What are the indication, dosing regimen, MRI monitoring schedule, and safety precautions for Leqembi (lecanemab) in amyloid‑β‑positive adults with early Alzheimer’s disease (mild cognitive impairment or mild dementia)?

Lecanemab (Leqembi) for Early Alzheimer's Disease

Indication

Lecanemab is FDA-approved for treating Alzheimer's disease in patients with mild cognitive impairment (MCI) or mild dementia stage of disease who have confirmed amyloid-β pathology. 1

• Treatment must be initiated only in patients with both objective cognitive impairment (MCI or mild dementia) and confirmed amyloid pathology—lecanemab is inappropriate for cognitively unimpaired individuals even with positive biomarkers 2, 3
• Amyloid pathology confirmation requires one of the following: amyloid PET imaging, CSF biomarkers (Aβ42/40 ratio), or blood-based biomarkers such as plasma p-tau217 (which has 92-98% accuracy for predicting amyloid status) 4, 2
• Objective cognitive impairment must be documented through comprehensive neuropsychological testing showing MoCA ≤25 or impairment in ≥1 cognitive domain 5

Dosing Regimen

The standard dosing is 10 mg/kg intravenous infusion every 2 weeks for the first 18 months, with optional transition to maintenance dosing of 10 mg/kg every 4 weeks after 18 months. 1

• Each infusion is administered over approximately one hour 1
• If an infusion is missed, administer the next dose as soon as possible 1
• The medication must be diluted before administration 1

MRI Monitoring Schedule

Mandatory brain MRI monitoring must be performed at three specific timepoints: before the 5th, 7th, and 14th infusions (approximately weeks 16,24, and 52). 2, 1, 3

Baseline MRI Requirements

• Obtain a recent baseline brain MRI before initiating treatment to screen for contraindications 1, 3
• Required MRI sequences include: DWI, T2 FLAIR, T2* gradient-echo or susceptibility-weighted imaging, preferably on a 3T scanner 4
• Screen for exclusionary findings: macrohemorrhages, microhemorrhages, superficial siderosis, vasogenic edema, and significant white matter hyperintensities 4

Symptomatic Monitoring

• If a patient develops symptoms suggestive of ARIA at any time, perform immediate clinical evaluation with MRI 1

Safety Precautions and ARIA Management

APOE ε4 Genotyping

APOE ε4 genotype testing should be performed prior to treatment initiation because homozygotes (approximately 15% of AD patients) have substantially higher risk of ARIA, including symptomatic, serious, and severe events. 1

• APOE ε4 homozygotes are approximately 4 times more likely to experience ARIA-E by 24 weeks compared to non-carriers 4
• Patients can still receive treatment without genotyping, but their risk cannot be stratified 1
• Discuss the risk-benefit profile across genotypes with patients before testing 1

ARIA-E (Edema) Management

For asymptomatic mild ARIA-E on MRI, treatment may continue; for moderate or severe ARIA-E, or any symptomatic ARIA-E, suspend dosing until radiographic resolution and symptom resolution occur. 1

• Asymptomatic + Mild ARIA-E: May continue dosing 1
• Asymptomatic + Moderate/Severe ARIA-E: Suspend dosing 1
• Mild symptoms + Any severity ARIA-E: May continue based on clinical judgment for mild radiographic findings; suspend for moderate/severe 1
• Moderate/Severe symptoms + Any severity ARIA-E: Suspend dosing 1
• Consider follow-up MRI 2-4 months after initial identification to assess resolution before resuming 1

ARIA-H (Hemorrhage) Management

For asymptomatic mild ARIA-H, treatment may continue; for moderate or severe ARIA-H, or any symptomatic ARIA-H, suspend dosing until radiographic stabilization. 1

• Asymptomatic + Mild ARIA-H: May continue dosing 1
• Asymptomatic + Moderate ARIA-H: Suspend dosing until stabilization 1
• Asymptomatic + Severe ARIA-H: Suspend dosing; use clinical judgment whether to continue or permanently discontinue 1
• Any symptomatic ARIA-H: Suspend dosing until stabilization and symptom resolution 1

Intracerebral Hemorrhage >1 cm

For intracerebral hemorrhage greater than 1 cm, suspend dosing until MRI demonstrates radiographic stabilization and symptoms resolve; use clinical judgment whether to resume or permanently discontinue. 1

• Serious intracerebral hemorrhages >1 cm can be fatal 1
• Overall incidence of ARIA-E is approximately 12.6% at the 10 mg/kg biweekly dose 4, 6

Critical Safety Warnings

• ARIA can mimic ischemic stroke: Consider whether focal neurologic deficits could be ARIA-E before administering thrombolytic therapy 1
• Anticoagulant interactions: Exercise additional caution when co-administering with anticoagulants or tissue plasminogen activator due to increased macrohemorrhage risk 3
• Infusion-related reactions: Most common adverse events include headache and infusion-related reactions, which require appropriate management 7, 3

Implementation Requirements

Treatment requires multidisciplinary teams with specialized training in ARIA management, and enrollment in a CMS-approved patient registry is mandatory for Medicare reimbursement. 8, 2

• Hub-and-spoke care models are being developed to address specialist shortages and enable broader access 8, 2
• Comprehensive counseling about benefits, risks, and monitoring requirements is essential before initiating therapy 8

Clinical Efficacy Context

• Lecanemab demonstrated 27-30% slowing of cognitive decline on ADCOMS and 26-33% on CDR-SB at 18 months compared to placebo 6
• Treatment resulted in significant reduction in brain amyloid burden (-0.306 SUVr units) 6
• Quality-of-life measures showed 49-56% less decline and 38% less increase in caregiver burden 9
• The clinical significance of these effects remains debated, as the magnitude may be smaller than the minimally important clinical difference perceptible to patients and caregivers 10