Introduction
Alzheimer’s Disease (AD) has long been a focal point of research, with amyloid plaques and tau tangles traditionally viewed as primary culprits. However, a recent Cochrane review raises critical questions about the efficacy of monoclonal antibodies targeting amyloid plaques. This article explores the findings of this review and the implications for Alzheimer’s research and treatment moving forward.
Part the First: Anti-amyloid Antibodies and Alzheimer’s Disease (AD). A Cochrane review of monoclonal antibodies targeting amyloid plaques in AD indicates that these treatments have minimal to no impact on the cognitive abilities of AD patients. Cochrane reviews are often regarded as the “gold standard” in evidence-based medicine. While useful, they do not always conclusively determine the effectiveness of treatments—this largely hinges on the quality of the published trials included in the review.
One significant issue is the lack of a definitive connection between amyloid plaques and the onset of AD. Although patients with AD often show plaque accumulation, this association is not enough to establish causality. This notion dates back over a century to Dr. Alois Alzheimer, who identified these plaques in his first patient, who suffered from dementia. However, he did not conduct necessary control studies to compare her brain with those of other similar patients who did not have AD, many of whom likely had similar plaque levels.
From the Cochrane study:
Included studies: Overall, this review encompassed 17 studies with a total of 20,342 participants. The average age of those involved ranged from 70 to 74 years. Of these studies, seven focused on individuals with mild dementia, while one targeted solely those with mild cognitive impairment. The rest examined a mixed population. Participants generally had been experiencing cognitive impairment for a duration between 17 to 52 months.
The studies assessed seven different amyloid-beta-targeting monoclonal antibodies: aducanumab (n = 3), bapineuzumab (n = 4), crenezumab (n = 2), donanemab (n = 1), gantenerumab (n = 4), lecanemab (n = 1), and solanezumab (n = 2), all compared against placebos. Eleven of the trials lasted 18 months, four extended to 24 months, and two surpassed 24 months.
All of these studies were funded by the pharmaceutical industry.
Cognitive Function: Compared to placebos, the amyloid-beta-targeting monoclonal antibodies seem likely to produce little to no significant change in cognitive function, as measured by the Alzheimer’s Disease Assessment Scale-Cognitive (ADAS-Cog) (standardized mean difference (SMD) −0.11, 95% confidence interval (CI) −0.16 to −0.06; 13 studies, 9,895 participants; moderate certainty).
Functional Ability: These antibodies appear to have minimal effects on functional ability, measured using the Alzheimer’s Disease Cooperative Study – Activities of Daily Living (ADCS-ADL) scale (SMD 0.09, 95% CI 0.03 to 0.16; 3 studies, 3,478 participants; moderate certainty) with a potential slight increase in functional ability as evaluated by the ADCS-iADL scale (SMD 0.21, 95% CI 0.10 to 0.32; 1 study, 1,252 participants; low certainty) or the ADCS-ADL-MCI (SMD 0.23, 95% CI 0.12 to 0.33; 4 studies, 2,802 participants; low certainty).
Authors’ Conclusions: The impact of amyloid-beta-targeting monoclonal antibodies on cognitive function and dementia severity after 18 months in mildly impaired patients is negligible, while any improvement in functional ability is minor. Furthermore, these antibodies increase the risk of amyloid-related imaging abnormalities. Both positive outcomes and adverse effects were reported inconsistently across the studies included in the review.
Eradicating amyloid from the brain appears dissociated from any clinically meaningful benefits for individuals with mild cognitive impairment or mild dementia due to Alzheimer’s disease. Future studies on disease-modifying treatments should investigate alternative mechanisms.
Despite ongoing research, it seems likely that amyloid plaques and tau proteins may result from underlying issues rather than being the roots of Alzheimer’s dementia. As Karl Herrup articulates in his book, the entire research “enterprise” concerning AD serves as a compelling case study in How Not to Study a Disease: The Story of Alzheimer’s. (previously discussed here). It is important to first examine the Acknowledgments section of any scientific paper to identify which organization funded the research. While the abstract or summary was traditionally the first port of call, this has shifted since the Bayh-Dole Act of 1980, which redirected the focus of biomedical research towards generating profits rather than understanding the natural progression of diseases. In this context, it’s crucial to note that all the studies reviewed were financed by the pharmaceutical industry, which inherently cannot claim unbiased interests in the research outcomes, regardless of their assertions to the contrary.
