Abstract

The fact that only symptomatic therapies of small effect are available for Alzheimers disease (AD) today highlights the need for new therapeutic targets with which to prevent a major contributor to aging-related cognitive decline. Here, we report the construction and validation of a molecular network of the aging human frontal cortex. Using RNA sequence data from 478 individuals, we first identify the role of modules of coexpressed genes, and then confirm them in independent AD datasets. Then, we prioritize influential genes in AD-related modules and test our predictions in human model systems. We functionally validate two putative regulator genes in human astrocytes: INPPL1 and PLXNB1, whose activity in AD may be related to semaphorin signalling and type II diabetes, which have both been implicated in AD. This arc of network identification followed by statistical and experimental validation provides specific new targets for therapeutic development and illustrates a network approach to a complex disease.\n\nOne sentence summaryMolecular network analysis of RNA sequencing data from the aging human cortex identifies new Alzheimers and cognitive decline genes.