Intensive Multimodal Lifestyle Intervention Improves Cognition and Function in Randomized Controlled Trial

Dean Ornish, MD

Recently published data from a multicenter, randomized controlled phase 2 trial, findings showed that comprehensive lifestyle changes through an intensive multimodal intervention significantly improved cognition and function after 20 weeks in patients with mild cognitive impairment (MCI) or early dementia due to Alzheimer disease (AD). The validity of these findings were supported by observed changes in plasma biomarkers and microbiome, and support longer follow-up and larger clinical trials.^1,2

The trial featured 51 patients aged 45-90 with MCI or early dementia due to AD who had a Montreal Cognitive Assessment (MoCA) score of 18 or higher. Patients were randomized to an intervention group (n = 26) that received the lifestyle intervention for 20 weeks or to a usual-care control group (n = 25) that was asked not to make any lifestyle changes. The multimodal lifestyle intervention included dieting, exercise, stress management, group support, and information on supplements. To reinforce this lifestyle intervention, each patient and their spouse or study partner met 3 times/week, 4 hours/session via Zoom.

The primary outcome measures were changes in cognition and function on the Clinical Global Impression of Change (CGIC), Alzheimer’s Disease Assessment Scale (ADAS-Cog), Clinical Dementia Rating–Sum of Boxes (CDR-SB), and Clinical Dementia Rating Global (CDR-G) after 20 weeks. At this time point, results of the primary analysis showed overall statistically significant differences between the intervention group and the randomized control group in cognition and function as measured by the CGIC (P = .001), CDR-SB (P = .032), and CDR-G (P = .037) tests, and of borderline significance in the ADAS-Cog test (P = .053).

"I'm cautiously optimistic and very encouraged by these findings, which may empower many people with new hope and new choices,” lead investigator Dean Ornish, MD, founder and president of the nonprofit Preventive Medicine Research Institute, said in a statement.¹ "We do not yet have a cure for Alzheimer's, but as the scientific community continues to pursue all avenues to identify potential treatments, we are now able to offer an improved quality of life to many people suffering from this terrible disease."

In comparison with the intervention group, controls showed worsened cognition and function on all 4 measures observed. In addition, after 20 weeks, the plasma amyloid-ß42/40 ratio was increased in the intervention group but decreased in the randomized control group (P = .003; two-tailed). Changes in Aß42/40, similar to other biomarkers observed, correlated with lifestyle at 20 weeks (P = .035; correlation, 0.306) as well as the degree of change in lifestyle (P =.068; correlation, 0.266).

Investigators observed additional statistically significant correlations between the degree of lifestyle change and the degree of change in many of the key biomarkers, including glycoprotein acetylation (correlation with lifestyle at 20 weeks: P = .011; correlation: 0.363; correlation with degree of change in lifestyle: P = .007; correlation: 0.383). This was also observed for LDL cholesterol (P <.0001; correlation: 0.678; degree of change: P <.0001; correlation: 0.628), beta-hydroxybutyrate (P = .013; correlation: 0.372; degree of change: P = .034; correlation: 0.320), phosphorylated tau 181 (P = .228; correlation: 0.177; degree of change: P = .135; correlation: 0.219), and glial fibrillary acidic protein (P = .096; correlation: 0.243; degree of change: P = .351; correlation: 0.138).

The study also looked at the degree of lifestyle change is correlated with improvement in cognitive function tests. In other words, what percentage of adherence to the lifestyle intervention was correlated with no change in MCI or dementia across both groups. All told, adherence rates were 71.4%, 120.6%, and 95.6% for ADAS-Cog, CDR-SB, and CDR-Global, respectively, to correlate with lifestyle at 20 weeks.

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In the study, investigators also observed a significant and beneficial change in the microbiome configuration in the intervention group but not in the control group. Several taxa, including Blautia and Eubacterium, involved in the reduction of AD risk were increased only in the intervention group. Also, there was a decrease in relative abundance of taxa involved in increased AD risk in the intervention group, e.g., Prevotella and Turicibacter, the latter of which has been associated with relevant biological processes such as 5-HT production.

"These results support the hypothesis that the lifestyle intervention may beneficially modify specific microbial groups in the microbiome: increasing those that lower the risk of AD and decreasing those that increase the risk of AD," the study authors wrote.

The study had several limitations, including the fact that it enrolled 51 patients from the original screening of nearly 1500 individuals. In addition, 20 weeks was considered a relatively short time for an intervention to show true efficacy in a patient populationwith MCI or early dementia due to AD. Furthermore, not all patients in the intervention group improved. Most showed improvements; however, some were unchanged and others worsened. In comparison with placebo, none improved.

Ornish et al noted, "The findings on the degree of lifestyle change required to stop the worsening or improve cognition and function need to be interpreted with caution. Since data from both groups were combined, it was no longer a randomized trial for this specific analysis, so there could be unknown confounding influences. Also, it is possible that those with improved changes in cognition were better able to adhere to the intervention and thus have higher lifestyle indices."

REFERENCES
1. Lifestyle Changes Significantly Improve Cognition and Function in Early Alzheimer's Disease for the First Time in a Randomized Controlled Trial. News release. Preventive Medicine Research Institute. June 7, 2024. Accessed June 19, 2024. https://www.prnewswire.com/news-releases/lifestyle-changes-significantly-improve-cognition-and-function-in-early-alzheimers-disease-for-the-first-time-in-a-randomized-controlled-trial-302166826.html
2. Ornish D, Madison C, Kivipelto M, et al. Effects of intensive lifestyle changes on the progression of mild cognitive impairment or early dementia due to Alzheimer’s disease: a randomized, controlled clinical trial. Alzheimers Res Ther. 2024;16(122). doi:10.1186/s13195-024-01482-z