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Physical exercise was found to be associated with a decreased risk of dementia and Alzheimer disease. We investigated whether physical exercise is also associated with mild cognitive impairment (MCI).
Population-based case-control study.
The Mayo Clinic Study of Aging, an ongoing population-based cohort study in Olmsted County, Minnesota, USA.
1324 non-demented subjects who completed a questionnaire on physical exercise.
An expert consensus panel classified each subject as either cognitively normal or affected by MCI using information from a Clinical Dementia Rating Scale administered to the subject and to an informant, a neurological evaluation, and neuropsychological testing to assess 4 cognitive domains.
We compared the frequency of physical exercise in 198 subjects with MCI to the frequency in 1126 cognitively normal subjects and adjusted analyses for age, sex, years of education, medical comorbidity, and depression. The odds ratio (OR) for any frequency of moderate-intensity exercise was 0.61 (95% confidence interval [CI], 0.43–0.88; P=.008) for exercise in midlife (aged 50–65 years), and 0.68 (95% CI, 0.49–0.93; P=.02) for exercise in late life. The findings were consistent in men and women. Light exercise and vigorous exercise were not significantly associated with MCI.
In this population-based case-control study, any frequency of moderate-intensity exercise carried out in either midlife or late life was associated with a reduced OR of MCI.
Mild cognitive impairment (MCI) is an intermediate state between the cognitive changes of normal cognitive aging and dementia.1–6 Subjects with MCI constitute a high risk group because they develop dementia at a rate of 10% to 15% per year compared with 1% to 2% per year in the general population.7 Therefore, it is critical to identify potential protective factors against MCI.
Physical exercise is associated with a reduced risk of heart disease, coronary artery disease, type II diabetes mellitus, some types of cancers, and overall mortality.8,9 A number of observational studies showed that physical exercise may also be protective against dementia and Alzheimer disease10–17 with few discrepant findings.18 Two studies also suggested a similar protective effect for MCI.19,20 We investigated whether physical exercise in midlife or proximate to the age at time of onset of MCI is associated with a reduced odds ratio (OR) of MCI in a case-control study derived from the Mayo Clinic Study of Aging.21
We conducted a population-based case-control study comparing subjects with MCI with cognitively normal subjects. This study was derived from the Mayo Clinic Study of Aging, which was described in detail elsewhere.21 Briefly, it is a population-based study designed to estimate the prevalence and incidence of MCI in Olmsted County, Minnesota. Elderly individuals were recruited using stratified random sampling from the target population of nearly 10 000 elderly individuals living in Olmsted County on October 1, 2004. The sampling involved equal allocation of men and women in 2 age strata, 70 to 79 years old and 80 to 89 years old. During the first follow-up performed from 2006 through 2008, subjects were asked to complete a self-reported questionnaire on physical exercise; therefore, the sample of this study was restricted to the 1324 non-demented study participants who completed the questionnaire.
Each participant in the Mayo Clinic Study of Aging underwent a baseline face-to-face evaluation including 3 components: (1) a neurological evaluation by a physician; (2) a risk factor assessment by a nurse or study coordinator; and (3) neuropsychological testing which was interpreted by a neuropsychologist. The interview by the nurse or study coordinator included administration of the Clinical Dementia Rating Scale (CDR)22 to the participant and to an informant. The neurological evaluation was performed by a physician and included administration of the Short Test of Mental Status (STMS),23 medical history review, and a complete neurological examination.
