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 the neurodegeneration, 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.
