Increasing evidence indicates that there are reductions in testosterone and estrogen levels in older men and women. These hormonal reductions may be risk factors for cognitive impairment and the development of Alzheimer's disease (AD). As testosterone levels decline as men age, there is an urge to treat this natural process with hormone replacement, just as it is done for many women undergoing menopause. The enzyme aromatase in the male brain converts some of the testosterone to the “female” hormone estrogen, which has its own neuroprotective features.
In a recent paper, researchers report that knocking out aromatase protects male transgenic mice against AD-like pathology and cognitive decline. In the knockout mice (which lacks the aromatase), testosterone is elevated in the brain, whih leads to a decrease in ß-secretase (BACE) and an increase in neprilysin—enzymes involved in the making and breaking, respectively, of amyloid-ß (Aß).
How does the increased testosterone prevent amyloid pathology? Testosterone can enhance Aß clearance via activating the enzyme neprilysin and decreasing BACE expression. As testosterone levels drop, more beta-amyloid is produced by BACE, and less beta-amyloid is removed by neprilysin. So, are we closer to a trial of testosterone for AD?
In fact, a small trial conducted at the University of California at Los Angeles found that male Alzheimer's patients given testosterone treatment reported some improvements to their caregivers in the parameters that measure quality of life. However, when these same patients were interviewed by clinicians involved in the study, no statistically significant improvement in cognitive function was measured.
Even so, the possibility of using testosterone for treatment of Alzheimer's remains an open question that is under investigation.
McAllister C, Long J, Bowers A, Walker A, Cao P, Honda S-I, Harada J, Staufenbiel M, Shen Y, Li R. Genetic targeting of aromatase in male amyloid precursor protein transgenic mice down-regulates beta-secretase (BACE1) and prevents Alzheimer-like pathology and cognitive impairment. J. Neurosci 2010 May 26; 30:7326-7334.
Michael S. Rafii, MD, PhD
Associate Medical Director
Alzheimer's Disease Cooperative Study