Managing blood pressure, cholesterol, and blood sugar may reduce the risk of developing Alzheimer’s disease and may prevent the worsening of dementia in patients with Alzheimer’s disease.
Current pharmacotherapeutic interventions are primarily symptomatic attempts to improve or maintain cognition. Table Treatment Options for Cognitive Symptoms in Alzheimer’s Disease may be used as an algorithm for managing cognitive symptoms in Alzheimer’s disease.
Treatment Options for Cognitive Symptoms in Alzheimer’s Disease
| In mild-moderate disease, consider therapy with a cholinesterase inhibitor. |
| — Donepezil, or |
| — Rivastigmine, or |
| — Galantamine |
| Titrate to recommended maintenance dose as tolerated. |
| In moderate to severe disease, consider adding antiglutamatergic therapy. |
| — Memantine |
| Titrate to recommended maintenance dose as tolerated. |
| Alternatively, consider memantine or cholinesterase inhibitor therapy alone. |
| Behavioral symptoms may require additional pharmacologic approaches. |
Successful treatment reflects a decline of less than 2 points each year on the Mini-Mental State Examination (MMSE) score.
Cholinesterase Inhibitors
Table Clinical Pharmacology of the Cholinesterase Inhibitors summarizes the clinical pharmacology of the cholinesterase inhibitors.
Clinical Pharmacology of the Cholinesterase Inhibitors
| Donepezil | Rivastigmine | Galantamine | |
| Brand name | Aricept | Exelon | Razadyne |
| Dosage forms | Tablet | Capsule | Tablet |
| Orally disintegrating tablet | Oral solution | Oral solution | |
| Patch | Extended-release (ER) capsule | ||
| Starting dose | 5 mg daily at bedtime | 1.5 mg twice a day4.6 mg/day (patch) | 4 mg twice a day(8 mg daily for ER) |
| Maintenance dose | 5-10 mg daily | 3-6 mg twice a day9.5 mg/day (patch) | 8-12 mg twice a day(16-24 mg daily for ER) |
| Meals | No effect of food | Take with food | Take with food |
| Half-life | 70 hours | 1.5 hours | 7 hours |
| Protein binding | 96% | 40% | 18% |
| Metabolism | Substrate (minor) of CYP2D6 and 3A4 | Cholinesterase-mediated hydrolysis | Substrate (minor) of CYP2D6 and 3A4 |
| Glucuronidation | – | Glucuronidation | |
| Renal elimination | Yes | Major pathway | Yes |
CYP, cytochrome P450
No direct comparative trials have assessed the effectiveness of one agent over another. Donepezil, rivastigmine, and galantamine are indicated in mild to moderate Alzheimer’s disease, while donepezil is also indicated in severe Alzheimer’s disease.
If the decline in MMSE score is more than 2 to 4 points after treatment for 1 year with the initial agent, it is reasonable to change to a different cholinesterase inhibitor. Otherwise, treatment should be continued with the initial medication throughout the course of the illness.
The most frequent adverse effects are mild to moderate GI symptoms (nausea, vomiting, and diarrhea), urinary incontinence, dizziness, headache, syncope, bradycardia, muscle weakness, salivation, and sweating. Abrupt discontinuation can cause worsening of cognition and behavior in some patients.
Donepezil (Aricept) is a piperidine derivative with specificity for inhibition of acetylcholinesterase rather than butyrylcholinesterase.
Rivastigmine has central activity at acetylcholinesterase and butyrylcho-linesterase sites, but low activity at these sites in the periphery.
Galantamine is a cholinesterase inhibitor that also has activity as a nicotinic receptor agonist.
Tacrine was the first cholinesterase inhibitor approved for the treatment of Alzheimer’s disease, but it has been replaced by safer drugs which are better tolerated.
Other Drugs
Memantine (Namenda) blocks glutamatergic neurotransmission by antagonizing N-methyl-D-aspartate receptors, which may prevent excitotoxic reactions. It is used as monotherapy, and data suggest that when it is combined with a cholinesterase inhibitor, there is improvement in cognition and activities of daily living.
- It is indicated for treatment of moderate to severe Alzheimer’s disease.
- It is not metabolized by the liver, but is primarily excreted unchanged in the urine (half-life of elimination = 60 to 80 hours).
- It is usually well tolerated, and side effects include constipation, confusion, dizziness, hallucinations, headache, cough, and hypertension.
- It is initiated at 5 mg/day and increased weekly by 5 mg/day to the effective dose of 10 mg twice daily. Dosing must be adjusted in patients with renal impairment.
Recent trials do not support the use of estrogen to prevent or treat cognitive decline.
Evidence related to the role of vitamin E in preventing Alzheimer’s disease is mixed, and conclusions cannot be drawn at this time.
Because of a significant incidence of side effects and a lack of compelling evidence, Nonsteroidal antiinflammatory drugs are not recommended for treatment or prevention of Alzheimer’s disease.
There is interest in the use of lipid-lowering agents, especially the 3-hydroxy-3-methylglutaryl coenzyme A-reductase inhibitors, to prevent Alzheimer’s disease. Pravastatin and lovastatin, but not simvastatin, were associated with a lower prevalence of Alzheimer’s disease. Further study is needed before these agents can be recommended for this use.
A metaanalysis indicated that EGb 761 (an extract of ginkgo biloba) may have some therapeutic effect at doses of 120 to 240 mg of the standard leaf extract twice daily. Because of limited efficacy data, the potential for adverse effects (e.g., nausea, vomiting, diarrhea, headache, dizziness, weakness, and hemorrhage), and the poor standardization of herbal products, it is recommended that ginkgo biloba be used only with caution.
Ginkgo biloba should not be used in individuals taking anticoagulants or antiplatelet drugs, and should be use cautiously in those taking nonsteroidal antiinflammatory drugs.
Although initial studies suggest potential effectiveness of huperzine A, it has not been adequately evaluated for treatment of Alzheimer’s disease.
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