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In histories written about Alzheimer’s disease, 2019 will turn up as a landmark year, one in which researchers, clinicians, patients, and their families were whipsawed from crushing despair to giddy optimism.

The year unfolded with a string of disappointments. One of the biggest came on March 21 when Boston-based Biogen announced it had pulled the plug on two clinical trials of aducanumab, a promising treatment for individuals with Alzheimer’s disease. The drug had failed a “futility analysis,” meaning it would not be able to achieve its objectives. More bad news came in the weeks and months to follow. An entire class of drugs called BACE inhibitors (pronounced “base” as in baseball) had failed.

By the annual international meeting of Alzheimer’s investigators in Los Angeles in July, a pervasive disappointment was enmeshed with embarrassment, heightened by the meeting’s timing on the 50th anniversary of the successful Apollo mission to the moon. A half a century ago, we were able to send someone to the moon, have him walk about, and return home but, despite all our time and effort and money since then, despite all the advances in genomics, proteomics, and other “omics,” despite precision medicine, we haven’t been able to make a dent in this disease.


Five months later, at the Clinical Trials in Alzheimer’s Disease (CtAD) conference on Thursday, December 5, I and other Alzheimer’s researchers gathered once again in California. This time the mood was giddy. The crowd in the Indigo ballroom at the San Diego Bayfront Hilton behaved more like a gathering at an awards ceremony than an early morning session at a scientific meeting. There were hugs, laughter, and backslaps.

Why the change? Biogen had somehow flipped the switch on aducanumab. According to its reanalysis of the clinical trial data, aducanumab wasn’t a flop but a success, and the company had decided to ask the FDA to approve aducanumab for the treatment of Alzheimer’s disease.


Samantha Budd Haeberlein, who heads late stage clinical development for Alzheimer’s disease at Biogen, spent 45 minutes explaining the complicated events leading up to and following the futility analysis. One key message was that the company had gathered more data in the three months between the start of the futility analysis and the decision to end the trial, but that data hadn’t been part of the analysis. After adding it into the analysis, a different picture emerged: The highest dose of aducanumab just might slow down the cognitive and functional decline caused by Alzheimer’s disease.

The much-used phrase “a shot heard ’round the world” comes from the dawn of the American Revolution. It evokes when war first broke out in and around Boston between British troops and American rebels. It sent a message to Britain’s George III and every other monarch and the aristocracies they sustained: Your days are numbered.

Biogen’s reinterpretation of its data must still be subjected to FDA and peer review, of course. But if it holds up, I believe that aducanumab will be a shot heard round the world: the beginning of the end of Alzheimer’s disease.

It won’t end Alzheimer’s because it cures the disease. It doesn’t do that. Aducanumab appears to slow, but does not stop, and certainly does not reverse, patients’ cognitive and functional declines. Given the past disputes over the effects of earlier Alzheimer’s drugs, experts will vigorously debate aducanumab’s benefits.

But as long as the benefits are judged to outweigh the risks, aducanumab won’t just treat individuals with Alzheimer’s disease. It will treat our Alzheimer’s culture.

When a disease is common, has unknown causes, and no effective treatments, stigma flourishes. The stigmas of Alzheimer’s are intense. They cause people to avoid seeking a diagnosis. They nudge some clinicians to hide the diagnosis. Patients who do learn their diagnosis experience self-stigma. They start to doubt their abilities and worth to others. Friends disappear. Caregivers worry about the future.

Stigma causes all kinds of language games. When Ronald Reagan announced his diagnosis of Alzheimer’s disease, he in fact didn’t say he had it. In a handwritten letter to his fellow Americans in 1994, the Great Communicator explained, “I have recently been told that I am one of the millions of Americans who will be afflicted with Alzheimer’s disease.” The “will be” stands out. It distanced him from his diagnosis.

What makes aducanumab so powerful is that it targets one of the pathologies of Alzheimer’s disease, and it does so in persons who are not yet diagnosed with dementia. A bit of history is needed to explain this novel way of labeling people with Alzheimer’s disease and why it is so significant.

For much of the 20th century, Alzheimer’s disease and dementia were enmeshed. A person had to have dementia to be diagnosed with Alzheimer’s disease. This made sense. You have to be ill to have a disease.

