Genetic drivers of hippocampal atrophy highlight the role of APOE functional variants and AD polygenicity in Mild Cognitive Impairment

The hippocampus, crucial in cognitive aging and Alzheimer's disease (AD), shows early atrophy during disease progression. This study investigated 5-year trajectories of hippocampal volumes across AD stages, focusing on genetic predisposition to AD, captured through the polygenic risk score for AD (PRS-AD) and APOE, and their impact on hippocampal atrophy. Analyzing data from 1,051 participants in the ADNI, we found that AD genetic risk accelerates a reduction in hippocampal volume, particularly in individuals with mild cognitive impairment (MCI). Effects were primarily driven by cerebrospinal fluid protein quantitative trait loci of APOE. Excluding the APOE region from analyses negated these effects, underscoring its critical role. This stage-specific effect suggested that AD genetic factors, particularly the APOE region, exert their influence primarily before or during the transition to MCI, highlighting the hippocampus's increased vulnerability during this period. These findings underscored the importance of targeting the MCI stage for early detection and intervention in AD. Further research is warranted to elucidate these dynamics and their potential clinical applications.