Fig. 4

a Simulated outcome of APOE genotype on changes in ADAS-Cog for placebo patients with mild Aβ starting load (4 units) over 78 weeks with APOE4^+/+ genotype implemented as having lower synaptic density (−20%) and lower clearance of Aβ. Platform outcome suggests that under these conditions APOE merely drives the baseline difference but does not affect disease progression. b Slopes of glutamate coupling (expressed as change in ADAS-Cog per % change in glutamate neurotransmission) as a function of disease progression (measured from start of a trial in a mild-to-moderate AD population) and APOE4 genotype. In the pathological state, defined by a range between 12 and 34 weeks into the trial, the system is maximally sensitive to NMDA conductance changes and therefore to Aβ-mediated effects. Note that while the APOE4^+/+ genotype has a greater sensitivity to Aβ load changes in the early pathology stages, the trend is reversed at more extensive pathology. However, with greater Aβ loads seen at later pathology stages, the range available to see an effect is reduced. This would also suggest that changes in amyloid levels from therapeutic interventions tend to have a maximal effect at 10–35 weeks in a trial with mild-to-moderate AD patients. ADAS-Cog Alzheimer Disease Assessment Scale, cognitive subscale, APOE apolipoprotein E, Glu glutamate