What issues should a neurologist discuss with an Alzheimer's disease patient considering Lecanemab (lecanemab)

Critical Discussion Points for Lecanemab Therapy in Alzheimer's Disease

A neurologist must discuss the serious risk of amyloid-related imaging abnormalities (ARIA), including potentially fatal brain hemorrhages, mandatory MRI monitoring requirements, APOE ε4 genetic testing implications, treatment eligibility criteria, and realistic expectations about modest clinical benefits before initiating lecanemab therapy. 1

1. ARIA Risks and Safety Profile

Understanding ARIA-E (Edema) and ARIA-H (Hemorrhage)

• ARIA-E occurs in 12.6% of lecanemab-treated patients and typically manifests within the first 3-6 months of treatment 2, 3
• ARIA-H (microhemorrhages and superficial siderosis) occurs in 15-20% of patients receiving anti-amyloid monoclonal antibodies 2
• Most ARIA cases are asymptomatic and detected only on MRI, but serious and life-threatening events can occur, including fatal intracerebral hemorrhages 1, 4
• Three deaths due to intracerebral hemorrhage occurred in clinical trials, particularly in patients on concurrent anticoagulation or thrombolytic therapy 3

APOE ε4 Genotype-Specific Risks

• APOE ε4 homozygotes (approximately 15% of AD patients) have dramatically higher ARIA risk, with ARIA-E occurring in 34.5% compared to 16.8% in heterozygotes 3
• Genetic testing for APOE ε4 status must be performed prior to treatment initiation to inform individualized risk discussions 1
• Patients can decline genetic testing and still receive treatment, but they cannot be informed of their specific risk profile without this information 1

2. Mandatory MRI Monitoring Requirements

Pre-Treatment Screening

• A baseline brain MRI within 12 months of treatment initiation is mandatory to identify exclusionary findings 2, 5
• Exclusionary MRI findings include: intraparenchymal macrohemorrhages >10 mm, ≥4 microhemorrhages <10 mm, superficial siderosis, vasogenic edema, significant white matter hyperintensities, multiple lacunar infarcts, and major vascular territory infarcts 2, 5

Ongoing Monitoring Schedule

• MRI must be obtained prior to the 5th, 7th, and 14th infusions of lecanemab 2, 1
• Required sequences include T2 FLAIR, T2* gradient-echo or susceptibility-weighted imaging, and diffusion-weighted imaging 2
• Additional MRI is required immediately if any symptoms suggestive of ARIA develop (headache, confusion, visual changes, altered mental status, seizures) 1

Treatment Interruption Protocols

• Asymptomatic mild ARIA-E may allow continued dosing, but moderate or severe ARIA-E requires treatment suspension regardless of symptoms 1
• Any symptomatic ARIA-E or moderate-to-severe ARIA-H mandates immediate treatment suspension until radiographic resolution 1
• Treatment resumption after ARIA requires clinical judgment and follow-up MRI 2-4 months after initial identification 1

3. Absolute and Relative Contraindications

Anticoagulation Status

• Patients requiring anticoagulants should not receive lecanemab until more safety data are available, given the risk of serious hemorrhage 4
• The three fatal hemorrhages in trials occurred in patients on anticoagulation or receiving tissue plasminogen activator 3

Pre-existing Cerebrovascular Disease

• Multiple lacunar infarcts, major vascular territory infarcts, and evidence of cerebral amyloid angiopathy are direct contraindications 2, 5
• Significant white matter hyperintensities and multiple microhemorrhages increase hemorrhage risk and may preclude treatment 5

Other Medical Considerations

• Patients with conditions requiring lumbar puncture contraindications (bleeding disorders, recent seizures, increased intracranial pressure) may face challenges with CSF biomarker confirmation if needed 2

4. Treatment Eligibility and Biomarker Confirmation

Disease Stage Requirements

• Treatment must be initiated in patients with mild cognitive impairment or mild dementia stage of disease—the population studied in clinical trials 1
• Patients with moderate or severe dementia were excluded from trials and should not receive lecanemab 4

