This project represents a formal research agreement between UA and on the other SAO. UA provides SAO research results mentioned in the title of the project under the conditions as stipulated in this contract.
We propose an integrated approach for high-profile translational genetic research of early-onset dementia. Our research builds on two major research strategies: early-onset dementia genetic research and translational biobanking.
In our early-onset dementia (EOD) research, we aim to contribute to the elucidation of the missing heritability of dementia by focusing on extreme-phenotype patients in terms of early onset or high familial load. Study of these high-genetic load patients combined with the latest next-generation sequencing and -omics technologies will lead to the discovery of new genetic factors for dementia. With translational biobanking, we build upon our existing biobank for neurodegenerative brain disease. We will further invest in the systematic collection of wide ranges of human samples from thoroughly characterized EOD patients through national and international collaborations. This will ensure that genetic findings can be translated to patient-derived material, such as e.g. body fluids for biomarker studies and brain material for expression or epigenetic studies. Through this integrated approach, we aim to facilitate the translation of genetic breakthroughs into biologically and clinically relevant approaches towards improved diagnostics, genetic counseling, and therapy of both early- and late-onset dementia.
Specifically, we will build a patient registry and biobank for EOD. The registry will hold standardized patient information (clinical, demographic, and biological data) together with information on available biomaterials (DNA, serum, plasma, fibroblasts, CSF, EBV-transformed lymphoblasts, frozen and formalin-fixed brain). We have recently developed a high-throughput and cost-effective diagnostic screening tool for the genetic screening of all known dementia genes into one single assay. This NGS-based resequencing assay of all genes associated with neurodegenerative brain diseases (NBD), referred to as the NBD MASTR assay, will be used for the deep genetic profiling of EOD patients that are submitted to the EOD registry.
The budget of this Pilot Grant will be allocated to a pilot project for the genetic profiling of 250 EOD patients using the NBD MASTR assay. This will provide epidemiological data on mutation frequencies across the NBD spectrum and reveal novel genotype-phenotype correlations. E.g. mutations in AD patients could be revealed in genes that are usually associated with other dementia types, yet unknown exon or whole-gene deletions could be detected that would otherwise be missed by classical Sanger sequencing. Patients that are negative for known genetic causes of dementia can subsequently be enrolled in whole-genome sequencing gene-discovery projects.