The Doctor's Corner

NUTRITION AND ALZHEIMER'S DISEASE

by John W. Crayton, MD, Professor of Psychiatry at Loyola University Medical School, Maywood, Illinois, Research Scientist, Biological Psychiatry Laboratories, Hines Veterans Administration Hospital, Hines, Illinois, and Member of the NOHA Professional Advisory Board.

It is a well-known fact that reduced amounts of certain dietary nutrients are associated with memory loss and other thinking problems-especially in older individuals. (For a detailed review, see Solfrizzi, Panza, and Capurso, 2003) And reduced levels of vitamins C and E have been associated with increased severity of Alzheimer's Disease (AD). High intake of cholesterol and saturated fats is also associated with an increased risk of Alzheimer's Disease.

A variety of epidemiological studies have suggested that certain substances regulated at least in part by diet, may be predisposing factors for Alzheimer's Disease. For example, elevated cholesterol levels, which can be lowered by diet, have been shown to be a risk factor for AD.

Vitamin E is an effective anti-oxidant substance. Particularly in the form of d-alpha tocopherol (a form that readily passes into the brain), it has been shown to slow the progression of Alzheimer's Disease in a group of moderately severely impaired individuals. (Sano, et al., 1997) However, based on a careful review of the various functions of the available anti-oxidant substances, Prasad has suggested that using several vitamins for AD prevention and treatment is the most rational approach. He suggests a regimen of vitamin A (retinyl palmitate, 5000 I.U./day), natural beta-carotene (15 mg/day), vitamin E (d-alpha tocopherol succinate, 100 I.U./day, vitamin C (calcium ascorbate, 500 mg/day), vitamin D (400 I.U./day), B-vitamin doses twofold to threefold higher than RDA values, selenium (100 mcg/day), chromium (50 mcg/day) and zinc (15 mg/day).

How does nutrition affect the brain?
There is still considerable work to be done into how these dietary changes are related to the development of AD. One of the most exciting current theories of the cause of Alzheimer's Disease is that it is due to a faulty bodily response to "oxidative stress." Oxidative stress refers to a class of metabolic responses of cells in the body which produce highly toxic "free radicals" such as elemental, highly reactive oxygen, which, in the presence of metals such as copper and iron, produce substances called "superoxides" and "hydroxyl radicals" which, in turn, cause a wide variety of tissue-damaging effects. Brains from Alzheimer's Disease patients show increases in a substance called amyloid-beta peptide. This substance has been associated with increased concentrations of free radicals. Once formed, free radicals can inflict a wide variety of injuries to the brain. For example, the brain's phospholipids, critical elements in the structure and function of the brain, are readily damaged by free radicals. [See the immediately preceding article in this NOHA NEWS by Professor Crawford, describing the highly unsaturated fatty acids-arachidonic and docosahexaenoic acids-used in the brain. These are most susceptible to oxidation. Eds.] It is easy to imagine how damage to the brain's phospholipids could lead to the progressive memory problems in someone with Alzheimer's Disease.
The process by which free radical oxygen destroys brain tissue has been compared to a forest fire (McCaddon, A, Hudson, P, et al., 2003):

Hydroxyl radicals react readily with membrane lipids, generating lipid peroxides and peroxyl radicals. These kindle a chain reaction of lipid peroxidation that propagates through surrounding membranes like a spreading forest fire. This process of partial combustion has been elegantly described as a "simmering biological fire of oxy-radical-based pathology." (Cohen, 1994)

Interestingly, copper and zinc, although they are normal constituents of brain, may play a role in this free radical-induced damage in AD. (e.g. Bush, et al., 2003) While the roles of these two metals are complex, and may be both protective as well as damaging, there is evidence that regulating these substances may provide an effective treatment for AD. A chelating agent, that is, a substance that binds and de-activates copper and zinc, called chloroquinol, has been shown to reduce the deposition of abnormal proteins in the brains of mice with a genetic predisposition to developing these proteins. (For a detailed review of this approach, see Cuajungco and Fagét, 2003)

What are metallothioneins and what do they do?
Another system involved in the regulation of copper, zinc, iron, and other metals is the metallothionein family of proteins. These substances, which occur in several forms, have a variety of functions in the brain. Much interest in the area of Alzheimer's Disease studies has focused on the metallothionein called MT-3, which, unlike other species of metallothioneins, occurs only in the brain.

One of the most important functions of the metallothioneins is to detoxify heavy metals in the brain. The "heavy metals" include cadmium, lead, zinc, cobalt, mercury, and copper. When excess amounts of one of these metals build up in the brain, the body's metabolic machinery goes into high-speed production of extra metallothionein. Of particular interest, is the observation that in experimental copper poisoning, markedly increased amounts of metallothionein have been found in precisely the same areas of the brain where the copper excesses occur. A direct experimental approach to demonstrating the effects of copper on brain function is the study by Sparks and Schreurs (2003) in which rabbits given a diet rich in cholesterol plus trace amounts of copper showed behavioral and neuropathological evidence of developing a form of dementia similar to AD.

