Amyloid and tau proteins are both involved in the disease pathology of Alzheimer’s disease. The diagnostic and treatment research focus has long been on amyloid, which has proven almost entirely fruitless after decades of effort. But tau is becoming better understood, as investigational tau imaging agents offer the ability to visualize its presence in the brain.

The latest research on this front comes from the Memory and Aging Center at the University of California at San Francisco (UCSF). A study of 32 early clinical stage Alzheimer's disease found that imaging tau tangles in the brain could enable the prediction of the location and degree of degeneration to expect within the next year or two. Imaging amyloid plaques in those same patients, however, wasn’t found to be useful in predicting disease progression. The research results were published in the Jan. 1, 2020 issue of Science Translational Medicine.

Understanding the extremes

“It's not a representative sample because we are really including patients that are at the extreme ends of the spectrum. We have very young patients with almost no memory problems but they have very strong and very precise language difficulties that we know are usually very indicative of Alzheimer’s. We have patients with memory deficits, we have patients with visual/spatial deficits,” the study’s lead author Renaud La Joie explained to BioWorld MedTech. He is a postdoctoral researcher in the lab of neurologist Gil Rabinovici, who leads the PET imaging program at the UCSF Memory and Aging Center.

“In this paper, we show that the relationship between tau and where the brain degenerates holds true whatever your disease looks like,” he continued. “So, we think that this paper is showing us that actually tau is a good predictor of where atrophy is going to be. And that this heterogeneity of symptoms also relates to where the tau is and where the brain atrophy is going to happen.”

La Joie noted that the current thinking around Alzheimer’s disease is that there are patient subsets who have distinct etiologies that are associated with particular kinds of symptoms and timelines. He added that the criteria for diagnosing Alzheimer’s disease have shifted so that it requires impairment in two cognitive domains, which may or may not include memory. The prior definition specifically required a memory deficit for an Alzheimer’s diagnosis.

The disease has remained difficult to definitively diagnose, particularly at the earliest stages. And it’s impossible to predict how Alzheimer’s will unfold in a particular patient. Imaging tau tangles could prove useful on both those fronts, which would offer advantages not only for patients desperate for accurate information about their own condition but also for clinical trials of potential Alzheimer’s treatments.

The FDA has urged biopharmaceutical researchers to target very early, even presymptomatic, Alzheimer’s disease patients in an effort to improve efficacy in a field where it’s thus far proven impossible to gain much traction. Imaging tau tangles could provide a potential method for screening at-risk patients, as well as predicting the likely pathway of patients with disease. This could better enable researchers to improve and assess patient outcomes in clinical trials. However, the current study was in early, symptomatic patients; a study to determine if imaging tau tangles is useful in identifying presymptomatic Alzheimer’s patients is expected to be upcoming.

“It makes a lot of sense to try to intervene in early presymptomatic stages before any major damage is done to the brain. The problem with all these studies in presymptomatic people is that it's hard to know if your drug actually does work,” said La Joie. “Because what should you be looking at as an outcome to measure the effectiveness of the treatment?”

“The issue is that if you have to wait to see if people actually develop dementia, it's going to take a decade or something,” he continued. “It's going to take a long time, because you can't expect everyone to decline so fast if they are cognitively normal at the beginning of the study. So, what we think we have here is an approach that could help us be more precise and a little more sensitive to detect change.”

Prognosis prediction?

In the study, researchers used PET scans with investigational tau tracer flortaucipir F18 to measure tau, as well as another tracer to measure amyloid. In addition, they received MRIs to gauge the structural integrity of the brain. After an initial measurement, there were follow-up assessments one year and again two years later.

Amyloid and tau PET scans, as compared to brain atrophy shown in a later MRI scan. Credit: The University of California, San Francisco

They found that tau levels in the brain at the start of the study predicted how much degeneration would have occurred by the time of the follow-up visit. In addition, tau buildup in specific locations predicted subsequent atrophy in those same places in the brain with more than 40% accuracy. That rate was only 3% for amyloid PET scans. The location of brain degeneration is also associated with the loss of specific functions.

The association between levels of tau buildup and the subsequent atrophy was stronger in younger patients. That led the researchers to suggest that distinct factors might be primary for patients depending on the age of onset, with other abnormal proteins or vascular injuries perhaps playing more of a role for late-onset Alzheimer’s patients.

Still, tau imaging has a long way to go. There are no FDA approved tau tracers. Eli Lilly and Co. and partner Avid Radiopharmaceuticals Inc. submitted flortaucipir F18 for FDA review after positive phase III results for the tracer in the fall of 2018. In that study, it met a pair of endpoints for predicting brain tau pathology and predicting Alzheimer's disease diagnosis.

Up next, the UCSF researchers plan to apply their approach to a larger, more heterogeneous dataset potentially as part of existing longitudinal Alzheimer’s studies such as the Alzheimer's Disease Neuroimaging Initiative (ADNI) or the Longitudinal Early-onset Alzheimer's Disease Study (LEADS). Within a few years, they expect to have a more definitive grasp on the role of tau imaging in predicting patient prognosis.

"The match between the spread of tau and what happened to the brain in the following year was really striking," summed up Rabinovici. "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."

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