Deconstructing and targeting the genomic architecture of human neurodegeneration

Abstract

The field of neurodegenerative disease research has seen tremendous advances over the last two decades as new technologies and analytic methods have enabled well-powered human genomic studies. Driven first by genetic studies and more recently by transcriptomic and epigenomic studies of proper size, we have uncovered a large repertoire of loci, genes, and molecular features that are implicated in discrete, syndromically defined neurodegenerative conditions, such as Alzheimer's disease, amyotrophic lateral sclerosis, frontotemporal dementia, multiple sclerosis, and Parkinson's disease. As we begin to understand the impact of these genomic features in each disease, we also appreciate that many aging individuals accumulate each of these pathologies without fulfilling criteria for syndromic diagnoses, that other pathologies are common in individuals with a given diagnosis, and that there may be shared protective factors against central nervous system injury. Thus, we now need to bring these disparate observations together into a person-centered approach that considers all neurodegenerative and protective processes simultaneously to modulate the trajectory of cognitive and functional decline that comes with brain aging.