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Physical Activity, Physical Function, and Incident Dementia in Elderly Men: The Honolulu–Asia Aging Study

¹ School of Human Movement Studies, Faculty of Health Sciences, and ² Centre of National Research on Disability and Rehabilitation Medicine, Faculty of Health Sciences, The University of Queensland, Brisbane, Australia.
³ Pacific Health Research Institute, Honolulu, Hawaii.
⁴ Department of Medicine and Geriatrics, John A. Burns School of Medicine, University of Hawaii, Honolulu.
⁵ Departments of Geriatric Medicine and Internal Medicine, Kuakini Medical Center, Honolulu, Hawaii.
⁶ Division of Biostatistics and Epidemiology, University of Virginia School of Medicine, Charlottesville.
⁷ Department of Health Science, Shiga University of Medical Science, Otsu, Japan.
⁸ Veterans Affairs Pacific Islands Health Care System, Honolulu, Hawaii.

Address correspondence to Dennis R. Taaffe, PhD, DSc, MPH, School of Human Movement Studies, Faculty of Health Sciences, The University of Queensland, Brisbane, QLD 4072, Australia. E-mail: dtaaffe{at}hms.uq.edu.au

	Abstract

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Background. Although evidence is accumulating for a protective effect of late life physical activity on the risk of dementia, the findings are inconsistent, especially in men. We examined the association of late life physical activity and the modifying effect of physical function with future risk of dementia in a well-characterized cohort of elderly men participating in the Honolulu–Asia Aging Study (HAAS).

Methods. Physical activity by self-report and performance-based physical function was assessed in 2263 men aged 71–92 years without dementia at the baseline examination of the HAAS in 1991–1993. Follow-up for incident dementia occurred at repeat examinations conducted in 1994–1996 and 1997–1999. Analyses were based on Cox proportional hazards models with adjustment for potential confounders, including age, baseline cognitive function, education, and apolipoprotein E genotype.

Results. There were 173 incident cases of dementia with a mean follow-up of 6.1 years. Although the incidence of dementia tended to decline with increasing physical activity and function, there was a significant interaction between the latter two factors on dementia risk (p =.022). For men with low physical function, high levels of physical activity were associated with half the risk of dementia versus men who were the least active (hazard ratio [HR], 0.50; 95% confidence interval [CI], 0.28–0.89), with a moderate level of physical activity also providing a protective effect (HR, 0.57; 95% CI, 0.32–0.99). Risk of dementia and Alzheimer's disease declined significantly with increasing physical activity. Findings persisted after age and risk factor adjustment. Similar associations were absent in men with moderate and high physical function.

Conclusions. In elderly men with poor physical function, increasing general physical activity may potentially confer a protective effect or delay the onset for dementia.

Key Words: Physical activity • Physical function • Dementia • Alzheimer's disease

However, several longitudinal studies have failed to find a protective effect of physical activity on risk of dementia (9–11). Apart from inconsistent findings, the gender-specific effect is unclear. Laurin and colleagues (1) reported that the association between physical activity and risk of dementia was stronger in women, and a recent meta-analysis of aerobic fitness and cognitive function in older adults found the association more pronounced in studies with a larger female population (12). It has been suggested that differences in hormone metabolism may account for the discordant findings by gender (1), and there is evidence that estrogen has beneficial and interactive effects with exercise and fitness on brain health and plasticity (13,14). Although prospective studies examining the association between physical activity and dementia adjusted for gender (2,3,9–11), interaction or effect modification may or may not occur in conjunction with confounding. Moreover, the finding by Larson and colleagues (3) that physical function modifies the association between physical activity and dementia risk is of interest, as it identifies a subset of older persons that may benefit most from targeted interventions. Similarly, the apolipoprotein E (APOE) genotype may also modify the association between physical activity and dementia risk, although findings to date are equivocal (2,15).

Consequently, it remains unclear how consistent and how strong the association is between physical activity and risk of dementia in elderly men. Moreover, apart from physical activity, the possible modifying role of physical function requires further investigation. Therefore, the purpose of this study was to examine the association of late life physical activity and physical function with incident dementia in a well-characterized cohort of Japanese American men participating in the Honolulu–Asia Aging Study (HAAS). In addition, we report on the potentially moderating influence of the APOE genotype.

