- Email: [email protected]
Physical activity and the maintenance of cognitive function
Alzheimer’s & Dementia 3 (2007) S38 –S44
Physical activity and the maintenance of cognitive function Kenneth Rockwood*, Laura Middleton Division of Geriatric Medicine, Department of Medicine, Dalhousie University, Halifax, Nova Scotia, Canada
Abstract
Experimental studies suggest that physical activity or exercise can prevent or delay the onset of age-related cognitive impairment or dementia. Several epidemiologic studies have attempted to address this issue by using widely varying definitions of physical activity as well as differing methods to assess cognitive function or dementia. Despite the variability in study design, longitudinal studies report that the risk of dementia, cognitive impairment, cognitive decline, and Alzheimer’s disease is lower among persons engaging in high levels of physical activity, relative to those engaging in low levels of physical activity. There is also evidence of a dose-response relationship between physical activity and preservation of cognitive function, even though small increases in physical activity from a sedentary state can reap comparatively large incremental benefits. Reductions in the relative risk of vascular dementia associated with physical activity were weaker and more variable. Although many studies had a follow-up duration of around 5 years, at least one study has found evidence that exercise in midlife reduces the risk of dementia in late life. How interactions between physical activity and the APOE e4 allele affect the risk of cognitive impairment is inconsistent. The available epidemiologic studies support the concept that physical activity might prevent or delay the onset of cognitive decline. Whether that effect will translate into a reduction in the prevalence of dementia is unknown. © 2007 The Alzheimer’s Association. All rights reserved.
Keywords:
Alzheimer’s disease; Dementia; Vascular dementia; Cognitive impairment; Exercise; Walking; Prevention
1. Introduction As discussed by Cotman [1], a host of studies in experimental models support the concept that physical exercise protects against the development of dementia. As reviewed here, epidemiologic studies in humans also provide evidence in support of this concept, although the body of epidemiologic studies is not as cohesive as is the body of experimental studies. Several factors contribute to this lack of cohesion. One such factor is the definition of dementia and its relationship to precursor states. Essentially all observational studies conducted to date have either adopted a view of dementia as a single disease entity or divided the syndrome into broad categories such as vascular dementia and Alz-
*Corresponding author. Tel.: 902-473-8687; Fax: 902-473-1050. E-mail address: [email protected]
heimer’s disease. As argued below, however, the extent to which we can extrapolate between dementia causes and precursor states is likely to vary between disease states, and this can confound our expectations and understanding of the extent to which exercise might be protective. A second factor hindering our ability to interpret epidemiologic studies is the likelihood that multiple mechanisms contribute to the beneficial effects of exercise on cognitive function. For example, Grodstein [2] mentioned the role of physical activity in reducing several risk factors for cognitive decline including hypertension, dyslipidemia, and diabetes. If these factors have variable effects on different diseases, and if exercise has variable effects on moderating their influences, expecting clear dose-response relationships might be unrealistic. A third factor contributing to the lack of cohesion among epidemiologic studies concerns our ability to assess outcomes. Just as physically active persons continue to experience declines in physical ability as they age (albeit at
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K. Rockwood and L. Middleton / Alzheimer’s & Dementia 3 (2007) S38 –S44
a slower rate than physically inactive persons), we should not expect any “preventive therapy” to completely prevent cognitive decline. Because there is no widely accepted definition of the clinical features of prevented dementia, studies attempting to identify preventive therapies (such as physical activity) have no common benchmark by which to determine success or failure. Finally, our ability to understand the benefits of exercise is limited by the inconsistency of what constitutes physical activity or fitness across different studies and by the lack of an accepted definition of physical fitness. For example, existing studies do not allow us to predict the relative merits of different exercise regimens, such as those incorporating different levels of resistive, cardiovascular, and flexibility training, which might be of concern to individuals adopting a fitness regimen. Despite these difficulties, there is much to be learned from epidemiologic studies of cognitive function and physical activity. Here we present an overview of this topic, beginning with a discussion of dementia as a preventable illness and strategies to achieve prevention through exercise. Next, we discuss studies that have attempted to quantify the effects of exercise on various measures of cognitive function, including dementia, cognitive impairment, cognitive decline, Alzheimer’s disease, and vascular dementia. Where data are available, we will discuss how these parameters are altered by physical activity during earlier stages of life, sex, fitness level, and apolipoprotein E (APOE) genotype before returning to the issue of dementia as a preventable illness. 2. Dementia as a preventable illness It appears that some degree of cognitive decline is inevitable with aging. If we accept that concept, then we must address the question of whether the less common condition of dementia is also inevitable, or whether it is preventable. If it is preventable in a biologic sense, then we must ask whether that goal can be achieved by public health strategies. When age-related dementia occurs, it occurs during the last years of life in nearly all cases. Therefore, it has been proposed that delaying the onset of dementia can effectively reduce its prevalence [3]. Indeed, an optimist’s view has emerged that proposes that if we could delay the onset of dementia by 2 years, we could reduce its prevalence by as much as 25%, ceteris paribus (all other things being equal) [4]. It is likely that a prospective observational study will never test this idea, simply because maintaining “all other things equal” is highly implausible. Nevertheless, good evidence is available from observational studies supporting the concept that cognitive impairment and dementia can be prevented by physical activity. Fig. 1 shows data on the prevalence of dementia and exercise among a group of 10,263 older persons living in Canada (based on further analyses of data from Laurin et al [5]). The prevalence of dementia increases from about 2%
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Fig. 1. Prevalence of dementia and exercise of different intensities among older persons living in Canada. From Canadian Study of Health and Aging (based on further analyses of data from Laurin et al [5]).