The current disillusionment with scientific research can be partly attributed to failings in understanding AD. The AD community has pointed out that Cochrane’s authors seem to overlook the hopes of individuals relying on the promise of these therapies. While this concern is valid, fostering false hope can be more detrimental than offering no hope at all.
Part the Second: There Is Always More to the Story. The neurologist Steven Novella at Science-Based Medicine (SBM) argues that the Cochrane review’s conclusions are contentious, as they may have included monoclonal antibodies previously deemed ineffective. From SBM:
Successful removal of amyloid from the brain does not seem to correlate with any clinically significant improvements in individuals with mild cognitive impairment or mild dementia due to Alzheimer’s disease. Future research should explore treatments that examine other mechanisms.
This critique is quite revealing. I found it alarming that the review encompassed 17 studies, as I did not believe there were that many trials involving the currently approved medications—they apparently included all monoclonal antibodies targeting amyloid, including those shown to be ineffective. Research included aducanumab, bapineuzumab, crenezumab, donanemab, gantenerumab, lecanemab, ponezumab, remternetug, and solanezumab (the “mab” stands for monoclonal antibody).
The debate over the exact role of amyloid in AD, as opposed to other potential mechanisms, is ongoing among researchers. After an array of unsuccessful clinical trials, many advocates shifted towards the narrative that amyloid might no longer be a viable therapeutic target. However, with lecanemab and donanemab demonstrating tangible—but modest—clinical benefits, those supporting the amyloid hypothesis seized the opportunity to celebrate what they interpreted as validation of their theory.
The current review can thus be seen as a counterpoint from the anti-amyloid faction, which may explain their decision to include all anti-amyloid monoclonal antibodies instead of just those with validated efficacy. Their bold closure—“Future research on disease-modifying treatments for Alzheimer’s should shift focus to alternative mechanisms”—raises questions about the direction of ongoing research efforts.
Moving forward, several strategies need to be implemented. First, we must enhance our screening efforts for early AD diagnosis, as timely intervention significantly improves treatment efficacy. Moreover, it’s essential to distinguish various subtypes of AD, confirming the role of amyloid while also evaluating tau’s contribution. Integrating genetic data and family histories will facilitate tailored treatment approaches for individual patients. Of course, this necessitates developing diverse, individualized therapies—anti-amyloid monoclonal antibodies are just the initial stepping stones.
Additionally, it’s crucial to explore other factors implicated in AD, such as inflammation and vascular pathology. In the next 20 to 30 years, or perhaps sooner, we might see a cocktail of treatments—each with modest benefits but collectively delivering substantial improvements in the management of AD. Given that AD typically manifests in older populations, effectively slowing its progression could lead to many patients living with the condition rather than succumbing to it, while maintaining functional capacities.
The purpose of this latest review, however, remains unclear. By amalgamating ineffective older treatments with newer, effective ones, it appears to obfuscate the findings and generate a misleading narrative. This confusion could be leveraged by regulators to deny funding for promising newer therapies.
The most productive path forward involves dedicating basic biomedical research to impartial scientists and giving them the long-term support necessary for progress. We have the resources to afford this investment, as its absence could be far more costly. I am not a neutral advocate, yet throughout my scientific journey, I have witnessed the transformative potential of “blue-sky” research. While it is often necessary to retrace our steps, these foundational inquiries are indispensable. As Dr. Novella highlights, by decelerating AD’s course, our successors might witness individuals aging with AD, rather than dying from it—a highly desirable outcome. Ultimately, the takeaway is that when confronted with sensational claims in clinical medicine, patience is essential as we await concrete results.
