Is Moderate Alcohol Consumption Dangerous?

Is Moderate Alcohol Consumption Dangerous?

Last month the Journal of Studies on Alcohol and Drugs (‘JSAD’) published a large data review comparing mortality rates in light-to-moderate drinkers with mortality among people who don’t drink alcohol. The NY Times [https://www.nytimes.com/2026/06/09/well/alcohol-health-risks-study.html] and others gleefully picked up the story, trumpeting the most provocative finding: Up to 1 in 25 moderate drinkers will die because of their alcohol intake. SAD! As always, the study deserves a close look. For my part, I did not know about the SAD journal, so this was a welcome chance for me to see what kind of SAD research it’s offering. It turns out the SAD paper is a review of earlier studies. No new data is offered. The researchers selected their data from earlier studies of “conditions with established causal relationships to alcohol.” Hmmm. There are only a few such causes of death that are ‘established’. For instance, deaths due to alcoholic liver failure, and fatal drunk driving accidents. Both can comfortably be attributed to alcohol. In contrast, as I’ve written [https://researchtranslation.substack.com/p/cancer-and-alcohol-revisited] before and shown extensively [https://researchtranslation.substack.com/p/unspun-alcohol-and-cancer-risk], on careful inspection almost every cancer that researchers have often claimed is caused by alcohol turns out to have, at best, a fatuous statistical association with alcohol. Indeed, not one of those associations can plausibly be described as causal (much less ‘established’) by any honest expert of epidemiology or research translation. This mis-attribution of cancer deaths isn’t a new problem. In 2024 the Surgeon General launched a campaign [https://time.com/7204606/surgeon-general-cancer-warning-alcohol/] making frightening claims about the dangers of moderate alcohol intake and cancer, only to be embarrassed a few days later when a comprehensive review [https://www.nationalacademies.org/projects/HMD-FNB-23-06/publication/28582] by the National Academy of Sciences—written by real researchers, carefully and honestly examining the data—found the opposite. Having sifted the alcohol data myself, I can confirm these findings. I can also testify to the hidden agenda driving many public health claims on alcohol: In 2009, while I was teaching a class in research translation at Columbia University, a prominent public health official asserted [https://academic.oup.com/jnci/article-abstract/101/5/282/913810?redirectedFrom=fulltext&login=false] that “There is no level of alcohol consumption that can be considered safe.” When my students and I emailed him to ask about the claim, he basically admitted [https://researchtranslation.substack.com/p/surgeon-generals-unwitting-message?utm_source=publication-search] that he knew this was untrue, but hoped scaring people might reduce drunk driving. SAD? Back to the SAD study: There is a wonderful and informative figure in the paper that, to my eye, answers a question the headlines never asked: What exactly are these ‘alcohol deaths’? The figure above shows accumulating causes of death in different color bands, on a graph that plots number of deaths against alcohol consumption. First, note that most deaths ‘caused by alcohol’ in men are due to injuries. Hmmm. How might we understand this finding in the context of the evening drink that most headline readers are now second-guessing? For instance, did my father’s longstanding tradition of an evening martini put him at risk of a tragic refrigerator incident? If so, I never saw any close calls. On the other hand, I suppose I can understand how, for people who find high speed driving and forestry irresistible after their martini, moderate drinking may represent a serious threat. Fortunately, my father doesn’t have that problem. After ‘injuries’, the next most important cause of death due to alcohol in the Figure is liver cirrhosis, for both men and women. Cirrhosis deaths rise with alcohol intake, as one would expect. But remarkably, the risk begins to appear in the Figure at one drink per week. Obviously, that suggests a problem in the data: reporting bias. These data are based on survey studies, and—shocker—people aren’t always honest about their drinking. Which seems pret-ty obvious when a study claims that a drink a week can cause fatal liver disease. Because that isn’t how liver disease works. In a recent review [https://pmc.ncbi.nlm.nih.gov/articles/PMC6776700/] more narrowly focused on cirrhosis risk, alcohol consumption was not even statistically associated with cirrhosis until respondents reported at least two drinks per day. It took five drinks a day for the numbers to look consistent and causal. But do we even need studies to know that claim was bunk? The notion that a drink a week can kill someone due to liver failure doesn’t pass the whiff test. Instead, it says more about the reliability of the data than it says about alcohol. SAD! Finally, the