Neurobiology of Aging 25 (2004) 141–147 Elevated sex-hormone binding globulin in elderly women with Alzheimer’s disease Elena K. Hoskin a,b , Ming X. Tang c,d , Jennifer J. Manly a , Richard Mayeux a,b,c,e,∗ a Gertrude H. Sergievsky Center, Columbia University, New York, NY 10032, USA b Department of Epidemiology, Joseph P. Mailman School of Public Health, Columbia University, New York, NY 10032, USA c Taub Institute for Research of Alzheimer’s Disease and the Aging Brain, Columbia University, New York, NY 10032, USA d Department of Biostatistics, Joseph P. Mailman School of Public Health, Columbia University, New York, NY 10032, USA e Department of Neurology, Columbia University College of Physicians and Surgeons, New York, NY 10032, USA Received 19 November 2002; received in revised form 13 February 2003; accepted 5 March 2003 Abstract Background: Hormone levels change significantly with increasing age. These changes may be related to, or be associated with, the emergence of age-related diseases, such as Alzheimer’s disease (AD). Methods: Five hundred and seventy-six women over the age of 65 were studied from the Washington Heights-Inwood Columbia Aging Project (WHICAP). These women were selected from a group of healthy Medicare beneficiaries that were aged 65 and older living in the geographically defined area of northern Manhattan in New York City. Serum levels of estrone (E1), estradiol (E2), total testosterone (TT), dehydroepiandosterone (DHEA), luteinizing hormone (LH), follicle stimulating hormone (FSH), and sex-hormone binding globulin (SHBG) were measured. Results: Significant differences were found between patients with AD and controls only in the level of SHBG, which was 20% higher in patients compared to controls (68.5 nmol/l versus 54.7 nmol/l, P< 0.001). We also estimated levels of total E2 because after menopause, E2 is largely derived from E1. AD patients had significantly lower levels of estimated E2 (AD 0.46 versus controls 0.49, P< 0.01). Differences remained significant after adjusting for age, ethnic group, education, and body mass index (BMI). Conclusions: A marked increase in SHBG levels was found in AD patients. SHBG normally responds to circulating testosterone and estrogen, therefore, elevated SHBG suggests an abnormal increase in its production and regulation. Further work is needed to clarify the cause and consequences of this observation. © 2003 Elsevier Science Inc. All rights reserved. Keywords: Alzheimer’s disease; Aging; Hormones; Estrogen; Dementia 1. Introduction With increasing age, hormone levels undergo dramatic changes, which can affect the emergence of age-related dis- eases such as Alzheimer’s disease (AD). Numerous stud- ies investigating the relationship between hormones and AD have produced inconsistent results. Estrogen has been stud- ied most extensively, as it has been shown to have protec- tive effects and appears to have numerous responsibilities outside the reproductive arena. Several studies have suggested that the decreasing lev- els of estrogen during and after menopause may play a role in the cognitive declines associated with AD. Before menopause, estrogen has been shown to promote cholin- ergic activity in the brain [25], stimulate dendritic spine formation, and axonal sprouting [29,51], and promote the ∗ Corresponding author. Tel.: +1-212-305-2391; fax: +1-212-305-2518. E-mail address: rpm2@columbia.edu (R. Mayeux). non-amyloidogenic metabolism of the amyloid precursor protein [15,21,53]. After menopause, estradiol (E2) levels decrease to approximately 1% of their midcycle levels, estrone (E1), though more abundant after menopause, de- creases as well [10,18,22,30]. Studies have reported con- tradicting results, finding AD patients to have significantly lower levels of E2 compared to controls [26] and another finding AD patients to have significantly higher levels of E2. With regards to E1, one study found AD patients to have increased levels of E1 compared to controls [11], while another found E1 levels to be lower in AD patients (though not significant) [26]. Although studies investigating endogenous estrogen lev- els are important in understanding its role in age-related cognitive decline, studies investigating estrogen replace- ment therapy (ERT) have contributed to our understanding of its function as well. In many epidemiological studies, post-menopausal women using ERT have been shown to have slower age-related cognitive declines [2,12,20,23] and 0197-4580/$ – see front matter © 2003 Elsevier Science Inc. All rights reserved. doi:10.1016/S0197-4580(03)00046-0