What is the first‑line treatment for mild Alzheimer’s disease?

First-Line Treatment for Mild Alzheimer's Disease

Start donepezil 5 mg once daily as first-line pharmacotherapy for mild Alzheimer's disease, increasing to 10 mg daily after 4-6 weeks if tolerated. 1, 2

Why Donepezil is the Preferred Initial Agent

Donepezil is recommended over other cholinesterase inhibitors due to several practical advantages:

• Once-daily dosing improves adherence compared to rivastigmine (twice daily) or tacrine (four times daily) 1, 2
• Favorable side effect profile with no hepatotoxicity, unlike tacrine which causes liver enzyme elevation in 40% of patients 3
• Straightforward titration requiring only one dose adjustment, whereas rivastigmine requires multiple 4-week titration steps 2
• Established efficacy across all disease stages with improvements in cognition, function, and behavior 4, 5

Dosing Algorithm

Initial Phase:

• Start at 5 mg once daily 1, 2
• Take with food to minimize gastrointestinal side effects 3

Dose Escalation:

• After 4-6 weeks, increase to 10 mg once daily if the patient tolerates the initial dose 1, 2
• While the 10 mg dose did not show statistically significant superiority over 5 mg in trials, dose trend analyses suggest some patients may derive additional benefit 4

Alternative Cholinesterase Inhibitors

If donepezil is not tolerated or contraindicated, consider:

Rivastigmine:

• Start 1.5 mg twice daily 1, 2
• Increase by 1.5 mg twice daily every 4 weeks as tolerated 1, 2
• Maximum dose: 6 mg twice daily 1, 2
• Must be taken with food to reduce adverse effects 3

Galantamine:

• Start 4 mg twice daily with meals 1, 2
• Increase to 8 mg twice daily after 4 weeks 1, 2
• May increase to 12 mg twice daily based on individual tolerability 1, 2
• Contraindicated in hepatic or renal impairment 3

Avoid tacrine as a first-line agent due to hepatotoxicity requiring biweekly liver monitoring and four-times-daily dosing 3, 2

Setting Realistic Expectations

Before initiating treatment, discuss with patients and families:

• Expected benefit: 5-15% improvement over placebo, equivalent to delaying decline by approximately one year 1
• Cognitive improvement: Average 2.7-point improvement on the ADAS-Cog scale, which is modest but clinically meaningful 5
• Treatment goal: Stabilization or slowed deterioration, not reversal of symptoms 1
• Time to benefit: 6-12 months of observation is necessary to adequately assess response 3, 1, 2

Monitoring and Assessment

Response evaluation should include:

• Physician global assessment 3, 1
• Caregiver reports of functional and behavioral changes 3, 1
• Neuropsychological testing (though brief mental status tests are relatively insensitive) 3, 2

Discontinuation criteria:

• Persistent side effects that do not resolve 3
• Poor adherence 3
• Continued deterioration at pre-treatment rate after 6-12 months 3, 2

Common Pitfalls to Avoid

Premature discontinuation: Most patients require 6-12 months to demonstrate benefit; avoid stopping treatment too early 1, 2

Inadequate dose titration: Ensure progression to 10 mg daily unless side effects prevent escalation, as some patients benefit from the higher dose 4

Unrealistic expectations: Brief mental status tests like MMSE are insensitive to cholinesterase inhibitor effects; use comprehensive assessments instead 3, 2

Ignoring gastrointestinal side effects: Nausea, vomiting, and diarrhea are the most common adverse effects but can be minimized by taking medication with food and gradual dose titration 3, 1, 2

Managing Side Effects

The most common adverse effects are cholinergic:

• Gastrointestinal: Nausea, vomiting, diarrhea (minimize by taking with meals and slow titration) 3, 1
• Neuropsychiatric: Initial increase in agitation typically subsides after a few weeks 3
• Discontinuation rate: Approximately 29% of patients discontinue due to adverse events versus 18% on placebo 5

When to Switch Agents

Patients who do not respond to one cholinesterase inhibitor may respond to another 3, though there is no convincing evidence that one agent is more effective than another 3, 5. Switching is most appropriate when:

• The patient cannot tolerate the current medication due to side effects 2
• After 6-12 months, there is no stabilization or benefit observed 3, 2

Comprehensive Management Beyond Medication

Immediately upon diagnosis, develop a comprehensive plan that includes:

• Advance planning: Driving safety, financial planning, healthcare directives 1
• Nonpharmacologic interventions: Caregiver education, support groups, environmental modifications 1
• Social services: Referrals to community resources and support agencies 1