www.andropause.org.uk

back to Programme

ALZHEIMER’S DISEASE: MOLECULAR RISK FACTORS AND THERAPEUTIC APPROACHES

Dr. Ralph N. Martins

Sir James McCusker Alzheimer's Disease Research Unit, Department of Psychiatry, University of Western Australia, Hollywood Private Hospital, Monash Avenue, Nedlands 6009.

Estrogen replacement therapy  (ERT) is widely prescribed to counteract the symptoms of menopause. Postmenopausal women taking estrogen enjoy a reduced risk of cardiovascular disease and osteoporosis. Recently, ERT has been shown to protect against Alzheimer's disease (1). However, like cardiovascular disease, oestrogen replacement does not appear to benefit women who already have the disease suggesting a role for this hormone more in prevention rather than treatment. There are now several studies which show that oestrogen acts by reducing the production of a small protein called b amyloid which is central to the pathogenesis of Alzheimer's disease(2,3).

Like oestrogen, studies have shown that testosterone can also reduce the levels of the toxic b amyloid protein in neuronal cells in culture (4) though unlike estrogen there is no information of its effects on protecting against Alzheimer's in elderly men.

Our recent study is the only clinical report to date which showed that testosterone withdrawal resulted in altered b amyloid levels in blood plasma (5). We now report that castration of guinea pigs resulted in increased Ab levels both in blood and the brain. These preliminary findings indicate that testosterone may regulates b amyloid levels in vivo and may function to protect against Alzheimer's disease. However, the clinical significance of testosterone in protecting against Alzheimer's disease must await a large-scale double blind clinical trial.

References

1.Tang, MX, Jacobs D, Stern Y, et al. Effect of oestrogen during menopause on risk and age at onset of Alzheimer's disease. Lancet. 1996; 34:429-432.

2.Xu H, Gouras GK, Greenfield JP, et al. Estrogen reduces neuronal generation of Azheimer's b-amyloid peptides. Nat med. 1998;4:447-451

3. Gouras GK, Xu H, Gross RS, et al. Testosterone reduces neuronal secretion of Alzheimer's b-amyloid peptides. Proc Natl Acad Sci USA. 2000;97:1202-1205.

4. Petanceska SS, Nagy V, Frail D, Gandy S. Ovariectomy and 17-b-estradiol modulate the levels of Alzheimer's amyloid b peptides in brain. Neurology. 2000; 54:2212-2217

5. Gandy S, Almeida O, Fonte J et al. Chemical Andropause and Amyloid-b Peptide JAMA 2001; 285: 2195-2196.

Dr. Ralph Martins, BSc, PhD.

Sir James McCusker Aizheimer's Disease Research Unit,

Department of Psychiatry, University of Western Australia,

Hollywood Private Hospital, Monash Avenue, Nedlands 6009,

Perth, Western Australia

Email: rmartins@cyllene.uwa.edu.au

Experience:

2001-current - Associate Professor, Department of Psychiatry and Neurogenetics, The University of Western Australia, Hollywood Private Hospital, Western Australia.

2001-2004 -Professor on Staff, Research Center and Community Services, Universitas Peila Harapan, Karawaci, Tangerang, Indonesia.

1997-2001 - Senior Research Fellow in Surgery, at the Hollywood Private Hospital, University of Western Australia, Nedlands, Perth, Western Australia 6009.

1990-1997 - Senior Research Officer at the Department of Pathology, University of Melbourne.

Collaboration has been ongoing for the last 8 years with Professor Sam Gandy from Cornell University and Drs Peter Hyslop and Paul Fraser from the University of Toronto to identify genetic risk factors in Alzheimer’s disease.  This collaboration has involved exchange of students and staff between the University of Western Australia and the American and Canadian institutes.  The collaboration with Professor Sam Gandy has resulted in his recent visit (Sept - November 2000) to the University of Western Australia as the Raine Visiting Professor and several joint publications including a recent publication in JAMA.

Recent collaboration has been established with Professor Malcolm Goyns from Sunderland University in England. Professor Malcolm Goyns is providing expertise in the use of molecular biology techniques for the identification of genes involved in Alzheimer’s disease.

My current research interests are focused on understanding the mechanisms and factor(s) leading to the abnormal release and deposition of A4 in Alzheimer's disease. The lipid transport protein, apolipoprotein E whose E4 isoform has been associated as a major risk factor for Alzheimer’s disease is being intensively investigated in my laboratory. Recently the presenilin genes have been identified and my laboratory together with others have shown that patients with mutations in the presenilin gene produce increased amounts of bA4. My laboratory is currently working to elucidate how the presenilin 1 protein regulates the metabolism of the amyloid precursor protein to produce bA4.  The function of the precursor of bA4, the amyloid precursor protein, is another important area where my interests lie.

Clinical research is underway to assess genetic and molecular risk factors in an attempt to predict individuals at high risk of developing Alzheimer's disease.  Commercial funding is currently being sought to undertake this clinical research and to develop therapeutic agents that neutralize the toxicity of bA4.