What are the recommended first-line treatments for patients with mild Alzheimer's disease and confirmed amyloid presence?

First-Line Treatments for Mild Alzheimer's Disease with Confirmed Amyloid Presence

The FDA-approved anti-amyloid monoclonal antibodies lecanemab and donanemab are the recommended first-line treatments for patients with mild cognitive impairment or mild dementia due to Alzheimer's disease with confirmed amyloid pathology in the brain. 1, 2, 3, 4

Approved Anti-Amyloid Therapies

• Lecanemab (Leqembi®) received full FDA approval in July 2023 and is indicated for patients with mild cognitive impairment or mild dementia stage of Alzheimer's disease with confirmed amyloid pathology 1, 3
• Donanemab (Kisunla™) received FDA approval in July 2024 and is similarly indicated for early symptomatic Alzheimer's disease with confirmed amyloid presence 1, 2, 4
• Aducanumab is no longer considered a first-line treatment as its development has been discontinued due to limited acceptance and reimbursement issues 1

Patient Selection Criteria

• Treatment should be initiated in patients with:
  • Mild cognitive impairment or mild dementia due to Alzheimer's disease 1, 3, 4
  • Confirmed amyloid pathology through one of the following methods:
    • Amyloid PET scan (now covered by Medicare since October 2023) 1
    • Cerebrospinal fluid (CSF) biomarkers 1
    • Emerging blood-based biomarkers 1
• Optimal results are seen in patients with moderate tau protein burden in the brain 2
• APOE ε4 genotyping is recommended prior to treatment to assess risk of ARIA (Amyloid-Related Imaging Abnormalities) 3, 5

Efficacy of Anti-Amyloid Therapies

• Both lecanemab and donanemab slow cognitive and functional decline by approximately 30% over 18 months 6
• Clinical benefit is observed when amyloid in the brain drops below 15-25 Centiloids 6
• In clinical trials:
  • 67% of patients on lecanemab reached this threshold after 79 weeks 7
  • For donanemab, 69% of patients were eligible to stop treatment at week 76 due to sufficient amyloid reduction 4
• These treatments preserve quality of life and reduce caregiver burden 7

Safety Monitoring Requirements

• Baseline brain MRI is required before initiating treatment 1, 3
• Regular MRI monitoring is mandatory during treatment:
  • For lecanemab: MRI before the 5th, 7th, and 14th infusions 1, 3
  • Additional MRIs should be performed if symptoms suggestive of ARIA develop 1
• Common adverse events include:
  • ARIA-E (edema): occurs in 12.6% of patients on lecanemab 1, 8
  • ARIA-H (microhemorrhages): occurs in 14% of patients 1
  • Infusion reactions: reported in 26.4% of patients on lecanemab 8
• APOE ε4 carriers, especially homozygotes, have higher risk of ARIA 3, 5

Treatment Administration

• Lecanemab is administered as an intravenous infusion of 10 mg/kg every two weeks 3
• Donanemab is administered as 700 mg IV every 4 weeks for the first 3 doses, then 1400 mg every 4 weeks 4
• Donanemab has a unique protocol where treatment can be discontinued once amyloid levels drop below specified thresholds 4

Implementation Considerations

• Treatment requires multidisciplinary teams with specialized training 1
• Hub-and-spoke care models are being developed to address specialist shortages 1
• Blood-based biomarkers are emerging as more accessible and cost-effective screening tools compared to PET scans or CSF analysis 1

Caveats and Pitfalls

• Anticoagulation increases risk of hemorrhage; patients requiring anticoagulants may not be suitable candidates for these therapies 5
• Patients should be thoroughly counseled about potential benefits, risks, and monitoring requirements 5
• Health equity remains a concern, with ongoing efforts needed to improve access for underrepresented groups, particularly Black communities 1
• These treatments do not cure Alzheimer's disease but slow its progression 6

Traditional Symptomatic Treatments

• Cholinesterase inhibitors (donepezil, rivastigmine, galantamine) and memantine may be used concomitantly with anti-amyloid therapies 4, 9
• However, these medications only provide symptomatic relief and do not modify disease progression 1