@article {pmid42813639,
year = {2026},
author = {Singh, AP and Prajapati, S and Yadav, S and Yadav, A},
title = {Lipid-based Nanocarriers for Neurodegenerative Disorders: Bridging Blood-brain Barrier Biology and Translational Drug Delivery.},
journal = {Current neurovascular research},
volume = {},
number = {},
pages = {},
doi = {10.2174/0115672026478560260909100922},
pmid = {42813639},
issn = {1875-5739},
abstract = {INTRODUCTION: Neurodegenerative disorders, including Alzheimer's, Parkinson's, Huntington's disease, and amyotrophic lateral sclerosis, remain difficult to treat because the Blood-brain Barrier (BBB) severely restricts therapeutic access to the central nervous system. This review evaluates BBB biology and the potential of lipid-based nanocarriers to improve brain-targeted drug delivery and facilitate clinical translation.

METHODS: A structured narrative review of peer-reviewed preclinical and clinical literature published between 2000 and 2025 was conducted using PubMed, Scopus, and Web of Science. Evidence concerning BBB structure and transport mechanisms, lipid-based nanocarrier design, physicochemical characteristics, drug-release behavior, computational modelling, therapeutic applications, and translational challenges was critically synthesized.

RESULTS: Liposomes, nanoemulsions, solid lipid nanoparticles, nanostructured lipid carriers, and lipid-polymer hybrid nanoparticles demonstrated improved drug solubility, stability, controlled release, systemic circulation, and brain targeting. Preclinical evidence indicates enhanced brain bioavailability and therapeutic effects, including reductions in neuroinflammation, oxidative stress, and disease-associated pathological processes. However, clinical translation remains constrained by formulation complexity, scalability, long-term safety, and inconsistent clinical outcomes.

DISCUSSION: Integration of BBB transport biology with surface functionalization, receptormediated targeting, formulation engineering, and computational modelling may enable more rational nanocarrier development. Nevertheless, standardized characterization, reproducible manufacturing, comprehensive safety evaluation, and stronger clinical validation are required to bridge the gap between promising preclinical findings and therapeutic implementation.

CONCLUSION: Lipid-based nanocarriers represent promising platforms for overcoming biological and pharmacokinetic barriers in neurodegenerative disorders. Further optimization and rigorous translational validation are essential to establish their safety, reproducibility, and clinical effectiveness.},
}

@article {pmid42813641,
year = {2026},
author = {Küpeli, E and Mancak, M and Cakirli, E and Bardakci, H and Avci, TB and Ozdemir, S},
title = {Solid and Nanostructured Lipid Carriers for Plant-Derived Neuroprotective Agents: Advances and Future Perspectives.},
journal = {Current pharmaceutical design},
volume = {},
number = {},
pages = {},
doi = {10.2174/0113816128509583260914134550},
pmid = {42813641},
issn = {1873-4286},
abstract = {Neurodegenerative disorders, particularly Alzheimer's disease (AD) and Parkinson's disease (PD), continue to pose a substantial therapeutic challenge, largely due to progressive neuronal degeneration and the limited effectiveness of currently available treatments. Plant-derived bioactive compounds-including polyphenols, alkaloids, terpenoids, and flavonoids-have shown notable neuroprotective properties. However, their clinical use remains constrained by low bioavailability and limited ability to cross the blood-brain barrier (BBB). Lipid-based nanocarrier systems, especially solid lipid nanoparticles (SLNs) and nanostructured lipid carriers (NLCs), have emerged as promising alternatives for improving delivery efficiency. This review evaluates recent advances in SLN and NLC formulations developed for phytochemical delivery in neurodegenerative conditions, focusing on formulation approaches, production methods, and the physicochemical factors that govern system performance. Preclinical findings consistently indicate enhanced solubility, improved stability, and more effective brain targeting with these systems. Even so, several challenges continue to impede their clinical translation. In particular, issues related to formulation reproducibility, scalability of production, and long-term safety remain unresolved. Alternative administration routes such as intranasal delivery offer a potential strategy to bypass the BBB, although their practical feasibility still requires further confirmation. SLN- and NLC-based systems offer a promising approach, although their clinical development is still ongoing. Future efforts should focus on establishing standardized formulation protocols, conducting rigorous in vivo studies, and ensuring alignment with regulatory requirements to facilitate successful clinical translation.},
}

@article {pmid42813688,
year = {2026},
author = {Yu, H and Chang, W and Mahmut, D and Huang, C and Zhang, B},
title = {Integrative transcriptomic and regulatory network analysis reveals associations of seven proposed risk genes with immune-related molecular features in Alzheimer's disease.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261493169},
doi = {10.1177/13872877261493169},
pmid = {42813688},
issn = {1875-8908},
abstract = {BackgroundAlzheimer's disease (AD) involves neuroinflammation influenced by genetic and immune dysregulation. Seven proposed AD risk genes (CACNA2D3, EPB41L2, INPP5D, MYO1F, RBM47, SSH2, TBXAS1) have been identified, but their associations with the immune microenvironment (IME) remain unclear.ObjectiveThis study investigates associations between these genes and the neuroimmune landscape in AD.MethodsIntegrative transcriptomic and regulatory network analysis was performed using the GSE53697 dataset (9 AD and 8 control samples) from the GEO. Immune cell enrichment scores and pathway activity were evaluated using single-sample Gene Set Enrichment Analysis (ssGSEA), and enriched pathways were identified through Gene Set Enrichment Analysis (GSEA). Upstream regulatory associations were explored by constructing miRNA-mRNA and transcription factor regulatory networks, and correlations between the risk genes and established AD-related genes were assessed using public databases.ResultsAD samples showed immune dysregulation, including reduced dendritic cell ssGSEA scores. All seven risk genes correlated with immune cell subsets and immunomodulatory molecules. Enrichment analysis revealed inflammatory pathways including NF-κB, IL-17, TNF, MAPK, and Notch, suggesting potential links to neuroinflammation and neuronal signaling disruption. Upstream analysis identified 85 miRNAs and several transcription factor motifs annotated to HOXA13, ESRRA, and SNAI1/2/3. Correlation analysis further revealed associations between risk genes and AD-related genes, placing these genes within established AD pathological networks in an exploratory manner.ConclusionsThis exploratory study provides insights into how AD risk genes are associated with the IME and may be linked to neuroinflammatory pathways and neuronal function, providing hypotheses for future studies of immune-genetic crosstalk in AD pathogenesis.},
}

@article {pmid42813805,
year = {2026},
author = {Feng, J and Nanshan, M and Shi, H and Wong, KY and Lam, KF and Cao, J},
title = {A regularized semiparametric cure-rate model with high-dimensional imaging data.},
journal = {Statistical methods in medical research},
volume = {},
number = {},
pages = {9622802261483498},
doi = {10.1177/09622802261483498},
pmid = {42813805},
issn = {1477-0334},
abstract = {Structural magnetic resonance imaging (MRI) is informative for studying progression from mild cognitive impairment (MCI) to Alzheimer's disease (AD), but incorporating high-dimensional images into survival models requires methods that accommodate irregular brain domains and yield interpretable spatial effects. We propose a regularized semiparametric mixture cure-rate model for high-dimensional imaging predictors that separates susceptibility to AD conversion from time to AD among susceptible subjects. Baseline MRI images are represented by bivariate Bernstein spline basis functions over a triangulation of the brain domain, and sparsity-inducing penalties are imposed on imaging effects in both incidence and latency components. This construction enables direct estimation of localized coefficient functions describing how image regions are associated with susceptibility and conversion time. We develop an expectation-maximization algorithm that updates latent susceptibility probabilities and solves penalized logistic and Cox regression subproblems, together with an efficient tuning strategy. Simulations show that the method can recover localized active regions and provide useful incidence and latency discrimination. An application to Alzheimer's Disease Neuroimaging Initiative data demonstrates susceptibility discrimination and interpretable brain-region coefficient maps.},
}

@article {pmid42814409,
year = {2026},
author = {Huang, S and Zhang, Z and Xia, J and Deng, M and Chen, F and Wang, M and Fei, Y and Jiang, Z and Lu, C and Fu, J and Guo, J and Zhou, H},
title = {ZBP1-mediated Treg cell dysfunction exacerbates neuroimmune dysregulation in Alzheimer's disease under metabolic stress.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {10},
pages = {e71896},
pmid = {42814409},
issn = {1552-5279},
support = {81871098//the National Science Foundation of China/ ; 81671392//the National Science Foundation of China/ ; 2021YFE0111800//National Key R&D Program of China/ ; ZY [2021-2023]-0207-01//National Key R&D Program of China/ ; shslczdzk02802//National Key R&D Program of China/ ; 2018SHZDZX01//National Key R&D Program of China/ ; },
mesh = {Animals ; *Alzheimer Disease/immunology/metabolism ; *T-Lymphocytes, Regulatory/immunology/metabolism ; Mice ; *Stress, Physiological/immunology ; *DNA-Binding Proteins/metabolism ; Humans ; *Neuroimmunomodulation ; Male ; Mice, Transgenic ; Disease Models, Animal ; Diet, High-Fat ; Brain/metabolism ; Female ; *RNA-Binding Proteins/metabolism ; },
abstract = {INTRODUCTION: Metabolic stress increases Alzheimer's disease (AD) risk, but mechanisms linking metabolic dysfunction to neuroimmune dysregulation remain unclear.

METHODS: We assessed cognition in community-dwelling participants and used high-fat diet (HFD)-fed 5xFAD mice, high glucose and high palmitate (HGHP)-treated regulatory T cell (Treg) co-cultures, and adoptive Treg transfer to evaluate metabolic stress-associated neuroimmune dysfunction. Flow cytometry, RNA sequencing, positron emission tomography computed tomography, and electrophysiology assessed Treg function, AD pathology, cerebral metabolism, and synaptic plasticity.

RESULTS: Metabolic stress impaired Treg stability and function, accompanied by increased Z-DNA-binding protein 1 (ZBP1) expression and activation of apoptotic and necroptotic signaling. Treg dysfunction was associated with enhanced glial activation and neuronal injury. Under HGHP stress, ZBP1-deficient Tregs showed improved survival and stronger immunosuppressive activity, more effectively limiting glial activation and preserving neuronal integrity. In vivo, ZBP1-deficient Treg transfer conferred greater neuroprotection than wild-type Treg transfer in HFD-fed AD mice.

DISCUSSION: ZBP1 may contribute to metabolic stress-induced Treg dysfunction and represent a candidate target to improve Treg-based therapy in HFD-fed AD mice.},
}

Animals
*Alzheimer Disease/immunology/metabolism
*T-Lymphocytes, Regulatory/immunology/metabolism
Mice
*Stress, Physiological/immunology
*DNA-Binding Proteins/metabolism
Humans
*Neuroimmunomodulation
Male
Mice, Transgenic
Disease Models, Animal
Diet, High-Fat
Brain/metabolism
Female
*RNA-Binding Proteins/metabolism

@article {pmid42814513,
year = {2026},
author = {Jia, H and Wu, S and Xue, X and Li, Z and Li, L and He, H and Wang, Q and Gao, H and Wen, C},
title = {A review on diffusion tensor imaging-based comprehensive intelligent diagnosis of Alzheimer's disease.},
journal = {Reviews in the neurosciences},
volume = {},
number = {},
pages = {},
pmid = {42814513},
issn = {2191-0200},
abstract = {AI-assisted early diagnosis of Alzheimer's disease (AD) has substantial clinical value, and diffusion tensor imaging (DTI), which captures white matter microstructural alterations, has considerable potential across the AD continuum. However, major barriers to clinical translation remain. This review systematically evaluated the evolution of algorithmic paradigms, the effectiveness of multimodal fusion, and barriers to clinical generalization in DTI-based AD diagnosis. Using an "Input-Model-Fusion" evaluation framework, we analyzed 98 studies published from 2010 to 2026 and compared sample size, diagnostic task, validation design, and methodological quality. Four findings emerged. 1) Modality selection should be task-driven; single-modality DTI and multimodal fusion have different applicability across diagnostic tasks. 2) Algorithm choice was closely related to sample size: conventional machine learning, particularly support vector machines, predominated in small-sample studies, whereas deep learning architectures, including convolutional neural networks, graph convolutional networks, and Transformers, were more widely used with large datasets. 3) Substantial performance degradation in multicenter or external validation highlighted persistent limitations in clinical generalizability. Data source, sample representativeness, feature processing, validation strategy, acquisition protocol, and software pipeline heterogeneity remain important constraints on clinical translation and cross-study comparability of DTI metrics. 4) Hippocampal pathways, the corpus callosum, fornix, and cingulum showed relatively stable discriminative value. Future research should move beyond "algorithm accuracy competition" toward clinical pragmatism by prioritizing task alignment, standardized DTI acquisition and processing, external validation, and neurobiological interpretability.},
}

@article {pmid42814589,
year = {2026},
author = {Singh, L and Gupta, GD and Singh, S},
title = {Neurobehavioral and Molecular Rescue by Dapagliflozin in Aluminum Chloride-Induced Alzheimer's Model: Possible Relevance of NF-κB and Aβ(1-42).},
journal = {Assay and drug development technologies},
volume = {},
number = {},
pages = {1540658X261486541},
doi = {10.1177/1540658X261486541},
pmid = {42814589},
issn = {1557-8127},
abstract = {Alzheimer's disease (AD), a progressive neurodegenerative disorder, characterized by the deposition of amyloid-β plaques in the hippocampus, leading to cognitive and behavioral impairments. This study investigated the neuroprotective outcome of Dapagliflozin (DAPA), a sodium-glucose cotransporter 2 inhibitor primarily used for glycemic control, which also exhibits notable anti-inflammatory, antioxidant, and neuroprotective properties. Using an aluminum chloride (AlCl3)-induced rat model of AD, the research evaluates behavioral, biochemical, and neuroinflammatory changes, particularly focusing on the nuclear factor kappa-B protein (NF-κB) signaling pathway. Rats were orally administered AlCl3 to induce AD-like pathology, followed by DAPA treatment (1 and 2 mg/kg, p.o.) over a 28-day period. Behavioral assessments, including the Morris water maze and Elevated Plus Maze, were used to evaluate spatial memory and anxiety. On day 29, hippocampal tissues were collected to assess neurotransmitter levels, oxidative stress markers (LPO, GSH, nitrite), and inflammatory cytokines (interleukin-1 beta, interleukin-6), along with the expression of NF-κB. AlCl3 exposure led to significant alterations in neurotransmitter balance (AChE, GABA, and glutamate), heightened oxidative stress, and increased neuroinflammatory responses. DAPA treatment significantly mitigated these changes, notably downregulating NF-κB, which correlated with decreased amyloid beta and expression in the hippocampus. These findings suggest that beyond its antidiabetic action, DAPA offers promising neuroprotection against AlCl3-induced neurotoxicity, potentially via modulation of the NF-κB signaling pathway.},
}

@article {pmid42814649,
year = {2026},
author = {Liguori, C and Carpi, M},
title = {The orexinergic system in Alzheimer's disease: from sleep disruption to accelerated neurodegeneration.},
journal = {European neurology},
volume = {},
number = {},
pages = {1},
doi = {10.1159/ene/acsag009},
pmid = {42814649},
issn = {1421-9913},
abstract = {BACKGROUND: Sleep-wake dysregulation is increasingly recognized as an early and clinically relevant feature of Alzheimer's disease (AD), with growing evidence supporting a bidirectional relationship between disturbed sleep and AD pathophysiology. Sleep fragmentation, reduced slow-wave and REM sleep may contribute to amyloid-β (Aβ) accumulation by increasing Aβ production during wakefulness and diminishing glymphatic clearance during sleep, while emerging amyloid pathology can further disrupt sleep architecture and circadian sleep-wake rhythm, reinforcing a feed-forward cycle.

SUMMARY: Within this framework, the orexinergic system, centered in the hypothalamus and crucial for arousal and sleep-wake stability, has been implicated as a mechanistic link between hyperarousal, impaired sleep consolidation, and altered amyloid dynamics. Preclinical studies suggested that orexin-A signaling can exacerbate Aβ and tau pathology and impair synaptic function, whereas biomarker studies reported high cerebrospinal fluid orexin-A levels in mild cognitive impairment and dementia due to AD. These observations raise the hypothesis that targeting orexin signaling and improving sleep may represent actionable strategies within the AD continuum.

KEY MESSAGES: Clinical evidence indicates that behavioral and pharmacological interventions can improve sleep in at-risk populations, yet robust proof of disease-modifying effects on AD biomarkers or clinical progression remains limited. Ongoing trials of dual orexin receptor antagonists may clarify whether sustained modulation of sleep-wake regulation can influence AD-related biology beyond symptomatic sleep benefits.},
}

@article {pmid42814823,
year = {2026},
author = {Hernandez, H and Pedraza, LK and Santamaria-Garcia, H and Moguilner, S and Legaz, A and Prado, P and Cuadros, J and Amoruso, L and Gonzalez, L and Dellavale, D and Espinoza-Puelles, JP and Espinosa, JP and Jarne, C and Mattiussi, F and Caccia, M and Welford, AS and Pelella, N and Inchauspe, J and Ferrante, FJ and Pérez, G and Maito, MA and Rocatti, G and Godoy, ME and Migeot, J and Orellana, P and Caviedes, A and Bruno, M and Takada, L and Slachevsky, A and Behrens, MI and Bruna, B and Aguillon, D and Zapata, L and Avila-Funes, JA and Custodio, N and Miller, B and Gorno-Tempini, ML and Escudero, SP and Reyes, P and Hu, K and de Oliveira, MO and Coronel-Oliveros, C and Cruzat, J and Cardona, JF and Corley, M and Meier, IB and Narayan, VA and Tagliazucchi, E and Baez, S and Duran-Aniotz, C and García, AM and Ibanez, A},
title = {Speech clocks decode dementia phenotypes, social exposome, and biological aging.},
journal = {Science advances},
volume = {12},
number = {40},
pages = {eaef9864},
pmid = {42814823},
issn = {2375-2548},
mesh = {Humans ; *Aging/physiology ; Female ; Phenotype ; *Speech/physiology ; Alzheimer Disease/physiopathology ; Male ; *Dementia/physiopathology/diagnosis ; Aged ; *Frontotemporal Dementia/physiopathology ; Cognitive Dysfunction/physiopathology ; },
abstract = {Biological aging clocks offer estimations of aging and dementia, yet scalability is limited. We introduce a large-scale, cross-national speech clock derived from 2928 individuals across five Latin American countries, spanning healthy controls (HCs), mild cognitive impairment (MCI), Alzheimer's disease (AD), and non-language/language-dominant frontotemporal dementia (nldFTD/ldFTD). Multimodal acoustic and linguistic features were trained with supervised models to estimate chronological age, generating speech age gaps (SAGs) as cross-sectional markers of deviations from chronological age, with positive values interpreted as relatively older-appearing speech profiles. SAGs differentiated diagnostic groups (HCs < patient groups, with AD < nldFTD < ldFTD). This pattern was associated with clinical/cognitive domains. SAGs correlated with phosphorylated tau (p-Tau217) in AD and social exposome in HCs and AD. Brain clocks (structural/functional/combined) were associated with SAG in AD, nldFTD, and ldFTD. Epigenetic age correlated with SAGs in HCs and AD across Hannum, Retroclock, and OMICmAge, whereas ldFTD associations were limited to Retroclock and OMICmAge. These results indicate that SAGs capture cross-sectional multilevel aging-related variation and may offer a scalable, culturally adaptable, low-cost biomarker candidate for research in underrepresented global settings.},
}

Humans
*Aging/physiology
Female
Phenotype
*Speech/physiology
Alzheimer Disease/physiopathology
Male
*Dementia/physiopathology/diagnosis
Aged
*Frontotemporal Dementia/physiopathology
Cognitive Dysfunction/physiopathology

@article {pmid42814956,
year = {2026},
author = {Lu, S and Hu, S and Huang, J and Shi, Y and Yu, D and Cao, W and Yin, M and Petersen, JD and Huang, B},
title = {Electroencephalography in Subjective Cognitive Decline and Mild Cognitive Impairment: Systematic Review of Biomarkers, Classification, and Prognostic Evidence.},
journal = {Journal of medical Internet research},
volume = {28},
number = {},
pages = {e92709},
pmid = {42814956},
issn = {1438-8871},
mesh = {Humans ; *Biomarkers ; *Cognitive Dysfunction/diagnosis/classification/physiopathology ; Disease Progression ; *Electroencephalography ; Prognosis ; },
abstract = {BACKGROUND: Subjective cognitive decline (SCD) and mild cognitive impairment (MCI) are heterogeneous clinical states that may represent early or at-risk stages of Alzheimer disease (AD) and other dementias in some individuals. Improved characterization and risk stratification in these populations may facilitate timely evaluation and intervention. Electroencephalography (EEG), a noninvasive, cost-effective neurophysiological technique with high temporal resolution, holds significant potential for elucidating neural mechanisms and providing candidate neurophysiological markers associated with SCD and MCI.

OBJECTIVE: The study aims to systematically synthesize evidence on group-level EEG biomarkers, EEG-based classification models, the evaluation of EEG in screening or diagnostic pathways, and EEG-based prediction of progression in SCD and MCI.

METHODS: A search was conducted across PubMed, Web of Science, Cochrane Library, MEDLINE (via Ovid), Scopus, Wanfang Data, CQVIP, Yiigle, and CNKI databases to include reports published in English or Chinese, which reported group-level EEG differences, EEG-based classification, screening or diagnostic evaluations, or prognostic outcomes in SCD and MCI. A total of 2 independent reviewers screened the titles and abstracts. Prediction-model reports were assessed using PROBAST+AI (Prediction Model Risk of Bias Assessment Tool and Applicability Assessment for AI), prognostic-factor reports using QUIPS (Quality in Prognosis Studies), and other observational reports using design-specific Joanna Briggs Institute checklists. Certainty of evidence was assessed using the GRADE (Grading of Recommendations Assessment, Development, and Evaluation) system.

RESULTS: A total of 20 reports were included, representing a maximum of 3853 confirmed-deduplicated participants after correction of a nested subsample and removal of confirmed duplicate participants across reports, of whom 2927 diagnosed with SCD/MCI/AD or other dementias. Of these, 10 reports were assessed as prediction or AI model reports, 9 as nondiagnostic observational reports, and 1 as a prognostic-factor study. Although potentially informative between-group EEG differences and preliminary model performance were reported, no conventional diagnostic test-accuracy study was identified. The certainty of evidence was very low across all 4 evidence bodies.

CONCLUSIONS: The available evidence suggests that EEG is a promising noninvasive modality for characterizing neurophysiological alterations associated with SCD and MCI. EEG-based classification and prognostic models have also shown encouraging preliminary performance. However, the current evidence is more supportive of biomarker discovery and model development than of established clinical screening or diagnosis. Translation into routine practice will require prospective reports with standardized EEG procedures, representative clinical populations, prespecified thresholds, participant-level data separation, and independent external validation. These findings provide a basis for evaluating EEG as a potential adjunctive or triage tool in future clinical pathways.},
}

Humans
*Biomarkers
*Cognitive Dysfunction/diagnosis/classification/physiopathology
Disease Progression
*Electroencephalography
Prognosis

@article {pmid42815043,
year = {2026},
author = {Shahbaz, S and Shahbaz, MH and Fatima, R and Mansoor, MH and Kharal, M and Bashir, M and Ul Abideen, Z and Nadeem, MS},
title = {Trends in mortality of Alzheimer's disease with comorbid hypertension in patients in the US from 1999-2020.},
journal = {Neurodegenerative disease management},
volume = {},
number = {},
pages = {1-12},
doi = {10.1080/17582024.2026.2739337},
pmid = {42815043},
issn = {1758-2032},
abstract = {AIMS: To examine temporal trends and demographic disparities in Alzheimer's disease (AD)-related mortality among adults aged ≥ 65 years with comorbid hypertension in the United States from 1999 to 2020.

MATERIALS AND METHODS: We conducted a population-based retrospective analysis using the Centers for Disease Control and Prevention Wide-ranging Online Data for Epidemiologic Research (CDC WONDER) Multiple Cause of Death database. Deaths involving AD (ICD-10 G30) and hypertension (ICD-10 I10-I15) were identified. Age-adjusted mortality rates (AAMRs) were assessed by sex, race/ethnicity, geographic region, urbanization level, and state. Temporal trends were evaluated using Joinpoint regression.

RESULTS: Between 1999 and 2020, 409,112 deaths involving AD and hypertension were recorded. The overall AAMR increased from 14.51 per 100,000 in 1999 to 69.06 in 2020, with a decline from 2007 to 2014 followed by an increase through 2020. Females had higher AAMRs than males, and non-Hispanic Black individuals had the highest AAMR among the racial and ethnic groups examined.

CONCLUSIONS: AD-related mortality among older adults with comorbid hypertension increased substantially during the study period, with notable demographic and geographic disparities.},
}

@article {pmid42815078,
year = {2026},
author = {Cho, Y and Dictus, C and Chan, YN and Teng, CH and Shieu, B and Wang, J and Crowder, V and Plassman, BL and Beeber, A and Bryant, AL and Wu, B and Anderson, RA},
title = {A qualitative comparison of care partner experiences supporting self-care of people living with mild cognitive impairment versus mild dementia: Insights from an oral hygiene intervention.},
journal = {Geriatric nursing (New York, N.Y.)},
volume = {74},
number = {Pt A},
pages = {104360},
doi = {10.1016/j.gerinurse.2026.104360},
pmid = {42815078},
issn = {1528-3984},
abstract = {PURPOSE/AIMS: Care partners play a crucial role in supporting people living with mild cognitive impairment (PLwMCI) and mild dementia (PLwMD) in daily tasks and health behaviors. Care partners' experiences may vary depending on the care recipient's degree of cognitive decline. Our objective was to compare the challenges and strategies of care partners supporting PLwMCI versus PLwMD.

METHODS: Guided by the Adaptive Leadership Framework for Chronic Illness, we conducted a qualitative directed content analysis of secondary data from audio recordings of coaching sessions led by a nurse in a pilot of an oral hygiene intervention designed to teach care partners skills to lead behavior change in PLwMCI and PLwMD.

RESULTS: Notable differences included that care partners of PLwMCI expressed concerns about future cognitive decline and engaged in more equal and collaborative communication. In contrast, care partners of PLwMD experienced greater distress when balancing the PLwMD's autonomy with the efficiency of care, and used more tactile cues and directive communication to facilitate new routines.

CONCLUSIONS/IMPLICATIONS: These findings suggest that tailoring interventions to the level of cognitive impairment may enhance the care partners' effectiveness in supporting health behavior change for PLwMCI and PLwMD.},
}

@article {pmid42815425,
year = {2026},
author = {Mohamed, M and Koubeisi, MW and Aljuaid, F and Alosman, K},
title = {CausalEvidentialFuse: A unified framework for trustworthy multimodal clinical data fusion in healthcare diagnosis.},
journal = {Computer methods and programs in biomedicine},
volume = {288},
number = {},
pages = {109647},
doi = {10.1016/j.cmpb.2026.109647},
pmid = {42815425},
issn = {1872-7565},
abstract = {BACKGROUND AND OBJECTIVE: Radiomics, the high-throughput extraction of quantitative imaging features from medical images, has transformed healthcare diagnosis by enabling the integration of heterogeneous clinical data sources such as electronic health records and medical imaging. However, existing multimodal fusion approaches suffer from critical trustworthiness limitations, including susceptibility to spurious cross-modal correlations, inadequate uncertainty quantification, and limited interpretability. These shortcomings impede clinical translation, where reliable and transparent predictions are essential. This study aims to develop a unified framework that simultaneously addresses causal robustness, uncertainty calibration, and clinical interpretability in multimodal clinical data fusion. To reflect the heterogeneous modality coverage of the four benchmark datasets used in this study-MIMIC-IV and eICU (structured EHR only), MIMICCXR (chest radiograph imaging plus radiomic features), and ADNI (MRI-derived radiomic features, cognitive scores, and APOE genotype)-we frame the framework as general multimodal clinical data fusion, with the radiomics-clinical fusion setting evaluated on the imaging-bearing cohorts (MIMICCXR and ADNI) and the genomic setting represented by the single APOE marker in ADNI.

