Lecanemab vs Donanemab in 2026: A Side-by-Side Update

Summary: As of 2026, both lecanemab (Leqembi) and donanemab (Kisunla) continue to show growing clinical benefit over time. The TRAILBLAZER-ALZ 6 study demonstrated that a modified titration of donanemab reduces ARIA-E (brain swelling) from 24 percent to 14 percent at 24 weeks, and from 57 percent to 19 percent in APOE4 homozygotes (the highest-risk genetic group). Lecanemab's 48-month CLARITY AD open-label extension shows continuing benefit accumulation, extending time spent in early disease by approximately 10-13 months versus matched untreated controls.

Both lecanemab (Leqembi) and donanemab (Kisunla) — the two FDA-approved disease-modifying therapies for early Alzheimer's disease — have accumulated meaningful new data since their initial approvals. As of the American Psychiatric Association 2026 Annual Meeting in May, the picture has sharpened in several specific ways: longer-term efficacy data, refined understanding of side effect risks (particularly ARIA), and a notable finding that a modified titration of donanemab can substantially reduce brain swelling without sacrificing efficacy.

This article is an update to our earlier lecanemab and donanemab patient guide. If you haven't read that one, it covers the basics — what these drugs are, who qualifies, what the infusion experience is like. This article goes deeper into the head-to-head comparison and what the most recent data adds.

Content reflects the discussion of biological advances in Alzheimer's disease at the APA 2026 Annual Meeting along with the broader published literature.

The big picture in 2026

Both medications are now established as the first disease-modifying therapies for Alzheimer's disease. After decades of trials that produced negative or marginal results, lecanemab (FDA approved July 2023) and donanemab (FDA approved July 2024) represent a meaningful inflection — modest but real clinical benefit by interfering with the disease's underlying biology.

Both drugs target the amyloid-beta protein that accumulates in plaques in Alzheimer's brains. They are monoclonal antibodies — laboratory-produced proteins that bind to amyloid and signal the immune system to clear it. The result is measurable clearance of amyloid plaques on PET imaging and, more importantly, modest but statistically significant slowing of cognitive decline.

The two-year story since approval can be summarized:

• Both drugs work — the slowing of decline is real and confirmed in independent extension data
• Both carry meaningful side effects, particularly ARIA (amyloid-related imaging abnormalities)
• APOE4 genetic status matters substantially for the risk-benefit calculation
• Long-term data shows growing benefit — treatment effects continue to accumulate over time
• Refined dosing protocols can reduce side effects without sacrificing efficacy

The clinical question is no longer "do these drugs work?" but "which patients should receive which drug, when, and how should we manage the risks?"

The updated efficacy data

Donanemab — TRAILBLAZER-ALZ 2 long-term

The original TRAILBLAZER-ALZ 2 trial (1,800 participants) demonstrated:

• 35% slowing of cognitive decline on CDR-SB in patients with intermediate tau levels
• 22.3% slowing in the combined population (low + intermediate tau)
• Reduction in p-tau217, a blood biomarker of Alzheimer's pathology

The newer long-term extension data, which has continued to follow patients well beyond the original 18-month trial period, shows a striking pattern: the treatment difference continues to grow over time.

In the early-start participants who met treatment completion criteria, the cognitive difference between treated patients and a matched control cohort from ADNI (Alzheimer's Disease Neuroimaging Initiative) widened progressively:

• 18 months: -0.6 CDR-SB difference (95% CI -0.8 to -0.3)
• 24 months: -1.1 (95% CI -1.5 to -0.7)
• 36 months: -1.3 (95% CI -1.9 to -0.7)

This is two years beyond treatment completion — patients who received donanemab continued to fare better than matched controls long after the medication was stopped. The interpretation: by clearing amyloid, donanemab appears to put the underlying disease process on a slower trajectory, with effects persisting even after treatment.

Lecanemab — Clarity AD open-label extension

The Clarity AD OLE (open-label extension) followed patients beyond the initial 18-month placebo-controlled trial. As of the data through 48 months presented at APA 2026:

• Lecanemab-treated patients continued to accumulate benefit over time
• The gap between treated patients and matched control cohorts (ADNI and BioFINDER databases) continued to widen through 48 months
• Lecanemab extends time spent in early disease by 10-13 months — the time it takes a treated patient to reach a CDR-SB score equivalent to where untreated patients reached at 18 months

In practical terms, this means a patient on lecanemab spends an additional ~10-13 months in mild cognitive impairment or mild dementia before progressing to moderate stages — extending the window of independent function. For families, that's roughly an extra year of higher functional status, which is meaningful.

