Genomic analyses reveal new insights into Alzheimer's disease

Abstract

Alzheimers disease (AD) is the most common cause of dementia, with global case numbers projected to reach 153 million in 20501. AD is highly heritable, with twin-based heritability estimates of 60-80%2. While 1,200 causal loci are predicted to exist for AD3, approximately 80 have been associated with AD in two recent studies4,5, suggesting that many loci remain to be discovered6. Here, we analyzed data from 109,479 cases, 74,141 proxy cases, 2,131,799 controls, and 499,708 proxy controls from diverse ancestries, identifying 118 loci in a multi-ancestry analysis and 9 additional loci in ancestry-specific analyses, 48 of which are new. We identified new AD risk genes, prioritized potential drug targets, and identified microglia and, for the first time, several neuronal cell types enriched for AD-associated genetic risk. Moreover, we improved polygenic prediction and estimated a single-nucleotide polymorphism (SNP) heritability of 16%. Together, our findings offer insights into the genetic architecture and potential pathobiology of AD, as well as specific targets for future drug development research.