FunGen-AD-funded research uses cerebrospinal fluids to develop new Alzheimer’s drugs

Research focused on identifying genes associated with Alzheimer’s disease (AD) commonly relies on postmortem brain tissue or blood samples; however, these sources provide a limited view of the disease. Post-mortem brain tissue usually represents late-stage AD, and blood is not specific to the brain. An international group of investigators, including Functional Genomics Consortium investigator Carlos Cruchaga at the Washington University School of Medicine, used cerebrospinal fluid (CSF) to identify AD-associated proteins.

The group leveraged biosamples from 3,506 healthy donors and people with AD from the Knight Alzheimer’s Disease Research Center and the Dominantly Inherited Alzheimer Network. Specifically, they used blood and CSF samples to generate genetic and proteomic data to generate a plasma protein quantitative trait loci (pQTL) atlas. The proteins identified in this atlas were then cross-referenced with existing studies that identified genes associated with AD, narrowing in on 1,883 proteins. After testing these AD-associated proteins through proteome-wide association study, colocalization, and Mendelian randomization analyses, 38 proteins were identified as likely having causal effects on AD progression. Notably, 15 of these proteins can be targeted by drug treatments that are currently available. Finally, the group developed a proteomics-based AD prediction model that is more accurate at predicting AD than a genetics-based model. This study demonstrates the promise of CSF proteomics studies to identify therapeutic targets for neurological disorders like AD.

This research, partially supported by FunGen-AD grant RF1AG058501, is published in Nature Genetics here. You can read more about these research findings at the following links: