Alzheimer's Protein Tau Tracks Symptoms Better Than Amyloid Does

June 09, 2016

New research has suggested that the Alzheimer's protein tau is a better marker of disease progression than is &β;-amyloid and that increased expression of both proteins are necessary for the disease to develop.

In the latest study, researchers from Washington University School of Medicine in St. Louis, Missouri, used a new tau-binding imaging agent (T807, Avid Radiopharmaceuticals/Eli Lilly) to map tau in the brain and correlate its expression in certain areas with other biomarkers and symptoms of cognitive impairment.

"The focus has been on amyloid for many years, but there is now a lot of interest in tau. Both proteins are implicated in Alzheimer's," senior author Beau M. Ances, MD, told Medscape Medical News.

"We believe that if you have increased amyloid then you are on the trajectory to develop Alzheimer's, but symptoms may not be apparent for many years," Dr Ances added. "Whereas tau appears to develop in the medial temporal lobe and the hippocampus as part of normal aging, but when it spreads into the lateral temporal lobe and parietal areas then that seems to trigger Alzheimer's symptoms. So tau could be useful as a diagnostic tool in patients with mild cognitive impairment."

The average tau accumulation (red) in the brains of cognitively normal people (left) and in the brains of people with mild Alzheimer's symptoms (right). Matthew R. Brier

Dr Ances explained that scientists have been able to map amyloid deposits for some years with positron emission tomography (PET). Several amyloid tracers have been approved for use by the US Food and Drug Administration. Now a similar radiotracer has been developed with affinity for tau, making it possible to also map this second protein.

For the current study, published online May 11 in Science Translational Medicine, Dr Ances and colleagues mapped both β-amyloid and tau in a cohort including both normal older individuals and patients with mild Alzheimer's. Results showed that tau deposition in the temporal lobe more closely tracked dementia status and was a better predictor of cognitive performance than β-amyloid deposition in any region of the brain.

"We found that β-amyloid is present in increased amounts earlier on in the disease process — before symptoms have developed — so is probably the better earliest diagnostic measure of the disease," Dr Ances said. "We have known β-amyloid is associated with Alzheimer's for many years, but it is not a straightforward relationship with symptoms. Some people can have high amyloid throughout their brain and not have any cognitive impairment. We now believe it is an early indicator that Alzheimer's will develop sometime in the future.

"But tau is different in that it starts to be seen in certain areas of the brain as symptoms are developing in mild cognitive impairment," he added. "It correlates better with symptoms of cognitive dysfunction than amyloid. We suspect that amyloid changes first and then tau, and it's the combination of both that tips the patient from being asymptomatic to showing mild cognitive impairment."

Dr Ances suggested that these results could also have implications for the development of new therapies. "Reducing both amyloid and tau together may be a promising approach. And we can use these imaging agents in therapeutic studies of new drugs directed at reducing these proteins to see if the burden of amyloid and tau is actually decreasing."

He said the new tau imaging tool is vital for gathering spatial information about affected brain areas. "Elevated tau measured in cerebrospinal fluid has long been a marker of dementia, but this could not pinpoint in which parts of the brain the abnormal proteins are accumulating. Our new study suggests you can tolerate a certain amount of tau clumped in the hippocampus, but once it starts spreading into other areas, especially the lateral temporal and parietal lobes, that seems to be the tipping point."

The current study included 36 control participants who were cognitively normal and 10 patients with mild Alzheimer's disease. Global cognitive and functional performance was assessed by using the clinical dementia rating scale.

Each participant underwent tau imaging using T807, β-amyloid PET imaging using florbetapir (Amyvid, Eli Lilly), and MRI. A subset of individuals also underwent lumbar puncture for cerebrospinal fluid assays and neuropsychological testing.

Results showed that cognitively normal participants had minimal tau tracer uptake throughout the brain with the exception of the basal ganglia, whereas cognitively impaired participants exhibited markedly increased tau tracer uptake in the temporal lobes and throughout the cerebral cortex.

Tau, specifically temporal lobe tau, was also more closely related to reduced performance on cognitive tests than β-amyloid.

The study builds on initial tau mapping research conducted by a team from Massachusetts General Hospital in Boston, which was the subject of a paper in Annals of Neurology published in January this year.

Senior author of that group, Keith A. Johnson, MD, described the study by Dr Ances and colleagues as "very nice work that is very consistent with our reports."

This study was funded by grants from the National Institutes of Health, National Science Foundation, the Charles F. and Joanne Knight Alzheimer's Research Initiative, Hope Center for Neurological Disorders, the Fred Simmons and Olga Mohan Fund, and the Paula and Rodger Riney Fund. Avid Radiopharmaceuticals (a wholly owned subsidiary of Eli Lilly) provided the imaging agents and partial financial support for the scanning sessions. Dr Ances has disclosed no relevant financial relationships; disclosures for coauthors appear in the paper.

Sci Translat Med. Published online May 11, 2016. Abstract

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