Part the Third: Books Worth Considering, in Brief, especially in an age where literature seems to be vanishing from university stores (and libraries—I share this from personal experience) or relegated to off-site repositories. In this future landscape, researchers, historians, and casual readers may never discover that the book they found in the catalog is in close proximity to another book they desperately needed. This situation presents an intriguing subject for discussion with the current president of my alma mater—though it’s unlikely that a typical university president has ears to hear much other than ESPN and US News and World Report.
Complete Works of Aristotle. Specifically, I refer to the Nicomachean Ethics. Hackett Publishing has produced a magnificent two-volume edition of Aristotle’s Complete Works. A friend of over fifty years introduced me to Book 4.3, which discusses Greatness of Soul. The Revised Oxford Translation in the Bollingen Series lacks a title for this portion and uses “Pride” in the opening line instead of “Greatness of Soul.” While pride resonates more in today’s context, I prefer the idea of Greatness of Soul (I can only phonetically parse a few Greek terms):
Greatness of soul (magalopsuchia), even from its name, appears to be concerned with great matters (megala), and our primary task is to discern what these great matters are… The person who believes themselves worthy of significant things and indeed is, seems to be great-souled; for someone who thinks the same without deserving them is foolish, while no one aligned with virtue can be unwise… A person who overestimates their worthiness for greatness when unworthy is conceited… The true great-souled person, if truly deserving of the greatest good, is undoubtedly the most virtuous; thus, a great soul would be commendable in every virtue. It would be uncharacteristic for a great-souled person to evaded danger or commit injustice… A thorough examination of specific instances will reveal that if a great-souled person isn’t virtuous, they appear utterly ridiculous. They would lack honor if they were base, for honor stems from virtue and is awarded to the good.
Finding individuals who embody goodness, greatness of spirit, honor, and virtue seems increasingly rare in our current leadership. How can we reclaim them? These figures transcend political boundaries—liberal, conservative, socialist, anarchist, pacifist—and are those willing to listen and collaborate. However, they are not represented in the public narratives perpetuated by those seen on screens, contributing to global decay. What would ancient Greek term megalomaniac? Google’s translation offers μεγαλομανής, yet Aristotle would have likely articulated a more nuanced concept.
Gilded Rage: Elon Musk and the Radicalization of Silicon Valley. Jacob Silverman is always worth reading, regardless of your stance. A few excerpts:
Often deriding their employees on social media, laying off multitudes to maintain dwindling profit margins, and endorsing inflammatory cultural figures such as Florida Governor Ron DeSantis (an alumnus of Yale and Harvard, who dismantled New College in Sarasota) before aligning with the authoritarian Donald Trump, tech industry leaders now pose a significant threat to democracy, fraying society’s already strained fabric.
Silicon Valley elites have commonly dismissed expertise. “Everything you read makes sense if you merely translate ‘experts’ into ‘crazy people,’” according to Marc Andreesen… Their worldview maintained that creative destruction and technological advancement were synonymous with progress, believing that if expertise is worthless—due to corruption of the old regime—then technology is the redemptive force, and its vanguards the saviors.
(Larry) Page (of Google) wasn’t the first to argue that technological advancements outpace democratic governance… But for Page and other tech leaders, this notion meant privileging technological evolution over democratic values.
Any efforts to curb or slow this progress—advocating for ethical considerations in AI and automation or regulating AI’s colossal data center resource consumption—were deemed immoral. By arguing that such regulations impede society’s access to AI’s promised future benefits across various sectors, they disregard public skepticism as detrimental to saving lives through AI, exemplified by systems aiding in the evaluation of CT scans and X-rays.
The Rule of Experts has contributed to our current predicament, but that does not suggest that relevant expertise is unnecessary. Irrespective of the situation: Neoliberalism advocates “prioritize markets, then go extinct.” Thank you, Lambert Strether. It’s ironic how Silicon Valley denizens laud markets while fervently striving for immortality, securing their hideaways in Hawaii and New Zealand. Yet, when the storm brews, can they genuinely depend on their security personnel? As Mark Blyth articulated, the Hamptons are not a defensible sanctuary. Nor are the remote locales of Hawaii or New Zealand.
