Astral Codex Ten

Down syndrome

29 min read

Down syndrome

Article

Down syndrome is a recurring concept in the Astral Codex Ten archive, appearing 5 times across 5 issues between July 12, 2024 and August 14, 2025. The archive places it in contexts such as “the dementia seen in Down syn”; “the dementia seen in Down syndrome (also, people with Down’s develop Alzheimer’s neuropathology 15+ years before symptom onset)”; “people with Down Syndrome have only half the expected rate of solid cancers (X)“. It most often appears alongside Chromosome 21, Alzheimer’s, 23andme.

Metadata

  • Category: Concepts
  • Mention count: 5
  • Issue count: 5
  • First seen: July 12, 2024
  • Last seen: August 14, 2025

Appears In

Source Context

Recovered passages from the original issue text. When the raw archive preserved outbound links inside the source passage, they are listed directly under the quote.

Your Book Review: The Family That Couldn’t Sleep
July 12, 2024 · Original source
What is Alzheimer’s? No, seriously, that’s an important question. “Alzheimer’s disease” originally referred to a rare, early-onset dementia. It’s always been characterised by a specific neuropathology, but the value of “specific” here is, uh, not specific, and Alzheimer’s-like pathology is seen in surprisingly many healthy elderly people. The neuropathology of autosomal dominant Alzheimer’s is not always identical to that of the sporadic disease, nor is that of the dementia seen in Down syndrome (also, people with Down’s develop Alzheimer’s neuropathology 15+ years before symptom onset, and some people with Down’s never get dementia despite having the pathology). It’s tricky to avoid the conclusion that modern Alzheimer’s is a wastebasket diagnosis.
Links For July 2025
July 01, 2025 · Original source
42: Did you know: people with Down Syndrome have only half the expected rate of solid cancers (X). Chromosome 21 includes some anti-cancer genes, and having an extra copy gives extra protection. Kesin says that there’s “no free lunch” because Down Syndrome patients also have much higher rates of leukemia, but that’s only true on a chromosome-wide basis; the specific genes that protect against solid tumors don’t cause the leukemia. What’s the downside of increasing those genes? Seems less well-understood, but might harm wound healing, placental implantation, and neurodevelopment.
Inline links: people with Down Syndrome have only half the expected rate of solid cancers (X)
Your Review: Of Mice, Mechanisms, and Dementia
July 11, 2025 · Original source
Second, the hypothesis was backed by powerful genetic evidence. Mutations in the APP gene on chromosome 21 were associated with early-onset Alzheimer’s. The case grew stronger with the observation that more than 50% of individuals with Down syndrome, who carry an extra copy of chromosome 21 (and thus extra APP), develop Alzheimer’s-like pathology by age 40.
Suddenly, Trait-Based Embryo Selection
July 31, 2025 · Original source
When a couple uses IVF, they may get as many as ten embryos. If they only want one child, which one do they implant? In the early days, doctors would just eyeball them and choose whichever looked healthiest. Later, they started testing for some of the most severe and easiest-to-detect genetic disorders like Down Syndrome and cystic fibrosis1. The final step was polygenic selection - genotyping each embryo and implanting the one with the best genes overall.