	METHODS

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Study Population
The HAAS, a prospective study of neurodegenerative diseases in the elderly population, is an extension of the Honolulu Heart Program (HHP). The cohort for the HHP, a prospective population-based study of heart disease and stroke, included 8006 Japanese American men born between 1900 and 1919 and who were living on the island of Oahu, Hawaii (16). The baseline HHP examination took place from 1965 through 1968 with several follow-up examinations. The HAAS commenced during examinations that were given from 1991 through 1993. Those examined were 3734 men 71–93 years old (approximately 80% of the surviving members of the original HHP cohort). This report is derived from the baseline examination of the HAAS and two repeat examinations in 1994–1996 and 1997–1999. This represents a nonconcurrent, longitudinal analytic design, based on approximately 6 years of follow-up of participants whose baseline cognitive function was normal, and for whom final diagnoses for cases of dementia developing in the subsequent two examination cycles are available and fully validated. The HAAS was approved by the institutional review boards of the Kuakini Medical Center (Honolulu) and the Honolulu Department of Veterans Affairs, and all participants gave written informed consent at each examination.

Analytical Sample
Of the 3734 participants in the HAAS, 226 had dementia at the baseline examination in 1991–1993 and were excluded from the incident cohort. We further sequentially excluded 129 men who had a Cognitive Abilities Screening Instrument (CASI) score <74 in the absence of further dementia screening, 62 men with a clinical dementia rating (CDR) score of 0.5, 31 men with Parkinson disease, 100 men with prevalent stroke, 9 men who used walkers, 41 men who used canes, 130 men with missing data for physical activity, 42 men with missing data for physical function, 161 men with missing data on covariates, 104 men who died before the first follow-up examination, and 436 men who failed or were unable to participate in follow-up dementia screening. The final sample included 2263 men.

Diagnosis of Dementia
Dementia case-finding followed a rigid multistep procedure that has previously been described in detail (16). Initial screening considered a participant's age and cognitive performance using the 100-point CASI. The CASI was designed for use in comparative cross-national studies of dementia in the United States and Japan (17) and includes nine cognitive domains. Scores < 74 were considered a priori as an indicator of possible dementia. Men with such scores were subjected to a second phase of dementia screening that included a repeat CASI and administration of the Informant Questionnaire on Cognitive Decline in the Elderly (IQCODE) (18). Men with a second CASI score < 74 or with a IQCODE score of 3.6 underwent a third phase that included a standardized interview, assessment by the Consortium to Establish a Registry for Alzheimer's Disease neuropsychological battery (19), a proxy interview, a neurological examination, neuroimaging, and blood tests.

For the repeat examinations, the CASI was administered once. For the first follow-up examination (1994–1996), men with a CASI score 77 with <12 years of education, a CASI score 79 with 12 years of education, or an absolute drop of 9 points from the baseline examination were recruited for complete dementia assessment. For the second follow-up examination (1997–1999), a complete assessment was undertaken for all participants with a CASI score <70.

Final diagnoses were assigned by a consensus panel consisting of a neurologist and at least two additional physicians with expertise in geriatrics and dementia. Dementia was diagnosed according to the Diagnostic and Statistical Manual of Mental Disorders, Revised Third Edition (DSM-IIIR) criteria (20). The diagnosis of Alzheimer's disease (AD) was performed according to the National Institute of Neurological and Communicative Disorders and Stroke–Alzheimer's Disease and Related Disorders Association (NINCDS–ADRDA) criteria (21) and vascular dementia by the California Alzheimer Disease and Treatment Centers criteria (22).

Physical Activity and Physical Function
Usual 24-hour physical activity was assessed based on questions regarding the average number of hours per day spent in five levels of activities, similar to that used in the Framingham (23) and Puerto Rico (24) heart studies. The activity levels were basal (sleeping or lying down), sedentary (e.g., sitting or standing, reading, eating), slight (e.g., walking on level ground), moderate (e.g., gardening or carpentry), and heavy (e.g., lifting or shoveling). As previously described and as used in the HHP (25), a weighting factor based on the approximate oxygen consumption required for each level of activity was multiplied by the hours spent in that activity and summed across the five levels to derive an index of physical activity. The weighting factors were: 1.0 for basal, 1.1 for sedentary, 1.5 for slight, 2.4 for moderate, and 5.0 for heavy activity.

Physical function was based on four objectively assessed performance tasks: 10-foot ( 3 m) timed walk, time to rise from a chair 5 times without using arms for support, grip strength of the dominant hand using a dynamometer (Smedley; Stoelting Co., Wood Dale, IL), and a balance test. The balance test involved four increasing levels of difficulty. The first level was standing for 15 seconds with eyes closed (if unable, then with eyes open). If this was successfully completed, they were then asked to perform a side by side stand, a semi-tandem stand, and a full tandem stand for 10 seconds, each performed with eyes open. Each test was scored 0–4 points based on the procedure used by Wang and colleagues (26). The performance-based physical function score was the sum of the four tests and ranged from 0 to 16, with higher scores indicating better function.

