@article {pmid42809130,
year = {2026},
author = {Lakra, A and Kumar, P},
title = {A multi-region transcriptomic framework reveals global and region-specific ubiquitin-proteasome system biomarkers in Alzheimer's disease.},
journal = {Functional & integrative genomics},
volume = {26},
number = {1},
pages = {},
pmid = {42809130},
issn = {1438-7948},
mesh = {Humans ; *Alzheimer Disease/genetics/metabolism/pathology ; *Proteasome Endopeptidase Complex/metabolism/genetics ; *Ubiquitin/metabolism/genetics ; Biomarkers/metabolism ; *Transcriptome ; Male ; Female ; Aged ; Hippocampus/metabolism ; },
abstract = {The involvement of ubiquitin-proteasome system (UPS) impairment in Alzheimer's disease (AD) is increasing gradually yet the molecular organization of the system throughout the AD brain is poorly understood, as is the distribution of molecular markers. To systemically identify UPS-associated molecular signatures, we carried out a multi-region transcriptomic analysis of six different brain regions in AD patients and age-matched controls. The molecular perturbation of regions recapitulated the known regional vulnerability hierarchy with significant changes observed in the entorhinal cortex and hippocampus as well as middle temporal gyrus and posterior cingulate. A synchronized downregulation of UPS components was observed in the vulnerable regions indicating towards the extensive dysfunction of ubiquitin-mediated protein surveillance and proteasomal degradation. The consistent features associated with UPS disruption were linked with synaptic dysfunction, mitochondrial impairment and loss of proteostatic homeostasis as revealed by the functional analyses. We formulated a framework based on composite prioritization which combined several aspects like differential expression, network topology, regional consistency and diagnostic performance for the purpose of identifying strong biomarker candidates. The analysis revealed the most eminent global biomarkers of AD associated with UPS, namely, PSMB4, SNCA, PSMB7, PSMD1, and UBE3A. UBE2R1 (CDC34) was used to define region-specific biomarker signatures in the entorhinal cortex, UBC in the hippocampus, PSMA3 in middle temporal gyrus, PSMD4 in posterior cingulate cortex and UBE2V2 in superior frontal gyrus. These exploratory results provide the first systems-level biomarker atlas of UPS dysfunction in distinct AD brain regions and suggest that there are potential global and region-specific UPS signatures that could be used in diagnostics and drug development.},
}

Humans
*Alzheimer Disease/genetics/metabolism/pathology
*Proteasome Endopeptidase Complex/metabolism/genetics
*Ubiquitin/metabolism/genetics
Biomarkers/metabolism
*Transcriptome
Male
Female
Aged
Hippocampus/metabolism

@article {pmid42809165,
year = {2026},
author = {Miccoli, L and Fullone, R and Delli Pizzi, S and Tomaiuolo, F and Sensi, SL and Floresta, G and Granzotto, A},
title = {Analysis of the off-target interaction of amyloid PET tracers with human brain sulfotransferases.},
journal = {Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology},
volume = {47},
number = {10},
pages = {},
pmid = {42809165},
issn = {1590-3478},
support = {D73C22002140007//Ministero della Salute/ ; },
mesh = {Humans ; *Positron-Emission Tomography ; *Brain/metabolism/diagnostic imaging ; *Sulfotransferases/metabolism ; Benzothiazoles/metabolism ; *Aniline Compounds/metabolism ; Molecular Dynamics Simulation ; Molecular Docking Simulation ; Alzheimer Disease/diagnostic imaging/metabolism ; Thiazoles/metabolism ; *Amyloid beta-Peptides/metabolism ; *Radiopharmaceuticals ; },
abstract = {BACKGROUND: Positron emission tomography (PET) tracers targeting amyloid-β (Aβ) are central to the diagnosis and staging of Alzheimer's disease (AD). However, growing evidence indicates that these tracers can engage off-target molecules, complicating signal interpretation. Sulfotransferases (SULTs) have been experimentally identified as binding partners of 11C-Pittsburgh Compound-B (PiB), but whether the clinically used fluorinated PiB derivatives interact with brain-expressed SULTs has not been explored.

OBJECTIVE: To assess whether PiB and its fluorinated derivatives flutemetamol and flutafuranol interact with the SULT isoforms expressed in the human brain, and to characterize the structural features of these interactions.

METHODS: We combined multi-omic transcriptomic profiling of the Genotype-Tissue Expression (GTEx) project and the Human Protein Atlas with molecular docking and molecular dynamics (MD) simulations to evaluate the structural interactions of SULT-tracer complexes.

RESULTS: SULT1A1, SULT1A3, and SULT4A1 were identified as the SULT isoforms predominantly expressed in the human brain, and all three are expressed in the cerebellum, the region used as a reference for Aβ PET signal normalization. Docking and MD simulations showed that all three tracers form energetically comparable complexes within the catalytic pockets of these isoforms, but their dynamic stability varied in an enzyme- and tracer-specific manner. PiB and flutemetamol were stably accommodated in SULT1A1, whereas PiB lost its initial pose in SULT4A1. Flutafuranol showed weaker binding to SULT1A1 but formed stable complexes in SULT1A3 and SULT4A1.

CONCLUSIONS: These findings provide a structural framework for off-target interactions between Aβ PET tracers and brain SULTs and suggest that the intracellular enzymatic environment may contribute to variability in Aβ PET signals beyond fibrillar Aβ deposition.},
}

Humans
*Positron-Emission Tomography
*Brain/metabolism/diagnostic imaging
*Sulfotransferases/metabolism
Benzothiazoles/metabolism
*Aniline Compounds/metabolism
Molecular Dynamics Simulation
Molecular Docking Simulation
Alzheimer Disease/diagnostic imaging/metabolism
Thiazoles/metabolism
*Amyloid beta-Peptides/metabolism
*Radiopharmaceuticals

@article {pmid42809225,
year = {2026},
author = {Gleason, C and Lambrou, N and Blind, M and Ketcher, D and Weigler, E and Dertinger, M and Johnson, J and Mason, A and Ninham, SL and Ojibwe, RLN and Pitawanakwat, K and Pederson, C and Metoxen Strong, L and Summers, M and Trudeau, R and Warry, W and Jacklin, K},
title = {Healthcare Provider Experiences Delivering Dementia Care in Indigenous Communities: Challenges and Recommendations.},
journal = {The Gerontologist},
volume = {},
number = {},
pages = {},
doi = {10.1093/geront/gnag230},
pmid = {42809225},
issn = {1758-5341},
abstract = {BACKGROUND AND OBJECTIVES: Little is known regarding the effects of Alzheimer's disease and related dementias (AD/ADRD) in in American Indian and First Nation (AI/FN) communities in the US and Canada. Yet, research suggests FN populations in Canada experience 34% higher dementia rates and over half of US-based Indigenous adults demonstrate incident cognitive impairment, including dementia due to AD and/or cerebrovascular disease. Already higher than the general population, rates will increase as Indigenous populations age. The Indigenous Cultural Understandings of ADRD-Research and Engagement (ICARE) project was established to understand lived-experiences of dementia in AI/FN communities around the Great Lakes. We report themes describing practitioner experiences providing dementia care in selected US and Canadian Indigenous communities.

RESEARCH DESIGN AND METHODS: Healthcare practitioners (n = 14) providing care in Indigenous communities were interviewed by community-based researchers using semi-structured guides exploring a range of topics. Thematic analysis was used to identify challenges and recommendations to improve care. Trustworthiness checks included reflexivity, consensus, prolonged engagement, member checking and audit.

RESULTS: Thematic analysis yielded six superordinate themes. Provider-perceived challenges included: 1) Limited Resources for Providing Dementia Care, 2) Need for Caregiver-focused Preparation and Support, 3) Communication and Relationship Gaps, 4) Low-levels of Community Dementia-related Awareness, Education and Engagement. Provider recommendations were characterized as: 5) Increase Dementia-related Awareness, Education and Engagement, 6) Invest in Dementia Caregiver Support and Community Strengths.

DISCUSSION AND IMPLICATIONS: Findings were contextualized with post-colonial and relational care frameworks. Providers described relevant challenges and provided culturally safe and equitable strategies to improve dementia care outcomes.},
}

@article {pmid42809251,
year = {2026},
author = {Udenia, H and Midha, N and Verma, R and Bari, A and Dada, T},
title = {Cognitive impairment in glaucoma.},
journal = {Indian journal of ophthalmology},
volume = {74},
number = {10},
pages = {1451-1461},
doi = {10.4103/IJO.IJO_3157_25},
pmid = {42809251},
issn = {1998-3689},
mesh = {Humans ; *Glaucoma/complications/physiopathology ; *Cognitive Dysfunction/etiology/diagnosis/physiopathology ; *Intraocular Pressure/physiology ; },
abstract = {Glaucoma, while regarded as an isolated ocular disorder, is now increasingly recognized as a component of a wider neurological spectrum. An accumulating body of neuroimaging-based studies have revealed structural and functional changes in the brain that are analogous to those observed in Parkinson's and Alzheimer's disease. These changes are further associated with systemic disturbances, including autonomic dysfunction, neuroinflammation, and elevated cortisol levels. This mounting evidence may elucidate the increased susceptibility of cognitive impairment and dementia observed in individuals with glaucoma. This article presents a narrative review of the existing literature. A thorough search was conducted across various databases, including PubMed, Scopus, and the Embase Library, without restriction on year of publication. This review consolidates various lines of evidence that underscore the common characteristic between glaucomatous optic neuropathy and neurodegenerative disorders. A range of pharmacological (anti-dementia medication, nootropic agent, cerebral metabolizers, and neutraceuticals) and nonpharmacological strategies (regular physical activity, meditation, sleep optimization, and dietary modification) and emerging modalities-including noninvasive brain stimulation, nanotechnology-based drug delivery systems, and artificial intelligence-guided therapeutic models-are broadening the scope of management beyond traditional approaches that not only target intraocular pressure reduction but also may support overall neuro-cognitive wellbeing. The establishment of a multidisciplinary framework is also vital, wherein an ophthalmologist works in collaboration with neurologists, psychologists, and rehabilitation specialists to facilitate thorough cognitive evaluation and timely treatment. This review underscores the need of safeguarding both visual and cognitive functions by recognizing glaucoma as an ocular disorder and neurodegenerative condition, aiming to improve long-term outcomes and quality of life.},
}

Humans
*Glaucoma/complications/physiopathology
*Cognitive Dysfunction/etiology/diagnosis/physiopathology
*Intraocular Pressure/physiology

@article {pmid42809371,
year = {2026},
author = {Yang, Z and Li, H and Wang, Z and Ju, H and He, Q and He, L and Zhou, J and Shi, C and Zhu, F and Hou, K and Li, L and Zhang, Z and Tai, Y and Ma, Q and Li, X and Jin, J and Liu, Z and Su, Y},
title = {Rbks plays a novel role in maintaining glycolipid metabolic homeostasis.},
journal = {Acta biochimica et biophysica Sinica},
volume = {},
number = {},
pages = {},
doi = {10.3724/abbs.2026126},
pmid = {42809371},
issn = {1745-7270},
abstract = {Elevated urinary D-ribose has been observed in patients with diabetes and Alzheimer's disease, although the underlying mechanism remains unclear. Since ribokinase (Rbks) catalyzes the phosphorylation of D-ribose to ribose-5-phosphate, we hypothesize that the Rbks gene plays a crucial role in regulating systemic glucose and lipid metabolism. To test this hypothesis, we generate Rbks-knockout (KO) C57BL/6J mice using CRISPR/Cas9 and conduct a 16-week phenotypic observation. Although KO mice exhibit normal physical appearance and body weight, they show reduced food consumption and water intake. Serum levels of total cholesterol (T-CHO) and low-density lipoprotein cholesterol (LDL-C) are decreased, accompanied by hepatic accumulation of T-CHO. Proteomic analysis identifies 117 differentially expressed proteins associated with glycolipid metabolism and oxidative phosphorylation. Metabolomic profiling reveals 414 altered metabolites enrich in lipid metabolism, central carbon metabolism, and amino acid metabolism pathways. Among these alterations, the most prominent change is enhanced hepatic cholesterol and bile acid (BA) synthesis, which is supported by elevated hepatic T-CHO levels and increased mRNA expressions of 3-hydroxy-3-methylglutaryl-CoA reductase (Hmgcr) and squalene epoxidase (Sqle). This study reveals a novel role for Rbks in maintaining glucose-lipid metabolic homeostasis, especially with potential implications for understanding metabolic disorders characterized by altered cholesterol flux.},
}

@article {pmid42809409,
year = {2026},
author = {Du, JT and Chartrand, T and Jayadev, S and Prater, KE and Lin, KZ},
title = {Integrating Morphology and Gene Expression of Neural Cells in Unpaired Single-Cell Data Using GeoAdvAE.},
journal = {Journal of computational biology : a journal of computational molecular cell biology},
volume = {},
number = {},
pages = {15578666261492321},
doi = {10.1177/15578666261492321},
pmid = {42809409},
issn = {1557-8666},
abstract = {Cellular morphological transitions are observed across many diseases, yet their functional role remains unclear because few technologies profile form and function in the same cell. Linking single-cell morphology to transcriptomics is difficult: The two modalities share no feature correspondence and are typically measured in different cells. We present GeoAdvAE, a geometry-aware adversarial autoencoder for diagonal (unpaired) integration of single-cell morphology and single-cell RNA sequencing. GeoAdvAE couples modality-specific variational autoencoders with a Gromov-Wasserstein regularizer and an adversarial discriminator to embed unpaired morphologies and transcriptomes into a shared latent space that preserves both reconstruction fidelity and cross-modal geometry. Using patch-seq neurons with joint morphology-RNA measurements as ground truth, GeoAdvAE attains the best cross-modal cell-type matching accuracy among diagonal integration methods, outperforming optimal-transport, latent-alignment, and adversarial baselines. Applied to 98 CAJAL-quantified microglial morphologies and 31,948 single-cell transcriptomes from the 5xFAD Alzheimer's disease model, GeoAdvAE recovers a one-dimensional axis that aligns the two modalities. Integrated-gradient attribution highlights transcriptomic shifts (DNA repair in ramified microglia; cell killing in amoeboid microglia), nominates gene markers (Ms4a6b; Ftl1/Fth1), and reveals disease-associated microglia signatures that are decoupled from morphology. GeoAdvAE provides a scalable, interpretable approach to connecting cellular "form" and "function" when joint profiling of morphology and transcriptomics is impractical. Our method is publicly available at https://github.com/turbodu222/GeoAdVAE.},
}

@article {pmid42809425,
year = {2026},
author = {Tamura, R and Kawabata, R and Lei, C and Li, H and Hayashi, D and Seki, M and Suzuki, Y and Hisatsune, T},
title = {Loss of Newborn Neuron Function Promotes Aβ Accumulation in an Alzheimer's Disease Mouse Model.},
journal = {Aging and disease},
volume = {},
number = {},
pages = {},
doi = {10.14336/AD.2026.0713},
pmid = {42809425},
issn = {2152-5250},
abstract = {Whether the loss of adult hippocampal newborn neuron (NBN) function contributes to Alzheimer's disease (AD) amyloid pathology remains unclear. Adult NBNs regulate dentate gyrus (DG) circuitry, and their decline has been observed during AD progression. To investigate their role, we generated NBN-APP mice by crossing APPswe/PS1dE9 mice with NBN-TeTX mice. Importantly, in vivo microdialysis in the DG molecular layer prior to plaque formation demonstrated that the loss of NBN function for 4 weeks, starting at 3 months of age (early phase), elevated soluble Aβ levels (p < 0.001). At this early phase, we also observed increased Aβ deposition in the lateral entorhinal cortex (p < 0.001). Furthermore, to evaluate chronic cumulative pathology, we extended the loss of NBN function to 8 weeks starting at 5 months of age (late phase), which resulted in enhanced Aβ plaque deposition in the DG molecular layer, widespread glial activation and inflammatory responses throughout the hippocampus, alongside cognitive alterations. Together, these findings demonstrate that the loss of NBN function consistently induces Aβ accumulation across both early and late phases, and is associated with glial activation, highlighting its contribution to AD pathology.},
}

@article {pmid42809426,
year = {2026},
author = {Kumar, M and Ray, S and Sil, S},
title = {Repurposing MitoQ10 as a Therapeutic for Established Alzheimer's Disease Pathology.},
journal = {Aging and disease},
volume = {},
number = {},
pages = {},
doi = {10.14336/AD.2026.0946},
pmid = {42809426},
issn = {2152-5250},
abstract = {Alzheimer's Disease (AD) is characterized by progressive amyloid accumulation, neuroinflammation, and neuronal loss, yet therapies targeting amyloid alone provide limited clinical benefit. Here, we evaluated whether pharmacological targeting of mitochondrial redox dysfunction using MitoQ10 (MitoQ), a mitochondria-targeted antioxidant, could modify AD pathology and behavioral deficits in symptomatic 5XFAD mice. Four-month-old 5XFAD mice received oral MitoQ for four months, and behavioral, histological, and biochemical analyses were performed at eight months of age. MitoQ administration significantly improved novelty-related exploration, attenuated hyper-locomotor activity, and broadly suppressed amyloid pathology, including pan-Aβ, oligomeric Aβ species, fibrillar plaques, and mature amyloid deposits across the cortex, hippocampus, thalamus, and amygdala. MitoQ also attenuated astrocyte and microglial reactivation, reduced pathological pTau622, and preserved neuronal integrity. Restoration of mitochondrial homeostasis was reflected by increased PDH-positive mitochondrial particle area, reduced oxidative DNA damage, and normalization of mitochondrial clearance via restoration of mitophagy-associated quality-control markers. Collectively, these findings show that MitoQ administration was associated with improvement in mitochondrial redox- and quality-control-related indices, accompanied by reductions in amyloid burden, gliosis, and neuronal injury in animals with established AD pathology. These findings support mitochondrial redox homeostasis as a therapeutically relevant target that may influence multiple pathological features of AD and provide a preclinical rationale for further evaluation of MitoQ as a potential therapeutic strategy for AD. Given that MitoQ has been evaluated in clinical studies in other conditions, the present preclinical findings support further investigation of its translational potential in AD; however, its safety and efficacy in individuals with AD require direct clinical evaluation.},
}

@article {pmid42809432,
year = {2026},
author = {Grigorova, IL and Varshavskaya, KB and Kuzubova, EV and Koltunova, LA and Kolobova, EA and Radchenko, AI and Chaprov, KD and Grishchenko, VV and Petrushanko, IY and Korokin, MV and Mitkevich, VA and Kechko, OI and Makarov, AA},
title = {Targeting isoD7 Neoepitope in Aβ for Alzheimer's Disease Immunotherapy.},
journal = {Aging and disease},
volume = {},
number = {},
pages = {},
doi = {10.14336/AD.2026.0695},
pmid = {42809432},
issn = {2152-5250},
abstract = {Alzheimer's disease (AD) is characterized by amyloid-beta (Aβ) accumulation, neuroinflammation and cognitive impairment. During AD pathogenesis, Aβ undergoes several post-translational modifications, the most common of which is the isomerization of aspartic acid (isoD7-Aβ), a modification that contributes to the disease development. Passive immunization with isoD7-Aβ-specific antibodies reduced cognitive impairment and amyloid deposition in 5xFAD mice. However, therapeutic application of anti-Aβ antibodies has important limitations, emphasizing the need for alternative approaches. Here, we evaluated the efficacy of isoD7-Aβ1-16-targeting immunization compared with Aβ1-16-targeting immunization on AD pathogenesis in APP/PS1 mice. Both isoD7-Aβ1-16 and Aβ1-16, conjugated with ovalbumin, induced Aβ1-16 - specific memory B cells and IgG in mice. However, only isoD7-Aβ1-16 conjugate promoted B cell and IgG response to the neoepitopes on isoD7-Aβ1-16. In the Y-maze test, only APP/PS1 mice immunized with isoD7-Aβ1-16 at 3 months of age retained spatial memory as they aged, in contrast to APP/PS1 mice immunized with Aβ1-16 at the same age. Immunization with both isoD7-Aβ1-16 and Aβ1-16 significantly reduced amyloid burden, lowered microglial and astrocyte activation. Furthermore, we assessed the effect of immunization in APP/PS1 mice at a later stage of AD pathogenesis, at 6 months of age. Even at the stage of advanced disease, immunization with isoD7-Aβ1-16 strongly impeded the formation of amyloid plaques and reduced brain-wide microglial and astrocyte activation, in contrast to immunization with Aβ1-16. Our results indicate the promise of targeting isoD7-Aβ for active AD immunotherapy, both for preventing the development of the pathology at its early stage and for ceasing the advanced AD pathogenesis.},
}

@article {pmid42809481,
year = {2026},
author = {Qin, R and Mao, Z and Chen, L},
title = {Trends and Projections of Alzheimer's Disease and Other Dementias in East Asia: Three Decades of Epidemiological Analysis (1990-2023) with Forecasts to 2050.},
journal = {Neuroepidemiology},
volume = {},
number = {},
pages = {1},
doi = {10.1159/ned/adwag040},
pmid = {42809481},
issn = {1423-0208},
abstract = {The burden of Alzheimer's disease and other dementias (ADOD) in East Asia remains understudied. Using Global Burden of Disease 2023 data, we analyzed age-standardized rates (ASRs) of incidence, prevalence, mortality, and disability-adjusted life years (DALYs), calculated average annual percentage change (AAPC) via Joinpoint regression, and forecasted trends to 2050 using the ARIMA model. In 2023, ASRs for prevalence, incidence, mortality, and DALYs were 906.49, 154.64, 28.83, and 538.71 per 100,000, respectively. Burden peaked at ages 80-84 and was higher in females. By 2050, incidence and prevalence are projected to rise to 175.84 and 1,036.46 per 100,000, mortality will remain stable, whereas DALYs show a mild downward trend. High fasting plasma glucose was the leading risk factor; females were more susceptible to high body mass index, males to smoking. These three modifiable risk factors were the top contributors to the ADOD burden in East Asia and were therefore the focus of this analysis. Targeted interventions addressing glucose control, smoking cessation, and weight management are urgently needed, alongside enhanced screening and care for high-risk populations.},
}

@article {pmid42809590,
year = {2026},
author = {Kim, B and Wang, SS and Kim, JR and Kim, J},
title = {Targeting Microglial Transcriptional Reprogramming as a Therapy Strategy for Alzheimer's Disease.},
journal = {BioEssays : news and reviews in molecular, cellular and developmental biology},
volume = {48},
number = {10},
pages = {e70186},
pmid = {42809590},
issn = {1521-1878},
support = {AARF-21-852175/ALZ/Alzheimer's Association/United States ; R01AG077829/AG/NIA NIH HHS/United States ; R01AG071281/AG/NIA NIH HHS/United States ; R21AG072738/AG/NIA NIH HHS/United States ; RF1AG074543/AG/NIA NIH HHS/United States ; P30AG072976/AG/NIA NIH HHS/United States ; },
mesh = {*Alzheimer Disease/genetics/therapy/metabolism ; Humans ; *Microglia/metabolism ; Animals ; Proto-Oncogene Protein Spi-1 ; Transcription Factors/metabolism/genetics ; Trans-Activators/genetics/metabolism ; MEF2 Transcription Factors/genetics/metabolism ; Interferon Regulatory Factor-8 ; *Cellular Reprogramming/genetics ; Transcription, Genetic ; Gene Expression Regulation ; Interferon Regulatory Factors/genetics/metabolism ; },
abstract = {Recent human genetic studies revealed that Alzheimer's disease risk loci are enriched in genes expressed in myeloid cells, including microglia, the brain's resident immune cells. Notably, several risk-associated genes, such as SPI1 and MEF2C, encode transcription factors (TFs) that control critical microglial functions, including phagocytosis, inflammatory responses, and neurotrophic support. The objective of this article is to review the recent progress in understanding these TFs and evaluate them as therapeutic targets rather than as markers of microglial state. We examine the genetic evidence implicating PU.1, MEF2C, IRF8, and BHLHE40/41, the in vivo evidence from animal models, the transcriptional network these factors regulate, and the barriers to clinical translation. Because these TFs orchestrate broad gene expression networks by regulating multiple disease-relevant downstream partners, targeting their expression level or activity could achieve greater therapeutic efficacy than targeting single genes, provided that the dose and disease stage of modulation are carefully considered.},
}

*Alzheimer Disease/genetics/therapy/metabolism
Humans
*Microglia/metabolism
Animals
Proto-Oncogene Protein Spi-1
Transcription Factors/metabolism/genetics
Trans-Activators/genetics/metabolism
MEF2 Transcription Factors/genetics/metabolism
Interferon Regulatory Factor-8
*Cellular Reprogramming/genetics
Transcription, Genetic
Gene Expression Regulation
Interferon Regulatory Factors/genetics/metabolism

@article {pmid42809711,
year = {2026},
author = {Burke, BI and Valentino, TR and Ismaeel, A and Wen, Y and McCarthy, JJ},
title = {Microbial-Derived Exerkines as a Model of Drug Discovery.},
journal = {American journal of physiology. Cell physiology},
volume = {},
number = {},
pages = {},
doi = {10.1152/ajpcell.90006.2026},
pmid = {42809711},
issn = {1522-1563},
support = {R01AR084282/AR/NIAMS NIH HHS/United States ; R00AR081367/AG/NIA NIH HHS/United States ; P20GM156679/GM/NIGMS NIH HHS/United States ; R01AR084282/AR/NIAMS NIH HHS/United States ; R00AR081367/AG/NIA NIH HHS/United States ; P20GM156679/GM/NIGMS NIH HHS/United States ; },
abstract = {There has been a growing interest in the utilization of the gut microbiome as a therapeutic tool. The relationship between the gut microbiome and exercise provides a unique opportunity to maximize the therapeutic capacity of the gut microbiome. Here, we summarize the potential of leveraging the gut microbiome to confer the health benefits of exercise through a novel class of microbial metabolites termed microbial-derived exerkines (MDEs). We identify multiple candidate and established MDEs described in the literature (e.g., pipecolic acid, succinate, short-chain fatty acids, indole-3-propionic acid, 3-hydroxyphenylacetic acid) and explore their implications in conditions such as inflammatory bowel disease, aging, skeletal muscle atrophy, cancer, diabetes, cardiovascular disease, and Alzheimer's disease. Given the beneficial effects of exercise on numerous diseases, we anticipate MDEs will be a productive avenue for drug discovery and therapeutic progress.},
}

@article {pmid42809780,
year = {2026},
author = {Özgöbek, HR and Ökem, ZG and Yüksel-Kaptanoğlu, İ and Kaya, S},
title = {Caregiver Perspectives on Alzheimer's Care in the Turkish Sociocultural Context.},
journal = {Dementia (London, England)},
volume = {},
number = {},
pages = {14713012261488608},
doi = {10.1177/14713012261488608},
pmid = {42809780},
issn = {1741-2684},
abstract = {In the context of global demographic change, the number of patients with Alzheimer's disease (AD) and other forms of dementia is steadily increasing. These individuals require ongoing care but often struggle to communicate their needs and preferences regarding quality care. This study re-examines existing qualitative data to explore perceptions of "quality care" for patients with AD within the Turkish sociocultural context. Building on a primary study of caregivers' definitions of quality care, it employs a secondary analysis approach to generate new insights without collecting additional data. The dataset includes face-to-face, semi-structured interviews conducted in 2018 with 15 formal and informal caregivers, including family members, professional caregivers, and managers from care institutions across four provinces in Türkiye. Analysis reveals that patients with AD often experience discomfort when their bodies are exposed or touched, particularly in ways that infringe upon their sense of privacy. Caregivers emphasised that protecting privacy relies on understanding the individual's life story, values, and preferences, highlighting the role of relational familiarity in delivering care. Many participants described forming close, family-like bonds, often adopting kinship roles to provide personalised support. These dynamics were also shaped by gender norms, with caregiving commonly framed through a mother-child lens, reflecting societal expectations that women assume primary caregiving responsibilities. The findings show how privacy, emotional closeness, and gender roles intersect to shape caregiving practices. These findings suggest that care quality for patients with AD in Türkiye may be enhanced by approaches that attend to cultural and relational dimensions, recognise caregiver support needs, and incorporate culturally attuned practices - though further research across diverse settings is needed to assess the broader applicability of these insights. These insights contribute to the international discourse on dementia care by showing how culturally specific practices can guide globally relevant approaches to quality care.},
}

