Abstract
Background and Objectives:
Participation in late-life cognitive activities has been associated with a slower rate of cognitive decline and reduced risk of dementia; however, whether this association is independent of earlier experiences is unclear. We examined the association of cognitive activities during early life, midlife, and late life with the risk of Alzheimer’s disease (AD) dementia.
Methods:
This study used data from the Chicago Health and Aging Project, a longitudinal population-based study from 1993 to 2012. Cognitive activity in early life, i.e., during childhood, was measured by the frequency of activities such as reading, storytelling, and playing games. Cognitive activity in midlife was estimated based on the participants’ occupational cognitive activity and complexity. Cognitive activity in late life was assessed by the frequency of participation in reading, watching TV, listening to the radio, visiting museums, and playing chess or checkers. Cognitive activity in early, midlife, and late life was standardized to the population standard deviation (SD) and was modeled continuously (i.e., per 1-SD increase) and categorically (i.e., tertiles). Clinical diagnosis of AD dementia was based on the established criteria by NINCDS-ADRDA. Logistics regression models were used to estimate the odds ratio (OR) and 95% confidence interval (CI) of cognitive activities with AD dementia.
Results:
Of the 1950 individuals included in the analysis, 63% were female, and 54% were Black adults. The average age of study participants was 73. Three hundred ninety-one (20.1%) individuals developed AD dementia during the study period. Cognitive activity in midlife and late life was independently associated with a lower risk of AD dementia, while early-life cognitive activity was not. The OR (95%CI) for a 1-SD increase in the cognitive activity score in early, midlife, and late life were 0.91 (0.71, 1.18), 0.66 (0.51, 0.87), and 0.50 (0.38, 0.65), respectively. Comparing people in the high cognitive activity group (3rd tertile) versus those in the lower group (1st tertile) provided similar associations.
Discussion:
Cognitive activity in midlife and late life was associated with a lower risk of AD dementia. In addition, this study supports the independent role of late-life cognitive activity on the risk of AD dementia.
Introduction
Participation in cognitively stimulating activities, such as reading books and visiting museums, has been associated with a slower rate of cognitive decline.1–3 When combined with other lifestyle factors like diet and exercise, we have shown that it is also associated with a lower risk of Alzheimer’s disease (AD) and dementia.4–6 The strong evidence linking cognitive activities to cognition and dementia has led clinical trials (e.g., US POINTER) to assess their causal effects, along with those of other lifestyle factors, on cognition in adults living in the United States.7 However, the majority of this data linking cognitive activities to dementia originates from studies that focus on assessing cognitive activities in old age (referred to as late-life cognitive activity), even though engagement in cognitive activities is a behavior that spans a lifetime.8 Consequently, it is plausible that cognitive activities in late life may not be associated with AD dementia risk independently of cognitive activities in early and midlife.9 This raises an important question about the success of cognitive activity interventions when solely focusing on late life as a preventive measure for cognitive impairment and dementia in older adults.
Therefore, in the present study, we extend this prior work by including early and midlife cognitive activity measures. Specifically, we conducted a study to examine the independent association of cognitive activities during early life, midlife, and late life with the risk of AD dementia.
