Feeding lecithin (phosphatidylcholine) to animals increases brain acetylcholine levels, but clinical trials using lecithin on Alzheimer’s patients has shown little or no improvement. Likewise, attempts to treat patients with drugs that stimulate acetylcholine receptors have been a failure. But acetylcholinesterase inhibitors have proven to be of therapeutic value.
Neurons send signals to other neurons by releasing chemicals into synapses. But signals are only effective when they have a beginning and an end. You can’t send Morse code by constant pressure on a telegraph key. Acetylcholinesterase, the enzyme that breaks down acetylcholine, ends the chemical signal that begins when acetylcholine is released into a synapse and then connects with a receptor. The memory loss effect that acetylcholinesterase plays in Alzheimer’s may be due to amplification of signals which would have been weakened by neurodegeneration.
The only two FDA-approved drugs for treatment of Alzheimer’s disease are both acetylcholinesterase inhibitors: tacrine (Cognex) and donepezil (Aricept). Huperzine-A, metrifonate, and rivastigmine are also acetylcholinesterase inhibitors — and the last two may receive FDA approval soon. Huperzine-A has been used for centuries in China as an herbal medicine prepared from the moss Huperzia serrata. Side effects from tacrine, including liver toxicity, are so severe that only donepezil (Aricept) is approved in Canada.
Currently, the most respected standard for assessing the neuropsychological status of Alzheimer’s patients is the Alzheimer’s Disease Assessment Scale — Cognitive Subscale (ADAS-Cog). Memory, orientation, language, and functionality are measured on a 70-point scale that increases (on average) by 7 to 10 points per year as the patient’s cognition worsens. An improvement of 4 points (4 point decline in score) corresponds to a clinically significant reversal of symptoms of nearly half a year.
Patients receiving 160 mg/day of tacrine in a 30-week double-blind, placebo-controlled study showed an ADAS-Cog improvement of 4.1 points if they completed the trial. But only 27% of the patients completed the trial, largely because tacrine is so toxic to the liver and causes other severe side effects. A clinical trial with donepezil (Aricept) (5 or 10 mg/day) showed a 3.1 point ADAS-Cog improvement, with only 12% dropping out due to side effects. Rivastigmine’s side effects are comparable to those of donepezil, but the ADAS-Cog is 4.9. Metrifonate has shown a 2.8 point ADAS-Cog improvement, with very few side effects. Clinical trials with higher doses of metrifonate are underway. Less than half of patients show any benefit at all from acetylcholinesterase inhibitors, even when there are no side effects, so the ADAS-Cog scores may greatly under-represent the improvement seen in patients who do benefit.
Although acetylcholinesterase inhibitors can apparently reverse symptoms by several months, they have not been shown to slow the progress of neuron degeneration. By contrast, a double-blind, placebo-controlled clinical trial with daily doses of 10 mg deprenyl (selegiline), 2000 IU vitamin E, or both, showed a 25% slowing of the progress of the disease — but without any cognitive improvement. There was no advantage to using both deprenyl and vitamin E, so vitamin E alone would be a less expensive and more convenient therapy for most patients.
Treatment of cultured neurons with vitamin E has been shown to protect them from beta-amyloid toxicity. This suggests that vitamin E and other antioxidants such as vitamin C (which regenerates vitamin E) and coenzyme Q10 may be of value in preventing Alzheimer’s disease. In fact, melatonin has been shown to protect cell cultures from beta-amyloid toxicity. N-acetylcysteine has protected cultured cells from oxidative stress due to AGE-modified tau-protein. (Advanced Glycation End-Products, AGEs, lead to the formation of toxic hydroxyl free radicals and impaired ion and glucose transport which cause neuron degeneration. This is discussed in detail further in the text.)
Gingko biloba not only has antioxidant properties, but is anti-inflammatory and promotes cerebral circulation. One double-blind, placebo-control trial with gingko biloba showed an ADAS-Cog of 1.4 points above placebo, although a meta-analysis of many such studies showed only a modest ADAS-Cog improvement.
The protective effect of estrogen against Alzheimer’s is well-documented, but remains controversial. Studies of 2529 women in the Leisure World Retirement Community cohort, 472 women in the Baltimore Longitudinal Study of Aging and 1124 women in a Manhattan cohort showed a 30%, 50%, and 60% lower risk, respectively, for Alzheimer’s disease among post-menopausal women taking estrogen-replacement therapy over those who were not. Animal experiments show that removal of the ovary can reduce choline uptake in the frontal cortex and hippocampus by 24% and 34% — and cause a 45% decline in mRNA for nerve growth factor (NGF) in the frontal cortex. Estrogen replacement mostly reverses these effects. The controversy is partly due to studies which have shown an increase in breast cancer incidence of 25% with estrogen replacement therapy. But other studies have shown colon cancer is reduced 50%, hip fractures (and osteoporosis) are reduced 40%, and risk of heart attack may also be reduced. A pilot study has shown significant ADAS-Cog improvement with tacrine and estrogen over tacrine alone. Large clinical trials with estrogen are currently in progress.
A 50% reduction of risk against Alzheimer’s disease is seen in elderly arthritic patients who have been taking non-steroidal anti-inflammatory drugs (NSAIDs) such as ibuprofen and indomethicin. Aspirin was only effective in dosages over 2.4 grams/day. A clinical trial of 100 to 150 mg/day of indomethicin for 6 months resulted in a 14-point ADAS-Cog improvement among the 79% of patients who did not drop out due to gastrointestinal side effects. Inflammation apparently contributes significantly to the final neurodegenerative processes which are initiated by beta-amyloid and neurofibrillary tangles.
A meta-analysis of studies using Hydergine (ergoloid mesylates) showed modest improvement for Alzheimer’s symptoms, but only in dosages of 4 to 9 mg/day, rather than the typical dose of 3 mg/day. So-called nootropics (Greek for “toward mind”) such as piracetam are usually ineffective because most Alzheimer’s patients have elevated corticosteriods, which suppresses the memory-improving effects.
Some, but not all, studies have shown a reduced incidence of Alzheimer’s disease among light smokers (less than 10 cigarettes per day), but an increased incidence of the disease among heavy smokers (more than 20 cigarettes per day). A pilot study with six patients using nicotine patches (to avoid the effects of the other toxic chemicals in cigarette smoke) showed some improvement in a learning task, but no effect on global cognition or short-term memory. Metanicotine is less toxic than nicotine and causes nearly the same acetylcholine release as nicotine.
Studies with 2 or 3 grams per day of acetyl-L-carnitine have shown a reduced rate of disease progression for Alzheimer’s patients. Acetyl-L-carnitine reduces lipofuscin in neurons. Although lipofuscin is cellular debris from glycation and oxidation, detrimental effects in general and a contribution to Alzheimer’s disease in particular have not been shown. The (modest) benefits of acetyl-L-carnitine are more likely due to its ability to normalize cell metabolism, increase NGF utilization, and increase acetylcholine synthesis.
The Japanese drug idebenone not only acts as an antioxidant, but it increases NGF and thereby improves cortical acetylcholine levels. Some improvement was also seen with 300 mg/day of phosphatidylserine. Desferrioxamine (which binds to aluminum and iron) given by intramuscular injection to a small group of Alzheimer’s patients reduced the rate of decline of daily living skills to half that of the no-treatment group. Aminoguanidine could be of value in reducing AGEs in Alzheimer’s patients. There are many such therapies that have shown some promise in small isolated studies, but which require large clinical trials if their merit is to be established with certainty.
Source: Life Extension Foundation 1998-1999