The Precipitate

Following up on yesterday's discussions about lecanemab , some points to address. Maybe I am old-fashioned, but I believe that science should be about well-defined entities and mechanisms. I also believe that scientific theories should not be self-contradictory and must make sense within the known laws of physics, chemistry, and biology. From this perspective, I do not think that the two major hypotheses used to describe the amyloid phenomenon (The Amyloid Cascade Hypothesis (ACH) & The Prion Hypothesis (PrH)) fulfill these criteria. I also think that this is the reason behind much of the confusion and the scarcity of clinical success in the field. The ACH & the PrH were unorthodox hypotheses when they were developed in the 80s & 90s. The ACH boldly stated, in contrast to conventional biological and physicochemical wisdom at the time, that the endogenous proteins that form aggregates, even if evolutionary conserved & highly expressed in their native state, are j...

For over a hundred years, since Alois Alzheimer published his famous plaque and tangle pictures, it has been taken for granted that these plaques and tangles are actively killing the neurons by being toxic. There was no proof needed of why or how they are toxic, the details and mechanisms were to come eventually over time to prove what we already knew all along, these structures are toxic. Observations and experiments were not performed to test the toxic gain -of-function ( GOF) theory of amyloid pathology, but just to verify what we already know, they are toxic. Here, and exactly here, is where the pathology (as a scientific discipline) got its own disease; confirmation bias. No amount of counterevidence was ever enough to challenge GOF. Any counterevidence was either accommodated somehow or simply dismissed, leading to a group of myths and contradictory arguments that are recited almost religiously in papers, reviews, conferences, and media interactions to defend GOF. A smokescreen o...