The Ketogenic Diet and Its Effects on Alzheimer’s Disease

Jennifer Crumm

NTR 416 Research Paper

April 23, 2010

Alzheimer’s Disease

Alzheimer’s disease is the most common form of mental illness and dementia

among the elderly. The disease is named for the German physician, Dr. Alois Alzheimer, who

discovered it in 1906 (1). Dr. Alzheimer found what are now considered significant signs of the

disease during the autopsy of a patient who died from an unusual mental illness. Abnormal

clumps, or amyloid plaques, and tangled bundles of fibers, or neurofibrillary tangles, were found

in the elderly patient of Dr. Alzheimer (2). Amyloid plaques clump together which prevents

neurons from functioning properly. This results in communicating, functioning, and repairing

difficulties in the cells (2). Neurofibrillary tangles are formed the tau protein. Tau is normally

found throughout the brain, but when these tangles form they eventually lead to cell death (2). As

the disease progresses, the brain areas that control memory and thinking skills are affected first

by the nerve cells shrinking and ultimately dying. With the disappearance of nerve cells, the

brain itself shrinks and the synapses, or “wrinkles”, of the brain vanish, leaving a smoother

surface (3).

Alzheimer’s disease is progressive and irreversible and advances in stages. Based on the

Alzheimer’s Association website (1), there are seven stages in the progression of Alzheimer’s

disease ranging from normal function or no impairment to very severe cognitive decline where

individuals loose their ability to respond, speak, or control movements. Symptoms emerge in

stage two and the deficiencies in stage three, such as memory loss and impaired concentration

becoming apparent to friends and families, may be measurable in clinical tests. As patients

progress through the stages of Alzheimer’s disease, they begin to display telling signs. The

Alzheimer’s Association website also outlines ten warning signs (1). Along with memory loss,

individuals may become confused about where they are and how they got there. Alzheimer’s
patients often misplace things and have difficulty retracing their steps. A more pronounced and

noticeable signs are significant changes in mood and personality which may begin to affect the

individual’s livelihood. Any expression of these signs should instigate a diagnostic test.

There are four components in the diagnosis of Alzheimer’s disease (4). First, physicians

take a medical history of the patient to review past medical conditions affecting all family

members and a list of the patient’s medications (1). Second, mental status tests are administered

to assess mental function. The mini-mental state exam is the most common test (1). It measures

memory retention, problem-solving abilities, visual and motor coordination, and abstract

thinking. Third, a physical exam and standard laboratory tests are completed to evaluate hearing

and sight, along with blood pressure and heart rate. The final test is a brain-imaging scan. There

are two imaging techniques to evaluate the brain (1). The first is structural imaging which

describes the shape and volume of the brain. Magnetic resonance imaging (MRI) or computed

tomography (CT) are used to evaluate structural imaging. The second is functional imaging

which describes how efficiently different parts of the brain use oxygen and glucose. Positron

emission tomography (PET) and MRI are used to evaluate functional imaging.

An estimated 4.5 million Americans are diagnosed with Alzheimer’s disease (2). The

prevalence of the disease will only increase as the baby-boomer generation continues to age and

as the number of cases steadily increases, so will healthcare costs (2). Pharmaceuticals are the

main treatment for Alzheimer’s disease. These medications are acetylcholinesterase and

glutamate receptor inhibitors. Acetylcholine is the neurotransmitter in the brain responsible for

learning and memory and occurs in lesser amounts in people with Alzheimer’s (1). By blocking

the breakdown of Acetylcholine, these drugs maintain the communication of memory and

learning information between nerve cells. Acetylcholinesterases include Aricept, Exelon, and
Reminyl. When nerve cells are exposed to excessive amounts of glutamate, they become

damaged and die due to glutamate excitotoxicity. The glutamate receptor inhibitor is Namenda.

Recently, study results have suggested that the effects of the ketogenic diet used to reduce

seizures in epilepsy may have protective effects in progressive neurological diseases such as

Alzheimer’s. The purpose of this paper is to examine the ketogenic diet and the purposed

mechanisms induced by ketosis with the potential to inhibit the progression of Alzheimer’s

disease.

