Leisure-time physical activity from mid- to late life, body mass index, and risk of dementia

Alzheimer’s & Dementia - (2014) 1-10

Research Article

Leisure-time physical activity from mid- to late life, body mass index, and risk of dementia Anna-Maija Tolppanena,*, Alina Solomona,b,c, Jenni Kulmalad, Ingemar K
areholtc,e, Tiia Ngandub,f, Minna Rusanena, Tiina Laatikainenf,g,h, Hilkka Soininena,i, Miia Kivipeltoa,b,c,f a Department of Neurology, University of Eastern Finland, Kuopio, Finland Alzheimer Disease Research Center, Karolinska Institutet, Stockholm, Sweden c Aging Research Center (ARC), Karolinska Institutet and Stockholm University, Stockholm, Sweden d Gerontology Research Center, Department of Health Sciences, University of Jyv€askyl€a, Jyv€askyl€a, Finland e Institute for Gerontology, School of Health Sciences, J€onk€oping University, J€onk€oping, Sweden f Department of Chronic Disease Prevention, National Institute for Health and Welfare, Helsinki, Finland g Institute of Public Health and Clinical Nutrition, University of Eastern Finland, Kuopio, Finland h Hospital District of North Karelia, Joensuu, Finland i Department of Neurology, Kuopio University Hospital, Kuopio, Finland b

Abstract

Background: Physical activity may be beneficial for cognition, but the effect may vary depending on personal characteristics. Methods: We investigated the associations between leisure-time physical activity (LTPA) from midto late life, the risk of dementia, and the role of body mass index, sex, and APOE in the CAIDE study during 28-year follow-up. Cognitive function of a random subsample was assessed at a mean age of 78.8 years (n 5 1511), and dementia/Alzheimer’s disease (AD) diagnoses were identified from national registers for the entire target population (n 5 3559). Results: Moderate (hazard ratio [HR], 1.46; 95% confidence interval [CI], 1.08–1.99) and low levels of midlife LTPA (HR, 1.39; 95% CI, 0.99–1.95) were associated with higher risk of dementia in comparison with the most active category. The benefits were more pronounced among men, overweight individuals, and APOE ε4 noncarriers. Maintaining high LTPA (HR, 0.16; 95% CI, 0.06–0.41) or increasing LTPA (HR, 0.19; 95% CI, 0.09–0.40) after midlife was associated with lower dementia risk. Similar results were observed for AD. Conclusions: The window of opportunity for preventive physical activity interventions may extend from midlife to older ages. Ó 2014 The Alzheimer’s Association. All rights reserved.

Keywords:

Cohort study; Dementia; Exercise; Life course; Obesity; Physical activity

1. Introduction Several modifiable risk or protective factors for dementia have been suggested, and refining available knowledge is essential for effective preventive interventions targeted at high-risk groups. Physical activity is a particularly important factor because of its broader effects on health in general and cardiovascular health in particular. Longitudinal studies *Corresponding author. Tel.: 1358 40 355 2015; Fax: 1358 17 162 048. E-mail address: [email protected]

have shown that physical activity may protect against dementia [1–4]. Higher levels of total daily physical activity [5] and participation in vigorous activities [1] have been associated with lower dementia incidence, but conflicting results exist as well [6–9]. Leisure-time, commuting, and work-related physical activities may have different effects on dementia risk [10,11]. Furthermore, the apolipoprotein E (APOE) genotype can modify the physical activitydementia relation [11]. Physical activity is strongly correlated with body mass index (BMI). Midlife overweight and obesity increase dementia risk, but associations are less

1552-5260/$ - see front matter Ó 2014 The Alzheimer’s Association. All rights reserved. http://dx.doi.org/10.1016/j.jalz.2014.01.008

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straightforward at older ages [12]. A U-shaped association between BMI and dementia has been suggested [12]. The effect of BMI on the relation between physical activity and dementia is not entirely clear. BMI changes with age [13], and there is additionally a pattern of BMI decline over time in individuals who develop dementia later on [14]. Changes in physical activity from mid- to late life have not been fully investigated in relation to dementia. Although the timing of studies (younger vs. older populations at baseline) and the length of follow-up can influence findings [15], few previous long-term studies have focused on middle-aged populations. The Cardiovascular Risk Factors, Aging and Dementia (CAIDE) study includes participants followed up from midto late life. We have previously reported that higher levels of leisure-time physical activity (LTPA) in midlife were related to lower dementia risk 20 years later in CAIDE participants [11]. This study aims to refine these findings by focusing on LTPA from mid- to late life and the role of BMI, sex, and APOE genotype in relation to dementia/Alzheimer’s disease (AD) risk 28 years later in the entire CAIDE target population.

2. Methods 2.1. Participants CAIDE participants were derived from four separate, independent, population-based random samples examined in the North Karelia Project and Monitoring Trends and Determinants in Cardiovascular Disease in Finland (FINMONICA) study in 1972, 1977, 1982, or 1987 (baseline/midlife visit) [16]. Participation rates in these surveys ranged from 82% to 90%. The CAIDE study focused on individuals aged 65 to 79 years at the end of 1997 and living in two geographically defined areas in or close to the towns of Kuopio and Joensuu, Finland. Of 3559 eligible persons, 875 (24.6%) had died before the end of 1997 and 2684 (75.4%) were alive. A random sample of 2000 survivors was invited for a first reexamination in 1998. Altogether, 1449 individuals (72.5%) participated, including 900 women (62.1%). A second reexamination was done in 2005 to 2008. Of the 2000 persons, 1426 were still alive and living in the region in the beginning of 2005 and 909 (63.7%) participated, including 590 women (64.9%). Altogether, 1511 persons participated in at least one reexamination: 750 persons attended both examinations and 659 and 102 only the first or second reexamination, respectively. The mean age 6 standard deviation (SD) was 50.6 6 6.0 years at baseline, 71.3 6 4.0 years at the first reexamination, and 78.6 6 3.7 years at the second reexamination. The CAIDE study was approved by the local ethics committee, and written informed consent was obtained from all participants at reexaminations. Derivation of the CAIDE study sample is presented in Fig. 1. Persons with missing data on variables of interest were excluded, leading to final sample sizes of 3242 individuals in the entire CAIDE target population (91.1%), 1432 participants in at least one CAIDE reex-

amination (71.6% of the invited random sample), and 1411 individuals with available data on changes in physical activity and dementia (70.6%). 2.2. Cognitive assessments During CAIDE reexaminations, cognition was assessed with a three-step protocol: screening, clinical phase, and differential diagnostic phase. In 1998, participants with
24 points on Mini-Mental State Examination (MMSE) at screening were referred to the clinical phase for further evaluations. In 2005 to 2008, participants with
24 points on MMSE, an MMSE decrease 3 points since 1998, ,70% delayed recall in the Consortium to Establish a Registry for Alzheimer’s Disease (CERAD) word list [17], or with informant concerns regarding the participant’s cognition were referred to the clinical phase. Clinical phase included detailed neurologic, cardiovascular, and neuropsychological examinations, and the differential diagnostic phase included brain imaging (magnetic resonance imaging [MRI]/computed tomography [CT]), blood tests, and cerebrospinal fluid analysis if considered necessary. A review board including the physician, neuropsychologist, and a senior neurologist ascertained the primary diagnosis based on all information. Dementia was diagnosed using the Diagnostic and Statistical Manual of Mental Disorders criteria [18]. Probable and possible ADs were diagnosed according to the National Institute of Neurological and Communicative Disorders and Stroke and the Alzheimer’s Disease and Related Disorders Association (NINCDS-ARDRDA) criteria [19]. 2.3. Dementia diagnoses in registers Data from the entire CAIDE target population were linked with national registers using social security numbers. Dementia diagnoses were identified from the National Hospital Discharge Register (HDR), Special Reimbursement Register, and Causes of Death Register (CDR). The HDR includes information on in-patient stays in public hospitals. The Special Reimbursement Register includes all citizens or long-term residents who have a clinically verified diagnosis and are treated with AD medication. These data are available since February 1999. The diagnosis needs to be confirmed by a neurologist or geriatrician after thorough examinations (including neuropsychological and laboratory tests and neuroimaging by MRI/CT). Reimbursement is not restricted by dementia severity, and people living alone or in nursing homes are also entitled to reimbursement. The start date of linkage for HDR and CDR was February 1972 (start of midlife examination) and February 1999 for the Special Reimbursement Register. The end date of linkage was December 31, 2008. The following International Classification of Diseases (ICD) codes were used to identify dementia diagnoses from registers: 290 and 290.10 (ICD-8); 290, 2912A, 2928C, 2941A, 3310A, 3311A, and 4378A (ICD-9); and F00, F01, F02, F03, F05.1, F10.73, F11.73,

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Fig. 1. Derivation of the study populations. CAIDE, Cardiovascular Risk Factors, Aging and Dementia.

