For a patient over 65 with mild cognitive impairment or mild dementia due to Alzheimer’s disease and confirmed amyloid‑β plaques, what are the FDA‑approved disease‑modifying therapies, their dosing regimens, and required monitoring?

FDA-Approved Disease-Modifying Therapies for Alzheimer's Disease with Confirmed Amyloid Plaques

For patients over 65 with mild cognitive impairment or mild dementia due to Alzheimer's disease and confirmed amyloid-β plaques, two FDA-approved anti-amyloid monoclonal antibodies are available: lecanemab (Leqembi) with full FDA approval and donanemab (Kisunla) with traditional approval, both requiring intravenous infusion, mandatory MRI monitoring for amyloid-related imaging abnormalities (ARIA), and enrollment in CMS registries for Medicare reimbursement. 1, 2

Current FDA-Approved Options

Lecanemab (Leqembi)

• Approval status: Full FDA approval granted July 2023, with CMS reimbursement available when patients are registered in CMS-approved registries 1
• Dosing regimen: 10 mg/kg intravenously every 2 weeks 3, 4
• Target population: Patients with mild cognitive impairment or mild dementia due to AD with confirmed amyloid pathology 1, 2
• Mechanism: Targets soluble protofibrils of amyloid-β, achieving marked reductions in brain amyloid burden 4, 5

Donanemab (Kisunla)

• Approval status: Traditional FDA approval following unanimous advisory panel recommendation in June 2024 1, 2
• Dosing regimen: 700 mg IV every 4 weeks for 3 doses, then 1400 mg IV every 4 weeks 6
• Target population: Early symptomatic AD (MCI or mild dementia) with confirmed amyloid pathology 2, 6
• Unique feature: Treatment can be discontinued once amyloid clearance is achieved (below 24.1 Centiloids), unlike lecanemab which requires ongoing therapy 2
• Optimal candidates: Patients with low-to-medium tau burden show greatest benefit; those with high tau burden demonstrate reduced clinical benefit 2

Aducanumab (Aduhelm)

• Status: Development and sale discontinued; CMS did not support payment, limiting its use 1
• Not recommended as a treatment option 2

Mandatory Biomarker Confirmation Requirements

Amyloid Pathology Documentation

Patients must have confirmed amyloid pathology through one of the following methods before initiating therapy: 1, 2, 7

• Amyloid PET imaging: Three FDA-validated tracers available with 89-98% sensitivity and 88-100% specificity; values above 30 Centiloids correspond to pathological amyloid levels 1, 2
• CSF biomarkers: Abnormal Aβ42/40 ratio and elevated p-tau levels 1, 7
• Blood-based biomarkers: Plasma p-tau217 is increasingly accepted as sufficient evidence, with high accuracy (AUC 0.92-0.98) for predicting amyloid status 2, 7

Clinical Documentation Requirements

Beyond biomarker positivity, patients must demonstrate: 6

• Objective cognitive impairment: MoCA score ≤25 or comprehensive neuropsychological battery showing impairment in ≥1 cognitive domain 6
• Appropriate disease severity: CDR score of 0.5 (MCI) or 1.0 (mild dementia) 6
• Documented functional impact: Measurable impairment on ADCS-iADL or similar functional scales 6

Critical caveat: Anti-amyloid therapies are explicitly inappropriate for cognitively unimpaired individuals, even with positive biomarkers, and for patients with subjective cognitive decline who are not at elevated risk 6, 7

Mandatory Safety Monitoring Protocol

Baseline MRI Requirements

Before initiating therapy, obtain baseline brain MRI without contrast to screen for contraindications: 2, 7

• Required sequences: DWI, T2 FLAIR, T2* gradient-echo or susceptibility-weighted imaging 2
• Preferred scanner: 3T MRI for greater sensitivity to microhemorrhages 2
• Exclusionary findings: Macrohemorrhages, multiple microhemorrhages, superficial siderosis, vasogenic edema, or significant white matter hyperintensities 2

Ongoing MRI Monitoring Schedule

Mandatory MRI monitoring must be performed at specific intervals to detect ARIA: 2, 6, 7

• Lecanemab: Before 5th, 7th, and 14th infusions (approximately weeks 16,24, and 52) 2, 7
• Donanemab: Before 5th, 7th, and 14th infusions 6

ARIA Management

• ARIA-E (edema): Occurs in 12.6% of lecanemab patients; may require temporary or permanent cessation and corticosteroid treatment 2, 7
• ARIA-H (microhemorrhages/superficial siderosis): More common in APOE ε4 carriers 2, 3
• APOE ε4 risk: Carriers are approximately 4 times more likely to experience ARIA-E events by 24 weeks, regardless of serum exposure 2