Inline links: 1
Sample Nucleus results. And this week, Herasight4 entered the space with the most impressive disease risk scores yet, an IQ predictor worth 6-95 extra points, and a series of challenges to competitors, whom they call out for insufficient scientific rigor. Their most scathing attack is on Nucleus itself, accusing its predictions of being misleading and unreliable. Let’s start with the science, then move on to the companies and see if we can litigate their dispute. In Theory, All Of This Should Work Polygenic embryo screening is a natural extension of two well-validated technologies: genetic testing of embryos, and polygenic prediction of traits in adults. Genetic testing of embryos has been done for decades, usually to detect chromosomal abnormalities like Down Syndrome or simple single-gene disorders like cystic fibrosis. It’s challenging - you need to take a very small number of cells (often only 5-10) from a tiny proto-placenta that may not have many cells to spare, and extract a readable amount of genetic material from this limited sample - but there are known solutions that mostly work. But most traits are polygenic, requiring information about thousands or tens of thousands of genes to predict. These are too complicated to understand fully at current levels of technology, but some studies have chipped away at the problem and gotten a partial understanding. Often this looks like being able to predict a few percent of the variance in a trait, and determine whether someone’s genetic risk is slightly higher or lower than average. Polygenic prediction of traits in adults is still young and full of hidden pitfalls. Last month, we discussed how some early studies unknowingly conflated direct genetic effects and various confounders6 - for example, they tended to pick up on genes associated with well-off ethnic groups or families who had good health outcomes for social reasons. Pinpointing the direct component requires an additional step where researchers validate their algorithms within families (for example, on pairs of siblings where one has a higher polygenic score than the other) to see how much predictive power remains. This is especially important for embryo selection companies, whose entire value proposition depends on comparing two genomes from the same family. How have they done? It depends on the number of embryos they have to work with; the more embryos, the better you can do by selecting the best. Herasight’s numbers on how breast cancer risk goes down with number of embryos used in selection. A typical round of IVF produces 1-10 embryos (younger women usually = more). Women with polycystic ovarian syndrome (prevalence: 10%) may get as many as 20. For more, you will probably need to do multiple IVF rounds. Here is a table of different companies’ reported risk reductions, slightly adjusted7 for different reporting conventions but otherwise taking all claims at face value (we’ll talk about how wise that is later). Relative risk reduction for five conditions (gray = no data / disputed data). Here baseline is for embryos neither of whose parents have the condition. GP and Orchid both say their technology has improved since reporting these numbers and they will report better numbers soon. GP numbers are not within-family validated and might be lower if they were. Absolute risk after selection for five conditions (gray = no data / disputed data), ibid. Some people might genuinely want to select on a single condition. For example, people with a strong family history of schizophrenia might want to minimize the chance of their children getting the disease; for these people, reducing schizophrenia risk by 58% (while keeping everything else constant) sounds pretty good. Everyone else probably wants a generically healthy embryo with low risk of all conditions. Exactly how this works depends on the customer’s own values - would they prefer an embryo with lower cancer risk to one who will have fewer heart attacks? - and the exact benefits will depend on how parents make that decision. Genomic Prediction and Herasight try to help by providing semi-objective measures of which embryo is overall healthiest according to different conditions’ effects on longevity and patient-rated quality of life. For Genomic Prediction, that’s the “embryo health score” If you selected the single highest-health-score embryo from a set of five, here’s how they’d do: For Herasight, it’s a “polygenic longevity index”. They don’t give exact risk reduction numbers for each disease, saying that it depends too much on a couple’s specific family history, but say that most people gain 1-4 years of healthy life (when I test it on a set of twenty embryos, the the healthiest gets an extra 1.66 years). How much would you pay to give your children an extra 1-4 years of healthy life? This is no longer a hypothetical question. Here are the costs of the companies in this space: Is it worth it? If: You’re already doing IVF
