Great writeup. I wonder if anyone has ever tried injecting anti-amyloid antibodies directly into cerebrospinal fluid (intrathecal delivery) to bypass the blood brain barrier.
Also, regarding γ-secretase modulators, a lot of work went into these in the early 2000s and they ended up making things even worse due to side effects. γ-secretase is involved in processing a lot of proteins, notably including Notch, and it's quite difficult to block APP cleavage selectively.
I'm not aware of any intrathecal amyloid antibody delivery in humans.
Regarding γ-secretase, yeah, so those were γ-secretase *inhibitors* and they did have a lot of off-target effects, because of the enzyme's large number of substrates. However, despite a wide variety of mutations, the Alzheimer-causing ones strongly negatively correlate age-at-onset with the number of large amyloid species they lead to. [1] So it's being looked at again, but via more precise targeting of just the amyloidogenic pathways, hence the term "modulator".
[1] Fernández, Sara Gutiérrez, et al. "Spectrum of γ-Secretase dysfunction as a unifying predictor of ADAD age at onset across PSEN1, PSEN2 and APP causal genes." Molecular Neurodegeneration 20.1 (2025): 48.
>I wonder if anyone has ever tried injecting anti-amyloid antibodies directly into cerebrospinal fluid
That was my first thought also. If I'm faced with the probability of dying a horrible death due to dementia, you can go ahead and inject whatever the heck you want into my spine using whatever experimental methods you want. It can't be worse than the alternative, right?
> injecting anti-amyloid antibodies directly into cerebrospinal fluid
I wonder if a better approach might not be nasal administration of amylophagous protists. I believe this has successfully been demonstrated as an effective route, with neti pots and "brain-eating amoebae."
These phase 1b tau trials are interesting. They were not designed to measure clinical efficacy but still it would have been nice to see some hint of it. Apparently we were not so lucky:
"Performance on functional, cognitive, psychiatric and neurologic clinical outcomes slightly declined as expected for participants with mild AD over the duration of the treatment and post-treatment periods." [116]
Are there any of these drugs you would take yourself in (say) your 50s in an attempt to slow down the progression to Alzheimers? It seems like the endgame of this research is likely to be that approximately everyone 50+ takes an anti-amyloid drug along with their statin, in order to delay the onset of mental decline from tau long enough to let them die of something else. And if that prevented most cases of Alzheimers and didn't have terrible side-effects, that would be a really good outcome.
If I were amyloid-positive (as determined by blood, plasma, cerebrospinal fluid, or PET scan) and pre-symptomatic, I'd try to enroll in the trontinemab prevention trial, which looks like the best bet right now. https://www.roche.com/media/releases/med-cor-2025-07-28
Trontinemab looks to have higher efficacy and much better safety than the on-market state-of-the-art.
If you’re worried about it, it would be good advice to get enough sleep, and regularly. Stage 3 sleep seems to be the time when vascular fluid “washes out” the brain, potentially removing proteins before they become aggregations. Also it’s good to get sleep in general, so you won’t be wasting your time even if it doesn’t end up mattering for Alzheimer’s
I'm not sure whether people are just not allowing enough time for stage 3 sleep, or if people at risk for Alzheimer's don't have a good capacity for stage 3 sleep.
Thanks! That was a great overview and clarified a lot of aspects for me. In particular, I didn't know that the tau folding is so specific to its cause.
My background is that I'm a working neuroscientist in a field far from Alzheimer's research. From talking with colleagues, I'd often gotten the impression that amyloid was a dead end. So it was helpful for me to read the section titled "Challenges translating from mouse models." With that context, it's clear to me that a lot of the pessimism among neuroscientists stems from stories of those early, poorly-conceived mouse experiments.
Neuroscience research is often plagued with an unhealthy optimism that if you squint hard enough at an experiment in a mouse, it will seamlessly provide a good model for what's happening in humans. There's a large contingent of scientists ready to jump on subfields that produce large quantities of thoughtless work that suck up attention and available funds. This was clearly appropriate for some Alzheimer's research, but not for the field writ large.
Yes. IIUC, the side effects of the existing (approved) treatments for Alzheimer's are sufficiently bad that you're just as well off not taking them. Which is a pretty thorough condemnation.
A quick summary: The much-touted “27–33% slower decline” with lecanemab and donanemab masks the reality that these effects are clinically trivial, well below the minimum change patients or caregivers can perceive. Even donepezil, widely regarded as only modestly effective, outperforms these numbers. Trials last just 18 months, leaving it unknown whether these gains (imperceivable to caregivers) persist.
Meanwhile, risks are substantial. Amyloid-targeting antibodies cause brain swelling, microhemorrhages, and deaths, with the greatest hazard in APOE4 carriers and women. The APOE4 risk association requires some unpacking to be sure! See here: https://www.eneuro.org/content/11/7/ENEURO.0319-23.2024
But proponents of treating earlier in the disease course have already tested this hypothesis to disappointing results: The ambitious A4 trial tested this idea by treating older adults who had elevated amyloid but no cognitive symptoms. For 4.5 years, participants received solanezumab, an antibody targeting amyloid. Participants treated with solanezumab saw no cognitive benefit whatsoever—in fact, they performed slightly worse than those who received placebo. See here: https://www.nejm.org/doi/full/10.1056/NEJMoa2305032
Through a different mechanism in the late 1990s, this hypothesis was also tested with the AN-1792 vaccine that cleared plaques but did not halt progression to severe dementia. The trial was halted early due to severe brain inflammation and post-mortem examinations revealed a profound disconnect: despite dramatically reduced amyloid plaques, these patients had continued to develop severe dementia anyway. See here: https://academic.oup.com/brain/article/142/7/2113/5510133?login=false
The field’s response to repeated underperformance has been to shift diagnostic definitions and adopt weaker outcome measures (“time spent in mild stage”) that exaggerate benefit while obscuring minimal impact on real-world function. See here: https://www.nature.com/articles/d41586-024-00756-8
Many of these points are addressed in the article, but to respond directly:
Unlike donepezil, which only mitigates symptoms and doesn't affect the underlying biology (if you go off it, you end up where you would have been had you never been on it), the benefit from the partially-effective amyloid antibodies seems to get larger over time (open-label extensions point to widening benefits through four years), and persists vs. placebo even if you go off them. Despite this, they're not where we'd like them to be on either safety or efficacy, and I offer my belief as to why in the article: difficulty crossing the blood-brain barrier and treatment too late to prevent tau pathology. Thankfully both of these matters are being addressed.
I agree the side-effects can be serious, and are especially common for ApoE4 carriers. New BBB-crossing approaches like trontinemab seem to mitigate that risk greatly for everyone. A new donanemab titration schedule also appears to bring the ApoE4 carrier risk much closer to that of non-carriers: https://www.alzforum.org/news/conference-coverage/donanemab-small-tweak-titration-big-gain-safety
The solanezemab trial failed but this is one of the antibodies that didn't clear out plaques. In the study you link: "Amyloid levels on brain PET increased by a mean of 11.6 centiloids in the solanezumab group and 19.3 centiloids in the placebo group." (So a small between-group difference, but still a net increase. Whereas lecanemab, donanemab, and especially trontinemab cause deep plaque clearance.) The preclinical prevention hypothesis will be better tested by the clinical trials I mention in the post.
