What is the appropriate treatment plan for a geriatric patient with early-stage Alzheimer's disease, considering the use of LEQEMBI (lecanemab)?

LEQEMBI (Lecanemab) for Early-Stage Alzheimer's Disease

LEQEMBI (lecanemab) is an FDA-approved, first-line disease-modifying therapy for geriatric patients with early-stage Alzheimer's disease (mild cognitive impairment or mild dementia) who have confirmed amyloid pathology, administered as 10 mg/kg IV infusions every 2 weeks with mandatory MRI monitoring for amyloid-related imaging abnormalities (ARIA). 1, 2

Patient Selection Criteria

Before initiating LEQEMBI, the following requirements must be met:

• Cognitive stage: Patient must have mild cognitive impairment (MCI) or mild dementia due to Alzheimer's disease, corresponding to a Clinical Dementia Rating (CDR) score of 0.5 or 1.0, with objective cognitive impairment established by MoCA score ≤25 or comprehensive neuropsychological battery 1

• Confirmed amyloid pathology is mandatory and can be established through: 1, 2

  • Positive amyloid PET imaging
  • Positive CSF biomarkers (amyloid-beta and tau)
  • Blood-based biomarkers, particularly plasma p-tau217 (increasingly accepted as sufficient evidence) 1, 3

• ApoE ε4 genotype testing should be performed prior to treatment initiation to inform ARIA risk, though treatment can proceed without testing if the patient accepts they cannot be risk-stratified 2

Pre-Treatment Safety Screening

Baseline brain MRI without contrast is mandatory to screen for contraindications including: 3, 2

• Macrohemorrhages
• Multiple microhemorrhages (>4)
• Superficial siderosis
• Vasogenic edema
• Significant white matter hyperintensities

Required MRI sequences include DWI, T2 FLAIR, T2* gradient-echo or susceptibility-weighted imaging, preferably on a 3T scanner for greater sensitivity 3

Treatment Administration

• Dosing regimen: 10 mg/kg IV infusion over approximately 1 hour, administered every 2 weeks 2

• Maintenance option: After 18 months, may continue biweekly dosing or transition to 10 mg/kg every 4 weeks 2

• Mandatory MRI monitoring: Obtain MRI prior to the 5th, 7th, and 14th infusions to screen for ARIA 3, 2

Safety Profile and ARIA Management

ARIA Risk Stratification by ApoE ε4 Status

The risk of ARIA varies significantly by genotype: 1, 3

• ApoE ε4 homozygotes (approximately 15% of AD patients): Highest risk, with ARIA-E occurring in approximately 34.5% and overall ARIA in 44% 4, 5
• ApoE ε4 heterozygotes: Intermediate risk, with ARIA-E in 16.8% and overall ARIA in 17% 4, 5
• Non-carriers: Lowest risk 4

ARIA Clinical Presentation

• ARIA-E (edema) occurs in 13.6% of patients overall, typically within the first 3-6 months of treatment 4
• ARIA-H (microhemorrhages) occurs in 16.0% of patients 4
• Most ARIA cases are radiographically mild-to-moderate and asymptomatic (75% asymptomatic in real-world data) 5
• Critical warning: ARIA-E can mimic ischemic stroke; consider ARIA-E before administering thrombolytic therapy 2

Dosing Interruption Guidelines for ARIA-E

The FDA label provides specific guidance: 2

Asymptomatic ARIA-E:

• Mild radiographic severity: May continue dosing
• Moderate radiographic severity: Suspend dosing until resolution
• Severe radiographic severity: Suspend dosing until resolution

Symptomatic ARIA-E (any severity):

• Mild symptoms with mild radiographic findings: May continue based on clinical judgment
• Moderate/severe symptoms OR moderate/severe radiographic findings: Suspend dosing until MRI demonstrates resolution and symptoms resolve 2

Dosing Interruption Guidelines for ARIA-H

Asymptomatic ARIA-H: 2

• Mild radiographic severity: May continue dosing
• Moderate/severe radiographic severity: Suspend dosing until stabilization

Symptomatic ARIA-H (any severity):

• Suspend dosing until MRI demonstrates stabilization and symptoms resolve 2

Infusion-Related Reactions

• Occur in 24.5% of patients, most commonly within 24 hours of first infusion 4, 5
• Most common symptoms: headaches (reported in 12 patients per 71 treated) and shaking/chills/rigors (11 patients per 71 treated) 5
• Generally manageable with supportive care and premedication strategies 5

Clinical Efficacy

• Demonstrates approximately 30% slowing of cognitive decline over 18 months in early AD patients 6, 1
• Significantly reduces cerebral amyloid burden as measured by PET imaging 6, 7
• Unlike donanemab, lecanemab requires ongoing therapy rather than treatment cessation after amyloid clearance 1

Contraindications and Special Populations

Absolute contraindications to lumbar puncture (if CSF biomarkers needed): 8

• Anticoagulant medications
• Blood clotting disorders
• Recent seizures
• Intracranial lesions with increased intracranial pressure
• Papilledema
• Impaired consciousness

High-risk scenarios requiring careful consideration:

• Patients on anticoagulation (3 deaths from intracerebral hemorrhage reported in clinical trials, 2 on concurrent anticoagulant/thrombolytic therapy) 4
• ApoE ε4 homozygotes should be counseled extensively about elevated ARIA risk before proceeding 2

Infrastructure Requirements

• Treatment requires multidisciplinary teams with specialized training in ARIA management 8, 1
• Hub-and-spoke care models are being developed to address specialist shortages and expand access to community settings 8, 1
• CMS reimbursement requires patient registration in a CMS-approved registry 8

Critical Caveats

• Co-pathologies are common: A substantial proportion of older adults with apparent AD have multiple pathologic changes at autopsy, which may influence treatment response 8
• Limited diversity in trials: Much research has not included ethnically and racially diverse participants, potentially limiting generalizability 8
• Women and ApoE ε4 homozygotes: One critical analysis suggests lecanemab did not slow cognitive decline in women or enhanced decline in ApoE ε4 homozygotes, though this contradicts FDA approval data and requires clinical judgment 9
• Mortality: While generally well-tolerated, 4 deaths in open-label extension were deemed possibly related to treatment, including 2 from intracerebral hemorrhage on concurrent anticoagulation 4