Divergent transcriptomic transition programs in Alzheimer disease: immune priming and synaptic collapse in females versus organelle membrane bifurcation in males

13 Jul 20264 min read0 viewsVerified Feed

GIST (Key Takeaways)

Alzheimer's disease (AD) disproportionately affects women, who account for approximately two-thirds of prevalent cases. Despite decades of research, the mechanistic basis for this profound sex disparity remains poorly resolved.
Prior transcriptomic studies have predominantly used pooled or female-enriched cohorts, obscuring whether the transition from normal cognition (NCI) to AD follows a common molecular program across sexes or reflects fundamentally divergent biology. Here, we analyzed bulk RNA-sequencing data from the dorsolateral prefrontal cortex of 624 individuals (401 females, 223 males) in the ROSMAP cohort using a transition-aware framework that separates variance instability along the disease axis from mean expression changes.
We demonstrate that female and male brains exhibit structurally distinct transcriptomic transition programs. Females display a sequential, multi-tier architecture: interferon and immune variance priming (628 genes) is detectable early at the NCI-to-mild cognitive impairment (MCI) interval, which structurally precedes a massive mean-level synaptic and neuropeptide loss (8,935 genes) in AD.
The female NCI-to-MCI interval alone produces 1,249 variance bifurcation events entirely absent in males. Conversely, males exhibit no early immune priming or powered mean-level changes.

Clinical Editorial

bioRxiv (Biomedical Preprints) published a clinical update in Research Highlights on 13 Jul 2026.

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