Potential Avenues for Exercise to Activate Episodic Memoryã¢â‚¬ârelated Pathways a Narrative Review

Context

• Some studies advise that people with high levels of physical action are less likely to develop dementia.

Content

• All 1740 participants in this accomplice report were 65 years of historic period or older and were cognitively intact at baseline. Over 6.two years, the rate of dementia was 13.0 per 1000 person-years in those who exercised iii or more times per week and nineteen.seven per grand person-years in those who exercised less than 3 times per calendar week.

Limitations

• The only measure of exercise intensity was self-reported frequency. The cohort was largely white and well-educated.

Implications

• This study adds to the evidence that regular exercise is associated with a lower run a risk for dementia. All the same, the existing testify does non prove that regular practice is associated with a lower dementia risk.

—The Editors

Alzheimer disease and other dementing illnesses are major sources of morbidity and mortality (1-3) that affect millions of persons in the increasingly crumbling society of the United states. Research designed to find strategies to delay onset and progression of these potentially devastating illnesses is ongoing worldwide. Effective prevention strategies would outcome in substantial benefits through improved quality of life, prolonged independent life expectancy, and reduced economic toll and social burdens. Regular physical exercise is an important element in overall health promotion (four) and might likewise be an effective strategy to delay onset of dementia (5). A biological footing for how concrete exercise might preserve encephalon function includes improved cerebral claret menses and oxygen delivery (6) and inducing fibroblast growth gene in the hippocampus (7). More contempo evidence suggests that reduced loss of hippocampal encephalon tissue in the aging brain is related to level of physical fettle (viii). Bear witness from some longitudinal studies and randomized trials suggests that concrete exercise enhances cognitive part in older adults (9-15), whereas other studies have failed to observe the benefits of physical do in preserving cognitive function (16-19).

Many people regard Alzheimer disease as one of the most dreaded consequences of aging. If regular physical exercise were shown to be effective in reducing the risk or delaying the onset of dementing illnesses, it would be another compelling reason to promote physical exercise. Few population-based longitudinal studies take examined the role of physical practice on the hazard for dementia in elderly persons. Ane contempo longitudinal study showed that concrete practise was associated with decreased adventure for decline in cognitive role (odds ratio [OR], 0.58), Alzheimer illness (OR, 0.50), and any dementia (OR, 0.63) (eleven), whereas another longitudinal study showed no clan between physical practise and dementia (xvi). More recent studies showed that walking was associated with a reduced risk for dementia and Alzheimer disease in a cohort of Japanese-American men (xx) and that engaging in more diverse physical activities was associated with a reduced run a risk for dementia in the Cardiovascular Health Written report (21).

The purpose of this study was 2-fold: 1) to determine whether regular do is associated with a reduced adventure for incidence of dementia (in detail, Alzheimer affliction) in a cohort followed biennially over 6 years and 2) to examine whether the association of physical exercise with incident dementia is modulated past other potential take a chance factors, such as depression, cardiovascular and cerebrovascular disease, diabetes, apolipoprotein Eastward ε4 allele, cerebral function, concrete function, cocky-rated health, and lifestyle characteristics.

Methods

Study Sample

The Adult Changes in Idea (Human activity) study is a population-based, longitudinal study of aging and dementia. The Act written report was designed to determine the incidence of Alzheimer disease, other types of dementia, and cognitive damage equally well equally to make up one's mind gamble factors for these conditions. The details of the Act study take been described elsewhere (22, 23). Briefly, a random sample of 6782 individuals was drawn from Seattle-area members of Group Health Cooperative (GHC), a consumer-governed health maintenance organisation. The participants were 65 years of historic period and older when the study began in 1994 to 1996. Those who had an existing diagnosis of dementia, were electric current residents of a nursing home, or were participating in other studies were ineligible (north = 1360). Of 5422 eligible persons, 2581 participated and 2841 declined participation. Age, sex, and ethnicity of the remaining 2581 participants did not differ significantly from those who were excluded. Nonresponse has been described elsewhere (22). Declining to participate was more common among the oldest age group (>85 years), women, and African-American and minority groups (22). Additional details regarding the incident rates of dementia and Alzheimer disease from the ACT study have been published elsewhere and are consistent with rates reported in U.South. and European cohort studies (22). The institutional review boards of the University of Washington and Grouping Health Cooperative canonical the Human action report.

