Genetic changes linked to new Alzheimer’s treatment pathway, US study finds

A research team from Carnegie Mellon University, the University of Pittsburgh, and the University of Washington has found that Alzheimer’s disease is associated with changes in DNA folding within specific brain cells, in addition to the well-known alterations in brain proteins.

The researchers explained that the three-dimensional organization of the genome differs in people with Alzheimer’s, affecting gene activity and the regulation of brain tissue.

The team used the “GAGE-seq” technique to measure gene expression and three-dimensional genomic interactions within individual cells, combining this data with spatial gene transcription maps.

This approach allowed them to link the physical organization of the genome with gene regulation and to pinpoint the locations of molecular changes associated with the disease.

The results showed that the boundaries between active and inactive genome regions in Alzheimer’s patients’ cells were less distinct, with increased overlap between these regions.

Researchers also observed weaker interactions between genes and nearby regulatory elements, along with changes in the activity of neuronal programs and metabolic processes.

Jian Ma, the study’s lead author, noted that the three-dimensional genome structure acts as a regulatory layer connecting DNA sequence to gene activity.

Hansruedi Mathys of the University of Pittsburgh said the new findings broaden the understanding of the disease’s molecular mechanisms, now including changes in chromatin structure.

The team used the artificial intelligence model “Hicformer” to study how genome structure affects cell behavior, with the model predicting gene activity levels based on genome folding data.

Yang Zhang explained that measuring gene activity and genome folding within the same cell enables a direct link between chromosome structure and disease-related genetic programs.

The study concluded that three-dimensional genome organization is a key layer in Alzheimer’s biology and offers a framework to investigate whether structural genome changes contribute to disease progression and if affected regulatory regions could become targets for new therapies.