What are the recommended first‑line pharmacologic treatments and dosing for Alzheimer‑type dementia, including cholinesterase inhibitors, memantine, and management of neuropsychiatric symptoms?

Pharmacologic Treatment of Alzheimer's-Type Dementia

First-Line Therapy Selection

For mild to moderate Alzheimer's disease, initiate donepezil 5 mg once daily with food, increasing to 10 mg after 4–6 weeks if tolerated; this provides the most straightforward titration, lowest hepatotoxicity, and comparable efficacy to other cholinesterase inhibitors. 1, 2, 3

Cholinesterase Inhibitor Options

Donepezil (preferred first-line agent):

• Start 5 mg once daily with food, increase to 10 mg after 4–6 weeks 2, 3
• Once-daily dosing improves adherence 4, 5
• No hepatotoxicity, unlike tacrine 3, 6
• Transdermal patch available for once-weekly dosing if oral route problematic 4, 5
• Caution: Monitor for cardiac conduction abnormalities (bradycardia, sick sinus syndrome) 3, 4

Rivastigmine (alternative):

• Start 1.5 mg twice daily with meals, titrate by 1.5 mg twice daily every 4 weeks to target 6–12 mg/day 2, 3
• Transdermal patch (13.3 mg/24 hours) reduces gastrointestinal side effects 3, 7
• One head-to-head trial showed rivastigmine superior to donepezil for global function and activities of daily living in moderately severe disease, but with higher nausea rates 8
• Fewer cardiac side effects than donepezil 4

Galantamine (alternative):

• Start 4 mg twice daily with meals, increase to 8 mg twice daily after 4 weeks, may escalate to 12 mg twice daily 2, 3
• Multiple metabolic pathways reduce drug-drug interactions 4
• Contraindicated in hepatic or renal impairment 3
• Monitor cardiac conduction 4

When to Use Memantine

Add memantine 20 mg/day (titrate by 5 mg weekly) when:

• Patient reaches moderate to severe Alzheimer's disease 2, 3
• Patient continues to decline after 3–6 months on optimized cholinesterase inhibitor monotherapy 1, 2, 3
• Combination therapy (memantine + donepezil) produces additional improvements of ~3.4 points on cognitive scales and ~1.4 points on activities-of-daily-living scales versus donepezil alone 3

Memantine dosing:

• Start 5 mg once daily, increase by 5 mg weekly to target 20 mg/day (10 mg twice daily or extended-release 20 mg once daily) 3, 7
• Reduce to 10 mg/day total if creatinine clearance ≤30 mL/min 3
• Common side effects: confusion, dizziness, falls, nausea, diarrhea 1, 3

Disease Stage-Specific Recommendations

Mild to moderate Alzheimer's disease:

• Initiate cholinesterase inhibitor (donepezil preferred) 1, 2, 3
• Benefits equivalent to delaying decline by approximately one year 2, 3

Moderate to severe Alzheimer's disease:

• Continue cholinesterase inhibitor AND add memantine 2, 3, 7
• Donepezil 10 mg and memantine 20 mg both FDA-approved for severe disease 7
• Rivastigmine transdermal patch 13.3 mg/24 hours approved for severe disease 7

Severe/end-stage dementia:

• Combination therapy remains appropriate if patient tolerates medications 7
• Discontinue only when entering terminal phase or when comfort is sole goal 1, 7

Other Dementia Types

Dementia with Lewy bodies or Parkinson's disease dementia:

• Start cholinesterase inhibitor immediately at diagnosis 1, 2
• These conditions respond particularly well to cholinergic enhancement 2

Vascular dementia or mixed dementia:

• Consider cholinesterase inhibitor at diagnosis, though evidence stronger for mixed presentations 2, 6

Frontotemporal dementia:

• Do NOT prescribe cholinesterase inhibitors—ineffective and may worsen agitation 1, 2

Monitoring and Assessment Timeline

Baseline evaluation before starting therapy:

• Document cognitive function with validated instruments (ADAS-Cog, MMSE, or MoCA) 3
• Record functional ability using ADL scales (IADL or ADCS-ADL) 3
• Obtain caregiver input on behavioral symptoms 3
• Screen for major depression (can mimic dementia) 3
• Assess cardiac conduction abnormalities 3, 4

Response evaluation:

