Some journalists fire another “silver bullet” at Alzheimer’s amyloid target

The following is a guest blog post from one of our regular contributors, Alan Cassels, who is an author, journalist, and drug policy researcher with an interest in how clinical research and experience on pharmaceuticals gets translated for policy-makers, prescribers and consumers.


A March 20th story in the Boston Globe. “Biogen drug offers hope for patients with Alzheimer’s,” was one of many stories last week that cast a glimmer of hope on new drug treatment to prevent Alzheimer’s Disease, which affects as many as 5 million Americans.

Those following the ups and downs of Alzheimer’s research will recognize the ‘feel good’ narrative of this story, where promising new pharmaceutical wizardry is once again on the cusp of a substantial advance to prevent the slow and, as yet, unpreventable slide into dementia.   Unfortunately this kind of news story is not designed for health consumers, but for investors, who are lured to bet again on a winning horse, with positive signs from a clinical trial held up as bait.  Surely it’s the size of the prize (a market for any Alzheimer’s drug that could actually work is potentially ginormous) that must be blinding them to the details.

Most of these stories include a few cautious caveats of the benefits and harms of the experimental treatment.  It was very helpful to mention that the trial was on a “small number of patients who had early indications and mild cases of the neurodegenerative disorder,”  yet the Boston Globe story wins the prize for using the most terms that Gary Schwitzer counsels journalists to strenuously avoid in health stories like “quite ecstatic”, “exceeded their expectations”, “significant breakthrough” and “in a different league.”  All this from an early-stage study of 166 patients?  C’mon folks, don’t treat us readers like a bunch of forgetful mice.

Anchorman Lester Holt of NBC Nightly News read his teleprompter, with a script that likened Biogen’s new drug to a “potential silver bullet to slow down memory loss.”

The Wall Street Journal joined the fray (“Biogen’s Alzheimer’s Drug Impresses in Early Trial”) adding to the enthusiasm:  “While still very early, these data are more impressive than anything we’ve seen in [Alzheimer’s disease], justifying the pre-data excitement,” said Christopher Raymond, a Robert W. Baird analyst. Saying something is ‘more impressive’ isn’t saying much at all, given how low the bar is in this field.  To its credit, though, the story explained: “the so-called ‘amyloid hypothesis’ is controversial, and other drugs targeted at amyloid plaques have failed in late-stage studies.”

The New York Times reported that Biogen’s aducanumab or BIIB037, is “designed to get rid of amyloid plaque in the brain, which is widely believed to be a cause of the dementia characteristic of the disease.” Really, “Widely believed?”   That’s a nose-stretcher for sure unless maybe I’ve been asleep for the last 20 years.   I thought the amyloid hypothesis was soundly discredited, a perennial and embarrassing, non-starter relegated to the graveyard of potential Alzheimer’s cures.   They’ve tried ultrasound, vaccines and many drugs to try to scour plaque out of our brains and nothing has even come close to finding a benefit in the human world (though to be fair, many of these treatments looked pretty good in mice).  The Times did follow up with this line, though: “However, other drugs designed to prevent or eliminate plaque have failed in large clinical trials, raising questions about what role the plaque really plays.”

But those almost-afterthought followup lines from the Wall Street Journal and New York Times didn’t go far enough.

I called up Linda Furlini in Montreal, one of Canada’s experts on Alzheimer’s Disease to get her general take on this story.  Following Alzheimer’s research developments for 25 years, she received a full-on education in the disease since both of her parents were diagnosed with it.  She ended up doing a PhD on the subject and has served both as a volunteer and a board member for Alzheimer’s associations in Canada.

She’s seen the story of Alzheimer’s disease cured so many times, they almost trigger a yawn.  “I’ve seen this stuff for 25 years and they should stop misinforming people about amyloid plaque,” she said, adding, “We don’t know if amyloid plaque is a precursor or an after-effect of the disease. Testing to get rid of it hasn’t worked for decades—so we’re beating a dead horse. We need more basic science.”   That viewpoint is also reflected in a Forbes Magazine article from 2012 around the failure of another amyloid-attacking drug. It said that by the end of 2012 “we will have data from six major Phase III trials without even a shred of support for the amyloid hypothesis.”  Saying that these facts are “hard to ignore,” the commentatory goes on to say that “amyloid optimism has required dismissing or minimizing the lessons of history.”

Would questioning the amyloid hypothesis (at all in some cases, or more deeply in others) have made a difference in this spate of news stories?  The most quickly measurable effect of not mentioning amyloid skepticism is the fact the shares of Biogen Idec rose $42.33 to $475.98 a share, gaining about 10 percent.  (Note: Biogen Idec, in the last day dropped the ‘Idec’ from its name.)

Linda Furlini says that drug discovery hullaballoo ignores the real issues around Alzheimer’s treatment which are as urgent as ever:  “Many elderly people—often seniors living at home– aren’t being diagnosed properly and are often left without the care they need.”  What that means, says Ms. Furlini who quotes from a recent letter in her hometown paper, the Montreal Gazette, is that “we still have the same state of care—where the needs of those with dementia are being ignored.”

Alzheimer’s drug discovery has sadly experienced an almost universal failure rate of preclinical and Phase I, II, and III testing and nothing seems to get through the pipeline as this recent infographic from Nature Reviews Drug Discovery suggests. (The funnels illustrate the average number of compounds needed at each stage of drug development in order to get one drug approved.)

