Is provision of substantial dietary interventions for brain health ethical?

Provision of substantial dietary changes for brain health: An intervention amenable to Ethical analysis

First, we draw on a classic distinction in the bioethics literature between research (which aims at producing generalizable knowledge) and practice (which aims to “enhance the well-being of a particular individual or groups of individuals”). ¹ Substantial dietary modifications overseen by a clinician are an intervention that we consider to be a form of innovation, understood here as “new non-validated practice” (NNVP). ² We will see in this Commentary that such practices are novel and non-validated insofar as they are currently based on epidemiological associations and multivariable clinical trials, which do not cross the evidence threshold for routine use in healthcare systems that generally approve treatment provision based on the results of single-variable clinical trials (for example, a drug or vaccine). The use of NNVP in brain health is fraught with ethical issues. ³ It is vital that truly balanced communication about conflicts of interest, the limits of diet and other risk factors be communicated so that consent be truly informed and false hope avoided. This is because uncertainty surrounds NNVP with respect to the therapeutic value it will have for patients, as well as any harmful effects.

Diet and brain health: A promising yet opaque association for individuals

A wealth of data suggests a strong relationship between diet and general brain health. Generally, diets abundant in phytochemical and antioxidant-rich plants, low in refined and animal products and with low insulinogenic effect, tend to reduce brain oxidation, neurodegeneration, the speed of aging and chronic inflammation.^4,5 In their review of dietary intake of phytochemicals, Davinelli et al. noted that “consumption of diets rich in phytochemicals can influence neuroinflammation and mediate the activation of signaling pathways, leading to the expression of cytoprotective and restorative proteins … Several studies have … revealed that the neuroprotective activities of phytochemicals typically occur in dose- and time-dependent manner”. ⁶ For instance, a meta-analysis of randomized controlled trials (RCTs) studying the relationship between the intake of certain plant carotenoids, and cognitive decline and function, found that higher such intake led to slower cognitive decline. ⁷ Notably, dietary intake of these compounds, not supplements, tends to have profounder effects. ⁸

There have been multiple RCTs testing the effects on cognition and neurological health by adding foods particularly rich in phytochemicals, such as berries, which have consistently shown both acute and long-term improvements in cognitive function and reduced neuronal inflammation and pathology.^9–16

The neuroprotective effects of the intake of whole-food nutrients is well-documented. Therefore, diet as a whole, and not selected and particular nutrients, should be of paramount focus when discussing how to promote general brain health with individuals. As Wang et al. informed ¹⁷ in their review: “Substantial evidence shows that a number of dietary or phytobioactive compounds have considerable anti-oxidant and anti-inflammatory effects, displaying an inhibitory role in the oxidative and inflammatory mechanisms associated with neurodegenerative disease”. But that pertains to “the therapeutic effects of whole foods and herbs as neuroprotective agents”. “Nature has packaged a wide array of phytochemicals that likely act in synergy to promote health and prevent aging”, they concluded. ¹⁷ In the DIRECT-PLUS RCT following participants assigned to a phytochemical–rich Mediterranean diet low in meat for 18 months, Kaplan et al. demonstrated significant reduction in brain volume decline compared to control, as measured by MRI. ¹⁸

Diet and dementia

How do the preceding facts, then, relate to dementia risk reduction? Neurodegenerative diseases like dementia have a significant pre-clinical phase, during which strong evidence suggests that hallmarks of neuropathology, neuronal inflammation, atherosclerotic stenosis, endothelial dysfunction and reactive oxygen species induce neurological damage and impair cognition.^19–21 Reducing the risk of cognitive decline and dementia through diet is plausible through a diet in which these risk factors are mitigated, i.e., a diet rich in whole-food plant material (fruits, vegetables, legumes, seeds, greens, whole grains, and so on) and its associated nutrient, as well as phytochemical antioxidant, synergistically bioactive components. A meta-analysis studying the risk of cognitive decline and intake of fruits and vegetables found “the intake of fruits and vegetables is inversely proportional and linearly associated with the prevalence of cognitive disorders in older adults”. ²² In a follow-up study of almost 2000 participants, each increase in the MedDietScore (for instance more fruits and vegetables, less animal products and saturated fats) index was associated with a 10% decreased risk of dementia. ²³ Correspondingly, in a study of similar design and using the same index scoring system, participants with the highest score had a 72% decreased risk of dementia compared to those with the lowest. ²⁴ In a study following more than 32,000 men for 25 years, those in the highest quintile of vegetable intake had 67% better cognitive function than those in the lowest. ²⁵ Similarly, a study following more than 4400 participants for 16 years, found that participants who had both high intake of fruits and vegetables, and high physical activity, had a 63% lower risk of cognitive decline. ²⁶ Most powerful in preventing cognitive decline, it seems, is intake of green leafy vegetables, rich in anti-inflammatory phytochemicals, antioxidants and carotenoids with specific affinity for brain tissue. Thus, in a prospective study following almost 1000 participants for just under five years, those in the highest quintile of green leafy vegetable intake experienced a slowing of cognitive decline equivalent to being 11 years younger in age compared to those in the lowest. ²⁷ Finally, beyond the presence of these components, there is also a solid argument for the removal of highly-processed foods, strongly associated with dementia risk. ²⁸