I had to read up on the AN1792 vaccine because I wasn't familiar with it. The main things I'd point out from that study are:
- The trial was interrupted because of meningoencephalitis in 6% of patients. [1]
- 5 of the 22 they examined post-mortem appeared to never have had amyloid plaques in the first place (sadly, it was uncommon back then to confirm Alzheimer's disease with biomarkers before clinical trial enrollment, which greatly reduced statistical power on many trials).
- They report that 7 of the remaining 17 only had "very limited" or "no" plaque removal.
- That leaves only 10 of 22 which had what they call "intermediate" or "very extensive" plaque removal.
- Treatment began after symptom onset, which is expected to be at best only somewhat effective under the ATN model.
- Despite this, there were hints of efficacy: p = 0.02 on their neuropsychological test battery for antibody responders. [1]
I wouldn't pin my belief on the amyloid hypothesis on this trial, but nor does it seem like clear evidence against it.
The anti-amyloid drugs we have now clear plaques more than enough to test the idea that removing amyloid will change the course of Alzheimer’s. That idea has been tested for decades, and it hasn’t delivered.
When you strip away the open-label extensions, which can’t prove durability because there’s no control arm and plenty of selective drop-out, the blinded trial data are all we can anchor to. The gains are statistically significant but far smaller than the minimal clinically important difference threshold, the point where patients or caregivers can actually feel a change. Even donepezil still compares at least as well in practical terms. Until a blinded trial shows a sustained, perceptible benefit, claims of “widening” or “persisting” effects are unwarranted.
Trontinemab may eventually offer a better safety profile, but right now that’s based on cross-trial comparisons and early-phase data. There’s already been at least one hemorrhagic death. We need fully powered, placebo-controlled Phase 3 trials before declaring the risk “greatly mitigated.”
And it’s worth remembering: even when AN-1792 produced substantial plaque clearance in half the treated group, those patients still progressed to severe dementia. That’s the core problem: namely, clearing plaques has not, so far, translated into meaningful change in the disease trajectory.
Instead of confronting that, the field keeps moving the goalposts. The latest proposed criteria would drop neurodegeneration entirely from the definition of Alzheimer’s and rely only on amyloid and tau biomarkers whose causal role remains unproven. Under that framework, many cognitively normal, amyloid-positive older adults would be labeled as having Alzheimer’s, while a neuroprotective drug that preserved function without touching amyloid or tau could be branded a failure. Critics have called for definitions rooted in clinical assessment and direct evidence of neurodegeneration, with biomarkers treated as unproven surrogates until they’re linked to patient-felt benefit.
Isn't it worth being a bit skeptical as to why these new definitions are being pushed? I am not anti-pharma by any means but there is a awful lot of money at stake here and these definitions seem bonkers given that ~1/3 of clinically normal older adults show substantial amyloid plaque deposition yet never develop Alzheimer’s disease during life. Keeping neurodegeneration as part of the criteria seems essential in distinguishing between normal aging and disease.)See a review by some alarmed neurologists here: https://pubmed.ncbi.nlm.nih.gov/38104639/
Until a treatment can meet that bar, durable, meaningful improvement at acceptable risk, changing definitions or endpoints won’t change what matters to patients and families.
I still think it's probably a mistake for drug research to target amyloid. Amyloid is produced because it has many benefits. So it seems somewhat likely that the high amyloid levels are a mostly desirable reaction to some other problems, and more attention should be devoted to the problems that are upstream of amyloid.
If this were the case, we'd expect ApoE3 homozygotes — and others who are not at much higher risk of Alzheimer's due to increased amyloid production or impaired clearance — to be dropping dead of infection left and right, or at least frequently enough to outweigh the much reduced risk of Alzheimer's. But we don't see that.
As a former (systems, not molecular) neuroscientist, I don't find this terribly convincing? Claims like "gene X does only Y" have a very very poor track record, and brains of a certain genotype may have perfectly good reasons for what seem to us like inexplicably excessive amyloid levels. This is also consistent with reports of negative side-effects from existing drugs.
Having said that, I think we must keep trying on amyloids and dealing with the consequences as they come.
It's quite plausible that overproduction of ANY of the body's proteins/hormone/etc. can be hazardous. It's what you should expect. And you should also expect every system to be interconnected with lots of other systems in ways that aren't obvious.
I truly expect that if you could clear out the (excess?) amyloid plaques without doing other damage it would be beneficial. Also that if you could eliminate the tau misfolding it would be beneficial. And it's quite plausible that these are connected. I also have a suspicion that the tau misfolding is more directly causal of Alzheimer's. If the amyloid causes tau misfolding, then removing the plaques should not be expected to solve the problem after it has initialed tau misfolding, because I believe that they tau misfolding, once initiated, is a prion disease. But it might well slow it down by halting the creation of new roots of misfolding trees.
Aducanumab, Lecanemab, Donanemab, oh my. Since they all end in ....mab I'm assuming there is some method to drug naming, does anyone have a pointer to the decoder ring? I had always just assume pharmaceutical companies had terrible marketing departments.
-mab means it is an antibody therapy, -ib is a small molecule inhibitor (typically kinase inhibitors). -vir are antivirals. More naming conventions: https://en.wikipedia.org/wiki/Drug_nomenclature
These are scientific names, like "acetaminophen", not commercial names like "tylenol". Commercial names are the ones that sound like they come out of marketing departments... most likely because they do.
I guess my question is: if this is a disease caused by amyloid overproduction, and we know which genes cause amyloid overproduction, can't we just do a CRISPR thing and, like... turn those genes off? Turn them down a bit?
Note that *most* instances of the disease are caused by impaired clearance, not overproduction. However, it is still possible that turning down production can help restore the balance.
Can some of the actual neuroscientists and medical practitioners chime in about having "smart guy from SpaceX" enter into the medical field of deciding what constitutes promising research after doing six months of reading?
This was a great piece and it seems convincing, but I don't know the field.
The last time a bunch of smart guys from SpaceX got into medical research.... It destroyed the NIH. I know some people forgot this ancient history because it was over a month ago, but a little bit of "I'm sorry that some of my former coworkers at the behest of my former boss cancelled funding for vast amounts of promising therapies in all medical fields, but here is my piece."
The idea that David Schneider-Joseph has worked at SpaceX in the past seems like interesting background but not relevant to his post. If he hadn't worked at SpaceX but had written the same words would that make his post more compelling?
Part of what we look for in anyone is "do we trust their background and who they are". We licence physicians and lawyers as a way to tell non specialists that the licensed individuals have a certain degree of training.
OK, so him disclosing not being a physician or neuroscientist is good.
If his previous job was being a plumber, that would actually be better.
But his previous job was SpaceX. Elon Musk's recent conduct at DOGE was to empower some very bright people (in his estimation) to take a blowtorch to medical grants that literally tens of thousands of researchers and millions of patients were depending on.