Inline links: Herasight, 4, 5, 6, https://substackcdn.com/image/fetch/$s_!VOdq!,f_auto,q_auto:good,fl_progressive:steep/https%3A%2F%2Fsubstack-post-media.s3.amazonaws.com%2Fpublic%2Fimages%2Fb1ba32f3-72fa-4be1-846c-6b0b04a5a213_774x279.png, 7, https://substackcdn.com/image/fetch/$s_!0oUh!,f_auto,q_auto:good,fl_progressive:steep/https%3A%2F%2Fsubstack-post-media.s3.amazonaws.com%2Fpublic%2Fimages%2Fe8419603-9239-43bb-8c79-77b078ff0789_548x136.png, https://substackcdn.com/image/fetch/$s_!rpEJ!,f_auto,q_auto:good,fl_progressive:steep/https%3A%2F%2Fsubstack-post-media.s3.amazonaws.com%2Fpublic%2Fimages%2Fc539a717-a130-460d-90c9-4ab64619f26d_548x133.png, https://substackcdn.com/image/fetch/$s_!3Kc6!,f_auto,q_auto:good,fl_progressive:steep/https%3A%2F%2Fsubstack-post-media.s3.amazonaws.com%2Fpublic%2Fimages%2Fbda325bb-13fb-4c27-b8c3-24facce5c71a_676x153.png, https://substackcdn.com/image/fetch/$s_!t1Am!,f_auto,q_auto:good,fl_progressive:steep/https%3A%2F%2Fsubstack-post-media.s3.amazonaws.com%2Fpublic%2Fimages%2F831ab3c6-4053-4ff9-bc2f-879aee4349cf_673x740.png, https://substackcdn.com/image/fetch/$s_!Q2vE!,f_auto,q_auto:good,fl_progressive:steep/https%3A%2F%2Fsubstack-post-media.s3.amazonaws.com%2Fpublic%2Fimages%2Fadcf2bb4-8dd1-4a88-9728-6953a820971b_422x575.png
Aside from two bright orange squares (gallstones vs. hypertension and hypothyroidism - I don’t know what’s up with this and it doesn’t seem to be a widely-appreciated result) we see that most correlations are zero or positive - that is, selecting against one disease selects against another or at worst does nothing. In this ocean of blue, worrying about those few orange squares feels a bit motivated. Hans Jonas-ism says that no medical intervention may ever cause any harm, no matter how much benefit it produces. By this standard, perhaps slightly raising the risk of gallstones in the process of preventing various cancers and psychoses and other forms of human misery is unacceptable. To anyone with the more normal perspective where something with large benefits and tiny downsides is still pretty good, I don’t think the antagonistic pleiotropy argument carries much weight. Ethical Objection: Cost No way around this one: if these products work, they mean that rich people can have healthier/smarter/taller/prettier kids than poor people. One might object that at least they’re in good company: other products which help rich kids get healthier/smarter/taller/prettier than poor kids include private tutors, gyms, hair salons, health insurance, clothing, books, and food. Is this really the time to declare ourselves against this kind of thing? But maybe we should fight against expanding this already-bloated category. Or maybe there’s something more final about a genetic advantage. Maybe a stronger argument is that rich people get first crack at every new technology, but poor people usually follow close behind. The first cellphone, in 1982, cost $12,000 in today’s dollars. Now you can get something a thousand times better for $50, and Kenyan pastoralists use cell phones to call up the local shaman. The trajectory of genetics has been even more striking: sequencing a single genome cost about $100 million in 2000 and is somewhere around $100 today. Polygenic embryo selection has the potential to follow a similar path. There are two associated costs - sequencing the embryos, and running the analysis. Sequencing costs are decreasing and may eventually be comparable to the sorts of genetic screening (for e.g. Down Syndrome) that most families get anyway. Analysis costs are mostly the one-time expense of inventing the predictor; we might expect these to follow the same pattern as generic medications, where cutting-edge technology is jealously guarded and expensive, but last decade’s technology has made its way off patent and is cheap-to-free. A few groups have already created free open-source predictors; so far these are much worse than the private companies’ versions, but one of last year’s ACX Grantees is working on a better one. Also, it would be crazy for any forward-thinking government not to cover this; it could save hundreds of thousands of dollars in future health care expenses. In countries with public health care, this comes directly out of the government treasury; even in the US, it’s covered by Medicare after age 65. The government should be begging people to select embryos. The most persistent cost barrier is likely to be in vitro fertilization itself, a necessary precursor. In the US, 2-3% of babies are born through IVF. For those kids, this is a no-brainer - even if the cost never comes down, the cheaper products are only a fraction of total IVF expense. What about the other 98%? If those parents feel like they have to get embryo selection (and therefore IVF) to keep up, this could be a significant burden. IVF isn’t fun - it requires pumping a woman full of mind-altering hormones for weeks, extracting eggs in a minor surgery, and then implanting embryos in another minor surgery, all with a decent chance that some step will fail and you’ll have to do it all again. It also costs $15,000 in the US (less in poorer countries), and unlike the genetics, the cost has barely gone down in the past twenty-five years. Some countries, including Israel, offer free IVF for anybody who wants it. And universal basic IVF is surprisingly popular even in the usually government-phobic United States - Donald Trump made it part of his campaign platform. So there’s a plausible path to embryo selection for everyone who wants it. But it’s still going to take a while, it will hit different people at different times, and so far11 there’s no way around the month or two of various miserable medical procedures for