Davis EJ, Broestl L, Abdulai-Saiku S, Worden K, Bonham LW, Miñones-Moyano E, Moreno AJ, Wang D, Chang K, Williams G, Garay BI, Lobach I, Devidze N, Kim D, Anderson-Bergman C, Yu GQ, White CC, Harris JA, Miller BL, Bennett DA, Arnold AP, De Jager PL, Palop JJ, Panning B, Yokoyama JS, Mucke L, Dubal DB. A second X chromosome contributes to resilience in a mouse model of Alzheimer's disease. Sci Transl Med. 2020 Aug 26;12(558) PubMed.

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  1. For many diseases, sex differences profoundly affect the risk, underlying mechanisms for the development and progression of disease, symptoms, treatment response, and overall morbidity and mortality. Within the dementia field, especially Alzheimer’s disease dementia, there has been an increased interest in identifying sex differences on a number of fronts, but this research topic is still in its infancy. This manuscript by Davis et al., which is very well-written and methodologically sound, focuses and expands on two specific aspects of sex differences in Alzheimer’s disease (AD): mortality bias and distinguishing hormonal effects from sex (XY) chromosome effects.

    First, the authors show, in a meta-analysis of cohort studies and among mice expressing a human amyloid precursor protein (hAPP), that male sex increased the risk for mortality, including among persons diagnosed with AD dementia. Giving that aging is the greatest risk factor for AD and other dementias, this study further highlights the importance of considering sex differences in mortality bias when conducting research on sex differences in risk factors and mechanisms for AD. Second, and perhaps even more intriguing, is their methodology to try to separate sex chromosomes from sex hormones. The authors uniquely show that the addition of an X (e.g., XX vs. XY) leads to brain resilience; thus, it is not the Y gene that is necessarily detrimental. This work suggests that the sex chromosomes largely governed the observed sex differences. However, the study did not specifically assess the activating effects of hormonal treatments, only loss of hormones through gonadectomy. Lastly, the authors demonstrate, through a number of experiments, that the gene Kdm6a, which escapes X inactivation, causes neural and cognitive resilience in the mouse studies. Thus, the more doses (i.e., XX vs. XY), the better resilience. 

    Notably, most GWAS studies have historically excluded the sex chromosomes. This study highlights the need to examine genes on the X and Y chromosomes for risk and resiliency to AD and other dementias. I look forward to the future results that will come from the focus on the sex chromosomes to better understand the sex differences for the risk and resiliency of AD.

    View all comments by Michelle Mielke

  2. This study is a fascinating deep dive into the effects of the X chromosome itself on vulnerability/resilience factors associated with AD. Lots of interest has been focused on the dichotomous indicator of biological sex and its impact on risk in recent papers, however, they did not get into the mechanism behind which risk or resilience to AD might be sex-dimorphic. A fascinating fact about the XY and XX chromosome configuration is that the XX combination is a “double dose” of the X chromosome. In order to compensate for this issue, either the maternal or paternal X chromosome is randomly inactivated. Intriguingly, some genes on the inactivated X chromosome will escape this inactivation. This could be random, but could also be more systematic.

    Kdm6a is a gene that more consistently escapes inactivation across the population, with a recent paper suggesting an increased risk for autoimmune diseases such as MS is due to its expression in CD4+ T lymphocytes in women (Itoh et al., 2020). The fact that increased Kdm6a gene expression was found to moderately associate with resilience to AD-related neurotoxicity and cognitive impairment in mouse models in the current paper alludes to the fact that downstream implications of this gene activation must be cell-type specific. This won’t be a one-size-fits-all risk gene.

    An interesting point to consider is the parental origin of the X chromosome; while there is research building to now examine the implications of escaped inactivation of X chromosomes in association with AD risk, it could also be quite interesting to examine the impact of epigenetic diversity that can be imparted by either parental X depending on which is inactivated. Either way, this paper by Dr. Dubal’s lab is an exciting and novel examination of the mechanisms that underlie sex differences in AD risk/resilience.

    References:

    Itoh Y, Golden LC, Itoh N, Matsukawa MA, Ren E, Tse V, Arnold AP, Voskuhl RR. The X-linked histone demethylase Kdm6a in CD4+ T lymphocytes modulates autoimmunity. J Clin Invest. 2019 Aug 12;129(9):3852-3863. PubMed.

    View all comments by Rachel Buckley

  3. Converging evidence demonstrates the enhanced reserve against Alzheimer’s disease that women show in comparison with men. However, it has been difficult to recapitulate this in animal models, which restricts the utility of translational research. Furthermore, the underlying mechanism for this sex difference remains unknown. Now, in this elegant series of experiments, Dr. Davis and her team led by Dr. Dubal manipulate various aspects of sex differences, including the presence or absence of gonads and second chromosomes, to hone in on the importance of a second X chromosome in protecting females from some of the deleterious effects of Alzheimer’s. They identify the candidate gene for a protective sex-linked effect, Kdm6a, which does not undergo X-linked inactivation. By crossing over into human tissue samples, they were able to identify the mRNA expression of KDM6A, finding enhanced expression in the temporal lobe but not the cerebellum across several datasets, especially in women.

