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ChiroCredit.com™ / OnlineCE.com presents Nutrition 122c

Nutritional Support for Alzheimer’s disease

Instructor: Ron Steriti, NMD, PhD

Important Notice: This download is for your personal use only and is protected by applicable copyright laws©. Its use is governed by our Terms of Service on our website (click on ‘Policies’ on our website’s side navigation bar).

Nutritional Support, Summary, Drug-Supplement Interactions

Acetylcholine Support

Phosphatidylcholine (Lecithin)

Lecithin (phosphatidylcholine) has a long history of use with Alzheimer’s disease.

Phosphatidylcholine is a source of choline, the major component of acetylcholine, which is needed

for cell membrane integrity and to facilitate the movement of fats in and out of cells.

When given to animals, lecithin causes increased acetylcholine levels. Clinical trials, however,

failed to show actual improvement. Alzheimer’s disease and other dementias do show increased

choline levels, which may indicate inadequate metabolism. Therefore, simply supplementing the

lecithin would not necessarily help the metabolic defect in the cellular use of phosphatidylcholine.

(Peters and Levin, 1979) (Thal et al., 1983) (Little et al., 1985) (Fitten et al., 1990) (Blusztajn et

al., 1987)

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A recent review article analyzed 12 clinical trials using lecithin to treat Alzheimer’s disease (265

patients), Parkinsonian dementia (21 patients), and subjective memory problems (90 patients). No

trial reported any clear clinical benefit of lecithin for Alzheimer’s disease or Parkinsonian

dementia. A dramatic result in favor of lecithin was obtained, however, in a trial of subjects with

subjective memory problems. (Higgins and Flicker, 2000)

Pantothenic Acid

The body uses choline and pantothenic acid (vitamin B5) to form acetylcholine. Pantothenic acid

is also needed to produce, transport and release energy from fats.

Antioxidants

Oxidative stress is very important in the development of Alzheimer’s disease. Anti-oxidant

supplements help block this process. (Feng and Wang, 2012)

“Beta-amyloid is aggregated and produces more free radicals in the presence of free radicals; beta-

amyloid toxicity is eliminated by free radical scavengers.” (Grundman, 2000)

Vitamin E

Researchers have shown that cultured cells are prevented from beta-amyloid toxicity with the

addition of vitamin E. (Grundman, 2000)

Researchers at the University of Kentucky published a ground-breaking article showing that

vitamin E prevented the increase of polyamine metabolism in response to free radical mediated

oxidative stress caused by the addition of beta-amyloid to the rat neurons. (Yatin et al., 1999)

Research conducted in Germany showed that both natural and synthetic vitamin E were more

effective than estrogen (17-beta estradiol) in protecting neurons against oxidative death caused by

beta-amyloid, hydrogen peroxide, and the excitatory amino acid glutamate. (Behl, 2000)

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Research conducted at the University of California, San Diego, School of Medicine studied the

protective effects of vitamin E in apolipoprotein E-deficient mice. Those treated with vitamin E

displayed a significantly improved behavioral performance in the Morris water maze. Also, the

untreated mice displayed increased levels of lipid peroxidation and glutathione, whereas the

vitamin E-treated mice showed near normal levels of both lipid peroxidation and glutathione.

(Veinbergs et al., 2000)

A study of 44 patients with Alzheimer’s disease and 37 matched controls showed that vitamin E

levels in the cerebral spinal fluid (CSF) and serum were significantly lower in Alzheimer’s

patients. (Jimenez-Jimenez et al., 1997)

In the Alzheimer’s disease Cooperative Study, 2000 mg of vitamin E were given to Alzheimer’s

disease patients. This slowed the functional deterioration leading to nursing home placement.

(Grundman, 2000)

An article published in the New England Journal of Medicine described a double-blind, placebo-

controlled, randomized, multi-center trial of patients with Alzheimer’s disease of moderate

severity. A total of 341 patients received the selective monoamine oxidase inhibitor selegiline (10

mg a day), alpha-tocopherol (vitamin E, 2000 IU a day), both selegiline and alpha-tocopherol, or

placebo for two years. The baseline score on the Mini-Mental State Examination was higher in the

placebo group than in the other three groups. Both vitamin E and segeline delayed the progression

of the disease with vitamin E acting slightly better than segeline (median time 670 vs. 655 days

respectively.) (Sano et al., 1997)

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A recent review of the published research on vitamin E for Alzheimer’s disease stated that,

although there is insufficient evidence of efficacy of vitamin E, there is sufficient evidence of

possible benefit to justify further studies. (Tabet et al., 2000)

Researchers are suggesting that the combination of vitamin E and donepezil be a current standard

of Alzheimer’s disease therapy. (Doody, 1999)

Vitamin C

An article published in the International journal Geriatric Psychiatry described a study of

