Modifying risk factors for Fronto Temporal Dementia – RiMod-FTD

Fronto Temporal Dementia (FTD) is a devastating pre-senile dementia characterized by the
progressive deterioration of the frontal and anterior temporal lobes. The most common symptoms
include severe changes in social and personal behaviour as well as a general blunting of emotions.
Clinically, genetically and pathologically there is considerable overlap with a wide spectrum of
neurodegenerative diseases. FTD has a very strong genetic influence. Up to 40% of cases have a
positive family history and this has been the key to the remarkable progress in our understanding of
the molecular basis of FTD. Currently, seven genes have been identified of which MAPT, GRN and
C9Orf72 explain >50% of familial cases, but how these different genes lead to a very similar clinical
phenotype despite very distinct pathologies, is still an unanswered question. For sporadic FTD the
role of genetic factors and their interplay with environmental risk factors is largely unknown.
Currently, there is no cure for FTD and the strategies for the development of successful therapies
will depend on whether a single therapy can be applied to all patients or if specific approaches are
needed for the distinct genetic, clinical and pathological subgroups. Therefore it is essential to identify all
major genetic risk factors and find both common environmental and genetic modifiers important in the
pathogenesis of the disease as well as factors that are specific for subgroups of patients.
To reach these goals we aim to use the extensive genetic and pathological knowledge that already
exists for FTD, including newly identified from our whole exome/genome sequencing and GWAS efforts,
as a starting point to decode common and distinctly affected processes and pathways in different groups
of Mendelian and sporadic FTD patients using a multi level approach based on a range of “omics” data
sets from selected patient groups as well as corresponding animal and cellular model systems. This
approach will allow us to work in a model guided and hypothesis driven fashion. Based on the
generated data, testable hypotheses on affected common and distinct gene networks will be
generated and the biological significance of identified networks will be validated in our cellular and animal
models in a targeted fashion and these experiments will pinpoint potential pathomechanisms that are
specific to a single FTD-subtype or common to all forms. The results will be utilized to refine
theoretical disease models and improve the quality of our approaches towards targeted intervention.