Why? Because Elon Musk is a smart guy. He and his underlings could decide what was good medical research... Trust them, they are smart and many of them worked on rockets!
So reading this, I am seeing "former SpaceX engineer says he knows better than medical professionals." That is a super negative prior for me personally based on what other people with similar biographies just did to American medical research.
I'm sorry that some of my former coworkers at the behest of my former boss cancelled funding for vast amounts of promising therapies in all medical fields, but here is my piece.
(In all seriousness, I'm very upset with what DOGE did.)
I write this not to tell Alzheimer researchers what they should be doing, but to convey what I learned about the field to other people, like myself, who are not in it.
It might be that you are not a lifelong medical researcher that contributes to the high readability of this piece. You've obviously learned an enormous amount about this issue in six months, and maybe it's your ability to think like someone not embedded deeply in the research that helps you translate what you've learned into such a readable piece for the rest of us.
> I am seeing "former SpaceX engineer says he knows better than medical professionals."
I know the author has already replied, but I want to point out I think there's a serious basic flaw with this observation.
The Amyloid hypothesis is still the orthodox position in the field. It's more contrarians and outsiders who have claimed that it's false. So my read is that this post is more "here's why the experts ARE right.
But actually, more basically: When there is disagreements amongst experts, you can't agree with *both* sides. So that means EVERYONE who is convinced by one side or the other will find themselves believing they know better than (some) experts; it's unavoidable, unless you're willing to hold off on making conclusions until and unless there is consensus in the field.
Well, Scott posted this, so presumably that's at least a once-over from him.
It's true that skepticism is warranted when people Do Their Own Research™ outside of their area of expertise, but for really high quality people it's not impossible for it to turn out well. I mean, what, do you want make it taboo for non-doctors to engage in any sort of public discussion of medical research? All that's necessary is for the person to readily disclose that they don't have formal training, which he did, and for the audience to keep that in mind while reading.
>a little bit of "I'm sorry that some of my former coworkers at the behest of my former boss cancelled funding for vast amounts of promising therapies in all medical fields, but here is my piece."
That level of guilt by association is not remotely healthy. He has no obligation whatsoever to preface an article completely unrelated to Elon Musk with something like that. You are trying to bully someone into going out of their way to help you spread your political opinions. Cut that out - in general, but especially in ACX comments.
Former neuroscientist: this seems fine? Specialists will have their careers and egos and grants tired up with very narrow sub-problems in Alzheimer's research---in this case, for instance, a particular dead-end mouse model---so a disinterested outsider may have an easier time seeing the big picture. Just obviously don't take it as gospel.
In terms of the substance of this post, the main red flag I noticed was this statement: "The clearest relationship is various genes which massively increase amyloid production (while doing nothing else)". In neuroscience, claims of this sort are almost always wrong and must be viewed with intense suspicion.
I am not a neuroscientist but I am a biomedical researcher who has followed Alzheimer's research for years -I think David did a good job summarizing the research consensus in a readable fashion, and I have no problem with this in general. Often researchers deep in the weeds have trouble explaining their field in a way that is easy for outsiders to understand, and they often are too busy with research to do even if they have the ability. In my own field of virology, I think Peter Miller did a better job than any virologist so far (including myself) of explaining the evidence for and against the lab leak hypothesis, and I've seen many colleagues with the same sentiments.
The real tricky stuff comes when an outsider with no relevant expertise tries to *disprove* a widely accepted hypothesis, instead of summarize a scientific consensus...still not out of bounds, but the odds of success are...much lower.
You mention "extremely rare protective genes" that can protect some people even after the amyloids take hold. Has there been any research into trying to copy those genes' effects for a later stage treatment?
Lexeo is trying to deliver protective ApoE variants via an AAV vector, and in some drugs (LX1020) also suppressing expression of the pre-existing harmful variants: https://www.lexeotx.com/programs/cns-programs/
I think the evidence is pointing to the harm (at the tau stage) mostly coming from ApoE4's gain of toxic function rather than loss of protective function, so I'm somewhat optimistic about LX1020 but not as much their others. But it's early for them.
It seems like somatic gene-editing could kill a lot of birds with one stone here, but I don't have a great idea about how safe/cheap/reliable the delivery vectors would be at the moment.
Yes, but that "somatic gene editing" would need to be done on the glia, or perhaps neurons, within the brain. This is both difficult and dangerous. Also, I believe that tau misfolding is a prion disease, so once it happens, fixing the genes won't fix the problem (though it might slow it down a lot).
Could I suggest adding a little summary at the end of the A->T->N pathway, and, in particular describing your argument that it's expected that anti-amyloid drugs have failed, given how they're used so far? (i.e. only after neurodegeneration has started). That was a surprisingly momentous/hopeful (and plausible) claim for being kind of just buried in the middle: that we basically already have a cure, and all that's needed to make it work is to scan everyone for amyloid buildup, so they can get the treatment a decade before symptoms would have started.
These extremely technical medical posts on here usually get the skimming treatment from me (and I suspect from a lot of other not-medically-literate readers) so ending summaries can be really helpful to reaching a wider audience! (I know you basically already have this under "The mechanistic claims", but that's still buried halfway through).
Also... I'm surprised this argument hasn't been put out in the press more. The total failure of anti-amyloid drugs seems like pretty damning evidence against the hypothesis, and such a plausible mechanism simultaneously explaining that failure and promising a cure seems like it would be an eyeball magnet for journalists.
This is a dense but highly readable analysis of the problem and I was surprised I stuck with it to the end. One thing I am curious about, is if AI can be of any help at leading to the proposed 75% solution mentioned under the testable prediction heading.
Neuroscientist working in an unrelated area, but I wanted to mention that a discussion of AD is not complete without mentioning the calcium hypothesis.
There is growing evidence that calcium dysregulation can drive both both amyloid aggregation and Tau cleavage, so there's the possibility that it may be upstream to both. Sleep disruption and TBIs also directly impact calcium homeostasis, so there's a mechanistic link.
I want to join in and praise this excellent summary! I was also skeptical of the amyloid hypothesis from a much more superficial engagement with the field 10-15 years ago, and you have convinced me otherwise.
One thing that you have to learn in biology is ignoring outliers, and I think that was something that I got wrong.
You used the phrase "all instances" in your prediction, which is fine as rhetoric device, but is not quite how reality works. *Almost* all patients with a clinical Alzheimer diagnosis have amyloid plaques revealed by PET. Where "almost all" apparently means 88%. I think this made me severely suspicious when I was younger, because it means that 12% of the people with Alzheimer apparently did not get it via amyloid. But I have learned since then that in biology, 88% means "almost all", and the rest is a lizardmen fraction where something was weird. Perhaps the PET measurement wasn't accurate, perhaps the diagnosis was wrong, perhaps the patients did have some sort of exceptional Alzheimer which developed via some weird different pathway.
But it does make me skeptical of your prediction. Not about the direction, but 75% slowdown seems huge. Because not 100% of patients will react to the therapy, some will not respond for unfathomable reasons. And if 25% don't respond, you would have to slow down the disease by 100% in the rest, or more realistically, the therapy would have to revert symptoms in some patients. Which may happen, but which seems a strong prediction even in your bullish view.
