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

Abstract

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 β-amyloid (Aβ) negative (Aβ-) or positive (Aβ+).

Methods: Australian Imaging, Biomarkers and Lifestyle study participants (age 58-91 years) 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, APOE ε4 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. Aβ+ was classified using 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- cognitively normal (CN) adults.

Results: We observed a significant Aβ group × CAIDE × time interaction on HV loss (β [SE] = -0.04 [0.01]; p < 0.000) but not EM decline (β [SE] = -2.33 [9.96]; p = 0.98). Decomposition revealed a significant CAIDE × time interaction in Aβ+ participants only. When modifiable/nonmodifiable 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 = 0.01). 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 = 0.02).

Discussion: 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- CN adults, 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.

Figure 1. Relationship Between the CAIDE Risk Score, the CAIDE-MR, and the Rate of Change in HV and EM in Aβ− and Aβ+ CN Older Adults Over Time

Relationship between the Cardiovascular Risk Factors, Aging and Incidence of Dementia (CAIDE) risk score (including both modifiable and nonmodifiable risk factor components), Cardiovascular Risk Factors, Aging and Incidence of Dementia modifiable risk score (CAIDE-MR), and the rate of change (slope) in hippocampal volume (HV) (A, C) and episodic memory (EM) (B, D) in Aβ− cognitively normal (CN; black line) and Aβ+ CN (red line) older adults over time. Slope values capture the rate of change in HV and EM for each individual in a single data point. Values on the y-axis that progressively become more negative reflect greater rates of HV loss and EM decline, respectively. Values on the x-axis represent the CAIDE risk score (3–15) or the CAIDE-MR (0–9) score, for which increasingly positive values are indicative of increased dementia risk. CAIDE-MR score models account for the variance associated with age, sex, and APOE ε4. Shading indicates 95% CIs.

Figure 2. Rates of Change in HV and EM in Aβ− and Aβ+ CN Older Adults Who Are APOE ε4 Carriers and Noncarriers Over Time

Rates of change in hippocampal volume (HV) and episodic memory (EM) in Aβ− cognitively normal (CN; black line) and Aβ+ CN (red line) older adults who are APOE ε4 carriers (dashed lines) and noncarriers (solid lines) over time (after accounting for variance associated with age, sex, and modifiable risk factors). Higher scores on the y-axis (HV and EM) are indicative of larger HV and better EM performance; lower scores are indicative of smaller HV and poorer EM performance. Timepoints are measured in 18-month intervals. Shading indicates 95% CIs.