Gilsanz P, Lee C, Corrada MM, Kawas CH, Quesenberry CP Jr, Whitmer RA. Reproductive period and risk of dementia in a diverse cohort of health care members. Neurology. 2019 Apr 23;92(17):e2005-e2014. Epub 2019 Mar 28 PubMed.

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  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:

    Buckley RF, Mormino EC, Rabin JS, Hohman TJ, Landau S, Hanseeuw BJ, Jacobs HI, Papp KV, Amariglio RE, Properzi MJ, Schultz AP, Kirn D, Scott MR, Hedden T, Farrell M, Price J, Chhatwal J, Rentz DM, Villemagne VL, Johnson KA, Sperling RA. 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.

    View all comments by Rachel Buckley

  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:

    Brinton RD, Yao J, Yin F, Mack WJ, Cadenas E. Perimenopause as a neurological transition state. Nat Rev Endocrinol. 2015 Jul;11(7):393-405. Epub 2015 May 26 PubMed.

    Yin F, Yao J, Sancheti H, Feng T, Melcangi RC, Morgan TE, Finch CE, Pike CJ, Mack WJ, Cadenas E, Brinton RD. 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.

    Klosinski LP, Yao J, Yin F, Fonteh AN, Harrington MG, Christensen TA, Trushina E, Brinton RD. 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.

    Mosconi L, Berti V, Guyara-Quinn C, McHugh P, Petrongolo G, Osorio RS, Connaughty C, Pupi A, Vallabhajosula S, Isaacson RS, de Leon MJ, Swerdlow RH, Brinton RD. Perimenopause and emergence of an Alzheimer's bioenergetic phenotype in brain and periphery. PLoS One. 2017;12(10):e0185926. Epub 2017 Oct 10 PubMed.

    Mosconi L, Berti V, Quinn C, McHugh P, Petrongolo G, Varsavsky I, Osorio RS, Pupi A, Vallabhajosula S, Isaacson RS, de Leon MJ, Brinton RD. 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.

    Mosconi L, Rahman A, Diaz I, Wu X, Scheyer O, Hristov HW, Vallabhajosula S, Isaacson RS, de Leon MJ, Brinton RD. 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.

    Zhao L, Yao J, Mao Z, Chen S, Wang Y, Brinton RD. 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.

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

    Brinton RD. 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.

    Karim R, Dang H, Henderson VW, Hodis HN, St John J, Brinton RD, Mack WJ. 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.

    View all comments by Roberta Diaz Brinton

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

    View all comments by Craig Atwood

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  1. From Menarche to Menopause: Shorter Span Linked to Higher Risk of Dementia