This is the conclusion of a meta-analysis published in the Journal of Neurology Neurosurgery & Psychiatry. Noradrenergic drugs, which are used to reduce symptoms of attention deficit hyperactivity disorder, may help reduce cognitive and neuropsychiatric symptoms of Alzheimer’s disease. A dozen studies, involving a total of 1,300 patients, report a significant positive effect of these treatments on global cognition and apathy.
Alzheimer’s disease is characterized by a dysfunction in a subcortical nucleus called blue room (CL); it is from this region of the brain that most of the neurons that use norepinephrine as a neurotransmitter arise—neurons that project throughout the brain. Noradrenaline (or norepinephrine) is essential for wakefulness and many cognitive processes, including attention, learning, memory, executive and inhibitory control.
Loss of LC noradrenergic neurons is directly associated with memory loss and attention deficit disorders that occur early in Alzheimer’s disease. It is also responsible for the apathy seen in many patients — motivation being influenced by the noradrenergic system. Current treatments for the disease target cholinergic and glutamatergic neurons, but have limited effects. Noradrenergic neurons appear today as a new potential therapeutic target.
An evaluation of the effects on cognitive abilities and behavior
There is already a whole range of drugs acting via noradrenergic pathways. These treatments inhibit the reuptake of norepinephrine (to increase its availability) and stimulate the receptors for this neurotransmitter. They are used to treat anxiety and depression, as well as attention deficit hyperactivity disorder.
Diagram showing the release of noradrenaline (NA) across the synapse, the action at the level of the three receptor subtypes (α1, α2 and β) and the reuptake by the noradrenaline transporter (NET). The drugs considered in the meta-analysis (and their presumed site of action) are indicated. © M. David et al.
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Diagram showing the release of noradrenaline (NA) across the synapse, the action at the level of the three receptor subtypes (α1, α2 and β) and the reuptake by the noradrenaline transporter (NET). The drugs considered in the meta-analysis (and their presumed site of action) are indicated. © M. David et al.
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Diagram showing the release of noradrenaline (NA) across the synapse, the action at the level of the three receptor subtypes (α1, α2 and β) and the reuptake by the noradrenaline transporter (NET). The drugs considered in the meta-analysis (and their presumed site of action) are indicated. © M. David et al.
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Diagram showing the release of noradrenaline (NA) across the synapse, the action at the level of the three receptor subtypes (α1, α2 and β) and the reuptake by the noradrenaline transporter (NET). The drugs considered in the meta-analysis (and their presumed site of action) are indicated. © M. David et al.
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These noradrenergic treatments were already the subject of a few small clinical trials, decades ago, to evaluate their effect on neurodegeneration. But for lack of significant evidence, this track was quickly abandoned. It is now clear that the noradrenergic neurons of the LC are involved very early in Alzheimer’s disease, which is arousing renewed interest in this potential therapeutic target.
British researchers have therefore carried out a systematic review and a meta-analysis of drugs with mainly noradrenergic action in Alzheimer’s disease. The objective was to specify the therapeutic benefit of these treatments on the cognitive and behavioral aspects of the disease. The team retained 19 studies in total, published between 1980 and 2021: six were of “good” quality, seven were judged “fair” and six “poor”. A dozen drugs were tested during these clinical trials, such as atomoxetine, methylphenidate and guanfacine.
Cognitive outcomes included both measures of “global cognition” and specific cognitive domains (attention, episodic verbal memory, episodic visual memory, executive functions and working memory, semantic memory, and visuospatial abilities). The effects of medications on agitation and apathy were also assessed.
Positive results on global cognition and apathy
Of the included studies, ten assessed change in global cognition. The researchers report “a small but significant positive effect of noradrenergic drugs compared to placebo”. Regarding the cognitive subdomains, a positive effect was shown on semantic memory; but following eliminating ‘poor’ quality studies, the result of the remaining studies was not significant. No significant effect was observed for the other subdomains.
To assess the effectiveness of drugs on the behavior and neuropsychiatric symptoms of patients, the researchers considered eight trials (ie 425 patients in total). These suggest “a large positive effect” of noradrenergic drugs on apathy — even following removing outliers to account for heterogeneity between studies. Methylphenidate was the most frequently tested drug for this symptom.
On the other hand, no significant effect on agitation and neuropsychiatric symptoms was demonstrated. The researchers believe this may simply be related to the inclusion of trials in which agitation was not a predominant symptom among participants.
« This meta-analysis suggests that drug redirection with established noradrenergic treatments, such as atomoxetine, methylphenidate, and guanfacine, may benefit people with Alzheimer’s disease. “, conclude the researchers. Even if these treatments do not seem to have beneficial effects on attention or episodic memory, they deserve to be evaluated in future clinical trials – especially since their safety is already established.
Doing so will require targeting appropriate subgroups of patients, the team says. It will also be essential to establish the dose-effect relationship of each drug and to monitor possible interactions with other treatments, in order to minimize the risks and maximize the therapeutic effects.
