NEW YORK (Reuters Health) - Free testosterone levels are lower among men who later develop Alzheimer's disease (AD), new study findings suggest.

Furthermore, decreases in free testosterone level may be mediated primarily by high levels of sex hormone-binding globulin in both men and women, according to another trial. Both studies are published in the January 27th issue of Neurology.

Other studies have reported decreased levels of testosterone in men with AD compared with non-demented subjects. According to Dr. Susan M., at the National Institute on Aging in Baltimore, and colleagues, those studies could not discern whether the low testosterone levels were the cause or the result of AD.

Therefore, Dr. Resnick's group examined data prospectively collected in the Baltimore Longitudinal Study of Aging, originally designed to examine factors associated with prostate health and disease. The 574 men were free of AD and ranged from 32 to 87 years of age at baseline. During an average follow-up of 19.1 years, 54 were diagnosed with AD.

According to their report, serum levels of total testosterone and sex hormone-binding globulin (SBHG) were not significantly associated with AD testosterone by sex hormone-binding globulin, was inversely associated with AD onset.

After adjusting for multiple confounders, there was a 26% reduction in the risk of AD with each 10-unit increase in FAI, suggesting a protective effect of testosterone on the development of AD.

In further analyses, "even when we used only those values obtained at least 10 years before AD diagnosis, we still found a significant effect," Dr. Resnick told Reuters Health, further support for the hypothesis that testosterone levels are not a consequence of AD.

These findings suggest that "men who maintain higher levels of free testosterone have a reduced risk for AD," she added.

In the second report, Dr. Gian Benedetto Melis and colleagues at the University of Cagliari, Italy, compared hormone levels in 32 men and 64 women diagnosed with AD with those in 32 men and 72 women without AD. Subjects' BMI ranged between 20 and 22.

SHBG levels were significantly higher and FAI was significantly lower in subjects with AD, both men and women. "A lower testosterone bioavailability mainly dependent on high SHBG levels is present in lean patients with AD," they write.

Explaining these results, Dr. Resnick pointed out that unbound testosterone can cross the blood-brain barrier, where it can "work as an androgen or be converted to estrogen," which is supported by previous research showing a beneficial effect of estrogen on the central nervous system.

"We hope these findings will motivate future research," Dr. Resnick said, cautioning that "we don't believe that testosterone supplements are warranted at this point to protect against AD or to improve memory."

In fact, she said, the NIH recently commissioned an Institute of Medicine panel to advise them as to future clinical trials of testosterone replacement in men. For the time being, "they recommend that small-scale clinical trials be conducted only in groups of men who have low testosterone levels, because of safety concerns."

Neurology 2004;62:188-193,301-303

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