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Basic Science and Pathogenesis.

Wei Tsai1, Ozkan Is1,2, Stephanie R Oatman1

  • 1Mayo Clinic, Jacksonville, FL, USA.

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

Alzheimer's disease (AD) involves cerebral amyloid angiopathy (CAA) and blood-brain barrier (BBB) leakage. This study reveals glia-to-pericyte communication networks perturbed by CAA, offering new therapeutic targets for AD.

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Area of Science:

  • Neuroscience
  • Genomics
  • Pathology

Background:

  • Cerebral amyloid angiopathy (CAA), prevalent in Alzheimer's disease (AD), involves Aβ40 deposition and blood-brain barrier (BBB) leakage.
  • CAA is linked to increased risk of stroke, hemorrhage, and cognitive decline.
  • Cell-type-specific mechanisms driving CAA and BBB integrity remain unclear.

Purpose of the Study:

  • To investigate cell type-specific gene expression and intercellular communication in Alzheimer's disease (AD) brains with varying cerebral amyloid angiopathy (CAA) severity.
  • To identify molecular mechanisms underlying CAA pathology and blood-brain barrier (BBB) integrity.

Main Methods:

  • Single-nucleus RNA sequencing (snRNAseq) of temporal cortex from 79 AD donors.
  • Correlation analysis of gene expression with Aβ40 levels and tight junction proteins (claudin-5, occludin).
  • Intercellular communication and gene regulatory network analyses.

Main Results:

  • Identified 25 cell clusters, including neuronal, glial, and vascular types.
  • Higher CAA and Aβ40 levels correlated with altered cell proportions (reduced neurons, increased glia/vasculature).
  • Discovered glia-to-pericyte communication pathways and pericytic gene networks associated with CAA and BBB integrity.

Conclusions:

  • Glia-to-pericyte interactions and pericytic gene networks are implicated in CAA and BBB dysfunction in AD.
  • Identified potential therapeutic targets within these regulatory networks.
  • Further validation using external datasets and functional studies is warranted.