November/December 2017

Nutrition: Diet and Alzheimer's Disease
By Charles Mobbs, PhD
Today's Geriatric Medicine
Vol. 10 No. 6 P. 8

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
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 ground-breaking epidemiological studies of Ancel Keys, who observed in the 1950s that cardiovascular disease in Naples appeared to be strikingly less common 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 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.

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, 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.

References
1. Alzheimer's Association. 2016 Alzheimer's disease facts and figures. Alzheimers Dement. 2016;12(4):459-509.

2. Raggi A, Tasca D, Panerai S, Neri W, Ferri R. The burden of distress and related coping processes in family caregivers of patients with Alzheimer's disease living in the community. J Neurol Sci. 2015;358(1-2):77-81.

3. Greig SL. Memantine ER/donepezil: a review in Alzheimer's disease. CNS Drugs. 2015;29(11):963-970.

4. Peters KR. Utility of an effect size analysis for communicating treatment effectiveness: a case study of cholinesterase inhibitors for Alzheimer's disease. J Am Geriatr Soc. 2013;61(7):1170-1174.

5. Eleti S. Drugs in Alzheimer's disease dementia: an overview of current pharmacological management and future directions. Psychiatr Danub. 2016;28(Suppl 1):136-140.

6. Ridge PG, Mukherjee S, Crane PK, Kauwe JS; Alzheimer's Disease Genetics Consortium. Alzheimer's disease: analyzing the missing heritability. PLoS One. 2013;8(11):e79771.

7. Hersi M, Irvine B, Gupta P, Gomes J, Birkett N, Krewski D. Risk factors associated with the onset and progression of Alzheimer's disease: a systematic review of the evidence. Neurotoxicology. 2017;61:143-187.

8. Zhang M, Poplawski M, Yen K, et al. Role of CBP and SATB-1 in aging, dietary restriction, and insulin-like signaling. PLoS Biol. 2009;7(11):e1000245.

9. Schroeder JE, Richardson JC, Virley DJ. Dietary manipulation and caloric restriction in the development of mouse models relevant to neurological diseases. Biochim Biophys Acta. 2010;1802(10):840-846.

10. Yusufov M, Weyandt LL, Piryatinsky I. Alzheimer's disease and diet: a systematic review. Int J Neurosci. 2017;127(2):161-175.

11. Gardener S, Gu Y, Rainey-Smith SR, et al. Adherence to a Mediterranean diet and Alzheimer's disease risk in an Australian population. Transl Psychiatry. 2012;2(10):e164.

12. Trichopoulou A, Costacou T, Bamia C, Trichopoulos D. Adherence to a Mediterranean diet and survival in a Greek population. N Engl J Med. 2003;348:2599-2608.

13. Keys A. Mediterranean diet and public health: personal reflections. Am J Clin Nutr. 1995;61(6 Suppl):1321S-1323S.

14. Mirra SS, Heyman A, McKeel D, et al. The Consortium to Establish a Registry for Alzheimer's Disease (CERAD). Part II. Standardization of the neuropathologic assessment of Alzheimer's disease. Neurology. 1991;41(4):479-486.

15. Wang M, Roussos P, McKenzie A, et al. Integrative network analysis of nineteen brain regions identifies molecular signatures and networks underlying selective regional vulnerability to Alzheimer's disease. Genome Med. 2016;8(1):104.

16. Schneider LS, Sano M. Current Alzheimer's disease clinical trials: methods and placebo outcomes. Alzheimers Dement. 2009;5(5):388-397.

17. Jellinger KA, Attems J. Neuropathological evaluation of mixed dementia. J Neurol Sci. 2007;257(1-2):80-87.

18. Morris MC, Tangney CC, Wang Y, Sacks FM, Bennett DA, Aggarwal NT. MIND diet associated with reduced incidence of Alzheimer's disease. Alzheimers Dement. 2015;11(9):1007-1014.

19. Morris MC, Tangney CC, Wang Y, et al. MIND diet slows cognitive decline with aging. Alzheimers Dement. 2015;11(9):1015-1022.

20. Bailey EE, Pfeifer HH, Thiele EA. The use of diet in the treatment of epilepsy. Epilepsy Behav. 2005;6(1):4-8.

21. Bravata DM, Sanders L, Huang J, et al. Efficacy and safety of low-carbohydrate diets: a systematic review. JAMA. 2003;289(14):1837-1850.

22. Kennedy AR, Pissios P, Otu H, et al. A high-fat, ketogenic diet induces a unique metabolic state in mice. Am J Physiol Endocrinol Metab. 2007;292(6):E1724-E1739.

23. Poplawski MM, Mastaitis JW, Isoda F, Grosjean F, Zheng F, Mobbs CV. Reversal of diabetic nephropathy by a ketogenic diet. PLoS One. 2011;6(4):e18604.

24. Xu WL, von Strauss E, Qiu CX, Winblad B, Fratiglioni L. Uncontrolled diabetes increases the risk of Alzheimer's disease: a population-based cohort study. Diabetologia. 2009;52(6):1031-1039.

25. Vagelatos NT, Eslick GD. Type 2 diabetes as a risk factor for Alzheimer's disease: the confounders, interactions, and neuropathology associated with this relationship. Epidemiol Rev. 2013;35:152-160.

26. Brownlow ML, Benner L, D'Agostino D, Gordon MN, Morgan D. Ketogenic diet improves motor performance but not cognition in two mouse models of Alzheimer's pathology. PLoS One. 2013;8(9):e75713.

27. Beckett TL, Studzinski CM, Keller JN, Paul Murphy M, Niedowicz DM. A ketogenic diet improves motor performance but does not affect beta-amyloid levels in a mouse model of Alzheimer's disease. Brain Res. 2013;1505:61-67.

28. Newport MT, VanItallie TB, Kashiwaya Y, King MT, Veech RL. A new way to produce hyperketonemia: use of ketone ester in a case of Alzheimer's disease. Alzheimers Dement. 2015;11(1):99-103.

29. Cunnane SC, Courchesne-Loyer A, St-Pierre V, et al. Can ketones compensate for deteriorating brain glucose uptake during aging? Implications for the risk and treatment of Alzheimer's disease. Ann N Y Acad Sci. 2016;1367(1):12-20.

30. Shimazu T, Hirschey MD, Newman J, et al. Suppression of oxidative stress by beta-hydroxybutyrate, an endogenous histone deacetylase inhibitor. Science. 2013;339(6116):211-214.

31. Newman JC. Ketogenic diet reduces midlife mortality and improves memory in aging mice. Cell Metab. 2017;26(3):547-557.