What is the first‑line pharmacologic treatment for Alzheimer’s disease in patients aged ≥ 65 years with mild‑to‑moderate dementia?

First-Line Treatment for Alzheimer's Disease

For patients aged ≥65 years with mild-to-moderate Alzheimer's disease, initiate donepezil 5 mg once daily as first-line pharmacologic therapy. 1, 2

Rationale for Donepezil as First-Line Agent

Donepezil is the preferred initial cholinesterase inhibitor because of:

• Once-daily dosing that improves adherence compared to twice-daily alternatives 2
• Absence of hepatotoxicity, unlike tacrine which requires biweekly liver monitoring 1
• No dose adjustment required for mild-to-moderate hepatic or renal impairment, whereas galantamine is contraindicated in hepatic/renal impairment 1, 3
• Straightforward titration with only two dose levels (5 mg and 10 mg) 1

Dosing Protocol

Initial dose: Start 5 mg once daily, taken in the evening with food to minimize gastrointestinal side effects 1, 2, 4

Dose escalation: After 4–6 weeks, if the patient tolerates the initial dose well, increase to 10 mg once daily 1, 2

• The 10 mg dose provides additional cognitive benefit (mean 2.92-point improvement on ADAS-Cog at 24 weeks) compared to 5 mg (2.02-point improvement) 1
• Higher doses are associated with more gastrointestinal adverse events but greater efficacy 5

Expected Benefits

Patients treated with donepezil 10 mg/day for 24–26 weeks demonstrate:

• Cognitive improvement: Mean 2.67-point benefit on ADAS-Cog (scale 0–70) and 1.05-point improvement on MMSE compared to placebo 5
• Functional benefit: Improvement in activities of daily living scores 5
• Global clinical improvement: Nearly twice as many treated patients show clinician-rated improvement (OR 1.92) 5
• These benefits represent modest improvement—roughly equivalent to delaying decline by 6–12 months 1, 2

Assessment Timeline

• Initial response evaluation: 3 months is sufficient to observe beneficial effects 1
• Full efficacy assessment: Requires 6–12 months of continuous treatment using cognitive testing, functional assessments, and caregiver reports—not brief mental status exams alone 1, 2

Common Adverse Effects and Management

Gastrointestinal symptoms (nausea, vomiting, diarrhea) are the most common side effects 1, 5

Mitigation strategies:

• Administer with food 1
• Use gradual dose titration over 4–6 weeks 1
• Ensure adequate hydration 6
• Most gastrointestinal effects resolve within a few weeks 1

Withdrawal rates: Approximately 24% of patients discontinue donepezil versus 20% on placebo, primarily due to adverse events 5

Contraindications and Precautions

Absolute contraindications:

• Known hypersensitivity to donepezil or piperidine derivatives 6

Use with caution in:

• Sick sinus syndrome or significant bradycardia (cholinesterase inhibitors can worsen bradyarrhythmias) 1, 2
• Active peptic ulcer disease or severe gastroesophageal reflux 1
• Uncontrolled asthma or chronic obstructive pulmonary disease 2
• Angle-closure glaucoma 2

No routine laboratory monitoring is required because donepezil lacks hepatotoxicity 1

Pre-Treatment Requirements

Before initiating donepezil:

• Exclude reversible causes: Rule out delirium (infection, metabolic disturbance), major depression, and medication-induced cognitive impairment 1
• Brain imaging (CT or MRI) is recommended but not mandatory before starting treatment; its purpose is to detect treatable structural lesions (subdural hematoma, tumor, normal-pressure hydrocephalus) 1
• Do not delay treatment while awaiting neuroimaging if acute reversible causes have been clinically excluded 1

Discontinuation Criteria

Stop donepezil if:

• Persistent adverse effects that do not resolve despite management strategies 1, 2
• Poor medication adherence 1, 2
• Continued deterioration at the pre-treatment rate after 6–12 months 1, 2
• Progression to severe or end-stage dementia with dependence in most basic activities of daily living 7, 2

Alternative Cholinesterase Inhibitors

If donepezil is not tolerated or ineffective after 6–12 months:

• Rivastigmine: Start 1.5 mg twice daily with food; increase by 1.5 mg twice daily every 4 weeks to a maximum of 6 mg twice daily 1, 2
• Galantamine: Start 4 mg twice daily with meals; increase to 8 mg twice daily after 4 weeks, with possible further increase to 12 mg twice daily 1, 2

No cholinesterase inhibitor has proven superiority over others in efficacy, so switching is only warranted for intolerance or lack of response 1, 8

Adjunctive Therapy

Vitamin E 2000 IU daily may be added as adjunct therapy to slow functional decline 1, 2

Common Pitfalls to Avoid

• Do not rely solely on MMSE scores to assess treatment response; brief mental status tests are relatively insensitive to cholinesterase inhibitor effects 1
• Do not discontinue prematurely; some patients require up to 12 months to demonstrate benefit 1
• Do not switch between cholinesterase inhibitors without adequate trial duration (6–12 months) unless intolerance occurs 1
• Do not prescribe for mild cognitive impairment without functional decline; donepezil is indicated only for dementia 1