Women with shorter-than-average reproductive periods are at a markedly increased risk for dementia, according to a paper published March 27 in Neurology. Researchers led by Paola Gilsanz at Kaiser Permanente Division of Research in Oakland and Rachel Whitmer at the University of California, Davis, reported that among more than 6,000 women in a diverse prospective cohort study, those who started menstruation at a later age, and/or entered menopause early, had more than 20 percent greater risk of developing dementia later on. The researchers attribute this reduced exposure to the neuroprotective effects of estradiol, the predominant estrogen secreted by the ovaries during the reproductive years. Women who have shorter lifetime exposure to the hormone miss out on its full benefits, they proposed.

  • Shorter reproductive span linked to increased dementia risk.
  • Late menarche and early menopause each correlated with dementia risk.
  • Hysterectomies linked to 8 percent higher dementia risk.

Gilsanz presented the gist of the findings at AAIC last year (Aug 2018 conference news). In her talk, she also reported that women who had more children had less risk of dementia, potentially owing to the surge in estrogen that occurs during pregnancy. Gilsanz told Alzforum that the pregnancy data will be published separately.

Two-thirds of people with AD are women (Mar 2014 news). While the reasons women shoulder more of the AD burden are complex, a drop off in neuroprotective estradiol at menopause is one potential factor.

To test the idea that shorter lifetime exposure to the hormone could be important, Gilsanz and colleagues analyzed data from female members of Kaiser Permanente Northern California (KPNC), an integrated health care system that now has 4 million members. Between 1964 and 1973, Kaiser offered optional evaluations called multiphasic health checkups. Women filled out questionnaires about menarche, menopause, and whether they had had a hysterectomy. Gilsanz’s study included women who were 40–55 years of age during that time. In 1996, when electronic health records became available and the women were an average of 76.5 years old, 6,137 who completed the questionnaire in midlife were still members of Kaiser, and had not been diagnosed with dementia. They were tracked until 2017, by which time 2,577 of them—42 percent—had been diagnosed with dementia.

Among the 6,137 women, the average ages at menarche and menopause were 13 and 45, respectively, meaning an average reproductive period of 32 years. A third of the women reported undergoing a hysterectomy. Those who didn’t began menopause at 47, on average, and their reproductive span was 34 years.

Menarche before age 13 was not associated with dementia risk. However, women who started menstruating at age 16 or 17 had a 23 percent greater risk of dementia than those who started at 13. Women who entered menopause between 41 and 46 years of age had a 29 percent greater risk of dementia than those who hit menopause between 51 and 55. All told, women with reproductive spans of between 14–20 and 21–34 years had a 55 and  26 percent higher dementia risk, respectively, than those with spans of 34 years or more. Findings were similar across racial and ethnic groups, and remained significant when controlling for midlife health factors such as hypertension and smoking, as well as late-life health problems such as stroke, diabetes, and heart disease.

Women who reported undergoing a hysterectomy had an 8 percent higher risk of dementia. However, the researchers did not have data on the ages women underwent their hysterectomies, or whether the procedures included removal of the ovaries, which are the primary source of estradiol.

The findings support the idea that longer lifetime exposure to estradiol protects against dementia. However, Gilsanz acknowledged that other hormones, such as progesterone, as well as social and lifestyle factors, could play a role too. While the data does not provide direct evidence that using hormone replacement therapy to extend estradiol exposure will protect against dementia, it is consistent with that idea, Gilsanz said. Studies on the effects of hormone replacement therapy have been controversial, some suggesting that starting therapy too late, or in women with health problems, might damage the brain instead (Jun 2013 newsSep 2015 news). 

“While there is some level of controversy surrounding the efficacy of hormone replacement therapy as a therapeutic intervention for Alzheimer’s disease dementia, this large epidemiological study supports the notion that estrogen may be one potential biological mechanism moderating the AD pathological trajectory,” commented Rachel Buckley of Massachusetts General Hospital in Boston. Buckley recently reported that women have more tau deposition in the entorhinal cortex than men, and wondered whether lifetime estrogen exposure played a role in that phenomenon, too (Feb 2019 news). 

“A really fantastic component of this study is the racial diversity of the cohort,” she added. “With this rich dataset, the authors were able to conclude that estrogen-related resilience may not be mediated by race.”

