Something was causing amyloid-β to be cut off from its precursor, then clump together, in people with dementia. If only we could stop it from aggregating or remove the aggregates from the brain, we could stop the disease, the conventional wisdom held.
In 2006, this idea looked even better, as a paper was published in Nature showing that memory loss was associated with a specific form of amyloid-β buildup outside of neurons.
Stay on target
A potential therapeutic target gave scientists something to aim for. As with so many other poorly understood, complex diseases, they set about studying it in mice. But like so many of those other complex diseases that afflict humans, mice don’t naturally get Alzheimer’s. They do if you insert a mutated copy of the human APP gene into their genome, however. Armed with this early mouse model, scientists got to work.
In 1999, Elan Pharmaceuticals created a vaccine to a particular part of amyloid-β and then showed that mice would clear plaques from their brains after treatment with the vaccine. Better still, it worked whether the vaccine was given to very young mice, before the plaques could form, or to older mice where the plaques were already present.
Vaccines work by prompting the body to produce antibodies against whatever the vaccine recognizes. So a few years later, Elan went on to show that anti-amyloid antibodies also cleared plaques in the transgenic mice’s brains when given directly.
But there’s many a slip between mouse and man. Elan tried its vaccine in human patients suffering mild to moderate Alzheimer’s disease but had to suspend the trial of 360 patients after a number developed brain inflammation. While Elan’s vaccine didn’t go anywhere, other pharmaceutical companies and biotechs were still on the case.
Trial after trial failed to arrest or reverse the disease, no matter the approach. Targeting different parts of the amyloid-β pathway also created side effects aplenty, some of them life-threatening or fatal. Regardless, amyloid-β remained the preferred target. Eventually, in 2021, the Food and Drug Administration approved an antibody called aducanumab, made by Biogen.