    Thus, this study taps into several exciting aspects of sex difference research in Alzheimer’s, including the importance of understanding genetic influences in men and women separately beyond apolipoprotein E, reflecting our own group’s recent findings (Fan et al., 2020). Furthermore, Davis and colleagues’ findings reflect a lack of sex difference in amyloid burden, consistent with findings from our own group and others’ that the sex difference in humans seems to be driven by excess tau deposition in women (Digma et al., 2020; Buckley et al., 2019). While sex differences in cognitive decline are perhaps more nuanced in humans, with women having an accelerated decline later in the MCI and in the early dementia period, and hence not showing sustained resilience, this paper is an important addition to our understanding of potential mechanisms of sex differences in Alzheimer’s.

    References:

    Fan CC, Banks SJ, Thompson WK, Chen CH, McEvoy LK, Tan CH, Kukull W, Bennett DA, Farrer LA, Mayeux R, Schellenberg GD, Andreassen OA, Desikan R, Dale AM. Sex-dependent autosomal effects on clinical progression of Alzheimer's disease. Brain. 2020 Jul 1;143(7):2272-2280. PubMed.

    Digma LA, Madsen JR, Rissman RA, Jacobs DM, Brewer JB, Banks SJ, Alzheimer’s Disease Neuroimaging Initiative. Women can bear a bigger burden: ante- and post-mortem evidence for reserve in the face of tau. Brain Commun. 2020;2(1):fcaa025. Epub 2020 Apr 14 PubMed.

    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 Sarah Banks

  4. Previous studies indicated that there were sex differences in mortality and cognitive deficits in human patients with Alzheimer’s disease (AD). This study by Davis et al. provides new evidence that sex chromosomes and their associated genes might play important roles in regulation of sex-specific vulnerability to AD.

    Specifically, the study started with a meta-analysis of mortality data in human populations worldwide and found that in AD patients, males had about 62 percent increased risk for death compared to females. The same sex-difference results were obtained in a transgenic mouse model of AD, in which mutated human amyloid precursor protein (hAPP) was expressed. In addition to mortality, the study also used the hAPP transgenic mice to determine if there were sex differences in multiple cognitive functions, such as spatial learning and memory (Morris water maze) and passive-avoidance testing (fear memory). To eliminate the influences of sex hormones on mortality and cognitive functions, the study performed gonadectomy to deplete the circulating hormones. The results demonstrated that female mice performed significantly better in all tests, although the AD-related pathological features in the brain were similar between the two sexes. These results suggest that different sex chromosomes, but not sex hormones, might underlie the observed differences in vulnerabilities to AD.

    To address the important roles of sex chromosomes, the study used two excellent mouse genetic models. One was the Four Core Genotype (FCG) mice, which allowed the generation of XX and XY mice, each with either female ovaries (XX-female, XY-female) or male testes (XX-male, XY-male). Together with gonadectomy, these mice allowed investigation of how sex chromosomes contribute to the disease of interest independent of sex hormones. By crossing these mice with hAPP mice, the study illustrated clearly that sex chromosomes determined the different vulnerabilities to AD between male and female mice. More specifically, the additional X chromosome in XX mice decreased the female vulnerability compared to XY mice. To further confirm the important roles of the X chromosome, a second set of transgenic mice were used, in which the Y* chromosome in the male mouse has a pseudoautosomal region recombining abnormally with the X chromosome during meiosis. As a result, crossing these XY* male mice with XX female mice generated XX and XO mice with ovaries and XY and XXY mice with testes. By crossing male XY* mice with female hAPP mice, the study revealed that XX-hAPP and XXY-hAPP mice survived longer than XY-hAPP and XO-hAPP mice, indicating one more X chromosome extended the life of AD mice. Similarly, the hAPP mice with two XX chromosomes had better cognitive function than those with only 1 X chromosome.

    How does the additional X chromosome contribute to the reduced vulnerability of female mice to AD? The female XX mice only express one active X, with the other X inactivated. However, a small number of genes can escape such X inactivation and thus have higher expression in females. One such gene is Kdm6a (also known as Utx), which is the demethylase for H3K27. Indeed, the expression level of Kdm6a was always proportionally higher based on the number of X chromosomes. More importantly, the protein level of KDM6A is higher in the brains of women and genetic variation-induced KDM6A upregulation was associated with higher cognitive resilience to AD in humans. Functionally, knocking down Kdm6a in neurons of XX mice reduced their resilience to Aβ-induced neurotoxicity, whereas overexpression of Kdm6a in XY neurons enhanced their resilience. Surprisingly, in vivo overexpression of Kdm6a in adult XY-hAPP mice attenuated their vulnerability to AD-related cognitive impairments.

