In Defense Of The Amyloid Hypothesis

A guest post by David Schneider-Joseph

The “amyloid hypothesis” says that Alzheimer’s is caused by accumulation of the peptide amyloid-β. It’s the leading model in academia, but a favorite target for science journalists, contrarian bloggers, and neuroscience public intellectuals, who point out problems like:

• Some of the research establishing amyloid's role turned out to be fraudulent.

• The level of amyloid in the brain doesn’t correlate very well with the level of cognitive impairment across Alzheimer’s patients.

• Several strains of mice that were genetically programmed to have extra amyloid did eventually develop cognitive impairments. But it took much higher amyloid levels than humans have, and on further investigation the impairments didn't really look like Alzheimer’s.

• Some infectious agents, like the gingivitis bacterium and the herpesviruses, seem to play a role in at least some Alzheimer’s cases.

• . . . and amyloid is one of the body's responses to injury or infection, so it might be a harmless byproduct of these infections or whatever else the real disease is.

• Anti-amyloid drugs (like Aduhelm) don't reverse the disease, and only slow progression a relatively small amount.

Opponents call the amyloid hypothesis zombie science, propped up only by pharmaceutical companies hoping to sell off a few more anti-amyloid me-too drugs before it collapses. Meanwhile, mainstream scientists . . . continue to believe it without really offering any public defense. Scott was so surprised by the size of the gap between official and unofficial opinion that he asked if someone from the orthodox camp would speak out in its favor.

I am David Schneider-Joseph, an engineer formerly with SpaceX and Google, now working in AI safety. Alzheimer’s isn’t my field, but I got very interested in it, spent six months studying the literature, and came away believing the amyloid hypothesis was basically completely solid. I thought I’d share that understanding with current skeptics.

The ATN model

The most plausible variant of the amyloid hypothesis is the A → T → N model: amyloid causes tau causes neurodegeneration.

1: Amyloid

The common entrypoint, typically at least 15 years before clinically detectable symptoms [1], is accumulation of amyloid-β deposits (especially Aβ42, one of several variants).

Amyloid-β is a peptide produced in healthy human beings and many other animals, probably for antimicrobial purposes [2, 3].

Factors which cause overproduction of amyloid also cause Alzheimer’s. Factors that cause decreased clearance of amyloid also cause Alzheimer’s. The clearest relationship is various genes which massively increase amyloid production (while doing nothing else); these genes are Alzheimer’s risk factors, with some of the rarer and more severe ones causing extreme versions of the disease that manifest at otherwise almost-never-seen ages.

One of the clearest examples is Down syndrome, which is caused by three (rather than the usual two) copies of chromosome 21. People with Down syndrome are at much higher risk of Alzheimer’s than the general population: two-thirds will have the condition by age sixty, and 15% have it by age forty.

APP, the gene for the amyloid precursor protein, is on chromosome 21. This means that people with Down syndrome will have an extra copy. This extra copy has been observed to lead to higher-than-normal amyloid levels. But there are many genes on chromosome 21; do we have additional evidence that it’s the amyloid one that’s involved?

Yes. Dozens of other mutations on APP cause the same sort of extremely young and severe Alzheimer’s. So do mutations on PSEN1 and 2, the genes for the enzyme that processes amyloid precursor protein into amyloid. So do mutations on several other amyloid-related genes. [6, 91 - 96] Researchers call these autosomal-dominant Alzheimer’s, meaning Alzheimer’s cases that get inherited from a single parent in a simple fashion typical of single-gene disorders. They make up about 1% of all cases, and are our strongest evidence for the causal role of amyloid in the disorder. To my knowledge, there is no serious claim that these genes could be working through any pathway other than their shared role in the amyloid system.

But these autosomal-dominant cases only make up about 1% of all Alzheimer’s patients. Might they be a different disease than the usual sporadic Alzheimer’s that strikes people without strong family histories at normal ages?

