1. Hereditary dementia in Australian families: could there be a protective gene? William Brooks, Olivier Piguet, Hayley Bennett, G Anthony Broe Prince of Wales Medical Research Institute

2. Presenter’s note This paper was intended to provide a general introduction to genetics and dementia as well as some feedback to the Association on the work done by Dr Piguet and colleagues with the Alzheimer’s Australia research grant he was awarded in 2002. We are very grateful to the Association for this support. Some of the slides presented in the talk have been removed from this version to avoid breaching copyright and to preserve the privacy of the individuals and families involved. I hope the gist of the talk remains reasonably clear. For details of published references and any enquiries please send an email to w.brooks@unsw.edu.au or telephone me on (02) 9399 1101.w.brooks@unsw.edu.au Bill Brooks

3. Acknowledgements Clinical assessment and ascertainment of families Professor Tony Broe, Dr Helen Creasey, Professor Henry Brodaty, Professor John Snowdon Laboratory genetic studies Professor Garth Nicholson, Concord Hospital Professor Peter Schofield, Dr John Kwok, Garvan Institute Dr Margaret Smith, Department of Pathology, University of Melbourne Professor Ralph Martins, Hollywood Hospital, University of WA, ECU Neuropathology Professor Glenda Halliday, Prince of Wales Medical Research Institute Associate Professor Jillian Kril, CERA, Concord Hospital, University of Sydney Funding: Alzheimer’s Australia, AAG, NHMRC Project grants, NHMRC Network of Brain Research into Mental Disorders

4. Acknowledgements Family members, for their helpful participation! Geneticists and counsellors from the state genetics services

5. Dominant inheritance Single gene involved Symptoms when 50% of the gene product is defective (unlike recessive illnesses) Finding the gene and working what it does should tell us something fundamental about the disease process, and Allow development of rational measures to treat or prevent the disease, which may be applicable to everyone.

7. www.alzforum.org

8. Dementia genes with causative mutations Alzheimer’s disease –Chromosome 21: Amyloid precursor protein gene –Chromosome 14: Presenilin-1 gene –Chromosome 1:Presenilin-2 gene Frontotemporal dementia with parkinsonism linked to C17 (FTDP-17) –Chromosome 17: Tau gene Others (Huntington’s, familial CJD, MJD etc)

9. Australian hereditary dementia families Familial Alzheimer’s disease –APP mutations4 families +1 HCHWA-D –Presenilin-1 mutations12 mutations in 16 families –Familial AD, mutation not known1 family –Familial AD/motor neurone disease2 families Frontotemporal dementia with parkinsonism linked to chromosome 17 (FTDP-17) –Tau gene mutations5 mutations in 7 families

10. Is spastic paraparesis protective? Why do some people with spastic paraparesis and PS-1 mutations have a later onset age and relatively preserved cognitive function? Is a genetic factor responsible? APOE genotype has no apparent modifying effect Studies currently underway at Garvan, including overseas families from Toronto, Belgium and Finland.

11. Summary and conclusions Studying families with hereditary dementia syndromes provides insights into the pathogenesis of Alzheimer’s disease and similar conditions Documenting variability in clinical and neuropathological features may lead to the discovery of beneficial genes as well as harmful ones