Chasing My Cure: A Doctor’s Race to Turn Hope into Action. Years ago, I had the privilege of hearing David Fajgenbaum recount his successful battle against idiopathic multicentric Castleman disease (TMI). His relentless pursuit of understanding the cellular mechanisms behind Castleman disease was vital for his success. This was made possible solely because of foundational research into signal transduction pathways, like the mTOR signaling pathway (mechanistic/mammalian target of rapamycin), discovered over sixty years ago through a project focused on identifying natural products with therapeutic potential (paraphrased from Wikipedia).
During my early scientific career, I collaborated with a group of organic chemists dedicated to isolating alkaloids from diverse biological sources. Some of my colleagues derided this effort as mere “stamp collecting,” unaware that we were guilty of the same. This form of projection is a common yet rarely innocent behavior. Both groups did not know what they might uncover, but some found compounds like rapamycin, named after Rapa Nui, Easter Island. A search on PubMed shows that yesterday there were 61,541 scientific papers involving rapamycin.
Capitalism and Its Critics – A History from the Industrial Revolution to AI. John Cassidy’s overview is among the most illuminating I’ve encountered. It includes familiar figures but offers fresh insights into their significance. Furthermore, there are critics of capitalism like Anna Wheeler, born in Ireland in 1785. In her speech in London in 1829 addressing the “Social Condition of Women”:
I recognize the struggle in balancing moderate language while discussing the grim reality of my gender’s status… However, what weighs on me the most—and I would dare say my “forlorn hope of this endeavor”—is the uncertainty regarding the tangible improvements that can emerge from lectures such as this, given the deep-seated corruption of our institutions, especially those perpetuating the injustices afflicting half of humanity: WOMEN!
Furthermore, Adam Smith, who astutely recognized the psyche of the ambitious businessman eager to impact the world rather than contribute as a good citizen and neighbor. The Scots, especially from Fife—the birthplace of golf—are notably perceptive. Regarding the East India Company, Smith noted in the third edition of The Wealth of Nations (1784):
Smith provided another reason for the financial troubles faced by chartered trading companies: they were joint-stock entities as opposed to traditional business partnerships. While many modern academic texts emphasize the benefits of stock investment in diversifying risks, Smith had a very different perspective. In partnerships, business owners risk all their wealth, fostering caution. Conversely, executives of joint-stock companies enjoy limited liability; their risk is confined to their shareholdings. Smith observed: “It cannot be expected that the directors of these companies, managing other people’s money rather than their own, would monitor their investments with the same diligence as partners in private partnerships often do… Consequently, negligence and waste are inevitable in the management of such companies.”
Thus speaks the supposed “unqualified defender of capitalism.” Yet, he lacked foresight regarding the repercussions unfolding in the nineteenth century and beyond.
Thank you for reading! I look forward to connecting with you next week from the road, as best as I can manage.
Note
[1] My (Mark Blyth) intention was not to advocate for invasion. Rather, I sought to illustrate that if rising inequality fuels the dissatisfaction driving today’s politics (it does), those benefiting most from it—the renowned top 1%—cannot shield themselves through private means such as private schooling, jets, estates, or security. History reveals that such strategies fail when the sentiments of the broader populace inevitably erupt, leaving those in power with a choice: either accept a political discourse that diminishes inequality or confront the wrath of the populace, even in the Hamptons, that affluent enclave associated with some of America’s wealthiest citizens.
Four years later, in the midst of a pandemic, it appears that those wielding pitchforks are increasingly aware of the location of the Hamptons, which renders it a less secure refuge. In response, those residing there have typically resorted to the tried-and-true response of threatened elites—hiring mercenaries—or, more accurately, increasing their private security. But the problem with such an approach is that you cannot buy a private solution for a public issue. Seeking Elysium or a secluded island off Fiji sustained by Bitcoin is not a realistic escape. Eventually, those in positions of power must acknowledge that their destinies are intertwined with those of their fellow citizens—who, indeed, are fellow citizens and not merely perceived threats. Historically, most elite classes have failed to recognize this connection, often leading to turbulence before resolution. Let us hope that the wise investors in the Hamptons heed the current warnings.