Probably not: the presentation and trajectory of autosomal-dominant and sporadic Alzheimer’s cases are strikingly similar. Both show an initial appearance of amyloid pathology starting in intrinsic connectivity networks in both autosomal-dominant [14] and sporadic [15–18] types, cortical tau appearing first in the medial temporal lobe and with the exact same fold in both disease types [97] (despite human tauopathies having at least seven other possible characteristic folds [36]), that tau pathology worsening and spreading outside this region only once amyloid pathology reaches sufficient severity [65], neurodegeneration progressing closely in step with the tau pathology, and the same usual approximate trajectory of cognitive symptoms due to the sequence of affected regions. So it’s as if two bank robberies occurred hours apart, in the same town, and in a highly similar and idiosyncratic manner, and we can positively identify the culprit of one on security camera footage. It’s a good bet the culprit of the other is the same.

Increased amyloid production → Alzheimer’s is an especially clear and simple pathway, but any other change in amyloid can also cause the disease. For example

• Overproduction or reduced clearance of amyloid due to impaired slow wave sleep. Aβ production is neuronal activity-dependent, and toxins (perhaps including Aβ) are cleared from the brain during sleep via the glymphatic system. Thus Aβ can accumulate if the brain is more active and/or has less opportunity for clearance. [7, 8, 9, 10, 11]

• Impaired amyloid clearance due to having one or (much worse) two copies of ApoE4 [12], which is by far the most common genetic risk factor. The mechanism here may be a loss of function in microglia, a type of immune cell in the brain which helps clear plaques. [13]

• Overproduction or reduced clearance due to microbial infection. Amyloid-β appears to be an antimicrobial peptide and will form plaques in response to infection. [2, 3] This explains various observations that have been used to support the “infectious hypothesis”, sometimes proposed as an alternative to the amyloid hypothesis. However, it can only explain a subset of cases and, as I argue below, is even then still mediated by amyloid via an “IATN” pathway: infection → amyloid → tau → neurodegeneration.

In cases of increased production, cerebrospinal fluid (CSF) will show elevated amyloid. In cases of reduced clearance, amyloid will decrease in CSF. In all cases, however, PET scans will show elevated brain amyloid, usually at first mainly in “intrinsic connectivity networks” such as the default mode network [14–20], which experience brain activity even at rest. These neurons are the most active - which causes more production and possibly less opportunity for clearance - so they tend to be the first to suffer from a production/clearance imbalance.

Over time, amyloid pathology spreads spatially throughout the brain. [14, 18] Aggregations of amyloid peptides induce more such aggregations. Some of our clearest evidence for this comes from growth hormone deficiency patients, who used to have cadaver-derived ground-up brain matter injected into their own brains to provide the missing hormones. If the ground-up brain matter was sourced from the corpse of an Alzheimer’s patient, the growth hormone deficiency patients would themselves develop Alzheimer’s at a young age, probably through prion-like spread of the misfolded proteins. [21, 22]

After ∼15 years of preclinical spread, the pathology eventually covers the whole brain. [14, 18] While some subtle cognitive impairment may occur during this time, it is usually not severe enough to be clinically detectable from amyloid alone. Indeed, in both humans [23–30] and mice [31–35], the severity of neurodegeneration and cognitive deficits is not a good spatiotemporal match for the severity of amyloid pathology (rather, it is a good match for the severity of tau pathology; see next section for more). These facts are often suggested as evidence against the amyloid hypothesis. However, amyloid is causally upstream of tau, as I will argue below. Therefore, the existence of cognitively normal individuals with amyloid pathology is expected in the ATN model - but typically only for a few decades, before progression to the next stage.

