The Encyclopedia of Natural Medicine, 3rd Ed.

Alzheimer’s Disease

image

• Progressive mental deterioration, loss of memory and cognitive function, inability to carry out activities of daily life

• Characteristic symmetrical, usually diffuse brainwave pattern seen on EEG

• Diagnosis usually made by exclusion; imaging techniques can help rule out other causes of dementia

• At this time, definitive diagnosis can be made only by brain biopsy after death.

Alzheimer’s disease (AD) is a degenerative brain disorder associated with progressive dementia—a deterioration of memory and cognition. In the United States, Alzheimer’s disease is now estimated to affect 1.6% of the population younger than 74, with the rate increasing to 19% in those between 75 and 84 and to 42% in those older than 84. These numbers are striking when compared with data from the 1960s indicating an incidence of only 2% in people over the age of 85. The tremendous increase in AD in people over 85 is often referred to as the “Alzheimer’s epidemic.”1

Causes

AD is the result of damage to many aspects of brain structure and function. One characteristic feature of AD is the development of distinctive brain lesions called plaques and tangles.1 Plaques are hard deposits of a protein, beta-amyloid, that are found between neurons. Amyloid is a general term for protein fragments that the body produces normally, and beta-amyloid is a fragment snipped from an amyloid precursor protein (APP). In a healthy brain, these fragments are broken down and eliminated, but in Alzheimer’s disease they accumulate to form plaques. Another type of lesion, neurofibrillary tangles, occurs within brain cells. In the healthy brain cell, a protein called tau forms structures called microtubules. In Alzheimer’s disease, however, the tau protein is abnormal and the microtubules collapse into a twisted mass. It is thought that the buildup of beta-amyloid triggers the changes in the tau protein. Both types of lesions disrupt message transmittal within the brain and eventually cause cell death.

Genetic factors play a major role and are estimated to account for up to 70% of cases of AD. The key appears to be genetically linked alterations in the ability of the immune system to regulate inflammation in the brain. Although the immune cells in the brain normally remove beta-amyloid, research is beginning to characterize a chronic and excessive inflammatory reaction to amyloid proteins in the brain that can promote AD in susceptible individuals.2Therapies designed to affect these immune cells in the brain are being investigated. Chief among these strategies is to immunize AD patients with beta-amyloid peptides so they will generate antibodies that bind to beta-amyloid and enhance its clearance.3 Although preclinical studies were successful, the initial human clinical trial of an active beta-amyloid vaccine was halted owing to the development of severe inflammation in the brain in approximately 6% of the vaccinated AD patients.

Although genes have a big part in determining susceptibility to AD, lifestyle and environmental factors also play a significant role, as they do in most chronic degenerative disease. Emerging research reveals that dietary factors are especially important. Poor-quality diets with excessive amounts of saturated or trans-fatty acids may predispose neurons to environmental toxicities.4,5 Some studies suggest that abnormal sleep-wake cycles and decreased morning light exposure may play a role in the expression of AD (see the section on melatonin later in this chapter). Traumatic injury to the head; chronic exposure to aluminum, silicon (most often due to occupational exposures in the construction, sandblasting, and mining industry), or both; exposure to neurotoxins such as mercury from environmental sources; and free radical damage have all been implicated as causative factors as well. As with other chronic degenerative diseases, there is considerable evidence that increased oxidative damage plays a central role. Therapies designed to support antioxidant mechanisms (discussed later) may be quite helpful in the prevention of AD.6

The tremendous increase in AD parallels the rise in type 2 diabetes and insulin resistance, suggesting a possible connection. It is well established that type 2 diabetics have a 1.5- to 4-fold increased risk for AD as well as for non-Alzheimer’s dementia caused by damage to the blood vessels of the brain. Impaired insulin signaling, insulin resistance in the brain, and a decrease in cerebral insulin receptors associated with aging may be other important factors in the development of AD. Measures to improve blood sugar control and improve insulin sensitivity appear to be important steps in the prevention of AD.7,8

Diagnostic Considerations

Comprehensive Evaluation

A comprehensive diagnostic workup is critical, as there are many conditions that can cause dementia. For example, depression is frequently seen in the elderly and can mimic dementia, and the most common reversible cause of dementia is drug toxicity. Other important causes are metabolic and nutritional disorders such as hypoglycemia, thyroid disturbances, and deficiency in vitamin B12, folate, or thiamine. A comprehensive evaluation should include the following:9

• A detailed history

• Neurological and physical examination

• Psychological evaluation with particular attention to depression

• A general medical evaluation with emphasis on the detection of subtle metabolic, toxic, or cardiopulmonary disorders that can precipitate confusion, especially in the elderly

• A series of standardized neurophysiology tests such as the mini–mental state examination (MMSE) or Folstein test to document the type and severity of cognitive impairment

• Appropriate laboratory assessment (see below for recommended tests)

• An electroencephalogram (EEG)

• Imaging techniques such as computed tomography (CT), magnetic resonance imaging (MRI), positron emission tomography (PET), or others

