Rare Variants in ATP8B4, ABCA1 Tied to Alzheimer's Disease Risk

Rare variants in ATP8B4 and ABCA1 may increase risk of developing Alzheimer's disease, a new study in Nature Genetics finds. An international team of researchers compared the gene-based burden of rare damaging variants in 16,036 individuals with Alzheimer's disease and 16,522 controls who had all undergone exome sequencing. They uncovered half a dozen genes with a differential burden of rare variants between cases and controls, five of which they confirmed in additional analyses. Those five also mapped to genome-wide association study loci, leading the researchers to look for potential driver genes and homing in on RIN3, CLU, ZCWPW1, and ACE. However, they note that the GWAS sentinel variants and the rare-variant burden appear to be independent. The researchers note that their analysis points to ATP8B4 and ABCA1 as new risk factors for Alzheimer's and also underscores the role of amyloid-β precursor protein processing, amyloid-β aggregation, lipid metabolism, and microglial function in the disease. "The associated genes strengthen our current understanding of [Alzheimer's disease] pathophysiology. When treatment options become available in the future, identification of damaging variants in these genes will be of interest to clinical practice," they write.