METHODS: We propose CausalEvidentialFuse, comprising three synergistic components. First, a Cross-Modal Causal Attention module leverages structural causal models and do-calculus to disentangle genuine cross-modal relationships from confounding factors including scanner variability and demographic biases. Second, an Uncertainty-Aware Evidential Fusion module, built upon Dempster-Shafer evidence theory, quantifies both aleatoric and epistemic uncertainty using Dirichlet evidence distributions. Third, a Clinical Knowledge Graph-Guided Feedback (CKGF) mechanism incorporates domain knowledge from clinical knowledge graphs (SNOMED CT and ICD-10) to regularize predictions; this module does not involve direct clinician participation, prospective clinician feedback, or explicit clinical guideline supervision, and the previous term "Clinical Knowledge Graph-Guided Feedback (CKGF)" (CKGF) has therefore been revised throughout the manuscript to CKGF. The framework was evaluated on four large-scale, de-identified, publicly available benchmark datasets spanning diverse clinical domains: Medical Information Mart for Intensive Care (version IV), its Chest X-Ray collection, the Alzheimer's Disease Neuroimaging Initiative, and the electronic Intensive Care Unit Collaborative Research Database.

RESULTS: CausalEvidentialFuse achieved the highest area under the receiver operating characteristic curve across all four datasets, with an average improvement of 2.5 percentage points (2.9% relative) over the best-performing baseline (EvidentialDL; mean AUC 0.899vs 0.874). The framework attained the lowest Expected Calibration Error of 0.031, indicating substantially better-calibrated uncertainty (a 35.4% relative reduction compared with EvidentialDL's ECE of 0.048, and a 54.4% reduction compared with the best non-evidential baseline MCAGN's ECE of 0.068). Epistemic uncertainty was reduced by 34.2% relative to baseline methods. Cross-dataset generalization demonstrated a performance retention rate of 91.8% (compared with 88.5% for the second-best method, EvidentialDL), and retrospective clinical validation confirmed clinically meaningful sensitivity and specificity across all diagnostic tasks. Inference time remained at 23 milliseconds, within clinical decision support requirements.

CONCLUSIONS: CausalEvidentialFuse establishes a new standard for trustworthy multimodal healthcare diagnosis by integrating causal reasoning, evidential uncertainty quantification, and clinical knowledge guidance within a single unified framework. The results demonstrate that addressing multiple trustworthiness dimensions simultaneously yields complementary benefits-the causal module, evidential fusion module, and knowledge-guided feedback each contribute partially independent improvements that combine favorably-achieving superior diagnostic accuracy while providing the calibrated uncertainty estimates and interpretable reasoning chains required for confident clinical adoption.},
}

@article {pmid42815436,
year = {2026},
author = {Maitri, SN and Chakre, RR},
title = {Mask attention layer modified residual vision transformer with transfer learning based features extraction for Alzheimer disease classification.},
journal = {Psychiatry research. Neuroimaging},
volume = {364},
number = {},
pages = {112341},
doi = {10.1016/j.pscychresns.2026.112341},
pmid = {42815436},
issn = {1872-7506},
abstract = {AD is an advanced neurodegenerative condition that requires precise and prompt examination for clinical involvement. Many deep learning (DL) algorithms for AD classification are computationally complex and unsuitable for real-time clinical applications. Hence, this study proposes a Mask Attention Layer Modified Residual Vision Transformer (MRViT) combined with transfer learning and Hiking Troops Optimization (HkTO) for effectual MRI-based AD classification. MRI images are gathered from the Open Access Series of Imaging Studies (OASIS) and the AD Neuroimaging (ADNI) dataset. Primarily, a Modified Pixel Gaussian filter is applied to eradicate noise and improve image quality. Afterward, deep features are extracted using transfer learning models, namely InceptionResNetV2, DenseEfficientNet-B3, and ConvoGoogleNet, to attain discriminative feature representations. The extracted features are then optimized using the HkTO algorithm to select the most relevant and non-redundant features, thereby dropping feature dimensionality. Also, HkTO is used to optimize the hyperparameters of the proposed MRViT classifier, refining classification accuracy and model robustness. Lastly, the certain optimal features are classified using the proposed MRViT architecture, including a mask attention mechanism to highlight disease-relevant regions while suppressing irrelevant information. Testing on the OASIS and ADNI datasets shows classification accuracies of 99.66 % and 99.89 %, proving the framework's precision and computational efficiency.},
}

@article {pmid42815452,
year = {2026},
author = {Oltra-Cucarella, J and Bonete-López, B and Iñesta, C and Guillén-Torrano, D and Ripoll, O and Obodo-Arroyo, CO and Pérez-Elvira, R and Wöbbeking, D and Sánchez-Sansegundo, M and Tomé, M and Freilich, B and Abellán-Miralles, I and Pérez-Carmona, N and Ruiz-Piñero, M and Sitges-Maciá, E},
title = {Sensitivity and specificity of the attention, memory, and frontal abilities screening test to identify objective cognitive impairment in older adults: a pilot study.},
journal = {Archives of clinical neuropsychology : the official journal of the National Academy of Neuropsychologists},
volume = {41},
number = {7},
pages = {},
doi = {10.1093/arclin/acag075},
pmid = {42815452},
issn = {1873-5843},
support = {GV/2021/139//Conselleria Innovación, Universidades, Ciencia i Sociedad Digital, Generalitat Valenciana/ ; CIGE/2023/29//Conselleria Innovación, Universidades, Ciencia i Sociedad Digital, Generalitat Valenciana/ ; },
mesh = {Humans ; Pilot Projects ; Female ; Aged ; Male ; *Neuropsychological Tests ; *Cognitive Dysfunction/diagnosis ; Sensitivity and Specificity ; Middle Aged ; *Attention/physiology ; *Memory/physiology ; Aged, 80 and over ; ROC Curve ; },
abstract = {OBJECTIVE: The use of screening tests is part of the neuropsychological assessment. Recently, the Attention, Memory and Frontal Abilities Screening Test (AMFAST) has been developed and translated to Spanish. However, its diagnostic properties have never been compared to other tests used to identify cognitive impairment. The goal of this pilot study is to compare the diagnostic properties of the AMFAST with those of the Consortium to Establish a Registry for Alzheimer's Disease (CERAD)-Neuropsychological Battery (CERAD-NB) in their ability to distinguish pre-defined clinical groups in a heterogeneous clinical sample of Spanish older adults.

METHODS: Ninety-four participants (66 cognitively unimpaired - CU; 28 cognitively impaired - CI) aged 50 or older were assessed with the AMFAST and the CERAD-NB, and differences between groups were analyzed with beta-binomial models. The diagnostic properties of both tests were calculated with adjusted-ROC curves, and areas under the curve (AUCs) were compared.

RESULTS: The CU group outperformed the CI group both on the AMFAST (b = -1.67, std. error (SE) = 0.19, p < .001) and on the CERAD-NB (b = -1.02, SE = 0.12, p < .001). The adjusted-ROC curves showed no differences in sensitivity and specificity compared to the model with test scores only, neither for the AMFAST (z = -1.03, p = .305) nor for the CERAD (z = -1.16, p = .246), with no statistically significant differences in the AUC (AMFAST = 0.954, CERAD = 0.954, p = .989).

CONCLUSIONS: Our preliminary results based on a small, diagnostically heterogeneous sample suggest that the AMFAST and the CERAD-NB did not differ significantly to identify objective cognitive impairment. Future studies with larger, more homogenous samples are needed.},
}

Humans
Pilot Projects
Female
Aged
Male
*Neuropsychological Tests
*Cognitive Dysfunction/diagnosis
Sensitivity and Specificity
Middle Aged
*Attention/physiology
*Memory/physiology
Aged, 80 and over
ROC Curve

@article {pmid42815597,
year = {2026},
author = {Kahou Tadah, RB and Bilanda, DC and Ngapout Fifen, JR and Kengne, SF and Owona, PE and Akamba Ambamba, BD and Tcheutchoua, YC and Bidinga A Goufani, CR and Follesa, P and Kamtchouing, P and Dzeufiet Djomeni, PD},
title = {Neuroprotective effects of Isodon ramosissimus (Hook.f.) Codd (Lamiaceae) aqueous extract against scopolamine-induced Alzheimer-like phenotype.},
journal = {Journal of ethnopharmacology},
volume = {},
number = {},
pages = {122429},
doi = {10.1016/j.jep.2026.122429},
pmid = {42815597},
issn = {1872-7573},
abstract = {Isodon ramosissimus is traditionally used in folk medicine for the management of neurological disorders. However, its neuroprotective properties against scopolamine-induced cognitive impairments have not yet been scientifically investigated.

AIM OF THE STUDY: This study investigated the anti-amnesic and neuroprotective effects of the aqueous extract of Isodon ramosissimus (IrAE) in a scopolamine-induced Alzheimer's-like phenotype in rats.

MATERIALS AND METHODS: Liquid chromatography-mass spectrometry (LC-MS) and quantitative phytochemical analyses were performed to tentatively identify IrAE bioactive compounds. Forty-eight male Wistar rats were randomly assigned to six groups receiving saline, scopolamine (1 mg/kg), scopolamine plus donepezil (5 mg/kg), or scopolamine plus IrAE (75, 150, or 300 mg/kg) for 14 consecutive days. Learning and memory were evaluated using the novel object recognition and Morris water maze tests. Cholinesterase activity, oxidative stress biomarkers, and histopathological changes in the prefrontal cortex and hippocampus were also assessed.

RESULTS: Scopolamine induced significant cognitive deficits (p < 0.01), increased Acetylcholinesterase activity and oxidative stress (p < 0.01), and caused substantial neuronal damage. IrAE treatment significantly reversed learning and memory deficits (p < 0.01), attenuated acetylcholinesterase activity and oxidative stress (p < 0.01), and preserved cortical and hippocampal neurons from scopolamine's neurotoxic effects. LC-MS analysis tentatively identified oridonin, stigmasterol, chrysoeriol, ferruginol, and corosolic acid, compounds with reported cognitive-enhancing, antioxidant, anti-inflammatory, anticholinesterase, and neuroprotective activities.

CONCLUSION: IrAE exerts marked anti-amnesic and neuroprotective effects, associated with cholinergic and antioxidant modulation. These findings provide preliminary pharmacological support for the traditional use of IrAE, warranting further preclinical investigation of its potential in the management of cognitive disorders.},
}

@article {pmid42815778,
year = {2026},
author = {Sasaguri, H},
title = {Current Status of Models for Alzheimer's Disease and Related Neurodegenerative Diseases.},
journal = {Neuroscience research},
volume = {},
number = {},
pages = {105126},
doi = {10.1016/j.neures.2026.105126},
pmid = {42815778},
issn = {1872-8111},
}

@article {pmid42815878,
year = {2026},
author = {Zhang, XT and Murphy, M and Riordan, H and Wang, K and Esquivel, R and Xu, W and Zhang, X and Gong, X and Sun, Y and Lu, Y},
title = {Understanding Alzheimer's disease through biomarkers: pathology, progression, and clinical application.},
journal = {Bioanalysis},
volume = {},
number = {},
pages = {1-11},
doi = {10.1080/17576180.2026.2740372},
pmid = {42815878},
issn = {1757-6199},
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder and the leading cause of dementia worldwide accounting for an estimated 60% to 80% of cases. Biomarkers play an integral role in AD randomized clinical trials (RCTs), providing objective measures of disease pathology, progression, and therapeutic efficacy. Key biomarkers, including amyloid-beta (Aβ), tau proteins, neuroinflammatory and neurodegeneration markers, as well as various neuroimaging modalities can help to facilitate the assessment of disease-modifying therapies, enable earlier detection of pathological changes before clinical symptoms emerge, and inform regulatory decision-making by demonstrating target engagement and possible treatment efficacy when linked to cognitive outcomes. This review examines the most salient biomarkers in AD RCTs and underlines their importance in advancing diagnostics, guiding therapeutic development, and improving clinical trial design to enable effective disease-modifying treatments. [Relevant literature was identified through searches of PubMed and Google Scholar for studies published through June 2026].},
}

@article {pmid42815901,
year = {2026},
author = {Dai, R and Dai, J and Yan, C and Shi, L and Bi, J and Huang, P and Zhai, Y and Sun, S and Zhu, WH and Guo, Z},
title = {Discriminating Monomers and Fibrils of Amyloid-β1-42 With Site-Ordered Peptide-QMFluors.},
journal = {Angewandte Chemie (International ed. in English)},
volume = {},
number = {},
pages = {e3711838},
doi = {10.1002/anie.3711838},
pmid = {42815901},
issn = {1521-3773},
support = {2023YFA1802000//National Key Research and Development Program/ ; 22225805//NSFC/China/ ; T2522013//NSFC/China/ ; 32121005//NSFC/China/ ; 32394001//NSFC/China/ ; 22378122//NSFC/China/ ; 23J21901600//Shanghai Science and Technology Innovation Action Plan/ ; //Shanghai Frontier Science Research Base of Optogenetic Techniques for Cell Metabolism/ ; 2021 Sci & Tech 03-28//Shanghai Municipal Education Commission/ ; 24DX1400200//Science and Technology Commission of Shanghai Municipality/ ; },
abstract = {The detection of soluble amyloid-β (Aβ), the most neurotoxic species in early Alzheimer's disease (AD), remains a major analytical challenge. Conventional probes are designed to target the β-sheet structures of mature fibrils and are thus blind to these transient, nonfibrillar species. Here, we introduce "site-ordered engineering" strategy, a peptide-conjugated QMFluors conjugate designed to selectively target Aβ1-42 monomers with high fidelity. We identified the conjugation site order on the fluorophore as the key parameter controlling this molecular topology and self-assembly behavior. This breakthrough is enabled by a hydrogen-bond-driven recognition mechanism, fundamentally departing from classical dyes that target the β-sheets of mature fibrils. This yields an unprecedented "inverted selectivity" with a 20-fold fluorescence enhancement for monomers over fibrils. Using probe N-QM-KLVFF with super-resolution microscopy, we reveal the nanoscale "core-shell" biophysical phase diagram of plaques, visualizing dense fibrillar cores surrounded by monomeric/oligomeric halos. Furthermore, the probe demonstrates a limit of detection of pg/mL level and excellent linearity, meeting the stringent requirements for trace cerebrospinal-fluid-biomarker analysis. This work provides not only a powerful tool for early diagnosis and pathological investigation, but also establishes "aggregation-regulated accessibility" as a generalizable principle for designing probes for other dynamic amyloid protein targets.},
}

@article {pmid42816030,
year = {2026},
author = {Zhu, W and Yuan, N and Tang, M and She, K and Chen, M and Huang, M and Feng, R and Ma, Q and Chen, J},
title = {From bench to beside: luteolin's therapeutic promise in neurological disorders.},
journal = {Chinese journal of natural medicines},
volume = {24},
number = {10},
pages = {1153-1162},
doi = {10.1016/S1875-5364(26)61211-3},
pmid = {42816030},
issn = {1875-5364},
mesh = {*Luteolin/therapeutic use/pharmacology/chemistry ; Humans ; Animals ; *Neuroprotective Agents/therapeutic use/pharmacology ; *Nervous System Diseases/drug therapy ; *Alzheimer Disease/drug therapy ; Oxidative Stress/drug effects ; Antioxidants ; *Parkinson Disease/drug therapy ; },
abstract = {Luteolin (3',4',5,7-tetrahydroxyflavone) is a naturally occurring flavonoid found in diverse plant families, including Apiaceae, Brassicaceae and Lamiaceae, and is a major bioactive component of Chinese medicines such as Chrysanthemum morifolium and Perilla frutescens. It possesses antidepressant, anti-inflammatory, antioxidant and neuroprotective activities, and has shown therapeutic potential in depression, Alzheimer's disease (AD) and Parkinson's disease (PD). Based on a comprehensive PubMed search, this review examines the shared pathological features-neuroinflammation, oxidative stress and synaptic dysfunction-across these three disorders and elucidates the pharmacological actions of luteolin. Clinical trial data were retrieved from NIH and ICTRP registries. We critically analyze current research limitations, including the lack of validated direct targets beyond PPARγ, the predominance of pathway-based evidence without orthogonal validation, and significant pharmacokinetic defects (low oral bioavailability, rapid glucuronidation, poor BBB penetration). While luteolin holds promise for central nervous system (CNS) disorders, its clinical translation requires advanced drug delivery systems (e.g., nano-formulations, brain-region-specific prodrugs), combination therapies or structural modification, and future cohort studies for prophylactic use. Addressing these priorities will be essential for its therapeutic development.},
}

*Luteolin/therapeutic use/pharmacology/chemistry
Humans
Animals
*Neuroprotective Agents/therapeutic use/pharmacology
*Nervous System Diseases/drug therapy
*Alzheimer Disease/drug therapy
Oxidative Stress/drug effects
Antioxidants
*Parkinson Disease/drug therapy

@article {pmid42816032,
year = {2026},
author = {Fan, L and Jiang, H and Yi, M and Peng, W and Zhang, Z},
title = {Icariin enhances PINK1-associated mitophagy to attenuate NLRP3/GSDMD-related microglial pyroptosis and cognitive impairment in Alzheimer's disease.},
journal = {Chinese journal of natural medicines},
volume = {24},
number = {10},
pages = {1176-1190},
doi = {10.1016/S1875-5364(26)61213-7},
pmid = {42816032},
issn = {1875-5364},
mesh = {Animals ; *NLR Family, Pyrin Domain-Containing 3 Protein/metabolism/genetics ; *Alzheimer Disease/drug therapy/metabolism/genetics ; *Microglia/drug effects/metabolism ; PTEN-Induced Putative Kinase ; Mice ; *Mitophagy/drug effects ; *Flavonoids/pharmacology ; *Pyroptosis/drug effects ; *Protein Kinases/metabolism/genetics ; *Cognitive Dysfunction/drug therapy/metabolism/genetics ; Humans ; Mice, Transgenic ; Molecular Docking Simulation ; Male ; },
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder in which microglia-mediated neuroinflammation contributes to disease progression. Icariin (ICA), a major bioactive flavonoid from Epimedium, has neuroprotective activity, but how it regulates mitochondrial quality control and inflammatory injury in microglia remains unclear. In the present study, APP/PS1 transgenic mice and Aβ1-42-stimulated BV-2 microglia were used to examine the effects of ICA on mitophagy, mitochondrial stress, NLRP3/GSDMD-related pyroptotic changes, and neuroinflammation. Behavioral testing, histological analysis, transcriptomic profiling, immunofluorescence, Western blotting, ELISA, molecular docking, molecular dynamics simulation, cellular thermal shift assay, Mdivi-1 co-treatment, and siRNA-mediated Pink1 knockdown were performed. ICA improved cognitive deficits in APP/PS1 mice and reduced microglial inflammatory activation. Transcriptomic and experimental analyses showed that ICA enhanced mitophagy-related responses, restored mitochondrial membrane potential, and reduced excessive mitochondrial reactive oxygen species accumulation. Molecular docking, molecular dynamics simulation, and cellular thermal shift assay supported potential engagement of ICA with PINK1. ICA also reduced NLRP3 inflammasome-associated inflammatory injury, GSDMD-related pyroptotic changes, and IL-1β and IL-18 release. In APP/PS1 mice, Mdivi-1 co-treatment weakened the anti-inflammatory effects of ICA. In Aβ1-42-stimulated BV-2 microglia, Pink1 knockdown reduced ICA-induced LC3/TOM20 colocalization and partially reversed the inhibitory effects of ICA on NLRP3 inflammasome-associated inflammatory markers. Overall, ICA enhances PINK1-associated mitophagy, alleviates mitochondrial stress, and attenuates NLRP3/GSDMD-related microglial pyroptotic injury in AD-related models. These findings suggest that PINK1-associated mitochondrial quality control contributes to the neuroprotective effects of ICA.},
}

Animals
*NLR Family, Pyrin Domain-Containing 3 Protein/metabolism/genetics
*Alzheimer Disease/drug therapy/metabolism/genetics
*Microglia/drug effects/metabolism
PTEN-Induced Putative Kinase
Mice
*Mitophagy/drug effects
*Flavonoids/pharmacology
*Pyroptosis/drug effects
*Protein Kinases/metabolism/genetics
*Cognitive Dysfunction/drug therapy/metabolism/genetics
Humans
Mice, Transgenic
Molecular Docking Simulation
Male

@article {pmid42816035,
year = {2026},
author = {Zhu, M and Wang, Y and Tang, H and Sun, Y and Feng, X and Wang, Q and Kuang, H},
title = {Data mining and multi-omics profiling to reveal the mechanisms of cold/hot property of traditional Chinese medicine in Alzheimer's disease treatment.},
journal = {Chinese journal of natural medicines},
volume = {24},
number = {10},
pages = {1221-1236},
doi = {10.1016/S1875-5364(26)61216-2},
pmid = {42816035},
issn = {1875-5364},
mesh = {Animals ; Humans ; Rats ; *Alzheimer Disease/drug therapy/metabolism/genetics ; Data Mining ; *Drugs, Chinese Herbal/pharmacology ; Gastrointestinal Microbiome/drug effects ; Medicine, Chinese Traditional ; Metabolomics ; Multiomics ; Oxidative Stress/drug effects ; Proteomics ; },
abstract = {Alzheimer's disease (AD) is a severely debilitating condition that significantly hampers independent living, with no effective treatments currently available. Traditional Chinese medicine (TCM) has shown substantial promise in both preventing and alleviating AD symptoms. The medicinal properties-specifically hot, warm, cool, and cold-serve as a critical link between TCM theory and clinical application. However, the majority of research has concentrated on individual herbs for AD, with relatively few comprehensive studies exploring the biological mechanisms through which these herbs exert their medicinal properties. In this context, data mining, network pharmacology, and multi-omics approaches, including metabolomics, gut microbiota analysis, and proteomics, were employed to elucidate the effects and mechanisms of action of three hot/warm property herbs (THPH) and three cold/cool property herbs (TCPH) in the treatment of AD. Findings indicated that the herbs effective against AD primarily possess warm properties. THPH demonstrated a significant enhancement in cognitive, learning, and memory functions in AD rat models when compared to TCPH, potentially achieving therapeutic effects by boosting the synthesis of the neurotransmitter acetylcholine. Furthermore, THPH modulated energy metabolism, corrected metabolic imbalances in both brain and serum within AD rat models, inhibited oxidative stress, restored synaptic plasticity-related proteins and signaling pathways, and maintained intestinal microbiota homeostasis. Consequently, this study offers valuable insights into the therapeutic implications of the hot (warm) and cold (cool) properties of TCM in the management of Alzheimer's disease.},
}

Animals
Humans
Rats
*Alzheimer Disease/drug therapy/metabolism/genetics
Data Mining
*Drugs, Chinese Herbal/pharmacology
Gastrointestinal Microbiome/drug effects
Medicine, Chinese Traditional
Metabolomics
Multiomics
Oxidative Stress/drug effects
Proteomics

@article {pmid42816467,
year = {2026},
author = {Brunwasser, SJ and McGregor, JN and Bhaskaran-Nair, K and Farris, CA and Elmore, H and Higashikubo, BT and Berriman-Rozen, ZD and Ko, D and Dyer, EL and Grady, JM and Whitesell, JD and Harris, JA and Hengen, KB},
title = {The default mode network exhibits circuit-specific selective vulnerability despite widespread amyloid burden in an animal model of Alzheimer's disease.},
journal = {Nature communications},
volume = {17},
number = {1},
pages = {},
pmid = {42816467},
issn = {2041-1723},
support = {R01AG091773//U.S. Department of Health & Human Services | National Institutes of Health (NIH)/ ; 1R01EB029852//U.S. Department of Health & Human Services | National Institutes of Health (NIH)/ ; A2022038S//BrightFocus Foundation (BrightFocus)/ ; R01AG047589//U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; R01 NS118442/NS/NINDS NIH HHS/United States ; R01 AG091773/AG/NIA NIH HHS/United States ; R01 EB029852/EB/NIBIB NIH HHS/United States ; },
mesh = {Animals ; *Alzheimer Disease/metabolism/physiopathology/pathology ; Disease Models, Animal ; *Amyloid beta-Peptides/metabolism ; Mice ; Hippocampus/metabolism/physiopathology/pathology ; Mice, Transgenic ; *Default Mode Network/physiopathology/metabolism/pathology ; Plaque, Amyloid/metabolism ; Male ; Amyloid beta-Protein Precursor/genetics/metabolism ; Neurons/metabolism ; Gyrus Cinguli/physiopathology/metabolism/pathology ; *Nerve Net/physiopathology/metabolism ; Female ; },
abstract = {In Alzheimer's Disease (AD) the default mode network (DMN) exhibits selective vulnerability to functional decline and amyloid beta (Aβ) plaques in early AD. DMN vulnerability may simply be the result of Aβ accumulation. Alternately, Aβ may unmask an intrinsic susceptibility of DMN circuits. Should DMN vulnerability persist amidst global Aβ deposition, this would support the latter hypothesis. We tested this using long-term, multi-region recordings of single units in mice characterized by widespread Aβ (APP/PS1). We tracked a neuronal population within the retrosplenial cortex (a DMN region) and two monosynaptically connected target populations, one within (anterior cingulate) and the other outside the DMN (primary visual cortex). We also recorded in hippocampus and examined interactions between the in-DMN and out-DMN circuits. Our data revealed progressive dysfunction restricted to the in-DMN circuit. In contrast, communication originating within but targeting an out-DMN population was unaffected by disease. Dysfunction was pronounced in sleep.},
}

Animals
*Alzheimer Disease/metabolism/physiopathology/pathology
Disease Models, Animal
*Amyloid beta-Peptides/metabolism
Mice
Hippocampus/metabolism/physiopathology/pathology
Mice, Transgenic
*Default Mode Network/physiopathology/metabolism/pathology
Plaque, Amyloid/metabolism
Male
Amyloid beta-Protein Precursor/genetics/metabolism
Neurons/metabolism
Gyrus Cinguli/physiopathology/metabolism/pathology
*Nerve Net/physiopathology/metabolism
Female

@article {pmid42816521,
year = {2026},
author = {Othman, M and Khedr, E and Fawi, G and Heikal, S and Mostafa, SA and Ibrahim, A and Qayaty, A and Ali, EM and Salama, M},
title = {Blood metal signatures and their association with Alzheimer's disease risk and cognitive decline in an Egyptian cohort.},
journal = {Communications medicine},
volume = {6},
number = {1},
pages = {},
pmid = {42816521},
issn = {2730-664X},
abstract = {BACKGROUND: Alzheimer's disease (AD) is a multifactorial disease in which environmental exposures may contribute to disease risk. This study aimed to investigate associations between blood concentrations of arsenic, lead, mercury, and lithium with AD risk and cognitive performance in an Egyptian cohort.