F14.73, F16.73, F18.73, F19.73, and G30 (ICD-10). Persons with ICD-8 code 290.10, ICD-9 code 3310, or ICD-10 codes F00 or G30 were considered to have AD. 2.4. LTPA LTPA was assessed at all examinations with the question: “How often do you participate in leisure-time physical activity that lasts at least 20–30 minutes and causes breathlessness and sweating?” Response options were (1) “daily”; (2) “2–3 times a week”; (3) “once a week”; (4) “2–3 times a month”; (5) “a few times a year”; and (6) “never due to illness or injury.” Because of low frequencies in some response categories, midlife LTPA was recoded into a three-category vari-

able indicating high (responses 1 and 2), moderate (responses 3 and 4), and low (responses 5 and 6) levels of LTPA in midlife. Changes in LTPA were calculated by subtracting responses at the last available reexamination from responses at midlife, and were categorized as always low, always moderate, always high, decreased, or increased. 2.5. Confounders and effect modifiers We considered age, sex, years of education, marital status, physically demanding occupation, midlife BMI, APOE genotype, and cardiorespiratory and musculoskeletal diseases as possible confounders. Possible effect modification by sex, BMI, and APOE genotype was also assessed.

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Baseline survey methods were carefully standardized and complied with international recommendations. The 1982 and 1987 surveys followed World Health Organization MONICA protocols, and methods used in 1972 and 1977 were comparable. During reexaminations, methods were similar to previous surveys. Data on sociodemographic characteristics, health-related behavior, and medical history were collected from questionnaires completed by participants and verified at the examination appointments. Height and weight were measured, and BMI was calculated as weight (in kilograms) divided by height squared (in meters). Data on occupational physical demands were probed by question with four answer options (“mainly sitting, e.g., clocksmith, seamstress, office work”/“walking, e.g., supervisor duties in factory, light industrial jobs, office jobs requiring walking”/“walking and lifting, e.g., industrial occupations, carpenter”/“heavy physical demands including lifting or carrying of heavy objects, shoveling, etc, e.g., heavy industrial work, jobs in agriculture or forestry, construction work”). A history of musculoskeletal conditions (rheumatoid arthritis or other joint disorders) diagnosed by a physician was assessed from questionnaires. Information on cardio/cerebrovascular and respiratory conditions (myocardial infarction, coronary artery disease, heart failure, atrial fibrillation, cardiovascular surgery, diabetes, stroke, asthma, or chronic obstructive pulmonary disease) was obtained from HDR. In participants in CAIDE reexaminations, APOE was genotyped from blood leukocytes at the first follow-up assessment [20]. 2.6. Statistical analyses Statistical analyses were performed with Stata 12.0 (Stata Corp, College Station, TX, USA). Baseline characteristics are reported as mean 6 SD for continuous variables and n (%) for categorical variables. Differences between participants and nonparticipants and among physical activity categories among participants were tested with linear regression and c2 tests for continuous and categorical variables, respectively. Associations between midlife LTPA and dementia/AD were evaluated in two sets of analyses: one for CAIDE participants (n 5 1432) and one for the entire CAIDE target population (n 5 3242) using combined CAIDE and register diagnoses for dementia. This enabled us to compare the magnitude of association in the whole study sample (including nonparticipants and nonsurvivors) and in the CAIDE participant sample. Associations between changes in physical activity and dementia could be investigated only in CAIDE participants. Because of variable follow-up times and an exponential increase in dementia risk with age, we fitted a parametric survival model with Gompertzdistributed baseline intensity using the streg command in Stata. The end of follow-up was defined as the date of dementia diagnosis, death, or December 31, 2008 (last date of register data linkage). The association between LTPA and dementia/AD was assessed in two models: (1) crude model adjusted for age, sex,

and education and (2) confounder-adjusted model including variables in model 1 and marital status, smoking, BMI, cardiorespiratory and musculoskeletal diseases, and workrelated physical activity in midlife. In participants in CAIDE reexaminations, analyses were additionally adjusted for APOE carrier status (n 5 1312). Effect modification by sex, BMI, or APOE genotype was assessed by including an interaction term (LTPA*sex, LTPA*BMI, or LTPA*APOE ε4 carrier status) in the model. Change in BMI from midto late life and midlife LTPA levels were also accounted for when the association between LTPA change and dementia/AD risk was assessed.

3. Results 3.1. Population characteristics Follow-up time in the entire CAIDE target population was 78,506 person-years. Average follow-up time was 24.4 years (range, 1–36 years). Among CAIDE participants, follow-up time was 40,481 person-years, with an average of 28.3 years (range, 11–36). Characteristics of nonsurvivors and nonparticipants compared with CAIDE participants are described in Supplementary Table 1. Nonsurvivors and nonparticipants were older at baseline, younger at the end of follow-up, had fewer education years, and higher BMI in midlife. They were also more likely to be men, smokers, have cardiorespiratory conditions, physically demanding jobs, lower LTPA levels, and be widowed, separated, or single. Dementia incidence was 16.6% in CAIDE participants and 14.4% in nonparticipants; CAIDE participants were 1.21 times more likely to develop dementia during followup (95% confidence interval [CI], 1.00–1.46, adjusted for age and sex). Half (50.0%) of the CAIDE participants who were included in the analyses attended both the follow-up examinations, 43.6% the first assessment and 6.4% the second assessment only. The characteristics according to follow-up attendance are given in Supplementary Table 2. Univariate associations between dementia and confounders are listed in Table 1. People with dementia were more likely to be older, have higher BMI, lower education levels, female sex, be smokers, or be widowed or separated. Occupational physical activity and cardiorespiratory or musculoskeletal conditions were not associated with dementia. Among CAIDE participants, decrement of LTPA levels from mid- to late-life or carrying APOE ε4 allele was associated with dementia. Supplementary Table 3 lists the univariate associations between confounders and LTPA in midlife. Older or married participants, men, those with physically demanding occupations, or lower BMI in midlife reported lower LTPA levels. Persons with cardiorespiratory or musculoskeletal conditions in midlife reported higher levels of LTPA, but they were also more likely to abstain from exercise because of injury or illness. Smoking and APOE genotype were not associated with LTPA. Among CAIDE participants, those

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Table 1 Characteristics of persons with and without dementia in the entire CAIDE target population (n 5 3559) Characteristic

No dementia (n 5 3015)

Dementia (n 5 544)

P

Age at midlife (n 5 3559) Age at the end of follow-up (n 5 3559) Education (n 5 3480), y Midlife BMI (n 5 3461) Serum total cholesterol level at midlife (n 5 3442) Systolic blood pressure at midlife (n 5 3459), mm Hg Sex (n 5 3559) Female Male Level of moderate-intensity leisure-time physical activity in midlife (n 5 3445) Low Moderate High Occupational physical activity in midlife (n 5 3515) Low Middle Mid-high High Smoking in midlife (n 5 3535) No Yes Marital status at midlife (n 5 3555) Married/cohabiting Single Widow/separated Cardiorespiratory conditions in midlife (n 5 3559) No Yes Musculoskeletal conditions in midlife (n 5 3559) No Yes Change in leisure-time physical activity (CAIDE participants only, n 5 1411) Always low Decreased Always moderate Always high Increased APOE ε4 carrier status (CAIDE participants only, n 5 1380) No Yes

