Magnesium
"Oxidative stress and neurodegenerative processes are
accompanied by a pronounced magnesium deficiency. This is also
true for diseases associated with premature aging such as Down
syndrome." (23)
"Magnesium deficiency affects calcium transport and iron
sequestration, impairs mitochondrial function, and induces radical
generation by redox recycling. In contrast, magnesium
administration improves energy and glucose utilization, stablizes
enzymes and membranes, and protects biomolecules against
oxidative damage by reactive radicals. It has been demonstrated
that magnesium exhibits potent chemo- and cardio-protective
actions. Newly developed magnesium salts, with greatly enhanced
oral bioavailability and exhibiting extremely low toxicity, have
been used sucessfully to counteract stress and age-related
excitotoxicity in experiments in animals and humans. The
administration of magnesium salts with high bioavailability
(magnesium chloride [Slo-Mag], magnesium citrate [Citroma],
magnesium hydroxide [Mag-Ox], magnesium pidolate)
[22]prolongs life span and reverses age-related morphological,
biochemical, electrophysiological, and behavioral impairments."
(23)
"The three major molecular mechanisms that have been identified
as being involved in the irreversible process of specific neuronal
death during aging are glutamate-mediated excitotoxicity, intra-
neuronal calcium overload, and hydroxyl radical-induced
peroxidation and oxidative damage to biomolecules." (23)
Magnesium affects all of these mechanisms favorably. Magnesium
also reverses the age-dependent decline in melatonin production.
"The elderly may be at risk of developing a magnesium dificiency
due to poor food selection, decreased absorption, diseases that
cause magnesium depletion, or medications that may increase
urinary loss of magnesium." (22)
I therefore suggest consumption of a magnesium salt sufficient to
provide 400 -800mg of elemental magnesium per day.. Example:
2 tablets of magnesium chloride (OTC: Slo-Mag) three times a day
(6 total/day) with meals.
IV Replacement of Hormones Known to be Deficient in
AD Patients
Melatonin.
Melatonin is a hormone produced at night in the pineal gland. It is
associated with sleep and circadian rhythm. It is a very potent and
efficient endogenous radical scavenger. It reacts with the highly
toxic hydroxyl radical and provides on-site protection against
oxidative damage to biomolecules within every cellular
compartment. Melatonin production declines in a very regular and
predictable way with age. While in young animals and humans the
24-hr cycle of melatonin is very robust, the cycle frequently
deteriorates during aging and is totally abolished in
neurodegenerative diseases such as Alzheimer's Disease (23,).
Agents that are active against the symptoms and progressions of
diseases associated with accumulating oxidative damage and
neuronal degeneration, such as acetyl-L-carnitine and
magnesium, prevent the age-associated decline in nocturnal pineal
and blood melatonin in rodents. (32) The exogenous
administration of melatonin substantially extends the life span in
experimental animals (32). Melatonin exerts direct and indirect
beneficial effects in delaying developmental and aging processes.
