Tau protein—not amyloid—may be key driver of Alzheimer’s symptoms

PET scans showing tau deposits in the brains of healthy people (top) and those with Alzheimer’s (bottom). The red areas indicate tau deposits.

Dr. Matthew Brier

Tau protein—not amyloid—may be key driver of Alzheimer’s symptoms

One of the telltale signs of Alzheimers disease (AD) is sticky plaques of ß-amyloid protein, which form around neurons and are thought by a large number of scientists to bog down information processing and kill cells. For more than a decade, however, other researchers have fingered a second protein called tau, found inside brain cells, as a possible culprit. Now, a new imaging study of 10 people with mild AD suggests that tau deposits—not amyloid—are closely linked to symptoms such as memory loss and dementia. Although this evidence won’t itself resolve the amyloid-tau debate, the finding could spur more research into new, tau-targeting treatments and lead to better diagnostic tools, researchers say.

Scientists have long used an imaging technique called positron emission tomography (PET) to visualize ß-amyloid deposits marked by radioactive chemical tags in the brains of people with AD. Combined with postmortem analyses of brain tissue, these studies have demonstrated that people with AD have far more ß-amyloid plaques in their brains than healthy people, at least as a general rule. But they have also revealed a puzzle: Roughly 30% of people without any signs of dementia have brains “chock-full” of ß-amyloid at autopsy, says neurologist Beau Ances at Washington University in St. Louis in Missouri.

That mystery has inspired many in the AD field to ask whether a second misfolded protein, tau, is the real driver of the condition’s neurodegeneration and symptoms, or at least an important accomplice. Until recently, the only ways to test that hypothesis were to measure tau in brain tissue after a person died, or in a sample of cerebrospinal fluid (CSF) extracted from a living person by needle. But in the past several years, researchers have developed PET imaging agents that can harmlessly bind to tau in the living brain. In the new study, Ances and colleagues used one of these tags and an amyloid-binding one to analyze deposits of both proteins in 10 people with mild AD and 36 healthy adults. The more tau deposits found in the temporal lobe, a brain region associated with memory, the more likely a person was to show deficits on a battery of memory and attention tests, the team reports today in Science Translational Medicine

The same relationship did not apply to ß-amyloid, suggesting that—although ß-amyloid PET scans can detect early stages of AD—tau is a better predictor of when people transition from the early, nonsymptomatic stages of the disease into mild Alzheimer's disease, Ances says. He suspects that it is the combined insults from ß-amyloid and tau that drive the often-dramatic decline: Although the brain may be able compensate for the deficits caused by ß-amyloid, once tau starts to spread, “that pushes you over,” he says.

When the team measured tau in the study participantsCSF, it found that higher levels were specifically correlated with increased tau in the temporal lobe, a region involved in memory processing, Ances says. Thats important, he suggests, because it means that one could potentially use tau in CSF as a diagnostic tool. 

Thats still a long ways off, says Pedro Rosa-Neto, a clinical neurologist at McGill University, Montreal, in Canada. The study took only a snapshot of participantsbrains at a single point in time, so it cant prove any association between increased tau and mental deterioration. Still, he says, “it is a very nice paper” that provides a “first glimpse” of how tau and amyloid contribute differently to cognitive decline.

Ances says that large, longitudinal studies tracking both tau and ß-amyloid in people over time are already underway. Ultimately, he says, the “dream” is that researchers will be able to tailor which AD therapy you need, “based on whats happening in your brain.”