Neuropsychological testing was performed using 9 cognitive tests to assess 4 cognitive domains: (1) Memory (Logical Memory-II [delayed recall] and Visual Reproduction-II [delayed recall] from Wechsler Memory Scale-Revised, and delayed recall from the Auditory Verbal Learning Test);24–27 (2) Executive Function (Trail Making Test B,28 and Digit Symbol Substitution from Wechsler Adult Intelligent Scale-Revised); (3) Language (Boston Naming Test,29 and category fluency);30 and (4) Visuospatial Skills (Picture Completion and Block Design from WAIS-R). We transformed the raw scores on each test into age-adjusted scores using Mayo’s Older American Normative Studies (MOANS) normative data. These adjusted scores were also scaled to have a mean of 10 and a standard deviation of 3.24–27
Domain scores were obtained for every subject by summing the age-adjusted scores within each domain. Because different numbers of tests were used to compute domain scores (ie, 2 tests for the executive function, language, and visuospatial domains vs 3 for memory), the domain scores were also scaled to allow comparisons across domains. In summary, the performance of a person in a particular domain was measured by comparing the person’s domain score with the score in normals, available from previous normative work in this same population.24–27,31,32 However, the final decision about impairment in any cognitive domain was made by consensus agreement between the examining physician, nurse, and neuropsychologist taking into account years of education, prior occupation, and other information.21
We considered as cases all the participants who met the revised Mayo Clinic criteria for MCI: (1) cognitive concern expressed by a physician, informant, participant, or nurse; (2) cognitive impairment in 1 or more domains (executive function, memory, language, or visuospatial); (3) normal functional activities; and (4) not demented.4,5 Subjects with MCI could have a Clinical Dementia Rating Scale score of 0 or 0.5; however, the final diagnosis of MCI was not based exclusively on the clinical dementia rating, but rather on all available data. We considered as controls all the participants who were cognitively normal according to published normative data developed on this community.24–27
We studied frequency and intensity of physical exercise using a self-reported questionnaire with ordinal responses. We used questions from 2 previously validated instruments, the 1985 Health Interview Survey,33 and the Minnesota Heart Survey intensity codes.34 The participants were asked directly to provide information about physical exercise carried out within 1 year of the date of cognitive assessment (late life physical exercise), and carried out at ages 50–65 years (midlife physical exercise). The questionnaire inquired about light, moderate, and vigorous exercise.
Light physical exercise was defined as bowling, leisurely walking, stretching, slow dancing, and golfing with a golf cart. Moderate physical exercise was defined as brisk walking, hiking, aerobics, strength training, golfing without a golf cart, swimming, tennis doubles, moderate use of exercise machines (eg, exercise bike), yoga, martial arts, and weight lifting. Vigorous physical exercise was defined as jogging, backpacking, bicycling uphill, tennis singles, racquetball, intense/extended use of exercise machines, and skiing. For each category of intensity, further inquiry was made as to the frequency of exercise (times per month or per week).
We considered as covariates age, sex, years of education, medical comorbidity, and depression. We measured medical comorbidity using the weighted Charlson index, which takes into account both number and severity of diseases (range, 0 to 33).35 We measured depression using the Beck Depression Inventory (BDI–II).36
We conducted a set of primary analyses considering only intensity of physical exercise to test whether any frequency of exercise was associated with MCI. The “once a month or less” category served as the reference. Prompted by the results of the primary analyses, we also conducted a set of secondary analyses considering both intensity and frequency. The strength of the association between physical exercise and MCI was measured using ORs and corresponding 95% confidence intervals (95% CI) after adjusting for age (continuous variable), sex, years of education (continuous variable), medical comorbidity (weighted Charlson index as a continuous variable), and depression (BDI-II score <13 vs ≥13).
Analyses were conducted separately for physical exercise carried out at ages 50–65 years, and for physical exercise carried out within 1 year of the date of cognitive assessment. We considered 3 levels of intensity of exercise (light, moderate, and vigorous) and 6 levels of frequency of exercise (once a month or less, 2 to 3 times per month, 1 to 2 times per week, 3 to 4 times per week, 5 to 6 times per week, and daily exercise). Since the 3 categories of intensity of exercise were not mutually exclusive, it was not possible to collapse these categories.
