Alzheimer’s Tau Protein Could Advance Cognitive Precision Medicine

Brain imaging of tau-protein “tangles” accurately predicted the location of brain atrophy in patients with Alzheimer’s a year or more in advance, according to a study published in Science Translational Medicine. The findings could boost precision medicine for Alzheimer’s and other cognitive disorders.

Researchers at the UC San Francisco Memory and Aging Center adopted tau PET imaging to examine the distribution of tau tangles in the normally aging brain, and in a smaller group of patients with Alzheimer’s. The team is the first to test whether tau levels in Alzheimer’s patients can predict future brain degeneration.

For decades, research has focused on the location of amyloid “plaques” to predict Alzheimer’s brain degeneration, with scientists attempting to delay Alzheimer’s progression with amyloid-targeting drugs.

Now, researchers are looking at tau protein to see whether it may be a significant biological driver of the condition. While amyloid accumulates widely across the brain, sometimes even in people with no symptoms of Alzheimer’s, autopsies of Alzheimer’s patients have shown that tau is concentrated where brain atrophy is most severe.

“No one doubts that amyloid plays a role in Alzheimer’s disease, but more and more tau findings are beginning to shift how people think about what is actually driving the disease,” explained Renaud La Joie, PhD, a postdoctoral researcher in the In Vivo Molecular Neuroimaging Lab, and lead author of the new study.

“Still, just looking at postmortem brain tissue, it has been hard to prove that tau tangles cause brain degeneration and not the other way around. One of our group’s key goals has been to develop non-invasive brain imaging tools that would let us see whether the location of tau buildup early in the disease predicts later brain degeneration.”

The research team recruited 32 participants with early-stage Alzheimer’s, all of whom received PET scans using two different tracers to measure levels of amyloid protein and tau protein in their brains. Participants also received MRI scans to measure their brain’s structural integrity, both at the start of the study and in follow-up visits one to two years later.

The results showed that overall tau levels in patients’ brains at the start of the study predicted how much degeneration would occur before the time of the follow-up visit, on average 15 months later. Local patterns of tau buildup predicted subsequent brain degeneration in the same areas with more than 40 percent accuracy.

In contrast, baseline amyloid-PET scans correctly predicted only three percent of future brain atrophy.

“The match between the spread of tau and what happened to the brain in the following year was really striking,” said neurologist Gil Rabinovici, MD, the Edward Fein and Pearl Landrith Distinguished Professor in Memory and Aging and leader of the PET imaging program at the UCSF Memory and Aging Center.

“Tau PET imaging predicted not only how much atrophy we would see, but also where it would happen. These predictions were much more powerful than anything we’ve been able to do with other imaging tools, and add to evidence that tau is a major driver of the disease.”

Additionally, PET scans showed that compared to older patients, younger participants had higher overall levels of tau protein in their brains, as well as a stronger link between baseline tau and subsequent brain atrophy. This finding indicates that other factors, such as other abnormal proteins or vascular injuries, could impact the progression of Alzheimer’s.

The findings support the use of tau-targeting drugs in slowing the progression of Alzheimer’s, researchers noted.

“Seeing that tau buildup predicts where degeneration will occur supports our hypothesis that tau is a key driver of neurodegeneration in Alzheimer’s disease,” La Joie said. 

The use of tau PET to predict later brain degeneration could also lead to more personalized dementia care and accelerate ongoing clinical trials.

“One of the first things people want to know when they hear a diagnosis of Alzheimer’s disease is simply what the future holds for themselves or their loved ones. Will it be a long fading of memory, or a quick decline into dementia? How long will the patient be able to live independently? Will they lose the ability to speak or get around on their own?” Rabinovici said.

“These are questions we can’t currently answer, except in the most general terms. Now, for the first time, this tool could let us give patients a sense of what to expect by revealing the biological process underlying their disease.” 

Predicting future brain atrophy based on tau PET imaging will allow Alzheimer’s clinical trials to uncover whether an experimental treatment will work for an individual patient. These insights could help providers know when to adjust dosages or switch treatments, advancing precision medicine for the condition.

“Tau PET could be an extremely valuable precision medicine tool for future clinical trials,” Rabinovici said. “The ability to sensitively track tau accumulation in living patients would for the first time let clinical researchers seek out treatments that can slow down or even prevent the specific pattern of brain atrophy predicted for each patient.”