METHODS: We conducted a cross-sectional study in 50 AD patients and 50 cognitively healthy controls recruited across multiple centres in Egypt. Blood metal concentrations were measured by inductively coupled plasma optical emission spectrometry. A tiered analytical strategy addressed variable left-censoring: group-stratified Kaplan-Meier imputation was applied for arsenic, lead, and lithium, followed by logistic and linear regression adjusted for age and sex, with a binary detection sensitivity analysis for lithium, lead, and mercury. Multiple testing was corrected using the Benjamini-Hochberg false discovery rate method.

RESULTS: Here we show that higher arsenic concentrations are strongly associated with increased odds of AD (OR = 1321.61, p = 3.48×10⁻⁶) and lower cognitive scores (β = -16.44, p = 1.46×10⁻⁸), both surviving false discovery rate correction. Higher lithium is associated with reduced disease odds (OR = 0.634, FDR-adjusted p = 0.022) and better cognitive performance (β = 1.21, FDR-adjusted p = 0.020), corroborated in sensitivity analyses. Mercury detection is markedly more frequent in patients than controls (24% vs. 2%, p = 0.002) and associates with lower cognitive scores (β = -7.08, p = 0.0003). Lead shows a borderline association with disease (OR = 1.53, p = 0.046) that does not survive correction.

CONCLUSIONS: These findings support arsenic neurotoxicity and lithium deficiency as potentially important contributors to AD risk in an Egyptian population, with implications for environmental public health in low- and middle-income settings.},
}

@article {pmid42816571,
year = {2026},
author = {Mason-Chalmers, K and Rodriguez, JA},
title = {Harmful tau spreads like self-propagating prion proteins.},
journal = {Nature},
volume = {},
number = {},
pages = {},
pmid = {42816571},
issn = {1476-4687},
}

@article {pmid42816601,
year = {2026},
author = {Nan, J and Boix, CA and Shi, S and Fan, X and Ni, J and Wang, K and Shuai, X and Ding, K and Wu, P and An, Y and Sun, N and Hou, L and Chen, K and Huang, X and Li, C and Akay, L and Louderback, K and Nawaid, H and Park, YP and Fu, X and Liu, C and Li, X and Yin, Y and Mo, W and Yang, Z and Ma, W and Hu, X and Bennett, DA and Kellis, M and Tsai, LH and Sunyaev, S and Li, J and Xiong, X},
title = {Single-cell profiling and genetic regulation of alternative polyadenylation in the human brain.},
journal = {Nature genetics},
volume = {},
number = {},
pages = {},
pmid = {42816601},
issn = {1546-1718},
support = {32422017, 92353301, 32370609//National Natural Science Foundation of China (National Science Foundation of China)/ ; 2024YFF1207600, 2023YFA1800700//Ministry of Science and Technology of the People's Republic of China (Chinese Ministry of Science and Technology)/ ; LR25C060002//Natural Science Foundation of Zhejiang Province (Zhejiang Provincial Natural Science Foundation)/ ; P30AG10161, P30AG72975, R01AG15819, R01AG17917, U01AG46152, U01AG61356//U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; },
abstract = {Alternative polyadenylation (APA) has a central role in regulation of the fate of mRNA and exhibits high variability in the brain and in neurons. However, brain APA regulation has not been mapped at cell type resolution, and the genetic control of APA in brain cell types and its contribution to genetic disease have remained unclear. Here we report a single-cell atlas of APA of the aged human brain across 2 million cells from 379 human postmortem brains across individuals with and without Alzheimer's disease (AD). We show that APA provides an independent mechanistic layer for understanding gene regulatory changes in AD, as genes with APA alterations are distinct from those with expression changes but often converge to similar pathways, including microglial activation and microtubule transport in neurons. We integrate APA variation with whole-genome sequencing to identify cell-type-resolved 3' untranslated region quantitative trait loci (3'aQTLs) for 4,288 genes. We find that 3'aQTLs preferentially colocalize with pQTLs over eQTLs. Across 17 brain traits and diseases, we identify 168 GWAS loci dependent on 3'aQTLs, of which only 17.5% are shared with eQTLs. These include PLEKHA1 and APOC2 for AD, PAK6 and AP3B2 for schizophrenia, NDUFA13 for bipolar disorder, MTCH2 for multiple brain traits, and SNCA, the top locus in Parkinson's disease. We show that 3' untranslated region choice alters SNCA mRNA localization within the cell, consistent with the observation that the SNCA risk locus acts in an eQTL-independent manner in neurons and oligodendrocytes. Our results provide a cell-type-specific foundation to interrogate the cis and trans regulation of APA and to understand the contribution to disease heritability of this key post-transcriptional layer.},
}

@article {pmid42816607,
year = {2026},
author = {Lövestam, S and Shimozawa, A and Tarutani, A and Ohtani, R and Masuda-Suzukake, M and Hasegawa, K and Robinson, AC and Saito, Y and Murayama, S and Yoshida, M and Suzuki, H and Onaya, M and Hasegawa, M and Goedert, M and Scheres, SHW},
title = {Prion-like transmission of human tau strains in the mouse brain.},
journal = {Nature},
volume = {},
number = {},
pages = {},
pmid = {42816607},
issn = {1476-4687},
abstract = {Most neurodegenerative diseases are thought to spread through the brain by prion-like mechanisms, in which filamentous protein assemblies self-propagate by templated seeding[1]. Distinct conformations of amyloid filaments may provide the physical basis for the strains that lead to different diseases[2]. However, a central pillar of the prion hypothesis, that strains retain their structural identity upon transmission, has not been demonstrated. Here we show that the injection of tau filaments from the brains of individuals with Alzheimer's disease or corticobasal degeneration into the brains of wild-type mice leads to the seeded assembly of amyloid filaments made of mouse tau with the same structures as those of the seeds. Thus, we show that, similar to prion strains, tau filaments propagate through templated seeding, and that the mouse is a suitable model to study the molecular mechanisms by which distinct tau folds drive disease-specific pathology in the brain.},
}

@article {pmid42816815,
year = {2026},
author = {Mar, J and Arrospide, A and Handels, R and Soto-Gordoa, M},
title = {Economic model of Alzheimer's disease that incorporates the uncertainty associated with measuring efficacy in clinical trials.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261490543},
doi = {10.1177/13872877261490543},
pmid = {42816815},
issn = {1875-8908},
abstract = {BackgroundClinical trials of Alzheimer's disease (AD) treatments are ongoing, and uncertainty about their efficacy is a key factor in their evaluation.ObjectiveThe objective of this study was to propose a new methodological approach for the economic evaluation of treatments to account for the uncertainty associated with measuring efficacy in clinical trials and the waning effect.MethodsA discrete event simulation model was built using data from a synthetic clinical trial dataset to model typical patient-level natural history trajectories of Clinical Dementia Rating scores from mild cognitive impairment to severe dementia using mixed regression models for repeated measures (MMRM). As the MMRM coefficients are correlated, this variability was incorporated into the model probabilistic sensitivity analysis using Cholesky decomposition. Uncertainty about treatment effect waning was addressed by scenario analysis (optimistic and pessimistic).ResultsAlthough the main contribution of this study is to describe an innovative model, the results of the hypothetical intervention are presented in the standard format of incremental cost-utility ratios (ICURs), cost-effectiveness and acceptability curves. Specifically, the ICUR of the hypothetical treatment ranged from €73,216 to €63,662 per quality-adjusted life year.ConclusionsWe present an innovative approach to the economic evaluation of Alzheimer's disease treatments, applying a Monte Carlo simulation approach (PSA) to two scenarios and shaping individual cognitive trajectories on a continuous scale to fit the target population of clinical trials. Its transparent design allows the economic model to be shared between the pharmaceutical company and the assessment agencies while keeping individuals' clinical trial data confidential.},
}

@article {pmid42816822,
year = {2026},
author = {Li, B and Shi, T and Yang, M and Liu, H},
title = {Nonlinear association between waist-to-height ratio and Alzheimer's disease among middle-aged and older adults: A cross-sectional study from NHANES.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261490818},
doi = {10.1177/13872877261490818},
pmid = {42816822},
issn = {1875-8908},
abstract = {BackgroundThe association between waist-to-height ratio (WHtR) and Alzheimer's disease (AD) remains unclear in the general population.ObjectiveThis study aimed to investigate the relationship between WHtR and AD using data from the nationally representative National Health and Nutrition Examination Survey (NHANES).MethodsThis cross-sectional study included participants aged ≥45 years from NHANES. Weighted multivariable logistic regression, restricted cubic spline (RCS), subgroup, and sensitivity analyses were performed to evaluate the association between WHtR (scaled by 10) and AD.ResultsHigher WHtR was significantly associated with greater odds of AD after adjustment for potential confounders (OR = 1.30, 95% CI: 1.18-1.42, p < 0.001). Significant interactions were observed for age (p for interaction = 0.017) and physical activity (p for interaction = 0.02). RCS analysis revealed a significant nonlinear U-shaped association between WHtR and AD (p for nonlinearity = 0.005), with the lowest odds observed at a WHtR value of 5.46 on the 10-fold scale. Sensitivity analyses showed generally consistent results.ConclusionsHigher WHtR was significantly associated with greater odds of AD among middle-aged and older adults. A nonlinear U-shaped association was also observed, suggesting that both lower and higher WHtR levels may be associated with increased odds of AD. Further prospective studies are warranted to confirm these findings.},
}

@article {pmid42816823,
year = {2026},
author = {Zhu, C and Li, H and Gao, J and Li, H and Qiao, Y and Li, J and Wang, Q and Gao, F and Shao, L and Wang, L and Wu, D and Zheng, Y and Gao, Q and Qiao, Y and Du, J and Zhang, J},
title = {Use of multiple post-diagnostic dementia services across healthcare tiers in Beijing, China: A caregiver-reported cross-sectional study.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261489615},
doi = {10.1177/13872877261489615},
pmid = {42816823},
issn = {1875-8908},
abstract = {BackgroundPost-diagnostic dementia care, including for Alzheimer's disease, is multi-component and requires coordinated access to cognitive assessment, medication management, consultation for behavioral and psychological symptoms of dementia (BPSD), and non-pharmacological interventions. Evidence on service use and tiered distribution in China remains limited.ObjectiveTo characterize the use, tiered distribution, and reasons for non-use of four post-diagnostic dementia services in Beijing, China, and to explore caregiver-related correlates of service use.MethodsFrom July to October 2025, 202 family caregivers were recruited by convenience sampling from three tertiary hospitals and six community health service centers across four Beijing districts. A structured questionnaire was administered through interviews. Four exploratory Firth penalized likelihood logistic regression models were fitted, with Benjamini-Hochberg correction as a supplementary assessment of multiplicity.ResultsService use varied substantially: cognitive assessment 95.5%, medication management 83.7%, BPSD consultation 61.8% (n = 131), and non-pharmacological interventions 25.7%. Only 16.8% of caregivers reporting BPSD accessed all four services. Tiered distribution was heterogeneous: non-pharmacological interventions concentrated in hospitals; medication management more often involved primary care. Higher income was associated with non-pharmacological intervention use, and regular clinic attendance with BPSD consultation. "Unaware" was the leading reason for non-use of BPSD consultation, cognitive stimulation, and cognitive training, whereas "no perceived need" predominated for ADL rehabilitation.ConclusionsPost-diagnostic dementia service use in Beijing was uneven across service types and healthcare tiers. The exploratory associations suggest that informational and economic factors may be relevant to access to underused services within China's tiered healthcare system.},
}

@article {pmid42816829,
year = {2026},
author = {Goncalo, AK},
title = {The role of neuroinflammation in the connections between autism spectrum disorder and Alzheimer's disease and related dementias: A review.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261491809},
doi = {10.1177/13872877261491809},
pmid = {42816829},
issn = {1875-8908},
abstract = {Recent evidence suggests a link between autism spectrum disorder (ASD) and early-onset Alzheimer's disease and related dementias (AD/ADRD), yet the mechanisms underlying this association remain poorly understood. This narrative review investigates whether early management of ASD may reduce the risk of developing AD/ADRD by targeting shared biological pathways. A literature search was conducted using PubMed and included English-language studies published from 1996 to 2026. Eligible studies addressed ASD, AD/ADRD, neuroinflammation, aging, or dementia, and included systematic reviews, meta-analyses, narrative reviews, clinical trials, randomized controlled trials, and translational animal studies. Studies lacking discussion of mechanisms relevant to ASD, neuroinflammation, aging, or dementia were excluded. Search terms included AD, dementia, ASD, inflammation, pregnenolone, omega-3, prednisolone, celecoxib, minocycline, N-acetylcysteine, sulforaphane, histamine receptor agonists, and GABA. Additional studies were identified through reference list screening. Of 170 records identified, 133 met the inclusion criteria and formed the basis for the review. Findings indicate that neuroinflammation is a central mechanism linking ASD-related comorbidities with established AD/ADRD risk factors. The evidence suggests that reducing neuroinflammation, particularly through interventions targeting microglial activation during childhood or early adulthood, may lower the likelihood of early-onset AD/ADRD in individuals with ASD. Although current evidence is primarily theoretical and indirect, it supports further investigation of anti-inflammatory strategies as potential preventive interventions. The review concludes by proposing future empirical studies to test whether early neuroinflammation-targeted treatment in ASD can reduce the incidence of early-onset AD/ADRD.},
}

@article {pmid42816830,
year = {2026},
author = {Pintus, M and Valletta, M and Sacchi, L and Carandini, T and Ghezzi, L and Pietroboni, A and Fenoglio, C and Serpente, M and Arcaro, M and Bruno, G and Galimberti, D and Canevelli, M and Arighi, A},
title = {Exploring the interplay between frailty, Alzheimer's disease biomarkers, and cognitive functioning in patients with mild cognitive impairment: A cross-sectional study.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261487377},
doi = {10.1177/13872877261487377},
pmid = {42816830},
issn = {1875-8908},
abstract = {BackgroundFrailty is characterized by declining homeostatic reserves and increased vulnerability to stressors, and has been associated with cognitive decline and dementia.ObjectiveTo examine the relationship between frailty, Alzheimer's disease (AD) biomarkers, and cognitive performance in individuals with mild cognitive impairment (MCI).MethodsWe enrolled 183 MCI patients from the Diagnostic Outpatient Service of the Neurodegenerative Diseases Unit at IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan. Cerebrospinal fluid (CSF) biomarkers amyloid-β42, total-tau, and phosphorylated-tau181were analyzed. Frailty was assessed using a 47-item frailty index (FI), and cognitive performance was measured with the Mini-Mental State Examination (MMSE).ResultsHigher FI scores were associated with lower MMSE scores, even after adjusting for amyloid and tau biomarkers (β = -0.72, 95% CI -1.20, -0.24). Compared to robust (FI ≤ 0.11) amyloid-negative subjects, individuals with higher FI (>0.11) and CSF amyloid positivity had significantly lower MMSE scores. Patients with lower FI had twice the odds ratio (OR 2.00, 95% CI 1.02-3.90) of presenting an amyloid-positive (A+) CSF profile compared to those with higher FI; similar trends were found for the amyloid and tau-positive (A + T+) profile (OR 2.29, 95% CI 1.14-4.61).ConclusionsFrailty modulates the phenotypic variability of AD, influencing its clinical expression in MCI. Specifically, it is associated with lower cognitive performance in MCI independently of AD biomarker status and contributes synergistically with amyloid pathology to cognitive decline. Moreover, lower frailty levels are associated with a higher likelihood of an AD-compatible CSF profile, suggesting that frailty assessment may aid in identifying patients at greater risk.},
}

@article {pmid42816862,
year = {2026},
author = {Woudstra, AL and Holtman, L and van Vliet, EA},
title = {Microglia-derived extracellular vesicle content as a biomarker for early detection of Alzheimer's disease.},
journal = {Translational neurodegeneration},
volume = {15},
number = {1},
pages = {},
pmid = {42816862},
issn = {2047-9158},
support = {20-11//EpilepsieNL/ ; },
mesh = {Humans ; *Microglia/metabolism/pathology ; *Alzheimer Disease/diagnosis/metabolism/pathology ; Biomarkers/metabolism ; *Extracellular Vesicles/metabolism/pathology ; Early Diagnosis ; Animals ; },
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by amyloid-beta aggregation, tau pathology, synaptic dysfunction, and neuronal loss. While current biomarker frameworks such as the A/T/N classification have advanced diagnosis, they predominantly reflect relatively late stages of disease, limiting opportunities for early intervention. This underscores the urgent need for biomarkers that are not only accessible and sensitive but also specific to the earliest pathogenic mechanisms of AD. Recent work has underscored the pivotal role of disease-associated microglia (DAM) in the onset and progression of AD. DAM exhibit dual roles: they promote protection by phagocytosing amyloid and debris, metabolizing lipids, and remodelling synapses, yet can also drive pathology through excessive cytokine release, chronic inflammatory signalling, and impaired aggregate clearance. DAM release extracellular vesicles (EVs) that encapsulate proteins, nucleic acids, and lipids, reflective of their state. These vesicles reflect microglial (dys)function and can be detected in cerebrospinal fluid and blood, offering a minimally invasive means to monitor early AD pathology. In this review, we examine the emerging evidence that the content of microglia-derived EVs may fulfil the criteria of ideal biomarkers with a focus on the detectability, sensitivity, specificity, and feasibility for longitudinal monitoring. We discuss their potential to overcome limitations of current fluid and imaging biomarkers by offering more stable cargo protection, cell-type specificity, and accessibility in peripheral fluids. Furthermore, we highlight the opportunities and challenges in isolating microglia-derived EVs, identifying reliable surface and cargo markers, and standardizing methodologies for reproducibility across studies. By integrating insights from microglial biology with EV research, we provide evidence for microglia-derived EV content as biomarkers for early detection of AD and propose a roadmap toward DAM-specific EV signatures that could transform early AD diagnosis and disease monitoring. Such advances hold promise not only for AD but also for broader applications in neurodegenerative and neuroinflammatory disorders.},
}

Humans
*Microglia/metabolism/pathology
*Alzheimer Disease/diagnosis/metabolism/pathology
Biomarkers/metabolism
*Extracellular Vesicles/metabolism/pathology
Early Diagnosis
Animals

@article {pmid42816892,
year = {2026},
author = {Wang, H and Fan, X and Ping, J and Shao, Q and Wang, C and Wang, H and Ji, Q and Su, M and Qian, W},
title = {Fyn kinase: a key mechanistic regulator and therapeutic target in tauopathy and neurodegenerative diseases.},
journal = {Translational neurodegeneration},
volume = {15},
number = {1},
pages = {},
pmid = {42816892},
issn = {2047-9158},
support = {JC2023042//Nantong Natural Science Foundation/ ; 82607575//National Natural Science Foundation of China/ ; 82473926//National Natural Science Foundation of China/ ; },
mesh = {Humans ; *Proto-Oncogene Proteins c-fyn/metabolism ; *Neurodegenerative Diseases/metabolism/enzymology ; *Tauopathies/metabolism/enzymology ; Animals ; tau Proteins/metabolism ; Signal Transduction/physiology ; },
abstract = {Synaptic dysfunction and intracellular accumulation of pathological tau are convergent hallmarks of Alzheimer's disease (AD) and related tauopathies, yet the molecular mechanisms coupling these events to widespread neurodegeneration remain incompletely understood. The Src family kinase Fyn has emerged as a critical signaling hub that integrates upstream pathogenic triggers, such as amyloid-β (Aβ), with downstream neurotoxic cascades. Here, we review the multifaceted roles of Fyn in orchestrating synaptic failure, highlighting how Fyn recruitment by mislocalized tau promotes N-methyl-D-aspartate receptor hyperactivation and calcium dysregulation. We examine the biophysical basis of Fyn-tau interactions, particularly the role of liquid-liquid phase separation in stabilizing toxic signaling complexes. We also discuss how aberrant Fyn signaling in microglia and astrocytes amplifies neuroinflammation. Finally, we evaluate the potential of Fyn as a therapeutic target, emphasizing the necessity of strategies that selectively uncouple pathological signaling from physiological functions to effectively halt disease progression.},
}

Humans
*Proto-Oncogene Proteins c-fyn/metabolism
*Neurodegenerative Diseases/metabolism/enzymology
*Tauopathies/metabolism/enzymology
Animals
tau Proteins/metabolism
Signal Transduction/physiology

@article {pmid42816922,
year = {2026},
author = {Ning, X and Xiao, Y and Wang, N and Jiao, X and Li, X and Zhang, Y and Zhao, Q},
title = {The efficacy of donepezil combination therapy strategies in Alzheimer's disease: A systematic review and network meta-analysis.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261491977},
doi = {10.1177/13872877261491977},
pmid = {42816922},
issn = {1875-8908},
abstract = {BackgroundAlzheimer's disease (AD) remains a therapeutic challenge, and adding other agents to donepezil may offer additional benefits.ObjectiveThis network meta-analysis aimed to compare the efficacy of donepezil-based combination therapies versus donepezil monotherapy in patients with AD.MethodsWe searched PubMed, Embase, Cochrane Library and Web of Science up to October 2025 for randomized-controlled trials comparing donepezil plus another drug with donepezil alone. The primary outcomes were cognitive function [Mini-Mental State Examination (MMSE), Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-cog)], behavioral function (Neuropsychiatric Inventory) and functional ability [Alzheimer's Disease Cooperative Study Activities of Daily Living (ADCS-ADL)]. A frequentist network meta-analysis was performed, and treatments were ranked by SUCRA (Surface under the cumulative ranking curve) values. Time-stratified analyses were also conducted.Results41 trials involving 9822 patients were included. Compared with placebo, several combinations significantly improved MMSE and ADAS-cog scores, with Don (Donepezil) + Mas (Masitinib) (97.5%, 92.9%), Don + NBP (DL-3-n-butylphthalide) (82.5%, 74.5%) and Don + DSC (Dengzhan shengmai capsule) (81.4%) ranking highest. For ADCS-ADL, Don + Mas (92.7%), Don + NBP (74.1%), and Don + DSC (77.1%) showed significant improvements. No combination was statistically superior to donepezil monotherapy for any outcome, but numerical trends favored combination therapy across all time windows. The certainty of evidence was mostly moderate to low.ConclusionsSeveral donepezil-based combination therapies, particularly those with masitinib, NBP, DSC, and memantine, are more effective than placebo in improving cognitive and functional outcomes in AD. Although direct comparisons with donepezil monotherapy did not reach statistical significance, consistent trends support the potential of add-on strategies. Longer-term trials are needed to confirm sustained benefits.},
}

@article {pmid42816923,
year = {2026},
author = {Smith, AN and Johnson, CN and Taylor, MK and Keller, JE and Suzuki, A and Payne, C and Burns, JM and Wilkins, HM and Sullivan, DK},
title = {APOE4 is associated with lower adiposity independent of total energy intake in cognitively normal older adults.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261493064},
doi = {10.1177/13872877261493064},
pmid = {42816923},
issn = {1875-8908},
abstract = {BackgroundApolipoprotein E ε4 (APOE4) carriers with cognitive impairment exhibit lower BMI than non-carriers, but whether APOE4 influences body composition in cognitively normal older adults remains unknown.ObjectiveTo examine the association between APOE4 carrier status and body composition in cognitively normal older adults.MethodsCross-sectional analysis of 203 cognitively normal older adults (mean age 71.4 ± 4.8 years). Body composition was assessed via dual-energy x-ray absorptiometry. Linear regression models adjusted for age, sex, total energy intake, and physical activity examined associations between APOE4 status and BMI, body fat percentage, fat mass index (FMI), and lean mass index (LMI).ResultsAPOE4 carriers (32%, n = 65) had lower BMI (β = -1.42 kg/m[2], p = 0.043), body fat percentage (β = -3.56%, p < 0.001), and FMI (β = -1.51 kg/m[2], p = 0.002) compared to non-carriers (68%, n = 138). LMI did not differ between groups (β = 0.18 kg/m[2], p = 0.43).ConclusionsAPOE4 carriers exhibited lower adiposity but not lean mass compared to non-carriers, independent of total energy intake and physical activity. These findings suggest APOE4 influences fat mass through metabolic mechanisms that emerge before cognitive decline. Longitudinal studies are needed to determine whether these differences contribute to AD pathogenesis.},
}

@article {pmid42816925,
year = {2026},
author = {Lopes-Gomes, E and Resende, FFB and Greuel, AM and Marina, CL and de Sant'Ana, FJF and Titze-de-Almeida, SS and Titze-de-Almeida, R},
title = {Clinical and neuropathological aspects of canine cognitive dysfunction syndrome and a translational perspective for Alzheimer's disease.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261491819},
doi = {10.1177/13872877261491819},
pmid = {42816925},
issn = {1875-8908},
abstract = {Canine cognitive dysfunction syndrome (CCDS) shares notable clinical and molecular similarities with Alzheimer's disease (AD), supporting the value of cross-species translational research to enhance diagnostic and therapeutic approaches for both conditions. These disorders are progressive neurological diseases characterized by abnormal accumulation of neurotoxic proteins, primarily amyloid-β and tau. Their pathological aggregation induces neural injury and cerebral dysfunction, culminating in comparable clinical manifestations in dogs and humans. Exosomal microRNAs represent a promising class of molecular biomarkers for early diagnosis and provide insights into disease progression. Current diagnostic strategies include neurological evaluation, advanced imaging techniques, and, in dogs, behavioral assessments based on owner-reported observations. These assessments employ standardized rating scales such as the Canine Cognitive Dysfunction Rating Scale, the Canine Dementia Scale, and the DISHA questionnaire, which evaluate key signs of CCDS, including disorientation, altered interactions, sleep-wake cycle disturbances, house-soiling, and anxiety. This review highlights advances in understanding AD and canine cognitive dysfunction syndrome, linking veterinary and human medicine to foster translational insights benefiting both fields.},
}

@article {pmid42816931,
year = {2026},
author = {Xiao, H and Wang, J and Wan, S},
title = {WIMOAD: Weighted Integration of Multi-Omics data with meta learning for Alzheimer's Disease diagnosis.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261491975},
doi = {10.1177/13872877261491975},
pmid = {42816931},
issn = {1875-8908},
abstract = {BackgroundAlzheimer's disease (AD), the most prevalent subtype of dementia, is characterized by a gradual decline in brain cognitive function. Early detection is critical for initiating timely interventions that may delay the severe progression of the disease. Recent advances in next-generation sequencing (NGS) offer promising, non-invasive, and cost-effective strategies for AD screening. However, most current approaches rely on single-omics data, which fail to capture the complex biological heterogeneity among individuals.ObjectiveTo develop a user-friendly and efficient framework that incorporates blood-based multi-omics for stage-specific AD classification and detects genetic markers associated with disease pathology.MethodsWe introduce WIMOAD, a stacking ensemble and weighted multi-omics integration for AD diagnosis. It leverages paired gene expression and methylation data from ADNI and presents a meta learning framework for multi-cognitive stage classification during AD progression.ResultsAcross tasks, WIMOAD consistently outperforms single-omics models and representative integration baselines, and surpasses existing integration methods in AD diagnosis. Its interpretability also facilitates the detection of novel biomarkers across different omics layers. The code is freely available at https://github.com/wan-mlab/WIMOAD.ConclusionsThe study believes WIMOAD is an interpretable, cost-effective and promising integrative framework for accurate AD diagnosis and biomarker discovery across different cognitive stages utilizing blood-based data, which eventually will have consequential impacts on early treatment intervention and personalized therapy design for AD.},
}

