A surprise revealed by tau PET imaging was that women tend to accumulate more tangles than men at the same clinical stage of Alzheimer’s disease. What might explain this? Some previous studies hinted at a hormonal cause, and new data strengthen this theory. In the May JAMA Neurology, researchers led by Rachel Buckley at Massachusetts General Hospital, Boston, report that women with early AD whose menopause began before the age of 46—or who had started hormone replacement therapy late—tended to have more tangles than their comparison groups. The data echo previous findings of greater dementia risk in women who started taking hormones many years after menopause.

  • Early menopause came with more tangles in women who had brain amyloid.
  • Ditto for hormone replacement therapy, when started late.
  • In male mice only, a protein arrests the hormonal stress response, slowing AD pathology.
  • Hormones influence the known sex difference in AD risk in multiple ways.

“To our knowledge, this is the first study to show that tau deposition may underlie the pre-established association between late HT intervention and AD dementia,” the authors wrote.

Even so, female sex hormones are not the whole story (for review, see Cui et al., 2023). Other studies have tied tangles to X-linked genes, as either risk or protective factors (Aug 2020 newsOct 2022 news). Furthermore, sex-specific stress responses via the body's hypothalamic-pituitary-adrenal axis may influence AD pathology, as well. In the May 2 Brain, researchers led by John Cirrito and Carla Yuede at Washington University in St. Louis reported that stress boosted release of Aβ from neurons only in female mice. Males had a protector, called β-arrestin. This type of stress has been linked to tau hyperphosphorylation and aggregation, as well.

Michelle Mielke at Wake Forest University in Winston-Salem, North Carolina, noted that women’s higher risk is likely to have multiple causes. “Hormones are a contributor, but there are a lot of other factors that differ for men and women, such as cardiovascular and metabolic risk, and responses to stress and depression,” she told Alzforum. The relative contribution of each remains unclear.

Hormones and Tangles. In multiple brain regions, women who had premature (orange), or early (blue), menopause had more tangles than those whose menopause started after age 45 (black). The association only held in the presence of amyloid plaque (dotted blue line). [Courtesy of Coughlan et al., JAMA Neurology, ©2023 American Medical Association, all rights reserved.]

Prior imaging studies from Buckley and others have reported more advanced tangle pathology in women than men at a given stage of AD (Aug 2018 conference news; Feb 2019 news; Nov 2019 news). To find out if hormones played a role, Buckley and colleagues mined data from the Wisconsin Registry for Alzheimer Prevention, an observational study of cognitively healthy older adults. First author Gillian Coughlan compared MK6240 tau PET scan data among 193 women and 99 men. Their average age was 67, and 52 of them were amyloid-positive on PiB PET.

In WRAP, as in prior studies, women had a higher average tau PET signal than age-matched men across several brain regions. This association between sex and tangles was only seen in the presence of amyloid plaques. The authors calculated the threshold needed to see this link as being between 19 to 38 centiloids; 24 is considered the threshold for brain-wide amyloid positivity.

The sample was tiny, though. Thirty-one women in the study were amyloid-positive. Among them, the six women whose menopause started before age 46 had worse tangles across multiple brain regions than did the others; the findings were statistically significant.

About half the women in WRAP had used hormone replacement therapy. Here, too, amyloid-positive women with a history of HRT had more tangles than those without. This effect was mostly in women who had started HRT more than five years after menopause.

This matches earlier data. The large Women’s Health Initiative first reported the link between HT and dementia (Jul 2002 news; Nov 2002 news; May 2003 news), causing a massive drop in the clinical use of HRT. Later studies refined this, showing that when given early, hormones do no harm (Jun 2013 news; Aug 2018 news).

In the present paper, Buckley and colleagues report that, besides the tangle effect, they see that the same two factors—early menopause and late HRT—correlated with subtle deficits on cognitive tests. They believe that future, larger studies should follow up on these data.

Mielke agreed. “The results need to be taken with caution, given that the sample size was so small,” she told Alzforum. Even so, she believes the findings add to the evidence that hormonal factors influence dementia risk in women. “What is it about the menopause transition that may be contributing to that risk?” she asked.

Roberta Brinton at the University of Arizon, Tucson, noted that Buckley’s data jibe with her own findings that women have more amyloid plaque than age-matched men, and that this accumulation often begins around menopause. “Women are at greater risk of AD not because they live longer than men, but because the disease can start earlier in women—during the menopausal transition,” she wrote to Alzforum (full comment below).

