The genetic architecture of resilience highlights the need for precision interventions.

We have identified a novel locus within the PRUNE2 gene that acts in an APOE-dependent manner to drive cognitive decline. This gene was previous implicated in hippocampal atrophy and synaptic function, making it a fascinating candidate. On the other end of the spectrum, we have identified multiple genes and pathways that appear to promote resilience and neuroprotection, particularly along vascular, metabolic, and sleep pathways that act in a sex-specific manner. Our findings from 3 parallel studies suggest that certain biological factors drive AD risk and resilience in a manner that depends on the genetic context (e.g., APOE genotype) and sex of the individual, providing an opportunity for precision interventions.