Using sophisticated brain mapping tools, a group of scientists have discovered evidence indicating that Alzheimer’s disease may damage the brain in two phases as well as which cell types may be harmed first. Details from the National Institutes of Health-funded study were published in Nature Neuroscience in a paper titled, “Integrated multimodal cell atlas of Alzheimer’s disease.”
The brains used for the study are from the Seattle Alzheimer’s Disease Brain Cell Atlas initiative (SEA-AD), which aims to map the brain damage that occurs during the disease. According to the findings, the first and earliest phase occurs before people experience the characteristic memory problems and the changes to the brain structure and networks, including plaque accumulation, are gradual and unobtrusive. In the second, late phase, the disease causes more widespread destruction. This phase also coincides with the appearance of symptoms and much more rapid accumulation of plaques and tangles.
The findings fly in the face of other studies that suggested that the damage caused by Alzheimer’s occurs in several stages characterized by increasing levels of cell death, inflammation, and protein accumulation.
Richard Hodes, MD, director of NIH National Institute on Aging believes these new results will “fundamentally alter scientists’ understanding of how Alzheimer’s harms the brain.” A key challenge with diagnosing and treating Alzheimer’s disease is that by the time the patient presents with symptoms, much of the damage has been done. “The ability to detect these early changes means that, for the first time, we can see what is happening to a person’s brain during the earliest periods of the disease,” he said.
Digging into the details of the study, the scientists analyzed brains from 84 people at different disease stages using tools developed as part of the NIH’s Brain Research Through Advancing Innovative Neurotechnologies (BRAIN) initiative. The cohort included 33 male donors and 51 female donors. They honed in on cells of the middle temporal gyrus, a part of the brain that controls language, memory, and vision, which is vulnerable to many of the changes observed in Alzheimer’s patients. It is also a part of the brain that researchers have thoroughly mapped for control donors which made it possible to compare their information with data from people with the disease. This way, the research team was able to create a genetic and cellular timeline showing the disease progression in the two phases.
Among the list of changes in the early phase is the death of cells called somatostatin (SST) inhibitory neurons, a finding that surprised the researchers. Scientists have long thought that Alzheimer’s primarily damages excitatory neurons, which send activating neural signals to other cells. In contrast, inhibitory neurons send calming signals to other cells. The team suspects that losing SST inhibitory neurons might be responsible for the changes to the brain’s neural circuitry that underlie disease development.
“This research demonstrates how powerful new technologies provided by the NIH’s BRAIN Initiative are changing the way we understand diseases like Alzheimer’s,” said John Ngai, PhD, director of the NIH’s BRAIN initiative. “The new knowledge provided by this study may help scientists and drug developers around the world develop diagnostics and treatments targeted to specific stages of Alzheimer’s and other dementias.”