Objective: To systematically identify phenotypes that consistently associate with the ε4-allele of apolipoprotein E (APOE-ε4) in α-synucleinopathies.

Background: The APOE-ε4 presents an elevated risk not only for Alzheimer’s disease (AD) but also for Parkinson’s disease dementia (PDD) and dementia with Lewy bodies (DLB). Indeed, the independent influence of APOE-ε4 on the promotion and exacerbation of α-synuclein pathology has recently been suggested.^1–3 However, the precise phenotypic associations of APOE-ε4 in α-synucleinopathies remain variable.

Method: PubMed/Medline, Embase, PsycINFO, Scopus, Cochrane and Web of Science were systematically searched from January 1^st, 1995 up until December 31^st, 2020, as per the PRISMA guidelines. Studies evaluating the association of APOE-ε4 with clinicopathological, cognitive, neuropsychiatric, and neuroimaging phenotypes in clinically and/or pathologically-diagnosed cases of Parkinson’s disease (PD), PDD, DLB, and multiple system atrophy (MSA) were critically reviewed.

Results: A total of 136 studies were included (Figure). APOE-ε4 was found to be consistently associated with: 1) lower cerebrospinal fluid levels of amyloid-β 1-42 in PDD and DLB, 2) cognitive deficits in the memory domain in PD, PDD, and DLB, 3) atrophy in the medial temporal lobe primarily in DLB, 3) cerebral amyloid angiopathy, shorter survival, and accelerated decline in global cognition in DLB, as well as 4) the co-occurrence of AD-type neuropathological features in PDD and DLB. Furthermore, APOE-ε4 was associated, albeit inconsistently, with: 1) the presence and severity of diffuse neocortical Lewy body pathology and, 2) elevated tracer retention on amyloid positron emission tomography in PD, PDD, and DLB, 3) greater odds of dementia in PD, and 4) other genetic and pathophysiological factors to elevate the cumulative risk for DLB. APOE-ε4 was not associated with disease risk or α-synuclein pathology in MSA. Studies also highlighted the possible relationship of APOE-ε4 with neuropsychiatric, epigenetic (DNA methylation), sleep, immunohistochemical, and biochemical factors in α-synucleinopathies, which will be presented.

Conclusion: In addition to its role in AD, APOE-ε4 influences the disease presentation and progression particularly in PDD and DLB. Guided by reliable biomarkers, further research to unravel the underlying mechanisms will assist in developing early prevention strategies targeting the APOE protein.

References: [1] Dickson DW, Heckman MG, Murray ME, et al. APOE ε4 is associated with severity of Lewy body pathology independent of Alzheimer pathology. Neurology 2018;91(12):e1182-e1195. [2] Davis AA, Inman CE, Wargel ZM, et al. APOE genotype regulates pathology and disease progression in synucleinopathy. Science Translational Medicine 2020; 12(529):eaay3069. [3] Zhao N, Attrebi ON, Ren Y, et al. APOE4 exacerbates α-synuclein pathology and related toxicity independent of amyloid. Science Translational Medicine 2020; 12(529):eaay1809.

« Back to MDS Virtual Congress 2021

MDS Abstracts - https://www.mdsabstracts.org/abstract/elucidating-multimodal-endophenotypes-of-apoe-%ce%b54-in-%ce%b1-synucleinopathies/