Follow the tau: This brain protein presents a possible path to earlier Alzheimer’s diagnosis

PROVIDENCE, R.I. [Brown University] — Alzheimer’s disease is commonly known for its symptoms — memory loss, cognitive impairment, difficulty with daily tasks — but can only be definitively diagnosed by a look at the brain. A scan must show the abnormal buildup of two distinct brain proteins, beta-amyloid and tau, and it’s the dual presence of both that distinguishes the disease from other forms of dementia.

Hwamee Oh, an associate professor of psychiatry and human behavior and of cognitive and psychological sciences at Brown University, is researching different positron emission tomography (PET) imaging methods of detecting Alzheimer’s disease as part of the HEAD study, a long-term project involving nine sites in the United States, Canada and Spain. Oh is the principal investigator of the Providence site, which has drawn participants from throughout New England.

In a new study published in the Lancet, HEAD researchers compared the effectiveness of two chemical detectors, called tau tracers, that detect tau in the brain. They found that an experimental tau tracer outperformed a clinically approved tau tracer — a discovery, Oh said, that could pave the way for earlier detection of Alzheimer’s disease. In this interview, Oh explains why better detection of Alzheimer’s disease is a critical piece of the larger scientific push toward prevention and treatment, and for a patient’s trajectory.

Q: How has the detection of Alzheimer’s disease evolved over time?

Alzheimer’s disease is characterized by the accumulation of beta-amyloid plaques and tau neurofibrillary tangles in the brain. Those pathological features were first described in 1906 by Alois Alzheimer, but it wasn’t until 2004 that we developed a PET imaging method to identify beta-amyloid plaques in living people. For tau, it was 2012.

Q: What are some challenges in diagnosing Alzheimer’s?

Currently, behavioral changes are an important part of diagnosing Alzheimer’s disease. But these symptoms can derive from many different causes. That’s why neuroimaging plays a key role. If someone presents symptoms of mild cognitive impairment, a clinician would recommend a PET scan to definitively determine their type of dementia. And that, in turn, would determine different treatment strategies for that person.

Because PET imaging is costly, one of the ongoing efforts in our lab — in collaboration with other Brown researchers and affiliated hospitals — is to develop more sophisticated behavioral markers using cognitive and computational approaches. Hopefully, these developments will facilitate earlier detection of disease-related brain changes. 

Q: Your research has focused on the detection of tau. What’s so significant about these proteins in the development of Alzheimer’s disease?

We don’t actually know how tau tangles lead to the clinical symptoms of Alzheimer’s disease. But we do know that tau is closely related to cognitive decline. If you see an abnormal presentation of tau — such as tangles or other buildup — in a part of the brain, you will probably see neuron loss in that same region later on. In fact, tau is linked to other neurodegenerative diseases, such as frontotemporal dementia. For Alzheimer’s, what’s interesting is that while beta-amyloid plaques rarely appear in the human brain before age 45, abnormal tau can be detected much younger — even in the brains of people in their teens and 20s.

Q: What are the implications of the recent HEAD study?

The HEAD study is the largest study to compare two PET tau detection methods in the same individual. We found that the experimental tracer [18F] MK6240 detected tau pathology more than twice as often as the clinically common tracer Flortaucipir in cognitively unimpaired individuals with beta-amyloid plaques. This highlights the growing importance of sensitive tau imaging for identifying patients earlier in the disease process.

That earlier detection gives us researchers a tremendous opportunity to understand how tau is going to be impacting and developing this disease over time and to assess treatment effects. From a clinical perspective, although [18F] MK6240 is not yet available for use with patients, it was submitted for U.S. Food and Drug Administration approval last year. There should be a review meeting by mid-August, and I hope our findings can be considered as part of that conversation.

Q: What are the benefits of detecting Alzheimer’s disease early?

Treatment or other preventive strategies are more effective when they are implemented earlier. If you wait, there is likely to be more damage to the neurons and other cell types in the brain, and intervention becomes more difficult. The majority of Alzheimer’s cases — about 95% — are non-genetic, and about 50% of these non-genetic cases have been suggested to be preventable. For example, one common risk factor for Alzheimer’s disease is poor vascular health in the form of high blood pressure or high cholesterol. If someone improves their vascular health, they can help maintain their cognitive health.

Q: If someone receives an Alzheimer’s diagnosis, what treatments are available?

For the past 20 years, there were no real treatments developed for Alzheimer’s disease. Pharmacological interventions alleviated impairment but only delayed symptoms. Current treatment development tries to actually remove the cause of the disease. A lot of effort has gone into developing drugs that target amyloid. Recently, those amyloid-targeting drugs have started to show they can slow the disease’s progression, but we still need to see how they work over time.

Q: How does your work fit into other Alzheimer’s research happening at Brown?

At the Center for Alzheimer’s Disease Research at Brown’s Carney Institute for Brain Science, there are a lot of exceptionally accomplished and talented researchers who use animal models to generate and test new hypotheses about the mechanisms of the disease. Our research provides the human-based findings. Collectively, we’re able to understand more about this disease and develop new treatments.

Overall, the culture at Brown — the collaborative nature across fields — is an important asset for me. There are researchers looking at aging at the molecular level, clinicians involved in clinical trials, neuroscientists studying fundamental brain mechanisms, and biostatisticians in the School of Public Health who I collaborate with. I’m grateful, too, for the participants who invest their time in our research. It’s a collective effort to improve cognitive and brain health in late life from people both outside and inside of the lab.