“Maybe we’re all just stumbling from the right questions to the wrong
answers, or maybe from the right answers to the wrong questions.” –Malek, R. Mr. Robot 2016
“This (the sola study) is confirmation of the amyloid hypothesis, our strongest confirmation todate.” –Aisen, P. 12/8/16 CTAD
Which just shows how low the amyloid bar is, confirmation-wise. The next issue of NeuroPerspective will take a more detailed look at what light Sola 3.0 and Adu 1.25 together shed on the ‘amyloid hypothesis’ and on the treatment of Alzheimer’s. But in the meantime, we have an example of a variant not posited by Mr. Robot, in this instance the conversation ricocheted from the wrong question to the wrong answer.
The wrong question: ‘What do these results say about the amyloid hypothesis?’
This infers that there is a single, archetypal amyloid hypothesis (AH), but in fact there are several. The original AH 1.0 says that Alzheimer’s is caused by the accumulation of amyloid plaque within the brain. If AH 1.0 were correct, aducanumab’s ability to reduce plaque deposition by 25-30% should translate into tangible cognitive/functional benefit. But while the 10mg dose showed a tentative signal on the CDR-SB, the 6mg dose, in spite of its similar PET-scan credentials, was a flop at 110 weeks. That could be the product of the variance produced by the analysis of small cohorts, only a larger trial will tell. And solanezumab, in spite of not binding to plaque at all, produced a consistent albeit clinically meaningless effect on cognition.
Any question about AH 1.0 is the wrong question. It’s like asking about the ‘link’ between vaccinations and autism.
Perhaps the questioner was referring to AH 2.0, which proposes that amyloid in some non-plaque form (fibril, oligomer, monomer) is the causal key to Alzheimer’s. One counterargument is offered by solanezumab, which produced a dramatic effect upon CSF amyloid, increasing it 500-800 fold, but the weakness of the therapeutic effect in the face of that CSF biomarker does not portend a robust relationship. The sola results neither prove nor disprove AH 2.0: We do not know if the weak response promoted by solanezumab means that the antibody binds to a suboptimal form of AB; not enough antibody reached the brain to bind enough AB; the patients were too advanced to benefit from a post hoc reduction of AB; or the answer includes a combination of some or all of these.
AH 3.0 suggests that amyloid is a secondary rather than primary pathophysiological feature; it is not the foremost pathological actor, but plays some facilitative or supportive role. This is consistent with a recent hypothesis that amyloid sets the stage for tau to disperse and cause the bulk of the direct damage. NIR’s own belief is that AH 3.0 is the best current model for understanding the data to this point, one that leaves open the possibility that targeting amyloid could have a clinically meaningful role in AD treatment–-but it is still just a hypothesis.
So the question posed to the sola panel at CTAD was ‘wrong’ because it referred to ‘the amyloid hypothesis’, as opposed to ‘an amyloid hypothesis,’ without specifying which one. And with all due respect to Paul Aisen, who knows far more about Alzheimer’s than NIR ever will, he provided the ‘wrong answer’, regardless of which AH species he may have been referring to. Nothing was ‘confirmed’ by the sola results. So much has been invested by so many in the amyloid hypotheses that any results that do not contradict it/them is seized upon like a drowning man grabbing hold of a flotation ring.
Two other thoughts about the aducanumab titration subsidiary study: Reducing the rate of ARIA 36% comes nowhere close to eliminating the problem. And when patients developed ARIA, it was at the 1 and 3mg dose levels, so ARIA cannot be avoided by stopping at 6mg dosing with APOE4-positive patients, as is currently being done by Biogen in Phase III.