The Role of Genomic-Informed Risk Assessments in Predicting Dementia Outcomes

Abstract Importance: By integrating genetic and clinical risk factors into genomic-informed dementia risk reports, healthcare providers can offer patients detailed risk profiles to facilitate understanding of individual risk and support the implementation of personalized strategies for promoting brain health. Objective: To develop a genomic-informed risk assessment composed of family history, genetic, and clinical risk factors and, in turn, evaluate how the risk assessment predicted incident dementia. Design: This longitudinal study included data from two clinical case-control cohorts with an average of 6.6 visits. Secondary analyses were conducted from July 2023 - March 2024. Setting: Data were previously collected across multiple US locations from 1994 to 2023. Participants: Older adults aged 55+ with whole-genome sequencing and dementia-free at baseline. Exposures: An additive score comprising the modified Cardiovascular Risk Factors, Aging, and Incidence of Dementia Risk Score (mCAIDE), family history of dementia, APOE genotype, and an AD polygenic risk score. Main Outcome(s) and Measure(s): The risk of progression to all-cause dementia was evaluated using Cox-proportional hazard models (hazard ratios with 95% confidence intervals [OR 9%CI]). Results: A total of 3,429 older adults were included (aged 75 +/- 7 years; 59% female; 75% non-Latino White, 15% Black, 5.2% Latino, 3.6% other, and 0.4% Asian; 27% MCI), with 751 participants progressing to dementia. The most common high-risk indicator was a family history of dementia (56%), followed by APOE*e4 genotype (36%), high mCAIDE score (34%), and high AD-PRS (11%). Most participants had at least one high-risk indicator, with 39% having one, 32% two, 9.8% three, and 1% four. The presence of 1, 2, 3, or 4 risk indicators was associated with a doubling (HR = 1.72, CI: 1.34-2.22, p = 2.5e-05), tripling (HR = 3.09, CI: 2.41-3.95, p = 4.4e-19), quadrupling (HR = 4.46, CI: 3.34-5.94, p = 2.2e-24), and a twelvefold increase (HR = 12.15, CI: 7.33-20.14, p = 3.2e-22) in dementia risk. Conclusion & Relevance: We found that most participants in memory and aging clinics had at least one high-risk indicator for dementia. Furthermore, we observed a dose-response relationship where a greater number of risk indicators was associated with an increased risk of incident dementia.