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

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 31^st, 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.

KEYWORDS:

• Alzheimer’s disease
• APOE
• hippocampus
• Lewy body dementia
• MRI
• neuroimaging
• systematic review

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 Figure 4.

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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Additional information

Funding

This work was supported by a Canadian Institutes of Health Research grant (MOP13129) to M Masellis, an Early Researcher Award to M Masellis from the Ministry of Research, Innovation, and Science (MRIS; Ontario), and with the support of the Ontario Brain Institute, an independent non-profit corporation, funded partially by the Ontario government. The opinions, results and conclusions are those of the authors and no endorsement by the Ontario Brain Institute is intended or should be inferred. Matching funds were provided by participating hospital and research institute foundations, including the Baycrest Foundation, Bruyère Research Institute, Centre for Addiction and Mental Health Foundation, London Health Sciences Foundation, McMaster University Faculty of Health Sciences, Ottawa Brain and Mind Research Institute, Queen’s University Faculty of Health Sciences, Providence Care (Kingston), Sunnybrook Health Sciences Foundation, St. Michael’s Hospital, the Thunder Bay Regional Health Sciences Centre, the University of Ottawa Faculty of Medicine, and the Windsor/Essex County ALS Association. The Temerty Family Foundation provided the major infrastructure matching funds. U Saeed was supported by Ontario Graduate Scholarship, Margaret & Howard Gamble Research Grant, and Scace Graduate Fellowship in Alzheimer’s Research, University of Toronto. P Desmarais was supported by the Fondation du Centre Hospitalier de l’Université de Montréal for postdoctoral training in Cognitive Neurology. The authors also gratefully acknowledge financial support from the following sources: M Masellis receives salary support from the Department of Medicine at Sunnybrook Health Sciences Centre and the University of Toronto, as well as the Sunnybrook Research Institute. The funders had no role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript.