Exome sequencing identifies rare damaging variants in ATP8B4 and ABCA1 as risk factors for Alzheimer's disease

Nat Genet. 2022 Dec;54(12):1786-1794. doi: 10.1038/s41588-022-01208-7. Epub 2022 Nov 21.


Alzheimer's disease (AD), the leading cause of dementia, has an estimated heritability of approximately 70%1. The genetic component of AD has been mainly assessed using genome-wide association studies, which do not capture the risk contributed by rare variants2. Here, we compared the gene-based burden of rare damaging variants in exome sequencing data from 32,558 individuals-16,036 AD cases and 16,522 controls. Next to variants in TREM2, SORL1 and ABCA7, we observed a significant association of rare, predicted damaging variants in ATP8B4 and ABCA1 with AD risk, and a suggestive signal in ADAM10. Additionally, the rare-variant burden in RIN3, CLU, ZCWPW1 and ACE highlighted these genes as potential drivers of respective AD-genome-wide association study loci. Variants associated with the strongest effect on AD risk, in particular loss-of-function variants, are enriched in early-onset AD cases. Our results provide additional evidence for a major role for amyloid-β precursor protein processing, amyloid-β aggregation, lipid metabolism and microglial function in AD.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, N.I.H., Extramural

MeSH terms

  • ATP Binding Cassette Transporter 1* / genetics
  • Adenosine Triphosphatases* / genetics
  • Alzheimer Disease* / genetics
  • Exosomes* / genetics
  • Genome-Wide Association Study
  • Humans
  • Risk Factors


  • ABCA1 protein, human
  • Adenosine Triphosphatases
  • ATP Binding Cassette Transporter 1
  • ATP8B4 protein, human
  • SORL1 protein, human