Part the First: Anti-amyloid Antibodies and Alzheimer’s Disease (AD). A Cochrane review of monoclonal antibodies targeting amyloid plaques in AD has found that these drugs have little to no effect on cognitive function of AD patients. Cochrane reviews are, to use one of the favorite tropes of the current administration, considered the “gold standard” of their kind. While they can be useful, they are not always conclusive in identifying what works and what doesn’t in the treatment of disease. It all depends on the published trials included in the review and how well done they were.
But in this case, a large problem is that there has never been any concrete linkage between amyloid plaques and AD, except that AD patients have plaques. This goes back more than 100 years to Dr. Alois Alzheimer and his first patient, a woman in late middle age, perhaps with early-onset AD, who had dementia. After she died, Dr. Alzheimer identified the eponymous plaques in her brain and concluded they caused her dementia. But he did not do the necessary control, which would have been to analyze postmortem the brains of similar and older subjects who did not have AD. Many of them would have had a plaque burden diagnostic of AD.
Selected from the Cochrane study:
Included studies: Overall, we included 17 studies with 20,342 participants. The mean age of participants in the studies ranged from 70 to 74 years. Seven studies enrolled only participants with mild dementia, and one study enrolled only participants with mild cognitive impairment. The remaining studies included a mixed population. The mean duration of participants’ cognitive impairment ranged from 17 to 52 months.
The 17 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 used placebo as a comparison. Eleven studies lasted 18 months, four lasted 24 months, and two lasted more than 24 months.
All of the studies were funded by the pharmaceutical industry. (italics not in the original)
Cognitive function: Compared to placebo, amyloid‐beta‐targeting monoclonal antibodies probably result in little to no difference in cognitive function as measured by the ADAS‐Cog (Alzheimer’s Disease Assessment Scale‐Cognitive) scale (standardized mean difference (SMD) −0.11, 95% confidence interval (CI) −0.16 to −0.06; 13 studies, 9895 participants; moderate certainty).
Functional Ability: Amyloid‐beta‐targeting monoclonal antibodies probably result in little to no difference in functional ability as measured on the ADCS‐ADL (Alzheimer’s Disease Cooperative Study ‐ Activities of Daily Living) scale (SMD 0.09, 95% CI 0.03 to 0.16; 3 studies, 3478 participants; moderate certainty) and may result in a small increase in functional ability if measured with the ADCS‐iADL (Alzheimer’s Disease Cooperative Study‐Instrumental Activities of Daily Living) scale (SMD 0.21, 95% CI 0.10 to 0.32; 1 study, 1252 participants; low certainty) or ADCS‐ADL‐MCI (Alzheimer’s Disease Cooperative Study ‐ Activities of Daily Living for Mild Cognitive Impairment) scale (SMD 0.23, 95% CI 0.12 to 0.33; 4 studies, 2802 participants; low certainty).
Authors’ conclusions: The effect of amyloid‐beta‐targeting monoclonal antibodies on cognitive function and dementia severity at 18 months in people with mild cognitive impairment or mild dementia due to Alzheimer’s disease is trivial, while on functional ability, it is small at best. Amyloid‐beta‐targeting monoclonal antibodies increase the risk of amyloid‐related imaging abnormalities. Both desirable outcomes and adverse events were inconsistently reported in the studies included in the review.
Successful removal of amyloid from the brain does not seem to be associated with clinically meaningful effects in people with mild cognitive impairment or mild dementia due to Alzheimer’s disease. Future research on disease‐modifying treatments for Alzheimer’s disease should focus on other mechanisms of action.
Whatever the eventual outcome of research on AD, it seems clear that the amyloid plaques and tau protein tangles may be a consequence of the underlying pathology instead of a cause of Alzheimer’s dementia. As Karl Herrup put it in his book, the entire research “enterprise” into AD is an objective lesson in How Not to Study a Disease: The Story of Alzheimer’s. (discussed previously here). And to reiterate something I tend to repeat, the first thing to read in a scientific paper is the Acknowledgments to determine what organization paid for the research. The most important first thing to read was previously the abstract/summary. That has changed since the Bayh-Dole Act of 1980 redirected basic biomedical research from explaining the natural history of disease to getting rich from basic biomedical research, whatever the outcomes were. In this case, the key is this: All of these studies were funded by the pharmaceutical industry, which by definition cannot be disinterested in the outcomes of the research, despite protestations to the contrary.
