👤 Ali Ezzati

Alzheimer's disease (AD) heterogeneity complicates early detection and trial design. Scalable predictors may aid risk stratification. We assessed whether scalable baseline plasma biomarkers and neuropsychological measures predict 5‑year cognitive and functional decline in cognitively unimpaired older adults. We analyzed 866 amyloid-positive participants from the Anti-Amyloid Treatment in Asymptomatic Alzheimer's Disease (A4) trial and 343 amyloid-negative individuals from the Longitudinal Evaluation of Amyloid Risk and Neurodegeneration (LEARN) study. Decline was defined as a ≥0.5 increase in Clinical Dementia Rating-Global Score over 240 weeks. The separate and joint value of demographics, apolipoprotein E ( The p-tau217 and PACC significantly improved prediction. Full models achieved areas under the curve (AUCs) of 0.78-0.80 across cohorts. Additional plasma biomarkers offered modest AUC gains (1%-3%). The p-tau217 and PACC enhanced prediction of preclinical decline, supporting their utility in early identification and trial enrichment in AD. Show less

Hippocampal atrophy is a key marker of Alzheimer's disease (AD)-related neurodegeneration; however, hippocampal volume alone may not fully capture heterogeneity in cognitive decline. Hemispheric hippocampal asymmetry may provide complementary information, but its prognostic value for cognitive decline and clinical progression remains unclear. We studied 1,142 dementia-free participants from the Alzheimer's Disease Neuroimaging Initiative (ADNI) with available baseline structural MRI, cerebrospinal fluid (CSF) amyloid-β (Aβ42) and phosphorylated tau (p-tau-181), and longitudinal cognitive follow-up. Total hippocampal volume (left + right) and hemispheric asymmetry (absolute left-right volumetric difference) were modeled simultaneously. Linear mixed-effects models examined associations with baseline performance and longitudinal change across memory, language, executive, and visuospatial domains. Cox proportional hazards models assessed risk of clinical progression to clinical dementia over up to 10 years of follow-up. All analyses adjusted for age, sex, education, APOE ε4 status, and CSF biomarkers, with stratification by amyloid status. The study cohort included 546 women (47.8%), with a mean age of 72.54 ± 6.98 years. Larger total hippocampal volume was consistently associated with better baseline performance and slower decline across all four cognitive domains, independent of amyloid and tau biomarkers. In contrast, greater hippocampal asymmetry was selectively associated with worse baseline memory performance and faster memory decline, independent of total hippocampal volume. In amyloid-stratified analyses, total hippocampal volume showed broad associations with cognition across all four domains among amyloid-positive participants and more limited, domain-specific associations among amyloid-negative participants, whereas hippocampal asymmetry was associated with memory only in amyloid-negative individuals. Regarding clinical progression to dementia, smaller total hippocampal volume was associated with higher risk of progression in the overall cohort and within both amyloid groups. In contrast, hippocampal asymmetry was associated with progression risk only among amyloid-negative individuals (hazard ratio per SD increase = 1.31, 95% CI: 1.03-1.65). Hippocampal total volume and asymmetry capture distinct aspects of neurodegeneration, with asymmetry providing additional prognostic information for memory decline and clinical progression in participants without detectable amyloid pathology. Show less