(28,32)
"The diurnal rhythm of melatonin can be substantially perserved
during aging by restriction of food intake or other nutritional and
pharmaceutical treatments in rodents; these treatments increase
life span and prevent premature aging as well as delay the onset of
neurodegenerative diseases." (33)
Melatonin has antagonistic effects on glutamate-mediated
excitotoxicity, one of the three mechanisms proposed for neuron
death during aging. Melatonin is a highly efficient free radical
scavenger, especially of hydroxyl, thus counteracting another of
these mechanisms, hydroxyl-radical induced peroxidation and
oxidative damage to biomolecules. Dementia due to premature aging
in patients with Down syndrome or accelerated aging in patients
with Alzheimer's disease may be attributed to an enhanced
exposure to hydroxyl radicals. Melatonin is the best known free
radical scavenger. Additionally, melatonin reportedly exerts
potent oncostatic, immunostimulatory, and rejuvenating effects in
old rodents. (22)
"Several lines of evidence suggest that abnormalities in oxidative
metabolism and specifically in mitochondria may play an
important role in Alzheimer's disease. The abnormalities include a
profound deficit in the activity of the ketoglutamate dehydrogenase
complex (KGDHC), which is likely to lead to impaired metabolism
of glutamate and might contribute to selective neuronal cell death
by excitotoxic mechanisms." (15)
"The plasma half-life of melatonin is relatively short. Plasma
profiles produced by oral formulations are markedly dissimilar to
the typical in vivo plasma profile. In healthy young subjects,
melatonin can be detected for 10-14 hr per night at a level that
typically varies between 100-300 fm/ml. In contrast, bolus oral
and i.v. doses typically produce pharmacological levels (in the
nanomolar range) that are excreted within 2-5 hr." (34) "The
difference between the endogenous profile and that produced by
exogenous administration may be of critical importance. Many of
the physiological effects of melatonin in animals appear to be
related to the duration of the plasma profile rather than the
plasma level per se. If melatonin is to be developed as a successful
clinical treatment, differences between the pharmacological
profile following exogenous administration and the normal
endogenous rhythm should be minimized. Continued development as
a useful clinical tool requires control of both the amplitude and
duration of the exogenous melatonin pulse. There is a need to
develop novel drug delivery systems that can reliably produce a
square-wave pulse of melatonin at physiological levels for 8-10
hr duration." (34)
Since there is not now available a commercial timed-release
formulation of melatonin, (it should be available relatively soon),
imitating the natural youthful physiologic profile should be
attempted by doing two things: Take a large initial dose (say, 6-10
mg) right before bed. Melatonin will remain in the blood longer.
And, if the patient wakes up in the middle of the night with at least
4 hours of sleep left, he/she should take another 3 mg capsule of
melatonin.
At extremely high doses (200 mg/day and above), melatonin
increases depression and insomnia. At doses of around 3-30
mg/day, no known side effects are evident, other than the hypnotic
effect (sleepiness). (34)
Melatonin should not be taken by patients with myelocytic
leukemia or multiple myeloma. Melatonin production is supressed
by vitamin B12 supplementation, a supplement frequently taken
by the elderly to avoid pernicious anemia.
I therefore suggest nightly consumption of 6 to 10 mg melatonin
just before going to sleep, and consumption of an additional 3 mg
if the patient wakes up in the night with at least 4 hours of sleep
to go. When timed-release melatonin becomes available, I suggest
using that.
Dehydroepiandrosterone (DHEA)
Dehydroepiandrosterone (DHEA) is a hormone of the adrenal
cortex. It peaks at around 20 to 30 years of age at 50 to 100
ug/dl, and declines thereafter at about 20% every decade after age
25, stabilizing at 5% of youthful levels at age 85. Administration
of DHEA or certain analogs produces an array of beneficial effects
on obesity, muscle strength and mass, type II diabetes, cholesterol
levels, autoimmunity, cancer initiation and proliferation,
osteoporosis, memory, and aging. It has been reported that an
increase in plasma DHEA is correlated with a 36% reduction in
mortality from all causes, and a 48% reduction in mortality from
cardiovascular disease. (35, 43)
"(It has been suggested) that acetylcholine (Ach)
neurotransmitter activity manifests its physiologic action through
inhibition of K+ channels in the cell membrane which serves to
maintain neuroexcitatory activity. Based on this, Roberts
postulated that the progressive debilitation of aging, as is seen in
AD, could be due to gradual decrease in 'the capability for genetic
transcription of major K+ channel components so that the ability
of cells to adjust to changing conditions would be lost.' He felt that
the progressive decline in the hormonal DHEA, DHEA-S levels
with advancing age may be a key factor producing the debility of
aging leading to AD through loss of K+ channel inhibition. The
postulate that DHEA would inhibit K+ channels was based on
DHEA's broad physiologic action: modulation of diabetes, tumor
induction, and effects on autoimmune response which Roberts felt
were key factors in preventing age-related events. Regardless of
the validity of his concept, he has found that DHEA and it's sulfate
in tissue culture enhanced neuron and glial survival...Robert's
concept may be further supported by the high concentration of
DHEA-S found in the brain (6.5 times plasma concentrations),
which suggests that DHEA may have modulating effects on cell
membranes which alter response to neurotransmitters." (35)
DHEA and it's sulphonated metabolite DHEAS are the major
secretory product of the human adrenal gland. "Reduced plasma
levels of DHEA (48% less than age matched controls) have been
found in AD patients. DHEA and DHEA-S enhance memory retention
in mice and block the memory impairing effects of scopalomine.
