Structural Variants and Individual RNA Isoforms in Top AD Genes in Brain

Despite remarkable efforts to defeat Alzheimer’s disease (AD), existing research has not realized an effective treatment because of the disease’s complexity. Researchers have, however, identified ~30 AD risk loci, allowing molecular researchers to begin establishing the underlying biology. Understanding how top AD risk genes drive disease is vital, yet few AD risk genes have a known functional mutation, and AD gene RNA isoforms are poorly characterized in diseased brains. For approximately 27 loci, it is not even clear which gene is involved (e.g., PICALM locus). We are missing most specific mutations initiating disease. Large short-read sequencing efforts are underway to identify small functional variants involved in AD, but structural DNA mutations also cause neurodegenerative disease. In fact, researchers discovered an ABCA7 repeat expansion associated with AD (OR=4.5). Similarly, most RNASeq studies ignore individual isoforms. We hypothesize that undiscovered structural mutations and aberrant RNA isoforms play a direct role in AD, and a thorough study targeting top AD loci in diseased brain with long-read DNA and RNA sequencing will complement current short-read efforts, providing important disease insights. Given the impending healthcare crisis from an aging population, identifying functional mutations and aberrant RNA isoforms in the diseased tissue is critical. Our central hypothesis is that structural DNA mutations and aberrant RNA expression in the brain cause, or increase risk for AD, and we seek to identify these mutations by targeting the diseased brain. Our aims are a focused approach to interrogate AD within the diseased tissue, which will ultimately be the fastest, most efficient path to reveal the underlying biology and facilitate diagnostics and effective therapeutics.