ABSTRACT
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.
Article highlights
APOE-ε4 was associated with greater rate of hippocampal atrophy in Alzheimer’s disease. Hippocampal atrophy rate quantified using serial MRI may serve as a useful structural biomarker of disease progression and treatment effectiveness in clinical trials.
APOE-ε4 may influence hippocampal atrophy in Lewy body dementia, a disorder that often presents with concomitant Alzheimer’s disease-related pathology, although further longitudinal investigations are needed for confirmation.
The influence of APOE-ε4 on hippocampal atrophy may predominantly be observed at milder disease stages prior to more widespread neurodegeneration. Therapeutic interventions that slow atrophy rate or stimulate neurogenesis early in the disease course would be highly beneficial.
APOE-ε4 may exacerbate the degeneration of hippocampal sub-regions typically atrophied in Alzheimer’s disease, primarily the cornu ammonis-1. A more precise delineation of hippocampal subfields can be achieved using ultra-high-field MRI, which may be utilized in future investigations.
APOE-ε4 carriers performed worse in the memory domain and presented with a more amnestic cognitive profile, as congruent with greater mediotemporal dysfunction associated with APOE-ε4.
Studies showed considerable variation in demographic, methodological, and analytical characteristics, which may contribute to inconsistent findings. Harmonization of neuroimaging protocols is recommended to enhance reproducibility and detection of treatment-related changes in clinical trials.
APOE-ε4 is a shared genetic risk factor across Alzheimer’s disease and Lewy body dementia. The elucidation of APOE-ε4-based mechanisms may assist not only in reducing hippocampal injury but also in delaying the onset of neurodegeneration in at-risk healthy APOE-ε4 carriers. Future research investigating the clinicopathological and neuroimaging relationships associated with APOE-ε2 variant is also desirable, as it may provide important clues to the APOE-ε2’s neuroprotective mechanisms.
Acknowledgments
The authors are grateful to Sylvain G. Bélisle for assistance in creating .
Declaration of interest
M Masellis reports grants from the Canadian Institutes of Health Research, Ministry of Research, Innovation and Science (MRIS; Government of Ontario), and the Ontario Brain Institute, during the conduct of the study. He is an Associate Editor of Current Pharmacogenomics and Personalized Medicine. He receives personal fees for Advisory Board work from Arkuda Therapeutics, Ionis, Alector, Biogen Canada, and Wave Life Sciences outside of this submitted work. Outside of this submitted work, he receives grants from Sunnybrook AFP Innovation Fund, Alzheimer’s Drug Discovery Foundation (ADDF), Brain Canada, Heart and Stroke Foundation Centre for Stroke Recovery, Washington University and Weston Brain Institute. He also receives royalties from Henry Stewart Talks. He is also funded for sponsored-clinical trials from Roche and Alector. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or conflict with the subject matter or materials discussed in this manuscript apart from those disclosed.
Reviewer disclosures
Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.
Supplementary material
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