With treatments to prevent progression of Alzheimer’s disease (AD) still proving to be elusive, Prof Philippe Amouyel, Director, DISTALZ (DISruptive Thinking for ALZheimer’s disease), talks with Shalini Gupta about how research offers a new ray of hope. According to the World Health Organization (WHO), approximately 34 million people worldwide will have AD by 2025, with the highest increase expected among developing countries. This September 2012 marks the first global World Alzheimer’s Month, an international campaign to raise awareness and challenge stigma
What does DISTALZ aim to do?
| Prof Philippe Amouyel |
DISTALZ aims to explore new pathways involved in Alzheimer’s pathophysiological processes, some being suggested by agnostic genomic approaches. New biological clues identified would then be developed as potential biomarkers and drug targets. Using a multidisciplinary approach, we will set up the clinical, social and ethical bases of new clinical trials to test promising new components in high-risk patients or individuals, identified thanks to a sophisticated battery of biomarkers, years before any conversion to AD.
We will offer a common identity with a competitive critical mass in terms of researchers and research capacities, potentiating the existing international visibility of each individual team, significantly increasing their attractiveness, offering a unique setting for higher-education programmes, favouring translational medicine, technological transfers and public information, able to compete and collaborate with other centres of excellence in neurodegenerative disease around the world.
What is the plan of action at DISTALZ?
Its plan of action will be developed along four research axes:
- From gene to pathophysiological hypotheses: We will pursue the characterisation of the genetic component of Alzheimer’s, decoding the missing heritability, performing a fine mapping of Alzheimer’s genes to identify functional variants and fuelling the following axes with putative new pathophysiological hypotheses.
- From pathophysiological hypotheses to biological pathways: The impact of these genes and pathways would then be studied on amyloid and tau metabolisms in experimental models and in particular the mechanisms controlling the enzyme activities that modulate production/clearance of Abeta, the implication of recently described APP fragments, the roles of Tau and finally the protein aggregation and propagation. This will lead to the development of more comprehensive experimental models for biological drug screening tests.
- From biological pathways to effective targets: Genetic and biological tests stemming from the results of axes 1 and 2 would then be studied. The necessary validation of the new biomarkers will be carried out in the framework of the epidemiological and clinical activities of our partners, taking into account the complex interactions with other neurodegenerative and cerebrovascular diseases and aiming ultimately at a personalised medicine approach.
- From effective targets to clinical trials: The new findings would then be translated to clinical activity by allowing access to precisely characterised patients at an early stage of the disease and by anticipating the psychological and social consequences of an early diagnosis, taking into account all ethical dimensions.
What past approaches to develop an effective cure for Alzheimer’s have failed and why?
Our understanding of Alzheimer’s pathophysiological pathways has considerably evolved over the last 15 years, unmasking new tracks and offering opportunities for the development of new pharmacological targets and cellular/animal models. However, to date, most treatments directed towards these pathways have failed in slowing down the degenerative processes. One possible explanation might be related to the long standing process of brain damage and the delayed initiation of treatment at a stage where dementia is irremediably present, with no hope of resilience of the brain functions. Identifying the optimal time windows for intervention remains a major challenge for treatment here. In parallel, other solutions aiming at preventing or slowing-down neurodegeneration through risk factor modifications such as physical exercise and vascular risk treatment have been also proposed but not yet clinically validated.
Is Alzheimer’s genetic or hereditary? What have been the findings of the researchers at Distalz?
As any complex chronic diseases, Alzheimer’s Disease result from interactions between environmental risk factors and a genetic susceptibility background. Some rare cases are hereditary characterised with the presence of a specific mutation in a specific gene, very often associated with an early age at onset, lower than 65 years (and sometimes less than 45). However, for the vast majority, we estimate that around 60 per cent is associated with a genetic susceptibility explained by multiple genes with minor effects. The characterisation of these genetic risk factors is essential for the identification of new causative pathways. Thanks to whole genome high-throughput techniques and the largest high quality collections of AD patients and controls from various countries which they have access to, DISTALZ partners systematically characterise the molecular bases of the genetic components. In the last three years, we have made progres in characterising AD genetic susceptibility using Genome Wide Association Studies (GWAS) to locate genes harbouring single nucleotide polymorphisms (SNP) associated with AD risk. The EADI consortium (European Alzheimer’s Disease Initiative), gathering five countries, 6,322 cases and 10,373 controls, has made it possible to identify 10 new genes, alone or in collaboration with other consortia including the European Alzheimer’s Disease Initiative (EADI), the Alzheimer’s Disease Genetics Consortium (ADGC), the Genetic and Environmental Risk in Alzheimer’s Disease (GERAD), the Cohorts for Heart and Aging in Genomic Epidemiology (CHARGE) and the International Genomics Alzheimer’s Project (IGAP).