women. Ethical Objection: Personhood Is it really correct to say that you have reduced someone’s risk of breast cancer by 46%, if what you’ve really done is closer to replacing them with a different person who is 46% less likely to have breast cancer? I cover this one in more depth here. Ethical Objection: Race This one is awkward: right now the technology works best for white people. Most genetic data available for research/commercial use comes from the UK, US, and Europe - areas which are mostly white. Asian biobanks, and those serving US minority communities, have been more reluctant to share data. So we know a lot about the genetics of white people, and only a limited amount about the genetics of anyone else. Companies are suitably embarrassed about this, and researchers in the field are working hard to wring every ounce of information out of the minority data they have. But for now, white people are the clear winner. Here’s data from Herasight: A European family with five embryos and no family history can cut their diabetes risk by 47%, and an African family 29%, with everyone else in between. As usual, all companies say that they adjust their scores based on the couple’s genetic ancestry. As usual, Herasight challenges them to publicly release data on exactly how they performed the adjustments and how well they work. All companies say they are working as hard as they can to improve cross-ancestry portability, but that progress will remain limited until governments collect/release better genetic data on non-white populations. Ethical Objection: Selection At some point, you’ve got to choose. Genomic Prediction and Herasight offer scores that aggregate overall health risks. Some people will follow them slavishly. Other people will try to second-guess them - would you prefer your child have lower cancer risk, or less chance of heart attacks? And this is the best case scenario! Herasight offers predictors for IQ, height and BMI; Nucleus offers those plus eye color and hair color12. A parent might encounter a situation where the embryo with their favorite eye color also has the highest cancer and schizophrenia risk, and choose to doom their child to cancer and schizophrenia because they really want pretty eyes. On average, even if everyone in the world selected for eye color, it wouldn’t raise cancer and schizophrenia risk. No not-deliberately-perverse polygenic selection choice can make your child worse off in expectation. Still, suppose you got cancer, and your mom admitted that she selected you for pretty eyes and didn’t even check the cancer column of the embryo selection report. How would you feel? And would you feel better or worse than someone whose parents didn’t do embryo selection at all, and spent the money on a Caribbean vacation? What if they selected your brother for everything great, then had you naturally? What if they selected you for IQ, but actually you are very stupid, and you were one of the 20% of cases where a predictor that’s right 80% of the time gets it wrong? Mark my words, one day there will be entire subfields of therapy dedicated to these issues. Going Nuclear Even as outsiders criticize the whole field, Herasight has launched a full-scale attack on competitor Nucleus. Herasight’s white paper compares its own predictors (favorably) to those of Orchid and Genomic Prediction… …but refuses to acknowledge Nucleus at all. In a supplementary note, the authors explain why: they accuse Nucleus of being so bad that it would “not yield a reliable or meaningful addition to our analysis”. They say Nucleus has inflated the accuracy of their scores. This is most dramatic for a few conditions like ADHD, where the leading published polygenic score is based on 2,300,000 variants but explains only ~1% of variance in the condition. Nucleus’ score is based on 12 variants13 and (implicitly) claims to explain 3-6%. This doesn’t make sense. Some of Nucleus’ other scores do use millions of variants. But many of these are 5-10 year old scores downloaded from open-source catalogs, whose accuracy statistics are easily available and far less than Nucleus claims. Here is what Herasight finds when they double-check Nucleus’ numbers: On their Substack, Herasight also criticizes Nucleus’ monogenic screening product. They point out cases where it fails to properly screen for the conditions it claims. For example, the Nucleus website advertises screening for spinal muscular atrophy: But on their gene list… …they don’t screen for SMN, which causes 95% of spinal muscular atrophy cases. They only screen for UBA1, which causes a distinct and much rarer condition called x-linked infantile spinal muscular atrophy. Professional organizations publish guidelines for what genes need to be screened in a screening product, and Nucleus does not appear to be following them. In further discussion, Herasight continued with exhaustive criticism of essentially everything Nucleus had ever done down to the smallest detail. Nucleus reports list the same baseline disease risk regardless of patient ancestry, but different ancestry groups should have different risks14. Nucleus’ physician reports sometimes list lower-than-average risk for patients with positive polygenic scores15. Nucleus’ age-based risk tables don’t distinguish between age and cohort effects (is this bad? see footnote16). My