Recommended Laboratory Tests for Dementia

TEST

RATIONALE

CBC

Anemia, infection

Electrolytes

Metabolic dysfunction

Liver function tests

Hepatic dysfunction

BUN

Renal dysfunction

TSH, T4, T3, T3U

Thyroid dysfunction

Serum B12 and RBC folate

Deficiency

Urinalysis

Kidney/liver dysfunction

Hair mineral analysis

Heavy metal intoxication

ECG

Heart function

EEG

Focal vs. diffuse brain lesions

CT scan

Atrophy, intracranial mass

Fingerprint Patterns

Abnormal fingerprint patterns are associated with both AD and Down syndrome.10 Compared with the normal population, Alzheimer and Down patients show an increased number of ulnar loops on the fingertips, with a decrease in whorls, radial loops, and arches. Ulnar loops (pointing toward the ulnar bone, away from the thumb) are frequently found on all 10 fingertips. Radial loops (pointing toward the thumb), when they do appear, tend to be shifted away from the index and middle fingers—where they most commonly occur—to the ring and little fingers. In patients with this fingerprint pattern, it is recommended that an aggressive, preventive approach be instituted immediately.

Therapeutic Considerations

The primary areas of intervention from a natural medicine perspective are prevention (addressing suspected causative factors) and treatment with natural measures (to improve mental function in the early stages of the disease). In the advanced stages of AD, natural measures will usually provide little benefit.

Diet

Dietary factors are clearly important in the development of AD. Food choices consistent with the standard American diet are associated with significant risk for the development of AD. A diet high in saturated fat and trans-fatty acids and low in dietary antioxidants may lead to increased serum and brain concentrations of aluminum and transition metal ions, which are implicated in oxidative stress. In addition, a poor-quality diet may cause inflammation in the brain.4,5,11

Many dietary risk factors are the same for both AD and atherosclerosis. Likewise, recent studies have provided clear evidence that following a Mediterranean-type diet does not just reduce the risk of heart disease but also is definitely associated with slower cognitive decline, lower risk for both pre-dementia syndromes and AD, and decreased mortality from all causes in AD patients.11,12

The key dietary factors that reduce AD risk are higher fish consumption (and omega-3 fatty acids), monounsaturated fatty acids (primarily from olive oil), light to moderate alcohol use (primarily red wine), and increased consumption of nonstarchy vegetables and fruits. It is likely that it is the combination of all of these factors that provides the highest degree of protection, rather than any single dietary factor.11,12

image

Fingerprint Patterns in Alzheimer’s Disease

One study in particular produced some very interesting findings. Given the ability of the Mediterranean diet to reduce inflammation and improve insulin sensitivity, many people assume that this plays a significant role in its ability to reduce AD. However, in a four-year prospective study, the lower risk of AD with the Mediterranean diet did not seem to be due to reducing atherosclerosis.13 It is therefore thought that other aspects of the diet or specific foods are probably responsible, possibly working directly on reducing beta-amyloid formation or deposition.1421 For example, polyphenols found in grapes, grape seed extract, and red wine have been shown to prevent beta-amyloid formation and promote disassembly of the neurofibrillary tangles.1921 Animal studies using grape polyphenols marked with radioactive particles show absorption into the brain after oral administration.22

Even something as simple as eating celery (Apium graveolens) may offer significant protection against AD. Celery and celery seed extracts contain a unique compound, 3-n-butylphthalide (3nB), that is responsible for both the characteristic odor of celery and its health benefits. In an animal model of AD, 3nB treatment significantly improved learning deficits as well as long-term spatial memory, significantly reduced total cerebral beta-amyloid plaque deposition, and lowered brain beta-amyloid levels. It was also shown that 3nB markedly directed amyloid precursor protein processing toward a pathway that precludes beta-amyloid formation. The researchers concluded that “3nB shows promising preclinical potential as a multitarget drug for the prevention and/or treatment of Alzheimer’s disease.”23

The research on grape polyphenols and 3nB raises a powerful question: how many other foods contain unique compounds that address the pathophysiology of Alzheimer’s disease? From preliminary investigations it looks as if there may be a great many. Especially promising are sources of phenols, polyphenols, and flavonoids.

Estrogen

Estrogen has been touted as offering protective and possibly therapeutic benefits in AD. However, the evidence to support the potential benefits of estrogen is contradictory. Yes, 16 population-based studies indicated that women on hormone replacement therapy (HRT) had a lower rate of AD.24 But the problem with these studies was that women taking HRT were much healthier before taking the hormones compared with the control group, who were more likely to have hypertension, diabetes, and a history of stroke.25 Data from the only large randomized controlled trial published to date, the Women’s Health Initiative Memory Study, did not confirm these observations and have even suggested an increase in dementia risk for women using HRT (and especially those given HRT after menopause) compared with controls.26 Clinical trials involving women with AD have concluded that estrogen therapy does not improve dementia symptoms in women with AD.2729 Given the cloud of uncertainty about the benefits of HRT, at this point it seems most reasonable to consider the risks of estrogen therapy as outweighing any possible benefit in the prevention of AD.

