Preventing amyotrophic lateral sclerosis: Risk, Resilience and Presymptomatic Biology

Monogenetic adult-onset neurodegenerative diseases have been considered deterministic. In genetic forms of Amyotrophic lateral sclerosis (ALS, also known as motor neuron disease, MND), incomplete and family-specific penetrance indicates that pathogenic rare variants are insufficient to explain disease expression. This implies a more complex biological architecture – in which rare variants establish vulnerability, whilst common genetic variants, ageing and broader systemic factors determine when compensatory mechanisms fail. Better understanding of the determinants of risk, prediction of who will develop ALS and the timing of disease onset is essential to preventing ALS as targeted genetic therapies become a reality.

In this seminar, I will describe work to understand the drivers of ALS risk including common and rare variant interactions and systemic metabolic factors. I will review longitudinal biomarker trajectories that are refining prediction of ALS onset and discuss necessary future developments to enable prevention of ALS.