Participants received the Cognitive Ability Screening Instrument (CASI) (24) as initial screening for cognitive role and were interviewed with structured questionnaires to obtain data, including demographic characteristics, medical history, retentivity and general operation, and potential epidemiologic risk factors. Persons scoring 86 or college on the CASI were entered directly into the Act cohort as being cognitively intact. (The CASI scores range from 0 to 100; a score of 86 corresponds to a Mini-Mental Country Examination score of 25 to 26.) Persons with a score lower than 86 had additional medical record review and standardized clinical and neuropsychological evaluation for dementia. Persons who did not meet established criteria for dementia (25) were included in the Deed cohort.

The current study sample was selected from the 2581 Deed participants to examine the temporal relationship of physical exercise preceding development of dementia. Past blueprint, we selected the 1895 persons whose CASI scores were above the 25th percentile—CASI scores 91 to 100. Nosotros excluded 686 persons whose CASI scores were in the lowest quartile—CASI scores 62 to 90—because the lowest quartile group might include persons who had mild cognitive impairment or impending dementia (26). We did not collect information about the history of exercise earlier the participants entered the report. Therefore, in the grouping with depression CASI scores, we could non be sure whether a reported depression level of physical exercise preceded the development of dementia or was a result of the development of cognitive impairment or dementia. Of 1895 participants selected, 155 withdrew after the baseline visit and did non have a follow-up examination and were thus excluded from the analyses, leaving the analytic sample of 1740 persons.

Incident Dementia

We conducted biennial examinations to identify cases of incident dementia, when participants were rescreened with the CASI. Those who scored 86 or college on the CASI remained in the ACT cohort. Scores on the CASI that were less than 86 at follow-upward prompted a full standardized clinical examination. The results of rescreening by the CASI and by the clinical and neuropsychological examinations were reviewed at a consensus diagnosis conference that included at least the examining doctor, a neuropsychologist, another study physician, and the study nurse. Persons who did not meet the criteria for dementia were considered equally non having dementia and were followed in the Human activity cohort (22, 23). Persons who met the Diagnostic and Statistical Manual of Mental Disorders, fourth edition (DSM-Iv), criteria (25) for dementia were considered to take incident dementia. Dementia blazon was adamant past the National Institute of Neurological and Communicative Diseases and Stroke-Alzheimer's Disease and Related Disorders Association (NINCDS-ADRDA) criteria (27) for Alzheimer illness and by the DSM-IV criteria (25) for other types of dementia. Level of physical activity was not considered at the consensus conference.

Concrete Do

Physical exercise was assessed at baseline by asking participants the number of days per week they did each of the following activities for at least 15 minutes at a time during the past year: walking, hiking, bicycling, aerobics or calisthenics, pond, h2o aerobics, weight training or stretching, or other exercise. The frequency of exercise was calculated by the times per calendar week that participants engaged in whatsoever of these forms of practise. In this study, persons who exercised at least iii times a week, to a higher place the lowest quartile, were classified as exercising regularly.

Baseline Variables as Potential Confounders

Numerous factors may influence the relationship between do and hazard for dementia, including concrete functioning, cerebral role, low, health conditions, and lifestyle characteristics. Physical role was assessed by a performance-based physical role (PPF) examination (23), which consisted of 4 functioning tests: 10-foot timed walk, time to stand from a seated position in a chair to a standing position 5 times, residue exam, and grip strength in the ascendant hand. Each test was scored from 0 to 4 points. The final PPF score was the sum of the scores for the 4 operation tests and ranged from 0 to 16; higher scores indicated better physical function. Details of the PPF exam have been reported elsewhere (23).

Cerebral function was assessed by using the CASI, which provides quantitative assessment of attending, concentration, orientation, curt-term memory, long-term memory, language power, visual construction, list-generating fluency, abstraction, and judgment (24). At baseline, depression was measured by using the xi-item Center for Epidemiologic Studies Depression (CES-D) scale (28). The CES-D scores ranged from 0 to 33, with higher scores representing more depressive symptoms.