It's true that in the past, Alzheimer's disease was diagnosed without biomarkers. Nowadays, the presence of amyloid pathology is considered part of the diagnostic criteria.
This doesn't make my mechanistic claim merely definitional or vacuous, because I framed it as a *counterfactual*: I'm saying that in all instances of Alzheimer's dementia (which I define in the following sentence as a whole collection of things including amyloid pathology), then counterfactually, amyloid-only therapy *would have* prevented dementia. (Of course, we can't directly test a counterfactual in individual cases, but that's why I made a separate prediction that can be tested.)
In an earlier draft, I had the parenthetical "(barring occasional instances of some other, separate and clearly distinct disease process, such as Parkinson’s disease dementia or a tauopathy with a different fold and different pattern of regional progression)". It was removed for brevity, but I still endorse it.
Ah ok, my number obviously doesn't make sense anymore if amyloid pathology has entered the diagnostic criteria. And thanks again! I still find the 75% in the testable prediction extremely optimistic, but it's not a fundamental disagreement. And time will resolve what the numbers are in the end.
This is a statement not a question: obviously a common reason for a non-specialist to get very interested in a medical disorder is because they or a loved one suffer from it (or are likely to). I hope that’s not the case here; if it is, my best wishes.
> Severe enough amyloid pathology is a sufficient cause of Alzheimer dementia in almost all brains.
I haven't seriously investigated this issue, but I thought this was ruled out by the nun study? Or, like, they came up with the idea of 'cognitive reserve' that meant you could have lots of amyloid in your brain and not have Alzheimer's because you were losing brain you weren't using and still had enough left, but I thought it was pretty suspicious that the first time they looked at a significant number of controls the relationship got substantially weaker.
I discuss the existence of amyloid-positive, cognitively normal individuals in the article. The nun study (which I did not specifically mention) is one frequently-cited study which shows the existence of such people. This is predicted by the ATN model since it says amyloid does not directly cause neurodegeneration, but does so mediated by tau, after a ~15 year preclinical phase (I detail all the evidence for this model in the article). The question isn't whether such people exist, the question is whether even the ones with extremely high amyloid burden (not merely nominal positivity, since there are varying levels of susceptibility to the A->T conversion) ever go ~30 years without dementia.
In a PET study (https://academic.oup.com/jnen/article-abstract/70/10/832/2917208 figure 4), you can see that some cognitively normal people with "amyloid positivity" (> 23 centiloids) did not develop tau pathology within five years, but nearly all of those people were below 60 centiloids, and none of them were above 100 centiloids, which is approximately where I might draw the "sufficient amyloid" line. The claim isn't "all amyloid positivity results in Alzheimer's dementia", it's that "amyloid negativity prevents Alzheimer's dementia, *sufficient* amyloid burden basically guarantees it, and in between you have monotonically increasing risk".
(Overall, I don't find "cognitive reserve" to be a very useful concept: I think it's more an artifact of dementia and mild cognitive impairment diagnoses employing cutoffs on cognitive tests, not any actual sparing from an underlying disease process.)
Very well written and interesting post. I've seen my father drift off in his eighties. He did much much more headers than me, maybe I got knocked out once or twice more and I like my drink maybe even a bit more than him. I think it will be ok when my time of dementia will arrive. I don't have that much to lose.
Why is it easier/more common to target amyloid than tau? Amyloid seems worse since it's not the proximate cause of neuropathy and needs to be targeted or symptomatically.
Also, is there useful work on identifying the early amyloid plaques cheaply so we can target anti-amyloid drugs when they're most useful?
I think it’s mainly just that the importance of tau in mediating the A->N connection only became clear about 20 years after the causal evidence for amyloid itself, and drug development takes ~15 years from the first preclinical experiments, to early failures (such as N terminal tau antibodies), to trying more promising approaches (such as midregion antibodies and the IMO even more promising antisense oligonucleotides).
As for identifying amyloid pathology early: yes, this is possible to do today (via PET, CSF, blood, or plasma) but it’s not common because there haven’t yet been proven prevention methods. But once prophylactics are proven, I assume it’ll become widespread practice.
Very interesting article, thank you. I notice that I think it makes me a bit more confident than the amyloid hypothesis is correct compare to the other but on the meta level it makes me feel like a weathervane.
One question: I lost a grandparent to Alzheimer's. I am now worried about one of my parents. If I understood everything correctly we would want to start treatment something like 15-20 years before Alzheimer's start striking, which if the timeline are the same for my grandparent and my parent should be in the next decade or so. What can I do? What is possible to do?
Great synthesis. The genetics + iatrogenic seeding cases make it hard to avoid an A→T→N view, and they also suggest where lifestyle might plausibly fit upstream of A: sleep quality and slow-wave depth modulate glymphatic clearance and neuronal activity, so AT(N) predicts small, long-horizon risk shifts from sleep/metabolic factors even if tau drives symptoms. I wrote a short, citation-based explainer connecting those dots for non-experts — including glymphatic basics, ApoE4 and clearance, and why “treat earlier” makes sense — Breakfast, Sleep & Brain Clearance — A Plain-English Guide read at here: https://mcd-breakfast-menu.com
Open to critique on whether that framing overstates the upstream role; thanks for the testable prediction — more of that in this field, please.
Great writeup. I wonder if anyone has ever tried injecting anti-amyloid antibodies directly into cerebrospinal fluid (intrathecal delivery) to bypass the blood brain barrier.
Also, regarding γ-secretase modulators, a lot of work went into these in the early 2000s and they ended up making things even worse due to side effects. γ-secretase is involved in processing a lot of proteins, notably including Notch, and it's quite difficult to block APP cleavage selectively.
I'm not aware of any intrathecal amyloid antibody delivery in humans.
Regarding γ-secretase, yeah, so those were γ-secretase *inhibitors* and they did have a lot of off-target effects, because of the enzyme's large number of substrates. However, despite a wide variety of mutations, the Alzheimer-causing ones strongly negatively correlate age-at-onset with the number of large amyloid species they lead to. [1] So it's being looked at again, but via more precise targeting of just the amyloidogenic pathways, hence the term "modulator".
[1] Fernández, Sara Gutiérrez, et al. "Spectrum of γ-Secretase dysfunction as a unifying predictor of ADAD age at onset across PSEN1, PSEN2 and APP causal genes." Molecular Neurodegeneration 20.1 (2025): 48.
>I wonder if anyone has ever tried injecting anti-amyloid antibodies directly into cerebrospinal fluid
That was my first thought also. If I'm faced with the probability of dying a horrible death due to dementia, you can go ahead and inject whatever the heck you want into my spine using whatever experimental methods you want. It can't be worse than the alternative, right?
Maybe it would if you had to do it 15 years before first sign of decline.
> injecting anti-amyloid antibodies directly into cerebrospinal fluid
I wonder if a better approach might not be nasal administration of amylophagous protists. I believe this has successfully been demonstrated as an effective route, with neti pots and "brain-eating amoebae."
