By Matthew E. Fink, MD, Editor
Recent clinical studies support the benefit of intensive lifestyle interventions, which should include a plant-based diet, exercise, stress management, and avoidance of smoking and alcohol, for the prevention of Alzheimer’s disease.
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.
Neuffer J, Wagner M, Moreno E, et al. Association of LIfestyle for BRAin health risk score (LIBRA) and genetic susceptibility with incident dementia and cognitive decline. Alzheimers Dement 2024;20:4250-4259.
These two recently published clinical studies have added to the growing body of observational research that strongly suggests that aggressive lifestyle interventions may have a positive effect and benefit to prevent Alzheimer’s disease as well as to treat mild cognitive impairment in its early stages. It is estimated that 40% of Alzheimer’s disease cases are attributable to environmental factors, which can be modified.
In the study by Neuffer et al, the LIfestyle for BRAin health (LIBRA) risk score was developed and validated as a composite of modifiable and environmental factors that contribute to the risk of Alzheimer’s disease. These factors are a healthy diet, physical activity, engagement in cognitively stimulating activities, low alcohol consumption, cessation or avoidance of smoking, heart disease, diabetes, high cholesterol, obesity, hypertension, renal dysfunction, and depression. Each one of these factors is assigned a numerical value, either positive or negative, based on the expected effect on long-term cognitive function and cardiovascular health. It has been well-documented that many of these factors also contribute to cardiovascular disease in addition to increasing the risk of Alzheimer’s disease.
Aggressive interventions that modify the development of coronary artery disease also may reduce the risk of Alzheimer’s disease. A composite score was generated for LIBRA with a higher number indicating a higher risk of developing Alzheimer’s disease. In addition, a composite genetic score was developed based on apolipoprotein E (APOE) ε4 carrier status, plus the inclusion of 75 additional common genetic risk loci that have been mapped to sporadic Alzheimer’s disease in genome-wide association studies. The investigators then undertook an analysis to determine the interactions between the genetic risk score and the LIBRA score for a group of elderly people who were normal at the time of the study and followed for a number of years to determine who developed mild cognitive impairment and Alzheimer’s disease.
The study was performed in France, in the cities of Bordeaux, Dijon, and Montpellier. A total of 9,294 community dwellers > 65 years of age were enrolled in the study. In-person follow-up was conducted every two to three years, and cognitive function was determined by a formal battery of neuropsychological tests at baseline and at each follow-up visit. Patients who were suspected of developing dementia then were examined by a second neuropsychologist, and then underwent a third examination by a neurologist. To follow changes over time, neuropsychological tests were repeated: Mini-Mental State Examination, Benton Visual Retention Test, Isaacs Set Test, and the Trail Making Test.
Subjects were divided into three groups based on LIBRA scores. Group 1 had low scores (-5.9; -1.0), group 2 had intermediate scores (-1; 2.7), and group 3 had high scores (2.7; 11.2). All three groups had a similar proportion of APOE ε4 carriers, ranging from 19.8% to 20.9% of each group. In addition, all three groups had similar proportions of the genetic risk scores, determined as low, medium, or high.
Over a mean follow-up time of 8.4 years, a total of 652 (13%) participants developed dementia. The incidence rate of dementia increased with increased LIBRA score per 100 person-years. The incidence rate in the lowest quartile was 1.1 per 100 patient-years and, in the highest quartile, the incidence rate of dementia was 2.3 per 100 patient-years. Dementia incidence was higher in participants with a higher genetic risk score: 2.1 per 100 patient-years for APOE ε4 carriers vs. 1.3 per 100 patient-years for non-carriers.
In all APOE ε4 carriers, incidence rates were 1.4 per 100 patient-years in the low LIBRA score participants vs. 3.3 per 100 patient-years in the high LIBRA score category. In a multivariate analysis, a higher LIBRA score was significantly associated with higher dementia risk, with no evidence of modification by genetic risk. Each one-point increase in LIBRA score was associated with a 9% increased risk of dementia in non-APOE ε4 carriers, and a 15% increased risk in carriers.
The results were striking in their consistency. The LIBRA score was associated with a higher incidence of dementia and no significant effect or modulation by the genetics score or the presence of APOE ε4 genes. Similar findings were obtained when analyzing the effect of the Global Risk Score from genetics and cognitive decline. The LIBRA score had the greatest predictive value for the development of mild cognitive impairment or dementia in all patients, regardless of APOE ε4 status.