@article {pmid42816938,
year = {2026},
author = {Chang, VW and Hayes-Larson, E and Zheng, H and Zhang, YS},
title = {Body mass index and mortality in incident dementia.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261491694},
doi = {10.1177/13872877261491694},
pmid = {42816938},
issn = {1875-8908},
abstract = {BackgroundLimited evidence suggests that higher body weight may be associated with improved survival among individuals with dementia relative to those in the normal weight range. The mechanisms underlying this association are uncertain and may include both physiological and methodological factors.ObjectiveTo examine the association between weight status at incident dementia and mortality and to assess potential sources of bias.MethodsWe examined the association between weight status at incident dementia and mortality in a large, U.S. population-based sample with extended follow-up. We also evaluated potential sources of bias affecting this association, including confounding due to weight loss, collider stratification bias, and survivor bias.ResultsCompared with the normal weight category, class I obesity at incident dementia was associated with a 27% lower risk of mortality (HR 0.73, 95% CI: 0.62-0.86). Overweight and class II/III obesity were also associated with lower mortality. Analyses evaluating potential sources of bias did not support these mechanisms as major contributors to the observed associations.ConclusionsIn a large, U.S. population-based sample with extended follow-up, overweight and obesity at incident dementia were associated with lower mortality relative to normal weight. While the underlying mechanisms are not fully understood, these findings suggest that weight status at diagnosis may serve as a useful prognostic indicator alongside other factors.},
}

@article {pmid42816978,
year = {2026},
author = {Anshika, and Tailor, NK},
title = {Cinnamic Acid-based Hybrid Molecules as Multitarget Therapeutic Agents for Cancer, Alzheimer's Disease, and Malaria: A Review.},
journal = {Mini reviews in medicinal chemistry},
volume = {},
number = {},
pages = {},
doi = {10.2174/0113895575495727260909051459},
pmid = {42816978},
issn = {1875-5607},
abstract = {Molecular hybridization has emerged as a powerful medicinal chemistry approach for address the limitations of conventional single-target therapeutics, particularly in the treatment of complex, multifactorial diseases. This strategy involves integrating two or more pharmacologically active pharmacophores into a single molecular framework, enabling enhanced biological activity, multi-target interactions, and improved pharmacokinetic properties. Among the diverse scaffolds investigated for hybrid drug design, cinnamic acid has attracted considerable attention owing to its structural simplicity, synthetic accessibility, and broad spectrum of biological activities. The incorporation of cinnamic acid into hybrid molecules has generated a wide range of compounds with improved therapeutic potential and selectivity. The pharmacological effects of cinnamic acid hybrids are associated with the modulation of key enzymes, including α-glucosidase, α-amylase, and acetylcholinesterase, as well as important signaling pathways such as NF-κB, COX-2, iNOS, PI3K/Akt/mTOR, and MAPK/ERK. These molecular interactions contribute to their diverse biological activities and therapeutic applications. This review provides a comprehensive overview of recent developments in cinnamic acid-based molecular hybrids, emphasizing design strategies, structure- activity relationships, pharmacological properties, and underlying mechanisms of action. Particular attention is given to their anticancer, neuroprotective, and antimalarial therapeutic applications. Furthermore, the review critically examines the advantages and current challenges of cinnamic acid hybridization and highlights future research directions. Overall, cinnamic acid-based molecular hybrids represent a promising platform for the development of multifunctional therapeutic agents with enhanced efficacy and broader clinical potential.},
}

@article {pmid42816980,
year = {2026},
author = {Pal, T and Singh, P},
title = {Oleandrin and PBI-05204 for Neuroprotection in Alzheimer's Disease, Parkinson's Disease, and Stroke: Preclinical Mechanisms, Blood-brain Barrier Penetration, and Clinical Translation Perspectives.},
journal = {Mini reviews in medicinal chemistry},
volume = {},
number = {},
pages = {},
doi = {10.2174/0113895575485020260907153210},
pmid = {42816980},
issn = {1875-5607},
abstract = {INTRODUCTION: Alzheimer's disease, Parkinson's disease, and ischemic stroke are increasingly becoming one of the major health concerns across the globe due to the scarcity of effective treatments for these conditions. Natural compounds like oleandrin and PBI-05204 that are extracted from Nerium oleander have been recognised for their promising qualities in the treatment and prevention of these conditions due to their ability to provide protection to the neurons in the brain.

METHODS: A systematic review was conducted to identify preclinical research articles related to oleandrin and PBI-05204 in the treatment of Alzheimer's disease, Parkinson's disease, and ischemic stroke. Searches were conducted on articles from January 2021 to March 2026 in Pub- Med/MEDLINE, Scopus, and Web of Science using the terms "oleandrin," "PBI-05204," "Nerium oleander," "blood-brain barrier," "neuroprotection," "Alzheimer," "Parkinson," and "stroke." Original in vitro or in vivo preclinical studies providing information on neuroprotective results, mechanistic information (BDNF, Nrf2-ARE, apoptosis, mitochondria), or information on blood-brain barrier permeability were included. Non-original articles (reviews, editorials), preclinical research not involving any neurobiological parameters, and articles in languages other than English were excluded.

RESULTS: Preclinical studies suggest that both oleandrin and PBI-05204 can diffuse across the BBB and provide neuroprotection. These molecules were shown to increase the expression levels of BDNF, promote ARE-dependent transcription, rehabilitate mitochondrial function, and regulate apoptosis. Though these results are highly hopeful, the major translational gap is in the ability to reproduce preclinical success in the clinical environment.

DISCUSSION: There is sufficient cellular-molecular evidence for the potential use of these compounds, namely oleandrin, as well as PBI-052040. Some challenges may arise when attempting to apply such observations as a new treatment modality at the clinical research stage. This is true for bioavailability, toxicity, and regulatory factors that need to be addressed.

CONCLUSION: Oleandrin and PBI-05204 make for very interesting compounds to consider for their neuroprotective properties in the context of neurodegeneration. Although there is promise in the preliminary human data from these compounds, there are also significant translational hurdles that must be cleared before their final application for human benefit.},
}

@article {pmid42817119,
year = {2026},
author = {Verma, A and Kushwaha, SKS and Kushwaha, N and Dutta, S and Nigam, P},
title = {Neuroinflammation and Autophagy in Neurodegeneration: Cellular Mechanisms and Therapeutic Strategies.},
journal = {CNS & neurological disorders drug targets},
volume = {},
number = {},
pages = {},
doi = {10.2174/0118715273459017260922073618},
pmid = {42817119},
issn = {1996-3181},
abstract = {Neurodegenerative diseases, including Huntington's disease, Parkinson's disease, Alzheimer's disease, and Amyotrophic Lateral Sclerosis (ALS), are characterized by progressive neuronal dysfunction and loss, often accompanied by toxic protein aggregation and chronic neuroinflammation. Increasing evidence indicates that dysregulated autophagy and persistent inflammatory responses are central drivers of disease onset and progression. Autophagy, a fundamental cellular degradation and recycling process, is essential for maintaining neuronal homeostasis by removing damaged organelles and misfolded proteins through mechanisms such as macroautophagy and mitophagy. However, key regulators of this pathway, including ULK1, Beclin-1, LC3, and p62/SQSTM1, are frequently impaired in neurodegenerative conditions, leading to the accumulation of pathogenic proteins such as tau, α-synuclein, and amyloid-β. Concurrently, aberrant activation of microglia and inflammasomes promotes the sustained release of pro-inflammatory cytokines, creating a neurotoxic environment that exacerbates neuronal injury. This review examines the molecular crosstalk between autophagy and neuroinflammation, with particular emphasis on disease-specific mechanisms, including LC3-associated endocytosis (LANDO) in Alzheimer's disease, tau-mediated pathology, and dopaminergic neurodegeneration in Parkinson's disease. Importantly, this review introduces a unifying conceptual framework in which neuroinflammation and autophagy are integrated as a dynamic, stagedependent immune-autophagy axis that governs neurodegenerative disease progression and therapeutic responsiveness. In addition, emerging multimodal therapeutic strategies targeting both autophagic flux and immune modulation are discussed, including mTOR inhibitors, mitophagy enhancers, GLP-1 receptor agonists, and nanomedicine-based delivery systems. Advances in three-dimensional organoids, induced Pluripotent Stem Cell (iPSC) models, and biomarker-driven clinical trials are further enhancing translational potential. In conclusion, understanding the interplay between autophagy and neuroinflammation provides critical insights into the pathophysiology of neurodegeneration and offers promising avenues for the development of targeted, disease-modifying therapies.},
}

@article {pmid42817127,
year = {2026},
author = {Wang, S and Wang, S and Sun, Y and Zhang, S and Wu, J and Xie, D},
title = {Beyond Fuel: Metabolic Intermediates as Signaling Molecules in Neuroinflammation and Neurodegeneration.},
journal = {Current neuropharmacology},
volume = {},
number = {},
pages = {},
doi = {10.2174/011570159X486332260921110838},
pmid = {42817127},
issn = {1875-6190},
abstract = {Historically, research has viewed substantial brain metabolic activity through the lens of energy production, primarily treating metabolites as substrates and products in bioenergetic pathways. However, this paradigm is now evolving. Key metabolic intermediates are recognized not only as components of Adenosine Triphosphate (ATP) synthesis, but also as potent signaling molecules that establish intricate communication networks. This "metabolic signaling language" profoundly influences inflammation, epigenetics, and cell fate by translating cellular metabolic conditions into certain functional outcomes. In this review, three prototypical metabolites, namely succinate, itaconate, and α-Ketoglutarate (α-KG), were discussed. We investigated succinate accumulation during ischemia and mitochondrial stress, which serves as an early alarm that drives inflammation through both intracellular and extracellular receptor-mediated mechanisms. Conversely, itaconate, an inducible metabolite produced by myeloid cells, exerts inhibitory effects and actively alleviates inflammation by covalently modifying proteins. Finally, we highlighted α-KG, a central metabolic hub that links metabolic status to cellular identity and aging by epigenetically regulating DNA and histone demethylase activity. By summarizing the functions of these metabolites across neurological disorders, including ischemic stroke, Alzheimer's disease, Parkinson's disease, and multiple sclerosis, we delineate a fundamental layer of biological regulation. Deciphering and therapeutic modulation of this metabolic language represent a frontier in neuroscience, offering novel targets for intractable neurological diseases.},
}

@article {pmid42817129,
year = {2026},
author = {Tian, W and Hao, Y and Qiu, S and Chen, Z and Wu, X and Yang, Y},
title = {Genetic Evidence of Association Between Plasma Cathepsin L2 and Alzheimer's Disease: A Mendelian Randomization Study.},
journal = {Current Alzheimer research},
volume = {},
number = {},
pages = {},
doi = {10.2174/0115672050504771260920194040},
pmid = {42817129},
issn = {1875-5828},
abstract = {BACKGROUND: Recent studies have suggested cathepsins, lysosomal cysteine proteases, are associated with Alzheimer's DISEASE (AD). This study conducted Mendelian Randomization (MR) analysis to systematically assess the causal effect of genetically predicted plasma cathepsins levels on AD and AD endophenotypes (cognition and brain structure).

METHOD: Recent large-scale Genome-Wide Association Studies (GWAS) in Europe provided summary statistics on plasma cathepsins, AD, cognition, and brain structure. The primary statistical estimate was employed by Inverse Variance Weighting (IVW). Various sensitivity analysis was performed to draw robust results, including Cochran's Q test, MR-Egger intercept test, and MR PRESSO.

RESULTS: Genetically predicted plasma cathepsin levels were not significantly associated with AD risk. Higher genetically predicted cathepsin L2 levels were associated with better fluid intelligence (β = 0.081, 95% CI 0.029 to 0.133, P = 0.00230, adjusted P = 0.0207). The associations of cathepsin L2 with general cognitive function (β = 0.081, 95% CI 0.010 to 0.152, P = 0.0247, adjusted P = 0.2226) and white matter hyperintensity volume (WMH, β = -0.068, 95% CI -0.134 to -0.002, P = 0.0433, adjusted P = 0.3898) were considered exploratory. Cathepsin L2 was also associated with monocyte count after correction across the three evaluated immune-cell traits (nominal P = 0.0133, FDR-adjusted P = 0.0285); the estimated indirect effect through monocyte count was -0.0016.

DISCUSSION: These findings identify cathepsin L2 as the most consistently associated candidate with fluid intelligence and additional exploratory signals across cognitive, neuroimaging, and peripheral immune-cell phenotypes. The association with monocyte count raises a testable hypothesis regarding a peripheral immune-related pathway. Further studies using larger protein GWAS datasets, stronger genetic instruments, and independent populations are required to validate these findings.

CONCLUSION: Genetically predicted plasma cathepsin L2 levels were associated with fluid intelligence after multiple comparisons. Although the immune-cell analyses raised the possibility of a monocyte-related peripheral pathway, the present findings did not establish a statistically supported mediating effect or a direct protective effect of cathepsin L2 against AD.},
}

@article {pmid42817135,
year = {2026},
author = {Chen, H and Xia, C and Li, Y and Sun, W and Wang, Y},
title = {ZhiXiaoSanZheng Decoction Ameliorates HGPA-induced HK-2 Cell Injury and Mitochondrial Metabolic Imbalance by Regulating the AMPK/PPARα/CPT1A Pathway.},
journal = {Current pharmaceutical design},
volume = {},
number = {},
pages = {},
doi = {10.2174/0113816128525206260914061658},
pmid = {42817135},
issn = {1873-4286},
abstract = {INTRODUCTION: ZhiXiaoSanZheng Decoction (ZXSZD) is a modern clinical Traditional Chinese Medicine (TCM) formula that exerts favorable clinical efficacy in the treatment of Diabetic Kidney Disease (DKD). However, its potential renal tubular protective mechanism remains unclear.

METHODS: Ultra-high-performance liquid chromatography-tandem mass spectrometry was employed to analyze and characterize the chemical ingredients of ZXSZD. An in vitro cell model was established by stimulating HK-2 cells with High Glucose-Palmitic Acid (HGPA) to mimic the metabolic microenvironment of DKD. Oil Red O staining was performed to assess intracellular lipid accumulation. Western blot and immunofluorescence assays were used to determine the protein expression levels of key molecules in the AMPK/ PPARα/CPT1A signaling pathway. Additionally, mitochondrial membrane potential, intracellular ATP content, activities of mitochondrial respiratory chain complexes (I and IV), oxidative stress levels, and concentrations of inflammatory cytokines were quantified.

RESULTS: A total of 141 chemical ingredients were preliminarily identified in ZXSZD. In HGPA-induced HK- 2 cells, ZXSZD significantly attenuated intracellular lipid accumulation, upregulated the protein expression of p-AMPK, PPARα, and CPT1A, ameliorated energy metabolism impairment and mitochondrial dysfunction, and suppressed oxidative stress as well as inflammatory responses.

DISCUSSION: The results indicate that ginkgolide effectively binds and stabilizes the ApoE4 N-terminal domain, supporting its potential role in modulating a key pathological factor in Alzheimer's disease. Its superior pharmacokinetic profile and interaction dynamics compared with those of curcumin and resveratrol suggest broader therapeutic relevance. These in silico insights provide a mechanistic basis for further investigation into ginkgolide's neuroprotective effects.

CONCLUSION: ZXSZD ameliorates energy metabolism impairment and mitochondrial dysfunction in HGPAinduced HK-2 cells by activating the AMPK/PPARα/CPT1A signaling pathway, while also inhibiting oxidative stress and inflammation.},
}

@article {pmid42817632,
year = {2026},
author = {Redeker, V and Melki, R},
title = {Differential proteostasis imbalance and the molecular basis of distinct synucleinopathies and tauopathies.},
journal = {Philosophical transactions of the Royal Society of London. Series B, Biological sciences},
volume = {381},
number = {1960},
pages = {},
pmid = {42817632},
issn = {1471-2970},
support = {//European Union Joint Programme on Neurodegenerative Disease/ ; //EraPerMed/ ; ANR-23-JPW2-0006//Agence Nationale de la Recherche/ ; ANR-21-HBPR-0003-01//Agence Nationale de la Recherche/ ; ANR-22-PERM-0006//Agence Nationale de la Recherche/ ; },
mesh = {*Proteostasis ; *Tauopathies/physiopathology/genetics/metabolism ; Humans ; *Synucleinopathies/physiopathology/genetics/metabolism ; *alpha-Synuclein/metabolism/genetics/chemistry ; *tau Proteins/metabolism/chemistry/genetics ; Proteotoxic Stress ; },
abstract = {This short review discusses the structural and molecular events at the origin of diverse debilitating neurodegenerative diseases. The pathological consequences owing to the primary, secondary, tertiary and quaternary structural diversity of alpha-synuclein and tau proteins and the aggregates they form are presented. The crosstalk between alpha-synuclein and tau proteins aggregates structural heterogeneity and cellular homeostasis, and more precisely the proteostasis network is next considered. Overall, the proteostasis network appears as the master regulator of distinct synucleinopathies and tauopathies progression depending on its capacity to clear and/or disassemble to completion structurally diverse alpha-synuclein or tau fibrillar aggregates or not. This article is part of the Theo Murphy meeting issue 'ProteostaSys: a systems view of proteostasis'.},
}

*Proteostasis
*Tauopathies/physiopathology/genetics/metabolism
Humans
*Synucleinopathies/physiopathology/genetics/metabolism
*alpha-Synuclein/metabolism/genetics/chemistry
*tau Proteins/metabolism/chemistry/genetics
Proteotoxic Stress

@article {pmid42817633,
year = {2026},
author = {Morley, JF},
title = {Proteostasis (in)action: the role of co-pathologies in neurodegenerative disease.},
journal = {Philosophical transactions of the Royal Society of London. Series B, Biological sciences},
volume = {381},
number = {1960},
pages = {},
pmid = {42817633},
issn = {1471-2970},
mesh = {*Proteostasis ; Humans ; *Neurodegenerative Diseases/physiopathology/pathology ; Animals ; Proteotoxic Stress ; Protein Folding ; },
abstract = {Clinically distinct neurodegenerative diseases, including Alzheimer's disease (AD), Parkinson's disease (PD) and amyotrophic lateral sclerosis (ALS), share in common progressive neuronal dysfunction and cell death associated with the accumulation of misfolded proteins. Central to these processes are the cellular and organismal proteostasis networks responsible for maintaining protein homeostasis through coordinated actions of molecular chaperones, the ubiquitin-proteasome system and autophagy-lysosomal pathways. As a consequence of ageing, genetic modifications and other disease-specific conditions, the proteostatic network becomes compromised, leading to the accumulation of toxic protein aggregates that disrupt neuronal function and lead to neurodegeneration. Specific misfolded proteins are associated with each neurodegenerative disease (i.e. α-synuclein in PD, amyloid-β/tau in AD and TAR DNA-binding protein 43/SOD in ALS). However, increasing evidence implicates more complex interactions of co-pathologies across these disorders, as Lewy bodies are common in AD brains and Alzheimer pathology is present in the majority of PD autopsy cases. These observations are consistent with the idea that disruption of proteostasis networks by one aggregation-prone protein could result in misfolding and aggregation of other neurodegeneration-related species. This review will examine the characteristics and consequences of co-pathologies in neurodegenerative disorders. Additionally, the review will outline emerging therapeutic strategies targeted at restoring proteostasis and mitigating the effects of co-pathological processes associated with neurodegenerative diseases. This article is part of the Theo Murphy meeting issue 'ProteostaSys: a systems view of proteostasis'.},
}

*Proteostasis
Humans
*Neurodegenerative Diseases/physiopathology/pathology
Animals
Proteotoxic Stress
Protein Folding

@article {pmid42817639,
year = {2026},
author = {Czyż, DM and Brown, BM},
title = {The microbiota-proteostasis axis: implications in neurodegenerative diseases.},
journal = {Philosophical transactions of the Royal Society of London. Series B, Biological sciences},
volume = {381},
number = {1960},
pages = {},
pmid = {42817639},
issn = {1471-2970},
support = {//American Federation for Aging Research/ ; //Glenn Foundation for Medical Research/ ; },
mesh = {*Proteostasis ; *Neurodegenerative Diseases/microbiology/physiopathology ; *Microbiota ; Humans ; Animals ; },
abstract = {Disruption of protein homoeostasis, or proteostasis, is a hallmark of protein conformational diseases (PCDs), including Alzheimer's and Parkinson's disease. These disorders are characterized by progressive protein aggregation and cellular dysfunction, yet no effective therapies exist. Emerging evidence indicates that microbial communities influence host proteostasis, giving rise to the concept of the microbiota-proteostasis axis. Microbes and their products can modulate host proteins by engaging with host proteostasis. As such, microbial dysbiosis has been linked to proteostasis disruption through the production of metabolites, extracellular vesicles, functional amyloids, and toxins or effector proteins capable of seeding or destabilizing host proteins associated with PCDs. These microbial factors have been shown in experimental models to converge on key proteostasis pathways, including protein synthesis, folding and clearance, thereby potentially reducing cellular buffering capacity and lowering the threshold for proteotoxic collapse. In parallel, microbiota-driven influence on inflammatory responses and immune signalling further amplifies systemic proteostasis disruption. In this review, we synthesize emerging evidence defining the microbiota-proteostasis axis and highlight how microbial factors influence host proteostasis. Importantly, these host-microbe interactions often precede neurodegeneration, suggesting potential for early detection and intervention. Together, these insights support targeting the microbiota as a potential strategy to enhance proteostasis and delay or prevent neurodegenerative disease. This article is part of the Theo Murphy meeting issue 'ProteostaSys: a systems view of proteostasis'.},
}

*Proteostasis
*Neurodegenerative Diseases/microbiology/physiopathology
*Microbiota
Humans
Animals

@article {pmid42817879,
year = {2026},
author = {Zheng, W and Ma, Y and Su, C and Qiu, Z and Yan, Z and Xu, G and Geng, D and Wang, A},
title = {Non-invasive neuromodulation in Alzheimer's disease: toward brain-heart coupling as a candidate framework for biomarker-guided adaptive intervention.},
journal = {Reviews in the neurosciences},
volume = {},
number = {},
pages = {},
pmid = {42817879},
issn = {2191-0200},
abstract = {Alzheimer's disease (AD) has entered an era of biologically informed, disease-modifying therapy, yet durable clinical benefit remains limited, highlighting the need for complementary interventions. Noninvasive neuromodulation has emerged as a promising strategy, but the field is still largely organized by device categories, stimulation targets, and short-term cognitive outcomes. This framing alone does not readily account for the marked heterogeneity, stage dependence, and limited durability reported across studies. This narrative review synthesizes clinical, preclinical, and mechanistic evidence across repetitive transcranial magnetic stimulation, transcranial electrical stimulation, sensory gamma entrainment, focused ultrasound, photobiomodulation, and transcutaneous vagus nerve stimulation. We propose that device classification is a useful starting point but an incomplete explanatory framework, because different modalities have been linked, with varying levels of evidence, to overlapping processes involving network reconfiguration, autonomic regulation, neurovascular function, inflammatory signaling, and clearance-related biology. Against this background, we examine the brain-heart axis and the central autonomic network (CAN) as a candidate intermediate level at which central neural and peripheral physiological responses to stimulation might be jointly characterized. Building on this view, we propose a biomarker hierarchy that extends from heart rate variability to directional and time-varying brain-heart coupling measures, which could be tested as candidate markers of physiological state, target engagement, and treatment responsiveness. At present, however, there is no prospective evidence that brain-heart coupling causally mediates the therapeutic effects of neuromodulation in AD. We, therefore, present brain-heart coupling as a testable candidate framework for studying state dependence, target engagement, and, ultimately, biomarker-guided adaptive neuromodulation.},
}

@article {pmid42817897,
year = {2026},
author = {Fisher, L and Hoang, MN and DuBose, L and Fan, Q},
title = {Psychological and Contextual Factors of AI Acceptance Among Informal Caregivers of People Living With Dementia: Cross-Sectional Pilot Study.},
journal = {JMIR formative research},
volume = {10},
number = {},
pages = {e104072},
pmid = {42817897},
issn = {2561-326X},
mesh = {Humans ; Cross-Sectional Studies ; *Caregivers/psychology/statistics & numerical data ; Female ; Male ; Middle Aged ; *Dementia/psychology/complications/nursing ; Pilot Projects ; Aged ; *Artificial Intelligence/standards/statistics & numerical data ; Adult ; Surveys and Questionnaires ; Aged, 80 and over ; },
abstract = {BACKGROUND: Informal caregivers make up a large share of the care provided to people living with dementia, and experience an elevated risk for anxiety, depression, and caregiving burden. Technology-based interventions, such as mobile apps, aim to support informal caregivers by providing information, training, and mental or social support. Considering the diverse nature of the caregiver experience, AI is being incorporated into such interventions to create more tailored and specific support; however, AI hesitancy may serve as a significant barrier to usage.

OBJECTIVE: The study aimed to preliminarily assess the levels of AI acceptance in adult informal caregivers of people living with dementia, and generate hypotheses regarding the psychological and contextual factors of AI acceptance.

METHODS: Adult, unpaid caregivers were recruited through social media and community partners. A cross-sectional, web-based survey was administered through Qualtrics (Qualtrics, LLC) to evaluate AI acceptance and psychological flexibility (PF). AI acceptance was measured using the Attitude Towards Artificial Intelligence (ATTARI-12) scale, while PF was measured using the Personalized Psychological Flexibility Index (PPFI). Social needs were assessed by the 'Accountable Health Communities Health Related Social Needs (AHC-HRSN) tool (Centers for Medicare and Medicaid Services). Descriptive, correlational, and regression analyses were performed to examine the associations between these factors and AI acceptance.

RESULTS: Overall, 31 informal caregivers of people living with dementia completed the survey. With an average age of 60 (SD 10.6) years old, the majority of caregivers were women (29/31, 94%), Caucasian (25/31, 81%), highly educated (24/31, 77% completed some form of higher education), and currently serving in a caregiver role (21/31, 68%). Mean PPFI and ATTARI-12 scores were moderate (66.4, SD 10.3, and 3.01, SD 0.55, respectively), demonstrating a neutral attitude regarding AI use. In bivariate analyses, ATTARI-12 differed by the caregiver-perceived illness severity (P<.001). Linear regression suggested trends that the PPFI acceptance subscale (β=.05, 95% CI 0.002-0.097; P=.04) was associated with ATTARI-12 scores.

CONCLUSIONS: This study suggests that caregivers' acceptance of such technology may vary according to their care recipient's disease severity and the acceptance subscale of the PPFI. Additionally, the study provides justification for using the ATTARI-12 and PPFI scales to assess AI acceptance and PF in informal caregivers of people living with dementia, respectively. Future research should explore these factors across a larger and more diversified cohort to further generalize and confirm our findings.},
}

Humans
Cross-Sectional Studies
*Caregivers/psychology/statistics & numerical data
Female
Male
Middle Aged
*Dementia/psychology/complications/nursing
Pilot Projects
Aged
*Artificial Intelligence/standards/statistics & numerical data
Adult
Surveys and Questionnaires
Aged, 80 and over

@article {pmid42817909,
year = {2026},
author = {LeBlang, S and Mehta, RI and D'haese, PF and Grinspan, A and Sokolov, A and Frazzetta, G},
title = {Focused ultrasound blood-brain barrier opening: a review of post-procedure MRI outcomes.},
journal = {Expert review of neurotherapeutics},
volume = {},
number = {},
pages = {1-13},
doi = {10.1080/14737175.2026.2737272},
pmid = {42817909},
issn = {1744-8360},
abstract = {INTRODUCTION: Focused ultrasound (FUS) blood-brain barrier opening (BBBo) is an incisionless technique that facilitates cerebral drug delivery by temporarily increasing BBB permeability. Clinical trials have shown that FUS produces reversible BBBo and is feasible in humans. There are currently no standardized imaging protocols for assessing the safety of FUS-BBBo, although MRI is commonly performed.

