goate lab
Genetics of Neuropsychiatric Disease

Observational study of familial frontotemporal dementia caused by MAPT mutations

The goal of this project is to integrate clinical, biomarker, and neuropathological findings from subjects carrying the disease causing mutations, MAPT P301L and MAPT R406W. We wish to take advantage of the scientific opportunity presented by the recent development of tau PET imaging agents that will enable the detection of tau aggregates in the living human brain in individuals at high-risk for development of frontotemporal dementia (FTD). We hypothesize that tau aggregates will be detected at least a decade before the onset of clinical symptoms and that the spread of disease will be slower in R406W family members compared with P301L family members. By recruiting members of MAPT P301L and R406W families, we will develop a well-characterized cohort of autosomal dominantly inherited FTD, providing a resource for future clinical trials of anti-tauopathy therapies. Furthermore, by developing induced pluripotent stem cells (IPSC) from this cohort we will be able to study cellular pathologies associated with these mutations and to compare them with physiological changes in fluid and imaging biomarkers seen in human subjects. In future we plan to perform similar assessments in asymptomatic MAPT A152T risk variant carriers

Karch CM, Jeng AT, Goate AM. Extracellular Tau levels are influenced by variability in Tau that is associated with tauopathies. J Biol Chem. 2012 Dec 14;287(51):42751-62. doi: 10.1074/jbc.M112.380642. Epub 2012 Oct 26.