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Basic Science and Pathogenesis.

Michael D Gallagher1, Wenjuan Du1,2, Moritz List1

  • 1Whitehead Institute, Cambridge, MA, USA.

Alzheimer'S & Dementia : the Journal of the Alzheimer'S Association
|December 24, 2025
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Summary
This summary is machine-generated.

This study uses induced pluripotent stem cell (iPSC)-derived cells and functional genomics to identify novel Alzheimer's (AD) and multiple sclerosis (MS) risk genes. Researchers pinpointed causal genes at 10 loci, revealing new links between neuroimmune pathways and disease.

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Area of Science:

  • Neuroscience
  • Genetics
  • Stem Cell Biology

Background:

  • Neurological diseases (NDs) like Alzheimer's (AD) and multiple sclerosis (MS) pose significant health and economic burdens.
  • Genome-wide association studies (GWAS) have identified numerous single nucleotide polymorphisms (SNPs) associated with ND risk, but most are in noncoding regions, complicating functional studies.
  • A major challenge is understanding the cell-type-specific roles of noncoding genetic variants in neurological disease pathogenesis.

Purpose of the Study:

  • To pinpoint causal genes at 10 loci associated with Alzheimer's (AD) and multiple sclerosis (MS) risk.
  • To leverage induced pluripotent stem cell (iPSC)-based models and functional genomics to overcome limitations in studying noncoding genetic variants.
  • To identify novel genes and pathways involved in the pathophysiology of AD and MS.

Main Methods:

  • Generation of neural progenitors, neurons, astrocytes, and microglia from iPSCs.
  • Integration of RNA-sequencing, H3K27ac ChIP-sequencing, and Promoter Capture Hi-C.
  • Comparison of iPSC-derived cells with primary human brain cells for physiological relevance.
  • CRISPR interference (CRISPRi) screening in iPSC-derived microglia-like cells (iMGLs) targeting AD and MS risk SNPs.

Main Results:

  • iPSC-derived cell types exhibited characteristic gene signatures and enhancer patterns, with iMGLs showing high similarity to primary microglia.
  • Enrichment of AD and MS risk SNPs was observed in cell type-specific enhancers, particularly in microglia.
  • Functional screening identified novel AD and MS risk genes, including MAF and ELMO1, with ELMO1 characterized as a new MS risk gene involved in microglial homeostasis.

Conclusions:

  • The combined approach of iPSC models and functional genomics effectively identified previously uncharacterized risk genes for AD and MS.
  • These findings highlight the role of neuroimmune pathways in disease pathophysiology by linking genetic risk variants to specific genes.
  • Further research is ongoing to elucidate the functional impact of identified genes, such as MAF and ELMO1, on microglial function and neuronal/astrocyte interactions.