@article {pmid42810101,
year = {2026},
author = {Alfonsín, S and Chino, B and de Frutos Lucas, J and Delgado-Losada, ML and Ojeda, N and Maestú, F},
title = {Resting-state functional and spectral alterations underlying cognitive decline in biomarker-confirmed Alzheimer's disease: A systematic review.},
journal = {NeuroImage. Clinical},
volume = {52},
number = {},
pages = {104070},
doi = {10.1016/j.nicl.2026.104070},
pmid = {42810101},
issn = {2213-1582},
abstract = {Alzheimer's disease (AD) is characterized by progressive cognitive decline associated with synaptic and large-scale network dysfunction. Resting-state alterations may provide functional correlates of AD pathology, but associations among intrinsic brain activity, biomarkers, and domain-specific cognition have not been systematically integrated across spectral and connectivity frameworks. We systematically reviewed PubMed, Scopus, and Web of Science through May 2025 (PROSPERO CRD42024575913). Thirty studies (N = 5898) examining resting-state EEG, MEG, or fMRI, AD biomarkers, and cognition were synthesized following SWiM guidance. Across studies, resting-state alterations showed converging associations with amyloid and tau measures from CSF, PET, and plasma. Five of six electrophysiological studies reported increased delta/theta activity and three of six reduced alpha/beta activity, supporting neural slowing. Greater low-frequency activity was generally associated with poorer global cognition and episodic memory, whereas reduced higher-frequency activity was linked to poorer attention and processing speed. Among 21 connectivity studies, 10 reported hyperconnectivity and 13 hypoconnectivity, with non-mutually exclusive categories. Hyperconnectivity, particularly within medial and anterior temporal circuits, was more frequent in earlier-stage groups and showed heterogeneous cognitive associations, including poorer and better-preserved performance. Broader hypoconnectivity across posterior default mode, medial temporal-posterior medial, and frontoparietal networks was more prominent in later-stage groups and more consistently associated with poorer global cognition, episodic memory, and executive function. These findings support spectral slowing and stage-related network reorganization as functional correlates of cognitive impairment in biomarker-characterized AD. However, 25 of 30 studies were cross-sectional; therefore, these connectivity patterns should not be interpreted as a demonstrated within-person trajectory.},
}

@article {pmid42810176,
year = {2026},
author = {Kumar, N and Kushwaha, VK and Singh, G and Ojha, S and Dash, AK and Shankar, G},
title = {Rivastigmine-centered molecular hybridization strategies for multi-targeted intervention in Alzheimer's disease: Advances (2020-2026).},
journal = {Bioorganic & medicinal chemistry},
volume = {143},
number = {},
pages = {118811},
doi = {10.1016/j.bmc.2026.118811},
pmid = {42810176},
issn = {1464-3391},
abstract = {Alzheimer's disease (AD) is a progressive and multifactorial neurodegenerative disorder characterized by cholinergic dysfunction, amyloid-β (Aβ) aggregation, tau hyperphosphorylation, oxidative stress, mitochondrial impairment, metal dyshomeostasis, and chronic neuroinflammation, collectively leading to irreversible cognitive decline and neuronal degeneration. Despite decades of intensive research, currently approved therapeutic agents, including cholinesterase inhibitors (ChEI) and NMDA receptor antagonists, provide only symptomatic relief and do not substantially alter disease progression. Among the clinically available ChEI, rivastigmine (RIV) has attracted considerable attention owing to its dual inhibitory activity against acetylcholinesterase (AChE) and butyrylcholinesterase (BChE), pseudo-irreversible mode of action, and established clinical efficacy in AD management. In recent years, RIV has emerged as a highly promising pharmacophoric scaffold for the development of multifunctional hybrid molecules designed according to the multi-target-directed ligand (MTDL) strategy to modulate multiple pathological pathways involved in AD simultaneously. This review comprehensively summarizes and critically analyzes advances reported from 2020 to 2026 in the design, synthesis, biological evaluation, and therapeutic potential of RIV-based hybrid molecules and scaffold modifications for AD treatment. The review places particular emphasis on the rational hybridization of RIV with diverse bioactive pharmacophores, including tryptamine, coumarin, flavonoids, melatonin, tacrine, ferulic acid, cannabidiol, benzimidazole, piperidine, aryloxacetic acid, and antioxidant motifs, to generate multifunctional agents with enhanced pharmacological profiles. The reviewed hybrids demonstrated remarkable multifunctional properties, including potent inhibition of AChE and BChE, suppression of Aβ aggregation, antioxidant and metal-chelating activities, anti-inflammatory effects, modulation of monoamine oxidases, neuroprotection, mitochondrial stabilization, and improved blood-brain barrier permeability. Several derivatives exhibited significantly greater potency and broader neuroprotective profiles than RIV itself, highlighting the therapeutic value of molecular hybridization approaches in AD drug discovery.},
}

@article {pmid42810344,
year = {2026},
author = {Khan, ZN and Clement, CC and Roßmüller, P and Antila, S and Sutherland, L and Kabarriti, R and Shafik, J and Smirnov, I and D'Alessandro, A and Dzieciatkowska, M and Roda, B and Marassi, V and Tsai, WL and Gadina, M and Tannenbaum, A and Varjosalo, M and Keskitalo, S and Piffkó, A and Koundal, S and Gursky, Z and Weichselbaum, RR and Prystowsky, MB and Ow, TJ and Formenti, S and Sorg, C and Zott, B and Alitalo, K and Benveniste, H and Kipnis, J and Santambrogio, L},
title = {Cervical lymphadenectomy impairs brain lymphatic clearance and synaptic proteostasis.},
journal = {Neuron},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.neuron.2026.09.005},
pmid = {42810344},
issn = {1097-4199},
abstract = {Meningeal lymphatic vessels drain brain fluid and waste into the cervical lymph nodes, but how removing these nodes during surgery affects brain health is unknown. Retrospective analysis of cancer patients who underwent neck lymphadenectomy without chemo-radiation therapy found that up to 25% developed mild-to-severe cognitive impairment, and neuroimaging showed accelerated temporal horn enlargement after bilateral surgery. To determine mechanistically how cervical lymphadenectomy contributes to cognitive impairment, mouse and rat models were utilized to phenocopy abrupt disruption of lymphatic flow to the cervical and submandibular nodes. Impaired lymphatic drainage induced a cerebrospinal fluid signature of metabolic stress and inflammation. In the hippocampus, redox stress drove oxidative posttranslational protein modifications and microaggregation with biochemical, molecular, and structural features distinct from amyloid aggregates in Alzheimer's models. Such changes were absent when lymphatic drainage was gradually reduced. The data link cognitive impairment following acute neck lymphadenectomy with the biochemical consequences of impaired metabolic waste clearance.},
}

@article {pmid42810460,
year = {2026},
author = {Gao, J and Zhang, W and Yang, F and Peng, G and Zhang, T and Dong, T and Wang, J},
title = {Ganoderma lucidum for Alzheimer's Disease: A Neuroinflammatory and Oxidative Stress Perspective.},
journal = {Journal of ethnopharmacology},
volume = {},
number = {},
pages = {122442},
doi = {10.1016/j.jep.2026.122442},
pmid = {42810460},
issn = {1872-7573},
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder that causes memory loss, cognitive decline, and ultimately dementia. Available pharmacotherapies mainly provide symptomatic relief and do not adequately address the underlying pathology. Ganoderma lucidum (Curtis) P. Karst (G. lucidum) is a widely used medicinal mushroom rich in bioactive compounds, including polysaccharides, triterpenoids, and proteins. These constituents may alleviate the neuroinflammation and oxidative stress involved in AD pathogenesis.

AIM OF THE REVIEW: This review critically integrates evidence for the therapeutic effects of G. lucidum on AD-associated neuroinflammation and oxidative stress. It has three aims: (1) to examine how G. lucidum may disrupt the bidirectional vicious cycle between neuroinflammation and oxidative stress; (2) to compare the pharmacological profiles of different preparations and purified constituents; and (3) to evaluate AD-specific barriers to translation and inform future clinical development.

MATERIALS AND METHODS: We searched PubMed, Web of Science, Google Scholar, and CNKI for studies on G. lucidum and AD through 2026 using combinations of the primary term "Ganoderma lucidum" with "Alzheimer's disease," "neuroinflammation," "oxidative stress," and related terms. Included were original research, mechanism-based studies, and clinical evidence on G. lucidum bioactives in AD or related models. Evidence was stratified by design robustness and presented as a narrative synthesis.

RESULTS: The available evidence indicates that G. lucidum may act on several pathological processes associated with AD. Experimental studies report effects on abnormal amyloid-β (Aβ) aggregation, tau hyperphosphorylation, cholinergic dysfunction, neuroinflammation, oxidative stress, and neuronal apoptosis. These findings illustrate the multi-target pharmacology of traditional Chinese medicines and help explain the potential activity of G. lucidum against AD.

CONCLUSIONS: G. lucidum has anti-inflammatory, antioxidant, and neuroprotective activities that may be relevant to AD management. This review summarizes its reported effects on AD-related neuroinflammation and oxidative stress and examines the underlying mechanisms. Clinical translation remains limited by poor blood-brain barrier (BBB) permeability, uncertain pharmacokinetics, and non-standardized dosing. Rigorous preclinical studies and controlled early-phase trials are therefore required. Addressing these barriers may inform the potential translation of G. lucidum as an adjunctive strategy in multimodal AD therapy. We also identify key evidence gaps and propose a component-specific framework for future research.},
}

@article {pmid42810502,
year = {2026},
author = {Zhou, J and Chen, X and Hong, H and Wang, C and Wang, S and Ren, J and Liu, S and Dou, W and Weng, Q and Wang, Q and Tang, C},
title = {Multi-Organ Per- and Polyfluoroalkyl Substances Accumulation Reveals Brain-Peripheral Metabolic Coupling and Glucocorticoid-Related Dysregulation in Mice.},
journal = {Environmental pollution (Barking, Essex : 1987)},
volume = {},
number = {},
pages = {129257},
doi = {10.1016/j.envpol.2026.129257},
pmid = {42810502},
issn = {1873-6424},
abstract = {Per- and polyfluoroalkyl substances (PFASs) are persistent synthetic chemicals increasingly linked to systemic metabolic dysregulation and potential Alzheimer's disease (AD) risk. However, whether chronic PFASs exposure disrupts metabolic crosstalk between peripheral organs and the brain remains unclear. This study aimed to systematically investigate multi-organ PFASs accumulation and associated metabolic disturbances under chronic PFASs exposure, with a particular focus on the brain. Six-month-old mice were exposed to PFASs for 7 weeks, and PFAS accumulation profiles and metabolic profiles across multiple tissues were characterized using liquid chromatography-mass spectrometry (LC-MS). Across most peripheral tissues, PFAS concentrations were generally comparable to those observed in the brain and showed a relatively consistent distribution pattern, with PFOS exhibiting the highest levels, followed by PFDA and PFNA at similar concentrations, and lower levels of PFHxS and PFOA. Brain differential metabolites (DEMs) showed substantial overlap with those detected in peripheral tissues, with the greatest number of overlapping DEMs and the strongest correlations observed between brain and plasma. Among PFAS exposure-associated DEMs, steroid hormones and their precursor-related metabolites showed the most pronounced fold changes in the brain, followed by metabolites involved in energy metabolism. Notably, 11-dehydrocorticosterone (11-DHC), a shared marker, showed an upregulated trend in both APP/PS1 model mice and PFAS-exposed mice. These findings indicate that PFASs induce concordant metabolic perturbations in the brain and peripheral tissues, prominently involving steroid hormone and energy metabolism pathways. The concordant metabolic signatures between brain and plasma suggest the potential utility of peripheral biomarkers for PFAS-related brain dysfunction. Moreover, metabolites commonly altered in both APP/PS1 model mice and PFAS-exposed mice may implicate glucocorticoid dysregulation as a mechanism that amplifies neuroendocrine stress and AD susceptibility.},
}

@article {pmid42810623,
year = {2026},
author = {Palollathil, A and Najar, MA and Pervaje, R and Raju, R and Keshava Prasad, TS and Modi, PK},
title = {Bacopa monnieri Attenuates Alzheimer's Pathology by Modulating RNA Metabolism, Cellular Stress Responses, and Rho GTPase Signaling: Phosphoproteomic Insights from a Cellular Model of Alzheimer's Disease.},
journal = {Neurochemistry international},
volume = {},
number = {},
pages = {106268},
doi = {10.1016/j.neuint.2026.106268},
pmid = {42810623},
issn = {1872-9754},
abstract = {Alzheimer's disease is a multifactorial disease characterized by proteinopathy caused by senile plaques and neurofibrillary tangles, leading to neuroinflammation and neuronal damage. Bacopa monnieri, with its extensive usage in the Indian traditional medicinal system, Ayurveda, holds promise in enhancing memory and improving neuronal functions. We performed quantitative phosphoproteomics analysis to understand the temporal dynamics of protein phosphorylation involved in Bacopa monnieri-mediated neuroprotection in the Alzheimer's disease model of IMR-32 cells. The quantitative phosphoproteomics analysis identified 5488 phosphopeptides corresponding to 1427 phosphoproteins. Among the dysregulated peptides in the Aβ42 treatment group, 430 were significantly hyperphosphorylated, and 540 were significantly hypophosphorylated. In contrast, the Bacopa monnieri co-treatment group exhibited 64 significantly hyperphosphorylated peptides and 69 significantly hypophosphorylated peptides. The phosphoproteins altered by Aβ42 were involved in biological functions such as RNA splicing, neuron axonogenesis in the central nervous system, and positive regulation of tau-protein kinase activity. Bacopa monnieri restored key pathways altered by Aβ42, including RNA metabolism, cellular response to stress, signaling by Rho GTPases, and RHOBTB2 GTPase cycle. Kinase mapping of differentially expressed phosphoproteins using the KinMap tool identified CDK11B, CDK12, PRKAA1, PRPF4B, STK10, ROCK1 and ROCK2 as downstream effectors of Bacopa monnieri. The network analysis of restored proteins revealed tight interactions between proteins associated with splicing regulation and stress response. This study offers a comprehensive understanding of phosphoproteome alterations involved in Alzheimer's disease in response to neuroprotection by Bacopa monnieri, which may pave the way for developing therapeutic strategies.},
}

@article {pmid42810652,
year = {2026},
author = {Perina, ML and Calcagno, D and Sbardella, D and Deodato, D and Distefano, A and Tuccitto, N and Oliveri, V and Schlotter, F and Faller, P and Grasso, G},
title = {The chemical oxidation of albumin affects its capability to bind amyloid beta 1-40 peptide and to inhibit its aggregation.},
journal = {International journal of biological macromolecules},
volume = {},
number = {},
pages = {154678},
doi = {10.1016/j.ijbiomac.2026.154678},
pmid = {42810652},
issn = {1879-0003},
abstract = {Human Serum Albumin (HSA) is the most abundant protein in the human body, exerting vital antioxidant and carrier functions. Beyond its systemic roles, HSA is clinically employed as a therapeutic tear supplement to restore the ocular surface proteome in severe dry eye and corneal diseases. However, the functional integrity of HSA is frequently compromised by oxidative stress, a hallmark of several neurodegenerative proteinopathies. While elevated levels of oxidised HSA have been documented in the blood and cerebrospinal fluid of Alzheimer's Disease patients, similar oxidative modifications are implicated in the pathogenesis of glaucoma and Age-related Macular Degeneration, where amyloid-beta (Aβ) peptides deposition and impaired protein clearance drive disease progression. Despite these clinical correlations, the specific impact of oxidative damage on the ability of HSA to chaperone and interact with Aβ peptides remains poorly understood. In this work, we applied several different experimental techniques to study the effect of oxidation on HSA conformation and oligomeric state when Chloramine T (CT) and hydrogen peroxide in Metal Catalysed Oxidation (MCO) are employed. ThT aggregation studies confirmed that the two different oxidised forms of HSA affect Aβ1-40 fibrillation differently. In addition, SPR interaction studies between the two differently oxidised forms of HSA and Aβ1-40 allowed us to prove that CT and MCO induce two different oxidative damages on HSA, which in turn induce lower binding capability towards Aβ1-40. Our results indicate a possible explanation for the role of oxidised HSA in the development and progression of brain and retinal neurodegeneration characterized by accumulation of Aβ.},
}

@article {pmid42810828,
year = {2026},
author = {Zhu, S and Omid-Fard, N and Martinez Imbett, RE and Dowling, T and Khazai, B and Gil, N and Romero, JM and Ford, J and Rohatgi, S},
title = {Perivascular Spaces and Diffusion Tensor Imaging Analysis Along the Perivascular Space Show Distinct Associations with Aging and Alzheimer's Disease.},
journal = {AJNR. American journal of neuroradiology},
volume = {},
number = {},
pages = {},
doi = {10.3174/ajnr.A9659},
pmid = {42810828},
issn = {1936-959X},
abstract = {BACKGROUND AND PURPOSE: MRI-visible perivascular spaces (PVS) are structural findings on T2-weighted MRI, whereas diffusion tensor imaging analysis along the perivascular space (DTI-ALPS) measures directional water diffusivity in deep white matter. We compared PVS burden and ALPS across young controls, elderly controls, and patients with Alzheimer's disease (AD).

MATERIALS AND METHODS: This retrospective, institutional review board-approved study included an acquisition-harmonized cohort of 16 young controls, 22 elderly controls, and 32 patients with biomarker-confirmed AD, all with DTI acquired on the same 3T Siemens MAGNETOM Vida platform. Two blinded readers graded basal ganglia (BG) and centrum semiovale (CSO) PVS on 2D axial T2-weighted images. PVS and ALPS were compared across the 3 groups; age- and sex-adjusted regression evaluated the elderly-control versus AD difference.

RESULTS: Interrater reliability was excellent (quadratic-weighted kappa = 0.873-0.929). Median combined PVS scores (range, 0-8) were 2.75, 5.00, and 4.75 in young, elderly controls, and AD, respectively (P < .001), with no elderly-control versus AD difference (P = .89). Median ALPS indices were 1.365, 1.235, and 1.102 (P < .001). In pairwise testing unadjusted for age or sex, the elderly-control versus AD ALPS difference did not reach statistical significance (P = .05). In age- and sex-adjusted regression, AD was associated with lower ALPS (beta = -0.080; 95% CI, -0.158 to -0.003; P = .04), and the association persisted after additional adjustment for combined PVS (beta = -0.082; P = .04).

CONCLUSIONS: In a single-scanner, acquisition-harmonized cohort, MRI-visible PVS burden was predominantly associated with older age, whereas a modest AD-associated reduction in ALPS emerged after covariate adjustment. PVS grading and ALPS characterize different structural and diffusion features and should not be considered interchangeable. Longitudinal validation with higher-resolution diffusion imaging is needed to determine whether ALPS provides additional clinical value.},
}

@article {pmid42810842,
year = {2026},
author = {Morato, X and Marquié, M and Tartari, JP and Lafuente, A and Sáez, ME and Montoliu-Gaya, L and Huber, H and Alegret, M and Jofresa, S and Buendía, M and Pancho, A and Aguilera, N and Ibarria, M and Diego, S and Cuevas, R and Cañada, L and Pérez-Cordón, A and Sanabria, A and De Rojas, I and Cano, A and Orellana, A and Montrreal, L and Rosende-Roca, M and Vargas, L and Espinosa, A and Ortega, G and Núñez-Llaves, R and Martínez-Lucas, M and Cantero-Fortiz, Y and Alarcón-Martín, E and Gurruchaga, M and Tárraga, L and Valero, S and Sanz-Cartagena, P and Mañes, S and Zetterberg, H and Ruiz, A and Boada, M},
title = {A single-center open-label, randomized, parallel-group controlled clinical trial on the long-term effect of the treatment with EGb 761 in blood markers of inflammation and neurodegeneration in patients with mild cognitive impairment: ACE-2020-EGb 761.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261490130},
doi = {10.1177/13872877261490130},
pmid = {42810842},
issn = {1875-8908},
abstract = {BackgroundNeuroinflammation plays a central role in Alzheimer's disease (AD) pathology and other dementias. EGb 761, a standardized Ginkgo biloba extract, has shown potential anti-inflammatory and neuroprotective properties.ObjectiveThis study evaluated the effects of EGb 761 on plasma proteins related to inflammation and neurodegeneration, cognitive performance, and core AD biomarkers in individuals with mild cognitive impairment (MCI).MethodsWe conducted a 12-month randomized, controlled, open-label clinical trial with a 12-month extension phase in 100 patients with MCI recruited at a single center. During the first 12 months, participants were randomly assigned to EGb 761 or no treatment. In the extension phase, all participants received EGb 761 for an additional 12 months. Plasma samples were collected at baseline and at 6-month intervals throughout both phases. Inflammatory and neurological proteomic profiles were assessed using the Olink Inflammation and Neurology panels. AD biomarkers including Aβ40, Aβ42, Aβ42/40 ratio, GFAP, NfL, and pTau231 were measured in plasma. Clinical, neurological, and neuropsychological assessments were performed at each visit.ResultsEGb 761 was associated with nominally significant longitudinal decreases in 15 plasma proteins linked to innate immunity and axon guidance, replicated in the delayed-start group.ConclusionsEGb 761 exposure is associated with longitudinal modulation of serum markers associated with systemic inflammation and neurodegeneration in MCI. Larger placebo-controlled biomarker-driven trials are warranted to confirm whether this translates into clinically meaningful neuroprotection.Trial registration:Registro Español de estudios clínicos (REec) 2020-003776-41, ClinicalTrials.gov NCT05594355, https://clinicaltrials.gov/study/NCT05594355.},
}

@article {pmid42811001,
year = {2026},
author = {Park, J and Bae, HG and Cho, Y and Baek, SH and Jo, DG},
title = {Transcriptional modulation of β-Secretase ameliorates amyloid pathology and cognitive deficits in Alzheimer's disease models.},
journal = {Signal transduction and targeted therapy},
volume = {11},
number = {1},
pages = {},
pmid = {42811001},
issn = {2059-3635},
support = {RS-2024-00453278//National Research Foundation of Korea (NRF)/ ; RS-2024-00453278//National Research Foundation of Korea (NRF)/ ; RS-2025-00561705//National Research Foundation of Korea (NRF)/ ; },
}

@article {pmid42811116,
year = {2026},
author = {Brooker, SM and Coukos, R and Krainc, D},
title = {Lysosomal dysfunction in neurodegenerative disease.},
journal = {Nature reviews. Neurology},
volume = {},
number = {},
pages = {},
pmid = {42811116},
issn = {1759-4766},
abstract = {Examination of genetic risk factors associated with neurodegenerative diseases has provided important mechanistic insights into the pathophysiology of these disorders, and it has implicated defects in lysosomal function as a key component of the neurodegenerative process. The lysosome has a primary role in mediating degradation of both intracellular contents and endocytosed material from the extracellular space. Aggregation of misfolded proteins is a pathological mechanism that is observed across neurodegenerative disorders, and aberrant lysosomal degradation of such proteins plays a pivotal part in driving neuronal dysfunction and cell loss. In addition to the crucial role of the endolysosomal system in degradation of intracellular constituents, lysosomes also serve as important nodes for intracellular signalling, participating in nutrient sensing, lipid metabolism, membrane repair and neuroinflammation. In this Review, we provide an overview of mechanisms of lysosomal dysfunction in neurodegenerative disease, with a particular focus on Parkinson disease, Alzheimer disease, frontotemporal dementia and amyotrophic lateral sclerosis.},
}

@article {pmid42811260,
year = {2026},
author = {Yu, X and Yao, S and Xu, P and Wang, A},
title = {[Mechanisms of cGAS-STING signaling pathway mediated neuroinflammation in central nervous system and their therapeutic implications].},
journal = {Zhejiang da xue xue bao. Yi xue ban = Journal of Zhejiang University. Medical sciences},
volume = {55},
number = {7},
pages = {638-651},
doi = {10.3724/zdxbyxb-2026-0036},
pmid = {42811260},
issn = {1008-9292},
mesh = {Humans ; cGAS-STING Signaling Pathway ; *Nucleotidyltransferases/metabolism ; *Membrane Proteins/metabolism ; Cyclic Guanosine Monophosphate-Adenosine Monophosphate Synthase ; Signal Transduction ; STING Protein ; *Neuroinflammatory Diseases ; *Central Nervous System Diseases ; *Central Nervous System/metabolism ; Animals ; },
abstract = {The cGAS-STING signaling pathway is a crucial mechanism by which cells sense aberrant DNA and trigger type Ⅰ interferon and inflammatory responses. Emerging evidence indicates that in various central nervous system (CNS) diseases, events such as mitochondrial damage, release of mitochondrial DNA, nuclear DNA damage, lysosomal rupture, and cell death-associated DNA leakage can activate cGAS-STING signaling pathway in microglia, astrocytes, and some neurons. This activation drives transcriptional programs involving IRF3 and NF-κB, cross-talks with autophagy and cell-fate decisions, and initiates and amplifies neuroinflammation, ultimately accelerating neuronal dysfunction. This review, structured around the framework of DNA sources, signaling mechanisms, cell-fate alterations, and pathological outcomes, systematically summarizes the common mechanisms and disease-specific features of cGAS-STING in pathological conditions such as Alzheimer's disease, Parkinson's disease, ischemic stroke, multiple sclerosis, and other disorders. Furthermore, it summarizes current intervention strategies, including small-molecule inhibitors of cGAS or STING, transcriptional axis blockade, and targeted delivery technologies. It also discusses key issues such as the cell-type-specific roles of cGAS-STING regulation in the CNS, blood-brain barrier penetration, and biomarker development, thereby providing a basis for cGAS-STING-targeted intervention in neuroinflammation.},
}

Humans
cGAS-STING Signaling Pathway
*Nucleotidyltransferases/metabolism
*Membrane Proteins/metabolism
Cyclic Guanosine Monophosphate-Adenosine Monophosphate Synthase
Signal Transduction
STING Protein
*Neuroinflammatory Diseases
*Central Nervous System Diseases
*Central Nervous System/metabolism
Animals

@article {pmid42811341,
year = {2026},
author = {Tasaki, S and Avey, DR and Kearns, NA and Yu, C and Tissera, S and Vyas, H and Cheng, L and Xu, J and Iatrou, A and Flood, DJ and Li, W and Barnes, LL and Rothamel, K and Wingo, AP and Wingo, TS and Seyfried, NT and He, C and De Jager, PL and Yeo, GW and Gaiteri, C and Bennett, DA and Wang, Y},
title = {The YTHDF proteins modulate Alzheimer's disease-associated brain gene signatures.},
journal = {Molecular neurodegeneration},
volume = {21},
number = {1},
pages = {},
pmid = {42811341},
issn = {1750-1326},
mesh = {*Alzheimer Disease/genetics/metabolism ; Humans ; *Brain/metabolism ; *RNA-Binding Proteins/metabolism/genetics ; Transcriptome ; *Nerve Tissue Proteins/metabolism/genetics ; },
abstract = {Gene signatures of Alzheimer's disease (AD) brains reflect the output of a complex interplay of genetic, epigenetic, epi-transcriptomic, and post-transcriptional regulations. To nominate candidate factors modulating these signatures, we developed a machine learning model to integrate cellular and molecular features explaining differential gene expression in AD. Among the features tested, YTHDF proteins, the canonical readers of N6-methyladenosine (m6A) RNA modification, are among the most influential predictors of AD gene signatures. Protein modules containing YTHDFs were downregulated in human AD brains, and knockdown or pharmacological inhibition of YTHDFs in iPSC-derived 2D and 3D neuronal models recapitulated key AD-associated gene signatures. Furthermore, eCLIP-seq revealed altered YTHDF binding to transcripts in AD brains, at both m6A-dependent and m6A-independent sites. Together, these results support an important role for YTHDF proteins in modulating AD-associated gene signatures in the human brain.},
}

*Alzheimer Disease/genetics/metabolism
Humans
*Brain/metabolism
*RNA-Binding Proteins/metabolism/genetics
Transcriptome
*Nerve Tissue Proteins/metabolism/genetics

@article {pmid42811373,
year = {2026},
author = {Kaufmann, P and Ilina, Y and Giontella, A and Press, M and Nägga, K and Hansson, O and Hampel, H and Bergmann, A and Melander, O},
title = {Impaired peptide amidation and risk of incident dementia in the Malmoe preventive project cohort.},
journal = {Alzheimer's research & therapy},
volume = {18},
number = {1},
pages = {},
pmid = {42811373},
issn = {1758-9193},
mesh = {Humans ; Female ; *Adrenomedullin/blood/metabolism ; Male ; Aged ; *Mixed Function Oxygenases/blood/metabolism ; *Multienzyme Complexes/blood/metabolism ; Sweden/epidemiology ; Cohort Studies ; *Dementia/epidemiology/blood ; *Alzheimer Disease/epidemiology/blood ; Incidence ; *Protein Precursors/blood ; Risk Factors ; Biomarkers/blood ; Proportional Hazards Models ; *Dementia, Vascular/epidemiology/blood ; Follow-Up Studies ; Peptide Fragments ; },
abstract = {BACKGROUND: Peptidylglycine α-amidating monooxygenase (PAM) is the key enzyme responsible for the C-terminal amidation of multiple vasoactive and neuroactive peptide hormones. Among these, amidated bioactive adrenomedullin (bio-ADM) is a critical regulator of endothelial- and blood-brain barrier (BBB) integrity and vascular homeostasis. Impaired peptide amidation may contribute to endothelial dysfunction and neurovascular dysregulation, mechanisms implicated in the pathogenesis of Alzheimer's disease (AD).