2: Tau pathology (T) and neurodegeneration (N)

Tauopathies are a range of prion-like diseases involving the tau protein [36], whose usual function is to assist in stabilizing microtubule structure. In a tauopathy, the tau protein misfolds, and induces other, nearby tau proteins to misfold into the same shape. [37–46]. Injecting nothing but misfolded tau fibrils into a mouse brain can recruit the endogenously-produced mouse tau into this pathology, which spreads far beyond the injection site, causing neurodegeneration wherever it goes. [35, 47–59]

There are at least eight distinct ways the tau protein can misfold in human disease [36], and over a dozen distinct human tauopathies, each involving a specific one of those misfoldings. These include chronic traumatic encephalopathy, Pick’s disease, corticobasal degeneration, progressive supranuclear palsy, and Alzheimer’s disease, with the last by far the most common. Each of these five diseases has its own distinct tau fold.

Most normal human beings eventually develop some tau pathology in adulthood, originating probably in the locus coeruleus [60–62], which is part of the brainstem. By middle age, some amount has usually spread to the hippocampus and entorhinal cortex in the medial temporal lobe, regions responsible for episodic memory. This is called primary age-related tauopathy (PART) [63], and has its own tau fold which is distinct from most tauopathies, but the same as Alzheimer’s. [36, 64] Usually, its local severity is mild and it doesn’t spread much beyond those regions. But with sufficient amyloid pathology, this “normal” tau pathology tends to both locally worsen and spread through the rest of the brain [65], becoming the tau pathology of Alzheimer’s.

Some genetic risk factors such as ApoE, in addition to affecting the clearance of amyloid-β, also increase the brain’s susceptibility to this A → T pathology conversion [66, 67]. But this is a matter of degree, as sufficient amyloid pathology seems to virtually guarantee the transition: Every 10-centiloid increase in amyloid pathology for a cognitively normal individual increases by 2.7x the probability of a PET scan detecting pathological levels of tau within five years [68]. The only known cases where patients with extremely high amyloid levels can go significant amounts of time without developing tau pathology are a few individuals with extremely rare protective genes, known only from a few case studies, e.g. [69]. Even in these instances, the individuals will eventually succumb to the tau phase, suffering neural atrophy and dementia. [70]

After it forms, the tau pathology no longer appears to require amyloid’s assistance to keep spreading (although amyloid may still accelerate it). This probably explains why existing anti-amyloid therapies have been only ∼30% effective in test patients, who are usually late in the amyloid → tau progression even if early in having symptomatic disease.

Neurodegeneration follows tau pathology extremely closely in time and space, in humans as well as basically all animal models, and cognitive impairments match the functions of the affected regions. There are rare reports of advanced tau pathology without cognitive decline, often in people with protective ApoE2 alleles [71], but even then, systematic analysis finds that actual density of tau inclusions is highly predictive of cognitive impairment, and that these exceptional cases usually involve widespread but locally sparse pathology [66].

The regional distribution of tau pathology explains why the first symptom of Alzheimer’s is typically impaired memory; the first cortical sites affected are usually in regions involved in memory formation. As the pathology spreads, further regions are affected, until eventually all cognitive functions are affected. As with most other aspects of the disease, the high-level picture seems relatively clear but the exact cellular and molecular pathways are not well understood (though may involve an assist from the innate immune system, especially microglia and astrocytes. [13, 35, 72])

Early Alzheimer mouse models were amyloid-only, with extremely heavy overproduction of Aβ, much more than required to recapitulate the human disease, and apparently enough to cause detectable cognitive dysfunction. However, normal mice do not get age-related tauopathy, so an amyloid-only mouse model - while useful for investigating certain questions - is not a full Alzheimer’s disease model.

Combined amyloid+tau pathology mouse models, which are transgenically modified and/or injected with misfolded human tau fibrils, display the property that the presence of amyloid pathology induces the worsening and spreading of tau pathology. This is also observed in vitro in human cells.

