~Alzheimer's Disease, Part 3 - Conventional Treatment
At present, there is no true prevention for Alzheimer's in conventional medicine, but there are ways to decrease the risk for developing the disease and also, possibly, slow the progression. Future research will concentrate on slowing disease progression as well as lessening the burden on caregivers via patient improvement. The following is a discussion of therapies from medical literature that have been tried in the treatment of Alzheimer's disease.
- Acetylcholinesterase Inhibitors
- Estrogen Replacement Therapy
- Anti-Inflammatory Drugs
Drug treatment with the acetylcholinesterase inhibitors (such as tacrine, donepizil, metrifonate, and rivastigmine) is currently prescribed after the disease has actually developed. This class of drugs increases the amount of neurotransmitter acetylcholine at the nerve terminal by decreasing its breakdown by the enzyme cholinesterase. Remember that in Alzheimer's disease, the levels of multiple neurotransmitters, especially acetylcholine, are decreased markedly. This loss of acetylcholine occurs mainly in the cortical areas of the brain.
Acetylcholinesterase inhibitors have been shown to modestly improve memory and language and decrease the emotional symptoms of apathy, anxiety, hallucinations, inappropriate behavior, and abnormal movement. None of these medications reverses the process and none is curative. The most that can be hoped for at this point is some improvement in symptoms. These drugs are prescribed after the disease has been diagnosed. Therefore, patients and their families should have realistic expectations with these drugs and not expect dramatic improvement or a reversal of the disease process. Less than half of patients show any benefit at all from acetylcholinesterase inhibitors, even when there are no side effects.
Donepezil (Aricept) is given for mild to moderate Alzheimer's disease at a dose of 5 mg orally at bedtime for 6 weeks and then increased to a dose of 10 mg at bedtime if tolerated. Nausea and diarrhea are the most common side effects. In patients with prior abnormally slow heart rate, asthma, or ulcer disease, a worsening of these processes can occur and should be watched for. However, their presence prior to treatment does not prevent the use of acetylcholinesterase inhibitors.
A clinical trial with donepezil at 5 or 10 mg a day showed a 3.1 point ADAS-Cog improvement, with only 12% dropping out due to side effects. Patients on donepezil remain in a nonsevere disease state for a longer time (Foster and Plosker 1999). An article published in the French journal Encephale described the first large-scale study of donepezil at a daily dosage of 5-10 mg conducted over 14 weeks. The results show a significant improvement in cognitive function in the treatment groups, compared to the placebo groups. The difference emerged after 3 weeks of treatment, lasted throughout the 12 weeks of the study, and was still very marked 3 weeks post-treatment discontinuation. The results of a second study conducted over 30 weeks were similar (Robert et al. 1999).
Phase II clinical trials of donepezil have demonstrated that donepezil improves cognition, global function, and activities of daily living. In addition, there were no clinically significant treatment-related effects on vital signs or laboratory values in any trial. Adverse events, when present, were generally mild in intensity, transient, and resolved during continued treatment with donepezil (Doody 1999a).
A review of the clinical trials, however, concluded that donepezil produced only modest improvements in cognitive function and that study clinicians had rated global clinical state more positively in treated patients. Further, in two of the four studies, the patient's own rating of their quality of life showed no benefit of donepezil compared with placebo. A variety of adverse effects were recorded, with more incidents of nausea, vomiting, diarrhea, and anorexia in the 10 mg a day group compared with placebo and the 5 mg a day group (Birks et al. 2000b).
Tacrine (Cognex) is another acetylcholinesterase inhibitor, although possible liver toxicity makes donepezil the first choice. Patients receiving 160 mg a 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, mostly because tacrine is so toxic to the liver and causes severe side effects (Birks et al. 2000b).
Estrogen Replacement Therapy
Estrogen replacement therapy (ERT) is useful both in preventing Alzheimer's disease as well as in treatment. 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 postmenopausal women taking estrogen-replacement therapy over those who were not (Paganini-Hill et al. 1994; Stern et al. 1994; Paganini-Hill et al. 1996).