METHODS: In 4543 dementia-free participants from the Malmö preventive project (MPP), plasma levels of mid-regional pro-adrenomedullin (MR-proADM), bio-ADM, and PAM activity (PAM-AMA) were measured at baseline, and incident dementia was ascertained through national registry data during follow-up. Associations were evaluated using Cox proportional hazards models with multivariable adjustment for common risk factors, false discovery rate correction, BMI-stratified analyses, and sensitivity analyses.

RESULTS: During a mean follow-up of 4.75 ± 1.3 years, 205 participants developed incident AD and 93 developed vascular dementia (VD). Lower PAM-AMA was associated with increased risk of incident AD (adjusted hazard ratio per 1 standard deviation decrease (aHR): 2.30; 95% confidence interval (CI): 1.31-4.02; q = 0.01). Lower bio-ADM levels were also associated with increased Alzheimer's risk (aHR: 1.62; 95% CI: 1.13-2.33; q = 0.01). A reduced bio-ADM/MR-proADM ratio and its interaction with PAM-AMA further strengthened AD risk estimates. Associations were independent of APOE ε4 carrier status, more pronounced among individuals with BMI < 30 and remained directionally consistent in sensitivity analyses. No consistent associations were observed for VD after multivariable adjustment.

CONCLUSIONS: Reduced PAM-AMA and lower bio-ADM levels were associated with increased risk of incident AD, but not VD. A reduced ADM-ratio further indicates precursor peptide accumulation. These findings suggest that impaired peptide hormone amidation may represent an early systemic marker of neurovascular vulnerability and support further investigation of C-terminal peptide amidation pathways in translational AD research, including studies with a longer follow-up period and biomarker-confirmed dementia diagnoses.},
}

Humans
Female
*Adrenomedullin/blood/metabolism
Male
Aged
*Mixed Function Oxygenases/blood/metabolism
*Multienzyme Complexes/blood/metabolism
Sweden/epidemiology
Cohort Studies
*Dementia/epidemiology/blood
*Alzheimer Disease/epidemiology/blood
Incidence
*Protein Precursors/blood
Risk Factors
Biomarkers/blood
Proportional Hazards Models
*Dementia, Vascular/epidemiology/blood
Follow-Up Studies
Peptide Fragments

@article {pmid42811478,
year = {2026},
author = {Miao, J and Wang, J and Li, Y and Zhang, H and Zhang, Y and Li, Q and Xiao, B and Zhou, W and Guo, J},
title = {Restores Aβ Clearance by Overcoming PCSK9-LRP1 Dysregulation and TRIB3-Mediated Autophagy Blockade in Alzheimer's Disease.},
journal = {Advanced science (Weinheim, Baden-Wurttemberg, Germany)},
volume = {},
number = {},
pages = {e77929},
doi = {10.1002/advs.77929},
pmid = {42811478},
issn = {2198-3844},
support = {32571692//National Natural Science Foundation of China/ ; 202303021222348//Fundamental Research Program of Shanxi Province/ ; 202303021221212//Fundamental Research Program of Shanxi Province/ ; 202303021212373//Fundamental Research Program of Shanxi Province/ ; 2021ZD0201801//STI2030-Major Projects/ ; 2023YFC3605400//National Key Research and Development Program of China/ ; },
abstract = {Alzheimer's disease (AD) is characterized by amyloid-β (Aβ) accumulation, neuroinflammation, and vascular dysfunction, yet effective therapies remain limited. Impaired Aβ clearance across the blood-brain barrier (BBB) is a key contributor to AD pathogenesis. Two sequential barriers to Aβ clearance are identified: proprotein convertase subtilisin/kexin type 9 (PCSK9) upregulation in cerebrovascular endothelial cells compromises low-density lipoprotein receptor-related protein 1 (LRP1)-mediated Aβ efflux, whereas increased intracellular Aβ handling after PCSK9 silencing induces tribbles pseudokinase 3 (TRIB3) upregulation and exposes an autophagy blockade restricting intracellular Aβ degradation. PCSK9 silencing restores LRP1 expression and enhances Aβ uptake and efflux, whereas TRIB3 knockdown restores autophagic flux and facilitates Aβ degradation. SITR (siPCSK9/siTRIB3@TPN-RAP), a RAP-modified siRNA nanodelivery system based on tea polyphenol nanoparticles (TPNs), enables brain-enriched co-delivery of siPCSK9 and siTRIB3. SITR enhances BBB penetration and preferentially accumulates in cerebrovascular endothelial cells and microglia. In APP/PS1 mice, SITR improves cognitive performance, reduces Aβ and cerebral amyloid angiopathy burden, preserves vascular and neuronal homeostasis, and suppresses neuroinflammation, while showing no overt short-term systemic toxicity under a 6-week regimen. These findings establish PCSK9 and TRIB3 as complementary therapeutic targets and support SITR as an effective nanoplatform integrating enhanced Aβ efflux with restored autophagic degradation for AD intervention.},
}

@article {pmid42811609,
year = {2026},
author = {Kim, D and Tithof, J},
title = {Fluid-structure interaction dynamics of cervical lymphatic vessel pumping and valvular function.},
journal = {Journal of the Royal Society, Interface},
volume = {23},
number = {242},
pages = {},
doi = {10.1098/rsif.2025.1261},
pmid = {42811609},
issn = {1742-5662},
support = {//Minnesota Office of Higher Education SCI-TBI/ ; },
mesh = {*Lymphatic Vessels/physiology ; Animals ; *Models, Biological ; *Cerebrospinal Fluid/physiology ; Mice ; Hydrodynamics ; },
abstract = {A substantial portion of cerebrospinal fluid (CSF) drains through cervical lymphatic vessels (CLVs), a pathway mediated by basal and dorsal meningeal lymphatics. Impaired drainage along this route has been implicated in ageing, Alzheimer's disease and traumatic brain injury. Despite considerable experimental investigation of CLV structure and function, computational modelling of this pathway remains limited. Here, we present a fully coupled two-dimensional fluid-structure interaction (FSI) model of a murine CLV constructed using the lattice Boltzmann method for fluid dynamics and the immersed boundary method for the vessel geometry. Distinct from previous lymphatic vessel models, this framework is parametrized using data from recent in vivo imaging studies of CLVs. Using this model, we characterize the transient FSI dynamics within a single lymphangion, the pumping performance across a chain of three lymphangions with varying contraction phase delays and the role of circular sinus geometry in regulating CSF transport under both favourable and adverse pressure gradients. Our results provide the first high-fidelity simulation of CSF drainage through CLVs, bridging a gap between experimental observations and mechanistic understanding. This work offers new insights into CLV pumping behaviour and valve function, which helps inform the design of future experiments and therapeutic strategies aimed at enhancing CSF clearance.},
}

*Lymphatic Vessels/physiology
Animals
*Models, Biological
*Cerebrospinal Fluid/physiology
Mice
Hydrodynamics

@article {pmid42811665,
year = {2026},
author = {Padilla, VJ and Otte, J and Sanford, K and Scullin, M and Corlett, C and Elkins, G},
title = {Hypnosis intervention for sleep quality in caregivers of individuals with Alzheimer's Disease.},
journal = {The American journal of clinical hypnosis},
volume = {},
number = {},
pages = {1-13},
doi = {10.1080/00029157.2026.2713606},
pmid = {42811665},
issn = {2160-0562},
abstract = {Poor sleep quality is a common health issue among caregivers of adults with Alzheimer's Disease and Related Dementias (ADRD). Behavioral interventions such as hypnosis have been proposed for improving sleep in this population since pharmacological measures can impair their ability to wake up readily to provide care. The present pilot study aimed to determine the feasibility of a hypnosis intervention program for improving sleep quality in caregivers of individuals with ADRD. A sample of 21 eligible adults was randomly assigned to either a self-administered hypnosis or a sham hypnosis group. The findings indicated feasibility of accrual, randomization, and intervention delivery. The mean treatment satisfaction rating score was 8.75 (SD = 1.28) in the treatment group, on a 0-to-10 numerical rating scale (0 = highly dissatisfied, 10 = highly satisfied). The mean ease-of-use rating for the treatment procedures was 8.50 (SD = .93) in the treatment condition. Results found improvements in sleep quality and duration as measured by the Pittsburgh Sleep Quality Index and sleep diaries.},
}

@article {pmid42811779,
year = {2026},
author = {Li, C and Zhao, C and Lan, Y and Ellis, RJ and Isaac, S and Zhang, S and Miller, GW and Sun, Y and Jain, S and Yadav, H and Gao, P and Patel, CJ},
title = {Exposome-wide association study and predictive risk score for incident Alzheimer's disease and related dementias.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {10},
pages = {e71842},
doi = {10.1002/alz.71842},
pmid = {42811779},
issn = {1552-5279},
support = {//Harvard Data Science Initiative Faculty Special Projects Fund/ ; U24ES036819/ES/NIEHS NIH HHS/United States ; R01ES032470/ES/NIEHS NIH HHS/United States ; R01AG074372/AG/NIA NIH HHS/United States ; },
mesh = {Humans ; *Alzheimer Disease/epidemiology/genetics ; Female ; Male ; Risk Factors ; *Exposome ; Aged ; *Dementia/epidemiology ; Risk Assessment ; *Environmental Exposure/adverse effects ; Proportional Hazards Models ; United Kingdom/epidemiology ; Incidence ; Middle Aged ; UK Biobank ; },
abstract = {INTRODUCTION: Environmental exposures contribute substantially to Alzheimer's disease and related dementias (ADRD), yet comprehensive exposome-wide investigations systematically evaluating multi-domain environmental factors remain limited and lacking utility for precision medicine.

METHODS: We conducted an exposome-wide association study (ExWAS) among 499,992 UK Biobank participants, examining 193 exposures across five domains (social, physical, chemical, lifestyle, and ecosystems). Cox proportional hazard models with Bonferroni correction identified ADRD-associated exposures. We used the XGBoost classifier to build a predictive model and further developed an exposomic risk score (ERS) for risk stratification.

RESULTS: During a 15.3-year median follow-up, 8881 participants (1.77%) developed ADRD, including 4000 with Alzheimer's disease. ExWAS identified 76 exposures after Bonferroni correction. The prediction model achieved area under the curve (AUC) = 0.718, outperforming demographics+apolipoprotein E (APOE) status alone (AUC = 0.678). The ERS stratified ADRD risk (highest vs lowest quartile hazard ratio [HR] = 2.97, 95% confidence interval [CI]: 2.59-3.41).

DISCUSSION: The ERS has the potential to contribute to clinically relevant prevention strategies for ADRD.},
}

Humans
*Alzheimer Disease/epidemiology/genetics
Female
Male
Risk Factors
*Exposome
Aged
*Dementia/epidemiology
Risk Assessment
*Environmental Exposure/adverse effects
Proportional Hazards Models
United Kingdom/epidemiology
Incidence
Middle Aged
UK Biobank

@article {pmid42811946,
year = {2026},
author = {Zhang, S and Roemer-Cassiano, SN and Chong, JR and Fang, T and Li, Y and Wang, Z and Zeng, T and Li, X and Deco, G and Venketasubramanian, N and Zhou, JH and Chen, CL and , and Lai, MKP and Franzmeier, N and Yeo, BTT},
title = {Excitation-inhibition imbalance links amyloid pathophysiology to cognition in non-demented individuals.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {10},
pages = {e71891},
doi = {10.1002/alz.71891},
pmid = {42811946},
issn = {1552-5279},
support = {NUHSRO/2020/124/TMR/LOA//NUS Yong Loo Lin School of Medicine/ ; OFLCG19May-0035//Singapore National Medical Research Council (NMRC) LCG/ ; CTGIIT23jan-0001//NMRC CTG-IIT/ ; OFIRG24jan-0006//NMRC OF-IRG/ ; OFIRG24jul-0049//NMRC OF-IRG/ ; STaR20nov-0003//NMRC STaR/ ; CG21APR1009//Singapore Ministry of Health (MOH) Centre Grant/ ; R01MH133334//United States National Institutes of Health/ ; 2R01MH120080//United States National Institutes of Health/ ; NRFI10-2024-0014//Singapore National Research Foundation (NRF) Investigatorship/ ; },
mesh = {Humans ; *Amyloid beta-Peptides/cerebrospinal fluid ; tau Proteins/blood/cerebrospinal fluid ; Female ; Male ; Magnetic Resonance Imaging ; *Cognition/physiology ; Aged ; Biomarkers/cerebrospinal fluid/blood ; *Brain/physiopathology ; Peptide Fragments/cerebrospinal fluid ; Middle Aged ; Phosphorylation ; Alzheimer Disease ; },
abstract = {INTRODUCTION: Excitation-inhibition (E/I) imbalance has been proposed as an early circuit-level mechanism in Alzheimer's disease (AD), but its relationship to molecular pathology and cognition in humans remains unclear.

METHODS: We integrated biophysical modeling of resting-state functional magnetic resonance imaging with cerebrospinal fluid (CSF) and plasma biomarkers to examine whether E/I ratio links amyloid pathophysiology to memory in non-demented individuals across two cohorts from North America (N = 302; CSF amyloid beta 42 [Aβ42]) and Singapore (N = 240; plasma phosphorylated tau 217 [p-tau217]).

RESULTS: Elevated E/I ratio was associated with lower CSF Aβ42 and higher plasma p-tau217, with greater sensitivity in sensory-motor regions. In contrast, elevated E/I ratio in association cortices was more strongly related to worse memory function. Mediation analyses indicated E/I ratio partially accounted for the AD biomarker-memory relationship.

DISCUSSION: E/I imbalance represents an intermediate, systems-level circuit mechanism that links AD pathophysiology to cognitive impairment, offering novel insight into early neurophysiological changes along the AD continuum.},
}

Humans
*Amyloid beta-Peptides/cerebrospinal fluid
tau Proteins/blood/cerebrospinal fluid
Female
Male
Magnetic Resonance Imaging
*Cognition/physiology
Aged
Biomarkers/cerebrospinal fluid/blood
*Brain/physiopathology
Peptide Fragments/cerebrospinal fluid
Middle Aged
Phosphorylation
Alzheimer Disease

@article {pmid42811972,
year = {2026},
author = {Kalendar, R},
title = {Mosaic Loss of Chromosome Y (LOY): From Genomic Instability to Disease and Single-Cell Detection.},
journal = {Frontiers in bioscience (Landmark edition)},
volume = {31},
number = {9},
pages = {55248},
doi = {10.31083/FBL55248},
pmid = {42811972},
issn = {2768-6698},
support = {BR24993023//Committee of Science of the Ministry of Science and Higher Education of the Republic of Kazakhstan/ ; },
mesh = {Humans ; Animals ; *Genomic Instability ; *Chromosomes, Human, Y/genetics ; *Mosaicism ; *Single-Cell Analysis/methods ; Male ; Cardiovascular Diseases/genetics ; Neoplasms/genetics ; },
abstract = {Mosaic loss of chromosome Y (LOY) is the acquired absence of the Y chromosome in a fraction of cells, is most readily observed in the haematopoietic compartment, and represents the most common form of clonal mosaicism in older men. Once dismissed as a benign correlate of aging, LOY is now recognized as a clinically meaningful biomarker associated with reduced survival and an expanding range of age-related disorders, including multiple solid and haematological cancers, cardiovascular disease, Alzheimer's disease, and type 2 diabetes mellitus. Large-scale genome-wide analyses have shown that susceptibility to LOY is highly heritable and associated with genes involved in cell cycle regulation, the DNA damage response, and apoptosis, supporting a model in which detectable LOY in blood reflects broader genomic instability across tissues. In parallel, functional studies in genetically engineered mice have demonstrated that haematopoietic LOY can contribute causally to pathologic processes such as cardiac fibrosis, indicating that loss of dosage-sensitive Y-linked genes in immune cells may exert direct effects rather than merely serving as a passive marker. Progress in this field has been constrained by detection methods that are laborious, costly, or insufficiently sensitive at low mutant cell fractions. This constraint is now easing on two fronts. Haplotype- and coverage-based callers can detect LOY from whole-genome and exome sequencing data generated for other purposes, extending measurement to ancestrally diverse cohorts and tumour genomes, while newer single-cell droplet-based approaches permit accurate quantification of LOY and its female counterpart, mosaic loss of chromosome X (LOX), at single-cell resolution. Here, we summarize the biology, genetic architecture, disease associations, and proposed mechanisms of LOY and discuss how improved detection may help clarify its causal contribution to human aging and disease.},
}

Humans
Animals
*Genomic Instability
*Chromosomes, Human, Y/genetics
*Mosaicism
*Single-Cell Analysis/methods
Male
Cardiovascular Diseases/genetics
Neoplasms/genetics

@article {pmid42812254,
year = {2026},
author = {Zhou, X and Hu, Y and Yang, Z},
title = {A meta-analysis of the effects of combined interventions centered on cognitive training on cognition, executive function, and negative emotions in patients with Alzheimer's disease.},
journal = {Frontiers in neurology},
volume = {17},
number = {},
pages = {1883995},
pmid = {42812254},
issn = {1664-2295},
mesh = {Humans ; *Alzheimer Disease/therapy/psychology ; *Cognitive Training ; *Executive Function/physiology ; *Emotions/physiology ; *Cognition/physiology ; Cognitive Enhancement ; Combined Modality Therapy ; Exercise Therapy ; Randomized Controlled Trials as Topic ; },
abstract = {OBJECTIVE: To systematically compare the effects of five intervention strategies centered on Cognitive Training (CT), including Routine Care (RC), CT, Physical Exercise (PE), Cognitive Plus Exercise Training (CET), and Cognitive Plus Non-Invasive Brain Stimulation (CNIBS), on cognitive function, executive function, and negative emotions in patients with Alzheimer's disease, using a network meta-analysis. The relative efficacy of different interventions was ranked to provide evidence-based support for optimizing combined treatment strategies in clinical practice.

METHODS: PubMed, Embase, Web of Science, Cochrane Library, and EBSCO databases were systematically searched to identify randomized controlled trials on CT and its combined interventions for Alzheimer's disease published from database inception to April 2026. A network meta-analysis was conducted within a frequentist framework using Stata 17.0 software. The efficacy of interventions was ranked using the surface under the cumulative ranking curve.

RESULTS: A total of 19 randomized controlled trials involving more than 2,000 patients were included. The network meta-analysis showed that, for cognitive function, CNIBS (SUCRA = 75.4%) and CET (SUCRA = 72.4%) ranked first and second, respectively, and were significantly superior to RC and single interventions. For executive function, CET ranked highest (SUCRA = 99.9%) and was significantly superior to PE alone (SMD = 3.71, 95% CI: 3.16 to 4.26) and RC (SMD = 1.69, 95% CI: 0.48 to 2.91), other interventions do not offer a significant advantage over RC. For negative emotions, CET ranked highest (SUCRA = 83.7%), followed by PE alone (SUCRA = 57.9%), and CNIBS was also superior to CT alone (SMD = 1.07, 95% CI: 0.53 to 1.61).

CONCLUSION: Combined interventions centered on CT are superior to single interventions in improving multidimensional symptoms in patients with Alzheimer's disease. Among them, CET shows the most prominent advantages in improving executive function and negative emotions, whereas CNIBS shows the greatest effect on overall cognitive function. In clinical practice, individualized intervention strategies should be selected according to the primary rehabilitation goal.},
}

Humans
*Alzheimer Disease/therapy/psychology
*Cognitive Training
*Executive Function/physiology
*Emotions/physiology
*Cognition/physiology
Cognitive Enhancement
Combined Modality Therapy
Exercise Therapy
Randomized Controlled Trials as Topic

@article {pmid42812304,
year = {2026},
author = {Ji, D and Zhao, J and Huang, X and Liu, X and Yang, Q and Li, X and Yan, L and Gao, D and Xiao, Y},
title = {A coordinated multi-target approach based on chondroitin sulphate nano-selenium mitigates Alzheimer's disease pathologies in APP/PS1 mice.},
journal = {Frontiers in pharmacology},
volume = {17},
number = {},
pages = {1936198},
pmid = {42812304},
issn = {1663-9812},
abstract = {Alzheimer's disease (AD) is a severe neurodegenerative disorder characterised by progressive memory loss and cognitive decline. Because of the lack of effective treatment modalities for AD, novel therapeutics that could delay the progression of AD are urgently required. In this study, the neuroprotective effects and mechanisms of chondroitin sulphate nano-selenium (CS@Se) were investigated by using APPSwe, PSEN1dE9 (APP/PS1) transgenic mice. We found CS@Se to exhibit potent multi-targeted anti-AD effects, and it showed excellent ability to effectively alleviate neuropathy and cognitive dysfunction. Behavioural experiments showed that CS@Se improved learning and memory capacity and enhanced motor activity. Mechanistically, CS@Se upregulated A disintegrin and metalloproteinase domain-containing protein 10 (ADAM10) expression while downregulating the levels of amyloid precursor protein (APP) and beta-secretase 1 (BACE1). Further studies revealed that CS@Se could reduce β-amyloid (Aβ) deposition and inhibit tau phosphorylation by promoting APP hydrolysis and inhibiting the glycogen synthase kinase (GSK)-3β signalling pathway in APP/PS1 mice. Additionally, CS@Se could alleviate oxidative stress damage, neuroinflammation, and cholinergic damage. In conclusion, CS@Se confers substantial neuroprotective effects by modulating several key pathological pathways, providing evidence for its multi-target therapeutic strategy against AD.},
}

@article {pmid42812383,
year = {2026},
author = {Yuhan, A and Swain, S and Zhao, R and Ramos, J and Rameau, A},
title = {The epistemic economy of vocal biomarker startups: a qualitative interview study of data practices and governance.},
journal = {Frontiers in digital health},
volume = {8},
number = {},
pages = {1895383},
pmid = {42812383},
issn = {2673-253X},
abstract = {BACKGROUND AND AIMS: Vocal biomarker technology has emerged as a promising non-invasive health assessment tool, with artificial intelligence enabling the screening, diagnosis, and monitoring of conditions including Parkinson's disease, Alzheimer's disease, depression, and heart failure. Vocal biomarkers are defined as vocal features, alone or in combination, validated as indicators of clinical outcomes. Startups in this space are generating substantial investment and anticipatory discourse around future commercialization, while the scientific foundation and governance framework remain unestablished. Drawing on Sabina Leonelli's epistemic economy framework, which analyzes how data are produced, valued, and governed within social, institutional, and commercial arrangements, we examine how voice data are converted into entities with clinical and commercial value, and at what scientific and ethical cost.

METHODS: We performed a qualitative interview study using an interpretive framework. Virtual semi-structured interviews were conducted with representatives from eleven vocal biomarker startups identified through purposive sampling. Interviews addressed data collection methods, IRB compliance, informed consent, participant demographics, geographic sourcing, and financial incentives. Two researchers independently performed thematic analysis, reconciling differences via discussion.

RESULTS: Six themes were identified: (1) the absence of shared data standards introduced substantial hardware and protocol heterogeneity, uncontrolled confounding, and label noise, undermining scientific validity; (2) IRB engagement ranged from robust multi-site review to complete absence of oversight; (3) consent practices varied from granular opt-in to implied consent and minimal disclosures; (4) voice data were acknowledged as inherently non-anonymizable, creating unresolved privacy and re-identification risks; (5) data sourcing was asymmetric, with collection from low- and middle-income countries in 4 out of 11 startups while targeting commercial deployment in high-income countries; and (6) commercial incentives produced proprietary protocols that preclude independent validation and impede data sharing.

CONCLUSION: The vocal biomarker startup ecosystem operates as an epistemic economy in which methodological, regulatory, and governance choices tend to favor commercial interests and high-income populations over scientific rigor and equity. Standardized data provenance requirements, reassessment of voice data's risk classification under existing privacy frameworks (e.g., HIPAA, GDPR), and participatory governance including source communities are urgently needed to ensure vocal biomarker products are scientifically valid, ethically grounded, and equitably developed.},
}

@article {pmid42812519,
year = {2026},
author = {Cheung, EYW and Shea, YF and Chiu, PKC and Chan, KH and Zhang, H and Yam, KK and Bae, KT and Mak, HKF},
title = {Longitudinal patterns of regional cerebral blood flow during anti-amyloid therapy in mild cognitive impairment: a pilot ASL MRI case series.},
journal = {Frontiers in aging neuroscience},
volume = {18},
number = {},
pages = {1903239},
pmid = {42812519},
issn = {1663-4365},
abstract = {INTRODUCTION: The neurovascular effects of anti-amyloid therapy remain incompletely understood. Arterial spin labeling (ASL) MRI enables non-invasive quantification of regional cerebral blood flow (rCBF) and may provide insight into perfusion patterns observed over the treatment period.

METHODS: This pilot observational case series included participants with MCI or very early Alzheimer's disease undergoing anti-amyloid therapy (lecanemab), who underwent longitudinal pseudo-continuous ASL MRI at baseline and predefined follow-up timepoints. Regional rCBF was quantified across predefined cortical and subcortical regions of interest. A comparison group of amyloid-positive participants with MCI who did not receive anti-amyloid therapy underwent baseline ASL MRI. Vascular and metabolic risk factors, including white matter hyperintensity burden and biochemical parameters, were assessed to characterize potential confounding influences.

RESULTS: Within the treated group, increased rCBF was observed at early follow-up in several frontal, sensorimotor, and subcortical regions. No statistically significant longitudinal changes were detected at intermediate follow-up. At later follow-up, increased rCBF was observed in the cerebellar cortex, while decreased rCBF was observed in bilateral medial temporal regions. Vascular and metabolic risk profiles, including WMH burden, were broadly comparable between groups.

DISCUSSION: The observed rCBF trajectories demonstrate region-specific and time-dependent perfusion changes over the treatment period. Given the small sample size, absence of longitudinal imaging in the control group, and residual vascular confounding, these findings should be interpreted cautiously as exploratory and hypothesis-generating rather than evidence of treatment efficacy.},
}

@article {pmid42812605,
year = {2026},
author = {Chen, IW and Chang, LC and Ho, CN and Hung, KC},
title = {Long-term risk of incident dementia following documented COVID-19 among older adults with type 2 diabetes: a propensity score-matched cohort study.},
journal = {Frontiers in aging neuroscience},
volume = {18},
number = {},
pages = {1927383},
pmid = {42812605},
issn = {1663-4365},
abstract = {BACKGROUND: Type 2 diabetes mellitus (T2DM) is a well-established risk factor for dementia, and COVID-19 has been associated with persistent neurological and cognitive sequelae. However, whether this association extends beyond the early post-infection period among older adults with T2DM-a population with compounded vascular and metabolic vulnerability-remains unclear.

METHODS: Using the TriNetX Global Collaborative Network, we conducted a retrospective cohort study of patients aged ≥65 years with T2DM, comparing those with documented COVID-19 to a matched unexposed cohort (1:1 propensity score matching). A 1-year landmark design was applied, with follow-up extending to 6 years after the index date. The primary outcome was incident overall dementia, which is a composite of vascular dementia, Alzheimer's disease, and unspecified/other dementia. The secondary outcomes included individual dementia subtypes, mild cognitive impairment, all-cause mortality, and cerebral infarction.

RESULTS: After matching, 449,745 patients were included in each group with well-balanced covariates (all standardized mean differences <0.1). Documented COVID-19 was associated with a significantly increased risk of overall dementia [hazard ratio (HR 1.51), 95% confidence interval (CI) 1.47-1.55, p < 0.001]. The secondary outcomes were similarly elevated, such as vascular dementia (HR 1.61), Alzheimer's disease (HR 1.41), mild cognitive impairment (HR 1.66), all-cause mortality (HR 1.56), and cerebral infarction (HR 1.33; all p < 0.001). The hazard ratio for overall dementia increased progressively across sequential landmark periods (1.51 at 1 year, 1.66 at 2 years, and 2.09 at 3 years), and the findings remained robust across sensitivity analyses, addressing survival, healthcare utilization, and exposure misclassification. The findings were consistent in separately constructed and propensity score-matched additional cohorts restricted to adults aged 50-65 years and to patients indexed during the Omicron-predominant period.

