What are the primary treatment options for Alzheimer's disease?

Alzheimer's Disease Treatment

Start donepezil 5 mg once daily as first-line pharmacotherapy for Alzheimer's disease, increasing to 10 mg daily after 4-6 weeks if tolerated, and add memantine 20 mg/day when patients progress to moderate or severe disease. 1

First-Line Pharmacologic Treatment

Donepezil is the preferred initial cholinesterase inhibitor due to several practical advantages over alternatives 1, 2, 3:

• Once-daily dosing improves adherence compared to twice-daily alternatives 1
• Favorable side effect profile with no hepatotoxicity risk (unlike tacrine) 1, 4
• Established efficacy across all disease stages from mild to severe 1, 3
• Straightforward titration schedule without complex dose adjustments 2

Donepezil Dosing Strategy

• Start at 5 mg once daily for at least 4-6 weeks 1, 2, 3
• Increase to 10 mg once daily after the initial period if well-tolerated 1, 2, 3
• Take with food to minimize gastrointestinal side effects 2
• The 10 mg dose provides greater cognitive benefit (2.21-point improvement on ADAS-Cog) compared to 5 mg (0.92-point improvement), though at the cost of slightly more adverse events 5

Alternative Cholinesterase Inhibitors

If donepezil is not tolerated or contraindicated, consider these alternatives 2, 3:

Rivastigmine:

• Start at 1.5 mg twice daily with food 2, 3
• Increase by 1.5 mg twice daily every 4 weeks as tolerated 2, 3
• Maximum dose: 6 mg twice daily (12 mg per day) 2, 3
• May be particularly beneficial in patients with rapid cognitive decline 2

Galantamine:

• Start at 4 mg twice daily with morning and evening meals 2, 3
• Increase to 8 mg twice daily after 4 weeks 2, 3
• May increase to 12 mg twice daily based on tolerability 2, 3
• Ranked second in both benefit and harm in network meta-analysis 5

Treatment for Moderate to Severe Disease

Add memantine 20 mg/day when patients progress to moderate or severe Alzheimer's disease 1, 2, 3:

• Shows statistically significant improvement in cognition 1, 2
• Can be used alone or in combination with cholinesterase inhibitors 1, 2
• When combined with donepezil, provides additional 3.3-point benefit on SIB scale at 24 weeks 6

Managing Side Effects

Common cholinergic adverse effects occur in 7-30% of patients but are generally mild and transient 1, 2, 4:

• Nausea, vomiting, diarrhea 1, 2, 4
• Dizziness, abdominal pain 1, 2
• Headaches and fatigue 2

Strategies to minimize side effects 1, 2:

• Take medication with food 2
• Use slower dose titration (minimum 4 weeks between increases) 7
• Consider switching to a different cholinesterase inhibitor if side effects persist 1

Important caveat: Donepezil 10 mg causes slightly more adverse events than 5 mg (OR 1.95 vs 1.22), but the cognitive benefit is greater 5. Galantamine 16-24 mg also shows increased adverse events (OR 1.57) 5.

Monitoring Treatment Response

• Allow 6-12 months to properly assess treatment benefit before considering discontinuation 1, 2, 3
• Use comprehensive assessments including 1, 2:
  • Physician global assessment 1, 2
  • Caregiver report of functional and behavioral changes 1, 2
  • Neuropsychological testing 1, 2
• Treatment effects abate within 6 weeks of discontinuation 8

Realistic expectations: Cholinesterase inhibitors provide 5-15% benefit over placebo, equivalent to delaying decline by approximately one year 3.

Nonpharmacologic Interventions

Implement these strategies alongside medication throughout the disease course 1, 2, 3:

• Provide predictable routines and simplify tasks 1
• Create a safe environment 1
• Use calendars and labels for orientation 1
• Exhaust nonpharmacologic interventions before adding medications for behavioral symptoms 1
• Consider day care programs 1
• Register in the Alzheimer's Association Safe Return Program 1

Comprehensive Management Plan

Develop immediately upon diagnosis 1, 2, 3:

• Address patient and family values, preferences, and comorbid conditions 1, 3
• Discuss realistic expectations for drug therapy 3
• Assist with advance planning including driving safety, financial planning, and healthcare directives 3
• Optimize management of comorbid conditions to reduce disability and maximize function 1
• Provide referrals to social service agencies and support resources 3
• Offer caregiver education and support groups 3

Behavioral Problems

When behavioral disturbances persist despite cholinesterase inhibitor therapy and nonpharmacologic interventions 2:

• Use of a psychotropic agent may be necessary 2
• Start with low doses and increase slowly 2
• Monitor carefully for side effects 2

Additional Considerations

Vitamin E: May slow progression of functional symptoms at 2,000 IU daily, based on expert consensus 2.