INTRODUCTION
Dementia is one of the most disabling and burdensome health conditions worldwide (Bermejo-Pareja, Benito-León, Vega, Medrano, & Román, Reference Bermejo-Pareja, Benito-León, Vega, Medrano and Román2008; Ferri et al., Reference Ferri, Prince, Brayne, Brodaty, Fratiglioni, Ganguli and Sacazufca2005). Unfortunately, no cure has yet been discovered, and many scientific studies focus on seeking strategies to delay the onset and progression of this devastating syndrome (Larson et al., Reference Larson, Wang, Bowen, McCormick, Teri, Crane and Kukull2014). In this context, physical activity (PA) has been consistently associated with a reduced risk of cognitive decline and dementia (Beeri & Middleton, Reference Beeri and Middleton2012), but the mechanisms implicated in this effect are unclear (Lautenschlager, Cox, & Kurz, Reference Lautenschlager, Cox and Kurz2010; Tortosa-Martínez & Clow, Reference Tortosa-Martínez and Clow2012).
Several prospective surveys have shown a lower incidence of dementia and Alzheimer’s disease (AD) in people who carry out PA (Buchman et al., Reference Buchman, Boyle, Yu, Shah, Wilson and Bennett2012; Larson et al., Reference Larson, Wang, Bowen, McCormick, Teri, Crane and Kukull2014; see Hamer & Chida, Reference Hamer and Chida2009, and Sofi et al., Reference Sofi, Valecchi, Bacci, Abbate, Gensini, Casini and Macchi2010, for a review and meta-analysis). However, some prospective randomized trials have shown contradictory results (Denkinger, Nikolaus, Denkinger, & Lukas, Reference Denkinger, Nikolaus, Denkinger and Lukas2012; Snowden et al., Reference Snowden, Steinman, Mochan, Grodstein, Prohaska, Thurman and Anderson2011; Wang, Xu, & Pei, Reference Wang, Xu and Pei2012). Moreover, the type and intensity of PA as a protective factor for dementia needs further investigation (Rolland, Abellan Van Kan, & Vellas, Reference Rolland, Abellan Van Kan and Vellas2008), and the presence of possible dose-effects is controversial (Scarmeas et al., Reference Scarmeas, Luchsinger, Schupf, Brickman, Cosentino, Tang and Stern2009; Wilson et al., Reference Wilson, Bennett, Bienias, Aggarwal, Mendes De Leon, Morris and Evans2002).
The aim of this study is to analyze whether PA is a protective factor against dementia after 3 years in a population-based sample of Spanish older people. In these terms, individuals were classified according to the intensity of PA (slight, moderate, or high), and dose effect was tested in a supplementary analysis.
METHODS
Participants
Data were collected from the Neurological Disorders in Central Spain (NEDICES), a population-based survey of older people’s (age 65 years and older) main age-related conditions, including Parkinson’s disease, essential tremor, stroke, and dementia. A signed informed consent was obtained from all participants at the time of enrolment. Ethical standards committees on human research at the University Hospitals “12 de Octubre” (Madrid) and “La Princesa” (Madrid) approved the protocol of the study as complying with the Declaration of Helsinki (World Medical Association, 1989).
A detailed account of the background, study population, and methods of the survey were previously reported (Bermejo et al., Reference Bermejo, Gabriel, Vega, Morales, Rocca and Anderson2001; Morales et al., Reference Morales, Bermejo, Benito-León, Rivera-Navarro, Trincado, Gabriel and Vega2004). Briefly, the NEDICES study was carried out in three well-defined geographic areas of central Spain to obtain a representative cohort of older people with different socioeconomic backgrounds. Thus, participants were collected from population censuses of three communities: Las Margaritas, a working-class neighborhood in Getafe (Greater Madrid); Lista, a professional-class neighborhood in the Salamanca district (Central Madrid); and 38 villages from the agricultural region of the Arévalo county (125 km northwest of Madrid). In Margaritas and Arévalo, every eligible subject was to be screened. However, because of the large number of older residents in Lista, proportionate stratified random sampling procedure was used to select subjects for screening.
Currently, two complete cross-sectional surveys have been performed: baseline wave (1994–5) and incidence wave (1997–8). At the time of their baseline assessment (1994–1995), 5278 census-based older people (57.6% women with a mean age of 74.31±6.97; 53,1% without a primary studies certificate) were interviewed face-to-face using a 500-item screening questionnaire that assessed demographic data, medical conditions, current medication, and lifestyle (e.g., consumption of alcohol, smoking habits, physical activity, self-reported health). Self-rated health was assessed with one question (“In general terms, how would you describe your health: very good, good, fair, poor, or very poor?” rated with 1 (very good) to 5 (very poor) points). Meanwhile, the comorbidity index was calculated based on the Romano’s adaptation (Romano, Roos, & Jollis, Reference Romano, Roos and Jollis1993). A short form of the questionnaire was mailed to participants who were unavailable for face-to-face or telephone screening.