Methods
Study Population
Chicago Health and Aging Project (CHAP) is a longitudinal population-based cohort study focused on assessing and evaluating the risk factors for AD dementia.10 Established in 1993, all residents aged 65 years and older from geographically defined neighborhoods on the south side of Chicago were invited to participate in the study. From all age-eligible people identified by the community census, 6157 (78.7%) were enrolled. In the following years, the CHAP study was extended to successive cohorts of residents as they became eligible (i.e., those aged>65 and residents of geographically defined research communities). A total of 10,802 people were enrolled from 1993 to 2012. Data collection was accomplished by trained personnel who obtained information about demographics, health-related behaviors, medical history, and cognitive tests in cycles approximately three years apart. Each data collection cycle has two stages: the first involves an in-home interview, where most data is gathered from all participants (n=10,802), while the second consists of an extended clinical evaluation for clinical Alzheimer’s disease, conducted with a stratified random sample of individuals (n=2,794). The stratified random sample was determined based on age, race, sex, and change in cognitive function. Sampling weights were used to account for unequal selection probabilities in the random sample. Further details on the methodology for the random sample for clinical diagnosis of Alzheimer’s disease have been provided in detail elsewhere.11
Assessment of Cognitive Activities during Early Life, Midlife, and Late Life
Cognitive activity in early life, i.e., during childhood, was measured using a combined index of three questionnaire items. These items measured the frequency of activities such as reading, storytelling, and playing games with the respondents when they were a child. Responses to each item used a five-point Likert scale, with scores ranging from 0 (“once a year or less”) to 4 (“every day or nearly every day”). The scores were then averaged across the three items, providing an overall score ranging from 1 to 5.12 Cognitive activity in midlife was estimated based on the participants’ occupational cognitive activity and complexity.13 CHAP participant data was linked with standardized worker attributes and job characteristics data from the Occupational Information Network (O*NET).14 Details of this approach are provided in an earlier CHAP publication.13 Briefly, each CHAP participant’s lifetime occupation was rated based on cognitive processes required in 10 work-related tasks (e.g., judging qualities of things, services, and people; evaluating information against standards; processing information; analyzing data or information; making decisions and solving problems).13 A summary measure of occupational cognitive requirements (possible range 0–7) was created and used in the analysis.13 Cognitive activity in late life comprises a composite measure of the frequency of participation in 7 cognitively stimulating activities during the past year. Activities include reading books, reading newspapers, reading magazines, watching TV, listening to the radio, visiting museums, and playing games such as chess or checkers. Participants who indicated daily activities such as watching TV and listening to the radio were asked to estimate average daily hours. In addition, participants were asked to provide details on the type of television programs (e.g., game shows, educational programs) and radio shows (e.g., sports, news). A panel of 10 doctoral psychologists and 20 laypersons was formed to estimate the level of cognitive intensity involved in each basic activity (e.g., watching television) and activity subtype (e.g., game shows on television). Participants were asked to rate each item on a 5-point scale for each question. The variable ranges from 1 to 5 and is calculated by averaging the individual item scores. Additional details on the assessment and scoring of cognitive activities are provided elsewhere.1
Assessment of covariates
Age was computed by subtracting the date of the examination (i.e., assessment of late-life cognitive activity) from the birthdate. Race, sex, and years of formal education were self-reported by study participants during a home interview, using questions from the 1990 U.S. Census. Apolipoprotein E (APOE e4) genotyping was measured on the single nucleotide polymorphisms of the rs7412 and rs429358 by the Broad Institute Center for Genotyping (Cambridge, Massachusetts) using the hME Sequenom MassARRAY platform.15 Physical activity was assessed through the 1985 US Health Interview Survey, where participants reported time spent in six activities, including walking for exercise, gardening or yard work, calisthenics or general exercise, bicycle riding, and swimming.16 Smoking status was self-reported, and participants were categorized as ever and never smokers.17 Neighborhood socioeconomic status was based on a composite area-based socioeconomic score developed by Diez Roux et al.,18 which comprised data on participants’ US census block groups. Block-specific measurements include the (1) median household income, (2) median home value, (3) percentage of households with income from interest, dividends, or rent, (4) percentage of adults who completed college, and (5) percentage of employed persons 16 years of age or older in executive, managerial, or professional specialty occupations. Each measure was z-scored and summed to provide an overall score, with higher scores indicating higher neighborhood socioeconomic status. Co-morbidities were self-reported and included diabetes, hypertension, cancer, broken hip, heart disease, and stroke.
