Endogenous sex hormones, cognitive decline and future dementia in old men

A prospective population-based study has found that higher estrogen levels in older men are associated with an increased risk of dementia. By contrast, levels of testosterone were not associated with cognitive decline.

The study is in the August issue of Annals of Neurology.

As our population ages, the impact of dementia will grow. By the year 2050, some 13 million Americans could have Alzheimer's disease, which is the most common cause of dementia. Researchers are searching to understand risk factors and some studies have suggested that sex hormones play a role. One large study showed that women receiving estrogen therapy had an increased risk of cognitive impairment and dementia. However, the evidence for how testosterone levels affect men is contradictory.

To better understand the role of sex hormones in dementia, researchers led by Mirjam Geerlings, Ph.D. of the University Medical Center Utrecht, studied whether older men's levels of testosterone and estrogen were associated with their risk of cognitive decline and developing dementia, including Alzheimer's disease.

They examined data from the prospectively studied population-based cohort of 2974 Japanese-American men aged 70 to 91 who participated in the Honolulu-Asia Aging Study. Participants showed no signs of dementia at baseline in 1991-1993, at which time fasting blood samples were drawn. The researchers measured the levels of testosterone and estradiol, the major estrogen in humans, in the samples and the men were reexamined for evidence of cognitive decline or dementia in 1994-1996 and 1997-1999 using the Cognitive Abilities Screening Instrument (CASI). At each exam, researchers also collected physical, demographic and medical information.

A total of 2300 men completed the study and 223 were diagnosed with incident dementia during the follow-up period. 134 men developed Alzheimer's disease, and 44 developed vascular dementia. The researchers used Cox regression analyses, adjusting for age and other covariates, to see if hormone levels were associated with risk of developing dementia

"Levels of bioavailable testosterone were not associated with risk of cognitive decline and incident dementia," they report. "In contrast, higher levels of bioavailable estradiol were associated with an increased risk for cognitive decline and Alzheimer's disease." For each standard deviation increase in estradiol level, the risk for the disease went up by 25 percent. Furthermore, compared with the lowest tertile of estradiol, men in the middle and highest tertile had .24 and .28 points lower CASI scores, respectively, for each year increase in age.

The researchers hypothesize that the estradiol association could be explained by increased aromatase activity in the brain which may be associated with a neurodegenerative process. It is then possible that the high levels of estradiol are a consequence or early marker of Alzheimer's disease rather than a cause.

Some caution is needed when interpreting the results, as, due to death or refusal, some men could not be given a diagnosis of dementia or follow-up cognitive testing.

In conclusion, the authors report, "our findings of an increased risk of cognitive decline and Alzheimer's disease associated with higher estradiol are similar to recent findings in postmenopausal women. Further studies are needed to examine whether there are mechanisms by which estradiol may increase risk of cognitive decline and dementia."