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Chemical Andropause and Amyloid- Peptide

To the Editor: Estrogen status appears to modify the risk of developing Alzheimer disease (AD).¹ It has recently been proposed that this may be due to the effect of gonadal hormones on amyloid- peptide (A), which is the main neurotoxic component of cerebral amyloid found in AD.^2-4 Furthermore, rising plasma A levels have been found to be associated with incipient AD,⁵ and a genetically linked phenotype of elevated plasma A levels appears to be related to the risk for late-onset AD.⁶ We studied the effect of gonadal hormone withdrawal in men on plasma levels of A^1-40.

Method
We measured plasma levels of testosterone, 17 -estradiol, and A^1-40 in 6 men aged 44 to 83 years who underwent hormonal suppressive therapy for adenocarcinoma of the prostate. For all 6 patients, the regimen was composed of flutamide (250 mg, 3 times daily) and leuprorelin acetate (22.5 mg, intramuscularly, weekly for 12 weeks). Samples were obtained 1 week prior to the first treatment and on weeks 4, 12, and 24.

Results
Plasma levels of testosterone and 17 -estradiol declined precipitously and then stabilized at low detectable levels during the first 2 months of therapy in all 6 patients (Figure 1). Plasma A^1-40 concentrations increased in a parallel manner by about 2-fold and then stabilized for at least 6 months (P<.01 for the comparison of mean A^1-40 level before treatment vs mean A^1-40 level following 24 weeks of treatment).

View larger version (11K): [in this window] [in a new window] Figure. Plasma Concentrations of Amyloid- Peptide (A), Testosterone, and 17-Estradiol From 6 Men With Adenocarcinoma of the Prostate Plasma concentrations were determined serially on samples drawn 1 week prior to initiating treatment with flutamide and leuprorelin acetate and on weeks 4, 12, and 24.

Comment
These data support the hypothesis that levels of circulating A may be under the control of gonadal hormones and suggest that gonadal hormone replacement therapy might prevent or delay AD in postandropausal men.³ Future studies should evaluate these biochemical parameters in other patients and determine whether such elevations in plasma A^1-40 levels in men are associated with an apparent icnreased risk of developing AD.^5-6

AUTHOR INFORMATION
Funding/Support: This study was sponsored by the Sir James McCusker Alzheimer's Disease Research Foundation, The Raine Medical Research Foundation, and the US National Institute on Aging program AG10491.

Acknowledgment: We thank Georgia Martins and Tammy Corica for their technical expertise.

Sam Gandy, MD,PhD; Osvaldo P. Almeida, MD,PhD,FRANZCP; Justin Fonte, MSc; David Lim, MBBS; Anna Waterrus; Nigel Spry, MBBS,FRACP; Leon Flicker, MD,PhD,FRACP; Ralph N. Martins, PhD
The University of Western Australia
Perth

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;348:429-432. FULL TEXT | ISI | PUBMED 2. Xu H, Gouras GK, Greenfield JP, et al. Estrogen reduces neuronal generation of Alzheimer beta-amyloid peptides. Nat Med. 1998;4:447-451. FULL TEXT | ISI | PUBMED 3. Gouras GK, Xu H, Gross RS, et al. Testosterone reduces neuronal secretion of Alzheimer's beta-amyloid peptides. Proc Natl Acad Sci U S A. 2000;97:1202-1205. FREE FULL TEXT 4. Petanceska SS, Nagy V, Frail D, Gandy S. Ovariectomy and 17-beta-estradiol modulate the levels of Alzheimer's amyloid beta peptides in brain. Neurology. 2000;54:2212-2217. FREE FULL TEXT 5. Mayeux R, Tang MX, Jacobs DM, et al. Plasma amyloid beta-peptide and incipient Alzheimer's disease. Ann Neurol. 1999;46:412-416. FULL TEXT | ISI | PUBMED 6. Ertekin-Taner N, Graff-Radford N, Younkin LH, et al. Linkage of plasma A42 to a quantitative locus on chromosome 10 in late-onset Alzheimer's disease pedigrees. Science. 2000;290:2303-2304. FREE FULL TEXT

Letters Section Editors: Stephen J. Lurie, MD, PhD, Senior Editor; Jody W. Zylke, MD, Contributing Editor.

JAMA. 2001;285:2195-2196.

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