Alzheimer's Disease Clinical Trials 2026: Leqembi, Kisunla & What's Next

The Alzheimer's field in 2026 looks almost unrecognizable compared to five years ago — not because the disease is solved, but because for the first time in history there are approved drugs that actually slow its progression rather than just managing symptoms. Lecanemab and donanemab's approvals changed what the research agenda is. The question is no longer "can anti-amyloid antibodies clear plaques?" — that was answered definitively. The questions now are: who benefits most, what do we do after clearing amyloid, can tau targeting provide additional benefit on top of amyloid clearance, and — most ambitiously — can we intervene before symptoms ever appear? That last question is where some of the most consequential science of the decade is being conducted right now.

Lecanemab and Donanemab: What the Phase 3 Data Actually Showed

Both lecanemab and donanemab are anti-amyloid-beta antibodies that clear amyloid plaques from the brain — the protein aggregates that accumulate 15–20 years before clinical symptoms appear. They target different forms of amyloid: lecanemab preferentially binds protofibrils (soluble amyloid aggregates), while donanemab targets pyroglutamate-modified amyloid-beta deposited in established plaques. This mechanistic difference may explain subtly different efficacy and ARIA profiles, though no head-to-head comparison exists.

In CLARITY AD (NCT03887455), lecanemab (10mg/kg IV biweekly) versus placebo over 18 months in 1,795 patients with early AD (MCI or mild dementia, confirmed amyloid by PET or CSF, CDR 0.5–1.0) showed a 27% slower rate of decline on the CDR-SB primary endpoint (mean difference −0.45 points, 95% CI −0.67 to −0.23, p<0.001). Amyloid PET showed near-complete plaque clearance at 18 months (mean reduction from 77 centiloids to 25 centiloids). ARIA occurred in 21.3% of lecanemab patients overall, with symptomatic ARIA in 2.8% — predominantly asymptomatic microbleeds and sulcal effusions on MRI. APOE4 carriers have higher ARIA rates and require more intensive MRI monitoring.

TRAILBLAZER-ALZ 2 (NCT04437511) showed donanemab (700mg/1400mg IV monthly) slowing CDR-SB decline by 35% in the low-medium tau population (p<0.001) and 22% in the combined population including high-tau patients. An important feature: donanemab was administered until amyloid clearance to near-zero was achieved, at which point the drug was stopped — a "treat to target" approach. 47% of participants had amyloid cleared and dosing suspended by 52 weeks. The implication is potentially time-limited treatment rather than indefinite dosing — which has significant quality-of-life implications if the efficacy persists after treatment cessation. Longer-term follow-up will be critical.

Active Trials in 2026: What's Being Studied Now

Subcutaneous lecanemab (AHEAD 3-45 Extension / New Phase 3)

Biweekly IV infusions are burdensome — requiring clinic visits every two weeks at an infusion center. Eisai is conducting a Phase 3 trial of a subcutaneous autoinjector formulation that patients can self-administer at home after supervised training. If the subcutaneous formulation achieves equivalent amyloid clearance and PK parameters to IV lecanemab, it could dramatically expand real-world uptake, which has been limited by infusion center capacity constraints. Phase 3 PK/PD bridging data expected in 2026.

Remternetug: Next-Generation Anti-Amyloid

Remternetug (LY3372993, Eli Lilly) is an anti-amyloid antibody with a different epitope than donanemab, designed for faster plaque clearance and potentially lower ARIA risk through modified Fc engineering. Phase 3 trials (TRAILBLAZER-ALZ 5 and 6) are enrolling patients with early symptomatic AD. If remternetug achieves donanemab-comparable amyloid clearance with lower ARIA rates, it would be a meaningful clinical advance — ARIA management is currently one of the major practical limitations of approved therapies.

Tau-Targeting Therapies

Tau neurofibrillary tangles correlate more closely with neurodegeneration and symptom severity than amyloid plaques — tau pathology spreads from the entorhinal cortex in a stereotyped pattern (Braak staging) that tracks with disease progression. Anti-tau antibodies semorinemab (Genentech, LAURIET Phase 2/3), zagotenemab (Eli Lilly), and tilavonemab are in Phase 2/3. The unresolved question: whether tau-targeting after amyloid clearance provides additive benefit or whether clearing amyloid reduces tau progression sufficiently. A lecanemab + semorinemab combination trial is being designed specifically to test this.

GLP-1 Trials for Alzheimer's

The EVOKE trial (NCT04777396, n=1,840) tested oral semaglutide 14mg in early Alzheimer's versus placebo — a 104-week randomized trial. The primary endpoint (CDR-SB change) was not met in the primary analysis. However, prespecified subgroup analyses suggested signals in specific populations, and mechanistic interest in GLP-1 receptors' neuroprotective effects (reducing neuroinflammation, promoting neurogenesis, reducing tau phosphorylation in animal models) remains high. Multiple follow-on trials with injectable semaglutide at higher doses and different biomarker-selected populations are recruiting in 2026.

