Mayo Clinic identifies key DNA changes driving Alzheimer’s patient variability

UAE—Researchers at the Mayo Clinic have identified specific DNA-level changes in the brains of people living with Alzheimer’s disease, offering fresh insights into why the condition develops and progresses differently among patients.

The findings, published in Nature Communications, could pave the way for new treatment strategies while also advancing research into other neurodegenerative disorders.

Mapping the brain’s hidden changes

Alzheimer’s disease remains the leading cause of dementia worldwide.

The condition is characterized by the accumulation of amyloid plaques and neurofibrillary tangles in the brain, which gradually damage and kill brain cells.

As the disease progresses, the brain shrinks, leading to worsening memory loss, cognitive decline, and, ultimately, severe disability.

To better understand the biological processes driving the disease, Mayo Clinic scientists examined brain tissue samples from 472 individuals with Alzheimer’s disease stored in the institution’s Department of Neuroscience Brain Bank.

The team focused on DNA methylation, a process that adds chemical markers to DNA and influences whether genes are switched on or off.

By combining genome-wide methylation analysis with detailed measurements of Alzheimer’s-related brain changes and protein levels, researchers created one of the most comprehensive datasets of its kind.

Their analysis revealed widespread alterations in DNA regulation that appear closely linked to disease progression.

“We wanted to ensure that both the data and findings could be shared with the broader scientific community while protecting donor privacy,” said Dr. Nilüfer Ertekin-Taner, Chair of Neuroscience at Mayo Clinic and senior author of the study.

She noted that relatively few research groups have the expertise and resources needed to analyze such large and complex datasets.

Tau protein linked to key DNA alterations

One of the study’s most significant discoveries involved the tau protein, a hallmark of Alzheimer’s disease.

Researchers found that nearly all major DNA methylation changes were associated with tau accumulation rather than amyloid plaques.

The team also identified substantial effects on oligodendrocytes, specialized brain cells responsible for producing myelin, the protective coating that enables nerve cells to communicate efficiently.

Damage to these cells may contribute to the communication breakdown between neurons that underlies many Alzheimer’s symptoms.

“Our team has previously shown that oligodendrocytes are affected in Alzheimer’s disease and in progressive supranuclear palsy, another tau-related disorder,” said Dr. Ertekin-Taner.

“These findings reinforce the idea that oligodendrocyte dysfunction and myelin damage play a central role in Alzheimer’s disease.”

Because epigenetic modifications, such as DNA methylation, can be reversed, researchers believe these molecular pathways may be promising targets for future therapies to slow or alter disease progression.

New genes and research resources identified

Beyond confirming known disease mechanisms, the study uncovered several genes that may contribute to Alzheimer’s disease, including LDB3.

The researchers validated many of their findings across multiple independent datasets, strengthening confidence in the results.

To support further discovery, the team also launched the Multiomic Atlas of AD Brain Endophenotypes, an interactive online platform that allows scientists to explore the dataset using gene names or chromosomal locations.

The freely available resource provides searchable tables and interactive visualizations designed to accelerate research into Alzheimer’s disease and related neurological disorders.

The project’s lead author, Dr. Stephanie Oatman, conducted the research during her doctoral training at Mayo Clinic and now serves as a postdoctoral fellow at Brigham and Women’s Hospital.

She emphasized that broad access to large-scale datasets will be critical for advancing understanding of Alzheimer’s disease and identifying new therapeutic opportunities.

Growing momentum in Alzheimer’s research

The Mayo Clinic findings arrive amid a period of rapid progress in Alzheimer’s research.

In recent weeks, scientists in Europe reported the discovery of a biological tipping point that may explain why some people with Alzheimer’s-related brain pathology develop dementia while others remain cognitively resilient.

The study highlighted changes in microglial immune cells as a potential therapeutic target.

At the same time, researchers continue to explore new diagnostic tools and treatment approaches, including blood-based biomarkers that can identify disease risk years before symptoms appear.

These advances, combined with growing understanding of the genetic and epigenetic mechanisms underlying Alzheimer’s disease, are helping researchers develop more precise strategies for diagnosis and intervention.