Ketogenic diet

The ketogenic diet was developed in the 1920’s after observations that fasting led to the

cessation of seizures (5). During fasting, the body enters a starvation state where body fat is

metabolized and undergoes beta-oxidation. Three ketone bodies, beta-hydroxybutyrate,

acetoacetate and acetate are formed then used as precursors for adenosine triphosphate (ATP)

production (5,6). It is though that the ketogenic diet induces similar metabolic effects of

starvation through a strict, high-fat/low-carbohydrate diet. The ketogenic diet is composed of 80-

90% of calories from fat with the remaining calories coming from protein and a miniscule

amount from carbohydrates (6). A common ratio of fats to proteins and carbohydrates is 4:1:1.

Despite the drastically increased fat intake and insufficient carbohydrate intake, the diet provides

enough protein for proper growth (6). In adults, the primary source of fuel for the brain is

glucose, but when subjected to the metabolic effects of the ketogenic diet, the ketone bodies

cross the blood-brain barrier and are utilized for energy (6). The efficacy of the ketoginc diet as a

treatment for epilepsy is proven and some aspects of the diet are thought to have similar effects

on other neurological diseases.

 With the advancement of research occurring in the field of neurological diseases, studies

have been conducted to examine the effect of the ketogenic diet on Alzheimer’s disease. Of the

studies selected, two predominate trends emerged as potential treatments. The first is a decline in

beta-amyloid (Aβ) peptides found in plaques (7,8,9) and the second is an increase in glutathione

concentration (9).

Decline in beta-amyloid (Aβ) peptides found in plaques

The decline in Aβ can occur in three ways. The first is through the reduction in the

cleavage of the amyloid precursor protein (APP) (7,9). The second way is by the role of

insulin/IGF-1 in regulating beta-amyloid (7). And finally, with the improvement of

mitochondrial efficiency in neurons through an increased reduction-oxidation potential of

NAD+/NADH (8,10). Also, there is evidence that medium-chain triglycerides induce similar

ketosis when compared to a ketogenic diet (8).

Reduction in the cleavage of the amyloid precursor protein (APP)

Two studies found the ketogenic diet to have a neuroprotective effect against the

formation of plaques. The Van der Auwera et al. study (7) examined the effects of high-

fat/reduced-carbohydrate diet on the deposition of Aβ and development of Alzheimer’s. Two

groups of three-month-old female mice with the genetic mutation of APP, which causes the

expression of amyloid plaques as early as three month, were fed either a standard diet of a high-

carbohydrate/low-fat diet or a ketogenic diet. When APP is cleaved it becomes either Aβ40 or

Aβ42, which is more likely to form. One brain hemisphere from each animal was examined for

Aβ40 and 42 levels. Levels of both Aβ were found to be significantly lower in the mice fed the

ketogenic diet (p = 0.016) (7). This suggests that a ketogenic diet either reduces the cleavage of

APP or diminishes Aβ.

 The second study authored by Mohamed et al. (9) examined the metabolic changes and

neuron degeneration and the neuroprotective effects of a ketogenic diet in obese rats. Two

groups of sexually mature, albino rats were designated to two groups when they reached a weight

gain 30% more than their normal body weight. The two groups were fed either a control diet,

which consisted of appropriate macronutrient distribution of calories, or the ketogenic diet, with

0.76% carbohydrates, 8% protein, and 79% from both saturated and unsaturated fat (9). When

the rats where analyzed, there was a significant difference in the downregulation of APP (p <

0.0001) between the control-obese and ketogenic-obese rats which led to a decrease in Aβ in the

ketogenic-fed rats (9). These results are promising because APP may be associated with

apoptosis of neurons attributing to the development of Alzheimer’s disease.

Role of insulin/IGF-1 in regulating beta-amyloid

The Van der Auwera et al. study (7) discusses the second process of Aβ degeneration.

One characteristic of the ketogenic diet is the imitation of starvation, similar to that of caloric

restriction. Both ketogenic diets and caloric restriction work in a similar fashion. Ketogenic diets

decrease insulin signaling and increase fatty acid oxidation. Caloric restriction reduces insulin

and insulin-like growth factors (IGF) as a result of decreased signaling. This affect on insulin is

important in Aβ deposition because decreased insulin/IGF-1 signaling halts protein synthesis and

causes the catabolism of protein which can lead to the elimination of amyloid peptides (7). This

mechanism is promising in the development of Alzheimer’s because the cortex of the brain,

which controls memory and thinking, contains receptors for insulin and IGF-1. With the absence

of the insulin/IGF-1, the development of Aβ is reduced (7).

