What is the role of monoclonal antibody (mAb) treatment, such as aducanumab (aducanumab), in managing Alzheimer's disease?

Monoclonal Antibody Treatment for Alzheimer's Disease

Direct Recommendation

Lecanemab and donanemab are the recommended first-line disease-modifying therapies for patients with mild cognitive impairment or mild dementia due to Alzheimer's disease with confirmed amyloid pathology, while aducanumab is no longer a viable treatment option due to discontinued development and lack of reimbursement. 1

FDA-Approved Anti-Amyloid Monoclonal Antibodies

Currently Available Therapies

• Lecanemab (Leqembi) received full FDA approval in July 2023 and is indicated for early symptomatic AD with confirmed amyloid pathology 1
• Donanemab (Kisunla) received traditional FDA approval in July 2024 for the same indication 2, 1
• Aducanumab (Aduhelm) received accelerated approval in June 2021 but is no longer considered first-line therapy due to CMS non-coverage, discontinued development, and lack of full FDA approval 2, 1, 3

Mechanism of Action

• All three antibodies selectively target aggregated forms of amyloid-β (Aβ) rather than non-toxic monomeric forms 4
• They reduce brain Aβ plaques in a dose- and time-dependent manner 5, 6
• Second-generation antibodies (lecanemab, donanemab) demonstrate superior clinical efficacy compared to first-generation agents that targeted monomeric Aβ 4

Patient Selection Criteria

Mandatory Requirements

Clinical Stage:

• Patients must have mild cognitive impairment (MCI) or mild dementia due to AD, not just biomarker positivity 1, 7
• CDR score of 0.5 (MCI) or 1.0 (mild dementia) is required 7
• MoCA score ≤25 or comprehensive neuropsychological battery showing impairment in ≥1 cognitive domain establishes objective cognitive impairment 7
• Cognitively unimpaired individuals with positive biomarkers are explicitly excluded from treatment, even with elevated amyloid or tau markers 7

Biomarker Confirmation:

• Confirmed amyloid pathology through positive amyloid PET imaging, CSF biomarkers, or blood-based biomarkers (plasma p-tau217) 2, 1
• Plasma p-tau217 alone is sufficient biomarker evidence to initiate lecanemab without requiring additional amyloid PET 1
• Amyloid PET quantification using Centiloid scale values above 30 CL corresponds with pathological amyloid amounts 1

Safety Screening:

• Baseline brain MRI (without contrast) is mandatory to screen for contraindications including macrohemorrhages, microhemorrhages, superficial siderosis, vasogenic edema, and significant white matter hyperintensities 1
• Required MRI sequences include DWI, T2 FLAIR, T2* gradient-echo or susceptibility-weighted imaging, preferably on 3T scanner 1

Comparative Efficacy

Clinical Outcomes

• Both lecanemab and donanemab demonstrate approximately 30% slowing of cognitive decline in early AD 1
• Aducanumab showed 22% reduction in cognitive decline (CDR-SB difference of -0.39 vs placebo, 95% CI -0.69 to -0.09, P=0.012) in the EMERGE trial, though the ENGAGE trial failed to meet endpoints 8
• Donanemab shows optimal results in patients with low-medium tau burden, with reduced clinical benefit in high tau burden patients 1

Amyloid Clearance

• Donanemab achieves more rapid amyloid reduction (60-85 Centiloid units) compared to lecanemab 1
• Donanemab allows treatment cessation once amyloid clearance is achieved (below 24.1 CL), whereas lecanemab requires ongoing therapy 1
• All agents demonstrate dose-dependent reduction in amyloid PET standard uptake value ratio scores 6

Tau Pathophysiology Effects

• Donanemab treatment leads to significant reductions in plasma p-tau217 levels, indicating effects beyond just amyloid clearance 1
• Aducanumab also demonstrated reduced plasma p181-tau levels 6

Safety Profile and Monitoring

Amyloid-Related Imaging Abnormalities (ARIA)

ARIA-E (Edema):

• Occurs in 12.6% of lecanemab-treated patients 1
• Aducanumab showed 425/1029 (41%) ARIA events in the 10 mg/kg high-dose group 6
• APOE ε4 carriers are approximately 4 times more likely to experience ARIA-E events by 24 weeks regardless of serum exposure 1

Monitoring Protocol:

• Mandatory MRI monitoring before 5th, 7th, and 14th infusions (approximately weeks 16,24, and 52) 1, 7
• ARIA may require temporary or permanent cessation of therapy and corticosteroid treatment 7

Infrastructure Requirements

• Treatment requires multidisciplinary teams with specialized training in ARIA management 7
• Hub-and-spoke care models are being developed to address specialist shortages and expand access 2, 1
• Enrollment in CMS registry is required for Medicare reimbursement 7

Treatment Administration

Dosing Regimens

• Lecanemab: Biweekly IV infusions (specific dosing per FDA label) 1
• Donanemab: 700mg IV every 4 weeks for 3 doses, then 1400mg every 4 weeks 7
• Treatment duration varies: donanemab can be stopped after amyloid clearance, while lecanemab requires ongoing therapy 1

Clinical Implementation Challenges

Diagnostic Workflow

• Blood-based biomarkers (plasma p-tau217) offer advantages in accessibility, cost, and patient acceptance compared to PET scans or CSF analysis 2, 1
• CMS eliminated the national coverage determination for amyloid PET in October 2023, making it reimbursable for Medicare beneficiaries 2
• Several new CSF assays for amyloid and tau have received FDA clearance 2

Healthcare System Preparedness

• The availability of disease-modifying therapies creates demand that could overwhelm an unprepared healthcare system 2
• Too few specialists are currently available to respond to the number of potential treatment candidates 2
• New models of hub-and-spoke dementia specialist-primary care collaborations are needed to address workforce gaps 2

Access and Equity Considerations

• Virtual or hybrid clinical trials with mobile nursing care can reduce burden on participants and reach underrepresented populations 2
• Tailored practices are needed to improve diversity, inclusion, and equity in access to healthcare resources for people of color and underrepresented populations 2
• Better inclusion of Blacks, Hispanic/Latinos, Asian Americans, Pacific Islanders, and Native Americans in clinical trials is crucial 2

Common Pitfalls to Avoid

Treating Asymptomatic Patients:

• Do not initiate therapy in cognitively unimpaired individuals with positive biomarkers alone, even with elevated amyloid or tau 7
• Patients with subjective cognitive decline without objective impairment should not receive anti-amyloid therapy 7

Inadequate Safety Screening:

• Never initiate therapy without baseline MRI to exclude contraindications 1
• Failure to monitor with serial MRIs during treatment increases risk of undetected ARIA 1, 7

Inappropriate Patient Selection:

• Donanemab shows reduced benefit in patients with high tau burden, making tau stratification important 1
• Treatment in advanced dementia stages is not indicated and lacks evidence 1, 7

Reimbursement Issues:

• Ensure CMS registry enrollment for Medicare patients to secure reimbursement 7
• Aducanumab lacks CMS coverage, making it effectively unavailable despite FDA approval 2, 1