Until now it was not known how, or when, these tau proteins began to accumulate into tangles in the brain. It was previously believed that isolated tau proteins didn’t have a distinctly harmful shape until they began to aggregate with other tau proteins. But the new research has revealed that a toxic tau protein actually presents itself as misfolded, exposing parts that are usually folded inside, before it begins to aggregate. It is these exposed parts of the protein that enable aggregation, forming the larger toxic tangles.
“We think of this as the ‘Big Bang’ of tau pathology,” says Diamond. “This is a way of peering to the very beginning of the disease process. It moves us backward to a very discreet point where we see the appearance of the first molecular change that leads to neurodegeneration in Alzheimer’s.”
From here the research is set to take two different prospective pathways. One will first look at developing a simple diagnostic test to detect signs of this abnormal tau protein, either through a blood test, or less ideally a spinal fluid test. If these toxic tau proteins can be easily detected then clinicians may be able to diagnose Alzheimer’s before major degenerative cognitive symptoms take hold.
Tafamidis was designed to delay impairment to nerve function caused by the toxic aggregation of a normally harmless protein called transthyretin and is currently approved for use in both Europe and Japan. However, the FDA has called for further clinical proof before approving the drug for use in the United States.
Now that this early alteration in the shape of tau molecules has been identified, researchers can more effectively focus on potential drug targets to inhibit the toxic aggregations at this stage.
“The hunt is on to build on this finding and make a treatment that blocks the neurodegeneration process where it begins,” says Diamond. “If it works, the incidence of Alzheimer’s disease could be substantially reduced. That would be amazing.”