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Basic Science and Pathogenesis.

Masataka Kikuchi1, Akinori Miyashita1, Yu Hirota2

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Summary
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Alzheimer's disease (AD) patients stratified by a microglial polygenic risk score (PRS) show varied microglial reactivity. This genetic stratification highlights personalized therapeutic potential for AD based on individual genetic predispositions.

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Area of Science:

  • Neuroscience
  • Genetics
  • Immunology

Background:

  • Microglia exhibit diverse gene expression in stress environments and become reactive in response to amyloid-beta (Aβ) accumulation, a hallmark of Alzheimer's disease (AD).
  • TREM2 gene mutations are linked to reduced microglial reactivity in AD, but polygenic influences are critical for understanding AD complexity.
  • A microglial polygenic risk score (PRS) was developed to quantify polygenic effects and stratify AD patients.

Purpose of the Study:

  • To investigate pathological differences between AD patients stratified by a microglial PRS.
  • To explore the role of polygenic influences on microglial responses in AD.

Main Methods:

  • Analysis of postmortem brain samples (n=100) with Braak staging for senile plaques (SP) and neurofibrillary tangles (NFT).
  • Whole-genome sequencing and bulk RNA sequencing (RNA-seq) of the frontal cortex.
  • Single-nucleus RNA-seq (snRNA-seq) and spatial transcriptomics on a subset of samples for higher-resolution analysis.

Main Results:

  • AD patients stratified into low-PRS and high-PRS groups revealed 112 differentially expressed genes related to autophagy and inflammation.
  • snRNA-seq identified distinct microglial clusters, showing significant variability in microglial reactivity to Aβ based on PRS.
  • Spatial transcriptomics supported heterogeneity in microglial responses, influenced by genetic predisposition within similar AD pathology.

Conclusions:

  • Microglial reactivity in AD varies with the strength of genetic predisposition, even with similar pathological diagnoses.
  • PRS-based stratification offers a method to identify distinct genetic profiles in AD patients.
  • Genetic stratification may enable the development of tailored therapeutic strategies for AD.