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Association of lifelong exposure to cognitive reserve-enhancing factors with dementia risk: A community-based cohort study

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Background Variation in the clinical manifestation of dementia has been associated with differences in cognitive reserve, although less is known about the cumulative effects of exposure to cognitive reserve factors over the life course. We examined the association of cognitive reserve-related factors over the lifespan with the risk of dementia in a community-based cohort of older adults. Methods and findings Information on early-life education, socioeconomic status, work complexity at age 20, midlife occupation attainment, and late-life leisure activities was collected in a cohort of dementia-free community dwellers aged 75+ y residing in the Kungsholmen district of Stockholm, Sweden, in 1987–1989. The cohort was followed up to 9 y (until 1996) to detect incident dementia cases. To exclude preclinical phases of disease, participants who developed dementia at the first follow-up examination 3 y after the baseline were excluded (n = 602 after exclusions). Structural equation modelling was used to generate latent factors of cognitive reserve from three periods over the life course: early (before 20 y), adulthood (around 30–55 y), and late life (75 y and older). The correlation between early- and adult-life latent factors was strong (γ = 0.9), whereas early–late (γ = 0.27) and adult–late (γ = 0.16) latent factor correlations were weak. One hundred forty-eight participants developed dementia during follow-up, and 454 remained dementia-free. The relative risk (RR) of dementia was estimated using Cox models with life-course cognitive reserve-enhancing factors modelled separately and simultaneously to assess direct and indirect effects. The analysis was repeated among carriers and noncarriers of the apolipoprotein E (APOE) ε4 allele. A reduced risk of dementia was associated with early- (RR 0.57; 95% CI 0.36–0.90), adult- (RR 0.60; 95% CI 0.42–0.87), and late-life (RR 0.52; 95% CI 0.37–0.73) reserve-enhancing latent factors in separate multivariable Cox models. In a mutually adjusted model, which may have been imprecisely estimated because of strong correlation between early- and adult-life factors, the late-life factor preserved its association (RR 0.65; 95% CI 0.45–0.94), whereas the effect of midlife (RR 0.73; 95% CI 0.50–1.06) and early-life factors (RR 0.76; 95% CI 0.47–1.23) on the risk of dementia was attenuated. The risk declined progressively with cumulative exposure to reserve-enhancing latent factors, and having high scores on cognitive reserve-enhancing composite factors in all three periods over the life course was associated with the lowest risk of dementia (RR 0.40; 95% CI 0.20–0.81). Similar associations were detected among APOE ε4 allele carriers and noncarriers. Limitations include measurement error and nonresponse, with both biases likely favouring the null. Strong correlation between early- and adult-life latent factors may have led to a loss in precision when estimating mutually adjusted effects of all periods. Conclusions In this study, cumulative exposure to reserve-enhancing factors over the lifespan was associated with reduced risk of dementia in late life, even among individuals with genetic predisposition.
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RESEARCH ARTICLE
Association of lifelong exposure to cognitive
reserve-enhancing factors with dementia risk:
A community-based cohort study
Hui-Xin Wang
1,2,3
*, Stuart W. S. MacDonald
4,5
, Serhiy Dekhtyar
6
, Laura Fratiglioni
2,7
1College of Public Health, Zhengzhou University, Zhengzhou, China, 2Aging Research Center, Department
of Neurobiology, Caring Sciences and Society, Karolinska Institutet and Stockholm University, Stockholm,
Sweden, 3Stress Research Institute, Stockholm University, Stockholm, Sweden, 4Department of
Psychology, University of Victoria, Victoria, British Columbia, Canada, 5Institute on Aging and Lifelong
Health, University of Victoria, Victoria, British Columbia, Canada, 6Department of Clinical Neuroscience,
Division of Psychology, Karolinska Institutet, Stockholm, Sweden, 7Stockholm Gerontology Research
Center, Stockholm, Sweden
*huixin.wang@su.se
Abstract
Background
Variation in the clinical manifestation of dementia has been associated with differences in
cognitive reserve, although less is known about the cumulative effects of exposure to cogni-
tive reserve factors over the life course. We examined the association of cognitive reserve-
related factors over the lifespan with the risk of dementia in a community-based cohort of
older adults.
Methods and findings
Information on early-life education, socioeconomic status, work complexity at age 20, midlife
occupation attainment, and late-life leisure activities was collected in a cohort of dementia-
free community dwellers aged 75+ y residing in the Kungsholmen district of Stockholm,
Sweden, in 1987–1989. The cohort was followed up to 9 y (until 1996) to detect incident
dementia cases. To exclude preclinical phases of disease, participants who developed
dementia at the first follow-up examination 3 y after the baseline were excluded (n= 602
after exclusions). Structural equation modelling was used to generate latent factors of cogni-
tive reserve from three periods over the life course: early (before 20 y), adulthood (around 30–
55 y), and late life (75 y and older). The correlation between early- and adult-life latent factors
was strong (γ= 0.9), whereas early–late (γ= 0.27) and adult–late (γ= 0.16) latent factor corre-
lations were weak. One hundred forty-eight participants developed dementia during follow-up,
and 454 remained dementia-free. The relative risk (RR) of dementia was estimated using Cox
models with life-course cognitive reserve-enhancing factors modelled separately and simulta-
neously to assess direct and indirect effects. The analysis was repeated among carriers and
noncarriers of the apolipoprotein E (APOE) ε4 allele. A reduced risk of dementia was associ-
ated with early- (RR 0.57; 95% CI 0.36–0.90), adult- (RR 0.60; 95% CI 0.42–0.87), and late-
life (RR 0.52; 95% CI 0.37–0.73) reserve-enhancing latent factors in separate multivariable
PLOS Medicine | DOI:10.1371/journal.pmed.1002251 March 14, 2017 1 / 17
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OPEN ACCESS
Citation: Wang H-X, MacDonald SWS, Dekhtyar S,
Fratiglioni L (2017) Association of lifelong
exposure to cognitive reserve-enhancing factors
with dementia risk: A community-based cohort
study. PLoS Med 14(3): e1002251. doi:10.1371/
journal.pmed.1002251
Academic Editor: Bruce L. Miller, University of
California San Francisco Memory and Aging
Center, UNITED STATES
Received: September 14, 2016
Accepted: February 2, 2017
Published: March 14, 2017
Copyright: ©2017 Wang et al. This is an open
access article distributed under the terms of the
Creative Commons Attribution License, which
permits unrestricted use, distribution, and
reproduction in any medium, provided the original
author and source are credited.
Data Availability Statement: Data are from the
Kungsholmen Project (KP), a population-based
study on aging and dementia (http://www.
kungsholmenproject.se/). Access to these original
data is available to the research community upon
approval by the KP data management and
maintenance committee. Applications for
accessing these data can be submitted to Maria
Wahlberg (Maria.Wahlberg@ki.se) at the Aging
Research Center, Karolinska Institute.
Cox models. In a mutually adjusted model, which may have been imprecisely estimated
because of strong correlation between early- and adult-life factors, the late-life factor pre-
served its association (RR 0.65; 95% CI 0.45–0.94), whereas the effect of midlife (RR 0.73;
95% CI 0.50–1.06) and early-life factors (RR 0.76; 95% CI 0.47–1.23) on the risk of dementia
was attenuated. The risk declined progressively with cumulative exposure to reserve-enhanc-
ing latent factors, and having high scores on cognitive reserve-enhancing composite factors
in all three periods over the life course was associated with the lowest risk of dementia (RR
0.40; 95% CI 0.20–0.81). Similar associations were detected among APOE ε4 allele carriers
and noncarriers. Limitations include measurement error and nonresponse, with both biases
likely favouring the null. Strong correlation between early- and adult-life latent factors may
have led to a loss in precision when estimating mutually adjusted effects of all periods.
Conclusions
In this study, cumulative exposure to reserve-enhancing factors over the lifespan was
associated with reduced risk of dementia in late life, even among individuals with genetic
predisposition.
Author summary
Why was this study done?
It has emerged from previous literature that lifestyle factors such as physical exercise,
intellectual stimulation, or leisure activities are associated with a reduced risk of
dementia occurrence in late life. One possibility is that these activities provide pro-
tection in the form of reserve, facilitating the maintenance of cognitive function in
the face of cumulative brain damage.
It is, however, still largely unknown how the risk of dementia is shaped by various
reserve-stimulating lifestyle factors simultaneously taking place throughout the
entire life course.