Alzheimer’s disease patients in the region of Toulouse, France. Plasma vitamin E and C levels

were measured and consumption of raw and cooked fruit and vegetables was evaluated in order to

determine the mean vitamin C intakes. Mini Nutritional Assessment (MNA) and plasma albumin

were used to measure nutritional status. The hospitalized Alzheimer’s subjects had lower MNA

scores and albumin levels but normal vitamin C intakes, but their plasma vitamin C was lower

than that of community-living subjects. In the home-living Alzheimer subjects, vitamin C plasma

levels decreased in proportion to the severity of the cognitive impairment despite similar vitamin

C intakes. (Riviere et al., 1998)

A prospective study of 633 persons 65 years and older examined the relation between use of

vitamin E and vitamin C and incidence of Alzheimer’s disease. After an average follow-up period

of 4.3 years, 91 of the participants with vitamin information met accepted criteria for the clinical

diagnosis of Alzheimer’s disease. None of the 27 vitamin E supplement users and none of the 23

vitamin C supplement users had Alzheimer’s disease. There was no relation between Alzheimer’s

disease and use of multivitamins. (Morris et al., 1998)

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A study of ten patients with Alzheimer’s disease showed that one month supplementation of 400

IU vitamin E and 1000 mg vitamin C significantly increased the concentration of both vitamins in

the plasma and cerebral spinal fluid. In contrast, supplementation with vitamin E alone increased

its CSF and plasma concentrations but was unable to decrease lipoprotein oxidizability. (Kontush

et al., 2001)

Acetyl-L-Carnitine

There are multiple modes of action for acetyl-L-carnitine, including antioxidant effects, molecular

chaperone effects, and others.

This agent possibly helps correct the acetylcholine deficit and has been tried in rodents.

(Butterworth, 2000)

Double-blind studies have been done and showed some benefit. (Pettegrew et al., 2000)

Acetyl-L-carnitine was shown to protect neurons from the detrimental effects of beta-amyloid in

the cortex of rats. (Virmani et al., 2001)

In humans, a one-year controlled trial in early Alzheimer’s disease measured ADAS-Cog and the

Clinical Dementia Rating Scale in 229 patients. Acetyl-L-carnitine use slowed the clinical

deterioration. This study concluded by recommending more research using both acetyl-L-carnitine

plus a cholinesterase inhibitor (such as donepezil, tacrine, Rivastigmine or Metrifonate). (Thal et

al., 2000)

Vitamin A

A recent study published in the European journal Neurology compared serum levels of beta-

carotene and alpha-carotene, and vitamin A of 38 Alzheimer’s disease patients and 42 controls.

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They found that the serum levels of beta-carotene and vitamin A were significantly lower in the

Alzheimer’s disease patient group. (Jimenez-Jimenez et al., 1999)

Coenzyme Q10

CoQ10 is used in the mitochondrial production of energy in the electron transport chain. A role

for mitochondrial dysfunction in neurodegenerative disease is gaining support. Studies have

implicated mitochondrial defects in Alzheimer’s disease and use of CoQ10 has been suggested for

this reason. (Beal, 1999) (Wadsworth et al., 2008)

Coenzyme Q10 was found to decrease amyloid pathology and improve behavior in a transgenic

mouse model of Alzheimer's disease. (Dumont et al., 2011)

N-Acetyl-Cysteine

N-Acetyl-cysteine (NAC) is a precursor of glutathione, a powerful scavenger of free radicals.

Glutathione deficiency has been associated with a number of neurodegenerative diseases,

including Lou Gehrig’s and Parkinson’s disease.

A recent study showed that NAC significantly increased the glutathione levels and reduced

oxidative stress in rodents treated with a known free-radical producer. (Pocernich et al., 2000)

NAC has been shown to protect mitochondrial respiration and neuronal microtubule structure from

the toxic effects of HNE (4-hydroxy-2-nonenal), a reactive aldehyde product of lipid peroxidation.

(Neely et al., 2000)

Flavonoids

A recent study showed that flavonoids have a protective effect on neurons exposed to oxidized

lipids in the form of low-density lipoprotein. (Schroeter et al., 2000)

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NADH

A recent study examined the changed in the expression of genes encoding cytochrome c oxidase

and NADH dehydrogenase in the brains of 10 Alzheimer’s disease patients and 10 age-matched

controls. They found a decreased expression of the gene NADH-4 which may lead to a reduction

in antioxidant activity of ubiquinone oxidoreductase. (Aksenov et al., 1999)

Anti-Inflammatory Supplements

Essential Fatty Acids

Essential fatty acids are found in oils including flax, borage, and fish oils. Fish oils contain EPA

(eicosapentaenoic acid) and DHA (docosohexanoic acid), both of which are omega-3 oils.

Essential fatty acids are important for healthy skin and hair. They also have significant anti-

inflammatory action.