What these long-term findings mean

Both drugs show a pattern that's encouraging: benefit continues to grow rather than plateau or reverse. This is consistent with the underlying biological theory — clearing amyloid early in the disease process puts the trajectory of the disease on a slower path that persists even after active treatment. It also raises the importance of starting these treatments as early as possible in the disease course, while there's still substantial functional capacity to preserve.

The TRAILBLAZER-ALZ 6 modified titration story

One of the most clinically significant findings discussed at APA 2026 was the TRAILBLAZER-ALZ 6 study, which tested whether a modified titration of donanemab could reduce the rate of ARIA-E (amyloid-related imaging abnormalities with edema, or brain swelling).

ARIA is the most clinically significant side effect of both medications. ARIA-E is brain swelling that's usually asymptomatic but can sometimes cause headache, confusion, seizures, or — rarely — more serious complications. ARIA-H is small areas of bleeding in the brain. Both are detected on MRI monitoring. The risk is substantially higher in patients with APOE4 (a genetic risk factor for Alzheimer's disease).

TRAILBLAZER-ALZ 6 tested a slower, more gradual titration schedule against the standard donanemab dosing. The primary endpoint was the proportion of patients with any occurrence of ARIA-E by week 24.

Results:

• ARIA-E rate: 14% with modified titration vs 24% with standard dosing — 41% lower relative risk
• APOE4 homozygotes specifically: 19% vs 57% — 67% lower relative risk in the highest-risk subgroup
• Infusion-related reactions: similar between arms — modified titration didn't compromise tolerability
• Efficacy: amyloid clearance was preserved

This is a significant finding. For APOE4 homozygous patients — the group at highest ARIA risk and where many clinicians have been hesitant to offer donanemab — modified titration substantially closes the safety gap. It also raises the possibility that similar approaches could improve the safety profile of lecanemab (studies are underway).

For patients currently considering donanemab, asking the prescribing clinician about whether modified titration is being used is a reasonable conversation.

Comparing ARIA rates between the two drugs

ARIA rates from the pivotal Phase 3 trials, stratified by APOE4 status:

Lecanemab (CLARITY AD)

| APOE4 Status | ARIA-E | ARIA-H | |---|---|---| | Non-carriers (no ε4) | 5.4% | 11.9% | | Heterozygotes (one ε4) | 10.9% | 14% | | Homozygotes (two ε4) | 32.6% | 39% |

Overall ARIA rate: 21.3%

Donanemab (TRAILBLAZER-ALZ 2, standard dosing)

| APOE4 Status | ARIA-E | ARIA-H | |---|---|---| | Non-carriers (no ε4) | 15.7% | 18.8% | | Heterozygotes (one ε4) | 22.8% | 32.3% | | Homozygotes (two ε4) | 40.6% | 50.3% |

Overall ARIA rate: 36.8%

Key takeaways from these numbers

• APOE4 status dramatically affects ARIA risk for both drugs — both ARIA-E and ARIA-H rates more than double from non-carriers to homozygotes
• Lecanemab has lower ARIA rates overall, particularly in non-carriers and heterozygotes
• Donanemab modified titration substantially narrows the gap in homozygotes (57% → 19% for ARIA-E in that group)
• Most ARIA is mild and asymptomatic — detected on MRI monitoring and managed by temporary treatment hold, with most patients able to resume therapy
• Symptomatic ARIA (causing headache, confusion, or other clinical symptoms) occurs in approximately 5% of patients across both drugs

Risk factors beyond APOE4

Additional factors that increase ARIA risk:

• Anticoagulation (blood thinners) increases ARIA-H risk specifically
• Antiplatelet agents (aspirin, clopidogrel) — modest increased risk
• Pre-existing cerebral amyloid angiopathy — significantly increased risk
• Prior microhemorrhages on baseline MRI — increased risk

These factors should be discussed with the treating clinician before starting either medication.

Side effects beyond ARIA

Other adverse events from the pivotal trials (drug vs placebo):

Lecanemab

• Headache: 11.0% vs 8.1%
• Falls: 10.4% vs 9.6%
• Infusion-related reactions: 26.4% vs 7.4%

Donanemab

• Headache: 14.0% vs 9.8%
• Falls: 13.4% vs 12.6%
• Infusion-related reactions: 8.7% vs 0.5%

Infusion reactions in context

Lecanemab has a notably higher rate of infusion reactions (26.4%), though most are mild to moderate. They typically occur during the first two infusions, resolve within 24 hours, and can usually be managed with acetaminophen or diphenhydramine. Significant reactions may require oral steroids; severe reactions are uncommon but can require treatment discontinuation.

