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BEHANDLING-God og treffsikker diagnostikk, behandling og rehabilitering

Identifying the polygenic architecture of dementia leveraging new statistical methods

Alternative title: null

Awarded: NOK 4.0 mill.

What we have seen in recent years is that dementia is quite heritable. We know that genetic vulnerability and environmental stress work together, but not how. If we find this relationship, one can more easily develop measures that work, says Professor Andreassen. He uses research to collect and examine several thousand samples of people in early stages of dementia. - The number of participants powers the analysis and makes it possible to find many more associations than in smaller studies, says Andreassen. His team is now working to find out which genes subjects have in common and what mechanisms control whether they translate into dementia, when it happens and why. To achieve this he must examine a large number of people with methods and techniques that have not existed before in recent years. Major disease group - In health care we have today three major diseases - heart disease, brain disorders and cancer. Now they have developed good treatment for heart disease. Cancer begins also getting better treatment. People may have a rich life longer and get treatment if they become ill. But if the brain is affected, we have much less knowledge and mistreatment. Do you think the treatment of the future first will be directed at individuals or preventive measures for the whole population? We do not know yet. Heart disease is a good example. During the 60s and 70s was a heart attack one of the leading causes of death and morbidity. People smoked and ate unhealthy. Then it was discovered that cholesterol was unfortunate and that smoking was dangerous. Government launched prevention measures while also developed treatment. Now the outcome is much better. The same concept can we use for dementia. It helps to investigate but improvements do not happen overnight.

Dementia includes a variety of clinical phenotypes characterized by cognitive, neuropsychiatric and behavioral dysfunctions, and constitutes a range of diagnoses with Alzheimers disease (AD) as the most prevalent. These disorders are severe and major pub lic health problems with high heritability, but the pathophysiology in relation to genetic factors are mainly unknown and there is no effective treatment. Disease genes have been identified, but many genes remain undiscovered, and there are indications of pleiotropy; the same gene can lead to different phenotypes. We will genotype a large sample (n=2000 cases and controls) of dementia focusing on AD, collected from our Scandinavian network of clinical sites. Patients are thoroughly described with standard ized clinical assessments, diagnostic procedures, symptom assessments, cognitive profiling, and brain MRI (in subsample) acquired with high quality protocol. Our collaborator deCODE (Iceland) will do state-of-the-art genotyping. We will analyze the data w ith our novel statistical framework to improve power for detecting small genetic influences in genome-wide association studies, enabling an informed approach to identify polygenic architecture. This will give us a unique opportunity to identify new geneti c variants and determine the association to phenotype characteristics. Through access to large international gene consortiums, we will identify the genetic overlap between different phenotypes, and replicate our findings. We will use newly developed Bayes ian statistical tools for testing the clinical usefulness of polygenic scores together with clinical and brain MRI measures, as diagnostic tools. The project builds on recent high impact discoveries by the project group members, who include Scandinavian l eaders in the field and strong international groups. The results will provide novel knowledge about the disease mechanisms of dementia, and may form the basis for future drug development.

Funding scheme:

BEHANDLING-God og treffsikker diagnostikk, behandling og rehabilitering