Nutrition: Diet and Alzheimer's Disease
Alzheimer's disease (AD) constitutes one of the greatest threats to public health in the 21st century. In the US 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 can also be overwhelming.2
Currently, four individual drugs and one combination drug are approved for use in patients with AD,3 but the effect sizes 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 is considerable latitude for environmental interventions. In a thorough analysis of factors most likely to protect against AD that have been gleaned from epidemiological studies, Hersi et al concluded that adherence to a Mediterranean diet was among the five factors most likely to protect.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 C. elegans,8 and mice.9 Furthermore, diet is one of the most accessible interventions available. Therefore, effects of diet on the risk of AD and mechanisms mediating these effects are of considerable interest.
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 et al, a Mediterranean type of diet was the most consistently protective dietary intervention to reduce the risk of AD.7 In 10 of 12 studies, a Mediterranean type of 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 et al,11 who used a prospective questionnaire-based (0–9 point) scale representing adherence to the Mediterranean diet developed by Trichopoulou et al12 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, body mass index, diabetes, and cardiovascular risk factor.11
Three Pertinent Questions
The scale developed by Trichopoulou et al, reflective of general practice in the field, was based on eight component characteristics: high monounsaturated to saturated fat ratio, moderate ethanol consumption, high consumption of legumes, high consumption of cereals, high consumption of fruits, high consumption of vegetables, low consumption of meat and meat products, and low consumption of milk and dairy products.12 Thus the majority of epidemiological studies examining the question have suggested that the higher a diet scores on this scale, the more protective the diet is, including 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,14,15 but such histological analysis is completely impractical for epidemiological or even most interventional studies. 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 cannot distinguish between various forms of dementia (eg, vascular vs AD) although AD is likely to constitute about 80% of dementia cases based on clinical diagnosis.17 Thus the epidemiological studies are probably fairly reflective of risk for AD 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 et al,18 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 a Mediterraneanlike diet, a diet designed to prevent hypertension (DASH diet), and a hybrid of the two (MIND diet). The intervention actually was to counsel the three groups of volunteers to consume one of the three diets, accompanied by questionnaires to assess adherence.
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 did not 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 a particular diet, ie, the MIND diet (followed by the classical Mediterranean and DASH diets), reduces the risk of AD.
Ketogenic diets, characterized by low carbohydrate and low protein, thus relatively high fat constitution, 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 to reduce adiposity and other risk factors for cardiovascular disease 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 do not 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 is plausible that a low-carbohydrate diet, and particularly a ketogenic diet, would be effective to reduce 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 is not palatable over the long term; it is useful in epilepsy only in children because it is 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 nematode 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 is 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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