Besides anti-amnestic effects, DHEA-S may protect partly
degenerated or at-risk brain cells." (42) "DHEA has been likened
to an "antihormone", which cannot serve to excite in the true
classical sense of hormone action, but deexcites metabolic
processes which overproduce when DHEA is in short supply. DHEA
may act by buffering or antagonizing the action of corticosteroids
to modify stress-mediated injury to tissue, an action which may
be critical to the diseases of aging." (43) "DHEA-S was shown to
block enzymatic effects of glucocorticoids, thus, a certain part in
the progression of AD may be played by the decrease in DHEA-S
and its antiglucocorticoid functions." (36)
"In a study of 24 AD patients and 50 controls, subjects were
examined for DHEA-S/cortisol ratios. A strong negative
correlation was found between age and DHEA-S, but no significant
correlation was found between cortisol levels and age; therefore,
the DHEA-S/cortisol ratio dropped remarkably in older normal
subjects as compared to young individuals. Interestingly, a trend
was found for a lower DHEA-S/cortisol ratio in AD patients
compared to age- and sex-matched controls. indicating that the
ratio could be an appropriate measure for the effects of DHEA-S as
an antiglucocorticoid by which subjects at risk for the neurotoxic
effects of glucocorticoids could be identified. These previous
results suggest a possible relation of cognitive impairment to
circulating corticoid levels (37, 43), and they indicate a possible
role of DHEA-S in diminishing cortisol effects on hippocampal
cells avoiding progressive hippocampal degeneration in AD." (38)
"While the nature of possible antiglucocorticoid effects is
unknown, several authors have reported physiological antagonism
by DHEA of corticosteroid effects such as thymic involution and
suppression of lymphocyte proliferation. We propose that, in
addition to such "pharmacodynamic" effects, DHEA may have a
"pharmacokinetic" effect on circulation cortisol levels.
Pharmacologically induced increases in DHEA levels are
significantly correlated with decreases in 4 p.m. serum cortisol
levels." (39)
"Physicians are testing DHEA as a possible therapy for systemic
lupus erythematosus, a chronic inflammatory disease. In lupus,
the immune system goes awry and makes abnormal antibodies that
can damage or sometimes destroy the kidneys, brain, or heart.
Experimental evidence that DHEA benefits mice that develop a
lupus-like disease, coupled with the observation that DHEA levels
are abnormally low in patients with lupus, led researchers to test
the hormone in 57 women with lupus. The women took 50-200
mg of oral DHEA every day for 3-12 months. About two-
thirdsreported some relief of symptoms including rashes, joint
pain, headaches, and fatigue. 'DHEA has the potential to be an
important drug in lupus, particularly because of its apparent
ability to significantly reduce the need for steroids', said one
scientist." (40) Thus, there are indications that DHEA
administration is helpful in mitigating an autoimmune
inflammatory response. AD has now been shown to have
autoimmune inflammatory etiology. DHEA's anti-inflammatory
effect could, therefore, be therapeutic for AD.