Our study was designed to examine the association between the risk of dementia
occurrence after age 75 and engagement in a variety of reserve-enhancing activities
over the entire life course.
What did the researchers do and find?
We estimated the risk of dementia occurrence in a cohort of individuals aged 75 y
and older conditional on their engagement in ten activities that were expected to
promote reserve in three stages over the life course.
We found that, on its own, engagement in early-, adulthood-, and late-life reserve-
enhancing activities was associated with a reduced risk of dementia. However, when
all three factors were simultaneously evaluated for their association with dementia, the
effects of early-life and adulthood factors were attenuated. This could be due to the
Cognitive reserve over the life course and dementia risk in late life
PLOS Medicine | DOI:10.1371/journal.pmed.1002251 March 14, 2017 2 / 17
Funding: Research grants were received from the
Swedish Research Council for Health, Working Life
and Welfare (FORTE; numbers: 2015-05998; 2013-
8676; recipient: LF), the Swedish Research Council
(VG; numbers: 2015-05998; 2013-8676; recipient:
HXW), the Dementia Association Sweden (number:
4-1676/2015 recipient: HXW), the Alzheimer
foundation Sweden (number: 2009-3 006;
recipient: HXW), the Swedish Brain Power
(number: 2009.0268; recipient: HXW), the Gun and
Bertil Stohnes foundation (number: 4-2901/2015;
recipient: HXW), the Gamla Tja¨narinnor foundation
(number: 2014-00022), the So¨derstro¨m-Ko¨nigska
foundation (number: 2009-22822; recipient: HXW),
the Konung Gustaf V:s och Drottning Victorias
Frimurare Foundation (number: 4-314/2014;
recipient HXW), and the Hja¨rnfonden (number:
2016-0095; recipient: LF). The funders had no role
in the study design; in the collection, analysis, and
interpretation of data; in the writing of the report; or
in the decision to submit the article for publication.
Competing interests: The authors have declared
that no competing interests exist.
Abbreviations: APOE, apolipoprotein E; MMSE,
Mini-Mental State Examination; OR, odds ratio; RR,
relative risk; SD, standard deviation; SEM,
structural equation model; SES, socioeconomic
status.
strong correlation between early-life and adulthood factors, whereas the late-life factor
was only moderately related to either early-life or adulthood markers of reserve.
An important finding was that increased frequency of engagement in stimulating
activities over the life course was associated with a progressively reduced risk of
dementia, suggesting a dose-response effect between life-course reserve and demen-
tia risk. This effect appeared to operate irrespective of genetic predisposition to
dementia.
What do these findings mean?
These findings strongly suggest that development of dementia is a lifelong process
that begins decades before the onset of the disease.
At the same time, it is never too late to initiate interventions aimed at risk modify-
ing, since late-life engagement in stimulating activities was associated with a lower
risk of dementia.
However, because reserve-enhancing activities are correlated over the life course,
and because the lowest risk is enjoyed by individuals with increased frequency of
stimulating engagements, the most effective strategies are likely to be those empha-
sizing risk reduction throughout the entire life course.
Introduction
The relevance of cognitive reserve-enhancing factors as contributors to dementia risk has
emerged from several longitudinal population-based studies [13] and has been confirmed by
pathological and clinical data [4]. Thus, numerous studies have reported an increased risk of
dementia in less educated persons [5,6]. Higher education could help build cognitive reserve—
a set of skills or repertoires that increase an individual’s ability to cope with dementia pathol-
ogy later in life [3,7]. Some studies have suggested that childhood socioeconomic status (SES)
may be of importance for the development of dementia in late life [8,9]. A poor-quality envi-
ronment during childhood or adolescence may prevent the brain from reaching full levels of
maturation, leading to low cognitive reserve, which in turn could put people at higher risk for
dementia. On the other hand, few years of schooling could be a marker of cognitive abilities
that may have both gestational and genetic origin [10]. In any case, the first decade of life
appears to be a critical period for developing dementia later in life [11,12].
In addition to early life contributors, the functional efficiency of cognitive networks may be
promoted by adulthood factors, such as occupational attainment or leisure activities, leading
to higher cognitive reserve. There is growing support for the hypothesis that mental stimula-
tion in middle age (e.g., mental occupational demands [13] and work complexity [1416]), as
well as in old age (e.g., leisure activities [1,17]), may reduce the risk of dementia. Biologically,
mental stimulation could selectively increase synaptogenesis in adulthood, whereas physical
exercise might enhance non-neuronal components of the brain, such as vasculature [18]. The
ability of the adult brain to respond to environmental stimuli by activating compensatory pro-
cesses, thus, could be sustained in late life [19]. Therefore, it appears that factors associated
Cognitive reserve over the life course and dementia risk in late life
PLOS Medicine | DOI:10.1371/journal.pmed.1002251 March 14, 2017 3 / 17
with dementia risk originate in different periods throughout the entire life course, including
early, adult, and late life.
Few studies have been able to examine the effects of cumulative exposure to cognitive
reserve-enhancing factors across the life span. Exposure to these factors during different life
periods may act alone or combine in clusters affecting health in later life [20,21]. It has been sug-
gested that dementia is not determined at a single time period but rather results from a complex
interplay between genetic and environmental exposures throughout the life course [22,23].
Although life-course models for late-onset diseases have received increased attention in the epi-
demiological field [21], this approach has not yet been widely applied to dementia [22], with the
exception of a few studies [12,24,25]. Using a life-course approach, this study aims to test the
hypotheses that (1) cognitive reserve-related factors operating at various life periods each are
potentially associated with decreased risk of the occurrence of dementia, (2) cumulative expo-
sure to reserve-related factors is associated with a progressively reduced risk of dementia, and
(3) the risk of dementia later in life is influenced by the interaction between lifelong exposure to
cognitive reserve-related factors and genetic factors (e.g., apolipoprotein E [APOE] ε4).
Methods
Ethical approval
All phases of the project received approval from the Ethics Committee at Karolinska Institutet
(Dnrs: 87:234; 90:251; 94:122; 97:413; 99:308; 99:025; 01:020). All individuals participating in
the study completed a written informed consent form as stipulated in the ethical approval. For
those participants who became cognitively impaired over time, consent was obtained from the
next of kin.
Study population
The study population is derived from the Kungsholmen Project, a longitudinal community-
based study that included all inhabitants of the Kungsholmen district in Stockholm, Sweden,
aged 75 y and older on 1 October 1987 (n= 2,368) [26,27]. Of the 1,810 baseline participants,
1,473 were diagnosed without dementia by the two-phased design. These participants were
approached again every 3 y for first, second, and third follow-up examinations. Because
impaired cognition or institutionalization may limit participants’ current activity [28], we
excluded 98 individuals with a baseline Mini-Mental State Examination (MMSE) score of less
than 23, as well as those residing in an institution. During the first follow-up examination 3 y
after the baseline, 441 of the baseline participants could not be clinically examined (269 died,
and 172 refused participation), whereas 158 individuals were diagnosed with dementia and
were excluded from the study to avoid the possibility that they may already have been in the
preclinical phase of dementia when interviewed at baseline [29]. Another 44 participants who
refused the second follow-up examination were also excluded. The resulting population eligi-
ble for analysis consisted of 732 individuals without dementia. Of these, we removed individu-
als with missing information on education (n= 3) and occupation (n= 109), as well as 18
women who never entered the labour market, resulting in 602 dementia-free participants at
both baseline and the first 3-y follow-up who were followed for up to 9 y to detect incident
dementia cases.
Dementia diagnosis
The clinical diagnosis of dementia was obtained in accordance with the third revised Diagnos-
tic and Statistical Manual of Mental Disorders (DSM-III-R), with some modification [30]. A
Cognitive reserve over the life course and dementia risk in late life
PLOS Medicine | DOI:10.1371/journal.pmed.1002251 March 14, 2017 4 / 17
two-phased diagnostic procedure [27] was employed, whereby two physicians working inde-
pendently made a preliminary diagnosis, and a third opinion was sought in the event of discor-
dant assessments by the original examiners. Modifications to the DSM-III-R criteria included
adding a diagnosis of questionable dementia for individuals with evident impairment in all
requisite functions except one and defining cognitive impairment on the basis of objective
neuropsychological assessment [31]. In the current study, only clinically definite cases of
dementia were included. The time of dementia onset was assumed to be the midpoint between
two examinations or the midpoint between examination and the date of death due to
dementia.
