For nearly 30 years, the hunt for a cure for Alzheimer’s disease has focused on a protein called beta-amyloid. Amyloid, the hypothesis goes, builds up inside the brain to bring about this memory-robbing disorder, which afflicts some 47 million people worldwide.
Billions of dollars have poured into developing therapies aimed at reducing amyloid — thus far, to no avail. Trials of anti-amyloid treatments have repeatedly failed to help patients, sparking a reckoning among the field’s leaders.
All along, some researchers have toiled in the relative shadows, developing potential strategies that target other aspects of cells that go awry in Alzheimer’s: molecular pathways that regulate energy production, or clean up cellular debris, or regulate the flow of calcium, an ion critical to nerve cell function. And increasingly, some of these scientists have focused on what they suspect may be another, more central factor in Alzheimer’s and other dementias: dysfunction of the immune system.
With the field’s thinking narrowed around the amyloid hypothesis, immunological ideas have struggled to win favor — and funding. “There was no traction,” says Malú Tansey, a University of Florida neuroscientist whose work focuses on immunology of the brain. The committees that review grant applications didn’t want to hear about immunological studies, she says.
But over the past decade, the immune system connection to Alzheimer’s has become clearer. In several massive studies that analyzed the genomes of tens of thousands of people, many DNA variants that were linked to heightened Alzheimer’s risk turned out to be in genes involved in immunity — specifically, a branch of the body’s defenses known as the innate immune system. This branch attacks viruses, bacteria and other invaders quickly and indiscriminately. It works, in part, by triggering inflammation.