. . . metallothioneins have a significant role to play in the normal regulation of the heavy metals like zinc and copper, and are not just involved in clearly toxic conditions.

The function of the metallothioneins in heavy metal toxicity appears to involve a "scavenger" role, whereby the metallothionein attaches itself to the toxic metal and renders it harmless. Experimental animals with higher concentrations of metallothioneins are more resistant to the effects of toxic doses of heavy metals, suggesting that the regulation of metallothionein levels in the body may prove to be an important aspect of the body's resistance to heavy metal toxins.

But while mercury, lead, and cadmium are extremely toxic foreign agents that do not belong in the body, zinc and copper are normal and essential components of a healthy body. So it is important to point out that metallothioneins have a significant role to play in the normal regulation of the heavy metals like zinc and copper, and are not just involved in clearly toxic conditions. Consequently, our bodies rely, on a day-to-day basis, on the metallothioneins to maintain proper amounts of zinc and copper.

In animals having a condition called "experimental autoimmue encephalomyelitis," which has many similarities to human multiple sclerosis, the injection of metallothioneins caused a significant improvement in their symptoms. Findings such as this raise the hope that therapeutic interventions that enhance the ability of metallothioneins to do their detoxification work, will prove beneficial to human disorders such as Alzheimer's Disease and multiple sclerosis.

Enhancing metallothionein activity: Nutritional approaches.
The available data from the medical literature supports the possibility that metallothionein efficacy may be enhanced via nutritional means.

NOHA Professional Advisory Board Member William Walsh, PhD, Director of the Health Research Institute and Pfeiffer Treatment Center in Warrenville, IL, has proposed that a carefully-selected formulation consisting of several agents known to enhance metallothionein activity will be effective in the treatment-and perhaps prevention-of AD. This novel approach to the clinical management of this crippling disorder opens up an entirely new area of clinical study of this condition. Patients with AD are currently being accepted into a program designed to assess the efficacy of this new approach. Individuals who have been diagnosed with AD or suspect that they may be developing it, may contact the Pfeiffer Treatment Center for more information about this study and, if interested, obtain application forms for the study.
Website: www.hriptc.org
Phone: (630) 505-0300
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Bush, A.L., Masters, C.L., Tanzi, R.E., "Copper, beta-amyloid, and Alzheimer's Disease: tapping a sensitive connection," Proceedings of the National Academy of Sciences, 100: 11193-94, 2003.

Cohen, G., "The brain on fire?" Annals of Neurology, 36: 333-4, 1994.

Cuajungco, M.P., Fagét, K.Y., "Zinc takes the center stage: its paradoxical role in Alzheimer's disease," Brain Research Reviews, 41: 44-56, 2003. Hidalgo, J., Aschner, M., Zatta P., and Vašák(space?) M., "Roles of the metallothionein family of proteins in the central nervous system," Brain Research Bulletin, 55: 133-45, 2001.

Marx, J., "Neuroscience. Possible role for environmental copper in Alzheimer's Disease," Science, 301: 905, 2003.
McCaddon, A., Hudson, P., Hill, D., et al., "Alzheimer's Disease and total plasma aminothiols," Biological Psychiatry, 53: 254-60, 2003.

Pappolla, M.A., Smith, M.A., Bryant-Thomas, T., Bazan, N., Petanceska, S., et al., "Cholesterol, oxidative stress, and Alzheimer's Disease: Expanding the horizons of pathogenesis," Free Radical Biology and Medicine, 33: 173-81, 2002.

Prasad, K.N., Cole, W.C., and Prasad, K.C., "Risk factors for Alzheimer's Disease: Role of multiple antioxidants, non-steroidal anti-inflammatory and cholinergic agents alone or in combination in prevention and treatment," Journal of the American College of Nutrition, 21: 506-22, 2002.

Sano, M., Ernesto, C., Thomas, R.G., Klauber, M.R., et al., "A controlled trial of selegiline, alpha-tocopherol, or both as treatment for Alzheimer's disease. The Alzheimer's Disease Cooperative Study," New England Journal of Medicine, 336:1216-22, 1997.

Solfrizzi, V., Panza, F., Capurso A.,
"The role of diet in cognitive decline," Journal of Neural Transmission, 110: 95-110, 2003.

Sparks, D.L., Schreurs, B.G., "Trace amounts of copper in water induce beta-amyloid plaques and learning deficits in a rabbit model of Alzheimer's disease," Proceedings of the National Academy of Sciences, 100: 11065-9, 2003.

Article from NOHA NEWS, Vol. XXIX, No. 2, Spring 2004, pages 5-6.