Health atmospheric condition were assessed by self-rated health and self-reported medical conditions. Participants were asked to rate their health every bit excellent, very good, good, off-white or poor. They were likewise asked whether a doctor had ever told them that they had diabetes mellitus or high blood sugar, hypertension, congestive heart failure, heart attack, angina pectoris, stroke, cognitive hemorrhage, or pocket-size strokes or transient ischemic attacks or whether they had ever had coronary bypass surgery. Coronary heart disease included congestive heart failure, heart attack, angina pectoris, and coronary artery bypass surgery. Cerebrovascular disease included stroke, cerebral hemorrhage, and small strokes or transient ischemic attacks.

The lifestyle characteristics assessed included smoking, consuming alcohol, and taking dietary supplements. Participants were asked at baseline whether they had smoked 100 cigarettes in their lifetime and whether they smoked currently; they were then classified as nonsmokers, former smokers, or current smokers. To assess booze consumption, participants were asked at baseline whether they had more than 5 drinks in the past year and whether they had problems considering of drinking. Nondrinkers were those who had fewer than 5 drinks a year; drinkers were those who had five drinks or more a twelvemonth merely did not have any bug related to alcohol consumption; and trouble drinkers were those who reported problems related to alcohol consumption. Participants were also asked whether they had taken vitamins or dietary supplements, including vitamin A, vitamin C, vitamin Due east, multivitamins, and fish oil supplements, for at least 1 week in the previous month. Demographic variables of age, sex, ethnicity, and years of pedagogy were included. Apolipoprotein E genotype, a genetic take chances factor for Alzheimer disease (29, 30), was as well included.

Statistical Assay

To investigate which baseline factors were associated with physical exercise, age- and sex-adapted odds ratios of exercising regularly (≥three times/calendar week) were obtained past using logistic regression. Practise was the response variable, and each of the other baseline variables was fitted into a separate model adjusting for age and sexual practice.

To evaluate the temporal human relationship of do with incident dementia, we used Cox proportional hazards regression models (31). Because dementia is highly historic period-related, nosotros used years of age during the report as the fourth dimension centrality, with left truncation at age of inbound the study, and kept age at baseline as a covariate in Cox models. Thereby, age was completely adjusted for in our analyses. The primary issue was historic period of onset of dementia. The take chances gene of primary interest was exercise at baseline. Persons who left the study before developing dementia were censored at their last examinations. Persons who remained dementia-free during the study were censored at the most contempo follow-up date. The Schoenfeld residuum examination (32) was used to check the proportional hazards assumption. The age- and sex activity-adjusted hazard ratio of dementia by exercise was estimated from the Cox model.

To investigate which baseline factors influence the association of exercise with incident dementia, nosotros fit a separate Cox model on potentially misreckoning baseline variables by keeping exercise as the main predictor and adjusting for historic period and sexual activity. We examined whether the hazard ratio of dementia for do was changed by adding the baseline variable into a model. To further examine potential effect modifications, the interaction terms of practice and each baseline variable were added into those Cox models. Effect modification was considered to be present if the coefficient for the interaction was establish to be statistically significant (P < 0.05). Finally, we examined the gamble ratio of dementia for practise by adjusting for all potential confounders simultaneously. For the master analyses reported here, we compared participants in the lowest quartile of frequency of practise (< iii times/week) with those in the top three quartiles. As a secondary analysis to determine whether in that location was a dose–response relationship of exercise, nosotros compared participants in each quartile group of practice frequency by assessing risk ratios for the second, 3rd, and fourth quartiles, compared with the everyman quartile (< 3 times/calendar week).

