What is the recommended pharmacologic and non‑pharmacologic treatment for an older adult with mild‑to‑moderate Alzheimer’s disease?

Treatment of Mild-to-Moderate Alzheimer's Disease

First-Line Pharmacologic Treatment: Cholinesterase Inhibitors

Initiate a cholinesterase inhibitor (donepezil, rivastigmine, or galantamine) as first-line pharmacologic treatment for mild-to-moderate Alzheimer's disease, with all three agents showing equivalent efficacy. 1

Choosing Among the Three Agents

The three cholinesterase inhibitors are equally effective first-line options, with no evidence of superiority among them for cognitive, functional, or behavioral outcomes. 2, 3 Your choice should be guided primarily by:

• Dosing convenience: Donepezil requires once-daily dosing, making it the most straightforward option. 2, 1
• Tolerability profile: Donepezil appears to cause fewer adverse events than rivastigmine, particularly gastrointestinal side effects. 2, 3
• Titration complexity: Donepezil has the simplest titration schedule, while rivastigmine and galantamine require more gradual dose escalation over several months to match donepezil's tolerability. 3

Specific Dosing Regimens

Donepezil (preferred for simplicity):

• Start 5 mg once daily (can be taken any time of day)
• Increase to 10 mg daily after 4–6 weeks
• Take with food to reduce gastrointestinal side effects 2, 1

Rivastigmine:

• Start 1.5 mg twice daily with food
• Increase by 1.5 mg twice daily every 4 weeks as tolerated
• Target dose: 6–12 mg/day in divided doses
• Higher doses are more efficacious but require careful titration 2, 1

Galantamine:

• Start 4 mg twice daily with meals
• Increase to 8 mg twice daily after 4 weeks
• Consider 12 mg twice daily based on individual tolerance
• Contraindicated in hepatic or renal insufficiency 2, 1

Tacrine should not be used due to hepatotoxicity requiring biweekly liver monitoring and four-times-daily dosing. 2, 1

Expected Benefits and Realistic Counseling

Before starting treatment, communicate these modest but meaningful benefits to patients and families:

• Average improvement of 2.7 points on the 70-point ADAS-Cog scale (equivalent to delaying decline by approximately one year) 2
• This represents a 5–15% benefit over placebo 2
• Only 20–35% of patients show clinically meaningful response 1
• Benefits are symptomatic, not disease-modifying—the disease continues to progress even during treatment 4, 5
• Improvements occur in cognition, function, and behavior 2, 4

Assessing Treatment Response

Wait 6–12 months before determining benefit, as brief mental status tests are relatively insensitive to cholinesterase inhibitor effects. 2 Use:

• Physician's global assessment
• Primary caregiver report
• Neuropsychologic assessment or mental status questionnaire
• Evidence of behavioral or functional stabilization 2

Discontinue the cholinesterase inhibitor if:

• Intolerable side effects develop and do not resolve
• Poor adherence persists
• Deterioration continues at the pretreatment rate after 6–12 months 2

If one cholinesterase inhibitor fails, consider switching to another, as patients who do not respond to one agent may respond to another. 2

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Non-Pharmacological Interventions (Essential Foundation)

Implement structured non-pharmacological interventions as the foundation of comprehensive Alzheimer's care, before and alongside any medication. 1, 6

Environmental Modifications

• Eliminate hazards (remove loose rugs, install grab bars and handrails)
• Install safety locks on doors and cabinets
• Use GPS pendants, in-home cameras, and electronic pill dispensers
• Ensure adequate lighting throughout the home
• Use calendars, labels, and color-coded environmental cues 1

Structured Daily Routine

• Establish predictable schedules for exercise, meals, and sleep
• Simplify tasks and provide meaningful activities tailored to abilities
• Use the "three R's" approach: Repeat, Reassure, Redirect 1

Cognitive and Physical Activities

• Structured exercise program: walking, aerobic exercise, resistance training, balance exercises
• Cognitive training: reading, games, music therapy
• At least 30 minutes of sunlight exposure daily 1

Dietary Recommendations

• Mediterranean diet
• Nuts, berries, leafy greens, fish 1

Caregiver Support (Critical Component)

Link families to community resources immediately upon diagnosis, as caregiver burden significantly impacts patient outcomes:

• Alzheimer's Association
• "Safe Return" program (for wandering prevention)
• Support groups
• Respite care
• Day treatment programs 1, 6

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Management of Comorbid Conditions

Aggressively treat comorbid conditions to reduce excess disability and maximize function. 1

Priority Conditions to Optimize

• Hypertension and diabetes: These significantly increase Alzheimer's disease risk and progression 1
• Depression: Common and often untreated; use SSRIs (citalopram or sertraline) with minimal anticholinergic effects 1
• Cardiovascular disease, infections, pulmonary disease, renal insufficiency, arthritis 1
• Vision and hearing deficits: Correction can improve cognitive function 1
• Pain syndromes: Untreated pain worsens behavioral symptoms 1

Medications to Avoid

• Anticholinergic medications
• Benzodiazepines
• Sedative-hypnotics
• Narcotics 1

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Management of Behavioral and Psychological Symptoms

Exhaust non-pharmacological strategies before using psychotropic medications, except in emergency situations involving imminent danger. 1, 6

Non-Pharmacological First-Line Approaches

• Use the "three R's": Repeat, Reassure, Redirect
• Simplify tasks and provide distraction
• Maintain predictable routines
• Ensure adequate supervision 1

When Pharmacologic Treatment Is Necessary

For depression or anxiety:

• SSRIs (citalopram or sertraline) are first-line 6

For severe agitation with psychosis or aggression:

• Atypical antipsychotics (risperidone, quetiapine, olanzapine) at the lowest effective dose for the shortest duration
• Discuss increased mortality risk (1.6–1.7 times higher than placebo) with family before initiating 7, 6

For insomnia:

• Trazodone is recommended 6

Avoid benzodiazepines except for alcohol or benzodiazepine withdrawal, as they increase delirium, cause paradoxical agitation in 10% of elderly patients, and worsen cognitive function. 7

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Advanced Disease and Combination Therapy

For moderate-to-severe Alzheimer's disease, combine a cholinesterase inhibitor with memantine (an NMDA antagonist), as this provides cumulative benefits over monotherapy. 1, 6

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Monitoring and Reassessment

• Reassess every 6 months as new symptoms emerge and the care plan needs modification 1
• Average decline is 3–4 points per year on the MMSE; more marked deterioration should trigger a search for complicating comorbid illness 1
• Discuss realistic expectations and assist with advance care planning early in the disease course 1

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Common Pitfalls to Avoid

• Do not delay cholinesterase inhibitor initiation in appropriate candidates, as benefits are dose-dependent and time-sensitive 2
• Do not use typical antipsychotics (haloperidol) as first-line for behavioral symptoms due to 50% risk of tardive dyskinesia after 2 years in elderly patients 7
• Do not add psychotropic medications without first optimizing non-pharmacological interventions and treating reversible medical causes (pain, infection, constipation, dehydration) 7, 1
• Do not continue antipsychotics indefinitely; attempt taper within 3–6 months 7