.1672-7347.2025.250186},
pmid = {41656821},
issn = {1672-7347},
support = {A2023423//the Medical Scientific Research Foundation of Guangdong Province, China/ ; CC BY-NC-ND 4.0 and //creativecommons.org/licenses/by-nc-nd/4.0///This is an open access article under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International/ ; },
mesh = {Humans ; *Tears/immunology ; *Autoimmune Diseases/immunology ; MicroRNAs ; Cytokines/immunology ; Biomarkers/analysis ; },
abstract = {Tear fluid, also referred to as tears or tear film, is an important biological fluid that plays a key role in maintaining ocular surface health and immune homeostasis. Recent studies have found that tear fluid not only participates in the occurrence and development of ocular diseases, but also exerts profound effects in the immune pathological mechanisms of systemic diseases, breaking through the inherent understanding previously held by the scientific community. Immune cells in tear fluid (such as T cells, neutrophils, natural killer cells, macrophages), cytokines, and immunoglobulins can specifically participate in autoimmune diseases (such as Sjögren's syndrome, rheumatoid arthritis, systemic lupus erythematosus, multiple sclerosis, Graves' ophthalmopathy) and systemic diseases (such as Alzheimer's disease, diabetes mellitus, graft-versus-host disease). The dynamic changes in tear fluid components can reflect systemic immune homeostasis imbalance. Tear fluid biomarkers, such as exosomal microRNA (miR)-204, miR-200b-5p, and the protein marker β2-microglobulin, have shown great potential in early disease screening, diagnostic stratification, and therapeutic target discovery. Tear fluid immune component analysis may provide innovative diagnostic tools and therapeutic targets for systemic diseases. Future research should focus on promoting the standardization and clinical transformation of tear fluid testing technologies and their clinical application.},
}

Humans
*Tears/immunology
*Autoimmune Diseases/immunology
MicroRNAs
Cytokines/immunology
Biomarkers/analysis

@article {pmid41656561,
year = {2026},
author = {Hosseini, SA and Servaes, S and Macedo, AC and Aumont, E and Rahmouni, N and Chan, T and Therriault, J and Trudel, L and Hall, B and Wang, YT and Arias, JF and Bezgin, G and Zheng, Y and Gonçalves, MP and Quispialaya Socualaya, K and Woo, MS and Tissot, C and Oliva-Lopez, D and Li, J and Mitchell, S and Lebrun, A and Hopewell, R and Chawla, S and Fonov, V and Massarweh, G and Medina, YI and Soucy, JP and Montembeault, M and Vitali, P and Blennow, K and Karikari, TK and Benedet, AL and Ashton, NJ and Zetterberg, H and Pascoal, TA and Gauthier, S and Klostranec, J and Zhuang, H and Cho, J and Collins, DL and Wang, Y and Rudko, DA and Rosa-Neto, P},
title = {Quantitative susceptibility mapping of the brain is associated with inflammatory changes in Alzheimer's disease related areas.},
journal = {Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism},
volume = {},
number = {},
pages = {271678X261417193},
doi = {10.1177/0271678X261417193},
pmid = {41656561},
issn = {1559-7016},
abstract = {Accumulation of paramagnetic substances in brain tissue may constitute a feature of Alzheimer's disease (AD) associated with inflammatory processes. This study employed MRI quantitative susceptibility mapping (QSM), as an index of paramagnetic load, to assess its association with brain Aβ and tau aggregates, as well as inflammatory biomarkers. We assessed QSM and T1-weighted MRI scans from 315 participants in the TRIAD cohort, including young-controls and individuals across the AD spectrum. Imaging was performed at baseline, with follow-up assessments at 12 and 24 months. Mean-cortical and subcortical susceptibility values were measured, and correlations with AD-relevant plasma and CSF inflammatory biomarkers. At baseline, AD patients had significantly greater QSM than age-matched controls in the posterior cingulate cortex, precuneus, and basal ganglia. After 24 months, QSM increased in the anterior cingulate in MCI, while dementia cases showed increase in the pallidum and hippocampus. Multiple comparison analysis indicated correlation between QSM and immune biomarkers IL-10RB, PD-L1, SCF, TWEAK, CSF-1, CXCL9, HGF, and CD40, but not with brain Aβ or tau-related biomarkers. Our findings reveal that the magnitude of tissue susceptibility load, as measured by QSM, reflects tissue inflammation rather than protein aggregation. QSM provides new insights into tissue dysfunction, with potential applications in AD therapeutic development.},
}

@article {pmid41656413,
year = {2026},
author = {Xiong, D and Liu, M and Liu, Z and Wang, J},
title = {Integrating standard and native spaces for radiomics and brain network analysis in Alzheimer's disease diagnosis and prognosis.},
journal = {Journal of neurology},
volume = {273},
number = {2},
pages = {124},
pmid = {41656413},
issn = {1432-1459},
support = {TJWJ2025ZD001//the Tianjin Health Research Project/ ; 25ZXWZSY00070//Tianjin Science and Technology Plan Project/ ; },
mesh = {Humans ; *Alzheimer Disease/diagnostic imaging/diagnosis ; Male ; Female ; Aged ; *Magnetic Resonance Imaging/methods ; *Cognitive Dysfunction/diagnostic imaging ; Prognosis ; Aged, 80 and over ; *Neuroimaging/methods ; Machine Learning ; Disease Progression ; *Brain/diagnostic imaging ; *Nerve Net/diagnostic imaging ; Cohort Studies ; Radiomics ; },
abstract = {INTRODUCTION: Structural MRI analysis for Alzheimer's disease (AD) is limited by balancing group-level comparability in standard space with anatomical fidelity in native space. We therefore propose a multi-space, hybrid-feature framework, integrating radiomics and network metrics from both spaces to classify AD and predict mild cognitive impairment (MCI) progression.

METHODS: An integrated dual-space analytical framework was applied to T1-weighted MRI data. Models were developed on 1,477 participants from Alzheimer's Disease Neuroimaging Initiative (ADNI) and externally tested on an independent cohort of 1,349 participants from National Alzheimer's Coordinating Center (NACC). The framework extracts parallel radiomic and graph-based network features from both Montreal Neurological Institute (MNI) standard space and native space. These features were used to build machine learning models for three-class diagnosis (NC vs. MCI vs. AD) and 6-year prognostic prediction of MCI-to-AD conversion. For each task, the models using standard-space, native-space, and combined-space features were systematically compared. Model interpretation was performed using Shapley Additive Explanations (SHAP), and the features were validated against established AD biomarkers.

RESULTS: The combined-space model demonstrated superior performance in both diagnostic classification (Macro-Averaged AUC: 0.96 in ADNI cohort, 0.94 in NACC cohort) and prognostic prediction of MCI-to-AD conversion (C-index: 0.83; HRs: 7.60, 95%CIs: 4.57-12.64). The extracted features in the ADNI cohort demonstrated significant correlations with APOE ε4 genotype, cognitive scores, and CSF biomarkers.

CONCLUSION: Integrating multi-scale features from both standard and native spaces enhances AD diagnosis and prognosis accuracy more effectively than conventional single-space analysis.},
}

Humans
*Alzheimer Disease/diagnostic imaging/diagnosis
Male
Female
Aged
*Magnetic Resonance Imaging/methods
*Cognitive Dysfunction/diagnostic imaging
Prognosis
Aged, 80 and over
*Neuroimaging/methods
Machine Learning
Disease Progression
*Brain/diagnostic imaging
*Nerve Net/diagnostic imaging
Cohort Studies
Radiomics

@article {pmid41661788,
year = {2024},
author = {McCormick, L and Bodla, AP and Rubin, RT},
title = {Very early onset dementias: Importance of differentiating from schizophrenia spectrum disorders.},
journal = {PLOS mental health},
volume = {1},
number = {3},
pages = {e0000107},
doi = {10.1371/journal.pmen.0000107},
pmid = {41661788},
issn = {2837-8156},
abstract = {Very early onset dementias and other neurodegenerative diseases often present with prominent behavioral disturbances and can be initially misdiagnosed as schizophrenia spectrum disorders. Differentiating a primary psychiatric condition from a neurodegenerative cause is important, because there are considerable differences in prognosis, treatment, and the services required for effective management. To illustrate the implications of misdiagnosis, we provide case examples of very early onset dementias, most of which were initially diagnosed as schizophrenia or other psychotic disorder, owing to their unusually young age of onset and initial behavioral presentations. We suggest how a clinician can differentiate schizophrenia from rarer, early onset neurodegenerative causes of altered behavior and mentation, including behavioral variant frontotemporal dementia (bvFTD), Wilson's disease, adult metachromatic leukodystrophy (MLD), Creuzfeldt-Jakob disease (CJD), and very early-onset Alzheimer's disease. Schizophrenia with prominent obsessive-compulsive (OC) symptoms is briefly discussed, given that OC symptoms can be a major feature of dementias with prominent behavioral components.},
}

