Therapeutic Targets and Diagnostics in Alzheimer's Disease

Grants and Contracts Details

Description

Abstract Our long-term goal is to help develop a meaningful therapeutic and pre-symptomatic diagnostic for Alzheimer’s disease (AD). We seek to contribute by discovering functional structural DNA variants (SVs) and aberrant RNA isoforms that directly drive disease development and progression using long-read DNA & RNA sequencing technologies. Unfortunately, most AD genes are only implicated through common non-functional variants, and it is still unclear how most AD genes are involved in disease. Likewise, individual RNA isoforms in diseased brains for top AD genes are poorly understood. Functional variants and RNA isoform sequencing 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 variants involved in AD, but SVs also cause neurodegenerative diseases—many of which directly affect downstream RNA and proteins. In fact, researchers discovered an ABCA7 repeat expansion associated with AD (OR=4.5). We hypothesize that undiscovered SVs and aberrant RNA isoforms play a direct role in AD. Work by Dr. Ebbert demonstrated long-range technologies are well-suited for our study. A thorough study in diseased brain using long-range DNA and RNA technologies will complement short-read efforts, providing important disease insights. We propose long-range DNA and RNA mapping and sequencing in diseased vs. control brain tissue to discover SVs, and aberrant RNA isoforms that associate with disease or clinicopathological phenotypes. This will be the first large-scale, long-range dataset for both DNA and RNA in the diseased brain, using samples from one of the best clinicopathologically- characterized cohorts in the world. We will use samples from the Mayo Clinic Brain Bank, overseen by Dr. Dennis Dickson. Dr. Dickson is a renowned neuropathologist. Our aims were carefully designed to be independent and synergistic to identify SVs in top AD genes that may be involved in disease, along with aberrant RNA isoforms in the brain.
StatusActive
Effective start/end date12/1/208/31/24

Funding

  • BrightFocus Foundation: $294,995.00

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