JPND:A European DNA bank for deciphering the missing heritability of Alzheimer's disease

Lead Research Organisation: Cardiff University
Department Name: School of Medicine

Abstract

Understanding the genetics of Alzheimer's disease is one of the best ways of improving our knowledge of the biology underpinning the disease. Genes are thought to account for around 80% of disease risk. Advances in the field of biomedical genetics have allowed the identification of 26 genes that act to increase a person's risk of developing disease. However, it is believed that there are at least the same number of genes that also contribute to disease risk are yet to be discovered.
To identify new disease related genes substantial additional efforts are required. It is particularly important to maximise sample numbers; studies of other complex genetic diseases have shown that the number of disease genes a study can identify increases with the sample size of the study.
Our primary objective is therefore to increase the number of Alzheimer's disease samples with genetic data to identify new risk genes for disease. We will achieve this via the creation of a European Alzheimer's Disease DNA BioBank (EADB). We have identified a European cohort of 31,911 AD cases (of which 24,049 have no genetic data) and 40,802 controls (of which 15,638 have no genetic data) from 11 countries. We will undertake genotyping of these 39,687 samples with no genetic data and analyse the new data along with existing genetic data via standard methods. This study plan will allow us to identify new Alzheimer's disease risk genes and the biological pathways in which these genes function. This initiative will increase the number of Alzheimer's disease samples available for genetic studies in Europe by more than 4-fold and worldwide by almost 2-fold.
In parallel, the EADB will collect samples from Europe's largest cohort of mild cognitive impairment cases, with a view to identifying genes that change the rate of disease progression and cognitive decline. We have available to us 9,109 mild cognitive impairment cases (of which 6,952 have no genetic data). The cohort includes data on conversion to Alzheimer's disease, cognitive and non-cognitive parameters, cerebrospinal fluid proteins and brain imaging.
The identification of genes that are functional in pathways that act to modify Alzheimer's disease risk and increase the rate of disease progression, or increase cognitive decline in mild cognitive impairment, is essential to allow the development and testing of novel treatments.

Technical Summary

Our objective is to significantly increase the generation of Genome Wide Association Study-based population data via the creation of a European Alzheimer's Disease DNA BioBank (EADB). We shall be able to collate 31,911 AD cases (of which 24,049 have yet to be genotyped) and 40,802 controls (of which 15,638 have yet to be genotyped) from 11 countries. GWASs and complementary statistical studies (based on genotype and imputation data) will be performed, in order to capture the missing heritability and identify potential disease pathways. This initiative will increase the number of AD samples available for genetic studies in Europe by more than 4-fold and worldwide by almost 2-fold.
In parallel, the EADB will collect DNA samples from Europe's largest longitudinal cohort of MCI cases, with a view to identifying genetic markers that modulate the rate of disease progression and cognitive decline. At present, we have compiled approximately 9,109 MCI cases (of which 6,952 have yet to be genotyped) and have data on AD conversion, neuropsychological parameters, cerebrospinal fluid biomarkers and neuroimaging for most of these samples. We shall investigate the influence of genetic risk factors for AD in a genome-wide- or hypothesis-based manner.
From a translational perspective, the identification of genetic factors in pathways that modulate the AD risk and increase the rate of disease progression/cognitive decline in MCI will be pivotal for the development and testing of therapeutic approaches.

Planned Impact

As a global and growing problem associated with an increasing aged population, studies to improve, focus and streamline research on Alzheimer's disease will have a universal impact.
In addition to the vast academic impact of this study, we anticipate a significant impact on the delivery of clinical trials for AD therapies, and any commercial private sector companies involved in these trials will benefit. Participants can be selected for trials based on their genetic profile, increasing the likelihood of success using a smaller study cohort. In addition, the biomarkers used to measure trial outcome will be more accurately defined leading to clearer interpretation of results. This will impact on study design and the financial investment required finding drugs effective in targeting AD.
The identification of as yet unaccounted for AD genetic risk factors will help guide the research undertaken by, or funded by, commercial companies, government agencies and charities. A better, more comprehensive, genetic profile of AD will improve research focus and deliver better value for money from AD research. This should lead to more impactful research studies for minimal investment.
In the long term, the accurate and early prediction of AD risk has impact for the entire general public through the implementation of early detection and development of personalised medicine. Those at high risk of AD can be identified, together with the specific pathophysiological pathways involved, before providing a personalised medicine to specifically target the manifestation of disease in the individual.

