Alzheimer's disease (AD) is one of the most researched ailments in the world of medicine. This discussion will explore the working hypothesis that caloric restriction may prevent Alzheimer's disease. In addition, the paper will explore the idea that individuals with the ApoE genotype and a higher intake of calories have a higher risk of AD than those who do not carry the apoE4 allele (diet-gene interaction). Let's begin the discussion by examining the genetics of AD. Genetics of AD - specifically the mechanism of apoE in AD

Alzheimer's Disease is a form of dementia that is marked by the loss of mental ability and various cognitive functions. The disease usually occurs in old age and is not detectable at birth. (Robinson) There is no consensus on the cause of AD but researchers have found a genetic link in the development of the disorder. The Gale Encyclopedia of Medicine explains that there are various genes that are implicated in AD. One such gene is amyloid precursor protein (APP), which creates amlyloid. When there are mutations in this gene the result is often the early onset of Alzheimer's disease. It is also reported that most individuals that have Down syndrome also develop AD. (Robinson)

The most substantial genetic link is ApoE, which is found on chromosome 19. The encyclopedia explains, gene on this chromosome, called apoE, codes for a protein involved in transporting lipids into neurons. ApoE occurs in at least three forms, called apoE2, apoE3, and apoE4. Each person inherits one apoE from each parent, and therefore can either have one copy of two different forms, or two copies of one. Compared to those without ApoE4, people with one copy are about three times as likely to develop late-onset AD, and those with two copies are almost four times as likely to do so. Despite this important link, not everyone with apoE4 develops AD, and people without it can still have the disease. Why apoE4 increases the chances of developing AD is not known. (Robinson)

Why did the caloric restriction/AD hypothesis originate

Studies concerning the impact of the diet on aging and various diseases have existed for decades. Researchers found that certain foods and caloric intake can accelerate the aging process. In addition, various studies that have been conducted concerning Caloric Restriction have concluded that CR can have very positive impacts on the body. An article entitled Less Calories More Life explains,

Only one intervention has been proven to extend both the average and maximum lifespan of all animal species tested: reducing the consumption of dietary calories, or caloric restriction (CR). While widely recommended, exercise and nutritional supplementation have not been shown to extend maximum lifespan. Because CR extends maximum lifespan, scientists believe it actually slows the process of aging. CR is therefore used as a means to study the process of aging." (Goddard)

In the early 90's scientists began to correlate caloric intake with increased occurrences of Alzheimer's disease. More recently, a comprehensive study at the Taub Institute for Research of Alzheimer's Disease and the aging brain at Columbia University found compelling evidence to support this hypothesis. The study, which will be discussed more thoroughly in the latter portion of this paper, asserts that caloric intake is directly correlated to AD.

How does caloric restriction relate to the risk of AD (i.e. mechanism hypothesized)?

An article entitled "Dietary Links to Alzheimer's Disease" provides details pertaining to the impact of caloric restriction and caloric intake on AD. The article explains, statistical findings indicate that fat and total caloric supply is highly associated with both incidence and prevalence of AD, it is interesting to examine the literature on the effects of both fat and high caloric consumption on body chemistry. First, both fat and high total-caloric consumption leads to the presence of more free radicals in the body. Fat easily oxidizes to generate free radicals, and free radicals are a natural by product of nutrient processing in the mitochondria. While a certain amount of free radicals are useful in the body, too many, such as found in a high-fat, high-caloric-consumption diet, are harmful, since they lead to more rapid aging."(Grant)

The article also explains that when individual consume diets that create an acidic digestive system can cause the body to loose base cations such as; calcium, potassium and magnesium. (Grant)

The author explains that diets that are high in protein can cause a lack of calcium in the bones. Additionally, diets that are high in fats, proteins, and simple carbohydrates are generally low in fresh fruits and vegetable. (Grant)

Fresh fruits and vegetables are high in vitamin C, selium and minerals. A study conducted by Salonen in 1988 found a negative correlation between blood pressure and serum antioxidants vitamin sC and selenium, damage done to the body by high blood pressure can lead to the development of AD in old age. The article concludes that,

The primary criteria for causality are listed and evaluated for high-fat-, high-total-caloric-consumption diets as the primary cause of sporadic AD and SD. By...

(Poirier et al.) As we have already reported caloric intakes that are high in fat and protein often cause the depletion of vital antioxidants. This coupled with a defect ApoE gene on the 19th chromosome increases an individuals risk for developing AD.
Another study published by the National Academy of Sciences explains that,

In the brain, apoE is expressed mainly in glial cells, and it is thought to be implicated in neuronal regeneration. Although the allele of apoE isoform 4 http://www.pubmedcentral.gov/corehtml/pmc/pmcents/epsiv.gif

4) is strongly associated with late-onset familial and sporadic Alzheimer's disease (AD), the role of apoE in the pathogenesis of AD is still unclear. The presence of apoE in amyloid plaques, the positive correlation between amyloid burden and the frequency of http://www.pubmedcentral.gov/corehtml/pmc/pmcents/epsiv.gif

4, and the in vitro binding of apoE to the amyloid ?-peptide (A?), the major component of AD amyloid, strongly suggest that apoE influences the rate of cerebral amyloidogenesis." (Russo et al.)

Review of animal and epidemiologic studies that support/refute hypothesis and additional comments on limitations of the studies reviewed.

The most recent study of the impact of caloric restriction on Alzheimer's, took place at the Taub Institute for Research of Alzheimer's Disease and the aging brain at Columbia University. The study examined 980 dementia-free people over the age of 65 who were members of a long-term aging project. (Smith) The article explains that,

Scientists divided people with the gene into four groups based on caloric consumption, and found that those with the highest caloric intake were 2.3 times as likely to develop Alzheimer's as those with the lowest. They found no correlation, however, between caloric consumption and dementia in those without the gene." (Smith)

Additionally, "The hazard ratios of AD for the highest quartiles of calorie and fat intake compared with the lowest quartiles in individuals without the apolipoprotein E. epsilon4 allele were close to 1 and were not statistically significant (P =.83 and P =.61, respectively) Higher intake of calories and fats may be associated with higher risk of AD in individuals carrying the apolipoprotein E. epsilon4 allele." (Luchsinger et al.) The researchers concluded that caloric restriction may decrease the death of nerve cells and promote the production of nerve protecting factors. The limit of this study is that it only examines the impact of caloric restriction on individuals that were over 65. The study does not examine whether or not the incidences of AD are reduced further if caloric reduction is practiced at an earlier age. In addition, it does not examine whether or not caloric restriction has an impact on those that are already suffering from dementia.

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