Shared Genetic Architectures of Epilepsy, Frailty, and Alzheimer’s Disease: Causal Inference, Cognitive Decline, and Drug Repurposing

Alzheimer’s disease (AD) is one of the leading causes of dementia in older adults. The global burden of AD is projected to grow substantially, with an estimated 139 million people affected by 2050. AD is highly heritable (∼60–80%), and genome-wide association studies (GWAS) have identified over 70 associated genetic loci. Despite this, the complete genetic architecture and mechanisms underlying AD remain poorly understood.

Emerging evidence highlights the role of additional risk factors—including epilepsy and frailty—in the progression of AD. Individuals with epilepsy appear to be at greater risk for developing AD and experiencing frailty, potentially through pathological neuronal hyperexcitability pathways that accelerate cognitive decline, particularly in frail individuals. However, the causal relationships between these conditions and whether they share underlying molecular genetic factors have yet to be established.

This project will investigate the shared and unique genetic relationships between epilepsy, frailty, and Alzheimer’s disease.

This project involves analysis of genetics and cognitive datasets. Students will have the opportunity to perform statistical genetics analyses including (but not limited to):

• Linkage disequilibrium score regression (LDSC) and genetic correlation analyses
• Mendelian Randomisation to test causal relationships between epilepsy, frailty, and AD
• Polygenic risk score (PRS) analyses to predict domain-specific cognitive decline in the Prospective Imaging Study of Aging (PISA) cohort
• Computational drug repurposing to prioritise therapeutic targets from shared genetic mechanisms.

No prior bioinformatics tools for genetic data analysis or R programming skills are not required as training to work on those platforms will be developed during honours.

Outcomes of this project are expected to:

• Provide evidence of causal relationships between genetic risk for epilepsy, frailty, and AD
• Identify individuals at increased risk of cognitive decline through polygenic risk prediction
• Prioritise repurposable drug compounds targeting shared genetic mechanisms
• Support the development of personalised prevention strategies for ageing populations.

There is strong potential for publication arising from this work.