Aluminum

Considerable attention has been focused on aluminum concentrations in neurofibrillary tangles. Whether the aluminum accumulates in the tangles in response to the formation of lesions or whether it actually initiates the lesions has not yet been determined, but significant evidence shows that it contributes, possibly significantly, to the disease.30 There is a great deal of circumstantial evidence linking chronic aluminum exposure to AD. Increasing aluminum concentrations in the brain could explain why the frequency of AD rises with increasing age. And those with AD have significantly higher aluminum levels than both normal people and patients with other types of dementia, such as those from alcohol, atherosclerosis, and stroke.31 The aluminum appears to come from the water supply, food, antacids, and antiperspirants. The most significant source is probably drinking water, as the aluminum in water is in a more bioavailable and thus potentially toxic form. Researchers measuring the absorption of aluminum from tap water added a small amount of soluble aluminum in a radioactive form to the stomachs of animals. They discovered that the trace amounts of aluminum from this single exposure immediately entered the animals’ brain tissue. The frightening news is that aluminum in water not only occurs naturally but also is added (in the form of alum) to treat some water supplies.32

Avoiding all known sources of aluminum—aluminum-containing antacids, aluminum-containing antiperspirants, cooking in aluminum pots and pans, wrapping food with aluminum foil, nondairy creamers containing the food additive sodium aluminosilicate, and some types of baking powder and table salt—certainly seems appropriate. In addition, citric acid and calcium citrate supplements appear to increase the efficiency of absorption of aluminum (but not lead) from water and food.33 Aluminum absorption can be decreased by magnesium, because magnesium competes with aluminum for absorption not only in the intestines but also at the blood-brain barrier.34 Focus on unprocessed foods, avoid milk and dairy products, and increase consumption of vegetables, whole grains, nuts, and seeds—all good sources of magnesium.

Nutritional Considerations

Nutritional status is directly related to mental function in the elderly.35 Given the frequency of nutrient deficiency in the elderly population, it is likely that many cases of impaired mental function may have a nutritional basis. As pointed out above, diet is critically important in the prevention and arrest of AD, with various components working together in a synergistic fashion to address many of the underlying features of AD.

Antioxidants

Prospective Studies of Antioxidants and Risk of AD

STUDY

FOLLOW-UP

FINDINGS

Rotterdam Study

6 years

Dietary vitamin E effective (more among current smokers)

Canadian Study of Health and Aging

5 years

Combination of vitamin E and vitamin C supplements and/or multivitamin consumption effective

Chicago Health Aging Study

3.9 years

Dietary vitamin E was effective only among a subset of individuals lacking a genetic risk factor (non-apoE4 carriers)

Washington Heights–Inwood Columbia Aging Project

4 years

No effect of vitamin E (diet or supplement)

Cache County Study

3 years

Vitamin E alone was not effective, but combined with vitamin C it was effective

Honolulu-Asia Aging Study

30 years

Dietary vitamin E was not effective

Duke Established Populations for Epidemiologic Studies of the Elderly

10 years

No effect of vitamin C and/or vitamin E

Group Health Cooperative

5.5 years

No effect of supplemental vitamin E and vitamin C alone or in combination

As noted previously, considerable evidence indicates that oxidative damage plays a major role in the development and progression of AD.6,36,37 Population-based evidence suggests that antioxidant nutrients offer significant protection against AD.4,38 Prospective and clinical studies have primarily focused on vitamin C, vitamin E, and beta-carotene, with somewhat favorable results (see the table below).36,3942 As with other chronic degenerative diseases, better results may be achieved with a broader range of supplemental nutrients. For example, in a French study of middle-aged adults, 13 years of daily supplementation with 120 mg vitamin C, 30 mg vitamin E, 6 mg beta-carotene, 100 mcg selenium, and 20 mg zinc compared with a placebo were significantly associated with better verbal memory, which is a cognitive domain that is particularly vulnerable to AD. These results appear to be significantly better than those achieved with vitamin C, vitamin E, and beta-carotene either alone or in combination without the minerals.

It is entirely possible (and very likely) that vitamin E, vitamin C, and beta-carotene may simply be markers of increased phytochemical antioxidant intake and do not play a significant role on their own. Fruit and vegetables contain an array of antioxidant compounds beyond these three, and some of the other compounds may have considerable benefit in AD. Often researchers make the mistake of thinking that the antioxidant activity of a particular fruit or vegetable is due solely to its vitamin C, vitamin E, or beta-carotene content. However, these nutrient antioxidants often account for a very small fraction of a food’s antioxidant effect—for example, only about 0.5% of the total antioxidant activity of an apple. The overwhelming antioxidant activity of fruit and vegetables comes from phytochemicals such as flavonoids, phenols, polyphenols, and other carotenoids.16 In particular, as detailed above, phytochemicals are showing tremendous promise in protecting against AD beyond their antioxidant effects by interfering with beta-amyloid formation and deposition.