figure makes it clear that if we remove injuries (don’t play with chainsaws) and remove liver failure (your ‘one’ drink shouldn’t be a Venti) all of the remaining risk was due to cancer. Here, once again, the problem is real—but it is relegated to severe alcoholics. I’ve been through [https://researchtranslation.substack.com/p/unspun-alcohol-and-cancer-risk] these data over [https://researchtranslation.substack.com/p/cancer-and-alcohol-revisited-10c] and [https://researchtranslation.substack.com/p/surgeon-generals-unwitting-message] over [https://researchtranslation.substack.com/p/the-alcohol-cancer-wars-when-studies] and I invite you to check my work. In short, esophageal and liver cancers occur more often in very heavy drinkers, but in moderate drinkers the numbers are barely [http://researchtranslation.substack.com/p/cancer-and-alcohol-revisited-10c] different. For most other cancers the numbers are similar for moderate- and non-drinkers. There are even a few cancers (kidney, thyroid, lymphoma) mathematically less common in drinkers than non-drinkers. Which brings us to an interesting finding: Check out the red areas on the graphs. Cardiovascular deaths, the most common cause of death, were LOWER with moderate alcohol intake. HAPPY! Unfortunately, none of the associations found in the underlying studies represents a cause-and-effect relationship. Even the ones we like. There is neither an important protective effect nor a mortality risk. Whether the category is cardiovascular death or cancer, the small differences found between moderate- and non-drinkers aren’t because of drinking habits. They are because people who do and don’t drink are different to begin with: genetically, environmentally, culturally, socio-economically, geographically, and otherwise. So they have different rates of cancer. Is moderate alcohol intake a threat to your health? The NY Times wants you to think so, as do the public health experts who wrote the study. But most readers who see the headline will naturally picture damage done by alcohol itself. Yet the majority of colored territory in the figure is for injuries—drunk driving, falls, drownings, violence, and other behavioral consequences that can be associated with alcohol use. Apparently the greatest danger from moderate drinking isn’t liver failure. It’s an irresistible urge to climb ladders, operate chainsaws, and drive into trees. Meanwhile, non-injury deaths in this dataset are almost entirely due to severe alcoholism. Headlines like “1 in 25 killed by moderate drinking” sound frightening because they invite you to picture something the study never actually observed: ordinary people dying because they enjoy a glass of wine with dinner. That’s not what this paper found. Instead, it bundled alcoholism, injuries, and weak associations into one emotionally charged statistic, then attached the words ‘moderate alcohol intake’. That’s how SAD research, and SAD translation works. It isn’t built on outright fabrication. Instead, it’s built on selecting words that lead people to picture something the data never actually showed. Get full access to Research Translation at researchtranslation.substack.com/subscribe [https://researchtranslation.substack.com/subscribe?utm_medium=podcast&utm_campaign=CTA_4]

Alzheimer's and Amyloid, A Summary

What you see below is not grape soda. It is urine from a human being—Purple Urinary Bag Syndrome, as it’s called, is quite something to behold. But it is brief, and happens when bacteria interact with the plastic of a urinary bag. Treating the underlying infection (typically mild, if there is one) is all that’s required. The color is a distraction. At the Royal Psychiatric Clinic in Munich, Germany, in 1906 a similar distraction was discovered by an enterprising young neurologist named Alois Alzheimer. On slides from the brain of a woman who died of early-onset dementia, Dr. Alzheimer saw plaques that looked deeply abnormal, crying out for explanation. Surely something so striking must be the cause, he thought. But that is not a question that can be answered by gestalt, as the German doctor might have said. It is a question for wissenschäft — for science. In part 1 [https://researchtranslation.substack.com/p/alzheimers-and-amyloid-5-the-big] we reviewed two autopsy studies from the 1990s, the first real scientific test of Dr. Alzheimer’s hypothesis that amyloid plaques cause dementia. His Amyloid Hypothesis failed: both found no association between amyloid burden and dementia. In Part 2 [https://researchtranslation.substack.com/p/alzheimers-and-amyloid-2-mistakes] we saw landmark studies from the early 2000s that again disproved the Hypothesis. In a mouse model of Alzheimer’s the plaques appeared—but only after dementia developed. Karl Popper, the father of modern scientific reasoning, would have called these findings ‘black swans’—each one potent enough by itself to discard the Amyloid Hypothesis. Popper argued that the surest path to truth is not proving hypotheses, but trying to disprove