oops!  forgot the enclosures I promised.  here they are.
Wendy
 
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I'm forwarding some research you might enjoy reading.
 
Fletcher
 
 
 
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I wrote this paper for my dad, who may have Alzheimer's Disease. It is the
result of about 100 hrs work on medline and at the biomedical library.
Alzheimer's is in many ways accelerated aging of specific neurons in the
brain. In doing research on this paper, I've modified my own anti- aging
strategy, most notably by adding Deprenyl, magnesium, selenium, Coenzyme
Q-10, DHEA, and pregnenolone (at the appropriate ages). I think most
readers of this newsgroup will find this paper interesting. If a doctor
says that there's no treatment for Alzhiemer's, the medical literature
proves him wrong. It's divided into 3 parts. Any feedback would be
appreciated.
 
Alzheimer's Disease: A Treatment Strategy
 
by James L. Rice, 12 December, 1994
 
Introduction
 
Alzheimer's Disease (AD) is a neurodegenerative disorder of the central
nervous system that affects almost 1 in 10 individuals who survive beyond
age 65. The disease afflicts 19% of individuals 75 to 85 years old, and 45%
of individuals over 85. It is characterized by cerebral cortical atrophy,
neuronal loss, neurofibrillary tangles, and neuritic plaques. The primary
neuropharmacologic defect involves reduced activity of the enzyme choline
acetyltransferase, causing reduced synthesis of acetylcholine (ACh). Other
neurotransmitters known to be deficient in AD include dopamine and
serotonin. Initially, components of short-term memory and immediate recall
are lost, plus a decline in other higher cognitive functions such as
attention. Eventually, memory loss is so severe that patients lose the
ability to care for themselves.
 
Why Not Tacrine/Cognex?
 
One pharmacologic approach to enhancing cholinergic function involves
inhibiting ACh degradation by inhibiting acetylcholinesterase
(physostigmine, tacrine). Results of studies involving this approach are
conflicting: no consistent benefit has been shown in patients with AD.
Although therapy with tacrine has been beneficial in some patients, it has
not been effective in all cases and has the potential to cause serious
adverse effects. "(With tacrine), the magnitude of the changes (in patients
receiving tacrine) was small, even in responsive patients, and many
patients responded only partially or not at all. Furthermore, it appears
that treatment response is obtained only at higher doses on the margin of
patient tolerability." (1) Tacrine appears to have marginal benefit and
major side effects "43% of tacrine treated patients had increases in serum
hepatic enzyme activity and 51% of tacrine treated patients had adverse
events related to treatment." (1) Tacrine is the only drug approved by the
FDA for use against AD.
 
An Alzheimer's Disease Strategy
 
A strategy against AD will, of necessity, involve elements not specifically
approved by the FDA for AD, but which have either direct evidence of
efficacy or a compelling rationalle for their effectiveness combined with
little or no risk. In fact, most of the elements in this strategy have
numerous benefits including anti- arteriosclerotic effects (slows or
prevents heart disease), oncostatic and anti-neoplastic effects (helps
fight and prevent cancer), immunostimulatory effects (fights disease), and
possibly even extended average and maximal lifespans.
 
The cause of AD is unknown, but there is a large and rapidly increasing
number of studies indicating an inflammation response, either due to local
insult or genetic mutation may be one source of the damaging processes.
 
My anti-Alzheimer's strategy is multifaceted. Two or more compounds that
operate by different mechanisms are likely to prove more effective than any
single agent administered alone. The strategy is:
 
I) Accurate diagnosis using the new eye test. (2, 3)
 
II) Drugs or compounds shown to have beneficial effects on AD with few if
any adverse effects (Deprenyl, Acetyl-L-Carnitine).
 
III) Replacement of hormones known to be deficient in AD patients (or the
elderly in general) to a level found in healthy young adults (DHEA,
Melatonin, Pregnenolone), and which have generalized geroprotective or
antiaging effects plus indications of efficacy against specific AD
etiology. Since AD is a disease of aging, a general anti-aging, or
geroprotective, strategy may prove beneficial.
 
IV) Antioxidants (Deprenyl, Melatonin, Magnesium, generalized vitamin therapy).
 
V) Anti-inflammatory Therapy: Drugs and Oral Tolerization
 
I. Diagnosis
 
Diagnosis of AD has been notoriously difficult, and it is frequently
misdiagnosed.
 
I suggest replicating the recently reported test for AD involving the
ability of a highly dilute solution of the cholinergic antagonist,
tropicamide, to dilate pupils in probable AD patients. The general
principle of the test is that in AD, acetylcholine-producing neurons
degenerate. The dilating compound tropicamide works by interfering with
acetylcholine. Presumably, AD patient's eye nerve cells produce very little
acetylcholine, so much less tropicamide is required to affect them. Because
this test has not yet been translated into a simplified clinical test, it
is important to replicate the actual experiment as closely as possible so
that results can be compared directly with the experimental data. (2, 3)
 
Procedure:
 
1) Call an opthalmologist affiliated with a hospital (a hospital will have
the ability to prepare the dilute eye drops in a sterile environment- a
pharmicist will not), and explain that you want to replicate as closely as
possible the procedure described in the article:
 
"A Potential Noninvasive Neurobiological Test for Alzheimer's Disease",
Science: Vol 266, 11 Nov 1994, pp. 1051-1053 (3)
 
Tell the ophalmologist that you will need a specially compounded
formulation of tropicamide, diluted to 0.01% (normal dilution is 0.5% to
1.0%), prepared prior to your arrival for your appointment, and that you
will want the patient's pupil diameter measured at intervals for one hour
after administration. Reading the experiment report and getting familiar
with the data recording sheets will take some time. Tell them to allow
about an hour and a half for the appointment.
 
2) Take a copy of the experiment write-up in with you, or send a copy to
the opthalmologist beforehand. Take the included graph, and blank data
table with you.
 
3) Actual Procedure:
 
A) Have the patient sit in a semidarkened room for 2 or 3 minutes. Measure
the resting pupil diameter for 1 minute. Record the average value on the
data sheet. Then administer one drop of the dilute solution of tropicamide
to one eye. Note the time. Begin timing from this point.
 
B) Examine the eye for pupil diameter for 30 seconds at the following times
after drop administration and record the average value of pupil diameter on
the data sheet.
 
Times: 2, 8, 15, 22, 29, 41, and 51 min after drop administration.
 
C) Perform the calculations indicated on the data sheet to convert raw
pupil diameter measurements to percentage changes from the baseline, or
initial measurement.
 
D) Plot the percentage changes at the measurement times on the included
graph. Compare the profile with the already plotted profiles of Alzheimer's
patients and healthy controls. Which profile more closely matches the
patients profile?
 
E) If the profile does not indicate Alzheimer's Disease, then consider the
possibility of non-Alzheimer's dementia, such as Korsakoff's syndrome,
multi-infarct demetia, and dementia with an extrapyramidal syndrome, and
get a doctor's advice on diagnosing and treating the problem. If the
profile more closely matches the AD patient's profile, then proceed with
the course of treatment indicated herein, in consultation with a physician.
 
