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

Abstract

Resilience from Alzheimer's disease (AD) is heritable trait with a largely unexplored genetic architecture. We have developed a harmonized resource called the Resilience from Alzheimer's disease database to enable the discovery of genetic factors that protect the brain from the consequences of AD neuropathology. We highlight a set of results from our team that suggests a precision medicine approach that considers the genetic context, amyloid status, and sex of the individual may be a promising path forward. We have harmonized cognitive data and genetic data from 23,490 individuals, including subsets that have harmonized measures of amyloid, tau, and brain atrophy. We leveraged this rich resource to identify gene modifiers of the well-established effects of APOE and baseline amyloid status on memory and hippocampal atrophy, highlighting genes and pathways implicated in resilience. We identified a novel locus for cognitive decline on chromosome 9 within the PRUNE2 gene that was associated with more rapid cognitive decline among APOE-ε4 carriers (p=1.9x10-8 ) but not non-carriers (p=0.61). We have also identified genetic modifiers of amyloid and tau pathology in parallel analyses reported elsewhere in this conference and notably our findings suggest that vascular and metabolic pathways contribute to resilience in a sex-specific manner. Specifically, our sex-stratified GWAS of resilience and cognitive performance highlight genetic predictors of healthy heart rate that predict resilience only among males, and genetic predictors of circadian rhythm that relate to resilience only among females. 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.