It has been known since the early 1900s that Alzheimer's disease is associated with two distinctive histologic changes in the brain: amyloid (“senile”) plaques and neurofibrillary tangles. Recent research has clarified the significance of these observations and provides a framework for experimentation with various medications.
The plaques are partly composed of a protein called beta amyloid, which is produced by the breakdown of amyloid precursor protein, a substance normally present in brain tissue. Genetic mutations may alter the amyloid precursor protein and make it more likely that beta amyloid is deposited in plaques. Specific genotypes may code for lipoproteins that make beta amyloid less soluble, enhancing plaque formation.1 These plaques may be associated, in demented patients, with oxidative damage and inflammation.
Neurofibrillary tangles are intracellular bodies derived from microtubules, the cellular structures responsible for intracellular transport. In Alzheimer's disease, microtubules become disordered and form neurofibrillary tangles because of excessive phosphorylation of microtubular tau proteins.2 Current research is examining the relationship between amyloid plaques, neurofibrillary tangles and the development of Alzheimer's disease.
Research has also demonstrated that patients with Alzheimer's disease have deficiencies in several neurotransmitters. Clinically, the most important of these is acetylcholine, associated with a loss of cholinergic neurons.3 The loss of acetylcholine in neuronal circuits responsible for learning and memory seems to cause the cognitive symptoms of Alzheimer's disease. Confirming this theory is the observation that anticholinergic medications often cause confusion and delirium in elderly patients and that these agents have been shown to interfere with learning in laboratory animals.4 Also, neuroleptic drugs used to control disturbed behavior in patients with Alzheimer's disease may worsen the disease as a consequence of their anticholinergic effects.5
Other biochemical changes that occur in patients with Alzheimer's disease include potassium and calcium channel disruption, (possibly caused by beta amyloid), which leads to interference with neuronal function and neurotransmission. Serotonin and norepinephrine levels are also affected in these patients, but most research has focused on acetylcholine deficiency.
The drugs that are available for the treatment of Alzheimer's disease can be divided into those whose actions enhance the effect of neurotransmitters and those thought to protect neurons. The former category represents the palliative approach, the latter the restorative approach.
The best known neurotransmission-enhancing drugs are the cholinesterase inhibitors, two of which have been labeled for this use by the U.S. Food and Drug Administration (FDA). Numerous other agents with similar effects have been studied, and limited evidence suggests that some may have a beneficial effect on cognition in patients with Alzheimer's disease.
Alzheimer's disease is associated with a decrease in acetylcholine levels, and it seems reasonable that replacement of this neurotransmitter might alleviate some of the clinical effects of the disease. One way to achieve higher levels of acetylcholine is to prevent its breakdown by acetylcholinesterase, also known as cholinesterase. This is what the cholinesterase inhibitors do.
Tacrine. A centrally acting cholinesterase inhibitor, tacrine (Cognex) is labeled for the treatment of mild to moderate Alzheimer's disease. Two manufacturer-sponsored studies comparing tacrine with placebo showed a small but statistically significant difference in cognitive function in treated patients.6 However, 30 percent of patients receiving tacrine develop elevated hepatic enzyme levels (Table 1). The manufacturer of tacrine is no longer aggressively marketing this drug, since a new and preferable agent is now available.
|ALT level||Treatment and monitoring regimen|
|< 2 times upper limit of normal||Continue treatment according to recommended titration and monitoring schedule.|
|> 2 to < 3 times upper limit of normal||Continue treatment according to recommended titration.|
|Monitor ALT levels weekly until levels return to normal limits.|
|> 3 to < 5 times upper limit of normal||Reduce the daily dose of tacrine by 40 mg per day.|
|Monitor ALT levels weekly.|
|Resume dosage titration and every-other-week monitoring when ALT levels return to normal limits.|
|> 5 times upper limit of normal||Discontinue tacrine treatment.|
|Monitor patient closely for signs and symptoms associated with hepatitis and follow until ALT levels are within normal limits.|
|Rechallenge may be considered, taking into account the risks and benefits of treatment.|
Donepezil. Treatment with donepezil (Aricept) is also associated with improvement in test performance, physicians' impression of change and Mini-Mental State scores, when compared with patients treated with placebo.7,8 Donepezil is not associated with the hepatotoxicity that occurs with tacrine. The initial dosage is 5 mg once daily; this may be increased to 10 mg per day after six weeks (Table 2).
