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

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.

Fair/Poor if too many questions cannot be answered. Questions were: 1. Was the study described as randomized, a randomized trial, a randomized clinical trial, or an RCT? 2. Was the method of randomization adequate (i.e., use of randomly generated assignment)? 3. Was the treatment allocation concealed (so that assignments could not be predicted)? 4. Were study participants and providers blinded to treatment group assignment? 5. Were the people assessing the outcomes blinded to the participants' group assignments? 6. Were the groups similar at baseline on important characteristics that could affect outcomes (e.g., demographics, risk factors, co-morbid conditions)? 7. Was the overall drop-out rate from the study at endpoint 20% or lower of the number allocated to treatment? 8. Was the differential drop-out rate (between treatment groups) at endpoint 15 percentage points or lower?  9. Was there high adherence to the intervention protocols for each treatment group? 10. Were other interventions avoided or similar in the groups (e.g., similar background treatments)? 11. Were outcomes assessed using valid and reliable measures, implemented consistently across all study participants? 12. Did the authors report that the sample size was sufficiently large to be able to detect a difference in the main outcome between groups with at least 80% power? 13. Were outcomes reported or subgroups analyzed prespecified (i.e., identified before analyses were conducted)? 14. Were all randomized participants analyzed in the group to which they were originally assigned, i.e., did they use an intention-to-treat analysis?

Protocol and registration
5 Indicate if a review protocol exists, if and where it can be accessed (e.g. web address), and, if available, provide registration information including registration number.

PROSPERO CRD42021277500
Eligibility criteria 6 Specify study characteristics (e.g., PICOS, length of follow-up) and report characteristics (e.g., years considered, language, publication status) used as criteria for eligibility, giving rationale.

Methods
Information sources 7 Describe all information sources (e.g., databases with dates of coverage, contact with study authors to identify additional studies) in the search and date last searched.
Methods, Figure 1 Search 8 Present full electronic search strategy for at least one database, including any limits used, such that it could be repeated. Table 2 Study selection 9 State the process for selecting studies (i.e., screening, eligibility, included in systematic review, and, if applicable, included in the meta-analysis).
Methods & Figure 1 Data collection process 10 Describe method of data extraction from reports (e.g., piloted forms, independently, in duplicate) and any processes for obtaining and confirming data from investigators.

Methods
Data items 11 List and define all variables for which data were sought (e.g., PICOS, funding sources) and any assumptions and simplifications made.
Methods & Table 1 Risk of bias in individual studies 12 Describe methods used for assessing risk of bias of individual studies (including specification of whether this was done at the study or outcome level), and how this information is to be used in any data synthesis.
Methods, results, Table S2 Summary measures 13 State the principal summary measures (e.g., risk ratio, difference in means). Methods

Synthesis of results
14 Describe the methods of handling data and combining results of studies, if done, including measures of consistency (e.g., I 2 ) for each meta-analysis.