Abstract
OBJECTIVE: ATP-binding-cassette transporter A7(ABCA7) is suggested to be involved in lipid transport as well as in phagocytosis of amyloid-β in the brain. We tested the hypothesis that a common genetic variant in ABCA7 is associated with dementia, ischemic heart disease, ischemic cerebrovascular disease, and with lipid levels in the general population, independent of the common apolipoprotein E(APOE) genotype. METHODS: For this purpose, we genotyped a common genetic variant in ABCA7, identified in genome-wide-association-studies of Alzheimer's disease, in 104,258 individuals from the Danish general population, and also meta-analyzed our results with publicly available consortia data. RESULTS: Multifactorially adjusted hazard ratios for Alzheimer's disease were 1.07 (95% confidence interval:0.93-1.23) and 1.72 (1.24-2.40) for GA and AA versus GG genotype. Results were similar after APOE genotype adjustment and when only APOE ɛ33 carriers were studied. Including 178,304 individuals, the meta-analyzed odds ratio for Alzheimer's disease per one allele ABCA7 rs4147929 increase was 1.15 (1.12-1.18). ABCA7 genotype was not convincingly associated with vascular dementia, ischemic heart disease, ischemic cerebrovascular disease, or with lipid levels. Including 288,563 individuals, meta-analyzed odds ratios for ischemic heart disease per one allele ABCA7 rs4147929 increase was 1.01 (0.99-1.03). INTERPRETATION: A common genetic variant in ABCA7 was associated with high risk of Alzheimer's disease independent of APOE genotype. The lack of association with vascular dementia, ischemic heart disease, ischemic cerebrovascular disease, and with lipid levels suggests that ABCA7 is not important for atherosclerosis. Thus, our findings support the suggested role of ABCA7 in Alzheimer's disease pathology and phagocytic clearance of amyloid-β in the brain.