How Enhancer Dysregulation Influences Alzheimer's Disease

Scientists have identified a new mechanism that accelerates aging in the brain and gives rise to the most devastating biological features of Alzheimer’s disease. The findings provide scientists with fresh avenues for screening compounds designed to slow or stop disease progression—something existing medications cannot do. The study was published today in Nature Communications.

“We now have a better understanding of the molecular factors that lead to Alzheimer’s disease, which we can leverage to develop improved and desperately needed treatment and prevention strategies,” says senior author Viviane Labrie of Van Andel Research Institute. “Alzheimer’s is a major growing public health problem around the world. We need better options for patients and we need them soon.”

Alzheimer’s disease is the sixth leading cause of death in the U.S. and the most common cause of dementia worldwide. An estimated 5.8 million people in the U.S. and 44 million people worldwide have Alzheimer's. By 2050, those numbers are expected to rise to 14 million and 135 million respectively, due in part to a growing and aging global population.

The findings center on genetic regions called enhancers, which turn the activity of genes up or down based on environmental factors. The researchers took a comprehensive look at enhancers in brain cells of people at varying stages of Alzheimer’s and compared them to the cells of healthy people. They found that in normal aging, there is a progressive loss of important epigenetic marks on enhancers. This loss is accelerated in the brains of people with Alzheimer’s, essentially making their brain cells act older than they are and leaving them vulnerable to the disease. At the same time, these enhancers over-activate a suite of genes involved in Alzheimer’s pathology in brain cells, spurring the formation of plaques and tangles, and reactivating the cell cycle in fully formed cells.

“In adults, brain cells typically are done dividing. When enhancers reactivate cell division, it’s incredibly damaging,” Labrie says. “The enhancer changes we found also encourage the development of plaques, which act as gasoline for the spread of toxic tangles, propagating them through the brain like wildfire. Taken together, enhancer abnormalities that promote plaques, tangles, and cell cycle reactivation appear to be paving the way for brain cell death in Alzheimer’s disease.”

The team next plans to develop experimental systems to screen compounds that may fix dysregulation in enhancers and potentially act as new treatments or preventative measures.