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AHEAD Study

Screening Closed
PIs:
Reisa SperlingMD, MMSc
Paul AisenMD
Keith JohnsonMD
NIA/NIH Grant #:
R01AG054029 (A3) and R01AG061848 (A45)
Duration:
4 years
Eligible Participants:
Individuals with normal cognition, elevated or intermediate amyloid levels, and ages 55 - 80

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.

 

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.

Publications

Racial and ethnic differences in plasma biomarker eligibility for a preclinical Alzheimer’s disease trial
Doris Patricia Molina-Henry, Rema Raman, Andy Liu, Oliver Langford, Keith Johnson, Leona K Shum, Crystal M Glover, Shobha Dhadda, Michael Irizarry, Gustavo Jimenez-Maggiora, Joel B Braunstein, Kevin Yarasheski, Venky Venkatesh, Tim West, Philip B Verghese, Robert A Rissman, Paul Aisen, Joshua D Grill, Reisa A Sperling
2024 April
  • Read the Abstract

    Introduction: In trials of amyloid-lowering drugs for Alzheimer’s disease (AD), differential eligibility may contribute to under-inclusion of racial and ethnic underrepresented groups. We examined plasma amyloid beta 42/40 and positron emission tomography (PET) amyloid eligibility for the ongoing AHEAD Study preclinical AD program (NCT04468659).

    Methods: Univariate logistic regression models were used to examine group differences in plasma and PET amyloid screening eligibility.

    Results: Of 4905 participants screened at time of analysis, 1724 were plasma eligible to continue in screening: 13.3% Hispanic Black, 24.7% Hispanic White, 20.8% non-Hispanic (NH) Asian, 24.7% NH Black, and 38.9% NH White. Plasma eligibility differed across groups in models controlling for covariates (odds ratio from 1.9 to 4.0 compared to the NH White reference group, P < 0.001). Among plasma eligible participants, PET eligibility did not differ by group.

    Discussion: These results suggest that prevalence of brain amyloid pathology differed, but that eligibility based on plasma was equally effective across racial and ethnic group members.

    Highlights: Plasma amyloid eligibility is lower in underrepresented racial and ethnic groups. In plasma eligible adults, positron emission tomography eligibility rates are similar across race and ethnicity. Plasma biomarker tests may be similarly effective across racial and ethnic groups.

    Keywords: amyloid; biomarker; ethnicity; plasma; positron emission tomography; race.

The AHEAD 3-45 Study: Design of a prevention trial for Alzheimer’s disease
Michael S Rafii, Reisa A Sperling, Michael C Donohue, Jin Zhou, Claire Roberts, Michael C Irizarry, Shobha Dhadda, Gopalan Sethuraman, Lynn D Kramer, Chad J Swanson, David Li, Stephen Krause, Robert A Rissman, Sarah Walter, Rema Raman, Keith A Johnson, Paul S Aisen
2023 April
  • Read the Abstract

    Introduction: The Alzheimer’s disease (AD) continuum begins with a long asymptomatic or preclinical stage, during which amyloid beta (Aβ) is accumulating for more than a decade prior to widespread cortical tauopathy, neurodegeneration, and manifestation of clinical symptoms. The AHEAD 3-45 Study (BAN2401-G000-303) is testing whether intervention with lecanemab (BAN2401), a humanized immunoglobulin 1 (IgG1) monoclonal antibody that preferentially targets soluble aggregated Aβ, initiated during this asymptomatic stage can slow biomarker changes and/or cognitive decline. The AHEAD 3-45 Study is conducted as a Public-Private Partnership of the Alzheimer’s Clinical Trial Consortium (ACTC), funded by the National Institute on Aging, National Institutes of Health (NIH), and Eisai Inc.

