What are the recommended pharmacologic treatments for Alzheimer's dementia, including dosing for mild-to-moderate and moderate-to-severe disease?

Pharmacologic Treatment of Alzheimer's Dementia

For mild-to-moderate Alzheimer's disease, initiate donepezil 5 mg once daily with food, increasing to 10 mg daily after 4-6 weeks if tolerated; for moderate-to-severe disease, add memantine 20 mg/day to ongoing cholinesterase inhibitor therapy. 1, 2

Mild-to-Moderate Alzheimer's Disease

First-Line Treatment: Donepezil

Donepezil is the preferred initial cholinesterase inhibitor due to once-daily dosing, absence of hepatotoxicity, and favorable tolerability compared to alternatives. 2

Dosing regimen:

• Start 5 mg once daily with food (reduces gastrointestinal side effects) 1, 2
• Increase to 10 mg once daily after 4-6 weeks if well-tolerated 1, 2, 3
• The 10 mg dose provides additional cognitive and functional benefit over 5 mg 1

Expected outcomes:

• Approximately 20-35% of patients achieve clinically meaningful improvement, roughly equivalent to delaying cognitive decline by one year 1
• Mean improvement of 2.7 points on the 70-point ADAS-Cog scale (statistically significant but modest) 1, 4
• Benefits include stabilization or slowing of decline in cognition, global function, activities of daily living, and behavior 5, 1
• Full efficacy assessment requires 6-12 months of continuous therapy 5, 1, 2

Alternative Cholinesterase Inhibitors

If donepezil is not tolerated or ineffective after 6-12 months, switch to another agent: 1, 2

Rivastigmine:

• Start 1.5 mg twice daily with food 1, 2
• Increase by 1.5 mg twice daily every 4 weeks as tolerated 1
• Maximum dose: 6 mg twice daily 1, 2
• Fewer cardiac side effects than donepezil but may cause local reactions with transdermal patch 6

Galantamine:

• Start 4 mg twice daily with meals 1, 2
• Increase to 8 mg twice daily after 4 weeks 1
• May increase to 12 mg twice daily based on benefit and tolerability 1, 2
• Contraindicated in hepatic or renal impairment 1
• Minimal drug-drug interactions due to multiple metabolic pathways 6

Tacrine is NOT recommended due to hepatotoxicity requiring bi-weekly liver monitoring and four-times-daily dosing. 5, 1

Choosing Between Cholinesterase Inhibitors

Base selection on tolerability, adverse effect profile, ease of use, and cost—not efficacy, as no cholinesterase inhibitor has proven superiority over others. 5, 1, 4

Moderate-to-Severe Alzheimer's Disease

Add Memantine to Ongoing Cholinesterase Inhibitor

For patients with moderate-to-severe disease or those declining on cholinesterase inhibitor monotherapy after 3 months, add memantine while continuing the cholinesterase inhibitor. 5, 1

Memantine dosing:

• Start 5 mg once daily 1
• Increase by 5 mg weekly in divided doses 1
• Target dose: 20 mg/day (10 mg twice daily or extended-release 28 mg once daily) 5, 1
• For severe renal impairment (CrCl ≈30 mL/min), reduce target to 10 mg/day total 1

Evidence for combination therapy:

• Adding memantine to donepezil produces a 3.4-point improvement on the Severe Impairment Battery (cognition) and 1.4-point improvement on ADL scales compared to donepezil alone 1
• Continuation of donepezil (rather than stopping) produces a 1.9-point advantage on SMMSE and 3.0-point advantage on functional scales 1
• Combination therapy does not increase serious adverse events relative to monotherapy 1

Contraindications and Precautions

Major contraindications to cholinesterase inhibitors and memantine include: 5

• Uncontrolled asthma
• Angle-closure glaucoma
• Sick sinus syndrome
• Left bundle-branch block or significant bradycardia 1

Additional precautions:

