In the 30 years that biomedical researchers have worked determinedly to find a cure for Alzheimer’s disease, their counterparts have developed drugs that helped cut deaths from cardiovascular disease by more than half, and cancer drugs able to eliminate tumors that had been incurable. But for Alzheimer’s, not only is there no cure, there is not even a disease-slowing treatment.
…In more than two dozen interviews, scientists whose ideas fell outside the dogma recounted how, for decades, believers in the dominant hypothesis suppressed research on alternative ideas: They influenced what studies got published in top journals, which scientists got funded, who got tenure, and who got speaking slots at reputation-buffing scientific conferences. The scientists described the frustrating, even career-ending, obstacles that they confronted in pursuing their research. A top journal told one that it would not publish her paper because others hadn’t. Another got whispered advice to at least pretend that the research for which she was seeking funding was related to the leading idea—that a protein fragment called beta-amyloid accumulates in the brain, creating neuron-killing clumps that are both the cause of Alzheimer’s and the key to treating it. Others could not get speaking slots at important meetings, a key showcase for research results. Several who tried to start companies to develop Alzheimer’s cures were told again and again by venture capital firms and major biopharma companies that they would back only an amyloid approach.
…For all her regrets about the amyloid hegemony, Neve is an unlikely critic: She co-led the 1987 discovery of mutations in a gene called APP that increases amyloid levels and causes Alzheimer’s in middle age, supporting the then-emerging orthodoxy. Yet she believes that one reason Alzheimer’s remains incurable and untreatable is that the amyloid camp “dominated the field”, she said. Its followers were influential “to the extent that they persuaded the National Institute of Neurological Disorders and Stroke [part of the National Institutes of Health] that it was a waste of money to fund any Alzheimer’s-related grants that didn’t center around amyloid.” To be sure, NIH did fund some Alzheimer’s research that did not focus on amyloid. In a sea of amyloid-focused grants, there are tiny islands of research on oxidative stress, neuroinflammation, and, especially, a protein called tau. But Neve’s NINDS program officer, she said, “told me that I should at least collaborate with the amyloid people or I wouldn’t get any more NINDS grants.” (She hoped to study how neurons die.) A decade after her APP discovery, a disillusioned Neve left Alzheimer’s research, building a distinguished career in gene editing. Today, she said, she is “sick about the millions of people who have needlessly died from” the disease.
Dr. Daniel Alkon, a longtime NIH neuroscientist who started a company to develop an Alzheimer’s treatment, is even more emphatic: “If it weren’t for the near-total dominance of the idea that amyloid is the only appropriate drug target”, he said, “we would be 10 or 15 years ahead of where we are now.”
Making it worse is that the empirical support for the amyloid hypothesis has always been shaky. There were numerous red flags over the decades that targeting amyloid alone might not slow or reverse Alzheimer’s. “Even at the time the amyloid hypothesis emerged, 30 years ago, there was concern about putting all our eggs into one basket, especially the idea that ridding the brain of amyloid would lead to a successful treatment”, said neurobiologist Susan Fitzpatrick, president of the James S. McDonnell Foundation. But research pointing out shortcomings of the hypothesis was relegated to second-tier journals, at best, a signal to other scientists and drug companies that the criticisms needn’t be taken too seriously. Zaven Khachaturian spent years at NIH overseeing its early Alzheimer’s funding. Amyloid partisans, he said, “came to permeate drug companies, journals, and NIH study sections”, the groups of mostly outside academics who decide what research NIH should fund. “Things shifted from a scientific inquiry into an almost religious belief system, where people stopped being skeptical or even questioning.”
…“You had a whole industry going after amyloid, hundreds of clinical trials targeting it in different ways”, Alkon said. Despite success in millions of mice, “none of it worked in patients.”
Scientists who raised doubts about the amyloid model suspected why. Amyloid deposits, they thought, are a response to the true cause of Alzheimer’s and therefore a marker of the disease—again, the gravestones of neurons and synapses, not the killers. The evidence? For one thing, although the brains of elderly Alzheimer’s patients had amyloid plaques, so did the brains of people the same age who died with no signs of dementia, a pathologist discovered in 1991. Why didn’t amyloid rob them of their memories? For another, mice engineered with human genes for early Alzheimer’s developed both amyloid plaques and dementia, but there was no proof that the much more common, late-onset form of Alzheimer’s worked the same way. And yes, amyloid plaques destroy synapses (the basis of memory and every other brain function) in mouse brains, but there is no correlation between the degree of cognitive impairment in humans and the amyloid burden in the memory-forming hippocampus or the higher-thought frontal cortex. “There were so many clues”, said neuroscientist Nikolaos Robakis of the Icahn School of Medicine at Mount Sinai, who also discovered a mutation for early-onset Alzheimer’s. “Somehow the field believed all the studies supporting it, but not those raising doubts, which were very strong. The many weaknesses in the theory were ignored.”