It is not too difficult to lay some of the current disappointment with the scientific “enterprise” at the feet of our failures with AD. The AD community has responded by noting that the Cochrane authors have forgotten that there are people whose hope is based on the promise of these drugs. This is indeed true, but false hope is worse than no hope.
Part the Second: There Is Always More to the Story. The neurologist Steven Novella at Science-Based Medicine (SBM) notes that the Cochrane review is controversial, for the good reasons that prompted me to note at the beginning of Part the First that Cochrane is not infallible. In this case they may have stacked the deck by including monoclonal antibodies that had previously been shown not to work. From SBM:
Successful removal of amyloid from the brain does not seem to be associated with clinically meaningful effects in people with mild cognitive impairment or mild dementia due to Alzheimer’s disease. Future research on disease‐modifying treatments for Alzheimer’s disease should focus on other mechanisms of action.”
That is pretty devastating. But the fact that they looked at 17 studies was an immediate red flag for me – I didn’t think there were 17 studies of the currently two approved drugs. There isn’t. The authors looked at every monoclonal antibody that targets amyloid, including those that have previously been shown not to work. They included aducanumab, bapineuzumab, crenezumab, donanemab, gantenerumab, lecanemab, ponezumab, remternetug, and solanezumab (the “mab” stands for monoclonal antibody).
…
It’s important to understand that the precise role of amyloid in AD vs other potential mechanisms is a decades-long heated debate among AD researchers. After decades of negative clinical trials, many researchers were pushing for the conclusion that amyloid is simply a dead end therapeutically. Then lecanemab and donanemab showed clear (but modest) clinical benefit, and it was the turn of the amyloid theory promoters to do their victory dance. Even though the clinical benefits might be small, it was taken as a proof of concept – the amyloid hypothesis must be onto something.
In this context, this latest review might be seen as a counterattack by the anti-amyloid brigade. That might explain why the researcher chose to include all anti-amyloid monoclonal antibodies, not just the ones that have been previously shown to work. It also explains their rather pointed conclusion – “Future research on disease‐modifying treatments for Alzheimer’s disease should focus on other mechanisms of action.” Should it, really?
…
Going forward we need to do several things. First, continue to advance our screening efforts and ability to diagnose AD early, because the earlier the treatment the more effective it is, and this can be a massive factor. Second, we need to separate AD into various subtypes – as the above study concludes, we need to confirm the role of amyloid and determine how much of a role tau is likely playing also. We need to combine this with genetic data and family history. Together we can then target a suite of specific treatments towards individual patients. But of course, we have to develop the individual treatments first, and the anti-amyloid mabs are just the first step.
Finally, we need to continue to explore other mechanisms at work in AD and target them as well, not just amyloid and tau, but inflammation and vascular pathology. Perhaps in 20-30 years, or even sooner, we will have a cocktail of treatments, each of which individually has a modest benefit, but together have a significant benefit for slowing down AD. Since AD tends to present in older age, slowing down progression can mean that many patients die with AD rather than from AD, and while still highly functional.
In the end, I am not even sure what role this latest review plays. By mixing older drugs that don’t work with newer ones that do it seems designed to muddy the waters, and to have a negative outcome. This is likely just to confuse the public, and is being used by regulators to justify not paying for these newer treatments.
The best path going forward is to return basic biomedical research to disinterested scientists while supporting them in the long term this research requires. We can afford it. Or more importantly, we cannot not afford it. Am I a disinterested advocate here? Absolutely not. But throughout my scientific career I have seen first-hand what so-called “blue sky” basic research can do. In this I have been very fortunate to contribute to research that turned out to be revolutionary. These first steps cannot be dispensed with, even if we must go back to the beginning after many years traipsing down the wrong path. And as Dr. Novella notes, maybe by slowing down AD progression our children my die with AD instead of from AD. This is devoutly to be wished. One lesson for today is when you read about the latest remarkable advances in clinical medicine, remain patient and wait to see what actually happens.
Part the Third: Books Worth Considering, in Brief, especially when books are disappearing from university bookstores (and libraries – I speak from experience) or hidden in off-site repositories where in the future, writers, historians, and general browsers will never know that the book they found the card catalog is next to the book they really need but didn’t know that until eyes were laid upon it. There is an essay in there somewhere for the current president of my undergraduate and graduate institution…not that the typical university president has ears to listen to much except ESPN and US News and World Report.
