A multi-institutional Science study shows that changes in the three-dimensional organization of the genome in specific brain cells are linked to Alzheimer's disease, offering insights beyond amyloid-beta and tau.

Researchers analyzed postmortem prefrontal cortex samples from individuals with and without Alzheimer's using GAGE-seq, enhanced by spatial transcriptomic maps to examine genome folding and gene activity at the single-cell level.

The work maps genome reorganization to how brain cells are spatially arranged in tissue, underscoring 3D genome structure as a key component of Alzheimer's biology and a potential target for therapies.

Future work aims to determine whether specific chromatin changes drive disease progression and to identify regulatory regions that could become therapeutic targets.

The study drew on postmortem prefrontal cortex samples and involved collaboration among CMU SCS, Pitt Neurobiology, UW, the Broad Institute, and other institutions, with NIH support.

Funding and collaboration details note support from NIH and partners including the Broad Institute, UCLA, and the Rush Alzheimer's Disease Center, with researchers from CMU, Pitt, and UW.

A new AI model called Hicformer integrates DNA sequence, genome folding, and DNA contact maps to predict cell-type–specific gene activity and explore how structural changes might drive disease pathways.

Hicformer enables prediction of gene activity across cell types by combining sequence data with genome structure, facilitating study of how genome architecture changes could drive Alzheimer’s biology.

In Alzheimer's brains, researchers observed increased compartment mingling and weaker interactions between genes and nearby regulatory elements, correlating with reduced neuronal and synaptic programs and altered metabolism and stress responses.

Alzheimer’s-affected cells show diminished neuronal/synaptic activity, altered metabolism and stress responses, and links to microglial senescence programs, indicating broad regulatory disruption beyond classical pathology.

Overall, there is stronger long-range genomic connectivity and weaker gene-regulatory interactions in Alzheimer's tissue, reflecting widespread changes in genome organization.