them. His touchstone example was black swans, clear proof that “All swans are white” is a hypothesis to be discarded. Despite repeated black swans for the Amyloid Hypothesis, in 2005 amyloid devotées pressed forward with a novel vaccine for people with early Alzheimer’s. The vaccine successfully cleared amyloid from the brain—and their dementia progressed, unchecked. It was the most irrefutable black swan yet. By every standard of scientific reason, the Amyloid Hypothesis was dead. Some amyloid researchers pivoted, perhaps desperately, hoping to find invisible precursors that might salvage a role for amyloid. This also did not end well: In Part 3 [https://researchtranslation.substack.com/p/alzheimers-and-amyloid-3-the-mistake] we reviewed the precursor ‘star-56’, presented in a 2006 paper. Its ‘discovery’ turned out to be, arguably, the greatest fraud in the history of modern neuroscience. We also saw that while amyloid’s star fell to earth, the clinical enterprise became increasingly invested in amyloid plaques. Imaging companies engineered PET scans to visualize them, chemistry companies developed blood tests to detect them, and pharmaceutical companies created dozens of drugs to remove them. Which led to something remarkable—though eerily familiar. Instead of asking whether removing amyloid helps people, the field gradually began asking whether removing amyloid… removes amyloid. The endpoint changed. The question was no longer whether people improved, it was whether amyloid improved. In Part 4 [https://researchtranslation.substack.com/p/alzheimers-and-amyloid-4-the-long] we therefore saw industry trials designed to find differences between their drug and a placebo that people could not perceive. Amyloid was removed. People didn’t get better. Then, in Part 5 [https://researchtranslation.substack.com/p/alzheimers-and-amyloid-5-the-big], we saw the final capitulation. Medical journals called amyloid drugs ‘disease-modifying’. PET scans and blood assays that were actually for amyloid became, in the lingo of the establishment, “tests for Alzheimer’s.” Alzheimer’s Disease, in other words, became Amyloid Disease. How could this happen? History is our guide—we have seen this movie before. Doctors and scientists, like all of us, are irresistibly attracted to elegant explanations. One lesion, one pathway, one cure. This plaque causes Alzheimer’s. This cholesterol causes heart disease. This tear causes knee problems. Human biology, however, is virtually never that simple. Which is why the history of medicine is littered with visually striking pathology that rises to mythical, unimpeachable status. Doctors, industries, and systems inevitably stake careers—and commerce—on finding and fixing these culprits. Remove amyloid! Open arteries [https://researchtranslation.substack.com/p/are-coronary-stents-killing-people]! Repair cartilage [https://researchtranslation.substack.com/p/surgery-to-treat-knee-degeneration]! Lower cholesterol [https://researchtranslation.substack.com/p/cholesterol-5-the-power-at-your-end?utm_source=publication-search]! It then takes generations to wind down the mythology. Why does this pattern repeat, and redound? Because humans and their systems are easily captivated by stories and pictures—in other words, by gestalt. In some domains, like art, this works in our favor. But in pursuit of scientific truth it does not. The purpose of wissenschäft, of science as described by Popper, is to force us, repeatedly and sometimes painfully, to abandon the theories that fail—the path to truth. Scientific, and thus human, progress depends on finding black swans, and even welcoming them. Sadly, after more than a century of amyloid research, including hundreds of billions in grants, laboratories, scanners, blood tests, and drugs, people with Alzheimer’s suffer much as they always have. Not because science failed—because we failed to follow it. Instead of abandoning a theory that failed, we abandoned scientific method. And in doing so, we abandoned the patient. Because disease is not what appears under a microscope. Disease is what happens to people. Get full access to Research Translation at researchtranslation.substack.com/subscribe [https://researchtranslation.substack.com/subscribe?utm_medium=podcast&utm_campaign=CTA_4]

Alzheimer's and Amyloid 5: The Big Mistake

