Approved Research

Deciphering the biological basis of and identifying therapeutic targets for Alzheimer disease

Lay summary

Alzheimer disease (AD) is a progressive neurodegenerative disease that is a staggering burden for those affected and their families, public health and society in general. Since 2003, 99% of drug trials for AD did not yield efficacious results and thus failed to get approval from the United States Food and Drug Administration (FDA). These disappointing outcomes support the idea that AD is multifactorial and etiologically heterogeneous disease. Therefore, there is an urgent need to develop multiple prevention and treatment options tailored to one's risk profile based on genetic, biomarker and other measurable factors. The proposed project will investigate extensive genetic, biomarker, brain imaging, cognitive, environmental exposure and lifestyle data to identify genetic factors that are associated with AD and AD-related traits using UKBB and other sources of data. To accomplish the objective, we will (1) attempt to replicate genetic association findings established in external datasets using UKBB data; (2) analyze a wide array of genetic, genomic, laboratory-based, cognitive, brain imaging and other data in the UKBB using multiple statistical and computational approaches to identify disease pathways and establish AD risk profiles; (3) prioritize drug targets for each risk subgroup, and (4) investigate differential medication effects between low- and high-risk network subgroups. By evaluating relationships of risk profiles of UKBB participants with health data including medication usage and bioassay data, we will identify and prioritize novel as well as existing drug targets for drug development or repositioning, respectively. The proposed work will establish a robust foundation of fast-track clinical translation for drug targets and repurposing via clinical trials.