The <i>APOE</i> ε4 variant and hippocampal atrophy in Alzheimer’s disease and Lewy body dementia: a systematic review of magnetic resonance imaging studies and therapeutic relevance

Introduction: The apolipoprotein E ɛ4-allele (APOE-ɛ4) increases the risk not only for Alzheimer’s disease (AD) but also for Parkinson’s disease dementia and dementia with Lewy bodies (collectively, Lewy body dementia [LBD]). Hippocampal volume is an important neuroimaging biomarker for AD and LBD, although its association with APOE-ɛ4 is inconsistently reported. We investigated the association of APOE-ε4 with hippocampal atrophy quantified using magnetic resonance imaging in AD and LBD. Areas covered: Databases were searched for volumetric and voxel-based morphometric studies published up until December 31st, 2020. Thirty-nine studies (25 cross-sectional, 14 longitudinal) were included. We observed that (1) APOE-ε4 was associated with greater rate of hippocampal atrophy in longitudinal studies in AD and in those who progressed from mild cognitive impairment to AD, (2) association of APOE-ε4 with hippocampal atrophy in cross-sectional studies was inconsistent, (3) APOE-ɛ4 may influence hippocampal atrophy in dementia with Lewy bodies, although longitudinal investigations are needed. We comprehensively discussed methodological aspects, APOE-based therapeutic approaches, and the association of APOE-ε4 with hippocampal sub-regions and cognitive performance. Expert opinion: The role of APOE-ɛ4 in modulating hippocampal phenotypes may be further clarified through more homogenous, well-powered, and pathology-proven, longitudinal investigations. Understanding the underlying mechanisms will facilitate the development of prevention strategies targeting APOE-ɛ4.