Age-associated androgen deficiency and Alzheimer's disease: a case in the making?

The role of sex steroids in the establishing and maintenance of cognitive functions is widely recognized. In vivo experimental studies have shown that testosterone affects learning and memory, independently or by conversion to estradiol [22]. In sharp contrast with the course of reproductive aging in women characterized by dramatic decline in the levels of circulating estrogens, men experience a slow and continual decline in circulating androgens during aging. This age-related, progressive decline in serum testosterone contributes to multiple psychosexual, physiological and cognitive changes referred to as andropause [4]. Epidemiological studies suggest a complex, curvilinear relationship between the levels of plasma testosterone and cognitive function in men, such that both high and low levels of testosterone associate with poor cognitive performance [15]. However in elderly men free or bioavailable testosterone positively correlate with cognitive performance; men classified as hypogonadal have significantly lower scores on memory measures and exhibit a faster rate of memory decline [17, 23]. Could age-related androgen deficiency be a contributing factor to the risk of Alzheimer’s disease in men? Men with Alzheimer’s dementia are more likely to have lower levels of total testosterone independent of confounding factors suggesting that low total testosterone is either a co-morbid feature of AD or a factor that exacerbates disease progression [11]. Lower total testosterone levels are also observed in cognitively healthy ApoE e4-positive men compared to nonApoE e4 carriers suggesting that as these subjects age, ApoE4 and testosterone interact to increase the risk of AD [12]. An androgen receptor polymorphism was found to associate with early onset AD in men and not in women [14]. Prospective longitudinal studies addressing the question whether testosterone deficiency precedes or follows the onset of Alzheimer’s disease are still lacking. This is in part due to the fact that there is a lack of consensus in terms of the cut-off value for testosterone levels used for determining hypotestosteronemia [10]. A number of in vitro and in vivo studies support the connection between low testosterone and cognitive decline and show that testosterone either independently or by conversion to estradiol can modulate processes relevant to Alzheimer’s disease pathology. Testosterone can reduce the production of Amyloid β (Aβ) peptides by neuronal cells in culture, and protect neurons from various cytotoxic such as well as prevent the hyperphosphorylation of tau [1,6–9,19]. Studies in senescence accelerated mice have revealed that aging and reduced testosterone levels interact and result in learning and memory deficits that can be corrected by chronic treatment with testosterone [8]. Testosterone treatment improved working memory in aged rats and altered the levels of NGF in the hippocampus [2]. Studies in human ApoE-expressing transgenic mice have shown that ApoE4 associates with reduced androgen receptor levels in the neocortex in both genders and that androgendependent pathways protect male mice from ApoE4induced behavioral deficits [20].