Reference
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
Study Objective
To assess the effect of an intensive lifestyle intervention on subjective and objective parameters of cognition in individuals with early Alzheimer’s disease (AD) or mild cognitive impairment (MCI)
Key Takeaway
An intensive diet, lifestyle, and nutritional supplement program significantly improved cognition and blood biomarker levels of AD over 20 weeks in 10 of 24 participants.
Design
Double-blind, randomized controlled phase II trial
Participants
All participants (n=51; mean age, 73.5 years) were aged 45 to 90 years, had a current diagnosis of MCI or early dementia due to AD, and had a Montreal Cognitive Assessment (MoCA) score of 18 or higher. The intervention group included 26 participants (19 men, 7 women), and the control group included 25 participants (13 men, 12 women) who were assigned to usual habits and care.
There were no significant differences in baseline characteristics between the 2 groups, including apolipoprotein E (APOE) status and baseline values for the AD biomarker amyloid β 42/40 (Aβ42/40) ratio.
Inclusion Criteria
In addition to established cognitive impairment, all participants were seeing a neurologist, willingly participated, and had an available spouse or caregiver to assist with study adherence.
Exclusion Criteria
Exclusion criteria included more advanced AD (moderate or severe dementia), physical disability that precluded exercise, evidence of other primary causes of neurodegeneration or dementia (eg, vascular dementia, Lewy body dementia, Parkinson’s disease, or frontotemporal dementia), ongoing psychiatric problems, or substance abuse.
Intervention
An intensive lifestyle program that included exercise, meditation, education, and both individual and group psychological support for 12 hours per week. The diet was restricted to a low-fat, vegetarian diet. The intervention group also received nutritional supplements known to support cognitive function. The control group was wait-listed and did not receive these interventions (they were informed that if randomized to the control group, they could participate in the intervention after the study).
Vegan Diet
Meals were provided by overnight shipment 2 times per week. Participants were asked to eat only the food provided for the 20-week course of the study. Specifically, they received 21 meals per week and snacks for themselves and their spouse or study partner. Meals were whole-food, minimally processed, plant-based (vegan), and high in complex carbohydrates (fruits, vegetables, whole grains, legumes, soy products, seeds, and nuts) and low in harmful fats, sweeteners, and refined carbohydrates. Macronutrient composition by calories was approximately 14% to 18% fat, 16% to 18% protein, and 63% to 68% (mostly complex) carbohydrates.
Intensive Lifestyle Intervention
There were 4 main components to the lifestyle aspect of the trial. To reinforce the intervention, each patient and their spouse or study partner met 3 times per week for 4-hour sessions via Zoom. Each session entailed 1 hour of supervised exercise (aerobic and strength training), 1 hour of stress management (stretching, breathing, meditation, imagery), 1 hour of group support, and 1 hour of lecture on lifestyle. Exercise was personalized to the participant’s age and fitness level.
Nutritional Supplements
Several nutritional supplements were taken throughout the 20-week study period, but only by those in the intervention group:
- Omega-3 fatty acids (1680 mg/d) with curcumin (800 mg/d) (Nordic Naturals ProOmega CRP)
- Multivitamin and minerals (Solgar VM-75 without iron, 1/d)
- Coenzyme Q10 (200 mg/d) (Nordic Naturals, 2/d)
- Vitamin C (1 g/d) (Solgar)
- Vitamin B12 (500 mcg orally/d) (Solgar)
- Magnesium threonate (144 mg/d) (Magtein)
- Hericium erinaceus (Lion’s Mane) (2 g/d) (Host Defense)
- Super Bifido Plus Probiotic (1 tablet/d) (Flora)
Study Parameters Assessed
Cognition and function tests were conducted at baseline and after 20 weeks. Tests included:
- Alzheimer’s Disease Assessment Scale–Cognitive Subscale (ADAS-Cog)
- Clinical Global Impression of Change (CGIC)
- Clinical Dementia Rating Sum of Boxes (CDR-SB)
- Clinical Dementia Rating Global (CDR-Global)
The tests were administered by trained psychometrists with clinical trial experience. All but the ADAS-Cog were conducted via Zoom.
Bloodwork: Biomarkers assessed included plasma Aβ42/40 ratio, phosphorylated tau 181 (pTau181), insulin, beta-hydroxybutyrate (ketone), LDL cholesterol, glial fibrillary acidic protein (GFAP), C-reactive protein (CRP), serum amyloid A (SAA), glycoprotein acetylation (GlycA), and telomere length.
A correlation of cognitive test scores and bloodwork with adherence to the study intervention was done.
Primary Outcome
Changes in cognition and function test scores from baseline to the end of the study.
Secondary Outcomes
Changes in plasma Aβ42/40 ratio, other biomarkers, microbial taxa, and correlations between lifestyle and changes in these measures.
