ADHD Drugs May Treat Alzheimer’s Cognitive Symptoms Effectively

Drugs with principally noradrenergic action — including ones prescribed for attention deficit-hyperactivity disorder (ADHD) or to treat hypertension or depression — may effectively treat cognitive symptoms and apathy in Alzheimer’s disease, a systematic review and meta-analysis suggested.

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=0.002), they reported in the Journal of Neurology, Neurosurgery, and Psychiatry. The effect persisted after removing outliers to account for heterogeneity across studies.

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

“This analysis shows there’s potential for repurposing medication already known to be safe and effective at improving certain symptoms in other patient populations for use in Alzheimer’s disease,” David told MedPage Today.

“Current Alzheimer’s treatments largely focus on boosting the acetylcholine system and have modest effects,” David pointed out. “Drugs that work on the noradrenergic system, like the ones in our analysis, have the potential to improve symptoms such as inattentiveness which, in turn, can improve memory and apathy.”

“It’s known that the area of the brainstem that produces noradrenaline is 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, in particular through its action in the prefrontal cortex.”

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

Overall, 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 good quality; seven were considered fair and six were considered poor. Nine studies involved norepinephrine reuptake inhibitors, with five of them assessing methylphenidate (Ritalin).

In 10 trials, cognition was assessed across 1,300 participants by the Mini-Mental State Examination or Alzheimer’s Disease Assessment Scale-Cognitive Subscale. Apathy outcomes were assessed in eight trials 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 measures of attention.

Pooled data also provided no support for noradrenergic drugs on agitation or general measures of neuropsychiatric symptoms.

“There were limitations to our study,” David acknowledged. “Most notably is the fact that the medications included in our analysis work in a variety of ways, and it is not currently clear what mechanism of action is likely to be most effective in this context.”

“More trials are needed to confirm these results and established what medications in which patients are most likely to be effective,” he said.

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

“Guanfacine was selected on the basis of promising data on its effects in animal studies and healthy volunteers as well work in other patient groups,” Paresh Malhotra, PhD, also of Imperial College London, told MedPage Today.

“Previous studies using guanfacine in Alzheimer’s disease had been relatively underpowered and at a relatively low dose,” added Malhotra, who is a co-author on the current study and NorAD principal investigator. “We felt there was justification for a powered trial with the modified-release version in combination with standard cholinesterase inhibitors to assess cognition and aspects of attention.”