CONCLUSION: In this large propensity score-matched cohort study, documented COVID-19 was associated with an increased long-term risk of incident dementia among older adults with T2DM, with the association persisting and strengthening beyond the early post-infection period. These findings support sustained attention to cognitive health in this metabolically susceptible population following COVID-19; however prospective studies incorporating standardized cognitive and biomarker assessments are needed to clarify underlying causes.},
}

@article {pmid42812614,
year = {2026},
author = {Kuang, Q and Li, S and Huang, W and Kuang, N and Liu, T and Huang, N and Luo, Y and Huang, J},
title = {TREM2-directed therapy in Alzheimer's disease: from therapeutic window to clinical translation.},
journal = {Frontiers in aging neuroscience},
volume = {18},
number = {},
pages = {1938062},
pmid = {42812614},
issn = {1663-4365},
abstract = {Alzheimer's disease (AD) is characterized by amyloid-β (Aβ) deposition, tau pathology, synaptic dysfunction, and a sustained neuroimmune response. Among immune-related targets, triggering receptor expressed on myeloid cells 2 (TREM2) is of particular interest because it is supported by human genetics, microglial biology, and expanding therapeutic development. TREM2 regulates microglial survival, phagocytosis, lipid handling, metabolic fitness, and plaque-associated responses, yet its therapeutic significance is more complex than a simple protective receptor model suggests. Although multiple TREM2-directed strategies have entered preclinical and early clinical development, recent evidence indicates that pharmacological target engagement does not necessarily translate into clinical benefit. We therefore propose that the therapeutic value of TREM2 is best understood through the concept of therapeutic window. TREM2 modulation is more likely to be beneficial when amyloid pathology is still being actively contained and microglial functional reserve remains preserved, whereas later disease stages, tau-associated neurodegeneration, receptor shedding, genetic heterogeneity, and pre-existing immune dysfunction may narrow or alter treatment benefit. Within this framework, soluble TREM2 (sTREM2) should be interpreted cautiously, as it may reflect receptor shedding, target engagement, microglial state, disease stage, or a combination of these processes rather than serving as a direct surrogate of efficacy. Viewed in this way, the central challenge of TREM2-directed therapy is to determine both when receptor modulation can still produce meaningful tissue protection and how the mode of receptor engagement shapes adaptive or maladaptive microglial programs.},
}

@article {pmid42812682,
year = {2026},
author = {Timashkov, A and Andreev, S and Safonova, A and Zangieva, S and Kadieva, D and Zinchenko, O},
title = {Correction: The inconsistent effects of tDCS in rehabilitation and cognitive enhancement: sources of variability and paths to personalization.},
journal = {Frontiers in human neuroscience},
volume = {20},
number = {},
pages = {1980636},
doi = {10.3389/fnhum.2026.1980636},
pmid = {42812682},
issn = {1662-5161},
abstract = {[This corrects the article DOI: 10.3389/fnhum.2026.1817726.].},
}

@article {pmid42812740,
year = {2026},
author = {Caro-Châtelier, I and Sargurupremraj, M and Yang, C and Akinleye, C and Trégouët, DA and Akinyemi, RO and Shigemizu, D and Coker, M and Akinyemi, JO and Tiwari, HK and Chasman, DI and Ovbiagele, B and Chabriat, H and Mooser, V and Couffinhal, T and Mishra, A and Cruchaga, C and Reitz, C and Kunkle, B and Kamatani, Y and Owolabi, MO and Mohammedi, K and Debette, S},
title = {Genetic Insights Into Protective Effects of GLP-1 Receptor Agonists on Stroke and Alzheimer Disease Across Ancestries.},
journal = {Neurology. Genetics},
volume = {12},
number = {5},
pages = {e200425},
pmid = {42812740},
issn = {2376-7839},
abstract = {BACKGROUND AND OBJECTIVES: Stroke and dementia are leading causes of death and disability worldwide, requiring enhanced preventive strategies. Glucagon-like peptide-1 receptor agonists (GLP-1RA), widely used for type 2 diabetes (T2D) and obesity, have demonstrated pleiotropic effects, including cardiovascular benefits, with mounting evidence also suggesting potential beneficial effects on brain health. The objective of this study was to investigate the genetically proxied effect of GLP-1RA on stroke, Alzheimer disease (AD), and related endophenotypes, in a cross-ancestry setting.

METHODS: We conducted a 2-sample Mendelian randomization (MR) study using both a locus-based and a protein quantitative trait loci (pQTL)-based approach. The study leveraged summary statistics from large-scale genome-wide association studies (GWAS). These GWAS comprised participants of European, East-Asian, and African ancestry with and without T2D, stroke, and AD, and with measurements of fasting glucose, glycated hemoglobin, stroke, and AD endophenotypes. Sample size ranged from 3,026 to 1,812,017 individuals. Genetically proxied GLP-1RA exposure was instrumented using independent T2D-associated variants (p < 5 × 10[-8]) within GLP1R (locus-based MR) and pQTLs for circulating GLP-1R protein levels (pQTL-based MR). Instruments were validated for effects on glycemic traits and GLP1R gene expression. Primary outcomes were stroke (any, ischemic, cardioembolic, small vessel, large artery, and intracerebral hemorrhage) and AD. Secondary analyses included etiologic factors and endophenotypes of stroke and AD: heart failure, atrial fibrillation, MRI markers (white matter hyperintensity volume, perivascular space burden, and hippocampal volume), and CSF biomarkers (beta-amyloid, tau). Outcomes were stratified by ancestry and meta-analyzed.

RESULTS: In Europeans, locus-based MR indicated significant protective associations of GLP-1RA with any stroke and ischemic stroke (p FDR < 0.05) and nominally (p < 0.05) with AD. Cross-ancestry meta-analyses strengthened protective effects of GLP-1RA on any stroke (OR, 0.75; 95% CI 0.63-0.89), ischemic stroke (0.72; 0.56-0.91), cardioembolic stroke (0.55; 0.35-0.86), and AD (0.51; 0.31-0.83), all with p FDR < 0.05. pQTL-based MR analyses suggested protective effects of genetically proxied GLP-1RA on atrial fibrillation (p FDR < 0.05) and, nominally (p < 0.05), on hippocampal perivascular space burden and CSF β-amyloid levels.

DISCUSSION: GLP-1RAs may confer protective effects against stroke (especially ischemic and cardioembolic) and AD risk, across ancestries. These findings warrant further investigation in experimental models and clinical trials to confirm benefits on brain health and understand underlying mechanisms.},
}

@article {pmid42812893,
year = {2026},
author = {Otoda, T and Nakajima, H and Takayama, T},
title = {Mitohormesis linking metabolic dysfunction and neurodegeneration: implications for dementia and therapeutic strategies.},
journal = {Frontiers in molecular neuroscience},
volume = {19},
number = {},
pages = {1892506},
pmid = {42812893},
issn = {1662-5099},
abstract = {Mitochondria are central regulators of cellular metabolism, redox homeostasis, and stress adaptation. Mitohormesis refers to an adaptive response in which mild or transient mitochondrial perturbation activates stress-response pathways that subsequently enhance mitochondrial or cellular resilience; however, persistent or excessive stress can overwhelm adaptive capacity and promote mitochondrial dysfunction and tissue injury. Metabolic diseases, including obesity and type 2 diabetes mellitus, are major risk factors for cognitive decline and dementia, and clinical studies have demonstrated associations between metabolic dysfunction, structural brain abnormalities, accelerated brain aging, and impaired cognitive function. However, direct evidence linking mitochondrial dysfunction to neurodegeneration in humans remains limited, with most mechanistic insights derived from experimental animal models and cultured neuronal systems. Experimental evidence indicates that chronic metabolic stress can disrupt mitochondrial quality control and proteostasis, increase mitochondrial reactive oxygen species production, and promote neuroinflammation and neuronal dysfunction. Conversely, adaptive mitochondrial stress responses can preserve mitochondrial integrity and cellular resilience through coordinated regulation of the integrated stress response, mitochondrial quality-control mechanisms, lysosomal-mitochondrial crosstalk, extracellular vesicle-mediated communication, and inter-organ signaling. In Alzheimer's disease, mitochondrial dysfunction and amyloid-β/tau pathology may interact bidirectionally, potentially generating self-reinforcing cycles of neuronal injury. Lifestyle and pharmacological interventions-including exercise; caloric restriction; nutritional ketosis; and the use of metformin, sodium-glucose cotransporter 2 inhibitors, and glucagon-like peptide-1 receptor agonists-have been associated with adaptive mitochondrial and metabolic responses involving AMP-activated protein kinase, nuclear factor erythroid 2-related factor 2, mitochondrial biogenesis, mitophagy, and redox signaling. However, evidence that mitohormesis directly mediates their beneficial effects varies substantially across interventions and remains predominantly indirect or hypothesized in humans. Moreover, the discrepancy between encouraging preclinical findings and clinical outcomes highlights important translational barriers, including the lack of validated biomarkers, uncertainty regarding optimal stress intensity and timing, and tissue- and disease-specific differences in adaptive capacity. Collectively, current evidence supports mitohormesis as a conceptual framework for integrating mitochondrial stress adaptation, metabolic dysfunction, and neuronal resilience rather than as an established unifying mechanism underlying neurodegeneration. Defining the conditions under which mitochondrial stress is adaptive, identifying reliable biomarkers of mitohormesis, and determining whether these responses can be safely and effectively modulated in humans will be essential for establishing its therapeutic relevance in metabolic and neurodegenerative diseases.},
}

@article {pmid42812986,
year = {2026},
author = {Zhao, S and Chen, J and Li, P and Zhao, L and Dong, C and Yu, L},
title = {Gray matter atrophy mediates the association between cerebral hypometabolism and cognitive impairment in Alzheimer's disease.},
journal = {Frontiers in neurology},
volume = {17},
number = {},
pages = {1919778},
pmid = {42812986},
issn = {1664-2295},
mesh = {Humans ; *Alzheimer Disease/metabolism/diagnostic imaging/pathology/complications ; Positron-Emission Tomography ; Atrophy/pathology/metabolism ; *Gray Matter/pathology/diagnostic imaging/metabolism ; Female ; Magnetic Resonance Imaging ; Male ; *Cognitive Dysfunction/metabolism/diagnostic imaging/pathology ; Aged ; Fluorodeoxyglucose F18 ; Aged, 80 and over ; *Brain/metabolism/pathology/diagnostic imaging ; },
abstract = {OBJECTIVE: Alzheimer's disease (AD) is characterized by amyloid deposition, brain hypometabolism, gray matter atrophy and cognitive decline, yet their causal interactions are poorly defined. This multimodal PET/MRI study explored regional gray matter volume (GMV) loss and glucose hypometabolism in AD patients, and clarified their correlations with distinct cognitive deficits alongside mediating pathways.

METHODS: 134 probable dementia patients were split into AD and non-AD dementia cohorts based on [18]F-AV45 PET amyloid-β (Aβ) load, all receiving structural MRI, [18]F-FDG and [18]F-AV45 PET scans. We compared intergroup GMV and metabolic discrepancies, analyzed imaging-cognition correlations adjusted for clinical and demographic confounders, and implemented mediation models to test whether GMV bridges cerebral metabolism and cognition.

RESULTS: AD patients exhibited prominent regional GMV shrinkage and FDG hypometabolism in vulnerable brain regions relative to non-AD dementia subjects. Covariate-adjusted analyses linked both imaging biomarkers to domain-specific cognitive performance. Primary mediation analyses showed that regional GMV significantly mediated the associations between FDG metabolism and visuospatial, executive, and language function, accounting for 40.36, 35.60, and 49.99% of the total effects, respectively. Reverse mediation models identified only a weak indirect effect of right superior temporal gyrus metabolism on the association between right inferior parietal lobule GMV and visuospatial ability, accounting for 13.26% of the total effect. Moreover, after multiple-imputation sensitivity analyses, most indirect effects became unstable or nonsignificant, suggesting that the FDG metabolism-cognition association is predominantly direct, with limited evidence for GMV mediation.

CONCLUSION: Integrated PET/MRI revealed AD-related patterns of regional atrophy and hypometabolism. Overall, the association between cerebral metabolic dysfunction and cognitive impairment appeared to be predominantly direct, with limited evidence supporting a mediating role of regional GMV.},
}

Humans
*Alzheimer Disease/metabolism/diagnostic imaging/pathology/complications
Positron-Emission Tomography
Atrophy/pathology/metabolism
*Gray Matter/pathology/diagnostic imaging/metabolism
Female
Magnetic Resonance Imaging
Male
*Cognitive Dysfunction/metabolism/diagnostic imaging/pathology
Aged
Fluorodeoxyglucose F18
Aged, 80 and over
*Brain/metabolism/pathology/diagnostic imaging

@article {pmid42812991,
year = {2026},
author = {Yu, Z and Li, Y and Zhang, Z and Yin, R},
title = {AAV-mediated gene therapy for Alzheimer's disease: neuroprotective mechanisms and translational challenges.},
journal = {Frontiers in aging neuroscience},
volume = {18},
number = {},
pages = {1901875},
pmid = {42812991},
issn = {1663-4365},
abstract = {Alzheimer's disease remains a major neurodegenerative disorder for which effective disease-modifying treatments are limited. Adeno-associated virus-mediated gene therapy provides a strategy for sustained modulation of disease-related pathways in the central nervous system. Recent studies have explored this approach for regulating amyloid-β (Aβ) metabolism, tau pathology, neuroinflammation, genetic risk factors and neurotrophic support. This review summarizes the biological basis for adeno-associated virus delivery in the central nervous system and discusses major therapeutic strategies for Alzheimer's disease, including approaches targeting Aβ production and clearance, tau expression and degradation, immune microenvironment remodeling, apolipoprotein E modulation and synaptic protection. We further examine key translational barriers, including blood-brain barrier restriction, cross-species differences, immune responses, dose-related toxicity, manufacturing constraints and limited clinical evidence. Finally, we propose that future development should move beyond delivery efficiency alone toward biologically informed vector design, target selection, disease-stage matching and biomarker-guided clinical evaluation.},
}

@article {pmid42813034,
year = {2026},
author = {Gao, Y and Li, ZK and Li, HN and Hu, JZ and Du, XZ and Yan, X and Liu, S},
title = {Cellular heterogeneity and multicellular mechanisms in the pathogenesis of late-life depression: insights from single-cell and spatial multi-omics.},
journal = {Frontiers in immunology},
volume = {17},
number = {},
pages = {1944035},
pmid = {42813034},
issn = {1664-3224},
mesh = {Humans ; Multiomics ; Animals ; Single-Cell Analysis ; *Depression/etiology/metabolism ; Aging ; Brain/metabolism/pathology ; },
abstract = {Late-life depression (LLD) is a heterogeneous disorder characterised by affective symptoms, cognitive decline, vascular burden, frailty, treatment resistance, and an increased risk of neurodegenerative progression, yet bulk molecular approaches may obscure the cell-type-specific alterations underlying this clinical and biological heterogeneity. This narrative review synthesises single-cell, single-nucleus, spatial, and multi-omic evidence concerning neuronal, glial, vascular, and peripheral immune alterations relevant to LLD, while distinguishing direct findings from clinically defined or older-adult depression cohorts from evidence extrapolated from major depressive disorder, ageing, mild cognitive impairment, Alzheimer's disease, and experimental models. The strongest current evidence implicates selective excitatory and inhibitory neuronal subtypes and astrocytes in prefrontal affective-cognitive circuit dysfunction, whereas endothelial and neurovascular-unit abnormalities, microglial reprogramming, oligodendrocyte-lineage dysfunction, hippocampal plasticity deficits, and peripheral immune remodelling represent biologically plausible but less well-validated mechanisms. Ageing-related cellular alterations, blood-brain barrier disruption, endothelial-astrocyte dysregulation, neuroinflammation, impaired myelin maintenance, and hippocampal vulnerability may interact to contribute to affective, cognitive, vascular, and treatment-resistant phenotypes. However, direct single-cell and spatial multi-omics evidence from clinically defined LLD cohorts remains scarce, and peripheral immune signatures should be interpreted primarily as accessible systemic correlates rather than direct measures of brain pathology. Overall, current evidence supports a hypothesis-generating multicellular framework rather than validated LLD-specific mechanisms or therapeutic targets. Future studies integrating single-nucleus and spatial multi-omics with longitudinal clinical phenotyping, neuroimaging, peripheral immune profiling, in situ validation, and functional perturbation are required to define LLD-specific cellular states, establish causal mechanisms, and identify clinically actionable biomarkers and therapeutic targets.},
}

Humans
Multiomics
Animals
Single-Cell Analysis
*Depression/etiology/metabolism
Aging
Brain/metabolism/pathology

@article {pmid42813059,
year = {2026},
author = {Li, W and Liang, Y and Li, L and Sun, H and Liu, Q},
title = {The brain's immune code: decoding antigen presentation at the meningeal-glymphatic interface in neurological disorders.},
journal = {Frontiers in immunology},
volume = {17},
number = {},
pages = {1960846},
pmid = {42813059},
issn = {1664-3224},
mesh = {Humans ; Animals ; *Antigen Presentation/immunology ; *Glymphatic System/immunology/metabolism ; *Meninges/immunology ; *Brain/immunology/metabolism ; *Nervous System Diseases/immunology ; Antigen-Presenting Cells/immunology ; Lymphatic Vessels/immunology ; },
abstract = {The classical view of central nervous system (CNS) immune privilege has evolved from isolation to regulated crosstalk. Perivascular cerebrospinal fluid-interstitial fluid transport and meningeal lymphatic vessels (mLVs) move brain-derived molecules toward immune-rich border tissues and cervical lymph nodes, where antigen-presenting cells (APCs) decode this molecular drainage into adaptive immunity. We frame this sequence as a brain-immune code, wherein the identity, timing, route, and cellular presenter of exported antigens collectively dictate whether T-cell responses become suppressive, inflammatory, or ineffective. By comparing aging and Alzheimer's disease, multiple sclerosis, experimental autoimmune encephalomyelitis, and brain tumors, we illustrate why this same interface can mediate proteostatic clearance, pathogenic autoimmunity, or insufficient antitumor immunity. Accordingly, therapeutic strategies should tune drainage and antigen interpretation in a disease-, stage-, and compartment-specific manner, rather than uniformly enhance or suppress lymphatic function. Key priorities include integrated measurement of glymphatic and mLV function, time-resolved immunopeptidome mapping, definition of non-redundant APC roles, and validated human biomarkers linking drainage to immune status.},
}

Humans
Animals
*Antigen Presentation/immunology
*Glymphatic System/immunology/metabolism
*Meninges/immunology
*Brain/immunology/metabolism
*Nervous System Diseases/immunology
Antigen-Presenting Cells/immunology
Lymphatic Vessels/immunology

@article {pmid42813225,
year = {2026},
author = {Park, S and Hwang, Y and Kwak, J and Lin, Y and Park, HY and Nam, E and Han, J and Park, S and Kim, H and Kim, JE and Kang, HG and Park, J and Lee, YH and Kim, KS and Lee, CH and Lee, SJ and Lim, MH},
title = {Zinc Fingers as Programmable Metalloprotein Scaffolds for Altering Pathogenic Biomolecular Phase Transitions.},
journal = {Advanced science (Weinheim, Baden-Wurttemberg, Germany)},
volume = {},
number = {},
pages = {e77886},
doi = {10.1002/advs.77886},
pmid = {42813225},
issn = {2198-3844},
support = {RS-2022-NR070709//National Research Foundation of Korea/ ; RS-2024-00407337//National Research Foundation of Korea/ ; RS-2024-00411134//National Research Foundation of Korea/ ; RS-2025-23292974//National Research Foundation of Korea/ ; RS-2021-NR057690//National Research Foundation of Korea/ ; RS-2022-NR069719//National Research Foundation of Korea/ ; RS-2025-25444385//National Research Foundation of Korea/ ; KGM1312612//KRIBB Research Initiative Program/ ; RS-2026-25541458//Korea Institute of the Marine Science & Technology Promotion by the Ministry of Oceans and Fisheries/ ; RS-2026-25508103//Korea Institute of the Marine Science & Technology Promotion by the Ministry of Oceans and Fisheries/ ; C623300//KBSI funds/ ; C623100//KBSI funds/ ; C612120//KBSI funds/ ; C623500//KBSI funds/ ; IBS-R010-A1//Institute for Basic Science/ ; },
abstract = {Tunable control over biomolecular phase transitions provides a powerful blueprint for engineering functional soft materials, yet generalizable protein scaffolds capable of rewiring pathological condensates remain largely unexplored. Here, we demonstrate that zinc finger (ZF) proteins function as programmable interaction units that modulate neurodegenerative amyloid liquid-liquid phase separation, redirect β-sheet-rich fibrillation toward nontoxic assemblies, and actively disassemble preformed fibrils. Multiscale investigations spanning molecular, cellular, and organismal levels reveal that tandemly arrayed ZF modules mediate direct, high-affinity protein-protein interactions, thereby mitigating amyloid pathogenicity. Through modular protein engineering, these protective effects translate in vivo, where a brain-penetrant ZF variant reduces amyloid deposition, suppresses neuroinflammatory responses, and improves cognitive performance in Alzheimer's disease transgenic mice. Furthermore, sequence-structure-function analyses identify key determinants governing amyloid assembly control, offering mechanistic principles for ZF-inspired protein engineering. Collectively, this work positions ZF proteins as versatile, chemically programmable platforms for engineering protein-based materials that regulate biomolecular phase behavior and toxicity, expanding their functional scope beyond traditional genetic regulation toward therapeutic applications.},
}

@article {pmid42803832,
year = {2026},
author = {Niu, B and Xia, MH and Wu, JX and He, P and Bo, L and Wu, HY and Lei, SF and Deng, FY},
title = {CRP-albumin-lymphocyte index and multisystem diseases: a phenome-wide Mendelian randomization study.},
journal = {Molecular genetics and genomics : MGG},
volume = {301},
number = {1},
pages = {},
pmid = {42803832},
issn = {1617-4623},
support = {82373587, 82173529, 82173598, and 82103922//Natural Science Foundation of China/ ; },
mesh = {Humans ; *Mendelian Randomization Analysis/methods ; Genome-Wide Association Study/methods ; *C-Reactive Protein/metabolism/genetics ; Polymorphism, Single Nucleotide ; Biomarkers ; *Lymphocytes/metabolism ; Phenotype ; Genetic Predisposition to Disease ; Phenomics/methods ; Inflammation/genetics ; },
abstract = {The C-reactive protein-albumin-lymphocyte (CALLY) index is a composite biomarker integrating inflammation, nutrition, and immune function, but its causal relationships with a broad spectrum of human diseases and potential utility for public health risk prediction remain unclear. We conducted a population-based genetic epidemiological study combining genome-wide association study (GWAS), phenome-wide association study (PheWAS), and two-sample Mendelian randomization (MR), using data from the UK Biobank (265,409 participants for GWAS; 113,747 participants for PheWAS) and FinnGen to construct genetic instruments for the CALLY index, perform PheWAS across 713 phenotypes, evaluate causal associations via two-sample MR, and conduct sensitivity analyses including linkage disequilibrium score regression and pleiotropy testing. GWAS identified 154 genomic loci significantly associated with the CALLY index; PheWAS detected 24 significant phenotype associations, with higher genetically predicted CALLY index linked to lower risks of Alzheimer's disease, Alzheimer's dementia, unspecified dementia, and lipid metabolism disorders. MR confirmed causal protective effects for these neurodegenerative outcomes while indicating a causal association with increased sleep disorder risk, and pleiotropic analyses highlighted shared biological pathways in lipid metabolism and inflammation. These findings demonstrate that the CALLY index is causally associated with neurodegenerative, metabolic, and sleep disorders, supporting its role as a promising integrated biomarker for disease risk stratification and public health applications.},
}

Humans
*Mendelian Randomization Analysis/methods
Genome-Wide Association Study/methods
*C-Reactive Protein/metabolism/genetics
Polymorphism, Single Nucleotide
Biomarkers
*Lymphocytes/metabolism
Phenotype
Genetic Predisposition to Disease
Phenomics/methods
Inflammation/genetics

@article {pmid42803875,
year = {2026},
author = {Zou, Y and Yang, J and Li, Y and Wang, G and Lu, W and Chen, X and Ma, X and Chen, K and Liang, P and Wu, Y and Zhuo, T},
title = {mTORC1 Activation Links Chronic Stress to Meso-Circuit Desynchronization and Accelerated Amyloid Pathology via Autophagic Dysfunction.},
journal = {CNS neuroscience & therapeutics},
volume = {32},
number = {10},
pages = {e71174},
pmid = {42803875},
issn = {1755-5949},
support = {GuikeAA22096030//Guangxi Science and Technology Major Project/ ; Z04J2025E170//2025 Bethune Charitable Foundation Shining Across China-Medicinal Research Fund/ ; HXXT-KY-LCYY2025MS-0145//2025 Clinical Rational Drug Use Practice Research/ ; },
mesh = {Animals ; *Autophagy/physiology ; *Mechanistic Target of Rapamycin Complex 1/metabolism/antagonists & inhibitors ; Mice ; *Amyloid beta-Peptides/metabolism ; *Stress, Psychological/metabolism/pathology ; Mice, Transgenic ; *Alzheimer Disease/metabolism/pathology ; Male ; },
abstract = {BACKGROUND: Although depression is a potent risk factor for Alzheimer's disease (AD), the underlying causal mechanisms remain unclear. This study investigated the molecular and circuit-level mechanisms linking chronic stress to accelerated AD pathogenesis and evaluated the therapeutic potential of precise mTORC1 targeting.

METHODS: A chronic restraint stress (CRS) paradigm was established in 5xFAD mice. Multi-scale neurofunctional and histopathological alterations were deconstructed using behavioral profiling, wide-field and two-photon calcium imaging, immunofluorescence, and bulk RNA-sequencing. Pharmacological intervention was conducted using the specific mTORC1 inhibitor EN6.

RESULTS: CRS severely impaired cortical slow-wave oscillations and induced aberrant prefrontal single-neuron hyperactivity, exacerbating cognitive decline. These network deficits were accompanied by accelerated AD hallmarks, including elevated Aβ deposition, dystrophic neurite aggravation, and reactive gliosis. Mechanistically, transcriptomic profiling and biochemical validation revealed that chronic stress suppresses autophagic pathways via selective hyperactivation of mTORC1 signaling rather than the AMPK pathway. Time-course analysis showed that mTORC1 activation and autophagy-related abnormalities preceded overt Aβ accumulation, while pharmacological mTOR activation with MHY1485 further aggravated autophagic impairment and increased Aβ42 levels. Crucially, targeted mTORC1 inhibition with EN6 ameliorated autophagy-related abnormalities and was associated with reduced BACE1 abundance and CTFβ generation, together with a diminished global Aβ burden. This microenvironmental stabilization attenuated neuroinflammation, realigned neural networks, and rescued both cognitive and emotional deficits.

CONCLUSION: Chronic stress-induced mTORC1 hyperactivation is associated with autophagic impairment, contributing to macro-circuit desynchronization and accelerated amyloid accumulation. Targeting the mTORC1-autophagy axis represents a potential therapeutic approach to mitigate neural network breakdown and neuropathology in stress-related neurodegenerative conditions.},
}

Animals
*Autophagy/physiology
*Mechanistic Target of Rapamycin Complex 1/metabolism/antagonists & inhibitors
Mice
*Amyloid beta-Peptides/metabolism
*Stress, Psychological/metabolism/pathology
Mice, Transgenic
*Alzheimer Disease/metabolism/pathology
Male

@article {pmid42803910,
year = {2026},
author = {Haji, B and Tahami Monfared, AA and , },
title = {From Biomarker Anchors to Disease-State Transitions: A Biologically Anchored Probabilistic Principal Component Analysis Framework for Alzheimer's Disease Progression Modeling.},
journal = {Neurology and therapy},
volume = {},
number = {},
pages = {},
pmid = {42803910},
issn = {2193-8253},
abstract = {INTRODUCTION: To develop and validate a biomarker-anchored probabilistic principal component analysis (PPCA) framework for identifying biologically interpretable latent dimensions of Alzheimer's disease (AD) and evaluating their utility for disease progression modeling.

METHODS: Data from 1058 participants that are amyloid-positive in the Alzheimer's Disease Neuroimaging Initiative (ADNI) were analyzed. Anchored PPCA used biomarker data only; cognitive, functional, diagnostic, and prognostic outcomes were withheld from latent-space construction and reserved for validation. Amyloid (A) and tau (T) factors were biologically anchored, neurodegeneration (N) was softly constrained, and a ventricular-vascular/residual (V/R) factor was empirically estimated. Robustness, reproducibility, held-out validity, clinical associations, prognostic performance, and clinical-state transitions were evaluated.