Thiamine (Vitamin B1)

Although severe thiamine deficiency is relatively uncommon (except in alcoholics), many Americans, and especially the elderly, do not consume even the RDI of 1.5 mg. In an attempt to gauge the prevalence of thiamine deficiency in the geriatric population, 30 people visiting a university outpatient clinic in Tampa, Florida, were tested for thiamine levels. Depending on the thiamine measurement (plasma or red blood cell thiamine), low levels were found in 57% and 33%, respectively, of the people studied.43

In addition to its role as a nutrient, thiamine demonstrates some pharmacological effects on the brain. Specifically, it both potentiates and mimics acetylcholine, an important neurotransmitter involved in memory.44 This effect explains the positive clinical results that have been noted for thiamine (3 to 8 g per day) in improving mental function in people with AD or age-related impaired mental function.45,46High-dosage thiamine supplementation has no side effects.

These results highlight the growing body of evidence that a significant percentage of the geriatric population is deficient in one or more of the B vitamins. Given the essential role of thiamine and other B vitamins in normal human physiology, especially cardiovascular and brain function, routine B vitamin supplementation appears to be worthwhile in this age group. AD may simply be the result of chronic low intake of essential nutrients—key among which are the B vitamins.

Vitamin B12

Another B vitamin linked to AD is vitamin B12. Vitamin B12 deficiency results in impaired nerve function, which can cause numbness, tingling sensations, or a burning feeling in the feet, as well as impaired mental function, which in the elderly can mimic AD.47,48 Vitamin B12 deficiency also is a major cause of depression in this age group.

Several investigators have found that the level of vitamin B12 declines with age (probably due to gastric atrophy) and that vitamin B12 deficiency is found in 3% to 42% of people 65 and older. One way to determine whether there is a deficiency is by measuring the level of cobalamin in the blood. In one study of 100 geriatric outpatients who were seen in office-based settings for various acute and chronic medical illnesses, 11 had serum cobalamin levels of 148 pmol/l or below, 30 had levels between 148 and 295 pmol/l, and 59 patients had levels above 296 pmol/l.49 After the initial cobalamin determination, the subjects were followed for up to three years. The patients with cobalamin levels below 148 pmol/l were treated and not included in the analysis of declining cobalamin levels. The average annual decline in serum cobalamin level was 18 pmol/l for patients who had higher initial serum cobalamin levels (224 to 292 pmol/l). For patients with lower initial cobalamin levels, the average annual decline was much higher, 28 pmol/l. These results indicate that screening for vitamin B12 deficiency appears to be indicated in the elderly given the positive cost-benefit ratio.5052 Other ways of screening for B12 deficiency involve measuring the level of methylmalonic acid in the urine or measuring the level of plasma homocysteine (which also serves to determine the status of folate). Having a high homocysteine level (>14 mmol/l) nearly doubles the risk of AD.53

The importance of detailed examination in elderly patients with mental symptoms is highlighted by results from a study that analyzed the plasma homocysteine, serum cobalamin, and blood folate in 296 patients referred to a geriatric psychiatric ward in Sweden for diagnosis of mental disease.54 Patients who were deficient in vitamin B12 or folic acid or who had elevated levels of homocysteine were given vitamin B12 (dosage not specified), folic acid (10 mg per day), or both. When individuals with low cobalamin levels were supplemented with vitamin B12, significant clinical improvements were noted.

In other studies, supplementation has shown tremendous benefit in reversing impaired mental function when there are low levels of vitamin B12.47 In one large study, a complete recovery was observed in 61% of cases of mental impairment due to low levels of vitamin B12.55 The fact that 39% did not respond is probably a result of long-term low levels of vitamin B12 causing irreversible damage. Several studies have shown that the best clinical responders are those who have been showing signs of impaired mental function for less than six months.16 In one study, 18 subjects with low serum cobalamin levels and evidence of mental impairment were given vitamin B12. Only those patients who had had symptoms for less than one year showed improvement.56 The importance of diagnosing and correcting low vitamin B12 levels in the elderly cannot be overstated.

Serum vitamin B12 levels are significantly low in AD patients.47,57,58 It has recently been demonstrated that an oral dose as low as 50 mcg per day can significantly increase serum vitamin B12 levels in vitamin B12–deficient elderly people.59 Supplementation of B12, folic acid, or both may result in complete reversal in some patients, but generally there is little improvement in mental function in patients who have had Alzheimer’s symptoms for more than six months.60

Vitamin B12 is available in several forms. The most common form is cyanocobalamin; however, vitamin B12 is active in the human body in only two forms, methylcobalamin and adenosylcobalamin. Although methylcobalamin and adenosylcobalamin are active immediately upon absorption, cyanocobalamin must be converted to either methylcobalamin or adenosylcobalamin. The body’s ability to make this conversion may decline with aging and may be another factor responsible for the vitamin B12 disturbances noted in the elderly population.

Finally, the damaging effects of low vitamin B12 levels are aggravated by high levels of folic acid that mask a vitamin B12 deficiency. While the addition of folic acid to the food supply in 1998 helped decrease neural tube defects in infants, it may also have worsened the problems caused by low vitamin B12.

