APOE ϵ4-Associated Hippocampal Atrophy Trajectories Across the Alzheimer's Disease Continuum: A Systematic Review, Meta-Analysis, and Longitudinal Validation

BackgroundThe role of APOE-{varepsilon}4 in hippocampal atrophy is contested. We aimed to determine whether it functions as a static risk factor or an amyloid-{beta} (A{beta})-dependent modulator of neurodegeneration. MethodsWe integrated a systematic meta-analysis of 18 studies (N = 3, 781) with longitudinal validation using linear mixed-effects models in the NACC and ADNI cohorts (N > 5, 000), employing biomarker stratification to test for gene-pathology interactions. ResultsThe meta-analysis confirmed significant atrophy in APOE-{varepsilon}4 carriers but with high heterogeneity. Longitudinal analysis resolved this by identifying a crucial interaction: in A{beta}-negative individuals, carrier atrophy rates were indistinguishable from non-carriers. However, A{beta} positivity triggered a dramatic, dose-dependent acceleration in atrophy among carriers, with homozygotes declining over three times faster. ConclusionsAPOE-{varepsilon}4 acts as a potent, conditional accelerator of neurodegeneration, not an independent driver. Its deleterious effect is contingent on the presence of A{beta} pathology. Clinical risk stratification should therefore integrate amyloid status with APOE genotype to accurately predict structural progression.