Sex Differences in Cognitive Decline Among US Adults. Deborah A. Levine et al. JAMA Netw Open. 2021;4(2):e210169. February 25, 2021, doi:10.1001/jamanetworkopen.2021.0169
Key Points
Question Does the risk of cognitive decline among US adults vary by sex?
Findings In this cohort study using pooled data from 26 088 participants, women, compared with men, had higher baseline performance in global cognition, executive function, and memory. Women, compared with men, had significantly faster declines in global cognition and executive function, but not memory.
Meaning These findings suggest that women may have greater cognitive reserve but faster cognitive decline than men.
Abstract: Importance Sex differences in dementia risk are unclear, but some studies have found greater risk for women.
Objective To determine associations between sex and cognitive decline in order to better understand sex differences in dementia risk.
Design, Setting, and Participants This cohort study used pooled analysis of individual participant data from 5 cohort studies for years 1971 to 2017: Atherosclerosis Risk in Communities Study, Coronary Artery Risk Development in Young Adults Study, Cardiovascular Health Study, Framingham Offspring Study, and Northern Manhattan Study. Linear mixed-effects models were used to estimate changes in each continuous cognitive outcome over time by sex. Data analysis was completed from March 2019 to October 2020.
Exposure Sex.
Main Outcomes and Measures The primary outcome was change in global cognition. Secondary outcomes were change in memory and executive function. Outcomes were standardized as t scores (mean [SD], 50 [10]); a 1-point difference represents a 0.1-SD difference in cognition.
Results Among 34 349 participants, 26 088 who self-reported Black or White race, were free of stroke and dementia, and had covariate data at or before the first cognitive assessment were included for analysis. Median (interquartile range) follow-up was 7.9 (5.3-20.5) years. There were 11 775 (44.7%) men (median [interquartile range] age, 58 [51-66] years at first cognitive assessment; 2229 [18.9%] Black) and 14 313 women (median [interquartile range] age, 58 [51-67] years at first cognitive assessment; 3636 [25.4%] Black). Women had significantly higher baseline performance than men in global cognition (2.20 points higher; 95% CI, 2.04 to 2.35 points; P < .001), executive function (2.13 points higher; 95% CI, 1.98 to 2.29 points; P < .001), and memory (1.89 points higher; 95% CI, 1.72 to 2.06 points; P < .001). Compared with men, women had significantly faster declines in global cognition (−0.07 points/y faster; 95% CI, −0.08 to −0.05 points/y; P < .001) and executive function (−0.06 points/y faster; 95% CI, −0.07 to −0.05 points/y; P < .001). Men and women had similar declines in memory (−0.004 points/y faster; 95% CI, −0.023 to 0.014; P = .61).
Conclusions and Relevance The results of this cohort study suggest that women may have greater cognitive reserve but faster cognitive decline than men, which could contribute to sex differences in late-life dementia.
Among 26 088 individuals pooled from 5 prospective cohort studies, women had higher baseline performance than men in global cognition, executive function, and memory. Women, compared with men, had significantly faster declines in global cognition and executive function but not memory. These sex differences persisted after accounting for the influence of age, race, education, and cumulative mean BP.
Our results provide evidence suggesting that women have greater cognitive reserve but faster cognitive decline than men, independent of sex differences in cardiovascular risk factors and educational years. Previous studies31 have shown that women have higher initial scores on most types of cognitive tests except those measuring visuospatial ability. Few studies have examined sex differences in cognitive trajectories in population-based cohorts of cognitively normal Black and White individuals. A 2016 study31 of older adults in Baltimore (mean ages 64-70 years) found that men had steeper rates of decline on 4 of 12 cognitive tests (mental status [Mini Mental State Examination], perceptuomotor speed and integration, visual memory, and visuospatial ability) but no sex differences in declines on 8 of 12 cognitive tests (verbal learning and memory, object recognition and semantic retrieval, fluent language production, attention, working memory and set-shifting, perceptuomotor speed, and executive function). Similarly, we found no sex differences in verbal learning and memory; but, in contrast, we found that women had faster cognitive decline in global cognitive performance and executive function than men. These latter results might differ because we included young and middle-aged adults (mean age 58 years). Our findings are consistent with studies showing that women with mild cognitive impairment or AD have faster decline in global cognition than men.32,33
Our results of sex differences in cognitive decline were consistent across most cohorts. The potential reasons for the finding of slower cognitive decline in women in the Framingham Offspring Study are unclear and might be due to socioeconomic, life stress, geographic, and environmental factors as well as cohort differences in sampling strategies, eligibility criteria, and cognitive tests. Although our finding that declines in memory do not differ by sex are consistent with other studies,31 the finding is surprising because memory decline is the clinical hallmark of AD, a common cause of dementia,1 and some studies suggest that women have higher incidence of AD.4-6 One explanation is that women manifest verbal memory declines at more advanced stages of neurodegenerative disease than men owing to women having greater initial verbal memory scores and cognitive reserve.34,35 However, evidence against this explanation is that women in our study had faster declines in global cognition and executive function despite having higher initial levels of these measures. Another explanation is that the memory measure was less sensitive than the global cognition and executive function measures to detect sex differences in cognitive decline.
