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Basic Science and Pathogenesis.

Lauren A Fish1, Saranya Canchi1, Maria Telpoukhovskaia2

  • 1University of Michigan, Ann Arbor, MI, USA.

Alzheimer'S & Dementia : the Journal of the Alzheimer'S Association
|December 23, 2025
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Summary
This summary is machine-generated.

Researchers identified a gene expression signature linked to cognitive resilience in Alzheimer's Disease (AD) using a diverse mouse model. This discovery offers new avenues for developing effective AD treatments by targeting specific neuronal pathways.

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Area of Science:

  • Neuroscience
  • Genetics
  • Pharmacology

Background:

  • Alzheimer's Disease (AD) drug development faces challenges due to limitations in animal models.
  • The genetically diverse AD-BXD mouse model exhibits variable onset and cognitive decline, mirroring human AD.
  • Previous work identified a resilience gene expression signature in excitatory neurons.

Purpose of the Study:

  • To identify novel, conserved gene expression signatures and neuronal subtypes associated with AD resilience.
  • To integrate mouse and human transcriptomic data for translationally relevant annotations.
  • To analyze differential gene expression in neuronal subclasses using a continuous cognitive resilience metric.

Main Methods:

  • Integrated AD-BXD mouse single-nuclei transcriptomic data with human ROSMAP data.
  • Annotated mouse cells using a human cell taxonomy.
  • Performed differential gene expression analysis on neuronal subclasses with a fear conditioning task as a covariate.

Main Results:

  • A continuous cognitive metric showed higher statistical power than a categorical one for differential gene expression analysis.
  • Identified differentially expressed genes (DEGs) in excitatory and inhibitory neuronal subtypes.
  • Layer 2/3 excitatory neurons showed the most DEGs, including SCG5, which is linked to AD risk.

Conclusions:

  • A transcriptomic signature associated with cognitive resilience was identified in a genetically diverse AD mouse model.
  • Ongoing research will investigate conserved resilience signatures and cell types across species.
  • Future analyses will focus on drug target nomination and repositioning for preclinical validation.