Alzheimer’s Disease: Part IV-Alternative Treatments

(10/20/08) A multicenter, randomized, double-blind clinical trial of high dose folate, vitamin B6 and vitamin B12 supplementation in 409 individuals with mild to moderate Alzheimer's Disease and normal folic acid, vitamin B12, and homocysteine levels was conducted between 2/20/03 and 12/15/06, at clinical research sites of the Alzheimer's Disease cooperative Study located throughout the United States.

This study and an editorial accompanying this study appeared in the Journal of the American Medical Association. Quoting from the editorial, "Until and unless new data suggest otherwise, there is insufficient evidence to justify routine use of homocysteine-lowering vitamin supplements for the prevention of Alzheimer disease and cognitive decline among individuals with normal vitamin status." (JAMA. 2008;300(15):1774-1783; JAMA. 2008;300(15):1819-1821)

(5/5/06)- A small study that was conducted at the Columbia University Medical Center in New York concluded that a Mediterranean-style diet helped protect against Alzheimer's disease, while at the same time cutting the risk of heart disease. Nikolaos Scarmeas was the lead author of the study. The results were published online by the Annals of Neurology.

The diet included eating lots of vegetables, legumes, fruits, cereals and fish, while limiting meat and dairy products, drinking moderate amounts of alcohol and emphasizing monounsaturated fats, such as in olive oil. The study involved 2,258 elderly residents of northern Manhattan whose dietary habits were followed for an average of four years.

The eating habits of the participants were detailed and then the participants were evaluated every 18 months for signs of dementia. None of the participants showed any signs of dementia at the start of the trial, but by the end of the study, 262 had developed Alzheimer's disease.

Researchers gave each participant a score of zero to nine on a scale that measured how closely they followed the Mediterranean diet. Those participants with the highest scores of adherence to the Mediterranean diet had about a 40% less risk of developing Alzheimer's disease.

(7/30/03)- The Alzheimer's Association and the Intel Corporation announced that they were forming a research consortium to explore the application of computer technologies and sensor networks to the care of patients with early and advanced cases of AD. According to statistics from the association one in 10 older Americans, and nearly half of those older than 65 now have AD.

The consortium hopes to develop existing and future computer-related devices that would be modified to permit Alzheimer's patients to live independently for longer periods. In addition the consortium hopes to develop elaborate monitoring networks that might help reduce the burden of caring for patients with advanced cases of the disease.

The project will be called Everyday Technologies for Alzheimer's Care and it will be funded with more than $1 million in research to develop systems for Alzheimer's care in the home. The Alzheimer's Association will manage the project, which as a starter hopes to develop affordable systems that can delay the effects of the disabling symptoms. One experimental device is the placing of a tiny radio transmitter in shoes to help track the wandering of an AD patient.

On May 3^rd1999, Joe Adcock, the power hitter for the Milwaukee Braves in the 1950’s died. He had Alzheimer’s disease. Joe Adcock, was part of the team that included Hank Aaron and Eddie Mathews and was credited with hitting some of the longest homers in the history of the game. He hit a 475 foot drive in the Polo Grounds off Jim Hearn on April 23, 1953. He hit a homer in Ebbets field that cleared the 83 foot-high roof above the 385-foot mark on June 17, 1956. He holds the major league record for total bases in a single game, which is 18, when he hit four home runs and a double against the Brooklyn Dodgers on July 31, 1962. We dedicate part IV of this series of articles on Alzheimer’s disease to Joe Adcock, a "ballplayer's ballplayer".

A "treatment program" for disease involves two potential avenues of approach: prevention of disease and/or treatment of the disease. The former is the ideal, since it eradicates the disease. Examples of this approach include polio and smallpox vaccination. This article will explore potential treatment ideas that could prevent or delay the start of Alzheimer’s disease.

In reading this article, be aware that no one has found a way to prevent the occurrence of this disease. Any treatment that has been developed to date only slows down the progressive nature of Alzheimer’s disease. In fact, there are those researchers who postulate the inevitable occurrence of this disorder as we survive to older ages. They feel the beginning of the disease is the result of the "dents and bruises" cells in the body experience in a lifetime. This sets off a cascade of neurophysiological and neurohormonal processes effecting the endosomal and lysosomal systems of a cell, and the entorhinal complex architecture of the brain, which eventually results in Alzheimer’s Disease. (Source of this information is a grand rounds lecture at Mount Sinai Medical Center.)