Assessment of life-course cognitive reserve factors
We assessed cognitive reserve-related indicators from three distinct periods of the life course:
early life, adult life, and late life.
Early life cognitive reserve-related factors (before 20 y) included the following:
Educational attainment collected from participants at the study baseline (1987–1989) as
a result of the structured questionnaire administered by one of the two trained nurses
(S2 Text). The highest degree achieved was recorded and subsequently categorized as ele-
mentary, professional, intermediate school, high school, or university.
Early-life SES measured by the number of siblings grown up with and substantive work
complexity at 20 y. A trained nurse recorded the number of siblings during the same
baseline interview in which educational attainment was assessed. We expected that a
larger number of siblings would be a proxy for lower SES, since research has shown that
around the time of this study population’s birth (1885–1912), elite socioeconomic groups
had started limiting their fertility, whereas the less privileged strata did not begin this
transition until several decades later [32]. Substantive work complexity at age 20 was col-
lected at an informant interview during the first follow-up examination (1990–1991; S2
Text) that aimed to retrospectively explore lifespan work activities, by inquiring about
the employer, job title, time period, and tasks at all jobs lasting at least 6 mo [33]. Sub-
stantive work complexity at 20 y was recorded in accordance with the work complexity
matrix [34] as reported below.
Adult life cognitive reserve-related factors (around 35–55 y) included the following:
Complexity of work with data and people for the longest-held occupation in adult life.
Work complexity scores were recorded in accordance with a work complexity matrix
[34] that was based on the estimation of more than 12,000 occupations rated during on-
site occupational assessments in the United States. Occupational categories of the 1980
Swedish census were matched to the best-fitting category in the 1970 US census [14]. The
measures for each occupation were created to reflect the levels of complexity at which a
worker in a particular occupation functions according to four dimensions: substantive
complexity of work (score range 0–10) and complexity of work with data (0–6), with peo-
ple (0–8), and with things (0–7), with higher scores indicating greater complexity. Work
complexity with things was excluded since it was not found to affect dementia in a previ-
ous study using the same material [16] and because of its weak contribution to the latent
variable. A large sample study assessing inter-rater agreement of the complexity ratings of
different occupations yielded reliability estimates: 0.85 for complexity of work with data
and 0.87 for complexity of work with people [35].
Cognitive reserve over the life course and dementia risk in late life
PLOS Medicine | DOI:10.1371/journal.pmed.1002251 March 14, 2017 5 / 17
Job demands and decision latitude for the longest-held occupation in adult life. Job
demands designate the use of skills to perform job tasks, whereas decision latitude indi-
cates the extent of decision authority at a workplace [36]. Both measures were derived in
accordance with a psychosocial job exposure matrix [37] for the longest occupational
period. If participants reported spending the longest portion of their life working inside
the household, their second-longest occupation was used. A high score indicates a higher
level of psychosocial job demands and decision latitude. The scores ranged from 2.5 to
9.0 for job demands and 2.2 to 8.6 for control at work. Job demand and job controls
derived from the job exposure matrix have been shown to correlate with self-reported
levels among the same individuals (average r = 0.6) in a validation study [38]. Informa-
tion on occupational attainment was collected from informants (relatives or other
knowledgeable person) at the first follow-up examination (1990–1991) during the inter-
view on lifetime work history. Interviews were conducted by one of the two nurses spe-
cially trained in occupational coding. Informants were used for individuals with
dementia as well as dementia-free participants (S2 Text). The interview questionnaire
was developed by an expert in occupational medicine and aimed to explore the lifespan
work activities of all jobs lasting at least 6 mo. Substantive complexity ratings were added
to occupations at 20 y, whereas measures of demands, decision latitude, and complexity
of work with data and with people were linked with the longest-held job.
Late-life cognitive reserve-related factors (75 y and older) included the following:
Late-life leisure activities. Information on leisure activities was obtained by means of a
personal interview conducted by trained nurses at baseline (1987–1989) (S2 Text). Partici-
pants were asked whether they regularly engaged in activities and what those specific
activities were, resulting in 29 being identified. A mental, social, and physical component
score was assigned to each of these activities, with grading of the three components
defined as follows: 0 = none, 1 = low, 2 = moderate, and 3 = high. The sum of the compo-
nent scores, which had a range of 0–18, was calculated based on the grading for each of
the three activities [39]. To validate the scoring, 13 cognitively intact raters, aged 75 y or
older, were asked to individually complete a questionnaire containing a list of the 29 activ-
ities together with scoring instructions. Reliability analyses revealed a satisfactory result:
values for Cronbach’s αwere 0.89 for the mental component, 0.95 for the physical compo-
nent, and 0.82 for the social component.
Covariates
All covariates were assessed at the study baseline (1987–1989). In addition to age and gender
(both extracted from the National Population Register), baseline cognitive functioning was
evaluated using the MMSE, with a score of 30 indicating unimpaired performance. Depression
was assessed through self-reported symptoms such as feeling lonely and constantly being in a
bad mood. Comorbidities were ascertained by reviewing the hospital discharge diagnoses
through the Stockholm computerized inpatient register system with coverage since 1969.
Based on the International Classification of Disease, 8th edition (ICD-8) [40], we identified
coronary heart disease (ICD-8: 410–414), cerebrovascular disease (ICD-8: 430–438), diabetes
mellitus (ICD-8: 250), malignancy (ICD-8: 140–208 and 230–239), and hip fracture (ICD-8:
820). Comorbidity was defined as the presence of any of these conditions. Genomic DNA was
prepared from peripheral blood samples at baseline, and APOE genotyping using a standard
Cognitive reserve over the life course and dementia risk in late life
PLOS Medicine | DOI:10.1371/journal.pmed.1002251 March 14, 2017 6 / 17
polymerase chain reaction procedure [41] was performed by two technicians who were blind
to all other data.
Statistical analysis
Logistic regression was used to examine differences between participants and nonparticipants.
Structural equation models (SEMs) were computed to derive the best-fitting measurement
model for ten individual lifelong reserve-enhancing indicators. Using various fit criteria
[42,43], three separate latent reserve measures were generated, comprised of early-, adult-, and
late-life cognitive reserve-enhancing composite indicators. Cox regression models (age- and
sex-adjusted) were then used to estimate the hazard ratio (HR) and 95% confidence intervals
of dementia occurrence for each of the three latent composite reserve-enhancing factors. In an
additional set of analyses, we further adjusted for late-life cognitive functioning as well as the
presence of comorbidity and depressive symptoms. The three latent composite factors were
analysed as continuous variables, quartile categories, and dichotomized variables contrasting
the top three quartiles versus the lowest one. First, each composite indicator for a specific life
period was analysed separately, and then all three were entered into the same model to verify
their independent effects.
We decomposed the total effect of early-, adult-, and late-life composite factors on dementia
risk. First, a full model including all three life-course factors and covariates was fit, with esti-
mated parameters producing the direct effects of early-, adult-, and late-life factors. Next, a
series of reduced models that included only early-, adult-, or late-life indicators was estimated,
with parameters from these models producing the total effect of each life-course indicator. The
difference between the total and the direct effect for each of the latent life-course factors yielded
an estimate of its indirect effect through all mediating factors. The significance of the indirect
effect was tested through the model likelihood ratio [44].
As the risk of dementia may be affected by an interaction between genetic and environmen-
tal factors [45], formal tests of statistical interactions between the life-course cognitive reserve-
enhancing composite factors and APOE ε4 status were performed by introducing an interac-
tion term. To further assess the possible interaction between genetic predisposition and cogni-
tive reserve, we estimated the effects of reserve-enhancing composite factors among both
APOE ε4 allele carriers and noncarriers.
Results
Logistic regression showed that the population analysed in the study (n= 602) and the eligible
individuals who were not included because of missing data on covariates (n= 130) did not
Table 1. Baseline characteristics of the study population including 454 persons who remained free of dementia during the follow-up and the 148
individuals who developed dementia over an average of 6 y of the follow-up.
Dementia-free (n= 454) Incident dementia (n= 148) p-Value
Age (years), mean ±SD 80.2 ±4.4 81.1 ±4.2 0.03
MMSE score (0–30), mean ±SD 27.6 ±1.4 27.3 ±1.3 0.04
Women, % 72.7 79.7 0.09
Depressive symptoms, % 24.7 33.8 0.03
Comorbidity, % 22.2 28.4 0.13
APOE ε4 allele, % 23.1 32.4 0.03
APOE, apolipoprotein E; MMSE, Mini-Mental State Examination; SD, standard deviation.
