What are the recommended treatments 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 for moderate to severe disease. 1

First-Line Pharmacologic Treatment

Cholinesterase Inhibitors for Mild to Moderate Disease

Donepezil is the preferred initial agent due to its once-daily dosing, favorable side effect profile, lack of hepatotoxicity, and established efficacy across all disease stages 1, 2. The dosing strategy is straightforward:

• Start at 5 mg once daily for at least 4-6 weeks 1, 2
• Increase to 10 mg once daily after the initial period if well-tolerated 1, 2
• Take with food to minimize gastrointestinal side effects 2
• Consider evening dosing if insomnia or nightmares occur 2

The evidence supporting donepezil is robust. At 26 weeks, donepezil 10 mg/day produces a mean improvement of 2.67 points on the ADAS-Cog scale and 1.05 points on the MMSE compared to placebo 3. While these improvements are modest (5-15% benefit over placebo, equivalent to delaying decline by approximately one year), they represent clinically meaningful benefits in cognitive function and global clinical state 1, 3.

Alternative Cholinesterase Inhibitors

If donepezil is not tolerated or ineffective, consider switching to another cholinesterase inhibitor, as patients who don't respond to one may respond to another 2:

• Rivastigmine: Start 1.5 mg twice daily, increase by 1.5 mg twice daily every 4 weeks to maximum 6 mg twice daily 1, 2
• Galantamine: Start 4 mg twice daily with meals, increase to 8 mg twice daily after 4 weeks, may increase to 12 mg twice daily based on tolerability 4, 1

Avoid tacrine as it is no longer considered first-line treatment due to hepatotoxicity (40% of patients develop elevated liver enzymes), four-times-daily dosing, and higher side effect burden 4, 2, 5.

Treatment for Moderate to Severe Disease

Adding Memantine

Add memantine 20 mg/day when patients progress to moderate or severe Alzheimer's disease 1. Memantine shows statistically significant improvement in cognition and can be used alone or in combination with cholinesterase inhibitors 1. The combination of memantine with donepezil produces additional cognitive benefits (3.3 units on the SIB scale) compared to donepezil alone in moderate to severe disease 6.

Higher-Dose Donepezil

For patients with moderate to severe disease already on donepezil 10 mg/day who continue to decline, a 23 mg/day formulation is available 7, 8. However, the 23 mg dose provides no greater efficacy benefits than 10 mg but is associated with higher rates of adverse events and treatment withdrawals 3. The 10 mg dose remains the optimal balance of efficacy and tolerability for most patients 3.

Monitoring Treatment Response

Allow 6-12 months to properly assess treatment benefit before considering discontinuation 1, 2. Use comprehensive assessments including:

• Physician global assessment 2
• Caregiver report of functional and behavioral changes 2
• Neuropsychological testing (ADAS-Cog, MMSE, or SIB depending on disease severity) 3
• Brief mental status tests alone are relatively insensitive measures 2

When to Consider Discontinuation

Stop cholinesterase inhibitors if 2:

• Side effects develop and do not resolve
• Adherence is poor
• Deterioration continues at pre-treatment rate after 6-12 months
• Patient progresses to severe or end-stage dementia

Managing Side Effects

Common adverse effects are cholinergic in nature and include nausea, vomiting, diarrhea, dizziness, and abdominal pain 4, 2, 5. These occur in 7-30% of patients but are generally mild and transient 5.

Strategies to minimize side effects:

• Take medication with food 4, 2
• Use slower dose titration (6 weeks rather than 1 week between increases) 9
• Consider switching to a different cholinesterase inhibitor if side effects persist 2

Donepezil causes more withdrawals (24% vs 20% placebo) and adverse events (72% vs 65% placebo) but has no hepatotoxicity unlike tacrine 3.

Nonpharmacologic Interventions

Implement nonpharmacologic strategies alongside medication throughout the disease course 1:

• Provide predictable routines for exercise, meals, and bedtime 4
• Simplify tasks and break complex activities into steps 4
• Create a safe environment with grab bars, safety locks, and removal of hazards 4
• Use calendars, clocks, labels, and color-coded cues for orientation 4
• Reduce excess stimulation and avoid crowded places 4
• Consider day care programs and register in the Alzheimer's Association Safe Return Program 4
• Provide caregiver education and support groups 1

Exhaust nonpharmacologic interventions before adding medications for behavioral symptoms 4. When drug therapy is required for agitation or mood disorders, concomitant nonpharmacologic interventions may enable dose reduction 4.

Comprehensive Management Plan

Develop a comprehensive management plan immediately upon diagnosis that addresses 1:

• Patient and family values, preferences, and comorbid conditions 1
• Realistic expectations for drug therapy (modest benefits equivalent to delaying decline by approximately one year) 1
• Future care choices and advance planning 1
• Driving safety, financial planning, and healthcare directives 1
• Referrals to social service agencies and support resources 1

Optimize management of comorbid conditions, as this can reduce disability and maximize function in elderly patients with Alzheimer's disease 4.

Common Pitfalls

• Do not use cholinesterase inhibitors in mild cognitive impairment (MCI) without dementia, as evidence doesn't support use in this population 2
• Do not rely solely on brief mental status tests to assess treatment response, as they are relatively insensitive to cholinesterase inhibitor effects 2
• Do not discontinue treatment prematurely—allow 6-12 months for proper assessment of benefit 1, 2
• Do not escalate to donepezil 23 mg expecting substantially greater benefits, as efficacy is similar to 10 mg with higher adverse event rates 3