AREAS COVERED: This structured narrative review summarizes neuroimaging techniques used to assess FUS-BBBo safety in clinical trials of participants with neurological disorders that reported post-procedural MRI findings. A search of PubMed from September 2014 to April 2026 was undertaken to identify clinical trials of FUS-BBBo (13 in patients with brain tumors and 16 in neurodegenerative diseases).

EXPERT OPINION: Localized T2* hypointense signals and T2 hyperintense signals are relatively common after FUS-BBBo. While these findings have been thought to be related to transient microhemorrhage or edema, no consistent association has been found between such findings and clinically significant adverse events. Further work incorporating standardized post-FUS-BBBo MRI safety assessments is needed to clarify the biological significance of these signal alterations, and to determine whether they indicate a potential long-term safety concern, are a harmless finding associated with the BBBo procedure, or are associated with the underlying diseases and/or concomitant drugs.},
}

@article {pmid42817939,
year = {2026},
author = {Karaahmet, B and Lama, T and Wang, A and Cao, W and Menon, V and Klein, HU and Bennett, DA and De Jager, PL and Zhang, Y and Taga, M},
title = {High-Dimensional Multi-Omic Mapping of Post-Mortem Human Brain Using Iterative Indirect Immunofluorescence Imaging on Xenium-Processed Tissues.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.09.16.751033},
pmid = {42817939},
issn = {2692-8205},
abstract = {UNLABELLED: Spatial transcriptomics approaches provide crucial insights into gene expression distribution within intact tissue architecture, but they encounter limitations in detecting morphologically complex cell types, assessing their spatial associations with pathology, and accurately annotating cell types using RNA data alone. Therefore, we developed a robust post-processing workflow integrating Xenium spatial technology with iterative indirect immunofluorescence imaging (4i) on formalin-fixed paraffin-embedded (FFPE) human brain tissue. The post-Xenium 4i protocol presented here allows multi-omic tissue mapping, enabling deeper investigation of pathological microenvironments defined by the spatial distribution of neuropathological hallmarks and enrichment of specific cell populations. We applied this workflow on calcarine cortex tissue sections where cerebral amyloid angiopathy (CAA) burden is present, in addition to amyloid plaques and tau pathology, generating a 15-plex image that captures the complexity of the pathological microenvironment.

MOTIVATION: The expansion of spatial transcriptomics (ST) technologies has enhanced our ability to dissect the complexity and diversity of the molecular organization of the human brain. Among these techniques, the Xenium platform enables high-plex, in situ gene expression profiling at subcellular resolution while preserving tissue architecture, thereby offering powerful insights into tissue organization. However, transcriptomic data can be greatly enriched by the inclusion of morphological, anatomical, pathological, and cellular markers at the protein level. Here, we report a post-spatial profiling workflow that combines the Xenium platform with iterative indirect immunofluorescence imaging (4i) on formalin-fixed paraffin-embedded (FFPE) human brain tissue to capture key pathological features for Alzheimer's disease (AD) and facilitate cell segmentation. This approach enables cost-effective and flexible multiplexed, multi-omic mapping of the same tissue section by registering Xenium transcript data with subsequent 4i immunostaining, which maximizes the RNA quality. Incorporating immunofluorescence (IF)-based cell-type markers alongside RNA profiles enables cell types to be annotated using robust protein markers rather than relying solely on transcriptomic information, thus reducing an important source of noise in downstream analyses. Immunofluorescence staining of FFPE tissue following Xenium processing also preserves cellular morphology, allowing the morphological complexity of distinct cell types to be captured and quantitated, especially for glial cells with highly ramified processes. To demonstrate the practical application of this workflow to AD studies, we developed a proof-of-concept deep learning framework to classify nuclei into specific major cell types of the brain using the IF data. Thus, we present an integrated experimental and analytic workflow optimized for the multi-omic characterization of human brain tissue in an AD context; these pipelines provide spatially resolved insights into pathological microenvironments found in the older human brain and can readily be adjusted to detect other proteins of interest or other pathological features. Altogether, this approach provides a comprehensive view of spatial architecture within pathologically affected regions and enables accurate transcript-independent cell-type annotation.

HIGHLIGHTS: Integrate Xenium and 4i to build a multi-omic map on the same FFPE brain tissueImprovement of cell-type annotationIdentify pathologic features and cross-register them into the transcriptomic and proteomic spatial matrix.},
}

@article {pmid42817989,
year = {2026},
author = {Aceituno, K and Granger, K and Leon, J and Godoy-Lugo, JA and Young, KE and Joseph, T and Liu, K and Kruijff, I and Morales, E and Hakian, M and Birnbaum, A and van der Kant, R and Hill, CM and Cortes, CJ},
title = {Long-term voluntary exercise reveals limited translation of hippocampal molecular responses into neuroprotection in 5xFAD mice.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.09.16.752181},
pmid = {42817989},
issn = {2692-8205},
abstract = {Physical exercise promotes systemic and neural adaptations that support healthy brain aging and may mitigate Alzheimer's disease (AD) progression. However, the capacity of the AD-afflicted brain to mount and translate exercise-responsive molecular adaptations into neuroprotection remains unclear. Here, we examined the effects of long-term voluntary wheel running (VWR) on molecular, neuropathological, and behavioral outcomes in independently studied male and female 5xFAD mice. VWR elicited expected metabolic and transcriptional remodeling of inguinal white adipose tissue, confirming engagement of exercise-responsive peripheral biology. In contrast, hippocampal transcriptional responses were modest, with few differentially expressed genes and coordinated changes emerging primarily at the pathway level. These responses involved synaptic, neuroimmune, mitochondrial, neurotrophic, and monoaminergic processes and differed qualitatively between the two groups. Several components of the canonical hippocampal exercise response also failed to converge into coordinated cellular adaptations: synaptic protein abundance changed without altering synapse density, while neurotrophic, neurogenic, and vascular responses showed little correspondence across molecular and cellular measures. VWR also produced little change in hippocampal amyloid pathology or behavioral function despite sustained exercise engagement. Together, these findings demonstrate that the 5xFAD brain retains modest molecular responsiveness to prolonged voluntary exercise but may be unable to mount a sufficiently robust or coordinated response to produce broad neuroprotective effects. These findings highlight disease context as an important determinant of the efficacy of exercise-based interventions in neurodegenerative disease.},
}

@article {pmid42818016,
year = {2026},
author = {Springer, KS and Driver, FC and Wang, X and Soh, H and Moulema, CD and Flynn, WF and Robson, P and Tzingounis, AV and Jackson, AC},
title = {Spatial organization of voltage-gated ion channel expression across molecularly defined neuronal populations in the mouse mammillary bodies.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.09.15.751911},
pmid = {42818016},
issn = {2692-8205},
abstract = {The mammillary bodies (MB) are a hypothalamic component of the limbic Papez circuit that plays a critical role in spatial and episodic memory in mammals. Degeneration of the MB occurs in disorders associated with cognitive impairment, including Korsakoff's syndrome and Alzheimer's disease, yet the molecular organization and intrinsic properties of MB neurons remain poorly understood. Recent single-cell RNA sequencing identified multiple transcriptionally distinct neuronal populations within the MB and suggested that they differentially express voltage-gated ion channels that regulate neuronal excitability. Here, we used fluorescence in situ hybridization (FISH) to define the anatomical organization of cluster-enriched molecular markers and determine the spatial distribution of transcripts encoding voltage-gated sodium (Na V), potassium (K V), and hyperpolarization-activated cyclic nucleotide-gated (HCN) channels among defined subregions of the mouse MB. We found that marker transcripts occupy characteristic but partially overlapping spatial domains that broadly correspond to classical anatomical subdivisions. In addition, several ion channel transcripts, including Scn1a, Scn2a, Kcnq2, Kcnq3, and Hcn1 , exhibited distinct patterns of enrichment across molecularly defined neuronal populations and MB subregions. Multiplex FISH further revealed unexpected co-expression of Scn1a and Scn2a within Pvalb -enriched neuronal populations, while whole-cell recordings demonstrated distinct intrinsic firing properties of neurons in the lateral and medial mammillary nuclei. Together, these findings establish a molecular framework linking neuronal population identity with voltage-gated ion channel expression in the MB and provide a foundation for future studies investigating how cell type-specific differences in intrinsic excitability contribute to memory function and neurological disease.},
}

@article {pmid42818075,
year = {2026},
author = {Bhatt, NN and Tabrizi, Z and Janulis, J and Chakraborty, S and Weick, M and Franciosa, SA and Rodriguez Moore, G and Agatemor, C and Galvin, JE and Bracko, O},
title = {Reducing Neutrophil Sialic Acid Residues Alleviates Cerebral Hypoperfusion in Alzheimer's Models.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.09.23.753660},
pmid = {42818075},
issn = {2692-8205},
abstract = {OBJECTIVE: Dysregulation of the immune system is increasingly recognized as a contributor to Alzheimers disease (AD) progression, partly through neutrophil adhesion to the cerebral vasculature, which promotes hypoperfusion in AD. Because sialic acid (SA) residues on membrane glycoproteins regulate neutrophil-endothelial interactions, we investigated whether neutrophil sialylation is altered in AD and whether reducing it improves cerebral vascular function.

APPROACH AND RESULTS: Lectin blots of isolated neutrophils showed increased SA levels in two AD mouse models, 5xFAD and APP-SAA. We identified α2,3 sialyltransferase-IN-1 as a small-molecule inhibitor that reduces sialylation in vivo. Treating 5xFAD mice with this inhibitor decreased SA on neutrophil membranes, increased cerebral blood flow, and reduced capillary stalling. Leukocytes from patients with preclinical AD and mild cognitive impairment also had higher SA levels than those from age-matched healthy controls.

CONCLUSIONS: Elevated terminal sialylation of neutrophil glycoproteins contributes to capillary stalling and cerebral hypoperfusion in AD. Neutrophil sialylation may serve as both a biomarker and a therapeutic target for improving cerebral blood flow and slowing disease progression.},
}

@article {pmid42818084,
year = {2026},
author = {Babtie, AC and Blake, GET and Consortium, YG and Clifton, NE and Hawes, T and Barroso, I and Mill, J},
title = {A single-nuclei multiomics resource across four brain regions prioritises human neural cell types influencing brain-related traits.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.09.24.754059},
pmid = {42818084},
issn = {2692-8205},
abstract = {Genetic studies have identified thousands of variants associated with brain-related traits. However, the majority of these map to non-coding regions and their causal roles and functional consequences are unclear. In this study, we profiled gene expression and chromatin accessibility in ∼140,000 individual nuclei from 40 post-mortem adult human brain samples from 11 donors spanning four brain regions (amygdala, hippocampus, hypothalamus and prefrontal cortex). Integrating these data with genome-wide association study statistics allowed us to prioritise specific neural cell populations relevant for complex traits. Concordant with epidemiological evidence, we prioritise similar neuronal cell populations for BMI, schizophrenia, bipolar disorder and age at menarche associated variants. Our paired multiomic data also provides support for putative enhancer-gene relationships relevant to Alzheimer's disease. These data provide a valuable resource to help interpret trait-associated genetic variation and nominate effector transcripts and cellular pathways relevant to brain-related phenotypes.},
}

@article {pmid42818091,
year = {2026},
author = {Sharma, A and Aylar, D and Lapin, D and Marambaud, P and Wang, P},
title = {Extracellular CIRP induces neurotoxic astrocytes via TREM-1 in Alzheimer's disease.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.09.18.752724},
pmid = {42818091},
issn = {2692-8205},
abstract = {Extracellular cold-inducible RNA-binding protein (eCIRP) is a crucial neuroinflammatory mediator in ischemic stroke and alcohol-induced memory impairment. We have recently discovered that amyloidβ causes microglia to release eCIRP, prompting us to investigate its role in Alzheimer's disease (AD). We found that eCIRP levels were significantly elevated in the cerebrospinal fluid (CSF) and plasma of AD patients compared with age-matched non-AD subjects, as well as in hTau.P301S mice (a model of AD tauopathy) compared with wildtype control mice. Plasma eCIRP strongly correlated with astrocyte activation marker glial fibrillary acidic protein (GFAP) in AD patients. eCIRP induced neurotoxic astrocyte-specific genes and astrocyte release of proinflammatory and neurotoxic factors in C8-D1a cells, primary murine astrocytes and intracerebroventricular eCIRP-injected C57BL/6 mice brains. In particular, eCIRP increased Complement 3, an astrocytic marker involved in neuroinflammation-associated neurodegeneration. Primary astrocytes from TREM-1 knockout mice were resistant to eCIRP induction of neurotoxic astrocytes. eCIRP increased TREM-1 expression and activation in astrocytes. Blocking CIRP/TREM-1 interaction using peptide M3, effectively attenuated eCIRP's induction of neurotoxic astrocytes. Thus, eCIRP strongly correlates with astrocyte reactivity in AD patients, and eCIRP induces neurotoxic astrocytes via TREM-1, which is attenuated by M3, suggesting a novel therapeutic opportunity to target neurotoxic astrocytes in AD.},
}

@article {pmid42818094,
year = {2026},
author = {Endresz, N and Fafouti, ME and Arbabi, K and Zhou, X and DeLong, T and Gonzalez-Burgos, G and Duncan, L and Sibille, E and Tripathy, SJ},
title = {Selective depletion of upper-layer somatostatin interneuron subtypes in schizophrenia.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.09.18.752621},
pmid = {42818094},
issn = {2692-8205},
abstract = {Schizophrenia (SCZ) is associated with cortical GABAergic dysfunction, but whether inhibitory interneurons are lost or persist in an altered molecular state remains unresolved. Here, we harmonized seven prefrontal post-mortem single-nucleus RNA-seq datasets onto a fine-grained taxonomy of cortical cell types and meta-analyzed their gene expression and abundance changes in SCZ (298 controls, 171 SCZ). First, we find a subclass-wide reduction of SST mRNA within somatostatin (Sst) neurons. Second, we find reduced abundance (depletion) of a subset of upper-layer Sst interneurons and increased abundance of L6b excitatory neurons, with both changes confirmed in spatial transcriptomics (12 controls, 12 SCZ). Notably, SCZ genetic risk is enriched in the most depleted Sst cells. Depleted Sst subtypes highly express HCN1 , partially correspond to primate-specialized CALB1 -expressing double-bouquet cells, and are among the cells lost earliest in Alzheimer's disease. These upper-layer Sst interneurons constitute an intrinsically vulnerable population and a promising target for neuroprotective and compensatory therapies.},
}

@article {pmid42818102,
year = {2026},
author = {Huang, Y and Toga, AW and Zhao, L and , },
title = {White Matter Slow-4 fALFF as a Complementary Marker in the Multimodal Alzheimer's Disease Biomarker Landscape.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.09.17.752468},
pmid = {42818102},
issn = {2692-8205},
abstract = {INTRODUCTION: White matter (WM) functional activity, quantified as slow-4 fractional amplitude of low-frequency fluctuations (fALFF; 0.027-0.073 Hz), may reflect Alzheimer's disease (AD) pathology, but its utility relative to established structural imaging markers remains poorly characterized.

METHODS: We analyzed 369 ADNI-3 participants with baseline resting-state fMRI. Global WM slow-4 fALFF (JHU-20 atlas) was compared against hippocampal volume, entorhinal cortical thickness, FA, and MD across 11 outcomes: plasma biomarkers (pTau217, Aβ42/40, NfL, GFAP; n = 108), PET (amyloid Centiloid, tau SUVR, FDG; n = 66-207), and cognition (MEM, EF, mPACC, MMSE; n ≈ 222-225) using head-to-head benchmarking and variance decomposition.

RESULTS: WM fALFF was significantly associated with GFAP (partial RZ = 5.35%), amyloid PET (partial RZ = 2.17%), tau PET (partial RZ = 3.52%), executive function (partial RZ = 2.61%), and mPACC (partial RZ = 3.53%). In trimmed models, fALFF explained unique variance in NfL and GFAP beyond FA and MD (unique ΔRZ: 3.65% and 4.45%) - nearly 8-fold greater than DTI's unique contribution for NfL. Gray matter markers showed larger associations with cognition and PET pathology. The incremental value of fALFF was modality-specific: it persisted beyond DTI markers (NfL, GFAP, amyloid PET, executive function, mPACC) and beyond gray matter markers (NfL, GFAP), but in every domain - plasma included - fALFF was no longer significant when all five imaging markers were entered simultaneously.

DISCUSSION: WM slow-4 fALFF captures neurodegeneration-related variance - particularly astroglial reactivity and axonal injury - incremental to DTI microstructure and partially independent of gray matter atrophy. These findings position WM functional activity as a complementary, non-invasive imaging marker in the multimodal AD biomarker landscape.

RESEARCH IN CONTEXT: Evidence before this study: White matter (WM) resting-state BOLD signals carry physiologically valid functional information. WM slow-4 fALFF is reduced in preclinical Alzheimer's disease (AD) and correlates with amyloid burden and cognition. Direct benchmarking against established structural imaging markers within matched samples has remained scarce.Added value of this study: In 369 ADNI-3 participants, we conducted a direct same-sample head-to-head comparison of global WM slow-4 fALFF versus hippocampal volume, entorhinal thickness, global FA, and MD across 11 pre-specified AD biomarker and cognitive outcomes. WM fALFF showed the largest covariate-adjusted association with GFAP (partial RZ = 5.35%) and uniquely explained ∼8× more NfL variance than DTI in trimmed models, contributing non-redundant functional information.Implications of all the available evidence: Global WM slow-4 fALFF, derived from standard resting-state fMRI, is a non-invasive complement to structural imaging that showed associations with markers of astroglial reactivity and neuroaxonal injury, and could augment multimodal AD biomarker panels without additional scanning cost.},
}

@article {pmid42818178,
year = {2026},
author = {Hu, M and Kershaw, A and Brunson, S and Li, Y and Zhao, D and Liu, S},
title = {Cell Type-Specific Structural and Functional Signatures of APOE4, Age and Sex in the Mouse Anterior Olfactory Nucleus.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.09.21.753183},
pmid = {42818178},
issn = {2692-8205},
abstract = {As the strongest genetic risk factor for late-onset Alzheimer's disease (AD), the human APOE ε4 allele alters neuronal physiology before overt pathology. However, how aging and sex modify these effects in the anterior olfactory nucleus (AON), an early AD-affected brain region, remains unclear. Here, we performed whole-cell recordings and post hoc morphological reconstructions of pyramidal cells (PCs) and interneurons (INs) in acute AON slices from adult and aged humanized APOE3 (E3) and APOE4 (E4) knock-in mice of both sexes with identification of context-dependent remodeling across structural, intrinsic, and synaptic domains. In PCs, morphology was broadly susceptible to APOE genotype x age x sex and their interactions. Functionally, aged E4 PCs exhibited a more depolarized resting membrane potential than aged E3 PCs. Additionally, afterhyperpolarization amplitude displayed a marked age x genotype interaction, reversing the direction of the E4 - E3 difference from adulthood to aging. Excitatory synaptic event frequency showed a complex genotype and age and sex interaction, whereas inhibitory synaptic event amplitude was elevated in E4 mice. In contrast, INs displayed far more restricted alterations. Morphological changes were limited to dendritic length, which was modulated by age and sex specifically in E4 mice. Physiologically, genotype effects were confined to action potential amplitude, while aging primarily altered membrane properties and excitatory synaptic inputs. Together, these findings demonstrate that APOE genotype cell-specifically shapes AON neuronal properties through interactions with age and sex, suggesting that APOE4 establishes altered cellular states that influence how this circuit responds to subsequent disease-related stress.},
}

@article {pmid42818216,
year = {2026},
author = {Falvey, A and Palandira, SP and Chaudhry, S and Strohl, JJ and Huerta, PT and Tsaava, T and Tynan, A and d'Abramo, C and Giliberto, L and Koppel, J and Al-Abed, Y and Brines, M and Marambaud, P and Chavan, SS and Chang, EH and Tracey, KJ and Pavlov, VA},
title = {Cholinergic impairment in the dorsal motor nucleus of the vagus during experimental Alzheimer's disease.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.09.19.752906},
pmid = {42818216},
issn = {2692-8205},
abstract = {Cholinergic neurons in the dorsal motor nucleus of the vagus (DMN) in the brainstem are a key source of efferent vagus nerve fibers that regulate vital functions, including heart rate and inflammation. Whether the integrity of DMN cholinergic neurons is affected during Alzheimer's disease (AD) remains unknown. Here, in female and male mice with experimental AD (5xFAD), which exhibit age-dependent memory impairment, basal forebrain cholinergic neurodegeneration, and microglial alterations, we observe a reduction in cholinergic neuron density in the DMN at 6 and 10 months of age. Furthermore, while an important physiological function of DMN cholinergic signaling, such as suppression of heart rate, is preserved in control mice upon electrical DMN stimulation, the extent of suppression diminishes with age in both female and male 5xFAD mice. In addition, while electrical DMN stimulation lowers pro-inflammatory cytokine levels in control mice subjected to endotoxemia, this anti-inflammatory effect is diminished with age in 5xFAD mice, with females showing earlier dysfunction at 6 months. These results reveal previously unrecognized age-dependent cholinergic deficits in the DMN and disrupted brain-to-periphery vagus nerve circuits in experimental AD. These findings advance our understanding of AD mechanisms and are of interest for the development of conceptually novel therapies.},
}

@article {pmid42818221,
year = {2026},
author = {Blanc, V and Griffiths, SJ and Haas, J and Davidson, NO and Lathe, R},
title = {mRNA editing of the Alzheimer's risk gene APOE.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.09.03.749263},
pmid = {42818221},
issn = {2692-8205},
abstract = {UNLABELLED: Variants in the human APOE gene govern the risk of Alzheimer's disease and other disorders. Three major APOE variants in humans reflect C→T replacements at two positions in a single exon: an upstream variant (AE4 site) that differs between the ancestral APOE ε4 allele (APOE4) (C) and human-specific APOE2 / E3 (T), and a downstream variant (AE2 site) that differentiates APOE3 / E4 (C)from APOE2 (T). It has long been assumed that APOE allelotypes are genomically encoded, but here we report that multiple individuals express brain APOE C or U/T variant transcripts that differ from genomically templated versions. We demonstrate up to 10% C→U or U→C nucleotide replacement at AE4 and AE2, but not at other sites, and with no corresponding changes in genomic DNA. Single-cell transcriptomic datasets from brain microglia revealed sporadic (up to ∼8%) C→U replacement at AE2. We found 0.4-1.6% of brain transcripts in human APOE knock-in mice harbor selective C→U changes at either AE4 or AE2 sites. Transfection of HepG2 or Huh7 cells with either mouse or human APOBEC1 led to efficient (>90%) C→U editing of APOE4 mRNA at the AE4 but not AE2 site, with lower (<10%) C→T editing of genomic DNA at the AE4 site by mouse, but not human, APOBEC1. Furthermore, interrogation of proteomic datasets revealed up to 4% of non-genomically encoded APOE peptides in human plasma, indicating that the edited APOE transcripts are functional in vivo . These data suggest that APOE mRNA is subject to RNA editing that interconverts the different allelic forms of APOE .

AUTHOR SUMMARY: Human APOE gene variants govern the risk of Alzheimer's disease (AD) and other disorders. Three alleles are widespread: ancestral E4 and human-specific E3 and E2 . AD risk declines in the order E4 > E3 > E2 . It has been assumed that the APOE allotype we inherit is laid down at birth, but we report that APOE mRNA is enzymatically edited to convert E4 to E3 / E2 , and/or E2 to E3 / E4 . Up to ∼10% conversion was seen in brain, and up to 100% in vitro driven by the RNA-editing enzyme APOBEC1. Proteomic analysis of human plasma argues that edited APOE transcripts are functional in vivo .},
}

@article {pmid42818224,
year = {2026},
author = {Jin, B and Li, Z and Hao, Y and Kowal, I and Epstein, J and Santiana, M and Weller, C and Nalls, MA and Tao, D and Fang, S and Narayan, P and Singleton, AB and Keuren-Jensen, KV and Ferrucci, L and Ward, ME and Cookson, MR and Lara, E and Ryan, VH and Qi, YA},
title = {Profiling of Aggregated Amyloid β42-induced Proteomic Alterations in KOLF2.1J Induced Pluripotent Stem Cell-derived Neurons.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.09.20.753014},
pmid = {42818224},
issn = {2692-8205},
abstract = {Amyloid[beta]; (A[beta];) plaques are a hallmark of Alzheimer[prime]s disease (AD). A human cellular neuronal model that recaptures A[beta];-induced pathology is critical for advancing AD research. However, comprehensive proteomic profiling of A[beta];-induced cellular model remains elusive. In this study, we investigated the proteomic changes in induced pluripotent stem cell (iPSC)-derived neurons (iNs) exposed to synthetic A[beta]; (1-42) peptides (A[beta];42A) to improve our understanding of the cellular responses of A[beta]; aggregates and to establish a human-related platform for AD research. A[beta];42A formed extracellular aggregates around neuronal soma and neurites, impaired neurite outgrowth, and induced the expression of multiple AD-associated genes, such as APOE, BACE1, ADAM10. To define the molecular landscape of A[beta];-induced neuronal dysfunction, we performed proteomic analyses of whole-cell lysates as well as soma- and neurite-enriched fractions. Proteomic profiling revealed extensive gene alterations in pathways associated with synaptic function, neuronal maintenance, and AD pathogenesis, such as the upregulation of APOE. Importantly, the A[beta];42A-iNs system recapitulated molecular signatures observed in AD brain tissue and cerebrospinal fluid. Representative protein changes, including APOE upregulation and its colocalization with A[beta]; aggregates, were further validated in postmortem human AD brain tissue. Together, these findings manifest that the A[beta];42A-iNs system reproduces multiple cellular and molecular features of AD and exhibits strongly consensus with clinical observations. It provides a valuable platform for investigating A[beta];-driven neurodegeneration and for the discovery of therapeutic targets for AD.},
}

@article {pmid42818366,
year = {2026},
author = {Nadarajah, CJ and Li, MY and Park, S and Lawrence, JH and Sharma, A and Danhash, EP and Karch, CM and Musiek, ES},
title = {Complement component C4 regulates amyloid pathology and glial reactivity in mouse model of Alzheimer's Disease.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.09.09.750237},
pmid = {42818366},
issn = {2692-8205},
abstract = {The complement system, a proteolytic cascade crucial for innate immune system function, is dysregulated in brain aging and neurodegenerative diseases, including Alzheimer Disease (AD). In models of AD, complement proteins, including C1q and C3, are upregulated and mediate microglial clearance of amyloid plaques and pruning of synapses. Among complement genes, C4b , which in mice encodes complement protein C4, is the most highly upregulated in astrocytes in the setting of aging and amyloid pathology. While C4 plays a key role in the complement cascade, there have been no investigations of the direct role of C4 in regulating AD pathology. To probe the function of C4 in amyloid plaque-related pathology, we crossed a germ line C4b knockout mouse (C4 KO) to the 5XFAD mouse model of AD-related amyloidosis. To our surprise, we observed striking reductions in amyloid plaque pathology across multiple brain regions in 5XFAD-C4 KO mice relative to standard 5XFAD controls. This reduction in plaque burden stands in sharp contrast to previous reports of C3 deletion in AD models, which increases plaques. Additionally, we observed a reduction in neuroinflammation and peri-plaque glial clustering in 5XFAD-C4 KO mice, suggestive of a role for C4 in regulating overall neuroinflammatory tone in AD. Finally, we observed a phenotypic shift of the peri-plaque microglia to a more reactive disease-associated microglia (DAM) phenotype, indicating that C4 could be an important factor in regulating microglial reactivity in AD. Altogether, our results demonstrate that C4 may have functions beyond the classical complement cascade and may serve as a key facilitator of AD-related glial function and pathology and a possible target for therapeutic modification.},
}

@article {pmid42818374,
year = {2026},
author = {Tüchler, SM and Falb, P and Milz, C and Murgaš, M and Reed, MB and Graf, S and Schlosser, G and Schmidt, C and Mayerweg, A and Klug, S and Pörnbacher, I and Artmeier, L and Harouak, A and Sahl, A and Grohmann, M and Nics, L and Godbersen, GM and Rasul, S and Rujescu, D and Hacker, M and Lanzenberger, R and Hahn, A and , },
title = {Network-specific metabolic cost of functional connectivity in the human brain.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.09.09.750304},
pmid = {42818374},
issn = {2692-8205},
abstract = {Despite decades of extensive research, the complex architecture underlying human brain signaling remains incompletely understood. Previous work investigating the relationship between brain glucose metabolism and functional connectivity (FC) employed whole-brain analysis, without accounting for network interactions, dependencies or hierarchies. Here, we assess network-specific differences in the relationship between FC and metabolic demand, using [18F]FDG PET/MR data from three independent datasets. The metabolic cost of FC, i.e., the change in glucose demand associated with corresponding changes in FC, was modeled at rest, during cognitive task performance and in Alzheimer's disease (AD). Our findings reveal network-specific differences in metabolic cost, with the default mode (DM), somatomotor (SM) and fronto-temporal networks accounting for highest, intermediate and lowest metabolic demands, respectively. Similarly, time-resolved variability of FC demonstrated highest costs for states with DM network involvement and lowest for SM network participation. This relationship was reversed in participants with AD, who exhibited decreased demands in the DM network and increased costs in the SM network. Cognitive performance consistently revealed cost reductions in the DM and SM networks, as well as increases in task relevant networks. Together, these results highlight the flexibility of functional network architecture associated with cognitive demands and neuropathology, and shed light on the complex interplay between glucose metabolism and network interactions.},
}

@article {pmid42818390,
year = {2026},
author = {Sloan, LJ and Garceau, DT and Ryan, NJ and Pomeroy-Tuck, J and Chidambaram, R and Ragan, T and Pandey, RS and Bloss, EB and Carter, GW and Oblak, AL and Sasner, M},
title = {Characterization of the knock-in App [SAA] mouse model as a powerful tool for Alzheimer's disease preclinical research.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.09.08.750179},
pmid = {42818390},
issn = {2692-8205},
abstract = {BACKGROUND: Preclinical Alzheimer's disease (AD) research requires models with age-dependent, physiologically relevant amyloid pathology, unlike overexpression in transgenic lines. We characterized the humanized App [SAA] knock-in model to define translationally relevant therapeutic windows.

