Single-cell transcriptomic atlas of Alzheimer's disease middle temporal gyrus reveals region, cell type, and sex specificity of gene expression with novel genetic risk for MERTK in female
TL;DR
Single-nucleus RNA sequencing of the Alzheimer's disease middle temporal gyrus revealed sex-specific microglial signatures and identified MERTK genetic variation as a female-specific risk factor.
Problem / question
Alzheimer's disease disproportionately affects women, who experience more severe neurodegeneration, but the cellular mechanisms driving these sex-specific brain changes in highly affected regions like the middle temporal gyrus remain unclear.
Methods
The researchers performed unbiased massively parallel single-nucleus RNA sequencing (snRNA-seq) on human Alzheimer's disease and control brain samples from the middle temporal gyrus, and integrated these transcriptomic profiles with genome-wide association study (GWAS) data.
Key findings
The study identified a selectively vulnerable subpopulation of layer 2/3 excitatory neurons that are RORB-negative and CDH9-expressing, which showed no sex differences. While reactive astrocyte signatures were also sex-independent, microglia signatures in diseased brains differed distinctly between males and females. By integrating this single-cell data with GWAS results, the authors identified genetic variation in the MERTK gene as a novel Alzheimer's risk factor exclusively in females.
Why it matters
This provides a high-resolution cellular map of how Alzheimer's disease affects the middle temporal gyrus differently in men and women, offering a mechanistic explanation for female-specific genetic risk factors like MERTK.
Limitations
The provided abstract does not explicitly state specific limitations, caveats, or constraints of the study.
Takeaway
Microglial responses in the Alzheimer's middle temporal gyrus are highly sex-specific, and genetic variation in MERTK specifically increases Alzheimer's risk in women.