International meeting of the French society of neurology 2013Preclinical trials in autosomal dominant AD: Implementation of the DIAN-TU trialLes essais précliniques sur la maladie d’Alzheimer autosomique dominante : mise en place de l’essai DIAN-TU
Introduction
Alzheimer's disease (AD) is a growing public and financial healthcare crisis. AD afflicts approximately 18 million people worldwide according to the World Health Organization (WHO) (Sato et al., 2007). By 2025, this estimate is projected to grow to 34 million people, with the highest increase expected among developing countries. AD causes loss of memory cognitive function, and ultimately independence, putting a heavy personal and financial burden on the patient and the family. Because of the severity and increasing prevalence of the disease, better treatments are urgently needed.
Autosomal dominant Alzheimer's disease (ADAD) has informed the field of AD research about the molecular and biochemical mechanisms that are believed to underlie the pathological basis of AD. Furthermore, mutations from autosomal dominant AD have provided animal and cellular models that are utilized to develop anti-amyloid-beta drugs considered as AD therapeutic agents. Due to the rarity of ADAD, the Dominantly Inherited Alzheimer Network (DIAN; U19 AG032438) was launched in 2008 to establish an international, multicenter registry of individuals at risk or with a known causative mutation of AD in the amyloid precursor protein (APP), presenilin 1 (PSEN1), or presenilin 2 (PSEN2) genes (Morris et al., 2012). The DIAN is now well established, having enrolled more than 330 participants. Interim cross-sectional analyses indicate a cascade of AD biomarker changes that begin at least 20 years before symptomatic onset of disease (Bateman et al., 2012).
The pathogenesis and pathophysiology of AD are best understood in the ADAD population. The DIAN study evaluates participants at entry and longitudinally thereafter with clinical and cognitive batteries, structural, functional, metabolic, and amyloid imaging protocols, and biological fluid (blood and cerebrospinal fluid) collection with the goal of determining the sequence of changes in presymptomatic gene carriers who are destined to develop AD. Because the clinical and pathological phenotypes of dominantly inherited AD appear similar to those for the far more common late-onset “sporadic” AD, the nature and sequence of brain changes in dominantly inherited AD are also likely relevant for sporadic AD. Many disease modifying therapies currently in development target amyloid-beta (Aβ), which is believed to be the initiator and earliest change in the AD process. We now have the opportunity to test whether drugs that were developed using animal models incorporating ADAD mutations will have similar biological and clinical effects in ADAD participants, testing fundamental questions of the potential efficacy of anti-Aβ agents. The AD pathological processes can be tracked with biomarkers (Blennow et al., 2012, May et al., 2011, Ostrowitzki et al., 2012, Salloway et al., 2009) to assess drugs developed to target these pathological processes (e.g., increased Aβ production, Aβ deposition, etc.). It is unlikely that a drug which does not engage its target in the brain will be effective in slowing cognitive decline (i.e., if the drug does not do what it was designed to do, it would have only a random chance of working) (Bateman and Klunk, 2008). Early analysis of DIAN longitudinal study has provided a suggestive algorithm of biomarker change in the ADAD population over time before the estimated age of onset of cognitive impairment (Bateman et al., 2012). This reinforces the rationale that biomarker changes are ongoing in presymptomatic ADAD participants and allows the estimation of effect size for clinical trials. Building on this information, the DIAN-TU trial will measure the effects of drugs on a comprehensive set of AD biomarkers (e.g., amyloid deposition, cerebrospinal fluid (CSF) Aβ and tau, magnetic resonance imaging (MRI) brain atrophy, and positron emission tomography (PET) imaging with 2-[18F] fluoro-2-deoxy-D-glucose (FDG PET)) to determine if a drug is likely to have a cognitive benefit in a subsequent cognitive endpoint trial.
Section snippets
Design
The DIAN-TU trial leverages several operational efficiencies in testing multiple drugs in a single trial while addressing challenges of managing a global trial of a geographically dispersed rare population. Very few eligible participants live within driving distance of sites possessing the necessary biomarker technology, requiring air travel and hotel stays for some visits, complex remote management and use of multiple local vendors for drug delivery and safety monitoring. The DIAN-TU has
Discussion
Persons carrying fully-penetrant ADAD mutations therefore provide a unique opportunity to test the ability of novel agents to prevent the onset of clinical AD. However, such trials present unique logistical and ethical issues which need to be considered in their design (Bateman et al., 2011, Ringman et al., 2009). The importance of potentially delaying or possibly preventing dementia in asymptomatic individuals is widely recognized. Diverse and committed collaborations between academia, patient
Disclosure of interests
R.J.B. has consulted for Pfizer, DZNE, Probiodrug AG, Medscape, En Vivo (SAB) and has research grants with AstraZeneca, Merck and Eli Lilly in the past year. Washington University and R.J.B. have a financial interest in C2 N Diagnostics, which uses the SILK methodology in human studies. R.J.B. is a co-inventor on U.S. patent 7,892,845 “Methods for measuring the metabolism of neurally derived biomolecules in vivo.” Washington University, with R.J.B. are co-inventors, has also submitted the U.S.
Acknowledgements
We gratefully acknowledge the Dominantly Inherited Alzheimer Network (DIAN; U19 AG032438; JC Morris, PI), the DIAN Pharma Consortium (Biogen Idec, Elan, Eli Lilly, Genentech, Hoffman La-Roche, Janssen, Mithridion, Novartis, Pfizer, Sanofi-Aventis), the Alzheimer's Association, all of the Cores of the DIAN-TU, and the participants and their families to whom we are especially indebted. The DIAN-TU is supported by funding from the Alzheimer's Association and the DIAN Pharma Consortium.
References (14)
- et al.
Measuring target effect of proposed disease-modifying therapies in Alzheimer's disease
Neurotherapeutics
(2008) - et al.
Commentary on “a roadmap for the prevention of dementia II: Leon Thal Symposium 2008.” Prevention trials in persons at risk for dominantly inherited Alzheimer's disease: opportunities and challenges
Alzheimers Dement
(2009) - et al.
Amyloid-related imaging abnormalities in amyloid-modifying therapeutic trials: recommendations from the Alzheimer's Association Research Roundtable Workgroup
Alzheimers Dement
(2011) - et al.
Autosomal dominant Alzheimer's disease: a review and proposal for the prevention of Alzheimer's disease
Alzheimers Res Ther
(2011) - et al.
Clinical and biomarker changes in dominantly inherited Alzheimer's disease
N Engl J Med
(2012) - et al.
Effect of immunotherapy with bapineuzumab on cerebrospinal fluid biomarker levels in patients with mild to moderate alzheimer disease
Arch Neurol
(2012) - et al.
Abnormal in vivo metabolism of apolipoprotein E4 in humans
J Clin Invest
(1986)
Cited by (120)
Overview of therapeutic targets in management of dementia
2022, Biomedicine and PharmacotherapyWhat contribution can genetics make to predict the risk of Alzheimer's disease?
2022, Revue NeurologiqueDisease-Modifying Therapies for Alzheimer’s Disease: More Questions than Answers
2022, NeurotherapeuticsIron and Ferroptosis as Therapeutic Targets in Alzheimer’s Disease
2021, NeurotherapeuticsDominantly Inherited Alzheimer Network Trials Unit (DIAN-TU): Trial Satisfaction and Attitudes towards Future Clinical Trials
2024, Journal of Prevention of Alzheimer's DiseaseDirect-to-participant investigational medicinal product supply in clinical trials in Europe: Exploring the experiences of sponsors, site staff and couriers
2023, British Journal of Clinical Pharmacology