Sensitivity analyses were conducted to evaluate whether a potential bias could be introduced by the censoring mechanism for persons who withdrew from the study or died. Because persons who had poor cognitive part (that is, a low CASI score) when they left the study would exist more than likely to develop dementia, the random censoring assumption for those persons might not be appropriate. We examined the concluding CASI scores for persons who withdrew or died. If a person'southward terminal CASI score was less than 86 before he or she left the study, we assumed that the person would develop dementia one year after the last visit. We then repeated the analyses to determine whether the association of do and incident dementia was changed. Statistical analyses were conducted by using Stata software, version seven (Stata Corp., Higher Station, Texas).

Role of the Funding Source

The funding source did not play a role in the blueprint, carry, or reporting of the study or in the decision to submit the manuscript for publication.

Results

Study participants were followed from May 1994 to Oct 2003, with a hateful follow-up of 6.two years (SD, 2.0). Of 1740 participants, 1185 remained dementia-costless, 158 developed dementia (107 developed Alzheimer disease, 33 developed vascular dementia, and 18 adult other types of dementia), 121 withdrew, and 276 died. Table 1 shows the baseline characteristics of study participants who remained dementia-costless, developed dementia, withdrew from the written report, or died. Tabular array 2 shows the baseline characteristics of study participants by levels of exercise.

Table 1. Baseline Characteristics by Follow-up Status

Table two. Baseline Characteristics of Written report Participants by Practise Levels

Baseline variables associated with do were self-rated health, PPF scores, CES-D scores, smoking, dietary supplements, and years of education. Odds ratios of doing regular exercise were 0.62 (95% CI, 0.41 to 0.92; P = 0.016), 0.49 (CI, 0.31 to 0.77; P = 0.002), and 0.10 (CI, 0.04 to 0.27; P < 0.001) for participants who rated their health as good, off-white, and poor, respectively, compared with those who rated their health equally excellent. In improver, ORs were 1.13 (CI, 1.08 to 1.17; P < 0.001) per ane-signal increment of PPF scores; 0.96 (CI, 0.93 to 0.98; P = 0.001) per 1-point increment of CES-D scores; 0.64 (CI, 0.42 to 0.98; P = 0.039) for electric current smokers compared with nonsmokers; 1.35 (CI, one.08 to 1.69; P = 0.009) for persons who took dietary supplements; and ane.07 (CI, one.02 to 1.11; P = 0.002) for ane-yr increment of education.

The incidence charge per unit of dementia was 13.0 per 1000 person-years for persons who exercised 3 or more than times per calendar week, compared with 19.7 per g person-years for persons who exercised fewer than 3 times per week. In Figure one, Kaplan–Meier survival estimates show that participants who exercised iii or more times per week had a higher probability of existence dementia-complimentary than those who exercised fewer than 3 times per calendar week. The age- and sexual activity-adjusted hazard ratio of dementia for the regular exercise group was 0.62 (CI, 0.44 to 0.86; P = 0.004).

Figure one. Kaplan–Meier survival estimates for the probabilities of being dementia-free.

Persons who exercised iii or more than times per week were more than probable to exist dementia-free than those who exercised fewer than iii times per calendar week.

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The betoken approximate and conviction interval of the gamble ratio of dementia for exercise inverse negligibly each time nosotros added a single covariate to the model. Covariates that were considered included booze consumption, smoking, supplement use, teaching, presence of apolipoprotein E ε4 alleles, diabetes, hypertension, cerebrovascular disease, coronary middle disease, self-rated health, physical performance, low, and cognitive functioning. We found that booze consumption, smoking, supplement apply, and level of education were non associated with dementia and that adjusting for those variables did not modify the point estimate for do; therefore, they were not included every bit potential confounders in the concluding model. When potential confounders were simultaneously adjusted for, the hazard ratio of dementia past exercise was 0.68 (CI, 0.48 to 0.96; P = 0.030).

The interaction of practise and PPF scores was statistically meaning (P = 0.013). In Effigy 2, Kaplan–Meier estimates show probabilities of being dementia-gratis by exercise at unlike PPF levels. The hazard reduction of dementia past practise was greater among participants with lower PPF scores than among those with higher PPF scores. The adjusted take chances ratios of dementia by exercise were 0.58 (CI, 0.39 to 0.84; P = 0.004), 0.66 (CI, 0.46 to 0.94; P = 0.023), and 0.75 (CI, 0.51 to i.09; P = 0.126) for persons with PPF scores of 10, xi, and 12, respectively. Amongst those who exercised fewer than 3 times per week, a ane-point increment of PPF score was associated with a risk ratio of dementia of 0.89 (CI, 0.82 to 0.96; P = 0.004), whereas among those who exercised iii or more times per week, each boosted 1-point increment of PPF score was associated with a risk ratio of dementia of ane.01 (CI, 0.93 to 1.09; P = 0.762).

