International meeting of the French society of neurology 2013
Preclinical 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
This manuscript is dedicated to the memory of Denise Heinrichs, devoted mother who led by gracious example. She is an inspiration for dominantly inherited Alzheimer's disease families, researchers and doctors.
The Dominantly Inherited Alzheimer's Network Trials Unit (DIAN-TU) was formed to direct the design and management of interventional therapeutic trials of international DIAN and autosomal dominant Alzheimer's disease (ADAD) participants. The goal of the DIAN-TU is to implement safe trials that have the highest likelihood of success while advancing scientific understanding of these diseases and clinical effects of proposed therapies. The DIAN-TU has launched a trial design that leverages the existing infrastructure of the ongoing DIAN observational study, takes advantage of a variety of drug targets, incorporates the latest results of biomarker and cognitive data collected during the observational study, and implements biomarkers measuring Alzheimer's disease (AD) biological processes to improve the efficiency of trial design. The DIAN-TU trial design is unique due to the sophisticated design of multiple drugs, multiple pharmaceutical partners, academics servings as sponsor, geographic distribution of a rare population and intensive safety and biomarker assessments. The implementation of the operational aspects such as home health research delivery, safety magnetic resonance imagings (MRIs) at remote locations, monitoring clinical and cognitive measures, and regulatory management involving multiple pharmaceutical sponsors of the complex DIAN-TU trial are described.
Résumé
Le Dominantly Inherited Alzheimer's Network Trials Unit (DIAN-TU) a été créé afin de structurer les essais thérapeutiques interventionnels internationaux destinés aux membres de DIAN concernés par la maladie d’Alzheimer autosomique dominante. L’objectif de DIAN-TU est de mettre en place des essais sécurisés ayant la plus grande probabilité de succès en fonction des avancées scientifiques concernant à la fois la compréhension de ces maladies et les effets cliniques des thérapeutiques proposées. Le DIAN-TU a lancé un essai thérapeutique qui s’appuie sur les infrastructures actuelles de l’étude observationnelle DIAN, considère les bénéfices de plusieurs cibles pharmacologiques, prend en compte les résultats les plus récents des biomarqueurs et des données cognitives collectés pendant l’étude observationnelle et intègre les biomarqueurs physiopathologiques de la maladie d’Alzheimer afin d’améliorer l’efficience du protocole. Le DIAN-TU est original par son protocole sophistiqué concernant plusieurs molécules, par le nombre de partenaires de l’industrie pharmaceutique et des promoteurs académiques, par la dispersion géographique d’une population rare et par les procédures multiples d’évaluation en termes de sécurité et de biomarqueurs. Cet article présente la mise en place des aspects opérationnels, tels que la délivrance des thérapeutiques à domicile, la réalisation des IRM de surveillance à distance des sites d’évaluation, le monitoring des données cliniques et cognitives et les aspects réglementaires impliquant plusieurs partenaires industriels de cet 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.
Dementia is defined as a gradual cognitive impairment that interferes with everyday tasks, and is a leading cause of dependency, disability, and mortality. According to the current scenario, millions of individuals worldwide have dementia. This review provides with an overview of dementia before moving on to its subtypes (neurodegenerative and non-neurodegenerative) and pathophysiology. It also discusses the incidence and severity of dementia, focusing on Alzheimer's disease with its different hypotheses such as Aβ cascade hypothesis, Tau hypothesis, inflammatory hypothesis, cholinergic and oxidative stress hypothesis. Alzheimer's disease is the most common type and a progressive neurodegenerative illness distinct by neuronal loss and resulting cognitive impairment, leading to dementia. Alzheimer's disease (AD) is considered the most familiar neurodegenerative dementias that affect mostly older population. There are still no disease-modifying therapies available for any dementias at this time, but there are various methods for lowering the risk to dementia patients by using suitable diagnostic and evaluation methods. Thereafter, the management and treatment of primary risk elements of dementia are reviewed. Finally, the future perspectives of dementia (AD) focusing on the impact of the new treatment are discussed.
Alzheimer's disease (AD) is the most common neurodegenerative disorder. Although its etiology remains incompletely understood, genetic variants are important contributors. The prediction of AD risk through individual genetic variants is an important topic of research that may have individual and societal consequences when preventive treatments will become available. However, the genetic substratum of AD is heterogeneous. In addition to the extremely rare and fully penetrant pathogenic variants of the PSEN1, PSEN2 or APP genes causing autosomal dominant AD, a large spectrum of risk factors have been identified in complex forms, including the common risk factor APOEɛ4, which is associated with a moderate-to-high risk, common polymorphisms associated with a modest individual risk, and a plethora of rare variants in genes like SORL1, TREM2 or ABCA7 with moderate to high-magnitude effect. Understanding how these genetic factors contribute to AD risk in a given individual, in additional to non-genetic factors, remains a challenge. Over the last 10 years, age-related penetrance curves have progressively incorporated advances in the knowledge of AD genetics, from APOE to common polygenic components and, currently, SORL1 rare variants, which represents an important step towards precision medicine in AD. In this review, we present the complex genetic architecture of AD and we expose the prediction of AD risk according to its underlying genetic component.
Scientific advances over the last four decades have steadily infused the Alzheimer's disease (AD) field with great optimism that therapies targeting Aβ, amyloid, tau, and innate immune activation states in the brain would provide disease modification. Unfortunately, this optimistic scenario has not yet played out. Though a recent approval of the anti-Aβ aggregate binding antibody, Aduhelm (aducanumab), as a “disease-modifying therapy for AD” is viewed by some as a breakthrough, many remain unconvinced by the data underlying this approval. Collectively, we have not succeeded in changing AD from a largely untreatable, inevitable, and incurable disease to a treatable, preventable, and curable one. Here, I will review the major foci of the AD “disease-modifying” therapeutic pipeline and some of the “open questions” that remain in terms of these therapeutic approaches. I will conclude the review by discussing how we, as a field, might adjust our approach, learning from our past failures to ensure future success.
Alzheimer's disease (AD), one of the most common neurodegenerative diseases worldwide, has a devastating personal, familial, and societal impact. In spite of profound investment and effort, numerous clinical trials targeting amyloid-β, which is thought to have a causative role in the disease, have not yielded any clinically meaningful success to date. Iron is an essential cofactor in many physiological processes in the brain. An extensive body of work links iron dyshomeostasis with multiple aspects of the pathophysiology of AD. In particular, regional iron load appears to be a risk factor for more rapid cognitive decline. Existing iron-chelating agents have been in use for decades for other indications, and there are preliminary data that some of these could be effective in AD. Many novel iron-chelating compounds are under development, some with in vivo data showing potential Alzheimer's disease-modifying properties. This heretofore underexplored therapeutic class has considerable promise and could yield much-needed agents that slow neurodegeneration in AD.