@article {pmid41656391,
year = {2026},
author = {Corriveau, RA},
title = {The many meanings of Alzheimer's disease and why they matter for policy, research, and care.},
journal = {GeroScience},
volume = {},
number = {},
pages = {},
pmid = {41656391},
issn = {2509-2723},
abstract = {Alzheimer's disease (AD) is a national priority with far-reaching implications for patients, families, clinicians, researchers, and policymakers. Yet the term AD refers to multiple distinct meanings that are often overlooked or ambiguously applied, risking misaligned research and policy priorities that affect patient outcomes. Recent FDA approvals of passive immunotherapies and related biomarker developments show that differing interpretations of AD complicate research, regulatory decisions, payer coverage, and clinical use. In contrast to efforts aimed at revising AD nomenclature, this paper clarifies five key meanings of AD as currently used. It provides a practical framework to indicate how the term AD is applied in different ways within and across clinical, research, regulatory, and policy contexts. Each key meaning-clinical (symptom-focused), genetically determined (mutation-driven), pathological (autopsy-confirmed), plaque-defined (amyloid-beta-plaque-positive), and broad (can encompass multiple dementia types)-may apply alone or in combination depending on context. These distinctions also raise ethical considerations, particularly for biomarker-based diagnoses and their impact on patient communication and decision-making. Using this framework helps decision-makers identify the intended AD meaning and align research, policy, and care for better patient outcomes.},
}

@article {pmid41656167,
year = {2026},
author = {Li, YJ and La, JO and Naj, A and Martin, ER},
title = {Leveraging genetic propensity to identify modifiable factors for the age at onset of Alzheimer's disease.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {2},
pages = {e71111},
doi = {10.1002/alz.71111},
pmid = {41656167},
issn = {1552-5279},
support = {RF1AG060472/AG/NIA NIH HHS/United States ; UO1AG032984/AG/NIA NIH HHS/United States ; },
mesh = {Humans ; *Alzheimer Disease/genetics/epidemiology ; Genome-Wide Association Study ; Age of Onset ; Diabetes Mellitus, Type 2/genetics/epidemiology ; Mendelian Randomization Analysis ; Educational Status ; Aged ; Male ; Female ; Multifactorial Inheritance ; Risk Factors ; Genetic Predisposition to Disease ; Cardiovascular Diseases/genetics/epidemiology ; },
abstract = {INTRODUCTION: Knowledge of modifiable factors influencing age at onset (AAO) of Alzheimer's disease (AD) remains limited. This study utilizes genetic information to uncover such factors.

METHODS: Using 43 exposure genome-wide association studies (GWAS) summary statistics, we calculated corresponding polygenic scores (PGS) for 9219 AD cases and 10,345 controls from the Alzheimer's Disease Genetic Consortium (ADGC). Linear mixed model and survival analyses were performed to identify exposure-PGS associated with AAO. Top exposures were cross-evaluated using PGS from the PGS Catalog and Mendelian randomization (MR) for causal relationships.

RESULTS: Eight exposures showed significant exposure-PGS associations with AAO of AD. Higher educational attainment, better cognitive performance, and greater relative fat intake were associated with later AAO; whereas the remaining were linked to earlier onset. MR analysis indicated a causal relationship between AAO and educational attainment, cardiovascular disease, and type 2 diabetes (T2D).

DISCUSSION: The eight modifiable factors, particularly educational attainment, cardiovascular disease, and T2D, may facilitate early intervention to delay the onset of AD.

HIGHLIGHTS: We screened 43 modifiable factors for their association with the age at onset (AAO) of Alzheimer's disease (AD) using polygenic scores (PGS) as the proxy for the exposure. Higher educational attainment, better cognitive performance, and greater relative fat intake were linked to later AAO, suggesting an enhanced resilience against AD. Type 2 diabetes, cardiovascular disease, major coronary heart disease, and increased low-density lipoprotein (LDL) -cholesterol and total cholesterol are associated with earlier AAO. Mendelian randomization analysis revealed causal effects of educational attainment, type 2 diabetes, and cardiovascular disease on AAO of AD.},
}

Humans
*Alzheimer Disease/genetics/epidemiology
Genome-Wide Association Study
Age of Onset
Diabetes Mellitus, Type 2/genetics/epidemiology
Mendelian Randomization Analysis
Educational Status
Aged
Male
Female
Multifactorial Inheritance
Risk Factors
Genetic Predisposition to Disease
Cardiovascular Diseases/genetics/epidemiology

@article {pmid41656106,
year = {2026},
author = {Zou, R and Takabayashi, K and Andica, C and Uchida, W and Kitagawa, T and Mizuta, K and Hagiwara, A and Kikuta, J and Aoki, S and Kamagata, K},
title = {White Matter Microstructural Alterations Mediate the Association between Polygenic Risk for Alzheimer's Disease and Cognitive Performance in Clinically Asymptomatic Adults.},
journal = {Magnetic resonance in medical sciences : MRMS : an official journal of Japan Society of Magnetic Resonance in Medicine},
volume = {},
number = {},
pages = {},
doi = {10.2463/mrms.mp.2025-0182},
pmid = {41656106},
issn = {1880-2206},
abstract = {PURPOSE: Alzheimer's disease (AD) is a progressive neurodegenerative disorder influenced by genetic factors, with a long preclinical phase characterized by subtle alterations in brain microstructure. Although the apolipoprotein E ε4 allele is a well-established genetic risk factor, AD is increasingly recognized as a polygenic condition. However, how polygenic risk manifests in white matter (WM) microstructure and cognition remains unclear. This study aims to investigate the associations between AD polygenic risk scores (ADPRS), WM microstructure, and cognitive performance in clinically asymptomatic adults.

METHODS: Data from 36400 individuals (aged 45-83 years) in the UK Biobank were analyzed. Diffusion tensor imaging and neurite orientation dispersion and density imaging metrics were extracted from 48 WM tracts. General linear models were used to examine associations between ADPRS, WM integrity, and 10 cognitive measures. Mediation analyses were conducted to test whether WM microstructure mediated the relationship between ADPRS and cognitive performance.

RESULTS: Higher ADPRS was significantly associated with reduced fractional anisotropy and intracellular volume fraction, and with increased mean, axial, and radial diffusivity, as well as isotropic volume fraction across limbic and association fibers, particularly in the cingulum hippocampus, fornix, posterior thalamic radiation, and superior fronto-occipital fasciculus. Higher ADPRS was also associated with poorer cognitive performance, most prominently on tests of executive function (Trail Making Test B), episodic memory (Paired Associate Learning), and processing speed (Symbol Digit Substitution). Mediation analysis revealed that WM microstructural alterations, especially increased radial diffusivity and reduced fractional anisotropy in the posterior thalamic radiation, partially mediated the association between ADPRS and cognitive performance, accounting for up to 4.88% of the total effect.

CONCLUSION: ADPRS is linked to selective WM microstructural alterations and subtle cognitive difference in clinically asymptomatic adults. WM microstructural changes partially mediate the association between ADPRS and cognitive performance.},
}

@article {pmid41656099,
year = {2026},
author = {Ma, YN and Huang, X and Xia, Y and Song, P and Hu, X},
title = {Protein persulfidation: The missing link in Alzheimer's disease defense mechanisms.},
journal = {Drug discoveries & therapeutics},
volume = {},
number = {},
pages = {},
doi = {10.5582/ddt.2026.01004},
pmid = {41656099},
issn = {1881-784X},
abstract = {Despite decades of research dominated by the amyloid-beta hypothesis, clinical treatment of Alzheimer's disease (AD) has yet to achieve a decisive breakthrough. This editorial advances an alternative pathological paradigm: the collapse of endogenous hydrogen sulfide (H2S) signaling represents a central failure point in the brain's intrinsic defense mechanisms against AD. We dissect the molecular cascade triggered by cystathionine γ-lyase (CSE) deficiency, focusing on how reduced persulfidation of glycogen synthase kinase 3β (GSK3β) directly promotes Tau hyperphosphorylation and subsequent neuronal injury. A critical message of this commentary is the need to dispel the oversimplified notion that sulfide supplementation alone can confer neuroprotection. Because H2S works within a narrow therapeutic window and has complex hormetic effects, untargeted dietary or environmental exposure cannot match the spatiotemporal precision of endogenous signaling. Instead, it may increase the risk of toxicity. By integrating analyses of transsulfuration metabolism, mitochondrial function, and nutritional status, we propose a precision medicine framework centered on brain-targeted delivery technologies and metabolic correction strategies to selectively restore compromised H2S signaling networks. This conceptual shift marks a new direction in AD research, shifting the focus from clearing toxic protein aggregates to restoring endogenous neuronal resilience.},
}

@article {pmid41655968,
year = {2026},
author = {Kim, KR and Stevenson, DG and Kim, J and Fabius, CD and Keohane, LM},
title = {Factors Associated With Initial Type of Long-Term Services and Supports Among Dual-Eligible Beneficiaries.},
journal = {Journal of the American Medical Directors Association},
volume = {},
number = {},
pages = {106136},
doi = {10.1016/j.jamda.2026.106136},
pmid = {41655968},
issn = {1538-9375},
abstract = {OBJECTIVE: To examine the association between individual characteristics and type of initial long-term services and supports (LTSS) among older adults receiving Medicaid home- and community-based services (HCBS) or nursing home (NH) care.

