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AlzRisk Risk Factor Discussion

Risk Factor:
Risk Factor Type: Behavior, Metabolic
Current Understanding:
The tables below present a modest number of reports whose results, taken collectively, suggest an inverse association between physical activity and risk for both Alzheimer disease (AD) and dementia. Overall, these data suggest that physical activity is a modifiable protective factor. Results from other lines of research corroborate the value of physical activity in relation to cognitive decline in older adults, and support many collateral benefits of physical activity as well. However, specific aspects of the relationship between physical activity and cognitive outcomes remain to be clarified, including the optimal duration, intensity, and timing during the lifespan of physical activity necessary to reduce cognitive risks, and the durability of the benefits of physical activity. For a review of the putative mechanisms by which physical activity may influence AD risk and detailed commentary on interpreting the findings below in a broader context, please view the Discussion.
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Last Search Completed: 06 July 2016 - Last content update released on 17 October 2016.

Risk Factor Overview

Cite as:

Arasaratnam M, Weuve J, Koyama A, Sheu YH, Jackson JW, Blacker D. "Physical activity." The AlzRisk Database. Alzheimer Research Forum. Available at: Accessed [date of access]*.

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Brief Introduction
The tables on the Risk Factor Overview present a modest number of reports whose results, taken collectively, suggest an inverse association between physical activity and risk for both Alzheimer disease (AD) and dementia.

Potential Mechanism of Action
Data from both human studies and animal models support several potential mechanistic links between physical activity and the prevention of dementia. Physical activity may act indirectly to reduce dementia risk through its well-established benefits for the prevention of cardiovascular disease (Thompson et al., 2003) and type 2 diabetes (Sigal et al., 2006), conditions that both appear to be linked to the risk for and/or progression of dementia and AD (Breteler, 2000; Stampfer, 2006; AlzRisk diabetes overview). Physical activity may act more directly on the central nervous system as well. For instance, physical activity may increase cerebral blood flow and oxygen delivery (Rogers et al.,1990; Swain et al., 2003; Colcombe et al., 2004), maintain neuronal plasticity (Cotman et al., 2002; Kronenberg et al.,2006) and brain volume (Colcombe et al., 2003), and may stimulate angiogenesis and neurovascular integrity (Swain et al., 2003). These benefits are especially notable in the hippocampal region, an early site of AD pathology. Furthermore, research in transgenic mice genetically engineered to exhibit AD neuropathological changes suggests that aerobic exercise delays β-amyloid accumulation, one of the pathological hallmarks of AD (Adalard et al., 2005). Another emerging theory is that physical activity may enhance brain-derived neurotrophic factor and insulin-like growth factor, which may be important to the development of synapses and neural growth and survival (Mattson, 2008; Cotman et al., 2007).

Methodological Issues
Exposure. Exposure assessment for physical activity is complicated because physical activity occurs in a variety of intensities and forms, such as leisurely walking, playing sports, or standing throughout the workday. Other important factors include the duration and frequency of activity and the timing of exercise during the lifespan. Studies vary in whether information about activity is obtained by observation or self report, how much detail is sought about the type, intensity, and duration of activity currently and over the lifespan, and how activity variables are coded and analyzed.

In many ways, direct measurement of activity levels (e.g., by pedometer) would be optimal, but this would limit studies to current rather than past activity levels, and would not be feasible in very large samples. All of the studies reported here use self-report measures (although some of the clinical trials and other studies described below include observational measures). The use of self-report measures probably reduces the reliability of exercise estimates, and it is likely that some individuals overestimate their activity levels; however, this should not be differential with respect to the AD outcome in prospective studies.

It is also ideal to measure all forms of activity, including both occupational and leisure-time physical activities. However, the studies reported here use instruments that focus solely on leisure-time physical activities. The omission of work-related activity means there is significant under-reporting for some subjects. This in turn may lead to confounding by social class or education, given the likely inverse relationships between workplace activity and social class and between workplace and leisure activity; however, most studies control at least for education, which should address this to a substantial extent. Moreover, the instruments used in the studies varied widely in level of detail. Some sought information on specific types of activities, such as walking or biking, while others asked more generically about participation in any activity. In addition, some studies gathered information in quantitative units, such as hours of exercise or miles walked per week; others used an ordinal scale, or even a small number of yes/no questions.

Studies are also inconsistent in the timing of obtaining the information, the span it covers, and the duration of follow-up. Repeated measures across the lifespan with follow-up into very old age would be optimal, but few studies can meet this standard. Although all studies are longitudinal, many begin relatively late in life, and choose not to obtain information about past activity—perhaps because they recognize that it is likely to be less reliable. Only a small number of studies reported here examined physical activity during midlife. However, it should be noted that available information suggests that while physical activity may change in character and decline over adulthood, the relative ranking of individuals’ activity levels (i.e., the least active to the most active) appears to remain fairly stable (Evenson et al., 2002). The average follow-up time in the studies reported here ranged from approximately four to seven years, which not only limits statistical power because of the small number of observed outcomes, it may not capture the relevant period of physical activity’s effects. In addition, relatively brief follow-up makes it harder to rule out the possibility that early symptoms (such as apathy or depression) are leading to inactivity.

