3D genome folding disruptions linked to Alzheimer's in brain cells
Researchers found that the three-dimensional organization of DNA is altered in brain cells affected by Alzheimer's, affecting gene regulation. The study combined single-cell and spatial techniques with deep learning to reveal this new layer of the disease. The findings may point to new treatment targets.
The research team examined postmortem prefrontal cortex tissue from individuals with and without Alzheimer's who had participated in a long-term dementia study. Using GAGE-seq, they measured gene expression and three-dimensional genome contacts within individual cells, then merged this data with spatial transcriptomic maps to preserve tissue context.
The findings establish higher-order chromatin alterations as part of Alzheimer's molecular pathology, complementing the known amyloid-beta plaques and tau tangles. The study's integration of single-cell technology, spatial mapping, and deep learning allowed researchers to connect genome folding changes to gene activity and tissue organization, potentially identifying new mechanisms to test for treatment.
This discovery could shift how researchers approach Alzheimer's treatment, moving beyond classic amyloid and tau targets toward chromatin structure. If validated, the findings may enable earlier detection or new therapeutic strategies for the seven million Americans currently affected. The study's methods could also inform research into other neurodegenerative diseases, though clinical applications remain distant and require further investigation.