DESIGN: Cohort study of traditional Medicare beneficiaries surveyed between 2002 and 2009 linked with Medicare and Medicaid administrative files through 2018.

SETTING AND PARTICIPANTS: The study population includes 581 dual-eligible individuals aged ≥65 at the time of initial LTSS use. Study population was predominantly Black (67.1%), female (69.0%), and with a household income below $15,000/year (78.3%).

METHODS: Initial HCBS and long-term NH use were identified using Medicaid data and Minimum Data Set (MDS) nursing home assessments. Sociodemographic factors were identified using the Southern Community Cohort Study (SCCS) survey dataset. Chronic conditions and prior health care use were identified using traditional Medicare claims. A multivariate logistic model predicted whether individuals initiated LTSS with HCBS use, adjusting for individual-level covariates and state and year fixed effects.

RESULTS: Half of the sample (N = 291) initiated LTSS with HCBS and the other half (N = 290) initiated with NH use between 2008 and 2018. Factors associated with a higher likelihood of initiating LTSS with HCBS included Black race (marginal effect [ME], 0.13; 95% CI, 0.05-0.21) and female sex (ME, 0.19; 95% CI, 0.12-0.26). Factors associated with higher likelihood of initiating LTSS with NH instead of HCBS included older age, Alzheimer's disease and related dementias (ADRD) diagnosis, recent hospitalization, and higher education levels. Among individuals with ADRD, several factors-Black race, living with others, and prior emergency room use-were associated with higher likelihood of initiating LTSS with HCBS and prior hospitalization was associated with initial NH use.

CONCLUSION AND IMPLICATIONS: Among dual-eligible older adults initiating LTSS, factors related to more complex medical needs were associated with a higher likelihood of NH use rather than HCBS use as their initial LTSS option.},
}

@article {pmid41655940,
year = {2026},
author = {Li, M and Ping, X and Song, H and Sun, J and Yang, Q and Gao, LN},
title = {PFOS promotes Alzheimer's disease through aggravating the cell apoptosis and AKT/GSK3β/NF-κB/NLRP3 pathway mediated inflammation.},
journal = {Toxicology},
volume = {},
number = {},
pages = {154423},
doi = {10.1016/j.tox.2026.154423},
pmid = {41655940},
issn = {1879-3185},
abstract = {Perfluorooctane sulfonate (PFOS) and its alternatives are widely utilized in industrial and commercial applications. However, their environmental persistence and widespread detection in diverse matrices in recent years have raised significant public health concerns. Studies reported that exposure to PFOS in cerebrospinal fluid will increase the risk of cognitive decline in humans. However, the underlying toxicological mechanism is still unclear. The aim of this study was to elucidate the possible toxic targets and potential molecular mechanisms of Alzheimer's disease (AD) induced by PFOS exposure through network toxicology, molecular docking and in vitro verification. Firstly, the results of network toxicology suggested that the mechanisms of PFOS-induced AD were mainly associated with the PI3K-AKT, neurodegeneration, apoptosis and NOD-like receptor signaling pathways. Subsequently, molecular docking simulations confirmed a strong binding interaction between PFOS and the key targets including SRC, ESR1, CASP3, BCL2, ERBB2, and TNF. Finally, we used HT22 and SH-SY5Y cell lines to validate the toxic effects of PFOS and found that PFOS aggravated neuronal cell apoptosis and AKT/GSK3β/NF-κB/NLRP3 pathway mediated inflammatory damages. Briefly, these findings indicated that PFOS exposure could contribute to the initiation and progression of AD by activating apoptosis and inflammatory related signaling pathways, thus affecting proliferation of neuronal cells. This study provides a theoretical basis for understanding the molecular mechanisms involved in PFOS-induced neurotoxicity.},
}

@article {pmid41655822,
year = {2026},
author = {Sultana, S and Xie, Y and Kamal, MS and Li, W},
title = {IUPHAR review: Pathophysiological significance of the TRPM2 ion channel as a potential target in cancer, neurological disorders, and ischemia/reperfusion injury.},
journal = {Pharmacological research},
volume = {},
number = {},
pages = {108132},
doi = {10.1016/j.phrs.2026.108132},
pmid = {41655822},
issn = {1096-1186},
abstract = {The transient receptor potential melastatin 2 (TRPM2) ion channel is a redox-sensitive, non-specific cation channel that plays a vital role in the regulation of Ca[2+] homeostasis and cellular functions in response to oxidative stress. However, aberrant expression of TRPM2 is associated with various pathological conditions. Overexpression of TRPM2 promotes cell survival in multiple malignancies, including neuroblastoma, lung, prostate, stomach, and pancreatic cancers. TRPM2 also mediates different neurological disorders, such as Alzheimer's disease (AD), Parkinson's disease (PD), and epilepsy, and contributes to ischemia/reperfusion (I/R) injuries. This review provides a comprehensive summary of the pathophysiological significance of TRPM2, covering the structural features, regulation, and oxidative stress signaling, with a major focus on the mechanistic pathways that link TRPM2 to these diseases. We discuss the therapeutic potential of TRPM2, its long non-coding antisense RNA (TRPM2-AS), and provide a comprehensive overview of currently available TRPM2 inhibitors, including adenosine diphosphate ribose (ADPR) analogs, small molecules, and peptides. This review covers an in-depth analysis of the structural activity relationships (SAR), pharmacokinetic (PK) properties of these TRPM2 inhibitors, detailing their preclinical efficacy studies, and outlining their shortcomings. Overall, we conclude that TRPM2 represents a promising drug target for effective therapies in several major disease indications.},
}

@article {pmid41655434,
year = {2026},
author = {Liu, Z and Wang, J and Chen, Z and Shi, C and Tang, Z and Wang, Y},
title = {BBB-permeable carbon dots ameliorate Alzheimer's-like phenotypes in mice by suppressing oxidative stress, neuroinflammation, and amyloid-β aggregation.},
journal = {International immunopharmacology},
volume = {173},
number = {},
pages = {116298},
doi = {10.1016/j.intimp.2026.116298},
pmid = {41655434},
issn = {1878-1705},
abstract = {Alzheimer's disease (AD) is a common neurodegenerative disorder wherein reactive oxygen species (ROS) and Amyloid-β-protein (Aβ) play critical roles. Inspired by traditional Chinese charcoal drug and the anti-inflammatory properties of some carbon dots, we developed Radix Isatidis derived carbon dots (RI-CDs) via a hydrothermal method. The RI-CDs can cross the blood-brain barrier (BBB) and were thus evaluated for AD therapy. In vitro, RI-CDs scavenged ROS, inhibited Aβ42 aggregation, protected SH-SY5Y cells, and regulated inflammatory factors. In AD mice, the Morris water maze test and nesting experiment demonstrated that RI-CDs improved the learning and memory ability of mice and improved their nesting ability. Importantly, RI-CDs reduced ROS/Aβ42 in the hippocampus of AD mice, downregulated NLRP3 pathway-related cellular inflammatory factors, and upregulated the expression of BDNF/SYN/PSD95, thereby restoring damaged neurons. These findings demonstrate the compelling neuroprotective efficacy of RI-CDs, highlighting their potential as a promising therapeutic agent for AD.},
}

