Combination Therapy Slows Cognitive Decline in Older Adults

An important new study led by the Centre for Addiction and Mental Health (CAMH), and with partnership across several Toronto Dementia Research Alliance (TDRA) sites— Baycrest, Sunnybrook Health Science Centre, Unity Health Toronto, and University Health Network— has demonstrated that a combination therapy can slow cognitive decline in older adults at risk for dementia.

The study was published today in JAMA Psychiatry: "Slowing cognitive decline in major depressive disorder and mild cognitive impairment: A randomized controlled trial", and reports the primary results of the Prevention of Alzheimer’s dementia with Cognitive remediation plus transcranial direct current stimulation in Mild cognitive impairment and Depression (PACt-MD) study.

PACt-MD was made possible by a grant from the Canada Brain Research Fund, a unique arrangement between Brain Canada and the Government of Canada through Health Canada, the Chagnon Family, and the CAMH Discovery Fund. The work focused on preventing cognitive decline in older adults with a condition that increases the risk for dementia: Major Depressive Disorder in remission (rMDD), Mild Cognitive Impairment (MCI), or both.

"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,” said the Honourable Mark Holland, Minister of Health. “This research contributes to advancing dementia care in Canada and improving quality of life for people living with dementia and caregivers.”

The study involved 375 older adults who received either a control (“sham”) intervention or a combination of two active therapies: the first involved specially designed Cognitive Remediation (CR) techniques—therapeutic interventions designed to improve cognitive functioning, like puzzles and logic problems. The second was transcranial direct current stimulation (tDCS)—a form of non-invasive brain stimulation. These therapies were delivered five days per week for eight weeks, followed by 5-day "boosters" every six months.

The study was randomized, controlled, and double-masked, with assessments conducted at baseline, month-2, and yearly for three to seven years.

The study found that participants receiving CR plus tDCS experienced slower cognitive decline over a median follow-up period of 4 years compared to those receiving the control intervention. The effects were more prominent in individuals with low genetic risk for Alzheimer's disease, and participants with rMDD (with or without MCI) showed better outcomes than those with MCI alone.

Cognitive decline is often the result of overlapping conditions, making combination therapies especially pertinent – they can improve patient outcomes by targeting different disease pathways in a synergistic way.

"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," said Dr. Tarek Rajji, lead author and one of the study Principal Investigators. "This study shows promise that multi-prong, non-pharmacological approaches for people with a high risk of developing dementia could help them live a more independent life for a longer time." Dr. Rajji is a former CAMH Senior Scientist, and now serves as Chair of the Department of Psychiatry at the University of Texas Southwestern Medical Center.

Dr. Benoit Mulsant, senior author and research team lead, explained the focus on the prefrontal cortex: "While there are several presumed mechanisms underlying the increased risk for dementia in older adults with depression, impaired brain plasticity, or the ability of the brain to compensate for damage, is thought to be one common pathway. In this study we targeted the prefrontal cortex for treatment because this is believed to be an area of the brain that is highly adaptable to change and critical to executive functioning." Dr. Mulsant is a Senior Scientist at CAMH, and the Labatt Family Chair for the Department of Psychiatry, Temerty Faculty of Medicine, at the University of Toronto.  

Reference: Rajji TK, Bowie CR, Herrmann N, et al. Slowing cognitive decline in major depressive disorder and mild cognitive impairment: a randomized clinical trial. JAMA Psychiatry. 2024. doi: 10.1001/jamapsychiatry.2024.3241

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