We assessed the potential synergistic effects of diet and exercise on a well-characterized biomarker of AD pathology in a 4-wk diet intervention study in older adults with normal cognitive status or amnestic MCI. For normals, the presumed deleterious effect of the HIGH diet on CSF Aβ42 was attenuated with increasing amounts of engagement in hi–PA whereas in MCI, hi–PA potentiated the beneficial effect of the LOW diet on this biomarker. Of note, synergistic diet and exercise effects were not observed at the extremes representing best case (normal cognitive status, LOW diet) and worst case (early AD pathology, HIGH diet) health scenarios in our study. These findings provide new evidence that exercise and diet may interact to modify AD pathophysiology. In addition, the results of our cross-sectional analyses examining baseline correlations between hi–PA, and CSF levels of total tau, p181-tau, and IL-8 suggest that exercise may play a role in the modulation of aging- or disease-related processes in normal asymptomatic adults.
Previously we reported marked diet-induced changes in CSF concentrations of Aβ42, and the nature of this effect across a continuum from lower to higher AD pathology was described by an inverted u-shaped function [27
]. For normals, CSF Aβ42 levels decreased in response to the 4-wk LOW diet and increased in response to the HIGH diet. That is, for cognitively healthy adults who fall on the left side of the apex (see ), the HIGH diet moved Aβ42 levels rightward toward the ‘tipping point’ when Aβ deposition begins (presymptomatic disease). For adults on the right side of the tipping point who already have AD pathology (amnestic MCI), the LOW diet had a pathology-decelerating effect, now moving Aβ42 leftward on the continuum in a direction consistent with an earlier stage of disease. CSF levels of Aβ42 were unaffected by the HIGH diet for adults with MCI, potentially because a more severe intervention is needed to modulate extant neuropathological processes.
In our study, more min/wk hi–PA was protective against the presumed pathological effects of the HIGH diet on CSF Aβ42 in normal adults. This presumption that increased peptide levels reflects relatively more pathology was supported by our finding that higher CSF Aβ42 levels in response to the HIGH diet predicted poorer visual memory, particularly for normals reporting fewer min/wk hi–PA. In animals, exercise has favorable effects on Aβ processing in transgenic mouse models of AD, reducing extracelluar Aβ burden [14
], even after the onset of pathology [46
]. Exercise also overrides deleterious effects of excessive energy intake or high fat diets on neurogenesis and neurotrophin expression [47
], and on aging-accelerating oxidative stress with favorable consequences for synaptic plasticity and cognition [50
]. Independent and additive effects of exercise and dietary composition on neuropathological processes in animals [51
] and incident AD in humans [30
] implies that the relative benefit of one may also neutralize the deleterious effect of the other, at least in the absence of AD pathology.
In our adults with MCI, hi–PA potentiated the beneficial effect of the LOW diet. That is, the combination of increased amounts of high-intensity PA plus
a healthy diet were needed to move Aβ42 levels in a direction consistent with less pathology, thus highlighting the potential role of lifestyle intervention potency
in the modulation of AD pathophysiological processes once initiated. Notably, in MCI, LOW diet-induced elevations in CSF Aβ42 were not correlated with visual memory scores on the BVMT in our study, thus failing to provide immediate behavioral confirmation of the presumed salutary biomarker response. The results of a recent report, however, indicate that at least for adults with early AD pathology, changes in CSF concentrations of Aβ42 are not necessarily coincident with changes in cognitive performance [52
]. Although large prospective cohort studies report additive effects of healthy diet and exercise on AD risk [30
], the preponderance of support for synergistic effects stems from animal work. In these studies, the combined regimen of exercise plus a healthy diet (i.e., low saturated fat, increased omega-3 fatty acids, or caloric restriction) with marked benefits on hippocampal function and neurotrophic factor expression, often exceeds that of either intervention alone [49
Our previous findings implicate a role of diet on Aβ processing in brain; the results of a recent cross-sectional study suggest that exercise can have a similar effect [15
]. In this study, older adults with increased fibrillar Aβ deposition in brain, as measured by positron emission tomography – Pittsburgh compound-B, and reduced CSF Aβ42 concentration consistently exercised less than older adults without this at-risk phenotype. Furthermore, older adults who met or exceeded the minimum American Heart Association exercise guidelines had higher levels of Aβ42 in CSF relative to levels for non-exercisers. These findings indicate not only that exercise likely has a favorable effect on Aβ processing in brain, but also that an exercise- and diet-related increase in CSF Aβ42 for at-risk older adults is likely a pathology-decelerating response.
