While Alzheimer’s disease is the most common cause of dementia, many of the molecular mechanisms that drive its progression remain poorly understood. While researchers have cataloged changes in gene activity across different brain cell types, a key unanswered question has been how the genome’s 3D organization influences those changes. Now, researchers have linked alterations in genome folding to disrupted gene regulation in Alzheimer’s disease, providing a new layer of insight into the biology of neurodegeneration.
The findings, published in Science in the paper “Single-cell multiomics connects 3D genome and transcriptome alterations in Alzheimer’s disease,” were reported by researchers from Carnegie Mellon University’s School of Computer Science, the University of Pittsburgh School of Medicine, the University of Washington, and collaborating institutions. Using single-cell multiomics, spatial transcriptomics, and artificial intelligence (AI), the team generated a multiscale view connecting genome structure, gene expression, and tissue organization in Alzheimer’s disease.
To investigate the role of genome architecture in Alzheimer’s disease, the researchers analyzed postmortem prefrontal cortex tissue from individuals with and without the disease. They used GAGE-seq (genome architecture and gene expression by sequencing), a technique that measures both gene expression and physical genome contacts in the same single cell. The team combined those data with chromatin accessibility data, spatial transcriptomic maps, and a transformer-based AI model called Hicformer, which integrates DNA sequence and 3D genome features to predict cell-type-specific gene activity.
The study revealed widespread changes in chromatin organization across major brain cell types. According to the paper, Alzheimer’s disease was associated with “reduced short-range interactions and increased longer-range interactions” within the genome. Active and inactive genomic regions also exhibited increased mixing, consistent with weaker compartment segregation. The researchers linked these structural changes to cell type–specific alterations in gene expression programs involved in disease-relevant pathways.
Researchers also observed weakening of promoter-proximal interactions and changes in regulatory elements, alongside evidence of senescence-related activation in microglia and sex-dependent dysregulation of X-linked genes in females. Integrating the molecular data with spatial transcriptomics revealed altered cellular neighborhoods and disrupted coordination of gene programs within diseased brain tissue. The authors wrote that the results connect “genome structure, gene regulation, and tissue organization through a unified multimodal analysis.”
Their predictive model Hicformer also demonstrated that “3D genome features provide information beyond DNA sequence alone for explaining AD-relevant gene expression, enabling prioritization of distal regulatory elements whose effects are mediated through chromatin contacts,” the authors wrote.
“Measuring gene activity and genome folding in the same cell allows us to directly connect chromosome structure with disease-related gene programs,” said Yang Zhang, PhD, a project scientist in Carnegie Mellon’s Computational Biology Department and co-lead author. “Across several kinds of brain cells, this paired view revealed a consistent signature of 3D genome reorganization in Alzheimer’s disease and helped us prioritize regulatory regions for future mechanistic and therapeutic investigation.”
The researchers concluded that genome folding represents a previously underappreciated regulatory layer associated with Alzheimer’s pathology. By creating a detailed map linking 3D genome remodeling to gene expression and tissue organization, the study provides a framework for future experiments aimed at determining which structural changes contribute directly to disease progression. This may also provide clues to future therapeutic focuses.
“Alzheimer’s disease cannot be understood one layer at a time,” said senior author Jian Ma, PhD, the Ray and Stephanie Lane Professor of Computational Biology at Carnegie Mellon University. “The genome’s 3D structure is a fundamental regulatory layer that helps to connect DNA sequence to gene activity. By integrating genome folding, cell state, and tissue context, we can move beyond cataloging disease-associated changes toward understanding how they fit together and which mechanisms to test next,” said Ma. “Alzheimer’s disease cannot be understood one layer at a time.”
