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. 2023 Feb 21;329(7):551-560.
doi: 10.1001/jama.2023.0268.

Association of African Ancestry-Specific APOE Missense Variant R145C With Risk of Alzheimer Disease

Yann Le Guen  1   2 , Ana-Caroline Raulin  3 , Mark W Logue  4   5   6   7 , Richard Sherva  6 , Michael E Belloy  1 , Sarah J Eger  1 , Annabel Chen  1 , Gabriel Kennedy  1 , Lindsey Kuchenbecker  3 , Justin P O'Leary  3 , Rui Zhang  4 , Victoria C Merritt  8   9   10 , Matthew S Panizzon  9   11   12 , Richard L Hauger  8   9   11 , J Michael Gaziano  12   13 , Guojun Bu  3 , Timothy A Thornton  14 , Lindsay A Farrer  6 , Valerio Napolioni  15 , Zihuai He  1   16 , Michael D Greicius  1
Affiliations

Association of African Ancestry-Specific APOE Missense Variant R145C With Risk of Alzheimer Disease

Yann Le Guen et al. JAMA. .

Abstract

Importance: Numerous studies have established the association of the common APOE ε2 and APOE ε4 alleles with Alzheimer disease (AD) risk across ancestries. Studies of the interaction of these alleles with other amino acid changes on APOE in non-European ancestries are lacking and may improve ancestry-specific risk prediction.

Objective: To determine whether APOE amino acid changes specific to individuals of African ancestry modulate AD risk.

Design, setting, and participants: Case-control study including 31 929 participants and using a sequenced discovery sample (Alzheimer Disease Sequencing Project; stage 1) followed by 2 microarray imputed data sets derived from the Alzheimer Disease Genetic Consortium (stage 2, internal replication) and the Million Veteran Program (stage 3, external validation). This study combined case-control, family-based, population-based, and longitudinal AD cohorts, which recruited participants (1991-2022) in primarily US-based studies with 1 US/Nigerian study. Across all stages, individuals included in this study were of African ancestry.

Exposures: Two APOE missense variants (R145C and R150H) were assessed, stratified by APOE genotype.

Main outcomes and measures: The primary outcome was AD case-control status, and secondary outcomes included age at AD onset.

Results: Stage 1 included 2888 cases (median age, 77 [IQR, 71-83] years; 31.3% male) and 4957 controls (median age, 77 [IQR, 71-83] years; 28.0% male). In stage 2, across multiple cohorts, 1201 cases (median age, 75 [IQR, 69-81] years; 30.8% male) and 2744 controls (median age, 80 [IQR, 75-84] years; 31.4% male) were included. In stage 3, 733 cases (median age, 79.4 [IQR, 73.8-86.5] years; 97.0% male) and 19 406 controls (median age, 71.9 [IQR, 68.4-75.8] years; 94.5% male) were included. In ε3/ε4-stratified analyses of stage 1, R145C was present in 52 individuals with AD (4.8%) and 19 controls (1.5%); R145C was associated with an increased risk of AD (odds ratio [OR], 3.01; 95% CI, 1.87-4.85; P = 6.0 × 10-6) and was associated with a reported younger age at AD onset (β, -5.87 years; 95% CI, -8.35 to -3.4 years; P = 3.4 × 10-6). Association with increased AD risk was replicated in stage 2 (R145C was present in 23 individuals with AD [4.7%] and 21 controls [2.7%]; OR, 2.20; 95% CI, 1.04-4.65; P = .04) and was concordant in stage 3 (R145C was present in 11 individuals with AD [3.8%] and 149 controls [2.7%]; OR, 1.90; 95% CI, 0.99-3.64; P = .051). Association with earlier AD onset was replicated in stage 2 (β, -5.23 years; 95% CI, -9.58 to -0.87 years; P = .02) and stage 3 (β, -10.15 years; 95% CI, -15.66 to -4.64 years; P = 4.0 × 10-4). No significant associations were observed in other APOE strata for R145C or in any APOE strata for R150H.

Conclusions and relevance: In this exploratory analysis, the APOE ε3[R145C] missense variant was associated with an increased risk of AD among individuals of African ancestry with the ε3/ε4 genotype. With additional external validation, these findings may inform AD genetic risk assessment in individuals of African ancestry.

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Conflict of interest statement

Conflict of Interest Disclosures: Ms Chen reported receipt of grants from Stanford Medical Scholars Research Program. Dr Merritt reported receipt of grants from Department of Veterans Affairs and salary support from the VA Clinical Science Research and Development Service. No other disclosures were reported.

Figures

Figure 1.
Figure 1.. Individuals Included in the Discovery (Stage 1) and Internal Replication (Stage 2) Samples
AD indicates Alzheimer disease; ADGC, Alzheimer Disease Genetic Consortium; ADSP, Alzheimer Disease Sequencing Project; and CH, cognitively healthy. In the bottom boxes, CC denotes homozygous for rs769455 reference allele; CT, heterozygous for rs769455; TT, homozygous for rs769455 alternate allele; GG, homozygous for rs376170967 reference allele; GA, heterozygous for rs376170967; and AA, homozygous for rs376170967 alternate allele.
Figure 2.
Figure 2.. Risk of Alzheimer Disease by APOE Genotype Including APOE ε3[R145C] Subtypes
Alzheimer disease risk by APOE genotype compared with the ε3/ε3 reference group (ie, odds ratio for ε3/ε3 = 1) in (A) the stage 1 discovery composed of next-generation sequencing data from the Alzheimer Disease Sequencing Project data set and in (B) the stage 2 internal replication composed of imputed microarray data. Whiskers indicate 95% CIs. Orange data markers indicate the APOE genotype corresponding to the main novel result. See eTable 16 in Supplement 1 for underlying data.
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References

    1. Corder EH, Saunders AM, Strittmatter WJ, et al. . Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer’s disease in late onset families. Science. 1993;261(5123):921-923. doi:10.1126/science.8346443 - DOI - PubMed
    1. Corder EH, Saunders AM, Risch NJ, et al. . Protective effect of apolipoprotein E type 2 allele for late onset Alzheimer disease. Nat Genet. 1994;7(2):180-184. doi:10.1038/ng0694-180 - DOI - PubMed
    1. Farrer LA, Cupples LA, Haines JL, et al. ; APOE and Alzheimer Disease Meta Analysis Consortium . Effects of age, sex, and ethnicity on the association between apolipoprotein E genotype and Alzheimer disease: a meta-analysis. JAMA. 1997;278(16):1349-1356. doi:10.1001/jama.1997.03550160069041 - DOI - PubMed
    1. Medway CW, Abdul-Hay S, Mims T, et al. . ApoE variant p.V236E is associated with markedly reduced risk of Alzheimer’s disease. Mol Neurodegener. 2014;9(1):11. doi:10.1186/1750-1326-9-11 - DOI - PMC - PubMed
    1. Le Guen Y, Belloy ME, Grenier-Boley B, et al. ; EADB, GR@ACE, DEGESCO, DemGene, GERAD, and EADI Groups . 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 - DOI - PMC - PubMed

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