Download Could there be a Protective Gene?

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
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 [email protected] or telephone me on (02) 9399 1101.
Bill Brooks
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
Acknowledgements
Family members, for their helpful
participation!
Geneticists and counsellors from the state
genetics services
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.
www.alzforum.org
Dementia genes with causative
mutations
Alzheimer’s disease
– Chromosome 21:
– Chromosome 14:
– Chromosome 1:
Amyloid precursor protein gene
Presenilin-1 gene
Presenilin-2 gene
Frontotemporal dementia with parkinsonism linked to
C17 (FTDP-17)
– Chromosome 17:
Tau gene
Others (Huntington’s, familial CJD, MJD etc)
Australian hereditary dementia families
• Familial Alzheimer’s disease
–
–
–
–
APP mutations
Presenilin-1 mutations
Familial AD, mutation not known
Familial AD/motor neurone disease
4 families +1 HCHWA-D
12 mutations in 16 families
1 family
2 families
• Frontotemporal dementia with parkinsonism linked to
chromosome 17 (FTDP-17)
– Tau gene mutations
5 mutations in 7 families
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.
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