Belloy, Michael E

Abstract The genetic contributions of the X chromosome to Alzheimer’s disease (AD) remain poorly understood yet are expected to importantly shape sex differences in AD. We therefore performed large-scale X-chromosome-wide association studies (N=1,240,451), evaluating differential risk due to sex, APOE *4, and escape from X-chromosome inactivation, finding most X-linked loci appear relevant to female-biased AD etiology. In evaluating genetic pleiotropy with hormonal, lipid, and brain imaging traits, we discovered X-linked AD loci converged on white matter traits, particularly in the anterior corona radiata and splenium of the corpus callosum. Through brain-centric functional genomics analyses, we then nominated candidate causal genes, including 5 that appeared highly robust. Notably, we found the escape gene RBBP7 decreases AD risk in APOE *4 carriers likely through higher expression in excitatory neurons to counter tau-related neurodegeneration. Altogether, we provide an atlas of sex and APOE *4-informed candidate X-linked AD risk loci, genes, and mechanisms that will guide future studies.

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.