Capturing polygenic risk for Alzheimer’s disease using induced pluripotent stem cells

Abstract

AbstractBackgroundOver 70 loci have been implicated in AD pathogenesis through genome‐wide association studies. Understanding of how these genetic variants interact with one another, as well as with unknown genetic variants of weak effect size to impinge upon biological processes and molecular pathway to affect risk and resilience to AD is key to unlocking appropriate therapeutic strategies for AD.MethodWe have generated iPSC lines from over 50 deceased individuals in the Religious Order Study (ROS) or Rush Memory and Aging Project (MAP) that span the clinical and neuropathological spectrum of aging. About one third of these individuals had clinical and neuropathological diagnoses of AD and Alzheimer’s dementia. We differentiated these lines into cortical neuronal fates, astrocyte fates and microglial fates and measured RNA and protein profiles as well as quantitative measures of APP cleavage products and tau species. In addition, we have measured autophagic and proteasome capacity, as well as synatic vesicle release and cytokine production.ResultWe identify specific proteins and pathways in neuronal and glial cultures that are associated with AD polygenic risk score (PRS), neuropathological burden, and/or cognitive trajectory in the donors and validate these findings through analyses of brain tissue. We identify an association of cognitive decline and measures of specific amyloid beta peptides and phospho‐tau species in iPSC‐derived neurons. We find that proteasome capacity and autophagic flux are influenced by genetic background, which in turn affects tau proteostasis. Intriguingly, different genetic backgrounds respond differentially to modulation of these protein degradation networks.ConclusionThe data presented establish this iPSC collection as a resource for investigating person‐specific processes in the brain that are encoded in part by polygenic risk for AD that can aid in identifying and validating molecular pathways underlying AD.