Alzheimer's and natural treatments
By * Dr Van Snick - Brussels
Described in 1907 by Dr Alois Alzheimer after autopsy of a patient suffering from dementia at the age of 55, it was originally described from the histological lesions which characterize it, amyloid plaques and neurofibrillary tangle.
Very often this dementia appears more frequently after 60 years, it is characterized by a neuronal destruction. It affects as much the men as the women.
It reaches 20% of people aged over 80 years, 40% over 85 years (10% over 65 years).
Alzheimer's disease is a neurodegenerative dementia with predominant cortical which primarily affects cognitive function and affects the behavior and social adaptation of patients.
It affects 100.000 persons in Belgium and 650.000 in France. Real social phenomenon it presents a huge financial burden for the future of society. The Alzheimer's disease represents two thirds of the dementias.
Classically, we base ourselves on ten clinical criteria to speak about Alzheimer's disease. They are the most frequent warning signs.
1 Memory disorders
2 Difficulties in the daily tasks
3 Problems of language
4 Spatiotemporal disorientation
5 Weakness of judgment
6 Difficulties with abstract thinking
7 Objects misplaced
8 Modifications of the humor
9 Modification of the personality
10 Loss of initiative
All these symptoms are justified by the histological and biological study.
The disorders appearing first of all are amnesiac and the disease evolves in variable speed until the loss of initiative and the complete asthenia.
Etiology and family character Summary
The presenile form, appearing before 60 years is transmitted in a way of dominant autosomal and involves mutations of chromosomes 14 and 21. But most of the dementias of Alzheimer type appear in a sporadic way after 60 years.
The risk factors are the transmission of one and especially two e4 alleles of apolipoprotein E, which carries cholesterol located on chromosome 19.
The certain risk factors are : family history of Alzheimer's disease; trisomy 21 (Down).
We note as likely risk factors: the traumatism; the age (doubling of frequency every 5 years from 65 years).
Curiously some substances seem to protect firstly : the tobacco and estrogen.
Pathophysiological mechanism Summary
Two histological lesions dominate the picture. The modifications concern like in normal aging, neuritic plaques and neurofibrillary buckles. These lesions are more concentrated in patients with Alzheimer's disease than in the normal patient.
The neuritic plaques called senile plaques are found in the cortex and hippocampus. They are constituted of a core of β-amyloid protein surrounded by dendrites and axons damaged. The free radicals have been cited to explain the formation of the protein and its aggregation via the excessive increase of the protein oxidation.
The neurofibrillary buckles are neurofilament helical which are transformed into aggregates by an excessive phosphorylation. The tau protein is a protein associated with microtubule of cytoskeleton. Its affinity for these structures is regulated by phosphorylation. A hyperphosphorylation of tau protein prevents this one from exercising its role of polymerization and of stabilization of microtubules in the neuronal cytoskeleton.
With these two histological lesions is added the cortical atrophy which is located mainly in the temporal zone.
1. The amyloid cascade
Explained in histological lesions, it is part of the known mechanisms, the role of Mercury as a pathogenic factor has been confirmed in several studies. The blood rate of Mercury is often more higher among patients who died of Alzheimer's than in the witness group.
2. The hyperphosphorylation of the protein tau
Head of neurofibrillary buckles, it is also described in the histology
3. The hypometabolism
In the early stages, we note a reduction of glucose utilization in the brain of the patients probably by decrease of the insulin receptors.
4. The oxidative stress
A correlation between hereditary mutations of mitochondrial DNA and Alzheimer's disease has been highlighted. The genes involved are those of cytochrome oxidase with an accumulation of active oxygen radicals.
5. The inflammation
Some epidemiological studies have shown a protective effect of anti-inflammatory drugs against Alzheimer's disease for patients with rheumatoid polyarthritis. We find by comparison with a healthy brain, an excess of cytokines (particularly interleukin-1-b) in the brains of patients affected by Alzheimer's disease. The cytokines may play a role in the neurotoxicity of amyloid protein. This inflammatory process may generate a local increase of free radicals.