In our study, more min/wk hi–PA predicted lower baseline CSF levels of total tau (and p181-tau) for cognitively normal older adults, consistent with reports of others [15
]. Here, we also report an association between min/wk hi–PA and CSF levels of the inflammatory marker IL-8, which in turn predicts CSF levels of tau in these adults. Inflammation is a key process in the pathogenesis of many neurodegenerative disorders and has received much attention as it relates to AD [54
]. In transgenic mouse models of AD, chronic exercise markedly decreases brain levels of total and p181-tau protein in a dose-dependent manner [55
], and reduces tau-related neuroinflammation [57
]. In a large cohort of older adults from the MacArther Studies of Successful Aging, higher PA levels were associated with lower levels of inflammatory markers in the periphery [58
]. Although synergistic effects of diet and exercise on the regulation of tau and cellular antioxidant systems have been documented in animal studies, associations of tau, p181-tau, and IL-8 to min/wk hi–PA at baseline were not perturbed by the HIGH or LOW diets in our 4-wk diet intervention study, implying that synergistic effects on these AD biomarkers likely require a longer period of dietary modification. Nonetheless, our cross-sectional data supplement the evolving extant literature and provide further evidence that increasing dose of exercise, at least in the absence of AD pathology, may predict a more favorable AD biomarker profile.
Our study has a number of limitations. Sample size was small necessitating replication in a larger cohort. The small sample also precluded an examination of other potential moderator variables such as gender or apolipoprotein E genotype, and increased risk of over-interpretation of the data. At baseline, total caloric intake for the diet intervention was adjusted for PA to ensure no weight change over the 4-wk period. As a consequence, greater amounts of hi–PA were always paired with higher daily caloric intake. Thus, effects linked to hi–PA in our study may also be related to total calories consumed. Another limitation relates to the reliance on self-report to quantify PA. Self-report measures of PA are notoriously variable with respect to validity. Variables that typically compromise validity include timing of record keeping relative to when activities occurred (e.g., activities in the last 7 days vs. activities in the last 12 months), and expectations regarding social customs (e.g., should be more active), self-perceptions (e.g., exercise perceived as more intense or longer in duration than actual episode), or demand characteristics of the study (e.g., expectations about what should be recorded) [59
]. In our study, 7-d physical activity information was collected during an in-person structured interview by medical personnel with extensive experience collecting sensitive medical and personal information from older adults. During the screening visit, the physical activity data was collected together with other health-related information, and the subject was not lead to believe that the physical activity report in any way affected eligibility for participation in the study. The validity of self-report is supported by the success with which we were able keep participants weight-stable over the 4-wk diet intervention period given that the daily caloric requirements took into account 7-d physical activity information. If the reports were inaccurate, pre-study estimates of calorie intake would have also been inaccurate, and subjects would have gained or lost weight while in the 4-wk trial. Objective criterion-based validity of self-report in our study is supported by a significant negative correlation between min/wk hi–PA and baseline pulse pressure, indicating that increased amounts of exercise are associated a reduction in age-related arterial stiffness. Finally, our interpretation of the data is based on CSF levels of amyloid as a surrogate marker of brain amyloid burden rather than other more direct measurements such as PET imaging with Pittsburgh Compound-B or potentially more sensitive markers such as soluble amyloid precursor proteins [60
]. Thus it is possible that asymptomatic subjects in our study, presumed to be free of AD pathology given the results of cognitive testing, were misclassified with potential consequences for data interpretation.
Lifestyle factors such as diet and exercise can have a daily cumulating impact on the state of the organism, for better or worse, and may interact to override or potentiate the effects of the other. Our results suggest that in normal aging, exercise may offset the potential pathological effects of a Western-type diet on AD biomarkers in brain; whereas for adults with amnestic MCI, the maximum pathology-decelerating effect may only be obtained through a lifestyle regimen that includes exercise plus a healthy diet low in saturated fats and refined carbohydrates. These findings provide new evidence to support potential synergistic effects of diet and exercise on AD biomarkers in humans, and set the stage for larger controlled trials to further examine the independent and combined effects of these lifestyle interventions on age- and disease-related neuropathological processes.