These phase 1b tau trials are interesting. They were not designed to measure clinical efficacy but still it would have been nice to see some hint of it. Apparently we were not so lucky:
"Performance on functional, cognitive, psychiatric and neurologic clinical outcomes slightly declined as expected for participants with mild AD over the duration of the treatment and post-treatment periods." [116]
Oh, wait, "favorable trends on multiple exploratory endpoints of cognition and activities of daily living in AD (n=46)"
https://investors.biogen.com/news-releases/news-release-details/new-data-biogens-investigational-antisense-oligonucleotide-aso
Thank you for this! What do you think about that new study on lithium deficiency and Alzheimer’s? Seems like it relates to plaque formation
https://www.science.org/content/blog-post/lithium-deficiency-and-alzheimer-s-disease
I second your question and re-up my post from the last open thread
https://www.astralcodexten.com/p/open-thread-394/comment/144263199
I had this question as well, and am still interested in David's response, but I found this discussion of that paper by Derek Lowe pretty encouraging:
https://www.science.org/content/blog-post/lithium-deficiency-and-alzheimer-s-disease
Are there any of these drugs you would take yourself in (say) your 50s in an attempt to slow down the progression to Alzheimers? It seems like the endgame of this research is likely to be that approximately everyone 50+ takes an anti-amyloid drug along with their statin, in order to delay the onset of mental decline from tau long enough to let them die of something else. And if that prevented most cases of Alzheimers and didn't have terrible side-effects, that would be a really good outcome.
If I were amyloid-positive (as determined by blood, plasma, cerebrospinal fluid, or PET scan) and pre-symptomatic, I'd try to enroll in the trontinemab prevention trial, which looks like the best bet right now. https://www.roche.com/media/releases/med-cor-2025-07-28
Trontinemab looks to have higher efficacy and much better safety than the on-market state-of-the-art.
If you’re worried about it, it would be good advice to get enough sleep, and regularly. Stage 3 sleep seems to be the time when vascular fluid “washes out” the brain, potentially removing proteins before they become aggregations. Also it’s good to get sleep in general, so you won’t be wasting your time even if it doesn’t end up mattering for Alzheimer’s
I'm not sure whether people are just not allowing enough time for stage 3 sleep, or if people at risk for Alzheimer's don't have a good capacity for stage 3 sleep.
Thanks! That was a great overview and clarified a lot of aspects for me. In particular, I didn't know that the tau folding is so specific to its cause.
Thanks, great writeup.
My background is that I'm a working neuroscientist in a field far from Alzheimer's research. From talking with colleagues, I'd often gotten the impression that amyloid was a dead end. So it was helpful for me to read the section titled "Challenges translating from mouse models." With that context, it's clear to me that a lot of the pessimism among neuroscientists stems from stories of those early, poorly-conceived mouse experiments.
Neuroscience research is often plagued with an unhealthy optimism that if you squint hard enough at an experiment in a mouse, it will seamlessly provide a good model for what's happening in humans. There's a large contingent of scientists ready to jump on subfields that produce large quantities of thoughtless work that suck up attention and available funds. This was clearly appropriate for some Alzheimer's research, but not for the field writ large.
This was cool, but I suppose it won’t be testable for a long time. A shame, because Alzheimer’s is a really bad disease
Yes. IIUC, the side effects of the existing (approved) treatments for Alzheimer's are sufficiently bad that you're just as well off not taking them. Which is a pretty thorough condemnation.
I, too, am not an Alzheimer's researcher so I defer to my betters--specifically, Derek Lowe's extensive reporting on the anti-amyloid therapies in his blog at Science. Lowe did work in the field and has been following it throughout this career: https://www.science.org/content/blog-post/does-it-work-does-it-do-harm-and-more-basic-questions.
A quick summary: The much-touted “27–33% slower decline” with lecanemab and donanemab masks the reality that these effects are clinically trivial, well below the minimum change patients or caregivers can perceive. Even donepezil, widely regarded as only modestly effective, outperforms these numbers. Trials last just 18 months, leaving it unknown whether these gains (imperceivable to caregivers) persist.
Meanwhile, risks are substantial. Amyloid-targeting antibodies cause brain swelling, microhemorrhages, and deaths, with the greatest hazard in APOE4 carriers and women. The APOE4 risk association requires some unpacking to be sure! See here: https://www.eneuro.org/content/11/7/ENEURO.0319-23.2024
Proposals to treat everyone with amyloid or tau under the expanded ATN criteria would expose millions of cognitively normal older adults (most of whom will never develop dementia) to these dangers. See here: https://www.alzforum.org/news/conference-coverage/revised-again-alzheimers-diagnostic-criteria-get-another-makeover
But proponents of treating earlier in the disease course have already tested this hypothesis to disappointing results: The ambitious A4 trial tested this idea by treating older adults who had elevated amyloid but no cognitive symptoms. For 4.5 years, participants received solanezumab, an antibody targeting amyloid. Participants treated with solanezumab saw no cognitive benefit whatsoever—in fact, they performed slightly worse than those who received placebo. See here: https://www.nejm.org/doi/full/10.1056/NEJMoa2305032
Through a different mechanism in the late 1990s, this hypothesis was also tested with the AN-1792 vaccine that cleared plaques but did not halt progression to severe dementia. The trial was halted early due to severe brain inflammation and post-mortem examinations revealed a profound disconnect: despite dramatically reduced amyloid plaques, these patients had continued to develop severe dementia anyway. See here: https://academic.oup.com/brain/article/142/7/2113/5510133?login=false
The field’s response to repeated underperformance has been to shift diagnostic definitions and adopt weaker outcome measures (“time spent in mild stage”) that exaggerate benefit while obscuring minimal impact on real-world function. See here: https://www.nature.com/articles/d41586-024-00756-8
Many of these points are addressed in the article, but to respond directly:
Unlike donepezil, which only mitigates symptoms and doesn't affect the underlying biology (if you go off it, you end up where you would have been had you never been on it), the benefit from the partially-effective amyloid antibodies seems to get larger over time (open-label extensions point to widening benefits through four years), and persists vs. placebo even if you go off them. Despite this, they're not where we'd like them to be on either safety or efficacy, and I offer my belief as to why in the article: difficulty crossing the blood-brain barrier and treatment too late to prevent tau pathology. Thankfully both of these matters are being addressed.
I agree the side-effects can be serious, and are especially common for ApoE4 carriers. New BBB-crossing approaches like trontinemab seem to mitigate that risk greatly for everyone. A new donanemab titration schedule also appears to bring the ApoE4 carrier risk much closer to that of non-carriers: https://www.alzforum.org/news/conference-coverage/donanemab-small-tweak-titration-big-gain-safety
The solanezemab trial failed but this is one of the antibodies that didn't clear out plaques. In the study you link: "Amyloid levels on brain PET increased by a mean of 11.6 centiloids in the solanezumab group and 19.3 centiloids in the placebo group." (So a small between-group difference, but still a net increase. Whereas lecanemab, donanemab, and especially trontinemab cause deep plaque clearance.) The preclinical prevention hypothesis will be better tested by the clinical trials I mention in the post.