P—values are from T-test for continuous variables or χ
2
test for categorical variables.
doi:10.1371/journal.pmed.1002251.t001
Cognitive reserve over the life course and dementia risk in late life
PLOS Medicine | DOI:10.1371/journal.pmed.1002251 March 14, 2017 7 / 17
differ with respect to age (odds ratio [OR] 0.98, 95% CI 0.94–1.03), sex (OR 0.92, 95% CI 0.58–
1.40), presence of depression (OR 1.16, 95% CI 0.76–1.77), or comorbidity (OR 1.27, 95% CI
0.89–1.81). Table 1 shows the characteristics of study participants 4–9 y before dementia diag-
nosis. As expected, individuals who would develop dementia later were relatively older, more
likely to be female, had more depressive symptoms, reported poorer cognitive functioning,
and were more likely to be APOE ε4 allele carriers.
The best-fitting latent measurement model for the three life-course cognitive reserve-
enhancing composite factors (early, adult, and later life) is presented in Fig 1. For each latent
factor, an individual’s factor score was estimated by (1) standardizing measurements on the
raw indicators, (2) multiplying the standardized score for each indicator by its corresponding
SEM factor-score weight, and (3) summing the products to yield three separate latent factor-
score estimates for the early-, adult-, and late-life periods (for more details, see S1 Text). The dis-
tribution of the latent variables was as follows: early life (range from 1 to 1, mean = 0.02, and
standard deviation [SD] = 0.491), adult life (range from 1 to 1, mean = 0.02, and SD = 0.372),
Fig 1. Standardized estimates from the structural equation model (SEM) for the three composite factors and
corresponding cognitive reserve indicators from three life periods (early life, adulthood, and late life). SEM fit
statistics: χ
2
= 99.81, df = 31, p<0.001; χ
2
/df ratio = 3.22; goodness-of-fit index (GFI) = 0.967; comparative fit index (CFI) =
0.901; and root mean square error of approximation (RMSEA) = 0.061.
doi:10.1371/journal.pmed.1002251.g001
Cognitive reserve over the life course and dementia risk in late life
PLOS Medicine | DOI:10.1371/journal.pmed.1002251 March 14, 2017 8 / 17
and late life (range from 1 to 1, mean = 0.10, and SD = 0.655). Relative risks from models with
latent variables should be interpreted as per a 1 unit SD increase in the underlying latent factor.
The correlation between the early- and the adult-life latent factors was strong (γ= 0.9).
We began by analysing the association between the risk of dementia occurrence and contin-
uous cognitive reserve-enhancing composite factors derived from the SEM model on the risk
of dementia (S1 Table). In separate minimally adjusted (age and sex) Cox models, a reduced
risk of dementia was associated with early- (relative risk [RR] 0.61; 95% CI 0.41–0.90), adult-
(RR 0.53; 95% CI 0.31–0.91), and late-life (RR 0.70; 95% CI 0.53–0.92) continuous composite
factors. Estimating the association between dementia occurrence and all three life-course
reserve factors in a simultaneous-entry model yielded nonsignificant risk estimates of early-
(RR 1.19; 95% CI 0.22–6.39), adult- (RR 0.57; 95% CI 0.06–5.26), and late-life factors (RR 0.80;
95% CI 0.58–1.09).
We then converted the continuous reserve-enhancing factors into four categories based on
the quartile distribution and assessed their associations with the risk of dementia occurrence,
first in minimally adjusted separate Cox models and then in a fully adjusted model with all
three factors estimated simultaneously (Table 2). In separate models, all quartile categories of
the early-life reserve composite factor were associated with a reduced risk, relative to the bot-
tom category, although only quartile four was statistically significant (relative risk [RR] 0.45;
95% CI 0.27–0.77). Similarly, all quartile categories of the adult-life reserve composite factor
were associated with a reduced risk of dementia, relative to the bottom quartile (quartiles two
and four were statistically significant; RR 0.57; 95% CI 0.37–0.89, and RR 0.46; 95% CI 0.27–
Table 2. Number of participants, incident dementia cases, and relative risk (RR) (95% confidence interval [CI]) of dementia in relation to the cogni-
tive reserve latent factors acting at different time periods in the life course.
Number of
participants
Number of cases RR (95% CI) RR (95% CI)
Reserve factors From separate models adjusted for age and
sex
From one model with full
adjustment
Early life
Quartile
categories
1st 149 43 1 1
2nd 152 40 0.71 (0.46–1.09) 1.03 (0.60–1.78)
3rd 151 38 0.75 (0.49–1.17) 1.15 (0.52–2.53)
4th 150 27 0.45 (0.27–0.77) 0.60 (0.17–2.17)
Adulthood
Quartile
categories
1st 150 46 1 1
2nd 151 34 0.57 (0.37–0.89) 0.58 (0.34–1.00)
3rd 150 40 0.76 (0.50–1.17) 0.83 (0.39–1.74)
4th 151 28 0.46 (0.27–0.77) 0.99 (0.29–3.41)
Late life
Quartile
categories
1st 150 50 1 1
2nd 151 37 0.60 (0.39–0.92) 0.68 (0.43–1.06)
3rd 151 33 0.52 (0.33–0.81) 0.62 (0.39–0.99)
4th 150 28 0.44 (0.28–0.71) 0.59 (0.35–0.99)
Full adjustment: age, sex, depressive symptoms, comorbidity, and baseline cognitive function.
doi:10.1371/journal.pmed.1002251.t002
Cognitive reserve over the life course and dementia risk in late life
PLOS Medicine | DOI:10.1371/journal.pmed.1002251 March 14, 2017 9 / 17
0.77, respectively). All three quartiles of the late-life reserve composite factor were associated
with a statistically reduced risk of dementia relative to the bottom quartile category. When all
three composite factors were simultaneously entered into a single fully adjusted model, only
the late-life composite factor (except quartile 2) preserved its statistical association with a
reduced risk of dementia, whereas early- and adult-life reserve composite factors were no lon-
ger associated with a reduced risk of dementia.
Next, we converted all reserve factors into a dichotomous variable derived from a quartile
distribution by combining the top three quartiles of each composite factor and contrasting
them against the bottom quartile. The association between the risk of dementia occurrence
and the dichotomized cognitive reserve latent factors was estimated in three separate mini-
mally adjusted models, as well as in a single fully adjusted Cox regression (Fig 2). Whereas all
three dichotomized life-course cognitive reserve-enhancing composite factors were associated
with a reduced risk of dementia (early-life RR 0.57; 95% CI 0.36–0.90; adult-life RR 0.60; 95%
CI 0.42–0.87; late-life RR 0.52; 95% CI 0.37–0.73) when analysed separately in minimally
adjusted models, only the late-life factor remained statistically associated with a reduced risk
of dementia (RR 0.65; 95% CI 0.45–0.94) in the simultaneous fully adjusted model. The associ-
ation between dementia risk and the adult-life dichotomized composite factor was attenuated
and remained marginally statistically significant (RR 0.73; 95% CI 0.50–1.06), whereas the
early-life reserve-enhancing composite factor was the most attenuated (RR 0.76; 95% CI 0.47–
1.23). In additional analyses (S2 Table), we found that 39.3% of the total association between
Fig 2. RRs and 95% CIs of dementia in relation to early-life, adulthood, and late-life cognitivereserve-
enhancing composite factors. The RRs and 95% CIs on the left-hand side were estimated from three
separate Cox models adjusted for age and sex. The RRs and 95% CIs on the right are from a single Cox
model that simultaneously estimated the effects of composite indicators with additional adjustment for age,
sex, depressive symptoms, comorbidity, and baseline cognitive function. Early-life, adulthood, and late-life
cognitive reserve-enhancing composite indicators are dichotomized (top three quartiles versus the bottom
quartile) based on the quartile transformation of continuous variables (factor scores) extracted from an SEM
model.
doi:10.1371/journal.pmed.1002251.g002
Cognitive reserve over the life course and dementia risk in late life
PLOS Medicine | DOI:10.1371/journal.pmed.1002251 March 14, 2017 10 / 17
the early-life composite factor and the hazard rate of dementia was attributed to its indirect
association with adult- and late-life factors.