among those aged 65 to 69 years to about 35% in those aged 85 years or older. Concurrently, the percentages of persons engaging in vigorous exercise or any exercise decline substantially. These data, of course, do not establish a causative relationship between dementia and exercise in either direction, but they do suggest a reciprocal relationship. Observational studies addressing such a relationship are presented below. 3. Physical activity as a preventive factor 3.1. Dementia, cognitive impairment, and cognitive decline The upper panel of Fig. 2 shows a summary of results from six observational studies that calculated the risk of dementia in elderly persons who exercised the most relative to those who exercised the least [5–10]. Although all the studies are longitudinal (the studies chosen for this summary included only those with about 5 years or more of follow up), most still involved relatively brief follow up. (Two studies, discussed in more detail in the section entitled “Modifying Factors,” have performed long-term [20 to 30 years] follow up to evaluate the effects of exercise in midlife on the risk of dementia at older ages.) A pooled relative risk has not been calculated because the studies used different definitions of exercise as well as different definitions of dementia. Although we have not conducted a formal systematic review, and there are likely to be other studies not included in this summary, in general there is agreement across the major studies that persons who exercise the most have a lower risk of dementia relative to those who exercise the least. The etiology of age-related dementia is not wellunderstood, but it is likely to be complex and multifactorial. Of particular interest has been the relationship between pre-dementia states and progression to dementia or Alzheimer’s disease. As reviewed elsewhere, some have argued in support of a model in which an underlying pathology gradually progresses through mild cognitive impairment and eventually to dementia, but there is now clear evidence that
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Fig. 2. Relative risk of dementia, cognitive impairment, or cognitive decline in observational studies with about 5 years or more of follow up, comparing persons who exercised the most versus those who exercised the least. Error bars denote 95% CIs. *In most studies, “Age” indicates the age at which cognitive function was initially assessed. The studies varied in follow-up duration (see text). †N values indicate the size of the entire study population.
some forms of cognitive impairment are more likely to progress to dementia than others, and that certain clinical factors predispose a patient to a high risk of future dementia [11]. For the purpose of our discussion of physical exercise as a protective factor, we need only suggest that it is valuable from an epidemiologic standpoint to view cognitive impairment as an independent outcome distinct from dementia, rather than as a mere precursor to it. With that in mind, several observational studies have examined whether physical exercise affects the risk of subsequent cognitive impairment or cognitive decline in elderly persons. Summary results from these studies are shown in the lower two panels of Fig. 2. These studies [5,12–17] support the concept that physical exercise reduces the risk or severity of cognitive decline in this age group. 3.2. Alzheimer’s disease and vascular dementia If regular physical activity reduces the risk of cognitive impairment or dementia, then does it reduce the risk of specific forms of dementia, such as Alzheimer’s disease or vascular dementia? Summary results from several observational studies addressing this question are shown in Fig. 3 [5–9,18]. As with dementia in general, several major studies have found that physical activity in elderly persons is associated with a reduction in the relative risk of Alzheimer’s disease (Fig. 3, top panel). With regard to vascular dementia (Fig. 3, lower panel), it is interesting that available studies are less convincing, with no large-scale studies showing a statistically significant effect of physical activity. However, it should be noted that
the number of patients diagnosed with vascular dementia is substantially lower in most studies, so that the confidence intervals (CIs) for the relative risk are quite wide. Nevertheless, these studies provide preliminary evidence that the preventive effects of physical activity might be weaker for vascular dementia than for Alzheimer’s disease or dementia in general. Larger studies will be required to confirm this observation. In the meantime, other explanations might warrant exploration. For example, the difference could arise from diagnostic preferences, particularly whether neuroimaging is involved. In addition, the difference might arise from how vascular dementia is conceptualized. For example, vascular dementia definitions that require the presence of stroke are less sensitive than definitions that do not require the dementia to be preceded by stroke [19]. The former definition would also make preventive effects more dependent on the prevention of stroke. Finally, a recent study suggests that precursor states to Alzheimer’s disease and vascular dementia might also differ in their susceptibility to modification by physical activity [20]. If this observation is confirmed, it could provide mechanistic support for the different effects of physical activity on these two forms of dementia.
4. Modifying factors 4.1. Duration or intensity of physical activity Several of the studies summarized in Fig. 2 attempted to determine whether there was a dose-response relationship
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Fig. 3. Relative risk of Alzheimer’s disease or vascular dementia in observational studies with about 5 years or more of follow up, comparing persons who exercised the most versus those who exercised the least. Error bars denote 95% CIs. *In most studies, “Age” indicates the age at which cognitive function was assessed. The studies varied in follow-up duration (see text). †N values indicate the size of the entire study population.