Donanemab has lower infusion reaction rates, perhaps related to less frequent dosing (every 4 weeks vs every 2 weeks) or to differences in the antibody itself.

Head-to-head feature comparison

| Feature | Lecanemab (Leqembi) | Donanemab (Kisunla) | |---|---|---| | Target | Amyloid protofibrils | Deposited amyloid plaques | | Dosing frequency | Every 2 weeks | Every 4 weeks | | Duration | Ongoing, potential maintenance dosing | Stop when amyloid levels minimal (often 12-18 months) | | Annual cost | ~$26,000 | ~$32,000 | | Route | IV (subcutaneous formulation in development) | IV | | Overall ARIA rate | 21.3% | 36.8% (standard) / lower with modified titration | | Infusion reaction rate | 26.4% | 8.7% | | Clearance of amyloid | Yes, demonstrated on PET | Yes, demonstrated on PET | | Efficacy | ~27-30% slowing of decline at 18 months; benefit grows through 48 months | ~22-35% slowing at 18 months; benefit grows 2 years beyond treatment | | Long-term extension data | 48 months published | 36+ months published |

Thinking through the decision

For a patient with confirmed early Alzheimer's disease who has been determined to be a candidate for amyloid-targeting therapy, the choice between lecanemab and donanemab depends on several factors.

Factors that might favor lecanemab

• APOE4 carrier (especially homozygote) — lower ARIA rates overall, particularly important in the highest-risk group
• Patient prefers ongoing treatment rather than a finite course
• Subcutaneous formulation becomes available — would offer significant convenience advantage
• More established long-term data (longer follow-up published)
• Lower cost (~$26k vs $32k annually)

Factors that might favor donanemab

• Patient or family prefers a finite treatment course — donanemab is designed to be stopped when amyloid is cleared
• Less frequent infusions (every 4 weeks vs every 2 weeks) — significant convenience factor for patients and families
• Lower infusion reaction rate
• TRAILBLAZER-ALZ 6 modified titration can be used to reduce ARIA risk, particularly important for APOE4 homozygotes
• Persistent benefit two years post-treatment demonstrated in extension data

Factors that affect both

• Brain MRI findings — significant microhemorrhages, cortical superficial siderosis, or evidence of significant cerebral amyloid angiopathy may make either drug inappropriate
• Anticoagulation status — increases ARIA-H risk for both
• Patient's stage — both work best in mild cognitive impairment or mild dementia; moderate-to-severe disease is outside the approved indication
• APOE4 genotype testing is essentially required to inform the decision adequately
• Access to required MRI monitoring — both require regular MRIs (4-7 over the first year typically), which has practical implications

Who is NOT a candidate

Both medications have specific contraindications and exclusions:

• Moderate or severe Alzheimer's disease — outside approved indication
• Non-Alzheimer's dementia (Lewy body, frontotemporal, vascular without significant Alzheimer's contribution) — not indicated
• No confirmed amyloid pathology — typically requires amyloid PET or CSF biomarkers
• >4 microhemorrhages on baseline MRI (specific thresholds vary)
• Cortical superficial siderosis on baseline imaging
• Significant prior intracerebral hemorrhage or large stroke
• Inability to undergo regular MRI monitoring
• Active malignancy or other significant medical comorbidity that limits life expectancy
• Pregnancy (rare in this age group but exclusion exists)

What this means for early diagnosis

The increasing efficacy of these medications, particularly with longer-term data showing growing benefit, makes early diagnosis of Alzheimer's disease more important than ever. The benefits accumulate over years of treatment and are most pronounced when treatment starts early — at the mild cognitive impairment stage or early dementia, before substantial functional capacity has been lost.

This represents a significant change in the value proposition of early dementia evaluation. For decades, the argument for early diagnosis was largely about planning, family communication, and ruling out reversible causes. Now there are specific medical interventions whose effectiveness depends on starting early.

If you or a family member has noticed cognitive changes, the time to seek evaluation is when you first notice the changes — not when they've become unmistakable. Our dementia diagnosis appointment post walks through what to expect.

The cost question

Both medications are expensive in absolute terms:

• Lecanemab: ~$26,000 per year
• Donanemab: ~$32,000 per year (though shorter treatment courses possible)
• Plus infusion center costs, MRI monitoring costs, and clinician visit costs

Medicare typically covers these medications with the patient responsible for the standard 20% Part B coinsurance. For a Medicare beneficiary with no supplemental coverage, this could be approximately $5,000-7,000 out-of-pocket per year for the drug alone, plus the patient's share of infusion and monitoring costs. With Medicare supplement (Medigap) plans, out-of-pocket costs may be lower.