50.9 6 6.0 74.9 6 8.8 8.2 6 3.3 26.8 6 4.0 6.8 6 1.3 147.8 6 21.9

53.1 6 5.7 77.5 6 5.4 7.6 6 3.4 27.2 6 4.0 7.0 6 1.2 149.9 6 22.0

,.001 ,.001 ,.001 .001 .003 .042 ,.001

1653 (54.8) 1362 (45.2)

358 (65.8) 186 (34.2) .57

1200 (41.0) 960 (32.8) 766 (26.2)

201 (38.7) 173 (33.3) 145 (27.9)

1252 (42.0) 964 (32.3) 546 (18.3) 219 (7.4)

209 (39.1) 185 (34.6) 109 (20.4) 31 (5.8)

1409 (47.1) 1585 (52.9)

306 (56.6) 235 (43.4)

2316 (76.9) 285 (9.4) 410 (13.6)

393 (72.2) 48 (8.8) 103 (18.9)

2829 (93.8) 186 (8.2)

505 (92.8) 39 (7.2)

1460 (48.4) 1555 (51.6)

271 (49.8) 273 (50.8)

.24

,.001

.005

.38

.55

,.001 68 (5.7) 49 (4.1) 388 (32.7) 166 (14.0) 515 (43.4)

13 (5.8) 26 (11.6) 44 (19.6) 49 (21.8) 93 (41.3)

779 (67.6) 373 (32.4)

110 (48.2) 118 (51.8)

,.001

Abbreviations: CAIDE, Cardiovascular Risk Factors, Aging and Dementia; BMI, body mass index; SD, standard deviation. NOTE. Data are given as mean 6 SD for continuous variables and n (%) for categorical variables.

with high levels of LTPA were most likely to retain their physical activity levels in late life. Majority (70.6%) of those unable to exercise in midlife due to injury or illness increased their LTPA during follow-up. 3.2. LTPA and dementia/AD risk Table 2 lists associations between midlife LTPA and incident dementia in the CAIDE target population and CAIDE participants. Compared with individuals with the highest LTPA levels (2 times/wk), those with lower LTPA levels tended to have higher relative risk of dementia during follow-up. The association was stronger in analyses restricted to CAIDE participants, indicating approximately

40% higher relative risk in the group with lower LTPA levels. Additional adjustment for APOE genotype did not change the results. Similar results were obtained when the analyses were restricted to AD instead of all dementias (Supplementary Table 4). There was some statistical evidence for different effects of LTPA by APOE genotype, BMI, and sex (in CAIDE participants, P values for interactions were .17, .16, and ,.001, respectively). Associations between midlife LTPA and dementia risk according to sex, midlife BMI categories, and APOE ε4 allele status are presented in Table 3. The LTPA-dementia relations per sex or BMI category were stronger in CAIDE participants than in the entire CAIDE target population. LTPA was not associated with dementia

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Table 2 Association between midlife leisure-time physical activity (LTPA) and risk of incident dementia in the entire CAIDE target population and CAIDE participants CAIDE target population (n 5 3242) LTPA

n (% with dementia)

Model 1* High 1308 (14.2) Moderate 1074 (15.5) Low 860 (16.1) Model 2y High 1308 (14.2) Moderate 1074 (15.5) Low 860 (16.1) Model 2 with APOE genotype (n 5 1313) High Not applicable Moderate Low

CAIDE participants (n 5 1432) HR (95% CI)

n (% with dementia)

HR (95% CI)

1.00 (Reference) 1.20 (0.97–1.48) 1.16 (0.93–1.45)

583 (13.9) 506 (16.8) 343 (19.3)

1.00 (Reference) 1.46 (1.08–1.99) 1.40 (1.01–1.95)

1.00 (Reference) 1.21 (0.98–1.50) 1.16 (0.93–1.46)

583 (13.9) 506 (16.8) 343 (19.3)

1.00 (Reference) 1.45 (1.06–1.97) 1.39 (0.99–1.95)

Not applicable

540 (13.5) 463 (17.3) 310 (19.4)

1.00 (Reference) 1.45 (1.06–1.97) 1.39 (0.99–1.95)

Abbreviations: CAIDE, Cardiovascular Risk Factors, Aging and Dementia; HR, hazard ratio; CI, confidence interval. *Model 1 is adjusted for age and sex. y Model 2 is adjusted for covariates in model 1 and education, midlife body mass index, marital status, occupational physical activity level, smoking, and cardiorespiratory and musculoskeletal conditions.

in women, whereas lower LTPA levels were associated with higher dementia risk in men. There was no significant relation between LTPA and dementia in individuals with normal midlife BMI. Among overweight individuals, moderate or low levels of LTPA were associated with 39% to 49% higher relative risk of dementia in the CAIDE target population and 69% to 97% higher relative risk in CAIDE participants. Among APOE ε4 noncarriers, lower LTPA levels were related to higher dementia risk, and a similar trend was observed among APOE ε4 carriers with moderate LTPA levels (Table 3). When the analyses were restricted to AD (Supplementary Table 5), similar interactions and results were observed. The point estimates in men, overweight, and obese participants were further away from the null, but the conclusions were similar as for all dementias. When we compared the other APOE genotype-LTPA combinations with APOE ε4 noncarriers with high LTPA levels, hazard ratio (HR) for dementia was 1.59 (95% CI, 0.99–2.56) in APOE ε4 noncarriers with moderate LTPA, 1.83 (95% CI, 1.12–2.98) in APOE ε4 noncarriers with low LTPA, 2.99 (95% CI, 1.87–4.77) in APOE ε4 carriers with high LTPA, 4.32 (95% CI, 2.74–6.81) in APOE ε4 carriers with moderate LTPA, and 3.25 (95% CI, 1.93–5.44) in APOE ε4 carriers with high LTPA. 3.3. Change in LTPA and dementia risk Association between changes in LTPA from mid- to late life and dementia was investigated only in CAIDE participants (Table 4). Participants who maintained high levels of LTPA or increased their LTPA level had lower dementia risk compared with participants with low LTPA at both time points, even after adjusting for confounders including LTPA levels in midlife, BMI changes (model 2), and APOE genotype. There were no differences in dementia

risk among those who had low or moderate levels of LTPA at both time points or whose LTPA levels decreased from mid- to late life. There was no statistical evidence for different association by APOE genotype or sex (in CAIDE participants, P values for interactions were .80 and .24, respectively), but some suggestion for effect modification by midlife BMI (P for interaction, .12) was found. In stratified analyses according to midlife BMI, changes in LTPA were not associated with dementia risk in participants with normal BMI. Among overweight participants, maintaining high levels or increasing LTPA levels was related to a lower dementia risk. This association was independent of comorbidities, socioeconomic position, APOE genotype, or changes in BMI. Among obese participants, point estimates were similar to the overweight group, but CIs were wider. Similar results were obtained when the results were restricted to AD (Supplementary Table 6). 4. Discussion Persons with higher levels of midlife LTPA had lower risk of dementia and AD. The benefit of midlife LTPA was more pronounced among men, overweight individuals, and APOE ε4 noncarriers. Higher levels of physical activity, especially LTPA, have been related to lower risk of dementia in some [1–5,9,15] but not all [6–8] longitudinal studies. The heterogeneity might be partly explained by timing (midvs. late-life assessments) and follow-up as studies with shorter follow-up time (which tend to include older populations at baseline) tend to show stronger protective effects [15]. Differential loss to follow-up due to differential mortality or participation rates among individuals with lower levels of physical activity or with dementia can also influence results. We accounted for participation bias by verifying dementia diagnoses in national registers for the entire CAIDE target population. The LTPA-dementia associations

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Table 3 Groupwise associations between midlife leisure-time physical activity (LTPA) and the risk of incident dementia per sex and midlife BMI category in the entire CAIDE target population (n 5 3242) and CAIDE participants (n 5 1432) and per APOE ε4 allele status in CAIDE participants (n 5 1313) CAIDE target population LTPA in midlife