In part 2 [https://researchtranslation.substack.com/p/alzheimers-and-amyloid-2-mistakes] of this series I described a trial [https://www.neurology.org/doi/10.1212/01.WNL.0000159740.16984.3C] in which researchers developed a novel vaccine for Alzheimer’s patients, designed to rid the brain of amyloid. The vaccine worked, clearing amyloid—but their dementia progressed, unabated. This was, in other words, a full debunking of any notion that amyloid plaques are the cause of Alzheimer’s and that removing them can cure the disease. Interestingly, in a 2008 follow-up report [https://www.thelancet.com/journals/lancet/article/PIIS0140673608610752/fulltext] on the study, a curious turn of phrase caught my eye: Do you see it? Did you feel the tectonic shift? In a single sentence the authors both tout their success with “disease modification,” and concede that removing amyloid didn’t help people. In other words, the ‘disease’ was not memory loss or crippling cognitive decline. It was amyloid. Which they ‘modified’. The operation was a success—but the patient died. RT is fully reader-supported. To keep doing it, I need help. Please consider paying for a subscription. Lest you believe this kind of language is isolated or antique, this week’s Journal of the American Medical Association, the worlds most circulated medical journal, includes an article about Alzheimer’s, with a review of the history of amyloid targeting. In it the author, an NIH neuroscientist, describes the anti-amyloid drug Aduhelm as “the first ever disease-modifying drug,” while acknowledging that it failed to help people. He also describes the two recent anti-amyloid drugs as beneficial, and ends with a breathless look to the future of amyloid research. Why should this language matter? Here is why: Incredibly, this 2024 NY Times article describes a study [https://jamanetwork.com/journals/jama/fullarticle/2821669] of a novel blood test for brain amyloid. Not for dementia. Or cognitive decline. Or human suffering. In other words, not for Alzheimer’s Disease—not as it is experienced by people—but for amyloid. Yet, the headline calls it ‘Alzheimer’s’. This is where decades of amyloid-centered thinking inevitably led. It began with the identification of brain amyloid, moved to the invention of highly specialized PET scans to see amyloid, and culminated in a blood test whose only purpose is to detect fragments of the amyloid seen on PET scans. The new blood tests are therefore not tests for Alzheimer’s disease. They are tests for amyloid, which they detect readily. And that is why they constantly miss Alzheimer’s when it is truly present, while labeling people with Alzheimer’s who don’t have it. (For the numbers, check out my 2024 piece [https://researchtranslation.substack.com/p/the-new-alzheimers-test-is-part-of]). The test, in other words, fails miserably to identify Alzheimer’s Disease, because amyloid and Alzheimer’s are not the same thing. The distinction may seem trivial, but it represents one of the most consequential shifts in modern medicine. For more than a century, Alzheimer’s was a human condition: progressive loss of memory, reasoning, language, independence, and ultimately self. It was a disease experienced by patients and families. Amyloid was just one proposed explanation. But when it repeatedly failed, something happened: Rather than abandon the explanation, the field redefined the disease. The question quietly changed from ‘Does this person have Alzheimer’s dementia?’ to ‘Does this person have amyloid?’ Everything else followed naturally. PET scans no longer needed to identify dementia—just amyloid. Blood tests no longer needed to predict who would lose their memory, they only needed to detect amyloid. Drugs no longer needed to help people, they had to remove amyloid. The microscope, the scanner, and the laboratory, all quietly replaced the patient. This is the Big Mistake, the same mistake that medicine repeatedly makes. In cholesterol [https://researchtranslation.substack.com/p/cholesterol-the-big-mistake], LDL gradually became more important than survival, or quality of life. In orthopedics [http://researchtranslation.substack.com/p/orthopedic-surgerys-big-problem], MRI abnormalities became more important than pain, or function. And now, in Alzheimer’s, amyloid became more important than dementia. People want to live longer and better, while doctors aim to seek pathology and diagnose disease. Doctors, and by extension the medical establishment, fail most tragically when they forget to put people first. Disease is not what appears on a PET scan, or an MRI, or in a cholesterol test, or under a microscope, or in a test tube. Disease is what happens to people. When medicine forgets that distinction, it treats pathology, not patients. And that is how Alzheimer’s gradually ceased to mean dementia, and came to mean amyloid. That is the Big Mistake. Next week we’ll talk about how intelligent, compassionate physicians can be swept up by pathology what it all means, and how you can avoid the traps that have been laid by a multi-industry machine carefully crafted to profit from the Big Mistake. Get full access to Research Translation at researchtranslation.substack.com/subscribe [https://researchtranslation.substack.com/subscribe?utm_medium=podcast&utm_campaign=CTA_4]

Alzheimer's and Amyloid 4: The Long Mistake

