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. 2018 Oct 14:4:542-555.
doi: 10.1016/j.trci.2018.09.001. eCollection 2018.

Synergism of antihypertensives and cholinesterase inhibitors in Alzheimer's disease

Ziheng Hu  1 , Lirong Wang  1 , Shifan Ma  1 , Levent Kirisci  1 , Zhiwei Feng  1 , Ying Xue  1   2 , William E Klunk  3 , M Ilyas Kamboh  4 , Robert A Sweet  3 , James Becker  3 , Qianzhou Lv  2 , Oscar L Lopez  5 , Xiang-Qun Xie  1
Affiliations

Synergism of antihypertensives and cholinesterase inhibitors in Alzheimer's disease

Ziheng Hu et al. Alzheimers Dement (N Y). .

Abstract

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.

Keywords: Alzheimer's disease; Antihypertensive medications; Cholinesterase inhibitors; Clinical data mining; Cognitive decline; Combination therapy; Systems pharmacology.

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Figures

Fig. 1
Fig. 1
The cognitive decline in set 1 patients by different aHTN treatment groups was analyzed using a mixed-effect regression model. Combination of diuretics, calcium channel blockers, and renin-angiotensin-aldosterone system inhibitors (diuretics + CCB + RAAS) was associated with the slowest rate of cognitive decline among all groups tested (Δβ = +1.46, P < .0001). This effect was most prominent in the first 3 years of aHTN treatment. Abbreviations: aHTN, antihypertensive; MMSE, Mini-Mental State Examination.
Fig. 2
Fig. 2
Annual MMSE decline in AD cases with hypertension (set 2) by ChEI and aHTN drug use. Trajectories for cognitive decline among different groups in set 2 were analyzed using a linear mixed-effect regression model. Bars and error bars represent the coefficient β and standard error of the mean for the time variable in each group, respectively. In ChEI+ group, concomitant use of aHTN drugs was associated with significantly slower cognitive decline (slope difference Δβ = +0.56, P < .01). The use of aHTN drug was not associated with a significantly different rate of cognitive decline in the ChEI− group (Δβ = −0.31, P = .53). Note that “+” denotes drug users and “−” denotes nonusers. For example, ChEI+/aHTN− represents patients who used ChEIs but not aHTN drugs. Abbreviations: AD, Alzheimer's disease; aHTN, antihypertensive; ChEI, cholinesterase inhibitor; MMSE, Mini-Mental State Examination.
Fig. 3
Fig. 3
Overlapping protein targets for Alzheimer's disease (red) and hypertension (cyan). Each node represents a protein target name that is associated with the disease(s) linked to it by a straight line. Targets highlighted in solid line circles indicate the drug classes that are shown to have potential synergetic effects by our data-mining analysis in clinical and molecular levels. Abbreviations: ACE, angiotensin-converting enzyme; AGTR1, angiotensin receptor 1; CACNA1A, calcium voltage-gated channel auxiliary subunit alpha1 A; CACNA2D1, calcium voltage-gated channel auxiliary subunit alpha2delta1; CACNA2D4, calcium voltage-gated channel auxiliary subunit alpha2delta4; CACNB2, calcium voltage-gated channel auxiliary subunit beta1; PPARγ, peroxisome proliferator–activated receptor gamma.
Fig. 4
Fig. 4
Chemogenomics systems pharmacology (CSP) target mapping analysis for the molecular mechanism of HCTZ, amlodipine, and losartan for AD treatment. Each blue circle represents an aHTN drug, and each of the other nodes represents a predicted protein target either with experimentally validated binding affinities (green) or without experimental validation (magenta). Each edge connecting an aHTN drug and a protein target represents either an unconfirmed (dashed line) or a confirmed (solid line) drug-target interaction predicted by the HTDocking algorithm. The numbers on the edges represent the docking scores (predicted log Ki's) of the drug-target interaction. Abbreviations: AD, Alzheimer's disease; AChE, acetylcholinesterase; ADRB2, β-2 adrenergic receptor; aHTN, antihypertensive; BChE, butyrylcholinesterase; CHRM2, cholinergic receptor muscarinic 2; COX, cyclooxygenase; MAOB, monoamine oxidase B; MAPK, mitogen-activated protein kinase; NOS, nitric oxide synthase; PDE, phosphodiesterase; PPARγ, peroxisome proliferator–activated receptor gamma.
Fig. 5
Fig. 5
Docking poses of the representative aHTN compounds against the predicted targets. Each of the aHTN compounds was docked against an experimentally validated target (left two columns—A, C, and E) and a nonvalidated target (right two columns—B, D, and F) predicted in our CSP-target mapping study. The first and third columns show the relative positions of the binding pockets (pink surfaces) in the proteins. The second and fourth columns show the detailed interactions between the aHTN compounds and the adjacent residues in the binding pocket of the protein targets. The aHTN compounds were shown as blue sticks, and the interacting residues were shown as orange sticks with residue numbers labeled. The polar interactions between the aHTN compounds and the protein targets were shown as dotted lines, and their bond lengths (Å) were labeled. Abbreviations: AChE, acetylcholinesterase; aHTN, antihypertensive; CCB, calcium channel blockers; COX, cyclooxygenase; CSP, chemogenomics systems pharmacology; HCTZ, hydrochlorothiazide; MAOB, monoamine oxidase B; MAPK, mitogen-activated protein kinase; PDE, phosphodiesterase; PPARγ, peroxisome proliferator–activated receptor gamma; RAAS, renin-angiotensin-aldosterone system.
Fig. S1
Fig. S1
Cognitive decline of patients with no hypertension (HTN) versus patients with HTN that did not use any anti-hypertensive drugs. No significant difference was found between the two groups using the mixed-effect regression model.
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