Astral Codex Ten

Tauopathies

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Tauopathies

Article

Tauopathies is a recurring concept in the Astral Codex Ten archive, appearing 2 times across 2 issues between July 12, 2024 and August 14, 2025. The archive places it in contexts such as “Tauopathies – which include Alzheimer’s – seem to be… prion-like”; “Tauopathies are a range of prion-like diseases involving the tau protein”. It most often appears alongside Alzheimer’s, Chromosome 21, Down syndrome.

Metadata

  • Category: Concepts
  • Mention count: 2
  • Issue count: 2
  • First seen: July 12, 2024
  • Last seen: August 14, 2025

Appears In

Source Context

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

Your Book Review: The Family That Couldn’t Sleep
July 12, 2024 · Original source
Remember, earlier, that we mentioned how pituitary growth hormone treatment can spread CJD. Turns out – probably – that it can also spread Alzheimer’s. Tauopathies – which include Alzheimer’s – seem to be...prion-like, in some way. Prusiner has been banging this particular drum since the 1980s, but hey, that’s part of what “good at getting grants” means.
Inline links: it can also spread Alzheimer’s, prion-like, in some way
In Defense Of The Amyloid Hypothesis
August 14, 2025 · Original source
Anti-amyloid drugs (like Aduhelm) don't reverse the disease, and only slow progression a relatively small amount. Opponents call the amyloid hypothesis zombie science, propped up only by pharmaceutical companies hoping to sell off a few more anti-amyloid me-too drugs before it collapses. Meanwhile, mainstream scientists . . . continue to believe it without really offering any public defense. Scott was so surprised by the size of the gap between official and unofficial opinion that he asked if someone from the orthodox camp would speak out in its favor. I am David Schneider-Joseph, an engineer formerly with SpaceX and Google, now working in AI safety. Alzheimer’s isn’t my field, but I got very interested in it, spent six months studying the literature, and came away believing the amyloid hypothesis was basically completely solid. I thought I’d share that understanding with current skeptics. The ATN model The most plausible variant of the amyloid hypothesis is the A → T → N model: amyloid causes tau causes neurodegeneration. 1: Amyloid The common entrypoint, typically at least 15 years before clinically detectable symptoms [1], is accumulation of amyloid-β deposits (especially Aβ42, one of several variants). Amyloid-β is a peptide produced in healthy human beings and many other animals, probably for antimicrobial purposes [2, 3]. Factors which cause overproduction of amyloid also cause Alzheimer’s. Factors that cause decreased clearance of amyloid also cause Alzheimer’s. The clearest relationship is various genes which massively increase amyloid production (while doing nothing else); these genes are Alzheimer’s risk factors, with some of the rarer and more severe ones causing extreme versions of the disease that manifest at otherwise almost-never-seen ages. One of the clearest examples is Down syndrome, which is caused by three (rather than the usual two) copies of chromosome 21. People with Down syndrome are at much higher risk of Alzheimer’s than the general population: two-thirds will have the condition by age sixty, and 15% have it by age forty. APP, the gene for the amyloid precursor protein, is on chromosome 21. This means that people with Down syndrome will have an extra copy. This extra copy has been observed to lead to higher-than-normal amyloid levels. But there are many genes on chromosome 21; do we have additional evidence that it’s the amyloid one that’s involved? Yes. Dozens of other mutations on APP cause the same sort of extremely young and severe Alzheimer’s. So do mutations on PSEN1 and 2, the genes for the enzyme that processes amyloid precursor protein into amyloid. So do mutations on several other amyloid-related genes. [6, 91 - 96] Researchers call these autosomal-dominant Alzheimer’s, meaning Alzheimer’s cases that get inherited from a single parent in a simple fashion typical of single-gene disorders. They make up about 1% of all cases, and are our strongest evidence for the causal role of amyloid in the disorder. To my knowledge, there is no serious claim that these genes could be working through any pathway other than their shared role in the amyloid system. But these autosomal-dominant cases only make up about 1% of all Alzheimer’s patients. Might they be a different disease than the usual sporadic Alzheimer’s that strikes people without strong family histories at normal ages? Probably not: the presentation and trajectory of autosomal-dominant and sporadic Alzheimer’s cases are strikingly similar. Both show an initial appearance of amyloid pathology starting in intrinsic connectivity networks in both autosomal-dominant [14] and sporadic [15–18] types, cortical tau appearing first in the medial temporal lobe and with the exact same fold in both disease types [97] (despite human tauopathies having at least seven other possible characteristic folds [36]), that tau pathology worsening and spreading outside this region only once amyloid pathology reaches sufficient severity [65], neurodegeneration progressing closely in step with the tau pathology, and the same usual approximate trajectory of cognitive symptoms due to the sequence of affected regions. So it’s as if two bank robberies occurred hours apart, in the same town, and in a highly similar and idiosyncratic manner, and we can positively identify the culprit of one on security camera footage. It’s a good bet the culprit of the other is the same. Increased amyloid production → Alzheimer’s is an especially clear and simple pathway, but any other change in amyloid can also cause the disease. For example Overproduction or reduced clearance of amyloid due to impaired slow wave sleep. Aβ production is neuronal activity-dependent, and toxins (perhaps including Aβ) are cleared from the brain during sleep via the glymphatic system. Thus Aβ can accumulate if the brain is more active and/or has less opportunity for clearance. [7, 8, 9, 10, 11]
Inline links: Aduhelm, David Schneider-Joseph
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: 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.
Inline links: below, probably through prion-like spread of the misfolded proteins, 10-centiloid, have been, the presence of amyloid pathology induces the worsening and spreading of tau pathology
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