Animal experiments show that surgical removal of the ovaries 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 reverses most of these effects.
Estrogen is an excellent neuroprotective agent and functions in a variety of ways, including antioxidant mechanisms (decreasing oxidative stress), protection against toxicity from beta-amyloid, encouragement of neuronal dentritic growth, increasing Nerve Growth Factor (NGF), stimulation of neuronal axonal sprouting, and modulation of apolipoprotein E expression. All of these pathways involve the development of Alzheimer's disease (Yaffe et al. 1998).
Risks of estrogen replacement therapy include increased risk of carcinoma of the breast and development of blood clots in the legs or lungs (only with oral estrogen, not transdermal or pellets). Benefits of estrogen therapy, in addition to treating and preventing Alzheimer's disease, include decreased osteoporosis risk and decreased risk of other cancers such as lymphoma and colon cancer. ERT, at present, is not available for men; but in the future, trials with less feminizing agents (such as 17-alpha-estradiol) may be considered.
More information about estrogen and other hormones can be found in the Female Hormone Modulation Therapy protocol.
- Cox-2 Inhibitors
Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) include drugs like aspirin, indomethicin (Indocin), ibuprofen (Motrin, Advil), relafen, and others. They all modulate inflammatory pathways by a chemical mechanism slightly different from the Cox-2 inhibitors.
Research into the mechanism of NSAID use in the treatment of Alzheimer's disease found that it is more likely to be through the suppression of microglial activity than by inhibiting the formation of senile plaques or neurofibrillary tangles (Mackenzie et al. 1998). A 50% reduction in risk against Alzheimer's disease is seen in elderly arthritic patients who have been taking the NSAIDs ibuprofen and indomethicin. Aspirin, however, was only effective in dosages over 2.4 grams a day. The effective dose of ibuprofen has been estimated to be 800 mg a day (see Life Extension Magazine, November 2000).
A clinical trial of 100-150 mg a 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.
In a population study in Cache County, Utah, 201 cases of Alzheimer's disease and 4425 participants with no indication of cognitive impairment were identified, interviewed, and their medicine chest assessed. Compared with cognitively intact individuals, the Alzheimer's disease cases had significantly less reported current use of NSAIDs, aspirin, and histamine H2 receptor antagonists (Anthony et al. 2000).
A longitudinal study of 1686 participants in the Baltimore Longitudinal Study of Aging examined whether the risk of Alzheimer's disease was reduced among reported users of aspirin or other nonsteroidal anti-inflammatory drugs (NSAIDs). The study found a decreased risk among those with 2 or more years of NSAID use (relative risk = 0.40) compared with those with less than 2 years of use (relative risk = 0.65). Aspirin use did not decrease the risk (relative risk = 0.74), nor did acetaminophen (relative risk = 1.35) (Stewart et al. 1997).
Ibuprofen was used in a study of transgenic mice displaying widespread microglial activation, age-related amyloid deposits, and dystrophic neurites. These mice were created by overexpressing a variant of the amyloid precursor protein found in familial AD. Treatment with ibuprofen produced significant reductions in interleukin-1 beta and in the number and total area of beta-amyloid deposits (Lim et al. 2000).
Cyclooxygenase-2 (COX-2) inhibitors are anti-inflammatory drugs that decrease inflammation by a pathway somewhat different from NSAIDs. They include medications like Celebrex. They have been shown to markedly decrease the chemicals causing inflammation. These and the NSAIDs block the free-radical attack on brain tissue mediated by inflammation (Scali et al. 2000).
- Acetylcholinesterase Inhibitors
- MAO-B Inhibitors
- Nerve Growth Factor
- Secretase Inhibitors
Rivastigmine is an acetylcholinesterase inhibitor that has not yet been approved for use by the FDA. It has been found to be equally as effective as donepezil with comparable side effects, but the ADAS-Cog improvement is 4.9 compared to 3.1 with donepezil (Birks et al. 2000a; Wettstein 2000).