METHODS: Homozygous App [SAA] and control mice were evaluated from 4 to 19 months using whole-brain 3D plaque imaging, cerebral amyloid angiopathy (CAA) quantification, multiplex neuropathology, brain transcriptomics, and plasma biomarkers. Hippocampal synaptic analysis and context-dependent memory was performed at 12 months.

RESULTS: Plaques, CAA, plaque-associated neuroinflammation, and dystrophic neurites accumulated with age. By 12 months, brain transcriptomes aligned with human AMP-AD co-expression modules, and plasma pTau-217, GFAP, and SNAP25 rose with age. App [SAA] mice retained associative memory but showed memory interference and CA1 dendritic-spine loss that was exacerbated in proximity to plaques.

CONCLUSIONS: App [SAA] mice recapitulate age-dependent, human-relevant AD phenotypes with defined therapeutic windows for preclinical research. The model is available without restriction from The Jackson Laboratory.},
}

@article {pmid42818396,
year = {2026},
author = {Biglari, S and Yeragi, E and Bamisaye, D and Gonzalez, C and Garcia, R and Losoya, A and Arekere, AD and Payne, C and Moulton, MJ and Keene, AC},
title = {Progressive behavioral and cognitive decline in Drosophila harboring AD- associated APOE4 variants.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.09.08.750261},
pmid = {42818396},
issn = {2692-8205},
abstract = {Alzheimer's disease (AD) is the most prevalent neurodegenerative disorder, and its incidence is rising rapidly with population aging. Pathologically, AD is characterized by the accumulation of amyloid-β (Aβ) plaques and hyperphosphorylated Tau neurofibrillary tangles. Human genomic studies have identified numerous risk alleles, with the APOE4 variant representing the strongest and most common genetic risk factor, present in approximately 75% of AD patients. However, APOE4 is neither necessary nor sufficient to cause disease, suggesting that additional genetic and environmental factors contribute to AD pathogenesis. Emerging evidence highlights a central role for oxidized lipid metabolism in AD. Disruption of lipid metabolism leads to lipid accumulation, reactive oxygen species (ROS) toxicity, and neurodegeneration, suggesting that oxidative stress may be a critical factor in enhancing AD susceptibility. To systematically investigate APOE function in vivo , we tested humanized Drosophila expressing the human APOE3, or APOE4 variants in place of the Drosophila ortholog Glial Lazarillo (GLaz). The lifespan of APOE3 and APOE4 flies do not differ under standard housing conditions, but the lifespan of APOE4 flies is significantly reduced when exposed to the ROS-promoting drug rotenone, supporting a multi-hit model of disease pathogenesis. APOE4 flies exposed to rotenone exhibit several AD-associated phenotypes, including age-related memory loss and chemosensory deficits, supporting the use of this model to investigate AD pathogenesis. Furthermore, progressive AD-associated phenotypes are also observed in APOE4 flies maintained on an obesogenic diet, suggesting that enhanced disease susceptibility is not specific to rotenone-induced stress but reflects a broader vulnerability to metabolic challenges. Together, these findings establish a scalable model to dissect APOE-dependent mechanisms and identify therapeutic targets in AD.},
}

@article {pmid42818400,
year = {2026},
author = {Algamal, M and Yokomizo, S and Ndambakuwa, W and Abdallah, S and Sanchez-Mico, MV and Gillani, R and da Silva, P and Rajput, A and Palanivelu, L and Lee, Y and Walsh, KR and Kumar, S and Kilic, K and El Khoury, J and Izzy, S and Kozberg, MG and Bacskai, BJ},
title = {Brain-resident myeloid cells promote rapid leukocyte adhesion in leptomeningeal vessels after anti-Aβ immunotherapy.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.09.07.749938},
pmid = {42818400},
issn = {2692-8205},
abstract = {Anti-amyloid-β (Aβ) immunotherapy improves cognitive outcomes in Alzheimer's disease (AD) but is associated with amyloid-related imaging abnormalities (ARIA), through poorly understood mechanisms. To define how anti-Aβ antibodies acutely engage brain immune and vascular compartments, we developed a longitudinal in vivo two-photon imaging platform to track microglial dynamics, peripheral immune cell recruitment, and vascular responses in APP/PS1 mice. Anti-Aβ antibodies, including aducanumab and lecanemab, rapidly initiated microglial activation and spatial reorganization within 24 hours of dosing, with recruitment to plaque-associated regions, stabilizing plaque growth. Aducanumab and lecanemab also triggered a rapid and transient cerebrovascular immune response characterized by rolling and adhesion of peripheral immune cells along leptomeningeal vessels, accompanied by endothelial activation. Immune cell characterization revealed recruitment of innate immune cells (Iba1[+]Ki67[+] monocytes and Ly6G[+] neutrophils) and proliferative CD3[+] T cells into the vascular compartment following treatment. Prophylactic treatment with high-dose dexamethasone reduced the number of adherent cells without affecting microglial activation. Depletion of brain-resident immune cells similarly reduced peripheral immune cell recruitment, supporting their contribution to leukocyte recruitment. Postmortem brain tissue from an AD patient treated with lecanemab showed higher proliferation-associated monocyte signature scores, suggesting translational relevance to the proliferative myeloid response observed in our mouse models. These findings demonstrate that anti-Aβ immunotherapy rapidly initiates a coordinated central and peripheral immune response at the leptomeningeal interface. These early immune-vascular interactions represent a plausible initiating mechanism for ARIA and provide a mechanistic framework to guide strategies for mitigating ARIA risk.},
}

@article {pmid42818402,
year = {2026},
author = {Ward, EL and Nelson, PT and Katsumata, Y and Fardo, DW and Jicha, GA and , and Miller, JB},
title = {Alzheimer's Polygenic Risk Scores Are Not Interchangeable: Evidence from 1,752 Models.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.09.02.26362060},
pmid = {42818402},
abstract = {INTRODUCTION: Polygenic risk scores (PRS) may improve Alzheimer's disease (AD) risk prediction before symptom onset, yet choosing an appropriate model can be challenging.

METHODS: Using the standardized GenoPred pipeline, 1,752 PRS models (9 algorithms; 584 configurations; 3 genome-wide association studies) were evaluated and stratified by genetic ancestry and APOE diplotype. PRS models were evaluated using 11,200 clinical or autopsy-confirmed AD cases and 19,321 controls age ≥65 from the Alzheimer's Disease Sequencing Project Release 5.

RESULTS: PRS results were not consistent across methodologies (Spearman's ρ: -0.49 to 1), with >95% of individuals having PRS in both the top and bottom risk deciles. Top-performing PRS were effective at stratifying AD risk across ancestries (AFR: P =2.04×10 [-] [26] ; AMR: P =4.57×10 [-21] ; EAS: P =6.21×10 [-40] ; EUR: P =7.90×10 [-187]).

DISCUSSION: PRS parameters should be optimized for each ancestry. Contradictory signals across methodologies underscore the need for carefully choosing suitable PRS methods and fine-tuning algorithmic parameters to ensure accuracy and consistency.

DATA AVAILABILITY: Access to the ADSP is controlled by The National Institute on Aging Genetics of Alzheimer's Disease (NIAGADS). All scripts used to analyze the data are freely available at https://github.com/jmillerlab/prs_comparisons .},
}

@article {pmid42818410,
year = {2026},
author = {Stricker, NH and Boots, EA and Taylor, R and Fan, WZ and Frank, RD and Christianson, TJ and Stricker, JL and Kremers, WK and Machulda, MM and Aduen, PA and Lucas, JA and Hughes, MA and Karstens, AJ and Day, GS and Lachner, C and Graff-Radford, NR and Hassenstab, J and Mielke, MM and Jack, CR and Boeve, BF and Graff-Radford, J and Petersen, RC},
title = {Diagnostic accuracy of remote self-administered digital cognitive assessment by clinical diagnosis and Alzheimer's disease PET imaging biomarkers.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.09.20.26362296},
pmid = {42818410},
abstract = {INTRODUCTION: Cognitive characterization is increasingly important for Alzheimer's disease treatment decisions, highlighting the need for scalable cognitive assessment. We evaluated the diagnostic accuracy of a remote self-administered cognitive screening battery, Mayo Test Drive (MTD), across clinically and biologically defined groups.

METHODS: In this prospectively designed study, 2,131 cognitively unimpaired (CU) and 118 cognitively impaired participants, including 96 with mild cognitive impairment and 22 with mild dementia (MCI/DEM), were recruited from observational cohort studies and completed MTD remotely (mean age=70 years, SD=12; 48% male; mean education=16 years, SD=2). Clinical diagnoses were determined by multidisciplinary consensus independently of MTD. Amyloid- and tau-PET were available for 1,224 participants. Logistic regression estimated associations between MTD and CU versus MCI/DEM, CU A-versus MCI/DEM A+, and A-T-versus A+T+. MTD diagnostic accuracy was compared with person-administered cognitive measures. Sensitivity and specificity across score types and comparison groups were examined.

RESULTS: MTD showed excellent discrimination of CU versus MCI/DEM (AUC=.89; 95% CI=.87-.92), and discriminability remained high for CU versus MCI (AUC=.88; 95% CI=.85-.92). Discriminability was highest when comparing CU A- and MCI/DEM A+ groups (AUC=.95; 95% CI=.92-.97). MTD outperformed estimated MMSE (p=.02) and was comparable to Mayo-PACC (p=.71) for A-T-versus A+T+ discrimination (AUC=.76; 95% CI=.71-.81). Combining both raw score and normative score cutoffs helped balance sensitivity and specificity relative to use of either cutoff in isolation. A two-stage interpretation framework further improved sensitivity while maintaining clinically useful specificity and informed development of an interpretation guide.

DISCUSSION: A remote self-administered digital cognitive assessment showed strong diagnostic accuracy for detecting MCI and mild dementia in a large, primarily population-based cohort. The remote, self-administered MTD composite also showed comparable performance to established in-person cognitive composites for differentiating amyloid and tau-defined biomarker groups. Remote self-administered digital cognitive assessment may complement existing cognitive evaluation approaches and support scalable cognitive characterization.

HIGHLIGHTS: Remote self-administered cognitive assessment showed strong differentiation of cognitively unimpaired and cognitively impaired participants.Diagnostic accuracy improved when amyloid PET biomarker status was incorporated.Remote assessment demonstrated sensitivity to amyloid and tau PET-defined Alzheimer's disease.Performance was comparable to established in-person composites and better than an in-person mental status screening measure.Digital cognitive screening may support scalable treatment and clinical trial workflows.},
}

@article {pmid42818413,
year = {2026},
author = {Kamal, F and Metz, A and Chadwick, K and Moqadam, R and Morrison, C and Dadar, M and , and , and , },
title = {Predicting Conversion from SCD to MCI: A Machine Learning Study.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.09.04.26362240},
pmid = {42818413},
abstract = {BACKGROUND: Subjective cognitive decline (SCD) may precede mild cognitive impairment (MCI), but not all individuals with SCD progress to MCI. Identifying which individuals are most likely to convert and over what time frame remains an important goal in Alzheimer's disease research. MRI measures of white matter hyperintensity (WMH) burden and gray matter (GM) atrophy may improve prediction beyond demographic and cognitive predictors, but their incremental value across different time intervals has not been established.

METHODS: Data were obtained from four longitudinal cohorts (ADNI, NACC, CIMA-Q, and PREVENT-AD). A total of 1,352 participants with SCD at baseline were included. Machine learning models (logistic regression, random forest, XGBoost) were used to predict conversion from SCD to MCI at 2 years, 3 years, 4 years, and 5-year horizons. Four feature sets were compared: base (age, sex, education, APOE4, hypertension), base and cognition (adding MoCA and Trail Making Test Part B), base and MRI (adding regional WMH and GM volumes), and combined (all features).

RESULTS: The base and MRI set achieved the highest Area Under the Curve (AUC) at the 3-year (0.900), 4-year (0.879), and 5-year (0.923) horizons. The combined set achieved the highest AUC at the 2-year horizon only (0.884). MRI features produced larger AUC gains over the base model than cognitive features at the 3, 4, 5-year horizons. Parietal WMH was the most frequently selected MRI predictor.

CONCLUSIONS: MRI features, particularly regional WMH and GM volumes, provided greater predictive value than cognitive features at longer prediction horizons. A select number of regional MRI features predicted SCD to MCI conversion with high accuracy up to 5 years in advance.},
}

@article {pmid42818421,
year = {2026},
author = {Wang, J and Pederson, AM and Flanders, MD and Choi, M and Buto, P and Sims, KD and Chen, R and Couch, E and Gilsanz, P and Hayes, KN and Zullo, AR and Stokes, A and Glymour, MM and Ackley, SF},
title = {Education and Alzheimer Disease Genetic Risk in Associations of GLP-1 Receptor Agonists With Dementia Among Adults With Type 2 Diabetes.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.09.04.26362304},
pmid = {42818421},
abstract = {OBJECTIVE: To evaluate whether educational attainment and Alzheimer disease genetic risk were associated with GLP-1 receptor agonist initiation and dementia incidence and whether adjustment for these measured factors materially changed the estimated association between GLP-1 receptor agonist initiation and incident dementia among adults with type 2 diabetes.

RESEARCH DESIGN AND METHODS: We conducted an observational cohort study using linked electronic health record, survey, and genetic data from 14,364 All of Us Research Program participants with type 2 diabetes. We estimated associations of educational attainment and Alzheimer disease genetic risk with treatment initiation and incident dementia and compared GLP-1 receptor agonist initiators with initiators of non-sodium-glucose cotransporter 2 inhibitor second-line therapies, with a separate sodium-glucose cotransporter 2 inhibitor comparison. Models were estimated before and after additional adjustment for educational attainment, APOE ε4, and non-APOE genetic risk.

RESULTS: Among 14,364 participants (mean age, 60.2 years; 54.2% female), the mean follow-up duration was 4.3 years. The estimated hazard ratio for dementia comparing GLP-1 receptor agonist initiation with non-SGLT2 inhibitor second-line therapy was 0.85 (95% CI 0.64-1.12) before adjustment for education or Alzheimer disease genetic risk and 0.84 (95% CI 0.64-1.12) after adjustment for educational attainment, APOE ε4, and non-APOE genetic risk.

CONCLUSIONS: Among adults with type 2 diabetes, adjustment for measured educational attainment and Alzheimer disease genetic susceptibility produced little change in the estimated association between GLP-1 receptor agonist initiation and incident dementia. These findings do not exclude confounding by these factors in other populations or residual confounding from socioeconomic, clinical, behavioral, and health-care-related factors.

HIGHLIGHTS: Observational studies have reported associations between GLP-1 receptor agonist use and lower dementia risk, but important social and genetic factors are often unavailable in electronic health record data.We examined whether educational attainment and Alzheimer disease genetic susceptibility were associated with treatment initiation and dementia and whether adjustment for these factors changed GLP-1 receptor agonist-dementia estimates.Adding measured education and genetic susceptibility produced little change in the estimated conditional hazard ratios.These results do not exclude residual confounding and should not be interpreted as evidence that GLP-1 receptor agonists prevent dementia.},
}

@article {pmid42818430,
year = {2026},
author = {Zhou, S and Borkowski, K and Liang, N and Beach, TG and Serrano, GE and Kim, K and Newman, JW and Maezawa, I and Jin, LW},
title = {Distinct lipid mediator profiles in brain and liver tissues in Alzheimer's disease.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.09.22.26363708},
pmid = {42818430},
abstract = {INTRODUCTION: Inflammation plays a central role in Alzheimer's Disease (AD), with oxylipins, endocannabinoids, and polyunsaturated fatty acids (PUFAs) acting as potent modulators. Soluble epoxide hydrolase (sEH), an enzyme with proinflammatory products, is upregulated in the AD brain. Emerging evidence suggests that AD-related inflammation may reflect systemic metabolic changes, however, peripheral organs remain understudied. Because the liver has a pivotal role in lipid metabolism and bioactive lipid mediator homeostasis, we hypothesized that inflammatory lipid mediator changes in the AD brain may be reflected in, and potentially shaped by, hepatic lipid metabolism.

METHODS: Paired postmortem brain and liver tissues from 16 cognitively normal and 63 AD donors with median postmortem intervals (PMI) of 3.08 hours were analyzed for free and esterified forms of oxylipins and endocannabinoids. ANCOVA models evaluated effects of AD diagnosis, sex, and AD-by-sex interactions, adjusting for analytical batch, age, body mass index, and PMI.

RESULTS: AD-associated differences in lipid mediator profiles were observed in both brain and liver, with a broader pattern of differences in liver. Differences involved CYP/sEH-related metabolites and fatty acid ethanolamides, with several metabolites also showing AD-by-sex interactions. Sex-associated differences were also more pronounced in the liver than the brain.

DISCUSSION: These results suggest AD-associated lipid dysregulation across both central and peripheral tissues. The prominent hepatic alterations highlight the liver as an important site of peripheral lipid mediator dysregulation in AD and suggest that hepatic metabolic changes may contribute to or reflect inflammatory lipid remodeling in the brain.},
}

@article {pmid42818458,
year = {2026},
author = {Valdespino, R and Hromas, G and Wang, CP and Paul, R and Nakasujja, N and Reynolds, Z and Atwiine, F and Tindimwebwa, E and Greene, M and Passell, E and Ritchie, CS and Hoeppner, SS and Tsai, AC and Seeley, J and Werry, A and Varfaj, E and Seshadri, S and Okello, S and Asiimwe, S and Saylor, D and Possin, KL and Tsoy, E and Siedner, MJ and Tanner, JA},
title = {Adaptation and Validation of Brief Tablet-Based Cognitive Assessment Tool in Uganda.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.09.21.26363152},
pmid = {42818458},
abstract = {BACKGROUND: Sub-Saharan Africa (sSA) faces accelerated growth in Alzheimer's disease and related dementias (ADRDs), including in older people living with HIV (PLWH). However, there are limited contextually relevant diagnostic tools to assess cognitive impairment in the region. The Tablet-based Cognitive Assessment Tool (TabCAT) is a digital platform hosting cognitive tests with automated scoring that can be administered by non-specialists and are designed for use across diverse cultures, languages, and education levels. We translated, adapted, and assessed the validity of a brief battery of TabCAT tests in the Uganda Aging and Dementia Cohort Study (UADCS), a prospective cohort of older PLWH and age- and sex-similar adults not living with HIV in southwestern Uganda.

METHODS: Four TabCAT tests were translated and culturally adapted through expert review and focus groups of adults at study sites. Psychometric validity was examined by assessing floor and ceiling effects, association with known demographic predictors, and concurrent and divergent validity against a reference-standard cognitive testing battery previously validated and employed in Uganda. Z-scores on all tests were derived using a regression-based normative approach to adjust for age, sex, education, urbanicity, and literacy. Receiver Operating Characteristic (ROC) curves were fit to assess the TabCAT Composite Score performance in discriminating objective cognitive impairment (defined using Jak/Bondi criteria) in the total sample, then stratified by HIV serostatus.

RESULTS: TabCAT tests were reported by local experts and focus groups to have acceptable face and content validity. Participants (n=563, mean age 60±6.4, 50% female, 51% did not complete primary school, 16% were not literate, 49% PLWH) completed the reference-standard and TabCAT battery. For TabCAT tests, there were no notable floor or ceiling effects, and test scores were associated with age and education as expected. Correlations between TabCAT and reference-standard tests were stronger in aligning cognitive domains (memory, executive function) than in non-aligning domains (motor). The TabCAT Composite Score discriminated cognitive impairment with good performance (c-statistic 0.77; 95% CI 0.72-0.81), including among PLWH.

DISCUSSION: TabCAT tests demonstrated face, content, construct, concurrent, and criterion validity for measuring cognition and detecting objective cognitive impairment among older adults in Uganda, including PLWH. These results support the potential of tablet-based brief cognitive assessment tools to measure cognitive performance and detect cognitive impairment in Uganda, including among older PLWH, and in populations with lower levels of education and literacy.},
}

@article {pmid42818464,
year = {2026},
author = {Li, X and Zhang, W and Wang, R and Tint, H and Fu, S and Quan, Q and Liang, F and Tint, C and Yuan, X and Liang, Y and Jiang, Y and Cao, W and Dong, Y and Zhao, Y and Saroukani, S and Zhang, Y and McCullough, L and Eltzschig, HK and Turan, A and Sessler, DI and Karikari, TK and Xie, Z},
title = {Elevation in Plasma p-tau217 Concentrations Among Blood Donors: An Exploratory Cross-Sectional Study.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.09.23.26363733},
pmid = {42818464},
abstract = {IMPORTANCE: Phosphorylated tau at threonine 217 (p-tau217) and brain-derived tau (BD-tau) are increasingly used as blood biomarkers of Alzheimer's disease (AD) and related neurological disorders. However, the distributions and biological correlates of elevated plasma p-tau217 and BD-tau in plasma from individuals eligible for blood donation remain unclear.

OBJECTIVE: To estimate the proportions of plasma p-tau217 and BD-tau exceeding exploratory study-specific thresholds, and examine associated inflammatory and transcriptomic features.

DESIGN: Cross-sectional study.

SETTING: Hospital blood bank.

PARTICIPANTS: 257 de-identified donor samples were obtained between September 2025 and June 2026. Plasma samples from 30 population reference participants and 20 AD patients were used to derive study-specific thresholds. Complementary transcriptomic analyses were performed in 29 fresh whole blood samples.

MAIN OUTCOMES AND MEASURES: The primary outcome was the proportion of donor samples exceeding the study-specific ROC-derived Youden threshold. The proportion exceeding the prespecified published p-tau217 threshold was the secondary outcome. Other measures included plasma concentrations of BD-tau, tumor necrosis factor α (TNF-α), and interleukin 6 (IL-6); correlations among plasma p-tau217, BD-tau and inflammatory cytokines; and associated transcriptomic alterations.

RESULTS: Plasma p-tau217 concentrations exceeded the study-specific ROC-derived Youden threshold in 53 of 256 donor samples (21%; 95% CI, 16%-26%) and the published threshold, used for a secondary comparison, in 99 of 256 samples (39%; 95% CI, 33%-45%). Plasma BD-tau concentrations exceeded the study-specific threshold in 89 of 257 samples (35%; 95% CI, 29%-41%). Plasma p-tau217 concentrations were positively associated with plasma TNF-α (Kendall's τ = 0.339; P < .001) and IL-6 (Kendall's τ = 0.310; P < .001) concentrations. Exploratory transcriptomic analyses identified gene expression patterns associated with p-tau217 concentrations. Measurement using a second p-tau217 antibody showed the similar findings.

CONCLUSIONS AND RELEVANCE: Plasma p-tau217 and BD-tau concentrations exceeded exploratory study-specific thresholds in a subset of blood-donor samples, and higher p-tau217 concentrations were associated with inflammatory biomarkers and exploratory transcriptomic differences. These findings raise the possibility of elevated circulating tau species in some blood donors, but their clinical significance requires confirmation. Whether elevated circulating p-tau217 in donated blood has biological consequences for transfusion recipients is unknown, but deserves investigation.

KEY POINTS: Question: How commonly are plasma p-tau217 and brain-derived tau concentrations elevated in blood donors, and are these elevations associated with systemic inflammatory and transcriptomic signatures? Findings: In this cross-sectional study of 257 blood-donor samples, 21% of evaluable samples exceeded the study-specific p-tau217 threshold and 35% exceeded the BD-tau threshold. Higher p-tau217 concentrations were associated with inflammatory biomarkers and exploratory differences in gene expression. Meaning: These findings raise the possibility of elevated circulating tau species in blood donor, although confirmation is needed to establish whether these concentrations represent clinically meaningful elevations.},
}

@article {pmid42818466,
year = {2026},
author = {Henley, B and Yang, Z and Sober, J and Calhoun, V and Goldstein, F and Hajjar, I},
title = {A neurocognitive speech taxonomy for voice biomarkers of Alzheimer's disease.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.09.23.26363671},
pmid = {42818466},
abstract = {INTRODUCTION: Voice data combined with large language models may detect cognitive impairment, yet an interpretable framework has not been formally established. We developed and validated a scalable and interpretable framework, the Neurocognitive Speech Taxonomy (NST).