Key Findings
Statistically significant differences between groups were found, with improvements seen only in the intervention group: CGIC (P=0.001), CDR-SB (P=0.032), and CDR-Global (P=0.037) tests, with borderline significance in the ADAS-Cog test (P=0.053).
Overall, only participants in the intervention group showed improvements. In the intervention group (n=24), 10 participants improved on the CGIC test, 7 were unchanged, and 7 worsened by the study’s conclusion (20 weeks). In contrast, no one in the control group improved, 8 were unchanged, and 7 worsened.
Correlation with Adherence: Adherence to the lifestyle program was calculated and correlated with improvement in cognitive assessments. Specifically, the following correlations were found:
- 71.4% adherence correlated with improved ADAS-Cog scores
- 120.6% adherence correlated with improved CDR-SB scores
- 95.6% adherence correlated with improved CDR-Global scores
Of the biomarkers assessed, the following showed significant differences between the control and intervention groups:
- Plasma Aβ42/40 ratio (P=0.003)
- Insulin (P=0.048)
- Beta-hydroxybutyrate (P=0.021)
- LDL cholesterol (P<0.001)
- Glycoprotein acetylation (P=0.005)
Microbiota changes were favorable in the intervention group only, with greater abundance of Blautia and Eubacterium and reduced abundance of Prevotella and Turicibacter.
Transparency
The trial is listed as NCT04606420. The sponsor is the Preventative Medicine Research Institute, a nonprofit founded by Dr Ornish. The institute offers a paid version of this protocol on its website. Funding sources include the supplement companies whose products were used. The authors state there was no involvement from the funders in the design, execution, or analysis of the data.
Practice Implications
This study is the first to assess an integrative medicine–only protocol in a 1:1 multicenter randomized controlled trial in patients with cognitive impairment. There was an appreciable improvement in cognition test scores in 7 of 24 patients in 20 weeks, compared with none in the control group. Favorable changes in plasma Aβ42/40 levels corroborated these findings. The correlations between improvements in cognition and study adherence strengthen the evidence that the intervention benefited participants. Although the number of participants was small, this proof-of-concept study yielded encouraging results.
In integrative medicine, we pride ourselves on treating each patient as an individual and sleuthing out the cause of each person’s condition. Terms such as personalized medicine, precision medicine, and individualized care are often used. This ability to personalize treatment is one reason people seek nonconventional medical practitioners. However, in this study, participants showed cognitive improvements without individualization. There was no bloodwork used to select participants with nutrient deficiencies, no infectious disease or mycotoxin testing, no diagnosis of an underlying dysbiosis, no detox or chelation of toxic metals, and no genomic testing to target the underlying causes.
These tests are commonly employed to assess the cause of a patient’s neurological degeneration, but are they the best use of a patient’s often limited resources? Should their time and money be spent on pursuing causes, or should it be directed toward executing a treatment that stabilizes or reverses cognitive deficits in one-third of patients with mild AD-dementia?
Perhaps it is both. While the workup for individualized care is being done, patients could partake in an "intensive lifestyle intervention" like the one used in this study. Given the results, if the diagnosis is specifically early Alzheimer’s disease, a trial of a similar intervention seems worth trying. Biomarker testing can be used to inform clinical decision-making and adjust treatments.
Dr Dean Ornish has been a staple in integrative medicine, especially in cardiovascular disease reversal and prevention, since at least the 1990s. In 1998, he and colleagues published a seminal study in JAMA showing reversal of atherosclerotic plaques in some individuals using an intense lifestyle and diet intervention.2 The “Ornish diet” has become synonymous with an ultra-low-fat (<10% of calories) whole-food vegan diet, which is well-known for its cardiovascular effects.
It is important to note that in the study under review, the total fat intake was a more generous 14% to 18% of calories, although still low. The exact foods consumed were not detailed in the publication or supplemental materials. The diet was described as a whole-food, minimally processed, plant-based (vegan) diet that was high in complex carbohydrates (primarily fruits, vegetables, whole grains, legumes, soy products, seeds, and nuts) and low in harmful fats, sweeteners, and refined carbohydrates.
In addition to the diet, which was provided to participants, there was an extensive lifestyle component. The lifestyle therapies entailed 12 hours of engagement per week, a significant time commitment to self-care. Participants and their caregivers attended 3 sessions per week of supportive oversight via Zoom, with each session lasting 4 hours. This continued for the entire 20-week trial. The level of commitment on the part of the participants is commendable, as only 2 participants dropped out (2 of 26) from the intervention arm. It is possible (though conjectural) that participants either enjoyed the sessions or were already perceiving cognitive benefits, which encouraged their continuation.