Assessment of Potential Confounders
Based on previous studies, we adjusted for a number of factors that could potentially confound the association between physical activity and dementia. Age and years of education were obtained by questionnaire, and body mass index (BMI) was calculated as weight in kilograms divided by the square of height in meters. Smoking was assessed as never, past, or current. Hypertension was defined as a systolic blood pressure (BP) 160 mmHg, a diastolic BP 95 mmHg, or BP medication use. As a marker of cumulative vascular function, we also included midlife systolic and diastolic BP based on the average of BPs assessed at three examinations in the HHP (1965–1968, 1967–1970, and 1971–1974). Total cholesterol was assessed at the University of Vermont using standard techniques. Diabetes was defined on the basis of medical history or use of insulin or hypoglycemic therapy. Prevalent coronary heart disease (CHD) included myocardial infarction, angina pectoris, and congestive heart failure. Depression was assessed using the Center for Epidemiologic Studies Depression (CES-D) Scale (27), with scores dichotomized as depressed (9) or not depressed. APOE genotype was categorized as the presence of at least one 4 allele versus no 4 allele based on genotyping performed at Duke University (Durham, NC) using standard methods (28).

Statistical Analysis
To compare the baseline characteristics of participants who remained dementia free and those who developed dementia, and to examine characteristics according to physical activity level, linear and logistic regression models were used with adjustments for age. A comparison of age was left unadjusted. Cox proportional hazards regression models were used to estimate hazard ratios (HR) and 95% confidence intervals (CI). Models included adjustments for age, education, baseline CASI score, APOE 4 status, BMI, smoking, midlife systolic and diastolic BP, hypertension, cholesterol, diabetes, prevalent CHD, and depression. Modification of risk in the association between physical activity and incident dementia by physical function was investigated using an interaction term. In addition, we also investigated if APOE 4 status (carriers vs noncarriers) modified the association. Time to event was calculated from the baseline examination to the date of diagnosis of dementia. Persons who underwent the first follow-up examination (1994–1996) but did not return for the second follow-up examination (1997–1999) were censored at the time of the first follow-up examination, whereas all others were censored at the second follow-up examination. Statistical analyses were performed using STATA statistical software (version 8; STATA Corp, College Station, TX). All tests were two-sided, and a p value <.05 was required for significance.

	RESULTS

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There were 173 incident cases of dementia with a mean follow-up of 6.1 years for an incidence rate of 12.6 per 1000 person-years. Men with incident dementia were older, had a lower age-adjusted CASI score, fewer years of education, and poorer physical function. Incident cases were also more likely to be APOE 4 carriers (Table 1). Compared to our study cohort, men who died before the first follow-up examination or who failed to appear for the first and second follow-up examinations were older (p <.001), had lower CASI scores (p <.001), had less education (p =.002), were less physically active (p <.001), had higher midlife systolic BPs (p =.020), and were more likely to be current smokers (p <.001) and have diabetes (p =.040).

	DISCUSSION

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In this prospective cohort study of 2263 nondemented elderly Japanese American men, we found that high levels of physical activity were associated with a reduction in the risk for incident dementia, but only in men with poor physical function as determined by a battery of performance-based tests. Compared to men in the lowest tertile of physical activity, the relative hazard for dementia in men in the highest tertile was 0.50 (95% CI, 0.28–0.89). This finding suggests that men with poor physical function may be a group that could especially benefit from enhancement of physical activity, potentially conferring a protective effect or delaying the onset of dementia.

Physical activity may directly influence brain structure and plasticity through a variety of cellular and molecular mechanisms (12), as well as indirectly through reduction in associated risk factors and morbidities (29). Moreover, physical activity itself may result in an enriched environment, both where the activity takes place and in the social situations encountered. In animal studies, enriched environments have resulted in a reduction in brain pathology, such as lower β-amyloid burden and higher levels of β-amyloid degradation enzymes, which would be protective for AD (30).

