Differences In Cognitive Reserve Research Articles

Cognitive reserve predicts episodic memory enhancement induced by transcranial direct current stimulation in healthy older adults

Episodic memory shows the largest degree of age-related decline. Anodal transcranial Direct Current Stimulation (tDCS) can enhance episodic memory in aging but there is also evidence of response variability even when using identical stimulation parameters. To explore which inter-individual factors (i.e. age, education, encoding performance, cognitive reserve, tDCS group and timing of tDCS application) may directly and/or indirectly modulate verbal memory recall, we used data from our previous tDCS studies that showed enhanced episodic memory recall in 80 healthy older adults. In these studies we used the same paradigm and stimulation parameters but tDCS was applied during different memory stages. Memory recall was tested 48 hours and 30 days after encoding. Univariate regression models showed that tDCS group (Anodal vs. Sham) predicted memory recall, indicating higher scores in the Anodal group than in the Sham group. Encoding performance predicted memory recall in both tDCS groups. Multiple regression models revealed that cognitive reserve, measured with a life experience questionnaire, predicted memory recall only for the Anodal group. Higher cognitive reserve was linked to better memory recall. Accounting for individual differences in cognitive reserve at baseline helps to explain tDCS responsiveness. This knowledge may contribute to optimize its use in older adults.

Women and the risk of Alzheimer's disease.

This review will elucidate reasons to explain why women may be at greater risk for Alzheimer's disease. Potential mechanisms to explain sex and gender differences in Alzheimer dementia include: differences in risk associated with the apolipoprotein E 4 allele; telomere shortening- which is linked with neurodegeneration, higher incidence of depression and insomnia in women as psychiatric co-morbidities which are linked with an increased Alzheimer disease risk, disorders of pregnancy including gestational hypertension and preeclampsia and psychosocial factors such as educational level which may contribute to differences in cognitive reserve. The sex and gender differences in Alzheimer's disease can be explained by biological and psychosocial factors.

Are sex differences in verbal memory related to sex differences in cognitive reserve?

AbstractBackgroundCognitive reserve (CR) is the capacity to maintain cognitive performances despite underlying brain pathology and a concept used in Alzheimer’s disease (AD) studies to explain clinical heterogeneity. Evidence for a female‐specific verbal memory reserve may contribute to sex disparities in AD incidence, via delayed diagnosis. However, whether sex differences in verbal memory relate to sex differences in CR, is unclear. The current study examined whether multiple measures of CR differed by sex and whether they mediated sex differences in verbal memory.MethodCross‐sectional data from 59 older adults (mean age = 68.1; SD = 10.7; Female = 62%; White = 70%), without a prior diagnosis of cognitive impairment, were included. Total recall from the immediate and delayed recall trials of the scores Hopkins Verbal Learning Test (HVLT) were used to assess verbal learning and memory. Years of education, self‐reported leisure activities, physical activity, mindfulness, and the MIND diet were used to assess CR. Sex differences in HVLT scores were tested with ANCOVAs, controlling for age and reran adjusting for education. A MANCOVA was used to assess sex differences on CR measures. A mediation analyses was used to test whether sex differences in CR measures mediated the association between sex differences and verbal memory.ResultWomen had higher scores on HVLT learning (M = 23.1, SD = 5.2; p<.01), delayed recall (M = 8.2; SD = 2.6; p<.01) and leisure activities (M = 35.93; SD = 7.9; p<.01) compared to men (learning: M = 19.5; SD = 5.2; delayed recall: M = 6.2; SD = 2.5; leisure: M = 28.5; SD = 10.9; p<.01). No other sex differences in CR measures were revealed. Leisure activities fully mediated sex and HVLT associations, such that women’s higher scores on leisure explained 39% and 35% of the variance between sex and HVLT learning and delayed recall, respectively.ConclusionWomen’s overall higher engagement in leisure activities accounted for their higher scores on HVLT learning and delayed recall relative to men. Increasing men’s engagement in leisure activities could attenuate sex differences in verbal learning/memory but warrants further investigation. Larger and more diverse samples are needed for follow‐up data analyses.

A - 72 Neuropsychological Test Performance in Mild to Moderate COVID-19 Patients with and without Subjective Cognitive Complaints.

