What are the recommended pharmacologic and non‑pharmacologic treatments for Alzheimer's disease, including dosing and management of side effects?

Alzheimer's Disease Treatment

For Alzheimer's disease, initiate cholinesterase inhibitors (donepezil, rivastigmine, or galantamine) for mild-to-moderate disease and add memantine for moderate-to-severe disease, while simultaneously implementing non-pharmacological interventions including cognitive stimulation therapy and case management throughout all disease stages.

Pharmacological Treatment

Cognitive Enhancers

The cornerstone of AD pharmacotherapy consists of two medication classes that provide symptomatic benefit 1:

Cholinesterase Inhibitors (ChEIs):

• Approved for: Alzheimer's disease, Parkinson's disease dementia, Lewy body dementia, and vascular dementia
• Options: Donepezil (most commonly prescribed due to once-daily dosing, cost-effectiveness, and tolerability), rivastigmine, or galantamine 2
• Mechanism: Increase acetylcholine levels, enhance oligodendrocyte differentiation, and protect against amyloid-beta toxicity 2

Memantine:

• Approved for: Moderate-to-severe AD, PDD, DLB, and vascular dementia
• Dosing: Once-daily (immediate or sustained-release formulations) 2
• Additional benefits: Anti-Parkinsonian effects, antidepressant properties, neuroprotection 2

Combination therapy with both a ChEI and memantine is supported for reducing cognitive and functional decline, decreasing neuropsychiatric symptoms, and postponing institutionalization when instituted early 3.

Side Effect Management

ChEI side effects to monitor:

• Severe nausea, vomiting, weight loss, anorexia, falls 1
• Cardiac conduction disturbances (particularly with donepezil and galantamine) - require regular cardiac monitoring 2
• Rivastigmine: local application-site reactions with transdermal patch 2

Memantine side effects:

• Confusion, dizziness, falls 1
• Generally better tolerated than ChEIs 2

Disease-Modifying Therapies

Anti-amyloid monoclonal antibodies (lecanemab, donanemab, aducanumab) represent a paradigm shift for early-stage AD 4, 2:

• Require biomarker confirmation of amyloid pathology
• Critical monitoring: Amyloid-related imaging abnormalities (ARIA), especially in ApoE4 carriers 2
• Lecanemab: IV infusion every 2 weeks
• Aducanumab: IV infusion every 4 weeks 2

These therapies slow cognitive decline in early AD but require specialized infrastructure for administration and monitoring 5, 4.

When to Continue or Discontinue Medications

Continue Treatment If:

• Clinically meaningful benefit observed (improvement, stabilization, or decreased rate of decline) 1
• Neuropsychiatric symptoms controlled by the cognitive enhancer - continue even with cognitive/functional decline 1
• Active psychotic symptoms, agitation, or aggression present - do NOT discontinue ChEIs until symptoms stabilize 1

Consider Discontinuation After >12 Months If:

1. Clinically meaningful worsening over past 6 months (excluding delirium or acute medical illness) 1
2. No benefit ever observed during treatment 1
3. Severe/end-stage dementia (dependent in most ADLs, limited life expectancy) 1
4. Intolerable side effects 1
5. Poor medication adherence 1

Deprescribing Protocol:

• Gradual taper: Reduce dose by 50% every 4 weeks until reaching starting dose, then discontinue after 4 additional weeks 1
• Reinitiate if clinically meaningful worsening occurs after cessation 1
• Do NOT use ChEIs or memantine for mild cognitive impairment 1
• Do NOT use ChEIs for frontotemporal dementia or other non-approved neurodegenerative conditions 1

Non-Pharmacological Interventions

These are core therapies, not adjuncts 5. Evidence supports their integration throughout all disease stages:

Cognitive Interventions

• Cognitive stimulation therapy (CST): Enhances cognitive abilities and quality of life 2, 6
• Cognitive training programs: Benefit behavioral and psychiatric symptoms 3, 7

Physical Activity

• Aerobic exercise and strength training: Improve cognitive and physical function 7
• Modulates inflammation and delays cognitive decline 7

Dietary Approaches

• Mediterranean diet, DASH diet, or MIND diet: Delay cognitive decline through anti-inflammatory mechanisms 7
• Evidence for supplements remains weak 7

Behavioral and Environmental Strategies

• Structured approaches for managing agitation 5
• Environmental modifications for safety 5

Support Systems

• Case management: Improves coordination and continuity of care delivery, including social aspects 1
• Caregiver support programs: Essential component across all stages 5, 8
• Dementia-friendly organizations/communities: Promote inclusion and improve outcomes 1

Clinical Decision Algorithm

Stage-based approach:

1. Early AD (mild): Anti-amyloid therapy (if biomarker-confirmed) + ChEI + non-pharmacological interventions 4
2. Moderate AD: ChEI + memantine combination + intensified non-pharmacological support 3
3. Severe AD: Continue medications only if demonstrable benefit; prioritize comfort, behavioral management, and caregiver support 1

Critical caveat: Decisions must involve patient preferences (when capable), prior expressed wishes, and collaboration with substitute decision-makers 1. However, the evidence clearly supports early initiation and maintenance of combination therapy when tolerated and beneficial.