INTRODUCTION Microglia regulate amyloid plaque-associated microenvironments that contribute to downstream tau pathology in Alzheimer’s disease (AD). Variants within the MS4A locus are strongly associated with AD risk and resilience and are linked to microglial biology; however, the functional role of MS4A4A in plaque-associated tau pathology remains poorly understood. METHODS Single-nucleus RNA sequencing (snRNA-seq) was performed on hippocampi from non-transgenic, Ms4a4a knockout (4A-KO), 5xFAD, and 5xFAD 4A-KO mice at 6 months of age. To assess plaque-associated tau pathology, AD-derived tau aggregates were injected into the hippocampus of 5xFAD and 5xFAD 4A-KO mice at 6 months, and histological analyses were performed 3 months later. RESULTS Amyloid pathology was the dominant driver of microglial state transitions, while Ms4a4a loss selectively remodeled activated microglial transcriptional programs enriched for interferon, lysosomal, autophagic, and proteostatic pathways. Activated microglia from 5xFAD 4A-KO mice exhibited altered expression of genes linked to immune signaling and protein handling. Following AD-tau inoculation, Ms4a4a loss did not significantly alter overall phospho-tau burden but selectively reduced dense-core plaque-associated neuritic plaque tau (NP-tau), particularly in the contralateral hemisphere. This phenotype was strongest surrounding X-34-positive fibrillar plaques and occurred without major changes in plaque-associated microgliosis. DISCUSSION These findings identify Ms4a4a as a regulator of plaque-associated microglial programs linked to NP-tau accumulation in the amyloid-bearing brain. More broadly, this work supports a model in which AD resilience-associated microglial pathways selectively shape plaque-associated microenvironments that promote downstream tau pathology.
E. Danhash, Shao-Yu Fang, Jacob A. Marsh et al.· bioRxiv· 0 citations
ABSTRACT INTRODUCTION Early detection of cognitive decline in Alzheimer's disease (AD), particularly in preclinical stages, is critical for evaluating therapeutic interventions. Traditional cognitive assessments often require lengthy in‐person visits, and may therefore limit scalability for younger, trial‐ready populations for primary and secondary prevention studies. We evaluated the feasibility, reliability, and validity of high‐frequency remote digital cognitive assessments in individuals with autosomal dominant AD (ADAD). METHODS One hundred twenty‐three mutation carriers and non‐carriers from the Dominantly Inherited Alzheimer Network Trials Unit from 20 international sites (Ages 19–66 years) completed remote assessments via personal smartphones, prompted four times daily for 7 days (≈ 3 minutes per session), and conventional in‐clinic cognitive testing at baseline. Adherence, between‐person reliability, test–retest reliability (intraclass correlation coefficients [ICCs]), construct validity (confirmatory factor analysis), and sensitivity to clinical disease progression were evaluated. RESULTS Remote measures demonstrated excellent reliability (ICCs > 0.90 after just 10 sessions) and strong construct validity, with tasks loading onto memory, attention, and executive function domains. A composite of the remote tests slightly outperformed a traditional composite at separating mutation carriers from non‐carriers. Average adherence to the study protocol was 42%, lower that observed in previous studies of older adults. DISCUSSION High‐frequency remote cognitive assessment is feasible, reliable, and valid in a relatively young international ADAD cohort. This approach offers substantial utility for clinical trials, including improved accessibility and enhanced reliability, supporting its integration into early‐intervention studies.
A. Aschenbrenner, H. Wilks, Matthew S. Welhaf et al.· Alzheimer's & Dementia· 1 citation
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