favorite critique is that Nucleus wrote a blog post criticizing competing company Orchid… …which included a section on how Orchid is a polygenic selection company, and polygenic selection companies are inherently “sketchy” and “honestly should be illegal”. But Nucleus is also a polygenic selection company! This is like Marlboro attacking Camel on the grounds that cigarettes are addictive and should be banned! Obviously something went wrong here - my guess is AI - and it’s a really bad look, especially when these scientific issues are so hard to litigate, and so many of us will have to go off gestalt impressions of corporate culture. Nucleus states that they validate their models internally and intend to make their results public soon. A Foothill Of The Future It’s hard not to love this technology. Lots of people (and the aforementioned professional organizations) manage anyway, but it’s hard. If this were a single-use medical treatment, delivered by a doctor after someone got the relevant condition, it would be one of the biggest advances of the decade - imagine a drug that cures 10 - 40%17 of breast cancers with no side effects! But in fact, it works for breast cancer, and schizophrenia, and heart attacks, and approximately everything else. The only things comparable are antibiotics and GLP-1RAs. And then there’s the IQ effects. Even after studying the literature, people have wildly different opinions about the importance of IQ. One of the most important debates is to what degree IQ differences are a cause of poverty, a consequence of poverty, or both. I lean towards both - a country with limited access to schools and medical care will have low average IQ, but as a consequence it probably won’t become the next big semiconductor hub. This technology could close half the IQ gap between poor and middle-income countries, or between middle-income and rich. Or it could give rich countries average IQs that have never been seen before, and let us see what kind of O-ring technologies (and new forms of social cooperation) lie just beyond the frontier. (this is the nice quantifiable argument in favor of IQ enhancement, but I find myself more convinced by fuzzier things - how much is it worth to be able to enjoy great art and literature? To fully comprehend what we know of nature, and be able to fully appreciate the mystery of the rest? To have a sense of why society works the way it does, instead of feeling like you’re being blown back and forth by institutions you don’t really understand? Amateur psychoanalysts like to say that the only people who care about IQ are those looking for an excuse to boast about how high their own is, but my experience is the opposite: I care about IQ because I bang up against the limits of my own a thousand times a day, and I hate it. I fantasize about ways to make my children smarter than I am for the same reason a dog confined in a tiny crate might fantasize about getting her puppies adopted out to a nice house with a big grassy yard.) My biggest qualm is that it might not matter. This is such a tiny foothill, flanking such a vast and foreboding range of mountains, that it might be a mistake to care about it at all. Selecting the best of five or ten embryos is not a very effective way to get the genes you want. There are things in the pipeline that will make this look like Hippocrates draining black bile. By the time the first polygenically selected children are adults, they’ll be old news. And then there’s AI. The average age at diagnosis for Type II diabetes is 45 years. Will there still be people growing gradually older and getting Type II diabetes and taking insulin injections in 2070? If not, what are we even doing here? Many people in the transhumanist community are still bullish on this technology. They think - well, there’s still an outside chance that something comes up and AGI takes another few decades. If we can enhance humans to be smarter, healthier, and more determined by the time it arrives, maybe we’ll have a better chance. Or maybe, if there’s a positive optimistic vision of a human-based high-tech future, people will be more willing to delay AI in the first place. I like this argument, but I also think it’s worth stepping back. What’s the point of anything? Why have kids at all in a world that’s changing this fast? Why save for the future? At some point your answer has to be romantic and aesthetic - it’s never been clear whether anything you do matters in any ultimate sense, but you’ve got to act as if it does and hope for the best. From that perspective, this is the most romantic technology of all. You’re not just giving a better life to your kids. Genes travel from generation to generation; you’re giving a better life your grandkids, your great-grandkids and so on to the point 1.77*log₂(population) generations from now when you are the ancestor of everybody and nobody. Somebody in Macaronesia in 3525 AD will avoid getting breast cancer because of you (if there is still cancer; if there are still breasts). Some combination of reasonable cost-benefit analysis and romantic/aesthetic commitments makes me want to have children despite the uncertainty, and the same combination made me sign up to use this technology despite the same. More later on how that’s going. 