Over the first three parts in this series we followed the rise and fall of the Amyloid Hypothesis. The plaques failed. The idea of toxic precursors failed. The most influential oligomer paper in the field was ultimately retracted. By any ordinary standard of scientific reasoning, this should have marked the end of amyloid as a central explanation for Alzheimer’s Disease. Instead, something remarkable happened: As the scientific case for amyloid weakened, the clinical investment in amyloid accelerated. Drug companies continued developing anti-amyloid therapies. Regulators continued evaluating them. Researchers continued measuring amyloid. Billions of dollars flowed into a treatment strategy increasingly disconnected from the evidence. The result was the modern anti-amyloid drugs. What follows is two short essays I wrote about the clinical trials that won FDA approval for two of them. In both cases drug makers quite literally designed the trials to prove that the drugs DON’T help people with Alzheimer’s, apparently with full confidence that they could spin the results to suggest the opposite. It is among the most brazen examples of FDA game theory, and snake oil sales, that I can recall in decades of reviewing FDA trials. New Alzheimer’s Drugs Are Bringing Back the Wrong Memories Apr 03, 2024 I remember when, in 1999, the FDA approved Vioxx, a pain reliever that went on to kill an estimated 50,000 Americans. According to whistleblowers [https://journals.plos.org/plosmedicine/article?id=10.1371/journal.pmed.0020209] the FDA not only had the data to prevent the tragedy, they obstructed the investigation. I also remember the inspiring story of Frances Kelsea, an FDA physician who in 1960 refused to approve thalidomide despite approval in dozens of other countries, and industry pressure. The drug caused over 10,000 birth defects worldwide, but just 17 in the US where it was never approved. Now, in 2024, the FDA is on the verge of approving [https://www.nytimes.com/2024/03/08/health/alzheimers-drug-donanemab.html] a third Alzheimer’s Disease drug. The first was Aduhelm in 2021, the second was Leqembi, in 2023. Donanemab, the third, is under review. The three are extremely similar. They’re all monoclonal antibodies, they all reduce amyloid plaques in the brain, and they all don’t work. In the 1980s researchers discovered amyloid plaques were associated with Alzheimer’s, spawning the ‘amyloid hypothesis’. If the plaques cause cognitive decline, it was hoped, removing them may slow or even reverse Alzheimer’s. Unfortunately, the theory has been dashed. First, studies show [https://jamanetwork.com/journals/jamaneurology/fullarticle/2427382] many with Alzheimer’s have no brain amyloid [https://www.alzforum.org/news/research-news/when-theres-no-amyloid-its-not-alzheimers]. Second, scientific reviews [https://www.sciencedirect.com/science/article/pii/S1568163721002439] show at least 72 anti-amyloid agents have been researched, and none have worked. This includes nine monoclonal antibodies, a class that has failed so miserably and consistently a 2021 meta-analysis announced [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8251763/] “the time has come to divert therapeutic efforts away from AAB [amyloid] immunotherapy.” Abject failure is certainly the case for Aduhelm [https://www.aafp.org/pubs/afp/issues/2022/0400/p353.html#afp20220400p353-b1]. Two FDA studies were halted early for futility [https://link.springer.com/article/10.14283/jpad.2022.30], and an expert panel voted 9-1 against approval (the FDA approved it anyway). Meanwhile, Leqembi ‘slowed cognitive decline’ [https://www.nejm.org/doi/full/10.1056/NEJMoa2212948] by just 0.45 points on an 18-point scale, less than half the 1-point minimum deemed meaningful [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3034393/]. Finally, the donanemab trial [https://jamanetwork.com/journals/jama/fullarticle/2807533#note-JOI230087-1] used a 144-point scale and reported a 3-point edge, well below the 9-point minimum determined by the company’s own research [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9169866/]. These failures highlight a crucial distinction: statistical versus clinical differences. Studies often find a ‘statistical’—meaning mathematically identifiable—difference between groups. But research is a human task and thus inherently biased, so trial results commonly lean toward the drug. Particularly in large trials (the Alzheimer’s trials enrolled thousands) this often leads to a ‘statistical’ difference. But a clinical difference affects people’s lives. Which is why there are thousands of studies examining and meticulously defining the ‘minimal clinically important difference [https://pubmed.ncbi.nlm.nih.gov/?term=minimal+clinical+difference]’ for scales like those in the Alzheimer’s trials. Those studies tell us the ‘differences’ in the antibody drug trials were so small that people with the disease, their families, and their doctors, would literally never notice them. In other words, they’re not real differences. Another issue may also be confusing starry-eyed loyalists. The drugs removed amyloid plaques quite effectively—a finding that closes the door on the amyloid hypothesis. Vanquishing amyloid plaques didn’t help people with Alzheimer’s. The chicanery of parading differences well below the thresholds for true benefit is happening now for a reason: