ADHD drugs can effectively treat Alzheimer’s cognitive symptoms

Drugs with primarily noradrenergic action — including drugs prescribed for ADHD or to treat hypertension or depression — may effectively treat cognitive symptoms and apathy in Alzheimer’s disease, a systematic review and meta-analysis suggests.

Noradrenergic drugs showed a significant small positive effect on global cognition with a standardized mean difference (SMD) of 0.14 (95% CI 0.03-0.25, p= 0.01), according to Michael David, MBBS, PhD, of Imperial College London and colleagues.

These drugs also showed a large positive effect on apathy (SMD 0.45, 95% CI 0.16-0.73, p=0.002they reported in the Journal of Neurology, Neurosurgery and Psychiatry† The effect persisted after removing outliers to account for heterogeneity between studies.

Noradrenergic drugs target noradrenaline, also called noradrenaline, which is primarily synthesized and released by noradrenergic neurons in the locus coeruleus in the brainstem. A common mechanism is inhibition of norepinephrine reuptake, thereby preventing synaptic clearance and prolonging its effect.

“This analysis shows that there is potential for reusing drugs that are known to be safe and effective in improving certain symptoms in other patient populations for use in Alzheimer’s disease,” David said. MedPage today.

“Current Alzheimer’s treatments are largely aimed at stimulating the acetylcholine system and have a modest effect,” David noted. “Drugs that act on the noradrenergic system, such as those in our analysis, have the potential to improve symptoms such as inattention, which in turn may improve memory and apathy.”

“The region of the brainstem that produces norepinephrine is known to be damaged early in Alzheimer’s disease, leading to a low noradrenergic state in some patients,” he added. “Adequate and appropriate brain noradrenaline is important in modulating attention, particularly through its action in the prefrontal cortex.”

The review included clinical trials published between 1980 and 2021 of noradrenergic drugs that may have been used to improve cognitive or neuropsychiatric symptoms in people with neurodegenerative disease.

In total, the researchers included 19 randomized controlled trials involving 1,811 participants that focused on noradrenergic drugs in Alzheimer’s disease or mild cognitive impairment. Six trials were judged to be of good quality; seven were considered fair and six poor. Nine studies involved norepinephrine reuptake inhibitors, five of which evaluated methylphenidate (Ritalin).

In 10 studies, cognition was assessed in 1,300 participants by the Mini-Mental State Examination of Alzheimer’s Disease Assessment Scale-Cognitive Subscale. Apathy outcomes were assessed in eight studies and 425 people; these studies often used the Apathy Evaluation Scale or the Neuropsychiatry Inventory-Apathy.

The effect size on global cognition of 0.14 was between that of cholinesterase inhibitors in Alzheimer’s disease (SMD 0.38, 95% CI 0.28-41.1) and mild cognitive impairment (SMD 0.06, 95% CI – 0.08 to 0.20), David and colleagues noted. The overall pooled effect was not significant for attentional measures.

Pooled data also did not support noradrenergic drugs on agitation or overall measures of neuropsychiatric symptoms.

“There were limitations to our study,” acknowledged David. “Most notably, the drugs included in our analysis act in different ways, and it is currently unclear which mechanism of action is likely to be most effective in this context.”

“More studies are needed to confirm these results and determine which drugs are most likely to be effective for patients,” he said.

In NorAD’s clinical trial, researchers are evaluating adjuvant extended-release guanfacine (Intuniv), a drug approved for ADHD in the US, versus standard cholinergic treatment in Alzheimer’s disease.

“Guanfacine was selected based on promising data on its effects in animal studies and healthy volunteers are also working in other patient groups,” Paresh Malhotra, PhD, also of Imperial College London, told me. MedPage today

“Previous studies of guanfacine in Alzheimer’s disease have been relatively ineffective and at a relatively low dose,” added Malhotra, who is a co-author of the current study and principal investigator of NorAD. “We found there was justification for a vigorous study using the controlled-release version in combination with standard cholinesterase inhibitors to assess cognition and attentional aspects.”

  • Judy George covers neurology and neuroscience news for MedPage Today, writing about brain aging, Alzheimer’s, dementia, MS, rare diseases, epilepsy, autism, headache, stroke, Parkinson’s, ALS, concussion, CTE, sleep, pain, and more. Follow


Researchers announced funding from the UK Medical Research Council, the National Institute for Health Research (NIHR) Biomedical Research Center at University College London Hospitals, the Wellcom Trust and the NIHR Cambridge Biomedical Research Centre.

Malhotra revealed that he led the NIHR-funded NorAD study, which provided an investigational drug through a drug-only grant from Takeda.

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