Basic Science and Pathogenesis

Area of Science:

• Neurogenetics
• Genomics
• Neurodegenerative Diseases

Background:

• Alzheimer's disease (AD) and Lewy body dementia (LBD) are neurodegenerative disorders with overlapping genetic and pathological features.
• Genome-wide association studies (GWASs) have identified genetic loci associated with AD and LBD, but pinpointing specific causal genes requires further functional analysis.
• Understanding the shared genetic risk mechanisms between AD and LBD is crucial for developing effective therapeutic strategies.

Purpose of the Study:

• To perform functional mapping by integrating AD and LBD GWAS summary statistics with cell type-specific epigenomic data.
• To nominate candidate causal genes and identify pathways involved in AD and LBD pathogenesis.
• To elucidate the overlapping genetic risk mechanisms between AD and LBD in specific brain cell types.

Main Methods:

• Developed a novel tool, annotation- and interaction-based MAGMA (AI-MAGMA), integrating GWAS summary statistics with epigenomic annotation and interaction data.
• Applied AI-MAGMA to AD and LBD GWAS data alongside microglial, neuronal, and oligodendroglial ChIP-seq and PLAC-seq datasets.
• Utilized gProfiler for enrichment analysis to identify disease-associated pathways.

Main Results:

• Nominated dozens of significant candidate causal risk genes for AD and LBD across microglial, neuronal, and oligodendroglial cell types.
• Pathway enrichment revealed shared mechanisms including microglial lipid metabolism and endocytosis, and oligodendroglial amyloid, lipid metabolism, and blood-brain barrier pathways in both AD and LBD.
• Identified cell-type-specific pathways, such as mitochondrial roles in LBD microglia and synaptic roles in LBD oligodendroglia.

Conclusions:

• Functional mapping successfully nominated numerous candidate causal genes for AD and LBD.
• Key shared pathophysiological mechanisms include microglial lipid metabolism and endocytosis, and oligodendroglial processes related to amyloid, lipid metabolism, and the blood-brain barrier.
• The study enhances the understanding of genetic risk factors and shared pathways in AD and LBD, offering insights for future research and therapeutic development.