|Drug||Starting dosage||Maximum dosage||Frequency||Cost*|
|Tacrine (Cognex)||10 mg four times daily||40 mg four times daily||Four times daily||$137|
|Donepezil (Aricept)||5 mg once daily||10 mg once daily||Once daily (at bed time)||$120|
The use of tacrine and donepezil is associated with cholinergic side effects, particularly nausea and vomiting. These effects may subside with continuing therapy. In addition, the beneficial effects of both drugs cease within weeks of discontinuation. Patients and their families should be informed that these drugs, although the best available and the only drugs labeled for this use at present, are only modestly effective and may be associated with intolerable side effects. In fact, clinical studies reveal that caregivers usually note no improvement.
Rivastigmine and metrifonate. Two investigational cholinesterase inhibitors, rivastigmine (ENA 713; Exelon) and metrifonate, are in phase 3 clinical trials. These medications, which are expected to be labeled for this use soon, also seem to have significant, although modest, effects on the cognition of patients with Alzheimer's disease.9 Other types of cholinergic therapy are currently under investigation (Table 3).
|Drug||Status||Mechanism of action|
|Tacrine (Cognex)||Labeling approved||Cholinesterase inhibitor|
|Donepezil (Aricept)||Labeling approved||Cholinesterase inhibitor|
|Epastigmine||Phase 3 trials||Cholinesterase inhibitor|
|Physostigmine (Synapton)*||Phase 3 trials completed||Cholinesterase inhibitor|
|Xanomeline†||Phase 2 trials||Cholinergic agonist|
|Milameline||Phase 3 trials||Cholinergic agonist|
|AF 102B||Phase 3 trials||Cholinergic agonist|
|SB202026 (Memric)||Phase 3 trials||Cholinergic agonist|
|Rivastigmine (ENA 713; Exelon)||Phase 3 trials||Cholinesterase inhibitor|
|Metrifonate||Phase 3 trials ‡||Indirect cholinesterase inhibitor|
|Heptylphysostigmine||Phase 2 trials||Cholinesterase inhibitor|
Hydergine is the trade name for a mixture of ergoloid mesylates that differs from other ergot alkaloids in having no vasoconstrictive effects. This agent enhances the sensitivity of neural receptors. It has been labeled by the FDA for use in treating the symptoms of an idiopathic decline in mental capacity not related to a potentially reversible condition. Once very popular, this drug has fallen out of favor. Some studies show a statistically significant improvement in alertness and recent memory, and a decline in confusion, but others show no benefit. A meta-analysis of Hydergine's efficacy,10 published in 1994, showed statistically non-significant improvement in some psychologic and behavioral measures in patients with Alzheimer's disease. Patients with vascular dementia were more likely than others to experience benefit from this product. The patients who responded best were taking a higher dosage (4 to 9 mg per day) than that recommended by the manufacturer (3 mg per day). A related compound, nicergoline, is in phase 2 trials in the United States. Nicergoline has been shown to be effective in improving cognition in vascular dementia and is currently in use in Europe.
Investigational Neurotransmission-Enhancing Drugs
Nicotine. This drug has been proposed as a treatment for Alzheimer's disease because patients with this disease have fewer nicotinic cholinergic binding sites than control subjects, and nicotine is known to stimulate acetylcholine receptors. The results of a small pilot study suggest that nicotine can improve cognition in some patients with Alzheimer's disease.11 Phase 3 trials presently under way may establish a role for nicotine in treating this disorder, but its use cannot be recommended at the present time.
Ginkgo biloba. Administration of a dried extract of leaves of the Ginkgo biloba tree has recently been approved in Germany for treatment of dementia. Results of European in vitro studies suggest that ginkgo may benefit patients with Alzheimer's disease, possibly through its ability to enhance neurotransmission by activating presynaptic receptors.12 Ginkgo may also have antioxidant properties. In a recent American trial,13 ginkgo-treated patients showed no worsening of their cognitive impairment, as measured by the cognitive portion of the Alzheimer's Disease Assessment Scale (ADAS), while a 1.5-point decline was demonstrated in the placebo-treated group. Caregivers also noted a mild but statistically significant improvement in the patients who received ginkgo, compared with significant worsening in the placebo group. The dosage used in the study was 40 mg three times daily.
