Basic Science and Pathogenesis.

Area of Science:

• Genomics
• Neuroscience
• Population Genetics

Background:

• Late Onset Alzheimer's disease (LOAD) is complex and heterogeneous, posing challenges for genetic studies.
• Most genetic research on LOAD has focused on European ancestry populations, neglecting other groups.
• Understanding genetic drivers across diverse ancestries is crucial for a comprehensive view of LOAD.

Purpose of the Study:

• To investigate the genetic underpinnings of LOAD in diverse populations.
• To identify shared (pan-ethnic) and distinct (ancestry-specific) genetic drivers of LOAD between European and African ancestries.

Main Methods:

• Single-nucleus multi-omics (snRNA-seq and snATAC-seq) were performed on cortical tissues from European (EA) and African ancestry (AA) LOAD and control donors.
• An integrative genomic pipeline was used to identify differentially expressed genes (DEGs) and candidate cis-regulatory elements (cCREs).
• Differential expression analysis and ancestry interaction modeling were employed to infer shared and divergent DEGs.

Main Results:

• 32 cell subtypes were identified in both EA and AA, with highest DEGs in specific neuronal and glial subtypes.
• Differential chromatin interactions were observed, impacting gene dysregulation across ancestries, exemplified by APOE regulation in microglia.
• Pan-ethnic DEGs were enriched in neuronal subtypes involved in cellular growth, extracellular matrix, and membrane trafficking.
• More ancestry-specific DEGs were found in AA, particularly in excitatory neurons (fatty acid metabolism, neuronal structure) and inhibitory neurons (respiration, synaptic transmission).

Conclusions:

• The study enhances understanding of shared and distinct cell-subtype gene dysregulation networks in LOAD.
• Biological processes underlying LOAD show both commonalities and differences between African and European ancestries.
• These findings contribute to a more nuanced view of LOAD genetics across diverse populations.