between the amount of exercise and the degree of protection from dementia or cognitive decline. Overall, the results are inconsistent, with some showing no dose-response relationship but others showing a significant dose-response relationship. One study that found a significant dose-response relationship between physical activity and cognitive function was conducted as part of the Nurses’ Health Study [16]. Levels of physical activity were assessed from biennial questionnaires in 18,766 women. After about 10 or more years of follow up (when the women were 70 to 81 years old), baseline cognitive function was assessed with several validated tests. Two years later, cognitive function was assessed again to evaluate the rate of cognitive decline. Women were divided into quintiles on the basis of their levels of exercise, and Fig. 2 has already presented the risk of cognitive impairment at follow-up in the quintile reporting the most exercise relative to the group reporting the least. After adjustment for numerous factors potentially influencing cognitive function, there were significant trends for a dose-response relationship in which those reporting the most physical activity scored higher on several baseline tests of cognitive function (P ⬍ .001). During the 2 years of additional follow up, there were again significant trends for a dose-response relationship in which those reporting the most physical activity exhibited the least decline in cognitive function (P values, .05 to ⬍.001) [16]. In an additional analysis, the authors found that even walking was associated with a dose-response relationship. Those in the highest quartiles for walking (an easy pace for at least 1.5 hours per week) had significantly higher cognitive scores than those walking less than 40 minutes per week (P values, .07 to ⬍.001). Another study that looked for a dose-response relationship was that of Lytle et al [13]. These investigators prospectively followed 1146 persons at least 65 years old and
recorded self-reported exercise levels as well as scores on the Mini-Mental State Examination (MMSE). Participants were divided into three groups on the basis of exercise levels: no exercise, low exercise, and high exercise. The high exercise group was defined as those participating in at least 30 minutes of aerobic exercise at least three times per week. Persons in the high exercise group had significantly lower odds of cognitive decline (odds ratio, 0.39; 95% CI, 0.19 to 0.78). When the threshold for high exercise was increased to 5 days per week, both the low and high exercise groups had a lower risk of cognitive decline, suggesting that higher activity levels might not be necessary for the benefit to be observed [13]. A study conducted as part of the Canadian Study of Health and Aging divided participants into four groups according to the duration and intensity of physical exercise [5]. Those in the high exercise group performed exercise that was more vigorous than walking at least three times per week. The study found significant trends for lower odds of cognitive impairment–no dementia (CIND), Alzheimer’s disease, and all-cause dementia among persons performing increasing levels of exercise, with those in the high exercise group exhibiting the lowest odds for impairment or dementia. Other studies also provide evidence for greater benefit from exercise of at least moderate intensity [12,21] or for longer durations each day [14]. Overall, observational studies provide good evidence for a dose-response relationship for the protective effects of exercise on cognitive function. Unfortunately, the studies varied widely in their definitions of beneficial, moderate, or high levels of exercise. Furthermore, these definitions will likely vary among different individuals according to age, fitness level, and other parameters. The good news is that the greatest incremental benefit was associated with the transition from no exercise to a low level of exercise in
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many studies. Therefore, all persons should be encouraged to participate in at least a low to moderate exercise regimen, such as the equivalent of 30 minutes of walking three times per week.
Dementia
4.2. Age: Exercise during midlife versus exercise during late life
Alzheimer’s Disease
As mentioned, many of the studies summarized in Figs. 2 and 3 followed participants for about 5 years. As a consequence, these studies are relevant to the beneficial effects of physical activity in late life. Two studies, however, have performed much longer follow-up, examining how physical activity during midlife affects the risk of dementia or cognitive impairment in late life [9]. One study, conducted in Finland, examined cognitive function in 1449 persons (aged 65 to 79 years) who had been followed for many years as members of other population-based cohorts. Information was available about each participant’s level of physical activity during midlife, with a mean follow-up of 21 years. In a multivariate analysis adjusted for numerous variables, persons who participated in “leisure-time physical activity” during midlife had significantly lower odds of dementia (odds ratio, 0.47; 95% CI, 0.25 to 0.90) or Alzheimer’s disease (odds ratio, 0.35; 95% CI, 0.16 to 0.80) as compared with sedentary persons [9]. This odds reduction is at least comparable to the odds reduction reported in studies of physical activity in older persons. Thus, midlife physical activity might be as important for preventing later cognitive decline as is physical activity at older ages. Another study has suggested that physical activity at even earlier ages (15 to 25 years) can improve or preserve cognitive ability in late life [22]. 4.3. APOE genotype APOE polymorphisms have been found to influence the risk of Alzheimer’s disease, with the epsilon4 allele associated with increased risk and the epsilon2 allele associated with decreased risk [23–27]. Furthermore, there has been intense interest in the issue of whether APOE polymorphisms interact with other traditional risk factors, including physical activity. The Finnish study described in the preceding section included an analysis of subgroups divided according to APOE e4 status [9]. The purpose of the analysis was to determine whether the beneficial effects of physical activity on cognitive function were affected by the presence of an APOE e4 allele. Fig. 4A shows the risk of dementia or Alzheimer’s disease in persons participating in leisure-time physical activity relative to those not participating, with subgroups separated according to the presence of an APOE e4 allele. Physical activity reduced the risk of dementia or Alzheimer’s disease regardless of APOE e4 status, but the relative reduction in risk was greater in persons with an APOE e4 allele. This result supports the concept that physical activity might counteract some of the
APOE e4 status
A
+ -
+ 0.1
1
10
Exercise better
Exercise worse
Relative Risk APOE e4 status
B Cognitive decline
+ -
Dementia
+ 0.1
10
1 Exercise better
Exercise worse
Relative Risk Fig. 4. Interaction of physical activity with APOE e4 status. (A) Relative risk of dementia or Alzheimer’s disease in persons participating in leisuretime physical activity relative to sedentary persons. Participants are grouped according to the presence of and absence of APOE e4 allele [9]. (B) Relative risk of cognitive decline and dementia among persons engaging in high levels of exercise relative to those engaging in low levels of exercise, with subgroups defined according to APOE e4 status [14,28].
detrimental effects of APOE e4. However, this finding has not been confirmed in all observational studies. For example, Fig. 4B shows summary results for dementia from two additional observational studies addressing the same issue. The study of Podewils et al [28] did not confirm beneficial effects of physical activity among persons with an APOE e4 allele. Thus, the question of whether physical activity can counteract some of the detrimental effects of APOE e4 remains unanswered. 4.4. Other factors Several other factors might affect the degree to which physical activity prevents or delays cognitive impairment. Laurin et al [5] reported that physical activity reduced the risk of cognitive impairment or dementia in women more than men. However, Simons et al [29] reported that walking reduced admissions for dementia in men but not in women. Physical activity might also interact with fitness level, with evidence that the greatest incremental benefit from physical activity is seen among those with the lowest fitness levels [8]. However, both better fitness level and better muscle
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strength have each been positively associated with better cognitive function in separate studies [30,31]. Finally, some studies have concluded that the beneficial effect of physical activity is increased when a variety of activities are performed [28,32].
