The field of research on Alzheimer’s disease is diversifying.
After decades of focusing on the sticky amyloid plaques and tangled tau fibers associated with the disease, brain researchers are looking for other potential causes of impaired memory and thinking.
That research is on full display this week at the Alzheimer’s Association’s international conference in San Diego, where sessions explore factors like genes, brain damage, clogged arteries and inflammation.
A group of Seattle researchers has even unveiled a very detailed atlas showing how different types of brain cells change in Alzheimer’s disease. The goal is to help scientists identify new treatment approaches.
“Certainly the plaques and tangles are a feature,” says Maria Carrillo, scientific director of the Alzheimer’s Association. “That doesn’t mean the plaques are the cause of cell death.”
Plaques are clumps of a protein called beta-amyloid that appear in the spaces between neurons. The tangles are made up of a protein called tau that appears inside a neuron.
Both proteins tend to build up in the brains of people with Alzheimer’s disease. But their role in the destruction of brain cells is still unclear.
Carrillo says the field of Alzheimer’s disease needs to turn to cancer research where a deeper understanding of the disease has led to better treatments.
The change comes after a series of experimental drugs succeeded in clearing amyloid plaques and tau tangles from the brain, but failed to stop the disease.
The Food and Drug Administration has approved an 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 doing recalibration.
“What we’re trying to do with this study is look at the vulnerability of cells early in the 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 researchers analyzed more than a million cells from 84 brains donated by people who had enrolled in Alzheimer’s disease research projects run by the University. of Washington and the Kaiser Permanente Washington Research Institute.
The brains came from donors “at all stages of the disease,” Keene says, “so we can identify what’s happening from the earliest levels 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 was born out of the realization that “if we are going to treat disease in an extremely complex cellular organ, you have to understand that organ much better than we do,” says Ed Lein, principal investigator at the Allen Institute for Brain. Science, which has played a key role in the analysis of brain tissue.
The team therefore spent years studying the cells in healthy brains before focusing on brains affected by Alzheimer’s disease.
“We’ve defined what a normal adult brain looks like,” Lein says, “and now we can use that knowledge and look for changes that occur in specific cell types.”
Find vulnerable brain cells
At the Alzheimer’s disease meeting, the team described changes seen in more than 100 types of cells taken from the cortex, an area of the brain important for memory and thinking.
One of the findings was that neurons that make connections in 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 is most likely why we have cognitive decline,” Lein says.
If so, a treatment designed to protect these vulnerable neurons could prevent the decline in memory and thinking linked to Alzheimer’s disease.
The team also discovered an overgrowth of brain cells that contribute to inflammation. These included certain immune cells and a type of cell that reacts to injury.
“So while neurons are lost, non-neuronal cells grow and change,” Lein says.
The finding supports the idea that inflammation plays an important role in Alzheimer’s disease and that anti-inflammatory drugs may 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 disease.
“We’ve created an open-access resource where the whole community can come and view this data,” says Lein. “They can leverage it to accelerate progress on the pitch as a whole.”
Accelerating progress is one of the reasons Kyle Travaglini, a researcher at the Allen Institute, jumped at the chance to work on the Alzheimer’s Project.
“My grandmother started to develop Alzheimer’s disease while I was going to university,” says Travaglini, who received her doctorate in 2021.
Travaglini says the atlas project is appealing because it’s not based on a preconceived idea about the causes of Alzheimer’s disease.
“It’s like looking at the same disease that everyone else has seen but in an entirely different way,” he says.