This cross-sectional study measured cognitive performance in mild-moderate COVID-19 patients with and without self-reported persistent cognitive complaints, while accounting for demographic variables, cardiovascular (CVD) risk factors, and mood symptoms. We hypothesized that individuals with persistent cognitive complaints would demonstrate lower global cognitive composite scores compared to those without. 67 adults aged 24-83 completed in-person neuropsychological testing in a hospital setting in Phoenix, Arizona. PCR-confirmed COVID-19 within 24months before evaluation and no pre-existing neurological conditions. The Long COVID (LC) group included those with persistent cognitive symptoms 4+ weeks after infection; COVID-positive Controls (CC) included those with prior infection but without persistent cognitive symptoms. Demographic information, CVD risk factors, and psychiatric history were collected. Neuropsychological evaluation included performance validity testing and validated measures of attention, language, visuospatial ability, executive function, and memory. T-scores from each domain were averaged to create a global cognitive composite score. Gender, age, race (white/non-white), mood disorder, and CVD were equivalent across groups. Education was significantly higher in the LC group, t(65) = 2.737, p = 0.008, and was included as a covariate in the model to account for differences in cognitive reserve. With this adjustment, there was not a statistically significant difference in global composite scores between groups, F(1, 64) = 0.13, p = 0.911, partial η2 = 0.000. Cognitive performance did not differ between LC and CC groups when demographics, cardiovascular risk, and mood symptoms were held constant, suggesting that other factors influence the development of persistent cognitive complaints in mild-moderate COVID-19 patients.

Sex differences in the protective effects of cognitive reserve

AbstractBackgroundCognitive reserve is the term used to describe the apparent ability of one’s cognitive processes or neural networks to adapt in response to neuropathology and brain injury. This protective ability is proposed to account for individual differences in age‐associated cognitive decline and Alzheimer’s disease (AD) risk, where higher levels of cognitive reserve are associated with more preserved cognitive functioning and delayed onset of AD dementia. Women have a higher prevalence of AD than men, and account for two‐thirds of AD diagnoses. Sex differences in the protective ability of cognitive reserve may account for differences in Alzheimer’s disease prevalence between men and women, but few studies have explored this possibility. This study evaluates sex as a moderator of the relationship between cognitive reserve and brain volume effects on executive function.MethodThe study used archival data from 997 older adult participants in the Australian Imaging, Biomarkers, and Lifestyle(AIBL) Flagship Study of Ageing (see Table 1 for descriptives). Structural equation modelling was used to estimate a proxy for cognitive reserve and to run the analytical model. Cognitive reserve was defined as the variance in episodic memory not explained by demographics (e.g., education) and brain integrity (i.e., the residual reserve index; Reed et al., 2010). Executive functioning intercept and slope – derived from up to 7 study visits (18‐month follow‐up intervals) – were regressed onto the main and interaction effects of the residual reserve index, brain integrity (i.e., the combination of grey matter, hippocampal, and white matter hyperintensity volumes), and sex, plus covariates (e.g., number of apolipoprotein alleles; age).ResultA significant three‐way interaction was observed between cognitive reserve, brain integrity, and sex; Women benefitted more than men from the protective effects of cognitive reserve at comparably low levels of brain integrity. Further analyses also showed that women, on average, have higher levels of cognitive reserve as reflected by the residual reserve index.ConclusionSex differences in cognitive reserve highlight a potential sex‐related mechanism by which cognitive reserve confers protection against cognitive decline in the face of low brain integrity. These findings further our understanding of potential factors that maximise the protective effect of cognitive reserve.

Age-Specific Activation Patterns and Inter-Subject Similarity During Verbal Working Memory Maintenance and Cognitive Reserve.