Effigy 2. Kaplan–Meier survival estimates by do and performance-based physical part (

PPF ) levels. Persons who exercised iii or more times per week had a higher probability of being dementia-free than those who exercised fewer than three times per calendar week if their PPF score was less than 13. This relative risk reduction of dementia past exercise was greater among persons with lower PPF scores than amidst those with college PPF scores.

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To examine the association of exercise with incidence of Alzheimer affliction, nosotros kept Alzheimer disease (north = 107) as incident cases and recoded other types of dementia (northward = 51) as beingness censored at the fourth dimension of diagnosis. The age- and sexual practice-adjusted chance ratio of Alzheimer disease past practice was 0.64 (CI, 0.43 to 0.96; P = 0.031). Afterwards we adapted for potential confounders, the run a risk ratio of Alzheimer affliction by do was 0.69 (CI, 0.45 to ane.05; P = 0.081). The interaction of do with PPF scores was also constitute in relation to Alzheimer illness (P = 0.021).

When persons who withdrew from the report or died were compared with those who were followed and remained dementia-free, persons who withdrew were older and less likely to exercise regularly; had lower CASI scores, lower PPF scores, and college CES-D scores; were more likely to have medical weather condition, such every bit coronary center disease, cardiovascular disease, and hypertension; and were more than likely to study their health equally poor, fair, or proficient at baseline. The mean final CASI score for persons who withdrew or died was 92.8, compared with 94.ii for persons who remained in the study. Of 397 participants who withdrew or died, 39 had a final CASI score of less than 86. Of these 39 participants, 12 (31%) exercised fewer than 3 times per week at baseline. These participants who had a CASI score of less than 86 were recoded every bit having incident dementia one year after leaving the study. Nosotros and then repeated the analyses and found that the age- and sex-adjusted risk ratio of dementia by do was 0.63 (CI, 0.46 to 0.84; P = 0.002.) After adjustment for potential confounders, the risk ratio of dementia by practise was 0.70 (CI, 0.51 to 0.96; P = 0.026). The interaction of exercise and PPF scores in relation to dementia also was non changed.

Discussion

This population-based, longitudinal written report involving the ACT accomplice found a reduced incidence rate of dementia for persons who exercised 3 or more times a week (13.0 per grand person-years) compared with those who exercised fewer than 3 times per calendar week (nineteen.vii per 1000 person-years). Persons who exercised three or more than times a week had a relative hazard of 0.68 (CI, 0.48 to 0.96) for developing dementia compared with those who exercised fewer than 3 times per calendar week when potential confounders were adjusted for; this corresponds to a 32% reduction in risk for dementia. Practise seemed to exist associated with the greatest gamble reduction in participants who had poor physical functioning at baseline.

Some longitudinal studies of the relationship between physical exercise and dementia, Alzheimer disease, and cognitive decline have observed a protective association, whereas others accept failed to notice this clan. One unique feature of our written report is the effort nosotros made in our blueprint to reduce the potential consequence that changes in concrete exercise related to the so-chosen prodromal phase of dementia might accept on our results. Information technology is now widely accepted that manifestations of behavior changes (including decline in habitual exercise) related to Alzheimer disease and other types of dementia with insidious onset can occur years before a person crosses a threshold that allows a definitive diagnosis of dementia to be made (33, 34). Although enrollment in the ACT cohort was restricted to persons without dementia, nosotros deliberately set a higher threshold for eligibility in our study, eliminating persons with CASI scores in the lowest quartile and thereby reducing the potential for this classification mistake.

