3 ms·

This is fascinating. I've been following, at a distance, the developments of AD research. The culprit is not Amyloid or Tau in themselves, but their misfolded

by pygy_ 14y ago

This is fascinating. I've been following, at a distance, the developments of AD research. The culprit is not Amyloid or Tau in themselves, but their misfolded variants, which have prion-like properties: they can't be degraded (and thus accumulate), and turn their respective healthy variants into their pathological counterparts. Misfolded Tau is intracellular, but it is known to propagate from cell [0,1], causing havoc on its way since its accumulation is sufficient to cause neurodegeneration. Misfolded Amyloid may not be toxic in itself, but it probably acts as a misfolding template for Tau (it does in vitro) [2]. -- 0. http://www.ncbi.nlm.nih.gov/pubmed/22365544 http://www.ncbi.nlm.nih.gov/pubmed/22365544 1. http://www.ncbi.nlm.nih.gov/pubmed/19282288 http://www.ncbi.nlm.nih.gov/pubmed/19282288 2. http://www.ncbi.nlm.nih.gov/pubmed/22965142 http://www.ncbi.nlm.nih.gov/pubmed/22965142 These may not be the best sources for these very points they're the first relevant papers I could find on the spot.

Daniel_Newby 14y ago
The Alzheimer's prion hypothesis is implausible, or at least incomplete. The proteins should spontaneously misfold at a small rate, followed by dementia 20-30 years later. The incidence at age 90 is something like 50%, and if we follow the exponential curve backwards, something like 0.5% of newborns should have tau prions, meaning several percent of teenagers should have early dementia. Instead the teenage dementia rate is vanishingly low, effectively zero. We would also expect clusters of Alzheimer's disease in young patients who were seeded by tissue contamination: recreational IV drug use, transplants, blood transfusions, etc. We do not observe this. The only obvious factor seems to be age. Something changes during aging that enables Alzheimer's disease. Before the change we are essentially bulletproof. After a steady increase sets in. I'm betting on some hormone being the culprit, possibly tied to a reactivated virus.
- pygy_ 14y ago
  Most interesting, thanks for the insight. I'd rather go for incomplete, then, since the evidence for tau neurotoxicity is there.

by pygy_ 14y ago

Daniel_Newby 14y ago

The Alzheimer's prion hypothesis is implausible, or at least incomplete. The proteins should spontaneously misfold at a small rate, followed by dementia 20-30 years later. The incidence at age 90 is something like 50%, and if we follow the exponential curve backwards, something like 0.5% of newborns should have tau prions, meaning several percent of teenagers should have early dementia. Instead the teenage dementia rate is vanishingly low, effectively zero. We would also expect clusters of Alzheimer's disease in young patients who were seeded by tissue contamination: recreational IV drug use, transplants, blood transfusions, etc. We do not observe this. The only obvious factor seems to be age. Something changes during aging that enables Alzheimer's disease. Before the change we are essentially bulletproof. After a steady increase sets in. I'm betting on some hormone being the culprit, possibly tied to a reactivated virus.

pygy_ 14y ago
Most interesting, thanks for the insight. I'd rather go for incomplete, then, since the evidence for tau neurotoxicity is there.