CAIDE participants

HR (95% CI) n (% with dementia) Model 1*

Men High 625 (9.0) 1 (Reference) Moderate 503 (13.3) 1.59 (1.11–2.28) Low 296 (15.9) 1.99 (1.34–2.95) Women High 683 (19.0) 1 (Reference) Moderate 571 (17.3) 1.02 (0.78–1.33) Low 564 (16.1) 0.90 (0.69–1.17) Normal weight in midlife (BMI ,25 kg/m2) High 446 (14.8) 1 (Reference) Moderate 373 (14.2) 0.93 (0.65–1.34) Low 288 (13.5) 0.98 (0.66–1.47) Overweight in midlife (BMI 5 25–29.9 kg/m2) High 647 (13.0) 1 (Reference) Moderate 521 (14.6) 1.45 (1.05–1.99) Low 380 (16.8) 1.39 (1.00–1.93) Obese in midlife (BMI 30 kg/m2) High 215 (16.7) 1 (Reference) Moderate 180 (20.6) 1.16 (0.73–1.83) Low 192 (18.2) 0.94 (0.59–1.51) APOE ε4 carriers High NA Moderate Low APOE ε4 noncarriers High NA Moderate Low

HR (95% CI) y

Model 2

n (% with dementia) Model 1*

Model 2y

Model 2 1 APOE

1 (Reference) 250 (10.4) 1.57 (1.09–2.27) 211 (17.1) 1.94 (1.29–2.90) 90 (24.4)

1 (Reference) 1 (Reference) 1 (Reference) 2.02 (1.21–3.39) 1.98 (1.17–3.34) 2.12 (1.21–3.70) 2.69 (1.51–4.82) 2.57 (1.40–4.73) 2.43 (1.25–4.71)

1 (Reference) 333 (16.5) 1.04 (0.80–1.36) 295 (16.6) 0.91 (0.69–1.19) 253 (17.4)

1 (Reference) 1 (Reference) 1 (Reference) 1.19 (0.81–1.75) 1.18 (0.80–1.74) 1.28 (0.85–1.92) 1.04 (0.70–1.55) 1.04 (0.70–1.55) 1.14 (0.75–1.74)

1 (Reference) 217 (12.9) 0.93 (0.64–1.35) 178 (13.5) 1.03 (0.68–1.54) 117 (15.4)

1 (Reference) 1 (Reference) 1 (Reference) 1.03 (0.59–1.78) 0.97 (0.56–1.68) 1.09 (0.62–1.92) 1.15 (0.63–2.10) 1.18 (0.64–2.18) 1.26 (0.66–2.41)

1 (Reference) 285 (12.3) 1.49 (1.08–2.05) 258 (15.5) 1.40 (1.00–1.97) 162 (20.4)

1 (Reference) 1 (Reference) 1 (Reference) 1.73 (1.09–2.76) 1.81 (1.13–2.90) 1.69 (1.03–2.77) 1.88 (1.15–3.07) 1.97 (1.19–3.25) 1.96 (1.17–3.30)

1 (Reference) 1.01 (0.63–1.62) 0.93 (0.57–1.50)

1 (Reference) 1 (Reference) 1 (Reference) 1.69 (0.89–3.18) 1.46 (0.74–2.89) 1.72 (0.85–3.49) 1.01 (0.51–2.02) 0.83 (0.40–1.73) 0.66 (0.30–1.49)

81 (22.2) 70 (30.0) 64 (23.4)

NA

184 (20.7) 172 (26.2) 111 (24.3)

1 (Reference) 1 (Reference) NA 1.51 (0.98–2.33) 1.47 (0.94–2.28) 1.16 (0.70–1.91) 1.24 (0.73–2.08)

NA

356 (9.8) 291 (12.0) 199 (16.6)

1 (Reference) 1 (Reference) NA 1.57 (0.98–2.53) 1.60 (0.99–2.59) 1.76 (1.09–2.87) 1.85 (1.12–3.06)

Abbreviations: BMI, body mass index; CAIDE, Cardiovascular Risk Factors, Aging and Dementia; HR, hazard ratio; CI, confidence interval; NA, not applicable. *Model 1 is adjusted for age, sex, and education. y Model 2 is adjusted for covariates in model 1 and midlife BMI, marital status, occupational physical activity level, smoking, and cardiorespiratory and musculoskeletal conditions.

were stronger in participants in CAIDE reexaminations compared with the entire CAIDE population. This may reflect an underestimation of dementia diagnoses in registers [21]. Furthermore, individuals with a sedentary lifestyle may have died before developing dementia. The CAIDE participants were younger in midlife, had better education and lower levels of cardiovascular risk factors, and were more likely to be women. All those factors are related to better survival and are suggestive of selective mortality. Stronger associations between physical activity and cognitive decline were reported in women compared with men [21,22], although a recent meta-analysis did not confirm any effect modification by sex [15]. APOE genotype has also been suggested to modify the association [11,23]. Interestingly, in a previous study in CAIDE participants, we observed that midlife LTPA was related to lower risk of dementia/AD 20 years later particularly in APOE ε4 carriers [11]. After extending the follow-up to nearly 30 years, this association was significant only among APOE ε4 noncarriers, although a similar pattern was observed among APOE

ε4 carriers. As expected, absolute risks of dementia were higher in APOE ε4 carriers compared with noncarriers in all physical activity categories. Some studies have suggested that physical activity [23] and other lifestyle factors such as dietary patterns [26,27] may not be enough to counteract the effects of ε4 allele. Other benefits of physical activity such as improvement in lipid levels or blood pressure seem to be stronger among APOE ε4 noncarriers [28–30]. However, findings from the CAIDE study suggest that the impact of a sedentary lifestyle may be lower among APOE ε4 carriers who survive to older ages. Some studies have also suggested that although APOE ε4 is associated with age of onset, its association with dementia may be weaker at older age [22]. Persons who maintained high levels or increased their LTPA from mid- to late life, regardless of their midlife LTPA, had lower risk of dementia/AD. The benefit of maintaining/increasing LTPA was particularly evident in overweight persons, and a similar trend was observed in the smaller group of obese individuals, although the CIs were

8

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Table 4 Associations between changes in leisure-time physical activity (LTPA) from mid- to late life and risk of incident dementia in CAIDE participants

LTPA in midlife and late life All CAIDE participants (n 5 1411) Always low Decrease from midlife Always moderate Always high Increase from midlife Normal weight in midlife (n 5 509) Always low Decrease from midlife Always moderate Always high Increase from midlife Overweight in midlife (n 5 693) Always low Decrease from midlife Always moderate Always high Increase from midlife Obese in midlife (n 5 209) Always low Decrease from midlife Always moderate Always high Increase from midlife

Model 1*

Model 2y

Model 2 1 APOE

n (% with dementia)

HR (95% CI)

HR (95% CI)

HR (95% CI)

75 (34.7) 215 (22.8) 81 (16.1) 432 (10.2) 608 (15.3)

1 (Reference) 0.72 (0.44–1.16) 0.78 (0.40–1.54) 0.31 (0.19–0.51) 0.54 (0.35–0.84)

1 (Reference) 0.70 (0.34–1.46) 0.45 (0.14–1.47) 0.23 (0.09–0.56) 0.35 (0.17–0.71)

1 (Reference) 0.34 (0.15–0.77) 0.38 (0.11–1.29) 0.16 (0.06–0.41) 0.19 (0.09–0.42)

24 (20.9) 65 (21.5) 31 (12.9) 173 (9.3) 216 (14.4)

1 (Reference) 1.07 (0.38–3.01) 0.97 (0.25–3.68) 0.55 (0.20–1.51) 0.83 (0.32–2.14)

1 (Reference) 0.94 (0.32–2.71) 0.91 (0.23–3.56) 0.47 (0.17–1.35) 0.67 (0.25–1.80)

1 (Reference) 0.58 (0.19–1.75) 0.67 (0.17–2.64) 0.37 (0.13–1.06) 0.48 (0.18–1.30)

