Roche Unveils PrevenTRON, a Phase 3 Prevention Trial of Trontinemab in Cognitively Unimpaired Individuals at High Risk of Alzheimer Decline

Roche presented the design of PrevenTRON, a phase 3 trial evaluating trontinemab in cognitively unimpaired individuals at high risk of progression to symptomatic Alzheimer's disease (AD), at the 2026 Alzheimer's Association International Conference (AAIC) in London.¹ The announcement extends Roche's trontinemab clinical program beyond its two pivotal early symptomatic studies (TRONTIER 1 and 2) into the preclinical prevention space, marking one of the most ambitious efforts yet to intervene before cognitive symptoms emerge.

Trontinemab is a bispecific 2+1 BrainShuttle monoclonal antibody engineered to leverage transferrin receptor 1-mediated transport across the blood-brain barrier (BBB), enabling efficient CNS delivery at substantially lower systemic doses than conventional anti-amyloid antibodies. It is a reformulation of gantenerumab, Roche's prior anti-amyloid antibody, redesigned using the BrainShuttle platform to improve CNS penetrance.

BRAINSHUTTLE Phase 1/2 Data

Presented by Janice Smith, PhD, global development lead at Roche, the PrevenTRON design is supported by a robust and growing body of evidence from the ongoing BRAINSHUTTLE AD phase 1b/2a study (NCT04639050). In the 3.6 mg/kg cohort, trontinemab reduced amyloid levels below the 24-centiloid positivity threshold in 91% of participants (n = 49/54) after 28 weeks of treatment; 72% (n = 39/54) achieved deep clearance below 11 centiloids. These reductions were accompanied by early and significant changes in CSF and plasma biomarkers of AD pathology, including total tau, phosphorylated tau 181, phosphorylated tau 217, and neurogranin.²

Amyloid-related imaging abnormalities with edema (ARIA-E) continued to be observed in fewer than 5% of participants across the 1.8 and 3.6 mg/kg dose cohorts combined (n = 4/149), with blinded data confirming this rate across the expanded program.² This ARIA-E rate is substantially lower than what has been observed with the approved anti-amyloid antibodies: 13% for lecanemab and 24% for donanemab, a profile the investigators have cited as a potential differentiating advantage for trontinemab.

At AAIC 2026, Roche presented new long-term safety, amyloid removal, and biomarker data from the BRAINSHUTTLE AD open-label extension, which also informed the dosing regimen selected for the TRONTIER and PrevenTRON trials.¹

PrevenTRON Trial Design

PrevenTRON is a randomized, multicenter, double-blind, placebo-controlled phase 3 study targeting approximately 1,600 cognitively unimpaired participants at high risk of progression to symptomatic AD.¹ Eligible participants must be aged 55 to 80 years, cognitively and functionally unimpaired (Clinical Dementia Rating-Global Score of 0, Mini-Mental State Examination of 27 or above with educational adjustment), and have confirmed elevated plasma phosphorylated tau 217 (p-tau217).

The dosing regimen follows a two-phase approach. During a 24-week induction phase, participants receive trontinemab 7 times at 3.6 mg/kg every 4 weeks, intended to achieve rapid and robust amyloid clearance. This is followed by a lower-frequency maintenance phase designed to sustain amyloid control while reducing participant burden. The primary endpoint is time to clinical progression, defined as a confirmed Clinical Dementia Rating-Global Score greater than 0. Secondary endpoints include the Cognitive Function Instrument, Logical Memory, activities of daily living measures, and longitudinal amyloid PET in a subset of participants. A long-term extension phase will follow, in which all participants receive trontinemab.

Key exclusion criteria include any prior amyloid-lowering treatment, MRI evidence of more than 4 microhemorrhages, superficial siderosis, or severe white matter disease, and any prior diagnosis of MCI or dementia.

Participant Identification: The TRAVELLER Pre-Screening Study

A notable infrastructure component of the PrevenTRON program is TRAVELLER, a master pre-screening study deployed across Roche's AD clinical trials.¹ TRAVELLER is designed to reduce screening burden at clinical sites by first evaluating a pool of potential participants using a cognitive test (International Shopping List Test) and Roche's Elecsys blood-based biomarker p-tau217 assay, without requiring prior amyloid biomarker confirmation. Participants recommended for screening are then referred to the relevant Roche trial (TRONTIER 1, TRONTIER 2, or PrevenTRON), and those not meeting criteria may re-enter TRAVELLER for future studies.

The use of plasma p-tau217 as the entry biomarker for PrevenTRON reflects growing evidence that elevated p-tau217 in cognitively unimpaired individuals is a robust predictor of future cognitive decline. Analysis of samples from the A4 and LEARN studies using the Elecsys Phospho-Tau 217P plasma assay established a framework for risk stratification, showing that the highest p-tau217 tertile was associated with substantially greater rates of confirmed Clinical Dementia Rating-Global Score progression over time.

Context Within the Trontinemab Program

TRONTIER 1 and TRONTIER 2, two identical phase 3 trials in early symptomatic AD enrolling approximately 1600 patients across 18 countries, were initiated in 2025.³ PrevenTRON extends the same therapeutic hypothesis one stage earlier in the disease continuum, targeting individuals who have the biological hallmarks of AD but not yet the clinical manifestations. This three-study phase 3 architecture positions trontinemab as a candidate therapy across the full spectrum of early AD intervention, from preclinical to mild dementia.

Click here for more AAIC 2026 coverage.

REFERENCES
1. Smith J, Mummery C, Cummings JL, et al. PrevenTRON: rationale and design of a phase III trial of trontinemab in cognitively unimpaired individuals with biomarkers of Alzheimer's disease at high risk of clinical decline. Abstract and presentation at: Alzheimer's Association International Conference (AAIC); July 2026; London, United Kingdom.
2. Roche presents new insights in Alzheimer's disease research across its diagnostics and pharmaceutical portfolios at AAIC. News release. Roche. July 28, 2025. Accessed July 16, 2026. https://www.roche.com/media/releases/med-cor-2025-07-28
3. Smith J, Mummery CJ, Cummings JL, et al. TRONTIER 1 and TRONTIER 2: pivotal trials of trontinemab in early symptomatic Alzheimer's disease. Alzheimers Dement. 2025. doi:10.1002/alz70859_104294. https://alz-journals.onlinelibrary.wiley.com/doi/abs/10.1002/alz70859_104294