Are women at greater risk of cognitive decline than men? In a way, yes, according to researchers led by Andrzej Galecki, University of Michigan, Ann Arbor. They pooled data from five well-established observational cohorts, analyzing cognition in 26,088 people over approximately a decade. In the February 25 JAMA Neurology, the scientists reported that women’s global cognition and executive function started out higher than men’s, but then declined faster. Memory slipped at the same rate in both sexes. At baseline, women performed better than men in all three categories, indicating they may have more cognitive reserve. These sex differences remained after correcting for other factors that affect cognition, including cardiovascular risk and education level.
- Women have more cognitive reserve than men.
- Their cognition and executive function slip faster, but not their memory.
- Sex differences remained after correcting for cardiovascular risk and education.
“These population health results can guide basic science research, or detailed clinical studies, to figure out why there are sex differences,” Marcel Salive, National Institute on Aging, Bethesda, Maryland, told Alzforum.
Some, but not all, previous studies suggest women are at greater risk of Alzheimer’s disease, leaving the question open. To address it, first author Deborah Levine at UMichigan and colleagues pooled volunteers ages 51–67 from five American cohorts: 13,143 from the Atherosclerosis Risk in Communities Study (ARIC), 3,397 from the Coronary Artery Risk Development in Young Adults Study (CARDIA), 5,042 from the Cardiovascular Health Study (CHS), 3,475 from the Framingham Offspring Study (FOS), and 1,031 from the Northern Manhattan Study (NOMAS). The 26,088 participants were chosen because they had data ranging from 1971–2017 and did not have dementia or a stroke before their first cognitive assessment. Fifty-five percent of participants were women, 23 percent self-identified as black. On average, participants were 58 years old at the first cognitive test and returned for two or three additional sessions over an eight-year follow-up period.
The researchers tracked changes in global cognition, executive function, and memory. Each cohort used a variety of cognitive tests, so the scientists created a standardized score measuring each of the three categories. To do this, they first assigned each test to the category it measured. Then, they corrected for how each test was administered, such as what questions were asked and how much time participants had to complete it, and how it was scored. Finally, they calibrated each test based on how highly predictive it was of each category, giving participants final scores in each of global cognition, executive function, and memory at follow-up visits. A 1-point score difference represents a 0.1-standard deviation difference in cognition.
At baseline, women as a group performed significantly better than men, scoring almost two points higher in each category. The authors interpret this as women having more cognitive reserve. However, women declined faster on global cognition and executive function tests than men. For example, white women aged 58 declined an average of 29 percent more each year than white men, dropping 0.27 points in the global cognition assessment compared to 0.21 points. Executive function also dropped 0.06 points per year faster than men.
Is this an important difference? Based on previous studies showing that dropping half a standard deviation represents clinically meaningful decline (e.g., Wolinsky et al., 2006), women in this sample will develop clinically meaningful deficits in cognitive and executive function 4.7 and two years faster than men, respectively. Estimated a different way, these sex differences amount to five or six years of cognitive aging. Levine and colleagues also noted that in older women, their higher baseline cognition means their deficit is usually caught later than men’s.
The researchers accounted for some other factors known to influence cognition, such as years of education, cardiovascular risk factors, APOE status, and heart attack or stroke during the follow-up period. They corrected for cumulative mean blood pressure, previously showing that higher average blood pressure is closely tied to faster cognitive decline (Levine et al., 2020). After accounting for each factor, the sex differences remained.
Most participants self-identified as white or black; only the NOMAS cohort recorded ethnicity, leading the researchers to exclude Hispanic participants in this current study. “Using other cohorts that include ethnicity, our next paper will look at cognitive decline and risk factors in Hispanic versus Caucasian individuals,” Levine told Alzforum.
Louisa Needham, a Ph.D. student in Marcus Richards’ lab at University College London, wondered what role menopause may be playing, as it is known to affect cognition (Mar 2019 news; Aug 2018 conference news). “Some women in this cohort may be going through menopause or have just finished their transition, while others may have transitioned years ago,” she told Alzforum. “Splitting the cohort by baseline age groups to see if there are differences in cognitive decline would be interesting.” (Full comment below.)
Intriguingly, no sex differences appeared on the memory-decline measures—men and women became forgetful at the same rate. This surprised the authors because women are thought to be more prone to Alzheimer’s, the quintessential memory disorder. However, they noted that fewer participants had undergone memory measurements and there was less longitudinal memory data. “This finding should be interpreted with caution; confirmatory studies are needed,” said Levine. Needham noted that this study was looking at normal cognitive aging, not at people with dementia.
Overall, researchers applauded this study. “Building off of strong population studies to create a large cohort, and adjusting for risk factors, can provide generalizable knowledge that you might not be able to get from smaller studies,” Salive said.
Denis Evans, Rush University, Chicago, Illinois, agreed that the large cohorts and analyses were strong, but noted that pooling data from multiple observational studies comes with its own limitations. “This leaves me uncertain … the results and conclusion may well be correct, but they also may not be,” Evans wrote to Alzforum.—Chelsea Weidman Burke
- From Menarche to Menopause: Shorter Span Linked to Higher Risk of Dementia
- Do Brain Changes at Menopause Make Women More Prone to Alzheimer’s?
- Wolinsky FD, Unverzagt FW, Smith DM, Jones R, Stoddard A, Tennstedt SL. The ACTIVE cognitive training trial and health-related quality of life: protection that lasts for 5 years. J Gerontol A Biol Sci Med Sci. 2006 Dec;61(12):1324-9. PubMed.
- Levine DA, Gross AL, Briceño EM, Tilton N, Kabeto MU, Hingtgen SM, Giordani BJ, Sussman JB, Hayward RA, Burke JF, Elkind MS, Manly JJ, Moran AE, Kulick ER, Gottesman RF, Walker KA, Yano Y, Gaskin DJ, Sidney S, Yaffe K, Sacco RL, Wright CB, Roger VL, Allen NB, Galecki AT. Association Between Blood Pressure and Later-Life Cognition Among Black and White Individuals. JAMA Neurol. 2020 Jul 1;77(7):810-819. PubMed.
- Levine DA, Gross AL, Briceño EM, Tilton N, Giordani BJ, Sussman JB, Hayward RA, Burke JF, Hingtgen S, Elkind MS, Manly JJ, Gottesman RF, Gaskin DJ, Sidney S, Sacco RL, Tom SE, Wright CB, Yaffe K, Galecki AT. Sex Differences in Cognitive Decline Among US Adults. JAMA Netw Open. 2021 Feb 1;4(2):e210169. PubMed.