The brain resilience initiative: genes shielding the brain from cerebrovascular insults – BRICS

A quantum leap in development of therapeutics of dementia can be achieved through improved understanding of the natural resilience mechanisms of brain cells to various noxious influences like vascular insults. However our understanding of such resilience pathways is limited, as majority of studies in past focused primarily on exploring the causes of neurodegeneration with little attention given towards understanding why some people besides at higher risk of cerebrovascular injury show minimal signs of neurodegeneration on MRI. I hypothesize that rare exonic variants with loss- or gain-of-function effects on genes involved in brain’s resilience pathways might protect brain cells from degeneration in individuals at an elevated common variant polygenic risk of cerebrovascular insults. I propose the Brain Resilience Initiative: genes shielding the brain from Cerebrovascular insultS (BRICS) project, which aims to identify rare and low frequency variants in genes involved in resilience mechanisms of the brain to cerebrovascular insults: ischemia and hemorrhage, using genetic instruments. This project will be performed on two well-characterized French population-based cohorts of older adults: 3C and MEMENTO, and large multi-cohort/biobank data from UKBB and the JPND-BRIDGET network, leveraging the cutting edge genetic and brain imaging data, to identify genetic variants associated with brain resilience to cerebrovascular insults. Identified genes would not only improve our understanding of the mechanism underlying brain resilience, but also serve as a potential drug targets for dementia prevention and treatment.