6. The neurotransmitters
Alzheimer's disease modifies neurotransmitter systems. The cholinergic system, monoaminergic and peptidergic are affected.
Neurotransmitter monoaminergic |
Alzheimer's disease |
Utility |
Acetylcholine |
↓ ↓ ↓ ↓ nucleus basalis of Meynert and median septum |
Memory, stimulation of interaction between neurons |
Noradrenaline |
↓ ↓ ↓ to 30-40 % in the cortex, hippocampus |
Vivacity, activity, positivity |
Serotonin |
↓ ↓ ↓ in cortical structures and subcortical |
Sleep, memory, learning, sex, temperature. |
Dopamine |
↓ |
Motricity, reactivity |
|
Neuropeptides
(somatostatin, neuropeptideY, substanceP
|
↓ ↓ in the temporal cortex and hippocampus |
Learning, emotional control |
|
Amino Acids
(glutamate)
|
↓ ↓ in the cortex and hippocampus
|
Neurotransmitter of pyramidal cells of the hippocampus and cortex |
The table above shows the importance of neurotransmitter systems. Cholinergic neurotransmission is particularly affected in the Alzheimer's disease, the study leads to therapeutic applications.
The cholinergic system is the first and most affected. The cholinesterase inhibitors are currently registered as medicines. They are most effective when they are taken originally from the disease. Unfortunately, if they slow down especially at the beginning the evolution of the disease, they do not block completely its evolution.
The neurological and behavioral damages of the disease are multifactorial and a global treatment must be undertaken.
The cholinesterase inhibitors increase the concentration in the synaptic cleft by slowing down its degradation.
Several recent studies show the essential role of the abnormal interactions at the level of the neo-cortex of the ions Zinc, Copper and Iron. The natural regulation of metallic ions is disrupted by the age. The remedies that prevent metal deposition in the brain, decrease the amount of amyloid.
Therapeutic strategies : Preventions and Treatments Summary
To date, the etiology of Alzheimer's disease is still unknown. The lack of reliable biological markers and the complexity of the physiopathology make extremely difficult the development of medicines in this indication. Yet currently, a consensus exists on the association of apolipoprotein E (epsilon-4) and Alzheimer's disease. The future research will probably make a predictive marker during genetic testing.
Preventive actions
The primary prevention Summary
Centred on the general population it aims at reduce risk factors and triggering of the disease. The only possible prevention is currently based on a proper diet and reducing known risk factors, hypertension, diabetes, arteriosclerosis.
o Reduced exposure to aluminium Aluminium is implicated in Alzheimer's disease. The link was not demonstrated but some statistics are nevertheless alarming. So, in France, a study of the INSERM realized in two departments indicate that the persons drinking a water containing more of 0,1mg aluminum by liter see their risk doubling or tripling. In Canada, the federal authorities apply the precautionary principle and required that the water supplied to the citizens contains less of 0,1mg/l.The source of aluminum due to the use of aluminum pans in cooking brings only 1mg to 2mg a day on the 9mg to 14mg absorbed every day by means of food.
o Decreasing lead exposure A lead exposure in the working middle can make triple and even quadruple the risk of having one day the Alzheimer's disease.
o A decrease in exposure to Mercury seems essential in the prevention of Alzheimer's disease (previous vaccine , dental fillings) ?
o A regulation of the presence of the ions Iron, Copper and Zinc is essential, the role of metal chelators is not currently the subject of study in vivo but has proved its positive action in vitro on the dissolution of amyloid deposits.
o Alimentation
A sufficient intake of calories is essential. The need for a regular supply of glucose, a copious lunch was proved. The slight overeating maintaining Bmi between 23 and 27 decreases the cognitive disorders.
If the Bmi is below 23, the Mini Mental State Examination is less good. Above 27 the mortality is significant.
The chocolate rich in tryptophan and in fats and sugars stimulates serotonin antidepressant, but increases irritability by decreasing dopamine. Tryptophan is essential for the formation of serotonin.
The aspartame decreases the concentrations of dopamine and serotonin.