32 (37.5) 105 (20.0) 38 (13.2) 213 (10.8) 305 (14.1)

1 (Reference) 0.61 (0.30–1.25) 0.61 (0.21–1.77) 0.24 (0.12–0.50) 0.43 (0.22–0.82)

1 (Reference) 0.57 (0.28–1.19) 0.61 (0.21–1.80) 0.22 (0.11–0.47) 0.41 (0.21–0.80)

1 (Reference) 0.51 (0.24–1.11) 0.53 (0.18–1.60) 0.22 (0.10–0.47) 0.38 (0.19–0.75)

19 (47.4) 45 (31.1) 12 (33.3) 46 (10.9) 87 (21.8)

1 (Reference) 0.65 (0.28–1.55) 1.08 (0.33–3.59) 0.26 (0.09–0.79) 0.56 (0.25–1.26)

1 (Reference) 0.64 (0.23–1.79) 1.01 (0.28–3.63) 0.23 (0.07–0.79) 0.46 (0.18–1.19)

1 (Reference) 0.63 (0.22–1.81) 2.18 (0.56–8.49) 0.32 (0.09–1.08) 0.42 (0.16–1.11)

Abbreviations: CAIDE, Cardiovascular Risk Factors, Aging and Dementia; HR, hazard ratio; CI, confidence interval. *Model 1 is adjusted for age, sex, and education. y Model 2 is adjusted for covariates in model 1 and midlife occupational physical activity level, midlife LTPA level, marital status, smoking, cardiorespiratory and musculoskeletal conditions, and change in BMI from mid- to late life.

wider because of the smaller number of obese people. These associations were independent of socioeconomic position, comorbidities, APOE genotype, and concomitant BMI changes. Nevertheless, declining physical activity may at least partly be an effect of ongoing pathologic processes leading to dementia. Physical activity can promote healthy aging in several ways. Protective mechanisms for cognition may include effects on cardiovascular risk factors such as obesity, blood pressure, cholesterol or diabetes, cerebro/cardiovascular diseases, inflammation, or neuroanatomic changes [23–26]. In addition, physical activity may be a surrogate for overall social activity and active lifestyle, which are related to cognitive benefits and longer life expectancy [27]. Interestingly, a previous study found that the inverse association between physical activity and fasting insulin was strongest among those with highest waist-to-hip ratio [28], suggesting that the benefits of physical activity may be especially high among overweight/obese individuals. Our study cohort is carefully phenotyped, and we accounted for survivor/healthy participant bias by using routinely collected register data. Because registers tend to underreport dementia diagnoses [20], our findings are likely to underestimate the physical activity-dementia associations. Data on LTPA were self-reported, and previous

studies have shown that the accuracy of questionnaire measurements varies by age, sex, and BMI, with men, younger individuals, and those with lower BMI reporting LTPA more accurately [29]. This could partly explain why we observed no associations in women or obese participants. In conclusion, higher midlife LTPA levels seem to be protective against dementia/AD, particularly among overweight individuals. Staying physically active, or becoming more active, after midlife may also contribute to lowering dementia risk, especially in people who are overweight or obese at midlife. Our findings suggest that the window of opportunity for physical activity interventions to prevent dementia may extend from midlife to older ages. Results from currently ongoing trials [30] may give more detailed information about the type, intensity, and duration of physical activity interventions that can be used for preventing late-life cognitive decline. Acknowledgments The authors gratefully acknowledge the participants of CAIDE and FINRISK studies as well as the contribution of study nurses, doctors, and database maintainers for the data acquisition.

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Anna-Maija Tolppanen and Hilkka Soininen acknowledge financial support by strategic funding of University of Eastern Finland; Alina Solomon received funding from the Academy of Finland (grant 251645), Saastamoinen Foundation, Alzheimerfonden, Stiftelsen Dementia, and Loo och Hans Ostermans stiftelse. Jenni Kulmala received funding from the Academy of Finland (grant 250385) and the European Regional Development Fund (EAKR and A31342). Hilkka Soininen and Miia Kivipelto acknowledge FP7 (LipidiDiet-project); Tiia Ngandu received funding from Swedish Society for Medical Research; Minna Rusanen received funding from the National Graduate School of Clinical Investigation and Miia Kivipelto from Academy of Finland (grants 218037 and 129 395) and Juho Vainio Foundation.

RESEARCH IN CONTEXT

1. Systematic review: PubMed query (LTPA OR physical activity OR exercise) AND (Alzheimer* OR dementia) AND (cohort OR prospective OR follow*) returned 630 entries. Screening of the titles and abstract identified 73 relevant articles. Taken together, they suggest that higher levels of leisure-time physical activity are associated with lower risk of dementia, but the associations are inconsistent. This might be explained by timing of assessments, duration of follow-up, or differential loss to follow-up. 2. Interpretation: Our findings from a cohort study and its entire target population suggest that the window of opportunity for physical activity interventions may extend from midlife to older ages. Staying or becoming physically active after midlife may contribute to lowering dementia risk, especially in people who are overweight or obese at midlife. 3. Future directions: Results from ongoing trials may give more detailed information on the type, intensity, and duration of physical activity interventions that can be used for preventing/delaying cognitive decline.

References [1] Bowen ME. A prospective examination of the relationship between physical activity and dementia risk in later life. Am J Health Promot 2012;26:333–40. [2] Ahlskog JE, Geda YE, Graff-Radford NR, Petersen RC. Physical exercise as a preventive or disease-modifying treatment of dementia and brain aging. Mayo Clin Proc 2011;86:876–84. [3] Sofi F, Valecchi D, Bacci D, Abbate R, Gensini GF, Casini A, et al. Physical activity and risk of cognitive decline: a meta-analysis of prospective studies. J Intern Med 2011;269:107–17.