Improvement of mitochondrial efficiency in neurons through an increased reduction-oxidation

(redox) potential of NAD+/NADH

 Two studies exhibit the final process of Aβ degeneration by the role of NAD+/NADH in

the mitochondria of the brain. The Henderson et al. study (8) administered an oral ketogenic

compound, AC-1202, in 152 subjects diagnosed with mild to moderated Alzheimer’s disease.

The purpose of this study was to examine if ketosis improves cognitive performance. Cognitive

function was measured by the Alzheimer’s Disease Assessment Scal-Cognitive subscale (ADAS-

Cog). Findings showed that AC-1202 elevated ketone bodies in alzheimer’s patients and resulted

in a significant difference in ADAS-Cog scores when compared to the placebo group (8). This

study also discussed the affect of AC-1202 on the mitochondrial function by reducing oxidative

damage. Ketone bodies such as beta-hydroxybutyrate produced during the ketogenic diet have

exhibited protective functions against the toxic effects of Aβ42. Along with the reduction in

glycolysis, increased metabolites from the TCA cycle and increased redox of NAD+/NADH

have increased mitochondrial efficiency (8). Mitochondria are present in very active cells and

considering the extreme activity of the brain, this mechanism is crucial in developing a treatment

for Alzheimer’s disease.

The Henderson et al. study is supported by the study conducted by Maalouf et al study

(10), which sought to examine the effect of the ketones and beta-hydroxybutyrate and

acetoacetate on dissociated rat’s neurons that have been exposed to glutamate excitotoxicity, or

the damage and death of neurons caused by glutamate (10). Results indicated ketones

significantly decrease (p < 0.01) mitochondrial excitotoxic changes by increasing NAD oxidation

(10). This mechanism is particularly important because the NAD+/NADH redox reaction is an

integral step in the electron transport chain, which occurs in the mitochondria and ultimately

produces ATP.

Medium-chain triglycerides inducing ketosis

 As Alzheimer’s disease progresses, a shift occurs towards preferring sweet, carbohydrate-

rich foods which may make complying with a strict, low-carbohydrate diet extremely difficult

(8). Researchers from the Henderson et al. study took advantage of the ability of medium-chain

triglycerides (MCT) to induce ketosis without restricting the diet. They achieved this through the

oral ketogenic compound AC-1202. Medium-chain triglycerides are 6 to 12 carbons long. One of

the most common medium chain fatty acids is the eight carbon caprylic acid, which is also found

in AC-1202 (8,11). The mechanism by which medium-chain triglycerides induce ketosis remains

unclear. MCT does not go through the normal digestion and absorption of long-chain fatty acids.

Instead, they are directly absorbed into the blood stream from the small intestine and are

transported to the liver where they are oxidized (10,11). This oxidation elevates acetyl CoA thus

increasing ketone bodies which, in rapid oxidation, lead to ketosis (10).

Increase in glutathione concentration

The second potential treatment for Alzheimer’s disease is an increase in glutathione

concentration. Glutathione (GSH) is the brain’s major antioxidant and plays an important

protective role in the brain (12). Free radicals, leading to oxidative damage, are known to be a

primary cause of degenerative disease like Alzheimer’s disease. When amyloid plaques develop

in the brain, the production of free radicals increases and oxidative damage occurs. This is where

the protective power of GSH comes into play. Precursors to GSH can prevent death of brain cells

by amyloid plaques (12). The Mohamed et al. study (9) discussed this activity of GSH activity

with a ketogenic diet. It has been demonstrated that a ketogenic diet increases the activity of

glutathione peroxidase, a main protective component in oxidative damage. Additionally, a

ketogenic diet plays a role in the synthesis of GSH by increasing the activity of glutamate

cysteine ligase, the rate-limiting step (9).

