Early-stage Alzheimer disease: getting trial-ready

Slowing the progression of Alzheimer disease (AD) might be the greatest unmet medical need of our time. Although one AD therapeutic has received a controversial accelerated approval from the FDA, more effective and accessible therapies are urgently needed. Consensus is growing that for meaningful disease modification in AD, therapeutic intervention must be initiated at very early (preclinical or prodromal) stages of the disease. Although the methods for such early-stage clinical trials have been developed, identification and recruitment of the required asymptomatic or minimally symptomatic study participants takes many years and requires substantial funds. As an example, in the Anti-Amyloid Treatment in Asymptomatic Alzheimer’s Disease Trial (the first phase III trial to be performed in preclinical AD), 3.5 years and more than 5,900 screens were required to recruit and randomize 1,169 participants. A new clinical trials infrastructure is required to increase the efficiency of recruitment and accelerate therapeutic progress. Collaborations in North America, Europe and Asia are now addressing this need by establishing trial-ready cohorts of individuals with preclinical and prodromal AD. These collaborations are employing innovative methods to engage the target population, assess risk of brain amyloid accumulation, select participants for biomarker studies and determine eligibility for trials. In the future, these programmes could provide effective tools for pursuing the primary prevention of AD. Here, we review the lessons learned from the AD trial-ready cohorts that have been established to date, with the aim of informing ongoing and future efforts towards efficient, cost-effective trial recruitment. Consensus is growing that intervention in the very early stages of Alzheimer disease is necessary for disease modification. Here, the authors discuss the challenges of recruiting asymptomatic or mildly symptomatic participants for clinical trials, focusing on ‘trial-ready’ cohorts as a potential solution. Trial-ready cohorts are an effective strategy for the identification of participants eligible for clinical trials in early-stage Alzheimer disease (AD). Building these cohorts requires considerable planning and technological infrastructure to facilitate recruitment, remote longitudinal assessment, data management and data storage. Trial-ready cohorts exist for genetically determined populations at risk of AD, such as those with familial AD and Down syndrome; the longitudinal data from these cohorts is improving our understanding of the disease progression in early stages, informing clinical trial design and accelerating recruitment to intervention studies. So far, the challenges experienced by trial-ready cohorts for early-stage AD have included difficulties recruiting an ethnically and racially representative cohort; and for online cohorts, difficulty retaining participants. The results of ongoing work will reveal the success of strategies to improve cohort diversity and retention, and the rates of referral to clinical trials. Trial-ready cohorts are an effective strategy for the identification of participants eligible for clinical trials in early-stage Alzheimer disease (AD). Building these cohorts requires considerable planning and technological infrastructure to facilitate recruitment, remote longitudinal assessment, data management and data storage. Trial-ready cohorts exist for genetically determined populations at risk of AD, such as those with familial AD and Down syndrome; the longitudinal data from these cohorts is improving our understanding of the disease progression in early stages, informing clinical trial design and accelerating recruitment to intervention studies. So far, the challenges experienced by trial-ready cohorts for early-stage AD have included difficulties recruiting an ethnically and racially representative cohort; and for online cohorts, difficulty retaining participants. The results of ongoing work will reveal the success of strategies to improve cohort diversity and retention, and the rates of referral to clinical trials.