Stress and Sex. In female mice, corticotropin releasing factor activates CRF receptors, boosting Aβ production. In male mice, β-arrestin removes CRF receptors, blocking the pathway. [Courtesy of Edwards et al., Brain.]

For their part, Cirrito and colleagues examined a different sex effect, and in mice instead of people. Because stress-related health conditions are more common in women than men of this generation, and hormones can alter stress responses, the researchers wondered if this might affect AD risk (Nolen-Hoeksema et al., 1999; Henein et al., 2022; Klusmann et al., 2023). 

First author Hannah Edwards measured, every hour for 18 hours, levels of Aβ40 in the interstitial fluid of APP/PS1 mice that were confined inside a tight plastic cone for three hours. This type of restraint spikes physiological signs of stress, and indeed, levels of plasma corticosterone rose in both male and female mice during this experience.

A sex difference appeared in the brain. In female mice, the stress hormone corticotropin releasing factor (CRF) signaled neurons in the hippocampus to dial up synaptic transmission, firing 10- to 30-fold more than before the stress. In male mice, the adaptor protein β-arrestin plucked CRF receptors off the surface of neurons, keeping their activity low. As a result, ISF Aβ40 shot up 50 percent in female mice within two hours after stress, and stayed high for the entire measurement period. In male mice, Aβ40 stayed unchanged.

Blocking the CRF receptor in females prevented a rise of Aβ in their interstitial fluid, while knocking out β-arrestin in male mice caused them to respond like females. As in females, blocking CRF-R in male β-arrestin knockouts prevented the spike in Aβ. “[Our study is] the first to determine at the cell signalling level why stress differentially affects disease-related proteins in males and females,” the authors wrote.

Cirrito and colleagues did not investigate what happened to tau after stress. However, a previous study from the late John Trojanowski and colleagues at the University of Pennsylvania, Philadelphia, found that restraint stress elevated tau hyperphosphorylation and aggregation in PS19 tauopathy mice. It also caused neurodegeneration and memory deficits. Blocking the CRF receptor stopped this, demonstrating that the underlying mechanism was the same as in Cirrito’s study. Trojanowski’s study did not break down effects by sex (Carroll et al., 2011).—Madolyn Bowman Rogers


  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.


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

    . 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.

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

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

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

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News Citations

  1. Does Second X Chromosome Boost Women’s Resilience Against Alzheimer’s?
  2. Ubiquitin Peptidase Linked to Increased Tau Pathology in Women
  3. Do Brain Changes at Menopause Make Women More Prone to Alzheimer’s?
  4. Is a Woman’s Brain More Susceptible to Tau Pathology?
  5. ApoE4 and Tau in Alzheimer’s: Worse Than We Thought? Especially in Women
  6. Safety Concerns Derail Estrogen/Progestin Trial
  7. Hormone Replacement Therapy Still up on Balance Beam
  8. Dementia Risk Increases, at Least in Those Who Start Hormone Therapy Late
  9. Early Hormone Therapy Does No Cognitive Harm
  10. Estrogen’s Benefit Tied to Age: Good for the Young, Bad for the Old

Paper Citations

  1. . Sex difference in biological change and mechanism of Alzheimer's disease: From macro- to micro-landscape. Ageing Res Rev. 2023 Jun;87:101918. Epub 2023 Mar 24 PubMed.
  2. . Explaining the gender difference in depressive symptoms. J Pers Soc Psychol. 1999 Nov;77(5):1061-72. PubMed.
  3. . The Impact of Mental Stress on Cardiovascular Health-Part II. J Clin Med. 2022 Jul 28;11(15) PubMed.
  4. . Menstrual cycle-related changes in HPA axis reactivity to acute psychosocial and physiological stressors - a systematic review and meta-analysis of longitudinal studies. Neurosci Biobehav Rev. 2023 May 4;:105212. PubMed.
  5. . Chronic stress exacerbates tau pathology, neurodegeneration, and cognitive performance through a corticotropin-releasing factor receptor-dependent mechanism in a transgenic mouse model of tauopathy. J Neurosci. 2011 Oct 5;31(40):14436-49. PubMed.

External Citations

  1. APP/PS1
  2. PS19

Further Reading

Primary Papers

  1. . 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.
  2. . Sex-dependent effects of acute stress on amyloid-β in male and female mice. Brain. 2023 Jun 1;146(6):2268-2274. PubMed.