Zinc

Zinc deficiency is one of the most common nutrient deficiencies in the elderly and has been suggested as a major factor in the development of AD, as most enzymes involved in DNA replication, repair, and transcription contain zinc.61 It has been suggested that dementia may represent the long-term cascading effects of error-prone or ineffective DNA-handling enzymes in nerve cells, possibly because of a long-term zinc deficiency.62 In addition, zinc is required by many antioxidant enzymes, including superoxide dismutase. With insufficient zinc, the end result could be the destruction of nerve cells and the formation of neurofibrillary tangles and plaques. Levels of zinc in the brain and cerebrospinal fluid in patients with AD are markedly decreased, and there is a strong inverse correlation between serum zinc levels and plaque count.63

Zinc supplementation has demonstrated good benefits in AD. In one study, 10 patients with AD were given 27 mg per day of zinc (as zinc aspartate). Only two patients failed to show improvement in memory, understanding, communication, and social contact. In one 79-year-old patient, the response was labeled “unbelievable” by both the medical staff and the family.64 Unfortunately, there does not seem to be much interest in the scientific community in following up these impressive results with zinc therapy.

There is ambivalence in recent medical literature about zinc because in vitro, zinc accelerates the formation of insoluble beta-amyloid peptide.65,66 Although zinc is neurotoxic at high concentrations and accumulates at sites of degeneration, total tissue zinc is markedly reduced in the brains of Alzheimer patients. Other research has shown a much higher concentration of copper-zinc superoxide dismutase in and around the damaged brain tissue of AD patients.67 This suggests that the increased concentration of zinc in the damaged areas is due to the body’s efforts to neutralize free radicals through the increased local production of dismutases. A possible explanation is that the higher localized levels of zinc result in increased amyloid formation when the free-radical-scavenging mechanisms have been inadequate.

Phosphatidylcholine and Other Sources of Choline

Because dietary phosphatidylcholine can increase acetylcholine levels in the brain in normal patients and AD is characterized by a decrease in acetylcholine function, it seems reasonable to assume that phosphatidylcholine supplementation would benefit Alzheimer’s patients by providing more choline. However, the basic defect in many patients with AD relates to impaired activity of the enzyme acetylcholine transferase. This enzyme combines choline (as provided by phosphatidylcholine) with an acetyl molecule to form acetylcholine, the neurotransmitter. Providing more choline does not necessarily increase the activity of this key enzyme, so phosphatidylcholine supplementation is not beneficial in the majority of patients with AD. In addition, choline levels are elevated in the cerebrospinal fluid in AD. When researchers measured the levels of the water-soluble metabolites of phosphatidylcholine (glycerophosphocholine [GPC], phosphocholine, and choline) in normal patients and age-matched AD patients, they found increased levels in the AD patients. GPC was increased by 76%, phosphocholine by 52%, and free choline by 39%. What these data demonstrate is that AD is associated not only with reduced acetylcholine manufacture but also with increased breakdown of phosphatidylcholine, which is a component of brain cell membranes.68

Not surprisingly, clinical trials using phosphatidylcholine have largely been disappointing. Studies have shown inconsistent improvements in memory from choline supplementation in both normal and Alzheimer patients.6972The studies have been criticized for small sample size, low dosage of phosphatidylcholine, poor design, and poor choice of choline form.73 Clinical studies with glycerophosphocholine (GPC) and citicoline (also known as cytidine diphosphate-choline or CDP-choline) have shown benefit in improving age-related memory decline; however, studies investigating the use of these agents in AD have usually shown only very slight benefits.73 In one double-blind study patients affected by mild to moderate AD were treated with GPC or a placebo for 180 days.74 Scores on standard assessments (e.g., the Alzheimer’s Disease Assessment Scale and the Global Improvement Scale) after 90 and 180 days showed improvement in the GPC group, whereas in the placebo group they remained unchanged or worsened. Study results with citicoline in AD have been inconsistent.75,76

Despite the questionable benefit specifically related to AD, in cases of mild to moderate dementia we recommend a 90-day trial of either GPC or CDP at dosages of 1,200 mg and 1,000 mg per day, respectively. Given the difficulty with diagnosing AD, it is possible that many cases of dementia are related to other factors that may respond to choline supplementation. If there is no noticeable improvement within the 90-day time frame, supplementation should be discontinued.

Phosphatidylserine

Phosphatidylserine (PS) is the major phospholipid in the brain, where it plays a significant role in determining the integrity and fluidity of cell membranes. Normally the brain can manufacture sufficient levels of phosphatidylserine, but a deficiency of methyl donors (such as S-adenosyl-methionine [SAM-e], folic acid, and vitamin B12) or essential fatty acids may inhibit production of sufficient PS. Low levels of phosphatidylserine in the brain are associated with impaired mental function and depression in the elderly. To date, 11 published double-blind studies have all reported the successful use of PS in the treatment of age-related cognitive decline, AD, or depression.7786 In the largest study a total of 494 patients between 65 and 93 years old with moderate to severe dementia were given either phosphatidylserine (100 mg three times per day) or a placebo for six months.72 The patients were assessed for mental performance, behavior, and mood at the beginning and end of the study. Statistically significant improvements were noted in mental function, mood, and behavior for the phosphatidylserine group.