Clinical Evaluation and Diagnosis of Alzheimer’s Dementia
Clinical evaluation and diagnosis of Alzheimer’s dementia have been described in detail previously.5,10,19 In short, cognitive assessments comprised 17 tests and were uniformly administered by examiners unaware of the population interview cognitive assessment and random sampling category. A neuropsychologist, blinded to age, sex, race, and most clinical data except for educational level, occupation, and details regarding sensory or motor deficits, evaluated impairment across five domains: orientation, attention, memory, language, and perception. In addition, each participant was reexamined by a board-certified neurologist to determine the diagnosis of Alzheimer’s dementia according to the criteria outlined by the collaborative working group of the NINCDS-ADRDA.20
Statistical Analysis
Characteristics of the study participants are summarized as mean and standard deviation (SD), median and interquartile [IQR], or as number (n) and percentages (%) of participants. Pearson correlation was used to estimate the correlation between cognitive activities. Logistic regression models were used to estimate the odds ratio (OR) and 95% confidence interval (95%CI) of the risk of AD dementia for cognitive activity during early life, midlife, and late life. Cognitive activity scores in early, midlife, and late life were standardized to the sample distribution [i.e., the respective score was divided by the standard deviation (SD) of the sample] to allow comparison of regression estimates for the risk of AD dementia. Cognitive activity scores were modeled continuously (i.e., per 1-SD increase) and categorically (i.e., tertiles). A 1-SD increase could be related to engaging in more activities (e.g., playing puzzle games) or engaging in an activity more frequently (e.g., reading daily). When the cognitive activity was evaluated as categorical, the bottom tertile (i.e., lowest engagement in cognitive activity) was the reference group. Regression models were adjusted by age, sex, race, APOE e4, education, physical activity, smoking, co-morbidities, and neighborhood socioeconomic status. In addition, we did adjust for a time [mean 3.9 (SD 0.9) years] from assessment of late life cognitive activities and covariates to clinical examination for incident AD dementia. Cognitive activity in early life, midlife, and late life were mutually added in the same regression model to evaluate their independent association with AD dementia.
In addition, we performed analyses stratified by sex (female and male), by race (Black and White), and by APOE carrier status (non-carrier and carrier). As a sensitivity analysis, we explored the role of education and socioeconomic status in our associations by developing additional models without adjusting for these variables when evaluating the association of cognitive activity in early, midlife, and late life with the risk of AD dementia.
Analyses were performed using R statistical computing, version 4.3.2 (R Foundation for Statistical Computing, Vienna, Austria).
Standard Protocol Approvals, Registrations, and Patient Consents
The Rush University Medical Center Institutional Review Board approved population interviews, clinical evaluations, and DNA extraction for this study before participant enrollment. The study obtained written and signed informed consent from all participants.
Data Availability
De-identified data may be available for investigators upon approval of a research proposal.
Results
Of 2,130 study participants with clinical data for incident Alzheimer’s dementia, we excluded people with missing data on cognitive activities (n=112) and covariates (n=68), comprising the sample for analysis of 1,950 individuals. The characteristics of the sample (n=1,950) are shown in Table 1. The average age of the study participants was 76, and they had about 13.0 years of schooling; 63% were female, and 54% were Black. The correlation coefficient between cognitive activity scores in early and late life was = 0.15, and between midlife and late life was = 0.24 (Supplementary Table 1).
Table 1.
Characteristics of study population (n=1950)
| Demographics | |||
| Age at baseline, years (mean (SD)) | 76.1 (6.1) | ||
| Sex, Males, n (%) | 725 (37.2%) | ||
| Race, Black, n (%) | 1,053 (54.0%) | ||
| Education, years (mean (SD)) | 13.0 (3.3) | ||
| Genetics | |||
| APOE e4 carrier, n (%) | 610 (31.3%) | ||
| Lifestyle | |||
| Physical activity, h/week (median [IQR]) | 0.9 [0, 3.2] | ||
| Ever smoker, n (%) | 996 (51.1%) | ||
| Cognitive activity, composite score (mean (SD)) | |||
| Early life | 3.4 (1.2) | ||
| Midlife | 2.3 (1.0) | ||
| Late life | 3.2 (0.7) | ||
| Socioeconomic status * | |||
| Neighborhood socioeconomic status (z-score median [IQR]) | −0.4 (−3.3, 4.1) | ||
| Comorbidities ** | |||
| None, n (%) | 636 (32.6%) | ||
| One, n (%) | 769 (39.4%) | ||
| Two, n (%) | 410 (21.0%) | ||
| Three or more, n (%) | 135 (7.0%) | ||
Abbreviation: SD, standard deviation; IRQ interquartiles.
Neighborhood socioeconomic status was based on a composite area-based socioeconomic score developed by Diez Roux et al., (2001) which comprised data on participants’ US census block groups. The score is scaled to population data (i.e., z-score) and higher scores indicating higher neighborhood socioeconomic status.