It has been proposed that a dietary deficiency of essential fatty acids could be a risk factor for

Alzheimer’s disease. (Newman, 1992) (Newman, 2000) (Youdim et al., 2000)

Several small studies have explored the use of essential fatty acids in the treatment of Alzheimer’s

disease and found it to be beneficial. (Corrigan et al., 1991) (Yehuda et al., 1996)

DHA

The neuron is composed of about 30% DHA (docosohexanoic acid), which is an important fatty

acid in the neuronal membrane. Most of our DHA comes from fish consumption but also may be

taken as a supplement. Low DHA has been found to be a risk factor for development of

Alzheimer’s disease. The decreased levels of DHA in later life could be related to decreased

synthesis secondary to lower levels of delta 6-desaturase activity. (Kyle et al., 1999) (Horrocks

and Yeo, 1999)

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EPA

A Japanese study found that administration of EPA (900 mg per day) in patients with Alzheimer’s

disease improved MMSE significantly with maximal effects at 3 months and the effects lasted 6

months. However, the score of MMSE decreased after 6 months. (Otsuka, 2000)

GLA

Researchers have proposed that fish oils and GLA (gamma linolenic acid) may help prevent

Alzheimer’s disease by it’s anti-inflammatory effect of suppressing interleukin-1 production by

monocytes. (McCarty, 1999)

Vitamin B12

Research has shown that low cobalamin (vitamin B12) levels are related to dementias in general.

A common cause of cobalamin deficiency in elderly people is protein-bound cobalamin

malabsorption due to atrophic gastritis with hypo- or achlorhydria (low stomach acid). Often,

however, the serum B12 levels are normal. The measurement of the metabolites homocysteine

and/or methylmalonic acid is recommended as a more accurate assessment of cobalamin status.

(Bopp-Kistler et al., 1999) (McCaddon et al., 2001)

Lower levels of vitamin B12 (below 200 pg/ml) in the blood are associated with dementia

symptoms. Because of this, and the absence of toxicity with use of vitamin B12, the argument has

been voiced to raise recommended minimum serum levels of vitamin B12 and also liberally

administer vitamin B12 to the elderly. “Vitamin B12 could play a role in the behavioral changes

in Alzheimer’s disease.” (Eastley et al., 2000)

A study was recently conducted with outpatients at a geriatric memory clinic. Seventy-three

consecutive outpatients with probable Alzheimer’s disease showed significant inverse associations

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between vitamin B12 status and the behavioral and psychological symptoms of dementia:

irritability (p=0.045) and disturbed behavior (p=0.015). Of the 73 participants, 61 patients had

normal and 12 patients (16%) had subnormal (

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adenosylhomocysteine (-56 to -79%) were found in all brain areas examined as compared with

matched controls (n = 14). (Morrison et al., 1996)

A review article of SAMe concluded that intravenous or oral administration of SAMe represents

a possible treatment for Alzheimer's dementia, subacute combined degeneration of the spinal cord

(SACD), and HIV-related neuropathies, as well as in patients with metabolic disorders such as

folate reductase deficiency. (Bottiglieri and Hyland, 1994)

Nervous System Support

Phosphatidylserine

Phosphatidylserine is a major building block for nerve cells. Phosphatidylserine has been studied

for use with Alzheimer’s disease and age-related mental decline. (Crook et al., 1992) (Delwaide

et al., 1986) (Engel et al., 1992)

In a study published in the journal Dementia, a six-month study of 70 patients with Alzheimer’s

disease divided into four groups indicated that phosphatidylserine treatment has an effect on

different measures of brain function. The improvements, however, were best documented after 8

and 16 weeks and faded towards the end of the treatment period. (Heiss et al., 1994)

Inositol

Inositol is required for the formation of cell membranes. It helps in transporting fats and affects

nerve transmission.

A double-blind controlled crossover trial examined use of inositol, at a dose of 6 grams per day

for one month, in eleven patients with Alzheimer’s disease. Language and orientation improved

significantly more on inositol than on placebo (glucose). (Barak et al., 1996)

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Vitamin K

A recent article published in the journal Medical Hypothesis proposes that vitamin K deficiency

may contribute to the pathogenesis of Alzheimer’s disease. The authors offer the following as

evidence:

A relative deficiency of vitamin K is common in aging men and women.

The concentration of vitamin K is lower in the circulating blood of APOE4 carriers than in that of

persons with other APOE genotypes. The ApoE4 genotype is associated with Alzheimer’s disease.

Vitamin K has important functions in the brain, including the regulation of sulfotransferase activity

and the activity of a growth factor/tyrosine kinase receptor (Gas 6/Axl).

Vitamin K may also reduce neuronal damage associated with cardiovascular disease.