 
II. Drugs or compounds shown to have beneficial effects on AD with few if
any adverse effects.
 
Deprenyl (Selegiline, Eldepryl)
 
(-)deprenyl is a drug with a unique pharmacological spectrum. It is a
highly potent and selective inhibitor of B-type monoamine oxidase (MAO), a
predominantly glial enzyme in the brain, whose activity increases
significantly with age. One of the monoamines oxidised by MAO-B is dopamine.
An inhibitor of MAO-B should, then, increase the dopamine content of the
brain. AD is characterized by death of dopamine-producing neurons. It is
the only safe MAO inhibitor which can be administered without dietary
restrictions. Additionally, maintenance on deprenyl enhances selectively
production of superoxide dismutase (SOD). A highly potent enzyme
antioxidant, SOD promotes catalase activities in the striatum, and
facilitates the activity of the nigrostriatal dopaminergic neurons (the
most rapidly aging neurons in the human brain) with remarkable selectivity.
It prevents the characteristic age-related morphological changes in the
neuromelanin granules of the neurocytes in the substance nigra. (18) Male
rats maintained on deprenyl lived longer (198 weeks average vs. 147 weeks
for controls in one trial- a 35% increase in average lifespan; in another
trial, average survival time increased from 115 to 134 weeks[18]) and
showed improved performance in learning tests (rats treated with deprenyl
improved 400% in a specific test administered over one year, while the
control rats performance declined 12%). Patients with Parkinson's disease
given deprenyl chronically from diagnosis required levodopa on average 550
days after diagnosis. Patients not given deprenyl required levodopa in 320
days. Patients with Parkinson's disease maintained on levodopa (a dopamine
precursor) and deprenyl (10 mg daily) live significantly longer than those
on levodopa alone. Continuous administration of deprenyl improves the
performance of patients with AD (4,5).
 
"Deprenyl increases the activity of the nigrostriatal dopaminergic system
and slows its age-related decline. Maintenance on deprenyl improves
significantly the performance of patients with AD. It is concluded that
Parkinson's disease and Alzheimer's disease patients need to be treated
daily with 10 mg deprenyl from diagnosis until death, irrespective of other
medication." (6)
 
"It is hoped that the conspicuous harmony between animal and human data
will give convincing ground for the proposal that the maintenance on small
doses of (-)deprenyl (10-15 mg weekly) from the age of 45 years is
reasonable and that continuous (- )deprenyl (10 mg daily) in Parkinson's
and Alzheimer's Disease is, irrespective of other therapies, not only
justified, but definitely mandatory." (6)
 
"The nigrostriatal dopaminergic neurons which contain 80% of all dopamine
are the most rapidly aging neurons in the human brain. The dopamine content
of the human caudate nucleus decreases enormously after age 45 by about 13%
per decade. Symptoms of Parkinson's disease appear if the dopamine content
of the caudate nucleus is less than 30% of the youthful level. Thus, the
aging of the striatal dopaminergic system is nromally slow enough to avoid
the appearance of such symptoms within the average lifespan. In 0.1% of the
population, however, the system deteriorates fast enough to cross the
critical threshold while the patient is still alive, and the symptoms of
"shaking palsey" are precipitated. MAO contributes to this decline in
dopamine by catalysing destructive reactions (oxidative deamination and
O-methylation). Also, when dopamine oxidises, it produces substantial
quantities of toxic free radicals and highly reactive quinones, which then
attack the nigrostriatal dopaminergic neurons. The waste products of these
reactions are thought to be what makes up the "age pigment", or lipofuscin,
which accumulates in the brain with age, and which may interfere with it's
functioning. The organism survives in the face of these attacks only by the
ability of superoxide dismutase (SOD) to counteract the free radicals.
Deprenyl enhances the production of SOD in the striatum of rats." (6)
 
Regarding cognitive enhancers, of which deprenyl is one, "A review of the
literature points out that the day-after approach of treatment (once severe
neuropathological damage has been established) is no longer feasable, or
has limited advantages. A different pharmacological approach, based on
preventive measures during the first stages of theneurodegeneration, seems
mandatory." (7)
 
"Regarding the consequences of the protecting effect of deprenyl in healthy
humans against the age related decline of the striatal dopaminergic system,
it is worth considering that just a small change in the rate of decline,
e.g. from 13% per decade to 10% per decade, anticipates at least a 15-year
extension in average lifespan and a considerable increase of the human
maximum possible lifespan, which is now estimated to be 115-120 years, to
145 years. Preventive deprenyl medication may also retard the precipitation
of Parkinson's and Alzheimer's diseases in the endangered population." (6)
 
"The beneficial effect of prolonged treatment with deprenyl on learning and
retention in selected low performer rats is in accordance with the rapidly
growing unequivocal clinical evidence that the administration of deprenyl
improves the performance of Alzhiemer's patients significantly. The
pharmacological profile and the safety of deprenyl allowed the conclusion
that in Parkinson's disease and Alzheimer's disease 10 mg of deprenyl daily
should be administered from diagnosis until death, independent of any other
kind of medication." (8)
 
Side effects of Deprenyl may include elevated dopaminergic symptoms and
elevated liver function enzymes. However, the risk of serious hepatic
toxicity is little or none. Other reported side effects include nausea
(14%), dizziness(12%), abdominal pain(4%). None of the side effects were
bad enough that treatment was discontinued. (9) Deprenyl (5 mg) should be
taken with breakfast and lunch to avoid reported insomnia with evening
dosing. (10)
 
"Selegiline (Deprenyl) seems to be safe in combination with low- dose
tacrine and it may reduce the dose of tacrine needed for a positive
treatment response in AD." (11)
 
"16 out of 18 available reports of clinical studies (including pen,
comparison, and double-blind, placebo-controlled designs) with a total of
approximately 790 AD patients, with 450 treated on selegiline from one to
12 months, indicate that selegiline in addition to providing a potential
symptomatic therapeutic efficacy, may retard the progression of AD." (12)
 
I therefore suggest 10 mg of deprenyl be taken daily (5 mg with breakfast,
5 mg with lunch) for any Alzheimer's patient.
 
