Multiple Mechanisms Linking Type 2 Diabetes and Alzheimer’s Disease: Testosterone as a Modifier

Article type: Review Article

Authors: Asih, Prita R.^{a; b} | Tegg, Michelle L.^c | Sohrabi, Hamid^{c; d; e; f} | Carruthers, Malcolm^g | Gandy, Samuel E.^h | Saad, Farid^{i; j} | Verdile, Giuseppe^{d; k} | Ittner, Lars M.^{a; l} | Martins, Ralph N.^{b; c; d; e; f; *}

Affiliations: [a] Department of Anatomy, Dementia Research Unit, School of Medical Sciences, Faculty of Medicine, University of New South Wales, Sydney, NSW, Australia | [b] KaRa Institute of Neurological Diseases, Sydney, NSW, Australia | [c] School of Medical and Health Sciences, Edith Cowan University, Perth, WA, Australia | [d] Australian Alzheimer’s Research Foundation Perth, WA, Australia | [e] Department of Biomedical Sciences, Macquarie University, Sydney, NSW, Australia | [f] School of Psychiatry and Clinical Neurosciences, University of Western Australia, Perth, WA, Australia | [g] Centre for Men’s Health, London, UK | [h] Departments of Neurology and Psychiatry and the Alzheimer’s Disease Research Center, Icahn School of Medicine at Mount Sinai, One Gustave L Levy Place, New York, NY, USA | [i] Bayer Pharma AG, Global Medical Affairs Andrology, Berlin, Germany | [j] Gulf Medical University School of Medicine, Ajman, UAE | [k] School of Biomedical Sciences, Curtin University of Technology, Bentley, WA, Australia | [l] Neuroscience Research Australia, Sydney, NSW, Australia

Correspondence: [*] Correspondence to: Professor R. N. Martins, Centre of Excellence in Alzheimer’s Disease Research and Care, School of Medical Sciences, Edith Cowan University, Joondalup,Australia. Tel.: +61 8 6304 5456; Fax: +61 8 93474299; E-mail: [email protected].

Abstract: Evidence in support of links between type-2 diabetes mellitus (T2DM) and Alzheimer’s disease (AD) has increased considerably in recent years. AD pathological hallmarks include the accumulation of extracellular amyloid-β (Aβ) and intracellular hyperphosphorylated tau in the brain, which are hypothesized to promote inflammation, oxidative stress, and neuronal loss. T2DM exhibits many AD pathological features, including reduced brain insulin uptake, lipid dysregulation, inflammation, oxidative stress, and depression; T2DM has also been shown to increase AD risk, and with increasing age, the prevalence of both conditions increases. In addition, amylin deposition in the pancreas is more common in AD than in normal aging, and although there is no significant increase in cerebral Aβ deposition in T2DM, the extent of Aβ accumulation in AD correlates with T2DM duration. Given these similarities and correlations, there may be common underlying mechanism(s) that predispose to both T2DM and AD. In other studies, an age-related gradual loss of testosterone and an increase in testosterone resistance has been shown in men; low testosterone levels can also occur in women. In this review, we focus on the evidence for low testosterone levels contributing to an increased risk of T2DM and AD, and the potential of testosterone treatment in reducing this risk in both men and women. However, such testosterone treatment may need to be long-term, and would need regular monitoring to maintain testosterone at physiological levels. It is possible that a combination of testosterone therapy together with a healthy lifestyle approach, including improved diet and exercise, may significantly reduce AD risk.

Keywords: Alzheimer’s disease, men, testosterone, type-2 diabetes, women

DOI: 10.3233/JAD-161259

Journal: Journal of Alzheimer's Disease, vol. 59, no. 2, pp. 445-466, 2017