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expert reaction to systematic review and meta-analysis looking at the evidence of whether noradrenergic drugs may be able to treat symptoms of Alzheimer’s disease

A study, published in the Journal of Neurology Neurosurgery & Psychiatry, looked at the evidence of whether noradrenergic drugs may be able to treat symptoms of Alzheimer’s disease.


Sian Gregory, Research Information Manager at Alzheimer’s Society said:  

“This promising new research could help to improve the lives of people living with Alzheimer’s disease in the future, helping to reduce the effect of common symptoms such as memory and thinking problems and improving apathy.   

“Because drugs that act on the chemical messenger noradrenaline are already commonly used to treat disorders like ADHD and depression, clinical trials to assess their benefit for people with Alzheimer’s disease should be straightforward.  

“Treatments to manage Alzheimer’s disease and other forms of dementia are few and far between, so it is of paramount importance that the Government now delivers on its moonshot promise to double dementia research funding. Dementia research needs this urgent shot in the arm to get the breakthrough treatments we desperately need.” 


Dr Andrew Reid, Assistant Professor of Psychology, University of Nottingham, said:

“The involvement of the brain’s noradrenaline system in early changes underlying Alzheimer’s disease is a promising new avenue of research. There is a lot of accumulating evidence that this system is changed very early on in the disease, which is exciting because it suggests a way to identify individuals at risk and treat them much earlier than is currently possible. This new study by David and colleagues reviewed a number of previous findings from the past few decades, which look at how well drugs targeting the noradrenaline system can prevent decline in memory performance. They conclude that these drugs can help improve memory performance, and their findings help pave the way for more focused new drug studies aimed at the early treatment of Alzheimer’s disease.”


Dr Maddie Groom, Associate Professor in Applied Developmental Cognitive Neuroscience, University of Nottingham, said:

“The evidence from this paper supports the need for further research into the role of noradrenaline in the cognitive difficulties of both ADHD and Alzheimer’s, and suggests that ADHD treatments which alter noradrenergic signalling may be a useful treatment in some people with Alzheimer’s Disease. The systematic review was conducted rigorously and the findings are reported in a balanced way. In particular, the authors emphasise the need for caution due to possible side effects or adverse reactions of these medications. They also highlight that these medications are unlikely to help everyone with Alzheimer’s as it will depend on the particular difficulties experienced by individuals. This is also true of people with ADHD; these medications are not effective for all, and some people experience side effects. We therefore need better ways of predicting which groups of patients are likely to benefit. Overall, this article offers support for the potential role of ADHD medications in treating some of the cognitive and neuropsychiatric features of Alzheimer’s; further research using well-controlled randomised clinical trials is needed.”


Prof Erik Cobo, Full Professor, statistician and physician at the Universitat Politècnica de Catalunya – BarcelonaTech (UPC), says:

“This systematic review has several quality indicators: (1) The study protocol was previously registered and, therefore, the study appears free of selective reporting bias (reporting what is convenient for us). (2) It is reported according to the PRISMA guideline, so the report aims to be transparent and reproducible. (3) It is based on clinical trials and therefore will not be affected by confounding of effects. (4) It combines effects using a more robust random effects model. (5) Its wording is cautious, tentative, warning of the steps needed before proposing a particular intervention (“there is a case for further clinical trials”).

“I have not found mention of the clinical value for patients of the main result: a standardised mean difference of 0.14, with CI [confidence interval] from 0.03 to 0.25. This means that the effect is about one seventh (0.14) of the usual differences between individuals. A very very small effect, therefore. As this is opinionated, my disappointment is that it does not dispute this.

“That said, the main result (and most secondary analyses) has a curious value of the I2 statistic, which they round to 0%, implying an implausible homogeneity of effect. This invites a very careful reanalysis of these results.”


Dr Rosa Sancho, Head of Research at Alzheimer’s Research UK, said:

“Alzheimer’s is a very complex disease. There are currently 143 drugs in clinical trials for Alzheimer’s, and while some counteract symptoms most target the various biological processes that could be driving the disease.

“There is currently a lack of drugs approved to treat apathy in Alzheimer’s, a symptom that has been linked to lower quality of life, faster decline and increased stress for carers.

“This well-conducted meta-analysis highlights the potential of noradrenergic drugs to treat some aspects of Alzheimer’s, but the evidence in the trials reviewed here varies in quality and it’s hard to directly compare results from each study because the methods used are not consistent.

“We can’t be sure yet what effect these drugs could have on a person’s day-to-day life, and we don’t know whether any benefits they provide would outweigh the risks.