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[4] Scarmeas N, Luchsinger JA, Schupf N, Brickman AM, Cosentino S, Tang MX, et al. Physical activity, diet, and risk of Alzheimer disease. JAMA 2009;302:627–37. [5] Buchman AS, Boyle PA, Yu L, Shah RC, Wilson RS, Bennett DA. Total daily physical activity and the risk of AD and cognitive decline in older adults. Neurology 2012;78:1323–9. [6] Broe GA, Creasey H, Jorm AF, Bennett HP, Casey B, Waite LM, et al. Health habits and risk of cognitive impairment and dementia in old age: a prospective study on the effects of exercise, smoking and alcohol consumption. Aust N Z J Public Health 1998;22:621–3. [7] Wilson RS, Bennett DA, Bienias JL, Aggarwal NT, Mendes De Leon CF, Morris MC, et al. Cognitive activity and incident AD in a population-based sample of older persons. Neurology 2002; 59:1910–4. [8] Verghese J, Cuiling W, Katz MJ, Sanders A, Lipton RB. Leisure activities and risk of vascular cognitive impairment in older adults. J Geriatr Psychiatry Neurol 2009;22:110–8. [9] de Bruijn RF, Schrijvers EM, de Groot KA, Witteman JC, Hofman A, Franco OH, et al. The association between physical activity and dementia in an elderly population: the Rotterdam Study. Eur J Epidemiol 2013;28:277–83. [10] Rovio S, Kareholt I, Viitanen M, Winblad B, Tuomilehto J, Soininen H, et al. Work-related physical activity and the risk of dementia and Alzheimer’s disease. Int J Geriatr Psychiatry 2007;22:874–82. [11] Rovio S, Kareholt I, Helkala EL, Viitanen M, Winblad B, Tuomilehto J, et al. Leisure-time physical activity at midlife and the risk of dementia and Alzheimer’s disease. Lancet Neurol 2005;4:705–11. [12] Anstey KJ, Cherbuin N, Budge M, Young J. Body mass index in midlife and late-life as a risk factor for dementia: a meta-analysis of prospective studies. Obes Rev 2011;12:e426–37. [13] Seidell JC, Visscher TL. Body weight and weight change and their health implications for the elderly. Eur J Clin Nutr 2000;54(Suppl 3):S33–9. [14] Qiu C, Xu W, Fratiglioni L. Vascular and psychosocial factors in Alzheimer’s disease: epidemiological evidence toward intervention. J Alzheimers Dis 2010;20:689–97. [15] Morgan GS, Gallacher J, Bayer A, Fish M, Ebrahim S, Ben-Shlomo Y. Physical activity in middle-age and dementia in later life: findings from a prospective cohort of men in Caerphilly, South Wales and a meta-analysis. J Alzheimers Dis 2012;31:569–80. [16] Vartiainen E, Puska P, Jousilahti P, Korhonen HJ, Tuomilehto J, Nissinen A. Twenty-year trends in coronary risk factors in north Karelia and in other areas of Finland. Int J Epidemiol 1994;23:495–504. [17] Morris JC, Heyman A, Mohs RC, Hughes JP, van Belle G, Fillenbaum G, et al. The consortium to establish a registry for Alzheimer’s disease (CERAD). Part I. Clinical and neuropsychological assessment of Alzheimer’s disease. Neurology 1989;39:1159–65. [18] American Psychiatric Association. Diagnostic and statistical manual of mental disorders. 4th ed. Washington DC: American Psychiatric Association; 1994. [19] McKhann G, Drachman D, Folstein M, Katzman R, Price D, Stadlan EM. Clinical diagnosis of Alzheimer’s disease: report of the NINCDS-ADRDA Work Group under the auspices of Department of Health and Human Services Task Force on Alzheimer’s disease. Neurology 1984;34:939–44. [20] Tsukamoto K, Watanabe T, Matsushima T, Kinoshita M, Kato H, Hashimoto Y, et al. Determination by PCR-RFLP of apo E genotype in a Japanese population. J Lab Clin Med 1993;121:598–602. [21] Solomon A, Ngandu T, Soininen H, Hallikainen MM, Kivipelto M, Laatikainen T. Validity of dementia and Alzheimer disease diagnoses in Finnish national registers. Alzheimers Dement 2013; http:// dx.doi.org/10.1016/j.jalz.2013.03.004. [Epub ahead of print]. [22] Farrer LA, Cupples LA, Haines JL, Hyman B, Kukull WA, Mayeux R, et al. Effects of age, sex, and ethnicity on the association between apolipoprotein E genotype and Alzheimer disease. A meta-analysis. APOE and Alzheimer Disease Meta Analysis Consortium. JAMA 1997;278:1349–56.

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[23] Dishman RK, Berthoud HR, Booth FW, Cotman CW, Edgerton VR, Fleshner MR, et al. Neurobiology of exercise. Obesity (Silver Spring) 2006;14:345–56. [24] Aarsland D, Sardahaee FS, Anderssen S, Ballard C, Alzheimer’s Society Systematic Review group. Is physical activity a potential preventive factor for vascular dementia? A systematic review. Aging Ment Health 2010;14:386–95. [25] Rovio S, Spulber G, Nieminen LJ, Niskanen E, Winblad B, Tuomilehto J, et al. The effect of midlife physical activity on structural brain changes in the elderly. Neurobiol Aging 2010; 31:1927–36. [26] Erickson KI, Voss MW, Prakash RS, Basak C, Szabo A, Chaddock L, et al. Exercise training increases size of hippocampus and improves memory. Proc Natl Acad Sci U S A 2011;108:3017–22.

[27] Seeman TE, Crimmins E. Social environment effects on health and aging: integrating epidemiologic and demographic approaches and perspectives. Ann N Y Acad Sci 2001;954:88–117. [28] Borodulin K, Tuomilehto J, Peltonen M, Lakka TA, Sundvall J, Jousilahti P. Association of leisure time physical activity and abdominal obesity with fasting serum insulin and 2-h postchallenge plasma glucose levels. Diabet Med 2006;23:1025–8. [29] Ferrari P, Friedenreich C, Matthews CE. The role of measurement error in estimating levels of physical activity. Am J Epidemiol 2007; 166:832–40. [30] Richard E, Andrieu S, Solomon A, Mangialasche F, Ahtiluoto S, Moll van Charante EP, et al. Methodological challenges in designing dementia prevention trials—the European Dementia Prevention Initiative (EDPI). J Neurol Sci 2012;322:64–70.

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Supplementary Table 1 Characteristics of CAIDE participants and the entire study population Characteristic

CAIDE participants (n 5 1511)

Age at midlife (n 5 3559) 50.6 6 6.0 Age at late life (censored, n 5 3559) 78.8 6 4.4 Education (n 5 3480), y 8.6 6 3.4 Midlife BMI (n 5 3461) 26.6 6 3.8 Serum total cholesterol level at midlife 6.8 6 1.2 (n 5 3442) Systolic blood pressure at midlife (n 5 3459), 144.3 6 20.0 mm Hg Sex (n 5 3559) Female 942 (62.3) Male 569 (37.7) Moderate-intensity leisure-time physical activity in midlife (n 5 3445) Daily 144 (9.8) 2–3 times/wk 451 (30.7) Once per week 327 (22.3) 2–3/mo 193 (13.1) Couple of times per year 302 (20.6) Cannot exercise due to injury or illness 52 (3.5) Occupational physical activity in midlife (n 5 3515) Low 585 (39.1) Middle 525 (35.1) Mid-high 299 (20.0) High 89 (5.9) Smoking in midlife (n 5 3535) No 859 (56.9) Yes 651 (43.1) Marital status at midlife (n 5 3555) Married/cohabiting 1206 (79.9) Single 115 (7.6) Widow/separated 189 (12.5) Cardiorespiratory conditions in midlife (n 5 3559) No 1439 (95.2) Yes 72 (4.8) Musculoskeletal conditions in midlife (n 5 3559) No 758 (50.2) Yes 753 (49.8) Dementia diagnosis (CAIDE and registers), n 5 3559 No 1261 (83.4) Yes 250 (16.6)

Nonparticipants and nonsurvivors (n 5 2048)

P

51.6 6 5.9 72.8 6 9.7 7.7 6 3.2 27.0 6 4.2 6.9 6 1.3

,.001 ,.001 ,.001 .001 .025

151.0 6 22.9

,.001 ,.001

1069 (52.2) 979 (47.8) ,.001 244 (12.4) 562 (28.4) 373 (18.9) 240 (12.2) 383 (19.4) 174 (8.8) .001 876 (43.4) 624 (30.9) 356 (17.7) 161 (8.0) ,.001 856 (42.3) 1169 (57.7) ,.001 1503 (73.5) 218 (10.7) 324 (15.8) .001 1895 (92.5) 153 (7.5) .12 973 (47.5) 1075 (52.5) .07 1754 (85.6) 294 (14.4)

Abbreviations: CAIDE, Cardiovascular Risk Factors, Aging and Dementia; BMI, body mass index; SD, standard deviation. NOTE. Data are given as mean 6 SD for continuous variables and n (%) for categorical variables.

