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Multiple factors can increase a person’s risk for dementia, including mild cognitive impairment. Gemma can fly/Stocksy
  • Both major depressive disorder in remission (rMDD) and mild cognitive impairment (MCI) can increase a person’s risk for dementia.
  • Researchers from the Centre for Addiction and Mental Health say a combination of two “active” therapies may help slow cognitive decline in high-risk older adults.
  • Scientists saw this decrease, especially in participants with rMDD and those at a low genetic risk for Alzheimer’s disease.

Researchers estimate that more than 55 million people around the world live with dementia — a chronic condition negatively impacting a person’s memory, concentration, and thinking skills.

Past studies show that both major depressive disorder in remission (rMDD) and mild cognitive impairment (MCI) can increase a person’s risk for dementia.

“It is important to slow cognitive decline to maintain independence in day-to-day functioning and ultimately prevent dementia in older adults, especially those at high risk of developing dementia, like in older adults with depression,” Tarek Rajji, MD, chair of the Department of Psychiatry at the UT Southwestern Medical Center and former senior scientist at the Centre for Addiction and Mental Health at the University of Toronto explained to Medical News Today.

Rajji is the lead author of a new study recently published in JAMA Psychiatry that has found a combination therapy of computerized memory and thinking exercises with non-invasive mild electrical stimulation may help slow cognitive decline in high-risk older adults, especially those with rMDD — with or without MCI — and those at a low genetic risk for a type of dementia called Alzheimer’s disease.

For this study, researchers recruited 375 older adults with an average age of about 72 years, who had either rMDD, mild cognitive impairment, or both.

Participants either received a “sham” control intervention or the combination of two “active” therapies — computer-based Cognitive Remediation (CR) techniques and a type of non-invasive brain stimulation called transcranial direct current stimulation (tDCS).

“CR consists of computerized memory and thinking exercises that are meant to improve these abilities,” Rajji said.

“The way we delivered them was in a classroom-like setting where groups of six to eight individuals were training on these exercises with the support of one or two coaches. We administered the classes five days a week for eight weeks and then five days a week every six months as boosters until the end of the study or until an individual left the study or progressed from having normal cognitive function to MCI or from MCI to dementia. In between boosters, individuals were asked to exercise on their own at home online for 20 to 40 minutes a day,” he explained.

“tDCS is a form of non-invasive mild electrical stimulation that is delivered by a portable machine the size of a smartphone,” he continued. “It delivers a 2 milliAmp current to the frontal region of the brain to enhance brain plasticity, i.e. the brain’s ability to change and learn. We delivered it for 30 minutes at the beginning of each class and while the individuals were performing thinking exercises. The goal was to prime the brain and optimize the ability to learn and benefit from the computerized exercises.”

“We chose these two therapies because we thought that they have synergistic effects. tDCS on its own was less likely to be effective but when combined with another therapy like CR — which typically has had mild benefit — it would increase its effect by priming the brain and increase its plasticity.”
— Tarek Rajji, MD

Throughout the study, researchers conducted participant assessments at the start of the study, two months in, and then yearly for three to seven years.

During these assessments, Rajji and his team found that participants receiving the combination therapy experienced slower cognitive decline over an average follow-up period of four years, compared to those receiving the “sham” intervention.

“We were very happy to see that our prediction was correct because, to date, no other therapy has been shown to have such an effect in these patients,” Rajji said.

Scientists reported the benefits of the combination therapy was more notable in participants with a low genetic risk for Alzheimer’s disease.

Additionally, study participants with rMDD, with or without MCI, experienced better outcomes than those with MCI only.

“Individuals with low genetic risk for Alzheimer’s disease are likely to be ineligible for the antibody intravenous infusion therapies so a therapy like ours could offer hope to these patients,” Rajji explained.

“The fact that we found the effect mainly in those individuals with remitted rMDD irrespective of whether they also had MCI or not is very exciting because this group has been consistently shown to be at double the risk of developing dementia yet none of the current treatments for MDD reduce this risk. Our treatment offers this possibility for these patients,” he said.

MNT also spoke with David Merrill, MD, PhD, a board certified geriatric psychiatrist at Providence Saint John’s Health Center in Santa Monica, CA, and Singleton Endowed Chair in Integrative Brain Health, about this study, who commented that this study highlights the potential benefits of combination therapies in addressing the multifactorial nature of cognitive decline.

“Unlike monotherapies that target isolated pathways, combination approaches recognize that cognitive decline often results from an interplay of genetic, lifestyle, vascular, and neuroinflammatory factors. Leveraging a combination strategy could address these varied risk factors more effectively, potentially delaying the onset of more severe cognitive impairment in at-risk populations. This aligns well with preventative strategies we are increasingly exploring in clinical practice, emphasizing early and multidimensional interventions.”
— David Merrill, MD, PhD

Building on this research, Merrill said it would be beneficial to see larger-scale studies that validate these findings across more diverse populations.

“Furthermore, exploring the interaction between combination therapies and individual genetic profiles — particularly among those with known risk factors such as the APOE ε4 allele — could illuminate how personalized interventions can be optimized. Integrating digital health technologies and biomarkers for real-time tracking of cognitive health and therapy efficacy would also be invaluable,” he said.

“Ultimately, I’d like to see the development of precision medicine frameworks that use multi-therapeutic approaches tailored to individual patient profiles, optimizing cognitive health and minimizing risks across the continuum of aging,” Merrill added.