@article {pmid41655411,
year = {2026},
author = {Zhang, L and Hu, S and Zhu, J and Jiang, G},
title = {Estrogen regulates cognitive function in APP/PS1 female mice via modulation of IDO1-mediated Trp/Kyn metabolism through ERβ.},
journal = {Hormones and behavior},
volume = {179},
number = {},
pages = {105891},
doi = {10.1016/j.yhbeh.2026.105891},
pmid = {41655411},
issn = {1095-6867},
abstract = {Alzheimer's disease (AD) is more prevalent in postmenopausal women, possibly due to estrogen deficiency. IDO1 (Indoleamine 2,3-dioxygenase 1), a tryptophan-metabolizing enzyme, mediates immunomodulation and neuroinflammation and may be related to cognitive impairment in AD. This study used APP/PS1 transgenic female mice with ovariectomy (OVX),E2, IDO1 inhibitor (1-MT), and agonists and antagonists of estrogen receptors to explore the potential roles of estrogen and IDO1 in AD. Results showed that OVX aggravated the cognitive function impairment of the APP/PS1 mice. OVX also decreased the serum E2 level and increased the hippocampal IDO1 level. The application of 1-MT reversed the cognitive impairment, suggesting the elevated IDO1 level to be a contributing factor for the high susceptibility to AD in females with estrogen deficiency. Interestingly, E2 alleviated the cognitive function of the APP/PS1 mice undergoing OVX. E2 also decreased hippocampal IDO1 level and impacted the metabolism of IDO1-mediated L-Tryptophan (Trp)/kynurenine (Kyn) pathway by decreasing the levels of Kyn, Kyn-to-Trp ratio, 3-hydroxykynurenine (3-HK) and quinolinic acid (QA) and increasing the levels of serotonin (5-HT), 5-HT-to-Trp ratio, and kynurenic acid (KA). The E2's effects were similar to those of the IDO1 inhibitor. Furthermore, the ERβ antagonist could reverse the effects of E2 and the ERβ agonist had comparable effects to E2 on the Trp/Kyn pathway. These findings indicate that E2 has positive effects on the cognitive function of the APP/PS1 female mice undergoing OVX, and the mechanism may be related to the modulation of IDO1-mediated Trp/Kyn pathway via activation of ERβ.},
}

@article {pmid41655407,
year = {2026},
author = {Kang, W and Li, B and Jiskoot, LC and De Deyn, PP and Biessels, GJ and Koek, HL and Claassen, JAHR and Middelkoop, HAM and van der Flier, WM and Jansen, WJ and Klein, S and Bron, EE and , and , },
title = {An interpretable machine learning framework with data-informed imaging biomarkers for diagnosis and prediction of Alzheimer's disease.},
journal = {Computerized medical imaging and graphics : the official journal of the Computerized Medical Imaging Society},
volume = {128},
number = {},
pages = {102722},
doi = {10.1016/j.compmedimag.2026.102722},
pmid = {41655407},
issn = {1879-0771},
abstract = {Machine learning methods based on imaging and other clinical data have shown great potential for improving the early and accurate diagnosis of Alzheimer's disease (AD). However, for most deep learning models, especially those including high-dimensional imaging data, the decision-making process remains largely opaque which limits clinical applicability. Explainable Boosting Machines (EBMs) are inherently interpretable machine learning models, but are typically applied to low-dimensional data. In this study, we propose an interpretable machine learning framework that integrates data-driven feature extraction based on Convolutional Neural Networks (CNNs) with the intrinsic transparency of EBMs for AD diagnosis and prediction. The framework enables interpretation at both the group-level and individual-level by identifying imaging biomarkers contributing to predictions. We validated the framework on the Alzheimer's Disease Neuroimaging Initiative (ADNI) cohort, achieving an area-under-the-curve (AUC) of 0.969 for AD vs. control classification and 0.750 for MCI conversion prediction. External validation was performed on an independent cohort, yielding AUCs of 0.871 for AD vs. subjective cognitive decline (SCD) classification and 0.666 for MCI conversion prediction. The proposed framework achieves performance comparable to state-of-the-art black-box models while offering transparent decision-making, a critical requirement for clinical translation. Our code is available at: https://gitlab.com/radiology/neuro/interpretable_ad_classification.},
}

@article {pmid41655130,
year = {2026},
author = {Xiang, Q and Liu, Y and Wang, J},
title = {Golgi fragmentation driven by the USP11-ITCH axis triggers autolysosomal failure in neurodegeneration.},
journal = {Autophagy},
volume = {},
number = {},
pages = {},
doi = {10.1080/15548627.2026.2629295},
pmid = {41655130},
issn = {1554-8635},
abstract = {Golgi fragmentation is a prominent early hallmark of neurodegenerative diseases such as Alzheimer disease (AD) and amyotrophic lateral sclerosis (ALS), yet the shared molecular mechanisms underlying this phenomenon remain poorly understood. Here we identify the E3 ubiquitin ligase ITCH as a central regulator of Golgi integrity and proteostasis. Elevated ITCH disrupts both cis- and trans-Golgi networks, dislocates lysosomal hydrolase sorting factors, and impairs maturation of hydrolases. The ensuing lysosomal dysfunction leads to autophagosome accumulation and defective clearance of accumulated cytoplasmic toxic proteins like TARDBP/TDP-43. Genetic and pharmacological inhibition of ITCH restores autolysosomal degradation and protects neurons in both mammalian and Drosophila models. Aberrant buildup of the deubiquitinase USP11 drives ITCH accumulation, intensifying neuronal proteotoxic stress in individuals with AD and ALS. These findings reveal a mechanistic pathway connecting Golgi disorganization, autolysosomal impairment, and proteotoxic stress in neurodegeneration.},
}

@article {pmid41654970,
year = {2026},
author = {Lu, W and Kawatani, K and Ren, Y and Nambara, T and Jia, L and Jeevaratnam, S and Lee, E and Martinez, PR and Izhar, T and Wang, N and Raulin, AC and Wszolek, ZK and Bu, G and Kanekiyo, T and Li, Y},
title = {CI-994 is a dual modulator of class I HDACs and Wnt/β-catenin signaling for the treatment of Alzheimer's disease.},
journal = {Alzheimer's research & therapy},
volume = {},
number = {},
pages = {},
doi = {10.1186/s13195-026-01982-0},
pmid = {41654970},
issn = {1758-9193},
support = {R21AG065653, R01AG078615, 24A07//NIH, Florida Department of Health Ed and Ethel Moore Alzheimer's Disease Research Program/ ; },
}

@article {pmid41519857,
year = {2026},
author = {Song, M and Zheng, H and Han, J and Xu, K and Zhang, DF and Cao, Q},
title = {The molecular fidelity of Aβ pathology in 5xFAD and App[NL-F]Psen1[P117L] mice revealed by cryo-EM.},
journal = {Molecular neurodegeneration},
volume = {21},
number = {1},
pages = {10},
pmid = {41519857},
issn = {1750-1326},
support = {32271276//National Natural Science Foundation of China/ ; 32571420//STI2030-Major Projects 2022ZD0212500/ ; },
abstract = {UNLABELLED: Animal models, particularly mouse models, are indispensable for understanding the pathogenic mechanisms and developing therapeutic and diagnostic drugs for Alzheimer’s diseases (AD). While most AD mouse models aim to mimic amyloid-β (Aβ) pathology in their brains, previous research has demonstrated that not all models succeed in reproducing Aβ fibril structures observed in the brains of AD patients. In this study, we determined cryo-electron microscopy (cryo-EM) structures of Aβ fibrils extracted from the brains of two AD models, 5xFAD and App[NL−F]Psen1[P117L]. The former represents one of the most widely used transgenic AD models, while the latter is the third-generation knock-in model designed to address the issues arising from App overexpression in conventional models. Our results revealed that fibrils from the 5xFAD mouse exhibit a structure nearly identical to human Type II Aβ fibrils found in AD patients, whereas the App[NL−F]Psen1[P117L] mouse predominantly possesses Type II Aβ fibrils but also contains another Aβ fibril species. A subtle discrepancy in main chain arrangement at the position of Val36 was noted among all reported human and mouse Type II structures, potentially originating from variations in the brain microenvironment between human and mice. In conclusion, our findings validated the replication of Aβ pathology in 5xFAD and App[NL−F]Psen1[P117L] mice and provide additional options for selecting appropriate animal models in studies necessitating molecular-level replication of Aβ structures.

SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s13024-026-00924-6.},
}

@article {pmid41507873,
year = {2026},
author = {Wang, M and Che, Y and Tan, X and Zhang, N and Yu, S and Yan, P},
title = {Association between green space exposure and elderly health: a systematic review and meta-analysis.},
journal = {BMC public health},
volume = {26},
number = {1},
pages = {491},
pmid = {41507873},
issn = {1471-2458},
support = {XYD2024C06//Xinjiang Medical University Research and Innovation Team Project/ ; 2022E02119//Science and Technology Aid to Xinjiang Project of the Natural Science Foundation of Xinjiang Uygur Autonomous Region, China/ ; },
abstract = {BACKGROUND: Exposure to green spaces is associated with many health benefits across various stages of life. However, no comprehensive synthesis currently exists to consolidate this evidence into a systematic body of knowledge that captures the overall impact of exposure to green space on the health of older adults. This systematic review seeks to address this gap by generating a thorough, integrated evidence base and offering valuable insights for future research directions and practical applications.

METHODS: We adopted an extensive search strategy, drawing from multiple electronic databases as well as the National Institute for Health and Clinical Excellence (United Kingdom) and the Guidelines International Network. The electronic databases searched included the Cochrane Library, Medline, Embase, CINAHL, PubMed, Web of Science, Scopus, Global Health, and CNKI, using the PEOS search framework. The search encompassed publications from the inception of each database to November 2024. A total of 5,749 records were initially identified, and, following a dual-reviewer screening and selection process, 27 studies were ultimately included in the review.