According to a study done at Boston University and Tufts University, people with high blood levels of a normal diet byproduct, homocysteine, have twice the average risk of developing Alzheimer's disease. Homcysteine is as amino acid, involved in the evolution of proteins. Its levels can rise when people eat too few fruits or leafy vegetables. Fruits and vegetables are essentials in providing vitamin B to the human body system.

Although the study found a strong link between homocysteine and dementia, it did not prove that the substance actually causes dementia. The study involved 1,092 people from 68 to 97 who were initially healthy and free of dementia. Their homocysteine levels were measured and their health was monitored for eight years. By the year 2000 111 had dementia, including 83 with Alzheimer's disease.

Subjects, whose homocysteine levels were higher than 14 micromoles per liter of blood, had nearly twice the Alzheimer's risk of those with lower levels. A level below 9 is considered "normal". The researchers concluded that more research has to be done to see whether or not the high homocysteine level is one of " cause or affect" with Alzheimer's.

The preventive techniques cited in this article have not been proven in robust scientific inquiry, but theoretically have heuristic value and in limited studies have evidenced delay in the onset of the disorder and its debilitating effect on cognitive functioning of the individual.. This article will not discuss the cholinesterase inhibitors (Tacrine (24), Aricept (37), Exelon (2) & Metrifonate (5)) which have been approved or awaiting approval by FDA. (See Alzheimer's Disease-Part II,). These medications appear to have "moderate" cognitive symptom help in the sense of delaying the downward slope of the cognitive process in certain individuals i.e. a proportion of caretakers report "a little" improvement in cognitive functioning;and takes longer for severe symptoms to show itself. New medications in the drug companies research and development programs may prove more helpful. Only time will tell.

This article will deal with products usually marketed as dietary supplements and are supposed to not have a "significant or unreasonable risk of illness or injury" under the Dietary Supplements Health and Education Act of 1994. No outcome studies have been done which combines these various treatments.

The following chart is based on a review article by Brian R. Ott, MD & Norma J. Owens, PharmD in the Journal of Geriatric Psychiatry and Neurology, Vol. 11, Winter 1998. It is presented in table form for easy referral. It will be followed by a bibliography of pertinent primary research articles for more details on the alternative treatments and results indicated in the chart. Again, none of these treatments are proven, but they may hold promise in the treatment of a disease that afflicts 4 million individuals in our society and whose numbers will increase as the baby boomers reach 65 years and older. For further information on each type of treatment, we suggest you look at the primary source cited.

