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Synergism of antihypertensives and cholinesterase inhibitors in Alzheimer's disease.

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 (?? = +1.46, P < .0001). aHTN medications slow down cognitive decline in ChEI users (?? = +0.56, P = .006), but not in non-ChEI users (?? = -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.

SUBMITTER: Hu Z

PROVIDER: S-EPMC6205113 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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Synergism of antihypertensives and cholinesterase inhibitors in Alzheimer's disease.

Hu Ziheng Z Wang Lirong L Ma Shifan S Kirisci Levent L Feng Zhiwei Z Xue Ying Y Klunk William E WE Kamboh M Ilyas MI Sweet Robert A RA Becker James J Lv Qianzhou Q Lopez Oscar L OL Xie Xiang-Qun XQ

Alzheimer's & dementia (New York, N. Y.) 20181014

<h4>Introduction</h4>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.<h4>Methods</h4>We compared the effect of aHTN drugs on Mini-Mental State Examination scores in 617 AD patients with hypertension, and studied the synergistic effects.<h4>Results</h4>The combination of diuretics, calcium channel blockers, ...[more]

PMID: 30386819

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Project description:IntroductionAnalyses of off-label use of acetylcholinesterase inhibitors (AChEIs) in mild cognitive impairment (MCI) has produced mixed results. Post hoc analyses of observational cohorts, such as the Alzheimer's Disease Neuroimaging Initiative (ADNI), have reported deleterious effects in AChEI-treated subjects (AChEI+). Here, we used neuroimaging biomarkers to determine whether AChEI+ subjects had a greater rate of neurodegeneration than untreated (AChEI-) subjects while accounting for baseline differences.MethodsWe selected 121 ADNI MCI AChEI+ subjects and 151 AChEI- subjects with a magnetic resonance imaging (MRI) scan; 82 AChEI+ and 110 AChEI- also had a fluorodeoxyglucose (FDG) scan. A subset (83 AChEI+ and 98 AChEI-) had cerebrospinal fluid (CSF) or amyloid positron emission tomography (PET) assessment for amyloid positivity. Linear regression models were used to compare the effect of treatment on changes in Mini-Mental State Examination and Clinical Dementia Rating-Sum of Boxes scores. We used standard regression in SPM (for baseline) and the SPM toolbox sandwich estimator, SwE (for longitudinal) for comparisons of AChEI+ and AChEI- FDG PET and MRI data.ResultsAt baseline, the AChEI+ group had significantly reduced cortical gray matter density (GMD) and more hypometabolism than AChEI- subjects. The greater rate of atrophy and hypometabolic changes over time in AChEI+ compared to AChEI- subjects did not survive correction for baseline differences. AChEI+ participants were more likely to be amyloid-positive and have lower GMD and FDG standardized uptake value ratio than AChEI- at baseline. AChEI+ subjects showed greater atrophy over time, which remained significant after controlling for amyloid status.DiscussionOur data suggest that the observed differences in rates of cognitive decline, atrophy, and hypometabolism are likely the result of significant baseline differences between the groups. Furthermore, the data indicate no treatment effect of AChEI (positive of negative), rather that physicians prescribe AChEI to subjects who present with more severe clinical impairment. This alone may account for the negative effect seen previously in the ADNI population of AChEI use among MCI subjects.

Dataset Information

Synergism of antihypertensives and cholinesterase inhibitors in Alzheimer's disease.

Publications

Synergism of antihypertensives and cholinesterase inhibitors in Alzheimer's disease.

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