March 2018 Issue

Senior Wellness: Diet and Alzheimer's Disease
By Charles Mobbs, PhD
Today's Dietitian
Vol. 20, No. 3, P. 18

Alzheimer's disease (AD) constitutes one of the greatest threats to public health in the 21st century. In the United States alone, the direct costs of AD are estimated to be $236 billion, with indirect financial costs to caregivers estimated to be nearly as much.1 The emotional toll on caregivers also can be overwhelming.2

Currently, four individual drugs and one combination drug are approved for use in patients with AD,3 but the side effects of these drugs are relatively modest and the clinical significance of these effects, especially whether the benefits outweigh the harm, have been widely questioned.4 Similarly, Eleti simply states that "the efficacy of these is widely debated."5 Clearly, better treatments to delay and even ameliorate AD are of the utmost priority.

Only about 33% of total phenotypic variance in AD is explained by all common single nucleotide polymorphisms.6 Thus, there's considerable latitude for environmental interventions—especially through proper nutrition. In a thorough analysis of factors most likely to protect against AD that have been gleaned from epidemiologic studies, Hersi and colleagues concluded that adherence to a Mediterranean diet was among the five factors most likely to be protective.7

On the other hand, dietary restriction is the single manipulation that most robustly delays all age-related diseases, including phenotypic impairments produced by transgenic expression of human genes implicated in AD in Caenorhabditis elegans (a species of roundworm) and mice.8,9 Furthermore, diet is one of the most accessible interventions available. As such, RDs should view AD prevention as part of their scope of practice and as something achievable for many patients.

Since pathology in AD progresses over decades, interventional studies are quite challenging, so the vast majority of studies examining the effects of diet on the risk of AD are essentially epidemiological. (However, there are a few outstanding interventional studies, described below.)

In a recent review, Yusufov examined studies assessing the effects of diet on the risk of AD.10 As indicated by Hersi and colleagues, the Mediterranean diet was the most consistently protective dietary intervention to reduce the risk of AD.7 In 10 of 12 studies, the Mediterranean diet was reported to be associated with reduced risk of AD, whereas in the other two, no effect was observed.10

A good example of such a study is that of Gardener and colleagues,11 who used a prospective questionnaire-based (0–9 point) scale representing adherence to the Mediterranean diet developed by Trichopoulou and colleagues12 to assess AD risk. In this study, adherence to the diet was the main predictor of AD and mild cognitive impairments in multinominal logistic regression models that were including all major known risk factors for AD, including education, apolipoprotein E genotype, caloric intake, smoking status, BMI, diabetes, and cardiovascular risk factors.11

Three Pertinent Questions
While compelling, such studies are subject to three main caveats. First is the question of what precisely constitutes a Mediterranean diet. Such diets originally came to public attention with the groundbreaking epidemiologic studies of Ancel Keys, PhD, who observed in the 1950s that CVD appeared to be strikingly less common in Naples than in other European or American cultures.13 Based on these and similar observations and studies, a prototypical apparently protective Mediterranean diet was developed.

The scale developed by Trichopoulou and colleagues, reflective of general practice in the field, was based on the following component characteristics: high monounsaturated to saturated fat ratio; moderate alcohol consumption; high consumption of legumes, cereals, fruits, and vegetables; and low consumption of meat and meat products and milk and dairy products.12 Thus, the majority of epidemiologic studies examining the question have suggested that the higher a diet scores on this scale, the more protective the diet is, including in reducing the risk of AD.

A second question concerning such studies involves the determination of AD. The most rigorous clinical diagnosis of AD can be determined only by postmortem histological analysis, but such histological analysis is completely impractical for epidemiologic or even most interventional studies.14,15 Therefore, such studies must rely on clinical impressions, at best supported by various standardized instruments such as the Mini-Mental State Exam.16

Such clinical impressions generally can't distinguish between various forms of dementia (eg, vascular dementia vs AD) although AD is likely to constitute about 80% of dementia cases based on clinical diagnosis.17 Thus, the epidemiologic studies are probably fairly reflective of AD risk but must be understood to be provisional based on the limitations of clinical diagnoses.

