In recent years, several conditions have been identified as risk factors for the development of Alzheimer's disease (AD). Two such risk factors are age-related testosterone loss in men and type 2 diabetes (T2D). It is unclear how these two conditions increase the risk for AD. Further, it is not known whether these conditions function as independent or related risk factors. In this application, we will evaluate the hypothesis that normal, age-related testosterone loss increases AD pathogenesis not only by direct effects on brain but also by promoting T2D. Similarly, we will investigate the complementary hypothesis that T2D increases AD pathology directly as well as by reducing testosterone levels. Thus, testosterone loss and T2D are postulated to be interrelated conditions that, in combination, cooperatively increase development of AD. Mechanistically, both low testosterone and T2D independently affect key features of AD neuropathology, including beta-amyloid accumulation, tau hyperphosphorylation, and inflammation. We hypothesize that testosterone and T2D cooperatively increase AD pathogenesis by interactions in the cell signaling pathways that regulate these three aspects of AD pathology. To investigate these hypotheses, we propose three specific aims.
In Aim 1, we will investigate the effects of experimentally induced T2D on levels of testosterone and AD in animal models of aging and AD.
In Aim 2, we will investigate the effects of experimentally-induced low testosterone on measures of T2D and AD in animal models of T2D. In both Aims 1 and 2, we will also examine the role of aging on identified relationships interactions between low testosterone and T2D. Finally, in Aim 3 we will evaluate candidate mechanisms underlying interactions between testosterone, focusing on signaling pathways that regulate beta-amyloid accumulation, tau hyperphosphorylation, and inflammation. Completion of our studies will characterize and mechanistically define relationships between testosterone and T2D and how they cooperatively act to promote development of AD, knowledge that will be invaluable in understanding and preventing AD in aging men.

Public Health Relevance

Most AD cases result not from a single genetic cause, but rather the combined effects of several risk factors. Our proposal will investigate the interactions between two prevalent but recently established risk factors for AD in aging men we hypothesize are mechanistically related: age- related testosterone loss and type 2 diabetes. Understanding the interactions between these risk factors will improve the ability to identify persons at high risk for Alzheimer's disease and foster the development of targeted, preventive interventions.

National Institute of Health (NIH)
National Institute on Aging (NIA)
Research Project (R01)
Project #
Application #
Study Section
Cell Death in Neurodegeneration Study Section (CDIN)
Program Officer
Miller, Marilyn
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Southern California
Other Domestic Higher Education
Los Angeles
United States
Zip Code
Uchoa, Mariana F; Moser, V Alexandra; Pike, Christian J (2016) Interactions between inflammation, sex steroids, and Alzheimer's disease risk factors. Front Neuroendocrinol 43:60-82
Moser, V Alexandra; Pike, Christian J (2016) Obesity and sex interact in the regulation of Alzheimer's disease. Neurosci Biobehav Rev 67:102-18
Jayaraman, Anusha; Lent-Schochet, Daniella; Pike, Christian J (2014) Diet-induced obesity and low testosterone increase neuroinflammation and impair neural function. J Neuroinflammation 11:162
Jayaraman, Anusha; Pike, Christian J (2014) Alzheimer's disease and type 2 diabetes: multiple mechanisms contribute to interactions. Curr Diab Rep 14:476
Barron, Anna M; Rosario, Emily R; Elteriefi, Reem et al. (2013) Sex-specific effects of high fat diet on indices of metabolic syndrome in 3xTg-AD mice: implications for Alzheimer's disease. PLoS One 8:e78554
Vest, Rebekah S; Pike, Christian J (2013) Gender, sex steroid hormones, and Alzheimer's disease. Horm Behav 63:301-7
Rosario, Emily R; Carroll, Jenna C; Pike, Christian J (2012) Evaluation of the effects of testosterone and luteinizing hormone on regulation of ýý-amyloid in male 3xTg-AD mice. Brain Res 1466:137-45