Vitamin B6 and magnesium are essential to the production of dopamine.
o Antioxidants
The antioxidants play a protective role. Vitamins A and E protect against intellectual deterioration. This interest is demonstrated by the study Suvimax (supplement of Selenium 100 µ, zinc 20 mgr, ß carotene 6 mgr, vitamin C 120 mgr and vitamin E 30 mgr in the prevention of the cardiovascular disorders and dementia).
o Unfavourable role of the homocysteine
The homocysteine plays a negative role on the cerebral circulation, its action in Alzheimer's disease is not known. Nevertheless, the increase of its elimination by B6 B9 B12 and betaine improves the cognitive function.
o Importance of estrogen
The glycine max (soya) seems to play a protective role of the cognitive function. A dosage of 100 mgr of isoflavones seems ideal in this indication. The substitute hormonotherapy in postmenopausal women has the same protective properties. The mechanism is not known.
o Anti-inflammatory taken
The taking of nonsteroid anti-inflammatory (such as aspirin and ibuprofen) may provide some protection against Alzheimer's disease, but it remains to prove. o Role of polyunsaturated fatty acids omega-3
The persons reached by dementia consume sharply less polyunsaturated fatty acids omega-3 than the others. The Alzheimer's disease could thus, as the coronary diseases and some cancers, be related to the lifestyle. The affected patients received 900 mg/day of omega-3 eicosapentaenoic acid form, which has significantly improved the results of cognitive tests.
o Behaviorism
The intellectual exercises could delay the dementia. The study « Nun Study » concerns the Alzheimer's disease. This study is ongoing since 1986 with 678 nuns of the order of the School Sisters of Notre Dame. With these nuns, in very demanding intellectual activity until late, more than 90 years, the rate of Alzheimer's disease is much more lower than the general population. It is difficult to separate these facts of a healthy diet.
The secondary prevention Summary
A screening for patients at risk, especially in families affected by Alzheimer's under its young shape (before 60 years) would allow to intervene prematurely. This action requires diagnostic and therapeutic means currently unavailable but in development like the dosage of apoprotein E.
The tertiary prevention Summary
It is the action on the consequences of the disease. Currently, only symptomatic treatments exist. However, other tracks are investigated and will certainly succeed in the years to come.
Both multifactorial origins, the multiple cellular mechanisms of degradation, and the polymorphic behavior disorders are a challenge in the treatment of Alzheimer's disease.
It is not sure yet that the Alzheimer's disease is a disease as such. It could be a syndrome reflecting pathophysiologic processes within distinct etiologies and leading to the same clinical panel.
The treatments susceptible to be implemented
All these objectives are met by
The amyloid cascade Summary
Current research focuses on substances such as the secretases (anti-protease) which may prevent amyloid formation. Another approach involves the stabilization of ionic homeostasis (especially calcic) cell, which would mitigate the toxic effects of amyloid β.
In natural medicine no evidence of an effective product is made so far.
Uncaria tomentosa could have a beneficial effect on memory in case of amnesia caused by cholinergic dysfunction. The alkaloids seem to increase the central cholinergic transmission by increasing levels of acetylcholine or by affecting the dopamine system who can increase cholinergic function. Another constituent, Uncarina E, could also affect the system glutamaterique who play a significant role in memory.
A study conducted by Professor Snow (Washington) has shown that deposits of beta-amyloid plaques in the brains of rats are significantly hampered by Uncaria tomentosa. In Alzheimer's disease, amyloid-beta protein settles in patches in the brain when brain cells form clusters stringy.
Researches in men are ongoing. The dose used in this indication is 60 mgr exempt extract of tetracyclic oxindole alkaloid in three doses per day.
The role of chelation of metal ions such as Iron, Copper, Zinc, Mercury is important, and despite the absence of clinical studies, its demonstration in vitro and its innocuousness makes it an important track of treatment.
The hyperphosphorylation of tau protein Summary
Another approach concerns the stabilization of ionic homeostasis (especially calcic) cell which would mitigate the toxic effects of β amyloid and block the hyperphosphorylation.
An action of a Magnesium supplement is possible theoretically but its action is not proven to date.