Early-life and adulthood latent factors were highly correlated (γ= 0.9). This implies that
total effects of either factor on dementia from individually estimated models might not be
independent and that the mutually adjusted effect of these variables might not be precisely esti-
mated because of collinearity. To better understand the structure of exposure status without
explicitly modelling the effect of each period, we divided participants into different groups
according to their exposure status (high versus low) at the three time periods (early, adult, and
late life). Because of study size limitations, we generated an index distinguishing between (1) a
high-reserve level for just a single life period, (2) a high level for two out of the three life peri-
ods, and (3) a high reserve for all three life periods. We then estimated the risk of dementia for
each of these three groups relative to those with a low level of reserve in all life periods (Fig 3).
Relative to individuals with low scores on all three life-course cognitive reserve-enhancing
composite factors over the life course, there was no significant reduction in the risk of demen-
tia for individuals with high scores on the composite indicator in one life period (RR 0.80; 95%
CI 0.46–1.41). Having high scores on the composite indicators in two life periods was associ-
ated with a significantly reduced risk of dementia (RR 0.50; 95% CI 0.27–0.91), with high
scores in all three life periods associated with an even greater dementia risk reduction (RR
0.40; 95% CI 0.20–0.81) in the model adjusted for age, sex, depressive symptoms, comorbidity,
and baseline cognitive function (Fig 3).
Finally, we found no evidence of a synergistic interaction between each of the life-course
cognitive reserve-enhancing composite factors and genetic predisposition (APOE ε4 status)
on risk of dementia (formal statistical test for interaction). Stratified analysis according to
APOE ε4 status furthermore revealed that having high cognitive reserve in two or three
Fig 3. RRs and 95% CIs of dementia in relation to cumulative exposure to reserve-enhancing
composite factors over the life course. Estimated from a simultaneous-entry Cox regression model
adjusted for age, sex, depressive symptoms, comorbidity, and baseline cognitive function.
doi:10.1371/journal.pmed.1002251.g003
Cognitive reserve over the life course and dementia risk in late life
PLOS Medicine | DOI:10.1371/journal.pmed.1002251 March 14, 2017 11 / 17
periods over the life course was associated with a lower risk of dementia in both ε4 allele carri-
ers (RR 0.5; 95% CI 0.3–0.9) and ε4 allele noncarriers (RR 0.7; 95% CI 0.5–0.97).
Discussion
Using a life-course approach, we found in our cohort that cognitive reserve-stimulating activi-
ties during early, adult, and late life were associated with a lower risk of dementia occurrence,
although the early-life association was partially (39.3%) mediated by mid- and late-life activi-
ties. We observed a reverse dose-response relationship between dementia risk and increased
duration of exposure to reserve-enhancing factors over the life course. However, the hypothe-
sized interaction between cumulative exposure to cognitive reserve factors and genetic predis-
position on the risk of dementia was not confirmed. The risk of dementia due to cumulative
exposure to cognitive reserve factors over the life course was reduced irrespective of individu-
als’ genetic predisposition to dementia.
This study has several strengths. First, this prospective study collected information on expo-
sures at least 4 y before incident dementia cases were diagnosed. Second, to avoid ascertain-
ment bias [46], only cognitively intact community dwellers with no dementia were included,
and people who developed dementia during the first 3 y were excluded from the study. Third,
the three latent reserve-enhancing composite factors were estimated using structural equation
modelling with a good overall fit. The use of latent factors has several advantages including (1)
the incorporation of the interrelated observed measures, (2) the pooling of common variance
across multiple index measures for each latent measure (increased convergent validity), and
(3) the correction for unreliability in observed measures by attenuating measurement error.
Limitations of this study include possible measurement error in measuring adult-life work
complexity, job demands, and decision latitude, as well as late-life leisure activities. However,
since information was obtained from the same source for all participants, the misclassification
is likely to be nondifferential and therefore should only lead to an underestimation of the true
population effects. In addition, nonresponse bias may have occurred, but it should not have
much bearing on the results because the distribution of participants and nonparticipants was
largely comparable with respect to demographic and health indicators. The correlation between
the early-life and the adulthood latent factors was strong (γ= 0.9). A respecified SEM model
was fit, excluding occupational complexity at 20 y as an indicator of the early-life factor, in an
attempt to reduce this association. While the correlation between the early and adult latent fac-
tors declined from 0.9 to 0.64, model fit deteriorated too. As one approach to circumventing
collinearity concerns, we examined the general exposure structure by evaluating the effects of
having high scores on latent factors over consecutive periods in life.
The results of the current study should first be considered in light of studies on cognitive
reserve measures collected at single periods during the life course [5,12,23]. Thus, consistent
with previous research, we have demonstrated that high scores on early-life measures of cogni-
tive reserve [5,12,24,47,48], engagement in adult reserve-enhancing activities, such as complex
occupational roles [6,12,16,24], and late-life engagement in leisure activities are all associated
with a lowered risk of dementia [49]. Although reserve-enhancing activities from distinct
periods of life have been individually linked with the risk of dementia previously, studies on
reserve contributors spanning several periods over the life course have been lacking, with the
exception of a few studies [12,24]. Notably, we extend this limited literature in an important
way by adding previously unmeasured markers of late-life reserve factors, as well as by simulta-
neously examining the effects of early-, adult-, and, crucially, late-life cognitive reserve factors
on dementia risk among the same individuals. Our findings underscore the contribution of
factors acting at different periods of the life course.
Cognitive reserve over the life course and dementia risk in late life
PLOS Medicine | DOI:10.1371/journal.pmed.1002251 March 14, 2017 12 / 17
A marked attenuation in the direct effect of the early-life composite factor on dementia risk
could be due to its correlation with the adult-life cognitive reserve-enhancing composite fac-
tor. It is noteworthy that the late-life factor was not strongly correlated with either the early- or
the adult-life composite factors. One possibility could be that disengagement from late-life lei-
sure activities is a sign of impending dementia, rather than a reflection of earlier-life reserve
contributors such as education or occupation. This could also account for the fact that associa-
tions between dementia risk and late-life factors were both significant and consistently esti-
mated, whereas the associations between dementia and early-life, as well as adult-life, factors
were less precise. Further studies using less correlated indicators are needed to explore the
independent effects of early-life influences on dementia risk. Our finding of a dose-response
relationship between the cumulative exposure to life-course cognitive reserve-enhancing com-
posite factors and dementia risk underscores the importance of exposures occurring at multi-
ple life periods.
Several biologically plausible hypotheses may explain the association between dementia risk
and cognitive reserve factors acting at different periods over the life course. The environment
plays a key role in influencing brain plasticity, which is the key element of the brain reserve
hypothesis, as well as influencing memory formations and learning processes that provide
the brain with a lifelong ability to change and to adjust [50]. Mental stimulation selectively
increases synaptogenesis, whereas physical exercise may enhance non-neuronal components
of the brain [18]. The ability of the brain to respond to environmental stimuli by adding new
neurons or by activating compensatory processes can be sustained in late life [51]. Previous
neuroimaging studies have shown that people with higher education, high occupational attain-
ment, or higher levels of intellectual, social, or physical activity may cope with brain damage
for a longer period of time [5255].
We found no evidence of an interaction between APOE ε4 status and cognitive reserve fac-
tors over the life course on risk of dementia, suggesting that protective effects of cognitive
reserve on dementia operate independently of genetic predisposition to the disease, which is
consistent with findings from a smaller study using a younger study population [56]. It is
known that the structural components of the nervous system are influenced not only by envi-
ronmental exposures but also as a function of genetic endowment. Although APOE ε2 has
been consistently shown to have neuroprotective effects and to increase synaptic plasticity
[57], APOE ε4 has been associated with negative effects on neurites and synaptic functions
[58,59]. Reserve-enhancing factors have been shown to enhance the functional organization of
the brain through greater resilience in neural circuits involved in cognition and to modify the
relationship between senile plaques and cognitive function [4]. Our findings suggest that
enhanced neuroplasticity by reserve-enhancing factors may compensate for the deterioration
of the brain function to the same extent in both APOE ε4 allele carriers and noncarriers.
Our findings point to the importance of adopting a life-course perspective in designing
interventions aimed at enhancing cognitive reserve in order to prevent or postpone dementia
incidence. It is never too late to initiate interventions because even late-life activities were asso-
ciated with lower risk of dementia in our study. Nevertheless, interventions aimed at earlier
life periods might be more beneficial, not only because greater exposure frequency has been
linked with a reduced risk but also because of the correlated nature of reserve contributors
over the life course. Importantly, these interventions should be equally effective among indi-
viduals with and without genetic susceptibility.
