Sex-Specific Brain Aging: Women Have Greater Cognitive Reserves But Faster Cognitive Decline
Cognitive decline and dementia become more common as we age, but there is much to be learned about sex-based differences in how the age-related disease develops and progresses. The advancement of the disease and the way dementia is treated are a result of these differences between men and women.
Now, new data from five studies were pooled to investigate whether cognitive decline among older U.S. adults varied by sex, finding that there are differences in cognitive decline between men and women. The results of this huge 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. A better understanding of the different ways age-related disease develops will potentially lead to a more tailored, personalized approach for prevention and treatment.
Differences in Cognitive Decline Between the Sexes
When it comes to Alzheimer’s, researchers are aware of many sex-specific differences. Men and women differ in how they are affected by cognitive decline. For example, women have a greater prevalence of Alzheimer’s disease compared to men, which may occur because women tend to live longer than men. There are also differences in symptoms, rate of progression, disease biomarkers, and risk factor profiles for both sexes. Underlying all of this are differences in the pathways that cause these changes between men and women.
For these reasons, treatment of dementia has marked differences between men and women. Previous studies have focused on the effects of cardiovascular risk factors, such as blood pressure, weight, , on the development of dementia. However, when taken into account, these factors do not paint a clear picture of why there are such marked differences in disease progression between the sexes.
Sex-Specific Effects of Genes and Hormones on Cognition
Research has shown that women tend to have a later onset of dementia, but, once the condition sets in, the decline in cognition is much sharper for females (1). Along these lines, studies show that once the dementia process begins, women’s brains atrophy at a faster rate. Women may be more susceptible to developing dementia if we take a look from a genetic perspective.
For instance, we know that a common gene linked to Alzheimer’s susceptibility known as APOE seems to carry more risk for the disease in women (2). Women who have just one copy of the gene have twice the risk of developing the disease than men who carry two copies of APOE. In addition, women who carry the APOE gene have faster rates of cognitive decline compared to men with similar genetic characteristics.
Female sex hormones like estrogen seem to have a powerful effect on the risk of developing dementia later in life. This may be explained by the beneficial effects that estrogen has on the cardiovascular system and, consequently, brain health. Evidence for the relationship between sex hormones and risk for cognitive decline can be found in the increased rates of dementia seen in women who have undergone menopause prematurely as a result of the surgical removal of their ovaries, a relatively common procedure (3).
To understand this hormone connection, researchers have examined the estrogen content of the brains of both men and women who developed Alzheimer’s disease, the most common form of dementia. Results from these examinations showed that women with Alzheimer’s had significantly lower levels of estrogen in their brains. In contrast, men’s brains did not have the variations in estrogen observed in women. These findings suggest that a decrease in estrogen levels can increase women’s vulnerability to Alzheimer’s disease (4).
Even though estrogen levels have not been linked to the development of dementia in men, there is evidence that cognition loss may be related to the decline in testosterone that occurs as part of the natural aging process. Studies that have examined testosterone levels in older males show that both total and bioavailable levels of testosterone are lower in males suffering from Alzheimer’s disease (5).
Current Findings and New Management Strategies for Dementia
Levine and colleagues published their study in JAMA, examining almost 50 years of data regarding risk factors and cognitive decline in adults to get a better idea of the differences in disease progression between sexes (6). The study showed that women had a higher baseline performance than men in global cognition, executive function, and memory, in addition to higher “cognitive reserves”. However, women have an accelerated rate of cognitive decline in old age once dementia sets in.
The study showed that the first signs of dementia tend to appear later in life for women, which increases the risk for delayed identification of the disease. Due to their faster cognitive decline, women may have greater needs for caregiving and functional support resources, particularly given women’s longer life expectancy compared with men.
The authors propose that the faster decline seen in women may be due to smaller total brain volumes. This places women at a disadvantage when compared to men because the brain shrinks as age increases. Higher losses of brain volume translate into a faster cognitive loss. Women are also more vulnerable to neurodegenerative diseases that diminish brain volumes, such as Alzheimer’s and Parkinson’s disease.
Reasons for these sex differences are complex and likely influenced by hormones, genes like APOE, and social and cultural factors. More research will be needed to develop a more precise approach for the treatment of dementia, with sex-specific strategies for prevention, detection, and treatment.
References:
- Ferretti MT, Iulita MF, Cavedo E, et al. Sex differences in Alzheimer disease - the gateway to precision medicine. Nat Rev Neurol. 2018;14(8):457-469. doi:10.1038/s41582-018-0032-9
- Riedel BC, Thompson PM, Brinton RD. Age, APOE and sex: Triad of risk of Alzheimer's disease. J Steroid Biochem Mol Biol. 2016;160:134-147. doi:10.1016/j.jsbmb.2016.03.012
- Bove R, Secor E, Chibnik LB, et al. Age at surgical menopause influences cognitive decline and Alzheimer pathology in older women. Neurology. 2014;82(3):222-229. doi:10.1212/WNL.0000000000000033
- Rosario ER, Chang L, Head EH, Stanczyk FZ, Pike CJ. Brain levels of sex steroid hormones in men and women during normal aging and in Alzheimer's disease. Neurobiol Aging. 2011;32(4):604-613. doi:10.1016/j.neurobiolaging.2009.04.008
- Paoletti AM, Congia S, Lello S, et al. Low androgenization index in elderly women and elderly men with Alzheimer's disease. Neurology. 2004;62(2):301-303. doi:10.1212/01.wnl.0000094199.60829.f5
- Levine DA, Gross AL, Briceño EM, et al. Sex Differences in Cognitive Decline Among US Adults. JAMA Netw Open. 2021;4(2):e210169. Published 2021 Feb 1. doi:10.1001/jamanetworkopen.2021.0169
