Is a Woman’s Brain More Susceptible to Tau Pathology?

Some studies of cerebrospinal fluid biomarkers suggest that women accumulate more tau pathology early in Alzheimer’s disease than do men. In the February 4 JAMA Neurology, researchers led by Rachel Buckley and Reisa Sperling at Massachusetts General Hospital, Boston, add tau PET data that supports this. In two aging cohorts, the researchers spotted more tangles in the entorhinal cortices (ERCs) of cognitively healthy, amyloid-positive women than in the ERCs of men.

  • In cognitively healthy people with amyloid plaques, women have more tau tangles in the entorhinal cortex than do men.
  • This sex difference was slightly more pronounced in ApoE4 carriers.
  • It is unclear if women are more susceptible or more resilient to tau than men.

But what does this mean? That tau accumulates faster in women? Or that women cope better with tau pathology, remaining clinically normal while men decline? Or both? The jury is out, but clearly, there is a sex difference in tau pathology, Buckley told Alzforum. She previously discussed some of these data at the 2018 AAIC in Chicago (Aug 2018 conference news). 

Buckley noted that this sex difference is small, and probably insufficient to explain why more women than men develop the disease. That said, it does hint at biological underpinnings of AD risk in women, and could affect treatment efficacy. “Researchers running clinical trials might want to stratify by sex for their primary analysis,” she suggested.

Faster Tau Accumulation? The more amyloid in the brain, the more tau tangles in entorhinal cortices of cognitively normal women (orange) compared to men (gray). [Courtesy of © 2019 American Medical Association. All rights reserved.]

Denise Park at the University of Texas, Dallas, emphasized the importance of understanding the basis for this difference. “This study adds to growing evidence that there are subtle differences between men and women’s brains in both health and disease. A challenge is to understand the developmental trajectory of these differences, and whether they were preordained by biology or emerged as a result of differences in environment and behavior,” Park wrote to Alzforum.

Previous studies have reported more tau in CSF of women than in men, although primarily in people who carry the ApoE4 risk allele (Altmann et al., 2014; May 2018 news). It remains unclear how CSF tau relates to tangles in the brain.

To study the effect of gender and genotype on regional brain pathology, Buckley and colleagues focused on the ERC and inferior temporal cortex, two areas that accumulate tangles early in AD. The authors examined flortaucipir PET images from 103 ADNI participants and 193 people enrolled in the Harvard Aging Brain Study (HABS). All were cognitively healthy, with an average age of 74.

In the two cohorts, there was no consistent effect of sex on tau deposition. However, in the subgroup of 89 participants with positive amyloid PET scans, women had about 6 percent more tau in the ERC than did men, which was statistically significant. The higher the Aβ burden, the greater this difference. Unlike in prior studies, female ApoE4 carriers did not have significantly more tau pathology, but ERC tau did trend higher in them, suggesting a larger study might detect a sex/ApoE4 interaction. Disease stage may also be a factor. In preliminary PET data from an MCI cohort, Buckley did detect a larger effect of ApoE4 on ERC tau tangles in women than in men. In ongoing work, she is investigating whether the interaction of sex and ApoE4 becomes greater as disease advances.

Why might women have more tangles? One theory blames hormonal changes in the aging brain (Aug 2018 conference news). Buckley and colleagues are examining tau PET scans from the Framingham Study to determine if tangle progression in men and women diverges after women go through menopause.

However, it is equally possible that the apparent higher tau in women is an artifact of the study design, which included only cognitively healthy people. Perhaps women remain cognitively healthy at a tau level where men are already impaired.

One bit of evidence in favor of female resilience comes from a new study led by Manu Goyal and Andrei Vlassenko at Washington University in St. Louis. Using PET, they compared brain glucose metabolism in 205 cognitively healthy adults ages 20 to 82. They were able to measure brain aging by way of metabolism because, over time, the brain shifts from using glycolysis to a mainly oxidative metabolism (Goyal et al., 2014; Goyal et al., 2017). Across adulthood, women’s brains remained about four years younger metabolically than men’s. The finding hints that women could be more resilient to age-related changes and pathologies than men, the authors note (Goyal et al., 2019). Buckley agreed this might be the case.

Buckley plans to follow people with preclinical AD and measure whether cognition declines more slowly in women than men with the same levels of pathology. She is also examining brain regions beyond the ERC and inferior temporal cortex in tau scans from about 800 participants in ADNI, HABS, and the A4 secondary prevention trial, with preliminary evidence pointing to additional regions with sex differences in tangle load.—Madolyn Bowman Rogers

Comments

    • User Profile Image Rena Li
      International Biomedical Research Training Program (IBRTP) Roskamp Institute,
    • Posted:

    This is a very interesting study that demonstrated normal females expressed more typical AD pathology than males by using PET imaging. While Aβ PET imaging has been frequently used in the clinic as an aid to AD diagnosis, and in AD clinical treatment trials as a confirmation of AD pathology since its 2012 approval by the FDA, tau imaging is relatively recent to clinical practice (Roberts et al., 2013; James et al., 2015). This study not only challenged whether tau and Aβ PET might be a preclinical AD biomarker instead of a disease biomarker, but also suggested the sex-specific prevalence of AD might be detected preclinically. 