Type of Treatment	Proposed Mechanism of Action	Pertinent Remarks on Treatment
Diet	Fat involved in oxidative stress and inflammation (17)	AD prevalence lower in countries where fat and caloric content was lower (17) Dietary fat intake associated with risk of developing dementia (21) High intake of linoleic acid (an n-6 polyunsaturated fatty acid), found in margarine, butter and other dairy products, positively associated with cognitive impairment (21)
Wine	Positive effects on vascular disease (22) Wine has flavonoids which have potent antioxidant effects. (22)	Alcoholism associated with traumatically induced dementia (18) Moderate wine consumption (3 to 4 glasses per day) inversely related to incidence of dementia. (30)
Vitamins
Vitamin B-1	Vitamin B-1 enzymes activity decreased in brains of person with AD (16) Involved in cholinergic neurotransmission at both pre-and postsynaptic junctions (12)	Studies indicate that best dosage varies from 4 to 8 grams. (28) Side effects are minor but include nausea and indigestion (28)
Vitamin B-12	Deficiency cause wide variety of neuropsychiatric disturbances (1)	Research studies are conflicting (3)
Ascorbic Acid (Vit. C) & Beta-carotene	In general, antioxidants work as restorative and preventative agents in AD (35)	Recent (1998) study found that plasma levels of ascorbic acid, beta carotene and Vit. E were not associated with risk of developing AD during a follow-up period of 10 years. (9)
Alpha-Tocopherol (Vit. E)	Antioxidant properties (41)	See Sano study, Alzheimer Disease: Part II, reported on this web site which indicated that the placebo group reached severe level of AD 6 months earlier than group taking Alpha-Tocopherol (1000 IU daily) and Selegiline (10 mg.) (39) Some increase in falls and syncope in treatment group. (39)
Other Metabolic Agents
Acetyl-l-Carnitine	Important in oxidative brain metabolism due to its scavenger ability for free radicals (36)	Two grams daily in a 1991 study indicated the treatment group declined at a slower rate than the placebo group on tests of cognition. (41) Minor side effects include body odor, increased appetite and rash. (43)
Choline & Lecithin	Used to augment cholinergic neurotransmission (33)	Studies have failed to show improvements in cognition or function (13)
Dimethyl- aminoethanol (DMAE)	Precursor of choline and supposed to improve neurological function through a nonspecific stimulation effect (15)	Side effects include insomnia, anxiety, drowsiness, headaches, confusion and muscle cramps (15) A number of studies have found no benefits for DMAE on tests of cognitive functioning (27)
Phosphatidifserine	A membrane modifying agent , maintains membrane fluidity, enhances acetylcholine function (19)	Earlier studies that showed memory improvement were not corroborated by subsequent studies. (19)
Coenzyme Q10 (Ubiquinone)	An active mitochondrial component of the electron transport chain involved in cellular metabolism (6) Has antioxidant properties (6) Protects against glutamate-induced excitotoxicity. (14 ) Sustains Vit. E’s antioxidant effect (6 )	Used in Japan to combat diseases of aging. (6) One of the most costly of the nutritional supplements (6) Side effects include gastric discomfort, loss of appetite, nausea and diarrhea.(6)
Herbs
Ginkgo Biloba	Antioxidant function plus inhibits platelet-activating factor and may also act as a vasodilator (25) In vivo studies indicated it has positive effects on cholinergic transmission, increasing rate of acetylcholine turnover. (23)	Herbal treatment most widely used for treatment of AD (See: Alzheimer’s Disease part III) (20) Side effects mild: gastrointestinal complaints, headaches and allergic skin reactions (29) Should be used cautiously by those taking anticoagulant drugs. (23)
Ginseng	Induces release of adrenocorticotropic hormones (29) Stimulates nerve growth factor (29) Exerts estrogen-like activity (29)	Used in Orient as a health tonic to relieve fatigue, diabetes, menopausal symptoms and various disorders of aging. (46) Some antiinflammatory effects (29) Raises high density lipoproteins (HDL) (29) Side effects include insomnia, hypertension, diarrhea, rash, anxiety and confusion (10) Dosages in studies vary from 0.15 to 3 grams (40) Contraindicated in individuals with asthma, emphysema, fibrocystic breasts, hypertension, clotting disorders, cardiac arrhythmias and in pregnant or lactating women (29)
Hormones
Neurosteroids: Pregnenelone Progesterone	Increases survival of neurons and glial cells (4) Modulate neurotransmission at the cellular membrane level (4)	Patients with cancer should avoid its use (4) No controlled studies on humans
Dehydroepiandrosterone (DHEA)	May have a role in amyloid precursor protein metabolism implicated in AD development (11) May enhance neuronal and glial survival (26)	DHEA declines with age in humans (42) Side effects include acne, hair growth, hirsuitism, low energy, irritability, insomnia, headache, menstral irregularity, increased ocular pressure and tachycardia (45)
Melatonin	Levels decrease with age suggesting that a deficient hormone state may play a role in sleep disturbance in AD (8) Crosses blood-brain barrier and is a potent free-radical scavenger neutralizing both oxygen-derived and carbon-centered free radicals. (32) Inhibits progressive formation of beta-sheets and amyloid fibrils by interacting with amyloid beta protein (31) Potentiates nerve growth factor, facilitating the growth of neuronal cells as well as regulating the metabolism of beta amyloid precursor protein (34)	No clinical trial has been published to test the efficacy of Melatonin in AD (8) Amount of Melatonin is variable in marketed products (8) Large doses may reduce fertility (8) High doses at night may cause drowsiness, confusion and headaches in the morning (8)

2. Anand R, Gharabawi G. Clinical development of Exelon (ENA-713). The ADENA programme. J Drug Dev Clin Prac. 1996;8:117-122

3.Basun H, Fratiglioni L, Winblad B. Cobalamin levels are not reduced in Alzheimer’s disease: results from a population based study. J Am Geriatr Soc 1994; 42:132-136.

4. Baulieu EE. Neurosteroids: of the nervous system, by the nervous system, for the nervous system. Recent Prog Horm Res 1997; 52:1-32.

