Short tandem repeats as a novel genetic driver of Alzheimer's disease - Project Summary The majority of the genetic risk for Alzheimer’s disease (AD) has yet to be identified. Even less is known about if and how genetics influence the age of onset and rate of progression of AD. Complex forms of genetic variation such as the ~1 million short tandem repeats (STRs) in the genome cause over 30 monogenic neurologic diseases, but the role of STRs in AD has not been explored. Inherited expansions in STRs not only cause these diseases, but somatic instability of these pathogenic expansions within brain tissues also contributes to earlier age of onset and faster rates of neurodegeneration. My preliminary studies have found that STR expansions associate with risk of AD and that they are somatically unstable in temporal lobes of patients with AD. However, it is not known how STR expansions promote neurodegeneration and whether they associate with faster progression of AD. This proposal will address these knowledge gaps to test the overarching hypothesis that inherited and somatic STR expansions promote neurodegeneration in AD. In Aim 1, I will test whether STR expansions correlate with age of onset and rate of progression in AD. I will use existing whole genome sequencing data in over 11,000 AD cases and controls and associate STR genotypes with longitudinal AD phenotypes. In Aim 2, I will test whether STRs become somatically unstable in neurons from patients with AD. I will sort neurons from multiple brain regions in the same individual and perform long-read sequencing to test for somatic STR instability. In Aim 3, I will test whether AD-associated STR expansions promote neurodegeneration in induced pluripotent stem cell models of AD. I will use genome engineering to cut- back an AD-associated STR expansion in a stem cell line from an individual with AD and test for alterations in gene expression, cell viability, and synapse formation in differentiated neurons. Together, this work will generate unprecedented insights into how an unexplored form of genetic variation underlies neurodegeneration in AD. I am uniquely suited to address these questions because of my deep expertise in human genetics and genomics in addition to my clinical expertise as a cognitive neurologist treating AD and related disorders. During my mentored training, I will develop new skills in analyzing the genetic basis of longitudinal AD phenotypes (Aim 1), performing genomics in post-mortem AD samples (Aim 2), and genome engineering in AD induced pluripotent stem cell models (Aim 3). My mentorship team of Dr. Jennifer Phillips-Cremins (expert in STRs, somatic instability, and genome engineering) and Dr. Edward Lee (expert in molecular mechanisms of neurodegeneration) are unique aligned toward these training goals. This powerful complement of skills I will develop and the insights I will derive from this work will form the foundation for a career as a physician-scientist uncovering the genetic and molecular drivers of neurodegeneration.
