A – 6 Curation and Characterization of Cognitive Screener Scores in the VA Million Veteran Program (MVP): Implications for Cognitive Aging and Alzheimer’s Disease and Related Dementias

Abstract Objective Electronic health record (EHR)-linked biorepositories provide powerful opportunities to advance epidemiological research in Alzheimer’s disease and related dementias (ADRD). The goal of this study was to determine the feasibility of using data from the VA Million Veteran Program (MVP)—the largest EHR-linked biorepository—to curate cognitive screener scores. We also examined associations between cognitive screener scores and apolipoprotein E (APOE), the strongest genetic risk factor for late-onset ADRD. Method The sample (N=49,555; 7.4% women) included a multiethnic cohort (European [69.3%], African [20.7%], Hispanic [9.1%], and Asian [0.8%]) with EHR-extracted and cleaned Mini-Mental State Examination (MMSE) total scores. Approximately 30.8% were APOE e4 carriers, and 25.8% had multiple MMSE scores. Analysis of variance was performed to examine cross-sectional associations between APOE e4 dosage (0, 1, 2) and first (M=27.3, SD=3.5) and lowest (M=26.7, SD=4.2) MMSE total scores. Results There was a significant dose-response relationship between APOE e4 genotype and MMSE scores. Homozygote e4 carriers performed worse than heterozygote e4 carriers (mean difference: first=-0.5; lowest=-0.9), who in turn performed worse than non-carriers (mean difference: first=-0.4; lowest=-0.6) for both first and lowest scores. Results remained unchanged after adjusting for genetic ancestry, sex, and age (all ps<.001; ηp2=.08-.11). Conclusion This proof-of-concept study is the first to demonstrate the feasibility of leveraging MVP to examine EHR-extracted cognitive test scores. Findings highlight the potential for harnessing MVP to explore additional genetic, environmental, and clinical factors that contribute to cognitive aging and ADRD in a diverse sample, offering a scalable framework for future studies on risk stratification and intervention.