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Review
. 2017;59(2):445-466.
doi: 10.3233/JAD-161259.

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

Prita R Asih  1   2 , Michelle L Tegg  3 , Hamid Sohrabi  3   4   5   6 , Malcolm Carruthers  7 , Samuel E Gandy  8 , Farid Saad  9   10 , Giuseppe Verdile  4   11 , Lars M Ittner  1   12 , Ralph N Martins  2   3   4   5   6
Affiliations
Review

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

Prita R Asih et al. J Alzheimers Dis. 2017.

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.

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Figures

Fig. 1.
Fig. 1.
Common pathogenic mechanisms linking T2DM and AD under low testosterone conditions, showing points (green arrows) at which testosterone treatment modifies this relationship. 1) T2DM patient have insulin resistance which downregulates the expression of phosphorylated IRS and downstream signaling of PI3K activation in the brain. As a result, GSK3β activity increases, and leads to Aβ and NFT deposition. 2) Hyperinsulinemia and IDE defects in T2DM patients lead to decreased clearance of Aβ in the brain. 3) Impairment in insulin-stimulated glucose uptake in the skeletal muscle of T2DM correlates with downregulated expression of GLUT-4 which in turn affects the glycolysis pathway. Although glucose is transported from skeletal muscle to the brain via GLUT-1, the role of testosterone in this pathway is not known. Testosterone also promotes GLUT4 translocation via LKB1/AMPK signaling and stimulates glucose transport in adipocytes, in which dysregulation of AMPK occurs in T2DM and AD. 4) Hypercholesterolemia and perturbations to the HDL:LDL ratio, as well as elevated VLDL, triglycerides and free fatty acids in T2DM contribute to the development of AD-related pathology and testosterone treatment has been shown to reduce all these parameters. 5) Possession of APOE ε4 genes causes impairments in lipoproteins and Aβ clearance, which confers a greater risk of T2DM and AD. 6) Peripheral and brain inflammation is associated with T2DM and AD and can exacerbate the underlying pathologies through increasing pro-inflammatory mediators. Inflammation is also closely linked to oxidative stress that causes reduction of eNOS and NO. T2DM, type 2 diabetes; AD, Alzheimer’s disease; IRS, insulin receptors; eNOS, endothelial nitric oxide synthase; NO, nitric oxide; GSK3β, glycogen synthase kinase 3p; PI3K, phosphatidylinositol 3-kinase; Ap, amyloid-β; NFT, neurofibrillary tangles; ApoE ε4, apolipoprotein E4; GLUT4, glucose transporter 4.
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