When should cholinesterase inhibitors be initiated in an older adult with mild‑to‑moderate Alzheimer’s disease after formal diagnosis and onset of clinically relevant cognitive or functional symptoms?

When to Initiate Cholinesterase Inhibitors in Dementia

Cholinesterase inhibitors should be started immediately at the time of diagnosis of mild-to-moderate Alzheimer's disease, as these medications provide modest but clinically meaningful cognitive benefits equivalent to delaying decline by approximately one year, and benefits are greatest when started early in the disease course. 1

Timing of Initiation by Dementia Type

Alzheimer's Disease

• Start cholinesterase inhibitors at diagnosis of mild to moderate Alzheimer's disease without waiting for symptoms to worsen 1
• The FDA has approved rivastigmine, donepezil, and galantamine for mild-to-moderate dementia of the Alzheimer's type 2
• Never delay treatment waiting for "worse" dementia—the therapeutic window is most favorable early in the disease course 1

Other Dementia Types

• Begin cholinesterase inhibitors immediately upon diagnosis of dementia with Lewy bodies or Parkinson's disease dementia, as these conditions respond particularly well to cholinergic enhancement 1
• Consider starting at diagnosis for vascular dementia or mixed dementia, though evidence is stronger for mixed presentations 1

When NOT to Initiate Treatment

Contraindicated Conditions

• Do not prescribe cholinesterase inhibitors for mild cognitive impairment—they are ineffective and not indicated 1
• Avoid in frontotemporal dementia, as they are ineffective and may worsen agitation 1
• Do not initiate in severe/end-stage dementia with complete dependence in basic activities of daily living, inability to respond to environment, or limited life expectancy 1, 3

Practical Initiation Strategy

Starting Doses and Titration

• Donepezil: Start 5 mg once daily, increase to 10 mg after 4-6 weeks if well tolerated; take with food to minimize gastrointestinal side effects 1, 4
• Rivastigmine: Start 1.5 mg twice daily with meals, increase by 1.5 mg twice daily every 4 weeks as tolerated to target 6-12 mg/day 1, 4, 2
• Galantamine: Start 4 mg twice daily with meals, increase to 8 mg twice daily after 4 weeks, consider 12 mg twice daily based on tolerability 1, 4

Monitoring Response

• Assess treatment effectiveness at 6-12 months using caregiver reports, functional assessments, cognitive testing, and global clinical impression 1, 4
• Brief mental status tests (e.g., MMSE) are relatively insensitive measures of cholinesterase inhibitor effects and require comprehensive assessments 4
• Continue medications if there is any evidence of stabilization, slowed decline, or improvement in cognition, function, or behavior 1

Critical Pitfalls to Avoid

• Never delay initiation hoping the patient will "get worse enough" to justify treatment—this wastes the most effective treatment window 1
• Do not discontinue medications simply because dementia progresses—continue as long as there is any clinical benefit, as progression would likely be faster without treatment 1
• Never stop cholinesterase inhibitors abruptly in patients with active psychosis, agitation, or aggression until these symptoms stabilize 1, 3
• Avoid unrealistic expectations—benefits are typically modest, with stabilization or slower deterioration constituting success rather than dramatic improvement 4
• Do not prematurely discontinue after only 3 months—most patients require 6-12 months to demonstrate full benefit 4

Managing Common Side Effects

• Gastrointestinal symptoms (nausea, vomiting, diarrhea) can be minimized by taking medications with food and using gradual dose titration 1, 4, 5
• Early agitation may occur with initiation but generally resolves within a few weeks 4
• If a patient does not respond to or cannot tolerate one cholinesterase inhibitor, switching to another agent may be beneficial 4, 6