Abstract
BackgroundDespite a tremendous amount of information on the role of amyloid in Alzheimer’s disease (AD), almost all clinical trials testing this hypothesis have failed to generate clinically relevant cognitive effects.MethodsWe present an advanced mechanism-based and biophysically realistic quantitative systems pharmacology computer model of an Alzheimer-type neuronal cortical network that has been calibrated with Alzheimer Disease Assessment Scale, cognitive subscale (ADAS-Cog) readouts from historical clinical trials and simulated the differential impact of amyloid-beta (Aβ40 and Aβ42) oligomers on glutamate and nicotinic neurotransmission.ResultsPreclinical data suggest a beneficial effect of shorter Aβ forms within a limited dose range. Such a beneficial effect of Aβ40 on glutamate neurotransmission in human patients is absolutely necessary to reproduce clinical data on the ADAS-Cog in minimal cognitive impairment (MCI) patients with and without amyloid load, the effect of APOE genotype effect on the slope of the cognitive trajectory over time in placebo AD patients and higher sensitivity to cholinergic manipulation with scopolamine associated with higher Aβ in MCI subjects. We further derive a relationship between units of Aβ load in our model and the standard uptake value ratio from amyloid imaging.When introducing the documented clinical pharmacodynamic effects on Aβ levels for various amyloid-related clinical interventions in patients with low Aβ baseline, the platform predicts an overall significant worsening for passive vaccination with solanezumab, beta-secretase inhibitor verubecestat and gamma-secretase inhibitor semagacestat. In contrast, all three interventions improved cognition in subjects with moderate to high baseline Aβ levels, with verubecestat anticipated to have the greatest effect (around ADAS-Cog value 1.5 points), solanezumab the lowest (0.8 ADAS-Cog value points) and semagacestat in between. This could explain the success of many amyloid interventions in transgene animals with an artificial high level of Aβ, but not in AD patients with a large variability of amyloid loads.ConclusionsIf these predictions are confirmed in post-hoc analyses of failed clinical amyloid-modulating trials, one should question the rationale behind testing these interventions in early and prodromal subjects with low or zero amyloid load.
Highlights
Despite a tremendous amount of information on the role of amyloid in Alzheimer’s disease (AD), almost all clinical trials testing this hypothesis have failed to generate clinically relevant cognitive effects
Constraining system parameters using clinical data The first major challenge is to obtain good estimates of the various parameters, notably x0, the position of the Amyloid-beta 1–40 (Aβ40) peak, δ, the magnitude of the Aβ40 beneficial effect, and α, α* and β, the slopes related to the reduction by both Aβ forms on Glu and Nicotinic acetylcholine receptor (nAChR) neurotransmission, respectively, in addition to the ‘units’ of Aβ load
Once we set the relation between Aβ units and the standard uptake value ratio (SUVR) of amyloid imaging we simulate the outcome of two clinical experiments: the effect of scopolamine on cognition in minimal cognitive impairment (MCI) subjects with and without Aβ load [18]; and the effect of Apolipoprotein E (APOE) genotype on cognitive trajectory in placebo-treated AD patients [19, 32]
Summary
Despite a tremendous amount of information on the role of amyloid in Alzheimer’s disease (AD), almost all clinical trials testing this hypothesis have failed to generate clinically relevant cognitive effects. Clear insights into the dynamics of various Aβ monomeric, oligomeric and aggregated forms, their impact on cognitive readouts and the effect of various therapeutic interventions with amyloid antibodies on the distribution of different forms in human patients are lacking. Recent stable isotope labeling kinetics (SILK) studies in humans have allowed one to numerically constrain the synthesis rates of Aβ and kinetic models have been developed to account for these observations [3, 4]. These results confirm the relatively greater level of the shorter Aβ40 over the longer Aβ42 form and suggest that the human brain cares less about restricting Aβ40 levels. Given that the oligomeric Aβ40 and Aβ42 peptides are probably the species that differentially affect synaptic function [8], how do changes in both Aβ levels impact clinically relevant cognitive outcomes as measured by the ADAS-Cog?
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