The proportion of Alzheimer’s disease attributable to Apolipoprotein E

Abstract

AbstractIntroductionThe extent to which genetic variation at theAPOElocus explains the burden of late-onset Alzheimer’s disease (AD) is poorly understood. We aimed to provide new estimates of the proportions of AD and all-cause dementia attributable to combined carriage of ε3 and/or ε4 alleles ofAPOE.MethodsWe conducted a nested case-control study using data from 171,133 participants of the UK Biobank cohort study, aged ≥60 years at baseline assessments in 2006-2010. Carriage of ε2/ε3/ε4 alleles ofAPOEwere coded from genotyped or imputed microarray data for single nucleotide polymorphisms rs7412 and rs429358. AD and all-cause dementia were ascertained from baseline self-report and follow-up via linked electronic health and death records up to December 2022 (minimum/maximum follow-up: 12.2 / 16.8 years). Risks of these outcomes due to ε3 and/or ε4 carriage were modelled with multivariable logistic regression, adjusting for age at baseline, self-reported sex and ethnicity, 10 genetic principal components and genotyping array. Odds ratios and prevalence of ε3 and ε4 carriage were used to calculate population attributable fractions (PAFs) of the outcomes due to these genotypes.Results99.4% of the sample had either ε3 and/or ε4 carriage. By the end of follow-up, 3026 (1.8%) and 6634 (3.9%) of the sample had AD and all-cause dementia, respectively. The odds ratio for AD risk due to ε3 and ε4 carriage with reference to ε2 homozygotes was 3.80 (95% CI:1.58, 9.17). The equivalent risk for all-cause dementia was 1.74 (95% CI: 1.16, 2.61). PAFs for AD and all-cause dementia burden due to ε3 and ε4 exposure were 73.6% (95% CI: 36.6, 89.0) and 42.4% (95% CI: 13.6, 61.6%), respectively.ConclusionsDifferences in the molecular physiology of Apolipoprotein E cause most AD and a large fraction of dementia cases. Research into this pathway should be prioritised to facilitate dementia prevention.