RESULTS: Anchored PPCA identified four biologically coherent dimensions: A, T, N, and V/R. Solutions were reproducible across repeated initializations and split-half analyses, and generalized to held-out participants, particularly for A, T, and N. The model explained approximately 60% of model-implied standardized biomarker variance, with highest explained variance for A and T and lowest for V/R. Latent factors explained variance in outcomes not used for model construction: 49.7% for ADAS-Cog13, 35.1% for CDR-SB, and 27.8% for FAQ; they also aligned with diagnostic classifications. Cox-model C-indices were 0.843 for latent factors alone and 0.933 for clinical-plus-latent factors, with better fit than the clinical benchmark. T showed the strongest prognostic association, followed by A, N, and V/R. After adjustment for baseline clinical severity, A, T, and N remained independently prognostic; V/R did not. Clinical-state transitions were predominantly monotonic and demonstrated marked sojourn-time dependence.

CONCLUSION: Biomarker-only anchored PPCA provides a biologically grounded representation of AD that validates against cognition, function, diagnosis, and clinical progression. A, T, and N may capture disease processes not fully reflected in cross-sectional clinical severity, whereas V/R appears more closely related to contemporaneous clinical status. Duration-dependent transitions support semi-Markov disease-progression and Shared Latent Disease Process models. External validation is warranted.},
}

@article {pmid42803964,
year = {2026},
author = {Joshi, N and Vaidya, B and Saha, P and Kashyap, M and Sharma, SS},
title = {Clemizole, a TRPC5 channel blocker rescues amyloid-β toxicity and cognitive impairment by modulating mitochondrial dysfunction and memory-related proteins.},
journal = {Naunyn-Schmiedeberg's archives of pharmacology},
volume = {},
number = {},
pages = {},
pmid = {42803964},
issn = {1432-1912},
abstract = {Amyloid β (Aβ)-induced neuronal dysfunction is a key pathological feature of Alzheimer's disease (AD), characterized by oxidative stress, mitochondrial impairment, and calcium dyshomeostasis. Transient receptor potential canonical 5 (TRPC5), a calcium-permeable cation channel, has been implicated in neurodegeneration, but its role in AD remains unclear. This study investigated TRPC5 involvement in Aβ-induced neurotoxicity and evaluated the neuroprotective potential of Clemizole, a TRPC5 blocker, in preclinical AD models. In SH-SY5Y cells, Aβ-induced neurotoxicity was assessed by measuring cell viability, intracellular and mitochondrial reactive oxygen species (ROS), mitochondrial membrane potential, and calcium influx. In rats, an intracerebroventricular (ICV) Aβ25-35 (10 μg) induced cognitive impairment model was used. Behavioral tests assessed cognitive function. Hippocampal TRPC5 expression and memory as well as calcium associated protein expressions (p-CaMKII, PSD-95, BDNF, calcineurin A) were analyzed, and acetylcholinesterase (AChE) activity was measured following 3 weeks of Clemizole (10 and 30 mg/kg) treatment. Aβ exposure reduced neuronal survival, increased ROS, disrupted mitochondrial membrane potential, and elevated calcium influx in vitro. Clemizole mitigated oxidative stress, restored mitochondrial function, and restored calcium homeostasis. In vivo, Aβ induced cognitive deficits and upregulated hippocampal TRPC5 expression in rats. Clemizole reduced TRPC5 levels, improved cognitive performance, enhanced p-CaMKII, PSD-95, and BDNF expression, decreased calcineurin A, and reduced AChE activity. TRPC5 contributes to Aβ-induced neurotoxicity and cognitive impairment, and Clemizole-mediated TRPC5 inhibition confers neuroprotection by restoring calcium balance and attenuating the decrease in memory-associated protein expression. These findings support TRPC5 as a potential therapeutic target in AD; however, further studies using a transgenic AD model are warranted before clinical translation.},
}

@article {pmid42804072,
year = {2026},
author = {Sun, Y and Guo, Z and Zhang, J and Pang, M and Chen, R and She, C and Zhou, S and Wang, H and Shao, X and Nie, S},
title = {Risk of Dementia With Renin-Angiotensin System Inhibitors Versus Calcium Channel Blockers in Hypertensive Adults: A Nationwide Multicenter Study.},
journal = {Drugs & aging},
volume = {},
number = {},
pages = {},
pmid = {42804072},
issn = {1179-1969},
support = {2021YFC2500204//National Key R&D Program of China/ ; 2021YFC2500200//National Key R&D Program of China/ ; },
abstract = {OBJECTIVE: The aim of this study was to evaluate whether renin-angiotensin system inhibitors (RASIs) reduce dementia risk independently of blood pressure control compared with calcium channel blockers (CCBs) in antihypertensive-naïve adults with hypertension.

METHODS: This multicenter, new-user active comparator study included antihypertensive-naïve adults initiating RASIs or CCBs across 28 hospitals. Participants were matched 1:1 on baseline characteristics using propensity score matching (PSM). The primary outcome was incident all-cause dementia; secondary outcomes were Alzheimer's disease and vascular dementia. Hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated using Cox proportional hazards regression.

RESULTS: Of 164,918 eligible patients (median age 65 years [interquartile range 55-74]; 51.2% male), 54,042 PSM pairs initiating RASIs versus CCBs were included. During a median follow-up of 516 days, 344 incident dementia cases occurred. The incidence rate of all-cause dementia was lower among RASI initiators than CCB initiators (1.26 vs 1.89 per 1000 person-years). Initiation of RASIs was associated with a significantly lower risk of all-cause dementia (HR 0.68, 95% CI 0.55-0.84) and Alzheimer's disease (HR 0.59, 95% CI 0.43-0.81), but not vascular dementia (HR 0.74, 95% CI 0.50-1.11), compared with CCBs. There was no significant difference in dementia risk between initiators of angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin II receptor blockers (ARBs).

CONCLUSIONS: In adults with hypertension, initiation of RASIs was associated with a significantly lower risk of dementia compared with CCBs. No significant difference was observed between ACEIs and ARBs. Further validation is warranted.},
}

@article {pmid42804231,
year = {2026},
author = {Jin, Z and , },
title = {Decoupling of local activity and interhemispheric connectivity in late mild cognitive impairment: A resting-state functional magnetic resonance imaging study.},
journal = {Neuropsychology},
volume = {},
number = {},
pages = {},
doi = {10.1037/neu0001124},
pmid = {42804231},
issn = {1931-1559},
support = {//Natural Science Foundation of Henan Province/ ; /AG/NIA NIH HHS/United States ; /EB/NIBIB NIH HHS/United States ; },
abstract = {OBJECTIVE: Mild cognitive impairment (MCI), a high-risk precursor to Alzheimer's disease, progresses through early (EMCI) and late (LMCI) stages. While distinct functional brain alterations between EMCI and LMCI have been reported, differences in regional brain activity and interhemispheric functional connectivity during resting-state remain incompletely characterized. The aim of the study was to systematically assess the differences in resting-state brain functional alterations between the LMCI patients and EMCI patients.

METHOD: We assessed resting-state functional alterations in EMCI and LMCI using fractional amplitude of low-frequency fluctuations (fALFF) and voxel-mirrored homotopic connectivity (VMHC). Data from 35 EMCI patients, 28 LMCI patients, and 37 individuals with normal cognition were analyzed from the Alzheimer's Disease Neuroimaging Initiative-Phase 2.

RESULTS: Compared to EMCI patients, LMCI patients exhibited increased fALFF in the left inferior temporal gyrus and left precentral gyrus, alongside decreased VMHC in the anterior cerebellar lobe and posterior cingulate cortex. Among MCI patients, Montreal Cognitive Assessment scores showed a significant negative correlation with fALFF in the left inferior temporal gyrus/left precentral gyrus but a significant positive correlation with VMHC in the anterior cerebellar lobe/posterior cingulate cortex.

CONCLUSIONS: These findings suggest that elevated regional activity (fALFF) may represent a compensatory mechanism, while reduced interhemispheric connectivity (VMHC) reflects a neuropathological basis underlying progression from EMCI to LMCI. (PsycInfo Database Record (c) 2026 APA, all rights reserved).},
}

@article {pmid42804353,
year = {2026},
author = {Garcia, D and Wang, HP and Saito, N and Beckett, L and Honig, LS and DeCarli, C and Rissman, RA and Teich, AF and Mungas, DM and Jin, LW and Dugger, BN},
title = {Cardiovascular risk factors and regional neuropathology in autopsy-confirmed Alzheimer disease.},
journal = {Journal of neuropathology and experimental neurology},
volume = {},
number = {},
pages = {},
doi = {10.1093/jnen/nlag081},
pmid = {42804353},
issn = {1554-6578},
support = {R01AG062517, P30AG072972, P30AG062429, P50AG008702, P30AG066530, and P30AG066462//the National Institute on Aging (NIA) of the National Institutes of Health (NIH)/ ; },
abstract = {Cardiovascular risk factors are implicated in Alzheimer disease (AD) progression and its neuropathological hallmarks but their specific contributions to regional brain pathology within AD remain understudied. In this cohort study (n = 276), we examined associations between diabetes, hypertension, and hypercholesterolemia (present vs absent), and neuropathologies in decedents with pathologically confirmed Intermediate/High AD from 3 Alzheimer's Disease Research Centers. Regional arteriolosclerosis, cerebral amyloid angiopathy (CAA), cored plaques (CPs), diffuse plaques (DPs), neurofibrillary tangles (NFTs), neuritic plaques (NPs), and neuropil threads (NTs) were semi-quantitatively assessed by adapting established scoring schemes. Differences in neuropathology by cardiovascular risk factor status were assessed using Wilcoxon rank-sum tests and ordinal logistic regression models adjusted for ethnicity, sex, age at death, and center. In adjusted analyses, diabetes was associated with higher frontal NTs (odds ratio, 3.2 [95% CI, 1.2-8.4]). Hypercholesterolemia was associated with higher CAA in the parietal lobe (odds ratio, 2.7 [95% CI, 1.3-5.8]) and posterior hippocampus (odds ratio, 2.8 [95% CI, 1.3-6.1]). None of these associations remained statistically significant following false discovery rate (FDR) correction. These findings suggest vascular risk factors do not substantially modify the burden of AD pathology once advanced disease is present and any independent effects on AD-related lesions are likely modest within this select cohort.},
}

@article {pmid42804373,
year = {2026},
author = {Beaudet, D and Berger, CL and Hendricks, AG},
title = {Tau hyperphosphorylation impairs cooperative binding to microtubules and perturbs organelle trafficking in neurons.},
journal = {eLife},
volume = {15},
number = {},
pages = {},
pmid = {42804373},
issn = {2050-084X},
support = {R01GM132646/NH/NIH HHS/United States ; PJT-185997/CAPMC/CIHR/Canada ; },
mesh = {*tau Proteins/metabolism/genetics ; *Microtubules/metabolism ; Phosphorylation ; *Neurons/metabolism ; Animals ; Kinesins/metabolism ; Lysosomes/metabolism ; Protein Binding ; Humans ; Rats ; },
abstract = {Tau, a neuronal microtubule-associated protein (MAP), organizes the axonal cytoskeleton, and regulates intracellular transport. Tau hyperphosphorylation is linked to neurodegeneration in tauopathies, including Alzheimer's disease. Tau binds microtubules cooperatively to form cohesive envelopes, which are thought to control access to the microtubule lattice and regulate the activity of motor proteins and other MAPs. However, how disease-related perturbations affect tau dynamics and its function as a selective barrier to intracellular transport remains unclear. Using tau phospho-variants in vitro and in live neurons, we show that tau hyperphosphorylation disrupts cooperative microtubule binding and dysregulates lysosome transport. Hyperphosphorylated tau does not form envelopes, distributes more uniformly along the axon, and dissociates faster from microtubules. Tau weakly inhibits KIF5C motility, but strongly inhibits KIF1A. Hyperphosphorylation reduces KIF5C inhibition but increases KIF1A inhibition by decreasing processivity and accelerating detachment. Consistent with these effects, hyperphosphorylated tau alters lysosome transport in neurons. While phospho-resistant tau inhibits processive lysosome motility, hyperphosphorylated tau weakens tau-mediated regulation of lysosome transport, mimicking tau knockout neurons that exhibit enhanced processivity. Altogether, these findings show that hyperphosphorylation disrupts tau envelopes and impairs lysosome trafficking, likely contributing to early defects in degradative pathways that drive neurodegeneration.},
}

*tau Proteins/metabolism/genetics
*Microtubules/metabolism
Phosphorylation
*Neurons/metabolism
Animals
Kinesins/metabolism
Lysosomes/metabolism
Protein Binding
Humans
Rats

@article {pmid42804522,
year = {2026},
author = {Li, X and Wu, D and Zhang, Y and Chen, M and Liu, C},
title = {Spatial cell-cell communication inference based on cell-spot-ligand-receptor heterogeneous graphs.},
journal = {PLoS computational biology},
volume = {22},
number = {9},
pages = {e1014835},
doi = {10.1371/journal.pcbi.1014835},
pmid = {42804522},
issn = {1553-7358},
abstract = {Cell-cell communication is essential for tissue homeostasis and disease-associated microenvironment remodeling. Spatial transcriptomics enables the study of communication events in situ, but single-cell-resolution inference from spot-based data remains challenging because of uncertain cell-to-spot mapping, limited use of local spatial information, and false positives from ligand-receptor co-expression. Existing methods increasingly emphasize spatial proximity in cell-cell communication inference, while integrating biologically informative signals remains important for improving the interpretability of candidate communication events. Here, we present SpaHCC, a heterogeneous graph learning framework that integrates single-cell transcriptomics, spatial transcriptomics, and prior ligand-receptor knowledge for spatial cell-cell communication inference. By jointly leveraging molecular features, spatial neighborhood information, and cellular functional states, SpaHCC prioritizes candidate communication events and supports their biological contextualization through pathway, transcription factor, and receptor-side response analyses. Benchmark and spatial consistency analyses showed that SpaHCC recovered spatially coherent candidate communication signals. In Alzheimer's disease data, SpaHCC identified recurrent excitatory neuron-associated candidate patterns, including NRXN- and FLRT2-related modules associated with synaptic remodeling and inflammation-related transcriptional programs. Cross-patient analyses showed recurrence of selected AD-associated candidate patterns, while representative cSCC and PDAC analyses illustrated the spatial interpretability of the framework in additional disease contexts. Overall, SpaHCC provides an effective and interpretable framework for spatially resolved cell-cell communication analysis in complex diseases.},
}

@article {pmid42804599,
year = {2026},
author = {Hensen, T and Khatib, L and Patel, L and McDonald, D and González, A and MahmoudianDehkordi, S and Blach, C and Knight, R and Kaddurah-Daouk, R and Thiele, I},
title = {Personalized whole-body modeling links gut microbiota to metabolic perturbations in Alzheimer's disease.},
journal = {Gut microbes},
volume = {18},
number = {1},
pages = {2732659},
doi = {10.1080/19490976.2026.2732659},
pmid = {42804599},
issn = {1949-0984},
mesh = {Humans ; *Alzheimer Disease/microbiology/metabolism/blood ; *Gastrointestinal Microbiome ; Male ; Female ; Aged ; Bacteria/classification/isolation & purification/genetics/metabolism ; Cognitive Dysfunction/metabolism/microbiology ; Aged, 80 and over ; Metabolome ; },
abstract = {The human gut microbiome has been linked to metabolic disturbances in Alzheimer's disease (AD). However, the mechanisms by which gut microbes might influence metabolic dysfunction in AD remain poorly understood. Previously, gut microbiome-personalized whole-body models of human metabolism have been applied to predict how altered gut microbiome compositions may influence metabolites in the blood of healthy aging individuals with increased risk of AD. However, these previous results have not been validated in AD. In this study, we aimed to test these prior predictions in a cohort of AD dementia patients and individuals with mild cognitive impairment (MCI) and a probable AD diagnosis. Therefore, we created gut microbiome-personalized whole-body metabolic models for 34 AD dementia patients, 51 MCI patients, and 298 healthy controls. These in silico models were profiled to predict the metabolic influences of gut microbiomes on blood metabolites with previously reported alterations in AD. We found increased capacities of the in silico host-microbiome co-metabolism to produce S-adenosyl-L-methionine, L-arginine, creatine, taurine, and formate in the blood of AD patients. The metabolic predictions were then linked to key microbial taxa using a novel method that combines modeling-informed prediction sensitivity to alternative microbial abundances with LASSO-based taxonomic stability selection and elastic net regressions. This method found that increased relative abundances of Bacteroides uniformis and Bacteroides thetaiotamicron in AD were major factors driving the predicted metabolic changes. Furthermore, the metabolic predictions were associated with allelic variations in the APOE risk gene in healthy individuals, confirming our previous findings. In conclusion, we identified blood metabolites with known links to AD that were differentially influenced by gut microbiota in AD, and identified possible microbial drivers of these predicted shifts in host-microbiome interactions. These findings may facilitate the development of microbiome-informed treatments of AD.},
}

Humans
*Alzheimer Disease/microbiology/metabolism/blood
*Gastrointestinal Microbiome
Male
Female
Aged
Bacteria/classification/isolation & purification/genetics/metabolism
Cognitive Dysfunction/metabolism/microbiology
Aged, 80 and over
Metabolome

@article {pmid42804638,
year = {2026},
author = {Augur, ZM and Fogo, GM and Benoit, CR and Kearney, MA and Terzioglu, G and Murphy, ZR and Arbery, MR and Comandante-Lou, N and Duong, DM and Seyfried, NT and De Jager, PL and Young-Pearse, TL},
title = {BAG3 coordinates astrocytic proteostasis of Alzheimer's disease-linked proteins via proteasome, autophagy, and retromer interactions.},
journal = {Proceedings of the National Academy of Sciences of the United States of America},
volume = {123},
number = {40},
pages = {e2528514123},
doi = {10.1073/pnas.2528514123},
pmid = {42804638},
issn = {1091-6490},
support = {F31AG082393-03//HHS | National Institutes of Health (NIH)/ ; R01AG055909//HHS | National Institutes of Health (NIH)/ ; R01NS117446//HHS | National Institutes of Health (NIH)/ ; K00AG079793//HHS | National Institutes of Health (NIH)/ ; },
mesh = {*Astrocytes/metabolism/pathology ; *Autophagy ; *Alzheimer Disease/metabolism/pathology/genetics ; Humans ; *Adaptor Proteins, Signal Transducing/metabolism/genetics ; *Proteostasis ; *Proteasome Endopeptidase Complex/metabolism ; Animals ; *Apoptosis Regulatory Proteins/metabolism/genetics ; Amyloid beta-Protein Precursor/metabolism/genetics ; Mice ; Neurons/metabolism ; Proteotoxic Stress ; Induced Pluripotent Stem Cells/metabolism ; },
abstract = {Bcl-2-associated athanogene 3 (BAG3) is a mediator of chaperone-assisted selective autophagy, and in the brain, is most highly expressed in astrocytes. However, its role in astrocytes remains poorly defined. Given the genetic and pathological links of BAG3 to proteostasis and neurodegenerative diseases, we investigated how BAG3 contributes to astrocyte function and Alzheimer's disease (AD). To define its function and relevance, we used single-nucleus RNA sequencing to confirm BAG3 enrichment in astrocytes and employed CRISPR/Cas9 editing of human induced pluripotent stem cells followed by proteomic and transcriptomic profiling, which revealed that BAG3 loss caused greater disruption in astrocytes than in neurons. BAG3-deficient astrocytes displayed reduced autophagy, lysosomal abundance and activity, and proteasome function. Coimmunoprecipitation identified BAG3 known binding partners (e.g., HSPB8, proteasome regulators), as well as an interactor in the retromer complex, VPS35. BAG3 deficiency resulted in altered retromer activity as measured by amyloid precursor protein (APP) localization in endosomes. In addition to validating these binding partners, integrative -omics analyses showed that BAG3 regulates AD-relevant proteins (GFAP, BIN1), as well as HSPB8. Functionally, BAG3 knockout astrocytes exhibited impaired amyloid-β proteostasis when cocultured with APP/PSEN1 mutant neurons, directly linking BAG3 to a disease-relevant astrocyte phenotype. Finally, analysis of postmortem human brain revealed that BAG3 expression marks a stress-responsive astrocyte subtype in aged individuals. Together, these findings demonstrate that BAG3 coordinates astrocyte proteostasis through interactions with regulators of autophagy, proteasome activity, and retromer function, positioning it as a potential therapeutic target and central node of astrocytic protein quality control in neurodegeneration.},
}

*Astrocytes/metabolism/pathology
*Autophagy
*Alzheimer Disease/metabolism/pathology/genetics
Humans
*Adaptor Proteins, Signal Transducing/metabolism/genetics
*Proteostasis
*Proteasome Endopeptidase Complex/metabolism
Animals
*Apoptosis Regulatory Proteins/metabolism/genetics
Amyloid beta-Protein Precursor/metabolism/genetics
Mice
Neurons/metabolism
Proteotoxic Stress
Induced Pluripotent Stem Cells/metabolism

@article {pmid42804712,
year = {2026},
author = {Avendaño-Arango, E and Salom-Palacio, I and Castillo-Támara, EE and Palacio-Villalba, B},
title = {Neuroepigenetics of the Environmental Exposome: Molecular and Clinical Implications in Neurodegeneration.},
journal = {The neurologist},
volume = {},
number = {},
pages = {},
doi = {10.1097/NRL.0000000000000694},
pmid = {42804712},
issn = {2331-2637},
abstract = {BACKGROUND: Neuroepigenetics studies the molecular mechanisms that regulate gene expression in the nervous system without altering the DNA sequence. The environmental exposome has emerged as a key factor influencing neuronal plasticity and brain homeostasis, contributing to vulnerability to neurodegeneration.

REVIEW SUMMARY: This narrative review analyzes the role of neuroepigenetic reprogramming as a central mechanism linking chronic environmental exposures with neurodegenerative diseases. Evidence indicates that alterations in DNA methylation, histone remodeling, and microRNA regulation contribute to mitochondrial dysfunction, oxidative stress, and chronic neuroinflammation. These mechanisms are critically involved in the pathogenesis of Alzheimer disease, Parkinson disease, and amyotrophic lateral sclerosis.

CONCLUSIONS: Neuroepigenetics represents a central mechanistic axis in neurodegeneration by integrating environmental exposures with intrinsic biological processes. This framework offers new opportunities for the development of early biomarkers and targeted preventive and therapeutic strategies.},
}

@article {pmid42804729,
year = {2026},
author = {Zafar, SF and Moura, LMVR and Gorham, B and Ndemo, E and Swanson, S and Day, GS and Schelke, M and Kummer, BR and Garg, N and Wilson, AM and Jones, LK},
title = {Geographic Variation in Diagnostic Codes Associated With Mild Cognitive Impairment, Alzheimer Disease, and Related Dementias.},
journal = {Neurology. Clinical practice},
volume = {16},
number = {6},
pages = {e200658},
doi = {10.1212/CPJ.0000000000200658},
pmid = {42804729},
issn = {2163-0933},
mesh = {Humans ; *Alzheimer Disease/epidemiology/diagnosis ; *Cognitive Dysfunction/epidemiology/diagnosis ; Female ; United States/epidemiology ; Aged ; Male ; Middle Aged ; Aged, 80 and over ; Comorbidity ; Disease Progression ; Prevalence ; *Dementia/epidemiology/diagnosis ; Registries ; International Classification of Diseases ; },
abstract = {BACKGROUND AND OBJECTIVES: Mild cognitive impairment (MCI), Alzheimer disease (AD), and AD-related dementias (ADRD) are growing public health concerns. Regional, demographic, and clinical differences in these diagnoses and associated comorbid conditions may inform strategies to improve prevention, care, and outcomes. To assess the demographic and geographic distribution of patients in the United States with coded MCI or AD/ADRD, the prevalence of common comorbidities, and the frequency and timing of progression to complicated MCI or AD/ADRD within 180 days, using data from the American Academy of Neurology's former Axon Registry.

METHODS: This observational study included adults aged 50-89 years with at least 1 outpatient encounter between 2017 and 2023 in 201 participating US neurology practices. Registry data were linked to the Centers for Disease Control and Prevention's 2019 Social Determinants of Health data set to assign patients to geographic regions. ICD-10 codes were used to identify MCI and AD/ADRD diagnoses, define comorbid conditions, and classify "complicated" MCI or AD/ADRD (e.g., with behavioral disturbances). The primary outcomes were odds of coded MCI/AD/ADRD, prevalence of top comorbidities, and proportion of patients progressing to complicated MCI/AD/ADRD within 180 days of initial diagnosis, stratified by region.

RESULTS: Of 1,144,081 individuals with at least 1 documented outpatient encounter, 146,273 (12.8%) had MCI or AD/ADRD ICD codes. Of those, 65,088 (44.5%) were in the South, 35,027 (23.9%) in the Midwest, 30,008 (20.5%) in the Northeast, and 16,134 (11.0%) in the West. Unadjusted odds of MCI/AD/ADRD codes were 0.170 (Northeast), 0.155 (South), 0.134 (West), and 0.125 (Midwest). Among those with uncomplicated MCI or AD/ADRD at first encounter, the highest proportion of progression to complicated codes within 180 days was in the Northeast (2.04%), followed by the West (1.91%), South (1.24%), and Midwest (1.06%). Common comorbidities included hypertension, depression or mood disorders, and gait abnormalities.

DISCUSSION: These findings highlight geographic and demographic variations in coded MCI/AD/ADRD prevalence and progression. Future studies should address underlying factors and the impact of comorbidities on outcomes, ultimately guiding more targeted approaches to dementia prevention and management. Future studies that phenotype AD/ADRD beyond the use of ICD codes can further validate the results.},
}

Humans
*Alzheimer Disease/epidemiology/diagnosis
*Cognitive Dysfunction/epidemiology/diagnosis
Female
United States/epidemiology
Aged
Male
Middle Aged
Aged, 80 and over
Comorbidity
Disease Progression
Prevalence
*Dementia/epidemiology/diagnosis
Registries
International Classification of Diseases

@article {pmid42804811,
year = {2026},
author = {Wang, K and Song, M and Lu, J and Li, D and Cui, H and Zhang, Y and Jiang, L and Wu, T and Zhang, Y and Xu, H and Li, Q and Wang, J and Nan, H and Xu, P},
title = {Global, Regional and National burden of dementia attributable to metabolic dysregulation from 1990 to 2021, with projections of burden to 2050: An analysis of the global burden of disease study 2021.},
journal = {Diabetes & metabolic syndrome},
volume = {20},
number = {8},
pages = {103486},
doi = {10.1016/j.dsx.2026.103486},
pmid = {42804811},
issn = {1878-0334},
abstract = {BACKGROUND AND AIMS: We quantified dementia burden attributable to high fasting plasma glucose (FPG) and high body mass index (BMI), projected trends to 2050, and examined metabolic traits using Mendelian randomization (MR).

METHODS: Global Burden of Disease (GBD) 2021 data from 204 countries and territories were analyzed by age, sex, and Socio-demographic Index. Future burden was projected using time-series and Bayesian age-period-cohort models. Two-sample MR used European-ancestry genetic summary data with inverse-variance weighted estimates and sensitivity analyses.

RESULTS: Metabolic-attributable dementia burden increased, with a steeper rise for high BMI than high FPG. Genetically predicted hypertension was associated most clearly with vascular dementia (odds ratio 2.72, 95% confidence interval 1.66-4.45; P = 0.0001) and was supported by the weighted-median estimator. Genetically predicted high-density lipoprotein cholesterol (HDL-C) showed only a nominal association with Alzheimer disease (odds ratio 1.09, 95% confidence interval 1.00-1.19; P = 0.0459) that was not consistently supported across MR methods. Mediation analyses were not significant.

