Synergism of antihypertensives and cholinesterase inhibitors in Alzheimer's disease

INTRODUCTION: We investigated the effect of antihypertensive (aHTN) medications and cholinesterase inhibitors (ChEIs) on the cognitive decline in patients with Alzheimer's disease (AD) and analyzed synergism by chemogenomics systems pharmacology mapping. METHODS: We compared the effect of aHTN drugs on Mini-Mental State Examination scores in 617 AD patients with hypertension, and studied the synergistic effects. RESULTS: The combination of diuretics, calcium channel blockers, and renin-angiotensin-aldosterone system blockers showed slower cognitive decline compared with other aHTN groups (Δβ = +1.46, P < .0001). aHTN medications slow down cognitive decline in ChEI users (Δβ = +0.56, P = .006), but not in non-ChEI users (Δβ = −0.31, P = .53). DISCUSSION: aHTN and ChEI drugs showed synergistic effects. A combination of diuretics, renin-angiotensin-aldosterone system blockers, and calcium channel blockers had the slowest cognitive decline. The chemogenomics systems pharmacology–identified molecular targets provide system pharmacology interpretation of the synergism of the drugs in clinics. The results suggest that improving vascular health is essential for AD treatment and provide a novel direction for AD drug development.