How do we know the amyloid causes the tau? Researchers have measured the correlation in many ways, from the spatiotemporal timeline (tau pathology only begins locally worsening and spreading outside the medial temporal lobe once amyloid reaches sufficient severity) [65], [98], to causal mediation modeling in the human disease [26], [99–101], to causal intervention using in vitro human cell studies [54, 102] and animal models [35, 55], [103 – 113]. But also, giving people drugs that reduce amyloid levels also decreases tau pathology. [78, 80, 82]

(I’ve left out or merely alluded to much other complexity, involving the innate immune system, lipid processing, and detailed molecular and cellular mechanisms, preferring to focus on the parts of the story which are crucial to deciding the causal role of amyloid, and for which I am aware of a satisfactory account from the literature. But I don’t intend to leave the impression that the above is all there is to Alzheimer’s disease, or that all cases progress in the same exact way.)

The mechanistic claims

I make the following two claims about amyloid-β’s role in Alzheimer’s:

1. Amyloid deposits are a necessary (i.e. but-for) cause in all instances of Alzheimer dementia. That is, if someone has PET or CSF positivity for amyloid and tau pathologies, and the tau pathology involves the Alzheimer tau fold and made its first cortical appearance in the medial temporal lobe, and then they developed medial temporal volume loss + amnestic mild cognitive impairment + later dementia, then counterfactually, early enough (probably ∼15 years before clinical presentation) causal intervention solely to remove the amyloid deposits would have prevented almost all tau pathology and symptoms.

2. Severe enough amyloid pathology is a sufficient cause of Alzheimer dementia in almost all brains. That is, if someone is PET- or CSF-positive for very severe amyloid pathology (such as the level resulting from typical cases of autosomal-dominant overproduction), lack extremely rare protective genetics preventing further disease progression [69], and is not treated with any recent medical interventions, then they will eventually (after typically 15-20 years, and rarely more than 30), develop tau pathology and neurodegeneration in the region of this tau pathology (unless some other disease kills them first). Usually this will start in the medial temporal lobe and affect memory, then spread to other regions and functions.

Mechanistic claims I am not making:

1. I am not claiming that environmental factors such as microbial infection can never be a cause of Alzheimer’s disease. However, I claim that in all such cases, they act upstream of the above-described disease process, inducing the formation of amyloid deposits leading to the disease. Furthermore, these cannot be all cases - there are instances of the disease in which amyloid deposits arise essentially entirely due to genetic factors (like the autosomal-dominant cases of overproduction).

2. I am not claiming that the disease is “as simple as” amyloid deposits directly inducing neurodegeneration. As described above, they act indirectly, via the eventual downstream tau pathology, and possibly an associated microglial/astrocytic inflammatory response. Therefore, there are many people in the preclinical, amyloid-only disease phase who will eventually progress to dementia but have not yet.

These two clarifications imply that even though amyloid pathology is a necessary and (in enough severity) sufficient cause of the disease under normal circumstances, therapies with other targets might still be effective, either intervening upstream such that amyloid deposits never occur, or downstream so as to prevent the neurodegenerative process.

The testable prediction

I would bet on the following: A therapy whose sole intended mechanism involves amyloid production or clearance, in a randomized, double-blind, placebo-controlled trial, will, in the next 12 years, achieve a slowdown of cognitive decline of at least 75%, with a p-value below 0.001, in its preregistered primary cognitive endpoint (or an average of all such endpoints if more than one exists). I’d eventually expect better than 75% efficacy, but getting stuff to work takes time, and I wanted to make a prediction which can be tested in a reasonable timeframe.

On the other hand, if a clinical trial completes earlier than 12 years from now (perhaps [73], reading out in 2027), sustains extremely good amyloid clearance at the preclinical stage, and has a good safety profile, but doesn’t make substantial progress towards this 75% goal, then I would consider this prediction refuted in advance.

For targeting amyloid, I’m most optimistic about a blood brain barrier (BBB)-penetrating antibody such as trontinemab [74–76], but with an epitope more like lecanemab’s, and given in the preclinical disease stage. Other options for targeting amyloid include antisense oligonucleotides for APP as well as γ-secretase modulators.

The successes and failures of amyloid antibodies

There have now been three amyloid antibodies with positive phase 3 (and earlier) clinical trials on cognitive endpoints (but with much less than 75% efficacy):

1. Aducanumab in phase 1b [77] (19% on my average across cognitive endpoints for the highest two doses) and one of two phase 3 trials [78] (22%, but negative 2% in the other trial, which also gave a lower dose on average).

2. Lecanemab in its phase 2b [79] (30% on the primary measure, though it technically failed because of its ambitious Bayesian endpoint) and phase 3 [80] (27%).

3. Donanemab in phase 2 [81] (32%) and phase 3 [82] (35%).

There have also been earlier antibodies that saw only failure in phase 3 – bapineuzumab [83, 84], crenezumab [85], solanezumab [86–88], and gantenerumab [88, 89]. These failed drugs didn’t just do a bad job treating Alzheimer’s. They also did a bad job clearing amyloid plaques, so their failure is consistent with the amyloid hypothesis. That said, just coupling the older, previously-unsuccessful antibody gantenerumab with a BBB-crossing mechanism produced extremely good target engagement and better safety in early clinical trials [74–76]. This makes me optimistic about a future BBB-crossing lecanemab (or similar), especially if given in the preclinical disease phase prior to significant tauopathy.

Each of the “successes” have shown about 25-30% slowing of decline over 18 months. Some object that this isn’t clinically meaningful because it’s only a slowdown of ∼0.5 points on an 18-point CDR-SB scale, but they don’t mention that the participants start about 3 points from a perfect score (since these are relatively early-stage patients) and worsen by ∼1.5 points in those 18 months when on placebo. A literally perfect drug - one which halted all further clinical progression - could therefore only achieve about 1.5 points of efficacy on that scale. The cruxy question is whether the drugs maintain a 30% reduction after 18 months. Preliminary signs from lecanemab’s and donanemab’s open-label extensions show that they do [90], so this would amount to about 40% more years of life at each disease stage.

But why have amyloid antibodies only achieved about 30% efficacy so far? The likely answer: mainly because they were given too late to prevent the downstream tau pathology cascade, but also because some of their side effects, like when they target amyloid-bearing blood vessels rather than brain tissue, can themselves worsen cognition.

That said, even achieving 30% efficacy proves that amyloid plays some causal disease role and isn’t merely a downstream, harmless pathology.

Why is the amyloid hypothesis unpopular?

The amyloid hypothesis remains popular in the Alzheimer’s disease research community, but most press coverage is negative. These challenges are understandable, and some of them make good points, but overall fail to address the evidence discussed above.

Failures and perceived failures of amyloid therapies

I discussed this above, but to recap:

• Early attempts had suboptimal epitopes which didn’t successfully engage their targets.

• Later attempts did engage their target, but have mostly been tested ∼15 years after the disease started, and so after downstream tau pathologies had already started.

• These later attempts demonstrated a ∼30% slowdown in clinical progression, which proves at least some causal role for amyloid. Some claim this isn’t clinically meaningful but they use misleading arguments (like saying it’s a 0.5-point benefit on an 18-point scale, when even a perfect drug which halted all clinical progression could only have achieved a 1.5-point benefit vs. placebo, since the patients start near a perfect score and the placebo group only worsens by about 1.5 points).

• In all mature antibodies so far, they have been attended with not-great side effects: brain swelling and bleeding, for reasons related to their difficulty crossing the BBB into brain tissue where they’re actually needed. A new generation of antibodies will cross the BBB, improving efficacy and safety.

It’s frustrating that getting even to a 30% slowdown has taken as long as it has, but all of this is consistent with the model of the disease I laid out, which has strong evidence behind it, and there’s every reason to expect that a new drug (A) with an optimal epitope, similar to lecanemab or donanemab, (B) given in the early preclinical phase, 10+ years earlier than currently, and (C) with a shuttle mechanism to cross the BBB, could be very successful.

The mature antibodies only have (A). There are ongoing trials combining (A)+(B) [73], [114], [115], and a shortly upcoming trial combining (B)+(C) [76], but not yet all three together. I’m optimistic about these but expect (A)+(B)+(C) to do especially well.

Unfortunately, this stuff is hard, slow, and over-regulated. Which means it’s taking longer than we’d like. But my guess is we’re on the right track.

Challenges translating from mouse models

The researchers who developed the early Alzheimer mouse models wanted the clearest possible window into disease progression, so they turned up an amyloid gene to extreme levels far beyond those of even severe human cases. This level of amyloid was so massive that it caused cognitive deficits directly, eg without any contribution from tau. And in fact, mouse proteins work differently from human proteins, and mice do not naturally get tauopathies.

So researchers increased amyloid, got cognitive deficits, and thought they were simulating Alzheimer’s. But they were actually doing something significantly different:

• Human patients: increased amyloid → tau → neurodegeneration and disease

• Mouse models: massively increased amyloid → neurodegeneration and disease

Then, since the mouse models didn’t really have Alzheimer’s the way it works in humans, most of the findings from the mouse models failed to translate into human Alzheimer’s patients. Since the findings from the amyloid mice did such a bad job matching human Alzheimer’s cases, some people concluded that amyloid did not cause Alzheimer’s.

There are now tauopathy mouse models. In those models, worsening amyloid pathology tends to cause the tau pathology to worsen as well. [35, 55, 103–113] I predict that findings from these mice are more likely to translate to human disease.

Fraud in amyloid research

There was some really bad fraud, such as documented in [123], which is the case that received the most attention. For another good overview of fraud in Alzheimer research (not all relating to amyloid-β), see [124]. The perpetrators should be institutionally severely punished.

This fraud has sometimes been framed by amyloid hypothesis critics as impacting very foundational work for the amyloid hypothesis. But this mostly isn’t true. [125] It concerns some specific variants of amyloid-β that are not prominent in nearly any of the literature I’ve encountered. When it was uncovered, I checked how many of the hundreds of papers in my notes seemed to be affected, and very few were.

For example, the main findings I have relied upon in this argument have, to the best of my understanding, survived unscathed:

• The smoking gun genetic evidence for amyloid’s causal role in the autosomal-dominant versions of the disease, and the extensive similarities between the autosomal-dominant disease and sporadic disease.

• The evidence that Aβ can potentiate or accelerate tau pathology (which itself is proximate to neurodegeneration), from studies in animal models, studies in human cells, the spatiotemporal disease course, causal mediation modeling of that disease course, and the tau biomarker effects from amyloid therapies.

The “amyloid mafia”

There is a perception that a combination of nefarious and misguided behavior has led to it being impossible to pursue alternative hypotheses or therapies, with the whole field pursuing a dead end.

I don’t have numbers for the more basic research, but we do have good data on the therapeutics being explored. In 2020, only 35% of hopefully-disease-modifying phase 3 trials and 20% of hopefully-disease-modifying phase 2 trials targeted amyloid; 65-80% target other pathways [126]. The breakdown for other years is similar (see e.g. [127]).

I support this, in part because it’s always good to test alternative possibilities, but in part because I expect that some of them can succeed even if the ATN model is right.

The compellingness of alternative hypotheses

A primary competitor of the amyloid hypothesis is the tau hypothesis. This naturally claims that the tau protein is the fundamental cause of Alzheimer’s, which makes good sense - the location and severity of tau pathology correlates better with the location and severity of neurodegeneration than does amyloid-β, in both humans [23 - 30] and combined amyloid/tau mouse models [31 – 35]. However, this is exactly as predicted by the ATN (amyloid → tau → neurodegeneration) model of the disease: amyloid pathology builds for 15–20 years, eventually inducing tau pathology; then the tau pathology causes neurodegeneration. Why not skip the amyloid step? Because as discussed above, we have extensive genetic and clinical evidence that the amyloid is the trigger for tau to spread in the first place.

(of course, this doesn’t mean tau is a bad target for therapy. I’m optimistic about tau antisense oligonucleotides such as BIIB080, which had a very promising phase 1b trial [116, 117] and is now in phase 2)

Another competitor is the microbial infection hypothesis. Again, there is good evidence this is true in some cases - multiple pathogens such as the periodontitis bacteria P. gingivalis [118] and various herpes viruses [3, 119] are correlated with the disease, which has tempted some microbiologists to treat amyloid as merely a harmless correlate: since amyloid is involved in the body’s immune response, maybe in the process of causing brain damage the microbes cause some amyloid deposition on the side. But again, these facts are also consistent with the ATN (or in this case IATN - infection → amyloid → tau → neurodegeneration) hypothesis.

(again, treating these microbes is still another promising target for treating or preventing Alzheimer’s)

These alternatives are a good reminder that the causal pathway can be hard to disentangle. But again, the strongest evidence for amyloid’s causal role is genetics: genes which increase amyloid increase Alzheimer’s risk, and rare mutations that massively increase amyloid massively increase the risk of Alzheimer’s (including unusually young or severe cases). Given this natural experiment, the most parsimonious explanation is that amyloid is intimately involved in Alzheimer’s, and then the most parsimonious explanation for the role of infection and tau is that they are part of the same I → A → T → N pathway.

The meta-psychological explanation: frustration at complexity and slow progress

Progress in biomedical research is slow. The disease (and amyloid-β’s prevalence in it) was discovered in 1906, the amyloid causal hypothesis was first proposed in 1992 after discovery of the genetic evidence [4], [5], the first amyloid antibody entered clinical trials in 2005 [128] - and now, in 2025, the best we have is ∼30% efficacy with potentially serious side effects.

But biology is messy, and we need to have comfort with complexity. Yes, there’s evidence that tau is responsible for the neurodegeneration in Alzheimer’s disease; no, this doesn’t contradict the amyloid hypothesis. Yes, Biogen screwed up in conducting the aducanumab phase 3 trials and this made the results harder to interpret; no, that doesn’t mean amyloid therapies have completely failed. Yes, it’s taken way too long to get even to this intermediate point of 30% efficacy, due to a combination of overregulation and biology just being damned hard; no, that doesn’t mean we’re on the wrong track with the underlying science.

Some years ago, I worked on the guidance and navigation software for the Falcon 9 first stage landing. The early attempts failed because of annoying issues like stuck propellant valves, running out of fin hydraulic fluid, and so on. It took many tries to iron out all those issues. Meanwhile, fans and critics kept proposing that SpaceX’s fundamental approach was flawed, and suggesting entirely different approaches. Most of that criticism was pretty uninformed.

This of course isn’t a general refutation of outsiders criticizing any field, as sometimes such criticism is necessary and right. But it does illustrate the need for patience when specialists are attempting something hard and unprecedented. Curing Alzheimer’s disease is much harder than landing a rocket. It’s important to understand the reasons for therapeutic failures (in this case, failure to engage the target) and underwhelming successes (probably due to treatment late in the disease progression, plus the challenges in crossing the BBB), to put that in the context of the scientific evidence from the basic research (which is very strong in this case), and to consider how compelling the alternative hypotheses are (not very).

Frustrated people who don’t have the time or capacity to study the science themselves often want someone to blame, and the “amyloid mafia” is a ready target. But there isn’t as much of a mafia as they think; biology is just hard.

My bottom line remains that no alternative hypothesis offers a plausible accounting of the evidence for amyloid’s causal role; whereas conversely, there is no evidence I’m aware of that the ATN model has great trouble accounting for.

I am grateful to Logan Thrasher Collins, Tommy Crow, Dan Elton, and Greg Fitzgerald for valuable feedback on this essay, and to Scott Alexander for edits which improved its structure and presentation.

Footnotes

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