Astral Codex Ten

Neuron

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Neuron

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Neuron is a recurring publication in the Astral Codex Ten archive, appearing 2 times across 2 issues between July 11, 2025 and August 14, 2025. The archive places it in contexts such as ""One tier down, you’ll find specialty journals like Neuron""; “Alzheimer’s Disease … Neuron”; “Neuron , vol. 109, no. 8, pp. 1283–1301.e6, Apr. 2021”. It most often appears alongside aducanumab, Alzheimer’s, Alzheimer’s Disease.

Metadata

  • Category: Publications
  • Mention count: 2
  • Issue count: 2
  • First seen: July 11, 2025
  • Last seen: August 14, 2025

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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 Review: Of Mice, Mechanisms, and Dementia
July 11, 2025 · Original source
First proposed by Hardy and Higgins in a 1992 Science perspective, the hypothesis suggested a clear sequence of disease-precipitating events: protein processing goes awry in the brain → beta-amyloid (Aβ) accumulates → plaques form → plaques trigger a cascade of downstream events, including neurofibrillary tangles, inflammation, synaptic loss, neuronal death, resulting in observable cognitive decline.
Inline links: 1992
Thus, like any robust causal theory, the amyloid cascade hypothesis offered explicit, testable predictions. As Hardy and Higgins outlined, if amyloid truly initiates the Alzheimer’s cascade, then genetically engineering mice to produce human amyloid should trigger the full sequence of events: plaques first, then tangles, synapse loss, and neuronal death, then cognitive decline. And the sequentiality matters: amyloid accumulation should precede other pathological features. At the time, this was a thrilling possibility.
To be considered a valid Alzheimer’s model, the Games mouse needed to express human APP at levels high enough to cause Alzheimer's-like pathology. Previous attempts by other labs had yielded mice that showed little to no amyloid plaques. Scientists suspected that higher expression levels might overcome this hurdle. They introduced the PDGF-β promoter, a genetic “on switch” that controls when and where a gene is activated to drive high expression in neurons; they included introns in the construct to allow for alternative splicing, a process that enables cells to produce different versions of a protein, in this case ensuring expression of the full range of amyloid-beta peptides seen in human Alzheimer’s.
Inline links: Previous, attempts
In Defense Of The Amyloid Hypothesis
August 14, 2025 · Original source
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]
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
[3] W. A. Eimer et al., “Alzheimer’s Disease-Associated β-Amyloid Is Rapidly Seeded by Herpesviridae to Protect against Brain Infection,” Neuron, vol. 99, no. 1, pp. 56–63.e3, Jul. 2018, doi: 10.1016/j.neuron.2018.06.030.
Inline links: 10.1016/j.neuron.2018.06.030