Clinical Efficacy and Expected Outcomes

Magnitude of Benefit

Both lecanemab and donanemab demonstrate: 3, 5, 8

• Approximately 30% slowing of cognitive and functional decline over 18 months 5, 8
• Amyloid reduction: Reductions of 60-85 Centiloids in Phase III trials; reductions below 15-25 Centiloids threshold associated with clinical benefit 2, 8
• Downstream effects: Reductions in plasma p-tau217 levels and markers of astroglial injury, indicating effects beyond amyloid clearance 2, 3

Treatment Duration Considerations

• Lecanemab: Requires ongoing therapy for sustained benefit 2
• Donanemab: Allows treatment cessation once amyloid clearance achieved (below 24.1 Centiloids), with off-treatment increases of 2.80 Centiloids/year 2

Implementation Requirements

Multidisciplinary Care Team

Treatment requires: 1, 6, 7

• Specialized training in ARIA management and monitoring protocols 6, 7
• Comprehensive multidisciplinary teams with sufficient resources for close collaboration 1
• Hub-and-spoke care models being developed to address specialist shortages and enable broader access 2, 7

Patient Counseling and Consent

Prior to initiating therapy, provide comprehensive counseling covering: 7

• Anticipated benefits: Modest slowing of cognitive decline (approximately 30%) 5, 8
• Potential risks: ARIA occurrence, infusion reactions, monitoring burden 6, 7
• Required monitoring schedule: Frequent MRI monitoring and IV infusions 7
• Health equity considerations: Access for underrepresented groups 7

Administrative Requirements

• CMS registry enrollment: Required for Medicare reimbursement 6, 7
• Insurance authorization: Pre-authorization typically required given high cost and monitoring demands 1

Common Pitfalls and How to Avoid Them

Inappropriate Patient Selection

Avoid treating: 1, 6

• Cognitively unimpaired individuals with positive biomarkers (preclinical AD) 6, 7
• Patients with subjective cognitive decline without elevated risk factors 1
• Patients beyond mild dementia stage (CDR >1.0) 6
• Patients with suspected Lewy body dementia 1

Inadequate Baseline Assessment

Ensure complete workup includes: 6

• Comprehensive neuropsychological testing documenting objective impairment 6
• Functional assessment with validated scales 6
• Baseline MRI with appropriate sequences on adequate scanner 2, 7
• APOE genotyping to assess ARIA risk 2, 3

Monitoring Failures

Critical monitoring elements: 2, 6, 7

• Adhere strictly to MRI monitoring schedule; delays increase ARIA risk 2, 7
• Use standardized MRI protocols with required sequences 2
• Have protocols in place for ARIA management before initiating therapy 6, 7

Biomarker Interpretation Errors

Important distinctions: 1, 6

• Positive biomarkers indicate amyloid pathology but do not alone justify treatment without objective cognitive impairment 6
• Co-pathologies (vascular disease, Lewy bodies, hippocampal sclerosis) are common in older adults and may influence outcomes 1
• Blood-based biomarkers offer accessibility advantages but atypical presentations may still warrant amyloid PET for confirmation 2

Practical Algorithm for Treatment Initiation

1. Confirm clinical eligibility: MCI or mild dementia (CDR 0.5-1.0) with objective cognitive impairment (MoCA ≤25) 6

2. Document amyloid pathology: Positive amyloid PET, CSF biomarkers, or plasma p-tau217 2, 7

3. Obtain baseline MRI: Screen for contraindications using required sequences on 3T scanner 2, 7

4. Assess ARIA risk factors: APOE genotyping, review anticoagulation status, evaluate baseline microhemorrhages 2, 3

5. Consider tau burden (for donanemab): Patients with low-to-medium tau show optimal benefit 2

6. Establish multidisciplinary team: Ensure ARIA management protocols and monitoring capacity in place 6, 7

7. Complete patient counseling: Discuss benefits, risks, monitoring requirements, and obtain informed consent 7

8. Enroll in CMS registry: Required for Medicare reimbursement 6, 7

9. Initiate therapy: Lecanemab 10 mg/kg IV every 2 weeks OR donanemab 700 mg IV every 4 weeks x3, then 1400 mg every 4 weeks 6, 3, 4

10. Implement monitoring schedule: MRI before 5th, 7th, and 14th infusions 2, 6, 7