Measures and Testing Procedure
a) Assessment of cognitive function and diagnosis of dementia
The NEDICES study was carried out in two phases: door-to-door screening (Phase 1) of eligible people and a neurologist’s examination of the individuals who screened positive (Phase 2).
The screening instruments for dementia included the Spanish adaptation of a 37-item version of the Mini-Mental State Examination (Prieto, Contador, Tapias-Merino, Mitchell, & Bermejo-Pareja, Reference Prieto, Contador, Tapias-Merino, Mitchell and Bermejo-Pareja2012; Tapias-Merino et al., Reference Tapias-Merino, Puertas-Martín, Vera-García, Lora-Pablos, Revuelta-Alonso and Bermejo-Pareja2010) and an adapted Spanish version of Pfeffer’s Functional Activities Questionnaire (FAQ; Olazarán, Mouronte, & Bermejo, 2005). This screening protocol for dementia was designed and validated in a World Health Organization (WHO) Aging Study demonstrating sensitivity greater than 90% (Baldereschi, Meneghini et al., Reference Baldereschi, Amato, Nencini, Pracucci, Lippi and Amaducci1994). Participants were considered to have screened positive for dementia if: (1) they scored <24 points on the 37-item version of the MMSE and >5 points on the Spanish version of Pfeffer’s FAQ; or (2) there were missing values (i.e., subject failed to provide an answer for any reason, or information was not available) on these screening instruments; or (3) the participants themselves or through their proxies reported of a history of cognitive decline (e.g., spontaneously during the interview or when checking the available information).
Every person who screened positive for dementia underwent a neurological examination at National Health Service clinics or at home. Institutionalized persons who were recruited in the study were also screened with the same procedure. The diagnosis of dementia was made by consensus of two neurologists using the Diagnostic and Statistical Manual of Mental Disorders-IV (DSM-IV) criteria. In this survey, the etiologic diagnosis of dementia were AD according to NINCDS-ADRDA criteria (including both possible and probable categories), vascular dementia (VaD), using DSM-IV criteria; dementia associated with Parkinson’s disease (PD), dementia with Lewy bodies or longstanding Parkinsonism (more than 6 months); and secondary dementia (known or probable specific dementia cause). Finally, the diagnosis of doubtful dementia (DD) was established in accordance with the categorization of the WHO program for research on aging (Baldereschi, Amato et al., Reference Baldereschi, Amato, Nencini, Pracucci, Lippi and Amaducci1994), which is comparable to the Clinical Dementia Rating (CDR) of 0.5 (Morris, Reference Morris1993). This category was assigned to persons with evidence of cognitive impairment in memory or other cognitive domains, but whose functional or social impairment were too slight to meet the criteria for dementia.
The methods for the diagnosis of dementia were similar in both waves. In addition, regardless of their screening results, reachable participants at follow-up underwent a short neuropsychological battery composed of different tasks: Trail Making Test-A (Army Individual Test Battery, 1944), naming and pictures recall (Peña-Casanova, Guardia, Bertran-Serra, Manero, & Jarne, Reference Peña-Casanova, Guardia, Bertran-Serra, Manero and Jarne1997), logical memory (Cornoni-Huntley, Brock, Ostfeld, Taylor, & Wallace, Reference Cornoni-Huntley, Brock, Ostfeld, Taylor and Wallace1986; Bermejo et al., Reference Bermejo, Alom, Pena-Casanova, del Ser, Acarin, Manubens and Gabriel1994), and semantic fluency (Isaacs & Kennie, Reference Isaacs and Kennie1973). The neuropsychological assessment at follow-up was independent of the clinical diagnosis (Serna et al., 2015).
b) Assessment of daily physical activity
The PA of individuals was collected at baseline (1994–1995) using an adapted modified version (four items) of the Rosow-Breslau physical function measure (Rosow & Breslau, Reference Rosow and Breslau1966). The measure assesses usual tasks faced by community-dwelling older adults (e.g., walk a half mile, walk up to the second floor and down, perform heavy housework) and its test–retest reliability (r=0.81) has been assessed in the Established Populations for Epidemiologic Studies of the Elderly (Smith et al., Reference Smith, Branch, Scherr, Wetle, Evans, Hebert and Taylor1990). Therefore, the measure seems sufficiently stable for longitudinal analyses, and concurrent validity was previously established (Reuben & Siu, Reference Reuben and Siu1990). The inability to perform the activities of the Rosow-Breslau questionnaire falls within the concept of disability of the International Classification of Impairments, Disabilities and Handicaps (WHO, 1980). This measure has also been related to functional disability and mortality in older populations (Brock, Lemke, Branch, Evans, & Berkman, Reference Brock, Lemke, Branch, Evans and Berkman1994; Thomas & Lichtenstein, Reference Thomas and Lichtenstein1986).
