AHEAD Study

AHEAD 3-45 is a global multicenter clinical trial aimed at preventing memory loss due to Alzheimer’s disease (AD) and combines two studies with distinct participant groups, but with a shared screening and recruitment to increase efficiency. 

A3 Study

The A3 Study aims to get closer to primary prevention of AD, through preventing amyloid build-up in the brain. The clinical trial targets cognitively normal individuals who are currently below the threshold for amyloid elevation on amyloid PET but are at high risk for further Aβ accumulation. The A3 Study is a global, multicenter, double-blind, randomized trial to compare the effects of low dose BAN-2401 vs. placebo, to test whether an anti-amyloid beta antibody targeted at protofibrils can slow brain amyloid accumulation at this very early stage of disease. The A3 Study also measures accumulation of tangle pathology using tau PET scans and exploratory cognitive outcomes.

A45 Study

The A45 Study targets the preclinical (pre-symptomatic) stage of AD. This clinical trial targets clinically normal participants (with little to no cognitive impairment) who have elevated levels of amyloid in brain and are at high risk for progression to mild cognitive impairment and AD dementia. The A45 Study is a global, multicenter, double-blinded, placebo-controlled, randomized trial of a treatment regimen consisting of an anti-amyloid beta antibody targeted at protofibrils to prevent cognitive decline and delay biomarkers of pathological progression versus placebo. In the active arm, individuals will be treated with high-dose BAN2401 to clear amyloid deposits and Aβ protofibrils from the brain, followed by low-dose BAN2401 to prevent re-accumulation of amyloid. The aim of this clinical trial is to slow or prevent decline in cognitive performance.

Key publications:

Molina-Henry DP, Raman R, Liu A, Langford O, Johnson K, Shum LK, Glover CM, Dhadda S, Irizarry M, Jimenez-Maggiora G, Braunstein JB, Yarasheski K, Venkatesh V, West T, Verghese PB, Rissman RA, Aisen P, Grill JD, Sperling RA. Racial and ethnic differences in plasma biomarker eligibility for a preclinical Alzheimer’s disease trial. Alzheimers Dement. 2024 Apr 17. doi: 10.1002/alz.13803. Epub ahead of print. PMID: 38629508.

Rafii MS, Sperling RA, Donohue MC, Zhou J, Roberts C, Irizarry MC, Dhadda S, Sethuraman G, Kramer LD, Swanson CJ, Li D, Krause S, Rissman RA, Walter S, Raman R, Johnson KA, Aisen PS. The AHEAD 3-45 Study: Design of a prevention trial for Alzheimer’s disease. Alzheimers Dement. 2023 Apr;19(4):1227-1233. doi: 10.1002/alz.12748. Epub 2022 Aug 15. PMID: 35971310; PMCID: PMC9929028.

Rissman RA, Langford O, Raman R, Donohue MC, Abdel-Latif S, Meyer MR, Wente-Roth T, Kirmess KM, Ngolab J, Winston CN, Jimenez-Maggiora G, Rafii MS, Sachdev P, West T, Yarasheski KE, Braunstein JB, Irizarry M, Johnson KA, Aisen PS, Sperling RA; AHEAD 3-45 Study team. Plasma Aβ42/Aβ40 and phospho-tau217 concentration ratios increase the accuracy of amyloid PET classification in preclinical Alzheimer’s disease. Alzheimers Dement. 2024 Feb;20(2):1214-1224. doi: 10.1002/alz.13542. Epub 2023 Nov 6. PMID: 37932961; PMCID: PMC10916957. 

ACTC Solution

ACTC designed and is conducting these two novel sister trials through a public-private partnership. Other innovations in the trial include the addition of plasma prescreening to reduce participant burden, as well as other recruitment approaches aiming to improve inclusivity of the trial. Even before enrollment was complete, methods and learnings from the pre-randomization data have been published, showing differences in racial in ethnic groups in plasma amyloid eligibility (see Molina-Henry above). Data sharing for this study will be a significant contribution to the field of Alzheimer’s research. All Pre-randomization data and imaging studies will be shared in 2025.