APOE missense variant R145C is associated with increased Alzheimer’s disease risk in African ancestry individuals with the APOE ε3/ε4 genotype

BACKGROUND The APOE gene has two common missense variants that greatly impact the risk of late-onset Alzheimer’s disease (AD). Here we examined the risk of a third APOE missense variant, R145C, that is rare in European-Americans but present in 4% of African-Americans and always in phase with APOE ε3 . METHODS In this study, we included 11,790 individuals of African and Admixed-African ancestry (4,089 cases and 7,701 controls). The discovery sample was composed of next generation sequencing data (2,888 cases and 4,957 controls), and the replication was composed of microarray data imputed on the TOPMed reference panel (1,201 cases and 2,744 contols). To assess the effect of R145C independently of the ε2 and ε4 alleles, we performed stratified analyses in ε2/ε3, ε3/ε3 , and ε3/ε4 subjects. In primary analyses, the AD risk associated with R145C was estimated using a linear mixed model regression on case-control diagnosis. In secondary analyses, we estimated the influence of R145C on age-at-onset using linear-mixed-model regression, and risk of conversion to AD using competing risk regression. RESULTS In ε3/ε4- stratified meta-analyses, R145C carriers had an almost three-fold increased risk compared to non-carriers (odds ratio, 2.75; 95% confidence interval [CI], 1.84 to 4.11; P = 8.3×10−7) and had a reported AD age-at-onset almost 6 years younger (β, -5.72; 95% CI, 7.87 to -3.56; P = 2.0×10−7). Competing risk regression showed that the cumulative incidence of AD grows faster with age in R145C carriers compared to non-carriers (hazard ratio, 2.42, 95% CI, 1.81 to 3.25; P = 3.7×10−9). CONCLUSION The R145C variant is a potent risk factor for AD among African ancestry individuals with the ε3/ε4 genotype. Our findings should enhance AD risk prediction in African ancestry individuals and help elucidate the mechanisms linking the apoE protein to AD pathogenesis. The findings also add to the growing body of evidence demonstrating the importance of including ancestrally-diverse populations in genetic studies. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement Supported by the National Institute of Health and National Institute of Aging grants AG060747 (MDG), AG066206 (ZH), AG066515 (ZH, MDG), 2R01-AG048927 (LAF), RF1-AG057519 (LAF), U19-AG068753 (LAF), U01-AG058654 (LAF), U01-AG062602 (LAF), the European Union's Horizon 2020 research and innovation program under the Marie Skłodowska-Curie (grant agreement No. 890650, YLG), the Alzheimer's Association (AARF-20-683984, MEB), and the Iqbal Farrukh and Asad Jamal Fund. Additional funders of individual investigators and institutions who contributed to data collection and genotyping are provided in the Supplementary Appendix. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: This study involves only openly available human data, which can be obtained from public repository (see Data availability statement and Supplementary Tables S2-S3.) Participants or their caregivers provided written informed consent in the original studies. The current study protocol was granted an exemption by the Stanford University institutional review board because the analyses were carried out on deidentified, off-the-shelf data; therefore, additional informed consent was not required. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable. Yes Data availability Data used in preparation of this manuscript can be obtained upon application at: - dbGaP (https://www.ncbi.nlm.nih.gov/gap/advanced_search/) - NIAGADS and NIAGADS DSS (https://www.niagads.org/) - LONI (https://ida.loni.usc.edu/) - Synapse (https://adknowledgeportal.synapse.org/) - RADC Rush (https://www.radc.rush.edu/) - NACC (https://naccdata.org/) Tables S2 and S3 provide the details of repositories and accession number per cohort-platform group.