    First, it is not really a surprise that females showed more advanced tau and Aβ changes than males, since this agrees with the sex-specific prevalence for AD reported extensively in the past decades. Based on previous studies indicating the higher risk for AD in aged females is partially due to the reduction of estrogen, animal studies demonstrated that estrogen can reduce tau phosphorylation and Aβ accumulation via estrogen-related receptors in various transgenic mouse models (Tang et al., 2018; Xiong et al., 2015). We also confirmed that estrogen deficiency induced early amyloidogenesis occurred before cognitive impairment in the APP23 transgenic mouse model (Yue et al., 2015). Therefore, it would be interesting to know whether the reported tau/Aβ imaging difference in clinically normal females versus males are related to estrogen levels. Correlating with age at menopause (spontaneous or surgical) and history of hormone therapy could help us further understand if sex hormones are related to tau and Aβ in clinically normal females. In addition, a follow-up on these subjects might be critical to determine whether those normal females with elevated expression of tau and Aβ would develop dementia sooner than those with no tau or Aβ.

    Furthermore, blood or CSF AD biomarkers in combination with PET information might improve diagnosis and provide additional understanding of the potential relationship between healthy controls and AD. For example, our previous studies (Zhong et al., 2007; Ewers et al., 2008; Shen et al., 2018) demonstrated that the level of BACE1, a key enzyme for Aβ production, is significantly elevated in the CSF and plasma from MCI subjects, in which the plasma changes occurred much earlier than the clinical diagnosis of AD. Moreover, endogenous estrogen deficiency triggers an even earlier elevation of BACE1 activity and amyloidogenesis before cognitive impairment in APP transgenic mice (Yue et al., 2015). Therefore, using multiple approaches to evaluate the tau and Aβ deposition in normal individuals would be very helpful in understanding sex differences in normal aging and in the risk for AD.

    References:

    Roberts JS, Dunn LB, Rabinovici GD. Amyloid imaging, risk disclosure and Alzheimer's disease: ethical and practical issues. Neurodegener Dis Manag. 2013;3(3):219-229. PubMed.

    James OG, Doraiswamy PM, Borges-Neto S. PET Imaging of Tau Pathology in Alzheimer's Disease and Tauopathies. Front Neurol. 2015;6:38. Epub 2015 Mar 9 PubMed.

    Tang Y, Min Z, Xiang XJ, Liu L, Ma YL, Zhu BL, Song L, Tang J, Deng XJ, Yan Z, Chen GJ. Estrogen-related receptor alpha is involved in Alzheimer's disease-like pathology. Exp Neurol. 2018 Jul;305:89-96. Epub 2018 Apr 8 PubMed.

    Xiong YS, Liu FF, Liu D, Huang HZ, Wei N, Tan L, Chen JG, Man HY, Gong CX, Lu Y, Wang JZ, Zhu LQ. Opposite effects of two estrogen receptors on tau phosphorylation through disparate effects on the miR-218/PTPA pathway. Aging Cell. 2015 Oct;14(5):867-77. Epub 2015 Jun 26 PubMed.

    Yue X, Lu M, Lancaster T, Cao P, Honda S, Staufenbiel M, Harada N, Zhong Z, Shen Y, Li R. Brain estrogen deficiency accelerates Abeta plaque formation in an Alzheimer's disease animal model. Proc Natl Acad Sci U S A. 2005 Dec 27;102(52):19198-203. PubMed.

    Zhong Z, Ewers M, Teipel S, Bürger K, Wallin A, Blennow K, He P, McAllister C, Hampel H, Shen Y. Levels of beta-secretase (BACE1) in cerebrospinal fluid as a predictor of risk in mild cognitive impairment. Arch Gen Psychiatry. 2007 Jun;64(6):718-26. PubMed.

    Ewers M, Zhong Z, Bürger K, Wallin A, Blennow K, Teipel SJ, Shen Y, Hampel H. Increased CSF-BACE 1 activity is associated with ApoE-epsilon 4 genotype in subjects with mild cognitive impairment and Alzheimer's disease. Brain. 2008 May;131(Pt 5):1252-8. PubMed.

    Shen Y, Wang H, Sun Q, Yao H, Keegan AP, Mullan M, Wilson J, Lista S, Leyhe T, Laske C, Rujescu D, Levey A, Wallin A, Blennow K, Li R, Hampel H. Increased Plasma Beta-Secretase 1 May Predict Conversion to Alzheimer's Disease Dementia in Individuals With Mild Cognitive Impairment. Biol Psychiatry. 2017 Mar 27; PubMed.

