I apologize if this is piling on, but I would like to note that this error strikes me as very similar to another one made by the same author in this comment, and which I believe is emblematic of a certain common failure mode within the rationalist community (of which I count myself a part). This common failure mode is to over-value our own intelligence and under-value institutional knowledge (whether from the scientific community or the Amazon marketplace), and thus not feel the need to tread carefully when the two come into conflict.
In the comment in question, johnswentworth asserts, confidently, that there is nothing but correlational evidence of the role of amyloid-β in Alzheimer’s disease. However, there is extensive, strong causal evidence for its role: most notably, that certain mutations in the APP, PSEN1, and PSEN2 genes deterministically (as in, there are no known exceptions for anyone living to their 80′s) cause Alzheimer’s disease, and the corresponding proteins are well understood structurally and functionally to be key players in the production of amyloid-β. Furthermore, the specific mutations in question are shown through multiple lines of evidence (structural analysis, in vitro experiment, and in vivo experiments in transgenic mice) to lead directly (as opposed to indirectly, via a hypothetical other Alzheimer’s-causing pathway) to greater production of amyloid-β.
(My background: I have a family member with Alzheimer’s and as a result I spent five months studying the scientific literature on the subject in detail. I am posting under a pseudonym to protect my family member’s privacy.)
I think one reason that this error occurs is that there’s a mistaken assumption that the available literature captures all institutional knowledge on a topic, so if one simply spends enough time reading the literature, they’ll have all requisite knowledge needed for policy recommendations. I realize that this statement could apply equally to your own claims here, but in my experience I see it happen most often when someone reads a handful of the most recently released research papers and from just that small sample of work tries to draw conclusions applicable that are broadly applicable to the entire field.
Engineering claims are particularly suspect because institutional knowledge (often in the form of proprietary or confidential information held by companies and their employees) is where the difference between what is theoretically efficient and what is practically more efficient is found. It doesn’t even need to be protected information though—it can also just be that due to manufacturing reasons, or marketing reasons, or some type of incredibly aggravating constraint like “two hoses require a larger box and the larger box pushes you into a shipping size with much higher per-volume / mass costs so the overall cost of the product needs to be non-linearly higher than what you’d expect would be needed for a single hose unit, and that final per-unit cost is outside of what people would like to pay for an AC unit, unless you then also make drastic improvements to the motor efficiency, thermal efficiency, and reduce the sound level, at which point the price is now even higher than before, but you have more competitive reasons to justify it which will be accepted by a large enough % of the market to make up for the increased costs elsewhere, except the remaining % of the market can’t afford that higher per-unit cost at all, so we’re back to still making and selling a one-hose unit for them”.
Concrete example while we’re on the AC unit debate—there’s a very simple way to increase efficiency of portable AC units, and it’s to wrap the hot exhaust hose with insulating duct wrap so that less of the heat on that very hot hose radiates directly back into the room you’re trying to cool. Why do companies not sell their units with that wrap? Probably for one of any of the following reasons—A.) takes up a lot of space, B.) requires a time investment to apply to the unit which would dissuade buyers who think they can’t handle that complexity, C.) would cost more money to sell and no longer be profitable at the market’s price point, D.) has to be applied once the AC unit is in place, and generally is thick enough that the unit is no longer “portable” which during market testing was viewed as a negative by a large % of surveyed people, or E.) some other equally trivial sounding reason that nonetheless means it’s more cost effective for companies to NOT sell insulating duct wrap in the same box as the portable AC unit.
A priori, before having clicked on your links, my guess would be that the studies in question generally diagnose Alzheimer’s by the presence of amyloid-β deposits. (That’s generally been the case in similar studies I’ve looked into in the past, although I haven’t checked the exact studies you link.) If they’re diagnosing based on the presence of amyloid-β, then obviously amyloid-β producing mutations will cause an Alzheimer’s diagnosis. The problem is that this diagnosis doesn’t reflect real Alzheimer’s, i.e. it doesn’t necessarily involve dementia.
We would expect such things to find strong, extensive evidence of causality. The problem is that it’s extensive evidence of the mutations causing amyloid-β plaques, not dementia.
(Also, a warning: this is exactly the sort of detail which overview articles tend to overlook and misstate—e.g. an overview article will say something like “so-and-so found that blah causes dementia” when in fact so-and-so were diagnosing amyloid plaques, not dementia. One does need to check the original papers.)
