Contributions of rare and common variation to early-onset and atypical dementia risk

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 sixty-eight newly described in this report. Of those sixty-eight, sixty-two patients reported Caucasian, non-Hispanic ethnicity and six 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 was calculated for Alzheimers patients in the total cohort and compared to the scores of a late-onset Alzheimers cohort and a control set. Patients with early-onset Alzheimers had higher non-APOE polygenic risk scores than patients with late onset Alzheimers, supporting the conclusion that both rare and common genetic variation associate with early-onset neurodegenerative disease risk.