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Current research has identified individuals who, despite carrying genetic variants typically responsible for devastating neurological conditions, maintain their cognitive function due to protective secondary gene variants, also known as modifier genes. The challenge lies in identifying these individuals, especially given their healthy status. In this article, we discuss strategies for uncovering genomic modifiers, including population studies in human samples and model organisms, genetic association studies and gene-editing approaches. We also highlight recent successful discoveries of modifiers genes in Alzheimer’s and Niemann–Pick Type C, two diseases with similar neuropathological and cognitive features. Understanding the mechanisms of neurological resilience will facilitate the design of therapeutics for susceptible individuals.
Szenfeld et al. (Mon,) studied this question.