Digital Clock Drawing as an Alzheimer’s Disease Susceptibility Biomarker: Associations with Genetic Risk Score and APOE in Older Adults

Background: Alzheimer’s disease (AD) is the leading cause of dementia in older adults, but most people are not diagnosed until significant neuronal loss has likely occurred along with a decline in cognition. Non-invasive and cost-effective digital biomarkers for AD have the potential to improve early detection. Objective: We examined the validity of DCTclock™ (a digitized clock drawing task) as an AD susceptibility biomarker. Design: We used two primary independent variables, Apolipoprotein E (APOE) ε4 allele carrier status and polygenic risk score (PRS). We examined APOE and PRS associations with DCTclock™ composite scores as dependent measures. Setting: We used existing data from the Framingham Heart Study (FHS), a community-based study with the largest dataset of digital clock drawing data to date. Participants: The sample consisted of 2,398 older adults ages 60–94 with DCTclock™ data (mean age of 72.3, 55% female and 92% White). Measurements: PRS was calculated using 38 variants identified in a recent large genome-wide association study (GWAS) and meta-analysis of late-onset AD (LOAD). Results: Results showed that DCTclock™ performance decreased with advancing age, lower education, and the presence of one or more copies of APOE ε4. Lower DCTclock™ Total Score as well as lower composite scores for Information Processing Speed (both command & copy conditions) and Drawing Efficiency (command condition) were significantly associated with higher PRS levels and more copies of APOE ε4. APOE and PRS associations displayed similar effect sizes in both men and women. Conclusions: Our results indicate that higher AD genetic risk is associated with poorer DCTclock™ performance in older adults without dementia. This is the first study to demonstrate significant differences in clock drawing performance on the basis of APOE status or PRS.