Paul et al. (Nature Rev. Drug Discov. 9, 203–214; 2010
Calcoen D, Elias L, Yu X. (Nature Rev. Drug Discov. 14. 161-2; 2015

Given the millions that the United States government has already dumped into NIH-Pharma partnerships over the years testing the amyloid hypothesis (only to come up empty-handed) you’d think it would lead to a taxpayer revolt.  But no, now it’s time to shakedown the British taxpayer to keep that horse alive.  The Globe story concludes by saying a number of major drug companies, including Biogen are joining with “the British government and a charity to establish a $100 million venture capital fund to bankroll research into Alzheimer’s and other forms of dementia.”

Perhaps the best thing we can say about the American reporting of aducanumab is that it could be worse.  See this rodent-themed story from Australia, proclaiming that a new Alzheimer’s treatment fully restores memory function.  In fact, “Of the mice that received the treatment, 75 percent got their memories back.”  It sounds like an article in The Onion, but it isn’t.

Beyond the inappropriate hype and failure to put these new discoveries into context, Linda Furlini and others are highly critical of the way the drug industry tries to develop preventive drugs.   Unless there is any conclusive evidence that amyloid plaque is a precursor or a result of Alzheimer’s, Furlini thinks “we should stop recruiting people with mild cognitive impairment who may never develop Alzheimer’s into clinical trials with untested anti-Alzheimer drugs.”

Now that may be an idea worth banking on.


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Comments (8)

Please note, comments are no longer published through this website. All previously made comments are still archived and available for viewing through select posts.

Susan Molchan, MD

March 25, 2015 at 7:46 am

The perseveration on amyloid never ceases to amaze me, but the really dark side is that so much has been invested, and so may academics on the payroll, that, with “public” pressure–from advocacy organizations also bankrolled by industry, the lowered bar for surrogate endpoints, and a pro-industry FDA, one of these drugs could actually get approved, even though they’re not effective (or safe).


March 25, 2015 at 7:48 am

The decimal is in the wrong place “Biogen Idec rose $42.33 to $475.98 a share, gaining about 10 percent” or some investors are awful, mighty happy.

Alan Cassels

March 25, 2015 at 3:12 pm

Hi Liz, Thanks for your comments. On March 19th, Biogen Idec’s stock price was $433.65 per share, and it rose to $475.98 a share (gaining $42.33 overnight) on March 20th. This works out to an 8.9% increase so almost a gain of 10%. It has dropped about 5% in the last four days.

James Lyons-Weiler

April 2, 2015 at 9:37 pm

These studies go beyond amyloid vs. Tau. Both studies used quantitative measures of cognitive ability. The Biogen Phase 1B human trial showed marked reduction in the rate of cognitive decline AND a reduction in amyloid plaque. The mouse study demonstrated recovery of lost cognitive abilities that are also well characterized by quantitative measures. They also demonstrated invasion of microglial cells.

Taken together, these study actually shed new light on, and bode well for, the amyloid hypothesis.

The existence of past controversy of amyloid vs. Tau cannot lead to easy dismissal of these results. I can understand skepticism, but an in-depth look at both reports – not just the news hype – might lead to a more optimistic review.

    Gary Schwitzer

    April 3, 2015 at 6:38 am


    Thanks for your note. But in response to your final comment, we review journalism on this site. That is our purpose.

    Gary Schwitzer

Lane Simonian

April 5, 2015 at 11:44 pm

The Biogen results were highly misleading. At 6 months, there was no significant differences between the placebo group and treatment groups in regards to the rate of decline in cognition. After six months, 35% of people with the ApoE4 gene receiving the 10mg dropped out of the trial due to severe adverse effects (ranging from headaches to brain swelling). At the earliest stages of cognitive decline, ApoE4 carriers experience more rapid rates of decline than non Apoe4 carriers. So most (perhaps all) of the slower rates in decline in the 10mg group were due to having fewer Apoe4 carriers compared to the placebo.

No matter how many efforts are made to rescue the amyloid hypothesis for Alzheimer’s disease, amyloid antibodies always fail in larger trials. The reason is simple: amyloid does not cause Alzheimer’s disease. The same is true for neurofibrillary tau tangles. At best (or worse), amyloid oligomers and neurofibrillary tangles only slightly increase the progression of the disease. All one needs for Alzheimer’s disease is caspase activion by peroxynitrites and the hyperphosphorylation and nitration of tau proteins also mediated primarily by peroxynitrites.

The following “proves” that neurodegeneration can proceed in Alzheiemer’s disease without amyloid:

Familial amyloid precursor protein mutants cause caspase-6-dependent but amyloid ?-peptide-independent neuronal degeneration in primary human neuron cultures.

These results indicate that overexpression of wild-type or mutant APP causes Casp6-dependent but A?-independent neuritic degeneration in human neurons. Because Casp6 is activated early in AD and is involved in axonal degeneration, these results suggest that the inhibition of Casp6 may represent an efficient early intervention against familial forms of AD. Furthermore, these results indicate that removing A? without inhibiting Casp6 may have little effect in preventing the progressive dementia associated with sporadic or familial AD.

Peroxynitrite scavengers such as eugenol in rosemary essential oil via aromatherapy (Jimbo, 2009) and ferulic acid, syringic acid, vanillic acid, p-coumaric acid, and maltol in red Korean panax ginseng and heat processed ginseng (Heo 2011 and 2012) have led to significant improvements in cognition in Alzheimer’s patients.

Alan Cassels

April 6, 2015 at 1:14 pm

Lane, you’re right in suggesting the tenuous nature of the amyloid hypothesis, and because of a growing body of rigorous research we can increasingly question the hypothesis. Having said that I believe that the substances you mention, the ‘peroxynitrite scavengers’ such as various oils, acids and ginsengs have not been able to demonstrate any sustained benefits in the treatment of Alzheimer’s patients. For example, as this systematic review of ginseng indicates, despite the many claims of its benefits the evidence is “scarce and inconclusive.” Like amyloid, I wonder if many of these substances too would fail in larger trials.