CONCLUSIONS: Metabolic-attributable dementia burden is increasing globally. High BMI was a prominent contributor in GBD analyses, whereas MR most strongly supported hypertension and vascular dementia. The HDL-C finding is exploratory, and MR does not directly validate the BMI or FPG burden estimates.},
}

@article {pmid42804920,
year = {2026},
author = {Abd Al Moaty, MN and Moustafa, A and Hegazy, AS and Sobhy, AA and Ghareeb, DA and Awad, LF and Ibrahim, NA},
title = {Novel pyrimidine-based N-Acylhydrazones as dual AChE inhibitors and antioxidants targeting Alzheimer's disease.},
journal = {Bioorganic chemistry},
volume = {183},
number = {},
pages = {110578},
doi = {10.1016/j.bioorg.2026.110578},
pmid = {42804920},
issn = {1090-2120},
abstract = {Alzheimer's disease (AD) is a multifactorial neurodegenerative disorder characterized by cholinergic dysfunction and oxidative stress, making the development of multi-target-directed ligands (MTDLs) an attractive therapeutic strategy. Herein, we designed and synthesized a novel series of pyrimidinone-based acyl hydrazones 6a-g bearing substituted aryl or heteroaryl (furan) moieties. The synthesized compounds were evaluated for their in vitro acetylcholinesterase (AChE) inhibitory and antioxidant activities. The synthesized pyrimidinone-based acyl hydrazones (6a-g) exhibited promising acetylcholinesterase (AChE) inhibitory activity. Compound 6 g emerged as the most potent inhibitor, with an IC50 value of 4.79 μM, corresponding to approximately 55.7-fold greater potency than tacrine hydrochloride (IC50 = 266 μM) under standardized parallel assay conditions. Compounds 6a, 6b, and 6f also demonstrated potent AChE inhibition, with IC50 values ranging from 15.9 to 128.65 μM, whereas the remaining derivatives exhibited moderate to weak inhibitory activity. The synthesized compounds also displayed promising antioxidant activity in DPPH and nitric oxide (NO) radical scavenging assays. Notably, 6g exhibit potent DPPH and nitric oxide radical scavenging activity, surpassing standard antioxidant (ascorbic acid) by approximately 35-fold and 9-fold, respectively. Molecular docking studies supported the experimental results by revealing favorable binding modes of the most active compounds within the AChE active site, while suggesting potential computationally predicted interactions with BuChE, 5-LOX, and COX-2. Furthermore, in silico drug-likeness and ADME analyses provided baseline pharmacokinetic profiles, guiding rational structural optimization strategies to enhance blood-brain barrier permeability. These findings identify pyrimidinone-based acyl hydrazones as promising multifunctional lead compounds for the development of novel therapeutic agents against Alzheimer's neurocognitive disorder.},
}

@article {pmid42804945,
year = {2026},
author = {Cui, M and Yang, J and Zhao, LS and Hu, X and Cong, W and Hu, H and Xu, F and Liu, S},
title = {Highly sensitive and specific high-throughput detection of Aβ42 in clinical specimens using a G-quadruplex-structured fluorescent aptamer analysis platform.},
journal = {Talanta},
volume = {313},
number = {Pt C},
pages = {130612},
doi = {10.1016/j.talanta.2026.130612},
pmid = {42804945},
issn = {1873-3573},
abstract = {The early diagnosis of Alzheimer's disease (AD) relies on highly sensitive detection of the biomarker amyloid-β 42 (Aβ42). Currently used methods for detecting Aβ42, such as enzyme-linked immunosorbent assay (ELISA) and mass spectrometry, have limitations including insufficient sensitivity, high cost, and limited throughput. This study aimed to develop a high-affinity, specific G-quadruplex aptamer for Aβ42 through rational sequence trimming and optimization. Both theoretical calculations and biolayer interferometry experimental data demonstrated that the 29-bp aptamer exhibited good binding affinity to Aβ42 protein, systematically validating the robust and specific interaction between this G-quadruplex and Aβ42. Building on this, thioflavin T was introduced as a fluorescent mediator to successfully construct a high-throughput fluorescent aptamer analysis platform based on G-quadruplex-assisted structural transformation. The analysis platform exhibited an excellent linear response within the Aβ42 concentration range of 0.01-100 pg/mL, with a limit of detection as low as 3 fg/mL, enabling ultrasensitive detection and demonstrating remarkable selectivity. Spiked experiments using plasma and serum samples showed that the method maintained a good linear relationship across the same concentration range. Furthermore, the robustness of this platform in complex biological matrices was systematically validated through parallel testing of clinical plasma samples from 13 patients with AD and 11 healthy controls. The test results showed a high correlation with the ELISA (R[2] = 0.9473), demonstrating the reliability and potential clinical applicability of this method. In summary, the developed high-throughput fluorescent aptamer analysis platform enabled ultrasensitive, rapid, and scalable detection of Aβ42, offering a promising diagnostic platform and a robust sensing strategy for the early clinical screening of AD.},
}

@article {pmid42805035,
year = {2026},
author = {Garcia, D and Saito, N and Tamizharasu, S and Sevilla, LNC and Luu, MN and Beckett, L and Honig, LS and DeCarli, CS and Coughlin, DG and Teich, AF and Mungas, DM and Jin, LW and Garcia, L and Dugger, BN},
title = {Regional distribution of mineralized blood vessels in Alzheimer disease and clinicopathological associations: A multicenter autopsy study.},
journal = {Neurobiology of aging},
volume = {169},
number = {},
pages = {141-152},
doi = {10.1016/j.neurobiolaging.2026.09.001},
pmid = {42805035},
issn = {1558-1497},
abstract = {Mineralized blood vessels (MBV) are a form of vascular pathology associated with cerebrovascular aging and neurodegeneration; however, their regional distribution and clinicopathological correlates in Alzheimer disease (AD) remain poorly characterized. We examined 265 decedents with intermediate/high AD neuropathologic change from three Alzheimer's Disease Research Centers (Columbia University, University of California San Diego, and University of California Davis). Hematoxylin and eosin-stained sections from the posterior hippocampus, putamen, and globus pallidus were evaluated for MBV. Associations with demographic, clinical, genetic, and neuropathological variables were assessed using bivariate tests and multivariable logistic regression adjusting for age at death, sex, ethnicity, and center. MBV frequency differed across regions, with highest involvement in the globus pallidus (58.3%), followed by the posterior hippocampus (28.6%), and putamen (13.8%) (all pairwise p < 0.001). After covariate adjustment, MBV presence was not associated with sex, ethnicity, education, APOE ε4 carrier status, or cerebral amyloid angiopathy (CAA). After correction for multiple comparisons, MBV remained associated with état criblé in the putamen and globus pallidus (both FDR-adjusted p < 0.01), and concomitant Lewy body disease remained associated with reduced MBV presence in the posterior hippocampus and globus pallidus (both FDR-adjusted p < 0.05). Nominal associations with a history of transient ischemic attack (TIA) did not remain significant after correction for multiple comparisons. This study identified MBV as a regionally selective feature of cerebrovascular aging in AD, enriched in deep gray matter. MBV may contribute to regional vulnerability and pathological heterogeneity in the aging AD brain.},
}

@article {pmid42805065,
year = {2026},
author = {Zong, X and Zhu, Z and Zhang, X and Li, Y and Bai, R},
title = {From orphan receptor to versatile regulator: Redefining LILRB3 as a context-dependent immune checkpoint and therapeutic target.},
journal = {International immunopharmacology},
volume = {190},
number = {},
pages = {117494},
doi = {10.1016/j.intimp.2026.117494},
pmid = {42805065},
issn = {1878-1705},
abstract = {The immune system maintains homeostasis through a delicate balance between activation and inhibition. While activating pattern recognition receptors (PRRs) are well-established initiators of innate immunity, the role of inhibitory PRRs (iPRRs) in providing negative regulation is an emerging paradigm. Among these, Leukocyte Immunoglobulin-Like Receptor Subfamily B Member 3 (LILRB3), a myeloid-specific receptor, has recently undergone a dramatic conceptual transformation. Once considered a minor "orphan" receptor, LILRB3 is increasingly recognized as a context-dependent immune checkpoint with diverse immunoregulatory functions. Breakthrough studies in recent years have revealed its role as a putative cell surface receptor for APOE4 in Alzheimer's disease, a supporter of leukemia development via a non-canonical TRAF2-cFLIP-NF-κB signaling axis in acute myeloid leukemia (AML), and a genetic risk factor for kidney transplant failure in African American recipients. This review synthesizes these recent advances to present a unified framework of LILRB3 biology. We comprehensively detail its polymorphic gene structure, multi-domain architecture, and complex regulatory mechanisms governing its cell-type-specific expression. We expand upon its diverse ligand repertoire, encompassing both HLA-I-dependent and independent molecules, and dissect its versatile signaling pathways, from canonical ITIM-SHP1/2-mediated inhibition to non-canonical, phosphatase-independent functions. A central theme is the context-dependent role of LILRB3 across diseases: it can be detrimental in cancer by fostering an immunosuppressive microenvironment or beneficial in maintaining tissue homeostasis. Finally, we critically evaluate the translational landscape, including antagonistic/agonistic antibodies, CAR-T therapies, and biomarker-driven strategies, while addressing key challenges like cross-reactivity with LILRA6. By positioning LILRB3 within the emerging iPRR framework, this review highlights its potential therapeutic relevance across immunology, neurology, and oncology, and outlines a roadmap for future research and precision targeting.},
}

@article {pmid42805444,
year = {2026},
author = {Cui, X and Liang, TY and Adeyosoye, M and Ezzati, M and Simkhada, B and Cabrerizo, M and Cid, RC and Rosselli, M and Barreto, A and Rishe, ND and Loewenstein, DA and Adjouadi, M},
title = {Multiscale Organization of Amyloid-Associated Vulnerability Across the Hippocampal Memory System.},
journal = {NeuroImage},
volume = {},
number = {},
pages = {122265},
doi = {10.1016/j.neuroimage.2026.122265},
pmid = {42805444},
issn = {1095-9572},
abstract = {Alzheimer's disease (AD) selectively affects interconnected components of the hippocampal memory system, yet most MRI biomarkers characterize neurodegeneration using whole-hippocampal or isolated regional measurements. We tested whether amyloid-associated structural vulnerability is selectively concentrated in the cornu ammonis 1 (CA1) and the dentate gyrus (DG), reproducible across independent 1Florida ADRC and ADNI cohorts, and spatially localized within these subfields. We integrated hippocampal subfield volumetry, covariate-adjusted amyloid-associated vulnerability scores, 10,000-resample bootstrap rank-stability analysis, complementary cross-sectional clinical-stage comparisons, exploratory diffusion MRI, and within-subfield occupancy mapping. The cornu ammonis 1 (CA1) region and the dentate gyrus (DG) retained the two highest covariate-adjusted amyloid-associated point rankings in both cohorts. In ADRC, the adjusted scores were 5.06% for CA1 and 4.38% for DG, with bootstrap Top-2 frequencies of 59.02% and 41.44%, respectively; in ADNI, the adjusted scores were 9.10% for CA1 and 9.37% for DG, with Top-2 frequencies of 73.60% and 76.40%, respectively. Bootstrap resampling quantified uncertainty in regional scores and rank positions and supported recurrent top two placement of CA1 and DG, while also demonstrating overlap in uncertainty among several ROIs. Complementary cross-sectional comparisons described CA1 and DG volume differences across clinical stages in ADRC and ADNI. Exploratory diffusion MRI identified effect-size differences in hippocampal-associated pathways, but none of the 20 region-metric comparisons survived Benjamini-Hochberg false-discovery-rate correction. Collectively, these findings support a reproducible cross-sectional pattern of amyloid-associated vulnerability within the hippocampal memory system, centered on CA1 and DG and accompanied by spatially heterogeneous within-subfield structural loss. The diffusion MRI findings are exploratory and provide anatomical context rather than evidence of temporal ordering. Longitudinal studies are required to determine the sequence in which these abnormalities emerge.},
}

@article {pmid42805736,
year = {2026},
author = {Qi, X and Ko, E and Ruan, JY and Jung, JH and Leong, IT and Pei, Y and Mao, W and Zheng, Y and Mittelman, MS and Wu, B},
title = {Sequential mediation of social resources, affiliate stigma, loneliness, and positive aspects of caregiving among Chinese and Korean American dementia caregivers.},
journal = {International journal of nursing sciences},
volume = {13},
number = {5},
pages = {497-504},
doi = {10.1016/j.ijnss.2026.08.009},
pmid = {42805736},
issn = {2352-0132},
mesh = {Aged ; Aged, 80 and over ; Female ; Humans ; Male ; Middle Aged ; *Asian/psychology ; *Caregivers/psychology ; China/ethnology ; *Dementia/nursing/psychology ; *Loneliness/psychology ; *Social Stigma ; *Social Support ; Republic of Korea/ethnology ; New York ; },
abstract = {OBJECTIVES: This study aimed to examine whether Asian American dementia caregivers' affiliate stigma and loneliness sequentially account for the associations of social network and social support with positive aspects of caregiving (PAC).

METHODS: The sample included 162 Korean and 176 Chinese American caregivers enrolled in a randomized clinical trial and recruited from New York, US (February 2023 to September 2025). We measured social network using the Lubben Social Network Scale-6, social support using the NIH Toolbox Social Support scales, affiliate stigma using the modified Affiliate Stigma Scale, loneliness using the University of California, Los Angeles Loneliness Scale (UCLA), and PAC using the 9-item PAC scale. We tested sequential mediation models while adjusting for sociodemographics, health status, and caregiving context. We tested indirect effects and the proportion mediated using bias-corrected bootstrap confidence intervals (CIs; 5,000 resamples).

RESULTS: Both social network (β = 0.137, 95 % CI: 0.018 to 0.254) and support (β = 0.265, 95 %CI: 0.166 to 0.360) were significantly associated with higher PAC. Total indirect effects through affiliate stigma and loneliness accounted for 38.2 % and 27.8 % of the total effects, respectively. Loneliness was the only single mediator that reached significance (social network β = 0.036, 95 %CI: 0.012 to 0.076; social support β = 0.048, 95 %CI: 0.011 to 0.098). The sequential pathway, lower stigma followed by lower loneliness, was significant for social support (β = 0.012, 95 %CI: 0.003 to 0.029) but not for social network (β = 0.008, 95 % CI: -0.000 to 0.024).

CONCLUSIONS: In this study, social resources were associated with more positive caregiving appraisals, and loneliness was the principal intervening variable. Because all measures were obtained at a single time point, these indirect effects are correlational and cannot establish causal ordering. Culturally tailored interventions should strengthen social ties and incorporate loneliness-targeted strategies, with anti-stigma components requiring further evaluation in adequately powered studies.},
}

Aged
Aged, 80 and over
Female
Humans
Male
Middle Aged
*Asian/psychology
*Caregivers/psychology
China/ethnology
*Dementia/nursing/psychology
*Loneliness/psychology
*Social Stigma
*Social Support
Republic of Korea/ethnology
New York

@article {pmid42805789,
year = {2026},
author = {Fujiwara, Y},
title = {From bilingual dementia screening to equitable clinical action in primary care.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261491982},
doi = {10.1177/13872877261491982},
pmid = {42805789},
issn = {1875-8908},
abstract = {Shah et al. embedded a brief bilingual dementia screening tool in the electronic health record and reported increases in diagnosis, referral, laboratory testing, and prescribing in a diverse primary care clinic serving patients at risk for Alzheimer's disease and related dementias. The novelty lies less in the test itself than in integrating culturally and linguistically responsive case finding into routine care and linking positive results to next clinical actions. This commentary considers how that implementation logic could be adapted to Japan.},
}

@article {pmid42805926,
year = {2026},
author = {Bizzi, I and Macedo, AC and Trudel, L and Therriault, J and Rahmouni, N and Lussier, FZ and Tissot, C and Bezgin, G and Aumont, É and Chan, T and Hosseini, SA and Oliva-Lopez, D and Gonçalves, MP and Povala, G and Ferreira, PCL and Bellaver, B and Amaral, L and Ruppert, E and Medeiros, MS and Mroué, R and Rocha, A and Ng, KP and Zimmer, ER and Masdeu, J and Pascual, B and Lowe, VJ and Oh, H and Soleimani-Meigooni, DN and Fortea, J and Ismail, Z and Baker, S and Pascoal, TA and Rosa-Neto, P and , },
title = {Tau-PET correlates of mild behavioral impairment in preclinical and prodromal Alzheimer's disease: A head-to-head comparison of Flortaucipir and MK6240.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {10},
pages = {e71861},
doi = {10.1002/alz.71861},
pmid = {42805926},
issn = {1552-5279},
support = {R01AG073267/AG/NIA NIH HHS/United States ; MOP-11-51-31//Weston Brain Institute, Canadian Institutes of Health Research (CIHR)/ ; RFN 152985 159815 162303//Weston Brain Institute, Canadian Institutes of Health Research (CIHR)/ ; MOP-11-51-31//Canadian Consortium of Neurodegeneration and Aging/ ; 2020-VICO-279314//the Fonds de Recherche du Québec - Santé/ ; 2024 VICO-356138//the Fonds de Recherche du Québec - Santé/ ; 34874//Fondation Brain Canada/ ; 33397//Fondation Brain Canada/ ; //the Colin J Adair Charitable Foundation/ ; INT21/00073//Fondo de Investigaciones Sanitario, Carlos III Health Institute/ ; PI23/01786//Fondo de Investigaciones Sanitario, Carlos III Health Institute/ ; //Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas Program 1/ ; //Fondo Europeo de Desarrollo Regional, Unión Europea, Una manera de hacer Europa/ ; SLT006/17/00119//Department de Salut de la Generalitat de Catalunya/ ; IIBSP-DOW-2020-151//Fundación Tatiana Pérez de Guzmán el Bueno/ ; //Horizon 2020 Framework Programme/ ; //Departament de Salut, Generalitat de Catalunya/ ; //Foundation for the National Institutes of Health/ ; //Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas/ ; //Instituto de Salud Carlos III/ ; //Fondo de Investigaciones Sanitario/ ; /ALZ/Alzheimer's Association/United States ; #0000000158//Alzheimer Society of Canada/ ; 88881.218211/2025-01//Coordenação de Aperfeiçoamento de Pessoal de Nível Superior/ ; //Consortium canadien en neurodégénérescence associée au vieillissement/ ; },
mesh = {Humans ; *Positron-Emission Tomography/methods ; *Alzheimer Disease/diagnostic imaging/metabolism ; *tau Proteins/metabolism ; Female ; Male ; Aged ; *Carbolines ; Prodromal Symptoms ; Brain/diagnostic imaging/metabolism ; Aged, 80 and over ; Radiopharmaceuticals ; *Cognitive Dysfunction/diagnostic imaging/metabolism ; Isoquinolines ; },
abstract = {INTRODUCTION: We compared the association between mild behavioral impairment (MBI) and first- versus second-generation tau-positron emission tomography (PET) tracers in preclinical and prodromal Alzheimer's disease (AD).

METHODS: We assessed 110 individuals with head-to-head [[18]F]MK6240 and [[18]F]Flortaucipir tau-PET. Voxel-wise and region-of-interest analyses investigated relationships between tau-PET and MBI Checklist (MBI-C) scores, which were also compared across tau-PET positivity and PET-Braak stages.

RESULTS: For both tracers, MBI severity was associated with tau-PET signal in all Braak regions and increased across PET-Braak stages. [[18]F]MK6240 showed more extensive voxel-wise associations with MBI-C scores and additional correlations with affective symptoms in stratified analyses by diagnostic groups. Tau positivity was associated with a higher frequency of MBI. Individuals positive for [[18]F]MK6240 but negative for [[18]F]Flortaucipir exhibited greater MBI burden than individuals negative for both tracers.

DISCUSSION: MBI in early AD is associated with tau-PET, with [[18]F]MK6240 providing greater sensitivity to detect MBI-related symptoms.},
}

Humans
*Positron-Emission Tomography/methods
*Alzheimer Disease/diagnostic imaging/metabolism
*tau Proteins/metabolism
Female
Male
Aged
*Carbolines
Prodromal Symptoms
Brain/diagnostic imaging/metabolism
Aged, 80 and over
Radiopharmaceuticals
*Cognitive Dysfunction/diagnostic imaging/metabolism
Isoquinolines

@article {pmid42805933,
year = {2026},
author = {Yu, F and Xu, J and Hou, Y and Zheng, H and Guo, L and Khutsishvili, D and Hai, C and Xu, W and Chen, B and Wang, Z and Ma, S},
title = {GLP-1R agonist semaglutide protects human forebrain organoids from cholesterol-induced neurotoxicity.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {10},
pages = {e71888},
doi = {10.1002/alz.71888},
pmid = {42805933},
issn = {1552-5279},
support = {2024YFA0919800//National Key Research and Development Program of China/ ; B2402009//Shenzhen Medical Academy of Research and Translation/ ; 32371470//National Natural Science Foundation of China/ ; 2023B0909020003//Key-Area Research and Development Program of Guangdong/ ; QNXMA20250701093300001//Shenzhen Natural Science Foundation/ ; JCYJ20241202123909013//Shenzhen Natural Science Foundation/ ; WDZC20231128170943001//Stabilization Support Program of Shenzhen Science and Technology Innovation Commission/ ; },
mesh = {Semaglutide ; Humans ; *Glucagon-Like Peptides/pharmacology ; *Cholesterol/metabolism/toxicity ; *Organoids/drug effects/metabolism ; *Glucagon-Like Peptide-1 Receptor Agonists ; *Prosencephalon/drug effects/metabolism ; *Neuroprotective Agents/pharmacology ; Neurons/drug effects/metabolism ; Induced Pluripotent Stem Cells ; },
abstract = {INTRODUCTION: Dysregulated cholesterol metabolism represents a critical metabolic stressor in the central nervous system, contributing to neuronal injury across multiple neurological conditions, including Alzheimer's disease (AD). While glucagon-like peptide-1 receptor (GLP-1R) agonists show neuroprotective potential, their capacity to directly mitigate cholesterol-induced metabolic stress in human neural cells remains to be established.

METHODS: Here, we modeled metabolic stress using human induced pluripotent stem cell-derived forebrain organoids exposed to cholesterol overload. The protective effects of the GLP-1R agonist semaglutide were characterized by integrating bulk/single-cell transcriptomics, calcium imaging, and biochemical assays. Furthermore, clinical translatability was supported by mapping organoid expression signatures against human post mortem neurodegenerative brain datasets.

RESULTS: Cholesterol overload induced cellular stress and transcriptomic alterations that partially overlapped with AD-associated signatures. Semaglutide protected neural cells from lipotoxic injury. Intracellularly, GLP-1R activation engaged the cyclic adenosine 3',5'-monophosphate-protein kinase A and phosphoinositide 3 kinase-protein kinase B-mechanistic target of rapamycin signaling pathways, consistent with reduced lipid droplet accumulation and oxidative stress. Intercellularly, single-cell analysis indicated partial preservation of disrupted cellular communication, including the neurotrophic midkine signaling network. Functionally, semaglutide stabilized cellular calcium activity patterns under metabolic stress.

DISCUSSION: These findings highlight the role of cholesterol homeostasis in maintaining neuronal integrity and position GLP-1R signaling as a candidate protective axis under metabolic stress, offering insights into therapeutic strategies for AD and broader neurodegenerative disorders.},
}

Semaglutide
Humans
*Glucagon-Like Peptides/pharmacology
*Cholesterol/metabolism/toxicity
*Organoids/drug effects/metabolism
*Glucagon-Like Peptide-1 Receptor Agonists
*Prosencephalon/drug effects/metabolism
*Neuroprotective Agents/pharmacology
Neurons/drug effects/metabolism
Induced Pluripotent Stem Cells

@article {pmid42805935,
year = {2026},
author = {Stenfors, CUD and Wu, J and Grande, G and Pyko, A and Löhmus, M and Pershagen, G and Rizzuto, D},
title = {Precision residential greenspace, urban environmental exposures, and incident dementia among older adults in Sweden: A 16-year cohort study.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {10},
pages = {e71835},
doi = {10.1002/alz.71835},
pmid = {42805935},
issn = {1552-5279},
support = {2020-00977//Swedish Research Council for Health, Working Life and Welfare/ ; 2017-01768//Swedish Research Council for Health, Working Life and Welfare/ ; 2021-00178//Swedish Research Council/ ; 2020-0501//Region Stockholm/ ; 201907930017//Chinese Scholarship Council/ ; LA2020-0026//Lindhés Advokatbyrå AB/ ; //The Swedish Ministry of Health/ ; },
mesh = {Humans ; Sweden/epidemiology ; *Dementia/epidemiology ; Male ; Female ; Incidence ; Aged ; *Environmental Exposure/statistics & numerical data ; Longitudinal Studies ; Aged, 80 and over ; Cohort Studies ; Urban Population ; *Parks, Recreational ; Risk Factors ; },
abstract = {INTRODUCTION: Residential greenspace is linked to mental and cardiometabolic health, but longitudinal studies on detailed greenspace and dementia incidence are limited.

METHODS: We followed 2993 dementia-free participants in the Swedish National Study on Aging and Care Kungsholmen for 16 years; 477 developed clinically diagnosed dementia. Greenspace was assessed using normalized difference vegetation index within 100-, 250-, and 500-m residential buffers. Cox models estimated hazard ratios (HRs) per interquartile-range greenspace increment and tested effect modification by air pollution, road traffic noise, blue space, age, sex, and apolipoprotein E-ε4 (APOE-ε4).

RESULTS: Higher greenspace within 100 m was associated with lower dementia incidence (HR = 0.79, 95% confidence interval [CI] = 0.64-0.96), whereas associations for larger buffers were attenuated. Associations were stronger in women (HR = 0.69, 95% CI = 0.54-0.89) than men (HR = 0.93, 95% CI = 0.71-1.24).

DISCUSSION: Close residential greenspace may reduce dementia risk in older adults, particularly women.},
}

Humans
Sweden/epidemiology
*Dementia/epidemiology
Male
Female
Incidence
Aged
*Environmental Exposure/statistics & numerical data
Longitudinal Studies
Aged, 80 and over
Cohort Studies
Urban Population
*Parks, Recreational
Risk Factors

@article {pmid42805938,
year = {2026},
author = {Mostafaei, S and Gustavsson, K and Hagelin, H and Mak, JKL and Vu, TN and Karlsson, IK and Hägg, S},
title = {Integrative prediction of Alzheimer's disease and related dementias using multi-omics aging clocks and genetic data.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {10},
pages = {e71869},
doi = {10.1002/alz.71869},
pmid = {42805938},
issn = {1552-5279},
support = {2022-01608 to SH//Swedish Research Council/ ; 2024-02163 to SM//Loo and Hans Osterman Foundation/ ; 2022-01247 to SM//Loo and Hans Osterman Foundation/ ; R01AG067996-01A1 to SH//Karolinska Institutet Foundations/ ; R01AG067996-01A1 to SH/AG/NIA NIH HHS/United States ; },
mesh = {Humans ; *Alzheimer Disease/genetics/diagnosis/epidemiology ; Genetic Risk Score ; *Aging/genetics ; Female ; Multiomics ; Male ; Aged ; UK Biobank ; United Kingdom/epidemiology ; Proteomics ; *Dementia/genetics/diagnosis ; },
abstract = {INTRODUCTION: We tested whether combining Alzheimer's disease and related dementias (ADRD) polygenic risk scores (PRS) with biological aging markers improves ADRD risk prediction.

METHODS: In 16,215 UK Biobank (UKB) participants free of ADRD at baseline (median follow-up: 10.08 years), 397 incident diagnoses were identified. Biological aging measures included clinical, telomere, proteomic, and metabolomic aging markers. External validation/replication was performed in TwinGene (N = 3772; 331 cases).

RESULTS: The fully integrated model achieved area under the curve (AUC) = 0.90 and area under the precision-recall curve (AUPRC) = 0.24 in the UKB held-out test set. PRS was the strongest predictor (subdistribution hazard ratio [sHR] = 2.24, 95% CI: 2.02-2.48), followed by ProtAge (sHR = 2.01, 95% CI: 1.13-3.58). The top predicted-risk quartile showed higher ADRD incidence (sHR = 16.73, 95% CI: 6.49-43.11). TwinGene showed moderate transportability (AUC = 0.757; AUPRC = 0.223) and preserved risk stratification (sHR = 4.02, 95% CI: 3.25-5.02).

