Researchers from the Indiana University School of Medicine have uncovered how a well-known genetic risk factor for Alzheimer’s disease worsens damage to white matter tissues in the brain. This white matter is crucial for communication between different brain regions.
This discovery, published in Alzheimer's & Dementia: The Journal of the Alzheimer's Association, opens a potential new direction for developing treatments aimed at protecting white matter in the brain and preserving brain function in people carrying the APOE4 gene variant, the most common genetic risk factor for Alzheimer’s disease.
The team, led by Jungsu Kim, PhD, the P. Michael Conneally Professor of Medical and Molecular Genetics, and Md Mamun Al-Amin, PhD, a postdoctoral fellow in medical and molecular genetics, found that animal models with the APOE4 Alzheimer’s disease gene variant see structural changes in brain tissue and a sharp decline of oligodendrocytes. These cells form and maintain myelin, the fatty coating that protects nerve fibers and enables efficient brain signaling.
“These findings suggest that APOE4 exacerbates myelin disruption and white matter injury in the presence of amyloid plaque buildup, a hallmark of Alzheimer’s disease,” said Al-Amin, the first author of the paper. “By pinpointing the role of actively myelinating oligodendrocytes in this process, the study provides an important insight into one of the cellular pathways that may drive cognitive decline and connectivity loss in Alzheimer’s disease.”
Every person inherits two copies of the APOE gene, one from each biological parent. Those with two copies of the APOE4 variant face up to a 15 times greater chance of developing the disease compared to those with the APOE3 variant, the most common form of the gene, said Al-Amin.
According to the National Institute on Aging, about 15% to 25% of people have at least one copy of the APOE4 variant, and 2% to 5% carry two copies.
The gene variant is associated with amyloid plaques and tau tangles in the brain — two main characteristics of Alzheimer’s disease — along with the shrinking of brain regions vital for memory and thinking. It also affects how brain cells handle cholesterol and other fats, disrupting normal communication and repair processes. This causes lipid buildup, weakens myelin in the brain and reduces the ability of neurons to form and maintain healthy connections, Al-Amin said.
“By uncovering how APOE4 disrupts lipid balance and brain connectivity, we aim to design therapies that target these pathways and protect the brain from neurodegeneration,” Al-Amin said.
The team discovered that the lack of oligodendrocyte cells protecting nerve fibers in the presence of the gene variant caused structural damage to the white matter brain tissue. Myelin insulates nerve fibers and allows them to pass messages quickly throughout the brain.
When oligodendrocyte cells malfunction, Kim said, brain connectivity suffers, undermining communication between neural networks in the brain.
“For decades, Alzheimer’s disease was viewed primarily as a disorder of neurons, the cell type that stores the memory and degenerates in the disease,” Kim said. “However, recent research is revealing that oligodendrocytes also play a crucial role in the disease’s onset and progression.”
The research team collaborated with the Roberts Translational Preclinical Neuroimaging Core, a partnership between the Stark Neurosciences Research Institute and the Medical Imaging Research Institute at the IU School of Medicine, to acquire high-quality MRI data.
The core’s expertise was critical in the team developing advanced, multimodal MRI techniques tailored to detect specific signs of brain pathology, Kim said. They were able to obtain detailed, high-resolution images needed to study changes in the brain linked to neurodegeneration.
Kim said the next phase of the research will focus on finding ways to support and protect the actively myelinating and mature oligodendrocyte cells that sustain healthy myelin and white matter, especially in individuals carrying the APOE4 gene variant. Future studies may explore new medications or interventions that can boost the function of these cells, with the goal of preserving brain connectivity and slowing the progression of Alzheimer’s disease.