Our results support the recent findings by Larson and colleagues (3) that late life exercise, in this case 3 times per week of 15-minute sessions compared to <3 times per week, was associated with a 38% lower incidence of dementia in men and women, which was more pronounced in those with poorer physical function. Of note is that our study and that of Larson and colleagues (3) provide evidence of an interaction between level of physical activity and physical function and dementia risk including AD in two cohorts of older adults with different ethnic and racial makeup and educational backgrounds. We chose the same components of the performance battery to assess physical function as did Larson and colleagues (3) and the same physical function cut points in an endeavor to confirm and extend their findings to elderly men who may not be as responsive to the effect of physical activity on cognitive function (1,12). However, in contrast to Larson and colleagues (3), who based their measure of exercise on average days per week for a number of physical activities, we used an index of customary physical activity over a 24-hour period with varying intensity levels that has been previously used in the HHP, the HAAS, the Framingham Study, and in the Puerto Rico Heart Health Program (23–25,31–33).

It is not readily apparent how physical function modifies the association between physical activity and dementia. All three are interrelated in that individuals with higher physical activity levels will generally have better physical function and, in turn, individuals who have good physical function are capable of engaging in various physical activities. In turn, for the planning and coordination of various motor tasks, especially complex motor tasks, an appropriate level of cognitive function, including executive control processes, is required. Gait and balance dysfunction has been found to be associated with pathologic changes in the brain such as white matter lesions (34), and decline in motor tasks may be related to the progression to dementia (35). Consequently, individuals with poor physical function may be at a higher risk to progress to dementia (35) and, as such, may be more susceptible to lifestyle interventions that may delay the onset, such as physical activity. In persons with high physical function, protection from the risk of dementia may be sufficiently high as to minimize any additional benefits derived from increases in physical activity. Physical activity in the latter group may still be important, although effects may be more subtle than in groups with low physical function. In any event, given the array of benefits that physical activity has in maintaining physical function, independence, and quality of life, a further beneficial effect on cognitive function is worth promoting to the elderly community. In this regard, for a certain group of individuals, that is, those with poor physical function, physical activity may conceivably act as a disease-modifying treatment. Given the concern of elders regarding dementia, awareness that a physically active lifestyle may confer a protective effect could possibly be a strong motivating force for initiation of activity (36).

We also examined the role of the APOE genotype on modifying the association between physical activity and dementia, as studies to date have been equivocal (2,15). However, we found that APOE carrier status did not modify the association between physical activity and dementia, even for those persons in whom AD was the sole or primary cause. Differences in the racial/ethnic composition of the cohorts studied, as well as gender, may account for the divergent findings.

Our study sample only included men without dementia at the baseline examination of the HAAS and who survived at least to the first follow-up examination. Moreover, we excluded men whose dementia status could not be confirmed and those who had a CDR score of 0.5, indicating very mild or borderline dementia. Hence, our cohort comprised dementia-free survivors in the HAAS. In addition, our analyses were adjusted for baseline CASI score as well as for genetic susceptibility to dementia as determined by the presence of one or two APOE 4 alleles. Consequently, although reverse causation bias cannot be ruled out, it is unlikely to be a major limitation in our study. In addition, we were able to adjust for a number of potential confounders, including age, education, and a number of comorbidities, although residual confounding may still exist.

We adopted a rigid and comprehensive protocol to identify dementia cases, and we believe that misclassification of dementia is not a potential source of bias. In addition, we objectively assessed physical function using standardized physical performance tests that can be easily performed with minimal equipment in the home or clinical setting. However, as performance on these tests requires the individual to understand the instructions and be motivated to undertake the tests, bias may enter as a result of persons with cognitive impairment. However, individuals with prevalent dementia and those whose dementia status could not be confirmed were excluded from the analyses. In addition, individuals need to be physically capable to undertake the performance tests. Hence, men with Parkinson disease, prevalent stroke, and those who used mobility aids were excluded from the analyses. Misclassification may exist for the self-reported physical activity index; however, given our inclusion criteria, this assessment is likely independent of the outcome; hence, if misclassification does exist, it would be nondifferential and attenuate the associations.

Summary
We found an association between higher levels of physical activity and a reduction in risk for dementia. However, the effect was evident only in men with poor physical function. It may well be worthwhile for physicians and other health care professionals to particularly target these individuals for programs aimed at increasing physical activity as a strategy to reduce the incidence of dementia and thereby maintain quality of life and independent living. These results need to be confirmed by clinical trials before definitive conclusions and recommendations can be made; nevertheless, this study provides additional evidence for a beneficial role for the enhancement of physical activity in the elderly population.

	Acknowledgments

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This study was supported by contract N01-AG-4-2149 from the National Institute on Aging, contract N01-HC-05102 from the National Heart, Lung, and Blood Institute, and by the Japan Society for the Promotion of Science.

	Footnotes

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Decision Editor: Luigi Ferrucci, MD, PhD

Received February 27, 2007

Accepted August 16, 2007

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