[P1–245]: HETEROGENEITY OF RISK ACROSS NON‐VASCULAR RISK FACTORS FOR SPECIFIC COGNITIVELY‐DEFINED ALZHEIMER's DISEASE SUBGROUPS

Preliminary work has revealed genetic heterogeneity among Alzheimer's disease (AD) subtypes defined by cognitive domain-specific impairments. There are currently no reports of risk factor associations for these AD subgroups. We used cognitive data from 825 Adult Changes in Thought (ACT) participants at the time they were identified with probable or possible AD to generate scores for memory, executive functioning/attention, language, and visuospatial ability. We determined individual mean scores across all domains, and identified specific impairments as >0.75 SD below each individual's mean domain score. Depressive symptom severity was measured with the CES-D, and study staff collected self-reported data on traumatic brain injury (TBI) exposure. We used multinomial logistic regression with the “no prominent domain group” designated as the reference category. We determined risk ratios for depression and TBI for each subgroup vs. the no prominent domain subgroup, and tested significance of any heterogeneity with an omnibus test. We controlled for age, sex, APOE genotype, and years of education. Characteristics of participants in each AD subgroup are shown in Table 1. Of 825 cases with data for all four domains, nearly half had no prominent domain, a few had multiple prominent domains, and a single domain was prominent for the remainder. Groups showed differences in APOE genotype, consistent with our previous reports. Risk factor results are shown in Table 2. Education's role as a risk factor varied across the five cognitively-defined AD subgroups (omnibus p=0.04). Education predicted development of memory prominent AD rather than AD with no prominent domain (risk ratio [RR] = 1.08 per year of education, 95% confidence interval (CI) 1.00, 1.16, p=0.05; omnibus p=0.04). Depression also varied across AD subgroups (omnibus p = 0.04). Higher CESD scores were associated with lower risk of developing memory prominent AD compared to no prominent domain AD (RR = 0.93 per point on the CESD, 95% CI 0.88, 0.98, p=0.01). We did not find differences in risk associated with TBI. Cognitively-defined AD subtypes show heterogeneity in their associations with depressive symptoms and education. It is possible that these risk factors are associated with biological differences across subgroups.