Complete Works of Aristotle. Or to be more precise, the Nicomachean Ethics. Hackett Publishing Company has recently published this magnificent two-volume edition of the Complete Works of Aristotle. A friend of more than fifty years put me onto Book 4.3, which is entitled Greatness of Soul. In the Revised Oxford Translation in the Bollingen Series, this section lacks a title and “Pride” is used instead of “Greatness of Soul” in the first sentence. Pride certainly seems more relevant to our world of today, but I’ll go with Greatness of Soul (not that I have any Ancient Greek myself beyond the ability to parse a few Greek words phonetically):
Greatness of soul (magalopsuchia), even from its name, seems to be concerned with great things (megala), and our first task is to grasp what sorts of things these are…
The person, then, who thinks himself worth of great things and is worthy of them seems to be great souled; for the person who does the same but not in accord with its worth is silly, while no one who is in accord with virtue is silly or lacks understanding…
The person who thinks himself worthy of great things when he is unworthy of them is conceited…
The great-souled person – if indeed he is worthy of the greatest things – would be the best person; for the better person is always worthy of what is greater, and the best worthy of what is the greatest. Therefore, the truly great-souled person must be good. Indeed, it would seem characteristic of the great-souled person to be great in each virtue. And it would never be fitting for the great-souled person to flee with his arms pumping like a runner’s or to do injustice…And if one investigates particular cases, the great-souled person would appear completely ridiculous if he were not good. Neither would he be worthy of honor if he were base; for honor is a prize of virtue and is awarded to good people.
Good, great-souled, honorable, virtuous. Where are these men and women today? Why are they so hard to find among our erstwhile leaders? How can we get them back? They are liberal, conservative, socialist, anarchist, pacifist, willing to listen and willing to work together. However, they are not part of the Uniparty, as seen on TV, that is destroying the world. What is ancient Greek for megalomaniac? Google translate says μεγαλομανής. But Aristotle undoubtedly had a better word.
Gilded Rage: Elon Musk and the Radicalization of Silicon Valley. Jacob Silverman is not to be missed, whether you are on this side or that side. Samples:
Ridiculing their own employees on social media, laying off masses of workers to preserve declining profit margins, and backing vulgar culture warriors like Florida governor Ron DeSantis (of Yale and Harvard, who has destroyed New College in Sarasota, which was a bright light in public higher education, largely because he couldn’t really defend himself from their implicit criticism) before lining up behind the authoritarian Donald Trump (a mild description), tech industry leaders have, it seems to me, become their own threat to democracy, clawing at society’s threadbare fabric rather than working to mend it.
Silicon Valley Elites tended to dismiss expertise. “Everything you read makes sense if you simply translate ‘experts’ into ‘crazy people, according to Marc Andreesen…Their worldview upheld the pretense that creative destruction and technological innovation were synonymous with progress. If expertise is worthless – because experts themselves represented the corruption of the ancient regime – then tech was a salvific force. And the people leading the tech vanguard were the ones doing the saving.
(Larry) Page (of Google) wasn’t the first to think that technological innovation was outstripping democratic governance…But for Page and other tech leaders, democracy’s supposed lagging behind capitalist technological innovation was to privilege the latter.
Any attempt to stop or slow this pursuit – to argue for a focus on the ethics of AI and automation; to curtail massive resource consumption of AI data centers – was immoral. Public skepticism and government regulation were delaying humanity’s enjoyment of the guaranteed future benefits of AI, which would extend across every industry and discipline. AI would save lives – already, some AI systems showed themselves to be useful at parsing CT scans and X-rays. If we tempered this technological progress through more regulation, people would die.
The Rule of Experts has largely gotten us into this jackpot, but the corollary is not that relevant expertise is unnecessary. Anyway: Neoliberalism: First markets, then go die! Thank you, Lambert Strether. Funny how the denizens of Silicon Valley love markets while working hard to live forever. They have their bolt holes in Hawai’i and New Zealand. But can they really trust their pilots and Pinkertons when the going gets really tough? As Mark Blyth has put it the Hamptons are not a defensible position. [1] And neither are the wilds of Hawai’i or New Zealand.
