For the first time in the century since Alois Alzheimer described the disease that bears his name, we have two FDA-approved therapies that demonstrably slow its progression. Lecanemab (Leqembi), approved in July 2023, and donanemab (Kisunla), approved in July 2024, both target amyloid-beta plaques — the protein aggregates considered central to Alzheimer's pathology — and both have demonstrated statistically significant slowing of cognitive decline in large Phase III trials. But the two drugs differ in meaningful ways, and navigating those differences has become a central question of Alzheimer's care in 2026.
Mechanism and Dosing
Both antibodies work by binding to aggregated amyloid-beta and triggering microglial-mediated clearance. The differences lie in specificity and dosing schedule:
- Lecanemab (Eisai/Biogen) targets both soluble amyloid protofibrils and insoluble plaques. Dosed as a 10 mg/kg IV infusion every two weeks indefinitely.
- Donanemab (Eli Lilly) targets a modified amyloid form (N3pG amyloid) found specifically in mature plaques. Dosed as a 700 mg or 1400 mg IV infusion every four weeks — and crucially, treatment stops once amyloid is cleared to a predefined threshold, which occurs in a majority of patients within 6–12 months.
Efficacy: How Much Slowing Is Meaningful?
Both trials used the Clinical Dementia Rating Sum of Boxes (CDR-SB) as the primary endpoint:
- CLARITY AD (lecanemab): 27% slowing in CDR-SB progression over 18 months vs placebo.
- TRAILBLAZER-ALZ 2 (donanemab): 35% slowing in CDR-SB in the primary population (low/medium tau) over 18 months. In patients with high tau burden, the benefit narrowed to non-significant — underscoring the importance of tau staging.
Translating these percentages into patient experience: in the lecanemab trial, the drug-placebo difference at 18 months on CDR-SB was approximately 0.45 points on an 18-point scale — statistically clear, clinically modest. Critics argue this represents a difference too small to be perceptible in daily function. Proponents note that early intervention, before significant neuronal loss, is expected to produce larger absolute benefits.
ARIA: The Safety Signal That Defines Patient Selection
Amyloid-Related Imaging Abnormalities (ARIA) — microbleeds and brain edema visible on MRI — are the dominant safety concern with both antibodies. ARIA is more common in APOE ε4 carriers, who are also at highest Alzheimer's risk:
- Lecanemab: ARIA-E (edema) in 12.6% of patients; ARIA-H (microhemorrhage) in 17.3%. Symptomatic ARIA in ~3%.
- Donanemab: ARIA-E in 24.0%; ARIA-H in 31.4%. Three deaths in the trial were attributed to ARIA, though all had confounding factors (concurrent anticoagulation).
In 2026, mandatory pre-treatment amyloid PET or CSF biomarker confirmation and serial MRI monitoring protocols have become standard. Patients on anticoagulants are generally excluded. APOE ε4 homozygotes (approximately 2% of the population, but overrepresented in AD) face the highest ARIA risk and require individualized shared decision-making.
Real-World Implementation Challenges
Two years into the post-approval era, real-world implementation has exposed practical barriers beyond the clinical trial setting:
- Infusion center capacity: biweekly infusions for lecanemab, with required MRI monitoring, have strained neurology infusion center infrastructure at major academic centers.
- Insurance coverage: CMS's National Coverage Determination was revised in 2024 to cover both drugs for Medicare beneficiaries with confirmed amyloid positivity — but prior authorization burden remains significant.
- Tau staging: real-world cohorts include higher proportions of high-tau patients than trials, potentially reducing average benefit.
The Next Generation: Trontinemab and Beyond
Roche's trontinemab, using brain shuttle technology to cross the blood-brain barrier more efficiently, achieved 71% amyloid clearance at 6 months in Phase I/II — potentially enabling subcutaneous dosing. If Phase III confirms efficacy, it could shift the entire paradigm toward more accessible treatment.
Conclusion
Lecanemab and donanemab represent a genuine inflection point in Alzheimer's disease — the first drugs that alter the disease's course rather than merely managing symptoms. The choice between them increasingly rests on patient APOE status, tau burden, anticoagulation status, and logistical preference for indefinite vs. time-limited treatment. For the first time, neurologists, patients, and families have real options to discuss. Healthcare facilities can find relevant diagnostic equipment in our catalog.