Cognitive reserve over the life course and dementia risk in late life
PLOS Medicine | DOI:10.1371/journal.pmed.1002251 March 14, 2017 13 / 17
Supporting information
S1 Table. Risk of dementia in relation to the continuous cognitive reserve latent factors.
Adjusted for age, gender, depressive symptoms, comorbidity, and baseline cognitive function.
(DOCX)
S2 Table. Total, direct, and indirect effects of cognitive reserve factors on dementia. Results
are from Cox models with dementia as the outcome variable. Exposures are the latent factors
from early-, adult-, and late-life portions of the life course categorized as dichotomous variables
identifying the top three quartiles versus the bottom quartile. First, a full model including all three
life-course factors and covariates was fit, with estimated parameters producing the direct effects
of early-, adult- and late-life factors. Next, a series of reduced models that included only early-,
adult-, or late-life indicators were estimated, with parameters from these models producing the
total effect of each life-course indicator. The difference between the total and the direct effect for
each of the latent life-course factors yielded an estimate of its indirect effect through all mediating
factors. The significance of the indirect effect was tested through the model likelihood ratio,
which is 2 times the difference of the log likelihood between the adjacent models, distributed as
χ
2
with the degree of freedom equal to the difference in the number of parameters between the
two models. All models are adjusted for age, gender, depressive symptoms, comorbidity, and
baseline cognitive function.
(DOCX)
S1 Text. SEM computation details.
(DOCX)
S2 Text. Questions on sibship size, education, occupation, and leisure activities.
(DOCX)
Author Contributions
Conceptualization: HXW LF.
Formal analysis: HXW SWSM.
Funding acquisition: HXW LF.
Methodology: HXW SWSM SD.
Software: HXW SWSM.
Validation: HXW SWSM SD.
Writing – original draft: HXW.
Writing – review & editing: HXW LF SWSM SD.
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Cognitive reserve over the life course and dementia risk in late life
PLOS Medicine | DOI:10.1371/journal.pmed.1002251 March 14, 2017 17 / 17
... In an attempt to disentangle the causal direction of effects, some researchers focus on data in which there is a relatively long lag between the measures of engagement and cognition (Hassing 2020). Another strategy to minimize any effects of cognitive status on activity engagement is through rigorous screening for dementia and mild cognitive impairment at baseline (Fabrigoule et al. 1995;Karp et al. 2006;Wang et al. 2002Wang et al. , 2017. Finally, when data for both engagement and cognition are available across time, the comparison of alternative causal models is ideal (Lövdén et al. 2005, Small et al. 2012. ...
... In a longitudinal sample that was determined to be dementia-free at baseline, Sörman et al. (2014) found that social activity (but not mental activity) decreased dementia risk up to five years after baseline. Based on a sample in which participants were selected for cognitive health at baseline, Wang et al. (2017) reported that, controlling for early-life education and midlife work complexity, individuals who engaged in activities rated by an independent group to be high in mental and social demands were at reduced risk for AD three years later [see also Wang et al. (2013), who controlled for apoE4 status. Retrospective reports of social and intellectual activities during midlife have been found to predict cognition at age 79 (Gow et al. 2017). ...
Article
Biologically based senescence processes and cumulative opportunities for experience collectively give rise to profound changes in cognition in later adulthood, the trajectories of which vary considerably across individuals. This review focuses on how cognitive aging is shaped by engagement—defined as the ongoing investment of personal resources (e.g., time, attention) to activities, social networks, and experiences—through the adult life span. We review evidence for the effects of different forms of engagement on cognitive aging and consider plausible mechanistic pathways for such effects. Working within an ecological framework, we consider “design solutions” for lifestyle engagement to shape adult cognitive development given the necessary trade-offs endemic to goal-directed systems (e.g., current needs versus long-term preparation, flexibility versus robustness, exploration versus exploitation). Given the limited evidence for broad-based effects of skill training on late-life cognitive health, we argue that a promising paradigm for successful cognitive aging will be to probe synergistic effects of engagement on cognitive aging. Recent developments in personal technology offer promise for innovation in intervention and in measurement. Expected final online publication date for the Annual Review of Developmental Psychology, Volume 4 is December 2022. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.
... This study investigated whether audiometric HL affected cognition-related indexes in a multicenter SCD cohort. For the cognitive performance of neuropsychological tests to be compared between the NH and HL groups, the age and education level should be controlled first [6,17,31]. Therefore, preadjusted z-scores were obtained with reference to age-, sex-, and education-stratified norms of the neuropsychological test battery used in this study. ...
... High-level engagement in social activity and large social networks are related to better cognitive function in later life [48]. A communitybased cohort study has demonstrated that early-life education, midlife occupational attainment, and late-life mentally stimulating leisure activities are cognitive reserve-enhancing factors which reduce the risk of dementia [31]. In short, HL may exert a direct adverse effect on cognitive performance through compensatory auditory processing consuming cognitive resources or an indirect negative effect on cognitive function through reduced cognitive reserve-enhancing factors. ...
Article
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Introduction: Subjective cognitive decline (SCD) is a self-reported cognitive decline without objective cognitive impairment. The relationship between audiometric hearing loss (HL) and cognitive function has not been reported in SCD. The purpose of this study was to investigate whether HL affects cognition-related indexes in SCD individuals. Methods: This is a cross-sectional study that used the baseline data of a multicenter cohort study that monitors clinical progression from SCD to dementia. Individuals aged ≥60 years who reported cognitive decline but had no objective cognitive impairment on comprehensive neuropsychological tests were recruited. Participants were grouped into the normal-hearing (NH) and bilateral HL groups. The demographics, clinical characteristics, dementia biomarkers, global cognition, questionnaire scores, neuropsychological test scores, and segmental brain volumes from MRI were compared between the groups. Results: Of a total of 120 participants, one hundred and two had NH (n = 57) or bilateral HL (n = 45). There were no group differences in the demographic and clinical data except the age. The biomarkers, global cognition, and questionnaire scores were not different between the groups. The HL group performed worse (the z-score of -0.06) in the Stroop Color Word Test than the NH group (0.27) (p = 0.025). Brain volumetric analysis revealed that the HL group had reduced gray matter volumes in four brain subregions: left temporal pole, left caudal middle frontal gyrus, left hippocampus, and right isthmus of the cingulate gyrus. Conclusion: In SCD, HL exerted an adverse effect on cognitive function, primarily frontal executive function tested in the Stroop task. HL was also related to gray matter volume reductions in brain subregions, although causality needs further investigation. This study may provide evidence for a potential link between hearing and cognition in SCD, an emerging clinical entity.
... First, individuals in more advantaged social classes have better access to education [10][11][12], creative and cognitively demanding occupations [10,13,14] and cognitively complex leisure activities such as going to the theatre, opera and museums [15,16]. Exposure to lifelong cognitive stimulation of this sort enables the development of so-called cognitive/brain reserve, delaying the clinical manifestation of existing dementia-type brain changes [17][18][19][20]. Second, these individuals endure less chronic background stress associated with, for example, insecure housing, work and bill payments [21,22]. ...
... Meanwhile, both education and occupational complexity are targets of interventions in public health, aiming to reduce the incidence of dementia [64][65][66][67]. The significance of education and occupation in our results shows that at least one casual pathway, linking belonging to a social class and the risk of dementia, might be cognitive/brain reserve [17][18][19][20]. Social characteristics of the residential neighbourhood as an indicator of social class also yielded a significant association with the risk of dementia in the crude model. ...
