What is the first-line medication for Alzheimer's disease?

First-Line Medication for Alzheimer's Disease

Donepezil (Aricept) is the first-line medication for Alzheimer's disease due to its once-daily dosing, favorable side effect profile, and established efficacy across mild to severe disease stages. 1

Rationale for Donepezil as First-Line Therapy

• Donepezil is recommended as the first-choice cholinesterase inhibitor due to its convenient once-daily dosing regimen and more favorable side effect profile compared to other options 2, 1
• Donepezil provides modest improvements in cognitive function, global clinical function, and can delay symptomatic progression of Alzheimer's disease 1, 3
• Unlike tacrine, donepezil does not cause hepatotoxicity and does not require liver function monitoring 2, 4
• Donepezil has been extensively studied and has demonstrated efficacy in both short-term (up to 24 weeks) and long-term (up to about 1 year) treatment of mild to moderate Alzheimer's disease 3

Dosing and Administration

• Initial dosage is 5 mg once daily; after 4-6 weeks, the dose can be increased to 10 mg once daily if needed and tolerated 2, 5
• Taking donepezil with food may help reduce gastrointestinal side effects 2, 1
• The 10 mg/day dose provides additional cognitive benefits over the 5 mg/day dose, but with increased side effects 6, 7

Efficacy Measures

• Donepezil improves cognitive function as measured by the ADAS-cog scale, with improvements of 2.6-4.9 points compared to placebo 5, 8
• Global clinical function, as assessed by clinicians using CIBIC-plus, shows statistically significant improvement with donepezil treatment 5, 7
• Donepezil may delay deterioration in activities of daily living by up to 55 weeks compared with placebo 3

Side Effects and Monitoring

• Most common side effects are mild and cholinergic in nature: nausea, vomiting, and diarrhea 2, 1
• Adverse events are generally mild to moderate in intensity and transient 3
• The incidence of serious adverse events is similar between donepezil (4-10%) and placebo (5-9%) in short-term trials 3
• Higher withdrawal rates are seen with cholinesterase inhibitors (29%) compared to placebo (18%) due to adverse events 7

Alternative Cholinesterase Inhibitors

• Rivastigmine (Exelon) and galantamine (Reminyl) are alternative cholinesterase inhibitors if donepezil is not tolerated or ineffective 2
• Both alternatives require twice-daily dosing, which is less convenient than donepezil's once-daily regimen 2, 4
• Rivastigmine may have more gastrointestinal side effects than donepezil, particularly during the titration phase 2, 7
• Tacrine is considered a second-line agent due to hepatotoxicity (elevated liver enzymes in 40% of patients) and four-times-daily dosing requirement 2

For Moderate to Severe Alzheimer's Disease

• Donepezil has demonstrated efficacy in severe Alzheimer's disease with improvements in cognitive function as measured by the Severe Impairment Battery (SIB) 5
• For moderate to severe AD, memantine may be used alone or in combination with donepezil 1, 9
• The combination of memantine and donepezil is recommended for severe AD in several clinical guidelines 2

Assessment of Response

• Beneficial response should be determined from physician's global assessment, caregiver reports, neuropsychological assessments, and evidence of behavioral or functional changes 2
• Brief mental status tests are relatively insensitive measures of the cognitive effects of cholinesterase inhibitors 2
• Observation for 6-12 months is usually necessary to assess potential benefit 2
• Consider discontinuation if side effects persist, adherence is poor, or deterioration continues at the pre-treatment rate after 6-12 months 2

Clinical Pearls and Pitfalls

• Patients who do not respond to donepezil may respond to another cholinesterase inhibitor 2, 1
• Set realistic expectations with patients and caregivers - benefits are modest and the medication does not cure the disease but may temporarily improve symptoms or slow decline 1, 7
• Vitamin E (2,000 IU daily) may be considered as adjunctive therapy to slow functional decline 2, 1
• Avoid tacrine due to its hepatotoxicity, which requires biweekly liver function tests during dose escalation and every three months thereafter 2