Roberta Brinton of the University of Arizona in Tucson noted that paper dovetails with numerous studies describing how loss of estrogen at menopause negatively impacts the brain. “The findings of Whitmer and colleagues are consistent with a loss of estrogenic mechanisms of action in brain, which can activate a cascade of events leading to the hallmark pathologies of Alzheimer’s disease, decline in brain glucose metabolism, white matter degeneration, and β-amyloid deposition,” she wrote.—Jessica Shugart

Comments

  1. This study by Gilsanz and colleagues examines the question of whether length of exposure to endogenous estrogen (here, measured with proxies of age at menarche, age at menopause, and length of reproductive period) is protective for risk of progression to dementia. Multiple epidemiological studies now suggest that women may show a greater rate of progression to dementia than men, leading to the question of why. The authors provided convincing evidence that earlier age at menarche, later age at menopause, and a longer reproductive period are all indicative of lowered risk of dementia, consistent with animal studies suggesting that endogenous estrogen is a protective factor of AD pathology.

    While there is some level of controversy surrounding the efficacy of hormone replacement therapy as a therapeutic intervention for Alzheimer’s disease dementia, this large epidemiological study supports the notion that estrogen may provide one potential biological mechanism moderating the AD pathological trajectory. Recent work from our group has shown that females exhibit elevated tau PET signal in the entorhinal cortex relative to males in those with higher levels of amyloid. What now needs to be examined is to what extent this tau finding is influenced by length (or level) of exposure to estrogen throughout life in studies that have these proxies as well as AD biomarkers.

    A really fantastic component of this study is the racial diversity of the cohort—with this rich dataset, the authors were able to conclude that estrogen-related resilience may not be mediated by race. Another strength is that this study factors in important confounds such as cardiovascular risk and educational attainment, and finds that these do not impact the magnitude of effect of their findings.

    What now remains to be answered are: 1) What other factors might influence greater female risk for AD dementia? While these findings were significant, the effect size implied that other factors may be at play. 2) Is it that estrogen itself is the protagonist? That is, this study only refers to proxies of endogenous estrogen, and so it is important to bear in mind that other behavioral/sociological correlates may play a role. 3) How does estrogen have a biological effect on the AD pathological trajectory?

    Answering these questions will certainly move us toward better understanding how the disease might differentially impact women and men.

    References:

    . Sex Differences in the Association of Global Amyloid and Regional Tau Deposition Measured By Positron Emission Tomography in Clinically Normal Older Adults. JAMA Neurol. 2019 Feb 4; PubMed.

  2. This report from Gilsanz and colleagues, indicating an association between fewer reproductive years and greater risk of Alzheimer’s, joins a large body of evidence indicating that loss of ovarian hormones, most notably estrogen, is a contributing factor to risk of AD. While their study did not address the mechanisms underlying the increased risk of AD associated with fewer years of ovarian hormone exposure, a body of scientific data provides a plausible rationale for their findings. Our own research over many years has sought to determine the molecular and systems-biology mechanisms through which estrogen and progesterone promote neurological health. At the systems level, estrogen promotes glucose transport into the brain and neural cells, glucose metabolism, and generation of mitochondrial ATP (Brinton et al., 2015; Yin et al., 2015). Loss of estrogen results in a 20–25 percent decline in brain glucose metabolism. Estrogen promotes the molecular mechanisms of glucose metabolism in brain while also simultaneously suppressing ketone metabolism. The loss of estrogenic control of brain glucose metabolism and concomitant decline in glucose-derived ATP production activates a starvation response in brain to utilize an auxiliary fuel, ketone bodies, derived from lipids (Brinton et al., 2015; Yin et al., 2015). While this adaptive response can be beneficial in the short term, it has dire consequences for the brain in the long term. Our discovery and mechanistic science indicate that the shift to utilizing an auxiliary fuel derived from lipids puts the brain white matter at risk of catabolism as a ready source of lipid-derived ketone bodies (Brinton et al., 2015; Klosinski et al., 2015). 

