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Alzheimer's
Disease Protocol
Coenzyme
Q10 (CoQ10)
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. However, the appropriate clinical studies using CoQ10 have not
yet been done (Beal 1999).
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
diseases. A 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 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).
Anti-Inflammatory
Supplements
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
(Joe 1997; Grilli 1999).
Essential
Fatty Acids
Essential fatty acids are found in oils including flax, borage, and
fish oils. Fish oils contain EPA (eicosapentaenoic acid) and DHA (docosahexaenoic
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 (docosahexaenoic 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 (Horrocks et al. 1999; Kyle et al. 1999). This means that while
the alpha-linoleic acid in flax oil may have converted to DHA in youth,
when people age beyond 50 years, a delta 6-desaturase enzyme deficit
develops, meaning that one has to eat lots of cold water fish or take
a supplement that contains DHA in order to obtain optimal quantities
of DHA.
EPA
A Japanese study found that administration of EPA (900 mg a day) in
patients with Alzheimer's disease improved MMSE significantly with maximal
effects at three months, while the effects lasted six months. However,
the score of MMSE decreased after six months (Otsuka 2000).
GLA
Researchers have proposed that fish oils and GLA (gamma-linolenic acid)
may help prevent Alzheimer's disease by its anti-inflammatory effect
of suppressing interleukin-1 production by monocytes (McCarty 1999).
Homocysteine
Vitamin
B12
Folate
SAM-e
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,
methylmalonic acid, or both is recommended as a more accurate assessment
of cobalamin status (Bopp-Kistler et al. 1999; McCaddon et al. 2001a).
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). Another
study was conducted with outpatients at a geriatric memory clinic. Seventy-three
consecutive outpatients with probable Alzheimer's disease showed that
low vitamin B12 status was related to an increase in behavioral and
psychological symptoms of dementia: irritability and disturbed behavior
(Meins et al. 2000).
A population-based
longitudinal study of 370 non-demented persons, aged 75 years and older,
conducted in Sweden found that subjects with low levels of B12 or folate
had twice the risk of developing Alzheimer's disease over the 3-year
period of the study (Wang et al. 2001).
Folate
Folate or folic acid derives its name from foliage (green plants). Folacin
was first isolated from spinach and other leafy green vegetables in
1941. Folic acid is needed for DNA synthesis and is also needed to make
S-adenosyl methionine (SAMe). A study of 126 patients, including 30
with Alzheimer's disease, found that the levels of folate in the cerebral
spinal fluid (CSF) were significantly lower in late-onset Alzheimer's
disease patients (Serot et al. 2001).
A study
by Renvall et al. (1989) found low levels of folate (along with deficiencies
of thiamin and vitamin B12) in elderly individuals with senile dementia
of the Alzheimer's type (22 subjects) as compared to the cognitively
normal control group (41 subjects).
SAM-e
SAMe is perhaps the safest and most effective antidepressant in the
world. SAMe is a precursor for glutathione, coenzyme A, cysteine, and
taurine.
One
study measured the postmortem levels of SAMe in the brains of 11 patients
with Alzheimer's disease. Decreased levels of S-adenosylmethionine (-67
to -85%) and its demethylated product S-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 et al. 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 (Delwaide et al. 1986; Crook et al. 1992; Engel et al. 1992).
In a study by Heiss et al. (1994), a 6-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 toward 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 a day
for one month, in 11 patients with Alzheimer's disease. Language and
orientation improved significantly more on inositol than on placebo
(glucose) (Barak et al. 1996).
Vitamin K
An article by Allison (2001) 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
ApoE e4 carriers than in that of persons with other ApoE genotypes.
The ApoE e4 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/L-Tyrosine
kinase receptor (Gas 6/Axl).
Vitamin K may also reduce neuronal damage associated with cardiovascular
disease.
Some have proposed 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 (Nitta et al. 1993;
Nitta et al. 1994; Yamada et al. 1997).
Treatment with idebenone and alpha-tocopherol prevented learning and
memory deficits caused by beta-amyloid in rats (Yamada et al. 1999).
Three hundred patients with Alzheimer's disease were randomized to receive
either placebo or idebenone, 30 mg 3 times a day, or 90 mg three times
a day for 6 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 3 times
a day group, as compared to placebo. (Bergamasco et al. 1994; Anon.
2001).
An
article by Weyer et al. (1997) 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 and treated for 6 months. After month 6, the idebenone
90 mg group showed statistically significant improvement in both the
Total and Cognitive Alzheimer's Disease Assessment Scales (Weyer et
al. 1997).
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 to help guide
appropriate supplementation.
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 melatonin in Alzheimer's
disease:
Melatonin
was shown to significantly inhibit the release of free radicals in neuroblastoma
cells (Lahiri et al. 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 of melatonin daily for 22 to 35 months. A significant improvement
of sleep quality was found (Brusco et al. 1999).
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).
Brusco
et al. 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 melatonin capsules daily at
bedtime for 22-35 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
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 30-40 minute morning sessions of music therapy 5 times a 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 might have contributed to patients' relaxed
and calm mood (Kumar et al. 1999).
