by Will Block
Twenty-five years ago, researchers discovered that people with Alzheimer's
disease suffered sharp declines in their brain levels of the important messenger
molecule acetylcholine (ACh).1
This finding was truly important, because life itself is dependent on
So ancient is this neurotransmitter in evolutionary biology that the
development of its neuronal receptors in primitive species preceded those of
adrenaline and dopamine (which govern excitatory and motor-function mechanisms,
respectively). This occurred before the divergence in the lineages of fish,
amphibians, and reptiles (vertebrates), and insects and spiders (arthropods).2
In humans, at the top of the evolutionary tree, ACh has been found to be
intimately involved in:
- Every motion of our muscles
- Every thought we have
- Every feeling we experience
- Everything that goes on at the foundation of memory and consciousness
ACETYLCHOLINE = NIMBLE MIND
Sadly, with advancing age, ACh levels drop - as does our ability to form
memories and to recall them readily. We are unable to use our minds as nimbly as
we once did. And as our nervous system degenerates and stumbles into dementia -
and for some, devolves into Alzheimer's disease - ACh levels drop dramatically.3
In advanced Alzheimer's disease (AD), acetylcholine levels drop by an
astonishing 90%, especially in the brain's hippocampus and cerebral cortex,
which are devastated by AD. Personality is weakened and diluted, and ultimately
disappears. Eventually, consciousness terminates, followed by life.
On a much happier note, it is now possible to enhance ACh function in normal
individuals, as well as in those with mild and even advanced dementias. A class
of compounds known as acetylcholinesterase
inhibitors (AChEIs) has been found to help maintain and restore ACh
levels, enabling proper memory function to prevail. (Acetylcholinesterase, or
AChE, is the enzyme that breaks down ACh, so compounds such as galantamine,
which inhibit AChE's function, serve to boost ACh levels.) These compounds,
found mostly in so-called medicinal plants, have been used in traditional
Chinese, Indian, and European folk medicines for the relief of cognitive
impairment in the elderly.4
The long-term use of AChEI-containing plant extracts in these traditional
medicines has demonstrated an impressive absence of toxicity.
Conceptually, hormone replacement therapy has created a new paradigm for our
thinking about some of the problems of aging, the idea being that what we lose
with age, we should replace by supplementation. With this model in mind,
researchers have looked at brain aging and proposed an equivalent model: cholinergic
In more familiar terms, it could be called memory
MILD MEMORY IMPAIRMENT
In the last few decades, other studies have verified and expanded upon the
earlier findings. They have shown that dramatic declines in ACh are tied to
memory impairment and that such impairment often precedes Alzheimer's disease.
According to a recent paper, mild cognitive impairment may be a marker (a
warning signal) for imminent progression to dementia or AD.6
If that is so, then halting the impairment may be helpful in thwarting the
development of more serious degradations, such as AD.
In the cholinergic nervous system, defined as that portion of our entire
nervous system (central and peripheral) for which acetylcholine is the
neurotransmitter, a number of important activities take place, including the:
- Synthesis of ACh
- Breakdown of ACh
- Neuroregulation of ACh
As recent studies have also found, the process of cholinergic decline entails
deterioration in the cells that use ACh and in the enzymes that take part in its
creation and activity. According to the cholinergic theory of memory decline,
cognitive deficits are related to the loss of central cholinergic activity, and
restoration of this activity produces improvement in cognitive function and
A MEMORY STREAM GONE DRY
At the beginning of life, ACh-mediated neurotransmission can be likened to a
rushing, bubbling stream. In the aging process, however, ACh levels decline, and
their receptors are degraded. As they degenerate, we lose the sharp edge of
mental function, and ultimately our stream of consciousness becomes a dry creek.
To date, much of the research on Alzheimer's has been directed toward seeking
compounds that could increase the levels of ACh, or replace the amount lost due
to rapid breakdown, or slow its breakdown (which has the same effect) - all in
the hope of finding an effective treatment. The two drugs that are currently
approved for use in treating AD - donepezil and tacrine - are
acetylcholinesterase inhibitors, which tend to maintain or increase ACh levels.
However, each of these drugs has serious side effects.
ENZYMES ARE ONLY PART OF THE
At the Mount Sinai Alzheimer's Disease Research Center in New York, scientists
have been thinking "outside the box" about the role of the cholinergic
system in the early stages of AD.7
In their study, the researchers asked: At what point does the loss of
cholinergic function in specific areas of the brain occur? Is it before, after,
or at the same time as the earliest signs of cognitive deterioration?
(FOR THE TECHNICALLY MINDED)
There are several problems with the aging cholinergic system that become
particularly rife in dementia and Alzheimer's:
- Decline of the cholinergic basal-cortical projection mechanism.11
When the cholinergic system is optimal, an excitation emanating from the
basal forebrain and projecting through to the cortical neurons directs the
release of ACh in the cortex of the brain.
- Cholinergic loss of neurons in the nucleus basalis, a structure of the
basal forebrain associated with focused attention.12
The nucleus basalis contains cholinergic neurons that project to most
regions of the neocortex.
- Reduced activity of the cholinergic synthesizing enzyme
acetylcholinetransferase. Less acetylcholine gets produced.13
- Decreased endurance of activity of acetylcholine. The enzyme
acetylcholinesterase is quicker to break it down to choline and acetate.
- Cortical plaque density increase. Including the deposition of amyloid and
the formation of neurofibrillary tangles, higher plaque density is directly
associated with cholinergic fiber loss.14
One of the distinctive symptoms (seen at autopsy) of cholinergic deficit is a
reduced number of acetylcholine receptors in the brain, especially the very
important ones that are called nicotinic receptors because of their
sensitivity to nicotine. Galantamine stimulates nicotinic receptor function,
thus mimicking the effects of ACh. Significantly, it does so in a manner that
avoids long-term desensitization of the receptors, which could lead to tolerance
and therefore reduced effectiveness.15
By binding to a site on the nicotinic receptor other than the one normally
occupied by ACh, galantamine actually amplifies the actions of ACh.