L-Acetylcarnitine

A great deal of research has been conducted with L-acetylcarnitine (LAC; also called acetyl-L-carnitine) in the treatment of AD, senile depression, and age-related memory defects. LAC is composed of acetic acid and L-carnitine bound together. This reaction occurs naturally in the human brain. Therefore it is not exactly known how much greater an effect is achieved with LAC vs. L-carnitine. However, LAC is thought to be substantially more active than other forms of carnitine in conditions involving the brain.87,88

The close structural similarity between LAC and acetylcholine led to an interest in using LAC in AD. Research has shown that LAC both enhances and mimics acetylcholine and is of benefit not only in patients with early-stage AD but also in elderly patients who are depressed or who have impaired memory.88 It has been shown to act as a powerful antioxidant within the brain cell, stabilize cell membranes, and improve energy production within the brain cell as well.89

In an analysis of studies of LAC in mild cognitive impairment and mild (early) AD, patients taking doses ranging from 1.5 to 3 g a day were assessed at 3, 6, 9, and 12 months. This analysis showed a significant advantage for LAC compared with a placebo. The advantage for LAC was seen by the time of the first assessment at three months and increased over time. Additionally, LAC was well tolerated in all studies.90

Further studies also show its efficacy in situations where AD patients were unresponsive to standard drug therapy (acetylcholinesterase inhibitors). One study showed LAC at 2 g per day increased the effectiveness of drugs such as donepezil and rivastigmine.91

Memory impairment need not be as severe as it usually is in AD in order for LAC to demonstrate a benefit.9294 In one double-blind study of 236 elderly subjects with mild mental deterioration, as evidenced by detailed clinical assessment, the group receiving 1,500 mg per day of LAC demonstrated significant improvement in mental function, particularly in memory and constructional thinking.94

Dehydroepiandrosterone (DHEA)

DHEA is the most abundant hormone in the bloodstream and is found in extremely high concentrations in the brain. Because DHEA levels decline dramatically with aging, low levels of DHEA in the blood and brain are thought to contribute to many symptoms associated with aging, including impaired mental function. In some studies DHEA supplementation has shown promise in enhancing memory and improving cognitive function.95 However, no effect was noted in the largest study as well as others.96,97 The only double-blind study in actual AD was a small pilot study (58 subjects) in which 50 mg DHEA was given twice a day. Although some benefit was reported at three months, DHEA did not significantly improve cognitive performance or overall change in severity.98

We feel that the failure of DHEA to provide benefits may have been due to not properly qualifying the patients. Measuring DHEA levels in the blood or saliva can help determine if DHEA may be of benefit. It is not likely to be of benefit in those with satisfactory levels for their age and sex. The dose of DHEA necessary to improve brainpower in men older than 50 appears to be 25 to 50 mg per day. For women, a dosage of 15 to 25 mg appears to be sufficient in most cases. As men and women reach their 70s, they may require higher levels (e.g., 50 to 100 mg). Excessive dosages of DHEA can cause acne and, in younger women, menstrual irregularities.

Melatonin and Bright Light Therapy

Test tube studies have shown that melatonin protects brain cells from heavy metal damage. For example, melatonin treatment prevented oxidative damage and beta-amyloid release caused by cobalt. Since cobalt is another toxic metal found in high levels in AD patients, melatonin may prove an important preventive treatment in AD.99

One double-blind study of AD patients involved subjects who got 3 mg melatonin or a placebo at 8:30 p.m. every day for a month. Based on standard dementia and AD assessment scales, the melatonin group had significantly increased sleeping time and decreased nighttime activity, with improved levels of mental function.100

Melatonin may also be helping by improving the disturbance in circadian (daily) rhythm common in AD. Circadian rhythm affects body functions such as sleep cycles, temperature, alertness, and hormone production. Impaired sleep and nocturnal restlessness place great burdens on both those who suffer from AD and their caregivers. Clinical research has shown that exposure to full-spectrum light throughout the day and darkness at night can help improve some aspects of AD, reducing agitation, increasing sleep efficiency (percentage of time in bed spent asleep), decreasing nighttime wakefulness, and decreasing nighttime activity. If natural sunlight exposure is not possible for at least an hour in the morning, light boxes are available that can simulate sunlight. Full-spectrum lightbulbs are available that can replace conventional bulbs as well.101103

Although bright light therapy during the day is often effective on its own, combining it with melatonin produces the best results.104

Botanical Medicines

Ginkgo Biloba Extract

Ginkgo biloba extract (GBE) has been extensively investigated in cases of dementia, including Alzheimer’s disease. In addition to GBE’s ability to increase functional brain capacity, it has been shown to normalize acetylcholine receptors in the brains of aged animals, increase cholinergic transmission, inhibit beta-amyloid deposition, and address many of the other major elements of AD.105 However, while preliminary studies with established AD patients were quite promising, it now appears that at best GBE can help to reverse or delay mental deterioration only in the early stages of AD. Even this may be in doubt, as in several double-blind studies no benefit over a placebo was observed in halting cognitive decline.106108 In other double-blind studies, though, the benefits of GBE in early-stage AD were quite evident, as they were in a meta-analysis of studies of more than six months’ duration.109 In one study, 216 patients with AD or multi-infarct dementia were given either 240 mg per day of GBE or a placebo for 24 weeks.110 Improvements were noted in several clinical areas, including the Clinical Global Impressions scale (described below). Similar results were seen in another double-blind study where the 240 mg dose was administered once per day.111