Acetyl-L-Carnitine
 
"Acetyl-L-Carnitine (ALC) is the acetyl ester of carnitine, a naturally
occurring substance that acts as a carrier of fatty acids from the cytosol
into the mitochondrial matrix where they can be subjected to B-oxidation.
ALC is freely exchanged across membranes and can provide acetyl groups from
which to regenerate acetyl-CoA, therefore facilitating the transport of
metabolic energy. ALC, unlike L-carnitine, easily enters the brain.
Experimental studies have demonstrated that ALC promotes Acetylcholine
synthesis and release." (13)
 
"Defects in cholinergic neurotransmission do not, by themselves, constitute
the sole pathophysiologic concomitants of AD. Recent findings point out
that abnormalities in membrane phospholipid turnover and in brain energy
metabolism may also characterize AD. ALC is an endogenous substance that,
acting as an energy carrier at the mitochondrial level, controls the
availability of acetyl-L-CoA. ALC has a variety of pharmacologic properties
that exhibit restorative or even protective actions against aging processes
and neurodegeneration. A review of a series of controlled clinical studies
suggests that ALC may also slow the natural course of AD." (13)
 
"In open studies, ALC has been administered to patients affected by
cognitive impairment or true AD. ALC proved to be safe and well tolerated,
inducing only minor and transient side effects (agitation, gastric upset).
Therefore, a series of double-blind, placebo-controlled trials have been
performed for better defining ALC's efficacy in patients with AD." (13) In
nine trials from 1985 to 1990, where daily doses of ALC from 1 to 3 grams
were administered, very good efficacy was obtained in four of the studies,
good efficacy was obtained in one, some efficacy was obtained in two, and a
mild negative efficacy was obtained in one. (13)
 
Generally, ALC slowed but did not stop the deterioration in cognitive
function. "Although further insights into the mechanisms underlying the ALC
effect are needed as are additional controlled trials on a larger number of
AD patients (currently in progress), we believe that preclinical and
clinical evidence supports the hypothesis that ALC has therapeutic impact
on the progression of AD." (13)
 
"There were no major adverse side effects associated with administration of
Acetyl-L-Carnitine." (14)
 
"Treatment with L-carnitine, a manipulation designed to mitigate
consequences of a mitochondrial abnormality, normalized several
non-mitochondrial abnormalities in cultured Alzheimers cells." (15)
 
I therefore suggest the consumption of 2 grams of Acetyl-L- Carnitine daily
in three divided doses by AD patients.
 
III. Generalized Antioxidant Therapy
 
"Reactive oxygen metabolites (ROM), namely superoxide and hydroxyl free
radicals and hydrogen peroxide, are produced as a consequence of the
physiological metabolic reactions and functioning of the central nervous
system. ROM have also been implicated in the aetiopathogenic processis of a
number of pathological conditions of the brain. While primarily indirect,
evidence for this view is accumulating, and credence for the participation
of free radical oxidative interactions in promoting tissue injury in such
conditions as brain trauma, ischaemia, and toxicity, and in
neurodegenerative diseases such as Parkinson's, Alzheimer's dementia,
multiple sclerosis, and lipofuscinosis, is growing. Concomitant with this
new understanding of the injurious role of free radical oxidants in neural
pathology, is the increasing appreciation of the need for both fundamental
and clinical research into the development of the potential preventative
and therapeutic benefits that are now being foreseen for a variety of
antioxidant nutritional and pharmacologic interventions." (16)
 
"Compelling evidence suggests that cerebral deposition of aggregating
B-amyloid protein may trigger the neurodegenerative cascades of AD, down
syndrome, and, to a lesser degree, normal aging. We propose further that
free oxygen radicals are critically involved in B-amyloidosis. Apart from
the established role of free radicals in other amyloidoses, this is
consistent with a large number of findings: a) the salient relationship of
AD with aging and the increase in free oxygen radical liberation with
advancing age; b) biochemical and analytic epidemiologic evidence that free
radical formation is increased in the disorder; c) preliminary evidence
that quenching free radicals slows the clinical progression of AD; d) the
early and invariable B-amyloid accumulation in trisomy 21, a syndrome
associated with elevated free radical activity and with concommittent high
levels of B- amyloid precursor protein." (17)
 
"Some direct evidence indicates that free radical activity may be increased
in AD. Numerous abnormalities in AD such as condensed chromatin and
increased membrane permeability are consistent with the free radical
hypothesis. Vitamin E has been reported in two studies to be depleted in
AD. A primary role for free oxygen radicals in AD implies that quenching
free radicals would provide an effective treatment strategy, an
extrapolation that is not without empirical support. Desferrioxamine is an
iron chelator that does not cross the blood-brain barrier and is known to
attenuate iron catalyzed radical formation. It has been reported that in
the first clinical trial of desferrioxamine mesylate in AD that the
chelating agent may retard the clinical progression of AD. Additionally,
deprenyl, a MAO-B inhibitor that has antioxidant properties, has been
reported to decelerate the rate of cognitive impairment in AD." (17)
 
"Initial studies using high dose nutritional antioxidant vitamins E and C
and the monoamine oxidase inhibitor Deprenyl, have culminated in a large
scale multicentre controlled trial with deprenyl and vitamin E which
demonstrated the efficacy of the drug regime in reducing the rate of
progression if Parkinson's disease." (16)
 
"Indirect evidence indicating an enhancement of oxidative stress in AD
stems from studies showing increased levels of brain glucose 6-phosphate
dehydrogenase and red cell glutathione peroxidase activities, elevated
susceptibility to membrane lipid peroxidation, and reduced plasma levels of
the antioxidant micronutrients vitamins A and E, and carotenoids....The
capacity of vitamin E to protect cultured nerve cells against the cytotoxic
effect of the B- amyloid protein associated with AD has significant
therapeutic implications... The in vitro induction of Alzhiemer-type paired
helical filaments following addition of oxidative phosphorylation
uncoupling agents to normal fibroblast cells, and the addition of glutamate
to human neurones, illustrates a potential oxidative pathogenic mechanism.
A recent report of enhanced susceptability of Alzheimer skin fibroblasts to
ROM-mediated damage, provides pertinent new evidence of a compromised
antioxidant defence system in AD." (16)
 
"Lipofuscin, or age pigment, has been shown to accumulate in human brains
with age, with further increases occuring in AD. The importance of
oxidant-mediated processes in lipofuscin formation has been demonstrated
using in vitro culture studies of human glial cells, showing that
prooxidants (ex.- iron) accelerate, while antioxidants (vitamin E,
selenium, and GSH) reduce lipofuscin levels." (16)
 
"Clinical investigations in elderly humans using nutritional supplements of
various mixtures of vitamins E, C, and selenium has provided some
encouraging results. The potential of nutritional and dietary modulation of
ROM-related tissue injury offers the general attraction of a
population-based, early, long term and minimally-hazardous intervention for
the prevention of neurodegenerative damage. It has been calculated that a
postponement of 5 years in the onset of AD could reduce morbidity by half."
(16)
 
"Cholinergic neurotransmission is known to be exquisitely sensitive to
conditions that impair oxidative metabolism and neuronal membrane
function." (18)
 
Vitamin E reduces the hepatotoxicity of tacrine, and so should be
considered a necessary adjunct to tacrine therapy. (19, 20)
 
A therapy of iron (50-150mg), vitamin B-6 (90-180mg), and Coenzyme Q10
(60-180mg) on 20 AD patients over a period of one year showed stabilized
disease and improved scores on the Mini Mental Status Exam. MMSE scores at
the start of treatment were 14.5+-7.0; at the end of one year 21.6+-6.5.
The logic of treatment was that iron, while normally an oxidant and free
radical generator, is nonetheless important to brain function. Coenzyme Q10
has antioxidant capabilities and stabilizes cell membranes, especially
mitochondrial membranes. CoQ10 may have neutralized the iron-derived free
radicals. Vitamin B6 is used in the biosynthesis of GABA
(gamma-aminobutyric acid). Glutamine induced neurotoxicity is postulated to
be one cause of neuronal cell death. GABA reduces glutathione. Given the
known free radical generating properties of iron, and the fact that the
iron-chelating drug desferrioxamine has reduced the rate of progression of
AD (16), I consider it somewhat unlikely that the iron supplements aided
the AD patients. I would therefore omit iron but include Coenzyme Q10 and
vitamin B-6 in an AD therapy. (21)
 
There are no known side effects at the recommended dosages for vitamins.
Selenium doses should be less than about 500 mcg/day, as some toxic effects
have been noted at 1000 mcg/day. No known toxic effects of Coenzyme Q10 are
present at recommended dosages.
 