    Methods: The AHEAD 3-45 Study was launched on July 14, 2020, and consists of two sister trials (A3 and A45) in cognitively unimpaired (CU) individuals ages 55 to 80 with specific dosing regimens tailored to baseline brain amyloid levels on screening positron emission tomography (PET) scans: intermediate amyloid (≈20 to 40 Centiloids) for A3 and elevated amyloid (>40 Centiloids) for A45. Both trials are being conducted under a single protocol, with a shared screening process and common schedule of assessments. A3 is a Phase 2 trial with PET-imaging end points, whereas A45 is a Phase 3 trial with a cognitive composite primary end point. The treatment period is 4 years. The study utilizes innovative approaches to enriching the sample with individuals who have elevated brain amyloid. These include recruiting from the Trial-Ready Cohort for Preclinical and Prodromal Alzheimer’s disease (TRC-PAD), the Australian Dementia Network (ADNeT) Registry, and the Japanese Trial Ready Cohort (J-TRC), as well as incorporation of plasma screening with the C2N mass spectrometry platform to quantitate the Aβ 42/40 ratio (Aβ 42/40), which has been shown previously to reliably identify cognitively normal participants not likely to have elevated brain amyloid levels. A blood sample collected at a brief first visit is utilized to “screen out” individuals who are less likely to have elevated brain amyloid, and to determine the participant’s eligibility to proceed to PET imaging. Eligibility to randomize into the A3 Trial or A45 Trial is based on the screening PET imaging results.

    Result: The focus of this article is on the innovative design of the study.

    Discussion: The AHEAD 3-45 Study will test whether with lecanemab (BAN2401) can slow the accumulation of tau and prevent the cognitive decline associated with AD during its preclinical stage. It is specifically targeting both the preclinical and the early preclinical (intermediate amyloid) stages of AD and is the first secondary prevention trial to employ plasma-based biomarkers to accelerate the screening process and potentially substantially reduce the number of screening PET scans.

    Keywords: Alzheimer’s disease; amyloid; immunotherapy; prevention.

    © 2022 The Authors. Alzheimer’s & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer’s Association.

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Plasma Aβ42/Aβ40 and phospho-tau217 concentration ratios increase the accuracy of amyloid PET classification in preclinical Alzheimer’s disease
Robert A Rissman, Oliver Langford, Rema Raman, Michael C Donohue, Sara Abdel-Latif, Matthew R Meyer, Traci Wente-Roth, Kristopher M Kirmess, Jennifer Ngolab, Charisse N Winston, Gustavo Jimenez-Maggiora, Michael S Rafii, Pallavi Sachdev, Tim West, Kevin E Yarasheski, Joel B Braunstein, Michael Irizarry, Keith A Johnson, Paul S Aisen, Reisa A Sperling; AHEAD 3-45 Study team
2023 November
  • Read the Abstract

    Introduction: Incorporating blood-based Alzheimer’s disease biomarkers such as tau and amyloid beta (Aβ) into screening algorithms may improve screening efficiency.

    Methods: Plasma Aβ, phosphorylated tau (p-tau)181, and p-tau217 concentration levels from AHEAD 3-45 study participants were measured using mass spectrometry. Tau concentration ratios for each proteoform were calculated to normalize for inter-individual differences. Receiver operating characteristic (ROC) curve analysis was performed for each biomarker against amyloid positivity, defined by > 20 Centiloids. Mixture of experts analysis assessed the value of including tau concentration ratios into the existing predictive algorithm for amyloid positron emission tomography status.

    Results: The area under the receiver operating curve (AUC) was 0.87 for Aβ42/Aβ40, 0.74 for phosphorylated variant p-tau181 ratio (p-tau181/np-tau181), and 0.92 for phosphorylated variant p-tau217 ratio (p-tau217/np-tau217). The Plasma Predicted Centiloid (PPC), a predictive model including p-tau217/np-tau217, Aβ42/Aβ40, age, and apolipoprotein E improved AUC to 0.95.

    Discussion: Including plasma p-tau217/np-tau217 along with Aβ42/Aβ40 in predictive algorithms may streamline screening preclinical individuals into anti-amyloid clinical trials.

    Clinicaltrials: gov Identifier: NCT04468659 HIGHLIGHTS: The addition of plasma phosphorylated variant p-tau217 ratio (p-tau217/np-tau217) significantly improved plasma biomarker algorithms for identifying preclinical amyloid positron emission tomography positivity. Prediction performance at higher NAV Centiloid levels was improved with p-tau217/np-tau217. All models generated for this study are incorporated into the Plasma Predicted Centiloid (PPC) app for public use.

    Keywords: blood-based biomarkers; mass spectrometry; plasma; tau.