Verdile and Martins review the relationship between dysfunction of the hypothalamic-pituitary-gonadal (HPG) axis, reduced levels of testosterone in men, cognitive decline, and risk of Alzheimer's disease (AD). Regulation of testosterone and luteinizing hormone (LH) are tightly linked, and following reproductive senescence declines in sex hormones are coupled with elevated gonadotropin levels. Several studies have reported that compared to controls, men with AD and other dementias have lower serum testosterone levels. Testosterone has been shown to have a number of neuroprotective effects, including reducing oxidative stress and inflammatory processes, which are key events in the AD brain. While animal and in vitro analyses have provided support for the therapeutic potential of testosterone, definitive benefits of testosterone therapy remain to be determined. The APOE ε4 allele appears to be a determining factor in the association between testosterone and the risk of developing dementia in men. It appears that both testosterone and LH can impact beta-amyloid accumulation and AD pathogenesis, although the relative contributions of each hormone remain undefined. Verdile and Martins propose that combinational hormone therapy (HT) may prove to be more efficacious in the prevention of AD.
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