Noradrenergic Drugs Improve Cognition, Apathy in Alzheimer Disease

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Researchers sought to evaluate the efficacy of noradrenergic drugs in the improvement of neuropsychiatric and cognitive symptoms in individuals with AD.

The use of pharmacotherapies that target the noradrenergic system has been shown to improve cognition and apathy among patients with dementia or mild cognitive impairment (MCI) associated with Alzheimer disease (AD). These are the findings of a systematic review and meta-analysis published in the Journal of Neurology, Neurosurgery, and Psychiatry.

Recognizing that noradrenergic dysfunction occurs early in the course of AD, researchers sought to evaluate the efficacy of noradrenergic drugs in the improvement of neuropsychiatric and cognitive symptoms in individuals with AD.

The researchers searched for studies that met the following criteria: (1) study populations defined as patients with AD, MCI, Parkinson disease, Lewy body dementia, frontotemporal dementia, or progressive supranuclear palsy; (2) prospective clinical trials that compared drugs that increase noradrenaline levels, or act on 1 of the 3 receptor classes, vs placebo; (3) studies that reported cognitive, behavioral, or neuropsychiatric outcomes.

Overall, 19 randomized controlled trials were included, which comprised 1811 patients. Of these studies, 6 were deemed of “good” quality, 7 of “fair” quality, and 6 of “poor” quality. A meta-analysis of 10 of these studies, which included a total of 1300 patients, demonstrated a significant, small positive effect of noradrenergic drugs on global cognition, based on the Mini-Mental State Examination or Alzheimer’s Disease Assessment Scale–Cognitive Subscale (standardized mean difference [SMD], 0.14; 95% CI, 0.03-0.25; P =.01). Following removal of the 1 “poor” quality study, the effect size remained unchanged (SMD, 0.14; 95% CI, 0.02-0.27; P =.03).

No significant effect was observed, however, with respect to measures of attention (SMD, 0.14; 95% CI, –0.17-0.19; P =.91).

Further in the meta-analysis on apathy, which involved 8 trials in 425 individuals, a significant, large positive effect of noradrenergic drugs was revealed (SMD, 0.01; 95% CI, 0.16-0.73; P =.002). This positive effect persisted after the removal of outliers to account for heterogeneity across the various studies.

Study limitations included the fact that the inclusion criteria used a threshold of noradrenergic action of the drugs, which was not based on any fixed pharmacodynamic or pharmacokinetic metrics. Instead, the relative action of drugs on noradrenergic and nonnoradrenergic systems at the doses utilized in current licensed applications was considered. Additionally, with respect to study quality, only 6 of the 19 trials were rated as “good.”

The researchers concluded that “Based on this meta-analysis, and recognition of the importance of [the locus coeruleus-noradrenaline] system in multiple neurodegenerative diseases, there is a case for further clinical trials of noradrenergic agents in Alzheimer’s disease and other neurodegenerative conditions.”

Reference

David MCB, Del Giovane M, Liu KY, et al. Cognitive and neuropsychiatric effects of noradrenergic treatment in Alzheimer’s disease: systematic and meta-analysis. J Neurol Neurosurg Psychiatry. Published online July 5, 2022. doi:10.1136/jnnp-2022-329136