Antiamyloid Monoclonal Antibody Therapy Protocol
Direct Recommendation
Lecanemab and donanemab are the recommended antiamyloid monoclonal antibodies for early symptomatic Alzheimer's disease (mild cognitive impairment or mild dementia with confirmed amyloid pathology), with both requiring mandatory baseline brain MRI screening and regular MRI monitoring for amyloid-related imaging abnormalities (ARIA). 1, 2
Patient Selection and Eligibility Criteria
Clinical Stage Requirements
- Treatment must be initiated in patients with mild cognitive impairment or mild dementia stage of Alzheimer's disease—this is the population studied in clinical trials and specified in FDA approvals 1, 2
- Patients with moderate or advanced dementia are not candidates for these therapies 1
Mandatory Biomarker Confirmation
Before initiating therapy, confirm amyloid pathology through one of the following methods:
- Blood-based biomarkers: Plasma p-tau217 with high accuracy (AUC 0.92-0.98) is now sufficient evidence without requiring additional amyloid PET 3, 1
- Amyloid PET imaging: Positive scan demonstrating amyloid burden, with Centiloid values above 30 CL corresponding to pathological amyloid levels 1
- CSF biomarkers: Positive Aβ42/Aβ40 ratio and tau markers 3, 1
Blood biomarkers offer significant advantages in accessibility and cost-effectiveness compared to PET or CSF testing, and are increasingly accepted as sufficient for treatment initiation. 3, 1
Genetic Testing for ARIA Risk Stratification
- APOE ε4 testing is mandatory before initiating treatment to inform ARIA risk 2
- APOE ε4 homozygotes have approximately 4-fold higher risk of ARIA-E events compared to non-carriers 1, 2
- Discuss genetic testing implications and ARIA risks across genotypes with patients before testing 2
Pre-Treatment Imaging Requirements
Mandatory Baseline Brain MRI
Obtain brain MRI without IV contrast on a 3T scanner (preferred) to screen for contraindications before initiating therapy: 3, 1, 4
Exclusionary findings that preclude treatment:
- Macrohemorrhages
- Multiple microhemorrhages (>4 microhemorrhages increases ARIA risk) 3, 1
- Superficial siderosis (increases ARIA risk) 3, 1
- Significant vasogenic edema
- Extensive white matter hyperintensities 1
Required MRI sequences:
- DWI (diffusion-weighted imaging)
- T2 FLAIR
- T2* gradient-echo or susceptibility-weighted imaging (critical for detecting microhemorrhages)
- 3T scanner preferred for greater sensitivity to microhemorrhages 1
Optional Pre-Treatment Amyloid PET
- Amyloid PET is recommended to confirm amyloid presence if blood biomarkers are not used 3, 1
- Consider amyloid PET in cases with atypical clinical features, very young onset, mixed clinical picture, or equivocal p-tau217 results 1
Dosing Protocols
Lecanemab Dosing
- 10 mg/kg intravenous infusion every 2 weeks 1
- Administered over approximately 60 minutes 1
- Ongoing therapy required—no treatment cessation protocol established 1
Donanemab Dosing (FDA-Approved Protocol)
- 700 mg IV infusion over 30 minutes every 4 weeks for first 3 doses 2
- Then 1400 mg IV infusion every 4 weeks for subsequent doses 2
- Treatment cessation option: Consider stopping when amyloid plaques reduced to minimal levels on amyloid PET (below 24.1 Centiloid units) 1, 2
- Off-treatment amyloid increases average 2.80 CL/year after cessation 1
Mandatory MRI Monitoring During Treatment
Lecanemab Monitoring Schedule
Obtain brain MRI without contrast prior to:
- 5th infusion
- 7th infusion
- 14th infusion 1
Enhanced clinical vigilance for ARIA is required during the first 24 weeks of treatment. 2
Donanemab Monitoring Schedule
Obtain brain MRI without contrast prior to:
- 2nd infusion
- 3rd infusion