METHODS: NST maps 314 voice features to 7 neurocognitive domains derived from neuropsychology, speech pathology, neurology and related fields. The domains capture features including articulatory precision, cognitive-linguistic, executive fluency & planning, phonation & laryngeal control, prosodic modulation, lexical-semantic, and morphosyntactic complexity. We evaluated NST structural stability, clinical validity and racial-educational equity in three cohorts (total N = 1,479). Cohort data included demographic and neuropsychological evaluations and AD biomarker status. We tested whether NST scores distinguish cognitive status (unimpaired vs impaired) and AD-biomarker status, track cognitive change, and correlate with AD neuroimaging measures.

RESULTS: NST showed stable cross-cohort structure (Mantel r = 0.71-0.77) and differentiated MCI (d = -0.39) and AD biomarker status (d = -0.23). NST tracked longitudinal cognitive change, correlated with hippocampal volume (r up to 0.28, P < .001), and showed smaller racial and educational disparities relative to standard cognitive testing (NST d = 0.03-0.33, MoCA d = 0.37-0.72).

DISCUSSION: NST provides a validated neurocognitive construct that facilitates interpretation of AI-driven voice biomarkers of AD. This study was not registered in a public trials registry.},
}

@article {pmid42818491,
year = {2026},
author = {Bao, R and Zhang, S and Wang, F and Cheng, W and Zhang, T and Ding, W},
title = {MRI-derived periventricular diffusivity contextualizes plasma pTau217 associations with Alzheimer pathology: a discovery-validation study.},
journal = {Research square},
volume = {},
number = {},
pages = {},
doi = {10.21203/rs.3.rs-10895317/v1},
pmid = {42818491},
issn = {2693-5015},
abstract = {Background Plasma phosphorylated tau 217 (pTau217) is a promising scalable marker of Alzheimer pathology, but discordance with positron emission tomography (PET) limits context-free interpretation. We tested whether magnetic resonance imaging (MRI)-derived periventricular diffusivity (PVeD) modifies associations between pTau217 and Alzheimer pathology. Methods In this observational discovery-validation study, standardized pTau217 × PVeD interactions were tested for amyloid PET, tau PET, structural and vascular MRI, and cognitive outcomes in 602 participants from the Alzheimer's Disease Neuroimaging Initiative (ADNI) and 2,313 participants from the Health and Aging Brain Study-Health Disparities (HABS-HD). Analyses were adjusted for prespecified covariates and false discovery rate correction. Results In ADNI, pTau217 associations with amyloid Centiloid (interaction β = -0.096, 95% confidence interval [CI] - 0.154 to - 0.037; adjusted P = .018) and meta-temporal tau PET (β = -0.092, 95% CI - 0.158 to - 0.027; adjusted P = .018) were stronger at lower PVeD. Among participants with high pTau217, low PVeD was associated with faster cognitive decline than high PVeD (difference = - 0.100 Preclinical Alzheimer Cognitive Composite [PACC] units/year, 95% CI - 0.161 to - 0.038; adjusted P = .002). HABS-HD replicated the amyloid interaction (β = -0.109, 95% CI - 0.147 to - 0.070; adjusted P < .001) and multiple tau PET interactions; the high-pTau217/low-PVeD profile also declined faster (difference = - 0.037 PACC units/year; adjusted P = .002). Conclusions PVeD reproducibly contextualized associations between plasma pTau217 and PET-defined Alzheimer pathology across cohorts with different participant composition, pTau217 assays, PET tracers, and cognitive measures. The findings motivate prospective evaluation of MRI-informed interpretation of blood biomarkers, but PVeD is an indirect diffusion marker and the observational design does not establish mechanism, clinical utility, or decision thresholds.},
}

@article {pmid42818507,
year = {2026},
author = {Baumel, J and Lutz, M and Ding, C and Capal, J and Ritter, D and Krueger, D and Salter, A and Werner, K and Liu, AJ},
title = {Amyloid-Independent Elevation of Plasma phosphorylated tau-217 Tracks Neurodegenerative Risk in Tuberous Sclerosis Complex: Implications for mTOR-Targeted Intervention.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.09.09.26362677},
pmid = {42818507},
abstract = {BACKGROUND: Tuberous sclerosis complex (TSC) is a rare autosomal dominant neurodevelopmental disorder caused by loss-of-function mutations in TSC1 or TSC2 , resulting in chronic hyperactivation of the mechanistic target of rapamycin (mTOR) pathway. TSC patients experience a wide spectrum of cognitive, behavioral, and psychiatric features collectively termed Tuberous Sclerosis Complex Associated Neuropsychiatric Disorders (TAND). Moreover, these patients develop a clinical trajectory in adulthood with clinical and neuropathological features overlapping those of Alzheimer's disease (AD). Prior neuropathological studies have shown accumulation of AD-type mixed 3R/4R tau isoforms in adults with TSC that is amyloid-independent.

METHODS: To further explore the biological convergence of TSC and AD, this study compared plasma levels of phosphorylated tau-217 (ptau-217), a sensitive and specific marker of early AD pathology, in 63 TSC, 25 AD, and 116 cognitively unimpaired (CU) patients.

RESULTS: Findings revealed elevated levels of plasma ptau-217 in individuals with TSC at younger ages with a parallel age-related trajectory between TSC, AD, and CU cohorts. Multivariable linear regression showed that the log 2 ptau-217 concentrations were significantly lower in the CU cohort relative to TSC (β = -0.21, SE = 0.05, p < 0.0001) but were not significantly different between the TSC and AD cohorts (β = 0.17, SE = 0.09, p < 0.071). The comparison of slopes analysis (ANCOVA) supported that the slopes for the regression of log 2 ptau-217 versus age are not significantly different for the TSC and CU cohorts (TSC slope = 0.030, SE = 0.008; CU slope = 0.019, SE = 0.006; p = 0.26), nor for the TSC and AD cohorts (TSC slope = 0.030, SE = 0.01; AD slope = 0.06, SE = 0.03; p = 0.099).

CONCLUSIONS: These results suggest a novel link between TSC and AD that substantiates shared downstream neurodegenerative pathways. Furthermore, these results support the potential utility of ptau-217 as a minimally invasive biomarker for TAND severity, neurodegenerative risk, and AD-like prognosis in TSC and as a tool to guide new mTOR-targeted therapeutic strategies.},
}

@article {pmid42818509,
year = {2026},
author = {Kim, H and Zang, C and Lee, J and Haddad, E and Park, G and Zhang, J and Kim, J and Choi, K and Chai, Y and Irimia, A and Rajagopalan, P and Moon, WJ and Shi, Y and Yang, HJ and Toga, A and Jahanshad, N},
title = {Tissue- and compartment-resolved brain age reveals vascular-metabolic and neurodegenerative aging.},
journal = {Research square},
volume = {},
number = {},
pages = {},
doi = {10.21203/rs.3.rs-10808325/v1},
pmid = {42818509},
issn = {2693-5015},
abstract = {Brain aging reflects heterogeneous vascular-metabolic and neurodegenerative processes, yet brain age is often reduced to a gray matter (GM)-dominant estimate. Emerging evidence suggests that subtle "dirty-appearing" T2-FLAIR abnormalities may mark diffuse white matter (WM) vulnerability that precedes or extends beyond overt WM hyperintensities (WMH). Here we developed a compartment-resolved framework integrating T1-weighted GM features with unthresholded T2-FLAIR WM signal across depth- and lobe-specific surfaces. In 26,446 UK Biobank and 992 ADNI participants, WM brain age captured variation beyond WMH burden and was preferentially associated with cardiometabolic risk before age 65; periventricular WM age statistically linked cardiometabolic burden to cognition. Across the Alzheimer's disease continuum, GM and WM brain age increased with diagnostic severity but showed distinct molecular associations: GM aging aligned more closely with amyloid burden, whereas WM aging showed prominent tau associations. These findings reveal complementary vascular-metabolic and neurodegenerative dimensions of brain aging obscured by global brain age estimates.},
}

@article {pmid42818533,
year = {2026},
author = {Ikezu, T and You, Y and Nguyen, S and Mann, S and Vadakattu, P and Kanekiyo, T and Zhang, Z and Ray, NB and Tuck, T and Tcw, J and Goate, A and Karch, C and Ikezu, S and Gonzalez-Perez, MP and Poon, W and Shaffer, S and Duong, A},
title = {Human iPSC models reveal APOE4-induced microglial remodeling and extracellular vesicle dysregulation in AD pathogenesis.},
journal = {Research square},
volume = {},
number = {},
pages = {},
doi = {10.21203/rs.3.rs-8594804/v1},
pmid = {42818533},
issn = {2693-5015},
abstract = {The apolipoprotein E ε4 (APOE4) allele is the strongest genetic risk factor for late-onset Alzheimer's disease (AD), yet the mechanistic underpinnings by which it alters human microglial function remain poorly understood. Here, we utilize CRISPR/Cas9-engineered isogenic human induced pluripotent stem cell-derived microglia-like cells (iMGs) expressing APOE3 or APOE4 to systematically interrogate genotype-dependent effects on microglial proteomes and their secreted extracellular vesicles (EVs) under basal and fibrillar amyloid-β (fAβ)-challenged conditions. Quantitative proteomics revealed that APOE4 iMGs exhibit downregulated RNA processing, impaired phagocytosis, and exacerbated pro-inflammatory signaling, particularly upon fAβ exposure. Functionally, APOE4 iMGs demonstrated increased NF-κB activation, enhanced neuronal apoptosis and tau pathology in 2D and 3D co-culture systems. Interestingly, APOE4 iMGs released greater amount of EVs enriched in proteasomal components over APOE3 iMG. Integrated proteomic analyses further highlighted APOE4 -specific selective packaging of EV cargo linked to neuron-glia communication, inflammatory signaling, and proteostasis dysregulation, suggesting a potent, non-cell-autonomous mechanism driving neuronal damage. Consistently, these APOE4 iMGEVs were preferentially internalized by neurons, leading to disrupted neuronal proteostasis, impaired neuronal firing, and increased tau phosphorylation, particularly under pathological stress. Notably, pharmacologic inhibition of NF-κB in APOE4 iMGs reduced EV cargo-loading of proteasomal molecules and mitigated iMGEV-driven neuronal dysfunction and tau pathology. These findings establish a mechanistic link between APOE4 , dysregulated microglial homeostasis, and microglial EV-mediated propagation of proteostatic dysfunction and neurodegeneration, advancing our understanding of how APOE4 contributes to AD pathogenesis.},
}

@article {pmid42818556,
year = {2026},
author = {Sharma, P and Devappa, R and Saroja, SR},
title = {Hippocampal/medial temporal sclerosis is associated with clinical severity, regional TDP-43, and hippocampal atrophy in Alzheimer disease.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.09.03.749099},
pmid = {42818556},
issn = {2692-8205},
abstract = {Alzheimer disease neuropathologic change (ADNC) does not fully explain clinical severity, suggesting important contributions from coexisting pathologies. We examined major co-pathologies in a multicenter autopsy cohort, focusing on hippocampal/medial temporal sclerosis (HS/MTL sclerosis), clinical severity, regional TDP-43 topography, clinical status near death, and gross hippocampal atrophy. We analyzed longitudinal clinical and neuropathology data from the National Alzheimer's Coordinating Center autopsy cohort. Form-specific definitions harmonized AD pathology, major co-pathologies, HS/MTL sclerosis, and regional TDP-43 findings across neuropathology versions 8-10. HS/MTL sclerosis was present in 13.0% of assessed AD cases and was associated with greater CDR® Dementia Staging Instrument sum-of-boxes severity in non-AD (odds ratio [OR], 4.93; 95% confidence interval [CI], 3.66-6.63) and AD strata (OR, 2.56; 95% CI, 2.15-3.04). In version 10, HS/MTL sclerosis was associated with higher regional TDP-43 topography (OR, 6.54; 95% CI, 3.88-11.02) and greater gross hippocampal atrophy (OR, 6.43; 95% CI, 4.97-8.32). Among AD cases assessed within 2 years of death, HS-negative participants had greater odds of non-dementia status than HS-positive participants (OR, 5.81; 95% CI, 2.80-12.06). HS/MTL sclerosis marked greater clinical severity in both AD and non-AD strata and co-occurred with regional TDP-43 involvement and hippocampal atrophy. Its absence identified a subset with intermediate/high AD pathology but no dementia near death. Clinical severity therefore cannot be inferred from ADNC alone.},
}

@article {pmid42818649,
year = {2026},
author = {Skolasinska, P and Wearn, A and O'Sullivan, D and Stallworthy, I and Brynildsen, JK and Leppert, IR and Tardif, CL and Turner, GR and Bassett, DS and Spreng, RN and , },
title = {Longitudinal changes in control energy of brain networks in older adults at familial risk for Alzheimers disease.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.09.06.749740},
pmid = {42818649},
issn = {2692-8205},
abstract = {The ability of structural brain networks to control neural dynamics is affected by healthy and pathological aging, including Alzheimers disease (AD). According to network control theory, transitions between functional brain states incur energetic costs. How these costs change longitudinally with aging remains unknown. Here, in 279 older adults at familial risk for AD, control energy increased longitudinally for state maintenance and transitions between sensorimotor and attentional networks, while decreasing for another sensorimotor-attentional transition. Changes in transition costs between higher-order networks were associated with cognitive performance: greater DorsAttn-Executive cost was associated with poorer immediate memory, while lower Executive-Def+Lim cost was associated with poorer attention. Higher plasma p-tau181 was associated with lower DorsAttn-Def+Lim transition cost. These findings reveal transition-specific alterations in the energetic landscape of aging and distinct relationships with cognition and AD pathology. Together, they highlight energetic constraints on brain network reconfiguration as a complementary perspective on neurocognitive aging.},
}

@article {pmid42818734,
year = {2026},
author = {Wang, X and Liu, X and Wang, Z and Jia, C},
title = {Neutrophil-to-lymphocyte ratio predicts early cognitive decline associated with tau pathology in Alzheimer's disease: a longitudinal study of the ADNI cohort.},
journal = {Frontiers in aging neuroscience},
volume = {18},
number = {},
pages = {1872617},
pmid = {42818734},
issn = {1663-4365},
abstract = {BACKGROUND: Neuroinflammation is a key driver of Alzheimer's disease (AD). Although the neutrophil-to-lymphocyte ratio (NLR) is an easily accessible peripheral inflammatory marker, yet its longitudinal association with domain-specific cognitive decline and the underlying neuropathological mechanisms during the preclinical and early stages of AD remain unclear.

METHODS: A total of 1,190 non-people living with dementia older adults from the AD Neuroimaging Initiative cohort were included, comprising 405 cognitively normal participants and 785 participants with mild cognitive impairment (MCI). Participants were stratified according to baseline NLR (≥ 3versus < 3). Linear mixed-effects models were used to examined the association between baseline NLR and longitudinal decline across multiple cognitive domains. Cox proportional hazards model assessed progression risk to MCI or AD. Mediation analyses evaluated whether cerebrospinal fluid (CSF) biomarkers, including amyloid-β42 (Aβ42), total tau (t-tau), and phosphorylated tau (p-tau), statistically accounted for the association between NLR and cognitive decline.

RESULTS: During follow-up, a high baseline NLR (≥ 3) was independently associated with accelerated decline in global cognition, memory, executive function, language, and visuospatial abilities (all p < 0.05), as well as a 20% higher risk of clinical progression per 1-unit increase in NLR (hazard ratio = 1.20, 95% confidence interval: 1.12-1.29, p = 0.001). Mediation analyses indicated that CSF t-tau and p-tau, but not Aβ42, partially explained the association between NLR and cognitive decline. The observed associations remained robust across sensitivity and subgroup analyses.

CONCLUSION: Elevated NLR was significantly and independently associated with accelerated decline across multiple cognitive domains and an increased risk of clinical progression in older adults at risk for AD. The observed associations with tau pathology are consistent with a potential role for peripheral immune dysregulation in early disease trajectories; however, formal predictive modeling and external validation are required before clinical application.},
}

@article {pmid42818797,
year = {2026},
author = {Le, HN and Ishrat, S and Yaghooti, B and Murad, T and Sapkota, R and Thakuri, DS and Wong, DF and Cruchaga, C and , and Chand, GB},
title = {Machine learning-derived Alzheimer's disease dimensions: neuroanatomical, cognitive, clinical, functional, and genetic risk heterogeneity signatures.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.09.02.26361668},
pmid = {42818797},
abstract = {Alzheimer's disease (AD) is characterized by substantial clinical and biological heterogeneity, with diverse neuroanatomical, cognitive, clinical, functional, and genetic risk profiles that are poorly captured by current diagnostic frameworks. Identifying reproducible disease dimensions is critical for understanding divergent pathophysiological mechanisms and designing future stratified therapeutic interventions. Herein, we applied a semi-supervised machine learning clustering framework and robust reproducibility validation strategies to structural MRI data from 1,757 participants, comprising 1,108 cognitively normal controls (CN) and 649 patients with mild cognitive impairment (MCI) or dementia due to AD. We identified two MRI-based neuroanatomical dimensions of AD: Dimension 1 (n = 393; prevalence ∼ 61%) and Dimension 2 (n = 256; prevalence ∼ 39%). Dimension 1 exhibited widespread cortical and subcortical atrophy, including involvement of the hippocampus, amygdala, parahippocampal, temporal, frontal, and occipital regions, while Dimension 2 showed relatively preserved brain patterns. The two dimensions were not statistically different in demographic characteristics, including age, sex, race, and education (all p > 0.05). Compared to Dimension 2, Dimension 1 had more severe cognitive and clinical impairment, greater functional impairment, elevated APOE ε4 carrier burden, and higher polygenic risk for AD (p < 0.05). Analysis of individual-level summary neuroanatomical signature expression scores, quantifying each subject's continuous position along two disease dimensions, revealed that Dimension 1 signature expression correlated strongly with cognitive impairment, clinical severity, functional impairment, and genetic risk, while Dimensional 2 signature expression showed relatively weaker associations. These results reveal that AD encompasses at least two biologically distinct dimensions identifiable from structural MRI profiles and their distinct associations with cognitive, clinical, functional, and genetic profiles. These findings may aid in AD patient stratification for designing targeted therapeutic approaches in the future.},
}

@article {pmid42818825,
year = {2026},
author = {Raeesi, S and Zeighami, Y and Morrison, C and Dadar, M},
title = {Sex Differences in the Associations between Education, Neuropathology, and Cognition.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.09.03.26362216},
pmid = {42818825},
abstract = {IMPORTANCE: Autopsy evidence on sex-specific associations of education with neuropathology and cognition is limited.

OBJECTIVE: To test sex differences in education associations with neuropathologic burden and cognition.

DESIGN: Cohort study of data collected from September 2005 through August 2024.

SETTING: Multicenter autopsy cohort from the National Alzheimer's Coordinating Center.

PARTICIPANTS: Adults aged 55 years or older; cross-sectional eligibility required a final CDR-SB assessment within 2 years before death, and longitudinal eligibility additionally required at least 3 assessments.

EXPOSURES: Years of formal education.

MAIN OUTCOMES AND MEASURES: Neuropathologic measures and the Clinical Dementia Rating Scale Sum of Boxes (CDR-SB). Linear regression and mixed-effects models tested associations and interactions of education with sex, neuropathology, and linear and quadratic time. Benjamini-Hochberg correction addressed multiple comparisons.

RESULTS: Among 2592 participants (mean [SD] age at death, 81.6 [10.8] years; 1188 [45.8%] female), 1969 contributed to longitudinal analyses. In female participants, higher education was associated with lower Thal amyloid phase, diffuse plaques, neuritic plaques, and Braak stage (β range, -0.097 to -0.071; q FDR <.026); none was significant among male participants. Education-by-sex interactions supported differences in Thal amyloid phase, and diffuse and neuritic plaques (β range, -0.119 to -0.097; q FDR <.045). Education was unrelated to final CDR-SB among female (β, -0.007; 95% CI, -0.052 to 0.038; P =.767) and male participants (β, -0.026; 95% CI, -0.071 to 0.019; P =.254), with no education-by-sex interaction (P =.660). The education-by-Braak-stage-by-sex interaction indicated that higher education was associated with a weaker Braak stage-CDR-SB association among females than males (β, -0.104; 95% CI, -0.171 to -0.038; q FDR =.022). Longitudinally, education was unrelated to linear CDR-SB change in either sex. Education-by-quadratic-time associations were observed among females (β, 0.002; 95% CI, 0.001-0.003; P <.001) and male participants (β, 0.001; 95% CI, 0-0.002; P =.037). The corresponding interaction with sex was also significant (P =.043).

CONCLUSIONS AND RELEVANCE: Among female participants, higher education was associated with lower selected Alzheimer's disease neuropathologic measures and weaker associations of tau pathology with cognition. Longitudinal trajectories were nonlinear, with slower earlier decline followed by later acceleration at higher education levels.

KEY POINTS: Question: Do associations between education, neuropathologic burden and cognition differ by sex?Findings: In this cohort study of 2592 autopsy participants, higher education was associated with lower Alzheimer's disease neuropathologic burden among female but not male participants, and education-by-sex interactions were significant for Thal amyloid phase, diffuse and neuritic plaques. Higher education was associated with a weaker Braak stage-CDR-SB association among female than male participants and with lower CDR-SB five years before death in both sexes. The associations persisted after adjustment for neuropathologic burden.Meaning: Education-neuropathology associations and the clinical expression of neuropathology may be sex-specific.},
}

@article {pmid42818865,
year = {2026},
author = {Metz, A and Polizzi, C and Moqadam, R and Chadwick, K and Tremblay, C and Chen, Z and Zeighami, Y and Villeneuve, S and , and , and , and , and Dadar, M},
title = {Data-driven subtypes of Alzheimer's Disease: A multicohort study.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.09.09.26362683},
pmid = {42818865},
abstract = {INTRODUCTION: Individuals with Alzheimer's disease (AD) exhibit substantial heterogeneity in the severity of vascular changes and neurodegeneration, making the identification of biologically meaningful subtypes across the AD spectrum critical for improving prognosis and tailoring interventions. We aimed to determine whether data-driven subtyping of individuals at risk for or diagnosed with AD, based on magnetic resonance imaging (MRI), can identify distinct trajectories of disease progression and clinical outcomes.

METHODS: We analyzed baseline biomarkers and longitudinal clinical and cognitive assessments from the PREVENT-AD, CIMA-Q, ALLFTD, and ADNI cohorts, including 1396 participants. Regional atrophy and White Matter Hyperintensity (WMH) burden were derived from T1-weighted MRI. The SuStaIn algorithm was applied to baseline data to infer individuals' subtypes and stages based on MRI biomarker profiles. The resulting subtypes were compared in terms of baseline molecular biomarker levels and vascular risk factors, longitudinal cognitive decline trajectories, and clinical and neuropathological outcomes.

RESULTS: Two distinct subtypes were identified across all cohorts: one characterized by early parahippocampal and cortical atrophy, and a second by initially elevated WMH volumes. Both subtypes showed abnormal tau and amyloid levels in- and ex-vivo, and subtype two exhibited increased vascular risk factors. Longitudinally, the atrophy-first subtype exhibited steeper cognitive decline than the WMH-first subtype. Accordingly, the atrophy-first subtype carried a higher risk of conversion to AD than the WMH-first group.

DISCUSSION: These findings, replicated in four diverse and independent datasets, support imaging-based subtyping as a scalable and clinically translatable approach for capturing heterogeneity in AD pathophysiology and associated cognitive trajectories.},
}

@article {pmid42818869,
year = {2026},
author = {Fin, S and Moayedikia, A},
title = {Structural, Functional and Cognitive Validation of a Deep-Learning MCI-to-AD Conversion Model in OASIS-3.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.09.05.26362318},
pmid = {42818869},
abstract = {BACKGROUND: Deep-learning models predict mild cognitive impairment (MCI)-to-Alzheimer's disease (AD) conversion from structural MRI with high accuracy. However, they are typically validated within a single cohort and judged on discrimination alone. Whether their risk scores are biologically grounded, and whether they generalise to independent data, remains unclear.

METHODS: We applied the ADNI-trained Temporal Adaptive Fusion Network (TAF-Net), without retraining, to 101 MCI participants from OASIS-3 (25 converters, 76 stable) and tested whether its conversion-risk scores were grounded in independent structural, functional, and cognitive markers of AD. Regional atrophy rates were derived from longitudinal FreeSurfer, cognition from longitudinal MMSE and CDR-Sum-of-Boxes, and baseline resting-state functional connectivity from fMRIPrep, in structural and functional subsamples of 41 and 40 participants. Associations used rank-based statistics with false-discovery-rate correction.

RESULTS: Higher TAF-Net risk tracked faster atrophy in medial-temporal AD-signature regions but not in AD-spared cortex - an anatomically specific coupling that survived adjustment for global atrophy. In external validation, risk discriminated converters (AUC = 0.72), comparable to native atrophy and strongly concordant with it; atrophy statistically accounted for the model's prognostic signal. Discrimination transferred but calibration did not: the two lowest tertiles of risk were assigned near-zero probability yet converted at 15%. Risk also tracked the multi-year rate of cognitive decline and, at baseline, was associated with reduced within-network functional-connectivity integrity, concentrated in salience and default-mode hubs; longitudinal functional analyses were underpowered.

CONCLUSIONS: A conversion model trained on one cohort produced risk scores that, in an independent cohort, were grounded in the structural, functional, and cognitive hallmarks of Alzheimer's disease - supporting biological validity and external generalisation. The score, however, largely re-expresses the neurodegenerative substrate captured by structural atrophy. Rank ordering transferred across cohorts but absolute risk did not, so the score requires recalibration before its values can be interpreted as individual probabilities.},
}

@article {pmid42818882,
year = {2026},
author = {Ramedani, M and Terli, JC and Singh, D and Peters, O and Hellmann-Regen, J and Priller, J and Spruth, EJ and Spottke, A and Boehlen, A and Weydt, P and Wüllner, U and Dinter, E and Günther, R and Wiltfang, J and Schott, BH and Düzel, E and Glanz, W and Buerger, K and Janowitz, D and Levin, J and Stockbauer, A and Mladinov, M and Prudlo, J and Hermann, A and Synofzik, M and Mengel, D and Petzold, GC and Schneider, A and Lüsebrink, F and Hetzer, S and Dechent, P and Ewers, M and Scheffler, K and Stöcklein, S and Teipel, S and Dyrba, M},
title = {Hybrid multimodal late fusion frameworks for bvFTD classification in imbalanced dementia datasets.},
journal = {Frontiers in aging neuroscience},
volume = {18},
number = {},
pages = {1892568},
pmid = {42818882},
issn = {1663-4365},
abstract = {BACKGROUND: Behavioral variant frontotemporal dementia (bvFTD) is an irreversible neurodegenerative disorder characterized by progressive changes in personality and behavior. Magnetic Resonance Imaging (MRI) is widely used to detect and assess structural brain alterations associated with the disease. However, due to the low prevalence of bvFTD among neurodegenerative diseases causing the dementia syndrome, conventional machine learning approaches may struggle to capture comprehensive feature representations. Therefore, this study proposes two late fusion frameworks that integrate a 3D convolutional neural network and a multilayer perceptron (MLP) for improved bvFTD diagnosis.

