Discordance Between Genetic Ancestry and Self-Reported Race Impacts Inference of Neuropsychiatric Burden in Alzheimer’s Disease

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ABSTRACT Introduction Neuropsychiatric symptoms (NPS)—including aggression, psychosis, anxiety, apathy, and depression—affect up to 85% of individuals with Alzheimer’s disease (AD) and are among its most disabling and costly manifestations, accelerating cognitive and functional decline, institutionalization, mortality, and healthcare costs. NPS prevalence has largely been characterized using self-reported race. Whether NPS differs across genetically defined ancestry groups—and whether self-reported race obscures these differences—remains unknown, limiting accurate risk stratification and treatment development. Methods Using whole-genome sequencing data from 7,118 ADSP participants, we defined three NPS clusters from the NPI-Q: early psychosis (CDR 0.5–1), late psychosis (CDR 2–3), and affective symptoms. Genetic ancestry was inferred by principal component clustering, identifying six groups (EUR, AFR, EAS, SAS, AMR, ADMIXED), and compared with self-reported race/ethnicity. NPS prevalence was compared across genetic ancestry groups and genetic ancestry and self-reported race using Fisher’s exact and regression models. Results Genetic ancestry assignment differed markedly from self-reported race, affecting NPS prevalence estimates. NPS prevalence also differed across ancestry groups; affective symptoms were highest in EAS (90%) and SAS (77%) and lowest in AFR (66%), while psychosis was highest in EAS (74%) and SAS (70%) and lowest in AMR (55%) and EUR (56%), with similar patterns for early and late psychosis.

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