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ANDROGENS, GONADOTROPHINS AND GENETIC VARIATIONS IN MEN WITH DEMENTIA.
Hogervorst, E., Bandelow, S., Combrinck, M, Smith, A.D.
Oxford Project To Investigate Memory and Ageing, Radcliffe Infirmary,
Oxford
The Oxford Project To Investigate Memory and Ageing (OPTIMA) was
among the first groups to report that low testosterone
levels were an independent risk factor for Alzheimer's
disease (AD) and cognitive decline in men (Hogervorst,
2001; 2003; 2004a and b). There have since been several
publications from other groups that substantiated
our findings. We found that AD cases (n=112) had significantly
higher levels of gonadotropins and lower free testosterone
levels than controls (n=98). LH, FSH and SHBG all
increased with age, while free testosterone decreased.
Low free testosterone was an independent predictor
for AD. Its variance was overall explained by high
SHBG, low total testosterone (TT), high LH, an older
age and low body mass index. In non demented participants,
subclinical hyperthyroid disease (an independent risk
factor for AD, van Osch 2004), which can result in
higher SHBG levels, was additionally associated with
low free testosterone. Lowering SHBG levels and/or
screening for subclinical thyroid disease could perhaps
prevent cognitive decline and/or wasting in men at
risk for AD (Hogervorst 2004a). Importantly, Testosterone
Replacement Therapy (TRT) has not always shown positive
effects on cognition and may, in some groups, actually
have detrimental effects on cognition (Hogervorst
2004b). It is possible that there is a window of time
during which TRT is most effective for cognitive maintenance.
Preliminary data-analyses of a cohort of healthy non-demented
men between 47 and 72 years of age from the Maastricht
Aging Study showed level dependent positive effects
of TT levels on verbal memory, while negative associations
of TT with verbal memory functions were found in non-demented
men over 72 using data of the MRC-Foresight Challenge
cohort from Oxfordshire (Hogervorst, 2004b). In addition,
men who had not been diagnosed with dementia but who
did have an APOE epsilon 4 allele, which is a genetic
risk factor for AD, already had lower levels of testosterone
than men who were not genetically at risk (Hogervorst,
2002). We also examined the CAG repeat polymorphism
in exon 1 of the androgen receptor (AR) in an OPTIMA
cohort of 101 AD cases and 140 controls. Short allele
variants (< or = 20 CAG repeats) were associated with
AD. Thus, this AR polymorphism is of potential relevance
to the risk of AD in men as it could affect the sensitivity
of AR to testosterone levels (Lehmann, 2004). These
findings combined could suggest that therapy may be
most effective for men of a certain age-group (i.e.
those younger than 72 years of age) and/or who are
genetically at risk and/or who have lower levels of
free ('active') testosterone.
References
Hogervorst E, Bandelow S, Combrinck M, Smith AD. Low free
testosterone is an independent risk factor for Alzheimer's
disease. Exp Gerontol. 2004 Nov;39(11): 1633-9.
van Osch LA, Hogervorst E, Combrinck M, Smith AD. Low thyroid-stimulating
hormone as an independent risk factor for Alzheimer
disease.Neurology. 2004 Jun 8;62(11):1967-71.
Lehmann DJ, Hogervorst E, Warden DR, Smith AD, Butler HT, Ragoussis
J. The androgen receptor CAG repeat and serum
testosterone in the risk of Alzheimer's disease in
men. J Neurol Neurosurg Psychiatry. 2004 Jan;75(1):163-4.
Hogervorst E, De Jager C, Budge M, Smith AD. Serum levels
of estradiol and testosterone and performance in different
cognitive domains in healthy elderly men and women.
Psychoneuroendocrinology. 2004 Apr;29(3):405-21.
Hogervorst E, Combrinck M, Smith AD.Testosterone and gonadotropin
levels in men with dementia. Neuro Endocrinol Lett.
2003 Jun-Aug;24(3-4):203-8.
Hogervorst E, Lehmann DJ, Warden DR, McBroom J, Smith AD.
Apolipoprotein E epsilon4 and testosterone interact
in the risk of Alzheimer's disease in men. Int J Geriatr
Psychiatry. 2002 Oct;17(10):938-40.
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