    View all comments by Rena Li

  2. I’m a co-author on this paper. I think this important work led by Dr. Buckley adds to a growing body of literature suggesting that there are notable sex differences in AD pathology, particularly along the tau pathway. This manuscript makes at least two critical additions to the literature. (1) The use of PET tau adds specificity to some of the previous work on CSF tau and suggests sex differences emerge in the temporal lobe. (2) Focusing on individuals who are cognitively normal suggests that sex differences in tau begin to emerge during the preclinical phase of AD, particularly in the presence of amyloidosis. Given previous evidence that APOE-ε4 is more strongly associated with CSF tau levels among females compared to males, it is notable that the APOE x sex interaction in Dr. Buckley's work only approached statistical significance. The lack of a statistically significant interaction, however, highlights a pressing need in the field for larger PET and autopsy samples to provide clarity around this potential interaction.

    Dr. Buckley also rightly points out the need to better understand how survival bias could contribute to these observed sex differences. As a field, I believe we need to initiate cross-disciplinary collaborations that can begin to probe and better understand such important potential confounding factors. Moreover, we need to work together to increase the diversity and representation in biomarker studies to better characterize sex differences across race, ethnicity, and socioeconomic status and ensure that our conclusions are relevant to the general population.

    Together with previous findings, this important work provides strong evidence that sex differences in tau emerge downstream of amyloidosis and may contribute to the clinical manifestation of disease.

    View all comments by Timothy Hohman

  3. In Alzheimer’s disease, sex differences emerged from different studies that focused on diverse aspects of the disease. Indeed, epidemiological and observational studies provide evidence for higher prevalence and incidence of AD in women than in age-matched men, with women presenting with a higher level of brain oxidative stress as well as more amyloid-β burden.

    This new study shows for the first time that in clinically normal adults, women with higher Aβ burden also show greater entorhinal cortical tau compared with men. Difference in sex hormones may explain these variations between men and women (reviewed in Grimm et al., 2016). Indeed, estrogen, the main female sex hormone, is known to exert neuroprotective effects during women’s reproductive lives. Cellular and animal studies revealed that estrogen is able to decrease Aβ accumulation and aggregation, and also reduces tau hyperphosphorylation. Therefore, the sudden drop of sex hormones at menopause and the loss of their protective effects in the brain may be correlated to the Aβ burden and the level of abnormal tau hyperphosphorylation in women.

    Our findings indicate that progesterone and estradiol are especially effective at maintaining energetic balance in the brain when tau pathology is present. Thus, one can speculate that loss of female sex hormones may worsen tau pathology in a vicious cycle together with Aβ (Ittner and Götz, 2011). Further investigations would be necessary to determine the correlation between sex hormone levels and the presence of AD hallmarks, including amyloid plaques and neurofibrillary tangles, in clinically normal adults. Such data might help to predict the evolution of the pathology.

    References:

    Grimm A, Mensah-Nyagan AG, Eckert A. Alzheimer, mitochondria and gender. Neurosci Biobehav Rev. 2016 Aug;67:89-101. Epub 2016 Apr 29 PubMed.

    Ittner LM, Götz J. Amyloid-β and tau--a toxic pas de deux in Alzheimer's disease. Nat Rev Neurosci. 2011 Feb;12(2):65-72. PubMed.

    View all comments by Anne Eckert View all comments by Amandine Grimm

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References

News Citations

  1. Do Brain Changes at Menopause Make Women More Prone to Alzheimer’s?
  2. Study Finds Sex Influences CSF Tau Levels in ApoE4 Carriers

Paper Citations

  1. Altmann A, Tian L, Henderson VW, Greicius MD, Alzheimer's Disease Neuroimaging Initiative Investigators. Sex modifies the APOE-related risk of developing Alzheimer disease. Ann Neurol. 2014 Apr;75(4):563-73. Epub 2014 Apr 14 PubMed.
  2. Goyal MS, Hawrylycz M, Miller JA, Snyder AZ, Raichle ME. Aerobic glycolysis in the human brain is associated with development and neotenous gene expression. Cell Metab. 2014 Jan 7;19(1):49-57. PubMed.
  3. Goyal MS, Vlassenko AG, Blazey TM, Su Y, Couture LE, Durbin TJ, Bateman RJ, Benzinger TL, Morris JC, Raichle ME. Loss of Brain Aerobic Glycolysis in Normal Human Aging. Cell Metab. 2017 Aug 1;26(2):353-360.e3. PubMed.
  4. Goyal MS, Blazey TM, Su Y, Couture LE, Durbin TJ, Bateman RJ, Benzinger TL, Morris JC, Raichle ME, Vlassenko AG. Persistent metabolic youth in the aging female brain. Proc Natl Acad Sci U S A. 2019 Feb 4; PubMed.

Further Reading

Primary Papers

  1. 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.

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