METHODS: A total of 5,928 participants were included, comprising 3,415 healthy controls (HC), 2,276 Alzheimer's disease (AD), and 237 bvFTD, resulting in a class imbalanced setting with bvFTD as the minority class. To address class imbalance, bvFTD data were initially augmented. A 3D-DenseNet was used to extract features from 3D T1-weighted MRI scans, while an MLP-based model was applied to regional brain volumetric measurements obtained from automated MRI-based brain segmentation. Twelve CNN models with different hyperparameter configurations were trained. Models with and without data augmentation, as well as two fusion-based approaches, were evaluated using accuracy, F1-score, and area under the curve (AUC).

RESULTS: Both fusion strategies improved accuracy, F1-score, and AUC compared to the baseline model without data augmentation. Notable improvement was also observed for the bvFTD class, with up to a 120% increase in F1-score. In one of the fusion frameworks, an accuracy of 0.95 ± 0.01 was achieved for bvFTD vs. HC classification. The results demonstrate the effectiveness of the fusion-based approaches compared to non-fused models, outperforming several state-of-the-art methods.

CONCLUSION: The proposed frameworks demonstrate that data augmentation and fusion strategies can improve accuracy, F1-score, and AUC, with statistically significant gains. Overall, the frameworks improve diagnostic performance and support the identification of relevant biomarkers associated with bvFTD pathology.},
}

@article {pmid42818885,
year = {2026},
author = {Kuik, EJ and Baena-Tan, C and Moriguchi, S and Braga, J and Miler, L and Rusjan, P and Bagby, M and Husain, MI and Vasdev, N and Tomoda, T and Banasr, M and Kloiber, S and Meyer, JH},
title = {Effects of sex, treatment resistance, and antidepressant treatment on monoamine oxidase B total distribution volume.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.09.08.26362462},
pmid = {42818885},
abstract = {Monoamine oxidase B (MAO-B) is a high-density protein located mainly in astrocytes that influences mitochondrial function and transition to astrogliosis. MAO-B produces hydrogen peroxide while metabolizing non-serotonergic monoamines. Elevated MAO-B level is implicated in the pathophysiology of several common neuropsychiatric diseases. The aims are to examine the effect of treatment resistant major depressive episodes, sex, and antidepressant treatment on MAO-B total distribution volume ([ [11] C]SL25.1188 V T), index of MAO-B level. [ [11] C]SL25.1188 PET was applied in 95 adults (29 with MDE and no history of treatment-resistance (NTR-MDE), 26 with MDE and history of treatment-resistance (TRD), and 40 healthy control (HC)). A subset of NTR-MDE and TRD (n=13) were scanned before and after treatment with phenelzine, rasagiline, or duloxetine. [ [11] C]SL25.1188 V T was higher in grey matter regions in females (10%, p <.001). [ [11] C]SL25.1188 V T was also higher in prefrontal cortex in TRD compared to HC (23%, p<.001) and TRD compared to NTR-MDE (6%, p =.033). Duloxetine had minimal effect on [ [11] C]SL25.1188 V T , but occupancy of rasagiline and phenelzine was ∼94%. This study discovered sex differences in MAO-B level, which may explain sex differences in prevalence or trajectory of illnesses with greater MAO-B level like Alzheimer's disease, traumatic brain injury and major depressive disorder. Given our findings of greater MAO-B level in prefrontal cortex of TRD and its insensitivity to serotonin reuptake inhibition, combined with potential harm of highly elevated MAO-B level, development of MAO-B inhibitors could be considered for a subset of TRD. Rasagiline and phenelzine demonstrate similarly potent occupancy in vivo at clinical dosage.},
}

@article {pmid42818896,
year = {2026},
author = {He, Y and Yang, H and Pan, T and Wang, F and Zeng, X and Huang, J and Yang, Q},
title = {Exploring the role of statin interventions on cognitive function by Mendelian randomization study.},
journal = {Journal of Alzheimer's disease reports},
volume = {10},
number = {},
pages = {25424823261440863},
pmid = {42818896},
issn = {2542-4823},
abstract = {BACKGROUND: While statin use is linked to cognitive impairment, causal relationships with specific dementia subtypes remain unclear.

OBJECTIVE: To investigate causal effects of statin medication, genetically mimicked statin effects, and plasma lipids on various cognitive impairments using Mendelian randomization (MR).

METHODS: Utilizing summary genome-wide association studies data, we identified genetic variants associated with statin medication, cholesterol-dependent/independent statin effects, and dementia subtypes, such as Alzheimer's disease (AD), dementia in Alzheimer's disease (ADD), late-onset Alzheimer's disease, dementia with Lewy body (DLB), dementia with Lewy body in APOE ε4[+] carriers, frontotemporal dementia, Parkinson's disease dementia, and vascular dementia. Univariable MR assessed causality, primarily via inverse variance weighting (IVW). Mediation effects were evaluated using the coefficient product method. Sensitivity analyses ensured robustness.

RESULTS: IVW-MR indicated statin medication significantly reduced AD risk but increased ADD and DLB risk. Elevated total cholesterol (TC) increased dementia, ADD, and DLB, while higher low density lipoprotein cholesterol decreased AD risk. Specific DHCR24 variants reduced DLB risk, while HMGCS1 variants increased it. RAC1 variants lowered AD risk, whereas RHOC mitigated ADD risk. Critically, TC mediated 93.91% (95% CI = 68.27%∼119.55%) of statins' effect on dementia, 84.37% (95% CI = 62.21%∼106.52%) on ADD, and 61.94% (95% CI = 43.47%∼80.42%) on DLB. The genetically mimicked effect of statins does not show a mediating role.

CONCLUSIONS: Statin medication, plasma lipids, and their genetic proxies exhibit causal links to cognitive impairment. Crucially, TC mediates statin-associated risks for cognitive impairment.},
}

@article {pmid42818907,
year = {2026},
author = {Ward, EL and Nelson, PT and Katsumata, Y and Fardo, DW and Jicha, GA and , and Miller, JB},
title = {Rare extreme polygenic risk scores strongly indicate Alzheimer's disease risk.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.09.08.26362504},
pmid = {42818907},
abstract = {BACKGROUND: Alzheimer's disease (AD) pathology often accumulates years before memory loss, creating a need to identify high-risk individuals presymptomatically. Polygenic risk scores (PRS) stratify AD risk, but individual-level predictions remain uncertain. Extreme PRS may identify high-risk individuals independent of APOE .

METHODS: Using GenoPred, extreme tails of 1,752 PRS methods were evaluated across four genetic ancestries using 11,200 autopsy- or clinically-defined AD cases and 19,321 controls (age ≥65) from the AD Sequencing Project (ADSP) Release 5.

RESULTS: Individuals in the extreme upper PRS tail were significantly enriched for AD in all ancestries: Admixed American (P adj =0.02727), African (P adj =0.004827), East Asian (P adj =0.02824), and European (P adj =2.3068×10 [-13]). No controls were observed among the 42 European- and 12 African-ancestry individuals with extreme PRS. Extreme PRS spanned APOE diplotypes; 38% occurred in non- APOE ε4 carriers.

CONCLUSIONS: Rare subsets of individuals at the most extreme PRS thresholds have markedly elevated AD enrichment across ancestries and APOE diplotypes.

DATA AVAILABILITY: All data are available through the ADSP, which is managed by The National Institute on Aging Genetics of Alzheimer's Disease Data Storage Site (NIAGADS).},
}

@article {pmid42818911,
year = {2026},
author = {Han, S and Liu, F and Wang, D and Song, G},
title = {Aildenafil citrate with superior PDE5 selectivity ameliorates cognitive and behavioral impairments in APP/PS1 Alzheimer's disease mice: a preclinical phenotypic study.},
journal = {Frontiers in pharmacology},
volume = {17},
number = {},
pages = {1933588},
pmid = {42818911},
issn = {1663-9812},
abstract = {INTRODUCTION: Alzheimer's disease (AD) imposes a significant global healthcare burden, and current available pharmacotherapies provide limited therapeutic benefits. Disrupted phosphodiesterase 5 (PDE5) signaling has been implicated in the pathogenesis of AD and other neurodegenerative disorders, positioning PDE5 inhibitors (PDE5Is) as a promising therapeutic strategy for AD treatment. This study evaluated the preclinical therapeutic potential of aildenafil citrate (AC), a selective PDE5I approved in China for the treatment of erectile dysfunction (ED), in AD treatment.

METHODS: Molecular docking, molecular dynamics (MD) simulations, and MM-GBSA binding free energy calculations were integrated to explore the molecular mechanisms of aildenafil. The APP/PS1 transgenic mouse model of AD was employed to assess the in vivo efficacy of AC through behavioral, pathological, and oxidative assessments.

RESULTS: In silico analyses indicated that aildenafil exhibited a higher predicted affinity through a strengthened electrostatic network anchored by key bidentate hydrogen bonds with Gln817 and enhanced π-π stacking interactions with Phe820. Behavioral assessments, including the Barnes maze and Open field tests, demonstrated that AC significantly ameliorates cognitive dysfunction and anxiety-like impairments. Pathological examinations revealed improved hippocampal morphology, upregulated neprilysin (NEP) expression, and reduced Aβ accumulation. The decreased malondialdehyde (MDA) levels further suggested a potential attenuation of systemic oxidative stress and provided preliminary support for further investigation into its effects on central redox status.

CONCLUSION: These findings offer an initial phenotypic characterization of AC in an AD mouse model, underscoring the need for comprehensive mechanistic studies to fully evaluate its potential as a repurposed AD therapeutic candidate.},
}

@article {pmid42818922,
year = {2026},
author = {Trujillo, A and Sohn, M and Macias, M and Grochowska, M and Joyce, J and Ber, IL and Huh, D and Schulmann, A and McMahon, F and Keuren-Jensen, KV and Latouche, M and Marsan, E},
title = {Selective vulnerability and resilience of thalamic neuronal populations in Frontotemporal Dementia.},
journal = {Research square},
volume = {},
number = {},
pages = {},
doi = {10.21203/rs.3.rs-10670822/v1},
pmid = {42818922},
issn = {2693-5015},
abstract = {Frontotemporal dementia (FTD) caused by progranulin (GRN) mutations is associated with pronounced thalamic degeneration, yet the cellular basis of selective thalamic vulnerability remains poorly understood. Here, we generated an integrated single-nucleus RNA-sequencing atlas of the human antero-median thalamus comprising 331,065 nuclei from 92 individuals across three independent cohorts spanning GRN-associated FTD, sporadic FTD with TDP-43 proteinopathy, Alzheimer's disease (AD), and neurologically normal aging. While AD samples exhibited minimal thalamic cellular remodeling, FTD cases were characterized by highly selective and reproducible degeneration of discrete neuronal populations across independent cohorts. In particular, two inhibitory neuronal populations were markedly depleted in FTD, which was accompanied by impaired GABAergic communication. Among excitatory neurons, RNF220+ neurons exhibited extensive transcriptional dysregulation, altered sterol metabolic pathways, together with robust TDP-43-associated STMN2 cryptic splicing pathology and reduced glutamatergic signaling. By contrast, RNF220- excitatory neurons were comparatively resilient, displaying preserved neuronal communication, and resistance to STMN2 cryptic exon accumulation. In control individuals, RNF220- excitatory neurons exhibited elevated GRN expression and an intrinsic enrichment of cytoskeletal maintenance programs. Spatial transcriptomics confirmed the anatomical distribution of vulnerable neuronal populations in the adult human thalamus. In parallel, FTD samples demonstrated expansion of vascular-associated and lymphocyte populations as well as reactive glial signatures. Together, these findings define a cellular framework for selective vulnerability and resilience in the human FTD thalamus and identify intrinsic molecular programs associated with resistance to neurodegeneration.},
}

@article {pmid42818937,
year = {2026},
author = {Aquino, J and Lee, A and Zheng, J and Ku, WL and Han, M and Chen, J},
title = {Isoform Remodeling and Promoter Switching Identify Altered Transcriptional Regulation in Alzheimer's Disease Frontal Cortex.},
journal = {Research square},
volume = {},
number = {},
pages = {},
doi = {10.21203/rs.3.rs-10820900/v1},
pmid = {42818937},
issn = {2693-5015},
abstract = {BACKGROUND Alzheimer's disease (AD) is associated with transcriptional dysregulation, but gene-level analyses may overlook isoform changes. We investigated how differential isoform usage, promoter selection, and splicing contribute to transcriptome remodeling in the AD frontal cortex. METHODS We analyzed Oxford Nanopore long-read RNA sequencing data from frontal cortex of six individuals with AD and six controls. Transcripts were quantified using Bambu, and differential isoform usage was assessed using IsoformSwitchAnalyzeR. Promoter usage and SUPPA2-derived percent-spliced-in values were tested using beta regression. Transcription factor motif enrichment was evaluated at differentially used promoters. Transcript-level effects were compared with an independent short-read cohort. RESULTS We identified 109 isoform-switching events involving 96 isoforms across 86 genes, including CLSTN3 , SNCA , BECN1 , USP10 , and EGFR . Several switches altered predicted nonsense-mediated decay sensitivity. Eleven genes exhibited promoter switching, comprising 46 differentially used promoters: 31 with increased and 15 with decreased usage in AD. These promoters were enriched for 179 TF motifs. IRF7, IRF8, IRF9, and STAT1::STAT2 motifs were top-ranked among promoters with increased usage, whereas NFKB1 and NFKB2 motifs were top-ranked among those with decreased usage. Targeted analysis identified 14 significant differential splicing events with sex-associated effects, including BECN1 . Although cross-platform concordance was weak, 16 of 26 transcripts with large effects in both datasets changed concordantly, and 13 showed large, concordant effects of similar magnitude. CONCLUSIONS AD-associated transcriptome remodeling extends beyond gene-level abundance to include changes in isoform proportions, promoter selection, and transcript structure. These findings implicate transcription initiation and RNA processing as complementary layers of dysregulation in AD.},
}

@article {pmid42818947,
year = {2026},
author = {Cheng, WKW},
title = {Limited incremental prognostic value of dyadic self- and informant-reported everyday cognition for incident MCI or Alzheimer's disease dementia in ADNI: an exploratory prognostic modelling study.},
journal = {Research square},
volume = {},
number = {},
pages = {},
doi = {10.21203/rs.3.rs-10884877/v2},
pmid = {42818947},
issn = {2693-5015},
abstract = {UNLABELLED: Background Subjective cognitive decline (SCD) measures, including self- and informant-reported concern, are candidate prognostic markers for Alzheimer's disease (AD), but their incremental value over conventional biomarkers is uncertain. We evaluated, in an internally cross-validated ADNI sample, whether a dyadic mean and self-informant gap of baseline Everyday Cognition (ECog) total scores improve prediction of first recorded clinical diagnosis of MCI or AD dementia beyond the prespecified conventional predictors.

METHODS: We included 1,762 cognitively normal at-risk ADNI participants (events = 288: 261 MCI, 27 AD dementia). Elastic-net Cox models (M2 conventional-predictor, M3 conventional-predictor + dyadic mean, M4 conventional-predictor + mean + gap) were fit using nested cross-validation with fold-wise imputation and standardization.

RESULTS: M2 C-index 0.682, M3 0.692, M4 0.687. Adding the dyadic mean yielded an estimated ΔC of 0.010 (95% CI -0.003 to 0.024), which was attenuated to ΔC = 0.002 (95% CI -0.013 to 0.018) after including landmark-year protocol-era candidate variables. The gap did not improve discrimination beyond the dyadic mean. In an exploratory biomarker-naive gatekeeping comparison, adding dyadic ECog to a clinical baseline of age, sex, education, and MMSE raised the C-index from 0.635 to 0.678 (ΔC = 0.044, 95% CI 0.023 to 0.064), nearly matching the biomarker-rich model (ΔC = 0.004, 95% CI -0.026 to 0.033 for M2 versus the gatekeeping model).

CONCLUSIONS: In this internally validated ADNI cohort, a baseline dyadic ECog mean provided at most a small and statistically uncertain increment in prognostic discrimination beyond conventional predictors (ΔC = 0.010, 95% CI -0.003 to 0.024), which was largely attenuated after including protocol-era and report-availability candidate variables (ΔC = 0.002). The self-informant gap provided no additional discrimination. Dyadic ECog may be better positioned as a low-cost gatekeeper in biomarker-naive settings than as an add-on to biomarker-rich models; neither role is established without external validation.},
}

@article {pmid42818965,
year = {2026},
author = {Rafie, F and Azimi, D and Nekouei, AH and Kim, H and Carroll-Sauer, CM and Hajjar, I and Wharton, W and Qiu, D and Goldstein, F and Mckay, JL and Hackney, ME},
title = {Feasibility, Safety, and Preliminary Efficacy of Partnered Rhythmic Rehabilitation in Prodromal Alzheimer's Disease: A 12-Month Pilot Randomized Controlled Trial.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.09.11.26362767},
pmid = {42818965},
abstract = {BACKGROUND: Non-pharmacological interventions may enhance motor-cognitive integration in prodromal Alzheimer's disease (pAD). Partnered Rhythmic Rehabilitation (PRR), an adapted dance-based intervention, is designed to engage the motor, cognitive, and social domains. However, no randomized trial has evaluated its feasibility or efficacy in pAD. This study evaluated the feasibility, safety, and preliminary efficacy of PRR compared to group walking (WALK) in adults with pAD and amnestic mild cognitive impairment (aMCI).

METHODS: In this single-blind, randomized controlled pilot trial (NCT04029623), 68 adults with pAD and aMCI were randomized to PRR or WALK. Prespecified feasibility criteria were attrition ≤15% and no injurious falls during interventions. Preliminary efficacy was examined on the primary outcome, the Four-Square Step Test (FSST). Secondary cognitive, motor, and psychosocial outcomes were also assessed to inform future definitive trials. Several modifications were made to the original protocol to ensure compliance with safety measures associated with the COVID-19 pandemic.

RESULTS: Attrition in the PRR group (15.2%) did not significantly exceed the prespecified threshold (P = .848), and 0 injurious falls were reported during the supervised sessions, meeting both feasibility and safety criteria. No significant group-by-time interactions were observed for FSST, but significant group-by-time interactions favoring PRR were identified for Timed Up-and-Go (TUG; P = .021) and jump distance (P = .014).

CONCLUSION: PRR was feasible and safe in adults with aMCI consistent with pAD but did not meet the prespecified efficacy endpoint on FSST. Our results showed that TUG and standing board jump distance may serve as potential outcomes in future definitive trials.},
}

@article {pmid42818993,
year = {2026},
author = {Neufang, S and Akhrif, A and Beyan, OD and Initiative, N},
title = {Gender bias in the diagnosis of Alzheimer's Disease.},
journal = {Research square},
volume = {},
number = {},
pages = {},
doi = {10.21203/rs.3.rs-10738736/v1},
pmid = {42818993},
issn = {2693-5015},
abstract = {Fairness in clinical machine-learning (ML) remains a critical challenge, particularly in neurodegenerative disease where demographic factors may confound disease-related patterns. We developed and evaluated bias-aware ML models for Alzheimer's disease (AD) classification using data from the Alzheimer's Disease Neuroimaging Initiative (ADNI), comprising 757 individuals with mild cognitive impairment (MCI) and AD. Four supervised learning algorithms (logistic regression, support vector machine, random forest, and XGBoost) were trained using demographic, genetic, neuropsychological, and MRI-derived features. Sex was treated as a protected attribute, and bias mitigation was implemented using pre-processing, in-processing, and post-processing methods within the IBM AI Fairness 360 framework. Bias mitigation reduced disparities in predictions, with disparate impact decreasing from 1.167 to 0.823. The logistic regression model with Disparate Impact Remover (LR/DIR) improved performance while maintaining fairness, whereas adversarial debiasing achieved the highest balanced accuracy (88.91%). Explainability analyses in the LR/DIR model using LIME showed altered feature attribution patterns with increased convergence between sexes and stronger contribution of clinical and gender-related variables after debiasing. SHAP analysis in the adversarial debiasing model confirmed that Mini-Mental State Examination score, functional status, age, and medial temporal lobe atrophy were the strongest predictors of AD. These findings demonstrate that fairness-aware ML can reduce sex-related bias in AD classification without loss of performance and improve interpretability through more balanced representation of disease determinants.},
}

@article {pmid42819170,
year = {2026},
author = {Silva-Olivares, F and Vidal, N and Acevedo-Hernández, P and Rabbia, V and Petermann-Rocha, F and Thomas-Valdés, S and Jorquera, G},
title = {Can live microbial interventions support healthy aging? A systematic review and meta-analysis of cognitive and muscle outcomes in aging adults.},
journal = {Frontiers in nutrition},
volume = {13},
number = {},
pages = {1869929},
pmid = {42819170},
issn = {2296-861X},
abstract = {INTRODUCTION: Preserving cognitive and physical function is central to healthy aging, and the gut microbiota may influence both brain and muscle physiology. We evaluated whether live microorganism-based interventions affect cognitive and muscle-related outcomes in aging adults.

METHODS: We systematically reviewed randomized placebo-controlled trials of probiotics, synbiotics, or fecal microbiota transplantation in populations with a mean age of at least 60 years. MEDLINE, Embase, Web of Science, and the Cochrane Library were searched. Random-effects meta-analyses used Hedges' g when at least three studies or independent comparisons reported sufficiently comparable outcomes. The protocol was prospectively registered in PROSPERO (CRD420251065993; https://www.crd.york.ac.uk/PROSPERO/view/CRD420251065993).

RESULTS: Twenty-four trials involving 1,809 participants were included qualitatively: 20 evaluated cognitive outcomes and four evaluated muscle-related outcomes. Eleven unique studies contributed to at least one meta-analysis. For Mini-Mental State Examination scores, the overall pooled estimate was positive (g = 1.02; 95% CI: 0.36-1.68; I [2] = 90.84%). In exploratory post hoc subgroup analyses, the estimate was positive in Alzheimer's disease (g = 1.46; 95% CI: 1.14-1.79) but not statistically significant in broader cognitive impairment (g = 0.49; 95% CI: -0.78 to 1.77); the subgroup difference was not significant (p = 0.15). Excluding both Akhgarjand et al. intervention arms yielded a positive estimate in Alzheimer's disease (g = 1.63; 95% CI: 1.21-2.06), although only two studies remained. The pooled Repeatable Battery for the Assessment of Neuropsychological Status result was not statistically significant (g = 0.46; 95% CI: -0.50 to 1.41). Handgrip strength showed a modest positive estimate (g = 0.46; 95% CI: 0.06-0.85), but exclusion of Qaisar et al. attenuated it to non-significance (g = 0.23; 95% CI: -0.27 to 0.73).

DISCUSSION: Live microorganism-based interventions showed preliminary short-term functional signals, but the small evidence base, high cognitive heterogeneity, short follow-up, and sensitivity to individual studies preclude firm efficacy conclusions. Subgroup and two-study sensitivity findings are exploratory. No eligible fecal microbiota transplantation trial was identified, so the evidence derives exclusively from probiotic and synbiotic studies.

https://www.crd.york.ac.uk/PROSPERO/view/CRD420251065993, unique identifier: CRD420251065993.},
}

@article {pmid42819414,
year = {2026},
author = {Bestard-Lorigados, I and Sterling, K and Li, L and Lin, Z and Wu, Z and Zhu, Q and Pan, W and Cai, F and Song, W},
title = {Presenilin 1 Mutations Converge on Aβ42/Aβ40 Elevation via Distinct Mechanisms.},
journal = {MedComm},
volume = {7},
number = {10},
pages = {e70978},
pmid = {42819414},
issn = {2688-2663},
abstract = {Mutations in Presenilin 1 (PS1) are the most common genetic cause of familial Alzheimer's disease (AD). However, the exact mechanisms by which these mutations alter amyloid precursor protein (APP) processing and drive amyloid β (Aβ) production remain unclear. In this study, five PS1 mutations (M146V, G384A, C410Y, Y115H, and the Notch-sparing mutation ΔS169) were transfected into neuroblastoma cells lacking endogenous PS1/PS2 expression and human embryonic kidney cells stably overexpressing either wild-type APP or the APP Swedish mutation. We investigated the effects of these mutations on APP processing, Aβ42/Aβ40 ratio, cytotoxicity, BACE1 expression, and PS1 endoproteolysis. Our results demonstrate that PS1 mutations differentially modulate APP processing, producing distinct Aβ profiles independent of their effects on Notch signaling. All mutations increased the Aβ42/Aβ40 ratio, while BACE1 levels were unchanged and no direct PS1-BACE1 interactions were found. All mutations increased cytotoxicity, whereas only the Notch-impairing mutations reduced cell viability, suggesting impaired Notch signaling may contribute to this effect. Lastly, the mutations exhibited distinct endoproteolytic rates that correlated only with APP-C83 levels. These findings provide novel insights into how distinct PS1 mutations impact amyloid pathology.},
}

@article {pmid42819435,
year = {2026},
author = {Li, Y and Menon, G and Long, JJ and Kim, B and Bae, S and Orandi, BJ and DeMarco, MP and Wu, W and Crews, DC and Purnell, TS and Thorpe, RJ and Szanton, SL and Segev, DL and McAdams-DeMarco, MA},
title = {Neighborhood Disadvantage and Dementia Risk Among Older Patients With Kidney Failure: Differences by Race/Ethnicity and Urbanicity.},
journal = {Kidney medicine},
volume = {8},
number = {10},
pages = {101479},
pmid = {42819435},
issn = {2590-0595},
abstract = {RATIONALE & OBJECTIVE: Among older patients with kidney failure, those who are minoritized or residing in rural areas experience a disproportionate burden of Alzheimer's disease and related dementias (ADRD). Neighborhood disadvantage drives health disparities, but few studies have directly examined its association with ADRD and whether this association varies by race/ethnicity and by urbanicity.

STUDY DESIGN: Cohort study.

SETTING & PARTICIPANTS: United States Renal Data System data; older patients (age ≥ 55 years) initiating dialysis in 2003-2021.

EXPOSURES: Residential neighborhood disadvantage was measured using a ZIP-code level index across 9 domains (built environment, criminal justice, education, employment, housing, poverty, social fragmentation, transportation, and wealth).

OUTCOME: ADRD using diagnosis codes.

ANALYTICAL APPROACH: We used cause-specific hazards models to quantify the adjusted hazard ratios (aHR) of ADRD diagnoses. We then used interaction terms to quantify whether these associations differed by race/ethnicity and urbanicity.

RESULTS: After adjustments, older patients in high-disadvantage neighborhoods had a higher risk of ADRD diagnoses (dementia: aHR = 1.09, 95% CI: 1.08-1.10; AD: aHR = 1.25, 95% CI: 1.22-1.27) compared with older patients in low-disadvantage neighborhoods; these associations differed by race/ethnicity (dementia: P interaction = 0.03; AD: P interaction = 0.002) and urbanicity (P interactions < 0.001 for both). Specifically, older Black patients in high-disadvantage neighborhoods had a higher risk of ADRD (dementia: aHR = 1.19, 95% CI: 1.17-1.21; AD: aHR = 1.31, 95% CI:1.28-1.35) compared with older Black patients in low-disadvantage neighborhoods. Within suburban, rural, and small-town areas, older patients residing in high-disadvantage neighborhoods had a higher risk of ADRD compared with those in low-disadvantage neighborhoods.

LIMITATIONS: ZIP codes as a proxy for neighborhoods.

CONCLUSIONS: Older patients with kidney failure residing in high-disadvantage neighborhoods, particularly Black patients and those in suburban, rural, or small-town areas, had a higher risk of ADRD compared with those in low-disadvantage neighborhoods. Multifaceted interventions (eg, cognitive screening, collaborative care) are needed to mitigate structural barriers associated with neighborhood disadvantage and preserve cognitive function in this population.},
}