Scientists Discover Alzheimer's Disease Scrambles the Brain's 3D Genetic Architecture

A New Window Into What Goes Wrong in the Brain

Researchers from Carnegie Mellon University's School of Computer Science, the University of Pittsburgh School of Medicine, and the University of Washington have shed new light on Alzheimer's disease — publishing findings in the journal Science that show the 3D genome architecture is organized differently in certain brain cells of people with Alzheimer's, uncovering a previously underexplored layer of the disease's biology. For the roughly seven million Americans currently affected by Alzheimer's — a number that continues to grow — the discovery adds a significant new chapter to our understanding of what the disease actually does inside the brain.

Inside every cell nucleus, DNA wraps around proteins to form chromatin. This packaging is not random. Chromatin bends and loops through three-dimensional space, bringing some stretches of DNA together while keeping others apart. The collaboration between Pitt and CMU researchers revealed that these chromosomes are organized differently in people with Alzheimer's compared to healthy brains — a finding that could reshape how scientists think about the disease's origins and potential treatments.

How a 15-Minute Walk Sparked a Breakthrough

The collaboration was born from curiosity and proximity. A key 2019 paper spelled out the first time scientists were able to split tissue from people with Alzheimer's disease into individual cells and sequence RNA — and its first author was Hansruedi Mathys, a Pitt assistant professor of neurobiology and Alzheimer's researcher. When CMU's Jian Ma came across that paper, he realized Mathys was just a 15-minute walk from his lab, and emailed him to propose a collaboration using his technology to learn more about brain cells and chromatin in the Alzheimer's disease state. Mathys was quick to accept, and the team then requested postmortem brain tissue from David Bennett, director of the Rush Alzheimer's Disease Center at Rush University Medical Center in Chicago.

The team got to work using Ma and collaborator Zhijun Duan's technology, called GAGE-Seq, a single-cell technology that can probe both gene activity and chromosome structure simultaneously. The research team linked genome folding to gene activity and brain tissue organization in Alzheimer's disease through single-cell technology, spatial mapping of brain tissue, and a new deep learning model.

AI Joins the Fight Against Alzheimer's

A key computational advance was an AI model called Hicformer, which combines DNA sequence, broad genome-folding features, and local 3D contact maps to predict gene activity in different kinds of cells. Doctoral student Xinyue Lu, who co-led the research, described Hicformer as a computational test bed for asking how altered genome folding may change gene activity. As Yang Zhang, a project scientist who co-led the research, put it: "Measuring gene activity and genome folding in the same cell allows us to directly connect chromosome structure with disease-related gene programs."

This spatial genome degradation weakens gene-regulatory contacts, leading to reduced synaptic function in neurons, metabolic stress, and cellular senescence in microglia. Outside researchers took notice. Ghada Abdelhady, a postdoctoral student specializing in genomics and identifying therapeutic targets for Alzheimer's disease at CMU, noted that she had used many of the same technologies — but never at the same time. "This is definitely something no one has done before," she said.

One Piece of a Very Large Puzzle

Pitt's Mathys framed the discovery in terms of what was already known: "We know the classic hallmarks of Alzheimer's disease — accumulation of amyloid-beta plaques and tau tangles — but our results establish higher-order chromatin alterations as a component of the molecular pathology associated with the disease." The findings identify 3D genome organization as an important layer of Alzheimer's biology and provide a framework for future experiments to determine which changes in genome structure contribute directly to the disease and whether they could reveal new therapeutic targets.

The study focused on the most extreme form of Alzheimer's, not milder forms or early stages of progression — a limitation the researchers acknowledge. "I would really love to see different time points, more donors and different stages of Alzheimer's to see whether you would come to the same conclusion," Abdelhady noted. Ma and Mathys hope to continue collaborating and that their teamwork encourages other scientists at Pitt and CMU to pair up. "These types of collaborations is where I think the science can be advanced more rapidly," Ma said. With Alzheimer's cases projected to keep climbing, that spirit of cross-campus partnership may prove to be as important as any single discovery.