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Clinical Manifestations.

Lindsey I Sinclair1, Mizuki Morisaki1,2, Peter P Henley3

  • 1University of Bristol, Bristol, United Kingdom.

Alzheimer'S & Dementia : the Journal of the Alzheimer'S Association
|December 25, 2025
PubMed
Summary
This summary is machine-generated.

This study investigated gene expression differences in Alzheimer's disease (AD) with and without depression. Researchers identified specific gene pathways, particularly in microglia, that may contribute to depression in AD patients.

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Area of Science:

  • Neuroscience
  • Genetics
  • Psychiatry

Background:

  • Depression is a common and distressing comorbidity in Alzheimer's disease (AD).
  • Current antidepressants are often ineffective for depression in AD.
  • The underlying mechanisms of depression in AD remain poorly understood.

Purpose of the Study:

  • To identify differential gene expression patterns in individuals with AD and depression compared to those with AD without depression.
  • To explore the influence of genetic risk for depression on gene expression in AD.

Main Methods:

  • Analysis of postmortem brain tissue (superior frontal gyrus and anterior insula) from individuals with AD with and without depression.
  • Cellular fractionation (neuronal and microglial) followed by microarray gene expression analysis.
  • Calculation of polygenic risk scores for depression (PRS-depression) and their correlation with gene expression.

Main Results:

  • No individual genes reached statistical significance for differential expression.
  • Gene Set Enrichment Analysis (GSEA) revealed significantly altered biological pathways in both neuronal and microglial cells.
  • Microglia exhibited a greater number of differentially expressed pathways compared to neurons, especially in the anterior insula.

Conclusions:

  • While no single gene was identified, GSEA highlighted specific pathways implicated in the development of depression in AD.
  • Microglia appear to play a significant role in the molecular pathways associated with depression in Alzheimer's disease.