AHEAD 3-45: Prevention in Cognitively Normal Adults

AHEAD 3-45 (NCT04468659) is testing lecanemab in cognitively normal adults aged 55–80 with intermediate (A3) or elevated (A45) amyloid on PET — people who have biomarker evidence of the disease process but no cognitive symptoms. The trial has two sub-studies with different amyloid thresholds and different lecanemab doses. The primary endpoint is change in amyloid PET over 4 years (not cognitive decline — that would require far longer follow-up). If lecanemab significantly reduces amyloid accumulation in asymptomatic individuals and this translates to delayed cognitive decline in long-term follow-up, it would establish the case for true primary prevention — treating Alzheimer's pathology the way we treat cardiovascular risk before a heart attack occurs.

Who Qualifies for Current Trials

Eligibility requirements for anti-amyloid trials are specific and require biomarker confirmation before screening. Understanding these requirements before approaching a trial saves considerable time:

• Treatment trials (Leqembi-type, Phase 3): Mild cognitive impairment or mild dementia due to AD; confirmed amyloid pathology via PET scan or CSF Abeta42/tau ratio; CDR (Clinical Dementia Rating) 0.5 or 1; MMSE ≥22 typically. APOE4 homozygotes may be excluded from some trials or require more intensive ARIA monitoring.
• Prevention trials (AHEAD-type): Cognitively normal (CDR 0); age typically 55–80; elevated amyloid on amyloid PET or blood p-tau217; APOE4 carriers often prioritized. These are the most inclusive in terms of cognitive status but require biomarker confirmation that most people don't have without a specific research workup.
• Tau trials: Typically target moderate Alzheimer's (CDR 1–2) where tau pathology is more prominent and potentially more tractable; amyloid confirmation often still required.

APOE genotyping is frequently part of trial screening. Blood-based biomarkers — particularly p-tau217 (measured by Roche, Lilly, Fujirebio assays) — are increasingly accepted as amyloid confirmation alternatives to PET in some trials, substantially reducing the cost and accessibility barriers to biomarker confirmation.

Accessing Alzheimer's Trials

The Alzheimer's Association Trial Match (alz.org/trialmatch) is the most accessible patient-facing matching service and handles the complexity of translating inclusion/exclusion criteria into plain-language eligibility questions. The Alzheimer's Prevention Registry (endalznow.org) maintains a registry for prevention-eligible individuals and sends trial alerts based on profile. Academic medical centers with dedicated Memory Disorder Clinics — Banner Alzheimer's Institute (Phoenix), Mayo Clinic (Rochester/Jacksonville/Phoenix), UCSF Memory and Aging Center, Johns Hopkins Memory and Alzheimer's Treatment Center — run the broadest portfolios and often have access to trials not yet widely publicized.

One practical note: the pre-screening workup for most anti-amyloid trials involves an MMSE or MoCA cognitive assessment, APOE genotyping, and amyloid biomarker confirmation. This multi-step process typically takes 4–8 weeks before enrollment decision. Starting the workup before the specific trial you want to enter is available often saves critical time.

Key Takeaways

• Lecanemab (CLARITY AD) showed 27% slower CDR-SB decline over 18 months; donanemab (TRAILBLAZER-ALZ 2) showed 35% in the low-medium tau population. These are the first disease-modifying approvals in Alzheimer's history.
• ARIA (amyloid-related imaging abnormalities) affects ~21% of lecanemab patients and requires regular MRI monitoring; APOE4 status significantly influences ARIA risk and monitoring requirements.
• Prevention trials (AHEAD 3-45) now enroll cognitively normal adults with biomarker evidence of amyloid — you don't need cognitive symptoms to be eligible for many Alzheimer's studies.
• Blood p-tau217 testing is increasingly accepted as an amyloid confirmation alternative to PET in some trials — ask your neurologist whether blood-based biomarker testing is available at their center.
• Subcutaneous lecanemab and next-generation agents (remternetug) in Phase 3 may reduce the IV infusion burden and ARIA rates that currently limit real-world uptake of approved treatments.

Actionable Steps

1. Register with the Alzheimer's Prevention Registry (endalznow.org) to receive alerts for prevention trials matching your profile.
2. Request APOE genotyping from your neurologist — knowing your status (particularly APOE4 carrier status) informs eligibility and ARIA risk monitoring requirements.
3. Ask about amyloid biomarker testing — blood p-tau217 or amyloid PET is required for most trials and establishes your eligibility before you approach a research team.
4. Contact the research coordinator at the nearest academic Medical Center with a Memory Disorder Clinic — they often have access to early-enrollment studies not yet broadly visible on ClinicalTrials.gov.
5. Search ClinicalMetric for "Alzheimer" or "MCI" filtered to Phase 3, Recruiting — these represent the most advanced interventions currently available to new enrollees.