Another Study to Argue that Tau is Primary and Amyloid Secondary in Alzheimer's Disease

The struggle to show meaningful progress in treatment of Alzheimer's disease via clearance of amyloid has fueled significant investment into alternative hypotheses regarding the disease process. The biochemistry of Alzheimer's - and the brain in general - is so very complex that at this point it is a challenge to say whether the issue is that it is intrinsically hard to produce a useful clearance therapy via the present approaches, or whether amyloid is the wrong target for best effect. A leading alternative candidate is a different form of metabolic waste, neurofibrillary tangles made of an altered form of the tau protein. Here is one of a number of studies that point the finger at tau rather than amyloid accumulation as the primary source of pathology:

By examining more than 3,600 postmortem brains, researchers have found that the progression of dysfunctional tau protein drives the cognitive decline and memory loss seen in Alzheimer's disease. Amyloid, the other toxic protein that characterizes Alzheimer's, builds up as dementia progresses, but is not the primary culprit, they say. The findings suggest that halting toxic tau should be a new focus for Alzheimer's treatment. "The majority of the Alzheimer's research field has really focused on amyloid over the last 25 years. 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."

Researchers were able to simultaneously look at the evolution of amyloid and tau using neuropathologic measures. "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.

"Tau can be compared to railroad ties that stabilize a train track that brain cells use to transport food, messages and other vital cargo throughout neurons. In Alzheimer's, changes in the tau protein cause the tracks to become unstable in neurons of the hippocampus, the center of memory. The abnormal tau builds up in neurons, which eventually leads to the death of these neurons. Evidence suggests that abnormal tau then spreads from cell to cell, disseminating pathological tau in the brain's cortex. The cortex is the outer part of the brain that is involved in higher levels of thinking, planning, behavior and attention - mirroring later behavioral changes in Alzheimer's patients."

"Amyloid, on the other hand, starts accumulating in the outer parts of the cortex and then spreads down to the hippocampus and eventually to other areas. Our study shows that the accumulation of amyloid has a strong relationship with a decline in cognition. When you account for the severity of tau pathology, however, the relationship between amyloid and cognition disappears - which indicates tau is the driver of Alzheimer's. 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. Although tau wins the 'bad guy' award from our study's findings, it is also true that amyloid brain scanning can be used to ensure patients enrolling for clinical trials meet an amyloid threshold consistent with Alzheimer's - in lieu of a marker for tau."

Link: http://www.eurekalert.org/pub_releases/2015-03/mc-mcs032315.php

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