I therefore recommend the AD patient take three times daily with meals at
least 400 i.u. of vitamin E, one half gram of vitamin C, 25,000 i.u. of
beta carotene (or, even better, consumption of a high dose multivitamin) ,
and 200 mcg of selenium. .Also take 120 mg Coenzyme Q10, and 120 mg B-6 in
three divided doses. I do not recommend taking supplemental iron.
Additionally, the patient should try to maximize his/her consumption of
fruits and green vegetables, striving for five to six servings a day.
 
 
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
prematureaging 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)
 
>From the Geriatric Research Education and Clinical Center,
Veterans Administration Medical Center, St. Louis, MO: "Immediate
post-training intracerebroventricular administration to male mice of
pregnenolone (P), pregnenolone sulfate (PS), dehydroepiandrosterone (DHEA),
dehydroepiandrosterone sulfate (DHEAS), androstenedione, testosterone,
dihydrotestosterone, or aldosterone caused improvement of retention for
footshock active avoidance training, while estrone, estradiol,
progesterone, or 16 beta-bromoepiandrosterone did not. Dose-response curves
were obtained for P, PS, DHEA, and testosterone. P and PS were the most
potent, PS showing significant effects at 3.5 fmol per mouse. The active
steroids did not show discernible structural features or known membrane or
biochemical effects that correlated with their memory-enhancing capacity.
The above, together with the findings that DHEA acted even when given at 1
hr after training and that P, PS, and DHEA improved retention over a much
wider dose range than do excitatory memory enhancers, led to the suggestion
that the effects of the active steroids converge at the facilitation of
transcription of immediate-early genes. P and PS, for which receptors have
not yet been demonstrated, may exert their effects by serving as precursors
for the formation of a panoply of different steroids, ensuring near-optimal
modulation of transcription of immediate-early genes required for achieving
the plastic changes of memory processes. Low serum levels of P in aging and
the increases of cancer and behavioral disorders in individuals receiving
drugs that block synthesis of cholesterol, the immediate precursor of P,
suggest possible clinical utility for P." (47)
 
I therefore suggest pregnenolone supplementation (30mg/day initially) for
Alzheimer's patients. Typical dosages vary from 10 to 100mg/day.
 
V. Anti-Inflammatory Therapy: Drugs and Oral Tolerance
 
"The etiology of AD is unknown. Recent evidence has demonstrated that
activation of inflammatory and immune mechanisms accompanies the
degenerative process in the disorder...In AD, physical examination does not
indicate inflammation, but more sensitive serologic and tissue studies do
provide evidence of inflammatory activity....These results indicate that a
process, perhaps the degeneration of brain tissue, is stimulating an acute
phase response in AD...The acute pahse response, whether systemic or local,
may thus be important in elevating levels of amyloid precursor protein and
creating a proteolytic environment favoring the production of amyloid B
protein, a component of amyloid placques associated with the disease." (48)
 
 
"What initiates the pathogenic mechanisms in AD?...If there is impairment
of the blood-brain barrier, previously protected brain antigens, or altered
antigens, may be exposed to the immune system. Inflammatory and immune
mechanisms may thus be initiated (and may be self-propagating), leading to
tissue destruction in the brain. Once inflammatory mechanisms are active in
brain tissue, they may contribute to disruption of the blood-brain
barrier." (48)
 
"Monozygotic twins show discordant expression of AD, indicating the
importance of nongenetic factors; variation in inflammatory response may be
one such factor. However, unaffected first-degree relatives of patients
with AD have elevated levels of acute phase reactants in the serum, in
addition to a 50% chance of contracting the disease; the the mean reactant
values are intermediate between those of normal subjects and those of AD
patients. If acute phase reactants are elevated in a population at high
risk but clinically unaffected, the inflammatory response in AD may not be
solely a reaction to tissue destruction. On the basis of the preceding
mechanisms, supression of the acute phase response and inhibition of
accumulation and activation of macrophages are potentially therapeutic and
pharmacologically feasable." (48)
 
"It is abundantly clear from papers submitted to this Forum (45th Forum in
Immunology, 1992) that elements of the immune system are involved in the
pathogenesis of the principle lesions characterizing AD. While the full
spectrum encompassing typical events involved in the classical inflammatory
response is not yet evident, present findings are in accord with features
associated with both the innate and adaptive immune mechanisms." (49)
 
"It appears that a prolonged exposure to the non-degradable but potentially
toxic amyloid substance may initiate an immune reaction and cause cell
injury that may provoke inflammatory responses." (49)
 
"The bulk of the evidence presented points to the operation of a chronic
inflammatory response which may begin insidiously as a "low grade
smoldering response" that does not resemble acute inflammation. The
evidence indicates tthat the inflammatory response is produced locally
within the parenchyma; however, it also seems to entail communication with
the circulation. Remarkably, the brain holds the capacity to produce almost
all the immune system mediators which largely seem to be generated by glia
composing both astrocytes and microglia (representatives of the immune
system's monocytes and macrophages, which contribute to inflammatory
responses). This fact beacons a fundamental change in our thinking that the
brain is not necessarily immunologically privileged as first impressions
would indicate, but seems to have its own immune system and can readily
mount a full immune attack." (49)
 
"Serum from AD patients contained antibodies that recognized cholinergic neu
ronal elements in the adult rat brain, namely the medial septum,
hippocampus, and cortex. Another group of investigators showed that AD
serum contained antibodies directed against the purely cholinergic Torpedo
electromotor neurons. Antibodies directed against microglial cells were
present in a much higher frequency in AD cerebrospinal fluid, compared to
CSF from other dementia patients." (50)
 
Anti-inflammatory Drugs
 
Corticosteroids. Glucocorticoids are the most broadly active anti-
inflammatory/immunosuppressive agents in clinical use. Steroids are the
mainstay of treatment for idiopathic inflammatory diseases of the central
nervous system. Unfortunately, there are serious drawbacks to clinical
trials of this class of drugs in AD. The known systemic toxic effects of
moderate to high doses of corticosteroids in humans are numerous.
Experiments in animals have demonstrated that prolonged exposure to
glucocorticoids is toxic to hippocampal neurons, and impairs the capacity
of neurons to survive insults; it is feared that patients with underlying
brain disease may be particularly prone to adverse effects of steroids.
(48)
 
