For several decades a division line has formed among Alzheimer’s researchers. This neuroscience version of the Montagues and Capulets was formed from findings surrounding two neuromolecular compounds, amyloid plaques and the microtubule associated protein tau. In recent years the amyloid camp has gained ground in research dollars and drug discovery focus. However, new research from the Mayo Clinic may prove to be a watershed moment for scientists that believe toxic tau protein has a much greater role than amyloid plaques in Alzheimer’s pathogenesis.
Investigators from the various campuses of the Mayo Clinic examined more than 3,600 postmortem brains to discover that the progression of dysfunctional tau protein was driving the cognitive decline observed in Alzheimer’s patients. Additionally, the results from the current study support a long held hypothesis by many neuroscientists, which is that amyloid protein accumulates as dementia progresses, i.e., it is a result of neurodegeneration, not the cause.
“The majority of the Alzheimer's research field has really focused on amyloid over the last 25 years,” said Melissa Murray, Ph.D., assistant professor of neuroscience at the Mayo Clinic in Jacksonville and lead author on the current study. “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.”
The findings from this study were published recently in Brain through an article entitled “Clinicopathologic and 11C-Pittsburgh compound B implications of Thal amyloid phase across the Alzheimer’s disease spectrum.”
Dr. Murray and her colleagues were able to view the evolution of amyloid and tau proteins simultaneously using neuroimaging techniques. Almost half of the 3,600 brains used in their analysis were confirmed Alzheimer’s cases at varying stages of dementia, which provided an extremely useful timeline into the disease progression.
“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,” explained Dr. Murray. “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 results from the brain scan analyses led the Mayo researchers to one main conclusion: that the severity of tau, and not amyloid, predicated the age of onset, mental deterioration, and duration of the disease.
“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,” stated Dr. Murray. “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.
The researchers from the tau and amyloid camps are certainly not mutually exclusive. Most scientists understand the importance of previous research done from all aspects of neurodegenerative diseases. Dr. Murray and her colleagues hope that neuroscience field will take a fresh look at the role tau plays in Alzheimer’s disease.
“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,” Dr. Murray concluded.
