Basic Science and Pathogenesis

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.