The authors propose that vitamin K supplementation may have a beneficial effect in preventing or

treating the disease. (Allison, 2001)

Idebenone

Idebenone is a synthetic analogue of coenzyme Q10 (CoQ10), a cell membrane antioxidant and

essential component of the mitochondrial electron transport chain which produces ATP (the energy

molecule of the body). The following mechanisms have been proposed for the use of idebenone in

Alzheimer’s disease:

Idebenone has been shown to stimulate nerve growth factor. (Yamada et al., 1997) (Nitta et al.,

1994) (Nitta et al., 1993)

Treatment with idebenone and alpha-tocopherol prevented learning and memory deficits caused

by beta-amyloid in rats. (Yamada et al., 1999)

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Three hundred patients with Alzheimer’s disease were randomized to receive either placebo or

idebenone, 30 mg three times per day, or 90 mg three times per day for six months. Statistically

significant improvement was noted in the total score of the Alzheimer’s disease Assessment Scale

(ADAS-total), and in one cognitive parameter (ADAS-cog) in the idebenone 90 mg three times

per day group, as compared to placebo. (2001) (Bergamasco et al., 1994)

An article in the journal Neuropsychobiology described the results of a double-blind, placebo-

controlled multi-center study using idebenone in patients suffering from mild to moderate

dementia of the Alzheimer type. A total of 300 patients were randomized to either placebo or

idebenone 30 mg or 90 mg 3 times a day (n=100, each) and treated for 6 months. After month 6,

idebenone 90 mg, showed statistically significant improvement in both the Total and Cognitive

Alzheimer’s Disease Assessment Scales. (Weyer et al., 1997)

Diabetes Testing and AGEs

Central to the process of forming Advanced Glycation End Products (AGEs) is the presence of

sugar (glucose) which is central to the diagnosis of both diabetes and insulin insensitivity (referred

to as Syndrome X). (Munch et al., 2003)

Appropriate lab tests would include the glucose tolerance test and insulin levels. Appropriate

treatment is covered in the section on diabetes.

Vitamins B1 and B6

Derivatives of vitamins B1 and B6 (thiamine pyrophosphate and pyridoxamine) have been shown

to decrease AGE formation. (Booth et al., 1996) (Booth et al., 1997)

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Carnosine

Carnosine is a multi-functional dipeptide made from a combination of the amino acids beta-alanine

and L-histidine. Meat is the main dietary source of carnosine. High doses of carnosine are

necessary for therapeutic effect because the body naturally degrades carnosine with the enzyme

carnisoninase.

Copper and zinc are released during normal synaptic activity. However, in the presence of a mildly

acidic environment which is a characteristic of Alzheimer’s disease, they reduce to their ionic

forms and become toxic to the nervous system. New research has shown that carnosine can buffer

copper and zinc toxicity in the brain. (Trombley et al., 2000) (Horning et al., 2000)

Carnosine has also been shown, in vitro, to inhibit non-enzymic glycosylation and cross-linking

of proteins induced by reactive aldehydes, including aldose and ketose sugars, certain triose

glycolytic intermediates, and malondialdehyde (MDA, a lipid peroxidation product). Carnosine

also inhibits formation of MDA-induced protein-associated advanced glycosylation end products

(AGEs) and formation of DNA-protein cross-links induced by acetaldehyde and formaldehyde.

(Hipkiss, 1998) (Hipkiss et al., 1998) (Preston et al., 1998) (Munch et al., 1997)

Lithium

Low dose lithium may be helpful for prevention of Alzheimer's disease. (Terao, 2007)

Lithium may reduce the risk for Alzheimer's disease in elderly patients with bipolar disorder.

(Nunes et al., 2007)

Lithium down-regulates tau in cultured cortical neurons, which may be a possible mechanism of

neuroprotection. (Rametti et al., 2008)

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Natural Hormone Replacement

Estrogen replacement therapy (ERT) was discussed previously as conventional treatment for the

prevention of Alzheimer’s disease. From a broader perspective, estrogen replacement is but one

hormone in a complex system that includes three forms of estrogen (estrone, estradiol, and estriol),

progesterone, testosterone, their precursors (DHEA and pregnenolone) and other hormones

(melatonin and cortisol). A comprehensive hormone panel is highly recommended to determine

which hormones are deficient or in excess and help guide appropriate supplementation.

A literature review indicates that age-related losses of estrogens in women and testosterone in men

are risk factors for AD. (Barron and Pike, 2012)

Estrogen

Overall, estradiol promotes the energetic capacity of brain mitochondria by maximizing aerobic

glycolysis (oxidative phosphorylation coupled to pyruvate metabolism). The enhanced aerobic

glycolysis in the aging brain would be predicted to prevent conversion of the brain to using

alternative sources of fuel such as the ketone body pathway characteristic of Alzheimer's. (Brinton,

2008)

Estrogen in Women

The Leisure World Cohort includes 8,877 female residents of Leisure World Laguna Hills, a

retirement community in southern California, who were first mailed a health survey in 1981. From

the 2,529 female cohort members who died between 1981 and 1992, the authors identified 138

with Alzheimer's disease or other dementia diagnoses likely to represent Alzheimer's disease

(senile dementia, dementia, or senility) mentioned on the death certificate. Four controls were

individually matched by birth date (+/- 1 year) and death date (+1 year) to each case. The risk of

