Transformative Network Modeling of Multi-omics Data Reveals Detailed Circuits, Key Regulators, and Potential Therapeutics for Alzheimer’s Disease

Neuron, 2020

Wang M, Li A, Sekiya M, Beckmann ND, Quan X, Schrode N, Fernando MB, Yu A, Zhu L, Cao J, Lyu L, Horgusluoglu E, Wang Q, Guo L, Wang, Y-S, Neff R, Song W-M, Wang E, Shen Q, Zhou X, Ming C, Ho S-M, Vatansever S, Kaniskan HU, Jin J, Zhou M-M, Ando K, Ho L, Slesinger PA, Yue Z, Zhu J, Katsel P, Gandy S, Ehrlich ME, Fossati V, Noggle S, Cai D, Haroutunian V, Iijima KM, Schadt E, Brennand KJ, Zhang B.


The authors sought to determine the molecular mechanism of late-onset Alzheimer's Disease (LOAD) in order to identify novel therapeutics.  By performing a network analysis of multiomics profiling of cortical samples from 364 donors with varying phenotypes.  The analysis revealed thousands of molecular changes and found ATP6V1A to be a key regulator.  It's role was evaluated in CRISPR manipulated hiPSC-derived neurons and Drosophila models.  Improvements to the neurodegeneration and impairment due to ATP6V1A was discovered due to repositioning NCH-51.  These network models are shown to be a possible model for determining therapeutic agents.