Genome-wide association studies (GWAS) have identified >80 Alzheimer’s disease and related dementias (ADRD)-associated loci. However, the clinical outcomes used in most prior studies belie the complex nature of underlying neuropathologies. Here, we performed GWAS on eleven ADRD-related neuropathology endophenotypes with participants drawn from three sources. 

National Alzheimer’s Coordinating Center (NACC), Religious Orders Study (ROS) and Rush Memory and Aging Project (MAP), and Adult Changes in Thought (ACT; n =7,804 total autopsied participants across all four studies). Deceased patients with genotype and brain autopsy data available were included. Patients of predominantly non-European ancestry were excluded due to small sample sizes. In NACC, patients with rare brain pathologies such as traumatic brain injuries or brain cancers were excluded.  

NACC draws participants from over 30 Alzheimer’s Disease Research Centers (ADRC) across the United States. Each ADRC has its own inclusion/exclusion and recruitment criteria, but their participants are typically drawn from clinical or local eldery community populations. ROS recruits elderly brothers and sisters in the Catholic Church, while MAP recruits elderly participants from the greater Chicago area. ACT recruits participants without dementia from the greater Seattle area without dementia at time of enrollment. 

Included neuropathology endophenotypes are neuritic plaques, tau neurofibrillary tangles, cerebral amyloid angiography, amyloid-beta plaques, TDP-43 deposits, Lewy body deposits, cerebral atherosclerosis, cerebral arteriolosclerosis, gross infarcts, microinfarcts, and hippocampal sclerosis. 

GWAS of neuropathology endophenotypes will confirm known ADRD risk loci and identify novel neuropathology risk loci.  

We identified eight independent significantly associated loci of which four were novel (COL4A1, PIK3R5, LZTS1, APOC2). Testing the remaining known ADRD loci, 19 loci were significantly associated with at least one neuropathology after false discovery rate adjustment.