5. Dementia as a preventable illness: Revisited The observational studies presented provide reproducible and robust evidence that physical activity reduces the risk of cognitive decline and dementia. From that standpoint, these studies provide yet more rationale for promoting an active lifestyle. At this point, however, we should return to the concept introduced at the beginning of this article: that delaying the onset of dementia (or cognitive impairment) by 2 years could reduce its prevalence by 25% [4]. There is evidence that physical activity could delay cognitive decline for such a duration. For example, Weuve et al [16] observed in their population-based study that women who performed regular moderate walking (an easy pace for at least 1.5 hours per week) exhibited cognitive function equivalent to less active women who were 1.5 years younger. Unfortunately, there is very little good evidence to substantiate the claim that such an effect will reduce the prevalence of cognitive impairment or dementia. The contrasting effect would be if physical activity delayed the onset of dementia while also prolonging lifespan, with the effect that the individual experiences the same degree and duration of dementia but later in life. We have shown, for example, that people who exercise exhibit less physical frailty [33]. Thus, it is clear that physical exercise is affecting more than just brain function. This dilemma also touches on another issue raised in the Introduction: that we have not defined the clinical characteristics of successfully treated or prevented dementia or Alzheimer’s disease. As drugs or treatment strategies are developed for these conditions, it will be necessary to define successful treatment and to recognize that successfully treated individuals will not be “cured” but will have unique needs that must be addressed by the healthcare community. An additional challenge to the concept of preventing dementia is the shifting definition of the disease state and its subcategories. In 1978, for example, 67% of dementia cases were diagnosed as Alzheimer’s disease, and 15% were diagnosed as vascular dementia [34]. More recently, only 39% of cases were diagnosed as Alzheimer’s disease, whereas 25% were diagnosed as vascular dementia [3]. With preliminary evidence that physical activity might affect the risk of these conditions differently, well-designed trials to test this concept (or other preventive approaches) will require widely accepted diagnostic criteria for each disease entity.
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6. Conclusion Robust and consistent results from observational studies provide evidence that physical activity reduces the risk of cognitive impairment and dementia in late life. At this time, it is not known whether public health measures to increase participation in physical exercise will reduce the overall prevalence of these conditions. In the meantime, the evidence supporting the beneficial effects of physical activity on brain health provide yet more reasons to encourage physical activity among persons of all ages.
Acknowledgment Kenneth Rockwood is supported by the Dalhousie Medical Research Foundation as the Kathryn Allen Weldon Professor of Alzheimer Research. Laura Middleton receives career support as recipient of a Killam Doctoral Prize.
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[15] Stewart R, Richards M, Brayne C, Mann A. Vascular risk and cognitive impairment in an older, British, African-Caribbean population. J Am Geriatr Soc 2001;49:263–9. [16] Weuve J, Kang JH, Manson JE, Breteler MM, Ware JH, Grodstein F. Physical activity, including walking, and cognitive function in older women. JAMA 2004;292:1454 – 61. [17] Yaffe K, Barnes D, Nevitt M, Lui LY, Covinsky K. A prospective study of physical activity and cognitive decline in elderly women: women who walk. Arch Intern Med 2001;161:1703– 8. [18] Yoshitake T, Kiyohara Y, Kato I, Ohmura T, Iwamoto H, Nakayama K, et al. Incidence and risk factors of vascular dementia and Alzheimer’s disease in a defined elderly Japanese population: the Hisayama Study. Neurology 1995;45:1161– 8. [19] Rockwood K, Black SE, Song X, Hogan DB, Gauthier S, MacKnight C, et al. Clinical and radiographic subtypes of vascular cognitive impairment in a clinic-based cohort study. J Neurol Sci 2006;240:7–14. [20] Middleton LE, Kirkland S, Rockwood K. Prevention of CIND by physical activity: different impact on VCI-ND compared with MCI. Alzheimer’s & Dementia 2006;2(Suppl 1):S408. [21] van Gelder BM, Tijhuis MA, Kalmijn S, Giampaoli S, Nissinen A, Kromhout D. Physical activity in relation to cognitive decline in elderly men: the FINE Study. Neurology 2004;63:2316 –21. [22] Dik M, Deeg DJ, Visser M, Jonker C. Early life physical activity and cognition at old age. J Clin Exp Neuropsychol 2003;25:643–53. [23] Corder EH, Saunders AM, Strittmatter WJ, Schmechel DE, Gaskell PC, Small GW, et al. Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer’s disease in late onset families. Science 1993; 261:921–3. [24] Chartier-Harlin MC, Parfitt M, Legrain S, Perez-Tur J, Brousseau T, Evans A, et al. Apolipoprotein E, epsilon 4 allele as a major risk factor for sporadic early and late-onset forms of Alzheimer’s disease: analysis of the 19q13.2 chromosomal region. Hum Mol Genet 1994; 3:569 –74.