1I’m slightly mixing up two different things here - Down Syndrome can be detected with an aneuploidy test, but cystic fibrosis takes a more involved PGT-M test. 2There are two separate questions here. First, how much would diabetes risk decline if you selected the embryo with the lowest risk for diabetes - something you have no reason to do, since you have no reason to privilege diabetes risk over risk of any other disease? Second, how much would diabetes risk go down if you selected the embryo with the lowest health risk overall? Genomic Prediction’s their risk calculator calculator shows, seemingly paradoxically, that you get -38% relative risk by selecting against diabetes alone, but -41% relative risk by selecting against everything at once. Over email, they stand by this surprising result, saying that “for a couple of diseases (type II diabetes and CAD), the EHS actually accomplishes a larger risk reduction than the individual predictors. The explanation is that the EHS takes into account multiple PRS of diseases with high comorbidity”. See eg Figure 3 here: …and the section of the post called “Antagonistic Pleiotropy” for more. However, this paradoxical benefit is only true for a few conditions like diabetes - for everything else, selecting on health index does better than you would naively think, but still does not decrease the risk of a given condition as much as selecting against that condition directly. 3That is, new mutations in that particular baby, as opposed to older mutations already present in the parents. 4Conflicts of interest: I have used Orchid’s and Herasight’s products on my own embryos (not the ones used to conceive my existing kids, but for a potential third child), employees of Genomic Prediction and Herasight have been extremely helpful in contributing expertise to ACX posts on genetics, and I might invest in this field at some point (though haven’t done so yet). This post started as Herasight asking me to write about their white paper, then spiraled out of control. There were some unexpected time pressures and the result is that I didn’t get a chance to run everything in Herasight’s white paper by their competitors as thoroughly as I would like. Although I talked to representatives of all four companies profiled here, I feel like this probably reflects Herasight’s perspective better than other companies’, and that this is a major flaw. If other companies have responses, I’ll publish them. Thanks to all companies involved for their assistance on this article. Finally, I am favorably disposed toward Herasight because of how I learned about them: a professor named Jonathan Anomaly got cancelled from Penn for being too gung-ho about genetic enhancement, and used his newfound freedom to join a very-early-stage Herasight, raise their ambitions, and sell everyone (including me) on the idea. I grew up on a diet of books and movies about mad scientists, and I’m a sucker for a story about a guy named Doctor Anomaly pursuing revenge against the small-minded fools who destroyed his career by creating a race of superbabies. 5The version of the tool I looked at said 5.9 points for five embryos, up to 9 points for twenty embryos. The version of the tool on their current said says 5.3 - 9, so they might have recalculated after I finalized this article. 6Used in quotation marks because these scores were fine for the predictive tasks they were applied for - they just weren’t finding genes that directly caused the outcome of interest. 7Conflict of interest notice: this table was originally unadjusted. A representative of Herasight claimed that this was unfair, because each company used slightly different reporting conventions, and offered to correct for this in a neutral way. I retraced their reasoning, confirmed that the correction did not especially benefit Herasight at the expense of other companies, and accepted the correction. The original unadjusted table is below: Herasight was insufficiently comfortable with Nucleus’ methodology to even be willing to posit a corrected value, so I left their self-reported value in gray. 8Zagorsky (2007) says an extra IQ point means $234-$616/year in higher salary. The midpoint of $425 equals $670 in today’s dollars; assuming a forty-year career, Nucleus’ +1 point estimate is worth $26,800 (vs. $9,249 Nucleus cost) and Herasight’s +6 point estimate is worth $160,800 (vs. $53,250 Herasight cost). 9As part of researching this article, I asked all four major companies about their within-family validation strategies. Here are some details: Genomic Prediction discusses their strategy in this paper. The results are complicated to interpret - the within-family numbers often have such wide error bars that they overlap with both the across-family numbers and with zero - but looking qualitatively it seems like most scores on average lose about 25% of their risk reduction ability (though averages might not be the right way to do this, and some might be much more affected than others). Their website reports unadjusted, not within-family validated numbers; GP says they say this clearly on their site (which is true), Herasight counters that they still present their numbers as applicable to embryo selection (which is also true). To get the most applicable-to-embryo-selection numbers, you might want to adjust GP’s stated numbers down somewhat; it’s hard to say exactly how much, but maybe 20 - 25%?