Metrifonate is an acetylcholinesterase inhibitor not yet approved by the FDA, with research data indicating it is equally effective to donepezil. Metrifonate has shown a 2.8 point ADAS-Cog improvement with very few side effects. Clinical trials with higher doses of metrifonate are underway (Wettstein 2000).
Selegilene. Selegilene (Eldepryl or Deprenyl) is a drug approved for use in Parkinson's disease that irreversibly inhibits monoamine oxidase type B (MAO-B). Monoamine oxidase is an enzyme that inactivates the monoamine neurotransmitters nor-epinephrine, serotonin, and dopamine. Selegilene is degraded in the liver into desmethyldeprenyl (the major metabolite), amphetamine, and methamphetamine, which are eliminated in the urine. Side effects include nausea, hallucinations, confusion, dizziness, depression, agitation, and tremors.
In a study using vitamin E, selegilene, or both, in Alzheimer's disease, there was a modest improvement in symptoms (Sano et al. 1997). In the Czech and Slovak Alzheimer's Disease Study Group using several well-accepted measurements of mental function (including MMSE, Sternberg's Memory Scanning Test, and others), Selegilene had a long-term helpful effect on memory in mild to moderate Alzheimer's disease. This was thought to be due to selegilene's effect on dopamine-rich prefrontal brain areas (Filip et al. 1999).
However, selegilene also has anti-apoptotic actions which may be helpful in Alzheimer's disease where cell death is important. Remember, apoptosis is the process of programmed cell death that occurs when cells are damaged. Apoptosis plays a role in the death of neurons in Alzheimer's disease as it does in all types of cell death. Limiting or reducing cell death in Alzheimer's may help prolong the life of needed neurons and possibly slow the disease process (Gelowitz et al. 1999; Suuronen et al. 2000). Another study showed that selegilene protected cells from toxic effects of beta-amyloid (Thomas 2000).
Selegilene was shown to significantly increase the number of branching points and intersections in both apical and basal dendrites in deprenyl-treated monkeys compared to controls. The authors of the study proposed that this may be the mechanism responsible for the enhancement of cognitive functions in Alz-heimer's disease patients following deprenyl treatment (Shankaranarayana Rao et al. 1999).
Thomas (2000) suggested that stimulation of nitric oxide production could be central to the action of selegilene. Deprenyl stimulates vasodilation and increases nitric oxide production in brain tissue and cerebral blood vessels. Because nitric oxide modulates activities including cerebral blood flow and memory, and reduced nitric oxide production has been observed in brains affected by Alzheimer's disease, stimulation of nitric oxide production by deprenyl could contribute to the enhancement of cognitive function in Alzheimer's disease.
Studies in rats show that the combination of selegilene with tacrine was remarkedly more effective than either agent alone (Dringenberg et al. 2000).
Nerve Growth Factor. Supplementing or increasing Nerve Growth Factor (NGF) may stimulate neuronal cell growth. This is a current area of research, although no large trials have yet been done (Gustilo et al. 1999).
Secretase Inhibitors. Secretase inhibitors are an area of future research. These substances decrease levels of beta-amyloid by affecting its cleavage and metabolism (Martin 1999).
Nicotine. Nicotine causes acetylcholine transmitter release and, therefore, is theoretically of benefit in Alzheimer's disease with its decrease in acetylcholine levels. Some, but not all, studies have shown a reduced incidence of Alzheimer's disease among light smokers (fewer 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. The scientific studies, however, are not conclusive (Lopez-Arrieta et al. 2001).
Metanicotine. Metanicotine is less toxic than nicotine and causes nearly the same acetylcholine release. Metanicotine is currently undergoing clinical studies for use in Alz-heimer's disease (Park et al. 2000).
Vaccines. Although vaccine trials in rodents are promising, and this work shows decreased behavioral effects and brain damage from beta-amyloid with the vaccine, a usable human vaccine is not likely in the near future (Chapman 2000).
Continued . . .
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