Using expression profiles from postmortem prefrontal cortex samples of 624 dementia patients and non‐demented controls, we investigated global disruptions in the co‐regulation of genes in two neurodegenerative diseases, late‐onset Alzheimer's disease (AD) and Huntington's disease (HD). We identified networks of differentially co‐expressed (DC) gene pairs that either gained or lost correlation in disease cases relative to the control group, with the former dominant for both AD and HD and both patterns replicating in independent human cohorts of AD and aging. When aligning networks of DC patterns and physical interactions, we identified a 242‐gene subnetwork enriched for independent AD/HD signatures. This subnetwork revealed a surprising dichotomy of gained/lost correlations among two inter‐connected processes, chromatin organization and neural differentiation, and included DNA methyltransferases, DNMT1 and DNMT3A, of which we predicted the former but not latter as a key regulator. To validate the inter‐connection of these two processes and our key regulator prediction, we generated two brain‐specific knockout (KO) mice and show that Dnmt1 KO signature significantly overlaps with the subnetwork (P = 3.1 × 10−12), while Dnmt3a KO signature does not (P = 0.017). Synopsis Network analysis of changes in gene co‐regulation, between large sets of Alzheimer's (AD) or Huntington's (HD) disease versus control brains, reveals that opposing dysregulation of two interacting processes, chromatin organization and neural differentiation, underlies both AD and HD. Postmortem prefrontal cortex samples of over 600 dementia patients (late‐onset AD or HD) and non‐demented controls were expression profiled. Pronounced global changes were observed in the gene–gene co‐expression patterns in AD or HD patients relative to the control group and revealed novel neurodegeneration‐associated genes. Network alignment uncovered shared dysregulation of two inter‐connected processes, chromatin organization and neural differentiation, as a common pathology of AD and HD. DNA methyltransferase, DNMT1, was validated as a key regulator of the inter‐connection between these two processes, using RNAseq data from brain‐specific knockout mice. Network analysis of changes in gene co‐regulation, between large sets of Alzheimer's (AD) or Huntington's (HD) disease versus control brains, reveals that opposing dysregulation of two interacting processes, chromatin organization and neural differentiation, underlies both AD and HD.