In our study, the magnitude of the reduced risk was similar regardless of the adjustments nosotros considered. Our study only measured frequency of practise, and we used information technology only to distinguish more regular exercisers from nonexercisers. We did not have a good measure of intensity and duration for calculating the dose of do and, non surprisingly, did non observe a dose–response event for practice frequency divided into quartiles. Compared with persons who were in the lowest quartile (exercised < 3 times/week), persons who were in the second quartile (exercised 3 to 5 times/calendar week) had a relative hazard of dementia of 0.57 (CI, 0.36 to 0.87; P = 0.009), those in the tertiary quartile (exercised 6 to 7 times/week) had a relative take a chance of 0.55 (CI, 0.35 to 0.88; P = 0.012), and those in the highest quartile (exercised > 7 times/week) had a relative hazard of 0.72 (CI, 0.48 to ane.06; P = 0.111). It is interesting that investigators from the Centers for Illness Control and Prevention, using Behavioral Risk Cistron Surveillance System data, did non detect a linear dose–response human relationship betwixt do duration and intensity and health-related quality of life. Instead, they found a more than curvilinear human relationship, with better health-related quality of life associated with moderate levels of practise compared with no do or longer duration and higher frequency of do (35). Additional research should evaluate the threshold of exercise for a biological benefit related to increased oxygen delivery (6), improved circulation, induced fibroblast growth in the hippocampus (7), and reduced cell loss in sensitive areas like the hippocampus (8) in a general population of gratuitous-living elderly persons. The threshold may be quite depression, especially in persons at lower levels of physical performance. Our measure of practise also did not include information about piece of work and nonleisure activities or changes subsequently baseline, and our adjustments in potential confounders are probably incomplete. Thus, residual misreckoning might explain some of the association nosotros observed. We likewise acknowledge that our population is relatively homogeneous and independent a relatively loftier proportion of persons who engaged in physical practice.

Our report found a potentially important result modification between practise and physical operation in relation to incident dementia likewise as Alzheimer illness. There was a greater risk reduction of dementia past exercise among persons with lower levels of physical functioning compared with those with higher levels of physical operation. Low levels of physical functioning were associated with an increased risk for dementia amid persons who exercised fewer than 3 times per week; nevertheless, this increased risk diminished among persons who exercised iii or more times per week. Our finding suggests that one of the means that exercise might reduce the gamble for dementia is through modulating the relationship between physical performance and dementia—an area worthy of additional investigation. The shape of the survival curves in Figures 1 and 2 suggests that exercise does not foreclose dementia but might be associated with a filibuster in onset. If these post hoc findings are confirmed, senior citizens may take more reason to "use it even after you are losing information technology."

Our results are consistent with before observations that modest levels of physical practice are associated with delayed onset of dementia or Alzheimer affliction (11, 20, 36). Nosotros believe that these findings are supported past experimental studies in healthy elderly persons, which showed that a workout program improves higher-order cerebral functions (typically executive function, retentivity, or visuospatial role [37-twoscore]). Changes in such higher-club functions are typically the starting time signs and symptoms of Alzheimer affliction, the most common dementing affliction. Our results might exist explained by the recent interesting finding that the expanse of the encephalon virtually susceptible to ischemic damage (the hippocampus), which is also i of the earliest areas of the encephalon to be affected by Alzheimer affliction, had less tissue loss in older persons at higher levels of physical conditioning (8).

Nosotros believe these findings may be useful if they are confirmed because Alzheimer disease is one of the almost feared illnesses of aging and is ofttimes cited as a reason for not wanting to "get one-time": People do not want to lose their independence and quality of life as a consequence of crumbling (41). Physicians and health-promotion programs might find this data valuable as our society works to detect truly effective means to promote physical activity for all its well-known benefits (42). Indeed, a recent randomized trial demonstrated that increasing the level of physical activity through habitual exercise besides benefits persons with established Alzheimer disease (43, 44). Future research is needed to investigate the consequence of the dose-versus-threshold-based association between practice and onset of dementia and the relationship among physical function, exercise, and the onset of dementia.

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Source: https://www.acpjournals.org/doi/10.7326/0003-4819-144-2-200601170-00004

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