We’re heading into a perfect storm of potential profit for AD drugs. Nearly 7 million in the US have symptomatic Alzheimer’s, with an expected doubling by 2050. This will likely balloon with the use of new, flawed blood tests that severely over-diagnose Alzheimer’s [https://www.nytimes.com/2024/03/04/health/alzheimers-amyloid-diagnosis.html]. And the drug, given through IV infusions, costs nearly $30K per year (not including infusion costs, facility fees, and other charges). A final tidbit: The drugs cause brain swelling, headaches, confusion, and occasionally death—in huge numbers. Donanemab, the latest, caused 24% of people’s brains to swell, while another 9% suffered infusion reactions. That’s 1 in 3 people seriously harmed by the drug, and zero helped. What’s worse, as noted in these pages [https://researchtranslation.substack.com/p/it-just-doesnt-matter-so-it-matters], one can always expect the harms to be greater and the benefits smaller than reported in trials. As the FDA wrestles with the amyloid drugs, it seems natural to remember the agency’s heroic performance on harmful drugs of the past. But an effective Alzheimer’s treatment would bring back different memories. Why the Alzheimer’s Drugs Won’t Make Your Burger Better Feb 04, 2025 I like a burger. With cheese. And lettuce and tomato and maybe onion and ketchup or sauce (house choice). I prefer it rare. Really rare. Like, true blue. This last part is the downfall of many a burger joint where, fearing liability, kitchens won’t make a rare burger. To me, besides corrupting its taste, this means dubious beef. Sushi, steak tartare, and raw bar items are much riskier than anything cooked, but they’re still common menu items. A kitchen that won’t make a rare burger doesn’t trust its sourcing and prep for burger meat. Sad! But crucially, rare burgers aren’t just hard to find, they’re also tricky to make because they must—MUST—be seared on the outside and lightly cooked on the inside. This delicate contrast, a pillowy but juicy inside with a firm outer layer, is the mouth-watering soul of a great burger. So for home burgering, I got a meat thermometer. To my surprise, the first time I used it the reading was 122.68°. Impressive precision! But this number was, as the kids say, TMI (not to mention sus). Because while my gifted palate is a wonder of epicurean virtuosity, I cannot tell a 1° difference in temperature, much less 0.01°. Those decimal points are not helping me. I can tell rare from medium-rare (I think). That’s about 10° different. Which means somewhere between 1° and 10°, for me, the difference becomes perceivable and thus potentially meaningful. If I was bored and curious I might experiment to find the threshold, and in research parlance we would call it the ‘clinically significant’ difference. This principle, also known as the minimal clinically important difference [https://pmc.ncbi.nlm.nih.gov/articles/PMC7366277/] (or ‘MCID’), defines the smallest improvement patients and doctors are able to perceive, a starting point for judging whether treatments provide a meaningful benefit. Curiously, however, all three FDA-approved Alzheimer’s drugs were tested in studies that are the equivalent of a 2-decimal point thermometer. Each trial enrolled way more people than needed to find improvements in dementia. Why? Because the more participants, the smaller a difference a study can find. But my thermometer, for instance, can detect differences that are much too tiny to matter. And so can studies. In research this is called over-powering, but in trials it’s very unusual. After all, genuinely helpful drug effects, even lowly MCIDs, aren’t tiny. So why would researchers go looking for tiny differences? Who even has the money and resources to enroll way too many people in a randomized trial?? Oh. Wait. As discussed in these pages before [https://researchtranslation.substack.com/p/new-alzheimers-drugs-are-bringing], a jarring attribute of the Alzheimer’s drugs is that trials proved they do not make a perceivable difference. One hapless employee at Eli Lilly even spent years studying (and writing at least seven reports [https://pubmed.ncbi.nlm.nih.gov/?term=%22Wessels%20AM%22%5BAuthor%5D]) to establish the MCID for cognitive impairment. He found it was at least 5 points on a 144-point scale for mild disease and 9 points for early Alzheimer’s. But his company’s drug Kisunla produced [https://jamanetwork.com/journals/jama/fullarticle/2807533] scores within 3 points of a placebo—in other words, indistinguishable from placebo. Meanwhile Biogen and Eisai’s drug Leqembi was within [https://www.nejm.org/doi/full/10.1056/NEJMoa2212948] 0.45 points of placebo on an 18-point scale—also less than half the established MCID [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3034393/] of 1 point. How could this happen? Were the studies purposefully over-powered? Or did they stumble upon tiny differences while seeking meaningful ones? In the Kisunla report [https://jamanetwork.com/journals/jama/fullarticle/2807533] Eli