Alzheimer’s disease genetics and real‐world patient data fuel target and drug discovery in European and African American ancestries

Abstract

AbstractBackgroundTranslation of massive genetic and genomic data into Alzheimer’s target and drug discovery has not materialized. One challenge in this process is ethnicity‐based differences in the field of Alzheimer’s disease (AD). For example, African Americans (AAs) and European Americans (EAs) differ in AD prevalence, risk factors, and symptomatic presentation, and AAs have historically been less frequently enrolled in AD clinical trials.MethodWe conducted ancestry genetic‐specific target and drug discovery by gathering large genetic data from a diverse population with real‐world patient data to boost the likelihood of identifying disease‐modifying drug targets and treatments for AD. We analyzed genetic data from 275,540 AD cases and 1.55 million controls across 7 AD genome‐wide association studies (GWAS) datasets for both EA and AA ancestries, using Mendelian randomization. We utilized the genetic instruments from 9 expression quantitative trait loci (eQTL) and 3 protein quantitative trait loci (pQTL) datasets from three large human brain biobanks: a) Mount Sinai Brain Bank (MSBB), b) Mayo clinic (Mayo), and c) Religious Orders Study (ROS) or the Rush Memory and Aging Project (MAP) (ROS/MAP).ResultWe identified 25 drug targets in EAs and 6 new drug targets in AAs among 1,176 investigated druggable targets. Notably, the inflammatory target of epoxide hydrolase 2 (EPHX2) emerged as a potent AD target in EAs, and treatment of transgenic TgF344‐AD rats with an EPHX2 inhibitor was therapeutic. Among 6 AA‐specific targets, we identified that TRPV3 is a potent drug target for AA individuals with AD, and further replicated our finding in AA‐specific eQTL data. We additionally identified 23 candidate drugs associated with reduced risk of AD in mild cognitive impairment (MCI) patients after analysis of ∼80 million electronic health records. Using a propensity score‐matched design, we identified that usage of either apixaban (hazard ratio [HR] = 0.74, 95% confidence interval [CI] 0.69 – 0.80) or amlodipine (HR = 0.91, 95% CI 0.88 – 0.94) were both significantly associated with reduced progression to AD in people with MCI.ConclusionCombining genetics and real‐world patient data has identified ancestry‐specific therapeutic targets and medicines for AD.