If the observed sex differences in declines in global cognition and executive function are causal, then they would be clinically significant, equivalent to 5 to 6 years of cognitive aging. The faster declines in mean cognitive scores associated with female sex can be related to approximate equivalent changes in years of brain or cognitive aging by calculating the ratio of slope coefficients for female sex and baseline age on cognition. Experts have defined clinically meaningful cognitive decline as a decline in cognitive function of 0.5 or more SDs from baseline cognitive scores.36-38 Women will reach the threshold of a 0.5-SD decrease from the baseline score 4.72 years faster than men for global cognition, 1.97 years faster for executive function, and 0.24 years faster for memory (eTable 7 in the Supplement). Based on this approach, sex differences in cognitive declines are clinically meaningful. Declines in global cognition and executive function markedly raise the risk of death, dementia, and functional disability.39-41 Diagnosis of the clinical syndrome of dementia/neurocognitive disorder requires cognitive decline by history and objective measurement.42 Our findings that women have faster declines in global cognition and executive function mean women would have greater risk than men for being diagnosed with dementia based on objectively measured cognitive decline. Our findings that women had higher initial cognitive scores suggest informants and clinicians might not observe significant cognitive decline in women until substantial loss and impairment has occurred.
Studies have consistently found evidence of sex differences in baseline cognitive functioning with women demonstrating stronger verbal cognitive skills than men, but men demonstrating stronger visuospatial skills than women (eg, mental rotations).31,43 Reasons for these sex differences are complex and likely influenced by biological (eg, sex hormones), genetic (eg, APOE), and social and cultural factors.43 While sex differences in cognitive reserve might also be associated with differences in life course risk factors such as vascular risk,44 education, and health behaviors such as smoking and exercise,45 our findings of sex differences in baseline cognitive performance independent of these factors suggest that additional contributors and biological pathways play a role.
Women might have faster cognitive decline than men because of differences in sex hormones, structural brain development, genetics, psychosocial factors, lifestyle factors, functional connectivity, and tau pathology.45-47 Women might have greater burden of small vessel disease, including white matter hyperintensity volume, and less axonal structural integrity that in turn leads to faster cognitive decline particularly in executive function and processing speed.48,49 Women also appear to have lower gray matter volume,50 so they might be more vulnerable to both the accelerated gray volume loss that occurs with aging and the differential volume loss in specific brain regions that occurs with neurodegenerative diseases.51 Recent studies suggest that women develop greater neurofibrillary degeneration, brain parenchymal loss, and cognitive decline.52-54 Our results suggest that women’s greater cognitive reserve might enable them to withstand greater AD-pathology than men.
Our study has several strengths. By pooling 5 large, high-quality cohorts, we had longitudinal cognitive assessments and vascular risk factor measurements in a large number of Black and White individuals who were young, middle-aged, and older-aged to estimate cognitive trajectories in men and women. We had repeated cognitive measures during up to 21 years of follow-up. The cohort studies included in our study systematically measured major cognitive domains important for daily, occupational, and social functioning: global cognition, executive function, and memory. Our findings were consistent across cohorts.
This study also has several limitations. While we adjusted for educational years, we could not adjust for educational quality, literacy, other socioeconomic factors,10 or depressive symptoms, because not all cohorts had these data at or before the first cognitive assessment. However, studies suggest that socioeconomic factors tend to influence initial cognitive scores (ie, intercepts) rather than the change in cognitive scores over time (slopes).55,56 Selective attrition of cognitively impaired participants could underestimate the rate of cognitive decline57 or not.58 Estimating the potential clinical impact of sex differences in cognitive decline by correlating it with decline due to aging is a common approach, but it does not directly measure clinical impact, and a clinically meaningful change might vary by an individual’s age, educational quality, race, and baseline cognition.59 There were no sex differences in participants excluded because of stroke or dementia before first cognitive assessment, so this would not influence sex differences in cognitive decline (eTable 8 in the Supplement).
We did not study incident dementia because some cohort studies lacked this information. By design, we did not adjust for baseline cognition. We also did not study any particular age interval associated with greatest risk of sex-related cognitive decline. Heterogeneity of the association of sex with cognitive decline between cohorts might have affected the statistical validity of the summary estimate of the effect in the pooled cohort. Smaller sample size and fewer cognitive assessments might have reduced precision of estimates of cognitive decline in executive function and memory (ie, the secondary outcomes). We did not have information on participants’ instrumental activities of daily living, family history of dementia, and hormone replacement therapy use. While the assumption that participants’ postmortem cognitive data are missing at random might lead to immortal cohort bias and underestimate memory declines,60 it is valid to answer the research question quantifying sex differences in cognitive trajectories through study follow-up. Women might have had a greater likelihood of regressing to a lower value than men at follow-up because they had higher baseline cognitive function than men. Using a fixed effect for cohorts might have produced conservative estimates of sex effects on cognitive slopes.
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