|
GENETIC FACTORS IN ANDROGEN DEFICIENCY AND ALZHEIMER'S DISEASE
E.J. Wahjoepramono1; L.K. Wijaya1; A. Barron, 1,2 K. Taddei1,2; G.
Martins1,2; M. Howard1,2; K. deRuyck1,2; K. Bates1,; S.S. Dhaliwal3;
G. Verdile1,2;. M. Carruthers4, R.N. Martins1
1 Centre of Excellence for Alzheimer's Disease Research and Care,
School of Exercise, Biomedical and Health Sciences, Edith Cowan
University, Joondalup, WA, Australia
2 School of Psychiatry and Clinical Neurosciences, Sir James McCusker
Alzheimer Unit, Hollywood Private Hosptial,
3 Curtin University, Bentley WA
4 Centre for Men's Health, London, UK.
rmartins@cyllene.uwa.edu.au
Males who become hypogonadal in later life often report problems
with their memory. Lower than normal testosterone levels have also
been detected in patients prior to the onset of AD, as well as in
younger late-onset male AD patients, when compared to appropriate
controls. The results of some small clinical trials suggest that
testosterone can improve cognitive function in andropause. In order
to under
stand the mechanism by which diminished testosterone levels leads
to neurodegeneration we have evaluated its effects on regulating
the levels of the amyloid ß-peptide (Aß) which is central to the
pathogenesis of AD. We initially reported that the testosterone
lowering agent, leuprolide, resulted in a marked rise in plasma
Aß ?levels. We subsequently showed in elderly cognitively impaired
men that plasma testosterone levels were negatively correlated with
plasma Aß ?levels and positive correlated with cognition and that
this effect was influenced by geneßtic factors particularly the
APOE gene. To determine whether changes in plasma A reflect changes
in the CNS we examined the effects of testosterone withdrawal and
replacement on both plasma and cerebrospinal fluid (CSF) levels
in guinea pigs. We report that castration resulted in increased
plasma and CSF Aß levels and this increase was attenuated in response
to testosterone replacement.
Since low testosterone levels are associated with elevated LH and
given that we have shown that LH per se increased Aß levels future
studies need to determine whether testosterone replacement in men
is sufficient to suppress LH levels while directly lowering Aß levels.
However directly lowering LH levels with leuprolide without testosterone
replacement is not recommended as plasma Aß levels increase markedly
with this therapeutic approach.
|