Most of the participants in Biogen’s trials, however, did not have dementia. They had what’s called mild cognitive impairment, known widely as MCI. Characterized in 1999 by researchers at the Mayo Clinic, MCI describes changes in individuals’ cognitive abilities that, while noticeable and often annoying, are not disabling. They don’t have dementia, nor do they have normal aging. They’re sort of in between.

The reason why the field cared about MCI was that the Mayo team showed it was a risk factor for developing Alzheimer’s disease, like smoking or obesity. The Mayo investigators reported that an individual with MCI had about a 15% per year chance of declining from MCI to dementia.

One other event is important. In 2002, investigators at the University of Pittsburgh stunned the Alzheimer’s field when they announced the discovery of a radiotracer they called Pittsburgh compound B that could visualize amyloid in the brain of a living person. Before this, the only way to see this characteristic pathology of Alzheimer’s disease was with a brain autopsy. A person with dementia had to die so their caregivers could learn the cause of their dementia. Amyloid imaging ended that Gothic horror story.

Which brings me back to Biogen’s trials. Eighty percent of the participants did not have dementia. They had MCI and PET scans that showed elevated amounts of amyloid in their brains. Some Alzheimer’s experts label this as “prodromal Alzheimer’s disease,” others as “MCI caused by Alzheimer’s disease.” Still others prefer the blunt label “Alzheimer’s disease.”

Patients will reject each of these labels. There’s maddening ambiguity around what MCI actually is. It’s like a semi-boneless ham. The term Alzheimer’s disease is unacceptable to individuals with MCI. It is hidebound to dementia, which they do not have.

Alzheimer’s is the senility of the 21st century. Patients and their families will give their own names to what they have and why they are getting treated. Perhaps they’ll say they have abnormal amyloid or, in a word, amyloidosis.

This renaming is sensible. A drug that targets a pathology targets stigma. It offers some explanation for what’s wrong, the hope of treatment, and a means to rethink and even rename a disease.

The statin drugs that reduced cholesterol, first tested in the 1980s, recast heart disease into a test for “good” and “bad” cholesterol. After fluoxetine was baptized Prozac and psychiatrist and author Peter Kramer counselled America to listen to it, antidepressants recast depression. Prozac and its many cousins didn’t just treat American depression and anxiety. Being on Prozac transformed depression into a problem of serotonin balance. A stigmatizing mental illness became a near universal experience.

So too shall be the recasting of Alzheimer’s disease. Because aducanumab isn’t just a drug — it’s also an idea. Just like the American Revolution and the shot heard ’round the world.

Jason Karlawish, M.D., is a professor of medicine, medical ethics and health policy, and neurology at the University of Pennsylvania and co-director of the Penn Memory Center. He reports receiving grant support for Alzheimer’s clinical trials from Eli Lilly and Co. and Novartis.

  • At first I though I was reading an attempt at a Great American Novel, rather than a not -so-great, not-so-novel amyloid polemic. The author suggests an American revolution to cure our addiction to Alzheimer’s and remove stigma at the same time- call it “amyloidosis” instead. Never mind that despite billions being spent we do not know the normal roles of amyloid, and we do know that many people without dementia have amyloid in their brains. Biogen and the allies has been manipulating the scientific stage claiming transparency behind smoke and mirrors. Analysts ask better questions that coopted experts. The science is unclear. Do another study and stop telling us about how many patients with develop dementia while we wait (but do mention how much a delay would affect your potential profits). This is not a democratic revolution; it is another neoliberal takeover of our economics and politics. Approving a biologic with at best very small effects is more likely to give us equally ineffective me-too drugs rather than a cascade of dramatic progress. So yes, let us hope this is the beginning of the end of our simplistic molecular thinking about dementia and remember the opportunity costs of not investing in community and public (brain) health.

    • So well said. Bravo, it was joyful reading your intelligent and lightly humorous response, Peter.

  • If you don’t have to be diagnosed to get this medication, and my family history of Alzheimer’s is very powerful, could I be treated even before any official diagnosis is made?