However, with the use of markers for inflammatory activity, possible
beneficial effects of low doses of steroids can be assessed. Chronic
administration of prednisone at low doses (i.e., 10 mg/day or less) to
elderly patients is well tolerated and effective in the treatment of
systemic inflammatory diseases such as rheumatoid arthritis. (48)
 
Nonsteroidal Anti-Inflammatory Drugs (NAID). These drugs are the first line
drugs for inflammatory diseases such as rheumatoid arthritis and gout. It
has been reported that the prevalence of AD in patients with rheumatoid
arthritis is unexpectedly low. Using Canadian and American hospital data
covering more than 12,000 patients older than age 64, only 0.39% of those
diagnosed with rheumatoid arthritis had also been diagnosed with AD,
whereas in the general population the same age group had an AD prevalence
of 2.7%. This leads to the hypothesis that medications administered to
arthritis patients, such as NAID, confer protection against AD. (51,53)
Additionally, a recent study comparing the drug-taking history and
likelihood of contracting AD of 50 pairs of elderly twins and found that
the twin who had been taking anti- inflammatory drugs had four times
greater likelihood of being the later-affected or non-affected member of
the pair. Anti- inflammatory drugs used by one of the twins included
ibuprofen, piroxicam, naproxen, and some steroids used in the 1950s and
1960s for arthritis but are no longer prescribed. (48,51)
 
Indomethacin. A recent 6-month controlled trial of indomethacin in patients
with AD showed stable cognitive function in the the drug-treated group and
declining function in the placebo group. The study was small (14 patients
in each group completed the study) and there was a relatively high rate of
adverse effects from indomethacin's gastrointestinal side effects, which
caused the drop-outs in the indomethacin-treated group. The other group
lost 20% of the subjects due to decline in behavior to the point that they
wouldn't take medicine or sit for the test anymore. That didn't happen with
the indomethacin patients (51,52). "100 to 150 mg/day indomethacin appeared
to protect mild to moderately impaired Alzheimer's disease patients from
the degree of cognitive decline exhibited by a well-matched,
placebo-treated group. Over a battery of cognitive tests, indomethacin
patients improved 1.3% (+/- 1.8%), whereas placebo patients declined 8.4%
(+/- 2.3%)--a significant difference (p < 0.003). Caveats include adverse
reactions to indomethacin and the limited scale of the trial." (52, 53)
 
Dapsone. "1991 brought additional evidence in favor of the inflammatory
hypothesis from an unexpected source. A local government health official
noted what appeared to be an extremely low incidence of dementia in a leper
colony on the island of Nagashima. Following up, a study on 4000 aged
Japanese leprosy patients was performed. The result: The incidence of
dementia wasonly 2.9% in those taking the leprosy drug dapsone, which also
has anti-inflammatory effects, but 6.25% among those who has not taken the
drug for 5 years. Another group of Japanese researchers analysed the
autopsied brains of 16 leprosy patients that had probably been treated with
dapsone. They found an unusual abscence of senole plaques in the leprosy
patients brains compared to those of age-matched controls. (51) Due to the
renal toxicity of Dapsone, I do not recommend it's use, since there are
other, much better tolerated anti-inflammatory drugs. Dapsone provides
further evidence of the efficacy of anti-inflammatory drugs, however.
 
"The rheumatologist's armamentarium offers a number of other candidates for
trials in patients with AD. Potent anti- inflammatory/immunosuppressive
agents such as methotrexate, azathioprine, and cyclophosphamide have proven
effective in ameliorating the manifestations of lupus, rheumatoid
arthritis, polymyositis, and the systemic vasculitides. These drugs have
the potential to cause life-threatening toxicity, but with close
monitoring, long-term administration may be feasable. Methotrexate may be
the best candidate in this group for study in AD. In rheumatoid arthritis,
it is highly effective and relatively well tolerated. Its mechanism of
action may involve interference with the activity of
interleukin-1...Interleukin-1 may be an important mediator of the
microglial proliferation in AD" (48)
 
Recommendations
 
There is evidence of AD amelioration with the anti-inflammatory ibuprofen.
Although there is no evidence for the specific antiinflammatory aspirin, in
view of the above information, if no antiinflammatory drugs are currently
being taken by the Alzheimer's patient, I recommend one enteric-coated
325-mg aspirin be taken with breakfast, and one ibuprofen tablet be taken
with dinner.
 
If the disease continues to progress with the above therapy, I recommend
initial therapy with indomethacin (100-150 mg/day). Due to possible
exacerbation of gastric problems, discontinue aspirin and ibuprofen therapy
during indomethacin use. If indomethacin cannot be tolerated, then
re-initiate aspirin and ibuprofin therapy, and try chronic administration
of prednisone at low doses (10 mg/day or less). Commence a search for a
nonsteroidal antiinflammatory drug which can be tolerated. Examination of
drugs used in rheumatoid arthritis, such as methotrexate, may provide
possible candidates.
 
 
Oral Tolerance
 
"Oral tolerance is a long recognized method to induce peripheral immune
tolerance. The primary mechanisms by which orally administered antigen
induces tolerance are via the generation of active suppression or clonal
anergy. Low doses of orally administered antigen favor active suppression
whereas higher doses favor clonal anergy. The regulatory cells that mediate
active suppression act via the secretion of suppressive cytokines such as
TGF beta and IL-4 after being triggered by the oral tolerogen. Furthermore,
antigen that stimulates the gut-associated lymphoid tissue preferentially
generates a Th2 type response. Because the regulatory cells generated
following oral tolerization are triggered in an antigen-specific fashion
but suppress in an antigen nonspecific fashion, they mediate bystander
suppression when they encounter the fed autoantigen at the target organ.
Thus it may not be necessary to identify the target autoantigen to suppress
an organ-specific autoimmune disease via oral tolerance; it is necessary
only to administer orally a protein capable of inducing regulatory cells
that secrete suppressive cytokines. Orally administered autoantigens
suppress several experimental autoimmune models in a disease- and
antigen-specific fashion; the diseases include experimental autoimmune
encephalomyelitis (EAE), uveitis, and myasthenia, collagen- and
adjuvant-induced arthritis, and diabetes in the NOD mouse. In addition,
orally administered alloantigen suppresses alloreactivity and prolongs
graft survival. Initial clinical trials of oral tolerance in multiple
sclerosis, rheumatoid arthritis, and uveitis have demonstrated positive
clinical effects with no apparent toxicity and decreases in T cell
autoreactivity." (55)
 
There is strong evidence that inflammatory processes are involved with AD,
via an autoimmune response. This is also the case in rheumatoid arthritis.
Antiinflammatory drugs which are used in arthritis also may have efficacy
in AD (51-53), indicating a common cause or disease process. Oral
tolerization has beneficial effects on arthritis. Therefore, it seems
logical to assume that it might be effective against AD. There is evidence
that brain tissue of non-human origin is similar enough to human tissue to
induce AD patient antibody recognition: "Serum from AD patients contained
antibodies that recognized cholinergic neuronal elements in the adult rat
brain, namely the medial septum, hippocampus, and cortex. Another group of
investigators showed that AD serum contained antibodies directed against
the purely cholinergic Torpedo electromotor neurons." (50) Consumption of
healthy animal brain tissue is not known to have adverse side effects .
Oral consumption of myelin has succeeded in reducing the frequency of
Multiple Sclerosis attacks. (56)
 
I therefore recommend daily or weekly consumption of small amounts of
healthy animal brain tissue by Alzheimer's patients. Preparation should be
directed toward leaving the tissue as intact as possible.
 
