Association of Rare APOE Missense Variants V236E and R251G With Risk of Alzheimer Disease

Abstract

IMPORTANCEThe APOE ε2 and APOE ε4 alleles are the strongest protective and risk-increasing, respectively, genetic variants for late-onset Alzheimer disease (AD). However, the mechanisms linking APOE to AD-particularly the apoE protein's role in AD pathogenesis and how this is affected by APOE variants-remain poorly understood. Identifying missense variants in addition to APOE ε2 and APOE ε4 could provide critical new insights, but given the low frequency of additional missense variants, AD genetic cohorts have previously been too small to interrogate this question robustly. OBJECTIVE To determine whether rare missense variants on APOE are associated with AD risk.DESIGN, SETTING, AND PARTICIPANTS Association with case-control status was tested in a sequenced discovery sample (stage 1) and followed up in several microarray imputed cohorts as well as the UK Biobank whole-exome sequencing resource using a proxy-AD phenotype (stages 2 and 3). This study combined case-control, family-based, population-based, and longitudinal AD-related cohorts that recruited referred and volunteer participants. Stage 1 included 37 409 nonunique participants of European or admixed European ancestry, with 11 868 individuals with AD and 11 934 controls passing analysis inclusion criteria. In stages 2 and 3, 475 473 participants were considered across 8 cohorts, of which 84 513 individuals with AD and proxy-AD and 328 372 controls passed inclusion criteria. Selection criteria were cohort specific, and this study was performed a posteriori on individuals who were genotyped. Among the available genotypes, 76 195 were excluded. All data were retrieved between September 2015 and November 2021 and analyzed between April and November 2021. MAIN OUTCOMES AND MEASURESIn primary analyses, the AD risk associated with each missense variant was estimated, as appropriate, with either linear mixed-model regression or logistic regression. In secondary analyses, associations were estimated with age at onset using linear mixed-model regression and risk of conversion to AD using competing-risk regression.RESULTS A total of 544 384 participants were analyzed in the primary case-control analysis; 312 476 (57.4%) were female, and the mean (SD; range) age was 64.9 (15.2; 40-110) years. Two missense variants were associated with a 2-fold to 3-fold decreased AD risk: APOE ε4 (R251G) (odds ratio, 0.44; 95% CI, 0.33-0.59; P = 4.7 × 10 −8 ) and APOE ε3 (V236E) (odds ratio, 0.37; 95% CI, 0.25-0.56; P = 1.9 × 10 −6 ). Additionally, the cumulative incidence of AD in carriers of these variants was found to grow more slowly with age compared with noncarriers. CONCLUSIONS AND RELEVANCEIn this genetic association study, a novel variant associated with AD was identified: R251G always coinherited with ε4 on the APOE gene, which mitigates the ε4-associated AD risk. The protective effect of the V236E variant, which is always coinherited with ε3 on the APOE gene, was also confirmed. The location of these variants confirms that the carboxyl-terminal portion of apoE plays an impo...

APOE in the bullseye of neurodegenerative diseases: impact of the APOE genotype in Alzheimer’s disease pathology and brain diseases

“…For instance, the APOE Jacksonville mutation (V236E), characterized by a mutation in the lipid-binding region, was reported to reduce Aβ aggregation in 5xFAD mice and manifested the relevance of lipid metabolism during AD [ 78 ]. Further, the R251G variant evidenced by Rabinovici and colleagues induces a single amino acid switch at position 251 and has been initially associated with decreased risk of suffering AD [ 769 ].…”

Global and local ancestry modulate APOE association with Alzheimer’s neuropathology and cognitive outcomes in an admixed sample

“…This observation corroborates the previous findings and offers a local ancestryspecific APOE expression regulation hypothesis and favoring the existence of a polygenic modulation of APOE net penetrance that can be proxied by global ancestry in admixed individuals. A recent study on rare APOE missense variants modifying common e3 and e4 association signals raises the possibility that apoE4 protein has a different molecular function (i.e., misfunction) in different ancestries [47]. Moreover, for the interaction analyses Finally, haplotypic structure of population-specific rare and common variant combinations may underlie the attenuation of APOE4 deleterious effect in AFR.…”

ApoE in Alzheimer’s disease: pathophysiology and therapeutic strategies

“…APOE4 is a major genetic risk factor for AD in a gene dose-dependent manner increasing risk by up to 15 fold in homozygotes [13], whereas APOE2 reduces AD risk by almost half and contributes to longevity [14]. In addition to the relatively common variants, there have been various rare variants of apoE identified, such as apoE3-R136S (apoE3-Christchurch; apoE3-Ch), apoE3-V236E (apoE3-Jacksonville; apoE3-Jac,) and apoE4-R251G [15][16][17][18][19], that are thought to confer some protection against AD pathology. These rare mutations are being investigated in the hope of identifying the molecular mechanisms involved in alleviating disease risks and developing novel therapeutic strategies.…”