Among the more than 90 identified genetic risk loci for late-onset Alzheimer's disease (AD) and related dementias, the apolipoprotein E (APOE) gene ɛ2/ɛ3/ɛ4 polymorphisms remain the longstanding benchmark for genetic disease risk with a consistently large effect across studies1-10. Despite this massive signal, the exact mechanisms by which ɛ4 increases and ɛ2 decreases dementia risk remain poorly understood. Notably, recent trials of anti-amyloid therapies suggest less efficacy and higher risks of severe side effects in ε4 carriers11-13, hampering the treatment of those with the highest unmet need. To improve our understanding of the genetic architecture of AD in the context of its main genetic driver, we performed genome-wide association studies (GWASs) stratified by ε4 and ε2 carrier status. HP1BP3, SLC50A1, PTPRC, NPAS3, DDHD1, CHST9, SMYD2, PRAMEF1 and GFRA1 emerged as new genomic signals for AD risk, appearing only when stratified by APOE carrier status. DDHD1 appeared especially promising, showing protective effects in ε4 carriers, being identified as an expression quantitative trait locus and being involved in rare neuronal diseases. Such APOE-stratified insights may help understand and overcome side effects, inform clinical trial enrollment strategies, and create the scientific basis for targeted, mechanism-driven therapies in neurodegenerative diseases.
J. Thomassen, H. Leonard, Brittany Ulms et al.· Nature Genetics· 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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