Lifestyle and genetic contributions to cognitive decline and hippocampal structure and function in healthy aging

Abstract

Background: Engagement in cognitively stimulating activities (CA) and leisure time physical activity (PA) have been associated with maintaining cognitive performance and reducing the likelihood of cognitive decline in older adults. However, neural mechanisms underlying protective effects of these lifestyle behaviors are largely unknown. In the current study, we investigated the effect of self-reported PA and CA on hippocampal volume and semantic processing activation during a fame discrimination task, as measured by functional magnetic resonance imaging (fMRI). We also examined whether possession of the apolipoprotein E (APOE) ε4 allele could moderate the effect of PA or CA on hippocampal structure or function.

Methods: Seventy-eight healthy, cognitively intact older adults underwent baseline neuropsychological assessment, hippocampal volume measurement via manually-traced structural MRI, and task-activated fMRI.

Results: After 18 months, 27 participants declined by one standard deviation or more on follow-up neuropsychological testing. Logistic regression analyses revealed that CA alone or in combination with baseline hippocampal structure or functional activity did not predict the probability of cognitive decline. In contrast, PA interacted with APOE 4 status such that engagement in PA reduced the risk of cognitive decline in APOE 4 carriers only. Furthermore, the benefits of PA appeared to diminish with reduced functional activity or volume in the hippocampus.

Conclusions: Our findings suggest that increased leisure time PA is associated with reduced probability of cognitive decline in persons who are at high risk for AD. The beneficial effects of PA in this group may be related to enhancement of the functional and structural integrity of the hippocampus.

Figure 1

Differences between predicted probabilities of decline for high and low PA groups, as a function of APOE ε4 allele status. Error bars reflect the 95% confidence intervals. Low PA ε4 carriers (n=11) demonstrated a higher probability of decline than low PA ε4 non-carriers (n=30), high PA ε4 carriers (n=15), and high PA ε4 non-carriers (n=22).

Figure 2

(upper two graphs). Simple effects of the APOE ε4 * PA interaction, holding hippocampal fMRI semantic processing activity constant at selected values 2 SD above and below the mean. Closed circles represent the predicted probability of decline for the low PA group minus the predicted probability of decline for the high PA group, and error bars reflect the 95% confidence intervals. Note that there is no significant difference between predicted probabilities of decline for low and high PA participants for hippocampal fMRI activity values at +2 and -2 SD from the mean. The difference between predicted probabilities of decline for high and low PA participants appears to be greatest at 0.5 SD above the mean and becomes smaller as hippocampal activity values decrease (possibly reflecting the loss of hippocampal function) or increase (possibly reflecting the effects of cognitive reserve). Figure 2 (lower two graphs). Simple effects of the APOE ε4 * PA interaction, holding hippocampal volume constant at selected values 2 SD above and below the mean. Closed circles represent the predicted probability of decline for the low PA group minus the predicted probability of decline for the high PA group, and error bars reflect the 95% confidence intervals. Note that there is no significant difference between predicted probabilities of decline for high and low PA participants for hippocampal volumes that are +2 SD from the mean, and the difference approaches 0 for hippocampal volumes that are -2 SD from the mean. As in Figure 1, the difference between predicted probabilities of decline for low and high PA participants appears to be greatest at 0.5 SD above the mean and becomes smaller as hippocampal volumes decrease (possibly reflecting the loss of hippocampal function) or increase (possibly reflecting the effects of cognitive reserve)