DISCUSSION: Integrating PRS and biological aging measures improved ADRD risk stratification.},
}

Humans
*Alzheimer Disease/genetics/diagnosis/epidemiology
Genetic Risk Score
*Aging/genetics
Female
Multiomics
Male
Aged
UK Biobank
United Kingdom/epidemiology
Proteomics
*Dementia/genetics/diagnosis

@article {pmid42805939,
year = {2026},
author = {Growdon, JH and Morris, JC and Petersen, RC and Sano, M and Schneider, LS},
title = {Perspectives from Alzheimer's Disease Research Centers site directors on the early steps and the lasting impact.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {10},
pages = {e71694},
doi = {10.1002/alz.71694},
pmid = {42805939},
issn = {1552-5279},
mesh = {*Alzheimer Disease/diagnosis/therapy ; Humans ; United States ; National Institute on Aging (U.S.) ; *Biomedical Research ; },
abstract = {Since the groundbreaking work of Alois Alzheimer in the early 1900s, Alzheimer's disease research has evolved immensely, most notably with the establishment of the Alzheimer's Disease Research Centers (ADRC). Fueled by the vision and funding of the National Institute on Aging (NIA), ADRCs have created a legacy through their work standardizing criteria for Alzheimer's disease diagnosis. Leveraging the experience of the Consortium to Establish a Registry for Alzheimer's Disease, the ADRCs advanced standardized assessment tools, including the Clinical and Neuropsychological Batteries, as well as the CDR, which would make way for uniform data collection, in what we know today as the National Alzheimer's Coordinating Center (NACC). Collaborative data collection was expanded by NIA to support the development of treatments for Alzheimer's disease and related disorders (ADRD) through the Alzheimer's Disease Cooperative Study (ADCS) and the Alzheimer's Clinical Trial Consortium (ACTC) programs. These NIA sponsored programs have created a foundation for today's pharmacological and non-pharmacological interventions to improve cognition and function in persons living with ADRD.},
}

*Alzheimer Disease/diagnosis/therapy
Humans
United States
National Institute on Aging (U.S.)
*Biomedical Research

@article {pmid42805944,
year = {2026},
author = {Popp, Z and James, A and Chivardi, M and Reimer, CJ and Robbins, C and Jenson, T and van Baar, JM and James, P and Lane, KJ and Jiménez, MP},
title = {Practical considerations for characterization of the external exposome in Alzheimer's disease and related dementias cohorts.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {10},
pages = {e71841},
doi = {10.1002/alz.71841},
pmid = {42805944},
issn = {1552-5279},
support = {1R01AG087199/AG/NIA NIH HHS/United States ; R00AG066949/AG/NIA NIH HHS/United States ; 1K99AG066949-01/AG/NIA NIH HHS/United States ; R01NS139186/NS/NINDS NIH HHS/United States ; },
mesh = {Humans ; *Alzheimer Disease/epidemiology ; *Exposome ; *Environmental Exposure/adverse effects ; Cohort Studies ; *Dementia/epidemiology ; United States/epidemiology ; },
abstract = {External exposome research offers opportunities to evaluate complex relationships between multiple environmental determinants of Alzheimer's disease and related dementias (ADRD). However, selecting specific exposure domains, identifying metrics, and downloading, processing, and managing big data are key challenges in translating the potential of exposome research into empirical data analyses. To overcome these issues, we have established a reproducible system that protects data privacy, setting the stage for an unparalleled examination of associations between environmental exposures and ADRD risk within an exposome framework. In this perspective, we provide a comprehensive guide, including examples, to linking natural, built, and social environment metrics to nationwide time-varying participants' residential address data. Further, as a proof of concept, we report descriptive statistics and spatial distribution of external exposome metrics across the contiguous United States in 2015. The external exposome can be securely and comprehensively characterized across multiple cohorts using this highly scalable approach.},
}

Humans
*Alzheimer Disease/epidemiology
*Exposome
*Environmental Exposure/adverse effects
Cohort Studies
*Dementia/epidemiology
United States/epidemiology

@article {pmid42805945,
year = {2026},
author = {Clouston, SAP and Huang, C and Askarov, T and Wang, Y and Chaudhry, Z and Carr, MA and Yang, Y and West, S and Mann, FD and Marquez, R and Vaska, P and Meliker, J and Gandy, S and Lucchini, RG and Luft, BJ and , },
title = {World Trade Center neurotoxicant exposure severity is associated with cortical thinning and regional brain atrophy: a neuroimaging study of general responders at midlife.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {10},
pages = {e71878},
doi = {10.1002/alz.71878},
pmid = {42805945},
issn = {1552-5279},
support = {U01OH011314/OH/NIOSH CDC HHS/United States ; R01AG049953//NIOSH/ ; R01AG067590//NIOSH/ ; P30 AG066514//NIOSH/ ; R01AG084699//Cure Alzheimer's Fund/ ; R01AG093879//Cure Alzheimer's Fund/ ; R01AG093281//Cure Alzheimer's Fund/ ; //I.B. Ertegun Project for Cognitive Health Extension at ISMMS/ ; U01 AG024904//(ADNI) (National Institutes of Health/ ; W81XWH-12-2-0012//DOD ADNI/ ; //AbbVie, Alzheimer's Association; Alzheimer's Drug Discovery Foundation; Araclon Biotech; BioClinica, Inc.; Biogen; Bristol-Myers Squibb Company; CereSpir, Inc.; Cogstate; Eisai Inc.; Elan Pharmaceuticals, Inc.; Eli Lilly and Company; EuroImmun; 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; and Transition Therapeutics/ ; /CAPMC/CIHR/Canada ; //Foundation for the National Institutes of Health/ ; },
mesh = {Humans ; *September 11 Terrorist Attacks ; Atrophy/pathology/chemically induced ; Male ; Female ; Middle Aged ; Adult ; Magnetic Resonance Imaging ; Aged ; *Cerebral Cortical Thinning/chemically induced/diagnostic imaging/pathology ; Neuroimaging ; *Emergency Responders ; *Brain/pathology/diagnostic imaging/drug effects ; *Cerebral Cortex/pathology/diagnostic imaging/drug effects ; },
abstract = {INTRODUCTION: Exposure to aerosolized pollutants is a risk factor for cognitive impairment and dementia, but the specific features of exposure-related neurodegeneration remain unclear.

METHODS: We measured the World Trade Center Neurotoxicant Exposure Severity Index (WTC-NESI) in 218 responders and unexposed controls aged 44-65 years. The main outcome was cortical thickness. Correlation analyses reported unadjusted associations and multiple linear regression to adjust for correlates. Vertex-wise analyses were used with threshold-free cluster enhancement to examine associations after adjusting for cross-vertex clustering in atrophy.

RESULTS: Cortical thickness was associated with WTC-NESI (R = -0.38, p < 0.001) that survived multivariable adjustment. Vertex-wise analyses revealed reduced cortical thickness across much of the cortical surface that was associated with WTC exposure severity. Results were right-hemisphere asymmetric and focused in the precentral regions (partial η[2] ≥ 0.07).

CONCLUSION: Our results provide an important reference for neurotoxicological investigators mapping the implications of airborne pollutant exposures. This study suggests that efforts to mitigate exposures in first responders might have long-term implications for cerebral health.},
}

Humans
*September 11 Terrorist Attacks
Atrophy/pathology/chemically induced
Male
Female
Middle Aged
Adult
Magnetic Resonance Imaging
Aged
*Cerebral Cortical Thinning/chemically induced/diagnostic imaging/pathology
Neuroimaging
*Emergency Responders
*Brain/pathology/diagnostic imaging/drug effects
*Cerebral Cortex/pathology/diagnostic imaging/drug effects

@article {pmid42805946,
year = {2026},
author = {Ashrafzadeh-Kian, S and Figdore, DJ and Bornhorst, JA and Vanderboom, PM and Callison, S and Day, GS and Lachner, C and Graff-Radford, N and Shir, D and Jack, CR and Knopman, DS and Graff-Radford, J and Petersen, RC and Ramanan, VK and Algeciras-Schimnich, A},
title = {Long term clinical performance and analytical robustness of the Lumipulse plasma p-tau217 assay in routine clinical practice.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {10},
pages = {e71887},
doi = {10.1002/alz.71887},
pmid = {42805946},
issn = {1552-5279},
mesh = {Humans ; *tau Proteins/blood/cerebrospinal fluid ; *Alzheimer Disease/diagnosis/blood/cerebrospinal fluid ; Female ; Reproducibility of Results ; Male ; Immunoassay/methods ; Amyloid beta-Peptides/cerebrospinal fluid ; *Cognitive Dysfunction/diagnosis/blood ; Aged ; Biomarkers/blood/cerebrospinal fluid ; Phosphorylation ; Positron-Emission Tomography ; Aged, 80 and over ; },
abstract = {INTRODUCTION: Plasma phosphorylated tau 217 (p‑tau217) immunoassays are increasingly being used to assess Alzheimer's disease (AD) pathology despite limited data affirming test reliability over time.

METHODS: Clinical performance of the Fujirebio Lumipulse G p‑tau217 assay was assessed in 744 Mayo Clinic patients presenting for evaluation of cognitive impairment between July 2024 and December 2025. Cerebrospinal fluid p‑tau181/amyloid beta 42 or amyloid positron emission tomography, within 1 year of p-tau217 testing, were used as reference. Analytical robustness was evaluated by tracking result frequencies over time, conducting quality control checks, performing 10 lot‑to‑lot comparisons, and comparing two versions of reagents.

RESULTS: Diagnostic accuracy for detection of AD pathology was 93% (95% confidence interval 91-95) with 23% intermediate results. Reduced estimated glomerular filtration rate was associated with increased intermediate results among amyloid-negative individuals. Result frequencies remained stable, average imprecision was 8%, and analytical bias between lots and version changes were ≤ 11%.

DISCUSSION: The findings support plasma p-tau217 reliability in clinical practice for evaluation of cognitively impaired individuals.},
}

Humans
*tau Proteins/blood/cerebrospinal fluid
*Alzheimer Disease/diagnosis/blood/cerebrospinal fluid
Female
Reproducibility of Results
Male
Immunoassay/methods
Amyloid beta-Peptides/cerebrospinal fluid
*Cognitive Dysfunction/diagnosis/blood
Aged
Biomarkers/blood/cerebrospinal fluid
Phosphorylation
Positron-Emission Tomography
Aged, 80 and over

@article {pmid42806197,
year = {2026},
author = {Wang, X and Xie, X and Tang, R and Wang, X and Xu, Z and Guo, Y and Liu, T and Chen, F},
title = {ADGPT: A Prior-Guided and GPT-Empowered Framework for MRI-Based Alzheimer's Disease Diagnosis.},
journal = {Journal of imaging informatics in medicine},
volume = {},
number = {},
pages = {},
pmid = {42806197},
issn = {2948-2933},
support = {82430065//National Natural Science Foundation of China/ ; 62206080//National Natural Science Foundation of China/ ; YSPTZX202514//Innovation Platform for Academicians of Hainan Province and Hainan Academician Innovation Platform Scientific Research Project/ ; },
abstract = {Existing artificial intelligence methods for Alzheimer's disease (AD) diagnosis predominantly emphasize classification performance while neglecting interpretability. Leveraging large language models (LLMs) for diagnostic reasoning to generate decisions alongside supporting rationales can improve interpretability, yet remains underexplored in neuroimaging-based AD diagnosis. We propose a prior-guided and GPT-empowered framework (ADGPT) for magnetic resonance imaging (MRI)-based AD diagnosis. We construct an AD prior knowledge collection (APKC) to provide priors for the LLM's diagnostic reasoning. The APKC integrates three information types: label text tokens, JSON-based default mode network (DMN) representations, and brain tissue volumes. For the label text tokens, we propose a label text-graph structure alignment paradigm, such that the aligned label text tokens enable the LLM to identify AD-related abnormal functional patterns from functional MRI. The JSON-based DMN representations encode DMN functional connectivity in a structured JSON format, enabling the LLM to analyze the functional characteristics of key brain regions. Brain tissue volumes are used to quantify brain atrophy revealed by structural MRI. Additionally, we design a customized prompt for AD diagnosis to provide task inputs and guide the reasoning process. Without fine-tuning the LLM, ADGPT enables joint analysis of functional and structural AD pathologies revealed by neuroimaging and provides case-level, traceable diagnostic rationales. Experiments on two databases demonstrate that ADGPT outperforms state-of-the-art methods, achieving accuracies of 0.914 and 0.825 for AD versus normal control (NC), 0.806 and 0.812 for AD versus mild cognitive impairment (MCI), and 0.886 and 0.784 for MCI versus NC. Moreover, interpretability analyses provide additional evidence supporting its interpretability.},
}

@article {pmid42806367,
year = {2026},
author = {Özdüzenciler, P and Müller, L and Kara, E and Weber, MC and Pils, M and Rehn, F and Bannach, O and Fink, GR and Willbold, D and Barbe, MT and Onur, OA and Tamgüney, G},
title = {Fecal Aβ and tau aggregates are elevated in cognitive impairment and reveal peripheral proteopathic alterations.},
journal = {Alzheimer's research & therapy},
volume = {18},
number = {1},
pages = {},
pmid = {42806367},
issn = {1758-9193},
mesh = {Humans ; *tau Proteins/metabolism ; Female ; Male ; *Amyloid beta-Peptides/metabolism ; *Feces/chemistry ; *Cognitive Dysfunction/metabolism/diagnosis ; Aged ; Biomarkers/metabolism ; Aged, 80 and over ; Middle Aged ; },
abstract = {BACKGROUND: Aggregation of amyloid-β (Aβ) and tau is central to Alzheimer's disease (AD) pathogenesis and forms the basis of established cerebrospinal fluid (CSF) and imaging biomarkers. However, increasing evidence suggests that AD involves systemic processes beyond the central nervous system. We previously demonstrated the presence of fecal Aβ aggregates. Here, we assessed the detectability of tau aggregates in human feces and examined the diagnostic value of combined fecal Aβ and tau quantification in cognitive impairment.

METHODS: Using surface-based fluorescence intensity distribution analysis (sFIDA), a single-particle assay selective for aggregated species, we quantified fecal Aβ and tau aggregates in individuals with cognitive impairment (dementia, MCI, SCD) and cognitively normal controls. Associations with CSF biomarkers were assessed, and classification performance was evaluated using cross-validated logistic regression models.

RESULTS: Tau aggregates were detectable in fecal samples. Both fecal Aβ and tau aggregate concentrations were significantly elevated in cognitively impaired individuals and remained independently associated with patient status after adjustment for age and sex. Fecal Aβ aggregates showed inverse associations with CSF tau biomarkers, particularly phosphorylated tau. In cross-validated models, fecal tau aggregates achieved stronger classification performance than fecal Aβ (AUC ~ 0.80 vs. ~ 0.68), and integration of fecal aggregates with demographic predictors improved discrimination to an AUC of 0.90.

CONCLUSIONS: Detection of fecal tau aggregates extends previous observations on fecal Aβ and supports the concept that stool-based aggregate measurements capture systemic aspects of proteopathic biology associated with cognitive impairment. These findings suggest that fecal aggregate quantification may provide a minimally invasive biomarker approach that complements established CNS-based biomarkers and may be useful for patient stratification and monitoring in neurodegenerative disease.},
}

Humans
*tau Proteins/metabolism
Female
Male
*Amyloid beta-Peptides/metabolism
*Feces/chemistry
*Cognitive Dysfunction/metabolism/diagnosis
Aged
Biomarkers/metabolism
Aged, 80 and over
Middle Aged

@article {pmid42806688,
year = {2026},
author = {Pluta, R and Bogucka-Kocka, A and Kocki, J and Bogucki, J and Czuczwar, SJ},
title = {Tau Protein, α-synuclein, and Amyloid Precursor Protein Processing Genes in the Frontal Cortex of an Ischemic Alzheimer's Disease Model.},
journal = {Current Alzheimer research},
volume = {},
number = {},
pages = {e15672050403689},
doi = {10.2174/0115672050403689251103120712},
pmid = {42806688},
issn = {1875-5828},
abstract = {INTRODUCTION: Information regarding the changes in tau protein, α-synuclein, and amyloid precursor protein processing genes in the frontal cortex post-ischemia, cannot be found in literature We decided to examine the expression of these genes in rats after 10-min of cerebral ischemia with survival of 2-30 days and 6-24 months.

METHODS: Gene expression was assessed by RT-PCR. The relative quantity (RQ) of the studied gene was shown using ΔCT, and the last value was shown as RQ = 2-ΔΔCT.

RESULTS: Two days, 12-18 months post-ischemia, the amyloid precursor protein gene was significantly overexpressed. However, the α-secretase gene was significantly overexpressed on day 2 and 12 months post-ischemia. At 1 year post-ischemia β-secretase gene was significantly overexpressed. Presenilin 1 and 2 genes at 2 days, 12 months post-ischemia were significantly overexpressed. At 12-18 months post-ischemia tau protein gene was significantly overexpressed, and at other times it was below control. At 2 days and 12-18 months post-ischemia, the α-synuclein gene was significantly overexpressed, and at other times it was below control.

DISCUSSION: The data indicate that after cerebral ischemia, there is no activation of genes that could influence amyloid production in the frontal cortex. However, the data indicate significant activation of tau protein and α-synuclein genes.

CONCLUSION: We revealed non-amyloidogenic metabolism of amyloid precursor protein in the frontal cortex post-ischemia. Moreover, the results showed increased expression of tau protein and α- synuclein genes at 12-18 months post-ischemia, suggesting the involvement of these genes in neurodegenerative processes in the frontal cortex.},
}

@article {pmid42806690,
year = {2026},
author = {Firoozi, M and Mahdavinezhad, A and Shirzad, M and Motevaseli, E and Dalirfardouei, R and Modarressi, MH and Najafi, R},
title = {Biotechnological Approaches to Probiotics and Postbiotics through the Gut-Brain Axis Modulation.},
journal = {Iranian biomedical journal},
volume = {30},
number = {4},
pages = {193-211},
doi = {10.22034/IBJ.30.4.193},
pmid = {42806690},
issn = {2008-823X},
abstract = {The gut microbiome and gut-brain axis are central to systemic homeostasis, with dysbiosis implicated in neurodegenerative (Alzheimer's and Parkinson's) disorders and gastrointestinal conditions (inflammatory bowel disease, irritable bowel syndrome, and fibromyalgia). These conditions are marked by a reduction in beneficial taxa (e.g., Faecalibacterium prausnitzii and Bifidobacterium) and an increase in harmful ones (e.g., Escherichia coli and Clostridium scindens). Probiotic, prebiotic, postbiotic, and symbiotic interventions show therapeutic promise, but results can vary. Biotechnological advances, including CRISPR-Cas9 and genetic kill-switch systems, enable precision-engineered probiotics and postbiotics, though concerns about safety, genetic stability, gene transfer, and immune compatibility persist. Encapsulation and nanoencapsulation strategies improve microbial viability and site-specific delivery; i.e., microencapsulating Lactobacillus acidophilus and Bifidobacterium animalis in alginate-pectin matrices enhances survival during freeze-drying, storage, and gastrointestinal transit. Advancing clinical translation requires integrating multi-omics and machine learning with bioengineering approaches. This review examines the microbial-neural interface and surveys emerging biotechnological strategies for improving microbial-based therapeutics.},
}

@article {pmid42806710,
year = {2026},
author = {Micovic, K and Olson, MF},
title = {The MICAL family at the Rho-Rab interface: coordinating actin dynamics through oxidation and scaffolding.},
journal = {The Biochemical journal},
volume = {483},
number = {10},
pages = {2035-2053},
doi = {10.1042/BCJ20250118},
pmid = {42806710},
issn = {1470-8728},
support = {P.CTIP.842//Ontario Institute for Cancer Research (OICR)/ ; 950-231665 CRC-2024-00113//Canada Research Chairs (CRC)/ ; RGPIN-2020-05388//Natural Sciences and Engineering Research Council of Canada (NSERC)/ ; },
mesh = {Humans ; *rho GTP-Binding Proteins/metabolism ; Oxidation-Reduction ; Animals ; *Actins/metabolism ; *Microfilament Proteins/metabolism ; *rab GTP-Binding Proteins/metabolism ; *Actin Cytoskeleton/metabolism ; Signal Transduction ; *Mixed Function Oxygenases/metabolism ; Calponins ; },
abstract = {The actin cytoskeleton is a complex network of proteins that is constantly being remodelled and reorganized to orchestrate numerous essential cellular processes. From the regulation of proliferation, motility, cytokinesis through to signal transduction, and beyond, the dynamic nature of the actin cytoskeleton is vital to the enactment of these cellular functions. As a result, when there are aberrations in cytoskeleton dynamics, adverse consequences may be triggered. For example, dysregulation of the actin cytoskeleton has been linked to several neurodevelopmental and neurodegenerative disorders, including Alzheimer's and Parkinson's diseases. Additionally, actin cytoskeleton dysregulation has been shown to drive cancer growth and invasion, with altered expression levels of actin effectors and regulators being frequently associated with poorer prognoses and more invasive phenotypes. Given the complex and varied roles of the actin cytoskeleton and the ramifications of its dysregulation, the characterization of its key regulators is essential to understand disease etiology and to identify potential new therapeutic targets. This review highlights the interconnections of three protein families that are central to actin cytoskeleton modification, regulation, and function: the MICAL monooxygenase family, and the Rho and Rab GTPase families. The roles of the MICAL protein family and its functions in connecting Rho and Rab protein signalling will be discussed, with a particular focus on MICAL1.},
}

Humans
*rho GTP-Binding Proteins/metabolism
Oxidation-Reduction
Animals
*Actins/metabolism
*Microfilament Proteins/metabolism
*rab GTP-Binding Proteins/metabolism
*Actin Cytoskeleton/metabolism
Signal Transduction
*Mixed Function Oxygenases/metabolism
Calponins

@article {pmid42806777,
year = {2026},
author = {J, K and K S, S and M, G and Francis, D and T G, A},
title = {Steered molecular dynamics and free-energy analysis of withanolide unbinding from tau kinases TTBK1 and GSK-3β.},
journal = {Journal of biomolecular structure & dynamics},
volume = {},
number = {},
pages = {1-22},
doi = {10.1080/07391102.2026.2736169},
pmid = {42806777},
issn = {1538-0254},
abstract = {Tau hyperphosphorylation is identified as a critical process in microtubule destabilisation, neurodegeneration and synaptic dysfunction. Considering the kinases involved in this process, Tau Tubulin Kinase 1 (TTBK1) and Glycogen Synthase Kinase-3β (GSK-3β) have emerged as potential therapeutic targets. Here, we employed an integrated molecular simulation approach to investigate the binding thermodynamics and unbinding mechanisms of five Ashwagandha-derived withanolides sominone, withanolide A, withanolide D, withanone and withaferin A targeting TTBK1 and GSK-3β. Principal component analysis and free-energy landscape mapping identified distinct conformational basins and representative bound-state structures for each protein-ligand complex. Steered molecular dynamics simulations, followed by umbrella sampling and weighted histogram analysis, were used to characterise ligand dissociation pathways and determine the potentials of mean force. The calculated binding free energies ranged from -9 to -13 kcal mol[-1], indicating favourable ligand binding affinity for both kinases. MM-GBSA analyses complemented these findings and identified van der Waals interactions as the primary contributors to protein-ligand complex stabilisation. Collectively, the results provide detailed molecular insights into ligand recognition, binding stability and dissociation energetics in tau-associated kinases. These findings highlight withanolidebased scaffolds as promising candidates for structure guided optimisation and the development of kinase targeted therapeutics against tau-related neurodegenerative disorders.Communicated by Kavitha J.},
}

@article {pmid42806951,
year = {2026},
author = {Bullock, H and Weaver, DF},
title = {Should Diabetes Be Considered "Pancreatic Alzheimer's Disease?".},
journal = {The Canadian journal of neurological sciences. Le journal canadien des sciences neurologiques},
volume = {},
number = {},
pages = {1-2},
doi = {10.1017/cjn.2026.10696},
pmid = {42806951},
issn = {0317-1671},
}

@article {pmid42807347,
year = {2026},
author = {Albarrán Morillo, C and Zheng, L and Ghanbarian, E and Khorsand, B and Glover, CM and Grill, JD and Sajjadi, SA and Ezzati, A},
title = {APOE and amyloid-tau pathology in cognitively unimpaired older adults.},
journal = {Alzheimer's & dementia (Amsterdam, Netherlands)},
volume = {18},
number = {3},
pages = {e70496},
pmid = {42807347},
issn = {2352-8729},
abstract = {INTRODUCTION: Apolipoprotein E (APOE) genotype shows well-established dose-dependent associations with higher amyloid in cognitively unimpaired (CU) adults. In contrast, associations with tau burden and cognition are less well characterized.

METHODS: We performed a cross-sectional analysis of CU participants from the Anti-Amyloid Treatment in Asymptomatic Alzheimer's Disease (A4), Alzheimer's Disease Neuroimaging Initiative (ADNI), Wisconsin Registry for Alzheimer's Prevention (WRAP), and National Alzheimer's Coordinating Center (NACC) within the harmonized multi-cohort Alzheimer's Disease Sequencing Project Phenotype Harmonization Consortium (ADSP-PHC) data. A total of 4380 CU participants were included with APOE genotype, amyloid PET, and cognitive data (memory, language, executive, and visuospatial function), including a subset of 758 with tau PET imaging.

RESULTS: Compared with ε33, ε24 (β = 18.340), ε34 (β = 23.850), and ε44 (β = 44.820) showed higher amyloid burden (all p < .001). Similarly, ε24 (OR = 4.180), ε34 (OR = 4.540), and ε44 (OR = 14.150) had higher odds of amyloid positivity (all p < .001). After adjustment for amyloid burden, ε4 carriers had higher tau burden in the entorhinal cortex (β = 0.026; false discovery rate [FDR] -adjusted p = 0.041) and amygdala (β = 0.040; FDR-adjusted p = 0.003). Higher tau burden was associated with lower memory (β = -0.439; FDR-adjusted p = 0.012) and language performance (β = -0.610; FDR-adjusted p = 0.020).

DISCUSSION: APOE ε4 showed a strong dose-dependent association with amyloid, with the highest levels observed among ε4 homozygotes. Associations between APOE and global tau were more modest and appeared to be driven mainly by ε4 homozygotes, while regional analyses showed localized APOE ε4-related associations in medial temporal regions. Independently, higher tau was associated with lower memory and language performance.},
}

@article {pmid42807379,
year = {2026},
author = {Callow, DD and Rani, N and Spira, AP and Moghekar, A and Wanigatunga, S and Pettigrew, C and Soldan, A and Albert, M and Bakker, A},
title = {Longitudinal associations of rest-activity rhythms with executive function, plasma biomarkers, and clinical outcomes in older adults.},
journal = {Frontiers in aging neuroscience},
volume = {18},
number = {},
pages = {1939060},
pmid = {42807379},
issn = {1663-4365},
abstract = {INTRODUCTION: Daily patterns of activity, rest, and sleep, referred to as rest-activity rhythms (RARs), can be characterized by their day-to-day regularity, within-day fragmentation, and contrast between active and rest periods across the 24-h cycle. Disruptions (e.g., irregular schedules, fragmented activity, or reduced day-night contrast) have been associated with cognitive decline among older adults. Few studies have used repeated actigraphy to distinguish person-level average RARs from visit-specific deviations.

METHODS: The sample included 169 older adults without MCI or dementia at the first actigraphy visit, based on consensus clinical and neuropsychological review. Seven-day wrist actigraphy required at least three 24-h intervals with <5% missing data each; 122 participants had repeated assessments (362 observations total). RARs were characterized using three non-parametric features: (1) day-night contrast [relative amplitude (RA)], (2) day-to-day regularity [interdaily stability (IS)], and (3) within-day fragmentation [intradaily variability (IV)]. Each metric was decomposed into a person-level average and a visit-specific deviation from that average. Linear mixed-effects models examined associations with executive function and BMI-adjusted plasma markers of Alzheimer's disease-related pathophysiology [pTau181/(Aβ42/Aβ40)], neuroaxonal injury (NfL), and astroglial activation (GFAP); exploratory Cox models evaluated incident MCI; and amyloid PET interaction models were conducted in participants with PET data (n = 141).

RESULTS: Higher average RA and IS and lower average IV were associated with higher executive function. At the visit level, higher-than-average RA and lower-than-average IV relative to each participant's own average were associated with higher executive function at corresponding assessments. Higher average RA was associated with lower risk of incident MCI. RAR metrics were not significantly associated with GFAP, NfL, or pTau181/(Aβ42/Aβ40) in the plasma biomarker models. Amyloid PET status moderated within-person RAR associations with executive function: higher-than-usual RA and IS and lower-than-usual IV were more strongly associated with better executive function among amyloid PET-positive participants. For the plasma biomarkers, the between-person IS × amyloid PET interaction remained significant after correction only for pTau181/(Aβ42/Aβ40).

DISCUSSION: These findings highlight the value of repeated actigraphy for distinguishing average RAR levels from assessment-level departures from each participant's own average RAR profile and suggest that visit-specific RAR variation may be particularly relevant to executive function among amyloid PET-positive older adults.},
}

@article {pmid42807496,
year = {2026},
author = {Cottingham, K and Goodarzi, N and Fries, D and Lirushie, G and Hall, H},
title = {Tau-induced increase in promoter-proximal RNA polymerase II pausing is linked to suppressed expression of long neuronal genes in a Drosophila tauopathy model.},
journal = {Frontiers in aging neuroscience},
volume = {18},
number = {},
pages = {1851916},
pmid = {42807496},
issn = {1663-4365},
abstract = {Tauopathies, including Alzheimer's disease, are age-related neurodegenerative disorders characterized by abnormal phosphorylation and buildup of microtubule-associated protein tau. Gene expression dysregulation is a key molecular feature of tauopathies, but how aging and disease interact to disrupt crucial transcriptional regulators and pathways remains largely unknown. Here, we examined how pathological tau affects gene expression programs in age-related neurodegenerative disease using a well-established Drosophila melanogaster tauopathy model with neuronal expression of the toxic human tau [R406W] . Transcriptomic analysis of tau-expressing fly heads showed a preferential downregulation of long neuronal genes with long introns. Notably, we found that these downregulated genes in the tauopathy model are marked by increased accumulation of initiating RNA polymerase II (RNAP II) near the transcription start site and reduced elongating RNAP II within gene bodies, indicating a problem with the transition from initiation to elongation. By calculating an RNAP II Pause Index (PI) for each gene, we identified a strong link between promoter-proximal RNAP II stalling, gene expression deficits, and gene length in the tauopathy model. Overall, we have uncovered the genomic and transcriptomic features of tau-dependent downregulated genes and identified increased RNAP II promoter-proximal stalling as a significant mechanism of transcription stress in tauopathy.},
}

@article {pmid42807678,
year = {2025},
author = {Dhana, K and Wilson, RS and Beck, T and Evans, DA and Rajan, KB},
title = {Cognitive Activity From Early to Late Life and the Risk of AD Dementia: A Life Course Study.},
journal = {Neurology open access},
volume = {1},
number = {1},
pages = {},
pmid = {42807678},
issn = {2998-7601},
abstract = {BACKGROUND AND OBJECTIVES: Participation in late-life cognitive activities has been associated with a slower rate of cognitive decline and reduced risk of dementia; however, whether this association is independent of earlier experiences is unclear. We examined the association of cognitive activities during early life, midlife, and late life with the risk of Alzheimer's disease (AD) dementia.