    These mechanistic findings predict that loss of estrogen would be associated with decline in glucose metabolism in the menopausal female brain and a concomitant loss in white matter volume. We tested this prediction in collaboration with Dr. Lisa Mosconi using 18F-FDG-PET, MRI and Pittsburgh compound B-PET brain imaging in pre-, peri-, and menopausal women (Mosconi et al., 2017; Mosconi et al., 2017; Mosconi et al., 2018). Results of brain imaging across the stages of endocrine aging in women indicated that decline in brain glucose metabolism paralleled a decline in white matter volume (Mosconi et al., 2017; Mosconi et al., 2017; Mosconi et al., 2018). Further, decline in glucose metabolism and white matter volume was associated with a rise in β-amyloid burden in brain (Mosconi et al., 2017; Mosconi et al., 2017; Mosconi et al., 2018). The rise in β-amyloid generation in brain is consistent with the loss of estrogenic control of β-amyloid degrading enzymes, insulin-degrading enzyme (IDE), and neprilysin (Zhao et al., 2011). 

    If fewer years of estrogen exposure in brain is associated with greater risk of AD, then the corollary should be that longer lifetime exposure to estrogen is associated with lower risk of AD and sustained cognitive capacity (Brinton, 2008; Brinton, 2009). In an analysis of postmenopausal women and cognitive function, earlier age at menarche, later age at last pregnancy, longer reproductive period, and use of oral contraceptives were positively related to aspects of cognition in later life (Karim et al., 2016). 

    The findings of Whitmer and colleagues are consistent with a loss of estrogenic mechanisms of action in brain which can activate a cascade of events leading to the hallmark pathologies of Alzheimer’s disease, decline in brain glucose metabolism, white matter degeneration, and β-amyloid deposition. Lack of clarity regarding underlying reasons for disparities between studies of cohorts of women continues to impede translational impact to reduce the risk of AD in women.

    References:

    . Perimenopause as a neurological transition state. Nat Rev Endocrinol. 2015 Jul;11(7):393-405. Epub 2015 May 26 PubMed.

    . The perimenopausal aging transition in the female rat brain: decline in bioenergetic systems and synaptic plasticity. Neurobiol Aging. 2015 Jul;36(7):2282-2295. Epub 2015 Apr 1 PubMed.

    . White Matter Lipids as a Ketogenic Fuel Supply in Aging Female Brain: Implications for Alzheimer's Disease. EBioMedicine. 2015 Dec;2(12):1888-904. Epub 2015 Nov 3 PubMed.

    . Perimenopause and emergence of an Alzheimer's bioenergetic phenotype in brain and periphery. PLoS One. 2017;12(10):e0185926. Epub 2017 Oct 10 PubMed.

    . Sex differences in Alzheimer risk: Brain imaging of endocrine vs chronologic aging. Neurology. 2017 Sep 26;89(13):1382-1390. Epub 2017 Aug 30 PubMed.

    . Increased Alzheimer's risk during the menopause transition: A 3-year longitudinal brain imaging study. PLoS One. 2018;13(12):e0207885. Epub 2018 Dec 12 PubMed.

    . 17β-Estradiol regulates insulin-degrading enzyme expression via an ERβ/PI3-K pathway in hippocampus: relevance to Alzheimer's prevention. Neurobiol Aging. 2011 Nov;32(11):1949-63. PubMed.

    . The healthy cell bias of estrogen action: mitochondrial bioenergetics and neurological implications. Trends Neurosci. 2008 Oct;31(10):529-37. PubMed.

    . Estrogen-induced plasticity from cells to circuits: predictions for cognitive function. Trends Pharmacol Sci. 2009 Apr;30(4):212-22. Epub 2009 Mar 18 PubMed.

    . Effect of Reproductive History and Exogenous Hormone Use on Cognitive Function in Mid- and Late Life. J Am Geriatr Soc. 2016 Dec;64(12):2448-2456. Epub 2016 Nov 7 PubMed.

  3. Another convincing study demonstrating that the length and timing of HPG axis balance dictates neurodegeneration and cognitive decline.

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References

News Citations

  1. Estrogen’s Benefit Tied to Age: Good for the Young, Bad for the Old
  2. Alzheimer’s Disease Hits Women Hardest
  3. Early Hormone Therapy Does No Cognitive Harm
  4. Estrogen Therapy Could Hold Back Alzheimer’s, Shrink the Brain?
  5. Is a Woman’s Brain More Susceptible to Tau Pathology?

Further Reading

Primary Papers

  1. . Reproductive period and risk of dementia in a diverse cohort of health care members. Neurology. 2019 Mar 28; PubMed.