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Alzheimer's disease and related dementia was less in estrogen users relative to nonusers (odds ratio

= 0.69, 95 percent confidence interval 0.46-1.03). The risk decreased significantly with increasing

estrogen dose and with increasing duration of estrogen use. Risk was also associated with variables

related to endogenous estrogen levels; it increased with increasing age at menarche and (although

not statistically significant) decreased with increasing weight. This study suggests that the

increased incidence of Alzheimer's disease in older women may be due to estrogen deficiency and

that estrogen replacement therapy may be useful for preventing or delaying the onset of this

dementia. (Paganini-Hill and Henderson, 1994) (Paganini-Hill and Henderson, 1996)

Testosterone in Men

A study included 28 older men with subjective memory loss or dementia. Serum total testosterone

and sex hormone binding globulin (SHBG) correlated inversely with plasma levels of amyloid

beta peptide 40 (Abeta40, r=-0.5, P=0.01 and r=-0.4, P=0.04, respectively). Calculated free

testosterone was also inversely correlated (r=-0.4, P=0.03), and all three relationships remained

statistically significant after allowing for age. A similar but non-significant trend was seen with

dehydroepiandrosterone sulphate (DHEAS), and neither luteinising hormone (LH) nor estradiol

correlated with Abeta40. These data demonstrate that lower androgen levels are associated with

increased plasma Abeta40 in older men with memory loss or dementia, suggesting that subclinical

androgen deficiency enhances the expression of Alzheimer's disease-related peptides in vivo.

(Gillett et al., 2003)

A study included 83 referred Dementia of the Alzheimer's Type (DAT) cases and 103 cognitively

screened volunteers (aged 75+/-9 years) from the Oxford Project To Investigate Memory and

Ageing. Men with DAT (n=39) had lower levels (p =0.005) of total serum testosterone (TT=14+/-

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5 nmol/L) than controls (n=41, TT=18+/-6 nmol/L). Lower TT was more likely in men with DAT,

independent of potential confounds (Odds Ratio=0.78, 95% C.I.=0.68 to 0.91). In women there

was no difference in TT levels between cases (n=44) and controls (n=62). (Hogervorst et al., 2001)

Melatonin

Melatonin is a hormone that is released in mammals during the dark phase of the circadian cycle.

Its production declines with age in animals and humans. The main use of melatonin is for insomnia

and to establish normal sleeping patterns after long air flights. The doses used in the research

studies were higher than the 1 to 10 mg most persons use. Higher doses may cause sleepiness,

although no other serious side effects have been found with melatonin.

Melatonin is an antioxidant that has been shown to be highly effective in reducing oxidative

damage to the central nervous system. Melatonin also stimulates several antioxidant enzymes,

including glutathione peroxidase and glutathione reductase. (Reiter et al., 1999)

Several studies have investigated the mechanism of action of melatonin in Alzheimer’s disease:

Melatonin was shown to significantly inhibit the release of free radicals in neuroblastoma cells.

(Lahiri and Ghosh, 1999)

Treatment of cells with high doses of melatonin have been found to decrease the secretion of

soluble beta-amyloid. (Lahiri, 1999)

Melatonin prevented damage by beta-amyloid to neuroblastoma cells. (Pappolla et al., 1999)

In a retrospective study, 14 Alzheimer’s disease patients received 9 mg melatonin daily for 22-35

months. A significant improvement of sleep quality was found. (Brusco et al., 1999)

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One study measured the melatonin levels in the cerebrospinal fluid (CSF) of 85 patients with

Alzheimer’s disease and in 82 age-matched controls. In Alzheimer’s disease patients the CSF

melatonin levels were only one-fifth of those in control subjects. (Liu et al., 1999)

A recent study examined the efficacy of melatonin in treatment of sleep and cognitive disorders of

Alzheimer’s disease. Fourteen patients (8 females, 6 males, mean age 72 years) received 9 mg

gelatin melatonin capsules daily at bedtime for 22 to 35 months. Overall quality of sleep was

assessed from sleep logs filled in by the patients or their caretakers. At the time of assessment, a

significant improvement of sleep quality was found in all cases examined. Clinically, the patients

exhibited lack of progression of the cognitive and behavioral signs of the disease during the time

they received melatonin. (Brusco et al., 2000)

Music Therapy and Melatonin

A novel study assessed the effects of music therapy on the concentrations of melatonin,

norepinephrine, epinephrine, serotonin, and prolactin in the blood of 20 male patients with

Alzheimer’s disease at the Miami Veterans Administration Medical Center, Miami, Florida.

