Early Signal AD Meds May Help Children With Autism and Low IQ

Early research has linked Alzheimer’s disease (AD) medications cholinesterase inhibitors and N-methyl-D-aspartate (NMDA) receptor antagonists to modest cognitive benefits in children and adolescents with autism spectrum disorder (ASD) and comorbid cognitive disability.

The preliminary evidence, which is drawn from a mix of randomized controlled trials (RCTs), cohort studies, case series, and case reports suggests these medications most frequently had a positive effect on learning and memory, though some improvements were also reported in complex attention, executive function, perceptual-motor functioning, and general cognitive ability. The only three drugs assessed were donepezil, rivastigmine tartrate, and memantine.

“Given the lack of FDA-approved treatments for cognitive impairment or core features of ASD, these findings highlight a critical opportunity to explore the therapeutic potential of these pharmacologic classes for improving neurocognition in this population,” investigators led by Nicholas Diamandis, research coordinator in the lab of senior author Kristina Denisova at The City University of New York, New York City, wrote.

“Given the promising evidence synthesized in the present scoping review, there may be a need to shift focus from treating core symptoms of ASD (social communication, restricted or repetitive behaviors or interests) to cognitive abilities,” they added.

Most of the studies were small, however, and several relied on findings only from case reports. The authors also noted substantial differences in what improvements were reported based on the age of the participants with younger children showing greater potential benefit and durations of treatment, which ranged from 1.5 to 212 weeks.

The study was published online on November 17 in Translational Psychiatry.

Potential Autism/AD Link

Children with ASD and co-occurring intellectual disability (ID) face particularly poor cognitive-development trajectories and have a nearly threefold increased risk of developing AD in later life compared with those without comorbid ID and the general population.

This suggests there could be an important mechanistic link underlying ASD and AD and that “individuals with these conditions may stand to benefit from similar psychopharmacological treatments,” the investigators noted.

To evaluate and synthesize the evidence on the effect of AD medications on neurocognitive outcomes in children and adolescents with ASD and low intelligence quotient (IQ) the researchers conducted a scoping review.

The investigators searched PubMed, PsycInfo, Scopus, and Web of Science to conduct a scoping review of studies in any language published through May 2025 that published empirical results on the use of FDA-approved AD medications in individuals aged 2-21 years with ASD and an IQ at least one SD below the mean.

The review included studies evaluating any of these AD drugs: donepezil, galantamine, rivastigmine, benzgalantamine, memantine, aducanumab, lecanemab, or donanemab.

The studies also needed to provide an estimate of intellectual ability and at least one outcome in one of the six domains of neurocognitive ability. These include complex attention, executive function, learning and memory, language, perceptual-motor function, and social cognition.

Of 404 studies initially identified, 12 studies, with a total of 353 participants and published between 2002-2024, met the criteria. They included four RCTs, a prospective open-label trial, a retrospective open-label trial, two retrospective observational studies, three retrospective case series, and one case report.

The majority of studies were conducted in the US, one was conducted in Canada, and two in Israel.

Mixed Findings

Six of the studies, with 152 combined participants, reported on treatment with a cholinesterase inhibitor, mostly donepezil plus one on rivastigmine tartrate. The other six studies included 201 participants and reported on the NMDA receptor agonist memantine.

Four of the five studies assessing language reported statistically significant improvements following treatment with a cholinesterase inhibitor. These included two RCTs of donepezil — one showing gains in receptive language among children but not adolescents, and another demonstrating improvements in both receptive and expressive language.

Two retrospective case series, one involving donepezil and the other rivastigmine tartrate, also reported improvements in expressive language.

Of the two studies evaluating executive function, a retrospective open-label series reported improvements in hyperactivity with donepezil, and another study showed gains on the Delis-Kaplan Executive Function System sorting test during an open-label extension that followed a negative RCT.

Only one study assessed complex attention, and it showed improvement after treatment with rivastigmine tartrate.

Two studies reported on general cognitive ability, with one finding significant improvements after 12 months of donepezil and the other finding no improvement.

Some Notable Improvements

Among the five studies reporting on memantine treatment and language, three of them showed improvements, but one was a case study and another was a case series of two patients, with both relying solely on clinical evaluations and caregiver reports rather than objective assessments. The third was a retrospective case series.

Four studies reported on executive function, and three found improvements. These included one case study and two observational studies, one retrospective with 18 participants and one prospective with 14 participants.

The same case study showed improvement in complex attention, the only study to report on this outcome with memantine, and it was among two of the three studies reporting improvement in visuospatial abilities. The other showed improvement in one of eight children in a case series.

One of the two studies reporting on general cognitive ability reported improvement, a small RCT in which five of seven participants receiving memantine improved in verbal IQ while no participants receiving placebo improved.

Finally, both studies looking at learning and memory after memantine treatment found significant improvements, 1 in 23 children after 24 weeks of treatment (but not 12 weeks) and 1 in 14 children after 8 weeks of treatment.

Although the results of the review suggest justification for further investigation of these medications in populations with ASD and low IQ, the authors emphasized both the lack of safety data for these medications in children and the poor understanding of how the drugs might work in pediatric patients.

More Research Needed

Commenting on the findings, Glen Elliott, MD, PhD, chief psychiatrist and medical director at the Children’s Health Council and part-time associate training director at Stanford Medicine’s Division of Child and Adolescent Psychiatry in Stanford, California, agreed that more investigation is necessary before any of these medications could be considered for pediatric populations.

“It’s far too early to believe that either of these medications are going to be provide a major contribution to the outcome of children with autism,” Elliott, who was not involved in the research, told Medscape Medical News. “The summary of the results are that we could call for more research, but these are not likely to become mainstream medication for use in autism spectrum disorder.”

Even with AD, Elliott noted that the therapeutic benefits of these medications can be marginal. Just as autism is complex, so is cognitive dysfunction, so attempting to identify therapies that address both is even more challenging, he added.

While both Elliott and the investigators noted that it’s not entirely clear why a drug with potential benefits for AD might also offer therapeutic value in children with autism autistic children, a leading hypothesis they both identified is that the drugs may influence the brain’s neuroplasticity, “particularly with language,” Elliott said. “You’d like the language areas to be more amenable to change, and these drugs may have that effect,” he added.

Like the investigators, Elliott underscored the importance of continued investigation into treatments for autistic children with significant cognitive dysfunction because many of those families feel left behind by autism research.

“The people who did these studies should be applauded for working on this particular population with medications that are different than what have been used traditionally,” Elliott said. “We don’t have much to offer this population in terms of medications.”

But he also does not advise that families try giving these medications to their autistic children, and even if they did so, they’re unlikely to see significant, notable improvement.

Statistically significant results reported in these studies do not necessarily translate to clinically significant results, and the medications are unlikely to make a substantially noticeable difference in everyday life, he said. “These are very modest results and certainly not what would be considered a breakthrough,” he said.

Note: This article originally appeared on Medscape.