The extensive media coverage of this study and the widespread availability of ginkgo extracts in health food and other stores suggest that physicians should inquire about use of this botanical agent because a significant number of patients with Alzheimer's disease will be taking it. Patients and families should be reminded that quality control measures may be lacking in this non-regulated product. Also, ginkgo tablets may be combined with other so-called “mind-enhancing” herbs in commercially available preparations, increasing the potential for undesirable effects.
Other Investigational Drugs. It is hypothesized that glutamate and aspartate accumulate at N-methyl-D-aspartate (NMDA) receptors in the brains of patients with Alzheimer's disease, causing hyperdepolarization and, possibly, degeneration of neurons. Drugs that can regulate or enhance the function of these NMDA receptors may have a positive effect on the disease. CX516 is a drug that has been shown in small trials to significantly improve learning and memory when compared with placebo.14 It did not improve all aspects of memory, but further research may prove that even selective improvement is useful in patients with Alzheimer's disease.
Neurotrophic factors. Stimulation of nerve growth with neurotrophic factors is also being considered as a treatment for degenerative disorders such as Alzheimer's disease.15
Investigational Neuroprotective Agents
No drugs thought to be restorative have been labeled by the FDA for use in treating the cognitive symptoms of patients with Alzheimer's disease. However, researchers are hopeful that some commonly used agents, such as estrogen, vitamin E and nonsteroidal anti-inflammatory drugs, may prove to be useful in the treatment of this disease (Table 4).
|Sabeluzole||Phase 3 trials|
|Alcar||Phase 3 trials|
|NSAIDs*||Not yet labeled|
|Estrogen||Not yet labeled|
|Vitamin E||Not yet labeled|
|Selegiline (Eldepryl)||Not yet labeled|
|Vitamin C||Theoretic benefit|
|Lazabemide||Phase 2 trials|
|Nicergoline||Phase 2 trials|
Estrogen. The facts that the risk of developing Alzheimer's disease increases dramatically after age 65 and that women seem to be more susceptible (independent of their longer life spans) has led researchers to investigate the possible cognitive effects of sex hormones, which decline in women after menopause (testosterone does not normally decline sharply in men). Animal studies have shown that administration of estrogen to estrogen-deficient laboratory animals restores the number of neural synapses, causes beta-amyloid to be more soluble and has an antioxidant effect.16 A recent descriptive study17 in which participants were asked to self-report their use of estrogen showed a lower relative risk (0.40) of Alzheimer's disease and a later onset of dementia in those who had taken estrogen, compared with those who had not. The optimal dosage to achieve these effects is uncertain. The apparent benefit was increased if the length of treatment was more than one year.
Prospective studies are lacking, and the evidence at this time is not sufficient to recommend administering estrogen to prevent or delay progression of Alzheimer's dementia. However, the preliminary (and somewhat promising) evidence of estrogen's effect on cognition should be reviewed with women who are considering the risks and benefits of estrogen replacement therapy. The Women's Health Initiative Memory Study and the Alzheimer's Disease Cooperative Study are currently conducting double-blind clinical studies of estrogen's effects on the development and course of cognitive impairment. Both trials should help determine if estrogen replacement therapy can prevent or delay the development of Alzheimer's disease.
Vitamin E and Selegiline. Substances that increase brain catecholamines and/or reduce oxidative damage to neurons may slow progression of Alzheimer's disease. Vitamin E has an antioxidant effect. Selegiline is a selective monoamine oxidase B (MAO-B) inhibitor that might be effective since MAO-B stimulates oxidation in the brain.
Higher levels of antioxidants in the blood correlate with better memory performance.18 A recent report on the Alzheimer's Disease Cooperative Study suggests that vitamin E (in a dosage of 1,000 IU twice daily) and selegiline (in a dosage of 5 mg twice daily) delay nursing home placement, loss of ability to perform basic activities of daily living and development of severe dementia.19 Patients taking vitamin E or selegiline fared better than those taking placebo or the two drugs together. The delay in functional decline was equal to approximately a seven-month delay in one of the above-mentioned outcomes. Cognitive function was not affected in any of the groups. Patients taking selegiline alone or in combination with vitamin E did have a non-significantly higher rate of falls than those taking placebo, although there were no serious injuries.