RESULTS: Exposure to green spaces was associated with effects on circulatory system disorders, mental health conditions, nervous system diseases, cognitive decline, metabolic disorders, and overall life satisfaction in older adults. Evidence regarding cardiovascular outcomes was mixed, with some studies indicating a U-shaped relationship for hypertension. Exposure to green space demonstrated a protective role against metabolic diseases and was positively associated with enhanced life satisfaction among older adults. Meta-analyses revealed that exposure to green space was associated with a lower risk of Alzheimer’s disease ( OR= 0.856, 95% CI: 0.769–0.943) and depression (OR= 0.724, 95% CI: 0.549–0.900).

CONCLUSIONS: This systematic review synthesizes the multifaceted health effects of green environments on ageing populations, critically evaluating empirical evidence on exposure to green space and health outcomes in older adults. The findings present a robust, evidence-based framework that underscores consistent associations between the accessibility and quality of green spaces and key indicators of geriatric health, thereby laying the groundwork for designing targeted, nature-based behavioral interventions.

TRIAL REGISTRATION: PROSPERO (CRD42024619700).

SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12889-025-26137-y.},
}

@article {pmid41507841,
year = {2026},
author = {Gao, R and Lam, LCW and Lee, ATC and Tang, NLS and Ma, SL},
title = {Functional significance of NLRP3 polymorphisms in mild cognitive impairment.},
journal = {BMC geriatrics},
volume = {26},
number = {1},
pages = {173},
pmid = {41507841},
issn = {1471-2318},
support = {09200246//Health and Medical Research Fund/ ; 2021.057//Chinese University of Hong Kong/ ; },
abstract = {BACKGROUND: Nucleotide-binding domain and leucine-rich repeat (LRR)-containing family protein 3 (NLRP3) inflammasome is an essential component of the innate immune system and regulates inflammation. NLRP3 inflammasome has been widely studied in the pathogenesis of mild cognitive impairments (MCI) and Alzheimer’s Disease (AD). Single nucleotide polymorphisms (SNPs) of NLRP3 gene are associated with various diseases, however the association between NLRP3 SNPs and downstream pathway is unclear.

METHODS: 12 tag SNPs and 2 previously reported SNPs were genotyped in 233 healthy controls (HC) and 332 MCI older adults. NLRP3 and other inflammation-related genes expression were quantified in peripheral blood mononuclear cells (PBMC) from the older adults by quantitative PCR (qPCR). Functional studies of selected mutations were performed by luciferase assay. The older adults were followed up for 2 years to investigate the relationship between NLRP3 SNPs and risk of cognitive decline.

RESULTS: Our study showed rs10754558 and rs7525979 were associated with an increased risk of MCI. The T allele of rs12564791 was associated with higher gene expression level of NLRP3, interleukin-18 (IL-18), PYCARD, and CASP1. rs12048215, rs10754555, and rs7525979 were associated with cognitive decline as shown by the reduction of Montreal Cognitive Assessment (MoCA) score. Functional studies showed that both rs10754558 and rs10754555 G to C mutation affected transcriptional activity. rs10754558 G to C mutation also disturbed the interaction between NLRP3 3’UTR and miR-425-5p. Plasma miR-425-5p expression was negatively correlated with MoCA score.

CONCLUSIONS: Our study suggested that genetic variations of NLRP3 could affect inflammatory gene expression, transcriptional activity and interaction between gene and miRNA, and therefore were associated with the risk of MCI and cognitive decline. Plasma miR-425-5p has the potential to be a biomarker for cognitive decline.

SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12877-025-06905-6.},
}

@article {pmid41654846,
year = {2026},
author = {Zhu, Q and Wu, S and Huang, P and Sun, Q and Liu, Z and Zhu, X and Lee, LP and Liu, F},
title = {AI-driven biomarker learning for the early diagnosis of neurodegenerative diseases: ABLEDx.},
journal = {Journal of nanobiotechnology},
volume = {},
number = {},
pages = {},
doi = {10.1186/s12951-026-04072-3},
pmid = {41654846},
issn = {1477-3155},
support = {22474092//National Outstanding Youth Science Fund Project of National Natural Science Foundation of China/ ; 202323257//Shenzhen Science and Technology Innovation Commission/ ; },
abstract = {BACKGROUND: Tears are an easily accessible biofluid that reflects both emotional states and disease conditions. They are particularly enriched in extracellular vesicles (EVs), which carry proteins and nucleic acids relevant to neurological health. This makes tear EVs a promising source for biomarker discovery. However, limited sample volume and variability pose challenges for identifying reliable biomarkers for clinical diagnosis.

RESULTS: We present AI-driven Biomarker Learning for the Early Diagnosis of Neurodegenerative Diseases (ABLEDx), which applies a conditional variational autoencoder (cVAE) to enhance proteomic analysis of tear EVs. This approach effectively addresses sample limitations and improves the identification of disease-associated biomarkers. Our results reveal that tear EVs capture molecular signals along the eye-brain axis, reflecting contributions from both ocular and central nervous system cells. ABLEDx identified clinically relevant protein modules, which were consistently elevated in patients with neurodegenerative diseases. Moreover, we recognize that KRAS is highly expressed in patients with Alzheimer's disease, Parkinson's disease, and ocular myasthenia gravis, and tear-EV-associated LRG1 and HSPG2 exhibit differentiation between Alzheimer's disease and Parkinson's disease.

CONCLUSIONS: ABLEDx demonstrates the utility of combining AI with tear-EV proteomics for non-invasive biomarker discovery. This strategy enables early and real-time detection of neurodegenerative and ocular diseases, offering new opportunities for clinical diagnostics and translational medicine.},
}

@article {pmid41654544,
year = {2026},
author = {Tran, M and Jeong, HW and An, M and Been, C and Jamsranjav, A and Kwak, SM and Lee, LP and Cho, H},
title = {A 3D gut-brain-vascular platform for bidirectional crosstalk in gut-neuropathogenesis.},
journal = {Nature communications},
volume = {},
number = {},
pages = {},
doi = {10.1038/s41467-026-69318-y},
pmid = {41654544},
issn = {2041-1723},
abstract = {A 'gut-brain axis' is an intricate bidirectional connection between the gut and the central nervous system, serving as a key pathway for signal exchange. However, current in vitro models do not fully capture these dynamic interactions, limiting mechanistic insight and therapeutic testing. Here, we show a 3D human gut-brain-vascular microphysiological platform that integrates lumenized villus-like intestinal barrier, blood vascular-astrocyte interactions, and brain tissue to model circulation-mediated crosstalk between the gut and brain. Using this system, we demonstrate gut-to-brain signaling by delivering bacterial-derived toxins to the gut compartment, which traverse the gut and neurovascular barriers and trigger neuroinflammatory responses and tau-associated pathology in the brain tissue. Conversely, we show that Alzheimer's- and Parkinson's-relevant stimuli applied to the brain compartment elicit neuroinflammation and disrupt both vascular and intestinal barrier integrity, indicating brain-to-gut feedback. Together, our platform provides a human-relevant tool to dissect mechanisms of bidirectional gut-brain communication and to evaluate therapeutic strategies for neurogastrointestinal disease.},
}

@article {pmid41654525,
year = {2026},
author = {Zhou, W and Xue, Z and Liang, J and Cui, J and Guo, X and Wen, Y},
title = {Modeling and application of alzheimer's disease complex trait prediction based on multi-task learning.},
journal = {Scientific reports},
volume = {},
number = {},
pages = {},
doi = {10.1038/s41598-026-37820-4},
pmid = {41654525},
issn = {2045-2322},
support = {82404384//the Young Scientists Fund of the National Natural Science Foundation of China/ ; 2025T180201//the Special Program of China Postdoctoral Science Foundation/ ; 2025M770735//the General Program of China Postdoctoral Science Foundation/ ; 82271925//the National Natural Science Foundation of China/ ; 82173632//the National Natural Science Foundation of China/ ; 202403021221159//the Basic Research Program of Shanxi Province/ ; },
}

