Phase 2 APPLAUDS Trial to Test Mivelsiran in Down Syndrome-Associated Alzheimer Disease

The design of APPLAUDS, the first phase 2 study evaluating an RNA interference (RNAi) therapeutic in people with Down syndrome (DS) and early-stage Alzheimer disease (AD), was presented at the 2026 Alzheimer's Association International Conference (AAIC) in London.¹ The trial is designed to test whether mivelsiran, an intrathecally administered small interfering RNA targeting amyloid precursor protein (APP), can meaningfully reduce amyloid burden and delay disease progression in a population with near-universal genetic predisposition to AD.¹

Led by Michael S. Rafii, MD, PhD, of the Alzheimer's Therapeutic Research Institute at the Keck School of Medicine, University of Southern California, APPLAUDS is a global, randomized, placebo-controlled phase 2 study enrolling cognitively stable adults aged 40 to 55 with early-stage DS-AD confirmed by elevated amyloid burden. The study comprises a 24-month double-blind treatment period and a 12-month open-label extension.

The study comprises a 24-month double-blind treatment period and a 12-month open-label extension. During the double-blind period, a pharmacokinetic/pharmacodynamic cohort will be randomized 1:1:1 to placebo or one of two doses of mivelsiran, after which a second larger cohort will receive placebo or the dose selected based on PK/PD cohort outcomes. All participants will receive mivelsiran in the open-label extension. The primary endpoint is change from baseline in amyloid PET at month 24 while other secondary endpoints include CSF concentrations of sAPPbeta, sAPPalpha, and amyloid-ß42; plasma phosphorylated tau 217 (p-tau217); and the modified Cued Recall Test. Enrollment is expected to begin in 2026 across approximately 30 sites worldwide.

For background, people with DS carry three copies of chromosome 21, which harbors the APP gene. This triplication results in APP overproduction, driving early and rapidly progressing amyloid accumulation, and virtually all individuals with DS develop AD pathology by age 40. Longitudinal studies estimate a lifetime dementia risk exceeding 90% in this population, with prevalence reaching 88% to 100% after age 65, compared to 10% to 15% in the general population. DS-associated AD is the leading cause of death among adults with DS, and it has historically received far less clinical trial attention than sporadic late-onset AD.

Mivelsiran (ALN-APP; Alnylam Pharmaceuticals) uses a C16-conjugated siRNA delivered intrathecally to silence APP mRNA in the CNS, reducing production of APP protein and all downstream cleavage products including amyloid-beta 42 and 40. In the phase 1 single ascending dose study (NCT05231785), 20 patients with early-onset AD were randomized to mivelsiran doses of 25 mg, 50 mg, or 75 mg intrathecally or placebo.

READ MORE: Phase 3 Biomarker Data Shows Valiltramiprosate Reduces Plasma p-Tau217 in APOE4/4 Carriers

Overall, data showed that all adverse events from the study were mild or moderate in severity, with no serious adverse events or deaths. Reductions from baseline in CSF soluble APPalpha and APPbeta were rapid and sustained through month 6 at the 50 mg dose and month 10 at the 75 mg dose, accompanied by sustained reductions in CSF Abeta42 and Abeta40.² Preclinical work in the 5xFAD mouse model showed APP-lowering siRNA prevented behavioral abnormalities through early intervention, and work in iPSC-derived neurons from people with DS showed reduced intracellular AD pathology.¹

APPLAUDS arrives at a pivotal moment for the DS-AD therapeutic landscape. The approval of lecanemab and donanemab for early-stage AD in the general population opened the door conceptually to anti-amyloid approaches in DS, but individuals with DS were excluded from those pivotal trials, leaving critical gaps in safety and efficacy data. Heightened amyloid burden in this population raises specific concerns around amyloid-related imaging abnormalities, a known risk of amyloid-targeted therapies that requires careful monitoring.³

Rafii and colleagues at ATRI are also preparing to initiate the ALADDIN trial, which will investigate donanemab specifically in people with Down syndrome.⁴ "Now someone with Down syndrome can go into one of these specialized research clinics and select from several trials," Rafii previously noted. "That's never been the case in this field."

Mivelsiran's upstream mechanism, reducing APP production before amyloid peptides are generated rather than clearing them after the fact, is conceptually appealing in DS-AD given the chronically elevated APP gene dosage. Whether reducing APP production through RNAi can achieve durable amyloid lowering and translate to cognitive benefit in this population will be the central question APPLAUDS is designed to answer.

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REFERENCES
1. Rafii MS, Ances B, Levin J, et al. Design of APPLAUDS, a phase 2 study of mivelsiran in people with Down syndrome and early-stage Alzheimer's disease. Abstract presented at: Alzheimer's Association International Conference (AAIC); 2026; London, United Kingdom.
2. Cohen S, Farrer M, Sostelly A, et al. Single ascending dose results from an ongoing phase 1 study of mivelsiran (ALN-APP), the first investigational RNA interference therapeutic targeting amyloid precursor protein for Alzheimer's disease. Alzheimers Dement. 2024;20:e084521. doi:10.1002/alz.084521. https://alz-journals.onlinelibrary.wiley.com/doi/abs/10.1002/alz.084521
3. Barroeta I, Levin J, Fortea J, et al. Current advances and unmet needs in Alzheimer's disease trials for individuals with Down syndrome: navigating new therapeutic frontiers. Alzheimers Dement. 2025;21:e70258. doi:10.1002/alz.70258. https://doi.org/10.1002/alz.70258
4. First participant with Down syndrome joins Alzheimer's prevention trial. Medical Xpress. April 11, 2025. Accessed July 13, 2026. https://medicalxpress.com/news/2025-04-syndrome-alzheimer-trial.html