A distinction is made in the literature between preclinical Alzheimer’s (the presence of neuropathology such as amyloid-β, without clinically detectable cognitive symptoms) and clinical Alzheimer’s (a particular cluster of cognitive symptoms along with the neuropathologies of Alzheimer’s). It’s currently believed that Alzheimer’s has a 15-20 year preclinical phase, the duration of which, however, can vary based on genetic and other factors.
In the case of the mutations I mentioned (which are early-onset causing), clinically-detectable cognitive decline typically starts around the age of 45, and nearly always by the age of 60. One of the only known examples in which symptoms didn’t start until a person was in her 70′s was so surprising that an entire, highly-cited paper was written about it: Arboleda-Velasquez et al (2019). Resistance to autosomal dominant Alzheimer’s disease in an APOE3 Christchurch homozygote: a case report. Note, however, that the typical cluster of symptoms did eventually occur.
Honestly, these particular mutations are so pervasively discussed in the literature, precisely due to their significance to the causal question, that I can tell you have not really engaged with the literature by your unawareness of their existence and the effects that they have on people.
I will readily acknowledge, by the way, that by themselves they don’t close the book on the causal question: someone could argue that early-onset, autosomal dominant Alzheimer’s due to these mutations is essentially a different disease than the much more prevalent late-onset, sporadic Alzheimer’s. While I don’t think this argument ultimately goes through, and I’d be happy to discuss why, my main point is not that there’s no residual question about the the etiology of the disease, but that the research community has intensely, intelligently, and carefully studied the distinction between correlative and causal evidence, as well as the distinction between neuropathology and cognitive symptoms. A lot of really smart, well-informed, careful practitioners work in this field, and it’s helpful to learn what they’ve discovered.
While I don’t think this argument ultimately goes through, and I’d be happy to discuss why...
I’d be interested to read that.
(Apologies for lack of citations in the below, I don’t have them readily on hand and don’t want to go digging right at the moment.)
You’re right that I never went that deep into the Alzheimer’s literature; it’s certainly plausible that I overlooked a cluster of actually-competently-executed studies tying Aβ-related genetic mutations to robust dementia outcomes. I did look deeply into at least one study which made that claim (specifically the study which I most often found at the root of citation chains) and it turned out to diagnose using the presence of plaques, not dementia. But that was a paper from the early 90′s, so maybe better results have come along since then.
However, the absence of evidence for Aβ causing Alzheimer’s was not the only thing pinning down my beliefs here. I’ve also seen papers with positive evidence that Aβ doesn’t cause Alzheimer’s—i.e. removing plaques doesn’t eliminate dementia. And of course there’s been literally hundreds of clinical trials with drugs targeting Aβ, and they pretty consistently do not work.
So if there is a cluster of genetic studies establishing that Aβ-related mutations are causal for dementia, then the immediate question is how that squares with all the evidence against causality of Aβ for dementia. If the early-onset autosomal dominant version of the disease is in fact a different disease, that would answer the question, but you apparently think otherwise, so I’m curious to hear your case.
In brief, the main reason I don’t think the argument works that autosomal-dominant Alzheimer’s has a different etiology than sporadic Alzheimer’s is that they look, in so many respects, like essentially the same disease, with the same sequence of biomarkers and clinical symptoms:
Amyloid pathology starts in the default mode network, and gradually spreads throughout the brain over 15-20 years.
It eventually reaches the medial temporal region, where Primary Age-Related Tauopathy is lying in wait.
Then, neurodegeneration follows in lockstep throughout the brain with the presence of tau pathology, with cognitive deficits matching those expected from the affected brain regions. In particular, since the hippocampal formation is located in the medial temporal region, anterograde amnesia is typically the first symptom in both types of Alzheimer’s (unlike many other forms of neurodegeneration, in which other clinical symptoms dominate in the early stages).
It’s as if two bank robberies occurred two hours apart in the same town, conducted in almost exactly the same manner, and in one we can positively ID the culprit on camera. It’s a reasonable conclusion that the culprit in the other case is the same.
The main genetic risk factors of sporadic, late-onset Alzheimer’s disease are shown to impair amyloid-β clearance or compaction (e.g. Castellano et al (2011). Human apoE Isoforms Differentially Regulate Brain Amyloid-β Peptide Clearance, among many others), although through less well-understood mechanisms, often involving lipid processing, so by itself this isn’t smoking gun evidence, but it is consistent with everything else that is known.