In this survey, trained interviewers asked the participants “How many hours do you dedicate daily to.....” (a) sedentary lifestyle (i.e., only minimal house chores or short walks at home); (b) slight physical activity (i.e., regular house chores, walks independently at home); (c) moderate physical activity (i.e., regular house chores, walks up to one kilometer per day); (d) high activity (i.e., performs heavy housework, walks more than one kilometer or practices any sport regularly). Therefore, PA was classified into four groups (sedentary, light, moderate, and high PA). These groups were formed with the aim of grading PA under a dose-effect hypothesis (Laurin, Verreault, Lindsay, MacPherson, & Rockwood, Reference Laurin, Verreault, Lindsay, MacPherson and Rockwood2001; Liu, LaCroix, White, Kittner, & Wolf, Reference Liu, LaCroix, White, Kittner and Wolf1990).
Statistical Analysis
Statistical analyses were performed with the SAS software (9.3 version, SAS Institute Inc, 2011). Baseline characteristics of the groups were compared using analysis of variance (ANOVA) tests for numerical variables and χ2 tests for categorical variables. Moreover, we calculated the effect sizes with Cohen's d index for continuous variables and Phi coefficient for categorical ones. Cox regression models were used to test the association between PA and the risk of dementia 3 years later, controlling for different covariates. A value of p<.10 was conservatively chosen to select different sources of confusion from the univariate analyses. Person-years for subjects who did not develop dementia were calculated as the time between the screening test for the baseline survey and the screening test for the follow-up survey or death. On the other hand, person-years for those subjects who developed dementia were calculated as the time between the screening test of the first wave and the reported dementia onset. When onset was unknown, person-years were calculated as the midpoint between the first wave screening test and the second wave screening test or death (Bermejo-Pareja et al., Reference Bermejo-Pareja, Benito-León, Vega, Medrano and Román2008). To test the dose-effect hypothesis, the number of hours was weighted, multiplying the sedentary category by 1; the slight PA by 1.2; the moderate PA by1.4; and the high PA by 1.8. Next, different cutoff points were calculated based on the quartile distribution to classify the subjects as follows: ≤15.6 hr (sedentary group), ≤17.6 hr (light PA group), ≤19.4 hr (moderate PA group), and >19.4 hr (high PA group). The presence of a dose-effect was tested using the incremental coding procedure (Rothman, Greenland, Greenland, & Lash, Reference Rothman, Greenland, Greenland and Lash2008).
RESULTS
Of the 5278 participants screened for neurological disorders at baseline (1994–1995), 306 prevalent dementia cases (5.8%) were excluded from further analyses. Therefore, 4972 participants were classified as non-demented at baseline. Of 3891 participants with available information at follow-up (1997 to 1998), 3891 participants were followed from baseline (1994–1995) for an interval of 3.2 years (range=0.03–6.6). In this cohort, 3105 individuals (134 incident dementia cases [70.9% with AD subtype] vs. 2971 without dementia) had available information about PA. No significant differences were found between the final sample and participants (N=786) without PA assessment in terms of age (p=.40) or sex (p=.18), but the educational level (years) was lower in individuals without PA information (3.88±4.21 vs. 7.02±5.27, p<.001). The flow chart of this survey is shown in Figure 1.
Fig. 1 Flow chart of the survey.
Table 1 compares the baseline characteristics of the groups with and without dementia at baseline. The findings show that higher age, lower educational level, hypertension, and history of stroke were associated with the incidence of dementia, whereas alcohol consumption was less frequent in those who progressed to dementia. Statistical trends were found between the development of dementia and health indicators (Charlson index and self-reported heath).
Table 1 Characteristics of participants at baseline: statistical comparisons
Note: Data are given as Mean±SD and frequency (%).
Effect sizes were calculated using Cohen's d index (continuous variables) and Phi coefficient (categorical variables).
