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 ε4 status such that engagement in PA reduced the risk of cognitive decline in APOE ε4 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.

Clinical Application of Apoe in Alzheimer’s Prevention: A Precision Medicine Approach

“…For example, in one study ε4 non-carriers who engaged in cognitively stimulating activities had the lowest risk of MCI (hazard ratio [HR] of 0.73), while ε4 carriers who did not engage in these activities had the highest risk (HR of 1.74) (33). Another study showed that engaging in cognitively stimulating activities was not associated with a reduced risk of cognitive decline in ε4 carriers, although this study had a smaller sample size and follow-up was only up to 18 months (39). Overall, the evidence suggests that increasing amounts of cognitive engagement may decrease the risk of AD, although it is unclear whether these activities have greater benefits for ε4 carriers or non-carriers.…”

“…Consistent with these findings, a neuroimaging study showed Aβ deposition was decreased in ε4 carriers who had greater lifetime cognitive activity (38). However, other studies suggest that non-carriers benefit more from cognitive engagement (33, 39). For example, in one study ε4 non-carriers who engaged in cognitively stimulating activities had the lowest risk of MCI (hazard ratio [HR] of 0.73), while ε4 carriers who did not engage in these activities had the highest risk (HR of 1.74) (33).…”

Interactive effects of physical activity and APOE-ε4 on white matter tract diffusivity in healthy elders

“…Participants who endorsed one of the two items indicating two or fewer days of low intensity PA (ranging from no PA to slow walking or light chores) were classified as physically inactive (Low PA). Participants endorsing one of the remaining three items describing moderate to vigorous intensity PA three or more days per week (ranging from brisk walking, jogging or swimming for 15 minutes or more, or moderately difficult chores for 45 minutes, to regular jogging, running, bicycling or swimming for 30 minutes or more, or playing sports such as handball or tennis for an hour or more) were classified as physically active (High PA)(Smith et al, 2011; Smith et al, 2014; Woodard et al, 2012). …”

“…Physical activity (PA), in both cross sectional and prospective studies, has been shown to protect healthy older adults against cognitive decline (Barnes & Yaffe, 2011; Etgen et al, 2010) and dementia onset (Beckett et al, 2015) and have beneficial effects on brain structure (Erickson et al, 2011) and function (Colcombe et al, 2004; Smith et al, 2013). PA has been shown to have a particularly strong protective effect among healthy older adult ε4 allele carriers, compared to non-carriers, in the maintenance of hippocampal volume (Smith et al, 2014) and cognitive function (Schuit et al, 2001; Woodard et al, 2012), protection against the accumulation of brain amyloid (Head et al, 2012), and enhancement of semantic memory network activation measured by fMRI (Smith et al, 2011). However, the neurophysiological mechanisms associated with the neuroprotective effects of PA in APOE-ε4 allele carriers have not been clearly defined.…”

“…We previously reported that over an 18-month period, greater levels of PA in APOE-ε4 allele carriers significantly reduced the risk for cognitive decline (Woodard et al, 2012) and preserved hippocampal volume (Smith et al, 2014) compared to physically inactive carriers. Moreover, we found that physically active APOE-ε4 allele carriers showed a greater intensity of brain activation during a semantic memory task.…”