With the aid of a five-year, $4.4 million grant from the National Institute on Aging, part of the National Institutes of Health, Wei-Qi Wei, MD, PhD, QiPing Feng, PhD, and a multidisciplinary research team at Vanderbilt University Medical Center will undertake a sweeping search for any drugs approved for other diseases that could warrant laboratory study, preparatory to clinical testing, for treating Alzheimer’s disease (AD) and related dementias (ADRD).
The study will apply innovative drug repurposing methods developed at VUMC by Wei, Feng and colleagues.
According to the Alzheimer’s Association, AD is estimated to affect 6.9 million Americans, and if no cure were to be found, would be expected to affect some 13.8 million Americans by 2060. AD accounts for 60%-80% of all dementia cases in the U.S. and is presently the country’s sixth leading cause of death.
“While a couple of new drugs have been shown to slow the progression of early-stage Alzheimer’s, there are currently no treatments available to halt or reverse the course of AD or any of the less prevalent major forms of dementia,” said Wei, associate professor of Biomedical Informatics. “We’ve meanwhile developed new, systematic methodologies for detecting drug repurposing signals in molecular data and validating them in patient data. Given the continued urgency around AD, we’re very pleased to be granted NIH support for applying our methods to ADRD.”
The team’s population for evaluating ADRD drug repurposing consists of more than 10 million individuals whose de-identified health information appears in various research data bases at VUMC and elsewhere, including some 700,000 individuals with genetic data linked to de-identified electronic health records.
• Diseases and drugs bear distinct gene expression signatures and when a disease and a drug push gene expression in opposite directions, it may be grounds for further testing. The team will undertake this two-way gene expression scan for ADRD and thousands of drugs.
• Using a technique called Mendelian randomization, the team will use drug target information and data from ADRD genome-wide association studies to check whether any drugs appear causally related to ADRD.
• With reference to the most promising candidates from the above two molecular analyses, the team will scan research databases of de-identified data from millions of patients for any associations these drugs may have with reduced ADRD risk among patients 65 and older.
• The team will undertake automated filtering of the research literature to identify leading candidates from among the more than 500 drugs that have been proposed for ADRD repurposing. Again, using de-identified patient data, the study will determine whether drug candidates are associated with lower risk of ADRD.
• Based on drug candidates emerging in previous steps, the team will use de-identified patient data to check whether any drug combinations are associated with lower ADRD risk.
• The team will share and maintain tools to systematically identify ADRD drug repurposing candidates going forward and will develop and share a standardized drug repurposing validation pipeline based on electronic health records.
The study is supported by NIH grant AG084550.
