Alzheimer's research reveals 3D genome disruption and protective protein effects on disease

Scientists have identified a fundamental alteration in the three‑dimensional organization of the genome in brain cells of individuals with Alzheimer’s disease. Using single‑cell GAGE‑seq, spatial transcriptomics and a new deep‑learning model called Hicformer, researchers found increased "compartment mingling" where active and inactive chromatin domains lose their separation, weakening gene‑regulatory contacts and contributing to reduced neuronal synaptic function, metabolic stress and microglial senescence.

A separate study of human brain aging showed a widespread erosion of 3D genome architecture across cell types and a marked replacement of embryonically derived microglia with blood‑like immune cells after age 50, raising inflammatory activity that may predispose to neurodegeneration. The loss of cells that maintain the blood‑brain barrier was also observed.

In experimental work on mice, increasing levels of the SORLA protein (encoded by SORL1) curtailed the spread of toxic tau aggregates, preserved neuronal connections and dampened harmful inflammation, suggesting a potential therapeutic avenue for Alzheimer’s and related tauopathies.