Publications

10 25 50
 
Description Brains for Dementia Research 
Organisation King's College London
Department Institute of Psychiatry, Psychology & Neuroscience
Country United Kingdom 
Sector Academic/University 
PI Contribution Management of Cardiff BDR Centre, recruitment and Brain Banking
Collaborator Contribution Site management, oversight of the BDR cohort
Impact BDR aims to set a gold standard for brain donation by coordinating brain banks across the country and providing high quality tissue to researchers. We hope to enable more people to get involved in brain donation, thus boosting the number of brains available for this important research. BDR is unique because every brain donor is monitored throughout their later life. This means that a complete medical history is available to accompany their donated brain tissue. This is crucial to allow researchers to make the most of donated tissue. BDR run an online database of brain tissue. Researchers can search the database and apply to BDR for samples.
Start Year 2015
 
Description Brains for Dementia Research 
Organisation Newcastle University
Country United Kingdom 
Sector Academic/University 
PI Contribution Management of Cardiff BDR Centre, recruitment and Brain Banking
Collaborator Contribution Site management, oversight of the BDR cohort
Impact BDR aims to set a gold standard for brain donation by coordinating brain banks across the country and providing high quality tissue to researchers. We hope to enable more people to get involved in brain donation, thus boosting the number of brains available for this important research. BDR is unique because every brain donor is monitored throughout their later life. This means that a complete medical history is available to accompany their donated brain tissue. This is crucial to allow researchers to make the most of donated tissue. BDR run an online database of brain tissue. Researchers can search the database and apply to BDR for samples.
Start Year 2015
 
Description Brains for Dementia Research 
Organisation University of Bristol
Country United Kingdom 
Sector Academic/University 
PI Contribution Management of Cardiff BDR Centre, recruitment and Brain Banking
Collaborator Contribution Site management, oversight of the BDR cohort
Impact BDR aims to set a gold standard for brain donation by coordinating brain banks across the country and providing high quality tissue to researchers. We hope to enable more people to get involved in brain donation, thus boosting the number of brains available for this important research. BDR is unique because every brain donor is monitored throughout their later life. This means that a complete medical history is available to accompany their donated brain tissue. This is crucial to allow researchers to make the most of donated tissue. BDR run an online database of brain tissue. Researchers can search the database and apply to BDR for samples.
Start Year 2015
 
Description Brains for Dementia Research 
Organisation University of Manchester
Country United Kingdom 
Sector Academic/University 
PI Contribution Management of Cardiff BDR Centre, recruitment and Brain Banking
Collaborator Contribution Site management, oversight of the BDR cohort
Impact BDR aims to set a gold standard for brain donation by coordinating brain banks across the country and providing high quality tissue to researchers. We hope to enable more people to get involved in brain donation, thus boosting the number of brains available for this important research. BDR is unique because every brain donor is monitored throughout their later life. This means that a complete medical history is available to accompany their donated brain tissue. This is crucial to allow researchers to make the most of donated tissue. BDR run an online database of brain tissue. Researchers can search the database and apply to BDR for samples.
Start Year 2015
 
Description Brains for Dementia Research 
Organisation University of Oxford
Country United Kingdom 
Sector Academic/University 
PI Contribution Management of Cardiff BDR Centre, recruitment and Brain Banking
Collaborator Contribution Site management, oversight of the BDR cohort
Impact BDR aims to set a gold standard for brain donation by coordinating brain banks across the country and providing high quality tissue to researchers. We hope to enable more people to get involved in brain donation, thus boosting the number of brains available for this important research. BDR is unique because every brain donor is monitored throughout their later life. This means that a complete medical history is available to accompany their donated brain tissue. This is crucial to allow researchers to make the most of donated tissue. BDR run an online database of brain tissue. Researchers can search the database and apply to BDR for samples.
Start Year 2015
 
Description CADR 
Organisation Bangor University
Country United Kingdom 
Sector Academic/University 
PI Contribution Sample collection, data analysis
Collaborator Contribution sample availability, data analysis, research management
Impact None yet, multidisciplinary across the arts, social and biomedical science
Start Year 2015
 
Description CADR 
Organisation Swansea University
Department Swansea University Medical School
Country United Kingdom 
Sector Academic/University 
PI Contribution Sample collection, data analysis
Collaborator Contribution sample availability, data analysis, research management
Impact None yet, multidisciplinary across the arts, social and biomedical science
Start Year 2015
 
Description Illumina Chip Development 
Organisation Illumina Inc.
Country United States 
Sector Private 
PI Contribution We are working with a Illumina to get chips for SNP detection into production. These chips will be the best and most up to date methods for detection of AD, and will be future-proofed for tailored experiments into pathways of disease and personalised medicines.
Collaborator Contribution Confidential
Impact Illumina Neurochip
Start Year 2016
 
Description Interview for National News 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Public/other audiences
Results and Impact Broadcast for BBC Wales on the research undertake
Year(s) Of Engagement Activity 2018
 
Description Piece for 'The Conversation' 
Form Of Engagement Activity A magazine, newsletter or online publication
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Public/other audiences
Results and Impact Lay person piece on the genetics of Alzheimer's disease
Year(s) Of Engagement Activity 2016
URL https://theconversation.com/if-you-develop-alzheimers-will-your-children-get-it-too-62986
 
Description Press release for new manuscript 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Media (as a channel to the public)
Results and Impact Press release for the Nature Genetics publication (2017)
Year(s) Of Engagement Activity 2017