A molecular network of the aging human brain provides insights into the pathology and cognitive decline of Alzheimer’s disease

Abstract

There is a need for new therapeutic targets with which to prevent Alzheimer's disease (AD), 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 build a molecular network using modules of coexpressed genes and then relate these modules to AD and its neuropathologic and cognitive endophenotypes. We confirm these associations in two independent AD datasets. We also illustrate the use of the network in prioritizing amyloid- and cognition-associated genes for in vitro validation in human neurons and astrocytes. These analyses based on unique cohorts enable us to resolve the role of distinct cortical modules that have a direct effect on the accumulation of AD pathology from those that have a direct effect on cognitive decline, exemplifying a network approach to complex diseases.

Molecular Networks and Key Regulators of the Dysregulated Neuronal System in Alzheimer’s Disease

“…A number of studies have performed large-scale molecular profiling (e.g. transcriptomics, proteomics and metabolomics) of postmortem brains from normal control and LOAD patients 7,8 . Integrating these more functionally relevant datasets holds promise for improving our understanding of the molecular mechanisms of the pathogenesis in sporadic LOAD 9 .…”

A single cell-based atlas of human microglial states reveals associations with neurological disorders and histopathological features of the aging brain

“…http://dx.doi.org/10.1101/343780 doi: bioRxiv preprint first posted online Jun. 11, 2018; We also evaluated modules of co-expressed genes defined in the aging human frontal cortex 21 that we had previously described as being enriched in microglial genes 7 .…”

Gene expression and DNA methylation are extensively coordinated with MRI-based brain microstructural characteristics

“…The molecular systems are identified without reference to neuroimaging, pathological variables or molecular ontologies; they are produced by the activity of regulatory systems and are highly reproducible (Gaiteri et al 2014;Mostafavi et al 2018). The specific MRI measure of R 2 characterizes the molecular environment and molecular motion within a given voxel (Brown et al 2014) such as cellular density, myelin content, or water content.…”

“…The consistency of correlations across multiple subcomponents of cognition, and various assays of AD pathology confirms the robustness of the findings. We also validated the relevance of m109 to AD pathology in vitro by testing the effects of influential genes within the module on Aβ42 levels in astrocyte cultures, showing significant effects for INPPL1 and PLXNB1 (Mostafavi et al 2018). …”