It is also significant that the stimulation of nicotinic receptors may be
associated with an inhibition of the formation of amyloid, a hard, waxy
substance that results from tissue degeneration and is often found in the brains
of Alzheimer's patients. Preventing amyloid formation may help to preserve or
What they found indicates that patients in the early stages of AD have
relatively normal levels of the enzymes that regulate ACh levels - even when
they first exhibit memory deficits and some of the classic brain-anatomical
signs of deterioration, such as plaques and tangles (which can be
detected only at autopsy). It is only in the later stages of the disease, when
severe conditions begin to manifest, that the researchers saw significantly
diminished levels of these enzymes.
Therefore, they concluded, overall deficits in these enzymes may not
be an early sign of damage in the disease. Instead they conjectured that either
the overall ACh levels (which cannot be directly measured) are lower for some
reason other than an enzyme deficit, or there is an enzyme deficit elsewhere in
the cholinergic system. As a third alternative, they speculated that there may
be losses in specific neuron populations early in the course of the disease.
Given these findings and hypotheses, it is possible that the positive effects
of AChEIs in mild to moderate Alzheimer's disease result from their ability to
boost normal levels of ACh, rather than just prevent them from falling.
Of all the AChEIs, the natural plant extract galantamine
is a standout. Not only has it been found (in studies dating back to the 1960s)
to help maintain proper ACh levels,8
but it also improves the activity of cholinergic neurotransmission. With the use
of galantamine, ACh levels can be higher - especially in the areas of the brain
that malfunction with age - and the ACh can be more easily released and made
bioavailable. Furthermore, galantamine can improve the responsiveness of certain
receptors to ACh by making them more sensitive.9
GALANTAMINE AFFECTS OTHER
There is another bonus in galantamine's action: it modulates the release of
other neurotransmitters, such as glutamate, serotonin, and GABA (gamma-aminobutyric
acid), that have been shown to be helpful in ensuring proper memory function.10
Galantamine's mechanism of action on the brain's nicotinic receptors is thus
believed to be responsible for significant therapeutic benefits in age-related
As a measure of galantamine's effectiveness, those who have taken it
continuously for at least one year have found that it holds the memory baseline,
i.e., memory decline stops.10
And, unlike any other phytonutrient or drug, galantamine may improve cognitive
function when it is used for at least one year. Such an outcome has not been
reported for any other AChE inhibitor. One possible explanation for
galantamine's sustained efficacy is that it may increase the synthesis of
Among the current nutritional strategies for increasing cholinergic activity and
reducing age-related memory decline are the following:10
AChEIs, such as galantamine and tacrine Cholinergic agonists,*
such as DMAE (dimethylaminoethanol) Nicotinic agonists (which are a special
class of cholinergic agonists, because nicotinic receptors are part of the
cholinergic nervous system), such as galantamine ACh precursors, such as choline
and CDP-choline ACh releasers, such as potassium-channel blockers, e.g.,
carbamates Acetylcholinetransferase restorers, such as vitamin E Stimulants of
nerve growth factors, such as neurotrophin
Unfortunately, most of these cholinergic strategies have proved to be far
from effective, or they are effective but too toxic, or they have not been fully
developed. Conventional medical wisdom has tended toward a heavy reliance on
drugs, which are typically laden with side effects.
*An agonist is a substance that can bind
to a receptor on a cell in such a way as to produce a physiological reaction
similar to that of the naturally occurring substance for which the receptor is
specific. In other words, it is a kind of stimulant for the system in question.
GALANTAMINE MAKES A
Only the AChEIs have demonstrated consistent symptomatic efficacy in trials
lasting from 3 to 12 months. For the most part, these have been standardized,
well-controlled, multicenter studies and have included agents such as tacrine,
physostigmine, donepezil, rivastigmine, and galantamine. But even in the AChEI
trials, dropouts have been common because of efficacy problems and especially
because of the long-term toxicity of some of the agents.
Galantamine is very well tolerated. Long-term studies have found cognitive
benefits in a substantial proportion of the subjects taking it, with few ongoing
side effects. The side effects that have been recorded seem to dissipate with
continued use or never manifest if the dosage is built slowly.
As the quintessential AChEI, galantamine is now moving strongly into the
forefront of nutritional therapies for age-related memory impairment. It owes
this in part to its multiple approach to the problem. As a replacement therapy,
it rectifies deficits and their consequences in the brains of those suffering
memory decline. As an enhancement therapy, it elevates receptor activity and
increases the utility of other neurotransmitters. If one day we look back and
see the present as pivotal in our being able to remember, we may very well have
galantamine to thank.
food for mind and
rescues brain cells
the old become young
- Davies P, Maloney AJ. Selective loss of central cholinergic
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- Fryxell KJ. The evolutionary divergence of neurotransmitter receptors and
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- Winblad B, Hardy J, Backman L, Nilsson LG. Memory function and brain
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- Schneider LS. The future of cholinergic replacement therapy in Alzheimer's
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- Shah S, Tangalos EG, Petersen RC. Mild cognitive impairment. When is it a
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- Davis KL, Mohs RC, Marin DB, Purohit DP, Perl DP, Lantz M, Austin G,
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- Iraizoz I, Guijarro JL, Gonzalo LM, de Lacalle S. Neuropathological
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- Maneesub Y, Sanvarinda Y, Govitrapong P. Partial restoration of choline
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- Geula C, Mesulam MM, Saroff DM, Wu CK. Relationship between plaques,
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