Chasing My Cure: A Doctor’s Race to Turn Hope into Action. Several years ago, I was privileged to hear David Fajgenbaum recount his successful struggle to overcome idiopathic multicentric Castleman disease (TMI). Dr. Fajgenbaum did this with a relentless drive to understand the underlying cellular pathways associated with Castleman disease. And he was successful only because of the basic research on signal transduction pathways. For example, the mTOR signaling pathway (mechanistic/mammalian target of rapamycin) that was crucial to success with Castleman disease was the outcome of a research project on Easter Island more than sixty (60) years ago “with the goal of identifying natural products from plants and soil with possible therapeutic potential” (from Wikipedia but a good basic description of the science).
Early in my scientific career I was adjacent to a group of organic chemists who isolated alkaloids from plants, fungi, and other soil organisms. Some of my colleagues called this “stamp collecting,” not having the self-knowledge we were doing the same thing. Projection is a common thing and seldom is it benign. The chemists never knew what they would find (neither did we), but some of them found compounds like rapamycin, named for Rapa Nui, Easter Island. As of yesterday, PubMed had 61,541 scientific papers that included the term “rapamycin.”
Capitalism and Its Critics – A History from the Industrial Revolution to AI. John Cassidy’s survey is one of the most useful I have ever read. The usual suspects are included, often with a fresh take on their significance. And then there are critics of capitalism such as Anna Wheeler, born in Ireland in 1785. From her speech in London in 1829 on the “Social Condition of Women”:
I feel the difficulty of employing a moderate language, in speaking of the degraded position of my sex…But what appears to me the most cheerless part of my task – I would almost say “forlorn hope of my enterprise” is that I am doubtful, whether any material good can be effected by this and simoiar lectures, seing as I do, the rottenness of our institutions, and those especially which smell of rank injustice, in the disabilities set up against half of the human race: WOMAN!
Likewise, Adam Smith, who always understood the mind of the big businessman eager to make his mark in and on the world rather than to be a good citizen and neighbor. The Scots, especially from Fife – the home of golf – they are a perspicacious bunch. Regarding the East India Company. From the third edition (1784) of The Wealth of Nations:
Smith adduced another reason why chartered trading companies tended to get into financial trouble: they were joint-stock companies rather than traditional business partnerships. Many modern textbooks emphasize how investing in stocks enables investors to spread their risks and protect their capital. Smith expressed a very different view. In a partnership…the owners of the business put their entire wealth on the line, which imbues them with some caution. By contrast, the executives of a joint-stock company enjoy limited liability: their financial risk is limited to the value of the shares they own. Smith warned: “The directors of such companies…being managers rather of other people’s money than their own, it cannot well be expected that they should watch over it with the same anxious vigilance with which the partners in private copartnery frequently watch over their own…Negligence and profusion, therefore, must always prevail, more or less, in the management of the affairs of such a company.”
So saith the “unqualified defender of capitalism” in the common understanding. But really, he had no idea of what was to come in the nineteenth century and thereafter.
Thank you for reading! See you next week from the road, as best I can.
Note
[1] My (Mark Blyth) point was not to recommend invasion. Rather, I was pointing out that if increasing inequality was behind the anger driving our politics today (it is), then those who benefitted most from that inequality – the famous top 1% – cannot self-insure against its effects with Private schools, Private Jets, Private Estates, and Private Security. History shows that eventually all such strategies fail as the anger in the wider society spills over, and then the folks at the top have a choice. They can either accept a politics that lowers the inequality, or they can face the proverbial pitchforks, even out in the Hamptons, that Long Island enclave long associated with the wealthiest Americans.
Four years later, in the middle of a pandemic, it seems that the folks with the pitchforks have figured out where the Hamptons are and it’s not a defensible position after all. In response, the folks in the Hamptons have done what threatened elites always do in such situations, they hire mercenaries, or as we call them today, more private security. The problem with such a move is that you can’t buy a private solution (build walls) for a public problem (rising anger). Finding Elysium or an island off Fiji run on Bitcoin, are not viable exits. Eventually, those on top need to recognize that their fates are not separable from those of their fellow citizens, and they are your fellow citizens, not a threat to be managed. Throughout history, most elites have failed to recognize this and things get worse before they get better. Let’s hope that the smart money in the Hamptons gets the memo this time around.