 
Alzheimer's Disease Therapy
Recommendations- A Summary
 
I suggest 10 mg of deprenyl be taken daily (5 mg with breakfast, 5 mg with
lunch) for any Alzheimer's patient.
 
I suggest the consumption of 2 grams of Acetyl-L-Carnitine daily in divided
doses with meals by AD patients.
 
I recommend the AD patient take three times daily with meals at least 400
i.u. of vitamin E, one half gram of vitamin C, 25,000 i.u. of beta carotene
(or, even better, consumption of a high dose multivitamin) , and 200 mcg of
selenium. Also take 120 mg Coenzyme Q10, and 120 mg B-6 in three divided
doses. Additionally, the patient should try to maximize his/her consumption
of fruits and green vegetables, striving for five to six servings a day.
 
I suggest consumption of a magnesium supplement sufficient to provide
400-800 mg of elemental magnesium per day. Example: 2 tablets of magnesium
chloride (OTC: Slo-Mag) three times a day (6 total/day) with meals. This
will provide about 400 mg of elemental magnesium per day.
 
I 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.
 
I suggest daily hormone replacement therapy with DHEA (one capsule in the
morning) to achieve youthful DHEA levels for Alzheimer's patients.
 
I suggest pregnenolone supplementation of 30mg/day initially for
Alzheimer's patients. Typical dosages vary from 10-100mg/day.
 
I recommend daily or weekly consumption of small amounts of healthy animal
brain tissue by Alzheimer's patients. Preparation should be directed toward
leaving the tissue as intact as possible.
 
If no antiinflammatory drugs are currently being taken by the Alzheimer's
patient, I recommend one enteric-coated 325-mg aspirin be taken with
breakfast, and one ibuprofen tablet be taken with dinner.
 
If the disease continues to progress with all of the above therapy
modalities, including aspirin and ibuprofen therapy, I recommend initial
therapy with indomethacin (100-150 mg/day). Due to possible exacerbation of
gastric problems, discontinue aspirin and ibuprofen therapy during
indomethacin use. If indomethacin cannot be tolerated, then re-initiate
aspirin and ibuprofin therapy, and try chronic administration of prednisone
at low doses (10 mg/day or less). Commence a search for a nonsteroidal
antiinflammatory drug which can be tolerated. References (Starred
references [*] are included in this package)
 
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autoantigens (1994) Annu Rev Immunol.12:809-37
56*. Double-Blind Pilot Trial of Oral Tolerization with Myelin Antigens in
Multiple Sclerosis (1993) Science 259:1321-1324
 
 
Alzheimer's Disease- Recommended Action Checklist
 
Make an appointment with an opthalmologist and have the eye test performed.
 
If the results are positive, make an appointment with your physician. Bring
the results of the patients eye test and this package Attempt to get
his/her cooperation in your program. If you have health insurance, try to
get a prescription for deprenyl and DHEA. Seeif any other listed compounds
could also be obtained via prescription so that your health insurance pays
for it. Discuss the advisability of commencing Indomethacin or other
nonsteroidal antiinflammatory drug therapy.
 
What you can do without your physician: Everything except Indomethacin or
other prescription nonsteroidal antiinflammatory drug therapy.
 
If you are unable to have the eye test done, and don't wish to involve a
physician, everything recommended here has general anti-aging effects, and
can be followed by most elderly persons who wish to retain their health.
 
Either in consultation with your physician, or on your own, order the
following products, and begin taking at the recommended dosages:
 
1. From Beyond-A-Century:
1-800-777-1324, phone credit card orders accepted.
 
200.2- Life extension mix, low niacin. If you can't take fairly large
tablets, they do have loose powder which can be mixed with water.
4 bottles of 315 tablets- $138
8 bottles of 315 tablets- $245
 
204.0- Selenium complex.
1 or 2 bottles of 200mcg x 100 tablets- $5 each
 
Optional but recommended:
003.5- Performance Extra- Arginine/OKG 2:1 mix, 250 gram bottle- $28.75 each
 
 
2. From Healing Alternatives Foundation: Use enclosed photocopy of order
form. Must mail-order. Credit cards or checks accepted.
 
Coenzyme Q-10 (150)
1 or 2 bottles 30mg x 100 capsules- $19.42 (Calif. residents $20.95).
 
DHEA-100
1 or 2 bottles 250mg x 100 capsules- $62.87 (Calif. residents $67.81).
 
OR: If you have health insurance and your doctor is willing, get your
doctor to prescribe DHEA as hormone replacement therapy at his recommended
dosage and get from your local pharmacy.
 
 
OR: If you would rather use a credit card and place a phone order for DHEA,
try:
 
 
Atlanta Buyer's Club
(404) 874-4845
AIDS Buyer's Club, takes phone credit card orders.
 
DHEA- 250mg x 100- Approx. $60.
 
 
3. From Life Extension Foundation:
1-800-841-5433, phone credit card orders accepted.
 
Melatonin
1 or 2 bottles 10mg x 60 capsules- $24 each 1 or 2 bottles 3mg x 60
capsules- $8 each
 
Acetyl-L-Carnitine
2 to 4 bottles 500mg x 100 capsules- $68 each
 
 
4. From A. Werner & Co.
PO Box 615
11121 Prague 1
Czech Republic
Mail orders only, use included photocopy of order form. Send airmail.
Checks or (recommended) money orders accepted. Could be up to 45 days for
delivery, so order sufficient quantity. Need 2 capsules per day.
 
Deprenyl-100x5 mg capsules-$95, 400x5 mg capsules-$360 Plus $7 shipping.
 
OR: If you have health insurance and your doctor is willing, get your
doctor to prescribe Deprenyl/Selegiline/Eldepryl, 10mg per day, and get
from your local pharmacy.
 
 
5. From Lifelink
445 Liery Lane
Arroyo Grande, CA 93420
(805)473-1389
 
Pregnenolone: 30mg x 50- $33, or 30mg x 150- $90, or 30mg x 500- $270,
prescription not required.
Plus $4 shipping.
 