Lilly says they aimed to find a 3-point difference (!!!). The authors calculated that 1,000 participants would give them a 95% chance, or ‘power’, to find it. So they enrolled 1,000 people. Then they enrolled 736 more. What about Leqembi? The FDA approval trial [https://www.nejm.org/doi/full/10.1056/NEJMoa2212948] also, amazingly, targeted 0.4 points better than placebo (!!!). This, they found, required 1,566 participants—and they enrolled nearly 1,800. This is over-over-powering. The original plans were over-powered, and then each study ADDED extra enrollments. These are confessions, hidden in plain sight in the methods sections of the papers, and they mean the companies knew before the trials started that their drugs don’t help. So they targeted statistical—not perceivable—differences, then convinced the FDA to approve the drugs.1 [https://researchtranslation.substack.com/p/why-the-alzheimers-drugs-wont-make#footnote-1] Bonus question: How could the companies feel confident the studies would generate a statistical advantage for their drug? Answer: The double-dog placebo [https://researchtranslation.substack.com/p/antidepressants-tamiflu-and-the-double]. In their brilliant, deeply researched investigation [https://www.levernews.com/the-deadly-secrets-behind-breakthrough-alzheimers-drugs/] Jeanne Lenzer and Shannon Brownlee describe a woman who was convinced, and whose friend was convinced, Leqembi was rapidly improving her memory. But she was receiving a placebo. As placebo researcher Irving Hirsch explains in his wonderful book [https://www.amazon.com/Emperors-New-Drugs-Exploding-Antidepressant/dp/0465022006], placebo effects are common, but they’re reliably larger when people experience drug side effects. Side effects effectively unblind study participants, letting them know they’re on a real drug and amplifying their expectations, excitement, and thus placebo effects. One of the great ironies of modern scientific rigor, therefore, is that ineffective drugs in double-blinded trials can generate statistical advantages if they have harmful side effects. People given Leqembi in trials had infusion reactions 19% more often than those given placebos, and brain swelling 11% more often. That’s a lot of unblinding, easily enough double-dog placebo to virtually guarantee an advantage.2 [https://researchtranslation.substack.com/p/why-the-alzheimers-drugs-wont-make#footnote-2] My burger thermometer gives me too much information, and so did the trials for the new Alzheimer’s drugs. Deliberately over-powered trials are a smoking gun, telling us what the companies knew all along: Their drugs don’t work. The story of the anti-amyloid drugs is often presented as a story of disappointing results. Placed within the chronology of amyloid research they are better described as a story of entirely predictable results. By the time these drugs entered clinical trials, the Amyloid Hypothesis was decimated. Plaques did not track with disease. Dementia could appear before plaques. Removing plaques did not stop dementia. The proposed replacement—the Amyloid Precursor Hypothesis—fared no better, collapsing under a combination of failed replication, failed trials, and outright fraud. The drug trials therefore did not rescue the theory. They confirmed its failure. This is why the central mystery of the Alzheimer’s story is not scientific, it is etiologic: How did this happen and why? If the plaques failed, why did amyloid remain the target? When the precursors failed, how could amyloid still be of interest? If removing amyloid then failed to help patients, why are we still chasing it? The answer lies in one of the most successful acts of disease redefinition in modern medicine. Next time we’ll examine the blood tests, PET scans, and diagnostic criteria that transformed amyloid from a failed explanation into the disease itself. Get full access to Research Translation at researchtranslation.substack.com/subscribe [https://researchtranslation.substack.com/subscribe?utm_medium=podcast&utm_campaign=CTA_4]

Alzheimer's and Amyloid 3: The Mistake of the Invisible Friend

Neuroscientists are not famous for being dumb. So when the following timeline unfolded, they should have understood exactly what it meant: First, autopsy studies in 1991 [https://onlinelibrary.wiley.com/doi/abs/10.1002/ana.410300410] and 1992 [https://www.neurology.org/doi/10.1212/wnl.42.3.631] found that amyloid plaques—supposedly the cause of Alzheimer’s, as the centerpiece of the Amyloid Hypothesis—did not scale with the disease. Then, in 2001 [https://www.jneurosci.org/content/21/2/372] and 2002 [https://www.jneurosci.org/content/22/5/1858], researchers published data showing that an Alzheimer’s mouse model developed dementia—before ever developing plaques. Finally, in 2004 [https://www.neurology.org/doi/10.1212/01.WNL.0000159740.16984.3C] a vaccine successfully removed plaques from the brains of Alzheimer’s patients—yet their dementia continued to spiral, unabated. RT is fully reader-supported. For the