The hypometabolism Summary
A healthy diet, non-restrictive and not particularly deficient in essential fatty acids and well-balanced carbohydrate are important. The treatment of hypoglycemia deficiency and diabetes are essential.
Oxidative stress Summary
An activity of certain vitamins have been demonstrated against oxidative processes and metabolism of
free radicals
The beta-carotene has shown some evidence of action. This action is synergistic to the presence of vitamin C, Zinc and vitamin E. The doses who have shown the most effectiveness are the following: beta-carotene 15 mg plus vitamin C 500 mg, zinc oxide 80 mg, and vitamin E 400 IU daily.
The Ginkgo biloba at a dose of 120 mg to 240 mg per day of standardized ginkgo extract EGb 761 showed its efficiency.
Several studies, conducted double-blind and controlled, showed that the use of extracts of ginkgo (or GBE for "Ginkgo biloba extract) can exert a modest effect, but significant, especially early in the disease.
In more severe cases, taking ginkgo would at least stabilize the condition or slowing down the progression of the disease. The efficiency of Ginkgo has also been compared to that of commonly used medicines (tacrine, donepezil, etc.).
The effect of ginkgo may take six to eight weeks before it appears.
Its multifactorial action justifies effectiveness in Alzheimer's disease. It affects the whole cascade of membrane disorders related to ischemia. Antiradical action, anti-inflammatory action, action on the microcirculation.
It also shows protection against ischemia
Efforts are also being made to block the chronic inflammation around the senile plaques.
Two natural substances have shown an effect in Alzheimer's disease. The Ginkgo is always at the good place, the second plant is the Oenothera biennis (Evening primrose oil). This oil rich in gamma-linolenic, in linolenic acid and vitamin C has anti-inflammatory action recognized by decreased production of interleukin 1. An average dosage of 2 grams per day seems effective.
The Neurotransmitters Summary
Inhibitors of acetylcholinesterase
Only an extract of Chinese plant appears to have a net inhibitory action of acetylcholinesterase. Huperzia serrata (Qian Ceng Ta).
We extract from this Chinese plant an alkaloid, huperzine A.
According to randomized and controlled studies conducted in China, the extract improves memory, cognitive function and behavior of people reached by Alzheimer's disease.
During a multicenter and randomized clinical study we note a significant improvement after eight weeks in subjects who used Huperzine A, versus the placebo (103 patients).
The huperzine A would act by limiting the destruction of acetylcholine by acetylcholinesterase, this action is more specific and longer in time than the classical cholinesterase inhibitors (donepezil and tacrine).
The second action is described, it presents antagonists properties of the receivers of N-methyl-D-aspartate, and thus protects the neurones from glutamate toxicity.
The side effects are similar to those of the classic inhibitors of the acetylcholinesterase (diarrhea, nausea, blurred vision, hypersalivation, bronchospasm ...)
During the studies (whose duration ranged between 8 and 12 weeks), the patients took a total of 400 µg of huperzine A per day (divided into two doses of 200 µg).
The precursors of acetylcholine Summary
Acetyl-L-carnitine.
This compound, made by acetic acid and by L-carnitine, occurs naturally in the brain. It enhances the action of acetylcholine, acetyl-L-carnitine has antioxidant effects, which explains why many researchers have studied its effects on people reached from Alzheimer's disease. Studies (1400 subjects) randomized and controlled, with 500 mg to 1000 mg of acetyl-L-carnitine thrice daily, show modest results on cognitive ability in people reached by the disease.
Other studies show a beneficial effect on memory, performance and behavior of patients reached by Alzheimer's disease.
The tolerance in therapeutic doses is good, with the exception of nausea and depression.
Choline
Choline is necessary in the membrane synthesis of phospholipids.
The betaine, one of its metabolite gives the methyl group, during the transformation of homocysteine to methionine.
Many researches are conducted on choline supplementation in Alzheimer's disease as a precursor of acetylcholine.
The concentration of choline and its metabolites does not seem increased in the brain by oral supplementation. A dose of 500 mgm three times a day seems to be effective in this indication and provides clinical results.
