Alzheimer’s disease is a highly heritable condition, but despite sample sizes of > 1 million individuals, existing genetic studies have uncovered only a small proportion of this heritability. Our lab will study whether repetitive regions of the genome that have been largely ignored in prior genetic work, particularly short tandem repeats (STRs), may confer risk of onset and progression of AD across populations. Moreover, at many of the genetic associations that have been identified for AD and other neurodegenerative conditions, we have limited understanding of the genetic variants and genes that drive disease pathology. We will integrate genetic fine-mapping, genomics assays, and genome engineering in cellular models of disease to identify mechanisms at specific genetic loci.

Many neurodegenerative conditions are characterized by aberrant patterns of gene expression and transcriptional regulation. Moreover, some proteins that aggregate in neurodegenerative conditions, such as TDP-43 in FTD/ALS, are normally RNA processing enzymes. We will map transcriptional changes in neurodegenerative disease states both in post-mortem tissues and in cellular models of disease. We will also study the role of dysregulation of RNA binding proteins in driving these transcriptional changes.