    In addition to the main conclusion, there are several very interesting observations that warrant further investigation. First, the mice with only one X (XO mice) consistently showed higher mortality and cognitive deficits compared with the XY mice, suggesting that some genes in the Y chromosome might somehow play protective roles. Second, in human AD patients the expression level of Kdm6a was only higher in temporal cortex, a brain region affected in early AD, but not in cerebellum, a region often spared in AD. Such a region-specific effect probably indicates that Kdm6a upregulation is a natural response of neurons encountering neurodegenerative stimuli. Third, in the Y chromosome there is a Kdm6a paralog Uty, sharing high homology but without the histone demethylase activity. Therefore, although not tested directly, it is very likely that H3K27 methylation and the subsequent epigenetic regulation of gene transcription is involved.

    The study did not explore further the cellular and molecular mechanisms by which X chromosome or Kdm6a regulated the observed neural responses to AD. For instance, by using the same transgenic mice, it will be of great interest to examine how adding one more X chromosome affects the neural development processes, such as neurogenesis, neuronal migration, axon growth and guidance, dendrite development, and synapse formation, either at the cellular or the circuit level. Advanced multiomics can be used to dissect out the differences in chromatin structure and transcriptomics of mature neurons. Are there other X chromosome genes besides Kdm6a that participate in the resilience of AD? Do non-neuronal cells in the nervous system participate in the sex-chromosomes-mediated effects?

    Recent studies in both mouse and human neural stem cells demonstrated that Kdm6a knockout impaired dendritic development and synaptic plasticity during development and cognitive deficits in adult mice. One important future direction is to investigate how upregulation of Kdm6a in neurons, either during development or in adult animals, affects neuronal function at the cellular or molecular level. As a H3K27 demethylase, Kdm6a is certainly able to modulate the epigenetic landscape and the transcription of many downstream genes. Lastly, the fast-developing iPSC and organoid approaches would allow direct experiments with human neurons both at cellular level and the circuit level.

    Collectively, this interesting study provides strong evidence that the X chromosome and the genes it harbors regulate the sex-based differences in symptoms of AD patients. In particular, Kdm6a overexpression in adult mice enhanced cognitive function in male mice, suggesting a potential therapeutic treatment for AD. More importantly, the research strategy and the genetic mouse models can be used to explore if sex chromosomes can regulate other neurodegenerative diseases, or more generally neurological diseases that show sex-based differences in symptoms.

    View all comments by Fengquan Zhou

  5. This is a provocative and exciting study that addresses the sex-specific effects in Alzheimer’s disease, an understudied topic with important impact on both basic mechanistic and translational efforts. Here, the dissociation of the sex chromosomes and sex hormones is rigorously investigated. The role of X chromosome-dosage effects, especially the effects of Kdm6a, is compelling.

    The study focuses on amyloid-mediated cognitive deficits. Sex-specific effects are also observed in response to tau pathology in mice, with male microglia exhibiting more transcriptomic changes than female microglia (Kodama et al., 2019). 

    The resilience observed in females could also potentially be modified by genetic risk alleles. For example, female ApoE4 knock-in mice appear to be more impaired cognitively than males. R47H mutation of TREM2 allele also appears to induce more severe cognitive decline in female mice than males, especially in the presence of tau pathology (Sayed et al., 2020). 

    References:

    Kodama L, Guzman E, Etchegaray JI, Li Y, Sayed FA, Zhou L, Zhou Y, Zhan L, Le D, Udeochu JC, Clelland CD, Cheng Z, Yu G, Li Q, Kosik KS, Gan L. Microglial microRNAs mediate sex-specific responses to tau pathology. Nat Neurosci. 2020 Feb;23(2):167-171. Epub 2019 Dec 23 PubMed.

    View all comments by Li Gan

  6. I have to applaud the researchers' use of intriguing methods to try to separate the effects of sex hormones from the genetic effects of sex chromosomes. Based on their report, it looks like they've found ways to address some of the primary questions that typically come up in many of the sex-specific studies of AD; namely whether sex differences are due to hormonal differences, genetic differences in the sex chromosomes, or other differences, such as environment.

    On the surface it looks like they've managed to control for potential confounding by hormonal and sex chromosome differences by removing one in the presence of the other (i.e., the XY mice with testes or ovaries and the XX mice with testes or ovaries), but I don't have enough experience in sexual biology to say what other complications could occur with these manipulations that could influence the results. As the authors pointed out, in addition to the usual limitations of modeling AD in mice, the study did not include other sex chromosome-based biological functions and they only focused on Kdm6a. Nevertheless, this paper is very intriguing and raises important questions and exciting avenues for exploration in human research.

    View all comments by Yuetiva Robles

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