Alzheimer's disease is a complex condition because the brain is a complex environment. Neurodegeneration is caused by the accumulation of two forms of protein aggregate, amyloid-β and tau. There is evidence to suggest that each can spur the generation of the other, and that they act in synergy to cause worse harm to the brain than either would alone, but the present consensus is that amyloid-β precedes tau in the development of the condition. It may even turn out to be the case that tau causes the majority of the damage in the later stages of the condition, not amyloid-β.
Whether this means that amyloid-β causes tau aggregration is another question entirely, and one that is unlikely to be adequately answered without the development of reliable means to clear amyloid-β from the brain. That has so far proven to be more challenging than was originally hoped, and even those clinical efforts that did remove amyloid-β to some degree failed to show benefits in patients. Varied factions within the research community have their theories as to why this might be the case, and scientists here note one of them - that by the time clinical symptoms manifest, it is past the point at which removing amyloid-β would be helpful, as tau has become the major issue.
The rate at which the protein amyloid-β accumulates into the sticky plaques associated with Alzheimer's disease (AD) is already slowing by the time a patient would be considered to have preclinical AD, according to a longitudinal study of healthy adults. The research suggests that anti-amyloid therapies would be most effective before individuals reach the threshold for preclinical AD, long before the first signs of memory issues. Determining how early to intervene is a central challenge in slowing the progression of AD. Clinical trials of drugs for lowering amyloid levels typically involve individuals who do not yet have symptoms but are considered "amyloid positive" and at risk for developing AD. These trials have been largely unsuccessful, perhaps because they begin too late.
To untangle the relationship between amyloid-β, the AD-associated protein tau, and memory impairment over time, researchers studied healthy men and women between the ages of 61 and 88 over a five-year period. Brain scans revealed that even trace amounts of amyloid-β predicted future levels of tau, and both preceded memory decline. The researchers found that greater baseline levels of amyloid-β were associated with a faster rate of accumulation, but only to a point, after which higher amyloid-β levels were associated with slower accumulation. "It appears rates of amyloid accumulation already begin to slow in preclinical AD, suggesting it is a relatively late stage of AD progression. Thus, it is crucial to examine older adults early, before amyloid levels have saturated, to intervene to slow disease progression."