David Schneider-Joseph, an engineer with experience at SpaceX and Google, dives into the amyloid hypothesis of Alzheimer’s, advocating for its validity despite widespread skepticism. He tackles the integrity issues of past research and discusses how amyloid might not be the villain it’s made out to be. The conversation illuminates the complexities in correlating amyloid levels with cognitive decline and debates the efficacy of anti-amyloid drugs. Schneider-Joseph’s insights reveal the ongoing struggle within the scientific community to reconcile data and prevailing theories.
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insights INSIGHT
A→T→N Explains Disease Sequence
The A→T→N model places amyloid accumulation first, then tau pathology, then neurodegeneration and symptoms.
Genetic mutations that increase amyloid production strongly support amyloid as the upstream trigger.
insights INSIGHT
Genetics Tie Amyloid To Causality
Autosomal dominant mutations (APP, PSEN1/2) dramatically increase amyloid and cause early Alzheimer's.
These familial cases mirror sporadic Alzheimer's in timeline and pathology, implying a shared causal route.
insights INSIGHT
Amyloid Accumulates Decades Before Symptoms
Amyloid accumulates years before symptoms and often in highly active brain networks like the default mode network.
PET shows brain amyloid while CSF changes depend on whether production or clearance is altered.
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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.
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