According to the level of PA, 790 individuals were classified as “sedentary lifestyle,” 865 as “light PA,” 681 as “moderate PA,” and 769 as “high PA” (see Table 2). As shown, the sedentary group was significantly older and had more men than the PA groups. Moreover, the sedentary group also showed a lower educational level, more of them were smokers, and more had a history of prior stroke than the other PA groups. Light and moderate PA were associated with better health in terms of morbidity and subjective health.
Table 2 Characteristics of participants stratified by the intensity of physical activity
Note: Data are given as mean±standard deviation or frequencies (%).
The Cox regression model showed that the light, moderate, and high PA groups have a lower risk for dementia at 3 years compared with the sedentary lifestyle group (see Table 3). Even when the Cox model was adjusted by controlling for significant covariates of the univariate analyses (age, sex, education, current alcohol consumption, previous stroke, hypertension, and comorbidity index), PA at any level versus sedentary lifestyle remained as a protective factor against dementia. Likewise, when self-rated health was introduced in the model in instead of the Charlson index, the hazard ratios (HRs) for PA remained significant as follows: light PA (HR=0.54; 95% confidence interval {CI} [0.35, 0.83]; p<.01), moderate PA (HR=0.47; 95% CI [0.28, 0.78]; p<.0.01), and high PA (0.30, 95% CI [0.17, 0.54]; p<.001). Finally, after the exclusion of subjects with doubtful dementia at baseline (n=61), all PA groups remained as a significant predictor of lower dementia risk.
Table 3 Cox regression models: risk of dementia and physical activity level.
PA=Physical activity; HRs=Hazard ratios
* age, sex, education, alcohol consumption, stroke, hypertension and Charlson Index.
DISCUSSION
This research shows that PA (vs. sedentary lifestyle) is associated with a lower risk of dementia after controlling for the effect of several covariates. These findings confirm previous epidemiological evidence about PA as a protective factor for dementia (Hamer & Chida, Reference Hamer and Chida2009; Smith et al., Reference Smith, Blumenthal, Hoffman, Cooper, Strauman, Welsh-Bohmer and Sherwood2011; Sofi et al., Reference Sofi, Valecchi, Bacci, Abbate, Gensini, Casini and Macchi2010). Our study did not yield a significant dose-effect according to PA intensity, but there was a tendency indicating that higher levels of PA are associated with lower risk of dementia. Similarly, some prospective cohort studies have shown a gradual reduction of risk for persons with higher levels of PA (Laurin et al., Reference Laurin, Verreault, Lindsay, MacPherson and Rockwood2001; Scarmeas et al., Reference Scarmeas, Luchsinger, Schupf, Brickman, Cosentino, Tang and Stern2009). It should be noted that other studies did not find this association (Wilson et al., Reference Wilson, Bennett, Bienias, Aggarwal, Mendes De Leon, Morris and Evans2002; Yamada et al., Reference Yamada, Kasagi, Sasaki, Masunari, Mimori and Suzuki2003), but methodological differences in terms of PA measures, duration of follow-ups, and covariates could explain the divergent results.
Considering that late life PA sustains cerebral perfusion and cognition (Rogers, Meyer, & Mortel, Reference Rogers, Meyer and Mortel1990; Smith et al., Reference Smith, Blumenthal, Hoffman, Cooper, Strauman, Welsh-Bohmer and Sherwood2011), knowledge of PA as a protective, modifiable factor of dementia in late life periods is of special interest for preventive strategies. It is well known that age is possibly the major risk factor for dementia (Bermejo-Pareja et al., Reference Bermejo-Pareja, Benito-León, Vega, Medrano and Román2008), with prevalence doubling every 5.5–6.3 years (Prince et al., Reference Prince, Bryce, Albanese, Wimo, Ribeiro and Ferri2013). However, it is important to determine whether PA is a late life protective factor after controlling for the effects of confirmed risk factors such as age and CR proxies, such as education (Contador, Bermejo-Pareja, Del Ser, & Benito-León, Reference Contador, Bermejo-Pareja, Del Ser and Benito-León2015). In fact, people with high educational or socioeconomic status may be more aware of the importance of PA, whereas the pattern of PA is not the same in older adults compared to middle-aged people. For instance, Matthews et al. (Reference Matthews, Chen, Freedson, Buchowski, Beech, Pate and Troiano2008) described that the most sedentary groups in the United States were older adolescents and adults over 60. In addition, Mace et al. (2015) showed that 65% of adults aged 65 or older did not meet the guidelines for regular PA (at least 150 min of PA per week). At this point, our study indicates that, even after controlling for the effect of important covariates such as age or education, regular PA is associated with a lower risk of dementia at a 3-year follow-up.
