Simulations of symptomatic treatments for Alzheimer's disease: computational analysis of pathology and mechanisms of drug action

Abstract

IntroductionA substantial number of therapeutic drugs for Alzheimer's disease (AD) have failed in late-stage trials, highlighting the translational disconnect with pathology-based animal models.MethodsTo bridge the gap between preclinical animal models and clinical outcomes, we implemented a conductance-based computational model of cortical circuitry to simulate working memory as a measure for cognitive function. The model was initially calibrated using preclinical data on receptor pharmacology of catecholamine and cholinergic neurotransmitters. The pathology of AD was subsequently implemented as synaptic and neuronal loss and a decrease in cholinergic tone. The model was further calibrated with clinical Alzheimer's Disease Assessment Scale-cognitive subscale (ADAS-Cog) results on acetylcholinesterase inhibitors and 5-HT6 antagonists to improve the model's prediction of clinical outcomes.ResultsAs an independent validation, we reproduced clinical data for apolipoprotein E (APOE) genotypes showing that the ApoE4 genotype reduces the network performance much more in mild cognitive impairment conditions than at later stages of AD pathology. We then demonstrated the differential effect of memantine, an N-Methyl-D-aspartic acid (NMDA) subunit selective weak inhibitor, in early and late AD pathology, and show that inhibition of the NMDA receptor NR2C/NR2D subunits located on inhibitory interneurons compensates for the greater excitatory decline observed with pathology.ConclusionsThis quantitative systems pharmacology approach is shown to be complementary to traditional animal models, with the potential to assess potential off-target effects, the consequences of pharmacologically active human metabolites, the effect of comedications, and the impact of a small number of well described genotypes.

Big data to smart data in Alzheimer's disease: Real‐world examples of advanced modeling and simulation

“…Localization of membrane receptors and ion channels and their intracellular regulation is derived from literature and reflects the domain expertise collected in the neuroscience community. Key biological coupling parameters between receptor activation and subsequent change in voltage-gated ion channels are calibrated using a correlation between model outcome and actual historical clinical outcomes for a large number of pharmacological interventions, such as ADAS-Cog changes over time with different doses of acetylcholinesterases and 5-H6 antagonist SB742457 [26].…”

A strategy for developing new treatment paradigms for neuropsychiatric and neurocognitive symptoms in Alzheimer’s disease

“…Details of the platform have been described elsewhere (Spiros et al, 2010; Roberts et al, 2012b). With regard to cognitive disorders, we have used this platform to explain the differential clinical effect of memantine and apolipoprotein E (APOE) on ADAS-Cog in Alzheimer patients (Roberts et al, 2012b).…”

“…With regard to cognitive disorders, we have used this platform to explain the differential clinical effect of memantine and apolipoprotein E (APOE) on ADAS-Cog in Alzheimer patients (Roberts et al, 2012b). The platform also predicted correctly a completely unexpected phase I outcome in humans with the lowest dose of a novel symptomatic compound on scopolamine-induced deficit that was different from what preclinical animal models suggested (Nicholas et al, 2012).…”

“…The cortical network model for cognitive function is described in detail elsewhere (Roberts et al, 2012b). Basically, we extended a biophysically realistic model of a network comprised of four-compartment pyramidal cells and two-compartment GABA interneurons (Durstewitz et al, 2000; DeFelipe, 2002) with the receptor physiology of 18 different dopaminergic, serotonergic, noradrenergic, and cholinergic receptors to a system of 80 four-compartment pyramidal cells and 40 two-compartment interneurons ( Figure 2 ).…”

Excitotoxicity and Glaucoma

“…The degree of blockade of the NMDA receptors is changed according to the concentration of memantine [128]. Memantine is a neuroprotective agent that has completed phase III clinical trial in patients with glaucoma [129,130]. The trial showed that memantine was ineffective by the primary end point, with the variable mechanisms of retinal ganglion apoptosis being offered as an explanation [131].…”