Why We Must Lance the Alzheimer’s Boil

Sometimes social pressures come to a head, and a moment of crisis offers opportunity. With the disastrous FDA approval of aducanumab (or Aduhelm, as the drug is known in its commercial existence) in June, the figurative “boil” of the Alzheimer’s disease movement has done just that. Will this swelling reach a point where we can “lance the boil” to relieve the pressure of false expectations and hopes, or will the infection spread and continue its permanent scarring of this wayward movement?

The Alzheimer’s advocacy field is vast but is led by the Alzheimer’s Association along with other smaller lay organizations like USAgainstAlzheimer’s and CureAD, and many academic, government, and industry experts. These advocacy groups, supported by a small but visible group of dementia experts (often paid well by industry), are largely responsible for this approval and its excesses. At least that is what the Alzheimer’s Association implied in their June 8th Special Volunteer briefing following aducanumab’s approval. The Association advocated for green-lighting this potentially dangerous drug (biologic) and supported an FDA commissioner and other leadership that has favored industry in other decisions. Most relatively unbiased experts (FDA statisticians, FDA panelists, and many, if not most, outside experts) said the science was not adequate to warrant approval and recommended further well-controlled studies. A few of the most coopted “experts” supported the decision and quickly developed treatment guidelines which are remarkable for how much knowledge is missing. The Accelerated Approval mechanism—itself controversial under other circumstances—was not presented in advance to the FDA expert advisory panel that voted nearly unanimously against approval and was based on biomarkers that have not been adequately validated. No fully published trials of anti-amyloid agents have clearly linked cognitive improvement to this biomarker or any other, at least in the view of most experts. So far Biogen has failed to publish the results of their pivotal studies in a peer-reviewed journal.

So who benefits from this scenario?

Clearly Biogen, whose financial fate was highly dependent on the outcome and chose to immediately announce a price ($56,000) far beyond what experts felt was fair. The company then stated it would not proceed with urgency on further studies required by the FDA as part of the approval. The FDA gave Biogen nine years to report and, critically, did not specify what kind of follow-up study would be required. More placebo controlled randomized trials would be optimal, but that should have been required before a decision was made (how do you randomize potential participants to placebo arms when there is an “approved” product?). Biogen has come out defensively saying their approval was based on science, is clinically effective, and will be offered using the narrower labeling the FDA reverted to (mild cases). They accused critics of being biased and unscientific. Meanwhile, Biogen is promoting a completely biased, broad in scope, and unscientific web-based program called “It’s Time to Know”, which declares the unsubstantiated claim that “About 1 in 12 Americans over 50 has MCI due to Alzheimer’s” and allows anyone online to take a test that almost invariably leads to a result suggesting they ought to be concerned about their cognition. Once people finish the quiz, they are guided in seeking out a nearby doctor or infusion center to discuss amyloid diagnostic imaging and IV treatments, which currently only leads to aducanumab.

The full implications of what we stand to lose due to FDA approval have not yet been laid out, but the financial cost to taxpayers could be enormous (indeed, along with related care the drug could cost over $100 billion a year, well in excess of the budget of NASA and the CDC), as will lost funding opportunities for public health measures that will improve brain health. One hope is that payers and policymakers will offer more reasonable voices that put a damper on the Biogen money machine. Recently for example, the Cleveland Clinic Foundation and the Veterans Administration said they would not support the use of aducanumab. However, already, drug companies like Lilly and others are quickly leveraging the aducanumab decision to seek accelerated FDA approval for their own biologics, which have similarly not proven effective. The FDA lowered the bar so far that a whole procession of me-too drugs can practically stumble over this pathetic regulatory hurdle.

The FDA has the power to rescind its approval if it receives further relevant information after the decision, and it has and should. The second line of defense, payers and professionals, should hold firm against using it.

Perhaps the biggest beneficiary of the approval is the Alzheimer’s Association and other members of the uncritical advocacy community. But it must be asked whether they have won a battle but perhaps lost the war with this Pyrrhic victory. The Alzheimer’s Association is the dominant purveyor of the scientism and economism of the field—as expressed in organizational advocacy phrases like, “Care today, cure tomorrow.” The field is littered by the Association’s claims (often echoed by the National Institute on Aging) of progress and assertions that ultimate success is just around the proverbial corner. Boxed in by limited thinking and accumulated power to influence the field, the Association and others have used fear (appealing to the “loss of self” and financial ruin the condition can engender) to shut off critical examination of their own self-serving behavior and of thinking and valuing in the field in general. It has resolutely failed to lance the aducanumab boil, and—worse yet—is itself a major source of the ongoing inflammation.

The organization is deeply imbricated in the market relationships that have defined the Alzheimer’s field since its modern inception in the 1970s, drawing significant money from drug companies but even more from their massive international conferences and development efforts to raise funds from other sources. Private donors are likely seduced by the claim that their donation will lead to a cure soon. The field has promoted diagnostic creep (like the controversial term Mild Cognitive Impairment and even worse so-called Subjective Cognitive Decline), biomarker zeal (panels of different biomarkers), distorted pharmacoeconomic models promising cost-saving, and unrealistic therapeutic expectations leading to people taking cocktails of personalized drugs. They are bought by pharmaceutical thinking if not money.

