During this year we have found several families with progranulin mutations and now have papers published and in press on this. This work has shown that progranulin mutations produce a fairly typical phenotype and are not associated with overlapping disorders such as amyotrophic lateral sclerosis. We have used dense SNP based linkage mapping to identify novel loci associated with familial frontotemporal dementia. This work shows linkage overlapping an extant locus on chromosome 9 and we are now involved in a positional cloning project to determine the underlying genetic mutation in this family; this project involves sequencing of approximately 80 genes within the critical interval and is currently 50% complete.? Our ongoing work on dementia with Lewy bodies and Parkinson's disease with dementia primarily focuses on analysis of loci identified in our genome wide association studies in Alzheimer's disease and Parkinson's disease to see if we can tease out the genetic basis of dementia in these disorders which neuropathologically sit between Alzheimer's and Parkinson's disease. This work complements our analysis of quantitative neuropathology in a series of brains from a longitudinal aging study from Finland; in particular the analysis of these neuropathological measures in terms of genetic risk - we have performed quantitative trait locus mapping in approximately 250 such brains and identified several loci positively associated with amyloid, tau and synuclein pathologies.
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