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Amyloid imaging to Prevent Alzheimer’s Disease – Sofia ref.: 115952

Periodic Reporting for period 3 - AMYPAD (Amyloid imaging to Prevent Alzheimer’s Disease – Sofia ref.: 115952)

Reporting period: 2018-10-01 to 2019-09-30

AMYPAD aims to determine the value of β-amyloid imaging as a diagnostic and therapeutic marker for Alzheimer’s disease. β-amyloid deposition is a necessary - but not sufficient - step on the path towards the development of Alzheimer’s disease (AD). The depiction of brain β-amyloid in vivo can therefore support an earlier diagnosis of AD, and, when recognized in a pre-symptomatic population, can also provide an opportunity for secondary prevention. Understanding the value of imaging β-amyloid plaques using positron emission tomography (PET) will provide a unique opportunity to achieve 3 major goals.

The first goal is to gain better understanding of the impact of amyloid PET imaging utilization on diagnostic thinking and patient management (Diagnostic Study). For this purpose, AMYPAD will scan a large cohort from memory clinics (n=900) suspected of Alzheimer’s disease, to determine the usefulness of β-amyloid PET imaging regarding diagnostic confidence, decision trees, change in diagnosis, as well as patient management and healthcare resource utilization. The primary objective is to measure the impact of early vs late knowledge of amyloid status via PET imaging on the physician’s confidence in an etiological diagnosis. The second goal is to better understand the natural history of Alzheimer’s disease in its preclinical and prodromal stages (Prognostic Study). To that aim, AMYPAD will leverage several Europe-wide networks in close collaboration with ongoing cohorts such as EPAD to study the earliest stages of Alzheimer’s disease in a longitudinal and multi-modal fashion, understanding several risk factors and the relationship between them. Additional cohorts such as EMIF-AD, ALFA+, FACEHBI and FPACK are also contributing to this Prognostic Study to reach out the study participants target and efficiently deliver on several objectives without exposing de novo participants (n=2000)

Lastly, the third goal is to support current and future trials in the selection of subjects for proof-of-concept studies aiming at preventing Alzheimer’s disease by ensuring more targeted enrolment and providing alternative measures of treatment effect.

There, the ultimate goal is to establish robust predictors of cognitive decline to help in the planning and monitoring of treatment.

AMYPAD will address the above goals in close collaboration with other initiatives, including IMI projects (EPAD, EMIF-AD, NEURONET) and through engagement with regulators, it will also maximize the value of its findings for pharmaceutical companies, healthcare providers, and patients.
Within the initial stages, the protocol for the Diagnostic Study was extensively discussed amongst partners to ensure a seamlessly integration of the study with each clinical practice. The study leads also requested advice on the design and outcomes of the study to regulatory agencies and the result was a robust study protocol approved and running at Geneva, Amsterdam, Toulouse, Barcelona, London, Stockholm and Lausanne. 600 patients have been enrolled as of November 2019.

Similarly, significant work has been put into activating the Prognostic Study by the engagement of additional sites and Parent Cohorts. The protocol has been finalized and initially approved in Amsterdam, Edinburgh, Barcelona, Toulouse, Geneva, and Stockholm. Within 2019, more sites have been approached, and currently the following are being initiated: Tayside, Nantes, Lille, Paris Nord, Montpellier, Paris La Pitie, Fundacion CITA, Gothenburg University, Leuven University, Cliniques Universitaires Saint-Luc and Fundació ACE. As of November 2019, 369 participants have been recruited (295 scanned).

In parallel, technical and operational aspects have been established and optimized. Some critical aspects are the efficient and balanced supply of radiotracers to participating sites, the harmonization of data across radiotracers and scanners at the different sites, their qualifications, and the optimization of data accuracy for high-quality standard of results. In this period, a dedicated team has mapped out the optimal radiotracer delivery and distribution, defined the optimal scanning protocols to maximize data quality, certified participating sites and developed pipelines for the harmonization of results. In addition, a strong focus has been put into developing open-source imaging processing pipelines, which will be provided to the community during and beyond AMYPAD’s lifetime.

Moreover, substantial work was put into setting up collaborations with external groups to establish a large-scale collection of existing amyloid PET images so that the AMYPAD team can start its disease modelling work from the beginning of the project. Several data donors expressed interest and provided access to data, and AMYPAD researchers have started preliminary work to understand the natural history of AD and improve risk-profiling methodologies, which will strengthen the community knowledge but also support better subject selection for the project itself. The first findings have been shared at several conferences, as well as through scientific journals (researchgate.net).
The recent regulatory approval of β-amyloid PET tracers for clinical use suggests its relevance as a non-invasive tool to study one of the key molecules associated with the development of Alzheimer’s Disease (AD) – an untreatable illness estimated to cost society 1% of global GDP. However, the potential of amyloid PET to improve patient outcomes and support the development of new treatments for AD hasn’t quite been realized. β-amyloid PET is not reimbursed in any major market, limiting its use to very few patients, and while β-amyloid PET has become widely used in clinical trials and research, results from recent studies (e.g. Roche and Janssen) suggest that the way in which β-amyloid biomarkers are used in clinical trial protocols needs to be improved.

AMYPAD will perform amyloid PET scans on an unprecedented scale of patients suspected to be in the early stages of AD. Data will be collected to determine the clinical added value in diagnosis and patient monitoring, by determining when and in whom β-amyloid PET makes a cost-effective contribution to advance patient care for patients suspected of AD. In addition, longitudinal data will be used to develop novel combination of biomarkers for use in clinical trials, by establishing how β-amyloid PET measurements, in combination with demographics and other measurements such as assessments of neurodegeneration, vascular disease and cognition, can better stratify patients to select targeted treatment populations, and to provide an early read-out of treatment effects.

Novel elements of AMYPAD include longitudinal imaging in up to 50% of subjects and improved quantitative analyses by performing dynamic scans in a large subset of participants. It is differentiated from other initiatives both by its large scale, and by focusing on subjects with very early stages of Alzheimer’s disease. In doing so, it will also bridge a gap between US and Australian initiatives that study either healthy aging (A4 and AIBL) or focus on more established disease stages (ADNI and IDEAS), often in elderly subjects.

Moreover, by serving as a registry of subjects qualified to enter intervention trials, AMYPAD may be able to identify subjects at the very earliest stages of disease progression when secondary prevention may offer the greatest benefit to society.
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