The Association says that they represent the “voice of patients.” But in our opinion their voice is narrow and serves the organization and biomedical model much more than people who are struggling. Local chapters certainly do much to support families and should be differentiated from the corporate behavior of the Alzheimer’s Association at the national and international levels, although the national organization took control of many of them in the early part of the last decade. People living with disease, including those with dementia, are citizens too, and they can be misled by self-serving experts. Selfish advocacy without regard for broader public health issues and costs represents neoliberal individualism and market fundamentalism at its worst. People with dementia need a voice that respects their experience, but not to excess, and recognizes that their voices are also diverse. Now other lay organizations (like the ALS Society) are trying to build on the “success” of the aducanumab approval by demanding more attention to their special interest, and it appears continuing to seek lower standards for drug approval as well.

The decision by the FDA to approve aducanumab represents the epitome of neoliberal, reductive, market-driven thinking about dementia and is an illustration of the dangers of these ideologies in general. Janet Woodcock, the Interim FDA Commissioner, admitted to problems with process publicly in the approval of aducanumab and called for an Inspector General investigation of her own organization. Hopefully, they will join other groups critically scrutinizing the process and leadership that have led to the wrongheaded greenlighting of aducanumab. Woodcock specially said she was not involved in the final decision to approve aducanumab. Does this clear her personally or is this worrisome that the most important regulatory decision in recent history (and probably its worst) did not get her input? There seems little doubt the FDA was too close to Biogen. FDA and Biogen leadership were on an NIA/Alzheimer’s Association position paper in 2018, moving the needle closer to biomarkers (as were lots of the experts pushing this approach as well). The FDA also co-presented with Biogen on the development of collaborative data sets involving academics and industry. Data sharing is a good idea in general to expand sample sizes, but how come they did not use this approach to investigate the clinical validity of biomarkers in the multiple studies from different sources that looked at this critical issue before approval was granted? The FDA appears not only to be too close to Biogen but was also being unfair to other companies in this process.

This unfortunate debacle is what happens when our public policy is shaped by the financial incentives of a politically powerful and highly profit-driven industry as well as narrowly focused advocacy groups. Ironically, recent research has shown that dementia rates have actually been in decline over the past decade in the US and in Western European countries. The reasons have little to do with drug companies and biotechnology, and much to do with mid-20th century public policy that was aimed at a common good—namely, increasing education (via the GI Bill and investment in state colleges and universities in the US), expanded healthcare and improved treatment of risk factors that affect the brain (i.e., vascular disease, high cholesterol, hypertension), remarkably successful smoking cessation programs, deleading gasoline, etc. Collectively, these state actions in service of public health are believed by most experts to have enhanced the resilience of our older neighbors who are advancing through their graying years.

Aducanumab, on the other hand, is an approach foisted upon us by a too strongly industry-influenced regulatory body that will ultimately serve short-term corporate health rather than population health. In fact, there’s a good chance that this “treatment,” which caused potentially serious side effects like brain swelling and brain bleeds in a disturbing 40% of patients in the initial trials, as well as high rates of headaches, falls, and diarrhea, will impose quite deleterious harms on people. Meanwhile, billions of dollars that could be flowing to 21st century “brain health” measures at the population level (e.g., getting lead out of drinking water, guaranteeing healthcare and higher education/vocational training for everyone) or to providing quality long-term care for every American, will be diverted to industry coffers. More ineffective combinations of drugs and biomarkers are likely to follow the all-too-easy path established by aducanumab. Presumably, as Biogen’s approach and other biologics prove ineffective as single treatments “experts” will continue telling us that, in order to treat “Alzheimer’s”—which, despite being culturally framed as a singular disease is actually a heterogeneous, multi-factorial syndrome intimately related to aging—we will require “panels” of expensive diagnostics and “cocktails” of drugs. None of this conversation ever considers societal costs (and opportunity costs), or deals with the inconvenient truth that Alzheimer’s, just like brain aging, is highly unlikely to be amenable to any universal cure.

Ultimately, aducanumab is not an example of “responsible innovation”; it is a product of institutional corruption. It represents not the best of collective human action but perhaps the worst—a grotesque outcome guided by an oligarchy of self-serving individual and collective market actors. It is time to stop covering up our intellectual and ethical disfigurement, lance this societal boil, and pursue a healthier collective destiny. This means investigating the approval process as politicians and public watchdogs have suggested. It may also mean firing those who do not put the public interest at the heart of their public service, and scrutinizing not only the FDA but our regulatory apparatus in other areas where industry capture has set in. We should not prescribe or pay for this drug, and we believe the decision should be reversed, however difficult this would be bureaucratically and politically. But most fundamentally, with respect to Alzheimer’s, we should place our support behind people, ideas, and plans that actually benefit people with cognitive challenges, their families and society at large.

Peter Whitehouse (peter.whitehouse@case.edu), MD, PhD and Daniel George (dgeorge1@pennstatehealth.psu.edu ), PhD, M.Sc, are authors of The Myth of Alzheimer’s: What You Aren’t Being Told About Today’s Most Dreaded Diagnosis (St. Martin’s Press 2008) and American Dementia: Brain Health in an Unhealthy Society (Johns Hopkins Press, 2021).