@article {pmid41654286,
year = {2026},
author = {Al-Ali, S and Balelli, I and , },
title = {Multi-channel causal variational autoencoder for multimodal biomedical causal disentanglement.},
journal = {Journal of biomedical informatics},
volume = {},
number = {},
pages = {104995},
doi = {10.1016/j.jbi.2026.104995},
pmid = {41654286},
issn = {1532-0480},
abstract = {The multimodal nature of clinical assessment and decision-making, and the high rate of healthcare data generation, motivate the need to develop approaches specifically tailored to the analysis of these complex and potentially high-dimensional multimodal datasets. This poses both technical and conceptual challenges: how can such heterogeneous data be analyzed jointly? How can modality-specific information be identified from shared information? Variational autoencoders (VAEs) offer a robust framework for learning latent representations of complex data distributions, while being flexible enough to adapt to different data types and structures, and having already been successfully applied for latent disentanglement of multimodal (multi-channel) data. We aim at tackling multi-channel disentanglement from a causal perspective, and seek at identifying causal relationships between channels, beyond simple statistical associations. To do that, we propose Multi-Channel Causal VAE (MC[2]VAE), a novel causal disentanglement approach for multi-channel data, whose objective is to jointly learn modality-specific latent representations from a multi-channel dataset, and identify a causal structure between the latent channels. Each channel is projected into its own latent space, where a causal discovery step is integrated to learn the hidden causal graph. Finally, the decoder takes into account the discovered graph to predict the data. Covariate of interest can be integrated as well when available, and accounted in the causal graph structure. Extensive experiments on synthetically generated multi-channel datasets demonstrate the ability of MC[2]VAE in effectively uncovering the underlying latent causal structures across multiple channels, hence making it a strong candidate for real-world multi-channel causal disentanglement. Application to multi-channel data on neurodegeneration extracted from the Alzheimer's Disease Neuroimaging Initiative highlights the existence of a biologically meaningful latent causal structure, whose pertinence is supported by multiple previous experimental and modelling work, and provides actionable insight for disease progression.},
}

@article {pmid41654149,
year = {2026},
author = {Yuan, J and Zhang, S and Dong, X and Han, D},
title = {Agrin at the Crossroads of Aging: A Pleiotropic Regulator in Age-Related Diseases.},
journal = {Pharmacological research},
volume = {},
number = {},
pages = {108131},
doi = {10.1016/j.phrs.2026.108131},
pmid = {41654149},
issn = {1096-1186},
abstract = {Aging is a significant risk factor for numerous age-related diseases, and elucidating its key molecular mechanisms is crucial for disease prevention and treatment. Agrin, initially identified for its role in neuromuscular junction development, is an extracellular matrix protein. Recent studies have revealed its broad functions in maintaining tissue homeostasis and facilitating cellular signal transduction. During aging, alterations in the expression and function of Agrin may participate in the regulation of tissue repair, inflammatory responses, and intercellular communication, thereby influencing the onset and progression of various age-related diseases. This review systematically examines the central role of Agrin in age-related diseases such as Alzheimer's disease, ischemic stroke, myocardial infarction, osteoarthritis, and type 2 diabetes. Accumulating evidence indicates that Agrin exhibits a distinct ''double-edged sword'' characteristic across different disease stages or tissue contexts-exerting protective effects in some scenarios while promoting pathological progression in others. We summarize current findings on the involvement of Agrin in disease mechanisms, including the regulation of amyloid deposition, blood-brain barrier integrity, synaptic function, inflammatory responses, and tissue repair. Furthermore, we discuss potential Agrin-targeted therapeutic strategies. We propose that Agrin represents a critical molecular node linking aging mechanisms with multiple age-related diseases. A deeper understanding of its context-dependent functional switching and the development of precise targeting approaches hold substantial promise for the prevention and treatment of age-related pathologies.},
}

@article {pmid41654144,
year = {2026},
author = {He, H and Zhu, S and Zhang, C and Wang, H and Li, Y and Qian, H},
title = {Neuroimmune Dysregulation in Alzheimer's Disease: Mechanisms and Therapeutic Strategies.},
journal = {Ageing research reviews},
volume = {},
number = {},
pages = {103055},
doi = {10.1016/j.arr.2026.103055},
pmid = {41654144},
issn = {1872-9649},
abstract = {Alzheimer's disease (AD) is a neurodegenerative disorder characterised by progressive memory loss and cognitive decline. With the global population ageing, the prevalence of AD continues to rise, posing a significant public health challenge. Historically, AD research has centred on two hallmark pathological features: β-amyloid (Aβ) deposition and tau protein hyperphosphorylation. However, repeated failures of therapeutic strategies targeting these pathways in clinical trials have prompted a paradigm shift toward a more integrated understanding of disease mechanisms. Accumulating evidence now demonstrates that neuroimmune dysfunction is not merely a secondary response but a central driver throughout AD progression, contributing to the initiation of pathology and perpetuating neuroinflammation, synaptic damage, and cognitive deterioration. This review highlighting the primary pathways involved in inflammation and neuroimmune dysregulation in AD, and the role of gut microbiota dysbiosis and systemic immunity in the pathogenesis. Furthermore, it discusses emerging neuroimmune-targeted intervention strategies such as activation of TREM2, CD33 antagonists or antisense oligonucleotides, aiming to provide a conceptual foundation for broadening mechanistic insights and guiding the development of novel therapeutic approaches.},
}

@article {pmid41653883,
year = {2026},
author = {Vanderlip, CR and Gillen, DL and Grill, JD and Stark, CEL},
title = {Digital memory assessments and plasma pTau217 enable efficient preclinical Alzheimer's trials.},
journal = {The journal of prevention of Alzheimer's disease},
volume = {13},
number = {4},
pages = {100503},
doi = {10.1016/j.tjpad.2026.100503},
pmid = {41653883},
issn = {2426-0266},
abstract = {BACKGROUND: Preclinical Alzheimer's disease (AD) trials enroll cognitively unimpaired, amyloid-positive older adults; however, most remain clinically stable over typical trial durations. Limited near-term decline reduces statistical power and drives large sample sizes and high costs. Scalable enrichment strategies capable of identifying individuals most likely to decline are critically needed.

OBJECTIVES: To determine whether a brief digital memory assessment (DMA) and plasma phosphorylated tau 217 (pTau217), individually or combined, identify preclinical AD participants at elevated risk for cognitive and biological progression, and whether such enrichment reduces clinical trial sample-size requirements.

DESIGN: Analysis of data from the Anti-Amyloid Treatment in Asymptomatic Alzheimer's Disease (A4) Study, a multicenter randomized clinical trial with 240 weeks of follow-up.

SETTING: Secondary-prevention trial conducted across sites in the United States, Canada, Australia, and Japan.

PARTICIPANTS: A total of 1,169 cognitively unimpaired adults aged 65-85 years who were amyloid-positive and completed both a baseline DMA and plasma pTau217 measurement.

MEASUREMENTS: Primary outcome was change in the Preclinical Alzheimer Cognitive Composite (PACC) over 240 weeks. Secondary outcomes included Clinical Dementia Rating-Sum of Boxes, Mini-Mental State Examination, Cognitive Function Instrument, and annualized change in amyloid PET, plasma pTau217, and tau PET.

RESULTS: Participants with both elevated pTau217 and low DMA exhibited the greatest cognitive decline and reached the 240-week PACC decline of the overall cohort 83 weeks earlier. Participants with neither marker showed minimal decline. Dual enrichment reduced sample-size estimates for a clinical trial from 3,252 to 818 participants per arm (75 % reduction). These individuals also demonstrated faster increases in plasma pTau217 and neocortical tau PET.

CONCLUSIONS: A brief DMA combined with plasma pTau217 identifies a subset of cognitively unimpaired, amyloid-positive older adults at highest risk for cognitive and biomarker progression. This dual-marker enrichment strategy enables smaller, shorter, and more cost-efficient preclinical AD trials and supports more targeted evaluation of preventive therapies.},
}

@article {pmid41653882,
year = {2026},
author = {Cui, L and Wang, QM and Zhang, Z and Wang, M and Tu, YY and Jiang, JH and Guan, YH and Li, YH and Xie, F and Guo, QH},
title = {Spatial amyloid-informed multimodal brain age as an early marker of Alzheimer's-related vulnerability and risk stratification.},
journal = {The journal of prevention of Alzheimer's disease},
volume = {13},
number = {4},
pages = {100501},
doi = {10.1016/j.tjpad.2026.100501},
pmid = {41653882},
issn = {2426-0266},
abstract = {BACKGROUND: Brain age gap (BAG)-the difference between predicted and chronological age-captures neurobiological aging, but MRI-only models insufficiently reflect Alzheimer's disease (AD) pathology. Whether incorporating regional amyloid-β (Aβ) positron emission tomography (PET) improves sensitivity to early AD processes remains unknown.

OBJECTIVES: To develop an amyloid-informed multimodal BAG model and examine its associations with cognition, plasma biomarkers, and functional connectivity across the AD continuum.

DESIGN: Cross-sectional analysis using integrated machine-learning models.

SETTING: Chinese Preclinical Alzheimer's Disease Study (CPAS), a cohort recruited from community settings and memory clinics.

PARTICIPANTS: Nine hundred ninety community-dwelling adults spanning normal cognition, subjective cognitive decline (SCD), mild cognitive impairment (MCI), and dementia.

MEASUREMENTS: Regional Aβ-PET and structural MRI informed BAG estimation. Cognitive tests, plasma biomarkers (p-tau217, p-tau181, neurofilament light [NfL], glial fibrillary acidic protein [GFAP], Aβ42/40), and hippocampus-default mode network (DMN) connectivity from resting-state fMRI were assessed.