Article
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Background The association between belonging to a disadvantaged socio-economic status or social class and health outcomes has been consistently documented during recent decades. However, a meta-analysis quantifying the association between belonging to a lower social class and the risk of dementia has yet to be performed. In the present work, we sought to summarise the results of prospective, longitudinal studies on this topic. Methods We conducted a systematic review and meta-analysis of prospective, longitudinal studies measuring the association between indicators of social class and the risk of all-cause/Alzheimer’s dementia. The search was conducted in four databases (Medline, Embase, Web of Science and PsychInfo). Inclusion criteria for this systematic review and meta-analysis were: (a) longitudinal prospective study, (b) aged ⩾60 years at baseline, (c) issued from the general population, (d) no dementia at baseline and (e) mention of social class as exposure. Exclusion criteria were: (a) study of rare dementia types (e.g. frontotemporal dementia), (b) abstract-only papers and (c) articles without full text available. The Newcastle–Ottawa scale was used to assess the risk of bias in individual studies. We calculated the overall pooled relative risk of dementia for different social class indicators, both crude and adjusted for sex, age and the year of the cohort start. Results Out of 4548 screened abstracts, 15 were included in the final analysis (76,561 participants, mean follow-up 6.7 years (2.4–25 years), mean age at baseline 75.1 years (70.6–82.1 years), mean percentage of women 58%). Social class was operationalised as levels of education, occupational class, income level, neighbourhood disadvantage and wealth. Education (relative risk (RR)=2.48; confidence interval (CI) 1.71–3.59) and occupational class (RR=2.09; CI 1.18–3.69) but not income (RR=1.28; CI 0.81–2.04) were significantly associated with the risk of dementia in the adjusted model. Some of the limitations of this study are the inclusion of studies predominantly conducted in high-income countries and the exclusion of social mobility in our analysis. Conclusions We conclude that there is a significant association between belonging to a social class and the risk of dementia, with education and occupation being the most relevant indicators of social class regarding this risk. Studying the relationship between belonging to a disadvantaged social class and dementia risk might be a fruitful path to diminishing the incidence of dementia over time. However, a narrow operationalisation of social class that only includes education, occupation and income may reduce the potential for such studies to inform social policies.
... Therefore, cognitive trajectories in neurodegenerative diseases such as Alzheimer's disease (AD) are highly variable between individuals (Perneczky et al., 2009;Reed et al., 2010;Valenzuela et al., 2009). Early-life education, good socioeconomic status, work complexity, midlife occupational attainment, and late-life leisure activities have been associated with lower dementia risk (Pettigrew and Soldan, 2019;Scarmeas et al., 2006;Wang et al., 2017). ...
Article
Alzheimer's disease (AD) is associated with alterations in functional connectivity (FC) of the brain. The FC underpinnings of CR, i.e. lifelong experiences, are largely unknown. Resting-state FC and structural MRI were performed in 76 CSF amyloid-β (Aβ) negative healthy controls and 152 Aβ positive individuals as an AD spectrum cohort (ADS; 55 with subjective cognitive decline, SCD; 52 with mild cognitive impairment; 45 with AD dementia). Following a region-of-interest (ROI) FC analysis, intrinsic network connectivity within the default-mode network (INC-DMN) and anti-correlation in INC between the DMN and dorsal attention network (DMN:DAN) were obtained as composite scores. CR was estimated by education and Lifetime Experiences Questionnaire (LEQ). The association between INC-DMN and MEM was attenuated by higher LEQ scores in the entire ADS group, particularly in SCD. In ROI analyses, higher LEQ scores were associated with higher FC within the DMN in ADS group. INC-DMN remains relatively intact despite memory decline in individuals with higher lifetime activity estimates, supporting a role for functional networks in maintaining cognitive function in AD.
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Background: It is now acknowledged that Alzheimer’s disease (AD) processes are present decades before the onset of clinical symptoms, but it remains unknown whether lifestyle factors can protect against these early AD processes in mid-life. Objective: We asked whether modifiable lifestyle activities impact cognition in middle-aged individuals who are cognitively healthy, but at risk for late life AD. Participants (40–59 years) completed cognitive and clinical assessments at baseline (N = 206) and two years follow-up (N = 174). Methods: Mid-life activities were measured with the Lifetime of Experiences Questionnaire. We assessed the impact of lifestyle activities, known risk factors for sporadic late-onset AD (Apolipoprotein E ɛ4 allele status, family history of dementia, and the Cardiovascular Risk Factors Aging and Dementia score), and their interactions on cognition. Results: More frequent engagement in physically, socially, and intellectually stimulating activities was associated with better cognition (verbal, spatial, and relational memory), at baseline and follow-up. Critically, more frequent engagement in these activities was associated with stronger cognition (verbal and visuospatial functions, and conjunctive short-term memory binding) in individuals with family history of dementia. Impaired visuospatial function is one of the earliest cognitive deficits in AD and has previously associated with increased AD risk in this cohort. Additionally, conjunctive memory functions have been found impaired in the pre-symptomatic stages of AD. Conclusion: These findings suggest that modifiable lifestyle activities offset cognitive decrements due to AD risk in mid-life and support the targeting of modifiable lifestyle activities for the prevention of AD.
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When we get older, we tend to have more trouble remembering things and we tend to forget certain things more often. It is normal to have a small decrease in memory with age, but when memory decreases too much it becomes a disease: what is called dementia. Unfortunately, there is currently no treatment for dementia. However, there are certain actions that can be taken to try to prevent dementia, or at least to delay the onset of dementia symptoms. One of these is to use video games to (re)train brain functions. Yes, you read that right—some video games can be used to train the memory!
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Background Recovery of cognitive function after stroke has inter-individual variability. The theory of cognitive reserve offers a potential explanation of the variability in cognitive function after stroke. Objective This study aimed to investigate the moderating effect of cognitive reserve on the relationship between the stroke severity and cognitive function after stroke. Materials and methods A total of 220 patients with Acute Ischemic Stroke (AIS) were recruited in 2021 from two stroke centers in Nanjing, China. The National Institutes of Health Stroke Scale (NIHSS) was used to assess stroke severity upon admission. Cognitive Reserve Index questionnaire (CRIq) and validated Montreal Cognitive Assessment, Changsha Version (MoCA-CS) were used to assess cognitive reserve and cognitive function within 7 days after stroke onset, respectively. A series of multivariate linear regression models were applied to test the moderating effect of cognitive reserve. Results Patients with a higher level of cognitive reserve had better cognitive function after stroke compared with those with a lower level of cognitive reserve (β = 0.074, p = 0.003). The interaction of NIHSS and cognitive reserve was statistically significant (β = −0.010, p = 0.045) after adjusting for some key covariates [e.g., age, marital status, Oxfordshire Community Stroke Project (OCSP) classification, Trial of ORG 10172 in Acute Stroke Treatment (TOAST) classification, cerebral vascular stenosis, diabetes and atrial fibrillation]. Conclusion Cognitive reserve may help to buffer the effect of stroke-related pathology on cognitive decline in Chinese acute stroke patients. Enhancing cognitive reserve in stroke patients may be one of the potential strategies for preventing vascular dementia.
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PurposeThis study aimed to explore the potential mediating effects of cognitive reserve on the association between frailty and cognition in the older people without dementia. Methods We performed a cross-sectional analysis of data from 3122 community-dwelling older adults (≥ 65-years-old) without dementia of the Cognitive Function and Ageing Study in Wales. A 31-item frailty index was used to assess frailty. A cognitive lifestyle score was constructed to evaluate cognitive reserve, which includes participants’ educational level, occupational attainment, and engagement in social and cognitive activities in later life. Linear regression and mediation modeling were used to investigate the relationship between frailty and cognition and the mediating effects of cognitive reserve as well as social and cognitive activities, an alterable component of cognitive reserve for older adults. ResultsFrailty was negatively associated with cognition. Cognitive reserve was a mediator of the association between frailty and global cognition (− 1.92; 95% CI: − 2.50, − 1.35), as well as individual cognitive domains, with indirect effects contributing to 13-59% of the total effects. Social and cognitive activities have smaller but similar mediating effects on these associations. Conclusions Negative effect of frailty on cognition was partially mediated by a reduction in cognitive reserve. Our results support the possibility that enhancing cognitive reserve, especially engagement in social and cognitive activities may protect cognitive health against frailty.
