Alzheimer's Disease: A Treatment Strategy

jarice at delphi.com jarice at delphi.com
Fri Jan 13 03:03:39 EST 1995


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.





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