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Menopause, Memory, and Alzheimer’s Disease

By Pauline M. Maki, PhD, University of Illinois at Chicago, Society for Women’s Health Research Interdisciplinary Network on Alzheimer’s Disease Member
When women think about menopause, they typically think about hot flashes. New research shows that memory problems are a common but under-recognized menopausal symptom.

Memory problems emerge during perimenopause, the time around the final menstrual period, before many women even realize that they are “going through the change.” Early research studies have documented an increase in memory complaints, such as forgetting names, as a woman enters the menopausal transition, while more recent studies have revealed measurable changes in verbal memory as a woman transitions through menopause [1,2].
Although decreases in memory are a normal part of aging, age does not account for the changes in memory that occur when a woman transitions through menopause. Similarly, although sleep disturbances and mood symptoms are common and can affect memory, they do not account for memory problems during this transition. Preliminary research links memory problems to hot flashes, (when hot flashes are measured objectively- using ambulatory monitors) but further research on this issue is needed [3,4]. The good news is that memory problems that can emerge during perimenopause seem to improve during the postmenopausal years [2].

Hormonal factors appear to play a role in memory changes during the menopausal transition. The ovaries are the primary source of estrogen in premenopausal women. In women who have not yet reached their final menstrual period, having their ovaries surgically removed leads to a decline in verbal memory, which is reversed when they take estrogen therapy [5]. Similarly, removing ovaries before age 48 has been associated with a 70 percent increased risk of cognitive impairment or dementia [6], but use of estrogen therapy until the typical age of menopause negates that risk.

When women are in their 50s and have transitioned through menopause, taking hormones does not seem to affect memory performance. For example, memory does not change when women begin hormone therapy within five years after their final menstrual period [6,7]. Meanwhile, initiating hormone therapy later in life – after age 65 – can actually increase the risk of memory problems and dementia [8,9]. It might be that women with hot flashes particularly benefit from hormone therapy. Initial evidence indicates that hormone therapy can improve memory and brain function in women with moderate to severe hot flashes [10], but more extensive studies are needed. Similarly, it is unknown how taking birth control pills containing estrogen can influence memory in perimenopausal women.

Women show a lifelong advantage in verbal memory compared to men. Interestingly, this advantage might make it more difficult for clinicians to detect a memory problem in women who are in the early stages of Alzheimer’s disease (AD). Before developing AD, patients transition though a stage called amnestic mild cognitive impairment, or aMCI. At this stage, memory problems exceed what is expected for age but do not reach the level of severity seen in AD. The female advantage in verbal memory persists in the aMCI stage. Consequently, women perform better than men despite showing the same level of AD disease on brain scans [11-13]. Although this could be seen as an advantage, women may be diagnosed with aMCI or AD at a later and more severe stage of the disease than men. Researchers are now exploring whether it might be useful for clinicians to use different cut-offs for memory tests in women and men, so that AD can be detected earlier in women.

Together, these studies demonstrate the important need to address how brain aging differs between women and men. By examining how menopause, estrogen, and other factors contribute to those differences, we can improve efforts to prevent, detect, and treat memory problems, and memory disorders such as AD. This is especially relevant for women, who make-up 3.2 million out of the approximately 5 million individuals in the U.S. living with AD. It is estimated that the prevalence of AD will triple by 2050 [14], and the associated costs will exceed $20 trillion U.S. dollars. For this reason, it is imperative that we continue to work together to fund AD research and support studies that recognize and address the ways in which this deadly disease can affect women and men differently.

There is still more to be done in investigating new AD risk factors and discerning how established risk factors vary by sex and gender. The Society for Women’s Health Research’s Interdisciplinary Network on Alzheimer’s Disease is committed to advocating for these goals in order to inform prevention and treatment, providing guidance for research, clinical trials, and policy. Click here to learn more about SWHR’s work in Alzheimer’s disease.

References:

1. Epperson CN, Sammel MD, Freeman EW. Menopause effects on verbal memory: findings from a longitudinal community cohort. J Clin Endocrinol Metab. 2013;98(9):3829-38.
2. Greendale GA, Wight RG, Huang MH, Avis N, Gold EB, Joffe H, et al. Menopause-associated symptoms and cognitive performance: results from the study of women’s health across the nation. Am J Epidemiol. 2010;171(11):1214-24.
3. Drogos LL, Rubin LH, Geller SE, Banuvar S, Shulman LP, Maki PM. Objective cognitive performance is related to subjective memory complaints in midlife women with moderate to severe vasomotor symptoms. Menopause. 2013;20(12):1236-42.
4. Maki PM, Rubin LH, Savarese A, Drogos L, Shulman LP, Banuvar S, et al. Stellate ganglion blockade and verbal memory in midlife women: Evidence from a randomized trial. Maturitas. 2016;92:123-9.
5. Sherwin BB. Estrogen and/or androgen replacement therapy and cognitive functioning in surgically menopausal women. Psychoneuroendocrinology. 1988;13(4):345-57.
6. Henderson VW, St John JA, Hodis HN, McCleary CA, Stanczyk FZ, Shoupe D, et al. Cognitive effects of estradiol after menopause: A randomized trial of the timing hypothesis. Neurology. 2016;87(7):699-708.
7. Gleason CE, Dowling NM, Wharton W, Manson JE, Miller VM, Atwood CS, et al. Effects of Hormone Therapy on Cognition and Mood in Recently Postmenopausal Women: Findings from the Randomized, Controlled KEEPS-Cognitive and Affective Study. PLoS medicine. 2015;12(6):e1001833; discussion e.
8. Resnick SM, Maki PM, Rapp SR, Espeland MA, Brunner R, Coker LH, et al. Effects of combination estrogen plus progestin hormone treatment on cognition and affect. J Clin Endocrinol Metab. 2006;91(5):1802-10.
9. Shumaker SA, Legault C, Rapp SR, Thal L, Wallace RB, Ockene JK, et al. Estrogen plus progestin and the incidence of dementia and mild cognitive impairment in postmenopausal women: the Women’s Health Initiative Memory Study: a randomized controlled trial. JAMA. 2003;289(20):2651-62.
10. Joffe H, Hall JE, Gruber S, Sarmiento IA, Cohen LS, Yurgelun-Todd D, et al. Estrogen therapy selectively enhances prefrontal cognitive processes: a randomized, double-blind, placebo-controlled study with functional magnetic resonance imaging in perimenopausal and recently postmenopausal women. Menopause. 2006;13(3):411-22.
11. Sundermann EE, Biegon A, Rubin LH, Lipton RB, Mowrey W, Landau S, et al. Better verbal memory in women than men in MCI despite similar levels of hippocampal atrophy. Neurology. 2016.
12. Sundermann EE, Biegon A, Rubin LH, Lipton RB, Landau S, Maki PM, et al. Does the Female Advantage in Verbal Memory Contribute to Underestimating Alzheimer’s Disease Pathology in Women versus Men? J Alzheimers Dis. 2017;56(3):947-57.
13. Sundermann EE, Maki PM, Rubin LH, Lipton RB, Landau S, Biegon A, et al. Female advantage in verbal memory: Evidence of sex-specific cognitive reserve. Neurology. 2016;87(18):1916-24.
14. Hebert LE, Scherr PA, Bienias JL, Bennett DA, Evans DA. Alzheimer disease in the US population: prevalence estimates using the 2000 census. Archives of Neurology. 2003;60(8):1119-22.

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