[25] Saunders AM, Strittmatter WJ, Schmechel D, George-Hyslop PH, Pericak-Vance MA, Joo SH, et al. Association of apolipoprotein E allele epsilon 4 with late-onset familial and sporadic Alzheimer’s disease. Neurology 1993;43:1467–72. [26] Corder EH, Saunders AM, Risch NJ, Strittmatter WJ, Schmechel DE, Gaskell PC Jr, et al. Protective effect of apolipoprotein E type 2 allele for late onset Alzheimer disease. Nat Genet 1994;7:180 – 4. [27] Poirier J, Davignon J, Bouthillier D, Kogan S, Bertrand P, Gauthier S. Apolipoprotein E polymorphism and Alzheimer’s disease. Lancet 1993;342:697–9. [28] Podewils LJ, Guallar E, Kuller LH, Fried LP, Lopez OL, Carlson M, et al. Physical activity, APOE genotype, and dementia risk: findings from the Cardiovascular Health Cognition Study. Am J Epidemiol 2005;161:639 –51. [29] Simons LA, Simons J, McCallum J, Friedlander Y. Lifestyle factors and risk of dementia: Dubbo Study of the elderly. Med J Aust 2006;184:68 –70. [30] Barnes DE, Yaffe K, Satariano WA, Tager IB. A longitudinal study of cardiorespiratory fitness and cognitive function in healthy older adults. J Am Geriatr Soc 2003;51:459 – 65. [31] Raji MA, Kuo YF, Snih SA, Markides KS, Peek MK, Ottenbacher KJ. Cognitive status, muscle strength, and subsequent disability in older Mexican Americans. J Am Geriatr Soc 2005;53:1462– 8. [32] Richards M, Hardy R, Wadsworth ME. Does active leisure protect cognition? evidence from a national birth cohort. Soc Sci Med 2003; 56:785–92. [33] Rockwood K, Howlett SE, MacKnight C, Beattie BL, Bergman H, Hébert R, et al. Prevalence, attributes, and outcomes of fitness and frailty in community-dwelling older adults: report from the Canadian study of health and aging. J Gerontol A Biol Sci Med Sci 2004;59: 1310 –7. [34] Wells CE. Dementia. Philadelphia: F A Davis Co, 1978.
Physical activity and the maintenance of cognitive function Kenneth Rockwood*, Laura Middleton Division of Geriatric Medicine, Department of Medicine, Dalhousie University, Halifax, Nova Scotia, Canada
Abstract
Experimental studies suggest that physical activity or exercise can prevent or delay the onset of age-related cognitive impairment or dementia. Several epidemiologic studies have attempted to address this issue by using widely varying definitions of physical activity as well as differing methods to assess cognitive function or dementia. Despite the variability in study design, longitudinal studies report that the risk of dementia, cognitive impairment, cognitive decline, and Alzheimer’s disease is lower among persons engaging in high levels of physical activity, relative to those engaging in low levels of physical activity. There is also evidence of a dose-response relationship between physical activity and preservation of cognitive function, even though small increases in physical activity from a sedentary state can reap comparatively large incremental benefits. Reductions in the relative risk of vascular dementia associated with physical activity were weaker and more variable. Although many studies had a follow-up duration of around 5 years, at least one study has found evidence that exercise in midlife reduces the risk of dementia in late life. How interactions between physical activity and the APOE e4 allele affect the risk of cognitive impairment is inconsistent. The available epidemiologic studies support the concept that physical activity might prevent or delay the onset of cognitive decline. Whether that effect will translate into a reduction in the prevalence of dementia is unknown. © 2007 The Alzheimer’s Association. All rights reserved.
Keywords:
Alzheimer’s disease; Dementia; Vascular dementia; Cognitive impairment; Exercise; Walking; Prevention
1. Introduction As discussed by Cotman [1], a host of studies in experimental models support the concept that physical exercise protects against the development of dementia. As reviewed here, epidemiologic studies in humans also provide evidence in support of this concept, although the body of epidemiologic studies is not as cohesive as is the body of experimental studies. Several factors contribute to this lack of cohesion. One such factor is the definition of dementia and its relationship to precursor states. Essentially all observational studies conducted to date have either adopted a view of dementia as a single disease entity or divided the syndrome into broad categories such as vascular dementia and Alz-
*Corresponding author. Tel.: 902-473-8687; Fax: 902-473-1050. E-mail address: [email protected]
heimer’s disease. As argued below, however, the extent to which we can extrapolate between dementia causes and precursor states is likely to vary between disease states, and this can confound our expectations and understanding of the extent to which exercise might be protective. A second factor hindering our ability to interpret epidemiologic studies is the likelihood that multiple mechanisms contribute to the beneficial effects of exercise on cognitive function. For example, Grodstein [2] mentioned the role of physical activity in reducing several risk factors for cognitive decline including hypertension, dyslipidemia, and diabetes. If these factors have variable effects on different diseases, and if exercise has variable effects on moderating their influences, expecting clear dose-response relationships might be unrealistic. A third factor contributing to the lack of cohesion among epidemiologic studies concerns our ability to assess outcomes. Just as physically active persons continue to experience declines in physical ability as they age (albeit at
1552-5260/07/$ – see front matter © 2007 The Alzheimer’s Association. All rights reserved. doi:10.1016/j.jalz.2007.01.003
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a slower rate than physically inactive persons), we should not expect any “preventive therapy” to completely prevent cognitive decline. Because there is no widely accepted definition of the clinical features of prevented dementia, studies attempting to identify preventive therapies (such as physical activity) have no common benchmark by which to determine success or failure. Finally, our ability to understand the benefits of exercise is limited by the inconsistency of what constitutes physical activity or fitness across different studies and by the lack of an accepted definition of physical fitness. For example, existing studies do not allow us to predict the relative merits of different exercise regimens, such as those incorporating different levels of resistive, cardiovascular, and flexibility training, which might be of concern to individuals adopting a fitness regimen. Despite these difficulties, there is much to be learned from epidemiologic studies of cognitive function and physical activity. Here we present an overview of this topic, beginning with a discussion of dementia as a preventable illness and strategies to achieve prevention through exercise. Next, we discuss studies that have attempted to quantify the effects of exercise on various measures of cognitive function, including dementia, cognitive impairment, cognitive decline, Alzheimer’s disease, and vascular dementia. Where data are available, we will discuss how these parameters are altered by physical activity during earlier stages of life, sex, fitness level, and apolipoprotein E (APOE) genotype before returning to the issue of dementia as a preventable illness. 