Dimethylaminoethanol (deanol) (DMAE)
The deanol is a precursor of choline and increases the formation of acetylcholine in the brain.
A direct relationship exists between the acetylcholine levels in the brain and cognitive and mnestic abilities.
In clinical trials, doses of 300 to 2000 mgm / day in three doses have been used.
Soy lecithin
The use of soy lecithin in Alzheimer's disease does not decrease the symptoms of dementia.
Lecithin is a phospholipid composed of phosphatidyl esters (phosphatides), consisting mainly of phosphatidylcholine, phosphatidylethanolamine, phosphatidylserine and phosphatidylinositol.
A dose of 20-45 grams daily has been used in clinical studies. The effects on cognitive function are slight.
Phosphatidylcholine
Phospholipids, the major constituent of lecithin, phosphatidylcholine contains choline. Choline is precursor of acetylcholine. Acetylcholine is involved in the mechanisms of memory.
It has proved its action on the mnestic capacity in Alzheimer's disease.
The dosage in clinical studies of 2 grams in one dose is classic.
Phosphatidylserine.
An essential component of cell membranes, the phosphatidylserine is the main phospholipid in the brain. Normally, the brain produces in sufficient quantities, but some conditions among the elderly, as dementia and depression, are associated with a deficiency in phosphatidylserine.
Controlled studies show that taking supplements of phosphatidylserine at the beginning of the disease improves cognitive function, the mood and the behavior. The studies reported no side effects over 6 months. The dosage used in studies is 300 mg per day in total, divided into three doses.
Neuronal Growth Factors Summary
One of the ways of current research concerns the NGF for Nerve Growth Factor and ganglioside (GM1). It is about molecules which stimulate the trophic actions of neurons.
These researches are restrained by the difficulties of administration (intra-cerebral ventricular injection) and the unwanted effects.
Works are currently in progress.
No natural substance has shown such action.
The nootropic and neuroprotective Summary
The nootropics improves cerebral metabolism and protects the brain from the accumulation of toxic effects (piracetam, EGb 761).
Other substances present properties of anti-free radical (a-tocopherol,) or anti-calcic neuroprotective.
Other medicines act indirectly on neuroprotection as anti-inflammatories and oestrogens.
Some authors have shown that ischemia increases the initial reaction b-amyloidogenic.
Vinpocetine (Eburnamenine-14-carboxylic acid, Ethyl ester)
The vinpocetine enhances memory, improves oxygenation and cerebral glucose utilization. It slows the evolution of Alzheimer's disease.
The vinpocetine is a synthetic derivative of the apovincamine, a substance extracted from Vinca minor.
Its mechanism of action is unknown. One of the likely mechanism is a nootropic-like effects by indirect action, or direct cholinergic. It increases the effects of norepinephrine on the cyclic AMP.
It also describes an antiplatelet action by inhibiting the PAF (antiplatelet factor).
The used dose is from 5 to 10 mgr three times a day.
Hormonal Action Summary
Dehydroepiandrosterone (DHEA)
The oral taking of DHEA does not seem particularly useful in Alzheimer's disease. In vitro studies show that DHEA prevents the formation of beta-amyloid. A theoretical action would be expected on Alzheimer's disease, unfortunately, this one is not currently confirmed by clinical studies.
Side effects are not harmless (cancer of prostate, breast, hair loss, hirsutism), it must be measure the risks before taking DHEA.
An action on the atony due to the disease was proved by improving in a temporary way the tonicity of the patient.
Melatonin.
The melatonin has proved in vitro (and only in vitro) its ability to prevent the effects of amyloid-b on cell death, increased intracellular calcium and lipid peroxidation induced.
According to a study, melatonin is effective in treating insomnia associated with Alzheimer's disease. The current data are insufficient to justify the widespread use of melatonin to all Alzheimer.
Vitamin A et E
The high blood rates of vitamin A and E are associated with important rates of memory performance.
Nevertheless, the taking of supplements does not show a decreased risk of Alzheimer's disease.
