Testosterone levels decline as men age, and the urge to treat this natural process with hormone replacement has sparked controversy lately, because the risks and benefits of such a course are not well known. One recently appreciated down side to testosterone loss is an increased risk of developing Alzheimer disease (Moffat et al., 2004; Rosario et al., 2004). A paper out this week in the Journal of Neuroscience, from Christian Pike’s lab at the University of Southern California in Los Angeles, shows that in a mouse model of AD, androgen depletion accelerates the age-dependent appearance of Aβ plaques and cognitive defects, while replacement therapy slows the process down. The results demonstrate one way that age-related testosterone loss could increase the risk of AD in men and support the idea that replacement therapy might be useful for the treatment or prevention of AD (see ARF related news story).

To understand the relationship between androgens and AD, first author Emily Rosario looked at the effect of androgen depletion on pathology in the triple transgenic AD mouse model (APPswe, PS1M146V, tauP301L) created in coauthor Frank LaFerla’s lab. When the researchers removed the animals’ testes at 3 months of age, the gonadectomized mice showed an increase in Aβ load in the brain at 7 months compared to their unaltered littermates. The accelerated Aβ accumulation was prevented by starting testosterone replacement at the time of surgery. Parallel to the Aβ accumulation, the researchers detected more severe deficits in a spontaneous alternation test in androgen-deprived mice. The behavior, which relies on hippocampal-dependent working memory, was also normalized by hormone replacement.

The pathway linking testosterone and Aβ accumulation is unknown, but the results are consistent with an increase in Aβ that was observed in normal rats after gonadectomy (Ramsden et al., 2003).

“Our findings extend a growing literature indicating that androgens can benefit cognitive abilities significantly by mechanisms that may include a reduction in Aβ levels,” the authors conclude. “The findings not only demonstrate a significant role of androgen depletion in AD pathogenesis, but also predict that androgen-based therapeutics may function effectively in the prevention of AD,” they write.—Pat McCaffrey

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References

News Citations

  1. Testosterone Therapy for Men with Alzheimer Disease?

Paper Citations

  1. . Free testosterone and risk for Alzheimer disease in older men. Neurology. 2004 Jan 27;62(2):188-93. PubMed.
  2. . Age-related testosterone depletion and the development of Alzheimer disease. JAMA. 2004 Sep 22;292(12):1431-2. PubMed.
  3. . Androgens modulate beta-amyloid levels in male rat brain. J Neurochem. 2003 Nov;87(4):1052-5. PubMed.

Further Reading

Papers

  1. . Androgens, aging, and Alzheimer's disease. Endocrine. 2006 Apr;29(2):233-41. PubMed.
  2. . Estrogen and androgen protection of human neurons against intracellular amyloid beta1-42 toxicity through heat shock protein 70. J Neurosci. 2004 Jun 9;24(23):5315-21. PubMed.
  3. . Androgens protect against apolipoprotein E4-induced cognitive deficits. J Neurosci. 2002 Jun 15;22(12):5204-9. PubMed.

Primary Papers

  1. . Androgens regulate the development of neuropathology in a triple transgenic mouse model of Alzheimer's disease. J Neurosci. 2006 Dec 20;26(51):13384-9. PubMed.