Vitamin E is considered to be safe and non-toxic, although patients may complain of nausea, intestinal cramping, fatigue or blurred vision. Gonadal dysfunction and abnormalities in serum creatine kinase, thyroid or lipid test values may also occur rarely. Vitamin E, especially in higher dosages, may also increase the risk of coagulation defects in patients with vitamin K deficiency and in those taking warfarin.20 Selegiline is associated with orthostatic hypotension. In addition, it should not be given to a patient taking selective serotonin reuptake inhibitors, tricyclic antidepressants or meperidine, or receiving general anesthesia, because of a risk of severe central nervous system toxicity. A tyramine-free diet is not required, since selegiline is a selective MAO-B inhibitor at the dosages considered here (no more than 10 mg per day). Patients should be warned about the possibility of hypertensive crisis with selegiline therapy and the symptoms to watch for, especially if the standard 10 mg per day dosage is exceeded. Selegiline is not labeled by the FDA for treatment of Alzheimer's disease.
The American Psychiatric Association has recently issued a practice guideline that recommends the use of vitamin E in patients with moderate Alzheimer's disease.21 It can probably be used safely in patients with mild or severe disease but has not been studied in these groups. Combination therapy with vitamin E and acetylcholinesterase inhibitors could also be considered. A trial of selegiline may be warranted in patients with moderate Alzheimer's disease who cannot take cholinesterase inhibitors and who have no contraindications.
Nonsteroidal Anti-inflammatory Drugs. Investigators noted in the 1980s that patients with rheumatoid arthritis had a lower incidence of dementia than would be expected in the general population. It was hypothesized that nonsteroidal anti-inflammatory drugs (NSAIDs) decreased inflammatory changes in the brains of patients with Alzheimer's disease. Participants in a recently reported long-term observational study on aging were asked to self-report their use of over-the-counter medications.22 The risk of developing Alzheimer's disease was found to be about 50 percent less in those who were using NSAIDs. (The most commonly used NSAID was ibuprofen; most people reporting aspirin use were taking dosages too low for an anti-inflammatory effect.) The optimal dosage for these medications is not known, but participants in the study had taken NSAIDs for more than two years.
NSAIDs are associated with gastrointestinal and renal complications. They cannot be recommended for the treatment of Alzheimer's disease at present, but patients who need NSAIDs for other indications should consider the early evidence of possible benefit in preventing Alzheimer's disease when deciding whether or not to take these medications.
The social costs of Alzheimer's disease are enormous. Medications that delay the need for nursing care or institutionalization may reduce those costs, both for society and for individuals, even if they are not curative. Observational studies of tacrine-treated patients suggest that use of this drug may delay nursing home placement by about six to 12 months.23 If this observation is confirmed by prospective research, it could translate to a cost savings of tens of thousands of dollars over a patient's lifetime.24
Current opinion favors offering donepezil to patients with mild or moderate impairment, since this approach seems most likely to lead to a delay in functional deterioration. Use of vitamin E, alone or in combination with a cholinesterase inhibitor, should also be considered at the early or middle stages of the disease. In end-stage disease, clinical judgment must guide the decision to continue these medications. Other reasons for stopping a medication might include the onset of a serious illness or the physician's assessment that the patient's cognition is too impaired or life expectancy too short to benefit from a costly drug.
Although current evidence offers little support for treating Alzheimer's disease with estrogen, ginkgo biloba or other unapproved agents, the physician may encounter persons in whom a trial of these drugs is warranted, or patients may decide to take a medication for its potential prophylactic effect.
Family physicians should be able to competently diagnose, evaluate and initiate treatment in most patients with dementia. In addition, treatment of comorbid conditions such as hypertension, smoking and diabetes mellitus may mitigate the severity of the dementing illness, since there is evidence that small vessel ischemia plays a part in the pathogenesis of Alzheimer's disease.
Physicians should be familiar with psychometric instruments such as the Mini-Mental State examination. These instruments are useful both in diagnosing Alzheimer's dementia and in following patients on therapy. However, they are not helpful in determining if medications are effective, since decline should be expected even with treatment. Early diagnosis and treatment will enable patients to retain the greatest possible functional capacity and may allow families to care for the patient successfully for longer periods of time. It should be remembered, however, that the most important factors in nursing home placement for patients with Alzheimer's disease are disturbed behaviors and incontinence. There is no evidence that these medications delay the onset of disturbed behaviors.