Conclusion

Currently, there is no cure for Alzheimer’s disease. However, advancements in research

generate promising results providing potential treatments to slow or even the halt the progression

of Alzheimer’s. Pharmaceuticals have been the popular treatment option for many years but with

increasing healthcare costs, alternative, often cheaper, treatment options are becoming the first

choice for patients. As arduous as a ketogenic diet may be, there is no denying the power of its

metabolic effects as a potential treatment option. Further research is required to fully understand

the mechanism by which a high-fat/low-carbohydrate diet and its resulting ketosis decreases the

formation of Aβ plaques and increases glutathione concentration, but it is certain that a ketogenic

diet will soon be the prescribed treatment for more than just epilepsy.
References

1) Alzheimer’s disease. Alzheimer’s Association website. 2010. Available at:

http://www.alz.org/alzheimers_disease_alzheimers_disease.asp. Accessed April 20, 2010.

2) *Neurological diseases: Dementia*. In. Nelms M, Sucher K. Long S. Nutrition Therapy

and Pathophysiology, 1st Edition. Brooks Cole: *State*; 2007:*pages*

3) Alzheimer’s disease fact sheet. U.S. National Institutes of Health- National Institute on

Aging website. 2010. Available at:

http://www.nia.nih.gov/Alzheimers/Publications/adfact.htm. Accessed April 20, 2010.

4) Understanding Alzheimer’s disease. Fisher Center for Alzheimer’s Research Foundation

website. 2010. Available at: http://www.alzinfo.org/understanding-alzheimers-

disease.asp. Accessed April 20, 2010.

5) Barañano K, Hartman A. The ketogenic diet: uses in epilepsy and other neurologic

illnesses. Current Treatment Options in Neurology. 2008;10:410-419. Available at:

http://www.springerlink.com/content/a623043470841350/fulltext.pdf. Accessed April 18,

2010.

6) Gasior M, Rogawski M, Hartman A. Neuroprotective and disease-modifying effects on

the ketogenic diet. Behav Pharmacol. 2006;17:431-439. Available at:

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2367001/pdf/nihms42857.pdf. Accessed

April 18, 2010.

7) Van der Auwera I, Wera S, Van Leuven F, Henderson S. A ketogenic diet reduces

amyloid beta 40 and 42 in a mouse model of Alzheimer’s disease. Nutr Metab (Lond).

2005;2:27. Available at: http://www.nutritionandmetabolism.com/content/pdf/1743-

7075-2-28.pdf. Accessed April 18, 2010.

8) Henderson S, Vogel J, Barr L, Garvin F, Jones J, Costantini L. Study of the ketogenic

agent AC-1202 in mild to moderate Alzheimer’s disease: a randomized, double-blind,

placebo-controlled, multicenter trial. Nutr Metab (Lond). 2009;6:31. Available at:

http://www.nutritionandmetabolism.com/content/pdf/1743-7075-6-31.pdf. Accessed

April 18, 2010.

9) Mohamed H, El-Swefy S, Rashed L, Abd El-Latif S. Biochemical effect of a ketogenic

diet on the brains of obese adult rats. J Clin Neurosci. 2010:[Epub ahead of print].

Available at: http://www.sciencedirect.com/science?_ob=ArticleURL&_udi=B6WHP-

4YVG81T-

2&_user=422010&_coverDate=04/14/2010&_rdoc=1&_fmt=high&_orig=search&_sort=

d&_docanchor=&view=c&_acct=C000019958&_version=1&_urlVersion=0&_userid=4

22010&md5=57b6c64a0bb26e4fdacf63fa30ecf5fe. Accessed April 18, 2010.

10) Maalouf M, Sullivan P, Davis L, Kim D, Rho J. Ketones inhibit mitochondrial production

of reactive oxygen species production following glutamate excitotoxicity by increase

NADH oxidation. Neuroscience. 2007;145:256-64. Available at:

http://www.sciencedirect.com/science?_ob=ArticleURL&_udi=B6T0F-4MVDVSC-

1&_user=422010&_coverDate=03/02/2007&_rdoc=1&_fmt=high&_orig=search&_sort=

d&_docanchor=&view=c&_acct=C000019958&_version=1&_urlVersion=0&_userid=4

22010&md5=4d41f172826e4ae0401cd0204b77eb24. Accessed April 19, 2010.

11) *Medium-chain triglycerides*. In. Nelms M, Sucher K. Long S. Nutrition Therapy and

Pathophysiology, 1st Edition. Brooks Cole: *State*; 2007:*pages*

12) Hareyan A. Glutathione- your brain’s master antioxidant defense. EmaxHealth website.

2004. Available at: http://www.emaxhealth.com/39/394.html. Accessed April 21, 2010.