Coughlan GT, Betthauser TJ, Boyle R, Koscik RL, Klinger HM, Chibnik LB, Jonaitis EM, Yau WW, Wenzel A, Christian BT, Gleason CE, Saelzler UG, Properzi MJ, Schultz AP, Hanseeuw BJ, Manson JE, Rentz DM, Johnson KA, Sperling R, Johnson SC, Buckley RF. Association of Age at Menopause and Hormone Therapy Use With Tau and β-Amyloid Positron Emission Tomography. JAMA Neurol. 2023 May 1;80(5):462-473. PubMed.

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  1. I was excited to read this paper. It replicated our earlier research showing that the perimenopausal transition is a transition from decline in glucose metabolism in the brain to activating metabolism of an auxiliary fuel—lipids. Our research at both the discovery and clinical science levels indicated that the lipids that are being utilized as an auxiliary fuel can be derived from white matter. We further have shown that the utilization of lipids as an auxiliary fuel can be associated with white-matter catabolism. We have also shown, at both the preclinical and clinical human brain imaging level, that women transitioning through the perimenopause can develop Aβ deposits in the brain and decline in white-matter volume. Both amyloid deposits detected by PIB-PET and decline in white-matter volume detected by MRI are greater in the postmenopausal brain.

    Regarding hormone therapy, we have extensively researched the impact of hormone therapy. Outcomes of our mechanistic and clinical science indicate that:

    1. Rachel’s data on tau is consistent with our findings both in preclinical and clinical studies over more than a decade that females have greater Aβ load than age-matched males. The emergence of Aβ can begin in the perimenopause and increase over the menopausal transition into post-menopause.
    2. Hormone therapy initiated at the time of and prescribed for menopausal symptoms reduces the risk of developing Alzheimer’s disease. We have published our own medical informatics on this issue, as well as a review on epidemiological vs. clinical trial data on hormone therapy.
    3. Hormone therapy after menopause and the cessation of menopausal symptoms is of no benefit. We are conducting extensive analyses to determine the process by which  the estrogen response in brain is dismantled. Our data thus far indicate that it is a step-wise systematic process of dismantling.
    4. Estrogen sustains brain health; it does not reverse brain disease. I wrote about this in a TIPS/Cell  review titled the Healthy Cell Bias of Estrogen Action.
    5. The increase in tau in hormone therapy users reported by Rachel and colleagues is likely due to the progestin component and not the estrogen component, as the estrogen-only users in the Women’s Health Initiative study exhibited no benefit and no harm. It was the medroxy-progesterone (MPA) component of the hormone therapy that was the culprit—which is consistent with our translational science outcomes. It would have been beneficial to provide information on the actual hormone therapy components and why women were prescribed hormone therapy in post-menopause.
    1. Overall, Rachel’s findings provide another set of evidence that hormone therapy is not beneficial in non-symptomatic post-menopausal women. The nuanced outcomes of the study are critical for considering the pros and cons of hormone therapy, and when hormone therapy is appropriate and when it is not.

    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.

    Kim YJ, Soto M, Branigan GL, Rodgers K, Brinton RD. Association between menopausal hormone therapy and risk of neurodegenerative diseases: Implications for precision hormone therapy. Alzheimers Dement (N Y). 2021;7(1):e12174. Epub 2021 May 13 PubMed.

    Kim YJ, Brinton RD. Precision hormone therapy: identification of positive responders. Climacteric. 2021 Aug;24(4):350-358. Epub 2021 Feb 22 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.

    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.

    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.

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

    View all comments by Roberta Diaz Brinton

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  1. Are Hormones To Blame for High Tau in Women?