We also conducted a set of sensitivity analyses using a composite score obtained by assigning a numeric score to frequency of physical exercise and adding the scores across the light, moderate, and vigorous strata (equal weighting to all strata). The scores were 0 for once a month or less, 0.5 for 2 to 3 times per month, 1.5 for 1 to 2 times per week, 3.5 for 3 to 4 times per week, 5.5 for 5 to 6 times per week, and 7 for daily. The total composite score ranged between 0 and 21. We consider these analyses as secondary (sensitivity analyses) because the results varied noticeably depending on the assumptions made in computing the scores (weights assigned to different responses).
Statistical testing was done at the conventional 2-tailed alpha level of 0.05. All analyses were performed by using SAS®, version 8 (SAS Institute, Cary, NC).
Table 1 summarizes the demographic characteristics of the 198 subjects with MCI and the 1126 subjects with normal cognition. Among the cognitively normal subjects, there were an equal number of men and women, whereas among the MCI group there were more men. The median age was 83 years (interquartile range, 78 to 86 years) for the MCI group and 80 years (interquartile range, 76 to 84 years) for the cognitively normal group.
We assessed the reliability of the physical exercise questionnaire in 2 ways. First, we studied its internal consistency using Cronbach’s alpha and observed a value of 0.71 (in the moderate to good range). Second, in a sub-sample of 87 subjects who completed the questionnaire at 2 successive visits, we computed a test-retest Spearman’s correlation coefficient. The correlation in the overall group was 0.47 for light exercise, 0.50 for moderate exercise, and 0.33 for vigorous exercise. Interestingly, the test-retest correlations were similar in the 73 cognitively normal subjects and in the 14 subjects affected by MCI (out of the 87 subjects with 2 interviews; data not shown).
Table 2 shows results of primary analyses dichotomizing physical exercise into any frequency of exercise vs none. Light intensity exercise had an OR of 0.90 (95% CI, 0.55–1.47; P=.68) for midlife and 0.69 (95% CI, 0.47–1.00; P=.048) for late life. Moderate intensity exercise had an OR of 0.61 (95% CI, 0.43–0.88; P=.008) for midlife and 0.68 (95% CI, 0.49–0.93; P=.02) for late life. The findings were consistent for men and women (Table 2, footnotes b and c). Vigorous exercise had an OR of 0.82 (95% CI, 0.59–1.15; P=.25) for midlife and 1.14 (95% CI, 0.72–1.81; P=.58) for late life. As expected, relatively fewer people reported vigorous exercise in late life; therefore, the non-significant associations for this analysis may be caused in part by lack of statistical power. Results using a composite score of physical exercise were comparable (Table 2, footnote a).
Table 3 shows our case-control analyses considering both intensity and frequency for physical exercise carried out in midlife (aged 50–65 years). The point estimates for nearly all frequencies of both light-intensity and vigorous-intensity exercise were between 0 and 1, suggesting a potential “protective” effect. However, none of these associations were statistically significant. On the other hand, several frequencies of moderate-intensity exercise were significantly associated with MCI. Table 4 shows our case-control analyses considering both intensity and frequency for physical exercise carried out in late life (within 1 year of the date of cognitive assessment). There was no significant association between physical exercise and MCI in any of the analyses except 1.
In this population-based case-control study, midlife moderate physical exercise was associated with a 39% reduced OR for MCI. Similarly, late life moderate physical exercise was associated with a 32% reduced OR for MCI. The ORs for light and vigorous exercise were also consistently smaller than 1.0 in most primary analyses; however, most of these associations were not statistically significant. This may be due in part to the limited statistical power.
Several observational studies have reported possible beneficial effects of physical exercise in cognitively normal elderly as well as in subjects with dementia and Alzheimer disease.10–14,16,17,37–42 By contrast, investigators from the Chicago Health and Aging Project reported that physical activity conducted within 2 weeks of the date of cognitive assessment was not associated with a decreased risk of cognitive decline in elderly population.18 That negative finding may have been caused in part by the timing of exercise proximate to the assessment of cognition.