5. Becker RE, Colliver J, Elble R, et al. Effects of metrifonate: A long acting cholinesterase inhibitor. Drug Dev Res. 1990; 19:425-434.

6. Beyer RE. An analysis of the role of coenzyme Q in free radical generation and as an antioxidant. Biochem Cell Biol 1992; 70:390-403.

7. Breitner JCS. Inflammatory process and anti-inflammatory drugs in Alzheimer’s disease: A current appraisal. Neurobiol Aging. 1996;17:789-794.

9. Chen CL, Muller DC, Andres R, et al. A prospective study of plasma levels of alpha-tocopherol (vitamin E), beta-carotine, and ascorbic acid in the Baltimore Longitudinal Study of Aging. Neurology 1998; 50(suppl): A231-A232.

10. Chong SKF, Oberholzer VG. Ginseng—is there a use in clinical medicine? Postgrad Med 1998; 64:841-846.

11. Danenboerg HD, Haring R, Fisher A, et al. Deydroepiandrosterone increases production and release of Alzheimer’s amyloid precursor protein. Life Sci 1996; 59:1651-1657.

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14. Favit A, Nicoletti F, Scapagnini U, Canonico PL. Ubiquinone protects against spontaneous excitotoxin-induced degeneration. J Cereb Blood Flow Metab 1992; 12:638-645.

15. Fisman M, Mersky H, Helmes E. Double-blind trial of 2-dimethylaminoethanol in Alzheimer’s disease. Am J Psychiatry 1981; 138:970-972.

16. Gibson GE, Sheu KFR, Blass JP. Et al. Reduced activities of thiamine-dependent enzymes in the brains and peripheral tissues of patients with Alzheimer’s disease. Arch Neurol 1988; 45:836-840

17. Grant WB. Dietary links to Alzheimer’s disease. Alz Dis Rev 1997;2:42-55.

18. Graves AB, van Duijin M, Centra V, et al. Alcohol and tobacco consumption as risk factors for Alzheimer’s disease: a collaborative re-analysis of case-control studies. Int J Epidemiol. 1991;20(suppl 2):S48-S57.

19. Heiss WD, Kessler J, Mielke R, et al. Long-term effects of phosphatidylserine, pyritinol and cognitive training in Alzheimer’s disease: a neuropsychological, EEG, and PET investigation. Dementia 1994; 5:88-98.

20. Itil T, Martorano D. Natural substances in psychiatry (Ginkgo biloba in dementia). Psychopharmacol 1995; 31:147-158.

21. Kalmijn S, Feskins EJM, Launer LJ, Kromhout D. Polysaturated fatty acids, antioxidants and cognitive function in very old men. Am J Epidemiol. 1997; 145:33-41.

22. Klatsky AL, Armstrong MA, Friedman GD. Red wine, white wine, liquor, beer, and risk for coronary artery disease hospitalization.. Am J Cardiol. 1997;80:416-420.

24. Knapp MJ, Knopman DS, Solomon PR, et al. A 30-week randomized controlled trial of high dose tacrine in patients with Alzheimer’s disease. JAMA 1994;271:985-991.

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28. Meador K, Loring D, Nichols M, et al. Preliminary findings of high-dose thiamine in dementia of Alzheimer’s type. J Geriatr Psychiatry Neurol 1993; 6:222-229.

29. Muller JL, Clauson KA. Pharmaceutical considerations of common herbal medicine. Am J Man Care 1997; 3:1753-1770.

30. Orgogozo JM, Dartigues JF, LaFont S, et al. Wine consumption and dementia in the elderly: a prospective community study in the Bordeaux area. Rev Neurol 1997; 153:185-192.

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32. Pappolla MA, Sos M, Omar RA, et al. Melatonin prevents death of neuroblastoma cells exposed to the Alzheimer amyloid peptide. J Neurosci 1997; 17:1683-1690.

33. Patel SH. Pharmacotherapy of cognitive impairment in Alzheimer’s disease. J Geriatr Psychiatry Neurol 1995; 8:81-95.

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FOR AN INFORMATIVE AND PERSONAL ARTICLE ON PRACTICAL SUGGESTIONS WHEN SELECTING A NURSING HOME SEE OUR ARTICLE "HOW TO SELECT A NURSING HOME".

By Harold Rubin, MS, ABD, CRC, Guest Lecturer
updated October 20, 2008

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