Cognitive Reserve (CR), according to a recent consensus definition of the NIH-funded Reserve and Resilience collaboratory,1 is constituted by any mechanism contributing to cognitive performance beyond, or interacting with, brain structure in the widest sense. To identity multivariate activation patterns fulfilling this postulate, we investigated a verbal Sternberg fMRI task and imaged 181 people with age coverage in the ranges 20–30 (44 participants) and 55–70 (137 participants). Beyond task performance, participants were characterized in terms of demographics, and neuropsychological assessments of vocabulary, episodic memory, perceptual speed, and abstract fluid reasoning. Participants studied an array of either one, three, or six upper-case letters for 3 s (=encoding phase), then a blank fixation screen was presented for 7 s (=maintenance phase), to be probed with a lower-case letter to which they responded with a differential button press whether the letter was part of the studied array or not (=retrieval phase). We focused on identifying maintenance-related activation patterns showing memory load increases in pattern score on an individual participant level for both age groups. We found such a pattern that increased with memory load for all but one person in the young participants (p < 0.001), and such a pattern for all participants in the older group (p < 0.001). Both patterns showed broad topographic similarities; however, relationships to task performance and neuropsychological characteristics were markedly different and point to individual differences in Cognitive Reserve. Beyond the derivation of group-level activation patterns, we also investigated the inter-subject spatial similarity of individual working memory rehearsal patterns in the older participants’ group as a function of neuropsychological and task performance, education, and mean cortical thickness. Higher task accuracy and neuropsychological function was reliably associated with higher inter-subject similarity of individual-level activation patterns in older participants.

Sex differences in the behavioral variant of frontotemporal dementia: A new window to executive and behavioral reserve

AbstractBackgroundThe behavioral variant of frontotemporal dementia (bvFTD) is characterized by progressive behavioral change along with social, cognitive, and functional deterioration. In contrast Alzheimer´s disease, patients with bvFTD show an anterior pattern of neurodegeneration with selective involvement of the frontotemporal cortex. Biological sex is an increasingly recognized factor driving clinical heterogeneity in Alzheimer's disease, but its role in bvFTD is unknown.MethodIn this multicenter study, we aimed to characterize the impact of sex on clinical presentation, longitudinal decline, and cortical thickness in bvFTD. We included 216 patients with bvFTD and 235 controls with MRI. We compared the clinical characteristics and cortical thickness between men and women with bvFTD and controls. We further explored the existence of sex differences in cognitive reserve by following the residuals approach to operationalize reserve as having better cognition and fewer behavioral changes than predicted by cortical thickness (a proxy of pathology). To do this, we modeled the relationship between cognition or behavior with cortical thickness and used each individual's residual as a proxy of their reserve.ResultAt diagnosis, women with bvFTD showed greater atrophy burden in frontotemporal regions compared to men despite very subtle differences in cognitive and functional impairment, progression, and survival. For a similar amount of atrophy, women demonstrated better‐than‐expected scores on executive function and less apathy, sleep, and appetite changes than men.ConclusionOur findings suggest that women might have greater behavioral and executive reserve than men. Future studies should examine the specific mechanisms underlying the observed differences and consider biological sex for the design of research studies and clinical trials in bvFTD and other frontotemporal lobar degeneration syndromes.

Sex differences in cognitive reserve among first episode of psychosis patients.

Cognitive reserve (CR) has recently been considered a key factor in the onset of a first episode of psychosis (FEP). However, the differences in CR in FEP patients according to sex have not yet been investigated. CR was estimated among 443 FEP patients (246 men and 197 women) and 156 healthy controls (96 men and 60 women) by using the proxies premorbid IQ, years of education and employment status. A neuropsychological battery was administrated to measure neurocognitive specific domains. Analyses of variance were used to make comparisons between groups. FEP women had greater CR than FEP men. This circumstance was not observed in healthy controls. Among the group of patients with low CR, FEP women outperformed FEP men in the cognitive domains verbal memory and processing speed. Meanwhile, among the FEP patients with high CR, men showed better performance in attention than women. Differences in CR observed between FEP men and women could be related to a number of specific factors, such as, age at illness onset, education level, and variability in performance in verbal memory, processing speed, and attention domains. These results provide background information about CR in FEP patients that will be useful in the design of sex specific cognitive remediation interventions.