As for the evidence from amyloid-targeting therapies, a few things can be said. I’ll focus on monoclonal antibodies, which are the most-favored approach in the research community today. I’m aware of seven such antibodies: aducanumab, donanemab, lecanemab, solanezumab, crenezumab, gantenerumab, and bapineuzumab. Of these, three have had promising, though not stellar, findings in clinical trials:
In the above cases, the reduction in the pace of cognitive decline is generally around 30% or so, with a fairly wide range around that. [Removed claim about the other antibodies “almost always” showing a nonsignificant directional effect, after reviewing the data again.] Furthermore, some of the failed studies skirted the edge of statistical significance, and when they have looked at earlier vs. later intervention have typically found that earlier intervention is more effective (e.g. Doody et al (2014). Phase 3 Trials of Solanezumab for Mild-to-Moderate Alzheimer’s Disease).
This is all what we expect if amyloid is causally far upstream of the more proximate causes of neurodegeneration: if you only start intervention in the clinical phase, then you’re 15-20 years into the disease and the tau pathology is already active and spreading and causing neurodegeneration on its own, thus you’ve effectively taken the gun out of the shooter’s hand after they’ve already pulled the trigger. This is helpful (and in Alzheimer’s, it appears to slow decline by ~30%). On the other hand, you either need to intervene much earlier (not yet tested, although the first results from such trials are expected later this year), or in a different manner (I favor tau antibodies for the clinical phase) if you expect to do more than that.
(I know I didn’t provide references to all my claims, but I can dig them up from my notes for anything specific if you’re curious.)
I’d also recommend this article, including the discussion in the comments by researchers in the field.
A crucial distinction I’d emphasize which is almost always lost in popular discussions is that between the toxic amyloid oligomer hypothesis, that aggregates of amyloid beta are the main direct cause of neurodegeneration; and the ATN hypothesis I described in this thread, that amyloid pathology causes tau pathology and tau pathology causes neurodegeneration.
The former is mainly what this research concerns and has been largely discredited in my opinion since approximately 2012; the latter has a mountain of evidence in favor as I’ve described, and that hasn’t really changed now that it’s turned out that one line of evidence for an importantly different hypothesis was fabricated.
Update today: Biogen/Eisai have reported results from Lecanemab’s phase 3 trial: a slowing of cognitive decline by 27% with a p-value of 0.00005 on the primary endpoint. All other secondary endpoints, including cognitive ones, passed with p-values under 0.01.
I apologize if this is piling on, but I would like to note that this error strikes me as very similar to another one made by the same author in this comment,
In general corrections are good contributions, thanks for your object-level points.
I apologize if this is piling on, but I would like to note that this error strikes me as very similar to another one made by the same author in this comment, and which I believe is emblematic of a certain common failure mode within the rationalist community (of which I count myself a part). This common failure mode is to over-value our own intelligence and under-value institutional knowledge (whether from the scientific community or the Amazon marketplace), and thus not feel the need to tread carefully when the two come into conflict.
In the comment in question, johnswentworth asserts, confidently, that there is nothing but correlational evidence of the role of amyloid-β in Alzheimer’s disease. However, there is extensive, strong causal evidence for its role: most notably, that certain mutations in the APP, PSEN1, and PSEN2 genes deterministically (as in, there are no known exceptions for anyone living to their 80′s) cause Alzheimer’s disease, and the corresponding proteins are well understood structurally and functionally to be key players in the production of amyloid-β. Furthermore, the specific mutations in question are shown through multiple lines of evidence (structural analysis, in vitro experiment, and in vivo experiments in transgenic mice) to lead directly (as opposed to indirectly, via a hypothetical other Alzheimer’s-causing pathway) to greater production of amyloid-β.
A detailed summary of this and further evidence can be found in section 1.1 “Rationale for targeting Aβ and tau” of Plotkin and Cashman (2020). Passive immunotherapies targeting Aβ and tau in Alzheimer’s disease. A good general survey on amyloid-β production is Haass et al (2012). Trafficking and Proteolytic Processing of APP.
(My background: I have a family member with Alzheimer’s and as a result I spent five months studying the scientific literature on the subject in detail. I am posting under a pseudonym to protect my family member’s privacy.)
