Using Long-Range Technologies as a Multi-omic Approach to Understand Alzheimer's Disease in Brain Tissue

PROJECT SUMMARY/ABSTRACT Our long-term goal is to help develop a meaningful therapeutic and pre-symptomatic diagnostic for Alzheimer’s disease because, while a disease-altering therapeutic is essential, it will not be sufficient without a diagnostic that identifies disease before symptoms onset. We seek to contribute to these long-term goals by helping identify specific molecular modifications, and therefore specific mechanisms, driving disease using long-range optical DNA mapping and sequencing technologies. Unfortunately, most Alzheimer’s disease genes are only implicated through common non-functional variants, and it is still unclear how most Alzheimer’s disease genes are involved in disease. Likewise, individual RNA isoforms in diseased brains for top Alzheimer’s disease genes and their involvement in disease are poorly understood. Functional variants and RNA sequencing at the isoform level in diseased brain tissue will provide specific mechanisms to target for therapeutics and diagnostics. Large short-read sequencing efforts are already ongoing to identify small functional variants involved in Alzheimer’s disease, but structural DNA variants—many of which directly affect downstream RNA and proteins—also cause neurodegenerative diseases. We hypothesize that undiscovered SVs and aberrant RNA isoforms play a direct role in Alzheimer’s disease. A thorough study in diseased brain using long-range DNA and RNA technologies will complement current short-read efforts, providing important disease insights.