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Background and objectives As the population ages, differences in cognitive abilities become more evident. We investigated key genetic and life course influences on cognitive state at age 69, building on previous work using the longitudinal MRC National Survey of Health and Development (the British 1946 birth cohort). Methods Multivariable regressions investigated the association between four factors :(1) childhood cognition at age 8; (2) a cognitive reserve index (CRI) composed of 3 markers: i. educational attainment by age 26, ii. engagement in leisure activities at age 43, and iii. occupation up to age 53; (3) reading ability assessed by the National Adult Reading Test (NART) at age 53 and (4) APOE genotype in relation to cognitive state measured at age 69 with Addenbrooke’s Cognitive Examination third edition (ACE-III). We then investigated the modifying role of the CRI, NART, and APOE in the association between childhood cognition and the ACE-III. Results The analytical sample was comprised of 1,184 participants. Higher scores in childhood cognition, CRI and NART were associated with higher scores in the ACE-III. We found that the CRI and NART modified the association between childhood cognition and the ACE-III: for 30 additional points in the CRI or 20 additional points in the NART, the simple slope of childhood cognition decreased by approximately 0.10 points (CRI= 70: Marginal Effects (ME) 0.22, 95% CI 0.12-0.32, p<0.001 versus CRI= 100: ME 0.12, 95% CI 0.06-0.17, p<0.001; NART=15: ME 0.22, 95% CI 0.09-0.35, p=0.001, versus NART= 35: ME 0.11, 95% CI 0.05-0.17, p<0.001). The association between childhood cognition and the ACE-III was non-significant at high levels of the CRI or NART. Furthermore, the e4 allele of the APOE gene was associated with lower scores in the ACE-III (ß=-0.71, 95% CI -1.36 to -0.06, p=0.03) but did not modify the association between childhood cognition and cognitive state in later life. Conclusion The CRI and NART are independent measures of cognitive reserve since both modify the association between childhood cognition and cognitive state.
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Large population-based studies on the associations of childhood factors with late-life cognition are lacking in many low and middle income countries including India. In this study, we assessed the prevalence of late-life cognitive impairment and examined the associations of childhood socioeconomic status (SES) and health conditions with cognitive impairment among older adults in India. Data for this study were derived from the Longitudinal Ageing Study in India conducted in 2017–18. The effective sample size was 31,464 older adults aged 60 years and above. Cognitive functioning was measured through five global domains (memory, orientation, arithmetic function, executive function, and object naming). The overall score ranged between 0 and 43, and the score was reversed indicating cognitive impairment. Descriptive statistics along with mean scores of cognitive impairment were presented. Additionally, moderated multivariable linear regression models were employed to examine the association between explanatory variables, including childhood SES and health conditions and late-life cognitive impairment. The mean score of cognitive functioning among the study participants was 21.72 (CI 2.64–21.80). About 15% of older adults had poor health conditions, and 44% had lower financial status during their childhood. Older adults who had a fair health during their childhood were more likely to suffer from cognitive impairment in comparison to older adults who had good health during their childhood (Coef: 0.60; CI 0.39, 0.81). In comparison to older adults who had good childhood financial status, those who had poor childhood financial status were more likely to suffer from cognitive impairment (Coef: 0.81; CI 0.56, 1.07). Older adults who had fair childhood health status and poor childhood financial status were more likely to suffer from cognitive impairment in comparison to older adults who had good childhood health and good financial status (Coef: 1.26; CI 0.86, 1.66). Social policies such as improving educational and financial resources in disadvantaged communities and socioeconomically poor children and their families, would help to enhance a better cognitive ageing and a healthy and dignified life in old age.
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Background: Cognitive reserve hypothesis predicts that intellectually demanding activities over the life course protect against dementia. We investigate if childhood school performance remains associated with dementia once education and occupational complexity are taken into account. Methods: A cohort of 440 individuals aged 75+ from the Kungsholmen Project was followed up for 9 years to detect dementia. To measure early-life contributors to reserve, we used grades at age 9-10 extracted from the school archives. Data on formal education and occupational complexity were collected at baseline and first follow-up. Dementia was ascertained through comprehensive clinical examination. Cox models estimated the relationship between life-course cognitive reserve measures and dementia. Results: Dementia risk was elevated [hazard ratio (HR): 1.54, 95% confidence interval (CI): 1.03 to 2.29] in individuals with low early-life school grades after adjustment for formal educational attainment and occupational complexity. Secondary education was associated with a lower risk of dementia (HR: 0.72, 95% CI: 0.50 to 1.03), although the effects of post-secondary and university degrees were indistinguishable from baseline. Occupational complexity with data and things was not related to dementia. However, an association was found between high occupational complexity with people and dementia, albeit only in women (HR: 0.39, 95% CI: 0.14 to 0.99). The pattern of results remained unchanged after adjustment for genetic susceptibility, comorbidities and depressive symptoms. Conclusion: Low early-life school performance is associated with an elevated risk of dementia, independent of subsequent educational and occupational attainment.
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We determined topographic selectivity and diagnostic utility of brain atrophy in probable Alzheimer's disease (AD) and correlations with demographic factors such as age, sex, and education. Computerized imaging analysis techniques were applied to MR images in 32 patients with probable AD and 20 age- and sex-matched normal control subjects using tissue segmentation and three-dimensional surface rendering to obtain individualized lobar volumes, corrected for head size by a residualization technique. Group differences emerged in gray and white matter compartments particularly in parietal and temporal lobes. Logistic regression demonstrated that larger parietal and temporal ventricular CSF compartments and smaller temporal gray matter predicted AD group membership with an area under the receiver operating characteristic curve of 0.92. On multiple regression analysis using age, sex, education, duration, and severity of cognitive decline to predict regional atrophy in the AD subjects, sex consistently entered the model for the frontal, temporal, and parietal ventricular compartments. In the parietal region, for example, sex accounted for 27% of the variance in the parietal CSF compartment and years of education accounted for an additional 15%, with women showing less ventricular enlargement and individuals with more years of education showing more ventricular enlargement in this region. Topographic selectivity of atrophic changes can be detected using quantitative volumetry and can differentiate AD from normal aging. Differential effects of sex and years of education can also be detected by these methods. Quantification of tissue volumes in vulnerable regions offers the potential for monitoring longitudinal change in response to treatment.
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The western fertility decline is arguably the most significant demographic change to have occurred in the past 200 years, yet its causes and processes are still shrouded in ambiguity due to a lack of individual-level longitudinal data. A growing body of research has helped improve our understanding of the decline's causes by examining the development of socioeconomic differences in fertility using historical micro-data, but these have largely only considered rural areas where fertility was generally slower to decline. This article contributes to the literature by utilizing individual-level data from the Roteman Database for Stockholm, Sweden between 1878 and 1926 to examine the association of socioeconomic status and fertility and the adoption of stopping behaviour during the city's transition. Using piecewise constant hazard models and logistic regression, we find that a clear class pattern arises in which the elite were early practitioners of fertility control, followed by the working classes. As the transition unfolded, socioeconomic differences in stopping behaviour disappeared and overall fertility differentials were also minimized, both of them being consistent with patterns observed in rural populations. The implications of these findings for major explanations of the decline are discussed in the concluding section.
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The recent availability of longitudinal data on the possible association of different lifestyles with dementia and Alzheimer's disease (AD) allow some preliminary conclusions on this topic. This review systematically analyses the published longitudinal studies exploring the effect of social network, physical leisure, and non-physical activity on cognition and dementia and then summarises the current evidence taking into account the limitations of the studies and the biological plausibility. For all three lifestyle components (social, mental, and physical), a beneficial effect on cognition and a protective effect against dementia are suggested. The three components seem to have common pathways, rather than specific mechanisms, which might converge within three major aetiological hypotheses for dementia and AD: the cognitive reserve hypothesis, the vascular hypothesis, and the stress hypothesis. Taking into account the accumulated evidence and the biological plausibility of these hypotheses, we conclude that an active and socially integrated lifestyle in late life protects against dementia and AD. Further research is necessary to better define the mechanisms of these associations and better delineate preventive and therapeutic strategies.
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Recent findings suggest that a rich social network may decrease the risk of developing dementia. The authors hypothesized that such a protective effect may be due to social interaction and intellectual stimulation. To test this hypothesis, data from the 1987-1996 Kungsholmen Project, a longitudinal population-based study carried out in a central area of Stockholm, Sweden, were used to examine whether engagement in different activities 6.4 years before dementia diagnosis was related to a decreased incidence of dementia. Dementia cases were diagnosed by specialists according to Diagnostic and Statistical Manual of Mental Disorders, Third Edition, Revised, criteria. After adjustment for age, sex, education, cognitive functioning, comorbidity, depressive symptoms, and physical functioning at the first examination, frequent (daily-weekly) engagement in mental, social, or productive activities was inversely related to dementia incidence. Adjusted relative risks for mental, social, and productive activities were 0.54 (95% confidence interval (CI): 0.34, 0.87), 0.58 (95% CI: 0.37, 0.91), and 0.58 (95% CI: 0.38, 0.91), respectively. Similar results were found when these three factors were analyzed together in the same model. Results suggest that stimulating activity, either mentally or socially oriented, may protect against dementia, indicating that both social interaction and intellectual stimulation may be relevant to preserving mental functioning in the elderly.