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Basic Science and Pathogenesis.

Beth Stevens1,2, Samuel E Marsh1,3, Rebecca Fulthorpe1,3

  • 1Boston Children's Hospital, Boston, MA, USA.

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

Researchers identified unique cerebrospinal fluid (CSF) macrophages enriched for Alzheimer's disease (AD) risk genes. These cells may play a crucial role in AD pathogenesis and waste clearance.

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Area of Science:

  • Neuroimmunology
  • Genetics of neurodegenerative diseases

Background:

  • Alzheimer's disease (AD) pathogenesis is linked to immune system dysfunction.
  • While microglia are implicated, peripheral immune cells' role in AD is less understood.
  • Investigating immune cell transcriptional changes across body compartments may reveal AD insights.

Purpose of the Study:

  • To investigate cross-compartment immune cell transcriptional changes in Alzheimer's disease (AD).
  • To understand how peripheral immune function is altered in AD by analyzing paired blood, cerebrospinal fluid (CSF), and brain samples.

Main Methods:

  • Performed single-cell RNA sequencing (scRNA-seq) on paired blood peripheral blood mononuclear cells (PBMCs), brain biopsies, and CSF from 100 idiopathic normal pressure hydrocephalus (iNPH) patients, including those with early AD.
  • Conducted a large-scale integrative analysis of previously published CSF scRNA-seq datasets (>200 patients, >400,000 cells).

Main Results:

  • Identified a unique population of CSF macrophages distinct from microglia and peripheral monocytes.
  • These CSF macrophages show enrichment for polygenic AD heritability, including high expression of APOE and TREM2.
  • Observed altered gene expression in these macrophages in patients with AD pathology or diagnosis.

Conclusions:

  • Discovered a unique CSF macrophage population enriched for AD risk genes, distinct from blood immune cells.
  • These CSF macrophages may perform critical scavenging and clearance functions in AD.
  • Further research is needed to clarify the specific role of these CSF macrophages in AD development and progression.