The field of Alzheimer’s research is evolving.
After decades of focusing on the sticky amyloid plaques and tangled tau strands associated with the disease, brain researchers are looking for other potential causes of memory and thinking decline.
The search will be on full display this week at the Alzheimer’s Association International Conference in San Diego, where sessions will examine factors such as genes, brain injury, clogged arteries and inflammation.
A team of researchers from Seattle has also uncovered a highly detailed atlas showing how different types of brain cells change in Alzheimer’s. The goal is to help scientists identify new treatments.
“Certainly, spots and tangles are the hallmarks,” says Maria Carrillo, chief research officer at the Alzheimer’s Association. “This does not mean that plaque is the cause of cell death.”
Plaques are clumps of a protein called beta-amyloid that form in the spaces between neurons. Tentacles are made up of a protein called tau that forms inside neurons.
Both proteins accumulate in the brains of people with Alzheimer’s disease. However, their role in killing brain cells is still unknown.
Carrillo said the Alzheimer’s field needs cancer research where a deeper understanding of the disease leads to better treatments.
The change comes after a series of experimental drugs succeeded in removing amyloid plaques and tau tangles in the brain, but failed to stop the disease.
The Food and Drug Administration has approved one amyloid drug, Aduhelm, but is still evaluating whether it actually helps patients.
The research that makes up the atlas is a symbol of the calibration of researchers.
“What we’re trying to do with this study is look at the vulnerability of the cell early in the disease. [people] they have plaques and wrinkles to cognitive impairment,” says Dr. C. Dirk Keen, a neurologist at the University of Washington.
To create the atlas, Keane and a team of researchers analyzed more than a million cells from 84 brains donated by people enrolled in Alzheimer’s research projects run by the University of Washington and the Kaiser Permanente Washington Research Institute.
The brains came from donors at “various stages of disease,” Keane says, “so we can see exactly what’s going on, from the earliest stages to people with advanced disease.”
The effort is funded by the National Institute on Aging and grew out of the federal BRAIN initiative launched by President Obama in 2013.
Ed Lane, a senior researcher at the Allen Institute for Brain Science, said: “If we want to treat diseases of a very complex cellular organ, we need to understand that organ much better than we do.” played a key role in the analysis of brain tissue.
So the team spent years studying cells in healthy brains before looking at brains affected by Alzheimer’s disease.
“We’ve figured out what a normal adult brain looks like,” says Lane, “and now we can use that knowledge to look for changes in specific types of cells.”
Finding vulnerable brain cells
At the Alzheimer’s meeting, the team described changes in more than 100 types of cells in the brain’s cortex, which are important for memory and thinking.
One finding was that neurons that made connections within the cortex were more likely to die than those that connected to distant brain regions.
“What we’re seeing has profound effects on cortical circuitry, which is the cause of our cognitive decline,” says Lein.
If so, treatments designed to protect those vulnerable neurons could prevent Alzheimer’s-related memory and cognitive decline.
The team also found an increase in brain cells that contribute to inflammation. These include some immune cells and a type of cell that responds to injury.
“So while the neurons are being lost, the non-neuronal cells are actually multiplying and changing,” says Lane.
The finding supports the idea that inflammation plays an important role in Alzheimer’s and that anti-inflammatory drugs can help protect the brain.
The Seattle team hopes other scientists will use the atlas of brain cells to come up with new treatments for Alzheimer’s.
“We’ve created an open resource where the whole community can come and look at this data,” says Lein. “They generally mine it to accelerate progress in the field.”
One reason Allen Institute researcher Kyle Travaglini jumped at the chance to work on the Alzheimer’s project is to speed up progress.
“My grandmother started to develop Alzheimer’s when I was just entering college,” says Travaglini, who will receive her PhD in 2021.
Travaglini says the atlas project is attractive because it doesn’t rely on preconceived notions about what causes Alzheimer’s disease.
“It’s like everyone is looking at the same disease, but in a completely different way,” he says.