Patients listened to 30- to 40-minute morning sessions of music therapy 5 times per week for 4

weeks. Melatonin concentration in serum increased significantly after music therapy and was

found to increase further at 6 weeks follow-up. Norepinephrine and epinephrine levels increased

significantly after 4 weeks of music therapy, but returned to pretherapy levels at 6 weeks follow-

up. The authors concluded that increased levels of melatonin following music therapy may have

contributed to patients' relaxed and calm mood. (Kumar et al., 1999)

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Tryptophan

Tryptophan is the precursor of serotonin and melatonin. It has been proposed that a dietary lack of

tryptophan may make deficiencies of serotonin and melatonin common. (Maurizi, 1990) (Widner

et al., 2000)

In a double-blind, crossover study of 16 patients with dementia of the Alzheimer type and 16

cognitively intact controls, subjects received either a tryptophan-free amino acid drink to induce

acute tryptophan depletion, or a placebo drink containing a balanced mixture of amino acids. On

each occasion, ratings of depressed mood were made at baseline and 4 and 7 hours later, and the

Modified Mini-Mental State was administered at baseline and 4 hours later. Patients with dementia

of the Alzheimer type had a significantly lower mean score on the Modified Mini-Mental State

after acute tryptophan depletion than after receiving placebo, while the comparison group showed

no difference. (Porter et al., 2000)

Stress

The relationship between age-related memory loss and stress is central to the protocol used by

Dharma Singh Khalsa. Excessive stress from a modern life causes the adrenal glands to secrete

excessive amounts of cortisol eventually leading to adrenal fatigue. (Khalsa, 1997) (Magri et al.,

2000)

DHEA

Alzheimer’s disease patients with higher DHEA levels did better on memory tests than those with

lower DHEA levels. (Carlson et al., 1999) (Murialdo et al., 2000)

Other data suggest that DHEA has a role in antioxidant status, Natural Killer (NK) cell immune

function and other immune functions. This study showed low DHEA was a risk factor for the

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development of Alzheimer’s disease but did not show that replacing DHEA was of benefit. These

studies still need to be done. (Hillen et al., 2000)

A study of adrenal secretion in 23 healthy elderly subjects, 23 elderly demented patients and 10

healthy young subjects found a significant increase in cortisol levels during evening and nighttime

in both groups of the aged subjects. In elderly subjects, particularly if demented, the mean serum

dehydroepiandrosterone sulfate (DHEAs) levels throughout the 24-hour cycle were significantly

lower than in young controls. (Magri et al., 2000)

A cross-sectional study, called the Berlin Aging Study, found lower levels of DHEA-s in cases

that developed dementia of the Alzheimer type within 3 years as compared to matched controls.

(Hillen et al., 2000)

Herbal Treatments

Huperzine A

Huperzine A is an alkaloid isolated from the Chinese herb Huperzia serrata.

A recent review and meta-analysis concluded that Huperzine A appears to have beneficial effects

on improvement of cognitive function, daily living activity, and global clinical assessment in

participants with Alzheimer's disease. (Yang et al., 2013)

Huperzine has anticholinesterase activity. (García et al., 2017) (Damar et al., 2017) (Wang and

Tang, 1998)

In experiments using rats, Hyperzine A improved the decrease in acetylcholine activity in cortex

and hippocampus. (Wang et al., 2000) (Bai et al., 2000) (Tang, 1996) (Cheng, 1996) (Camps et

al., 2000)

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Huperzine has also been found to protect against the toxic effects of beta-amyloid. (Xiao et al.,

2000b) (Xiao et al., 2000a)

A double-blind, multi-center study of Huperzine A was conducted in China. Fifty patients were

given 0.2 mg Huperzine and 53 patients were given placebo for eight weeks. About 58% (29/50)

of patients treated with Huperzine showed improvements in their memory and cognitive and

behavioral functions. The efficacy of Huperzine was better than placebo (36%, 19/53) (p < 0.05).

No severe side effect was found. (Xu et al., 1995)

Ginkgo Biloba

Ginkgo biloba is the world’s oldest living tree. It has been traditionally used for improving memory

and Alzheimer’s disease. It is a powerful antioxidant and also functions as a mild vasodilator

(improves circulation), anti-inflammatory (via antioxidant effects), membrane protector, anti-

platelet agent and neurotransmitter modulator. (Perry et al., 1998) (Diamond et al., 2000) (Aranda-

Abreu et al., 2011)

Ginkgo was shown to protect neurons against toxicity induced by beta-amyloid fragments, with a

maximal and complete protection at the highest concentration tested. Ginkgo also completely

blocked beta-amyloid-induced events, such as reactive oxygen species accumulation and apoptosis

(cellular death). (Bastianetto et al., 2000) (Yao et al., 2001)

A study of the effects of bilobalide, the main constituent of the non-flavone fraction of ginkgo

biloba, provided the first direct evidence that bilobalide can protect neurons against oxidative

stress. Bilobalide may block the apoptosis in the early stage and then attenuate the elevation of c-

Myc, p53, and Bax genes and activation of caspase-3 in cells. (Zhou and Zhu, 2000)

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An article published in the journal Brain Research showed that pretreatment of nerve cells with

isolated ginkgolides, the anti-oxidant component of ginkgo biloba leaves, or vitamin E, prevented

the beta-amyloid-induced increase of reactive oxygen species (ROS). Ginkgolides, but not vitamin

E, inhibited the beta-amyloid-induced HNE (4-hydroxy-2-nonenal) modification of mitochondrial

proteins. (Yao et al., 1999)

A 52-week, double-blind, placebo-controlled, fixed dose, parallel-group, multi-center study of

ginkgo biloba at a dose of 120 mg (40 mg three times a day) was conducted and published in 2000.

