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Study Reveals Tau as Driver of Alzheimer’s Disease

Finding throws cold water on amyloid-targeting drugs

By examining more than 3,600 postmortem brains, researchers at the Mayo Clinic’s campuses in Jacksonville, Florida, and Rochester, Minnesota, have found that the progression of dysfunctional tau protein drives the cognitive decline and memory loss seen in Alzheimer’s disease (AD). Amyloid, the other toxic protein that characterizes AD, builds up as dementia progresses but is not the primary culprit, they say.

The findings, published in Brain, offer new information in the long and ongoing debate about the relative contribution of amyloid and tau to the development and progression of cognitive dysfunction in AD, says lead author Melissa Murray, PhD, a neuroscientist at the Mayo Clinic in Jacksonville.

The findings also suggest that halting toxic tau should be a new focus for AD treatment, the researchers say.

“The majority of the Alzheimer’s research field has really focused on amyloid over the last 25 years,” Murray says. “Initially, patients who were discovered to have mutations or changes in the amyloid gene were found to have severe Alzheimer’s pathology — particularly in increased levels of amyloid. Brain scans performed over the last decade revealed that amyloid accumulated as people progressed, so most Alzheimer’s models were based on amyloid toxicity. In this way, the Alzheimer’s field became myopic.”

But researchers at the Mayo Clinic were able to look simultaneously at the evolution of amyloid and tau using neuropathologic measures. “Imagine looking at the rings of a tree — you can identify patterns, like the changing seasons and the aging of the tree, when viewing the tree’s cross-section,” Murray says. “Studying brains at different stages of Alzheimer’s gives us a perspective of the cognitive impact of a wide range of both amyloid and tau severity, and we were very fortunate to have the resource of the Mayo brain bank, in which thousands of people donated their postmortem brains, that have allowed us to understand the changes in tau and amyloid that occur over time.”

The new study was conducted in two parts. Researchers at the Mayo Clinic in Florida examined 3,618 brains in its postmortem brain bank, of which 1,375 brains were confirmed to have AD. These patients died at different ages and at different stages of dementia, providing a valuable timeline into disease progression.

The researchers used recommended scoring systems to examine the evolution of amyloid and tau in dissected brain tissue. They found that the severity of tau, but not amyloid, predicted a person’s age at the onset of cognitive decline, the duration of the disease, and mental deterioration.

The second part of the study was conducted with collaborators at the Mayo Clinic in Rochester. Together, the teams examined amyloid brain scans taken of patients prior to death and compared the scans with measures of tau and amyloid brain pathology.

The investigators found that the signal from amyloid brain scans corresponded with amyloid pathology specific to the brain and not to amyloid found in vessels, and did not correspond to tau pathology. The brains of some participants had amyloid visible at pathology that did not reach the threshold for what would be found in AD brain scans. This is important, as amyloid can be found in brains of older individuals who have not experienced cognitive decline, the researchers say.

“Our findings highlight the need to focus on tau for therapeutics, but it also still indicates that the current method of amyloid brain scanning offers valid insights into tracking Alzheimer’s,” Murray says.

According to the Bloomberg Business website, the new findings throw cold water on promising early data reported by Biogen for their investigational AD therapy BIIB037, which targets amyloid protein fragments. Moreover, Eli Lilly & Co. is currently retesting its amyloid-focused drug solanezumab in earlier-stage AD patients, and Roche is continuing to sponsor a trial of its amyloid-targeting drug in AD patients with mild dementia, although in December it abandoned a study of patients with early stages of the disease because of poor results, according to Bloomberg.

Several companies, including Johnson & Johnson, Biogen, and AbbVie, have products in the early stages of development that target tau in the brain. TauRx Pharmaceuticals Ltd., a Singapore-based drug developer, is testing a tau-targeting compound in broader human trials.

Sources: Mayo Clinic; March 23, 2015; and Bloomberg; March 24, 2015.

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