Alzheimer's Disease: A Treatment Strategy

jarice at delphi.com jarice at delphi.com
Fri Jan 13 03:04:11 EST 1995


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)
 



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