What are the recommended medications for treating Alzheimer's disease and dementia?

Recommended Medications for Alzheimer's Disease and Dementia

First-Line Treatment: Cholinesterase Inhibitors

Donepezil is the preferred first-line medication for Alzheimer's disease across all stages (mild, moderate, and severe) due to its once-daily dosing, favorable side effect profile, and established efficacy. 1, 2

Donepezil (Aricept)

• Start at 5 mg once daily, increase to 10 mg once daily after 4-6 weeks 1
• FDA-approved for mild, moderate, and severe Alzheimer's disease 2
• Can be taken with or without food, though taking with food may reduce gastrointestinal side effects 1
• Does not require liver function monitoring, unlike tacrine 1
• Most common side effects are mild and cholinergic: nausea, vomiting, diarrhea (9-12% in treatment groups) 3, 1
• For moderate to severe disease, a 23 mg sustained-release formulation is available 4

Alternative Cholinesterase Inhibitors

• Galantamine (Reminyl): Start 4 mg twice daily with meals, increase to 8 mg twice daily after 4 weeks, maximum 12 mg twice daily 5, 6
• Rivastigmine (Exelon): Start 1.5 mg twice daily, increase by 1.5 mg twice daily every 4 weeks as tolerated, maximum 6 mg twice daily 5
• Both require twice-daily dosing compared to donepezil's once-daily regimen 1
• Tacrine (Cognex) is second-line due to hepatotoxicity requiring liver monitoring and four-times-daily dosing 1

Second-Line Treatment: Memantine

Memantine is indicated for moderate to severe Alzheimer's disease and can be used alone or in combination with a cholinesterase inhibitor. 7, 5

• Standard dose: 20 mg/day 3
• Provides cumulative, additive benefits when combined with donepezil 5
• Shows statistically significant but not clinically important improvement in cognition scores 3
• Common side effects: nausea, dizziness, diarrhea, agitation (9-12% in treatment groups) 3
• Limited evidence shows improvement in quality of life and caregiver burden 3

Comparative Effectiveness

No convincing evidence demonstrates that one cholinesterase inhibitor is more effective than another. 3

• Donepezil vs. galantamine: No statistical differences in function at 52 weeks 3
• Donepezil vs. rivastigmine: Rivastigmine showed some advantages in global function and activities of daily living, but had higher rates of nausea and adverse events 3
• Donepezil appears better tolerated than rivastigmine with fewer adverse events 8

Expected Treatment Effects

Benefits are modest: average improvement of 2.7 points on the 70-point ADAS-Cog scale, which is statistically significant but not clinically important for most patients. 3, 8

• Clinically important improvement defined as ≥4 points on ADAS-Cog or ≥3 points on MMSE 3
• Beneficial response may include stabilization or delayed deterioration rather than improvement 1
• Treatment effects are generally modest, with improvements of 1.8 to 4.9 points on ADAS-Cog over 6 months 9
• Approximately 29% of patients discontinue cholinesterase inhibitors due to adverse events vs. 18% on placebo 8

Treatment Decision Framework

Base the decision to initiate therapy on evaluation of benefits versus risks for each patient, recognizing that benefits are modest and may not be clinically meaningful. 3

When to Initiate Treatment:

• Mild to moderate Alzheimer's disease: Start with donepezil 1, 2
• Moderate to severe Alzheimer's disease: Consider memantine alone or combined with donepezil 5, 7
• Vascular dementia: Donepezil or memantine have evidence 3

When to Consider Discontinuation (per 2020 Canadian guidelines):

• Clinically meaningful worsening over past 6 months despite treatment 3
• No clinically meaningful benefit observed at any time during treatment 3
• Severe or end-stage dementia with dependence in most basic activities 3
• Development of intolerable side effects (severe nausea, vomiting, weight loss, falls) 3
• Poor medication adherence 3

Critical Caveats

• Communicate realistic expectations: Benefits are 5-15% over placebo and represent stabilization or slowing of decline, not cure 1
• These medications do not alter the underlying disease process; patients continue to decline over time 5
• If no response to one cholinesterase inhibitor, consider switching to another as individual responses vary 1
• In advanced dementia, family may not view stabilization as desirable if quality of life is poor 3
• Avoid medications with anticholinergic properties that can worsen cognitive symptoms 5