Comorbidities include hypertension, diabetes, hip fracture, cancer, heart disease, or stroke.
Table 2 presents the association of cognitive activity in early, midlife, and late life with the risk of AD dementia. Three hundred ninety-one (20.1%) individuals developed AD dementia during the study period. Cognitive activities in midlife and late life were independently associated with a lower risk of AD dementia, while early life cognitive activity was not. Specifically, for a 1-SD increase in cognitive activity score in midlife, corresponding to a 1.0 point increase (range 0.5–5.1), the relative risk of AD dementia was lower by 34% (OR 0.66, 95%CI 0.51, 0.87). In late life, a 1-SD increase [0.7 points (range 1.0–5.0)] in cognitive activity was associated with 50% (OR 0.50, 95%CI 0.38, 0.65) lower the risk of AD dementia. The OR (95%CI) for a 1-SD increase [1.2 points (range 1.0–5.0)] in early life cognitive activity was 0.91 (0.71, 1.18). Comparing individuals in the top tertile (higher cognitive activity score) with those in the bottom (lower cognitive activity score) provided similar associations for early, midlife, and late life and risk of AD dementia.
Table 2:
Association of cognitive activities in early, midlife, and late life with the risk of AD dementia
| Cognitive activities | No. of individuals with AD dementia | Total no. of individuals | OR (95%CI) | ||
|---|---|---|---|---|---|
| Early life | Continuous | ||||
| 1-SD increase* | 391 | 1950 | 0.91 (0.71, 1.18) | ||
| Categorical | |||||
| 1st tertile | 136 | 601 | 1 (reference) | ||
| 2nd | 141 | 745 | 0.94 (0.54, 1.63) | ||
| 3rd | 114 | 604 | 0.73 (0.41, 1.30) | ||
| Midlife | Continuous | ||||
| 1-SD increase | 391 | 1950 | 0.66 (0.51, 0.87) | ||
| Categorical | |||||
| 1st tertile | 160 | 639 | 1 (reference) | ||
| 2nd | 124 | 661 | 1.11 (0.62, 2.00) | ||
| 3rd | 107 | 650 | 0.51 (0.28, 0.94) | ||
| Late life | Continuous | ||||
| 1-SD increase | 391 | 1950 | 0.50 (0.38, 0.65) | ||
| Categorical | |||||
| 1st tertile | 227 | 660 | 1 (reference) | ||
| 2nd | 99 | 623 | 0.55 (0.32, 0.96) | ||
| 3rd | 65 | 667 | 0.23 (0.14, 0.38) | ||
Abbreviation: AD, Alzheimer’s dementia; No., number; OR, odds ratio; CI, confidence interval; SD, standard deviation.
A 1-SD increase could be related to engaging in more activities (e.g., playing puzzle games) or engaging in an activity more frequently (e.g., reading daily). Due to different score ranges and distribution, a 1-SD increase in early life corresponds to an average of 1.2 (range 1.0–5.0), in midlife of 1.0 (range 0.5–5.1), and in the late life of 0.7 (range 1.0–5.0).
Models adjusted by age, sex, race, education, APOE e4, physical activity, smoking, comorbidities, and neighborhood socioeconomic status and time from variable assessments to clinical examination for AD dementia. Each model (i.e., continuous and categorical) is also mutually adjusted by cognitive activities in early, midlife, and late life.
Table 3 shows the OR and 95%CI for the associations of cognitive activity in early, midlife, and late life with the risk of AD dementia stratified by sex, race, and APOE e4 carriership. These analyses showed similar results to the primary analysis; however, minor differences were noted. Specifically, the association of late-life cognitive activity (per a 1-SD increase) with AD dementia was stronger in females (OR 0.44, 95%CI 0.31–0.61) than in males (OR 0.62, 95%CI 0.42–0.92). Cognitive activity in midlife was more strongly associated with AD dementia in White individuals (OR 0.58, 95%CI 0.40–0.84) than in Black adults (OR 0.66, 95%CI 0.46–0.96) and APOE e4 non-carrier (OR 0.59, 95%CI 0.43, 0.81) than carriers (OR 0.72, 95%CI 0.45, 1.14). No association between early life cognitive activity and the risk of AD dementia was observed in the stratified analyses.