Large-scale clinical studies are now underway of DHEA and AD
patients at the National Institute of Mental Health. (41)
Cognitive impairment due to endogenous hypercortisolemia may be
prevented by anticorticoid hormonal treatment. (37) Chronic
glucocorticoid administration leads to hippocampal damage in the
rat and, due to a dysfunction of the hypothalmic-pituitary-adrenal
axis, to progressive dementia. (36)
"Based on animal studies, the anticipated potential benefits of
DHEA replacement therapy would be: (a) increased mitochondrial
respiration of the liver, (b) increased fatty acid deacylation, (c)
reduced blood serum cholesterol, (d) reduced LDL cholesterol, (e)
increased memory retention, (f) increases in calcium deposition
and bone density, (g) increased muscle mass and strength, (h)
increased skin thickness, (i) stimulation of the immune system as
measured by an antiviral and antibacterial action, (j) reduced
shrinkage of the thymus gland, (k) chemo-preventative activity
for certain cancers (breast and colon) (l) decreased blood
pressure, (m) anti-obesity action by reducing blood sugar and
insulin, (n) reduced negative effects of stress, and (o) increased
sex drive and performance." (42)
"Possible side effects, based on animal studies at extremely high
doses, are: (a) male pattern baldness, (b) hirstutism, (c)
pituitary tumors, (d) liver hypertrophy, and (e) prostate
hypertrophy. It is not likely that doses needed to give a blood level
equivalent to a 25 year old would cause any problem. With proper
physiological monitoring, the potential benefits may greatly
outweigh any potential risks for many people." (42) There have
been suggestions that since DHEA has an androgenic role, it might
exacerbate prostate cancer, and thus tests to ensure the absence of
prostate cancer were recommended proir to starting a DHEA
replacement program for men. Recent studies show no effect on
prostate growth (35), and DHEA had no proliferative effect on
transplanted prostatic cancer cells in mice. (46) Prostate cancer
tests prior to DHEA replacement are therefore probably
unnecessary (they may be valuable in their own right,
however).In fact, given the oncostatic and anti-neoplastic
properties of DHEA, DHEA may actually help prevent and fight
prostatic cancer.
I therefore suggest daily hormone replacement therapy with DHEA
(one capsule in the morning) to achieve youthful DHEA levels for
Alzheimer's patients.
Guidelines:
It is important to use antioxidants with DHEA because of the
possibility of oxidative stress on the liver. Uptake of DHEA varies
from person to person. Because of that, testing at intervals is
important to ensure proper levels of DHEA are being achieved.
Step One: Get a DHEA-Sulfate blood test. A doctor must order this
test. Analyze the results compared to a normal 25 year old's
serum levels. Average DHEAS levels in young men are 9.2
umol/litre. Average levels for young women are 7.1 umol/litre.
Average levels for both sexes age 85 and older are 1.7 umol/litre.
(30) If you take too much DHEA, there could be an inhibition of
the adrenal glands to produce any DHEA. Assuming you are
deficient as shown by the test, initiate your DHEA intake at
doctor-recommended levels.
Note: given average DHEAS levels in young and old people and the
standard deviation around those levels, a dose of 200-250 mg
DHEA/day would be very unlikely to be excessive if you are over
70 years of age, even without an initial test for DHEAS levels.
Step Two: After using DHEA for two months, obtain another DHEAS
test. Have your blood drawn at least 3 hours after your normal
morning dose of DHEA, and at the same time of the day as your first
test (DHEA secretion varies during the day according to your
circadian rhythm. Adjust your dose, if necessary.
Pregnenolone
"An additional approach (to ameliorating corticosteroid-associated
behavioral and cognitive impairment in certain patients),
involving the administration of precursor steroid hormones, has
been recently proposed. The biosynthesis of steroid hormones
begins with cholesterol, from which the glucocorticoids,
mineralcorticoids, and sex steroids all derive. Pregnenolone, a key
cholesterol metabolite, is the major precursor for the steroid
hormones. Its formation, regulated by pituitary hormones, may
become rate-limiting in aging, stress, and other conditions,
resulting in steroid imbalances. The recent findings of a striking
memory-enhancing effect of pregnenolone and literature showing
virtually no human toxicity, suggest that administration of
pregnenolone may help reestablish normal relations among the
various steroids when abnormalities occur." (39)