I had to read up on the AN1792 vaccine because I wasn't familiar with it. The main things I'd point out from that study are:
- The trial was interrupted because of meningoencephalitis in 6% of patients. [1]
- 5 of the 22 they examined post-mortem appeared to never have had amyloid plaques in the first place (sadly, it was uncommon back then to confirm Alzheimer's disease with biomarkers before clinical trial enrollment, which greatly reduced statistical power on many trials).
- They report that 7 of the remaining 17 only had "very limited" or "no" plaque removal.
- That leaves only 10 of 22 which had what they call "intermediate" or "very extensive" plaque removal.
- Treatment began after symptom onset, which is expected to be at best only somewhat effective under the ATN model.
- Despite this, there were hints of efficacy: p = 0.02 on their neuropsychological test battery for antibody responders. [1]
I wouldn't pin my belief on the amyloid hypothesis on this trial, but nor does it seem like clear evidence against it.
[1] https://www.neurology.org/doi/10.1212/01.WNL.0000159740.16984.3C
The anti-amyloid drugs we have now clear plaques more than enough to test the idea that removing amyloid will change the course of Alzheimer’s. That idea has been tested for decades, and it hasn’t delivered.
When you strip away the open-label extensions, which can’t prove durability because there’s no control arm and plenty of selective drop-out, the blinded trial data are all we can anchor to. The gains are statistically significant but far smaller than the minimal clinically important difference threshold, the point where patients or caregivers can actually feel a change. Even donepezil still compares at least as well in practical terms. Until a blinded trial shows a sustained, perceptible benefit, claims of “widening” or “persisting” effects are unwarranted.
Trontinemab may eventually offer a better safety profile, but right now that’s based on cross-trial comparisons and early-phase data. There’s already been at least one hemorrhagic death. We need fully powered, placebo-controlled Phase 3 trials before declaring the risk “greatly mitigated.”
And it’s worth remembering: even when AN-1792 produced substantial plaque clearance in half the treated group, those patients still progressed to severe dementia. That’s the core problem: namely, clearing plaques has not, so far, translated into meaningful change in the disease trajectory.
Instead of confronting that, the field keeps moving the goalposts. The latest proposed criteria would drop neurodegeneration entirely from the definition of Alzheimer’s and rely only on amyloid and tau biomarkers whose causal role remains unproven. Under that framework, many cognitively normal, amyloid-positive older adults would be labeled as having Alzheimer’s, while a neuroprotective drug that preserved function without touching amyloid or tau could be branded a failure. Critics have called for definitions rooted in clinical assessment and direct evidence of neurodegeneration, with biomarkers treated as unproven surrogates until they’re linked to patient-felt benefit.
Isn't it worth being a bit skeptical as to why these new definitions are being pushed? I am not anti-pharma by any means but there is a awful lot of money at stake here and these definitions seem bonkers given that ~1/3 of clinically normal older adults show substantial amyloid plaque deposition yet never develop Alzheimer’s disease during life. Keeping neurodegeneration as part of the criteria seems essential in distinguishing between normal aging and disease.)See a review by some alarmed neurologists here: https://pubmed.ncbi.nlm.nih.gov/38104639/
Until a treatment can meet that bar, durable, meaningful improvement at acceptable risk, changing definitions or endpoints won’t change what matters to patients and families.
As someone who both worked on the Falcon 9 and on Alzheimer's disease, how often do you make "it's not rocket science"/"it's not brain surgery" jokes?
I'm partial to "it's not rocket surgery".
I tend to say that rocket science is high school physics. It's rocket *engineering* that's a pain.
Most of what you say here sounds reasonable.
I still think it's probably a mistake for drug research to target amyloid. Amyloid is produced because it has many benefits. So it seems somewhat likely that the high amyloid levels are a mostly desirable reaction to some other problems, and more attention should be devoted to the problems that are upstream of amyloid.
If this were the case, we'd expect ApoE3 homozygotes — and others who are not at much higher risk of Alzheimer's due to increased amyloid production or impaired clearance — to be dropping dead of infection left and right, or at least frequently enough to outweigh the much reduced risk of Alzheimer's. But we don't see that.
As a former (systems, not molecular) neuroscientist, I don't find this terribly convincing? Claims like "gene X does only Y" have a very very poor track record, and brains of a certain genotype may have perfectly good reasons for what seem to us like inexplicably excessive amyloid levels. This is also consistent with reports of negative side-effects from existing drugs.
Having said that, I think we must keep trying on amyloids and dealing with the consequences as they come.
It's quite plausible that overproduction of ANY of the body's proteins/hormone/etc. can be hazardous. It's what you should expect. And you should also expect every system to be interconnected with lots of other systems in ways that aren't obvious.
I truly expect that if you could clear out the (excess?) amyloid plaques without doing other damage it would be beneficial. Also that if you could eliminate the tau misfolding it would be beneficial. And it's quite plausible that these are connected. I also have a suspicion that the tau misfolding is more directly causal of Alzheimer's. If the amyloid causes tau misfolding, then removing the plaques should not be expected to solve the problem after it has initialed tau misfolding, because I believe that they tau misfolding, once initiated, is a prion disease. But it might well slow it down by halting the creation of new roots of misfolding trees.
Aducanumab, Lecanemab, Donanemab, oh my. Since they all end in ....mab I'm assuming there is some method to drug naming, does anyone have a pointer to the decoder ring? I had always just assume pharmaceutical companies had terrible marketing departments.
-mab means it is an antibody therapy, -ib is a small molecule inhibitor (typically kinase inhibitors). -vir are antivirals. More naming conventions: https://en.wikipedia.org/wiki/Drug_nomenclature
Thank you very much. This helps...some.
Thanks, this is fascinating - I always assumed drug companies were just going the Chinese junk brand route of keyboard mashing.
These are scientific names, like "acetaminophen", not commercial names like "tylenol". Commercial names are the ones that sound like they come out of marketing departments... most likely because they do.
MAB = Monoclonal AntiBody
I guess my question is: if this is a disease caused by amyloid overproduction, and we know which genes cause amyloid overproduction, can't we just do a CRISPR thing and, like... turn those genes off? Turn them down a bit?
There is a phase 1 trial for a drug to turn down amyloid production: https://capella.alnylam.com/wp-content/uploads/2025/07/AAIC-Phase-1_OP_SUBMITTED28Jul.pdf
Note that *most* instances of the disease are caused by impaired clearance, not overproduction. However, it is still possible that turning down production can help restore the balance.
Can some of the actual neuroscientists and medical practitioners chime in about having "smart guy from SpaceX" enter into the medical field of deciding what constitutes promising research after doing six months of reading?
This was a great piece and it seems convincing, but I don't know the field.
The last time a bunch of smart guys from SpaceX got into medical research.... It destroyed the NIH. I know some people forgot this ancient history because it was over a month ago, but a little bit of "I'm sorry that some of my former coworkers at the behest of my former boss cancelled funding for vast amounts of promising therapies in all medical fields, but here is my piece."
