Invited critical review Insulin resistance and cognitive dysfunction Lina Ma, Jieyu Wang, Yun Li ⁎ Department of Geriatrics, Xuan Wu Hospital, Capital Medical University, Beijing 100053, China abstract article info Article history: Received 24 December 2014 Received in revised form 25 January 2015 Accepted 27 January 2015 Available online 4 February 2015 Keywords: Insulin resistance Mild cognitive impairment Insulin Alzheimer's disease Epidemiologic and biologic studies support a link between type 2 diabetes mellitus and Alzheimer's disease, but the precise mechanism linking the two remains unclear. Growing evidence supports the concept that insulin re- sistance is important in the pathogenesis of cognitive impairment and neurodegeneration. Insulin plays a pro- found role in cognitive function. Impaired insulin signaling in the advancement of cognitive dysfunction is relevant to the pathophysiologic mechanisms of cognitive impairment. In this paper we discuss the relationship between insulin resistance and cognitive impairment and review potential mechanisms of this disease process. Evidence, to date, suggests that brain insulin resistance is an independent risk factor for cognitive impairment. © 2015 Elsevier B.V. All rights reserved. Contents 1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18 2. Insulin resistance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19 2.1. Physiological functions and secretion regulation of insulin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19 2.2. The role of insulin in the nervous system . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19 2.3. The role of insulin resistance in the nervous system . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19 3. Insulin resistance and cognitive impairment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19 3.1. Insulin resistance is an important risk factor for cognitive impairment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19 3.2. Insulin can improve cognitive dysfunction caused by insulin resistance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19 4. Mechanisms of insulin resistance on cognitive impairment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20 4.1. Insulin resistance prominently affects hippocampal plasticity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20 4.2. Insulin resistance affects APP metabolism . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20 4.3. Insulin resistance increases tau protein concentration . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20 4.4. Insulin resistance affects brain inflammatory reaction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20 4.5. Insulin resistance and the ApoE ε4 allele . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21 5. Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21 Conflicts of interest . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21 Acknowledgments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21 1. Introduction Epidemiologic and biologic evidence supports a link between type 2 diabetes mellitus (T2DM) and Alzheimer's disease (AD), ie, those with T2DM have a higher incidence of cognitive decline [1]. The prevalence of both T2DM and AD increases with age, and both diseases are chronic and are the leading causes of morbidity and mortality. Mild cognitive impairment (MCI) is a state between normal aging and AD. The MCI conversion rate to AD is high [2], and there is a high risk of MCI develop- ing into dementia. Moreover, the incidence of MCI increases to 32.7% in diabetic patients [3]. The precise mechanism linking T2DM and cogni- tive impairment remains to be found out. Growing evidence supports the concept that insulin resistance (IR) plays an important role in the pathogenesis of cognitive impairment and neurodegeneration [1]. Clinica Chimica Acta 444 (2015) 18–23 ⁎ Corresponding author at: Department of Geriatrics, Xuan Wu Hospital, Capital Medical University, #45 Changchun Street, Xicheng District, Beijing 100053, China. Tel./fax: +86 10 83198707. E-mail address: liy_xw@sina.com (Y. Li). http://dx.doi.org/10.1016/j.cca.2015.01.027 0009-8981/© 2015 Elsevier B.V. All rights reserved. Contents lists available at ScienceDirect Clinica Chimica Acta journal homepage: www.elsevier.com/locate/clinchim