A final question involves the many limitations of epidemiology, most importantly that factors examined, such as diet, may well be confounded with factors not examined, such as exercise. Addressing this concern, some studies entailed a form of intervention, although for dietary studies over prolonged periods of time (up to six years) such interventions are necessarily compromised.

An excellent example of such studies is that of Morris and colleagues, which compared the effects of three closely related interventions on the risk of AD. In this study, the authors attempted to distinguish between the effects of the Mediterranean diet, the DASH (Dietary Approaches to Stop Hypertension) diet, and a hybrid of the two, the MIND (Mediterranean-DASH Intervention for Neurodegenerative Delay) diet. The intervention was to counsel the three groups of volunteers to consume one of the three diets, accompanied by questionnaires to assess adherence.18

Using this methodology, patients counseled to adhere to the MIND diet exhibited reduced risk of AD compared with the other two groups. These results were consistent with a similar study focusing on age-related cognitive decline.19 Although strictly speaking these studies didn't constitute a rigorous interventional trial (as can be carried out only in short-term studies with isolated patients subject to complete dietary supervision), these studies provide probably the most compelling evidence that the MIND diet (followed by the classical Mediterranean and DASH diets) reduces the risk of AD.

Additional Prospects
Although less well established, another dietary intervention, characterized by relatively low carbohydrate content, is beginning to show great promise. While apparently contradictory to the relatively high carbohydrate constitution of the Mediterranean diet, low-carbohydrate diets have been developed in part because of their basis as ketogenic diets.

Ketogenic diets, which are low in carbohydrates and protein and high in fat, were first introduced clinically to treat epilepsy, where they continue to be safe and effective even in patients refractory to drug treatment.20

Low-carbohydrate diets have long been advocated for weight control, although until recently little evidence supported their efficacy for this purpose, and even the best current evidence is that low-carbohydrate diets are effective in reducing adiposity and other risk factors for CVD only over a relatively short term in humans.21

Nevertheless, studies in mice demonstrate a remarkably robust effect to reduce adiposity and risk factors over a relatively much longer period of time, under circumstances in which mice don't have the option of choosing other diets.22 Similarly, a ketogenic diet largely reverses hyperglycemia in mouse models of type 1 diabetes and reverses diabetic kidney failure in mouse models of both type 1 and type 2 diabetes.23

Because diabetes appears to be a major risk factor for AD,7,24,25 it's plausible that a low-carbohydrate diet, and particularly a ketogenic diet, would be effective in reducing the risk of AD in humans.

Evidence that a ketogenic diet would be protective in human AD remains mixed. Certainly in mouse models of AD the ketogenic diet appears to improve motor performance but not cognitive function.26,27 One case study has been reported indicating that treatment with a ketone ester was effective in improving mood, affect, self-care, and cognitive and daily activity performance.28

Studying the long-term effects of a ketogenic diet in humans is highly challenging because the very high-fat diet isn't palatable over the long term; it's useful in epilepsy only in children because it's possible to maintain strict supervision over their diet. In adults with more autonomy, the classic ketogenic diet is almost impossible to maintain over long periods.

Nevertheless, the rationale for developing more palatable forms of the diet to treat AD is quite strong. First, elevated plasma ketones could provide metabolizable carbons to compensate for the decrease in glucose metabolism observed in AD.29 Second, the main product of the ketogenic diet, 3-hydroxybutyrate (3-OHB), is highly neuroprotective, such as against oxidative stress.23,30 Third, 3-OHB is an inhibitor of HDAC activity,30 plausibly mimicking effects of dietary restriction to enhance activity of Creb-binding protein, which mediates many protective effects of dietary restriction, including on lifespan and pathology in a roundworm model of AD.8 Finally, lifelong exposure to a ketogenic diet increases lifespan and maintains cognitive function in aging mice.31

Therefore, developing a ketogenic diet that's easier to maintain appears to be a highly promising dietary method to treat AD.

— Charles Mobbs, PhD, is a professor of neuroscience, geriatrics, and endocrinology at the Icahn School of Medicine at Mount Sinai in New York. He studies mechanisms mediating protective effects of dietary restriction on lifespan and age-related diseases, including Alzheimer's disease.

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