The APOE ε4 variant and hippocampal atrophy in Alzheimer's disease and Lewy body dementia: a systematic review of magnetic resonance imaging studies and therapeutic relevance.

IntroductionThe ɛ4-allele of apolipoprotein E (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-e4 with hippocampal atrophy quantified using magnetic resonance imaging in AD and LBD.Areas coveredElectronic 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-e4 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-e4 with hippocampal atrophy in cross-sectional studies was inconsistent, which may be attributed to variability in age and/or disease severity, (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 association of APOE-e4 with hippocampal sub-regions and cognitive performance.Expert opinionThe role of APOE-ɛ4 in modulating hippocampal phenotypes may be further clarified through more homogenous, well-powered, pathology-proven, longitudinal investigations. Understanding the underlying mechanisms will facilitate development of prevention strategies targeting APOE-ɛ4.