 
6. From Local Drug Store:
1 bottle enteric-coated aspirin, 325 to 400 mg tablets- Approx. $6
1 bottle Ibuprofin- Approx. $6
 
7. From Local Meat Market
Fresh, healthy animal's brains. Begin consuming a small amount daily or weekly.
 
Note: All of the above compounds should be refrigerated prior to use, with
the exception of Deprenyl, which should be stored at room-temperature.
 
Alzheimer's Disease- Treatment Resources
 
1. Melatonin- Cost/Day: $0.13 to $0.26. Dosage: One to three 3 mg capsules
or one 10 mg capsule 1/2 hour before sleep, plus an. additional 3 mg
capsule if you wake up with at least 4 hours to go. Source: Life Extension
Foundation (1-800-841- 5433), Vitamin Research Products, or
Beyond-A-Century.
 
2. Life Extension Mix- Cost/Day: $1.09 to $0.88 (depending on whether 1,4,
or 8 bottles of 315 tablets are bought at once). Dosage: 3 tablets with
each meal (9 per day). Source: Beyond-A-Century.
 
Life Extension Mix (LEF) contains the following components which are
specifically called for in my Alzheimer's Treatment Strategy:
 
Numerous generalized antioxidant and immune system boosting compounds
(vitamins C, E, etc.)
Vitamin B-6: 200 mg
Magnesium (in chloride, aspartate, and succinate forms): 1 gram Selenium
(in sodium selenate and methionine complex): 100 mcg
 
Contains 50 antioxidant ingredients based on latest scientific and medical
research. Example: Vitamin E was shown in a very large study to be
associated with a 37% reduction in risk of coronary disease in men and a
41% reduction for women. Formula updated regularly. One of the best high
doseage multivitamins on the market. This formula is not like a typical
multivitamin that you can get at a drug store, in two important ways: 1.
The sophistication of the formula, and 2. The total amounts. L.E. Mix
contains far more of each component than a typical multivitamin. Example:
to have the anti-arteriosclerotic effect of vitamin E mentioned above, you
need to take at least 100 i.u. (International Units- a measure of
bioactivity) of vitamin E per day. A typical mulitvitamin has perhaps 37
i.u. L.E. Mix has 600 i.u. of vitamin E.
 
Current formula of Life Extension Mix- 9 tablets, capsules or powder in
three divided doses with meals:
 
Vegetable Complex
Beta-Carotene (ROCHE)- 25,000 i.u.
Xanthophyll complex- 7500 i.u.
Lycopene complex- 10,000 i.u.
Broccoli concentrate- 500 mg
Cabbage concentrate- 500 mg
Vitamin A- 5000 i.u.
 
B Complex
B1 (Thiamin HCL)- 250 mg
B2 (Riboflavin)- 50 mg
B3 (Niacin 75 mg, Niacinamide 100 mg)- 175 mg B5 (Calcium pantothenate)- 750 mg
B6 (pyridoxine HCL)- 200 mg
B12 (ion exchange resin)- 100 mcg
PABA- 50 mg
Folate Triglutamate- 800 mcg
Biotin- 200 mcg
 
Ascorbate Complex
Vitamin C (from Calcium, Magnesium, and niacinamide ascorbates)- 2500 mg
Ascorbyl palmitate- 500 mg
Acerola juice powder- 300 mg
 
Tocopherol Complex
Vitamin E (D, L- alpha tocopherol acetate)- 300 i.u. Vitamin E (D- alpha
tocopherol succinate)- 300 i.u.
 
Amino Acid Complex
L-taurine- 500 mg
N-acetyl-cysteine- 200 mg
L-glutathione- 15 mg
 
Mineral Complex
Magnesium chloride- 800 mg
Magnesium aspartate- 100 mg
Magnesium succinate- 100 mg
Potassium aspartate- 50 mg
Potassium chloride- 49 mg
Calcium citrate- 500 mg
Calcium stearate- 250 mg
Vitamin D- 200 i.u.
Selenium (sodium selenate)- 50 mcg
Selenium (seleno-methionine Nutr 21)- 50 mcg Optizinc (tm)- 20 mg
Zinc succinate- 15 mg
Chromate (tm) (GTF chromium niacin bound)- 50 mcg Chromium picolinate- 50 mcg
 
Plus Cholinergic and Flavinoid Complexes.
 
I will assume that the patient is taking this formulation in recommending
doses for the following supplememental compounds.
 
3. Enteric Coated Aspirin- Cost/day: pennies. Dosage: 1 325mg tablet/day
with breakfast. Source: Any drugstore.
 
Low-dosage aspirin has a dramatic effect on lowering heart disease. In a
study of 22,071 physicians over a 60 month period, those doctors over 50
years of age taking aspirin had a 44% reduction in heart attacks. In people
with pre-existing heart disease, aspirin reduced the risk by 47%. Those
people with heart disease that took both aspirin and beta carotene had NO
heart attacks. It also has an effect on cancer apparently by reducing
"platelet-aggregability", or the tendency of cells to attach to other
cells. This is how it prevents heart disease (arteriosclerosis), and how it
also inhibits cancer's "metastasizing", or spreading, because the cancer
cell which floats free must anchor itself somewhere to begin growing again.
Aspirin should be used cautiously if at all by persons with diabetic
retinopathy or poorly controlled high blood pressure; i.e., those at risk
of bleeding-type disorders.
 
4. Ibuprofin- Cost/day: pennies. Dosage: 1 tablet/day with dinner. Source:
drug store.
 
Ibuprofin is an anti-inflammatory drug. People who use ibuprofin
chronically (every day) tend to get Alzheimer's Disease at lower rates than
those who don't.
 
5. Deprenyl or Eldepryl- Cost/day: $1.80 to $4.80. Dosage: 10 mg/day. One 5
mg tablet with breakfast, one with lunch. Source: local pharmacy with
prescription (100 x 5mg- $220) or, much cheaper, without prescription, A.
Werner & Co. (100 x 5mg-$95, 400 x 5mg-$360)
 
6. DHEA- Cost/day: $0.68 to $2.00. Dosage: approximately 100-250 mg/day.
Source: Most (not all) local compounding pharmacies($2 for a 100 mg
capsule), or Lifelink (25mg x 180- $40, 195mg x 50- $40, 195mg x 150- $108,
195mg x 500- $340), or, cheapest, Healing Alternatives Foundation (250mg x
100- $67.81) or Atlanta Buyer's Club (250mg x 100- approx $60)
 
7. Selenium complex- Cost/day: pennies. Dose- Two tablets/day. Source:
Beyond-A-Century (200mcg x 100- $5)
 
8. Acetyl-L-Carnitine- Cost/day: $2.72. Dose- Four 500 mg capsules/day. Two
with breakfast, and one with lunch and dinner. Source: Life Extension
Foundation.
 
9. Pregnenolone- Cost/day: $0.60. Dose- 10 to 100 mg; start with 30mg.
Source: Lifelink.
 
10. Coenzyme Q10- Cost/day: $0.75 to $0.56. Dose- Four 30 mg capsules/day.
Two with breakfast, one with lunch and dinner. Source: Beyond-A-Century,
or, cheapest, Healing Alternatives Foundation.
 
