Differential Effects of APOE and Modifiable Risk Factors on Hippocampal Volume Loss and Memory Decline in Aβ- and Aβ plus Older Adults

Background and Objectives This prospective study sought to determine the association of modifiable/nonmodifiable components included in the Cardiovascular Risk Factors, Aging, and Incidence of Dementia (CAIDE) risk score with hippocampal volume (HV) loss and episodic memory (EM) decline in cognitively normal (CN) older adults classified as brain beta-amyloid (A beta) negative (A beta-) or positive (A beta+). Methods Australian Imaging, Biomarkers and Lifestyle study participants (age 58-91 years) who completed >= 2 neuropsychological assessments and a brain A beta PET scan (n = 592) were included in this study. We computed the CAIDE risk score (age, sex, APOE epsilon 4 status, education, hypertension, body mass index [BMI], hypercholesterolemia, physical inactivity) and a modifiable CAIDE risk score (CAIDE-MR; education, hypertension, BMI, hypercholesterolemia, physical inactivity) for each participant. A beta+ was classified using Centiloid >25. Linear mixed models assessed interactions between each CAIDE score, A beta group, and time on HV loss and EM decline. Age, sex, and APOE epsilon 4 were included as separate predictors in CAIDE-MR models to assess differential associations. Exploratory analyses examined relationships between individual modifiable risk factors and outcomes in A beta- cognitively normal (CN) adults. Results We observed a significant A beta group x CAIDE x time interaction on HV loss (beta [SE] = -0.04 [0.01]; p < 0.000) but not EM decline (beta [SE] = -2.33 [9.96]; p = 0.98). Decomposition revealed a significant CAIDE x time interaction in A beta+ participants only. When modifiable/nonmodifiable CAIDE components were considered separately, we observed a significant A beta group x CAIDE-MR x time interaction on EM decline only (beta [SE] = 3.03 [1.18]; p = 0.01). A significant CAIDE-MR score x time interaction was observed in A beta- participants only. Significant interactions between APOE epsilon 4 and age x time on HV loss and EM decline were observed in both groups. Exploratory analyses in A beta- CN participants revealed a significant interaction between BMI x time on EM decline (beta [SE] = -3.30 [1.43]; p = 0.02). Discussion These results are consistent with studies showing that increasing age and APOE epsilon 4 are associated with increased rates of HV loss and EM decline. In A beta- CN adults, lower prevalence of modifiable cardiovascular risk factors was associated with less HV loss and EM decline over similar to 10 years, suggesting interventions to reduce modifiable cardiovascular risk factors could be beneficial in this group.