- 4th infusion
- 7th infusion 2
MRI Monitoring Rationale
- Only MRI can detect ARIA—no other imaging modality is appropriate for post-treatment monitoring 3
- ARIA-E (edema) occurs in 12.6-35.2% of treated patients, with 72.7% of initial events occurring within first 8 doses 1, 5
- Most ARIA-E events (98.2%) resolve radiographically, with 82.8% resolving within 16 weeks 5
ARIA Management Algorithm
ARIA-E (Edema) Management
If ARIA-E detected on monitoring MRI:
- Asymptomatic mild ARIA-E: Continue treatment with increased monitoring frequency 2, 5
- Asymptomatic moderate ARIA-E: Suspend dosing until radiographic resolution, then consider resuming 2
- Symptomatic ARIA-E or severe ARIA-E: Discontinue treatment permanently 2
ARIA-H (Microhemorrhages/Superficial Siderosis) Management
- New microhemorrhages (<10): Continue treatment with increased monitoring 2
- Multiple new microhemorrhages (≥10) or new superficial siderosis: Suspend dosing and reassess 2
- Serious intracerebral hemorrhages >1 cm: Discontinue treatment permanently 2
Symptomatic ARIA Recognition
Common symptoms requiring immediate clinical evaluation and MRI:
- Headache (most common—46.6% of symptomatic cases) 5
- Confusion (14.6%) 5
- Dizziness (10.7%) 5
- Nausea (7.8%) 5
- Focal neurologic deficits mimicking ischemic stroke 2
Infusion-Related Reaction Management
Prevention Strategy
- Consider pre-treatment with antihistamines, acetaminophen, or corticosteroids prior to subsequent dosing if prior infusion reactions occurred 2
Acute Management
- Reduce infusion rate or discontinue infusion if reactions occur 2
- Initiate appropriate symptomatic therapy as clinically indicated 2
Patient Selection Optimization
Tau Burden Stratification (Donanemab-Specific)
- Optimal candidates: Patients with low-to-intermediate tau PET burden show greatest clinical benefit 1
- Reduced benefit: Patients with high tau burden demonstrate diminished clinical response 1, 6
- Tau PET imaging should be considered for patient stratification when available 1
Contraindications
- Known serious hypersensitivity to donanemab or excipients 2
- Pre-existing significant microhemorrhages or superficial siderosis on baseline MRI 3, 1
- Moderate to severe dementia (beyond mild stage) 1
Treatment Cessation Considerations
Donanemab-Specific Protocol
- Amyloid PET quantification between 11-25 Centiloid units guides treatment cessation decisions 1
- Consider stopping when amyloid clearance achieved (below 24.1 CL) 1, 2
- Monitor for amyloid re-accumulation after cessation (average 2.80 CL/year increase) 1
Lecanemab Protocol
- No established treatment cessation protocol—ongoing therapy required 1
Clinical Efficacy Expectations
Realistic Outcome Counseling
- Both agents demonstrate approximately 30% slowing of cognitive decline in early Alzheimer's disease 1
- Clinical benefit is modest but statistically significant on CDR-SB (Clinical Dementia Rating-Sum of Boxes) 1, 7
- Greatest benefit occurs when treatment initiated in mild cognitive impairment or mild dementia stage 1, 6
- Donanemab achieves more rapid amyloid reduction (60-85 Centiloid unit reductions) compared to lecanemab 1
Critical Implementation Pitfalls to Avoid
Common Errors
- Initiating treatment without baseline MRI screening—this misses contraindications and increases ARIA risk 3, 1
- Skipping APOE ε4 testing—this prevents proper risk stratification and informed consent 2
- Using CT instead of MRI for ARIA monitoring—only MRI can detect ARIA 3
- Treating patients beyond mild dementia stage—no evidence of benefit in moderate/advanced disease 1
- Failing to obtain scheduled monitoring MRIs—most ARIA events occur early in treatment and require detection 2, 5