RESULTS: Higher BAG was associated with greater odds of SCD, MCI, or dementia across the cohort, with stronger effects in Aβ-positive individuals. BAG explained more cognitive variance than global Aβ burden and was linked to multidomain cognitive deficits. Elevated BAG corresponded to higher p-tau217, p-tau181, NfL, and GFAP and lower Aβ42/40, indicating early biomarker alterations. BAG was also associated with reduced hippocampus-DMN connectivity.

CONCLUSIONS: An amyloid-informed multimodal BAG model captures convergent AD-related pathology, biomarker alterations, and cognitive vulnerability beyond amyloid burden alone, supporting its value for individualized risk s2tratification and prevention-focused assessment.},
}

@article {pmid41653881,
year = {2026},
author = {Kasuga, K and Kikuchi, M and Kikkawa-Saito, E and Tsukie, T and Ishiguro, T and Miyashita, A and Iwatsubo, T and , and Ikeuchi, T},
title = {Evaluation of plasma p-tau217 biomarkers in detecting amyloid pathology and predicting cognitive outcomes: Observations from Japanese Alzheimer's disease neuroimaging initiative cohort.},
journal = {The journal of prevention of Alzheimer's disease},
volume = {13},
number = {4},
pages = {100502},
doi = {10.1016/j.tjpad.2026.100502},
pmid = {41653881},
issn = {2426-0266},
abstract = {BACKGROUND AND OBJECTIVES: Plasma phosphorylated tau 217 (p-tau217) has shown strong potential as a blood-based biomarker for detecting amyloid pathology in Alzheimer's disease. This study evaluated the diagnostic and prognostic utility of plasma biomarkers, including p-tau217, in participants from the Japanese Alzheimer's Disease Neuroimaging Initiative (J-ADNI) cohort.

METHODS: We analyzed paired plasma and CSF samples from 172 J-ADNI participants. CSF and plasma biomarkers were quantified using the LUMIPULSE platform, and the same plasma samples were analyzed using the Simoa platform. The diagnostic accuracy for detecting amyloid pathology and the prognostic value of plasma p-tau217 biomarkers were assessed. Associations between plasma p-tau217 and polygenic risk scores (PRS), as well as potential confounding factors, were examined.

RESULTS: Plasma p-tau217 levels measured using Lumipulse and Simoa assays were highly correlated (p < 0.001). All plasma p-tau217 assays showed high diagnostic accuracy for CSF Aβ42/Aβ40-defined amyloid pathology (AUC = 0.98). A single cutoff point based on the Youden index for p-tau217 and p-tau217/Aβ42 achieved >90% specificity and >90% sensitivity. The predefined FDA-approved two-cutoff model for p-tau217/Aβ42 was applicable to this cohort. PRS was significantly associated with plasma p-tau217 independently of APOE genotypes. Subjects with higher plasma p-tau217 levels showed a significantly increased risk of conversion to dementia and larger longitudinal cognitive declines. Plasma p-tau217 levels were significantly influenced by the body mass index, estimated glomerular filtration rate, and high-density lipoprotein cholesterol.

CONCLUSIONS: Plasma p-tau217 and p-tau217/Aβ42 are robust biomarkers for AD diagnosis and prognosis in the Japanese population.},
}

@article {pmid41653841,
year = {2026},
author = {Pallawi, S and Singh, DK},
title = {LEFF-ViT: A locally enhanced vision transformer framework for accurate Alzheimer's Disease classification from brain MRI.},
journal = {Psychiatry research. Neuroimaging},
volume = {358},
number = {},
pages = {112155},
doi = {10.1016/j.pscychresns.2026.112155},
pmid = {41653841},
issn = {1872-7506},
abstract = {Early and accurate diagnosis of Alzheimer's Disease (AD) is critical for effective disease management and progression delay. Researches have been done in past towards better study of Alzheimer's, but advancements in feature engineering-cum-learning methodologies have still created scope to overcome the limits of previous methods and achieve more accurate modelling and classification. Here, we propose a novel model, LEFF-ViT (Locally Enhanced Feedforward Vision Transformer), for AD classification along with a framework culminating an idea of using separate segmented brain subregions as a marked feature engineering element. For this Segmentation of MRI images are done to extract White Matter (WM), Gray Matter (GM), and Cerebrospinal Fluid (CSF) regions using a Deep Residual Squeeze-Inception U-Net (De-RIS U-Net). Subsequently, a novel DWFE-Net is employed to extract discriminative spatial features. Finally, LEFF-ViT integrates a Vision Transformer with Multi-Head Self-Attention and a Locally Enhanced Feedforward Network (LFFN) to effectively capture both local and global contextual information for accurate classification. The experimental results demonstrate that the proposed model achieves an accuracy of 98.68 %, a sensitivity of 96.45 %, a specificity of 98.17 %, a Dice score of 96.36 %, and a Jaccard index of 92.31 %, which nearly outperforms the existing state-of-the-art methods across multiple evaluation metrics.},
}

@article {pmid41653511,
year = {2026},
author = {Nie, RZ and Luo, HM and Wang, H and Yang, YR and Wang, YZ and Zhang, SZ and Feng, K and Li, YL and Chen, FY and Duan, CX and Chen, JY and Ma, T and Li, PF},
title = {The inhibitory mechanisms of PGG, a natural polyphenol enriched with gallate moieties, against Aβ42 amyloid aggregation: A unified experimental and molecular dynamics simulation study.},
journal = {Bioorganic & medicinal chemistry},
volume = {136},
number = {},
pages = {118584},
doi = {10.1016/j.bmc.2026.118584},
pmid = {41653511},
issn = {1464-3391},
abstract = {Alzheimer's disease currently affects over 44 million individuals worldwide. Inhibiting Aβ aggregation and preventing the formation of toxic Aβ oligomers were regarded as promising therapeutic approaches. Experimental studies demonstrated that 1,2,3,4,6-Penta-O-galloyl-β-d-glucopyranose (PGG), a natural polyphenol enriched with gallate moieties, significantly inhibited Aβ42 oligomerization and amyloid formation both in vitro and in vivo, underscoring its potential as a promising lead compound for AD therapy. Nevertheless, the detailed molecular mechanisms remained mostly unknown. Herein, we employed relevant biophysical methods to investigate the inhibitory effects of PGG and its analogs on Aβ42 amyloid aggregation, particularly on oligomer formation, providing direct evidence for the influence of gallate moiety number on its inhibitory activity against Aβ42 amyloid aggregation. Moreover, we further conducted 1500 ns all-atom MD simulations to explore how PGG inhibited Aβ amyloid aggregation. The simulations revealed that PGG promoted the adoption of a more loosely packed conformation of the Aβ42 dimer, and completely prevented the helix-to-β-sheet conformational change. Moreover, the binding of PGG molecules to the Aβ42 dimer resulted in the disruption of the inter-peptide interactions, and dramatically weakened the intra-peptide contacts. We observed that, apart from the usual hydrogen bonds and hydrophobic interactions, both π-π and cation-π interactions were also detected between specific residues of the Aβ42 dimer and the gallate moieties of PGG. We believed that these results might provide novel insights into the mechanisms underlying the inhibitory effects of PGG on Aβ42 amyloid aggregation and further support its potential for AD prevention and treatment.},
}

@article {pmid41653475,
year = {2026},
author = {Kwan, D and Rashidi-Ranjbar, N and Marinas, JE and Namasivayam, A and Churchill, N and Fornazzari, LR and Ismail, Z and DeLuca, V and Schweizer, TA and Munoz, DG and Fischer, CE and , },
title = {Peripheral Blood Epigenetic Age Acceleration is Associated With Psychosis in Female APOE4 Carriers With Mild Cognitive Impairment and Alzheimer's Disease: A Pilot Study.},
journal = {Journal of geriatric psychiatry and neurology},
volume = {},
number = {},
pages = {8919887261424535},
doi = {10.1177/08919887261424535},
pmid = {41653475},
issn = {1552-5708},
abstract = {ObjectivePsychosis is a significant neuropsychiatric symptom in Alzheimer's Disease (AD) and Mild Cognitive Impairment (MCI). While female APOE4 homozygotes are at the highest risk of psychosis, mechanisms underlying this association remain unclear. We investigated whether epigenetic age acceleration (EAA) is associated with psychosis in individuals with AD and MCI, and whether this association varies by sex and APOE4 status.MethodsParticipants with clinical MCI or AD were drawn from the Alzheimer's Disease Neuroimaging Initiative database. EAA was calculated from DNA methylation data using the PhenoAge epigenetic clock, with the Horvath and Hannum clocks included for comparison. Psychosis status was defined as experiencing hallucinations or delusions at any time, based on the Neuropsychiatric Inventory Questionnaire. Logistic regression models were used to assess associations between EAA and psychosis, including three-way interactions with sex and APOE4 carrier status.ResultsAmong 418 total participants (54 with psychosis, 84 female APOE4 carriers), EAA was not associated with psychosis for any of the 3 clocks utilized. However, a significant three-way interaction between sex, APOE4 carrier status, and PhenoAge EAA in predicting psychosis was observed (P = 0.013). Elevated PhenoAge EAA was associated with higher odds of psychosis in female APOE4 carriers (OR = 1.76 per 5-year, P = .025), whereas no associations were observed for other subgroups or clocks.ConclusionsPhenoAge EAA may serve as a novel biomarker of psychosis among female APOE4 carriers. These findings highlight the potential of second-generation epigenetic clocks for early risk stratification and biological investigations into psychosis in AD and MCI.},
}

