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Basic Science and Pathogenesis.

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  • 1Broad Institute of MIT and Harvard, Cambridge, MA, USA.

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Summary
This summary is machine-generated.

Normal pressure hydrocephalus (NPH) biopsies reveal cellular changes linked to Alzheimer's disease (AD) pathology and cognitive resilience. This study integrates living and postmortem brain data to uncover disease mechanisms and resistance factors.

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Area of Science:

  • Neuroscience
  • Genetics
  • Pathology

Background:

  • Postmortem brain tissue is the primary source for studying Alzheimer's disease (AD) cellular phenotypes, but it has limitations including late-stage disease, postmortem artifacts, and lack of cognitive data.
  • Normal pressure hydrocephalus (NPH) patients undergoing frontal cortex biopsies offer a unique opportunity to study cellular states in living human brain tissue, especially when amyloid and/or tau pathology is present.

Purpose of the Study:

  • To identify cellular and molecular phenotypes associated with AD pathology in living human brain specimens.
  • To investigate the relationship between specific cellular states, AD pathology (amyloid and tau), and cognitive trajectories.
  • To pinpoint the cellular sites of action for genetic loci associated with AD.

Main Methods:

  • Single-nucleus RNA sequencing (snRNA-seq) was performed on frontal cortex biopsies from 294 NPH patients (including controls and those with amyloid/tau pathology).
  • The NPH data was integrated with snRNA-seq data from 885 postmortem AD case-control subjects, creating a large dataset of 10 million cell profiles.
  • Analyses included identifying cellular substates linked to pathology, eQTL and mediation analyses for genetic loci, and tracking cognitive trajectories of NPH donors.

Main Results:

  • Amyloid and tau pathologies induced distinct changes in neuronal and glial cell proportions.
  • Microglia exposed to amyloid showed expanded GPNMB- and LPL-expressing substates enriched for AD-GWAS genes, with most risk genes acting broadly but some being state-specific.
  • Cognitive analyses identified molecular markers associated with resilience and vulnerability to amyloid-related cognitive decline over time.

Conclusions:

  • NPH biopsies provide valuable insights into cellular states associated with amyloid pathology and cognitive resilience in AD.
  • Integrating snRNA-seq data from living NPH patients and postmortem AD tissues bridges knowledge gaps, revealing molecular and cellular changes underlying AD progression and resistance.