One study worth special mention was the first U.S. clinical study on GBE published in the Journal of the American Medical Association.112 The study was conducted at six research centers. Harvard Medical School and the New York Institute for Medical Research approved the design of the study, in which 202 patients with AD were given either a modest dose of GBE (120 mg per day) or a placebo for one year. GBE not only stabilized AD but also led to significant improvements in mental function in 64% of the patients. There were no side effects with GBE.

Clinical Global Impression Ratings: Ginkgo Biloba Extract (GBE) vs. Placebo

STATUS

GBE (%)

PLACEBO (%)

Very much improved

3

1

Much improved

29

16

Slightly improved

41

38

Unchanged

28

30

Moderately worse

0

14

Much worse

0

1

Ginkgo has been used extensively as a medicinal agent worldwide for centuries. It is the most frequently prescribed medicinal herb in Europe, with hundreds of studies reporting positive effects from taking ginkgo for both prevention and treatment of various health complaints. The most dramatic benefits are reported in improving circulation in the elderly. This can enhance memory, possibly delaying the onset of Alzheimer’s disease, reducing other forms of dementia, and improving tinnitus and vertigo. Ginkgo’s memory-enhancing effects are reported in younger populations as well.

In the most recent study, 410 patients with mild to moderate dementia were randomly assigned to receive either 240 mg GBE or a placebo per day for 24 weeks. The results revealed that treatment with the ginkgo biloba extract led to significant improvements in the symptoms of apathy/indifference, sleep/nighttime behavior, irritability/lability, depression/dysphoria, and aberrant motor behavior. These results indicate that even if GBE does not improve cognitive function, it may produce significant improvements in mood and behavior.112 This would at the very least help enable patients to maintain a normal life and avoid being institutionalized.

It is important to point out that studies directly comparing gingko with standard drug regimens indicate that they offer similar efficacy in AD, but ginkgo has fewer side effects. A comparative analysis of studies of at least six months’ duration demonstrated that GBE and second-generation cholinesterase inhibitors (tacrine, donepezil, rivastigmine, metrifonate) were equally effective in treating mild to moderate AD.113 In a meta-analysis of 50 studies that examined the effect of ginkgo on objective measures of cognitive function in patients with AD using standardized measures of cognition, it was concluded that GBE produced benefits comparable to those of standard drug therapy.114

In addition to possibly being beneficial in early-stage AD, if the mental deficit is due to vascular insufficiency or depression and not AD, GBE is usually effective in reversing the deficit. GBE should be taken consistently for at least 12 weeks in order to determine its effectiveness. Although in some people with AD benefits are reported within two or three weeks, most will need to take GBE for a longer period.

Huperzine A

Huperzine A, an alkaloid isolated from the moss Huperzia serrata, has been shown to potentiate the effects of acetylcholine in the brain by inhibiting the enzyme acetylcholinesterase, which breaks down acetylcholine. It is significantly more selective and substantially less toxic than the acetylcholine esterase inhibitors currently used in conventional medicine (physostigmine, tacrine, and donepezil). In contrast, huperzine A has been used as a prescription drug in China since the early 1990s and has reportedly been used by more than 100,000 people with no serious adverse effects.115

In one of the first double-blind clinical studies, huperzine A at a dose of 200 mcg twice per day produced measurable improvements in memory, cognitive function, and behavioral factors in 58% of AD patients.116 In contrast, in the placebo group only 36% showed improvement.

In a more recent double-blind study, 210 individuals with AD were randomly assigned to receive a placebo or huperzine A (200 mcg or 400 mcg twice per day) for at least 16 weeks. The 200-mcg dose did not produce any change in cognitive assessment score, but patients taking the 400-mcg dose showed a 2.27-point improvement in this score after 11 weeks compared with a 0.29-point decline in the placebo group, and a 1.92-point improvement after 16 weeks compared with a 0.34-point improvement in the placebo group.117

Adverse reactions have been noted with huperzine A, including hyperactivity, nasal obstruction, nausea, vomiting, diarrhea, insomnia, anxiety, dizziness, thirst, and constipation. One trial reported abnormalities in electrocardiogram patterns (cardiac ischemia and arrhythmia).