Once measured, there are a variety of options for modeling the exposure. The “units” of physical activity varied widely across studies, including variables representing derived energy expenditure and categories of miles walked per week. While a few studies treated physical activity as a continuous variable, most studies categorized physical activity: some studies dichotomized the exposure, while others used three or more categories, such as none, low, moderate or high level of physical activity. The use of categorical variables may reduce the influence of “extreme” exposures that can arise with many self-report instruments (e.g., very high levels of total activity among individuals who report frequent participation in many activities), but also may reduce a study’s ability to identify a significant effect. Moreover, in some studies, the range of measured activity among participants is narrow, which can further dampen a study’s statistical power.

Ultimately, the heterogeneity in exposure definitions and analytic approaches across the studies makes it impossible to perform a credible meta-analysis. However, taken as a whole, the results suggest an inverse association between physical activity and dementia risk.

Confounding and intermediate variables. The results reported are here are from observational studies, and thus differences in risk cannot be assumed to be due to physical activity alone. It remains possible that these differences could be explained, at least in part, by variables that are correlated with an increase in physical activity, such as education, socioeconomic status, lean muscle mass, physical ability, and other healthy lifestyle and dietary factors, or variables that are inversely associated with physical activity, such as smoking, obesity, and cardiovascular disease. Failure to adequately adjust analyses for potential sources of confounding can bias the effect estimates in either direction depending on how these factors relate to physical activity and AD. The issue is further complicated because some confounding variables, such as disability, hypertension, or other cardiovascular risk factors, may be intermediates on the causal pathway between physical activity and AD. Thus, adjusting analyses for these factors may result in an underestimate of the overall effect of physical activity on AD.

Effect modification. Observational studies are often underpowered to examine for effect modification, but several have explored the moderating influence of different factors. A possible sex-specific effect has been reported. In a Canadian cohort the association between physical activity and AD was stronger in women (Laurin et al., 2001), a result supported by a meta-analysis of aerobic fitness and cognitive function reporting a more pronounced association in studies with larger female populations (Colcombe & Kramer, 2003). This observation may be a reflection of effect modification by sex or an artifact of differential survival by sex (Herbert et al., 2001; Glymour et al., 2008). Another promising line of research is exploring effect modification by physical function. In the Adult Changes in Thought cohort, those with lower levels of physical functioning had a greater reduction in AD risk by exercise (Larson et al., 2006). Similarly, in a stratified analysis among men in the Honolulu-Asia Aging Study, there was a significant trend of reduced risk for AD with increasing level of physical activity only in those with poor physical function (Taaffe et al., 2008). This finding contradicts a claim that the effect of physical activity is simply a reflection of being disability-free. Further exploration of these potential effect modifiers and others, such as APOE genotype and diet, may help target physical activity interventions toward the highest risk populations.

Results from Other Lines of Research
Numerous other large cohort studies have reported reduced cognitive decline or risk of overall dementia with increasing physical activity (Fabrigoule et al., 1995; Lytle et al., 2004; Sturman et al., 2005; Wang et al., 2002; Weuve et al., 2004; Yaffe et al., 2001). Randomized trials of physical activity have also provided evidence of cognitive benefits (Angevaren et al., 2008; Colcombe et al., 2003). However, the trials are more often designed with relatively brief follow-up periods powered to detect cognitive decline rather than AD as the outcome, particularly when they begin with subjects free of dementia at baseline. A meta-analysis of trials reported a moderate protective association based on 18 studies that randomized participants to aerobic fitness training vs. a usual or alternative activity program (Colcombe & Kramer, 2003). The largest positive effect estimate was observed for measures of executive function. The magnitude of the estimate was moderated by numerous factors, including the length, type, and duration of the intervention and the sex of the study participants. Since the meta-analysis report, additional trials have been conducted to include populations with less mobility at baseline and longer intervention (12 months). Williamson et al. reported a protective role of physical activity on cognitive function, however the results did not reach statistical significance (Williamson et al., 2009). In a randomized trial of individuals who reported memory problems but did not meet the diagnostic criteria for dementia, those in the treatment group had significantly less decline than did those in the control group on the Alzheimer Disease Assessment Scale-Cognitive Subscale after 18-months of follow-up (Lautenschlager et al., 2008). However, neither participants, family members, nor clinicians could easily detect that level of difference, despite its statistical significance. Taken together, however, these results further corroborate that physical activity can reduce the rate of cognitive decline in older adults.

Discussion and Recommendations
Overall, the body of evidence suggests a modest protective role for physical activity in the development of AD and cognitive decline. Some ambiguities remain regarding the association; areas warranting further research include the optimal duration, intensity, timing during lifespan, and the durability of the effect of physical activity. Nevertheless, physical activity is a potentially modifiable protective factor with established collateral benefits, such as the prevention of cardiovascular disease and diabetes. Individuals with a history of cardiovascular disease or other medical limitations should review any potential exercise program with their physicians.


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