Gender differences in cognitive reserve: implication for subjective cognitive decline in women

BackgroundSubjective Cognitive Decline (SCD) is a self-experienced decline in cognitive capacity with normal performance on standardized cognitive tests, showing to increase risk of Alzheimer’s Disease (AD). Cognitive reserve seems to influence the progression from SCD to Mild Cognitive Impairment (MCI) and to AD. The aim of our study was to investigate gender differences in cognitive reserve evaluating how sex might modulate the role of cognitive reserve on SCD.MethodsWe included 381 SCD patients who underwent clinical evaluation, neuropsychological assessment, evaluation of premorbid intelligence by the Test di Intelligenza Breve (TIB), cognitive complaints by the Memory Assessment Clinics Questionnaire (MAC-Q), and apolipoprotein E (APOE) genotyping.ResultsThe proportion between women and men was significantly different (68.7% [95% CI 63.9–73.4 vs 31.4%, 95% CI 26.6–36.0]). Women were younger than men at onset of SCD and at the baseline visit (p = 0.021), had lower years of education (p = 0.007), lower TIB scores (p < 0.001), and higher MAC-Q scores (p = 0.012). TIB was directly associated with age at onset of SCD in both women and men, while years of education was inversely associated with age at onset only in women. Multivariate analysis showed that sex influences TIB independently from years of education. TIB was directly associated with MAC-Q in men.ConclusionsSex interacts with premorbid intelligence and education level in influencing the age at onset and the severity of SCD. As the effect of education was different between men and women, we speculated that education might act as a minor contributor of cognitive reserve in women.

Gender differences in cognitive reserve: Implication for subjective cognitive decline in women

Subjective Cognitive Decline (SCD) is as a self-experienced decline in cognitive capacity with normal performance on standardized cognitive tests and has been shown to increase risk of Alzheimer’s Disease. The aim of our study was to evaluate factors influencing age at onset and severity of SCD.

The higher, the better: Cognitive reserve contributes to lifestyle activities in older age

The study aimed at investigating age and gender differences in cognitive reserve (CR) and whether CR can contribute to everyday and physical activity and fluid reasoning in older adults. Participants (N = 294), categorized into three age groups: young-old, middle-old, and old-old, completed the Cognitive Reserve Index questionnaire (CRIq), the Everyday Activity Questionnaire (EAQ), the Physical Activity Scale for the Elderly (PASE), and the Unbalanced Structure Test (UST). The old-old had significantly lower scores on CRI-Total, CRI-Working activity, and CRI-Leisure time compared to young-old and middle-old. Men showed higher scores than women on all CR subscales except for CRI-Leisure time where no significant difference was found. Younger age and higher CRI-Leisure time predicted higher scores on PASE, EAQ, and UST, while higher scores on CRI-Education predicted EAQ and UST. Higher CR seems to enable a more active and healthier lifestyle, while CRIq is a useful tool in the assessment of cognitive potential in the elderly.

The effect of memory cue duration on performance in the directed forgetting task in healthy aging

ABSTRACT Although forgetting is usually considered a memory error, intentional forgetting can function as an adaptive mechanism. The current study examined the effect of increased processing time on directed forgetting in aging as a mechanism to compensate for age-related forgetting. Specifically, an item-method directed forgetting paradigm was used in conjunction with Remember/Know/New responding to examine the effect of cue duration (1, 3, 5 s) on directed forgetting and remembering in younger and older adults. Results indicated that increased processing time improved performance in both age groups. Critically, older adults exhibited a linear increase in directed remembering performance across all cue durations which was related to individual differences in cognitive reserve. Specifically, those older adults with the highest levels of cognitive functioning showed the greatest memory benefit in the longest cue duration condition. These findings indicate the importance of processing time in accounting for intentional memory performance in older adults.

Role of cognitive reserve in cognitive variability in euthymic individuals with bipolar disorder: cross-sectional cluster analysis.

People with bipolar disorder have moderate cognitive difficulties that tend to be more pronounced during mood episodes but persist after clinical remission and affect recovery. Recent evidence suggests heterogeneity in these difficulties, but the factors underlying cognitive heterogeneity are unclear. To examine whether distinct cognitive profiles can be identified in a sample of euthymic individuals with bipolar disorder and examine potential differences between subgroups. Cognitive performance was assessed across four domains (i.e. processing speed, verbal learning/memory, working memory, executive functioning) in 80 participants. We conducted a hierarchical cluster analysis and a discriminant function analysis to identify cognitive profiles and considered differences in cognitive reserve, estimated cognitive decline from premorbid cognitive functioning, and clinical characteristics among subgroups. Four discrete cognitive profiles were identified: cognitively intact (n = 25; 31.3%); selective deficits in verbal learning and memory (n = 15; 18.8%); intermediate deficits across all cognitive domains (n = 30; 37.5%); and severe deficits across all domains (n = 10; 12.5%). Cognitive decline after illness onset was greater for the intermediate and severe subgroups. Cognitive reserve scores were increasingly lower for subgroups with greater impairments. A smaller proportion of cognitively intact participants were using antipsychotic medications compared with all other subgroups. Our findings suggest that individuals with cognitively impaired profiles demonstrate more cognitive decline after illness onset. Cognitive reserve may be one of the factors underlying cognitive variability across people with bipolar disorder. Patients in the intermediate and severe subgroups may be in greater need of interventions targeting cognitive difficulties.

