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Basic Science and Pathogenesis.

Aura M Ramirez1, Luciana Bertholim Nasciben1, Sofia Moura1

  • 1University of Miami Miller School of Medicine, Miami, FL, USA.

Alzheimer'S & Dementia : the Journal of the Alzheimer'S Association
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Summary
This summary is machine-generated.

Ancestry significantly impacts Alzheimer's disease (AD) gene regulation, especially in brain cells like astrocytes and neurons. Understanding these ancestry-specific differences is key for developing targeted AD treatments.

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Area of Science:

  • Genomics
  • Neuroscience
  • Population Genetics

Background:

  • Genome-wide association studies (GWAS) reveal Alzheimer's disease (AD) genetic variants with varying effect sizes across populations.
  • Ancestry-dependent genomic regulatory architecture (GRA) differences contribute to this variability.
  • Local ancestry's influence on AD risk is pronounced in APOE4 carriers.

Purpose of the Study:

  • Investigate ancestry- and cell-type-specific regulatory landscapes of AD GWAS genes.
  • Utilize induced pluripotent stem cell (iPSC)-derived neural spheroids from diverse ancestries (African, Amerindian, European).

Main Methods:

  • Generated iPSC lines from peripheral blood mononuclear cells (PBMCs) of individuals with defined global ancestry.
  • Differentiated iPSCs into neural spheroids containing astrocytes, neurons, and oligodendrocytes.
  • Performed multiomic profiling (scATAC-seq, scRNA-seq, Hi-C) to analyze ancestry-dependent GRA.

Main Results:

  • Astrocytes showed the highest number of differentially expressed AD GWAS genes (DEAGG), followed by neurons.
  • Amerindian ancestry comparisons yielded the most DEAGG across all cell types.
  • Key AD genes like APOE, PSEN2, SORL1, and TMEM106B exhibited differential expression in specific cell types and ancestries.

Conclusions:

  • Ancestry plays a critical role in shaping the regulatory landscape of AD-related genes, particularly in astrocytes and neurons.
  • Findings enhance understanding of ancestry-specific GRA in AD.
  • Provides a foundation for precision medicine approaches in Alzheimer's disease.