Single-nucleus epigenomic dysregulation unmasks genetic risk-associated neurodegenerative glia states.

The accumulation of abnormal tau protein selectively affects distinct brain regions and specific populations of neurons and glial cells in tau-related dementias, such as Alzheimer's disease, Pick's disease and progressive supranuclear palsy. Although the three disorders share the feature of tau protein pathology, the regulatory circuitry of non-coding genetic variants underlying risk-associated cell states remains to be elucidated. Using paired single-nucleus profiling of chromatin accessibility and gene expression across the three conditions, we define cell-type-specific cis-regulatory elements across six cell types and fifty subclasses. Comparing disease-dynamic cis-regulatory elements across three disorders, we find that glia overrepresent disorder-specific gene regulation related to dynamic cellular response to stress. We show that human genetic variants affecting microglial gene regulation converge into distinct and co-regulated modules affecting specific cellular functions. Moreover, polygenic risk modifiers are maximally co-accessible in disorder-specific glial states, modifying distinct pathways such as sphingomyelin regulation in Pick's disease. Our study informs glial regulators linked to polygenic modifiers of primary tauopathy, establishing modifiable pathways governing resilience.