A decade of gene discovery by the Alzheimer’s Disease Sequencing Project

Alzheimer’s disease (AD) is caused in part by variation in genes and genetic regulatory elements. Early work identified autosomal dominant mutations in APP, PSEN1 and PSEN2 that cause AD, and large effect size variants in APOE. However, most of AD genetic risk is caused by variants that result in a modest change in risk. These variants are spread across many genetic elements. In 2009, genome‐wide association studies (GWAS) began to identify these AD loci (> 60 sites). While these studies continue to be productive, GWAS lacks the resolution to identify the critical AD genes and causative variants responsible for risk/protective signals. In 2012, the Alzheimer’s Disease Sequencing Project (ADSP) was initiated to use Next Generation Sequencing methods for AD gene discovery. Sequence data has single nucleotide resolution with the potential to identify causative common and rare variants and to detect structural variants (SVs; insertions, deletions, copy number variation, etc.).