I think one reason that this error occurs is that there’s a mistaken assumption that the available literature captures all institutional knowledge on a topic, so if one simply spends enough time reading the literature, they’ll have all requisite knowledge needed for policy recommendations. I realize that this statement could apply equally to your own claims here, but in my experience I see it happen most often when someone reads a handful of the most recently released research papers and from just that small sample of work tries to draw conclusions applicable that are broadly applicable to the entire field.
Engineering claims are particularly suspect because institutional knowledge (often in the form of proprietary or confidential information held by companies and their employees) is where the difference between what is theoretically efficient and what is practically more efficient is found. It doesn’t even need to be protected information though—it can also just be that due to manufacturing reasons, or marketing reasons, or some type of incredibly aggravating constraint like “two hoses require a larger box and the larger box pushes you into a shipping size with much higher per-volume / mass costs so the overall cost of the product needs to be non-linearly higher than what you’d expect would be needed for a single hose unit, and that final per-unit cost is outside of what people would like to pay for an AC unit, unless you then also make drastic improvements to the motor efficiency, thermal efficiency, and reduce the sound level, at which point the price is now even higher than before, but you have more competitive reasons to justify it which will be accepted by a large enough % of the market to make up for the increased costs elsewhere, except the remaining % of the market can’t afford that higher per-unit cost at all, so we’re back to still making and selling a one-hose unit for them”.
Concrete example while we’re on the AC unit debate—there’s a very simple way to increase efficiency of portable AC units, and it’s to wrap the hot exhaust hose with insulating duct wrap so that less of the heat on that very hot hose radiates directly back into the room you’re trying to cool. Why do companies not sell their units with that wrap? Probably for one of any of the following reasons—A.) takes up a lot of space, B.) requires a time investment to apply to the unit which would dissuade buyers who think they can’t handle that complexity, C.) would cost more money to sell and no longer be profitable at the market’s price point, D.) has to be applied once the AC unit is in place, and generally is thick enough that the unit is no longer “portable” which during market testing was viewed as a negative by a large % of surveyed people, or E.) some other equally trivial sounding reason that nonetheless means it’s more cost effective for companies to NOT sell insulating duct wrap in the same box as the portable AC unit.
Example of an AC company that does sell an insulating wrap as an optional add-on: https://www.amazon.com/DeLonghi-DLSA003-Conditioner-Insulated-Universal/dp/B07X85CTPX
A priori, before having clicked on your links, my guess would be that the studies in question generally diagnose Alzheimer’s by the presence of amyloid-β deposits. (That’s generally been the case in similar studies I’ve looked into in the past, although I haven’t checked the exact studies you link.) If they’re diagnosing based on the presence of amyloid-β, then obviously amyloid-β producing mutations will cause an Alzheimer’s diagnosis. The problem is that this diagnosis doesn’t reflect real Alzheimer’s, i.e. it doesn’t necessarily involve dementia.
We would expect such things to find strong, extensive evidence of causality. The problem is that it’s extensive evidence of the mutations causing amyloid-β plaques, not dementia.
(Also, a warning: this is exactly the sort of detail which overview articles tend to overlook and misstate—e.g. an overview article will say something like “so-and-so found that blah causes dementia” when in fact so-and-so were diagnosing amyloid plaques, not dementia. One does need to check the original papers.)
A distinction is made in the literature between preclinical Alzheimer’s (the presence of neuropathology such as amyloid-β, without clinically detectable cognitive symptoms) and clinical Alzheimer’s (a particular cluster of cognitive symptoms along with the neuropathologies of Alzheimer’s). It’s currently believed that Alzheimer’s has a 15-20 year preclinical phase, the duration of which, however, can vary based on genetic and other factors.
In the case of the mutations I mentioned (which are early-onset causing), clinically-detectable cognitive decline typically starts around the age of 45, and nearly always by the age of 60. One of the only known examples in which symptoms didn’t start until a person was in her 70′s was so surprising that an entire, highly-cited paper was written about it: Arboleda-Velasquez et al (2019). Resistance to autosomal dominant Alzheimer’s disease in an APOE3 Christchurch homozygote: a case report. Note, however, that the typical cluster of symptoms did eventually occur.
Honestly, these particular mutations are so pervasively discussed in the literature, precisely due to their significance to the causal question, that I can tell you have not really engaged with the literature by your unawareness of their existence and the effects that they have on people.
