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Rare Missense Variant of APOE Shows Increased Risk of Alzheimer Disease in African Ancestry

Using several large-scale cohorts, findings showed that cumulative incidence of Alzheimer disease grows faster with age in R145C variant carriers compared with noncarriers, contradicting prior research results.

Findings from a genome-wide study of participants with African ancestry showed that a third apolipoprotein (APOE) missense variant, R145C (rs769455-T), is associated with a significantly greater risk of developing Alzheimer disease (AD) in those of African descent. Additionally, disease onset came significantly earlier for carriers of the missense variant compared with noncarriers.1

In stratified meta-analyses, R145C carriers had an almost 3-fold increased risk compared with noncarriers (odds ratio [OR], 2.75; 95% CI, 1.84-4.11; P = 8.3 x 10-7) and had a reported AD age-at-onset almost 6 years younger (ß = –5.72; 95% CI, –7.87 to –3.56; P = 2.0 x 10-7) than their counterparts. The findings, presented at the 2022 Alzheimer’s Association International Conference (AAIC), July 31 to August 4, in San Diego, California, highlight the R145C variant as a risk factor for individuals with African ancestry with the APOE ε3/ε4 genotype.

Recent literature has suggested that when examining variants at the APOE locus, APOE-stratified analyses may provide better statistical power than standard APOE-adjusted models. Using this approach, lead investigator Yann Le Guen, PhD, assistant director of computational biology, Stanford University, and colleagues included data from the original stage 1 discovery (2888 cases; 4957 controls) case-control cohort, the stage 2 replication cohort imputed on the TOPMed panel (1201 cases; 2744 controls) and stage 3 replication cohort from the Million Veteran Program (733 cases; 19,406 controls).

In the Million Veteran Program, investigators found increased risk (OR, 1.90; 95% CI, 1.84-4.11; P = .027) and earlier AD onset (ß = –10.15; 95% CI, –15.66 to –4.64; P = 2.0 x 10-4) among R145C carriers that resembled the initial findings from the first 2 case controls. Additionally, cumulative incidence of AD grew fasters with age in R145C carriers vs noncarriers on risk regression models. "Our findings should enhance the AD risk prediction in African ancestry individuals and help elucidate the mechanisms linking the APOE protein to AD pathogenesis," Le Guen et al wrote.

READ MORE: Discrimination Plays Role in Late-Life Cognitive Inequalities

Most recently, Le Guen and his colleagues conducted a large-scale genetic associationstudy that included 544,384 participants from multiple studies to answer whether APOE missense variants, other than the common APOE alleles ε2 and ε4, are associated with AD risk. Among their findings were 2 missense variants were associated with a 2-fold to 3-fold decreased AD risk: APOE ε4 (R251G; odds ratio [OR], 0.44; 95% CI, 0.33-0.59; P = 4.7 x 10-8) and APOE ε3 (V236E; OR, 0.37; 95% CI, 0.25-0.56; P = 1.9 x 10-6). Contrary to the results presented at AAIC, the cumulative incidence of AD in carriers of these variants were found to grow more slowly with age compared with noncarriers.2

"What was nice is that we know that this [R251G] variant may have an impact on the risk that’s associated with ε4," Le Guen told NeurologyLive®. "The ε4 risk of Alzheimer disease is unseen, actually. It is decreased due to an alteration of amino acid that probably changed the structure of APOE and made it, apparently, less likely to oligomerize, improve lipid binding, and reduce insoluble [amyloid-ß]."

When asked how the findings would impact drug development, he added, "Our findings enter this framework of saying, ‘If you target APOE and change its conformation, notably the ε4 allele, then you may be able to modify one individual’s Alzheimer risk.’ These findings are also interesting because they talk about APOE conformation. Of course, one would have to do cryo-[electron microscopy] or crystallography to characterize the structure of APOE with and without the brand. But, once this is all done, you can think about developing some small molecule that target APOE ε4 and behave the same way as this variant."

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1. Le Guen Y, Raulin A, Logue MW, et al. Association of African ancestry-specific APOE missense variant R145C with risk of Alzheimer disease. Presented at: Alzheimer’s Association International Conference; July 31-Aug 4. San Diego, CA. 58883
2. Guen YL, Bellow ME, Grenier-Boley B, et al. Association of rare APOE missense variants V236E and R251G with risk of Alzheimer disease. JAMA Neurol. 2022;79(7):652-663. doi:10.1001/jamaneurol.2022.1166.