Curcumin

There is considerable experimental evidence that curcumin protects against age-related brain damage and in particular Alzheimer’s disease. Researchers began exploring this effect after noting that elderly residents of rural India who eat large amounts of turmeric have been shown to have the lowest incidence of Alzheimer’s disease in the world: 4.4 times lower than that of Americans. In test tube and animal studies curcumin has been shown to inhibit beta-amyloid and have other effects beneficial in AD. Unfortunately, the two clinical trials conducted to date failed to show any benefit.118 However, the failure to produce positive results may have been due to the poor absorption profile of the curcumin used in the trials. There now exist a number of methods and products that enhance the absorption of curcumin. In one product, Meriva, the curcumin is complexed with soy phospholipids. Absorption studies in animals indicate that peak plasma levels of curcumin after administration of Meriva were five times higher than those after administration of regular curcumin.119 Studies with another advanced form of curcumin, Theracurmin, show even greater absorption (27 times greater than regular curcumin).120

image

QUICK REVIEW

• AD is the result of damage to the brain that affects the activity of the neurotransmitter acetylcholine.

• Research is beginning to identify a chronic and excessive inflammatory reaction to amyloid proteins in the brain in individuals susceptible to AD.

• Although genes play a big part in determining susceptibility to AD, lifestyle and environmental factors also have a significant role.

• Traumatic injury to the head; chronic exposure to aluminum, silicon, or both; exposure to neurotoxins from environmental sources; and free radical damage have all been implicated as causative factors.

• Measures to improve blood sugar control and improve insulin sensitivity appear to be important steps in the prevention of AD. Abnormal fingerprint patterns are associated with both Alzheimer’s disease and Down syndrome.

• From the perspective of natural medicine, the primary goals of intervention are prevention and using natural measures to improve mental function in the early stages of the disease.

• In the advanced stages of AD, natural measures will usually provide little benefit.

• There is evidence to suggest that antioxidants offer significant protection against Alzheimer’s disease as well as therapeutic benefits.

• Aluminum absorption can be decreased by magnesium, as magnesium competes with aluminum for absorption pathways.

• Polyphenols found in grapes, grape seed extract, and red wine have been shown to prevent beta-amyloid formation and promote disassembly of neurofibrillary tangles.

• A significant percentage of the geriatric population is affected by B vitamin deficiencies linked to Alzheimer’s disease.

• Zinc supplementation is demonstrating good results in the treatment of Alzheimer’s disease.

• The results of using L-acetylcarnitine to delay the progression of Alzheimer’s disease have been outstanding.

• DHEA shows promise in enhancing memory and improving mental function in the elderly.

• It appears that ginkgo biloba helps reverse or delay mental deterioration only during the early stages of Alzheimer’s disease.

• Huperzine A is more selective and substantially less toxic than the acetylcholine esterase inhibitors currently used in conventional medicine.

• There is considerable experimental evidence that curcumin protects against age-related brain damage and, in particular, Alzheimer’s disease.

image

TREATMENT SUMMARY

The primary therapeutic goal is prevention; follow the recommendations below under “Lifestyle,” “Diet,” and “Nutritional Supplements.” When symptoms begin to appear, it is important to increase nutritional support, as described under “Therapeutic Supplements”; we also offer suggestions under “Botanical Medicines.” Keep in mind that in advanced AD, treatment is less likely to be of benefit. In general, we recommend a trial for a minimum of 90 days in attempting to improve AD with natural measures. If no benefit is seen during this time, further therapy is unlikely to provide benefit.

Lifestyle

• Follow the recommendations given in the chapter “A Health-Promoting Lifestyle.”

• Avoid aluminum (often found in antiperspirants, antacids, and cookware).

Diet

Follow the recommendations given in the chapter “A Health-Promoting Diet.” In particular, apply the principles of the Mediterranean diet; increase whole food products, including fish, cereals, vegetables, and monounsaturated fats; avoid high-glycemic foods and unhealthy fats; achieve ideal body weight; and take measures to improve insulin sensitivity.

Nutritional Supplements

• A high-potency multiple vitamin and mineral formula as described in the chapter “Supplementary Measures”

• Vitamin C: 500 to 1,000 mg per day

• Vitamin E: 100 to 200 IU per day

• Fish oils: 1,000 mg EPA + DHA per day

• Grape seed or pine bark extract (>95% procyanidolic content): 150 to 300 mg per day

• In high-risk individuals, choose one of the following forms of bioavailable curcumin:

  images Meriva: 1,000–1,200 mg per day

  images Theracurmin: 300 mg per day

Therapeutic Supplements

The following are in addition to all of the supplements listed under “Nutritional Supplements” above:

• Thiamine: 3 to 8 g per day

• One of the following:

  images Glycerophosphocholine: 1,200 mg per day

  images Citicoline: 1,000 mg per day

• Phosphatidylserine: 100 mg three times per day

• L-acetylcarnitine: 1,500 mg per day

• Methylcobalamin: 1,000 mcg upon arising each day

• Melatonin: 3 mg in the evening at least a half hour before bedtime

Botanical Medicines

• Ginkgo biloba (24% ginkgo flavonglycosides): 240 to 320 mg per day

• Huperzine A: 200 to 400 mcg per day

• Curcumin, one of the following:

  images Meriva: 500 to 1,000 mg twice daily

  images BCM95 Complex: 750 to 1,500 mg twice daily

  images Theracurmin: 300 mg one to three times daily