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

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

Cholinesterase Inhibitors Overview

Cholinesterase inhibitors are the mainstay of pharmacological treatment for Alzheimer's disease (AD). They work by inhibiting acetylcholinesterase, thereby raising acetylcholine levels in the brain. The four available agents are:

• Donepezil (Aricept) - first-line choice due to once-daily dosing and favorable side effect profile 1
• Rivastigmine (Exelon) - alternative option requiring twice-daily dosing 1
• Galantamine (Reminyl) - alternative option requiring twice-daily dosing 1
• Tacrine (Cognex) - considered second-line due to hepatotoxicity and four-times-daily dosing 1

Donepezil Dosing and Administration

• Initial dosage: 5 mg once daily 1, 2
• After 4-6 weeks, may increase to 10 mg once daily (maximum standard dose) 1, 2
• For moderate to severe AD, doses up to 23 mg daily may be considered 2, 3
• Take with or without food (taking with food may reduce gastrointestinal side effects) 1

Efficacy of Donepezil

• Provides modest improvement in cognitive function as measured by ADAS-cog and MMSE 1, 2, 4
• Improves global clinical function as assessed by CIBIC-plus 1, 2, 4
• Benefits in activities of daily living, particularly for higher doses in more advanced disease 2, 4
• Efficacy has been demonstrated for up to 4.9 years 1, 5
• May delay symptomatic progression of the disease 1, 5

Side Effects and Monitoring

• Most common side effects are mild and cholinergic in nature: nausea, vomiting, diarrhea 1, 5
• Some patients may experience initial increase in agitation that typically subsides after a few weeks 1
• Unlike tacrine, donepezil does not cause hepatotoxicity and does not require liver function monitoring 1
• Higher doses (10 mg vs 5 mg) are associated with increased efficacy but also increased side effects 1, 4

Assessment of Response

• Beneficial response may include stabilization or delayed deterioration of cognitive or behavioral problems 1
• Response assessment should include:
  • Physician's global assessment 1
  • Primary caregiver's report 1
  • Neuropsychological assessment or mental status questionnaire 1
  • Evidence of behavioral or functional changes 1
• Brief mental status tests are relatively insensitive measures of response 1
• Observation for 6-12 months is usually necessary to assess potential benefit 1

When to Discontinue

Discontinue donepezil if:

• Side effects develop and do not resolve 1
• Adherence is poor 1
• Deterioration continues at the pre-treatment rate after 6-12 months of treatment 1

Alternative Medications

• For patients who don't respond to donepezil, consider switching to another cholinesterase inhibitor 1
• For moderate to severe AD, memantine may be used alone or in combination with donepezil 1
• Vitamin E (2,000 IU daily) may slow functional decline and can be considered as adjunctive therapy 1

Clinical Pearls and Pitfalls

• Communicate realistic expectations to patients and caregivers before starting treatment - benefits are modest (5-15% over placebo) 1
• Donepezil does not cure AD but may temporarily improve symptoms or slow decline 1, 4
• Patients who do not respond to one cholinesterase inhibitor may respond to another 1
• Higher doses provide marginally greater benefits but with increased side effects 1, 4
• Abrupt discontinuation may lead to rapid worsening of symptoms 2, 5