Whole-exome sequencing study identifies genes associated with Alzheimer's disease and related dementias

Alzheimer's disease (AD) is the most common form of late-onset neurodegenerative disease. Previous genome-wide association studies have identified numerous common genetic variants associated with AD. The contribution of rare variants to AD remains to be uncovered. AD-by-proxy, based on parental AD status, showed superior statistical power boost in recent AD studies. Using the UK Biobank (UKB) 368,865 whole-exome sequences of white British ancestry and AD-by-proxy (57,976 proxy AD cases and 310,889 non-AD proxy controls), we conducted the largest exome-wide association study of proxy AD to date. We identified 38 novel genes harboring rare variants for AD, such as ANKRD36 (P = 6.02 x 10-31), MMP13 (P = 1.08 x 10-6), TUBA4A (P = 7.15 x 10-12), and ZNF296 (P = 4.19 x 10-14), demonstrating the power boost of aggregating rare variants and utilizing AD-by-proxy in gene discovery. We further replicated these genes in the FinnGen dataset. Notably, MMP13 is a current drug target for AD and TUBA4A is a drug target for cognitive impairment in clinical trials. These results expand our knowledge of the genetic architecture of AD, especially the role of rare variants, and potential drug targets for AD.