  • Given the results of trials on a variety of anti-amyloid beta monclonal antibodies (solanezumab, bapineuzumab, aducanumab), unfortunately it almost proves that monoclonals are not the way to go. Data dredging the adu trials on non-prespecified endpoints or patient subgroups is not proof of anything that should support an FDA approval. However, if the FDA feels compelled to boost its year-end approval numbers and throw the Alzheimer’s community a bone, the drug will get approved. What should happen is that the FDA tells Biogen to run another Phase 3 trial with whatever Biogen believes to be appropriate prespecified endpoints. If Biogen accepts, that would be a good indication that it believes the current data are solid and that data from another trial could support approval. If Biogen declines to run another Phase 3, then it suggests the company is doing a Hail Mary submission to the FDA with the current data. The world certainly needs an effective AD drug but not one that is minimally effective and provides only false hope.
    One good outcome of the failed mAb trials is that more research is being done on other possible pathogeneses of the disease, which is good, especially in light of the failure of BACE inhibitors in addition to the failues of mAb’s. Taken together, these failures of drugs using two different approaches to the amyloid beta problem suggest that amyloid beta may not be the problem or at the least, may not be the whole story. Finally, many (most?) cases of dementia are a mixed bag of Alzheimer’s and vascular dementia (from microvascular cerbral insults to stroke). At this point, the best preventive strategies probably involve minimizing the same risk factors that affect blood vessels in general, ie, stop smoking, control LDL, overweight, and sources of systemic inflammation, as well as getting regular aerobic exercise. Treatment of existing MCI/AD is another matter.

  • Throughout my career as a health care professional, I was cognizant of declining mental acuity that often attacked the elderly. A physician and I were about to begin a longitudinal study when I had an accident which not only damaged me physically, but attacked me mentally as well. It took longer than 2 years for me to fully recover my mental facilities.
    However, Alzheimer’s has intrigued me for many years, and although at the age of 83 I am not interested in beginning a longitudinal study, I suggest that testing should be done on volunteers beginning at the age of their legal independence. These studies could run for many decades, and their is no limit on what might be learned throughout the course of such a study.

  • My mom was diagnosed of Alzheimer’s disease last June. It was heartbreaking. She is 63 and I want to fight. Hope this medicine will help her. I love my mom so much. We’re from the Philippines, hope I can get these Medicine. Thanks.

  • Priests say there’s a cure to Alzheimer’s. They’ve been saying it a long time. Ten or fifteen years. They also say it never goes well to cure it. There’s also a new pill that restores working memory according to the mental health authority or nih. The thing about therapy is you can have everything and it s treated by one pill. Or you can have one diagnosis and be on ten pills.

  • The title of this article (which I understand is beyond the authors control) is absurd. The drug somehow magically “wasn’t a flop but a success”?? Doesn’t sound like a medical revolution to me, but rather a marketing revolution. The beginning of the end of Alzheimer’s disease?, or the beginning of massively expensive putatively preventative therapies with at best marginal efficacy.

    Big shocker: the author has received hundreds of thousands of dollars of research funding from Eli Lilly for research on this very drug according to open payments data.

    I wish we could read an impartial analysis of the topic as opposed to what sounds like a marketing promotion.

    • My thoughts exactly. And somehow it happened to require “the highest dose of aducanumab” ie the most expensive dose, to give a “just might” benefit. Convenient.

  • A promotional article. Despite the articles’ views, Alzheimer’s is a metabolic disease that is being promoted as a cognitive impairment syndrome, and being researched accordingly. The human brain functions by neurons genes, DNA, and proteins. An amyloid peptide and Tau fibrils and tangles drive Alzheimers pathology. Amyloid aggregates (asymptomatic stage) to trigger Tau fibrils and tangles, that then cause neurons to die (Prodromal stage), which becomes the point where cognitive impairment efficacy becomes incresingly more unlikely. Treating patients pass this point competes with the Brains immune system which is not well understood. Treating amyloid after neuron damage was shown ineffective in the 2002 AN-1792 Alzheimer’s vaccne trial. The Aducanumab trial treated patients who had already started neuron loss.

    Unless Biogen request FDA approval to treat Asymptomatic candidates for prevention of neuron loss, the only success of a FDA approval will be for Congress and NAPA to claim meeting their 2025 goal.

    The slowing effect of Aducanumab is basically meaningless to patient and caregivers. See my blog “The Aducanumab Story” at

    Bruce Bauer
    Caregiver –> now in my nineteehth year.

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