Astral Codex Ten

APP

7 min read

APP

Article

APP is a recurring concept 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 “human APP expression levels in your mouse model”; “PDAPP mouse carries 40 copies of the APP transgene”; “PDAPP mouse makes human APP”. It most often appears alongside aducanumab, Alzheimer’s, Alzheimer’s Disease.

Metadata

  • Category: Concepts
  • Mention count: 2
  • Issue count: 2
  • First seen: July 11, 2025
  • 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 Review: Of Mice, Mechanisms, and Dementia
July 11, 2025 · Original source
The hypothesis was compelling for several reasons. First, the discovery of the enzymatic steps by which amyloid precursor protein (APP) is processed into Aβ offered multiple potential intervention points—ideal for pharmaceutical drug development.
What the Heck is Going on in Panel d? Panel d is an immunoblot (Western blot), a technique that tells us whether a specific protein is being produced in a sample. The figure compares human amyloid precursor protein expression in samples from three brains, corresponding to the three “lanes” shown along the top: a normal mouse (Lane 1), a mouse with the human APP transgene (Lane 2), and a human who had Alzheimer’s disease (Lane 3). The blots (the bands and blobs) are the data. For purposes of this figure, proteins can differ in two important ways: They can differ in molecular weight (size), scored on the scale along the vertical axis on the left.
Evidence that APP overexpression isn't driving toxicity, which can cause similar damage to the brain. This is very hard to control for, so the best course of action is to try to match human APP expression levels in your mouse model.
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
[93] J. A. Maloney et al., “Molecular Mechanisms of Alzheimer Disease Protection by the A673T Allele of Amyloid Precursor Protein*,” Journal of Biological Chemistry, vol. 289, no. 45, pp. 30990–31000, Nov. 2014, doi: 10.1074/jbc.M114.589069.
Inline links: 10.1074/jbc.M114.589069
[95] B. De Strooper et al., “Deficiency of presenilin-1 inhibits the normal cleavage of amyloid precursor protein,” Nature, vol. 391, no. 6665, pp. 387–390, Jan. 1998, doi: 10.1038/34910.
Inline links: 10.1038/34910