“While there are limitations to the evidence reviewed in this paper, it highlights a need for well-conducted clinical trials to determine whether drugs that already treat conditions like ADHD could be safe and beneficial for people with Alzheimer’s. Through research, we will help keep people connected to their families, their worlds and themselves for longer.”


Prof David Smith, Professor Emeritus of Pharmacology, University of Oxford, said:

“This is an important and well-performed analysis which examined the possible effects of noradrenergic drugs on several aspects of Alzheimer’s disease, with some positive results. There was no evidence that the drugs influenced the progression of the disease but they did improve a few symptoms, notably apathy. A small, probably not clinically relevant, improvement in cognition was also found. The report should stimulate further trials in particular with combinations of these drugs with other symptomatic treatments.”


Dr Mark Dallas, Associate Professor in Cellular Neuroscience, University of Reading, said:

“Scientists are looking to offer up new drugs that can help tackle dementia and repurposing drugs that already exist is an exciting prospect. This review has looked at the ability of drugs to modulate levels of noradrenaline and the impact they have on dementia. Noradrenaline produces many different effects in the body and is associated with the ‘fight or flight’ response to perceived danger. Examining existing data measuring brain activity, they report a small improvement in cognitive ability in individuals that were taking the medicines that aimed to increase levels of noradrenaline activity. In addition, there was improvement in behavioural symptoms observed with those individuals taking these types of medicines. The review relied on existing data which has its limitations, but on the evidence presented more research into the use of these drugs to manage dementia is merited. In the search for dementia medicines this review provides an interesting teaser that drugs used to manage other conditions could join the fight against dementia.”


Prof Roxana Carare, Professor of Clinical Neuroanatomy, University of Southampton, said:

“In this systematic review and meta-analysis the effects of noradrenergic treatments were analysed in 1300 patients with Alzheimer’s disease, demonstrating an effect in improving cognition and neuropsychiatric symptoms. Alzheimer’s disease (AD) is characterised by age-related failure of elimination of amyloid-β (Aβ) from the brain.

“Aβ is eliminated along membranes in the walls of cerebral capillaries and arteries: the “Intramural Peri-Arterial Drainage (IPAD) pathways1. In ageing and the possession of the Apolipoprotein E4 genotype (which provides an increased risk of Alzheimer’s disease), we can see the accumulation of insoluble Aβ in this pathway decades before symptoms of the disease occur. 2

“Our work has shown that the IPAD pathways are driven by the contraction of arterial smooth muscle cells, and these depend on innervation from the Locus Coeruleus (LC) and cholinergic innervation from the nucleus basalis of Meynert (NBM), both of which are compromised early in AD 3

“This paper therefore provides further support to the hypothesis that noradrenergic medication may improve the elimination of Aβ along IPAD to delay the onset and progression of AD.  As the authors state, the effects are probably optimal if both adrenergic and cholinergic systems are targeted. There are wider applications, as LC and NBM are involved in other psychiatric conditions and a better understanding of how their activity declines over the lifecourse will inform therapy for other mental health conditions.”

  1. Albargothy, N.J., et al. Convective influx/glymphatic system: tracers injected into the CSF enter and leave the brain along separate periarterial basement membrane pathways. Acta neuropathologica (2018).
  2. Carare, R.O., Hawkes, C.A., Jeffrey, M., Kalaria, R.N. & Weller, R.O. Review: cerebral amyloid angiopathy, prion angiopathy, CADASIL and the spectrum of protein elimination failure angiopathies (PEFA) in neurodegenerative disease with a focus on therapy. Neuropathology and applied neurobiology 39, 593-611 (2013).
  3. Aldea, R., Weller, R.O., Wilcock, D.M., Carare, R.O. & Richardson, G. Cerebrovascular Smooth Muscle Cells as the Drivers of Intramural Periarterial Drainage of the Brain. Frontiers in aging neuroscience 11, 1 (2019).


‘Cognitive and neuropsychiatric effects of noradrenergic treatment in Alzheimer’s disease: systematic review and meta-analysis’ by Michael C B David et al. was published in The Journal of Neurology Neurosurgery & Psychiatry at 23:30 UK time on Tuesday 5 July.

DOI: 10.1136/jnnp-2022-329136


Declared interests

Dr Maddie Groom: No declarations

Dr Rosa Sancho: Study authors Rob Howard, James Rowe and Paresh Malhotra sit on Alzheimer’s Research UK’s Trustee, Research Strategy, and Grant Review boards respectively.

Prof David Smith: No conflicts of interest in this field.

Dr Mark Dallas: Nothing to declare

Prof Roxana Carare: Prof Carare is an author on the research papers referenced. Prof Carare is a consultant for several companies but none relevant to this piece of work.

For all other experts, no reply to our request for DOIs was received.

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