Table 3:
Association of cognitive activities in early, midlife, and late life with the risk of AD dementia in models stratified by sex, race, and APOE e4
| Cognitive activities per 1-SD increase* | Sex | Race | APOE e4 carriership | |||
|---|---|---|---|---|---|---|
| Female (n=1,225) | Male (n=725) | Black (n=1,053) | White (n=897) | e4 carrier (n=610) | Non e4 carrier (n=1,340) | |
| OR (95%CI) | OR (95%CI) | OR (95%CI) | OR (95%CI) | OR (95%CI) | OR (95%CI) | |
| Early life | 0.89 (0.62, 1.26) | 1.00 (0.70, 1.42) | 0.86 (0.61, 1.21) | 1.04 (0.78, 1.38) | 0.78 (0.56, 1.08) | 1.01 (0.71, 1.44) |
| Midlife | 0.68 (0.44, 1.06) | 0.64 (0.46, 0.90) | 0.66 (0.46, 0.96) | 0.58 (0.40, 0.84) | 0.72 (0.45, 1.14) | 0.59 (0.43, 0.81) |
| Late life | 0.44 (0.31, 0.61) | 0.62 (0.42, 0.92) | 0.51 (0.36, 0.72) | 0.51 (0.37, 0.71) | 0.55 (0.39, 0.79) | 0.46 (0.32, 0.66) |
Abbreviation: AD, Alzheimer’s dementia; No., number; OR, odds ratio; CI, confidence interval; SD, standard deviation.
A 1-SD increase in early life corresponds to an average of 1.2 (range 1–5), in midlife of 1.0 (range 0.5–5.1), and in the late life of 0.7 (range 1–5).
Models adjusted by age, sex (when applicable), race (when applicable), education, APOE e4 (when applicable), physical activity, smoking, comorbidities, and neighborhood socioeconomic status and time from variable assessments to clinical examination for AD dementia. Each model (e.g., female, male) is also mutually adjusted by cognitive activities in early, mid, and late life.
Sensitivity Analyses
Education and neighborhood socioeconomic status had a negligible impact on the association of cognitive activity in early, midlife, and late life with the risk of Alzheimer’s dementia (Supplementary Table 2).
Discussion
In this study of adults 65 years and older residing on the south side of Chicago, cognitive activity in midlife and late life was associated with a lower risk of AD dementia. The association of late-life cognitive activity with AD dementia was independent of early and midlife cognitive activity among other confounders, including education levels and neighborhood socioeconomic status, suggesting that cognitive activities during late life may serve as a preventive strategy within intervention studies.
Epidemiological studies have shown that late-life cognitive stimulating activities are associated with a lower risk of AD dementia.2,21 In addition, late-life cognitive activity is associated with cognitive decline independent of neuropathologic burden, supporting the cognitive reserve hypothesis.22 We have further complemented the evidence of cognitive activity and dementia risk by showing that cognitive activity, in combination with other lifestyle factors, including diet and physical activity, is associated with a longer life expectancy, and a larger proportion of these remaining years were lived without AD dementia.5 Motivated by these observation studies, clinical trials around the world,23 such as US POINTER in the United States,7 are investigating the effect of lifestyle interventions, including cognitive activities, on cognition among older adults. However, participating in cognitively stimulating activities is a behavior that occurs throughout life, raising the question of whether the observed association of late-life cognitive activity on dementia risk is independent of cognitive activities earlier in life and during midlife. In the current investigation, we evaluated the association of late-life cognitive activity with the risk of AD dementia while accounting for early and midlife cognitive activities, among other confounders, including education and neighborhood socioeconomic status. Our data showed that the association between cognitive activity in late life and the risk of AD dementia was independent of early and midlife activities. This finding suggests that cognitive activity interventions later in life could offer cognitive benefits for older adults. These findings support the current designs of clinical trials focusing on lifestyle interventions and cognition.