The idea that David Schneider-Joseph has worked at SpaceX in the past seems like interesting background but not relevant to his post. If he hadn't worked at SpaceX but had written the same words would that make his post more compelling?
Part of what we look for in anyone is "do we trust their background and who they are". We licence physicians and lawyers as a way to tell non specialists that the licensed individuals have a certain degree of training.
OK, so him disclosing not being a physician or neuroscientist is good.
If his previous job was being a plumber, that would actually be better.
But his previous job was SpaceX. Elon Musk's recent conduct at DOGE was to empower some very bright people (in his estimation) to take a blowtorch to medical grants that literally tens of thousands of researchers and millions of patients were depending on.
Why? Because Elon Musk is a smart guy. He and his underlings could decide what was good medical research... Trust them, they are smart and many of them worked on rockets!
So reading this, I am seeing "former SpaceX engineer says he knows better than medical professionals." That is a super negative prior for me personally based on what other people with similar biographies just did to American medical research.
I'm sorry that some of my former coworkers at the behest of my former boss cancelled funding for vast amounts of promising therapies in all medical fields, but here is my piece.
(In all seriousness, I'm very upset with what DOGE did.)
I write this not to tell Alzheimer researchers what they should be doing, but to convey what I learned about the field to other people, like myself, who are not in it.
It might be that you are not a lifelong medical researcher that contributes to the high readability of this piece. You've obviously learned an enormous amount about this issue in six months, and maybe it's your ability to think like someone not embedded deeply in the research that helps you translate what you've learned into such a readable piece for the rest of us.
I do appreciate you saying it.
I really like the piece and I find it pretty convincing.
> I am seeing "former SpaceX engineer says he knows better than medical professionals."
I know the author has already replied, but I want to point out I think there's a serious basic flaw with this observation.
The Amyloid hypothesis is still the orthodox position in the field. It's more contrarians and outsiders who have claimed that it's false. So my read is that this post is more "here's why the experts ARE right.
But actually, more basically: When there is disagreements amongst experts, you can't agree with *both* sides. So that means EVERYONE who is convinced by one side or the other will find themselves believing they know better than (some) experts; it's unavoidable, unless you're willing to hold off on making conclusions until and unless there is consensus in the field.
Well, Scott posted this, so presumably that's at least a once-over from him.
It's true that skepticism is warranted when people Do Their Own Research™ outside of their area of expertise, but for really high quality people it's not impossible for it to turn out well. I mean, what, do you want make it taboo for non-doctors to engage in any sort of public discussion of medical research? All that's necessary is for the person to readily disclose that they don't have formal training, which he did, and for the audience to keep that in mind while reading.
>a little bit of "I'm sorry that some of my former coworkers at the behest of my former boss cancelled funding for vast amounts of promising therapies in all medical fields, but here is my piece."
That level of guilt by association is not remotely healthy. He has no obligation whatsoever to preface an article completely unrelated to Elon Musk with something like that. You are trying to bully someone into going out of their way to help you spread your political opinions. Cut that out - in general, but especially in ACX comments.
Well said!
Former neuroscientist: this seems fine? Specialists will have their careers and egos and grants tired up with very narrow sub-problems in Alzheimer's research---in this case, for instance, a particular dead-end mouse model---so a disinterested outsider may have an easier time seeing the big picture. Just obviously don't take it as gospel.
In terms of the substance of this post, the main red flag I noticed was this statement: "The clearest relationship is various genes which massively increase amyloid production (while doing nothing else)". In neuroscience, claims of this sort are almost always wrong and must be viewed with intense suspicion.
I am not a neuroscientist but I am a biomedical researcher who has followed Alzheimer's research for years -I think David did a good job summarizing the research consensus in a readable fashion, and I have no problem with this in general. Often researchers deep in the weeds have trouble explaining their field in a way that is easy for outsiders to understand, and they often are too busy with research to do even if they have the ability. In my own field of virology, I think Peter Miller did a better job than any virologist so far (including myself) of explaining the evidence for and against the lab leak hypothesis, and I've seen many colleagues with the same sentiments.
The real tricky stuff comes when an outsider with no relevant expertise tries to *disprove* a widely accepted hypothesis, instead of summarize a scientific consensus...still not out of bounds, but the odds of success are...much lower.
You mention "extremely rare protective genes" that can protect some people even after the amyloids take hold. Has there been any research into trying to copy those genes' effects for a later stage treatment?
Lexeo is trying to deliver protective ApoE variants via an AAV vector, and in some drugs (LX1020) also suppressing expression of the pre-existing harmful variants: https://www.lexeotx.com/programs/cns-programs/
I think the evidence is pointing to the harm (at the tau stage) mostly coming from ApoE4's gain of toxic function rather than loss of protective function, so I'm somewhat optimistic about LX1020 but not as much their others. But it's early for them.
It seems like somatic gene-editing could kill a lot of birds with one stone here, but I don't have a great idea about how safe/cheap/reliable the delivery vectors would be at the moment.
Yes, but that "somatic gene editing" would need to be done on the glia, or perhaps neurons, within the brain. This is both difficult and dangerous. Also, I believe that tau misfolding is a prion disease, so once it happens, fixing the genes won't fix the problem (though it might slow it down a lot).
Point taken. I'm pretty leery about most applications of ML/AI, but I have to wonder if AlphaFold could design a protein to counteract prion folding?
Thank you for this excellent write up!
Wow!!! Thank you so much for this clear and cohesive breakdown of the theory and science underlying the disease.
Excellent write-up. Thanks for putting it together. Does anyone have more info on clearing the tau proteins directly and how that effort is going?
Could I suggest adding a little summary at the end of the A->T->N pathway, and, in particular describing your argument that it's expected that anti-amyloid drugs have failed, given how they're used so far? (i.e. only after neurodegeneration has started). That was a surprisingly momentous/hopeful (and plausible) claim for being kind of just buried in the middle: that we basically already have a cure, and all that's needed to make it work is to scan everyone for amyloid buildup, so they can get the treatment a decade before symptoms would have started.
These extremely technical medical posts on here usually get the skimming treatment from me (and I suspect from a lot of other not-medically-literate readers) so ending summaries can be really helpful to reaching a wider audience! (I know you basically already have this under "The mechanistic claims", but that's still buried halfway through).
Also... I'm surprised this argument hasn't been put out in the press more. The total failure of anti-amyloid drugs seems like pretty damning evidence against the hypothesis, and such a plausible mechanism simultaneously explaining that failure and promising a cure seems like it would be an eyeball magnet for journalists.
This is a dense but highly readable analysis of the problem and I was surprised I stuck with it to the end. One thing I am curious about, is if AI can be of any help at leading to the proposed 75% solution mentioned under the testable prediction heading.
Neuroscientist working in an unrelated area, but I wanted to mention that a discussion of AD is not complete without mentioning the calcium hypothesis.
There is growing evidence that calcium dysregulation can drive both both amyloid aggregation and Tau cleavage, so there's the possibility that it may be upstream to both. Sleep disruption and TBIs also directly impact calcium homeostasis, so there's a mechanistic link.