Amyloid Pathology Confirmation

• Presence of amyloid beta pathology must be confirmed prior to initiating treatment through amyloid PET, CSF biomarkers, or blood-based biomarkers (plasma p-tau217) 2, 1
• Blood-based biomarkers offer advantages in accessibility and cost, with plasma p-tau217 showing high accuracy (AUC 0.92-0.98) for predicting amyloid status 2, 6

5. Realistic Expectations About Clinical Benefits

Magnitude of Treatment Effect

• Lecanemab slows cognitive and functional decline but does not stop or reverse Alzheimer's disease 7
• The clinical benefit is modest—patients should understand this represents slowing of decline, not improvement or cure 8, 7
• Treatment effects were demonstrated over 18 months in clinical trials; longer-term benefits remain uncertain 3

Treatment Burden and Logistics

• Lecanemab requires intravenous infusion every 2 weeks for 18 months, then potentially monthly maintenance dosing 1
• Each infusion takes approximately one hour and must be administered in a facility equipped to manage infusion reactions 2
• Infusion-related reactions occur in 24.5% of patients (compared to 7% with placebo) 3, 9

6. Multidisciplinary Care Requirements

Infrastructure and Expertise Needs

• Treatment requires comprehensive multidisciplinary teams with specialized training in monoclonal antibody therapy and ARIA management 2
• Protocols for managing serious adverse events, including symptomatic ARIA and infusion reactions, must be established before treatment initiation 4
• Access to emergency MRI and neurology consultation is essential for managing acute complications 2

Care Partner Involvement

• Both patients and care partners must understand potential benefits, harms, and monitoring requirements before consenting to treatment 4
• Care partners play a critical role in monitoring for symptoms of ARIA and ensuring adherence to the intensive monitoring schedule 8

7. Insurance Coverage and Registry Requirements

Medicare Coverage Stipulations

• CMS requires enrollment in a CMS-approved patient registry for Medicare reimbursement of lecanemab 2
• This registry requirement adds administrative burden but is mandatory for coverage 2

8. Health Equity and Access Considerations

Representation in Clinical Trials

• Clinical trials of lecanemab included approximately 20% non-White individuals, limiting generalizability to diverse populations 2
• All participants in the qualitative study examining patient perspectives were White, highlighting gaps in understanding diverse patient experiences 8

Workforce and Access Limitations

• Too few dementia specialists are available to meet potential demand, creating access barriers particularly for underserved populations 2
• Hub-and-spoke care models and primary care-specialist collaborations are being developed to address workforce gaps 2

9. Shared Decision-Making Framework

Information Sources and Patient Perspectives

• Patients seek information from advocacy organizations, the Internet, and clinicians—neurologists should provide accurate, balanced information to counter potential misinformation 8
• Patients desire individualized risk-benefit discussions and opportunities to hear from others who have taken the medication 8
• The existential threat of dementia drives willingness to accept treatment, with some patients willing to accept treatment "at any cost" while others carefully weigh risks 8

Key Elements to Communicate

• Discuss that ARIA can mimic ischemic stroke, and thrombolytic therapy should not be given without first considering ARIA as the cause of symptoms 1
• Explain that treatment may need to be permanently discontinued if serious ARIA develops 1
• Address the possibility that despite all monitoring and precautions, serious adverse events including death can occur 3

10. Alternative Treatment Options

Comparison to Other Anti-Amyloid Therapies

• Donanemab is another FDA-approved option with similar mechanism but different dosing and monitoring requirements 6
• Aducanumab is no longer considered first-line due to limited acceptance and reimbursement issues 6

Non-Disease-Modifying Approaches

• Traditional symptomatic treatments (cholinesterase inhibitors, memantine) remain options for patients who decline or are ineligible for lecanemab 7
• Management of vascular risk factors, cognitive rehabilitation, and supportive care continue to be important regardless of lecanemab eligibility 2