Most major commercial insurance plans now cover these medications, though prior authorization is typically required.

Patient assistance programs from the manufacturers (Eisai for lecanemab, Eli Lilly for donanemab) may help patients with limited resources or significant out-of-pocket exposure. A specialty memory clinic's social worker or financial counselor can help navigate.

A note on prevention trials

The same medications are being studied for primary prevention of Alzheimer's disease — meaning use in cognitively normal individuals with biomarker evidence of amyloid accumulation, before symptoms develop. Trials are ongoing for both lecanemab (the AHEAD 3-45 study) and donanemab (TRAILBLAZER-ALZ 3). Additional anti-amyloid antibodies in development include remternetug.

If primary prevention trials succeed, the implications would be substantial: identifying patients with amyloid accumulation before symptoms (via blood biomarkers or PET imaging) and treating early to prevent or delay clinical Alzheimer's disease. This is the new frontier in Alzheimer's prevention.

Tau-targeting therapies are also in development, with the potential to complement amyloid-targeted treatment — addressing both major proteins implicated in Alzheimer's pathology.

What questions to ask the clinician

If you or a family member is considering one of these medications, productive questions include:

• Is the Alzheimer's diagnosis definitively confirmed, including with amyloid biomarker testing?
• What is my APOE4 status and how does it affect my risk profile?
• Which medication is recommended for my situation and why?
• For donanemab: are you using the modified titration approach?
• What does my baseline MRI show? Are there any findings that affect the decision?
• What's the schedule? Visits, infusions, MRIs, follow-up
• What ARIA monitoring plan will we use?
• What symptoms should prompt immediate contact?
• How will we assess whether the medication is helping?
• What's the plan for stopping (donanemab) or continuing (lecanemab) treatment?
• What does insurance cover in my specific case?

Closing

The Alzheimer's disease-modifying landscape in 2026 is meaningfully different from 2023. Two effective medications now have multi-year clinical experience. Long-term data confirms growing benefit over time. Refined dosing protocols are reducing the most concerning side effects. APOE4 genotyping is becoming routine. Early diagnosis is more clinically actionable than at any previous point in the disease's history.

The medications are not cures. They slow the disease by a meaningful but modest amount, and they carry real risks. But they represent a turning point in the field — and for families navigating an Alzheimer's diagnosis in 2026, the question of whether one of these treatments is appropriate deserves serious consideration with a specialist familiar with the current evidence.

Related reading

• Lecanemab and Donanemab: A Patient's Guide — the original primer
• Alzheimer's Disease: A Complete Guide
• Dementia Medications: What Actually Helps, Explained
• Mild Cognitive Impairment (MCI): Is It Dementia?
• Dementia Diagnosis Appointment: What to Expect
• Is Dementia Hereditary? Family Risk, Explained

References

• Anderson AA, Aga VM. Biological Advances in Alzheimer's Disease. Annual Meeting of the American Psychiatric Association, San Francisco, May 20, 2026.
• van Dyck CH, Swanson CJ, Aisen P, et al. Lecanemab in early Alzheimer's disease. New England Journal of Medicine. 2023;388(1):9-21. (CLARITY AD)
• Sims JR, Zimmer JA, Evans CD, et al. Donanemab in early symptomatic Alzheimer disease: the TRAILBLAZER-ALZ 2 randomized clinical trial. JAMA. 2023;330(6):512-527.
• TRAILBLAZER-ALZ 6 study findings on modified titration of donanemab. (Eli Lilly clinical communications, 2024-2025).
• Clarity AD open-label extension 48-month data presented at APA 2026.
• Cummings J, Apostolova L, Rabinovici GD, et al. Lecanemab: Appropriate Use Recommendations. Journal of Prevention of Alzheimer's Disease. 2023;10(3):362-377.
• Centers for Medicare & Medicaid Services. National Coverage Determination — Monoclonal Antibodies Directed Against Amyloid.

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Disclosure: Dr. Shimada is the founder of Tokei Health. This article is informational and is not a substitute for individual medical advice from your own clinician. The data summary here reflects content presented by Drs. Allan A. Anderson and Vimal M. Aga at the American Psychiatric Association 2026 Annual Meeting, with additional context from cited published sources. Specific treatment decisions require evaluation by a clinician familiar with the patient's situation.