Association of serum dehydroepiandrosterone sulfate and cognition in older adults: sex steroid, inflammatory, and metabolic mechanisms.

Dehydroepiandrosterone (DHEA) and its sulfate (DHEAS) are steroids second only to cholesterol in abundance in the circulation in humans (Watson, Huls, Araghinikuam, & Chung, 1996). Synthesized from pregnenolone, DHEAS can subsequently be converted into the androgens testosterone and androstenedione, which in turn can be metabolized into estrogens. The biological effects of DHEAS are unclear. The marked decline in DHEAS levels with aging (Labrie, Belanger, Cusan, Gomez, & Candas, 1997) has led to speculation that it may have a role in supporting cognitive function, which also declines with age (Salthouse, 1996). Although the majority of DHEAS is synthesized in the adrenal cortex, this steroid is also produced in neurons and glial cells, primarily astrocytes (Benarroch, 2007). As a neurosteroid, DHEAS has been shown to interact with several receptors important in learning, memory, motor function, and behavior (Benarroch, 2007; Wigstrom & Gustafsson, 1985). Low levels of DHEAS have been reported in the cerebrospinal fluid and plasma of patients with Alzheimer's disease (AD; Genedani et al., 2004), and experimental models of AD have demonstrated neuroprotective effects of DHEAS derivatives in vivo (Dudas, Hanin, Rose, & Wulfert, 2004). The mechanisms for the purported effects of DHEAS on cognition are unknown. Previous studies have demonstrated different effects of DHEAS in men compared with women with respect to cardiovascular disease (Tchernof & Labrie, 2004), suggesting an indirect mechanism of action via conversion to sex hormones. DHEAS has also been implicated in the immune dysregulation associated with aging. Low DHEAS levels have been associated with elevated levels of inflammatory cytokines, which in turn have been linked to cognitive decline (Weaver et al., 2002). Declining DHEAS levels with age may thus shift the immunologic milieu toward an increased production of proinflammatory cytokines, resulting in CNS inflammation and ultimately neurodegeneration. DHEAS levels have also been in versely related to glucose and insulin concentrations (Haffner, Valdez, Mykkanen, Stern, & Katz, 1994). Hyperglycemia (Cukierman, Gerstein, & Williamson, 2005) and hyperinsulinema (Luchsinger, Tang, Shea, & Mayeux, 2004) have been associated with cognitive impairment, thus attenuation of the neuroprotective properties may be another potential mechanism for the effect of DHEAS on cognition. Previous studies of DHEAS and cognition have been mixed, and to our knowledge have not examined potential mechanisms. We report here results of a cross-sectional study of serum DHEAS levels and cognition in a sample of healthy older adults. We selected three cognitive domains a priori—executive function, working memory, and processing speed—based on previous studies, suggesting these abilities may be influenced by DHEAS (Barrett-Connor & Edelstein, 1994; Berr, Lafont, Debuire, Dart-igues, & Baulieu, 1996; Davis et al., 2008). In addition, these are closely related areas of cognitive functioning, often impaired in association with a nonspecific response to a wide range of conditions affecting the central nervous system. We then extended previous research by exploring potential mechanisms for the effect of DHEAS on cognition by examining the association of sex hormones, inflammatory markers, and glucose tolerance with the cognitive outcomes of interest.