status is associated with increased risk of cognitive decline and elevated amyloid deposition (4
). In contrast, exercise engagement has been associated with reduced risk of cognitive decline (19
) and lower levels of amyloid deposition (12
). In the current investigation we sought to replicate effects of APOE
genotype and exercise engagement on amyloid deposition and further examine whether exercise moderates effects of APOE
genotype on amyloid deposition.
Consistent with several past findings (12
), the presence of an APOE
ε4 allele was associated with elevated amyloid deposition as assessed with PET-PIB. In addition, we observed lower PIB binding for individuals who exercised at or above levels recommended by AHA, similar to our previous study of 69 individuals (12
). However, here we report the novel finding of a significant interaction between APOE
and exercise engagement for cerebral amyloid burden. Specifically, a significant effect of exercise engagement was present for APOE
ε4 carriers but not for non-carriers, with sedentary ε4+ individuals evidencing greater MCBP compared to active ε4+ individuals. In fact, post-hoc analyses indicate that the magnitude of MCBP was equivalent between active ε4+ individuals and all ε4− individuals (t=.07; p=.414), and between active ε4+ individuals and active ε4− individuals (t=−.722; p=.238). Collectively, these findings suggest that the combination of ε4+ status and a sedentary lifestyle may place individuals at augmented risk for amyloid deposition, as assessed via PET-PIB. This result remained robust after controlling for significant group differences in demographic and health variables, and for additional health variables that did not differ between groups but may have potentially contributed to observed findings.
A greater effect of exercise engagement in APOE
ε4 carriers is consistent with and extends existing data demonstrating increased risk of cognitive decline and dementia in sedentary ε4+ individuals (24
; but see 30
). Greater exercise-related improvements in cognitive performance and markers of hippocampal plasticity in APOE
ε4 transgenic mice is also supportive of differential benefits for ε4 carriers (43
ε4 appears to be associated with reduced neuronal plasticity (44
), and it has been argued that this inherent neurophysiological disadvantage makes beneficial lifestyle factors, such as exercise, preferentially important for ε4 carriers (28
). The MCBP findings support the idea that a physically active lifestyle may allow ε4 carriers to experience brain amyloid levels equivalent to ε4− individuals. Although mechanisms through which exercise may influence amyloid deposition remain unclear, there may be both relatively direct effects on amyloid precursor protein metabolism (21
) and indirect effects through influences on neurotrophic factors, neuroinflammation, cerebrovascular functioning or glucose metabolism (46
In terms of CSF Aβ42
, we again observed that the APOE
ε4 allele had a negative influence, with ε4+ individuals evidencing lower CSF Aβ42
, consistent with past reports (12
). Exercise engagement was again associated with a more beneficial profile such that those who met AHA recommendations evidenced higher CSF Aβ42
. However, there was no interaction between APOE
status and exercise engagement for CSF Aβ42
. Unlike for MCBP, sedentary ε4+ individuals did not evidence a significantly greater effect of exercise engagement on CSF Aβ42
compared to active ε4+ individuals.
The reason for the discrepancy between MCBP and CSF Aβ42
is uncertain. The two largely reflect complimentary estimates of the same process of amyloid plaque development in the brain and are strongly associated (e.g., 38
). However, PET-PIB identifies only fibrillar Aβ whereas CSF Aβ42
levels may reflect nonfibrillar Aβ species as well (50
). In addition, while CSF Aβ42
estimates could conceivably reflect amyloid deposition in various regions of the brain, the MCBP estimate represents select regions of high amyloid deposition, and this difference may contribute to our findings. It is also possible that the current sample size was insufficient to detect differences in exercise effects on APOE
groups in terms of CSF Aβ42
The current investigation provides support for an association between exercise engagement and amyloid deposition, with stronger associations in ε4+ individuals in terms of MCBP. However, several limitations must be considered. It is conceivable that confounds not assessed here (e.g., socioeconomic status, ability to engage in physical exercise, personality) may have influenced our results, and are thus relevant to examine in future investigations. Inferences about causal flow between exercise and amyloid deposition are not possible given the cross-sectional design. While it is possible that subclinical dementia may have subtly influenced exercise engagement or reporting of exercise in ε4+ individuals, neither the proportion of individuals meeting AHA-recommended levels nor mean exercise levels differed between APOE
groups. Another potential concern is use of a self-report measure of exercise engagement and use of phone administration in contrast to the in-person interview used in the validation study (37
). Furthermore, the measure is significantly, but not perfectly, correlated with cardiorespiratory fitness. Although the validation sample included older adults and the magnitude of association with cardiorespiratory fitness was similar with and without controlling for age, the measure may still be limited by older adults’ ability to accurately recall and report their exercise behavior over an extended time span.
In summary, our findings suggest that exercise at levels recommended by the AHA may be particularly beneficial for cognitively normal ε4+ individuals in reducing risk of brain amyloid deposition. Longitudinal investigations and intervention studies that incorporate measures through which exercise may influence amyloid deposition are warranted to address causality and mechanisms.