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Supplementary Table 2 Characteristics of the CAIDE participants (n 5 1432) according to follow-up attendance Characteristic Age at midlife assessment Age at the end of the follow-up BMI in midlife BMI in first follow-up BMI in second follow-up Years of education MMSE score in fist follow-up* MMSE score in second follow-up* CERAD delayed word recall, number of words, second follow-up* LTPA level in midlifey Low Moderate High LTPA level in first follow-upy Low Moderate High LTPA level in second follow-upy Low Moderate High Change in LTPA from mid- to late lifey Decreased Same Increased Musculoskeletal diseases in midlifey Cardiorespiratory conditions in midlifey Incident dementia during the follow-upy Smoker

Attendees of the first follow-up only (n 5 624)

Attendees of the second follow-up only (n 5 92)

Attendees of both followups (n 5 716)

51.6 (6.0) 79.4 (5.0) 26.8 (3.8) 27.7 (4.2) NA 8.0 (3.3) 26 (24–27) NA NA

49.9 (6.0) 78.3 (3.7) 26.3 (3.5) NA 27.4 (5.0) 9.2 (3.5) NA 25 (23–27) 5 (3–7)

49.7 (5.7) 78.3 (3.4) 26.6 (4.9) 27.9 (4.4) 27.5 (4.5) 8.0 (2.5) 27 (25–28) 26 (24–28) 6 (4–7)

168 (26.9) 206 (33.0) 250 (40.1)

24 (26.1) 33 (35.9) 35 (38.0)

151 (21.1) 267 (37.3) 298 (41.6)

102 (16.9) 88 (14.6) 415 (68.6)

NA NA NA

42 (5.9) 91 (12.8) 576 (81.2)

NA NA NA

20 (22.0) 13 (14.3) 58 (63.8)

93 (13.2) 111 (15.8) 500 (71.0)

127 (20.5) 142 (22.9) 351 (56.6) 351 (53.3) 39 (5.9) 176 (26.7) 323 (49.0)

31 (31.6) 17 (17.4) 50 (51.0) 52 (51.0) 3 (2.9) 17 (16.7) 46 (45.1)

138 (18.9) 181 (24.8) 411 (56.3) 350 (46.7) 30 (4.0) 57 (7.6) 282 (37.7)

Abbreviations: CAIDE, Cardiovascular Risk Factors, Aging and Dementia; BMI, body mass index; NA, not applicable; MMSE, Mini-Mental State Examination; CERAD, Consortium to Establish a Registry for Alzheimer’s Disease; LTPA, leisure-time physical activity. NOTE. Data are given as mean (%) unless otherwise indicated. *Data are given as median (interquartile range). y Data are given as n (%).

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Supplementary Table 3 Characteristics of the whole study sample according to their leisure-time physical activity in midlife (n 5 3445)

Characteristic

Daily (n 5 388)

2–3 times/wk (n 5 1013)

Age at midlife (n 5 3445) 53.0 6 6.0 51.4 6 6.1 Age at late life (censored, n 5 3445) 74.4 6 9.4 75.9 6 8.2 Education (n 5 3374), y 7.3 6 2.8 8.4 6 3.5 Midlife BMI (n 5 3356) 27.1 6 4.1 26.5 6 3.7 Serum total cholesterol level at midlife 6.9 6 1.4 6.7 6 1.3 (n 5 3337) Systolic blood pressure at midlife (n 5 3354), 151.0 6 23.3 148.1 6 21.7 mm Hg Sex (n 5 3445) Female 228 (58.8) 508 (50.2) Male 160 (41.2) 505 (49.9) Occupational physical activity in midlife (n 5 3409) Low 208 (54.5) 440 (43.8) Middle 88 (23.0) 347 (34.6) Mid-high 55 (14.4) 162 (16.1) High 31 (8.1) 55 (5.5) Smoking in midlife (n 5 3423) No 193 (50.4) 480 (47.6) Yes 190 (49.6) 528 (52.4) Marital status at midlife (n 5 3441) Married/cohabiting 269 (69.5) 796 (78.7) Single 40 (10.3) 89 (8.8) Widow/separated 78 (20.2) 126 (12.5) Cardiorespiratory conditions in midlife (n 5 3445) No 350 (90.2) 948 (93.6) Yes 38 (9.8) 65 (6.4) Musculoskeletal conditions in midlife (n 5 3445) No 177 (45.6) 509 (50.3) Yes 211 (54.4) 504 (49.8) Change in leisure-time physical activity (CAIDE participants only, n 5 1448) Always low 0 0 Decreased 37 (27.8) 107 (24.2) Always moderate 0 0 Always high 96 (78.2) 336 (75.9) Increased 0 0 APOE ε4 carrier status (CAIDE participants only, n 5 1343) No 89 (67.4) 273 (65.3) Yes 43 (32.6) 145 (34.7)

Couple of Never due to Once per week 2–3 times/mo times per year injury/illness (n 5 700) (n 5 433) (n 5 685) (n 5 226)

P

50.0 6 5.4 75.6 6 7.6 8.6 6 3.4 26.5 6 3.8 6.8 6 1.3

49.6 6 5.5 74.7 6 9.1 8.6 6 3.5 26.9 6 3.7 6.8 6 1.3

50.7 6 5.9 75.8 6 7.9 7.8 6 3.0 26.8 6 4.1 6.8 6 1.2

54.0 6 5.8 72.6 6 9.5 6.8 6 2.8 28.2 6 5.2 6.9 6 1.3

.042 .11 .008 .004 .67

145.7 6 20.3

145.7 6 21.1

147.3 6 20.9

155.1 6 22.9

.78

383 (54.7) 317 (45.3)

223 (51.5) 210 (48.5)

443 (64.7) 242 (35.3)

147 (65.0) 79 (35.0)

241 (34.9) 265 (38.4) 136 (19.7) 49 (7.1)

135 (31.5) 164 (38.3) 97 (22.7) 32 (7.5)

213 (31.3) 236 (34.7) 164 (24.1) 67 (9.9)

163 (72.8) 31 (13.8) 22 (9.8) 8 (3.6)

336 (48.2) 361 (51.8)

183 (42.8) 245 (57.2)

337 (49.5) 344 (50.5)

115 (50.9) 111 (49.1)

560 (80.0) 58 (8.3) 82 (11.7)

343 (79.4) 42 (9.7) 47 (10.9)

520 (75.9) 59 (8.6) 106 (15.5)

146 (64.6) 28 (12.4) 52 (23.0)

673 (96.1) 27 (3.9)

417 (96.3) 16 (3.7)

663 (96.8) 22 (3.2)

183 (81.0) 43 (19.0)

360 (51.4) 340 (48.6)

218 (50.4) 215 (49.7)

331 (48.3) 354 (51.7)

80 (35.4) 146 (64.6)

0 35 (16.3) 50 (61.7) 0 226 (37.2)

0 36 (19.3) 31 (16.6) 0 120 (64.2)

60 (21.0) 0 0 0 226 (79.0)

15 (29.4) 0 0 0 36 (70.6)

185 (62.3) 112 (37.7)

115 (64.6) 63 (35.4)

171 (63.3) 99 (36.7)

35 (72.9) 13 (27.1)

,.001 ,.001

.22

,.001

,.001

.001

,.001

.72

Abbreviations: BMI, body mass index; CAIDE, Cardiovascular Risk Factors, Aging and Dementia; SD, standard deviation. NOTE. Data are given as mean 6 SD for continuous variables and n (%) for categorical variables.

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Supplementary Table 4 Association between midlife leisure-time physical activity (LTPA) and the risk of incident Alzheimer’s disease (AD) in the entire CAIDE target population and CAIDE participants

LTPA Model 1* High Moderate Low Model 2y High Moderate Low Model 2 with APOE genotype (n 5 1278) High Moderate Low

CAIDE target population (n 5 3087)

CAIDE participants (n 5 1394)

n (% with AD)

HR (95% CI)

n (% with AD)

HR (95% CI)

1249 (10.7) 1023 (11.2) 815 (11.4)

1.00 (Reference) 1.21 (0.93–1.56) 1.14 (0.87–1.49)

570 (11.9) 491 (14.2) 333 (16.8)

1.00 (Reference) 1.44 (1.03–2.02) 1.40 (0.98–2.01)

1249 (10.7) 1023 (11.2) 815 (11.4)

1.00 (Reference) 1.20 (0.93–1.55) 1.15 (0.88–1.51)

570 (11.9) 491 (14.2) 333 (16.8)

1.00 (Reference) 1.43 (1.02–2.01) 1.40 (0.97–2.02)

Not applicable

Not applicable

528 (11.6) 449 (14.7) 301 (16.9)

1.00 (Reference) 1.52 (1.06–2.16) 1.44 (0.98–2.12)

Abbreviations: CAIDE, Cardiovascular Risk Factors, Aging and Dementia; HR, hazard ratio; CI, confidence interval. *Model 1 is adjusted for age and sex. y Model 2 is adjusted for covariates in model 1 and education, midlife BMI, marital status, occupational physical activity level, smoking, and cardiorespiratory and musculoskeletal conditions.

