Alzheimer's Linked to Disrupted 3D Genome Folding in Brain Cells — SkimNews
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- Carnegie Mellon, Pitt, and University of Washington researchers published in Science a study showing that 3D genome organization is disrupted in several brain cell types from Alzheimer's patients, with structural changes linked to altered gene activity and tissue architecture.
- The team combined GAGE-seq, which measures gene expression and 3D genome contacts in single cells, with spatial transcriptomic maps of postmortem prefrontal cortex samples from Alzheimer's patients and controls in a long-term dementia cohort.
- Alzheimer's brain cells displayed "increased compartment mingling" — less sharply defined boundaries between active and inactive genome regions — along with fewer local interactions, more long-range contacts, and weaker connections between genes and their regulatory elements.
- Cells with greater compartment mingling tended to show lower overall gene activity, reduced neuronal and synaptic programs, and links to senescence-related programs in microglia, the brain's immune cells.
- The researchers developed Hicformer, a deep learning model that predicts gene activity from DNA sequence and genome folding patterns, as a computational test bed for exploring how structural changes might drive disease.
- The findings establish higher-order chromatin alterations as a component of Alzheimer's molecular pathology alongside amyloid-beta plaques and tau tangles, giving researchers a framework to test which structural changes might drive progression in a disease affecting seven million Americans.
Why it matters: Alzheimer's research has long been defined by amyloid-beta plaques and tau tangles, with limited therapeutic payoff; identifying 3D genome reorganization as a distinct molecular layer gives drug hunters a new set of regulatory regions to target in a disease that already affects seven million Americans.
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