The placebo group showed a statistically significant worsening in all domains of assessment, while

the group receiving ginkgo biloba was considered slightly improved on the cognitive assessment

and the daily living and social behavior. No differences in safety between ginkgo biloba and

placebo were observed. (Le Bars et al., 2000)

A similar 52-week, randomized double-blind, placebo-controlled, parallel-group, multi-center

study of ginkgo biloba by the same research team was published in 1997. The group treated with

ginkgo biloba had an ADAS-Cog score 1.4 points better than the placebo group (p=.04) and a

Geriatric Evaluation by Relative's Rating Instrument (GERRI) score 0.14 points better than the

placebo group (p=.004). (Le Bars et al., 1997)

In an analysis of various studies and as measured by the ADAS-Cog, the 4 anti-cholinesterases

and ginkgo were equally effective in mild to moderate Alzheimer’s disease. Tacrine had a high

drop-out rate due to side effects. Most studies showed benefit from ginkgo but one did not. (van

Dongen et al., 2000)

Extracts of ginkgo contain different amounts of the various active substances and are also of

variable quality. (Kidd, 1999)

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Salvia

Several types of salvia may be helpful in preventing Alzheimer's disease, including Salvia

officinalis (Garden sage, common sage) and Salvia miltiorrhiza (red sage, Chinese sage, tan shen,

or danshen).

Some active ingredients of Salvia miltiorrhiza have attracted increasing attention for the treatment

of neurodegenerative diseases. Salvianic borneol ester was shown to reduce beta-amyloid

oligomers and prevent cytotoxicity. Salvianic borneol ester had the bifunctional activities of anti-

amyloid and neuroprotection. (Han et al., 2011)

The spice sage and its active ingredient rosmarinic acid may protect PC12 cells from amyloid-beta

peptide-induced neurotoxicity. (Iuvone et al., 2006)

Cognitive dysfunctions induced by a cholinergic blockade and Abeta 25-35 peptide are attenuated

by salvianolic acid B. (Kim et al., 2011)

In Salvia miltiorrhiza, phenolic acids possess protective properties against amyloid beta-induced

cytotoxicity, and tanshinones act as acetylcholinesterase inhibitors. (Zhou et al., 2011)

KUT

KUT is a Japanese herbal formula named “Kami-Umtan-To” that consists of 13 different herbs.

KUT has been used since 1626 for neuropsychiatric problems. KUT has been shown to increase

choline acetyltransferase levels and nerve growth factor in cultured rat brain cells.

In a 12-month open clinical trial using KUT and estrogen, vitamin E and NSAIDs, the rate of

cognitive decline per year was measured using the Mini-Mental Status Exam (MMSE). Twenty

patients with Alzheimer’s disease (MMSE score: 18.6 +/- 5.8) received extracts from original KUT

herbs, 7 Alzheimer’s disease patients (MMSE score: 21.3 +/- 2.8) were placed on the combination

23

therapy, and 32 patients served as controls (MMSE score: 20.8 +/- 5.6). The rate of cognitive

decline per year was significantly slower in the KUT group (1.4 points) and the combination group

(0.4 points) as compared to the 32 control patients who received no medicine (4.1 points). The

efficacy of KUT alone was most noticeable after 3 months of use. (Arai et al., 2000)

Curcumin

Curcumin, the active ingredient in the herb turmeric, is being investigated for use in Alzheimer’s

disease due to its potent anti-inflammatory action. (Grilli, 1999) (Joe, 1997) (Begum et al., 2008)

(Mishra and Palanivelu, 2008) (Mutsuga et al., 2011)

Thirty-four subjects began the 6-month trial. The lack of cognitive decline on placebo in this 6-

month trial may have precluded any ability to detect a relative protective effect of curcumin, which

presumably would have appeared as a slower decline rather than an improvement in cognition.

Although serum Amyloid ß40 levels did not differ significantly among doses, serum Aß40 tended

to rise on curcumin, possibly reflecting an ability of curcumin to disaggregate Amyloid ß deposits

in the brain, releasing the Amyloid ß for circulation and disposal. (Baum et al., 2008)

Green Tea

A study aimed to examine the neural effects of green tea extract on brain activation in humans.

