Prescreening for European Prevention of Alzheimer Dementia (EPAD) trial-ready cohort: impact of AD risk factors and recruitment settings

Lisa Vermunt, Graciela Muniz-Terrera, Lea Ter Meulen, Colin Veal, Kaj Blennow, Archie Campbell, Isabelle Carrié, Julien Delrieu, Karine Fauria, Gema Huesa Rodríguez, Silvia Ingala, Natalie Jenkins, José Luis Molinuevo, Pierre-Jean Ousset, David Porteous, Niels D Prins, Alina Solomon, Brian D Tom, Henrik Zetterberg, Marissa Zwan, Craig W Ritchie, Philip Scheltens, Gerald Luscan, Anthony J Brookes, Pieter Jelle Visser, IMI-EPAD collaborators, Lisa Vermunt, Graciela Muniz-Terrera, Lea Ter Meulen, Colin Veal, Kaj Blennow, Archie Campbell, Isabelle Carrié, Julien Delrieu, Karine Fauria, Gema Huesa Rodríguez, Silvia Ingala, Natalie Jenkins, José Luis Molinuevo, Pierre-Jean Ousset, David Porteous, Niels D Prins, Alina Solomon, Brian D Tom, Henrik Zetterberg, Marissa Zwan, Craig W Ritchie, Philip Scheltens, Gerald Luscan, Anthony J Brookes, Pieter Jelle Visser, IMI-EPAD collaborators

Abstract

Background: Recruitment is often a bottleneck in secondary prevention trials in Alzheimer disease (AD). Furthermore, screen-failure rates in these trials are typically high due to relatively low prevalence of AD pathology in individuals without dementia, especially among cognitively unimpaired. Prescreening on AD risk factors may facilitate recruitment, but the efficiency will depend on how these factors link to participation rates and AD pathology. We investigated whether common AD-related factors predict trial-ready cohort participation and amyloid status across different prescreen settings.

Methods: We monitored the prescreening in four cohorts linked to the European Prevention of Alzheimer Dementia (EPAD) Registry (n = 16,877; mean ± SD age = 64 ± 8 years). These included a clinical cohort, a research in-person cohort, a research online cohort, and a population-based cohort. Individuals were asked to participate in the EPAD longitudinal cohort study (EPAD-LCS), which serves as a trial-ready cohort for secondary prevention trials. Amyloid positivity was measured in cerebrospinal fluid as part of the EPAD-LCS assessment. We calculated participation rates and numbers needed to prescreen (NNPS) per participant that was amyloid-positive. We tested if age, sex, education level, APOE status, family history for dementia, memory complaints or memory scores, previously collected in these cohorts, could predict participation and amyloid status.

Results: A total of 2595 participants were contacted for participation in the EPAD-LCS. Participation rates varied by setting between 3 and 59%. The NNPS were 6.9 (clinical cohort), 7.5 (research in-person cohort), 8.4 (research online cohort), and 88.5 (population-based cohort). Participation in the EPAD-LCS (n = 413 (16%)) was associated with lower age (odds ratio (OR) age = 0.97 [0.95-0.99]), high education (OR = 1.64 [1.23-2.17]), male sex (OR = 1.56 [1.19-2.04]), and positive family history of dementia (OR = 1.66 [1.19-2.31]). Among participants in the EPAD-LCS, amyloid positivity (33%) was associated with higher age (OR = 1.06 [1.02-1.10]) and APOE ɛ4 allele carriership (OR = 2.99 [1.81-4.94]). These results were similar across prescreen settings.

Conclusions: Numbers needed to prescreen varied greatly between settings. Understanding how common AD risk factors link to study participation and amyloid positivity is informative for recruitment strategy of studies on secondary prevention of AD.

Trial registration: ClinicalTrials.gov NCT02804789.

Keywords: Amyloid; Engagement; Prescreening; Recruitment; Registries; Secondary prevention trials; Trial-ready cohort.

Conflict of interest statement

Lisa Vermunt, Graciela Muniz-Terrera, Lea ter Meulen, Colin Veal, Archie Campbell, Julien Delrieu, Isabelle Carrie, Karine Fauria, Silvia Ingala, Natalie Jenkins, Pierre-Jean Ousset, David Porteous, Alina Solomon, Brian Tom, Marissa Zwan, and Anthony Brookes declare that they have no competing interests.

Kaj Blennow has served as a consultant or at advisory boards for Alector, Alzheon, CogRx, Biogen, Lilly, Novartis, and Roche Diagnostics, has received research support from Roche Diagnostics, and is a co-founder of Brain Biomarker Solutions in Gothenburg AB, a GU Venture-based platform company at the University of Gothenburg. José Luis Molinuevo is a consultant for the following for-profit companies: Alergan, Roche diagnostics, Genentech, Novartis, Lundbeck, Oryzon, Biogen, Lilly, Janssen, Green Valley, MSD, Eisai, Alector, Raman Health. Niels Prins serves on the advisory board of Boehringer Ingelheim and Probiodrug and is a member of the DSMB of Abbvie’s M15-566 trial; he has received consultancy or speaker fees from Sanofi, Takeda, Janssen, and Novartis and he is CEO and co-owner of the Brain Research Center, Amsterdam. Henrik Zetterberg has served at scientific advisory boards for Roche Diagnostics, Wave, Samumed, and CogRx, has given lectures in symposia sponsored by Biogen and Alzecure, and is a co-founder of Brain Biomarker Solutions in Gothenburg AB, a GU Ventures-based platform company at the University of Gothenburg. Craig Ritchie is the co-coordinator and academic lead for the EPAD (European Prevention of Alzheimer’s Dementia) Project which has numerous commercial partners in keeping with the mechanisms of the European Union’s Innovative Medicine’s Initiative. These companies are as follows: Janssen, Eisai, Pfizer, Eli Lilly, Roche Diagnostics, Boeringher Ingleheim, Novartis, AC Immune, Ixico, Aridhia, Amgen, Berry Consultants, Lundbeck, Sanofi, Quintiles (IQVIA), and Takeda.

Philip Scheltens has acquired grant support (for the institution) from GE Healthcare, Danone Research, Piramal, and Merck. In the past 2 years, he has received consultancy/speaker fees (paid to the institution) from Lilly, GE Healthcare, Novartis, Sanofi, Nutricia, Probiodrug, Biogen, Roche, Avraham, and EIP Pharma. Gerald Luscan is a Pfizer employee. Pieter Jelle Visser reports non-financial support from GE Healthcare, other from Eli-Lilly, other from Janssen Pharmaceutical, grants from Biogen, outside the submitted work.

Figures

Fig. 1
Fig. 1
Prescreening to enrolment: flow from EPAD Registry to EPAD trial-ready cohort. Legend: CSF = cerebrospinal fluid; EPAD = European Prevention of Alzheimer Dementia
Fig. 2
Fig. 2
Multivariate model for enrolment and amyloid positivity. Legend: EPAD-LCS = EPAD longitudinal cohort study (trial-ready cohort). APOE = apolipoprotein E gene. Shown effect sizes are: Age per 5 years older at baseline, APOE ɛ4 in contrast to no APOE ɛ4, male in contrast to female, highly educated in contrast to low or normal level educated, family history for dementia positive in contrast to family history for dementia reported

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