2. Dementia as a preventable illness It appears that some degree of cognitive decline is inevitable with aging. If we accept that concept, then we must address the question of whether the less common condition of dementia is also inevitable, or whether it is preventable. If it is preventable in a biologic sense, then we must ask whether that goal can be achieved by public health strategies. When age-related dementia occurs, it occurs during the last years of life in nearly all cases. Therefore, it has been proposed that delaying the onset of dementia can effectively reduce its prevalence [3]. Indeed, an optimist’s view has emerged that proposes that if we could delay the onset of dementia by 2 years, we could reduce its prevalence by as much as 25%, ceteris paribus (all other things being equal) [4]. It is likely that a prospective observational study will never test this idea, simply because maintaining “all other things equal” is highly implausible. Nevertheless, good evidence is available from observational studies supporting the concept that cognitive impairment and dementia can be prevented by physical activity. Fig. 1 shows data on the prevalence of dementia and exercise among a group of 10,263 older persons living in Canada (based on further analyses of data from Laurin et al [5]). The prevalence of dementia increases from about 2%
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Fig. 1. Prevalence of dementia and exercise of different intensities among older persons living in Canada. From Canadian Study of Health and Aging (based on further analyses of data from Laurin et al [5]).
among those aged 65 to 69 years to about 35% in those aged 85 years or older. Concurrently, the percentages of persons engaging in vigorous exercise or any exercise decline substantially. These data, of course, do not establish a causative relationship between dementia and exercise in either direction, but they do suggest a reciprocal relationship. Observational studies addressing such a relationship are presented below. 3. Physical activity as a preventive factor 3.1. Dementia, cognitive impairment, and cognitive decline The upper panel of Fig. 2 shows a summary of results from six observational studies that calculated the risk of dementia in elderly persons who exercised the most relative to those who exercised the least [5–10]. Although all the studies are longitudinal (the studies chosen for this summary included only those with about 5 years or more of follow up), most still involved relatively brief follow up. (Two studies, discussed in more detail in the section entitled “Modifying Factors,” have performed long-term [20 to 30 years] follow up to evaluate the effects of exercise in midlife on the risk of dementia at older ages.) A pooled relative risk has not been calculated because the studies used different definitions of exercise as well as different definitions of dementia. Although we have not conducted a formal systematic review, and there are likely to be other studies not included in this summary, in general there is agreement across the major studies that persons who exercise the most have a lower risk of dementia relative to those who exercise the least. The etiology of age-related dementia is not wellunderstood, but it is likely to be complex and multifactorial. Of particular interest has been the relationship between pre-dementia states and progression to dementia or Alzheimer’s disease. As reviewed elsewhere, some have argued in support of a model in which an underlying pathology gradually progresses through mild cognitive impairment and eventually to dementia, but there is now clear evidence that
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Fig. 2. Relative risk of dementia, cognitive impairment, or cognitive decline in observational studies with about 5 years or more of follow up, comparing persons who exercised the most versus those who exercised the least. Error bars denote 95% CIs. *In most studies, “Age” indicates the age at which cognitive function was initially assessed. The studies varied in follow-up duration (see text). †N values indicate the size of the entire study population.
some forms of cognitive impairment are more likely to progress to dementia than others, and that certain clinical factors predispose a patient to a high risk of future dementia [11]. For the purpose of our discussion of physical exercise as a protective factor, we need only suggest that it is valuable from an epidemiologic standpoint to view cognitive impairment as an independent outcome distinct from dementia, rather than as a mere precursor to it. With that in mind, several observational studies have examined whether physical exercise affects the risk of subsequent cognitive impairment or cognitive decline in elderly persons. Summary results from these studies are shown in the lower two panels of Fig. 2. These studies [5,12–17] support the concept that physical exercise reduces the risk or severity of cognitive decline in this age group. 3.2. Alzheimer’s disease and vascular dementia If regular physical activity reduces the risk of cognitive impairment or dementia, then does it reduce the risk of specific forms of dementia, such as Alzheimer’s disease or vascular dementia? Summary results from several observational studies addressing this question are shown in Fig. 3 [5–9,18]. As with dementia in general, several major studies have found that physical activity in elderly persons is associated with a reduction in the relative risk of Alzheimer’s disease (Fig. 3, top panel). With regard to vascular dementia (Fig. 3, lower panel), it is interesting that available studies are less convincing, with no large-scale studies showing a statistically significant effect of physical activity. However, it should be noted that
the number of patients diagnosed with vascular dementia is substantially lower in most studies, so that the confidence intervals (CIs) for the relative risk are quite wide. Nevertheless, these studies provide preliminary evidence that the preventive effects of physical activity might be weaker for vascular dementia than for Alzheimer’s disease or dementia in general. Larger studies will be required to confirm this observation. In the meantime, other explanations might warrant exploration. For example, the difference could arise from diagnostic preferences, particularly whether neuroimaging is involved. In addition, the difference might arise from how vascular dementia is conceptualized. For example, vascular dementia definitions that require the presence of stroke are less sensitive than definitions that do not require the dementia to be preceded by stroke [19]. The former definition would also make preventive effects more dependent on the prevention of stroke. Finally, a recent study suggests that precursor states to Alzheimer’s disease and vascular dementia might also differ in their susceptibility to modification by physical activity [20]. If this observation is confirmed, it could provide mechanistic support for the different effects of physical activity on these two forms of dementia.
