Differential Effects of APOE and Modifiable Risk Factors on Hippocampal Volume Loss and Memory Decline in AB- and AB+ Older Adults.

Abstract

This prospective study sought to determine the association of modifiable/non-modifiable 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 β-amyloid negative (Aβ-) or Aβ+. Australian Imaging, Biomarkers and Lifestyle study participants (aged 58-91) who completed ≥2 neuropsychological assessments and a brain Aβ PET scan (N=592) were included in this study. We computed the CAIDE risk score (age, sex, Apolipoprotein E (APOE) ε4 status, education, hypertension, body mass index (BMI), hypercholesterinemia, physical inactivity) and a modifiable CAIDE risk score (CAIDE-MR; education, hypertension, BMI, hypercholesterinemia, physical inactivity) for each participant. Aβ+ was classified using a Centiloid >25. Linear mixed models assessed interactions between each CAIDE score, Aβ group and time on HV loss and EM decline. Age, sex and APOE ε4 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 Aβ- CN adults. We observed a significant Aβ group × CAIDE × time interaction on HV loss (β(SE)=-0.04(0.01); p<.000) but not EM decline (β(SE)=-2.33(9.96); p=.98). Decomposition revealed a significant CAIDE × time interaction in Aβ+ participants only. When modifiable/non-modifiable CAIDE components were considered separately, we observed a significant Aβ group × CAIDE-MR × time interaction on EM decline only (β(SE)=3.03(1.18); p=.01). A significant CAIDE-MR score × time interaction was observed in Aβ- participants only. Significant interactions between APOE ε4 and age × time on HV loss and EM decline were observed in both groups. Exploratory analyses in Aβ- CN participants revealed a significant interaction between BMI × time on EM decline (β(SE)=-3.30(1.43); p=.02). These results are consistent with studies showing that increasing age and APOE ε4 are associated with increased rates of HV loss and EM decline. In Aβ- CNs, lower prevalence of modifiable cardiovascular risk factors was associated with less HV loss and EM decline over ∼10 years, suggesting interventions to reduce modifiable cardiovascular risk factors could be beneficial in this group.