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<p>Alzheimer’s disease (AD) disproportionately affects women, yet the biological basis of this sex bias remains unclear. Here, we identify sex-dependent interferon signaling as a contributor to this disparity. Transcriptomic profiling of <i>postmortem</i> AD tissue and APP/PS1 mice revealed preferential enrichment of interferon-responsive gene programs in females. In APP/PS1 mice, heightened interferon responses were associated with increased neurodegenerative features, and single-cell transcriptomic analyses identified microglia as a major cellular compartment engaging interferon responses. To test causality, we manipulated interferon signaling in vivo. Acute systemic interferon activation promoted AD-like neuropathological alterations. Genetic amplification of interferon signaling in microglia exacerbated neuroinflammatory and neurodegenerative features in APP/PS1 mice, whereas pharmacological inhibition through cGAS-STING blockade suppressed interferon responses, reduced neuropathology, and preserved cognitive performance in female APP/PS1 mice. Together, these findings identify microglial interferon signaling as a modifiable contributor to AD-associated neuropathology and suggest a neuroimmune mechanism underlying the increased vulnerability of females to the disease.</p>

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Sex-dependent interferon signaling contributes to female-biased vulnerability in Alzheimer’s disease

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2026年5月4日

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  • Verónica López-López,
  • Gerard Iniesta,
  • Marcos Galán-Ganga,
  • Alejandro Expósito-Coca,
  • Violeta Durán-Laforet,
  • Aysha M. Bhojwani-Cabrera,
  • Carmen M. Navarrón,
  • Marina Guillot-Fernández,
  • Jose L. Venero,
  • Jose V. Sánchez-Mut,
  • Angel Barco,
  • Albert Giralt,
  • José P. López-Atalaya

摘要

Alzheimer’s disease (AD) disproportionately affects women, yet the biological basis of this sex bias remains unclear. Here, we identify sex-dependent interferon signaling as a contributor to this disparity. Transcriptomic profiling of postmortem AD tissue and APP/PS1 mice revealed preferential enrichment of interferon-responsive gene programs in females. In APP/PS1 mice, heightened interferon responses were associated with increased neurodegenerative features, and single-cell transcriptomic analyses identified microglia as a major cellular compartment engaging interferon responses. To test causality, we manipulated interferon signaling in vivo. Acute systemic interferon activation promoted AD-like neuropathological alterations. Genetic amplification of interferon signaling in microglia exacerbated neuroinflammatory and neurodegenerative features in APP/PS1 mice, whereas pharmacological inhibition through cGAS-STING blockade suppressed interferon responses, reduced neuropathology, and preserved cognitive performance in female APP/PS1 mice. Together, these findings identify microglial interferon signaling as a modifiable contributor to AD-associated neuropathology and suggest a neuroimmune mechanism underlying the increased vulnerability of females to the disease.