Both amyloid-β and tau aggregate in clumps and fibrils in aging brains, but much more so in the brains of Alzheimer's patients. The network of relationships and damage surrounding these aggregates is dense and still to be fully mapped. The progression of Alzheimer's disease is very complex at the detail level, as can be judged by the wide variety of theories proposed in just the past few years, as well as by the great diversity of efforts to determine how exactly the damage is done to brain cells and how to prevent it. The research noted here is an example of one particular class of efforts undertaken to better understand Alzheimer's, those involving the creation of models of the condition in animal lineages:
For decades, Alzheimer's disease, the most common cause of dementia, has been known to be associated with the accumulation of so-called neurofibrillary tangles, consisting of abnormal clumps of a protein called tau inside brain nerve cells, and by neuritic plaques, or deposits of a protein called beta-amyloid outside these cells along with dying nerve cells, in brain tissue. In Alzheimer's disease, tau bunches up inside the nerve cells and beta-amyloid clumps up outside these cells, mucking up the nerve cells controlling memory. What hasn't been clear is the relationship and timing between those two clumping processes, since one is inside cells and one is outside cells.
In humans, the lag between development of the beta-amyloid plaques and the tau tangles inside brain nerve cells can be 10 to 15 years or more, but because the lifetime of a mouse is only two to three years, current animal models that successfully mimic the appearance of beta-amyloid plaques did not offer enough time to observe the changes in tau. To address that problem, researchers genetically engineered a mouse model that used a tau fragment to promote the clumping of normal tau protein. They then cross-bred these mice with mice engineered to accumulate beta-amyloid. The result was a mouse model that developed dementia in a manner more similar to what happens in humans.
Prior studies of early-onset Alzheimer's disease have suggested that the abnormal accumulation of beta-amyloid in the brain somehow triggers the aggregation of tau leading directly to dementia and brain cell degeneration. But new research suggests that the accumulation of beta-amyloid in and of itself is insufficient to trigger the conversion of tau from a normal to abnormal state. Instead, it may set off a chain of chemical signaling events that lead to the "conversion" of tau to a clumping state and subsequent development of symptoms. "For the first time, we think we understand that the accumulation of amyloid plaque alone can damage the brain, but that's actually not sufficient to drive the loss of nerve cells or behavioral and cognitive changes. What appears to be needed is a second insult - the conversion of tau - as well." One implication of the new research, is to possibly explain why some drugs designed to attack the disease after the conversion of tau haven't worked. The work also suggests that combination therapy designed to prevent both the beta-amyloid plaque formation as well as pathological conversion of tau may provide optimal benefit for Alzheimer's disease.