Of all the columns I’ve written, no topic has brought more agonized, heartfelt and desperate-sounding emails than Alzheimer’s disease. Back in 2004, I wrote three columns (when I was at The Wall Street Journal) on how one particular theory of what causes this awful disease—and therefore the best approach for treating it—has had the field in a headlock, censoring competing theories. That closed-mindedness, I quoted scientists as saying, had a lot to do with why there is not only no cure or preventive for Alzheimer’s, but not even a treatment that slows down the inexorable cognitive decline.
The emails, as you might expect, told me about loved ones who had been lost to Alzheimer’s, and expressed frustration, anger and fury that part of the reason for the lack of progress might be that scientists were not open-minded about any but their pet hypothesis.
This all came rushing back to me this week when Myriad Genetics, Inc., reported that a Phase 3 clinical trial (the last one before a company seeks FDA approval for a new drug) it had been testing for an experimental Alzheimer’s drug had failed. The drug, Flurizan, is called a “selective amyloid lowering agent,” or SALA. Amyloid is a peptide (part of a protein). The amyloid known as Aβ42 is—according to the dogma—the “primary initiator of neurotoxicity and amyloid plaque development in the brains of Alzheimer’s disease patients,” as Myriad puts it. And indeed, in human cells growing in lab dishes as well as in lab animals, Flurizan reduces levels of Aβ42.
But when Myriad gave it to people with early-stage Alzheimer’s, it didn’t help them a bit. We don’t know why. Maybe Flurizan did not reduce Aβ42 in the patients. Or maybe—and this would be disastrous for the field—it did reduce Aβ42 but that had no beneficial effect. If the latter, it is more proof that the amyloid dogma—Aβ42 causes Alzheimer’s, therefore get rid of Aβ42 and you’ll cure the disease—is wrong. I call it “disastrous” because a huge majority of the research and drug-development efforts in Alzheimer’s assumes that Aβ42 causes the disease and that getting rid of Aβ42 is the holy grail.
At the risk of being obnoxiously self-referential, let me re-cycle some of what I said about the amyloid dogma back in 2004:
I’m afraid that’s still where things stand, four years after I wrote that. Now let me share a note I just got from a scientist who has long questioned the amyloid dogma:
“Beliefs about what causes this merciless disease have taken on such a religious fervor that one group is called tauists, after a protein called tau that forms 'neurofibrillary tangles' inside the neurons and, say these scientists, kills neurons responsible for memory and thought. Another is called baptists, after the [Aβ42] that forms plaques around brain neurons and, say its accusers, causes neuron-killing tau tangles or kills neurons directly, or both. Apostates think amyloid plaques sop up neurotoxic proteins along with poisonous metals such as zinc and copper, and that eliminating plaques could therefore harm patients. . . . [But] there are growing doubts that amyloid is guilty as charged. Autopsies of people with early-stage Alzheimer's show that the tangles form first, before plaques, in brain regions initially affected by the disease. 'If you look at the evidence, it's the tangles that cause neuronal degeneration, and they come first, before the amyloid,' says neurologist Patrick McGeer of the University of British Columbia. Another problem for the amyloid dogma, ... adds neurobiologist Nikolaos Robakis of Mount Sinai School of Medicine, New York City, is that autopsies of the brains of Alzheimer's victims show that 'plaques don’t correlate with neuronal death. The amyloid is here and the dead neurons are somewhere else.' . . . 'If amyloid were the answer,' says Dr. McGeer, 'the disease would have been solved by now.'
“I couldn’t resist contacting you....not with glee [about the Myriad failure], instead sadness at how scientific narcissism [he means the focus on the amyloid hypothesis to the near-exclusion of everything else] fails every damn time. . . . As far as Flurizan is concerned, I am sure the amyloid contingent will make their excuses: blame the drug, the placebo group (for not falling fast enough!), the timing (clearly we need to start anti-amyloid therapy in utero!) and, ultimately, the species (humans simply are not as good responders as mice). However, at this stage, I sense that the heads are beginning to drop and the swagger has disappeared. . . . While my hope is that this will open the field to all manner of crazy hypotheses, my fear is that the excuses will be persuasive enough. At this point, everything that lowers amyloid in mice/cells has failed in human trials. Perhaps a coincidence? Maybe. However, the alternate is never really considered. All of this is not to say that I was right [that amyloid is not the cause of Alzheimer’s and therefore cannot be the target of drugs to treat it]. I still don't know exactly how amyloid fits into the puzzle. But betting the house on 00 in roulette is no way to conduct science. Trouble is, we mostly are not gambling with our own money or lives.”
No, they are gambling with the lives of patients now and in the future whose lives are being taken by Alzheimer's. On that depressing note, Happy 4th.