A supplement of vitamin E at the rate of 2000 daily UI decreases the mnestic disorders in the early stages of the disease.
Vitamin C
Its antioxidant action at 500 mgm per day should theoretically limit the damage of excessive oxidation responsible in foreground of the amyloid cascade.
The absence of clinical studies does not allow to make it an official treatment of the Alzheimer's disease.
Vitamin B6 (pyridoxine)
The taking of pyridoxine from 50 to 200 mgr a day, decreases the blood rate of homocysteine.
Vitamin B9
In the treatment of hyperhomocysteinemia, 0.5 to 5 mgm / day are used, against oxidative stress, the dose can go up to 10 mgm per day.
Vitamin B 12
Taking vitamin B 12 at 0.5 mgr / day in association with folic acid (vitamin B9) 0.5 to 5 mgr daily and pyridoxine (vitamin B6) reduces the blood rates of homocysteine.
Centella asiatica
Its activity is due to triterpene acids and their esters, asiatic acid, madecassic acid, asiaticoside, asiaticoside A (madecassoside) and asiaticoside B.
The extract contains essential oils, flavonoids and flavones including quercetin and kaempferol.
Their actions are multiple, acting on the microcirculation it also presents an antioxidant activity.
The standard daily dose is 600 mgr three times a day for a dry extract.
In Alzheimer's Center at the Mayo Clinic, in the United States, we strongly encourage the practice of exercise for people reached by Alzheimer's disease.
Physical exercise has beneficial effects specifically in cases of Alzheimer's: It helps to keep the motor skills, is relaxing and keeps the balance, it reduces the risk of falls.
A study conducted at Oxford Dementia Center (Great Britain) in patients suffering from dementia subjected to a vigorous exercise program showed a marked improvement of their general situation.
Conclusion
The Alzheimer's disease is far from having revealed all its secrets, the multifactorial origin, the multiple clinical aspects, the mechanisms of development of the disease make that there is probably no single way to approach the disease. The alternative medicine brings numerous substances which combined can lead an improvement of the situation without being at present able to propose a cure.
All these objectives are met by
|
PRODUCT
NAMED ABOVE
|
EFFECTIVENESS |
TOXICITY |
DOSE |
ACETYL-CARNITINE |
++ |
+ |
1500 to 3000 MGR |
BETAINE |
++ |
0 |
350 MGR/DAY |
CENTELLA ASIATICA |
++ |
+ |
1800 MGR/DAY |
CHOLINE |
+ |
0 |
1500 MGR/DAY |
DHEA |
+ |
+ |
25 to 100 MGR/DAY |
DMAE |
+ |
+ |
300 to 2000 MGR/DAY |
GINKGO BILOBA |
++++ |
+ |
120 to 240 MGR/DAY |
GLYCINE MAX |
++ |
0 |
100 MGR ISOFLAVONES/J |
HUPERZINE A |
++++ |
++ |
400 MICROGR |
LECITHIN |
+ |
0 |
20 to 40 GR/DAY |
OENOTHERA BIENNIS |
++ |
0 |
2000 MGR/DAY |
OMEGA 3 |
++ |
0 |
2000 MGR/DAY |
PHOSPHATIDYLCHOLINE |
++ |
+ |
2 GR/DAY |
PHOSPHATIDYLSERINE |
++ |
0 |
300 MGR/DAY |
SELENIUM |
+ |
0 |
100 MICROGR/DAY |
UNCARIA TOMENTOSA |
++ |
0 |
180 MGR/DAY |
VINPOCETINE |
++ |
+ |
15 to 30 MGR/DAY |
VIT B6 |
++ |
0 |
50 to 200 MGR/DAY |
VIT A |
+ |
0 |
6 to 15 MGR/DAY |
VIT B 12 |
++ |
0 |
0.5 MGR/DAY |
VIT B9 |
++ |
+ |
0.5 to 5 MGR/DAY |
VIT C |
+ |
0 |
120 to 500 MGR/DAY |
VIT E |
++ |
+ |
400 to 2000 UI/DAY |
ZINC |
++ |
0 |
20 to 80 MGR/DAY |
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