The association between cognitive reserve and performance-related brain activity during episodic encoding and retrieval across the adult lifespan

Remembering associations between encoded items and their contextual setting is a feature of episodic memory. Although this ability generally deteriorates with age, there is substantial variability in how older individuals perform on episodic memory tasks. A current topic of debate in the cognitive neuroscience of aging literature revolves around whether this variability may stem from genetic and/or environmental factors related to reserve, allowing some individuals to compensate for age-related decline through differential recruitment of brain regions. In this fMRI study spanning a large adult lifespan sample (N = 154), we tested whether higher cognitive reserve was associated with better task-fMRI context memory performance, and functional compensatory activity patterns in the aging brain. We used multivariate Behaviour Partial Least Squares (B-PLS) analysis to examine how age, retrieval accuracy, and a proxy measure of cognitive reserve [i.e., a composite score consisting of years of education (EDU) and crystallized IQ], impacted brain activity during the encoding and retrieval of spatial and temporal contextual details. The results indicated that age-related increases in encoding activity within anterior and lateral frontal, inferior parietal, occipito-temporal and medial temporal cortices, was correlated with better subsequent memory performance; and may be indicative of age-related functional compensation at encoding. Interestingly this compensatory pattern was not correlated with our proxy measure of cognitive reserve but was associated with total brain volume (a measure of brain reserve). However, cognitive reserve was associated with age-invariant and task-general activity in superior temporal, occipital, and left inferior frontal regions. We conclude that the relationship between cognitive reserve, brain reserve and age-related functional compensation is complex, and that EDU and IQ may not fully account for individual differences in cognitive reserve when studying well educated, healthy aging cohorts.

Sex Differences in Neurocognitive Function in Adults with HIV: Patterns, Predictors, and Mechanisms.

Sex differences in cognitive function are well documented yet few studies had adequate numbers of women and men living with HIV (WLWH; MLWH) to identify sex differences in neurocognitive impairment (NCI) and the factors contributing to NCI. Here, we review evidence that WLWH may be at greater risk for NCI. We conducted a systematic review of recent studies of NCI in WLWH versus MLWH. A power analysis showed that few HIV studies have sufficient power to address male/female differences in NCI but studies with adequate power find evidence of greater NCI in WLWH, particularly in the domains of memory, speed of information processing, and motor function. Sex is an important determinant of NCI in HIV, and may relate to male/female differences in cognitive reserve, comorbidities (mental health and substance use disorders), and biological factors (e.g., inflammation, hormonal, genetic).

Motivation as a Mediator of the Relation Between Cognitive Reserve and Cognitive Performance

Interindividual differences in cognitive aging may be explained by differences in cognitive reserve (CR) that are built up across the life span. A plausible but underresearched mechanism for these differences is that CR helps compensating cognitive decline by enhancing motivation to cope with challenging cognitive situations. Theories of motivation on cognition suggest that perceived capacity and intrinsic motivation may be key mediators in this respect. In 506 older adults, we assessed CR proxies (education, occupation, leisure activities), motivation (perceived capacity, intrinsic motivation), and a global measure of cognitive functioning. Perceived capacity, but not intrinsic motivation, significantly mediated the relation between CR and cognitive performance. Complementary with neurobiological and cognitive processes, our results suggest a more comprehensive view of the role of motivational aspects built up across the life span in determining differences in cognitive performance in old age.

