What is the newest most promising disease‑modifying therapy for early Alzheimer’s (mild cognitive impairment or mild dementia) with confirmed amyloid pathology, and what are its dosing schedule and monitoring requirements?

Newest and Most Promising Treatment for Alzheimer's Disease

Donanemab (Kisunla) represents the newest FDA-approved disease-modifying therapy for early Alzheimer's disease, receiving traditional approval in July 2024, and offers a unique advantage over lecanemab through potential treatment cessation once amyloid clearance is achieved. 1, 2

Currently Approved Anti-Amyloid Therapies

First-Line Treatment Options

• Lecanemab (Leqembi) received full FDA approval in July 2023 and is administered as 10 mg/kg IV infusion every 2 weeks indefinitely, requiring ongoing therapy without a defined stopping point 1, 3

• Donanemab (Kisunla) received traditional FDA approval in June 2024 and is dosed as 700 mg IV every 4 weeks for 3 doses, then 1400 mg every 4 weeks, with the distinctive feature of treatment cessation once amyloid plaques are reduced to minimal levels (below 24.1 Centiloids on amyloid PET) 1, 2

• Aducanumab (Aduhelm) has been discontinued from commercial sale and is no longer a treatment option due to CMS declining payment coverage 1

Comparative Efficacy

Both lecanemab and donanemab demonstrate approximately 30% slowing of cognitive decline over 18-month trials in early Alzheimer's disease, but donanemab achieves more rapid amyloid reduction (60-85 Centiloid units) compared to lecanemab's similar but potentially slower trajectory 1, 4, 5

Patient Selection Criteria

Mandatory Requirements

• Clinical stage: Mild cognitive impairment (MCI) or mild dementia due to Alzheimer's disease—NOT cognitively unimpaired individuals, even with positive biomarkers 1, 6

• Biomarker confirmation: Documented amyloid pathology via amyloid PET scan (>30 Centiloids), CSF biomarkers (abnormal Aβ42/40 ratio with elevated p-tau), or increasingly accepted blood-based biomarkers (plasma p-tau217) 7, 1

• Objective cognitive impairment: MoCA score ≤25 or comprehensive neuropsychological battery showing impairment in ≥1 cognitive domain 6

• Disease severity: CDR score of 0.5 (MCI) or 1.0 (mild dementia) 6

Critical Exclusions

• Cognitively unimpaired individuals in the preclinical stage should NOT receive anti-amyloid therapy, regardless of positive biomarkers 1, 6

• Patients with suspected Lewy body dementia are excluded 1

• Subjective cognitive decline without elevated risk factors (age, APOE genotype, family history) is inappropriate for treatment 6

Dosing and Administration

Donanemab Protocol

• Initial dosing: 700 mg IV infusion over 30 minutes every 4 weeks for first 3 doses 2

• Maintenance dosing: 1400 mg IV every 4 weeks thereafter 2

• Treatment cessation: Consider stopping when amyloid plaques reach minimal levels on PET imaging (below 24.1 Centiloids), with off-treatment increases averaging only 2.80 Centiloid/year 1, 2

Lecanemab Protocol

• Standard dosing: 10 mg/kg IV infusion every 2 weeks indefinitely 3, 8

• No defined stopping point: Requires ongoing therapy without treatment cessation criteria 1

Mandatory Safety Monitoring

Pre-Treatment Requirements

• Baseline brain MRI (without contrast) is mandatory to screen for contraindications including macrohemorrhages, microhemorrhages (>4), superficial siderosis, vasogenic edema, and significant white matter hyperintensities 1, 6

• MRI sequences required: DWI, T2 FLAIR, T2* gradient-echo or susceptibility-weighted imaging, preferably on 3T scanner 1

• APOE ε4 genotyping should be performed to inform ARIA risk—homozygotes have 4 times higher risk of ARIA-E by 24 weeks compared to non-carriers 1, 9

During-Treatment MRI Monitoring

For Donanemab:

• Obtain MRI prior to 2nd, 3rd, 4th, and 7th infusions (approximately weeks 16,24, and 52) 6, 2

For Lecanemab:

• Obtain MRI prior to 5th, 7th, and 14th infusions 1

ARIA Management

• ARIA-E incidence: 12.6% with lecanemab, higher with donanemab in APOE ε4 carriers 1, 8

• ARIA-H (microhemorrhages): Risk increased in patients with pre-existing microhemorrhages or superficial siderosis 2

• Symptomatic ARIA: Can mimic ischemic stroke with focal neurologic deficits; may require temporary or permanent treatment cessation and corticosteroid therapy 6, 2

• Anticoagulation: Patients requiring anticoagulants should NOT receive these therapies due to increased hemorrhage risk 9

Implementation Requirements

Infrastructure Needs

• Multidisciplinary teams with specialized training in ARIA detection and management are mandatory for safe administration 1, 6

• Hub-and-spoke care models are being developed to address specialist shortages and enable broader access 1

• CMS registry enrollment is required for Medicare reimbursement of both lecanemab and donanemab 1, 6

Biomarker Accessibility

• Blood-based biomarkers (particularly plasma p-tau217) demonstrate high accuracy (AUC 0.92-0.98) for predicting amyloid status and are increasingly accepted as sufficient evidence to initiate therapy without requiring amyloid PET 7, 1

• Blood biomarkers offer advantages in accessibility, cost, and patient acceptance compared to PET or CSF testing 7, 1

Key Clinical Advantages of Donanemab

• Treatment cessation capability: Unlike lecanemab's indefinite dosing, donanemab allows stopping therapy once amyloid clearance is achieved, reducing long-term treatment burden and cost 1, 5

• Rapid amyloid reduction: Achieves faster plaque clearance than lecanemab, potentially shortening treatment duration 1

• Tau stratification: Optimal results in patients with low-medium tau burden, making patient selection more precise 1

Critical Pitfalls to Avoid

• Do NOT treat biomarker-positive but cognitively normal individuals—this is explicitly inappropriate and not FDA-approved 1, 6

• Do NOT initiate therapy without baseline MRI—contraindications must be ruled out before first infusion 1, 2

• Do NOT continue therapy in patients on anticoagulation—hemorrhage risk is substantially elevated 9

• Do NOT skip APOE ε4 genotyping—this information is essential for informed consent discussions about ARIA risk 1, 9

• Do NOT assume all early AD patients benefit equally—donanemab shows reduced benefit in high tau burden patients, requiring tau PET stratification for optimal outcomes 1