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Supplementary Table 5 Groupwise associations between midlife leisure-time physical activity (LTPA) and risk of incident Alzheimer’s disease (AD) per sex and midlife BMI category in the entire CAIDE target population (n 5 3242) and CAIDE participants (n 5 1432) and per APOE ε4 allele status in CAIDE participants (n 5 1313) CAIDE target population

CAIDE participants

HR (95% CI) LTPA in midlife

n (% with AD)

Model 1*

Men High 603 (5.6) 1 (Reference) Moderate 481 (9.4) 1.76 (1.12–2.78) Low 278 (10.4) 2.12 (1.28–3.53) Women High 646 (14.4) 1 (Reference) Moderate 542 (12.9) 1.00 (0.73–1.36) Low 537 (11.9) 0.88 (0.64–1.21) Normal weight in midlife (BMI ,25 kg/m2) High 432 (12.0) 1 (Reference) Moderate 355 (9.9) 0.76 (0.50–1.18) Low 274 (9.1) 0.79 (0.49–1.28) Overweight in midlife (BMI 5 25–29.9 kg/m2) High 615 (8.5) 1 (Reference) Moderate 503 (11.5) 1.80 (1.23–2.65) Low 359 (12.0) 1.51 (1.00–2.29) Obese in midlife (BMI 30 kg/m2) High 202 (11.4) 1 (Reference) Moderate 165 (13.3) 1.06 (0.59–1.90) Low 182 (13.7) 1.06 (0.60–1.86) APOE ε4 carriers High NA Moderate Low APOE ε4 noncarriers High NA Moderate Low

HR (95% CI) y

Model 2

n (% with AD)

Model 1*

Model 2y

Model 2 1 APOE

1 (Reference) 1.73 (1.09–2.74) 2.13 (1.27–3.58)

242 (7.4) 206 (15.1) 87 (21.8)

1 (Reference) 2.56 (1.41–4.65) 3.42 (1.76–6.64)

1 (Reference) 2.64 (1.44–4.85) 3.54 (1.77–7.07)

1 (Reference) 3.13 (1.62–6.04) 3.53 (1.64–7.60)

1 (Reference) 1.00 (0.73–1.37) 0.90 (0.65–1.23)

328 (15.2) 285 (13.7) 246 (15.0)

1 (Reference) 1.05 (0.69–1.60) 0.97 (0.63–1.49)

1 (Reference) 1.03 (0.67–1.57) 0.96 (0.62–1.47)

1 (Reference) 1.09 (0.70–1.69) 1.05 (0.67–1.65)

1 (Reference) 0.75 (0.48–1.16) 0.83 (0.51–1.35)

216 (12.5) 175 (12.0) 112 (11.6)

1 (Reference) 0.93 (0.52–1.64) 0.85 (0.43–1.67)

1 (Reference) 0.88 (0.49–1.57) 0.85 (0.43–1.69)

1 (Reference) 1.00 (0.55–1.82) 0.85 (0.40–1.77)

1 (Reference) 1.81 (1.23–2.67) 1.53 (1.01–2.33)

278 (10.1) 252 (13.5) 159 (18.9)

1 (Reference) 1.91 (1.14–3.20) 2.20 (1.29–3.74)

1 (Reference) 1.97 (1.17–3.32) 2.29 (1.33–3.94)

1 (Reference) 1.84 (1.06–3.20) 2.34 (1.33–4.13)

1 (Reference) 0.92 (0.51–1.69) 1.00 (0.56–1.80)

76 (17.1) 64 (23.4) 62 (21.0)

1 (Reference) 1.69 (0.80–3.57) 1.17 (0.54–2.54)

1 (Reference) 1.45 (0.65–3.26) 0.94 (0.42–2.13)

1 (Reference) 1.76 (0.78–3.99) 0.78 (0.32–1.90)

NA

176 (17.0) 165 (23.0) 106 (20.8)

1 (Reference) 1.61 (0.99–2.60) 1.17 (0.67–2.04)

1 (Reference) 1.58 (0.97–2.57) 1.27 (0.71–2.26)

NA

NA

352 (8.8) 284 (9.9) 195 (14.9)

1 (Reference) 1.43 (0.85–2.41) 1.79 (1.06–3.00)

1 (Reference) 1.46 (0.87–2.46) 1.84 (1.08–3.14)

NA

Abbreviations: BMI, body mass index; HR, hazard ratio; CI, confidence interval; NA, not applicable. *Model 1 is adjusted for age, sex, and education. y Model 2 is adjusted for covariates in model 1and midlife BMI, marital status, occupational physical activity level, smoking, and cardiorespiratory and musculoskeletal conditions.

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A.-M. Tolppanen et al. / Alzheimer’s & Dementia - (2014) 1-10

Supplementary Table 6 Associations between changes in leisure-time physical activity (LTPA) from mid- to late life and the risk of incident Alzheimer’s disease (AD) in CAIDE participants

LTPA in mid- and late life All CAIDE participants (n 5 1411) Always low Decrease from midlife Always moderate Always high Increase from midlife Normal weight in midlife (n 5 509) Always low Decrease from midlife Always moderate Always high Increase from midlife Overweight in midlife (n 5 693) Always low Decrease from midlife Always moderate Always high Increase from midlife Obese in midlife (n 5 209) Always low Decrease from midlife Always moderate Always high Increase from midlife

Model 1*

Model 2y

Model 2 1 APOE

n (% with AD)

HR (95% CI)

HR (95% CI)

HR (95% CI)

71 (31.0) 208 (20.2) 80 (15.0) 425 (8.7) 592 (13.0)

1 (Reference) 0.73 (0.43–1.23) 0.87 (0.43–1.78) 0.31 (0.18–0.53) 0.53 (0.33–0.86)

1 (Reference) 0.66 (0.32–1.39) 0.44 (0.14–1.45) 0.22 (0.09–0.54) 0.33 (0.16–0.67)

1 (Reference) 0.34 (0.15–0.78) 0.37 (0.11–1.28) 0.16 (0.06–0.41) 0.18 (0.08–0.40)

22 (13.6) 65 (21.5) 31 (12.9) 172 (8.7) 211 (12.3)

1 (Reference) 1.69 (0.48–5.97) 1.63 (0.36–7.43) 0.86 (0.25–3.02) 1.16 (0.35–3.86)

1 (Reference) 1.60 (0.44–5.85) 1.64 (0.35–7.65) 0.79 (0.22–2.86) 1.01 (0.30–3.46)

1 (Reference) 1.00 (0.26–3.84) 1.23 (0.26–5.74) 0.63 (0.17–2.27) 0.73 (0.21–2.52)

31 (35.5) 101 (16.8) 37 (10.8) 210 (9.5) 299 (12.4)

1 (Reference) 0.54 (0.25–1.15) 0.54 (0.17–1.75) 0.22 (0.10–0.48) 0.41 (0.21–0.80)

1 (Reference) 0.52 (0.24–1.13) 0.54 (0.16–1.75) 0.22 (0.10–0.47) 0.40 (0.20–0.80)

1 (Reference) 0.43 (0.18–1.00) 0.44 (0.13–1.47) 0.21 (0.09–0.46) 0.36 (0.17–0.74)

18 (44.4) 43 (27.9) 12 (33.3) 43 (4.7) 82 (17.1)

1 (Reference) 0.68 (0.27–1.71) 1.25 (0.37–4.27) 0.12 (0.03–0.58) 0.49 (0.20–1.17)

1 (Reference) 0.70 (0.23–2.11) 1.16 (0.31–4.33) 0.10 (0.02–0.51) 0.39 (0.14–1.08)

1 (Reference) 0.85 (0.27–2.64) 3.00 (0.70–12.91) 0.16 (0.03–0.87) 0.40 (0.14–1.17)

Abbreviations: HR, hazard ratio; CI, confidence interval. *Model 1 is adjusted for age, sex, and education. y Model 2 is adjusted for covariates in model 1 and midlife occupational physical activity level, midlife LTPA level, marital status, smoking, cardiorespiratory and musculoskeletal conditions, and change in BMI from mid- to late-life.