I will readily acknowledge, by the way, that by themselves they don’t close the book on the causal question: someone could argue that early-onset, autosomal dominant Alzheimer’s due to these mutations is essentially a different disease than the much more prevalent late-onset, sporadic Alzheimer’s. While I don’t think this argument ultimately goes through, and I’d be happy to discuss why, my main point is not that there’s no residual question about the the etiology of the disease, but that the research community has intensely, intelligently, and carefully studied the distinction between correlative and causal evidence, as well as the distinction between neuropathology and cognitive symptoms. A lot of really smart, well-informed, careful practitioners work in this field, and it’s helpful to learn what they’ve discovered.
I’d be interested to read that.
(Apologies for lack of citations in the below, I don’t have them readily on hand and don’t want to go digging right at the moment.)
You’re right that I never went that deep into the Alzheimer’s literature; it’s certainly plausible that I overlooked a cluster of actually-competently-executed studies tying Aβ-related genetic mutations to robust dementia outcomes. I did look deeply into at least one study which made that claim (specifically the study which I most often found at the root of citation chains) and it turned out to diagnose using the presence of plaques, not dementia. But that was a paper from the early 90′s, so maybe better results have come along since then.
However, the absence of evidence for Aβ causing Alzheimer’s was not the only thing pinning down my beliefs here. I’ve also seen papers with positive evidence that Aβ doesn’t cause Alzheimer’s—i.e. removing plaques doesn’t eliminate dementia. And of course there’s been literally hundreds of clinical trials with drugs targeting Aβ, and they pretty consistently do not work.
So if there is a cluster of genetic studies establishing that Aβ-related mutations are causal for dementia, then the immediate question is how that squares with all the evidence against causality of Aβ for dementia. If the early-onset autosomal dominant version of the disease is in fact a different disease, that would answer the question, but you apparently think otherwise, so I’m curious to hear your case.
In brief, the main reason I don’t think the argument works that autosomal-dominant Alzheimer’s has a different etiology than sporadic Alzheimer’s is that they look, in so many respects, like essentially the same disease, with the same sequence of biomarkers and clinical symptoms:
Amyloid pathology starts in the default mode network, and gradually spreads throughout the brain over 15-20 years.
It eventually reaches the medial temporal region, where Primary Age-Related Tauopathy is lying in wait.
At this point, tau pathology, a prion-like pathology which in Alzheimer’s has a very specific conformation, starts spreading from there. The tau protein misfolds in the exact same way in both forms of the disease (Falcon et al (2018). Tau filaments from multiple cases of sporadic and inherited Alzheimer’s disease adopt a common fold), however it misfolds in a different way in the large majority of other known tau pathologies, of which there are a dozen or so (Shi et al (2021). Structure-based classification of tauopathies).
Then, neurodegeneration follows in lockstep throughout the brain with the presence of tau pathology, with cognitive deficits matching those expected from the affected brain regions. In particular, since the hippocampal formation is located in the medial temporal region, anterograde amnesia is typically the first symptom in both types of Alzheimer’s (unlike many other forms of neurodegeneration, in which other clinical symptoms dominate in the early stages).
It’s as if two bank robberies occurred two hours apart in the same town, conducted in almost exactly the same manner, and in one we can positively ID the culprit on camera. It’s a reasonable conclusion that the culprit in the other case is the same.
Some further evidence:
There has been extensive causal mediation modeling, e.g. Hanseeuw et al (2019). Association of Amyloid and Tau With Cognition in Preclinical Alzheimer Disease, which so far as I’m aware always fits the amyloid → tau → neurodegeneration (ATN) model of the disease, and generally doesn’t fit contradictory models.
There have been extensive in vitro and in vivo studies showing that amyloid pathology can directly induce tau pathology (which, as mentioned above, correlates with the location and severity of neurodegeneration). He et al (2018). Amyloid-β plaques enhance Alzheimer’s brain tau-seeded pathologies by facilitating neuritic plaque tau aggregation and Lodder et al (2021). CSF1R inhibition rescues tau pathology and neurodegeneration in an A/T/N model with combined AD pathologies, while preserving plaque associated microglia are just two of dozens of examples.
