Apolipoprotein E Gene in α-Synucleinopathies: A Narrative Review

Abstract

In this narrative review, we delved into the intricate interplay between Apolipoprotein E (APOE) alleles (typically associated with Alzheimer’s disease—AD) and alpha-synucleinopathies (aS-pathies), involving Parkinson’s disease (PD), Parkinson’s disease dementia (PDD), dementia with Lewy bodies (DLB), and multiple-system atrophy (MSA). First, in-vitro, animal, and human-based data on the exacerbating effect of APOE4 on LB pathology were summarized. We found robust evidence that APOE4 carriage constitutes a risk factor for PDD—APOE2, and APOE3 may not alter the risk of developing PDD. We confirmed that APOE4 copies confer an increased hazard towards DLB, as well. Again APOE2 and APOE3 appear unrelated to the risk of conversion. Of note, in individuals with DLB APOE4, carriage appears to be intermediately prevalent between AD and PDD-PD (AD > DLB > PDD > PD). Less consistency existed when it came to PD; APOE-PD associations tended to be markedly modified by ethnicity. Finally, we failed to establish an association between the APOE gene and MSA. Phenotypic associations (age of disease onset, survival, cognitive–neuropsychiatric- motor-, and sleep-related manifestations) between APOE alleles, and each of the aforementioned conditions were also outlined. Finally, a synopsis of literature gaps was provided followed by suggestions for future research.

More evidence for widespread antagonistic pleiotropy in polymorphic disease alleles

“…The E4 allele appears to be ancestral with E3 arising later and E2 arising from the E3 allele ( McIntosh et al, 2012 ). Carriers of the E4 allele have greater cholesterol levels than carriers of the E3 and E2 alleles, possibly due to more efficient intestinal absorption ( Tikkanen et al, 1990 ), and possession of the E4 allele is associated with increased risk of hypertension ( Niu et al, 2009 ), cardiovascular disease ( Song et al, 2004 ) and Alzheimer’s disease ( Goldman, 2012 ; O'Neil, 2023 ; Liampas et al, 2024 ).…”