APOE ε 4 -Associated Hippocampal Atrophy Trajectories Across the Alzheimer's Disease Continuum: A Systematic Review,...

The role of APOE- $\epsilon 4$ in hippocampal atrophy is contested. We aimed to determine whether it functions as a static risk factor or an amyloid- $\beta \left(\text{A}\beta \right)$ -dependent modulator of neurodegeneration.

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.

The meta-analysis confirmed significant atrophy in APOE- $\epsilon 4$ carriers but with high heterogeneity. Longitudinal analysis resolved this by identifying a crucial interaction: in $\text{A}\beta$ -negative individuals, carrier atrophy rates were indistinguishable from non-carriers. However, $\text{A}\beta$ positivity triggered a dramatic, dose-dependent acceleration in atrophy among carriers, with homozygotes declining over three times faster.

APOE- $\epsilon 4$ acts as a potent, conditional accelerator of neurodegeneration, not an independent driver. Its deleterious effect is contingent on the presence of $\text{A}\beta$ pathology. Clinical risk stratification should therefore integrate amyloid status with APOE genotype to accurately predict structural progression.