Conserved epigenomic signals in mice and humans reveal immune basis of Alzheimer’s disease

Analysis of transcriptional and epigenomic changes in the hippocampus of a mouse model of Alzheimer’s disease shows that immune function genes and regulatory regions are upregulated, whereas genes and regulatory regions involved in synaptic plasticity, learning and memory are downregulated; genetic variants associated with Alzheimer’s disease are only enriched in orthologues of upregulated immune regions, suggesting that dysregulation of immune processes may underlie Alzheimer’s disease predisposition. Recent genome-wide association studies have shown substantial genetic variation in non-coding regions associated with Alzheimer's disease, suggesting the involvement of aberrant gene regulation. However, the functional significance of these variants remained unclear. By profiling transcriptional and chromatin state dynamics in a mouse model, Elizabeta Gjoneska and colleagues now show that the immune response genes and their regulatory regions are upregulated, whereas those involved in synaptic plasticity and learning and memory are downregulated. These changes are highly conserved between the mouse model and the human disease. Surprisingly, Alzheimer's disease-associated genetic variants are mainly enriched in higher-activity, immune-related enhancers, and are depleted in lower-activity, neural enhancers. This suggests that genetic predisposition to Alzheimer's may be primarily associated with immune functions, while neuronal plasticity may be affected primarily by non-genetic effects. Alzheimer’s disease (AD) is a severe1 age-related neurodegenerative disorder characterized by accumulation of amyloid-β plaques and neurofibrillary tangles, synaptic and neuronal loss, and cognitive decline. Several genes have been implicated in AD, but chromatin state alterations during neurodegeneration remain uncharacterized. Here we profile transcriptional and chromatin state dynamics across early and late pathology in the hippocampus of an inducible mouse model of AD-like neurodegeneration. We find a coordinated downregulation of synaptic plasticity genes and regulatory regions, and upregulation of immune response genes and regulatory regions, which are targeted by factors that belong to the ETS family of transcriptional regulators, including PU.1. Human regions orthologous to increasing-level enhancers show immune-cell-specific enhancer signatures as well as immune cell expression quantitative trait loci, while decreasing-level enhancer orthologues show fetal-brain-specific enhancer activity. Notably, AD-associated genetic variants are specifically enriched in increasing-level enhancer orthologues, implicating immune processes in AD predisposition. Indeed, increasing enhancers overlap known AD loci lacking protein-altering variants, and implicate additional loci that do not reach genome-wide significance. Our results reveal new insights into the mechanisms of neurodegeneration and establish the mouse as a useful model for functional studies of AD regulatory regions.