Importantly, as suggested above, Scarmeas et al. note that evidence for dietary dementia prevention “is somehow stronger for healthy dietary patterns, such as the Mediterranean-type diet, than for individual nutrients and food groups, possibly because of the cumulative beneficial effects of the many ingredients in these diets”. ²⁹ This characteristic of diet and dementia leads this relationship to exhibit what we term “epistemological opacity,” which has two main components. Firstly, low applicability to individuals. Indeed, “in epidemiology, the data are often woolly and unreliable”, ³⁰ making causal inference difficult with respect to diet and dementia. Secondly, the untestability of the hypothesis that changing diets will actually improve measurable outcomes because the complexity of such interventions makes them very uncontrolled experiments. ³¹

Thus, paradoxically, substantial dietary modifications cross the threshold of a minimum evidence base to motivate dietary interventions (based on epidemiological associations and multivariable clinical trials), and yet at the individual level, we do not know if dietary changes will have an impact because identifying the active components of such changes is virtually impossible for multivariable trials. ³²

But new clinical data on dietary impact in the context of dementia is arriving. In a newly published randomized control trial of 51 participants with early stage dementia and mild cognitive impairment, Ornish et al. tested for the first time what effect a healthy lifestyle and plant-based diet would have on cognitive function. While patients in the control arm, who made no changes to diet and lifestyle, worsened in terms of cognitive function, the participants given the intervention improved—not just stabilized—their cognitive function as measured by Clinical Dementia Rating (CDR) global (p < 0.05) and Alzheimer's Disease Assessment Scale-Cognitive (p = 0.053) scoring test after just 20 weeks, and markedly slowed cognitive decline as measured by CDR-SB (p < 0.05). Of note, biomarkers of Alzheimer's disease, such as Amyloid-β_42/40 ratio improved in the intervention arm, too, while worsening in the control arm. The authors note: “the more these AD patients changed their lifestyle in the prescribed ways, the greater was the beneficial impact on their cognition and function”, which “helps to explain in part why some patients in the intervention group improved and others did not, but there are likely other mechanisms that we do not fully understand that may play a role”. ³³

Conclusion: The need for balanced communication, informed consent, and follow-up

We argue that the ethical priorities for substantial dietary modifications for dementia risk reduction should be focused on balanced communication to establish informed consent to avoid false hope, and follow-up to be sure that dietary changes are well-tolerated and feasible for individuals. Truly informed consent requires full disclosure of any financial or other conflicts of interest a clinician may have with any recommended protocol or products. ³ We consider the priority should be on dietary changes rather than supplementation, as the evidence base for supplements and brain health is weak, and the possibility of financial harm and false hope is significant. ³⁴ Nevertheless, even diet is not sufficient for brain health, which also requires reducing exposure to risk factors such as smoking, alcohol, and air pollution, while maximizing social and cognitive stimulation and physical activity. ³⁵ Lifestyle recommendations should not be proposed as though health were a super-value in itself. Health-related priorities should be discussed with individuals alongside non-health priorities, with which they may clash, so as to promote balance that is likely to lead to higher adherence to dietary changes, and therefore better brain health, in the long run. ³¹ This is important because data show that “bootcamp” approaches to lifestyle changes are associated with high attrition rates, even among motivated and educated individuals. ³⁶ New data may become available to validate certain dietary protocols for dementia, ³⁷ requiring more formal interventions for those populations who would benefit from them.