Neuroimaging-based drug discovery for amyloid clearance therapy in Alzheimer's disease using validated causation analysis

Abstract

Aging-induced hepatic dysfunction can impair cholesterol metabolism, reducing the availability of cholic acid (CA, bile-acid) in brain. CA is reported to have neuroprotective characteristics in preclinical investigations of Alzheimer's disease (AD). Our aim is to probe the causal-connectivity between the players: amyloid, cholic acid and cerebral-blood-flow, and thereby explore therapeutic applicability in AD. From AD neuroimaging initiative biospecimen platform, we evaluated serum cholic-acid (182 healthy/136 AD individuals). We also assessed 50 healthy/50 Alzheimer's subjects containing MRI-ASL scanning (cerebral blood-flow, CBF) and PET-AV45 scanning (amyloid-load). We performed computational causal connectivity to determine the cause-effect relationship among the parameters. Serum cholic acid in AD subjects substantially decreased to half of controls. Causal-connectivity revealed two novel causative pathways: (i) Decreasing serum CA markedly increased amyloid-load; (ii) Increasing amyloid-load distinctly decreased CBF. We substantiated these two causation pathways respectively with collateral available preclinical observations: (a) increased cholic acid reduces amyloid formation by diminishing gamma-secretase; (b) this decreased amyloid induces capillary-flow enhancement by relaxing vascular pericytes. Indeed, cholic acid can increase amyloid-clearance factor. Neuroimaging-based causal connectivity analysis showed that repositioned pharmacological modulation by cholate derivatives may have appreciable potential as novel window for therapeutic approach to AD. Indicative clinical validation is furnished from available therapeutic trial leads.