The study by Ornish et al claims to be the first randomized controlled trial of intensive lifestyle interventions for the treatment of early Alzheimer’s disease. Ornish has many years of experience studying and treating patients with severe coronary artery disease with lifestyle interventions, and has shown that they can dramatically benefit people who have coronary artery atherosclerosis and other cardiovascular diseases.1 By taking the observational studies that suggest similar interventions can have an effect on the development of Alzheimer’s disease, his team organized a randomized clinical trial to attempt to answer that question.
This study was a multicenter, randomized and controlled Phase II trial with 51 Alzheimer’s disease patients with mild cognitive impairment (Montreal Cognitive Assessment score 18 or higher), who were randomized to an intensive lifestyle intervention protocol for 20 weeks, compared to 25 subjects randomly assigned to usual habits and care as a control group. At the end of 20 weeks, the control group was offered the interventional protocol. The investigators thought that it would be extremely difficult to maintain the intensity of this intervention for more than 20 weeks, based on prior experience with patients who have cardiovascular disease.
The intensive multimodal lifestyle intervention included a diet of whole foods that was based on minimally processed plant-based foods, high in complex carbohydrates and low in harmful fats, sweeteners, and refined carbohydrates. All the food was provided to the patients by the investigators, based on the caloric content that was considered to be appropriate for their size and level of activity. Exercise was required (at least 30 minutes per day of aerobic exercise), with mild strength training three times per week.
Subjects underwent stress management supervision with meditation, gentle yoga-based postures, and breathing exercises for one hour per day supervised by a stress management expert. There was group therapy support for one hour three times per week. They also were prescribed supplements of omega-3 fatty acids, curcumin, multivitamin, coenzyme Q10, vitamin C, vitamin B12, magnesium, a natural herb known as lion’s mane, and a probiotic.
The subjects underwent rigorous neuropsychological assessments throughout the trial, which included the Alzheimer’s Disease Assessment Scale – Cognitive Subscale, Clinical Global Impression of Change, the Clinical Dementia Rating Sum of Boxes, and the Clinical Dementia Rating Global Scale. Biomarkers were measured with plasma A-beta 42/40 ratios, measured at the beginning and at the end of the trial. Fifty-one Alzheimer’s disease patients, mean age 73.5 years, were enrolled and randomized. There were no significant differences in baseline measurements. All patients had plasma A-beta 42/40 ratios that were low and strongly supportive of the diagnosis of Alzheimer’s disease.
After 20 weeks of lifestyle intervention, there were significant differences between the two groups in all primary measures of cognitive function, with less decline in the interventional group compared to the control group. Some of the measures demonstrated improvements in cognitive function, compared to the control group. The A-beta 42/40 ratio also increased in the interventional group and decreased in the control group.
There was a significant relationship between lifestyle intervention and both cognitive function and plasma A-beta 42/40 biomarkers. There also was a change in the microbiome of the interventional group, with a shift to microorganisms that are believed to be beneficial for cognitive function. The investigators concluded that multimodal lifestyle interventions in patients with mild cognitive impairment from Alzheimer’s disease were beneficial in slowing — and in some cases, reversing — cognitive decline.
COMMENTARY
After many years of speculation about the possible benefit of lifestyle interventions in reducing the risk of Alzheimer’s disease and the possible treatment of early Alzheimer’s disease, these two studies have added to the body of evidence that supports the hypothesis. Modifiable cardiovascular risk factors also are modifiable risk factors for Alzheimer’s disease. Aggressive lifestyle interventions to reduce and eliminate these factors can have a beneficial effect on Alzheimer’s patients. The evidence for slowing or delaying the onset of Alzheimer’s disease is becoming stronger. The Ornish study is the first to show any evidence for improvement in cognitive function, and this deserves further investigation. The Ornish study needs to be replicated with a larger number of people participating and for a longer period.
However, the lifestyle interventions that are being recommended certainly will result in excellent health for the participants. Therefore, although it is important for us to obtain scientifically valid evidence regarding its effects, there is no reason to delay in making these recommendations to our patients while we continue to gather more information. But we must recognize that multimodal lifestyle intervention is a major commitment that requires a great deal of work, effort, and added expense to be successful. There needs to be close interaction between the clinician, caregivers, and the patients for this to be successful.
In our current structure for health insurance, these interventions, which may be costly, are not likely to be covered by current health insurance policies. This also will be a barrier to implementation. However, these results are exciting and should generate a great deal of enthusiasm among the community of Alzheimer’s clinicians as well as patients and their families.
REFERENCE
- Ornish D, Scherwitz LW, Billings JH, et al. Intensive lifestyle changes for reversal of coronary heart disease. JAMA 1998;280:2001-2007.
