Combination Therapy Shows Promise in Slowing Cognitive Decline in Older Adults

A groundbreaking study led by the Centre for Addiction and Mental Health (CAMH) and partnered with several sites from the Toronto Dementia Research Alliance (TDRA)—including Baycrest, Sunnybrook Health Science Centre, Unity Health Toronto, and University Health Network—has demonstrated that a combination therapy can effectively slow cognitive decline in older adults at risk for dementia. This significant research was published today in *JAMA Psychiatry* under the title "Slowing cognitive decline in major depressive disorder and mild cognitive impairment: A randomized controlled trial." The study reports the primary findings of the PACt-MD (Prevention of Alzheimer's dementia with Cognitive remediation plus transcranial direct current stimulation in Mild cognitive impairment and Depression) project, which received funding from the Canada Brain Research Fund.

The PACt-MD study focused on preventing cognitive decline in older adults suffering from conditions that heighten the risk for dementia, specifically Major Depressive Disorder in remission (rMDD), Mild Cognitive Impairment (MCI), or both. The Honourable Mark Holland, Minister of Health, emphasized the importance of this long-term research, stating, "Investing in long-term, comprehensive research like this is not only a commitment to science but to the millions of individuals, families, and caregivers affected by dementia."

In total, 375 older adults participated in the study, receiving either a control (“sham”) intervention or a combination of two active therapies. The first therapy involved specially designed Cognitive Remediation (CR) techniques aimed at improving cognitive functioning through activities like puzzles and logic problems. The second therapy was transcranial direct current stimulation (tDCS), a form of non-invasive brain stimulation. These therapies were administered five days a week for eight weeks, with follow-up “boosters” every six months.

The study was designed as a randomized, controlled, and double-masked trial, with assessments conducted at baseline, two months, and annually for a period of three to seven years. Results revealed that participants who received the combination of CR and tDCS experienced a slower rate of cognitive decline over a median follow-up period of four years compared to those who received the control intervention. Notably, the benefits were more pronounced in individuals with a lower genetic risk for Alzheimer's disease. Moreover, participants with rMDD (with or without MCI) showed better cognitive outcomes than those with MCI alone.

The overlapping nature of conditions contributing to cognitive decline underscores the importance of combination therapies, which can target different disease pathways synergistically to enhance patient outcomes. Dr. Tarek Rajji, lead author and Principal Investigator of the study, expressed satisfaction with the results, stating, "We are very pleased to show, after seven years of close monitoring, that this combination of therapies is effective in slowing down cognitive decline for some of our most vulnerable populations."

Dr. Benoit Mulsant, senior author and lead of the research team, elaborated on the study's focus on the prefrontal cortex, an area of the brain essential for executive functioning and believed to be highly adaptable. He noted, "While there are several presumed mechanisms underlying the increased risk for dementia in older adults with depression, impaired brain plasticity is thought to be one common pathway. In this study, we targeted the prefrontal cortex for treatment."

As this promising research moves forward, it highlights the potential for non-pharmacological approaches to support individuals at high risk for dementia, helping them maintain independence for longer periods. The study's findings may pave the way for enhanced care strategies for those living with cognitive impairment.

The work was supported by the Canada Brain Research Fund, in collaboration with Brain Canada and the Government of Canada, along with funding from various partners within the Toronto Dementia Research Alliance.