After finally getting the message that they need to look beyond amyloid to treat Alzheimer’s disease, pharmas are lining up behind tau as the next big target. The question is whether they can pick out the lessons from the amyloid saga to avoid following the same storied path.
At least four Phase II readouts of anti-tau antibodies are on the horizon. But there remain a number of questions, from the target’s biology to how best to translate that biology, plus the beginnings of a lemming effect, that serve as warning echoes (see “How the Amyloid Hypothesis Holds its Grip”).
The amyloid hypothesis was rooted in multiple lines of genetic data pointing to β amyloid as a causative agent in AD. In contrast, tau mutations are not found in AD patients, though they do occur in frontotemporal dementia (FTD), another neurodegenerative disease that leads to cognitive decline.
But tau is an obvious choice as the next-best chance for the disease because its aggregation in neurons -- in neurofibrillary tangles -- is one of the two major pathological hallmarks found in patient brains, the other being the extracellular deposits of β amyloid in plaques.
And there’s good reason to think tau could be a better target than β amyloid -- the timing and location of tau aggregation correlate much better with the onset and nature of patients’ symptoms.
Tau builds up closer to clinical onset, and in the right places to explain early cognitive deficits, suggesting a role in progression to clinical disease. Amyloid accumulates decades before symptoms arise, and in a wide variety of brain regions, not specifically the areas that drive symptoms.
“Tau has really emerged as the leading target in Alzheimer’s.”
“Tau has really emerged as the leading target in Alzheimer’s,”