The contribution of apolipoprotein E genetic variation to dementia risk in British South Asians

Understanding the genetic basis of dementia in diverse populations is essential to ensure that efforts to predict, prevent and treat dementia are equitable. The strongest genetic risk factor for dementia-APOE genotype-has not been assessed in population-scale cohorts of South Asian ancestry. To test whether APOE variation is associated with all-cause dementia in British South Asians, we analysed data from 51 104 volunteers in the Genes & Health study-a cohort study of British Bangladeshi and British Pakistani individuals who have undergone genotyping and consented for lifelong (England & Wales National Health Service) linkage to healthcare records. All-cause dementia was defined using electronic healthcare records. APOE genotypes were defined using phased, imputed genotype data. Cox proportional hazards models were used to assess the relationship between APOE genotype and dementia. Population attributable fractions were calculated for each APOE genotype. Phenome-wide association tests were performed to determine the impact of APOE genotype on a range of traits and diseases. We identified 614 cases of dementia and 50 490 controls without any dementia diagnostic codes. Dementia cases (n = 614, of which 451 [73.5%] were incident) were recruited at an older age (median 71.3 versus 39.0), were more likely to be male (58.6% versus 44.5%), and were more likely to carry at least one APOE ε4 allele (26.4% versus 19.6%) than controls without dementia (n = 50 490). The APOE ε4 allele was associated with all-cause dementia in a dose-dependent fashion (APOE ε4/ε4: Hazard ratio [HR] 2.7, 95% CI 1.7-4.2, P < 0.0001; APOE ε4/ε3: HR 1.5, 95% CI 1.2-1.8, P < 0.001; Cox multivariable regression models adjusted for age at recruitment, gender, genetic principal components 1-10, and genetic ancestry; all models used APOE ε3/ε3 as reference). The overall proportion of all-cause dementia cases which could be attributed to this allele was 12.9% (95% CI -5.9%-25.5%). APOE ε4 was also associated with elevated triglycerides and low-density lipoprotein (LDL) cholesterol. APOE ε4-the major genetic risk factor for sporadic dementia in European-ancestry populations-has a similar impact on dementia risk in British South Asians. Prediction and prevention studies aiming to use APOE to identify people at high risk of dementia should be inclusive of all ancestries. Genetic analysis of dementia risk in diverse populations is essential for ensuring that the downstream benefits-for prediction, prevention and drug discovery-are shared equitably.