One study reported a suggestive but not significant association between physical activity and reduced risk of amnestic MCI.19 A number of observational studies also reported an association of physical exercise with decreased risk of cognitive decline. Although cognitive decline does not coincide with our definition of MCI, these studies are relevant to the interpretation of our findings. The Nurses’ Health Study involving 18 766 women participants aged 70 to 81 years reported that long term physical activity was associated with a reduced risk of cognitive decline.43 Similarly, the Monongahela Valley Independent Elders Survey (MoVIES) reported that higher exercise level (defined as aerobic exercise for 30 or more minutes carried out 3 or more times per week) was associated with a reduced risk of cognitive decline.13 The MoVIES study had a complete survey of exercise including duration, intensity and frequency of exercise; however, its outcome measure was limited to a Mini-Mental State Examination score.44 The Canadian Health and Aging Study examined the association of physical exercise with Cognitive Impairment No Dementia (CIND) and dementia in a nested case-control study. Even though CIND is not identical with MCI, CIND and MCI are similar constructs describing the gray zone between normal cognitive aging and dementia. The Canadian investigators reported that physical activity was associated with a 42% reduced risk of CIND.10
Recently, a team of Australian investigators conducted a clinical trial of 170 volunteers aged 50 years and older who reported memory problems but did not meet the criteria for dementia. The participants were randomized to either a program of education and usual care or to a 24-week home-based program of physical activity. Exercise improved cognitive function in older adults at risk for Alzheimer disease including an unspecified number of subjects with MCI. These benefits were observed 6 months after initiation of the physical activity, and were sustained at 12 months after the intervention was discontinued.20
All the above observational studies used retrospective questionnaires and interviews to measure physical exercise; hence, some degree of recall bias is inherent in all of them. However, it is reassuring that a University of San Francisco study that objectively measured physical fitness, reported similar findings. The investigators prospectively followed 349 community dwelling elderly women for a duration of 6 to 8 years. At baseline, they objectively measured physical fitness using a treadmill duration test and a peak oxygen consumption test. They also used the oxygen uptake efficiency slope which is a measure of cardiorespiratory fitness independent of motivation and effort. The investigators observed that subjects who were in the highest tertile of cardiorespiratory fitness experienced less cognitive decline over a 6 years follow-up period.11,40
The findings of our study should be interpreted within the context of the following limitations. The first limitation pertains to study design. Both the exposure (physical exercise) and the outcome (MCI) were measured at a cross-sectional point in time. Therefore, it is difficult to study the direction of causality. The second limitation pertains to the measurement of exercise. As in many other observational studies, we used a self-reported questionnaire to collect exercise data. Such a measurement is prone to recall bias.13,45 Third, few people engaged in vigorous exercise in late life; thus, the statistical power was limited for that analysis.
Our study did not address mechanisms of action. Based on the literature, we can speculate that physical exercise may be directly protective against MCI via increased production of neurotrophic factors,46 increased cerebral blood flow, increased neurogenesis, enhanced neuronal survival, mobilization of gene expression impacting neuronal plasticity,47,48 and decreased risk of cardiovascular and cerebrovascular diseases.49 A second possibility is that physical exercise may be a marker for a healthy life style. A person who engages in regular physical exercise may also show the same type of discipline in dietary habits, accident prevention, compliance with preventive intervention, compliance with medical care, and similar health promoting behaviors.
In summary, our findings contribute to the growing body of literature that indicates the potentially beneficial relationship between physical exercise and cognition. A future population-based cohort study is needed to confirm whether physical exercise is associated with a decreased risk of incident MCI. The population-based setting will improve generalizability, and the prospective cohort design will strengthen etiologic inferences.
Funding/Support: This study was supported by grants from the National Institutes of Health (K01 MH068351, U01 AG006786, K01 AG028573, P50 AG016574, R01 AR030582, and R01 NS033978), by the Robert H. and Clarice Smith and Abigail Van Buren Alzheimer’s Disease Research Program, and by the Harold Amos (RWJ) Medical Faculty Development Program.
Additional Contributions: We would like to thank David A. Mrazek, MD, FRCPsych, for his administrative support in the design and conduct of the K01 MH068351 grant.
Financial Disclosure: None reported.