• Assess at 6–12 months using physician global impression, caregiver reports, and cognitive testing 1, 2, 3
• Brief mental status tests (MMSE) are relatively insensitive to drug effects—use comprehensive functional assessments 3
• Beneficial effect, if any, generally observed within 3 months 8

Continue therapy when:

• Cognitive function stabilizes or declines more slowly than pre-treatment trajectory 3
• Caregivers report stable or improved activities of daily living 3
• Approximately 20–35% of patients achieve clinically meaningful improvement 3

Discontinuation Criteria

Stop cholinesterase inhibitors when:

• Clinically meaningful worsening despite treatment after 6–12 months 1, 3
• No observed benefit after adequate trial 1
• Progression to terminal/end-stage dementia where comfort is sole goal 1, 7
• Intolerable side effects persist despite dose adjustment 1, 3
• Poor medication adherence 1

Critical exception: Do NOT discontinue cholinesterase inhibitors in patients with active psychosis, agitation, or aggression until these symptoms stabilize 1, 2

Deprescribing protocol:

• Reduce dose by 50% every 4 weeks until reaching initial starting dose 1
• After 4 weeks at starting dose, discontinue 1

Management of Neuropsychiatric Symptoms

Agitation and behavioral symptoms:

• Cholinesterase inhibitors may delay development of behavioral and psychological symptoms 4
• Exhaust non-pharmacologic interventions (predictable routines, environmental simplification) before antipsychotics 3
• Initial increase in agitation may occur in first few weeks but typically resolves 3
• FDA-approved for agitation: Brexpiprazole (atypical antipsychotic, once daily) 4

Sleep disturbances:

• Suvorexant (orexin receptor antagonist) FDA-approved for insomnia in dementia 4

Depression:

• Treat depression separately; antidepressants do not improve cognitive outcomes unless mood disorder specifically present 3

Adverse Effects and Management

Gastrointestinal effects (most common):

• Nausea, vomiting, diarrhea, anorexia occur more frequently than placebo 8, 3
• Mitigation strategies: Take with food, gradual dose titration, adequate hydration, judicious antiemetic use 3, 6
• Rivastigmine has highest nausea rates during titration 8

Cardiac effects:

• Cholinesterase inhibitors can exacerbate bradyarrhythmias 3, 4
• Monitor patients with sick sinus syndrome or significant bradycardia 3
• Donepezil requires regular cardiac monitoring 4

Other effects:

• Weight loss (monitor body weight) 3
• Memantine: confusion, dizziness, falls 1, 3
• Rivastigmine transdermal: local application-site reactions 4

Serious adverse events:

• No statistically significant difference between donepezil and placebo for serious adverse events 3
• Withdrawal rates: 29% for cholinesterase inhibitors vs. 18% for placebo 9

Comparative Effectiveness

No convincing evidence demonstrates superiority of one cholinesterase inhibitor over another 8, 9

Switching between agents:

• Reasonable only when current medication not tolerated 3
• Patients who do not respond to one cholinesterase inhibitor may respond to another 3
• Do NOT switch as first-line strategy for non-responders—add memantine instead 3

Common Pitfalls to Avoid

• Expecting dramatic improvements: Benefits are modest; stabilization or slowed decline constitutes success 8, 1
• Premature discontinuation: Do not stop before 6–12 months unless side effects intolerable 3
• Inadequate titration: Attempt escalation to target doses (donepezil 10 mg, rivastigmine 6–12 mg/day, galantamine 16–24 mg/day) 2, 3
• Using for mild cognitive impairment: Ineffective and not indicated 2
• Continuing without reassessment: Periodically evaluate medication effectiveness 1
• Abrupt discontinuation: Taper gradually over weeks 1
• Over-reliance on MMSE: Use comprehensive functional and caregiver assessments 3
• Delaying treatment: Benefits greatest when started early in disease course 2
• Stopping during disease progression: Continue as long as any clinical benefit persists 2

Drug Interactions

Monitor closely when combining with:

• Cimetidine, theophylline, warfarin, digoxin 3
• Anticholinergic medications (reduce efficacy) 3

Adjunctive Therapy

Vitamin E:

• 2,000 IU daily may slow functional decline 3, 6
• Low cost and safe; recommended as adjunct to cholinesterase inhibitor 6