By Chloe Teng
Alzheimer’s disease is an irreversible brain disorder characterised by a progressive loss in memory and cognitive abilities, as well as the leading cause of dementia for those in their mid-60s. Over the last decade, the mortality rate of Alzheimer’s disease has increased despite contrasting decreases in mortality rates for other leading causes of death such as ischaemic heart diseases and lung cancer. The World Health Organisation predicts that the global number of deaths due to dementia is set to increase by 41% by 2030. Of those afflicted, there appears to be a greater prevalence in women, along with a greater severity in the presentation of the disease. Data shows that in the UK 16.5% of women died of Alzheimer’s disease and other dementias in 2018, compared to 8.7% of men (Alzheimer’s Research UK, 2018). Interestingly, recent research now challenges this stigma that women are more susceptible to Alzheimer’s disease.
Previous studies have proven that the main genetic determinant of Alzheimer’s disease is a variant of the apolipoprotein E gene (APOE) on chromosome 9 (Liu et al., 2013). By having one or two APOE ɛ4 alleles, which are the risk-factor variants, individuals have an increased risk of developing Alzheimer’s disease as well as potentially an earlier age of disease onset. Other gene mutations associated with Alzheimer’s disease include that of the amyloid precursor protein (APP) on chromosome 21, which leads to the characteristic amyloid plaques found in patients. However, these identified risk-factor genes are located on autosomes, and therefore have no variation in significance between different sexes. Previously, genome-wide association studies usually focused on autosomes and thus overlooked investigations into sex chromosomes. In contrast, new research has reported that X chromosomes affect vulnerability to Alzheimer’s disease in mouse models and imply that a second X chromosome has the potential to offer resilience towards the disease (Davis et al., 2020).
Firstly, mice models with different dosages of X and Y chromosomes expressing the human amyloid precursor protein (hAPP) were compared. Independent of the presence of a Y chromosome, hAPP mice with one X chromosome showed significantly greater mortality rates and memory retention impairment compared to those with two X chromosomes. Even so, further investigation of how a second X chromosome could increase resilience against Alzheimer’s disease was required, as X chromosome inactivation should traditionally lead to the transcription of just one allele.
To understand the phenomenon, the candidate gene KDM6A was selected. KDM6A, which is located on the X chromosome, allows for the synthesis of lysine-specific demethylase A. Mutations in KDM6A have previously been detected in Kabuki syndrome patients, which is known to result in intellectual disabilities and developmental delays (Larrhoven et al., 2015). Besides that, KDM6A is also a rare X-linked gene that escapes X inactivation. This explains its higher expression in XX mice and consequently its effect in protection against Alzheimer’s disease. By assessing databases of gene expression studies and Alzheimer’s disease patients, the minor allele of a genetic variant, rs128450057, was found to increase the expression of KDM6A in the brain. Increasing the dose of the KDM6A variant significantly reduced cognitive decline in linear mixed-effects regression models. Thus, it appeared that the variant of KDM6A conferred resilience to Alzheimer’s disease, with its most prominent effect in women as they are able to carry two copies of the allele.
As confirmation of the effect of having two copies of KDM6A in XX mice, mRNA levels of KDM6A were detected in female mice. It was found that XX mice synthesised significantly higher levels of KDM6A protein in the hippocampus, which is usually damaged as a symptom of Alzheimer’s disease. Moving forward, a new model was produced by breeding mice with toxic amyloid beta in their brains, similar to that of a human Alzheimer’s disease patient. Male XY-hAPP mice were given two X chromosomes instead, which yielded lower mortality rates and better results in cognitive tests. For female Alzheimer’s disease mice models, their second X chromosome was deleted, to which they presented worse cognitive results and died faster.
With the knowledge that the presence of a second X chromosome provides better survival for the mice models, the study then attempted to prove that the cause of such results was solely due to increased KDM6A expression. For the XY-hAPP mice, a lentivirus containing KDM6A was injected into the dentate gyrus. When KDM6A mRNA expression increased to that expected in XX females, the spatial memory abilities of these mice significantly improved in comparison to that of control XY-hAPP mice.
Ultimately, the study seems to imply that when a rare variant of KDM6A is expressed to greater levels due to its presence in two copies of X chromosomes, Alzheimer’s disease symptoms can be attenuated to a certain extent. Increasing KDM6A levels, whether it be by direct injection or introduction of another X chromosome, appeared to provide a protective mechanism for the hAPP mice. However, such results may not be able to be replicated in humans, as methods such as a second X chromosome introduction would lead to various negative effects. Perhaps other techniques to boost KDM6A levels will then need to be investigated. Besides that, the research itself also overlooks certain limitations, such as the potential contributions of other X- or Y-based functions. Even so, the results from this study are important to challenge our previous understanding of Alzheimer’s disease, and help suggest a potential target for new treatments in the future.
Alzheimer’s Research UK. Deaths due to dementia. Available from: https://www.dementiastatistics.org/statistics/deaths-due-to-dementia/ [13th September 2020]
Liu, C. C., Kanekiyo, T., Xu, H., & Bu, G. 2013. Apolipoprotein E and Alzheimer disease: risk, mechanisms and therapy. Nature reviews. Neurology, 9(2), 106–118. https://doi.org/10.1038/nrneurol.2012.263
Davis et al. 2020. A second X chromosome contributes to resilience in a mouse model of Alzheimer’s disease. Science Translational Medicine. 12(558). 10.1126/scitranslmed.aaz5677
Laarhoven et al. 2015. Kabuki syndrome genes KMT2D and KDM6A: functional analyses demonstrate critical roles in craniofacial, heart and brain development. Human molecular genetics, 24(15), 4443–4453. https://doi.org/10.1093/hmg/ddv180