The Elusive Cure

June 12, 2018: Another day, another scrapped clinical trial of a high-profile Alzheimer's drug. This time it was lanabecestat, which performed so poorly that after 31/2 years, researchers pulled the plug.

Despite massive (and increasing) efforts, the search for a cure for Alzheimer's, the most common form of dementia, has come up empty. One by one, drugs with names that sound like incantations to summon a genie - aducanumab, solenezemab - have raised hopes that were later dashed. In a dozen years, not a single new medicine for Alzheimer's has been approved for consumers.

Why is this so hard?

One reason is that there's no agreed-upon cause of the disease. Two kinds of proteins run dangerously in a brain addled by Alzheimer's. One is beta-amyloid, which clumps into sticky plaques that block cell-to-cell signalling and shut those cells down. The second is tau protein, which forms tangles inside brain cells that finish them off.

The question of which is the most likely culprit behind the disease has split the scientific community into the so-called "BAPtists" and the "Tau-ists," says Jack Jhamandas, a professor of neurology and Alzheimer's researcher in the Faculty of Medicine & Dentistry.

Jhamandas calls himself a "BAPtist with an open mind." Not long ago, he and his research team discovered that a compound called AC253, originally developed for diabetes, appears to protect brain cells from the worst effects of beta-amyloid plaques, at least in mice.

But he admits - and here's the open mind part - that the strategy of clearing or preventing beta-amyloid plaques could be a dead end. No one knows whether either protein is a cause or a consequence of the disease. It could be both are byproducts of the fundamental process that's actually driving the train.

Indeed, some researchers are taking completely different tacks, focusing, for example, on the neurocircuitry of the hippocampus, where memories are formed and socked away for later retrieval. Cautious optimism surrounds an experimental procedure called optogenetics. A Columbia University study used lasers on mice to activate the neurons that store memories, suggesting lost memories might still exist in the brain and be recovered. On another tack, a research paper published in June in Neuron has reawakened interest in the theory that viruses might play a role in Alzheimer's.

Another prime suspect is inflammation. Introduced decades ago by Vancouver researchers Edith and Patrick McGeer, the neuro-inflammation theory fell out of favour. But as our understanding of inflammation has evolved, "the pendulum has swung back," says Jhamandas. Since inflammation has been linked to gut health, this theory invites the appealing idea that Alzheimer's might have some relation to the bacteria and other organisms that colonize the gut and thus may be preventable, at least in some people, by lifestyle interventions such as a change in diet.

Indeed, some researchers are starting to think of Alzheimer's disease more the way we think of chronic diseases such as hypertension and diabetes, which are known to respond to improved health habits. A small study out of UCLA by neurologist Dale Bredesen created a protocol of lifestyle changes for early-stage Alzheimer's patients, including such things as intermittent fasting and improved sleep habits. The protocol not only slowed but actually seemed to reverse symptoms. Of six participants who had stopped working because of cognitive fog, all six were able to return to the job, Bredesen reported in 2014 in the Journal of Aging.

The cruel irony of Alzheimer's disease is that many of the brain abnormalities are present at least 20 years before symptoms typically appear, at which point the damage is done. For scientists, that means identifying those who are at risk of developing the condition but show no symptoms - and treating them with everything that's deemed safe to try.

"Of course, you want to hit a home run - find the cure," says Jhamandas. "But a more realistic expectation in the short run is that we can modify the trajectory of the disease: delay its onset, mitigate its severity."