Abdulai-Saiku S, Gupta S, Wang D, Marino F, Moreno AJ, Huang Y, Srivastava D, Panning B, Dubal DB. The maternal X chromosome affects cognition and brain ageing in female mice. Nature. 2025 Jan 22; Epub 2025 Jan 22 PubMed.
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Loma Linda University School of Medicine
This very interesting paper addresses questions about which I have been thinking for a while. It deals with elucidating the elusive role of the X chromosome in contributing to the development of late-onset cognitive decline. It showed that, in female mice, the unbalanced expression of maternally derived X chromosomes may convey a greater risk than does the equal expression of maternally and paternally derived chromosomes. The authors attributed the difference to the operation of epigenetic mechanisms, causing shutdown of some gene expression in maternally derived X chromosomes that are expressed in an unbalanced manner. They restored expression by CRISPR activation of these genes.
These are fascinating and important observations, because they show how the X chromosome might contribute to the impaired development of neural function, and greater susceptibility to late-onset decline in function, without appearing to be genetically different from X chromosomes that were associated with normal development and normally sustained function.
Any explanation that assumes greater robustness to a paternally derived X chromosome needs to consider that all paternally derived X chromosomes came from the father's mother (that is, started out as maternally derived), and that paternally derived X chromosomes in a female become maternally derived when passed on to her offspring. It would be necessary to postulate that something happens to modify a maternally derived X-chromosome due to its passage in a male that would make it more robust to withstand harmful epigenetic influences, and that this effect would wane after passage in a female.
Further—having two copies of the X chromosome is better than one, in terms of reduced risk to develop ALS, Parkinson's disease, and amnestic mild cognitive impairment. The latter condition is frequently the forerunner of Alzheimer's disease (as determined before biomarkers became available), and its incidence is greater in men when using population-based, age-adjusted data. The greater prevalence of Alzheimer's disease in women is due to their greater longevity. The observation that balanced expression of both X chromosomes is better than reliance on one is consistent with these clinical observations.
The authors did not check what would happen in female mice if there were an unbalanced expression of paternally derived X chromosomes, compared with equal expression of maternally and paternally derived chromosomes. The authors also point out that comparison of their results to what might be seen in males (who only have a maternally derived X chromosome) was not done. We are therefore lacking two comparison groups that would be needed to fully understand the implications of the current observations. It may be best to withhold further speculation until these data are available.
View all comments by Carmel ArmonMassachusetts General Hospital/Harvard Medical School
This is an amazing paper. It goes to the heart of trying to understand how the X chromosome, paternal history, and epigenetics all combine to influence rates of cognitive decline. We have seen increasing evidence over the years of maternal family history having an influence on Alzheimer’s disease risk. Dr. Mabel Seto from our group had a recent paper showing that maternal family history is associated with higher levels of amyloid in offspring of either sex, regardless of the maternal age of onset (Seto et al., 2024).
This work fits with the growing literature on the importance of X-linked genes and their impact on AD. While this focuses on epigenetics on the maternal X, there are a broad range of questions being asked by many groups (citations below) that are trying to get to the bottom of whether, why, and how X-linked genes are associated with amyloid, tau and cognitive decline, in postmortem tissue and whole blood (RNA-Seq) as well as in DNA (GWAS). I think the exciting thing about the X is that we’re seeing more and more evidence of protection on this chromosome and not just risk.
We can’t yet draw conclusions from Abdulai-Saiku et al. to human cohorts because we haven’t directly tested these questions, but the paper certainly gives us food for thought about the impact of sex-specific biological pathways that might echo through the generations. We should work on understanding how much these animal model findings can be replicated and how much they tell us about what is happening in the human condition.
References:
Seto M, Hohman TJ, Mormino EC, Papp KV, Amariglio RE, Rentz DM, Johnson KA, Schultz AP, Sperling RA, Buckley RF, Yang HS. Parental History of Memory Impairment and β-Amyloid in Cognitively Unimpaired Older Adults. JAMA Neurol. 2024 Aug 1;81(8):798-804. PubMed.
Belloy ME, Le Guen Y, Stewart I, Williams K, Herz J, Sherva R, Zhang R, Merritt V, Panizzon MS, Hauger RL, Gaziano JM, Logue M, Napolioni V, Greicius MD. Role of the X Chromosome in Alzheimer Disease Genetics. JAMA Neurol. 2024 Oct 1;81(10):1032-1042. PubMed.
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.
View all comments by Rachel BuckleyWashington University in St. Louis
This tremendous and sophisticated study highlights the complexity of how the X chromosome may be involved in brain aging and neurodegeneration.
It is a striking observation that when the maternally inherited X chromosome is not inactivated (while the paternal one is), some of its genes are additionally silenced due to imprinting with subsequent effects on cognition. This imprinting on the maternal X chromosome, if observed in humans, would likely lead to heterogeneity in brain aging in women and may cause a subset of women to have increased risk for neurodegenerative disorders such as Alzheimer's disease.
This mechanism is to my knowledge essentially unexplored in human studies. It is very exciting to think that future epigenetic and genetic studies may shed light on X chromosome imprinting and the imprinted genes prioritized by Abdulai-Saiku et al. We will certainly keep a close look at these genes in ongoing X chromosome genetic studies of Alzheimer's disease to understand how they may tie into female risk biases.
View all comments by Michael BelloyMake a Comment
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