ADHD Medication Could Have Benefits for Alzheimer’s Disease Symptom

A new study has suggested that noradrenergic drugs, a class of compounds that includes antidepressants, hypertension aids and the attention deficit hyperactivity disorder (ADHD) drug ritalin, could help treat selected symptoms of Alzheimer’s disease.

A new target for Alzheimer’s research

The analysis, conducted by a team at Imperial College London, examined the evidence around the efficacy of noradrenergic compounds, which modify the brain’s release of the hormone norepinephrine.

“[Norepinephrine] is produced in the brainstem at the base of the brain and released around the whole brain,” explains study author Michael David, a clinical research fellow at the UK Dementia Research Institute. The hormone primarily affects attention, with secondary effects on memory and cognitive function. “We know that in Alzheimer’s, the part of the brainstem that releases this chemical gets damaged very early on,” David adds.

Alzheimer’s disease has proved notoriously hard to treat. Up until the qualified approval of aducanumab in 2021, two decades of research into the condition had produced constant failure, at a cost of billions of dollars of research funding. Previously approved drugs, which are able to slightly delay but not prevent that delay cognitive decline, tend to target another neurotransmitter, acetylcholine.

David’s team believe that the limited effects of these approved drugs could be enhanced by also addressing the decline in the noradrenergic system – potentially improving patients’ ability to pay attention, form new memories and even behavioral deficits.

Impacts on apathy

The analysis looked at the currently published literature around noradrenergic drugs and Alzheimer’s disease. The team, led by Imperial’s Professor Paresh Malhotra, reviewed the studies from 1980 to the present day. The team identified 19 gold-standard randomized controlled trial-style studies of noradrenergic compounds for treating symptoms in people with neurodegenerative disorders.

The collection of published work involved a total of 1300 patients, and each study was rated on the quality of the trial design.

These studies deployed a range of metrics to measure the drugs’ effect. The team, using a standardized value to make them comparable, showed how an overall analysis of the 10 studies that measured global cognition demonstrated noradrenergic drugs had a small but significant beneficial effect.

They also identified a larger impact on apathy, a secondary symptom of Alzheimer’s. “People with Alzheimer’s might seem like the don’t have motivation or the energy to get out,” explains David. “They might seem reluctant or just too tired to do things. That comes under the umbrella of apathy.” Apathy stands apart from the physical frailty that elderly individuals with dementia might display – a mental process that David suggests is a symptom that is neglected by available treatments.

Paying attention to ADHD drugs

The team’s analysis also produced the surprising result that, over the meta-analysis, noradrenergic drugs failed to have any impact on attention in dementia patients – a surprising result, given these drugs’ widespread use in ADHD. David suggests a few reasons for this finding: the inconsistent methods used to assess attention across the papers may have caused any effect to be muted, the measures used may have missed the type of attention boosts caused by these drugs or “maybe [the drugs] just didn’t work.”

Whatever the reason, the mixed picture from the analysis will require more research to be done, which will need to remedy the failures of past research. The team’s analysis of the 19 studies rated them individually for the quality of their study design, and just six were rated to be of “good” quality, with an additional seven rated “fair” and six found to be “poor” in their design.

“A number of the studies included in this meta-analysis were conducted many years ago, in the 80s or 90s, when practice was not as well-honed in terms of what makes a good clinical trial,” says David. “It’s important that that we do collect good quality evidence going forward.” That will means mimicking high patient numbers and rigorous controls that are more common in modern research.

The next generation of Alzheimer’s drugs

Future studies will also need to consider whether combining available treatments that target acetylcholine with noradrenergic drugs might achieve an enhanced effect. “Things like apathy are not really addressed using the cholinesterase system,” says David. “That’s something that might potentially be benefitted by tuning the noradrenergic system – perhaps that can bring the best out of the effects that we see from the cholinesterase treatments.”

Luckily, such a trial is already underway – Malhotra is leading NorAD, an ongoing study of the therapeutic effects of the ADHD and high blood pressure treatment guanfacine in combination with current Alzheimer’s treatments targeting acetylcholine.

Dr. Rosa Sancho, head of research at Alzheimer’s Research UK, who was not involved in the study, said in a press release, “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. Research like this will help keep people connected to their families, their worlds and themselves for longer.”

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