@article {pmid41653457,
year = {2026},
author = {Liu, YC and Hsu, WL and Ma, YL and Yin, CY and Lee, EH},
title = {E2F Transcription Factor 8 Contributes to the Pathogenesis of Alzheimer's Disease Accompanied with Decreased Expression of Matrix Metalloproteinase-9 and B-cell Lymphoma 2.},
journal = {Journal of physiological investigation},
volume = {69},
number = {1},
pages = {17-30},
doi = {10.4103/ejpi.EJPI-D-25-00064},
pmid = {41653457},
issn = {2950-6344},
}

@article {pmid41653452,
year = {2026},
author = {Chen, Y and Yang, W and Li, G and Hu, Y and Zhang, J},
title = {Development of Hierarchical Tandem Heterojunction with Visible Light Enhanced Peroxidase-Like Activity for All-in-Capillary Self-Calibrating SERS Immunoassay of Aβ1-42.},
journal = {Analytical chemistry},
volume = {},
number = {},
pages = {},
doi = {10.1021/acs.analchem.5c07211},
pmid = {41653452},
issn = {1520-6882},
abstract = {Aiming to meet the critical need for user-friendly and sensitive clinical analysis platforms, an all-in-capillary SERS analytical system integrated with a visible-light-enhanced nanozyme for highly sensitive and convenient biomarker detection was developed. The system employs a hierarchical tandem heterojunction (TiO2/MoS2/CoFe2O4) as a peroxidase-like nanozyme, which significantly enhances separation and transfer of photogenerated charges under visible light. This nanozyme catalyzes the oxidation of leucocrystal violet to crystal violet, generating a characteristic Raman signal at 923 cm[-1]. To ensure analytical reliability, the inner wall of the capillary was modified with TiO2 as an internal standard, enabling signal self-calibration. This integrated platform allows direct sampling of finger blood without any pretreatment, performing all-in-capillary SERS detection. The proposed method achieves ultrasensitive detection of Alzheimer's disease biomarker Aβ1-42, with a wide linear range of 1.0 × 10[-3] to 1.0 × 10[-7] μg/mL, a low detection limit of 0.089 pg/mL, and satisfactory recovery of 94.3%-101% in human serum. The method was successfully applied to clinical serum samples from Alzheimer's patients and controls of different groups, revealing statistically significant differences in Aβ1-42 levels. Furthermore, the results showed excellent agreement with those obtained by the reference ELISA method, demonstrating high accuracy and practical applicability of our assay for early diagnosis and population screening. By combining rational nanozyme design with a miniaturized and calibration-free sampling interface, this work provides a streamlined bioanalytical strategy with great potential for point-of-care testing in early disease diagnosis.},
}

@article {pmid41653259,
year = {2026},
author = {Zhang, X and Zhang, X},
title = {Nanogel Delivery of Plumbagin from Nepenthes Khasiana Attenuates Neuroinflammation and Cognitive Decline in Alzheimer's Mice Models.},
journal = {Applied biochemistry and biotechnology},
volume = {},
number = {},
pages = {},
pmid = {41653259},
issn = {1559-0291},
support = {202203021221247//Shanxi Basic Research Program (Free Exploration Category), Natural Science Research Project/ ; },
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative condition characterized by memory deficits, oxidative stress, and neuroinflammation. Plumbagin (PB), a bioactive naphthoquinone derived from Nepenthes khasiana, possesses therapeutic potential but is limited by poor solubility and bioavailability. To overcome these challenges, PB was encapsulated into hyaluronic acid nanogels (PB-NGs) and systematically evaluated for anti-Alzheimer's efficacy. The study aimed to evaluate the neuroprotective and anti-inflammatory properties of PB-NGs by in vitro and in vivo analyses. PB-NGs were synthesized and characterized using FT-IR, NMR, and TEM, confirming successful encapsulation. In silico docking demonstrated strong binding affinities of PB to β-amyloid and tau proteins, suggesting potential inhibition of AD-related pathological processes. In vitro, PB-NGs significantly decreased ROS production, mitigated pro-inflammatory cytokines (IL-1β, TNF-α), and improved cell viability in LPS-stimulated SH-SY5Y cells relative to free PB. In vivo, administration of PB-NGs to AD-induced mice significantly improved behavioral outcomes, including enhanced spatial memory and exploratory activity in Y-maze, open field, and Morris's water maze tests. Biochemical assays further revealed reduced oxidative stress (decreased MDA, increased SOD, CAT, GST) and modulation of cholinergic dysfunction (reduced AChE, increased ChAT). Histopathological analysis supported neuronal protection with diminished amyloid burden. Collectively, these findings demonstrate that PB-NGs effectively enhance bioavailability and exert significant neuroprotective and anti-inflammatory effects, supporting their potential as a promising nanotherapeutic approach for mitigating cognitive deficits in AD.},
}

@article {pmid41653257,
year = {2026},
author = {Chen, P and Li, G and Cheng, L and Liu, Y and Liu, Y},
title = {HCG18 is a Potential Pathogenic Factor and Diagnostic Biomarker Alzheimer's Disease.},
journal = {Neurochemical research},
volume = {51},
number = {1},
pages = {64},
pmid = {41653257},
issn = {1573-6903},
mesh = {Humans ; *Alzheimer Disease/diagnosis/blood/metabolism/cerebrospinal fluid ; Male ; Female ; Biomarkers/blood/cerebrospinal fluid/metabolism ; Aged ; Amyloid beta-Peptides ; *RNA, Long Noncoding/blood/genetics/metabolism ; MicroRNAs/metabolism ; Animals ; Middle Aged ; Mice ; Oxidative Stress/physiology ; Apoptosis/physiology ; Peptide Fragments ; Aged, 80 and over ; Cell Line ; },
abstract = {Alzheimer's disease (AD), a major neurodegenerative disorder, lacks effective early diagnostic and therapeutic strategies. This study aimed to investigate the diagnostic utility of Long non-coding RNAs HLA Complex Group 18 (HCG18) in AD and elucidate its molecular mechanisms in neuronal injury. Eighty-three AD patients and 83 healthy controls (HC) were enrolled. Serum samples were analyzed for HCG18 expression using qRT-PCR and cerebrospinal fluid (CSF) samples were analyzed for AD biomarkers by ELISA. Diagnostic performance was assessed using ROC analysis. Aβ1-42-treated HT22 cells (Immortalized murine hippocampal neuronal-like cell line) were employed to model neuronal injury, with HCG18 knockdown and miR-425-3p inhibition experiments conducted to validate functional interactions. HT22 cell apoptosis, oxidative stress markers (SOD, GSH-Px, MDA, ROS), and HCG18/miR-425-3p interactions were evaluated through flow cytometry, biochemical assays, and dual-luciferase reporter systems. Serum HCG18 levels were significantly elevated in AD patients compared to HC (P < 0.001), exhibiting strong diagnostic accuracy (AUC = 0.889). HCG18 expression correlated negatively with CSF Aβ1-42 (r=-0.709) and MMSE scores (r=-0.657), but positively with t-tau (r = 0.591) and p-tau181 (r = 0.582). In Aβ1-42-treated HT22 cells, HCG18 knockdown reduced apoptosis, suppressed ROS, and normalized oxidative stress markers. Mechanistically, HCG18 directly bound to and acted as a molecular sponge for miR-425-3p, sequestering its function; the downregulation of miR-425-3p mediated by a synthetic inhibitor reversed the protective effects of HCG18 silencing. HCG18 serves as a potential non-invasive biomarker for AD, exacerbating neuronal injury via sponging miR-425-3p to disrupt redox balance. Targeting the HCG18/miR-425-3p axis may offer new therapeutic strategies for AD.},
}

Humans
*Alzheimer Disease/diagnosis/blood/metabolism/cerebrospinal fluid
Male
Female
Biomarkers/blood/cerebrospinal fluid/metabolism
Aged
Amyloid beta-Peptides
*RNA, Long Noncoding/blood/genetics/metabolism
MicroRNAs/metabolism
Animals
Middle Aged
Mice
Oxidative Stress/physiology
Apoptosis/physiology
Peptide Fragments
Aged, 80 and over
Cell Line