Clinical dementia severity associated with ventricular size is differentially moderated by cognitive reserve in men and women

BackgroundInterindividual differences in cognitive reserve (CR) are associated with complex and dynamic clinical phenotypes observed in cognitive impairment and dementia. We tested whether (1) CR early in life (E-CR; measured by education and IQ), (2) CR later in life (L-CR; measured by occupation), and (3) CR panel (CR-P) with the additive effects of E-CR and L-CR, act as moderating factors between baseline ventricular size and clinical dementia severity at baseline and across 2 years. We further examined whether this moderation is differentially represented by sex.MethodsWe examined a longitudinal model using patients (N = 723; mean age = 70.8 ± 9.4 years; age range = 38–90 years; females = 374) from the Sunnybrook Dementia Study. The patients represented Alzheimer’s disease (n = 439), mild cognitive impairment (n = 77), vascular cognitive impairment (n = 52), Lewy body disease (n = 30), and frontotemporal dementia (n = 125). Statistical analyses included (1) latent growth modeling to determine how clinical dementia severity changes over 2 years (measured by performance on the Dementia Rating Scale), (2) confirmatory factor analysis to establish a baseline E-CR factor, and (3) path analysis to predict dementia severity. Baseline age (continuous) and Apolipoprotein E status (ɛ4−/ɛ4+) were included as covariates.ResultsThe association between higher baseline ventricular size and dementia severity was moderated by (1) E-CR and L-CR and (2) CR-P. This association was differentially represented in men and women. Specifically, men in only the low CR-P had higher baseline clinical dementia severity with larger baseline ventricular size. However, women in the low CR-P showed the (1) highest baseline dementia severity and (2) fastest 2-year decline with larger baseline ventricular size.ConclusionsClinical dementia severity associated with ventricular size may be (1) selectively moderated by complex and additive CR networks and (2) differentially represented by sex.Trials registrationClinicalTrials.gov, NCT01800214. Registered on 27 February 2013.

Sex differences in Alzheimer's disease.

Women are more impacted by Alzheimer's disease than men - they are at significantly greater risk of developing Alzheimer's disease, and recent research shows that they also appear to suffer a greater cognitive deterioration than men at the same disease stage. The purpose of this article is to review recent studies on examining sex differences in cognitive function in Alzheimer's disease. We searched electronically for articles, reviews and meta-analyses published between 1/2016 and 12/2017 and identified 298 articles on sex differences in cognition in Alzheimer's disease. The key themes to emerge were sex differences in cognitive function, risk factors, resilience, and cognitive reserve. Evidence is steadily and increasingly accumulating to confirm the poorer cognitive outcome for women than men with Alzheimer's disease. Although small in size, the effects occur across a broad range of cognitive domains including visuospatial, verbal, episodic memory, and semantic memory - some of which typically reveal a sex-related processing advantage for healthy women. Explanations have been linked to a variety of factors including differences in cognitive reserve, resilience, as well as genetics (apolipoprotein ε4) and functional and structural brain changes. Sex-related differences in risk factors, resilience, cognitive reserve, and rates of deterioration have implications for clinical practice.

Manipulating cognitive reserve: Pre-injury environmental conditions influence the severity of concussion symptomology, gene expression, and response to melatonin treatment in rats

In an effort to understand the factors that contribute to heterogeneity in outcomes often associated with mTBI in youth, this study examined the role of premorbid differences in cognitive reserve on post-concussive symptoms (PCS), molecular markers, and treatment response. Male and female rats matured in one of three environmental conditions (Stress, Enrichment, Control), received a mTBI in adolescence, and were randomized to melatonin or placebo treatment. All animals underwent a behavioural test battery designed to examine PCS. Using prefrontal cortex and hippocampus tissue, expression of 9 genes was assessed in an effort to determine how the brain's epigenome was influenced by cognitive reserve, mTBI, and melatonin. Enrichment increased cognitive reserve (CR) and prevented lingering symptoms. Conversely, stress was associated with progressive worsening and manifestation of PCS in the longer-term. Melatonin was able to restore baseline function for control and enriched animals, but was ineffective for the stress condition. Epigenetic change in the prefrontal cortex was largely driven by the injury, while gene expression changes in the hippocampus were dependent upon cognitive reserve. The occurrence and severity of PCS is dependent upon a complex and multifaceted array of factors that modify behavioural and epigenetic responses to mTBI and its treatment.

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

BackgroundVariation 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 findingsInformation 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.ConclusionsIn 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.