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 at 4 and 7 hours later, and the Modified Mini-Mental State was administered
at baseline and 4 hours later. Patients with dementia of the Alz-heimer
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).
Adrenal
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).
DHEA
Alzheimer's disease patients with higher dehydroepiandrosterone (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 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 DHEAs in
cases that developed dementia of the Alzheimer type within 3 years as
compared to matched controls (Hillen et al. 2000).
Inhibition
of AGE Formation
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). 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).
Carnosine
Carnosine is a multifunctional 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
carnosinase.
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. Research has shown that carnosine can buffer
copper and zinc toxicity in the brain (Horning et al. 2000; Trombley
et al. 2000).
Carnosine
has also been shown, in vitro, to inhibit nonenzymic 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 (Munch et al. 1997; Hipkiss 1998; Hipkiss et al. 1998;
Preston et al. 1998).
Herbal
Treatments
is an alkaloid isolated from the Chinese herb Huperzia serrata.
In experiments using rats, improved the decrease in acetylcholine
activity in cortex and hippocampus (Cheng 1996; Tang 1996; Bai et al.
2000; Wang et al. 2000). A double-blind, multicenter study of was conducted in China. Fifty patients were given 0.2 mg nd 53 patients were given placebo for 8 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. No severe side effects were found (Xu et al. 1995).
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, seven Alzheimer's disease patients (MMSE score: 21.3 ±
2.8) were placed on the combination 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).
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 classified as idiopathic (of unknown cause) by conventional
medicine. There is much discussion about the cause of Alzheimer's disease
and many consider that Alzheimer's disease 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 on 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.
Most
of the medical treatments listed here are used only after Alzheimer's
disease develops. Some, such as folic acid, vitamin B12, and antioxidants,
are important in preventing dementia also.
Treatment
Protocols
There
are a vast number of choices in both drugs and nutritional supplements
available for patients with Alz-heimer'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
and drugs that have been covered in this protocol along with standard
daily dosages:
Acetylcholine
support
Take
6 capsules daily of a choline-based multi-nutrient formula called Cognitex
An additional 10 grams a day of soy lecithin may be considered
Antioxidants
Ginkgo
biloba, 120 mg in the morning
Vitamin E, 2000 mg a day
Vitamin C, 1000 mg a day
N-acetyl cysteine, 600 mg once a day
Anti-inflammatory
Essential
fatty acids (DHA, EPA, and GLA). Six capsules daily of a formula called
Super GLA/DHA provides an ideal balance
Curcumin (turmeric), 900 mg twice a day
Homocysteine reduction
Vitamin
B12, 1000 mcg or more a day
Vitamin B6, 500 mg a day
Folic acid, 800 mcg a day
SAMe, 400-1600 mg a day, particularly if there are signs of depression
Neuronal protection
Methylcobalamin,
the neurologically active form of vitamin B12, 5-40 mg daily to protect
against excitotoxity
Phosphatidylserine, 100 mg 3 times a day
Acetyl-L-carnitine, 1500 mg twice a day
Melatonin, 3-10 mg at bedtime, particularly if there is insomnia
Inhibit glycation
Carnosine,
1000 mg a day (minimum) should be considered
Based upon the results of appropriate lab testing (see the lab section
at the beginning of this protocol), the following may be used in addition:
Hormone
replacement therapy, preferably with natural forms of progesterone,
testosterone, and estrogen.
DHEA supplementation. The usual dose is 15-50 mg in females and 50-75
mg in males.
Innovative drug strategies can include the following
Hydergine,
10-20 mg daily
Piracetam, 2400-4800 mg daily
Deprenyl, 5 mg, twice weekly
Drug-Supplement Interactions
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 et al. 2000).
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 et
al. 2000).
Vitamin K directly counteracts the action of warfarin. Patients taking
warfarin should seek qualified medical advice before taking vitamin
K (Harkness et al. 2000).
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.
The Life Extension Foundation has designed several products specifically
for neurological support. These include:
Cognitex
contains phosphatidycholine, phospha-tidylserine, vinpocetine, and pregnenolone.
It is available with and without pregnenolone. Take 5 capsules in the
morning and 5 in the evening.
Chronoforte contains acetyl-L-carnitine, alpha-lipoic acid, carnosine,
and zinc.
CDP choline is a unique form of choline that readily passes through
the blood-brain barrier directly into brain tissue where it enhances
cerebral energy metabolism.
Life Extension Foundation offers several forms of ginkgo biloba, including
Super Ginkgo Extract, ginkgo with DMAE (DMAE-Ginkgo Caps), and ginkgo
with phosphatidyl choline (PC-Ginkgo Caps).
The Life Extension Mix has a wide variety of antioxidants, vitamins,
and minerals.
Essential Fatty Acids are available from several oils. Super GLA/DHA
(also containing EPA) will help to control inflammation by balancing
essential fatty acid intake.
For more information
Contact
the Alzheimer's Association (800) 272-3900.
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