Functional magnetic resonance imaging was recorded while 12 healthy volunteers performed a

working memory task following administration of 250 or 500 ml of a milk whey based green tea

containing soft drink or milk whey based soft drink without green tea as control in a double-blind,

controlled repeated measures within-subject design with counterbalanced order of substance

administration. A whole-brain analysis with a cluster-level threshold of P

24

cortex (DLPFC) including a cluster-level threshold of P

25

Summary

The incidence of Alzheimer’s disease is increasing at an alarming rate along with the aging of our

population. The vast majority of Alzheimer’s disease is acquired or idiopathic (of unknown cause)

by conventional medicine. There is much discussion about the cause of Alzheimer’s disease. Many

consider that it may not be caused by a single agent. The causes discussed here encompassed many

diverse medical theories, including the biochemistry of acetylcholine and neurotransmitters,

inflammation, oxidative stress and free radicals, and homocysteine. Recent advances in lab testing

may help identify the key areas in which to focus the therapies.

One interesting study showed that persons who had a love of reading and read frequently in

childhood had a very decreased incidence of Alzheimer’s disease. Regularly engaging in mental

activity is necessary for preservation of brain function. (Wilson et al., 2013)

Most of the medical treatments listed here are used only after Alzheimer’s disease develops. Some,

such as estrogen, vitamin B12, and antioxidants, are also important in preventing dementia.

Treatment Protocols

There are a vast number of choices in both drugs and nutritional supplements available for patients

with Alzheimer’s disease. A well-informed holistic or naturopathic medical doctor can be of great

help in ordering the appropriate lab tests and identifying the key supplements that will provide the

greatest benefit. The following are several of the supplements that have been covered in this

protocol along with standard daily dosages:

Acetylcholine support

Phosphatidylcholine derived from lecithin or capsulized with other cognitive enhancers.

Antioxidants

26

Ginkgo biloba, 120 mg in the morning or 60 mg three times daily

Vitamin E, 2000 mg per day

Vitamin C, 1,000 mg per day

Acetyl-L-carnitine, 500 mg twice a day

N-Acetyl cysteine, 500 mg twice a day

Anti-inflammatory

Essential fatty acids (including omega-3 and omega-6 fatty acids, DHA, EPA and GLA). Dosage

depends on the form.

Curcumin (Turmeric), 400 mg three times a day

Homocysteine

Vitamin B12, 1000 mcg a day or by injection

Vitamin B6, 500 mg a day

Folic acid, 400 mcg a day

SAMe, 400-1600 mg a day, particularly if there are signs of depression

Nervous system support

Methylcobalamin, the neurologically active form of vitamin B12; up to 5-10 mg daily for brain

aging

Phosphatidylserine, 100 mg three times a day

Inhibit AGEs

Carnosine, 1000 mg per day (minimum) should be considered

27

Based upon the results of appropriate lab testing (see the lab section at the beginning of this article),

the following may be used in addition:

Hormone replacement therapy, preferably with natural forms of progesterone and estrogen.

DHEA supplementation. The usual dose is 10-50 mg in females and 40-100 mg in males.

Melatonin, 10 mg at bedtime, particularly if there is insomnia

Innovative drug strategies can include the following:

Hydergine

Piracetam

Drug-Supplement Interactions

Ginkgo biloba

Ginkgo acts to thin the blood by reducing the ability of platelets (blood-clotting cells) to stick

together. Care should be used when using Ginkgo with other agents that thin the blood, such as

heparin, warfarin, aspirin, and some NSAIDs. (Harkness and Bratman, 2000)

Vitamin E

Vitamin E has a long history of safe use. Vitamin E may add to the blood thinning effect of aspirin

and cause an increased risk of bleeding. Care should be taken when taking aspirin with vitamin E.

(Harkness and Bratman, 2000)

Vitamin K

Vitamin K directly counteracts the action of warfarin. Patients taking warfarin should seek

qualified medical advice before taking vitamin K. (Harkness and Bratman, 2000)

28

EPA and DHA

EPA and DHA have been shown to inhibit abnormal clotting in blood vessels. Care should be used

with those taking anticoagulant medications such as warfarin.

29

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Nutritional Support for Alzheimer’s diseaseAcetylcholine SupportPhosphatidylcholine (Lecithin)Pantothenic AcidAntioxidantsVitamin EVitamin CAcetyl-L-CarnitineVitamin ACoenzyme Q10N-Acetyl-CysteineFlavonoidsNADHEssential Fatty AcidsDHAEPAGLAVitamin B12Folate

Nervous System SupportPhosphatidylserineInositolVitamin KIdebenone

Diabetes Testing and AGEsVitamins B1 and B6CarnosineLithium

Natural Hormone ReplacementEstrogenEstrogen in WomenTestosterone in MenMelatoninMusic Therapy and MelatoninTryptophanStressDHEA

Herbal TreatmentsHuperzine AGinkgo BilobaSalviaKUTCurcumin

Green TeaCannabis

SummaryTreatment ProtocolsDrug-Supplement InteractionsGinkgo bilobaVitamin EVitamin KEPA and DHA