Study reveals how Alzheimer’s may cause brain damage in two distinct phases

Alzheimer’s disease can damage the brain in two distinct stages, based on new research funded by the National Institutes of Health (NIH) using advanced brain-mapping tools. According to researchers who discovered this new view, the first, early phase occurs slowly and silently; before people get memory problems -; damage only a few vulnerable cell types. In contrast, the second, late phase causes damage that is more broadly destructive and coincides with the onset of symptoms and the rapid accumulation of plaques, tangles, and other hallmarks of Alzheimer’s disease.

One of the challenges of diagnosing and treating Alzheimer’s disease is that much of the damage to the brain occurs long before symptoms appear. The ability to detect these early changes means that for the first time we can see what happens to a person’s brain during the earliest periods of the disease. The results fundamentally change scientists’ understanding of how Alzheimer’s disease damages the brain and will guide the development of new treatments for this devastating condition.”

Richard J. Hodes, MD, Director, NIH National Institute on Aging

Scientists analyzed the brains of 84 people and the results were published in Nature Neurosciencesuggest that damage to one type of cell, a so-called inhibitory neuron, during the early phase may cause the neural circuit problems that underlie the disease. In addition, the study confirmed previous findings about how Alzheimer’s disease damages the brain and identified many new changes that can occur during the disease.

Specifically, the scientists used advanced genetic analysis tools to study the cells of the middle temporal gyrus, a part of the brain that controls language, memory and vision. The gyrus has been shown to be vulnerable to many of the changes traditionally seen during Alzheimer’s disease. It is also a part of the brain that researchers have thoroughly mapped for control donors. By comparing data from control donors with that of people who had Alzheimer’s disease, the scientists created a genetic and cellular timeline of what happens during the disease.

Traditionally, studies have suggested that the damage caused by Alzheimer’s disease occurs in several stages, characterized by increasing levels of cell death, inflammation and the buildup of proteins in the form of plaques and tangles. In contrast, this study suggests that the disease changes the brain in two “time periods” -; or phases -; with many of the changes traditionally studied occurring rapidly during the second phase. This coincides with the onset of memory problems and other symptoms.

The results also suggest that the first changes occur gradually and ‘quietly’ in the first phase, before symptoms appear. These changes include a slow build-up of plaques, activation of the brain’s immune system, damage to the cellular insulation that helps neurons send signals, and the death of cells called somatostatin (SST) inhibitory neurons.

The latter finding was surprising to the researchers. Traditionally, scientists have thought that Alzheimer’s disease mainly damages excitatory neurons, which send activating neural signals to other cells. Inhibitory neurons send calming signals to other cells. The authors of the paper hypothesized how the loss of SST inhibitory neurons could cause the changes in the brain’s neural circuits that underlie the disease.

Recently, a separate NIH-funded brain mapping study by researchers at MIT found that a gene called REELIN may be linked to the vulnerability of some neurons to Alzheimer’s disease. It also showed that star-shaped brain cells called astrocytes can be resilient to or resist the damage caused by the disease.

Researchers analyzed brains that are part of the Seattle Alzheimer’s Disease Brain Cell Atlas(link is external) (SEA-AD), which is designed to create a highly detailed map of the brain damage that occurs during the disease. The project was led by Mariano I. Gabitto, Ph.D., and Kyle J. Travaglini, Ph.D., of the Allen Institute, Seattle. The scientists used tools -; developed as part of the NIHs Brain research by promoting innovative neurotechnologies® (BRAIN) Initiative – Cell Census Network (BICCN) -; to study more than 3.4 million brain cells from donors who died at various stages of Alzheimer’s disease. Tissue samples were obtained from the Adult Changes in Thought study and the University of Washington Alzheimer’s Disease Research Center.

“This research shows how powerful new technologies from the NIH’s BRAIN Initiative are changing the way we understand diseases like Alzheimer’s. These tools allowed scientists to detect the earliest cellular changes in the brain to create a more complete picture of what happens throughout the course of the disease,” said John Ngai, Ph.D., director of The BRAIN Initiative®. “The new knowledge provided by this study could help scientists and drug developers around the world develop diagnostics and treatments targeting specific stages of Alzheimer’s disease and other forms of dementia.”

This study was funded by NIH grants: U19AG060909, P30AG066509, U19AG066567, U01AG006781. Additional funding was provided by the Nancy and Buster Alvord Endowment. Rush University Alzheimer’s Disease Center, Chicago, Illinois, shared metadata from donors to the Religious Orders Memory/Memory and Aging Project.

Researchers can obtain data from the SEA-AD study by visiting the study’s website: https://portal.brain-map.org/explore/seattle-alzheimers-disease.