Inline links: Hans Jonas-ism, somewhere around $100 today., Donald Trump made it part of his campaign platform, 11, here, https://substackcdn.com/image/fetch/$s_!1Alk!,f_auto,q_auto:good,fl_progressive:steep/https%3A%2F%2Fsubstack-post-media.s3.amazonaws.com%2Fpublic%2Fimages%2F1af69f39-f353-4aa6-acb9-d8c3b05c7bac_728x895.jpeg, 12, Herasight’s white paper, https://substackcdn.com/image/fetch/$s_!S7lY!,f_auto,q_auto:good,fl_progressive:steep/https%3A%2F%2Fsubstack-post-media.s3.amazonaws.com%2Fpublic%2Fimages%2F738260ba-8fe2-4647-8ca2-eeb4d13e0fce_605x341.png, 13, https://substackcdn.com/image/fetch/$s_!u7YE!,f_auto,q_auto:good,fl_progressive:steep/https%3A%2F%2Fsubstack-post-media.s3.amazonaws.com%2Fpublic%2Fimages%2F451c286b-c677-47af-8c07-f0d993a14384_612x345.png, their Substack, the Nucleus website, https://substackcdn.com/image/fetch/$s_!XmL4!,f_auto,q_auto:good,fl_progressive:steep/https%3A%2F%2Fsubstack-post-media.s3.amazonaws.com%2Fpublic%2Fimages%2Ff77915b4-3b36-4908-8f9f-032b7cf865ff_562x432.png, https://substackcdn.com/image/fetch/$s_!bxjb!,f_auto,q_auto:good,fl_progressive:steep/https%3A%2F%2Fsubstack-post-media.s3.amazonaws.com%2Fpublic%2Fimages%2F2df9ffe5-17a3-4448-9a20-e9b27ac9a519_1250x795.png, publish guidelines, 14, 15, 16, a blog post criticizing competing company Orchid, https://substackcdn.com/image/fetch/$s_!MZCB!,f_auto,q_auto:good,fl_progressive:steep/https%3A%2F%2Fsubstack-post-media.s3.amazonaws.com%2Fpublic%2Fimages%2F2cf9cbf4-825b-4373-9052-80e43c36febf_718x1035.png, 17, GLP-1RAs, O-ring technologies, things in the pipeline, everybody, nobody, 1, 2, their risk calculator, everything, here, https://substackcdn.com/image/fetch/$s_!jtkY!,f_auto,q_auto:good,fl_progressive:steep/https%3A%2F%2Fsubstack-post-media.s3.amazonaws.com%2Fpublic%2Fimages%2Fd645c392-fed1-4f02-9a2e-878b8c7ef7f2_909x878.png, 3, 4, 5, 6, 7, https://substackcdn.com/image/fetch/$s_!Vimq!,f_auto,q_auto:good,fl_progressive:steep/https%3A%2F%2Fsubstack-post-media.s3.amazonaws.com%2Fpublic%2Fimages%2Fca0f1f15-268d-465a-a70f-b7f1173c6111_566x166.png, https://substackcdn.com/image/fetch/$s_!3B0A!,f_auto,q_auto:good,fl_progressive:steep/https%3A%2F%2Fsubstack-post-media.s3.amazonaws.com%2Fpublic%2Fimages%2Faccc7a65-b142-4bf6-927d-53eb607d71ef_552x155.png, 8, 9
In Defense Of The Amyloid Hypothesis
August 14, 2025 · Original source
Anti-amyloid drugs (like Aduhelm) don't reverse the disease, and only slow progression a relatively small amount. Opponents call the amyloid hypothesis zombie science, propped up only by pharmaceutical companies hoping to sell off a few more anti-amyloid me-too drugs before it collapses. Meanwhile, mainstream scientists . . . continue to believe it without really offering any public defense. Scott was so surprised by the size of the gap between official and unofficial opinion that he asked if someone from the orthodox camp would speak out in its favor. I am David Schneider-Joseph, an engineer formerly with SpaceX and Google, now working in AI safety. Alzheimer’s isn’t my field, but I got very interested in it, spent six months studying the literature, and came away believing the amyloid hypothesis was basically completely solid. I thought I’d share that understanding with current skeptics. The ATN model The most plausible variant of the amyloid hypothesis is the A → T → N model: amyloid causes tau causes neurodegeneration. 