price of a cup of coffee once a month from you, I can continue RT—please become a paid subscriber. It is hard to imagine a more obvious demise for the Amyloid Hypothesis. Some researchers, however, particularly those with funding and livelihoods tied to it, concentrated on the possibility that amyloid precursors might still be involved. If true, such a finding could preserve a role for amyloid researchers and their laboratories. But most precursors, detailed above, were well known, well studied, and stubbornly non-toxic. They could not explain the Alzheimer’s hallmarks of damaged tissue, lost synapses, and tangled detritus. Except, perhaps, for one, which remained a mystery. ‘Soluble oligomers’, theoretically the building blocks of fibrils, are exceedingly difficult to isolate because they are transient, tiny, and live in a dissolved state. Few labs had ever found them, much less studied their effects. Which is why it was blockbuster news in 2006 when Sylvain Lesné, at the University of Minnesota lab, pulled off a miracle with the potential to energize (read: fund) amyloid theorists everywhere. Despite the world’s prior work yielding—at best—messy, shaky evidence of oligomers, Lesné reported a clean, concrete, and copious yield of a new oligomer named beta-amyloid-*56, or ‘star-56’. Based on gel photos in Lesné’s paper [https://www.nature.com/articles/nature04533] the oligomer was clearly detectable in a mouse’s brain just days before the onset of dementia. Based entirely on this 2006 paper (since no other lab has ever reproduced the star-56 finding), for 16 years the star shone bright, offering an exciting new offshoot: The Amyloid Precursor Hypothesis. Then, barely in its adolescence, the new star flickered—and died. Matthew Schrag, an MD/PhD neuroscientist at Vanderbilt University, was hired by investors who suspected that an anti-amyloid drug maker’s claims were exaggerated. Schrag dug deep into the Amyloid Hypothesis and its derivatives, and came to Lesné’s study. In 2022, on a geeky post-publication review site called PubPeer [https://pubpeer.com/publications/8FF7E6996524B73ACB4A9EF5C0AACF], Schrag posted the following images and coolly accused the report of being a fraud. Soon, other super-sleuths jumped in. By the end, multiple forensic investigators and leading researchers flagged over 70 images from Lesné papers as likely to have been tampered with. For those interested in a full anatomy of the fraud, you can find it in Science [https://www.science.org/content/article/potential-fabrication-research-images-threatens-key-theory-alzheimers-disease], where the story [https://www.science.org/content/article/potential-fabrication-research-images-threatens-key-theory-alzheimers-disease] broke. On PubPeer you can also read the often cringe-worthy, years-long dialogue [https://pubpeer.com/publications/8FF7E6996524B73ACB4A9EF5C0AACF] between the researchers, Schrag, and others. In 2024 the paper was retracted after the Minnesota group (sans Lesné) finally conceded it had to be. Then, in a real head-scratcher, the senior author Dr. Ashe published a new paper [https://www.cell.com/iscience/fulltext/S2589-0042(24)00460-7?_returnURL=https%3A%2F%2Flinkinghub.elsevier.com%2Fretrieve%2Fpii%2FS2589004224004607%3Fshowall%3Dtrue] purporting to show that the original claims were all correct. The whole saga, she seemed to suggest, was just a silly misunderstanding. Who cares if you can’t see our friend Snuffleupagus—we can! The response from the research community was a collective eye roll. Dr. Schrag, for one, wasn’t having it. When Ashe touted their new paper in the PubPeer string [https://pubpeer.com/publications/8FF7E6996524B73ACB4A9EF5C0AACF], Schrag eviscerated each and every claim, concluding that the new version “objectively falls short of reproducing the earlier result.” Awkward. In any case, with the Amyloid Hypothesis dead, the crucial question was whether the Amyloid Precursor Hypothesis was viable, and the best answer is this: It’s been two decades, and no other research group has been able to even confirm the existence of star-56, much less replicate its effects. The few other oligomers that have been isolated suffer the same problem. The cherry on this debunking pie is the story of the BACE and GSI drugs, which inhibit the ‘secretase’ enzymes and therefore reduce virtually every precursor: monomers, oligomers, fibrils, and plaques. In clinical trials comparing them to a placebo, neither [https://www.nejm.org/doi/full/10.1056/NEJMoa1210951] drug class improved dementia—they both worsened [https://www.nejm.org/doi/full/10.1056/NEJMoa1812840] it. So, um, no. The Amyloid Precursor Hypothesis is no more viable than its fallen father. Next week, we’ll examine the unblushing audacity of anti-amyloid drug makers, who continue to make it clear that for them, amyloid IS the disease. Get full access to Research Translation at researchtranslation.substack.com/subscribe [https://researchtranslation.substack.com/subscribe?utm_medium=podcast&utm_campaign=CTA_4]