Multi-class Modeling Identifies Shared Genetic Risk for Late-onset Epilepsy and Alzheimer's Disease.

Area of Science:

• Neurogenetics
• Genomics
• Epilepsy and Alzheimer's Disease Research

Background:

• Late-onset epilepsy (LOE) and Alzheimer's disease (AD) share established links, but their common genetic underpinnings beyond the APOE gene are not fully understood.
• Investigating shared genetic factors is crucial for understanding the co-occurrence and potential shared biological pathways of AD and LOE.

Purpose of the Study:

• To identify shared genetic factors contributing to both Alzheimer's disease and late-onset epilepsy.
• To interpret the biological pathways implicated by these shared genetic risks.
• To evaluate the mediating role of LOE in the relationship between shared genetic risks and AD onset.

Main Methods:

• Phenotype definition using phecodes for patients aged 60-90.
• A two-step Least Absolute Shrinkage and Selection Operator (LASSO) workflow integrated AD Genome-Wide Association Study (GWAS) data with functional genomics.
• Causal mediation analysis using an AD-LOE shared risk score, with validation in UCLA Health and All of Us EHR databases.

Main Results:

• Identified 34 shared genetic loci between AD and LOE, including the APOE region, mapping to 65 genes.
• Enrichment analysis revealed involvement in tau protein binding and lipoprotein metabolism.
• Higher shared risk scores correlated with increased risk for AD, LOE, or both; LOE partially mediated AD-LOE genetic risk on AD (15% on average).

Conclusions:

• Machine learning identified shared genetic risks for AD and LOE, highlighting the APOE-TOMM40-APOC1 gene cluster and uncovering novel contributing genes.
• This research provides novel insights into common and disease-specific mechanisms underlying AD and LOE, utilizing the All of Us genetic data.
• Findings have significant implications for developing targeted prevention and treatment strategies for the co-occurrence of AD and LOE.