METHODS: This study used data from the Chicago Health and Aging Project, a longitudinal population-based study from 1993 to 2012. Cognitive activity in early life, i.e., during childhood, was measured by the frequency of activities such as reading, storytelling, and playing games. Cognitive activity in midlife was estimated based on the participants' occupational cognitive activity and complexity. Cognitive activity in late life was assessed by the frequency of participation in reading, watching TV, listening to the radio, visiting museums, and playing chess or checkers. Cognitive activity in early, midlife, and late life was standardized to the population standard deviation (SD) and was modeled continuously (i.e., per 1-SD increase) and categorically (i.e., tertiles). Clinical diagnosis of AD dementia was based on the established criteria by NINCDS-ADRDA. Logistics regression models were used to estimate the odds ratio (OR) and 95% confidence interval (CI) of cognitive activities with AD dementia.

RESULTS: Of the 1950 individuals included in the analysis, 63% were female, and 54% were Black adults. The average age of study participants was 73. Three hundred ninety-one (20.1%) individuals developed AD dementia during the study period. Cognitive activity in midlife and late life was independently associated with a lower risk of AD dementia, while early-life cognitive activity was not. The OR (95%CI) for a 1-SD increase in the cognitive activity score in early, midlife, and late life were 0.91 (0.71, 1.18), 0.66 (0.51, 0.87), and 0.50 (0.38, 0.65), respectively. Comparing people in the high cognitive activity group (3rd tertile) versus those in the lower group (1st tertile) provided similar associations.

DISCUSSION: Cognitive activity in midlife and late life was associated with a lower risk of AD dementia. In addition, this study supports the independent role of late-life cognitive activity on the risk of AD dementia.},
}

@article {pmid42807723,
year = {2026},
author = {Quan, Q and Pan, R and Liu, H and Zheng, L and Zhang, R},
title = {Potential Role of Red Yeast Rice in the Prevention and Treatment of Alzheimer's Disease.},
journal = {International journal of medical sciences},
volume = {23},
number = {10},
pages = {3101-3111},
pmid = {42807723},
issn = {1449-1907},
mesh = {*Alzheimer Disease/prevention & control/drug therapy/diet therapy ; Humans ; *Biological Products/therapeutic use/pharmacology/chemistry ; Monascus/metabolism/chemistry ; Antioxidants/therapeutic use/pharmacology ; Neuroprotective Agents/therapeutic use/pharmacology ; Lovastatin/therapeutic use/pharmacology ; Amyloid beta-Peptides/metabolism ; gamma-Aminobutyric Acid/therapeutic use/pharmacology ; Fermentation ; },
abstract = {Red Yeast Rice (RYR) fermented from Monascus is a traditional fermented product with both dietary and medicinal uses and is widely used for lipid regulation. Clinically, it is utilized to lower blood lipid levels and manage hyperlipidemia. Contemporary research indicates that RYR is abundant in secondary metabolites, such as monacolin K, Monascus pigments, and γ-aminobutyric acid, which contribute to its lipid-lowering, blood sugar-reducing, anti-inflammatory, neuroprotective, and antihypertensive properties. These metabolites may play a significant role in the prevention and treatment of Alzheimer's disease (AD) through mechanisms that include cholesterol-dependent pathways, anti-neuroinflammation, antioxidant activity, neuroprotection, modulation of intestinal flora, inhibition of high-risk factors for AD, and suppression of AD-related β-amyloid peptide deposition and tau protein hyperphosphorylation. Consequently, RYR demonstrates potential for a multi-component synergistic approach to preventing and treating AD. However, current research on the use of RYR for AD prevention and treatment remains limited. This review focuses on the primary functional substances in RYR, elucidates the anti-AD effects and mechanisms of each metabolite, analyzes the advantages of its multi-component and multi-target properties, and provides a foundation for the further development of RYR.},
}

*Alzheimer Disease/prevention & control/drug therapy/diet therapy
Humans
*Biological Products/therapeutic use/pharmacology/chemistry
Monascus/metabolism/chemistry
Antioxidants/therapeutic use/pharmacology
Neuroprotective Agents/therapeutic use/pharmacology
Lovastatin/therapeutic use/pharmacology
Amyloid beta-Peptides/metabolism
gamma-Aminobutyric Acid/therapeutic use/pharmacology
Fermentation

@article {pmid42808071,
year = {2026},
author = {Sucharska, M and Gardas, K and Hernik, K and Brudek, A and Pawlasek, J and Piwar, H and Lis, M and Sucharski, M and Kisiel, S and Cierpial, P and Mikolajczak, P and Puziuk, M and Kupczyk, K and Jedra, Z},
title = {Diet, Microbiota and Memory: How What We Eat Affects Memory and Cognitive Processes and Whether Diet Can Help Prevent the Onset of Dementia.},
journal = {Cureus},
volume = {18},
number = {8},
pages = {e115384},
pmid = {42808071},
issn = {2168-8184},
abstract = {This paper was written in response to the growing interest in the influence of the gut-brain axis on the development of dementia and cognitive disorders. The main aim was to review and summarise the latest findings in this area. The article was divided into a section on animal studies, which sought to link specific macronutrient ratios in diets to general behavioural disturbances in organisms, alongside the development of hypotheses regarding changes in the levels of substances responsible for, or indicative of, neurodegenerative processes. Subsequently, the impact of diets containing carbohydrates, proteins, and fats on cognitive processes and memory in humans was discussed. Deterioration was observed particularly among groups consuming large amounts of fat and experiencing a caloric surplus, which led to the development of obesity. Finally, the study presented both dietary interventions and multifactorial lifestyle changes aimed at improving memory function in patients, including older adults and those with Alzheimer's disease. A particularly significant factor highlighted in most studies was adherence to the Mediterranean and Mediterranean-DASH Intervention for Neurodegenerative Delay (MIND) diets, which most likely contributed to slowing the progression of dementia in the majority of patients. Several studies have demonstrated a link between the qualitative composition of the diet and the development of dementia. Obesity, resulting from a high intake of fat and/or carbohydrates, and the inflammation it provokes, including within the central nervous system, plays a key role in this process. The most beneficial effects were demonstrated by the MIND and Mediterranean diets when combined with comprehensive lifestyle changes, which is why the authors were cautious about drawing definitive conclusions.},
}

@article {pmid42808122,
year = {2026},
author = {Lee, H and Ye, Z and Chen, C and Kochunov, P and Hong, LE and , and , and Chen, S},
title = {Fast autoregressive model for multivariate dependent outcomes with application to lipidomics analysis for Alzheimer's disease and APOE-ε4.},
journal = {Computational statistics & data analysis},
volume = {215},
number = {},
pages = {},
pmid = {42808122},
issn = {0167-9473},
abstract = {Association analysis of multivariate omics outcomes is challenging due to the high dimensionality and inter-correlation among outcome variables. In practice, the classic multi-univariate analysis approaches are commonly employed, utilizing linear regression models for each individual outcome followed by adjustments for multiplicity through control of the false discovery rate (FDR) or family-wise error rate (FWER). While straightforward, these multi-univariate methods overlook dependencies between outcome variables. This oversight leads to less accurate statistical inferences, characterized by lower power and an increased false discovery rate, ultimately resulting in reduced replicability across studies. Recently, advanced frequentist and Bayesian methods have been developed to account for these dependencies. However, these methods often pose significant computational challenges for researchers in the field. To bridge this gap, a computationally efficient autoregressive multivariate regression model is proposed that explicitly accounts for the dependence structure among outcome variables. Through extensive simulations, it is demonstrated that the approach provides more accurate multivariate inferences than traditional methods and remains robust even under model misspecification. Additionally, the proposed method is applied to investigate whether the associations between serum lipidomics outcomes and Alzheimer's disease differentiate in ε4 allele carriers and non-carriers of the apolipoprotein E (APOE) gene.},
}

@article {pmid42808164,
year = {2026},
author = {Mortada, I and Paul, K and Rice, J and Joseph, N and Raum, TL and Albayyaa, M and Gaalema, D and Jehle, D and Blackwell, TA and Jneid, H},
title = {Benefits of sodium-glucose cotransporter 2 inhibitors versus glucagon-like peptide-1 receptor agonists in older patients with type 2 diabetes.},
journal = {Diabetes & vascular disease research},
volume = {23},
number = {5},
pages = {14791641261495569},
doi = {10.1177/14791641261495569},
pmid = {42808164},
issn = {1752-8984},
mesh = {Humans ; *Diabetes Mellitus, Type 2/drug therapy/diagnosis/mortality ; *Glucagon-Like Peptide-1 Receptor Agonists ; Aged ; Female ; *Sodium-Glucose Transporter 2 Inhibitors/therapeutic use/adverse effects ; Retrospective Studies ; Male ; Treatment Outcome ; Risk Factors ; *Incretins/adverse effects/therapeutic use ; Risk Assessment ; Time Factors ; Age Factors ; Middle Aged ; United States/epidemiology ; Aged, 80 and over ; Glucagon-Like Peptide-1 Receptor ; },
abstract = {BackgroundType 2 diabetes mellitus (T2DM) increases the risk of cardiovascular and neurocognitive complications. GLP-1 receptor agonists (GLP-1 RAs) and SGLT2 inhibitors (SGLT2is) have pleiotropic effects beyond glycemic control, but comparative long-term data on dementia, cardiovascular events, and mortality in older adults are limited.MethodsThis retrospective cohort study used the TriNetX US Collaborative Network. Adults ≥60 years with T2DM on metformin plus either GLP-1 RAs or SGLT2is (n=56,211 per cohort after matching, 2014-2020) were propensity-score matched on demographic and clinical characteristics. Five-year outcomes included incident Alzheimer's disease, vascular dementia, other dementia, dementia-related medication use, NSTEMI, STEMI, and all-cause mortality.ResultsAfter propensity-score matching, GLP-1 RA use was associated with higher risks of Alzheimer's disease (RR 1.33, 95% CI 1.18-1.48), vascular dementia (RR 1.56, 95% CI 1.39-1.76), other dementia (RR 1.33, 95% CI 1.21-1.47), dementia-related medication initiation, and all-cause mortality (RR 1.11, 95% CI 1.08-1.15) compared with SGLT2is. NSTEMI and STEMI risks did not differ significantly between groups.ConclusionsIn older adults with T2DM, SGLT2is were associated with lower risks of dementia, dementia-related medication use, and all-cause mortality compared with GLP-1 RAs in propensity-score matched cohorts. These observational findings are hypothesis-generating and should be confirmed in prospective studies.},
}

Humans
*Diabetes Mellitus, Type 2/drug therapy/diagnosis/mortality
*Glucagon-Like Peptide-1 Receptor Agonists
Aged
Female
*Sodium-Glucose Transporter 2 Inhibitors/therapeutic use/adverse effects
Retrospective Studies
Male
Treatment Outcome
Risk Factors
*Incretins/adverse effects/therapeutic use
Risk Assessment
Time Factors
Age Factors
Middle Aged
United States/epidemiology
Aged, 80 and over
Glucagon-Like Peptide-1 Receptor

@article {pmid42808238,
year = {2026},
author = {Kuzuya, A and Ohara, T and Akamatsu, N},
title = {Plain language summary of the mechanisms behind epilepsy in Alzheimer's disease and the use of perampanel.},
journal = {Expert review of neurotherapeutics},
volume = {},
number = {},
pages = {1-9},
doi = {10.1080/14737175.2026.2733194},
pmid = {42808238},
issn = {1744-8360},
}

@article {pmid42808300,
year = {2026},
author = {Veres, M and Kannan, L and Kennedy, Z and Gobeo, A and Yamaguchi, T and Giovannetti, T and Schmitter-Edgecombe, M and Duff, K},
title = {Convergent validity of measures of daily functioning in older adults.},
journal = {Journal of clinical and experimental neuropsychology},
volume = {},
number = {},
pages = {1-9},
doi = {10.1080/13803395.2026.2740482},
pmid = {42808300},
issn = {1744-411X},
abstract = {INTRODUCTION: Although information on daily functioning is needed for accurate diagnoses of neurocognitive disorders, little has been published on the psychometric properties of measures of daily functioning. Convergent validity is one such psychometric property that examines the relationship between scales that purport to assess the same construct. Whereas the convergent validity of measures of daily functioning has typically been examined relative to cognitive tests, the current objective was to analyze the relationships between different measures of daily functioning in older adults.

METHODS: Two hundred thirty-seven older adults (age: M = 74.8, SD = 5.6; education: M = 16.9, SD = 2.4) completed a battery of functional assessments, including two subjective scales (Alzheimer's Disease Cooperative Studies - Activities of Daily Living for Mild Cognitive Impairment 23-item version and Quick Dementia Rating System) and three performance-based measures (Independent Living Scales, Night-Out Task, and Virtual Kitchen Challenge). Scales were initially compared with Spearman's correlations and then factor analysis.

RESULTS: Small to medium but statistically significant correlations (p < 0.01) were found among the scores of all functional measures, with better functioning on one scale being seen on other scales (rs = 0.21 to 0.61). Three factors were identified, and scores loaded together based on type of scoring (i.e. correct/incorrect vs. timed) and by assessment method (i.e. subjective vs. performance-based).

CONCLUSIONS: Despite differences between these measures that assess daily functioning, their associations suggest that they tap a similar construct. Factor loadings were based on type of scoring within the performance-based measures (i.e. correct/incorrect vs. timed) and type of assessment method (i.e. subjective or performance-based). While further exploration is needed in larger, more diverse samples and using additional functional scales, these findings have implications for both clinical practice and research.},
}

@article {pmid42808485,
year = {2026},
author = {Aaby, P and Arnold, SE and Benn, CS and Ben-Haim, S and Bishai, W and Dow, CT and Faustman, D and Gofrit, ON and Greenblatt, CL and Itzhaki, R and Klein, B and Lathe, R and Netea, MG and Sankin, A and Scherrer, JF and Schaltz-Buchholzer, F and Schulz, PE and Taquet, M and Tariot, PN and Weinberg, MS and , },
title = {Immune boosting to combat Alzheimer's disease: Position statement.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261472830},
doi = {10.1177/13872877261472830},
pmid = {42808485},
issn = {1875-8908},
abstract = {The societal cost of Alzheimer's disease (AD) and related dementias is immense, but there are no effective treatments. Emerging evidence suggests that AD brain pathology may be triggered by microbial infection, and that the diagnostic protein deposits in AD brain represent an antimicrobial defense mechanism. This raises the prospect of protection against AD through stimulation of the immune system. Specifically, non-specific activation through 'trained immunity' or 'immunopotentiation' is now known to offer protection against unrelated pathogens as well as against diverse diseases. Earlier findings that vaccine recipients are at reduced risk of developing AD have now been replicated around the world. Protection has been reported for diverse types of vaccines, and the effect sizes are clinically meaningful. Although these studies are predominantly observational, and are thus at risk of confounders such as 'healthy vaccinee' bias, several studies based on 'natural experiments' avoid this bias and provide stronger evidence that vaccine administration can reduce dementia risk. Most such vaccines can be obtained for a few dollars, although others are a little more expensive. But the cost of vaccination is entirely trivial compared to the financial burden of AD. Both clinical trials of immunopotentiation in AD and further research into the underlying mechanisms will be essential. This Position Statement briefly summarizes current knowledge and recommends that immune boosting should be placed at the top of the AD public health R&D agenda.},
}

@article {pmid42808493,
year = {2026},
author = {Lin, X and Honardoost, MA and Ahern, S and Taylor, C and Ward, S and de Laguiche, E and Adesanya, E and Brodaty, H and Pearson-Stuttard, J and Holloway, S and Woodward, M},
title = {Rural-urban disparities in the clinical diagnostic pathway of patients with all-cause mild cognitive impairment and dementia due to Alzheimer's disease in Australia.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261489828},
doi = {10.1177/13872877261489828},
pmid = {42808493},
issn = {1875-8908},
abstract = {BackgroundAccess to high-quality and timely dementia diagnoses varies between rural and urban location.ObjectiveWe examined rural-urban disparities in key indicators for high-quality and timely diagnoses of mild cognitive impairment (MCI) and Alzheimer's disease (AD) dementia in Australia.Methods3648 patients with all-cause MCI or AD dementia were geographically classified into major cities (75.7%), inner (15.8%) and outer (8.4%) regional areas. We used regression analyses to assess rural-urban disparities in completion of key diagnostic investigations and diagnostic wait times.ResultsParticipants in inner regional areas were more likely (odds ratio [OR] = 1.55; 95% confidence interval [CI] = 1.14, 2.13; p = 0.006) to have had more basic diagnostic investigations completed (including core blood tests, cognitive assessments, functional assessments, structural neuroimaging) compared to those in major cities. However, participants in inner regional (OR = 0.37; 95% CI = 0.28, 0.48; p < 0.001) and outer regional (OR = 0.32; 95% CI = 0.21, 0.48; p < 0.001) areas were less likely to have functional neuroimaging completed. Median wait times for an initial appointment following referral to a memory clinic were up to 28 days longer for rural compared to urban participants (Inner regional: Beta (median) = 12.91; 95% CI = 5.15, 20.69; p = 0.001; Outer regional: Beta (median) = 27.50; 95% CI = 18.80, 36.20; p < 0.001), whereas median wait times from initial appointment to diagnosis were up to 47 days shorter in rural compared to urban residents (Inner regional: Beta (median) = -46.83; 95% CI = -52.35, -41.32; p < 0.001; Outer regional: Beta (median) = -44.42; 95% CI = -50.35, -38.49; p < 0.001).ConclusionsFindings suggest disparities in access to advanced diagnostic investigations and timely initial appointments in rural Australia, and increased need for enhanced workforce and diagnostic infrastructure in these areas.},
}

@article {pmid42808495,
year = {2026},
author = {Yu, L and Deng, H and Yang, M and Jiang, DS and Liao, C and Sun, D and Song, J and Luo, H and Liu, W and Wang, X},
title = {Accelerated biological aging in the association between early-life tobacco smoke exposure and dementia risk: An exploratory mediation analysis.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261492699},
doi = {10.1177/13872877261492699},
pmid = {42808495},
issn = {1875-8908},
abstract = {BackgroundEarly-life tobacco smoke exposure, including maternal smoking during gestation and smoking during childhood or adolescence, may have long-term health consequences, but its association with dementia remains uncertain.ObjectiveTo examine the associations of prenatal tobacco smoke exposure and childhood/adolescence smoking with incident dementia and to explore whether biological-age acceleration represents a potential intermediate component of these associations.MethodsWe conducted a prospective cohort study of 285,009 dementia-free participants from the UK Biobank. Biological aging was assessed using Klemera-Doubal method biological age acceleration (KDM-BA) and phenotypic age acceleration (PhenoAge). Cox proportional hazards models estimated hazard ratios (HRs) for incident dementia, and exploratory mediation analyses evaluated model-based indirect components through biological-age acceleration.ResultsDuring a mean follow-up of 13.67 years, 4621 incident dementia cases were documented. Prenatal tobacco smoke exposure (HR = 1.094, 95% CI 1.025-1.168) and childhood/adolescence smoking (HR = 1.187, 95% CI 1.106-1.275) were associated with higher dementia hazards. The corresponding standardized 10-year absolute risk differences were 0.063 and 0.124 percentage points. For childhood/adolescence smoking, the combined indirect effect through KDM-BA and PhenoAge acceleration was small (HR = 1.0062, 95% CI 1.0002-1.0125), with an estimated mediated proportion of 3.63% (95% CI 0.11%-8.77%).ConclusionsEarly-life tobacco smoke exposure was associated with modestly higher hazards of incident dementia. Exploratory mediation analyses identified a small estimated indirect component through biological-age acceleration for childhood/adolescence smoking.},
}

@article {pmid42808496,
year = {2026},
author = {Park, BY and Jo, SW and Park, TY and Kim, H and Kim, MS and Kang, SY and Cho, SJ and Kim, J and Kim, S},
title = {Feasibility and safety of repeated low-intensity ultrasound in amyloid PET-positive early Alzheimer's disease: A prospective pilot study.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261493067},
doi = {10.1177/13872877261493067},
pmid = {42808496},
issn = {1875-8908},
abstract = {BackgroundLow-intensity ultrasound (LIUS) is a potential noninvasive neuromodulatory approach for Alzheimer's disease (AD), but clinical evidence on repeated stimulation in biomarker-confirmed early AD remains limited.ObjectiveTo evaluate the feasibility, safety, and exploratory clinical effects of a 4-week repeated LIUS protocol in amyloid positron emission tomography (PET)-positive early AD.MethodsTwenty patients with amyloid PET-positive prodromal AD or mild AD dementia underwent LIUS targeting bilateral frontal and temporal regions three times weekly for 4 weeks. Safety was assessed by neurological examinations and brain magnetic resonance imaging (MRI). Exploratory outcomes included the Trail Making Test-Black & White (TMT-B&W) parts A and B, Attention Questionnaire Scale (AQS), Korean version of Quality of Life (KQoL), Mini-Mental State Examination (MMSE), and Neuropsychiatric Inventory (NPI). Resting-state functional MRI was analyzed in an exploratory subset.ResultsNo severe adverse events occurred, and post-treatment MRI showed no intracerebral hemorrhage, microbleeding, or brain edema. Completion times decreased on TMT-B&W part A (105.3 ± 63.3 versus 84.2 ± 46.6 s, p = 0.012) and part B (280.1 ± 139.9 versus 212.8 ± 59.7 s, p = 0.038). NPI scores also decreased (9.8 ± 14.7 versus 4.5 ± 8.8, p = 0.006). KQoL, AQS, and MMSE did not change significantly.ConclusionsRepeated LIUS over 4 weeks was feasible and well tolerated in amyloid PET-positive early AD. Exploratory changes in executive function and neuropsychiatric symptoms were observed; however, the single-arm design precludes causal inference. Randomized, sham-controlled studies are warranted to determine the therapeutic potential of LIUS.},
}

@article {pmid42808497,
year = {2026},
author = {Tian, Q and Deng, C and Liao, J and Dai, Y and Lu, T},
title = {Age-frailty status jointly modifies the nonlinear association between systolic blood pressure and annual cognitive aging rate: A community-based cohort study.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261492695},
doi = {10.1177/13872877261492695},
pmid = {42808497},
issn = {1875-8908},
abstract = {BackgroundCognitive impairment (including Alzheimer's disease), frailty, and hypertension are interlinked challenges in older adults. Among non-frail adults, prefrail older adults represent a crucial window for prevention. However, whether systolic blood pressure (SBP) affects cognitive decline differently across age-frailty strata, or what constitutes an optimal age-frailty-stratified target, remains unclear.ObjectiveTo investigate the association of SBP with annual cognitive aging rate in non-frail adults (robust/prefrail, ≥45years), focusing on nonlinearity and modification by age-frailty status, and to explore optimal SBP thresholds, especially in prefrail older adults.MethodsThis longitudinal analysis included 4723 non-frail adults from China Health and Retirement Longitudinal Study (2011-2018). SBP and annual cognitive aging rate (Z-score) were measured, with age and frailty categorized as middle-aged (45-64 years)/older (≥65 years), robust/prefrail. Linear regression and restricted cubic splines assessed associations, with interaction effect tested. Exploratory threshold and piecewise linear regression identified optimal SBP ranges and breakpoints.ResultsBesides linearity, a significant inverted U-shaped relationship existed between SBP and annual global cognition aging rate (p-nonlinear=0.049), with a peak at 120.1 mmHg overall, jointly modified by age-frailty status. A steep, distinct curve with a higher peak (130.8 mmHg; p-nonlinear=0.005) was found in prefrail older adults. The SBP-by-age-frailty nonlinear interaction was significant (p = 0.010) and improved model fit (p = 0.001). Divergent coefficients across breakpoints corroborated the robustness of the nonlinear SBP-cognition association in both populations. Episodic memory analyses showed highly concordant patterns above.ConclusionsTo optimize cognitive aging prevention, personalized SBP targets should be set based on age-frailty status, with relaxed thresholds for vulnerable prefrail older adults.},
}

@article {pmid42808498,
year = {2026},
author = {Simon, KE and Panek, WK and Fefer, G and Mondino, A and Yang, CC and Rafatpanah Baigi, S and Khan, MZ and Case, BC and Griffith, E and Gruen, ME and Olby, NJ},
title = {Aging dogs exhibit heterogeneous cognitive decline trajectories: A longitudinal comparative model.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261487575},
doi = {10.1177/13872877261487575},
pmid = {42808498},
issn = {1875-8908},
abstract = {BackgroundBoth dogs and humans experience substantially variable cognitive decline with age. In humans, this ranges from healthy cognitive aging to early onset Alzheimer's disease. While different rates of cognitive decline have been described in purpose-bred beagles, few studies have examined longitudinal trajectories in companion dogs.ObjectiveThe aim of this study was to describe cognitive changes in a cohort of 92 senior dogs (aged ≥ 8 years).MethodsData were collected on 7 cognitive outcomes (2 caregiver questionnaires and 5 cognitive tests) every 6 months from enrollment to withdrawal/death. A principal components analysis reduced the dimensionality of these outcomes into a single global cognitive score. A mixed effect model was built using this composite score to examine within-subjects cognitive changes, while accounting for chronological age and study participation effects. Finally, a hierarchical cluster analysis identified statistically distinct groups of cognitive trajectories.ResultsAll seven outcomes loaded strongly, with consistent directionality, onto the first principal component (PC1) at each timepoint. Global cognitive score significantly declines with increasing age (β = -0.60, p < 0.0001). Despite a non-significant population-level subject*age interaction (p = 0.14), individual random slopes (rate of change with age) ranged from -0.20 and 0.15, suggesting meaningful variability. Cluster analysis revealed two groups differing in trajectories at the population level and subject level.ConclusionsThese findings provide evidence that while age is a significant predictor of cognitive decline at the population level, individual trajectories vary. The heterogeneity of canine cognitive aging presents an opportunity to investigate the biologic drivers of age-associated cognitive decline.},
}

@article {pmid42808512,
year = {2026},
author = {Weidling, I and Schueddig, E and Wang, X and Novikova, L and Menta, BW and Roberts, A and Ranjan, A and Kemna, R and Morris, JK and Wilkins, HM and Pei, D and Swerdlow, RH},
title = {Chronic mitochondrial DNA depletion alters MAPT splicing and increases tau levels.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261492673},
doi = {10.1177/13872877261492673},
pmid = {42808512},
issn = {1875-8908},
abstract = {BackgroundIn Alzheimer's disease (AD), tau protein aggregates to form neurofibrillary tangles (NFTs). The cellular changes favoring AD brain NFT formation remain incompletely understood. AD brains also display mitochondrial defects, including reduced mitochondrial DNA (mtDNA) copy number.ObjectiveWe considered whether mtDNA depletion alters tau homeostasis.MethodsWe assessed tau mRNA using short-read mRNA sequencing and PCR, and tau protein using immunochemistry, in SH-SY5Y cells with chronic mtDNA depletion (ρ0).ResultsmtDNA depletion increased tau expression and resulted in alternatively spliced isoforms, elevated 4R and exon 4a-containing MAPT transcripts, and consistently detectable big tau protein. ρ0 cells also displayed an elevated MAPT exon 13 3'Untranslated Region (UTR): Coding DNA sequence (CDS) ratio. Phosphorylation at amino acid positions 217 and 181 decreased.ConclusionsMitochondrial dysfunction affects tau expression, splicing, and 3'UTR retention while increasing tau protein levels and modifying its phosphorylation. These studies hold AD relevance as they provide evidence for a relationship between two AD-associated phenomena, defective mitochondrial function and altered MAPT regulation.},
}