There are several hypotheses about the physiological mechanism underlying the effect of PA as a preventive factor of cognitive decline and dementia. Evidence from animal and human research suggests that PA moderates the stress cascade, promotes angiogenesis and neurogenesis, reduces amyloid load, inflammatory markers, insulin resistance, and oxidative stress, while it may increase brain-derived neurotrophic factor (BDNF) and serotonin function (Tortosa-Martínez & Clow, Reference Tortosa-Martínez and Clow2012). Moreover, Radack et al. (Reference Radak, Hart, Sarga, Koltai, Atalay, Ohno and Boldogh2010) showed that PA enhances the endurance of cells and tissues to oxidative stress, vascularization, energy metabolism, and neurotrophin synthesis. Finally, PA influences cardiovascular risk factors linked to cognitive decline such as hypertension, diabetes, and cholesterol (Hayes, Alosco, & Forman, Reference Hayes, Alosco and Forman2014; Murtagh et al., Reference Murtagh, Nichols, Mohammed, Holder, Nevill and Murphy2015).
Focusing on neuroimaging studies, a randomized controlled trial with 120 older adults showed that aerobic exercise training increased the size of the anterior hippocampus, leading to improvements in spatial memory (Erickson et al., Reference Erickson, Voss, Prakash, Basak, Szabo, Chaddock and Kramer2011). Likewise, Smith et al. (Reference Smith, Nierlson, Woodard, Seidenberg, Durgerian, Hazlett and Rao2014), demonstrated a protective effect of PA on hippocampal volume, but this effect was specific for persons at genetic risk for AD over a relatively brief period (18-month follow-up). Moreover, Yuki et al. (Reference Yuki, Lee, Kim, Kozakai, Ando and Shimokata2012) showed that a high level of PA and total energy expenditure suppressed the frontal lobe atrophy progression associated with aging. Finally, Lamont, Mortby, Anstey, Sachdev, and Cherbuin (Reference Lamont, Mortby, Anstey, Sachdev and Cherbuin2014) suggest that sulcal width provides additional information and may be a more sensitive marker than cortical volume.
This study has several limitations. First, information about PA was collected by a self-report questionnaire more weighted toward functionality at home and walking abilities, whereas other studies have used a daytime actigraphy to measure PA objectively (Buchman et al., Reference Buchman, Boyle, Yu, Shah, Wilson and Bennett2012). Second, non-exercise PA in daily life was not measured, which may play an important role on the benefits of total activity. Third, individuals who developed dementia may have experienced a higher decline in PA, but our findings did not change after adjusting for subjects under suspicious of dementia (CDR 0.5). Fourth, although an important group of covariates were controlled, others such as apolipoprotein E genotype were not available for the study. Fifth, the follow-up was relatively short compared to other studies, but it was long enough to find a significant effect of PA on dementia incidence. Finally, the NEDICES study showed an attrition rate of 28.1% at follow-up, which is similar to other longitudinal studies on aging (Chatfield, Brayne, & Matthews, Reference Chatfield, Brayne and Matthews2005; Vega et al., Reference Vega, Benito-León, Bermejo-Pareja, Medrano, Vega-Valderrama, Rodríguez and Louis2010). In this study, the presence of a possible bias should not be ignored, due to the fact that 20% of the subjects who were reachable at follow-up did not have any PA information. The group without PA information showed a lower educational level, which limits generalization. However, we highlight that the final sample is mainly composed by people with a low educational level but the results remained stable after controlling for its effect.
In this research, several strengths should be highlighted. All participants were selected from a prospective population-based study. In this regard, a broad spectrum of older Spanish individuals was analyzed. Moreover, dementia incidence was diagnosed by expert neurologists based on a uniform clinical evaluation, which reduces the likelihood of misclassification.
To sum up, regular PA in older people (aged 65 and older) seems to be a protective factor against dementia and AD in later life. These findings have relevant implications for preventive health care. Therefore, active lifestyle in aged people may increase late life physical and cognitive health. Future studies should focus on how various types, intensities, and frequencies of PA could influence the risk of dementia and prevent late life cognitive decline.
ACKNOWLEDGMENTS
Sara Llamas is supported by the Instituto de Salud Carlos III (ISCIII; Spanish Biomedical Research Institute) through a “Río Hortega” contract. The Spanish Health Research Agency and the Spanish Office of Science and Technology have supported NEDICES and details about funding are listed on www.ciberned.es/estudio-nedices. The authors thank all collaborators for their involvement in the NEDICES study. The authors report no conflict of interest.