1: Amyloid The common entrypoint, typically at least 15 years before clinically detectable symptoms [1], is accumulation of amyloid-β deposits (especially Aβ42, one of several variants). Amyloid-β is a peptide produced in healthy human beings and many other animals, probably for antimicrobial purposes [2, 3]. Factors which cause overproduction of amyloid also cause Alzheimer’s. Factors that cause decreased clearance of amyloid also cause Alzheimer’s. The clearest relationship is various genes which massively increase amyloid production (while doing nothing else); these genes are Alzheimer’s risk factors, with some of the rarer and more severe ones causing extreme versions of the disease that manifest at otherwise almost-never-seen ages. One of the clearest examples is Down syndrome, which is caused by three (rather than the usual two) copies of chromosome 21. People with Down syndrome are at much higher risk of Alzheimer’s than the general population: two-thirds will have the condition by age sixty, and 15% have it by age forty. APP, the gene for the amyloid precursor protein, is on chromosome 21. This means that people with Down syndrome will have an extra copy. This extra copy has been observed to lead to higher-than-normal amyloid levels. But there are many genes on chromosome 21; do we have additional evidence that it’s the amyloid one that’s involved? Yes. Dozens of other mutations on APP cause the same sort of extremely young and severe Alzheimer’s. So do mutations on PSEN1 and 2, the genes for the enzyme that processes amyloid precursor protein into amyloid. So do mutations on several other amyloid-related genes. [6, 91 - 96] Researchers call these autosomal-dominant Alzheimer’s, meaning Alzheimer’s cases that get inherited from a single parent in a simple fashion typical of single-gene disorders. They make up about 1% of all cases, and are our strongest evidence for the causal role of amyloid in the disorder. To my knowledge, there is no serious claim that these genes could be working through any pathway other than their shared role in the amyloid system. But these autosomal-dominant cases only make up about 1% of all Alzheimer’s patients. Might they be a different disease than the usual sporadic Alzheimer’s that strikes people without strong family histories at normal ages? Probably not: the presentation and trajectory of autosomal-dominant and sporadic Alzheimer’s cases are strikingly similar. Both show an initial appearance of amyloid pathology starting in intrinsic connectivity networks in both autosomal-dominant [14] and sporadic [15–18] types, cortical tau appearing first in the medial temporal lobe and with the exact same fold in both disease types [97] (despite human tauopathies having at least seven other possible characteristic folds [36]), that tau pathology worsening and spreading outside this region only once amyloid pathology reaches sufficient severity [65], neurodegeneration progressing closely in step with the tau pathology, and the same usual approximate trajectory of cognitive symptoms due to the sequence of affected regions. So it’s as if two bank robberies occurred hours apart, in the same town, and in a highly similar and idiosyncratic manner, and we can positively identify the culprit of one on security camera footage. It’s a good bet the culprit of the other is the same. Increased amyloid production → Alzheimer’s is an especially clear and simple pathway, but any other change in amyloid can also cause the disease. For example Overproduction or reduced clearance of amyloid due to impaired slow wave sleep. Aβ production is neuronal activity-dependent, and toxins (perhaps including Aβ) are cleared from the brain during sleep via the glymphatic system. Thus Aβ can accumulate if the brain is more active and/or has less opportunity for clearance. [7, 8, 9, 10, 11]
Inline links: Aduhelm, David Schneider-Joseph