11. Magnesium- Cost/day: $0.10 to $1.50. Dose- None, if taking Life
Extension Mix. Otherwise, two tablets magnesium chloride or one tablet
magnesium oxide with each meal. Source: drugstore.
 
12. Vitamin B-6. Cost/day: pennies. Dose- None, if taking Life Extension
Mix. Otherwise, 250mg/day. Source: Drugstore or mail-order vitamin supply.
 
13. Nonsteroidal Anti-Inflammatory Drug- Ex.- Indomethacin. Cost/day:
unknown. Dose Depends on compound. For Indomethacin, 100-150 mg/day.
Source: Local pharmacy, doctor prescribed.
 
14. Fruits & Vegetables In Your Diet
 
A large study, published April 14, 1994, tested whether high- dose beta
carotene and/or a small dose of vitamin E taken for five years by men who
had smoked for at least 30 years would reduce lung cancer. It did not.
Carcinogenesis may take longer than 5 years; if so, the vitamin intake was
started too late. Beta carotene has been shown in other studies to prevent
impairment of the immune system by UV light and inhibit mouth and cervical
cancer. In another study, beta carotene reduced the risk of heart attacks
in people with preexisting heart disease by 41%. People with heart disease
that took both aspirin and beta carotene had NO heart attacks.
 
The evidence supports taking some beta carotene, and Life Extension Mix
contains this compound. The amounts of vitamin E used in the study were not
enough to have any effects, based on amounts used in previous studies, so
the study has no relevance on vitamin E's effectiveness or lack thereof.
Bottom line, the substances in fruits and vegetables which prevent cancer
have not yet been completely identified. It may also be that diets high in
fruits & vegetables are also low in fat, which may be a contributing factor
for cancer reduction.
 
Therefore, good judgement dictates that in addition to strategic
supplements, one should try to eat as many fruits & vegetables as possible.
 
OPTIONAL BUT RECOMMENDED:
 
15. Growth Hormone Releaser-Cost/Day: $.48. Performance Powder Extra
(Arginine/Ornithine alpha-keto glutamate (OKG)) 2:1 mix, 300 gram package,
cat. no. 003.5, $28.75 for 300 grams). Dosage: Men-2 level tablespoons.
Women-1 level tablespoon. Source: Beyond-A-Century.
 
As you age, your body's production of growth hormone declines. Certain
amino-acid formulations can stimulate growth hormone release if taken at
the proper time and on an empty stomach. The idea is to mimic the natural
release of growth hormone by a young person. GH is normally released in
reaction to two events: maximum effort exercise (not just jogging, but the
100 yard dash, for example), and sleep. Take on an empty stomach just
before going to bed (stomach acids associated with foods, especially sugar,
destroy the amino acids). Start with a low dosage and work your way up.
Benefits for both men and women include more rapid healing, a leaner, more
muscular body, and significantly increased immune response (ability to
fight off disease in all it's forms- from colds to cancer). When taken
before sleep, it increases REM sleep and may produce a sense of well-being.
It should not be taken by someone who has existing cancer. Arginine has
recently been associated with nitric oxide metabolism in the human body.
Nitric oxide appears to be very important for many basic processes,
including blood pressure. Arginine lowers blood pressure, perhaps because
it is a precursor of NO. Arginine is being added to some intraveinous
solutions given surgery patients after surgery in an attempt to speed
healing time.
 
 
Resources
 
Beyond-A-Century
PO Box 713
Greenville, ME 04441
1-800-777-1324
 
Products offered- most. Free catalog.
Life Extension Mix: Bottle of 315 tablets (35 days worth)- $30.62 if 8
bottles bought.
Selenium: 100 x 200 mcg selenium complex-$5 Plus $4.50 shipping.
 
 
Life Extension Foundation
PO Box 229120
Hollywood, FL 33022-9120
1-800-841-5433
 
Melatonin: 60 x 3mg: $8, 60 x 10mg: $24
Acetyl-L-Carnitine: 100 x 500mg: $68
 
 
Vitamin Research Products
3579 Hwy 50 East
Carson City, NV 89701
(702) 884-1300 & (800) 877-2447 fax-(800) 877-3292
 
Products offered-most. A research and vitamin formulation sales company
similar to LEF Outstanding free research newsletter/catalog. Appear to be a
conscientious company with integrity.
 
 
Lifelink
445 Liery Lane
Arroyo Grande, CA 93420
(805)473-1389
 
DHEA-25mg x 180: $40, 195mg x 50: $40, 195mg x 150: $108, 195mg x 500:
$340, prescription not required. Pregnenolone: 10mg x 90: $20, 30mg x 50:
$33, 30mg x 150: $90, 30mg x 500: $270, prescription not required. Plus $5
shipping.
 
 
Atlanta Buyer's Club
(404) 874-4845
 
DHEA- 250mg x 100: approx $60, phone credit card orders taken.
 
 
Healing Alternative Foundation
1748 Market Street, Suite 205
San Francisco, CA 94102
(415)626-2316
 
Free catalog. AIDS buyers club: must join ($1 first time you order)
DHEA: 100 x 250mg capsules: $62.87 ($67.81 for Calif. residents)
Coenzyme Q-10: 150 x 30mg: $19.42 ($20.95 for Calif. residents)
Plus $6 shipping.
 
 
A. Werner & Co.
PO Box 615
11121 Prague 1
Czech Republic
 
Deprenyl-100x5 mg capsules-$95, 400x5 mg capsules-$360 Plus $7 shipping.
 
Eye Test for Alzheimer's Disease: Procedure
 
 
1) Prepare a dilute solution of tropicamide (0.01%).
 
2) Have the patient sit in a semidarkened room for 2 or 3 minutes. Measure
the resting pupil diameter for 1 minute. Record the average value on the
data sheet. Then administer one drop of the dilute solution of tropicamide
to one eye. Note the time. Begin timing from this point.
 
3) Examine the eye for pupil diameter for 30 seconds at the following times
after drop administration and record the average value of pupil diameter on
the data sheet.
 
Times: 2, 8, 15, 22, 29, 41, and 51 min after drop administration.
 
4) Perform the calculations indicated on the data sheet to convert raw
pupil diameter measurements to percentage changes from the baseline, or
initial measurement.
 
5) Plot the percentage changes at the measurement times on the included
graph. Compare the profile with the already plotted profiles of Alzheimer's
patients and healthy controls. Which profile more closely matches the
patients profile?
 
6) If the profile does not indicate Alzheimer's Disease, then consider the
possibility of non-Alzheimer's dementia, such as Korsakoff's syndrome,
multi-infarct demetia, and dementia with an extrapyramidal syndrome, and
get a doctor's advice on diagnosing and treating the problem. If the
profile more closely matches the AD patient's profile, then proceed with
the course of treatment indicated herein, in consultation with a physician.
 
 
 
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