In addition to late-life cognitive activities, cognitive activity during adulthood (i.e., midlife) was also associated with the risk of AD dementia. We assessed midlife cognitive activity using O*NET constructs, which measure the cognitive activity and complexity of occupations across various cognitive domains.14 This makes midlife cognitive activity comparable to early and late-life cognitive activities in CHAP.13 These findings align with our earlier investigation in CHAP and other cross-sectional studies in which occupation-related cognitive activity is associated with higher cognitive function scores.13,24–26 The mechanism linking occupation-related cognitive activity and dementia risk, while unknown, supports the hypothesis that cognitively stimulating environment through job complex tasks in midlife could help prevent or delay the onset of AD dementia.
Cognitive activity in childhood (i.e., early life) was not associated with the risk of AD dementia, suggesting that while important, early life cognitive simulating activities alone may not provide cognitive benefits against AD dementia as older adults age. Alternatively, these findings could be interpreted as the cognitive advantages of early life exposures having to be sustained in the midlife and late life to see a potential benefit. The latter could be supported by the hypothesis that biological processes, such as dementia-related brain pathologies, that drive the cognitive decline in aging populations are less affected by the type of cognitive activities in early life but impact activities throughout the lifespan.6 In line with these findings, we have shown that early life conditions, as defined by higher socioeconomic position during childhood or more exposure to a cognitively stimulating environment, were not associated with the rate of cognitive decline in late life.12 However, childhood conditions are strongly associated with cognitive development in early life27–29, and late life.30,31 Therefore, additional research is warranted to determine the role of early life cognitive activity and the incidence of Alzheimer’s dementia and potentially to brain health.
Cognitive activities could be related and attributed to education levels and neighborhood socioeconomic status.1–3 Therefore, we conducted analyses with and without adjustment for education and neighborhood socioeconomic status and re-evaluated the association of cognitive activities with the risk of AD dementia. We did this analysis to show to what extent, beyond education and neighborhood socioeconomic status, cognitive activities are associated with the risk of AD dementia. We found that odds ratios were similar, suggesting that cognitive activities, while related to education level and socioeconomic status, their role in the risk of Alzheimer’s dementia is not explained by the education level or socioeconomic status. These findings encourage promoting cognitive activities across education levels and socioeconomic status.
The strengths of our study include the study design, availability of cognitive activity assessment in early, midlife, and late life, and accurate diagnosis of Alzheimer’s dementia through structured clinical neurological evaluations with neuropsychological testing. Our study has several limitations. Self-reported information on early life cognitive activity may be affected by inaccurate recall. We assume that the main lifetime occupation was the predominant job throughout the life course or that individuals with a particular occupation had identical levels of occupational cognitive complexity. We standardized the cognitive activities in early life, middle life, and late life to compare the odds ratios of each cognitive activity with the risk of Alzheimer’s dementia; however, we acknowledge that each activity during the life course may have different weights on Alzheimer’s dementia. We could not account for potentially confounding factors of participants in early and midlife. Hence, residual confounding may exist in the reported associations. Although we investigate cognitive activities across life courses, including cognitive activities in middle life based on the participants’ occupational cognitive activity and complexity, which are less prone to reverse causality, and we excluded people with prevalent Alzheimer’s at baseline, yet our study is prone to reverse causality bias. Also, we should not generalize the findings of this study to other populations without additional research and validation. The diagnosis of Alzheimer’s dementia in CHAP was based on the criteria by the NINCDS-ADRDA. Although the NINCDS-ADRDA criteria is universally adopted and highly effective, it yet could be prone to misdiagnosing people with AD dementia.
In conclusion, cognitive activity in midlife and late life was associated with a lower risk of AD dementia. In addition, this study supports the independent role of late life cognitive activity on the risk of AD dementia.
Supplementary Material
Acknowledgments
The authors thank all the participants in the Chicago Health and Aging Project. They also thank the staff of the Rush Institute of Healthy Aging.
Study funding:
This study was supported by the National Institute on Aging of the National Institute of Health (R01AG073627, R01AG058679, and UH2AG083289) and Alzheimer’s Association Research Grant (AARG-22-974154). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health or Alzheimer’s Association.
Footnotes
Conflict of Interest: All authors report no conflicts of interest.
Disclosure: The authors report no disclosures relevant to the manuscript.
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