Study identifies DNA changes in Alzheimer’s brains that could reveal new treatment targets

Researchers at Mayo Clinic say they have uncovered new molecular clues that could help explain why Alzheimer’s disease affects people differently and may open new paths for treatment.

In a study published in Nature Communications, the team mapped changes in DNA regulation in the brains of people with Alzheimer’s disease, focusing on a biological process known as DNA methylation. These chemical tags attach to DNA and influence whether genes are turned on or off without altering the genetic code itself.

By analyzing brain tissue from 472 people with Alzheimer’s disease stored in the Mayo Clinic Department of Neuroscience Brain Bank, researchers identified patterns of methylation linked to key biological changes associated with the disease. The samples included detailed measurements of both visible brain damage and the levels of hallmark Alzheimer’s proteins.

Nearly 7 million people are affected

Alzheimer’s disease — the most common cause of dementia — affects about 6.9 million Americans age 65 and older. The condition is characterized by the buildup of amyloid plaques and tangled tau proteins in the brain, which damage and kill nerve cells over time, eventually leading to brain shrinkage and severe cognitive decline. There is currently no cure.

The Mayo study suggests that many of the newly identified DNA changes are tied to tau, a protein already known to play a major role in Alzheimer’s-related brain damage.

Researchers also found that the epigenetic changes appear to affect oligodendrocytes — brain cells that produce myelin, the insulating layer that allows nerve cells to communicate efficiently.

“Myelin acts like insulation around electrical wiring in the brain,” explained Nilüfer Ertekin-Taner, M.D., Ph.D., chair of neuroscience at Mayo Clinic and senior author of the study. 

When oligodendrocytes or myelin are disrupted, communication between neurons can break down, potentially contributing to the symptoms of Alzheimer’s disease.

“Our team has previously shown that oligodendrocytes are affected in Alzheimer’s and another tau-related disease,” Ertekin-Taner said. “These new results further highlight that problems in oligodendrocytes and myelin are central to Alzheimer’s and point to specific molecular pathways that could be targeted in future therapies.”

Several genes play a role

The findings also revealed several genes that may play previously unrecognized roles in Alzheimer’s disease, including one known as LDB3. Identifying such genes could help scientists design studies aimed at reversing harmful methylation changes or protecting oligodendrocytes and myelin.

Because epigenetic changes can potentially be reversed, they are considered promising targets for new treatments.

Beyond the biological findings, the research team also made its extensive dataset publicly available through a new interactive platform called the Multiomic Atlas of AD Brain Endophenotypes. The tool allows scientists to explore the data by gene or chromosome location and view results through searchable tables and visual plots.

The researchers say the work may not only deepen understanding of Alzheimer’s disease but could also provide insights into other neurodegenerative disorders linked to tau and similar molecular processes.