4. Modifying factors 4.1. Duration or intensity of physical activity Several of the studies summarized in Fig. 2 attempted to determine whether there was a dose-response relationship
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Fig. 3. Relative risk of Alzheimer’s disease or vascular dementia in observational studies with about 5 years or more of follow up, comparing persons who exercised the most versus those who exercised the least. Error bars denote 95% CIs. *In most studies, “Age” indicates the age at which cognitive function was assessed. The studies varied in follow-up duration (see text). †N values indicate the size of the entire study population.
between the amount of exercise and the degree of protection from dementia or cognitive decline. Overall, the results are inconsistent, with some showing no dose-response relationship but others showing a significant dose-response relationship. One study that found a significant dose-response relationship between physical activity and cognitive function was conducted as part of the Nurses’ Health Study [16]. Levels of physical activity were assessed from biennial questionnaires in 18,766 women. After about 10 or more years of follow up (when the women were 70 to 81 years old), baseline cognitive function was assessed with several validated tests. Two years later, cognitive function was assessed again to evaluate the rate of cognitive decline. Women were divided into quintiles on the basis of their levels of exercise, and Fig. 2 has already presented the risk of cognitive impairment at follow-up in the quintile reporting the most exercise relative to the group reporting the least. After adjustment for numerous factors potentially influencing cognitive function, there were significant trends for a dose-response relationship in which those reporting the most physical activity scored higher on several baseline tests of cognitive function (P ⬍ .001). During the 2 years of additional follow up, there were again significant trends for a dose-response relationship in which those reporting the most physical activity exhibited the least decline in cognitive function (P values, .05 to ⬍.001) [16]. In an additional analysis, the authors found that even walking was associated with a dose-response relationship. Those in the highest quartiles for walking (an easy pace for at least 1.5 hours per week) had significantly higher cognitive scores than those walking less than 40 minutes per week (P values, .07 to ⬍.001). Another study that looked for a dose-response relationship was that of Lytle et al [13]. These investigators prospectively followed 1146 persons at least 65 years old and
recorded self-reported exercise levels as well as scores on the Mini-Mental State Examination (MMSE). Participants were divided into three groups on the basis of exercise levels: no exercise, low exercise, and high exercise. The high exercise group was defined as those participating in at least 30 minutes of aerobic exercise at least three times per week. Persons in the high exercise group had significantly lower odds of cognitive decline (odds ratio, 0.39; 95% CI, 0.19 to 0.78). When the threshold for high exercise was increased to 5 days per week, both the low and high exercise groups had a lower risk of cognitive decline, suggesting that higher activity levels might not be necessary for the benefit to be observed [13]. A study conducted as part of the Canadian Study of Health and Aging divided participants into four groups according to the duration and intensity of physical exercise [5]. Those in the high exercise group performed exercise that was more vigorous than walking at least three times per week. The study found significant trends for lower odds of cognitive impairment–no dementia (CIND), Alzheimer’s disease, and all-cause dementia among persons performing increasing levels of exercise, with those in the high exercise group exhibiting the lowest odds for impairment or dementia. Other studies also provide evidence for greater benefit from exercise of at least moderate intensity [12,21] or for longer durations each day [14]. Overall, observational studies provide good evidence for a dose-response relationship for the protective effects of exercise on cognitive function. Unfortunately, the studies varied widely in their definitions of beneficial, moderate, or high levels of exercise. Furthermore, these definitions will likely vary among different individuals according to age, fitness level, and other parameters. The good news is that the greatest incremental benefit was associated with the transition from no exercise to a low level of exercise in
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many studies. Therefore, all persons should be encouraged to participate in at least a low to moderate exercise regimen, such as the equivalent of 30 minutes of walking three times per week.
