Carter A. Wright1,2, Jared W. Taylor1, Meagan Cochran1, James M.J. Lawlor1, Belle A. Moyers1, Michelle D. Amaral1, Zachary T. Bonnstetter1, Princess Carter3, Veronika Solomon3, Richard M. Myers1, Marissa Natelson Love3, David S. Geldmacher3, Sara J. Cooper1, Erik D. Roberson3 and J. Nicholas Cochran1,3 1HudsonAlpha Institute for Biotechnology, Huntsville, Alabama 35806, USA; 2University of Alabama in Huntsville, Huntsville, Alabama 35899, USA; 3Alzheimer's Disease Center, Department of Neurology, University of Alabama at Birmingham, Birmingham, Alabama 35294, USA Corresponding author: ncochranhudsonalpha.org; erobersonuabmc.edu Abstract

We collected and analyzed genomic sequencing data from individuals with clinician-diagnosed early-onset or atypical dementia. Thirty-two patients were previously described, with 68 newly described in this report. Of those 68, 62 patients self-reported white, non-Hispanic ethnicity and 6 reported as African–American, non-Hispanic. Fifty-three percent of patients had a returnable variant. Five patients harbored a pathogenic variant as defined by the American College of Medical Genetics criteria for pathogenicity. A polygenic risk score (PRS) was calculated for Alzheimer's patients in the total cohort and compared to the scores of a late-onset Alzheimer's cohort and a control set. Patients with early-onset Alzheimer's had higher non-APOE PRSs than patients with late-onset Alzheimer's, supporting the conclusion that both rare and common genetic variation associate with early-onset neurodegenerative disease risk.

Received January 31, 2023. Accepted June 7, 2023.