Generally speaking, “lifestyle interventions” include diet and habits, so the use of nutritional supplements in this study was somewhat surprising. The supplements chosen were rational, given that some nutrient deficiencies (eg, vitamin B12, omega-3 fatty acids) are linked to cognitive impairment.2 The study went beyond nutrient repletion and into the realm of nootropics. Participants in the intervention arm received daily doses of 2 g of Lion’s Mane mushroom, 800 mg of curcumin, and Bifido bacteria supplementation. Each of these has evidence of independently exerting favorable benefits on brain health and cognition, with curcumin showing evidence of preventing amyloid-beta aggregation as well.3-5
While the intent of this study was to determine if an “all-in” diet and lifestyle treatment could make a measurable difference, it is not clear which component of the program had the greatest impact. Was it the diet, the supportive care, the exercise, or the supplements? This study cannot determine that. Future studies with multiple arms for comparison could help clarify the contributions of each component.
Improvements in cognition also correlated with study adherence, strengthening the evidence that the intervention benefited participants.
By providing participants with all of their meals and supplements for the duration of the study, the hypothesis being tested was the effectiveness of the treatment, not its feasibility. There are ways to recreate aspects of this study at home using diet apps or food delivery services that mimic the macronutrients and maintain the whole-food veganism inherent in the diet. Joining a gym or exercise program for strength training and aerobic workouts is another option. Ensuring that whoever the patient lives with is supportive, informed, and ideally engaged in the same diet is important as well. Some aspects, such as the close oversight that included mental-emotional support three times a week, may be more challenging to replicate.
It is important to note that this study focused on individuals with established mild AD, as determined by biomarkers (ie, Aβ42/40 ratio) and cognitive testing, making the diet therapeutic rather than preventative. Diets such as the Mediterranean–Dietary Approaches to Stop Hypertension (DASH) Intervention for Neurodegenerative Delay (MIND) diet have shown some evidence of reducing the risk of developing dementia, but evidence of their effectiveness as a therapeutic intervention is not as strong.6 To be fair, the MIND diet alone is not equivalent to this study’s much more intense intervention. One observational study showed better cognitive function near death in those with the greatest adherence to the MIND diet and a healthy lifestyle, regardless of the type of dementia.7
Another therapeutic diet for neurodegenerative diseases that is gaining popularity and evidence is the ketogenic diet. There are many ways to achieve ketosis, typically through a high-fat, low-carbohydrate, moderate-protein macronutrient profile. Intermittent fasting or therapeutic fasting also induces ketosis. A 2022 review of studies on ketogenic diets for AD found that ketones, whether endogenous or exogenous, are a promising tool for slowing or reversing AD cognitive decline, and larger trials are warranted.8
The therapeutic effect of endogenous ketosis on neurodegeneration is largely due to beta-hydroxybutyrate (B-HB).9 Some mechanisms of B-HB’s neuroprotective effects include regulation of synaptic neurotransmission (increasing GABA and decreasing glutamate stimulation), inhibiting inflammation, and lowering oxidative stress.10 While B-HB has received much attention, acetoacetate, another endogenous ketone, may also have ameliorating effects.11
Remarkably, in this study, the diet given to participants led to mild ketosis, as evidenced by increased levels of circulating B-HB in the intervention group. This is intriguing, given that the diet was approximately 65% complex carbohydrates. Whether increased B-HB contributed to the therapeutic effect of the intervention is unclear from this study.
If we take the data at face value and believe that both a vegan, low-fat, whole-food diet and a ketogenic, whole-food diet can lead to cognitive improvement or reversal of dementia, we are left to consider what commonalities they share. First, whole foods and plant-based foods are included in both. There is no diet proven to reduce dementia risk that does not emphasize plant-based eating. Another potential commonality is ketosis, as demonstrated in this study. Finally, the avoidance of processed foods, trans fats, and refined carbohydrates is consistent between the diets. The favorable changes in the microbiota seen in the intervention group may also play a role.
Limitations
As mentioned, this treatment encompassed more than lifestyle changes. While the diet and lifestyle were intense interventions, the participants also consumed an array of supplements at therapeutic doses. Employing a single aspect of this study is unlikely to yield the same results, as the totality of the intervention was assumed to work in concert to improve brain function. Recreating this in anything but a formalized program would be challenging for most clinics. Additionally, this study was small, so a larger-scale replication would be ideal.
For now, clinicians may want to recommend a plant-based, whole-food diet limited enough in calories or timing to create mild ketosis in patients with mild AD. Whether this is achieved through a healthy ketogenic diet or the Ornish diet may depend on the patient’s preferences and home environment. Bouts of ketosis represent a return to the natural physiology of feast and famine. If ketosis is therapeutic, how it is achieved may matter less than achieving it in some way.
