The field of Alzheimer's research is branching out.
After decades of focusing on the sticky amyloid plaques and tangled tau fibers associated with the disease, brain researchers are searching for other potential causes of impaired memory and thinking.
That search is on full display this week at the Alzheimer's Association International Conference in San Diego, where sessions are exploring factors including genes, brain injury, clogged arteries and inflammation.
A group of researchers from Seattle even unveiled a highly detailed atlas showing how different types of brain cells change in Alzheimer's. The goal is to help scientists identify new approaches to treatment.
"Certainly, plaques and tangles are a hallmark," says Maria Carrillo, chief science officer of the Alzheimer's Association. "It doesn't mean plaques are the cause of cell death."
Plaques are clumps of a protein called beta-amyloid that appear in the spaces between neurons. Tangles are made up of a protein called tau that appears inside a neuron.
Both proteins tend to accumulate in the brains of people with Alzheimer's. But their role in killing brain cells is still unclear.
Carrillo says the Alzheimer's field needs to look to cancer research where a deeper understanding of the disease has led to better treatments.
The shift comes after a series of experimental drugs have succeeded in removing amyloid plaques and tau tangles from the brain, but failed to halt the disease.
The Food and Drug Administration has approved one amyloid drug, Aduhelm, but is still evaluating whether it actually helps patients.
An Alzheimer's Atlas
The study that produced the atlas is emblematic of how researchers are recalibrating.
"What we're trying to do with this study is to look at cell vulnerability early on in disease, before [people] have plaques and tangles, before they have cognitive impairment," says Dr. C. Dirk Keene, a neuropathologist at the University of Washington.
To create the atlas, Keene and a team of researches analyzed more than a million cells from 84 brains donated by people who'd signed up for Alzheimer's research projects run by the University of Washington and Kaiser Permanente Washington Research Institute.
The brains came from donors "at all different stages of disease" Keene says, "so we can pinpoint what's happening from the earliest levels all the way through 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.
The atlas came from the realization that "If we want to treat diseases of an extremely complex cellular organ, you need to understand that organ much better than we do," says Ed Lein, a senior investigator at the Allen Institute for Brain Science, which played a key role in analyzing the brain tissue.
So the team spent years studying cells in healthy brains before looking at brains affected by Alzheimer's.
"We've defined what a normal adult brain looks like," Lein says, "and now we can use that knowledge and look for changes that are happening in specific kinds of cells."
Finding vulnerable brain cells
At the Alzheimer's meeting, the team described changes they saw in more than 100 types of cells taken from the cortex — an area of the brain which is important to memory and thinking.
One finding was that neurons that make connections within the cortex itself were much more likely to die than those that connect to distant areas of the brain.
"What we're seeing is a profound effect on cortical circuitry that very plausibly is the reason we have cognitive decline," Lein says.
If so, a treatment designed to protect those vulnerable neurons might prevent declines in memory and thinking linked to Alzheimer's.
The team also found a proliferation of brain cells that contribute to inflammation. These included certain immune cells and a type of cell that responds to injury.
"So while the neurons are lost, the non-neuronal cells are actually increasing and changing" Lein says.
The finding supports the idea that inflammation plays an important role in Alzheimer's, and that anti-inflammatory drugs might help protect the brain.
The Seattle team hopes other scientists will use the brain cell atlas to come up with new treatments for Alzheimer's.
"We've created an open-access resource where the whole community can come and look at this data," Lein says. "They can mine it to speed up progress in the field as a whole."
Speeding up progress is one reason Kyle Travaglini, a researcher at the Allen Institute, jumped at the chance to work on the Alzheimer's project.
"My grandmother started developing Alzheimer's disease when I was just going off to college," says Travaglini, who received his PhD in 2021.
Travaglini says the atlas project is appealing because it isn't based on a preconceived idea about what causes Alzheimer's.
"It's like looking at the same disease that everyone has been looking at but in an entirely different way," he says.