The EPAD project has been established to overcome the major hurdles hampering drug development for secondary prevention of AD dementia, by conducting the EPAD LCS (fed mainly from existing Parent Cohorts (PC) across Europe) in alignment with the adaptive design EPAD PoC trial. Both EPAD LCS and EPAD PoC trial will be run in an exclusive network of highly selected, expert Trial Delivery Centres (TDC) that will be selected on the basis of strictly applied criteria to ensure the highest possible data quality, successful recruitment and adherence to the EPAD principles.

While interventions must start early in the course of AD, accurate disease models covering the entire course of AD before dementia onset are lacking. Estimating with reasonable confidence an individual's overall probability of developing AD dementia over a defined time period must take into account multiple dimensions simultaneously (e.g. cognition, biomarkers, traditional risk factors - genetic and environmental). This will allow any given individual to be placed somewhere on a probability spectrum from negligible probability to high probability. Because individuals with similar overall probability may have very different contributions from various components in each dimension, flexible algorithms are needed instead of simple cut-offs to identify a probability-spectrum population adequate for both disease modelling and for providing a sufficient number of potential trial participants (especially in adaptive trials with multiple arms testing drugs with different mechanisms of action).

EPAD LCS is designed to address the dual need for development of accurate longitudinal models for AD covering the entire disease course, and development of adequate infrastructure for facilitating identification of research participants and clinical trial recruitment. EPAD LCS will have a probability-spectrum population selected mostly from already existing PCs across Europe to facilitate fast recruitment. Different types of PCs will be considered (e.g. memory clinic-based, population-based). Due to the variety of PCs, some EPAD LCS research participants will be e.g. memory clinic patients without dementia, while others will be e.g. participants without dementia from the general population. The variety of PC settings will ensure that the EPAD LCS probability-spectrum population can cover the entire continuum of probability for AD dementia development. Regular EPAD LCS follow-up with clinical, cognitive and biomarker assessments will provide a well-phenotyped probability-spectrum population, generating high-quality data for updating disease models, for easier identification of individuals suitable for trial inclusion, and for use as trial run-in data and reference for evaluating intervention efficacy.

The flow of research participants from the population at large to the trial is divided into the following stages: firstly, EPAD will engage existing PCs from across Europe who may have eligible research participants for the EPAD LCS. The next step is drawing research participants from the PCs into the EPAD LCS to maintain a suitable population of approximately 6,000 research participants. Recruitment will be complemented with research participants who are recruited from a clinical setting by their referring clinician. To enable access to the EPAD LCS for these potential participants, the referring clinician will check if they match the flexible algorithm. Finally, research participants in the EPAD LCS who fulfil trial inclusion criteria (approximately 1,500 research participants), will be invited to enter the EPAD PoC (PoC) trial for evaluation of treatment for secondary prevention of AD dementia. This trial is a standing, adaptive, PoC trial that could involve multiple arms running concurrently. Successful graduation through PoC into phase 3 confirmatory trials of single or combinatorial interventions will be based on success against an intermediary, target specific biomarker and then success against a cognitive measure.

Once recruitment is completed, at any given time there should be approx. 6,000 research participants in the EPAD LCS and approx. 1,500 in the EPAD PoC, hence the need to replenish each from PCs as participants are lost through attrition. EPAD LCS will initially run until the end of December 2019, and extension of consent will be sought after 4 years.