The main genetic risk factors of sporadic, late-onset Alzheimer’s disease are shown to impair amyloid-β clearance or compaction (e.g. Castellano et al (2011). Human apoE Isoforms Differentially Regulate Brain Amyloid-β Peptide Clearance, among many others), although through less well-understood mechanisms, often involving lipid processing, so by itself this isn’t smoking gun evidence, but it is consistent with everything else that is known.
As for the evidence from amyloid-targeting therapies, a few things can be said. I’ll focus on monoclonal antibodies, which are the most-favored approach in the research community today. I’m aware of seven such antibodies: aducanumab, donanemab, lecanemab, solanezumab, crenezumab, gantenerumab, and bapineuzumab. Of these, three have had promising, though not stellar, findings in clinical trials:
Aducanumab passed its cognitive endpoint in its phase 2 trial (Sevigny et al (2016). The antibody aducanumab reduces Aβ plaques in Alzheimer’s disease), and one of two phase 3 trials (Haeberlein et al (2022) Two Randomized Phase 3 Studies of Aducanumab in Early Alzheimer’s Disease).
Donanemab passed its primary endpoint in its phase 2 trial. Mintun et al (2021). Donanemab in Early Alzheimer’s Disease (It hasn’t yet reported from a phase 3 trial.)
Lecanemab was found, in a Bayesian analysis of its phase 2 trial, to have a 64% chance of slowing cognitive decline by at least 25% (however, the primary endpoint was an 80% chance, so it technically failed its trial). Swanson et al (2021). A randomized, double-blind, phase 2b proof-of-concept clinical trial in early Alzheimer’s disease with lecanemab, an anti-Aβ protofibril antibody (It also hasn’t yet reported from phase 3. [Update Sep 27, 2022: Now it has. Slowdown of cognitive decline by 27% with a p-value of 0.00005.])
In the above cases, the reduction in the pace of cognitive decline is generally around 30% or so, with a fairly wide range around that. [Removed claim about the other antibodies “almost always” showing a nonsignificant directional effect, after reviewing the data again.] Furthermore, some of the failed studies skirted the edge of statistical significance, and when they have looked at earlier vs. later intervention have typically found that earlier intervention is more effective (e.g. Doody et al (2014). Phase 3 Trials of Solanezumab for Mild-to-Moderate Alzheimer’s Disease).
This is all what we expect if amyloid is causally far upstream of the more proximate causes of neurodegeneration: if you only start intervention in the clinical phase, then you’re 15-20 years into the disease and the tau pathology is already active and spreading and causing neurodegeneration on its own, thus you’ve effectively taken the gun out of the shooter’s hand after they’ve already pulled the trigger. This is helpful (and in Alzheimer’s, it appears to slow decline by ~30%). On the other hand, you either need to intervene much earlier (not yet tested, although the first results from such trials are expected later this year), or in a different manner (I favor tau antibodies for the clinical phase) if you expect to do more than that.
(I know I didn’t provide references to all my claims, but I can dig them up from my notes for anything specific if you’re curious.)
I happened to be reading this post today, as Science has just published a story on a fabrication scandal regarding an influential paper on amyloid-β: https://www.science.org/content/article/potential-fabrication-research-images-threatens-key-theory-alzheimers-disease
I was wondering if this scandal changes the picture you described at all?
Not a ton.
I’d also recommend this article, including the discussion in the comments by researchers in the field.
A crucial distinction I’d emphasize which is almost always lost in popular discussions is that between the toxic amyloid oligomer hypothesis, that aggregates of amyloid beta are the main direct cause of neurodegeneration; and the ATN hypothesis I described in this thread, that amyloid pathology causes tau pathology and tau pathology causes neurodegeneration.
The former is mainly what this research concerns and has been largely discredited in my opinion since approximately 2012; the latter has a mountain of evidence in favor as I’ve described, and that hasn’t really changed now that it’s turned out that one line of evidence for an importantly different hypothesis was fabricated.
Thanks, that was helpful!
Update today: Biogen/Eisai have reported results from Lecanemab’s phase 3 trial: a slowing of cognitive decline by 27% with a p-value of 0.00005 on the primary endpoint. All other secondary endpoints, including cognitive ones, passed with p-values under 0.01.
Note I’ve edited the third-to-last paragraph in the above to remove an overly-strong claim about the four antibodies I didn’t discuss in detail.
In general corrections are good contributions, thanks for your object-level points.