. 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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  1. 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., 2013James 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.


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    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.


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    View all comments by Amandine Grimm

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