• Assess for peptic ulcer disease or severe gastroesophageal reflux (may worsen with cholinergic effects) 1
• Cardiac monitoring recommended for cholinesterase inhibitors due to potential conduction disturbances 6
• No routine laboratory monitoring needed for donepezil (not hepatotoxic) 1

Managing Adverse Effects

Common gastrointestinal side effects (nausea, vomiting, diarrhea) can be minimized by: 1, 7

• Taking medication with food 1
• Gradual dose titration 1
• Adequate hydration 7
• Judicious use of antiemetics 7

Withdrawal rates due to adverse events:

• Cholinesterase inhibitors: 29% vs. 18% placebo 5
• Memantine: 9-12% vs. 7-13% placebo 1
• No significant difference in serious adverse events between donepezil and placebo 1

Monitoring and Assessment

Baseline assessments before initiating therapy: 1

• Document cognitive function with validated instruments (ADAS-Cog, MMSE, or MoCA)
• Record functional ability using standardized ADL scales (IADL or ADCS-ADL)
• Obtain caregiver input regarding behavioral symptoms and functional changes
• Screen for major depression (can mimic dementia)
• Assess cardiac conduction abnormalities

Ongoing monitoring:

• Reassess at 4-6 weeks when increasing donepezil dose 1, 2
• Full efficacy evaluation at 6-12 months using physician global assessment, caregiver reports, and functional/behavioral measures—not just brief mental status tests like MMSE 5, 1
• Brief mental status examinations are relatively insensitive to drug effects 1

Discontinuation Criteria

Stop cholinesterase inhibitors or memantine if: 5, 1, 2

• Persistent adverse effects that do not resolve despite management strategies
• Poor medication adherence
• Continued deterioration at the pre-treatment rate after 6-12 months
• Progression to severe or end-stage dementia where slowing decline is no longer a goal
• Patient or caregiver preference after informed discussion

Adjunctive Therapy

Vitamin E supplementation:

• Dose: 2,000 IU daily 1, 2
• May slow functional decline 1, 2
• Low cost and favorable safety profile support use as adjunct to cholinesterase inhibitors 2, 7

Vascular risk factor control:

• Smoking cessation, regular exercise, healthy diet 2
• Blood pressure and lipid management 1
• Essential for patients with vascular contributions to dementia 1

Setting Realistic Expectations

Critical counseling points before initiating therapy: 5, 1, 2

• Cholinesterase inhibitors provide modest benefits (5-15% improvement over placebo) and do not alter underlying disease progression 2
• All patients continue to experience decline over time, even with appropriate treatment 2
• Treatment may stabilize cognition or slow decline temporarily—it does not cure or reverse dementia 1
• Cannot predict which patients will respond before treatment 5
• Benefits are symptomatic only, not disease-modifying 8, 9

Common Pitfalls to Avoid

• Do not delay treatment awaiting neuroimaging when acute reversible causes (delirium, infection, metabolic disturbance) have been clinically excluded 1
• Do not discontinue prematurely—some patients require up to 12 months to demonstrate benefit 1
• Do not rely solely on MMSE scores to assess treatment response; use comprehensive assessments including caregiver reports 1
• Do not switch cholinesterase inhibitors without adequate trial—allow 6-12 months on optimal dose before concluding lack of efficacy 1
• Do not prescribe for mild cognitive impairment without functional decline 1

Disease-Modifying Therapies (Emerging)

Anti-amyloid monoclonal antibodies (lecanemab, donanemab) represent the first disease-modifying therapies targeting underlying pathology rather than symptoms. 10

Key requirements:

• Confirmed brain amyloid pathology via amyloid PET imaging or CSF testing before initiation 10
• Blood biomarker tests emerging as more accessible alternatives (require sensitivity ≥90%, specificity ≥85-90%) 10
• Risk of amyloid-related imaging abnormalities, especially in ApoE4 carriers 6

These agents are administered by infusion (lecanemab every 2 weeks, aducanumab every 4 weeks) and require specialist referral. 6 For patients not eligible for anti-amyloid antibodies, donepezil remains the preferred symptomatic agent. 10