Journal of Alzheimer’s Disease 12 (2007) 129–142 129 IOS Press Androgens in the Etiology of Alzheimer’s Disease in Aging Men and Possible Therapeutic Interventions Stephanie J. Fuller a , Robert S. Tan b and Ralph N. Martins a,* a Centre of Excellence for Alzheimer’s Disease Research and Care, School of Exercise, Biomedical and Health Sciences, Edith Cowan University, Joondalup, WA, Australia; and Sir James McCusker Alzheimer’s Disease Research Unit, School of Psychiatry and Clinical Neurosciences, University of Western Australia, Hollywood Private Hospital, Nedlands, WA, Australia b University of Texas Medical School & Garden Terrace Alzheimer’s Center of Excellence, Houston, TX 77030, USA Abstract. Animal experiments and cell biology studies have provided evidence that both estrogens and androgens can play a protective role against Alzheimer’s disease (AD) related neurodegeneration. Males who become hypogonadal in later life often report problems with their memory. Lower than normal testosterone levels have also been detected in patients prior to the onset of AD, as well as in younger late-onset male AD patients, when compared to appropriate controls. The results of some small clinical trials suggest that testosterone can improve cognitive function in andropause. Although such improvement in cognitive function is subtle, patients on testosterone replacement therapy have reported memory improvements in both declarative and procedural domains. In contrast, there is no clinical evidence to date which suggest that the hormone dihydroepiandrosterone (DHEA) can improve cognitive function. Rises in the levels of the gonadotropins, follicle stimulating hormone (FSH) and luteinizing hormone (LH), have been associated with AD, but the clinical effects of reducing their levels remain to be determined. We hypothesize that androgens, gonadotropin modulators, or perhaps selective androgen receptor modulators may be useful components of therapy aimed at preventing the onset or delaying the progression of AD in male patients. Keywords: Testosterone, andropause, amyloid-β, Alzheimer’s disease, leuprolin, cognition, dehydroepiandrosterone, go- nadotropin, androgen receptor Abbreviations: Aβ, amyloid-β; AD, Alzheimer’s disease; AβPP, amyloid-β protein precursor; A.D.A.M., androgen decline in aging males; AR, androgen receptor; CSF, cerebrospinal fluid ; DHEA(S), Dihydroepiandrosterone (sulphate); DHT, dihy- drotestosterone; hsp40, hsp70, hsp90, heat shock proteins 40, 70, or 90; sAβPPα, secreted soluble form of AβPP; SARMS, se- lective androgen receptor modulators; MENT, 7α-methyl-19-nortestosterone; NFT, neurofibrillary tangles; SAMP8, senescence accelerated mice-prone/8. INTRODUCTION AD occurs more frequently in women than men. This gender difference was originally thought to be * Corresponding author: Ralph N. Martins, Centre of Excellence for Alzheimer’s Disease Research and Care, School of Exercise, Biomedical and Health Sciences, Edith Cowan University, 100 Joon- dalup Drive, Joondalup, Western Australia 6027, Australia. Tel.: +61 8 6304 5456; Fax: +61 8 6304 5851; E-mail: r.martins@ecu.edu.au. simply a function of longevity, as women live longer than their male counterparts on average, and incidence of AD is known to increase with age [108]. Differ- ent study approaches to this issue, however, have pro- duced different conclusions. One study of remaining lifetime risk of developing AD or dementia has shown that women have a higher risk of developing either AD, or dementia in general [109], whereas a large study conducted in Rochester, USA still argues that AD may be as common in men as in women after corrections for ISSN 1387-2877/07/$17.00  2007 – IOS Press and the authors. All rights reserved