An ABCA1 missense variant decreases cholesterol efflux and confers Alzheimer's disease risk in the Chinese population

Background Genetic studies have revealed that single-nucleotide polymorphisms (SNPs) of ABCA1 are associated with Alzheimer's disease (AD) risk. However, their AD-related effects in non-European populations are not well studied. Moreover, the functional implications of these AD-associated SNPs remain unclear. Objective We examined the AD associations of ABCA1 SNPs in the Chinese population and investigated the underlying mechanisms whereby these SNPs modulate AD risk. Methods We conducted a genetic analysis in a Hong Kong Chinese AD cohort ( n = 332 patients with AD, n = 316 normal controls). Specifically, we analyzed 6 independent ABCA1 SNPs reported to be associated with AD risk in populations of European descent. To investigate the effects of these SNPs on ABCA1 protein function and brain molecular phenotypes, we analyzed cholesterol efflux in human glioblastoma cells as well as the associations between the AD risk SNPs and brain transcriptomic profiles, respectively. Results The ABCA1 coding SNP, rs2230806 (p.R219 K), was significantly associated with AD in the Chinese population, specifically in females (odds ratio [95% confidence interval] = 1.65 [1.16–2.33]). Notably, human glioblastoma cells expressing the ABCA1 R219 K showed a 17% cholesterol efflux reduction ( p < 0.001). Moreover, ABCA1 rs2230806 was associated with changes in the expression of oligodendrocyte genes involved in myelination in the brain in females. Conclusions We identified a significant AD risk ABCA1 coding variant in the Chinese population and demonstrated its effects on cholesterol efflux and brain molecular phenotypes. These results shed light on the genetic basis whereby an ABCA1 genetic variant contributes to AD pathogenesis.