What are the practical and clinical barriers to implementing lecanemab (anti-amyloid therapy) in routine practice for early Alzheimer's disease treatment?

Practical and Clinical Barriers to Implementing Lecanemab in Routine Practice

The implementation of lecanemab faces substantial infrastructure barriers including mandatory diagnostic confirmation with biomarkers, intensive MRI monitoring protocols requiring specialized radiology capacity, multidisciplinary team requirements with specialist shortages, and complex safety management systems—all of which create significant access limitations particularly for non-academic centers and underserved populations. 1, 2, 3

Diagnostic and Biomarker Testing Barriers

Amyloid Confirmation Requirements

• All patients must have confirmed amyloid pathology before initiating lecanemab, which can be established through amyloid PET imaging, CSF biomarkers, or blood-based biomarkers like plasma p-tau217 4
• Amyloid PET scans are expensive, not universally available, and require specialized nuclear medicine facilities with limited geographic distribution 1
• CSF analysis via lumbar puncture is invasive, requires technical expertise, and faces patient acceptance barriers 1
• Blood-based biomarkers (plasma p-tau217) offer the most accessible option with high accuracy (AUC 0.92-0.98), but are not yet widely available in all clinical settings and require laboratory infrastructure for processing 1, 2

Clinical Staging Requirements

• Patients must have documented objective cognitive impairment with MoCA score ≤25 or comprehensive neuropsychological battery showing impairment in ≥1 cognitive domain 5
• CDR score must be 0.5 (MCI) or 1.0 (mild dementia) to establish appropriate disease stage 5
• This requires access to trained neuropsychologists and standardized testing protocols, which are scarce in many community settings 1

Genetic Testing Infrastructure

• ApoE ε4 genotype testing should be performed prior to treatment initiation to inform ARIA risk, as homozygotes have significantly higher rates of symptomatic and severe ARIA 4
• Approximately 15% of AD patients are ApoE ε4 homozygotes who face 4 times higher risk of ARIA-E by 24 weeks 1
• Genetic testing requires counseling infrastructure and raises ethical considerations about disclosure 4

MRI Monitoring and Radiology Capacity Barriers

Baseline MRI Requirements

• A baseline brain MRI within 12 months of treatment initiation is mandatory to identify exclusionary findings 2, 4
• Exclusionary 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
• This requires radiologists with expertise in identifying these specific contraindications 2

Intensive Serial MRI Monitoring

• Mandatory MRI monitoring must occur prior to the 5th, 7th, and 14th infusions (approximately weeks 16,24, and 52) 1, 5, 4
• ARIA-E occurs in 12.6% of lecanemab-treated patients and typically manifests within the first 3-6 months, requiring prompt detection 2, 6
• ARIA-H (microhemorrhages) occurs in 16.0% of patients 6
• Each MRI requires specialized reading for ARIA detection, with both local and central review recommended 6

Radiology Workforce Limitations

• There is insufficient neuroradiology capacity to meet the demand for serial MRI monitoring if lecanemab is widely adopted 2
• Radiologists need specific training in ARIA identification and severity grading (mild, moderate, severe) to guide dosing decisions 4
• Access to emergency MRI is essential for managing acute complications when patients develop symptoms 2

Multidisciplinary Team and Specialist Shortage Barriers

Required Team Composition

• Treatment requires comprehensive multidisciplinary teams with specialized training in monoclonal antibody therapy and ARIA management 1, 2
• Teams must include: neurologists with dementia expertise, neuroradiologists, infusion nurses, neuropsychologists, genetic counselors, and care coordinators 3, 7
• Hub-and-spoke care models are being developed to address specialist shortages, but implementation is incomplete 1

Dementia Specialist Shortage

• Too few dementia specialists are available to meet potential demand, creating access barriers particularly for underserved populations 2
• This shortage is most acute in rural and non-academic settings 2
• The multidisciplinary team requirement creates a significant barrier for community neurology practices 3

Training Requirements

• All team members require specialized training in ARIA recognition, management protocols, and infusion reaction handling 1, 2
• Institutional infrastructure must be established before treatment initiation, including electronic medical record tools and standardized workflows 3

Safety Monitoring and Management Barriers

ARIA Management Complexity

• ARIA can be fatal, with serious intracerebral hemorrhages >1 cm observed in this drug class 4
• ARIA-E in ApoE ε4 homozygotes occurs in 34.5% of patients, requiring careful risk-benefit discussions 6
• Complex dosing interruption algorithms must be followed based on ARIA severity and symptom status 4
• Asymptomatic mild ARIA-E may allow continued dosing, but moderate-to-severe or symptomatic ARIA requires treatment suspension 4

Emergency Response Capacity

• ARIA-E can cause focal neurologic deficits mimicking ischemic stroke, requiring clinicians to consider ARIA before administering thrombolytic therapy 4
• Facilities must have immediate access to neurology consultation and emergency MRI 2
• Three deaths due to intracerebral hemorrhage occurred in clinical trials, including patients on concurrent anticoagulation or tissue plasminogen activator 6

Anticoagulation Contraindications

• Patients on anticoagulants face substantially higher hemorrhage risk and may be excluded from treatment 6
• This creates difficult clinical decisions for patients with atrial fibrillation or other indications for anticoagulation 6

Infusion Infrastructure Barriers

Administration Requirements

• Lecanemab requires intravenous infusion every 2 weeks for 18 months, then potentially monthly maintenance dosing 2
• 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, requiring monitoring and management protocols 6

Geographic Access

• Infusion centers must be within reasonable travel distance for biweekly visits over 18+ months 3
• This creates substantial burden for patients in rural areas or those with limited transportation 2

Financial and Reimbursement Barriers

Registry Requirements

• CMS requires enrollment in a CMS-approved patient registry for Medicare reimbursement 1, 2
• Registry participation adds administrative burden and data collection requirements 5

Cost Analysis Requirements

• Institutions must conduct cost analyses showing financial sustainability before implementation 3
• The drug cost, infusion costs, monitoring costs (serial MRIs, biomarker testing), and personnel costs create substantial financial barriers 3

Health Equity and Access Barriers

Limited Diversity in Clinical Trials

• Clinical trials of lecanemab included approximately 20% non-White individuals, limiting generalizability to diverse populations 2
• Real-world effectiveness in diverse populations remains uncertain 7

Differential Access

• Academic medical centers have greater capacity to implement lecanemab programs compared to community practices 3, 7
• Underserved populations face compounded barriers from specialist shortages, geographic distance, and limited institutional infrastructure 2

Real-World Implementation Experience

Feasibility Factors

• Successful implementation requires: enterprise-wide project management, electronic medical record tool development, standardized referral systems, and multidisciplinary team consensus processes 3, 7
• The Tel Aviv Medical Center experience demonstrated feasibility with dedicated infrastructure, screening 169 patients and initiating treatment in 86 between July 2023 and January 2025 7
• Treatment discontinuation occurred in 19.8% of patients due to ARIA, financial barriers, comorbidities, or personal preference 7

Common Pitfalls

• Inadequate baseline MRI screening leading to treatment of patients with contraindications 2
• Insufficient radiology capacity for serial monitoring causing delays in ARIA detection 2
• Lack of emergency response protocols when symptomatic ARIA occurs 2
• Underestimating the administrative burden of registry enrollment and documentation requirements 5