Alzheimer’s Starts Slow, Then Gets Faster
A new study reveals that Alzheimer’s disease advances in two distinct phases, with the second phase causing the most damage to brain cells and specific neurons. Scientists believe this discovery could help to create new treatments for the progressive brain disorder.
Nearly seven million people in the United States are living with Alzheimer’s disease in 2024, according to the Alzheimer’s Association. Alzheimer’s symptoms, such as a decline in memory and thinking skills, poor judgment, confusion, and trouble solving problems, become worse as the disease progresses and interferes with a person’s ability to perform daily living activities.
The study’s findings, published in the journal Nature Neuroscience, suggest that treatments for Alzheimer’s are more effective during the early stages of the disease, particularly to protect certain neurons that are vulnerable to the disease.
“There’s an early phase where there’s a very slow increase in the amount of pathology,” Ed Lein, a senior investigator at the Allen Institute of Brain Science in Seattle, told NPR. “Then a more exponential phase where suddenly things get really bad.”
The National Institutes of Health (NIH) noted that previous studies have suggested that the brain damage caused by Alzheimer’s occurs in several stages, marked by increasing levels of cell death, inflammation, and protein accumulation in the form of plaques and tangles
The most recent study, however, indicates that the earliest changes happen gradually and “quietly” in the first phase before any symptoms appear. Then, the damage Alzheimer’s causes, such as memory problems, occurs quickly in the second phase.
Lein and a team of nearly 100 other scientists said they found evidence that a small subset of neurons, known as somatostatin inhibitory neurons, begin to die off during the early phase of Alzheimer’s.
“That was quite a surprise,” Lein told NPR, noting that Alzheimer’s researchers have largely overlooked these neurons. Somatostatin neurons regulate the functioning of brain networks that play a role in thinking and memory. Any decline in these cells could upset the “delicate balance” in the brain between inhibitory and excitatory neurons.
Excitatory neurons are often compared to the accelerator in a car because they stimulate other neurons to “fire” and pass messages on to the next neuron. In contrast, inhibitory neurons are like the brakes in a car. Inhibitory neurons connect with nearby excitatory neurons and control their activity by slowing them down or stopping them.
“They’ve produced a picture of what’s going on that no one could have anticipated just a few years ago,” Dr. Richard Hodes, director of the NIH National Institute on Aging, which provided funding for the research, told NPR.
Use of New Technologies Provided New Insights
Scientists uncovered specific details about millions of brain cells by using artificial intelligence, advanced imaging, and genetic methods. The research team used resources from the NIH’s Brain Research Through Advancing Neurotechnologies (BRAIN) Initiative—Cell Census Network (BICCN).
“With these tools, scientists were able to detect the earliest cellular changes to the brain to create a more complete picture of what happens over the entire course of the disease,” John Ngai, director of The BRAIN Initiative, said in a statement. “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.”
The research team used BRAIN to study 3.4 million cells from 84 cadaver brains of people who were 65 years old or older when they died. Some had Alzheimer’s disease, and others did not. The scientists focused on the middle temporal gyrus, an area in the brain involved in language, vision, and memory. The gyrus has been shown to be vulnerable to many of the changes typically associated with Alzheimer’s disease. Any damage to this area impairs new learning and memory acquired before the damage occurred.
The team compared cells at different stages of Alzheimer’s. By making comparisons, the scientists were able to develop a genetic and cellular timeline of what happens throughout the disease, including how Alzheimer’s changes the brain.
“We measure all the genes in each individual cell,” Lien said. “That allows you to not only identify those cells, but look for changes in those cells as a result of disease.”
The investigators said they thought the excitatory neurons would be the first to change. This aligns with previous studies by scientists who thought that Alzheimer’s primarily damages excitatory neurons. But “it turns out that the first cells lost are actually some of the inhibitory neurons,” Lein said.
If this is so, Dr. Hodes said that treatment for the disease should begin before too many inhibitory neurons are lost.
“The fact that there is a process early on that is slow is an inviting opportunity to intervene,” Dr. Hodes said.
Source Links:
https://www.npr.org/sections/shots-health-news/2024/11/11/nx-s1-5183228/alzheimers-brain-timeline-shift-trickle-torrent
https://www.nih.gov/news-events/news-releases/alzheimer-s-disease-may-damage-brain-two-phases#
