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. 2022 Jul 5;93(10):1080-1090.
doi: 10.1136/jnnp-2022-329136. Online ahead of print.

Cognitive and neuropsychiatric effects of noradrenergic treatment in Alzheimer's disease: systematic review and meta-analysis

Michael C B David  1   2   3 , Martina Del Giovane  4   2 , Kathy Y Liu  5 , Benjamin Gostick  5 , James Benedict Rowe  6 , Imafidon Oboh  7 , Robert Howard  5 , Paresh A Malhotra  4   2   3
Affiliations

Cognitive and neuropsychiatric effects of noradrenergic treatment in Alzheimer's disease: systematic review and meta-analysis

Michael C B David et al. J Neurol Neurosurg Psychiatry. .

Abstract

Background: Dysfunction of the locus coeruleus-noradrenergic system occurs early in Alzheimer's disease, contributing to cognitive and neuropsychiatric symptoms in some patients. This system offers a potential therapeutic target, although noradrenergic treatments are not currently used in clinical practice.

Objective: To assess the efficacy of drugs with principally noradrenergic action in improving cognitive and neuropsychiatric symptoms in Alzheimer's disease.

Methods: The MEDLINE, Embase and ClinicalTrials.gov databases were searched from 1980 to December 2021. We generated pooled estimates using random effects meta-analyses.

Results: We included 19 randomised controlled trials (1811 patients), of which six were judged as 'good' quality, seven as 'fair' and six 'poor'. Meta-analysis of 10 of these studies (1300 patients) showed a significant small positive effect of noradrenergic drugs on global cognition, measured using the Mini-Mental State Examination or Alzheimer's Disease Assessment Scale-Cognitive Subscale (standardised mean difference (SMD): 0.14, 95% CI: 0.03 to 0.25, p=0.01; I2=0%). No significant effect was seen on measures of attention (SMD: 0.01, 95% CI: -0.17 to 0.19, p=0.91; I2=0). The apathy meta-analysis included eight trials (425 patients) and detected a large positive effect of noradrenergic drugs (SMD: 0.45, 95% CI: 0.16 to 0.73, p=0.002; I2=58%). This positive effect was still present following removal of outliers to account for heterogeneity across studies.

Discussion: Repurposing of established noradrenergic drugs is most likely to offer effective treatment in Alzheimer's disease for general cognition and apathy. However, several factors should be considered before designing future clinical trials. These include targeting of appropriate patient subgroups and understanding the dose effects of individual drugs and their interactions with other treatments to minimise risks and maximise therapeutic effects.

Prospero registeration number: CRD42021277500.

Keywords: Alzheimer's disease; apathy; cognition; dementia; psychiatry.

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Conflict of interest statement

Competing interests: None declared.

Figures

Figure 1
Figure 1
Preferred Reporting Items for Systematic Reviews and Meta-Analyses flow diagram for search for studies reporting the use of noradrenergic therapies in neurodegenerative conditions. Some records excluded for more than one reason.
Figure 2
Figure 2
Schematic showing release of norepinephrine (NA) across the synapse, action at the three receptor subtypes and reuptake through the norepinephrine transporter (NET). Presumed site of therapeutic action of the drugs included in this review are shown.
Figure 3
Figure 3
Forest plot of noradrenergic drugs on global cognition. Comparison of drug and placebo for effect on global measures of cognition between baseline and end of treatment. IV, inverse variance.
Figure 4
Figure 4
Forest plot of noradrenergic drugs on cognition subdomains. Comparison of drug and placebo for effect on cognitive subdomains between baseline and end of treatment. IV, inverse variance.
Figure 5
Figure 5
Forest plot of noradrenergic drugs on digit span. Comparison of drug and placebo for effect on global measures of cognition between baseline and end of treatment. IV, inverse variance.
Figure 6
Figure 6
Forest plot of noradrenergic drugs on neuropsychiatric symptoms. Comparison of drug and placebo for effect on global measures of cognition between baseline and end of treatment. IV, inverse variance.
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