See, for example:
https://www.sciencedirect.com/science/article/pii/S0021925819580760
https://www.sciencedirect.com/science/article/pii/S2090123225000268
Author makes two claims why ATN framing is preferred over the alternatives:
- tau hypothesis (TN) omits 'A' step, which is often precursor of 'T'
- infection hypothesis (IATN) adds unnecessary 'I' step, which is not directly causal with N and is sometimes unnecessary
I find this inconsistent.
Moreover, if the facts are layed out correctly (I have no idea), then TN/ATN/IATN are not really different hypothesis at all
I want to join in and praise this excellent summary! I was also skeptical of the amyloid hypothesis from a much more superficial engagement with the field 10-15 years ago, and you have convinced me otherwise.
One thing that you have to learn in biology is ignoring outliers, and I think that was something that I got wrong.
You used the phrase "all instances" in your prediction, which is fine as rhetoric device, but is not quite how reality works. *Almost* all patients with a clinical Alzheimer diagnosis have amyloid plaques revealed by PET. Where "almost all" apparently means 88%. I think this made me severely suspicious when I was younger, because it means that 12% of the people with Alzheimer apparently did not get it via amyloid. But I have learned since then that in biology, 88% means "almost all", and the rest is a lizardmen fraction where something was weird. Perhaps the PET measurement wasn't accurate, perhaps the diagnosis was wrong, perhaps the patients did have some sort of exceptional Alzheimer which developed via some weird different pathway.
But it does make me skeptical of your prediction. Not about the direction, but 75% slowdown seems huge. Because not 100% of patients will react to the therapy, some will not respond for unfathomable reasons. And if 25% don't respond, you would have to slow down the disease by 100% in the rest, or more realistically, the therapy would have to revert symptoms in some patients. Which may happen, but which seems a strong prediction even in your bullish view.
It's true that in the past, Alzheimer's disease was diagnosed without biomarkers. Nowadays, the presence of amyloid pathology is considered part of the diagnostic criteria.
This doesn't make my mechanistic claim merely definitional or vacuous, because I framed it as a *counterfactual*: I'm saying that in all instances of Alzheimer's dementia (which I define in the following sentence as a whole collection of things including amyloid pathology), then counterfactually, amyloid-only therapy *would have* prevented dementia. (Of course, we can't directly test a counterfactual in individual cases, but that's why I made a separate prediction that can be tested.)
In an earlier draft, I had the parenthetical "(barring occasional instances of some other, separate and clearly distinct disease process, such as Parkinson’s disease dementia or a tauopathy with a different fold and different pattern of regional progression)". It was removed for brevity, but I still endorse it.
Ah ok, my number obviously doesn't make sense anymore if amyloid pathology has entered the diagnostic criteria. And thanks again! I still find the 75% in the testable prediction extremely optimistic, but it's not a fundamental disagreement. And time will resolve what the numbers are in the end.
Thanks very much for this article.
This is a statement not a question: obviously a common reason for a non-specialist to get very interested in a medical disorder is because they or a loved one suffer from it (or are likely to). I hope that’s not the case here; if it is, my best wishes.
> Severe enough amyloid pathology is a sufficient cause of Alzheimer dementia in almost all brains.
I haven't seriously investigated this issue, but I thought this was ruled out by the nun study? Or, like, they came up with the idea of 'cognitive reserve' that meant you could have lots of amyloid in your brain and not have Alzheimer's because you were losing brain you weren't using and still had enough left, but I thought it was pretty suspicious that the first time they looked at a significant number of controls the relationship got substantially weaker.
I discuss the existence of amyloid-positive, cognitively normal individuals in the article. The nun study (which I did not specifically mention) is one frequently-cited study which shows the existence of such people. This is predicted by the ATN model since it says amyloid does not directly cause neurodegeneration, but does so mediated by tau, after a ~15 year preclinical phase (I detail all the evidence for this model in the article). The question isn't whether such people exist, the question is whether even the ones with extremely high amyloid burden (not merely nominal positivity, since there are varying levels of susceptibility to the A->T conversion) ever go ~30 years without dementia.
In a PET study (https://academic.oup.com/jnen/article-abstract/70/10/832/2917208 figure 4), you can see that some cognitively normal people with "amyloid positivity" (> 23 centiloids) did not develop tau pathology within five years, but nearly all of those people were below 60 centiloids, and none of them were above 100 centiloids, which is approximately where I might draw the "sufficient amyloid" line. The claim isn't "all amyloid positivity results in Alzheimer's dementia", it's that "amyloid negativity prevents Alzheimer's dementia, *sufficient* amyloid burden basically guarantees it, and in between you have monotonically increasing risk".
(Overall, I don't find "cognitive reserve" to be a very useful concept: I think it's more an artifact of dementia and mild cognitive impairment diagnoses employing cutoffs on cognitive tests, not any actual sparing from an underlying disease process.)
Very well written and interesting post. I've seen my father drift off in his eighties. He did much much more headers than me, maybe I got knocked out once or twice more and I like my drink maybe even a bit more than him. I think it will be ok when my time of dementia will arrive. I don't have that much to lose.
Why is it easier/more common to target amyloid than tau? Amyloid seems worse since it's not the proximate cause of neuropathy and needs to be targeted or symptomatically.
Also, is there useful work on identifying the early amyloid plaques cheaply so we can target anti-amyloid drugs when they're most useful?
I think it’s mainly just that the importance of tau in mediating the A->N connection only became clear about 20 years after the causal evidence for amyloid itself, and drug development takes ~15 years from the first preclinical experiments, to early failures (such as N terminal tau antibodies), to trying more promising approaches (such as midregion antibodies and the IMO even more promising antisense oligonucleotides).
As for identifying amyloid pathology early: yes, this is possible to do today (via PET, CSF, blood, or plasma) but it’s not common because there haven’t yet been proven prevention methods. But once prophylactics are proven, I assume it’ll become widespread practice.
Very interesting article, thank you. I notice that I think it makes me a bit more confident than the amyloid hypothesis is correct compare to the other but on the meta level it makes me feel like a weathervane.
One question: I lost a grandparent to Alzheimer's. I am now worried about one of my parents. If I understood everything correctly we would want to start treatment something like 15-20 years before Alzheimer's start striking, which if the timeline are the same for my grandparent and my parent should be in the next decade or so. What can I do? What is possible to do?
Great synthesis. The genetics + iatrogenic seeding cases make it hard to avoid an A→T→N view, and they also suggest where lifestyle might plausibly fit upstream of A: sleep quality and slow-wave depth modulate glymphatic clearance and neuronal activity, so AT(N) predicts small, long-horizon risk shifts from sleep/metabolic factors even if tau drives symptoms. I wrote a short, citation-based explainer connecting those dots for non-experts — including glymphatic basics, ApoE4 and clearance, and why “treat earlier” makes sense — Breakfast, Sleep & Brain Clearance — A Plain-English Guide read at here: https://mcd-breakfast-menu.com
Open to critique on whether that framing overstates the upstream role; thanks for the testable prediction — more of that in this field, please.