APOE ε4-associated hippocampal atrophy trajectories across the Alzheimer's disease continuum: a systematic review, meta-analysis, and longitudinal validation

Abstract Background The role of APOE- ε 4 in hippocampal atrophy is contested. We aimed to determine whether it functions as a static risk factor or an amyloid- β (A β )-dependent modulator of neurodegeneration. Methods We 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. Results The meta-analysis confirmed significant atrophy in APOE- ε 4 carriers but with high heterogeneity. Longitudinal analysis resolved this by identifying a crucial interaction: in A β -negative individuals, carrier atrophy rates were indistinguishable from non-carriers. However, A β positivity triggered a dramatic, dose-dependent acceleration in atrophy among carriers, with homozygotes declining over three times faster. Conclusions APOE- ε 4 acts as a potent, conditional accelerator of neurodegeneration, not an independent driver. Its deleterious effect is contingent on the presence of A β pathology. Clinical risk stratification should therefore integrate amyloid status with APOE genotype to accurately predict structural progression.