The physical differences between men and women are all too obvious, but the biological divide goes right down to the cellular level in the b
By: Paul Arnold
Published: Apr 18, 2026
The physical differences between men and women are all too obvious, but the biological divide goes right down to the cellular level in the brain, according to a new study published in the journal Science.
While we have known for a long time that men and women face different risks for brain disorders such as depression and Alzheimer's, we haven't always known why. Although this latest research doesn't directly answer this, it could help us better understand the underlying biology.
Most previous research has focused on broad sections of brain tissue, but in this study, a team of researchers analyzed more than one million nuclei from six different cortical regions from 30 donors.
Decoding brain differences
Previous MRI scans of these brain regions had shown physical differences in size or volume between the sexes. The scientists wanted to see if gene activity matched the physical differences seen on the scans.
The technique they used was single-nucleus RNA sequencing, which allows researchers to examine the genetic instructions within individual cells. Specifically, the focus was on how gene expression varies across different cell types and regions.
The study identified more than 3,000 genes that differ in expression between males and females. These differences included how genes are turned on or off and how active genes are in producing RNA messages that guide protein production. What's more, they aren't spread evenly across the brain, as the team explains, "Broader effects of sex on autosomal expression are captured in 13 core signatures with varying cell type versus region specificity."
For example, the differences were much stronger (a higher number of genes were behaving differently) in certain areas like the fusiform cortex, which is a part of the brain involved in face recognition and complex visual processing.
Some of the strongest variations were seen in glial cells, which insulate neurons, but perhaps not surprisingly, the biggest differences were in the sex chromosome genes (X and Y). However, hundreds of genes across the entire genome are also influenced by sex.
Disease risk
When it comes to disease risk, the study found that some of the genes showing sex differences are the same ones linked to brain conditions that affect men and women differently, such as autism, ADHD, Alzheimer's disease and mood disorders. "This study substantially advances the breadth, depth, and granularity of knowledge on sex differences in the human brain," added the team.
The researchers explain that while their study has provided a massive amount of data, it is just the beginning. Future research could focus on when the changes appear and how they are influenced by the environment.
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https://www.science.org/doi/10.1126/science.aea9063
Sex effects on gene expression across the human cerebral cortex at cell type resolution
Editor’s summary
Several neurological disorders exhibit sex biases, and sex-determined differences in gene transcription in the brain might explain some of them. DeCasien et al. performed single-cell transcriptomic analysis of the adult human cerebral cortex across six cortical regions (see the Perspective by Tollkuhn and Breedlove). Differences between male and female brain donors varied according to cell type and region specificity, many of which were linked to known disease loci. At the cellular level, the authors did not detect any sex-biased changes in cellular proportions, suggesting that a sex difference in gene expression does not influence cell-type composition. These results are a valuable resource for understanding the mechanisms underlying sex differences in brain function and the relationship between sex and neurological disorders. —Mattia Maroso
Structured Abstract
INTRODUCTION
Sex differences in brain-related health outcomes may be a consequence of differences in gene expression, which are likely to be influenced by both sex chromosome complement and circulating hormone levels.
RATIONALE
Most current knowledge of molecular brain sex differences relies on studies of bulk tissue or isolated brain regions. We present a large-scale single-cell analysis of transcriptomic sex differences in the adult human brain, using 169 samples from 15 females (age 26 to 71 years) and 15 males (age 27 to 78 years) across six cortical regions, selected on the basis of in vivo neuroimaging measures of sex-biased volume.
RESULT
We found that sex effects on gene expression are highly patterned across cortical regions, cell types, and genes. They are most pronounced in (i) multiple cell types in the fusiform cortex (linked to male-biased volume and sex-biased behaviors); (ii) oligodendrocytes, astrocytes, and excitatory neurons across regions; and (iii) a subset of sex chromosome and autosomal genes. More than 3000 distinct genes exhibit sex-biased expression, with 133 genes (119 autosomal) showing consistent sex differences across all region × cell type combinations. Sex chromosome genes show the largest sex differences in expression, driven by conserved X-Y gametologs, cell type–specific biases in certain X- and Y-linked genes, and escape from X-inactivation—with the list of known escapees substantially expanded through our single-cell allele-specific expression analysis. Broader effects of sex on autosomal expression are captured in 13 core signatures with varying cell type versus region specificity. These signatures are (i) shaped by regional differences in cortical metabolism and laminar architecture, (ii) enriched for diverse cellular compartments and biological processes, (iii) regulated by sex steroids and X-linked transcription factors, and (iv) linked to sex-specific genetic risk factors in sex-biased neuropsychiatric and neurodegenerative diseases.
CONCLUSION
This study substantially advances the breadth, depth, and granularity of knowledge on sex differences in the human brain and provides a new open data resource to support future research. Future studies will be needed to illuminate when sex differences emerge during development and whether they are consistent across populations.
[ Sex differences in the human brain at cell type resolution. ]
Abstract
Sex differences in neurodevelopmental, psychiatric, and neurodegenerative disease susceptibility may arise from sex chromosome and hormonal influences on cell type–specific gene expression. We present a single-cell transcriptomic analysis of adult human cortex performed using 169 samples from 15 females and 15 males (age 26 to 78 years) across six regions selected according to their sex-biased volumes. Sex-based analysis identified the strongest differences in the fusiform cortex, glia, and excitatory neurons and among sex-chromosome genes. More than 3000 genes showed sex-biased expression, including 133 with consistent effects across regions and cell types. Core autosomal signatures linked sex differences to cortical architecture, hormone-responsive regulation, and genetic risk for sex-biased brain disorders. This study advances our understanding of sex differences in human brains and provides a valuable resource to support future research.
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Sex differences are still real.