Dementia
4.2. Age: Exercise during midlife versus exercise during late life
Alzheimer’s Disease
As mentioned, many of the studies summarized in Figs. 2 and 3 followed participants for about 5 years. As a consequence, these studies are relevant to the beneficial effects of physical activity in late life. Two studies, however, have performed much longer follow-up, examining how physical activity during midlife affects the risk of dementia or cognitive impairment in late life [9]. One study, conducted in Finland, examined cognitive function in 1449 persons (aged 65 to 79 years) who had been followed for many years as members of other population-based cohorts. Information was available about each participant’s level of physical activity during midlife, with a mean follow-up of 21 years. In a multivariate analysis adjusted for numerous variables, persons who participated in “leisure-time physical activity” during midlife had significantly lower odds of dementia (odds ratio, 0.47; 95% CI, 0.25 to 0.90) or Alzheimer’s disease (odds ratio, 0.35; 95% CI, 0.16 to 0.80) as compared with sedentary persons [9]. This odds reduction is at least comparable to the odds reduction reported in studies of physical activity in older persons. Thus, midlife physical activity might be as important for preventing later cognitive decline as is physical activity at older ages. Another study has suggested that physical activity at even earlier ages (15 to 25 years) can improve or preserve cognitive ability in late life [22]. 4.3. APOE genotype APOE polymorphisms have been found to influence the risk of Alzheimer’s disease, with the epsilon4 allele associated with increased risk and the epsilon2 allele associated with decreased risk [23–27]. Furthermore, there has been intense interest in the issue of whether APOE polymorphisms interact with other traditional risk factors, including physical activity. The Finnish study described in the preceding section included an analysis of subgroups divided according to APOE e4 status [9]. The purpose of the analysis was to determine whether the beneficial effects of physical activity on cognitive function were affected by the presence of an APOE e4 allele. Fig. 4A shows the risk of dementia or Alzheimer’s disease in persons participating in leisure-time physical activity relative to those not participating, with subgroups separated according to the presence of an APOE e4 allele. Physical activity reduced the risk of dementia or Alzheimer’s disease regardless of APOE e4 status, but the relative reduction in risk was greater in persons with an APOE e4 allele. This result supports the concept that physical activity might counteract some of the
APOE e4 status
A
+ -
+ 0.1
1
10
Exercise better
Exercise worse
Relative Risk APOE e4 status
B Cognitive decline
+ -
Dementia
+ 0.1
10
1 Exercise better
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Relative Risk Fig. 4. Interaction of physical activity with APOE e4 status. (A) Relative risk of dementia or Alzheimer’s disease in persons participating in leisuretime physical activity relative to sedentary persons. Participants are grouped according to the presence of and absence of APOE e4 allele [9]. (B) Relative risk of cognitive decline and dementia among persons engaging in high levels of exercise relative to those engaging in low levels of exercise, with subgroups defined according to APOE e4 status [14,28].
detrimental effects of APOE e4. However, this finding has not been confirmed in all observational studies. For example, Fig. 4B shows summary results for dementia from two additional observational studies addressing the same issue. The study of Podewils et al [28] did not confirm beneficial effects of physical activity among persons with an APOE e4 allele. Thus, the question of whether physical activity can counteract some of the detrimental effects of APOE e4 remains unanswered. 4.4. Other factors Several other factors might affect the degree to which physical activity prevents or delays cognitive impairment. Laurin et al [5] reported that physical activity reduced the risk of cognitive impairment or dementia in women more than men. However, Simons et al [29] reported that walking reduced admissions for dementia in men but not in women. Physical activity might also interact with fitness level, with evidence that the greatest incremental benefit from physical activity is seen among those with the lowest fitness levels [8]. However, both better fitness level and better muscle
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strength have each been positively associated with better cognitive function in separate studies [30,31]. Finally, some studies have concluded that the beneficial effect of physical activity is increased when a variety of activities are performed [28,32].
5. Dementia as a preventable illness: Revisited The observational studies presented provide reproducible and robust evidence that physical activity reduces the risk of cognitive decline and dementia. From that standpoint, these studies provide yet more rationale for promoting an active lifestyle. At this point, however, we should return to the concept introduced at the beginning of this article: that delaying the onset of dementia (or cognitive impairment) by 2 years could reduce its prevalence by 25% [4]. There is evidence that physical activity could delay cognitive decline for such a duration. For example, Weuve et al [16] observed in their population-based study that women who performed regular moderate walking (an easy pace for at least 1.5 hours per week) exhibited cognitive function equivalent to less active women who were 1.5 years younger. Unfortunately, there is very little good evidence to substantiate the claim that such an effect will reduce the prevalence of cognitive impairment or dementia. The contrasting effect would be if physical activity delayed the onset of dementia while also prolonging lifespan, with the effect that the individual experiences the same degree and duration of dementia but later in life. We have shown, for example, that people who exercise exhibit less physical frailty [33]. Thus, it is clear that physical exercise is affecting more than just brain function. This dilemma also touches on another issue raised in the Introduction: that we have not defined the clinical characteristics of successfully treated or prevented dementia or Alzheimer’s disease. As drugs or treatment strategies are developed for these conditions, it will be necessary to define successful treatment and to recognize that successfully treated individuals will not be “cured” but will have unique needs that must be addressed by the healthcare community. An additional challenge to the concept of preventing dementia is the shifting definition of the disease state and its subcategories. In 1978, for example, 67% of dementia cases were diagnosed as Alzheimer’s disease, and 15% were diagnosed as vascular dementia [34]. More recently, only 39% of cases were diagnosed as Alzheimer’s disease, whereas 25% were diagnosed as vascular dementia [3]. With preliminary evidence that physical activity might affect the risk of these conditions differently, well-designed trials to test this concept (or other preventive approaches) will require widely accepted diagnostic criteria for each disease entity.
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6. Conclusion Robust and consistent results from observational studies provide evidence that physical activity reduces the risk of cognitive impairment and dementia in late life. At this time, it is not known whether public health measures to increase participation in physical exercise will reduce the overall prevalence of these conditions. In the meantime, the evidence supporting the beneficial effects of physical activity on brain health provide yet more reasons to encourage physical activity among persons of all ages.
Acknowledgment Kenneth Rockwood is supported by the Dalhousie Medical Research Foundation as the Kathryn Allen Weldon Professor of Alzheimer Research. Laura Middleton receives career support as recipient of a Killam Doctoral Prize.
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