Abstract
Obesity, metabolic syndrome, and type 2 diabetes (T2D) are related disorders with widespread deleterious effects throughout the body. One important target of damage is the brain. Persons with metabolic disorders are at significantly increased risk for cognitive decline and the development of vascular dementia and Alzheimer’s disease. Our review of available evidence from epidemiologic, clinical, and basic research suggests that neural dysfunction from T2D-related disease results from several underlying mechanisms, including metabolic, inflammatory, vascular, and oxidative changes. The relationships between T2D and neural dysfunction are regulated by several modifiers. We emphasize 2 such modifiers, the genetic risk factor apolipoprotein E and an age-related endocrine change, low testosterone. Both factors are independent risk factors for Alzheimer’s disease that may also cooperatively regulate pathologic interactions between T2D and dementia. Continued elucidation of the links between metabolic disorders and neural dysfunction promises to foster the development of effective therapeutic strategies.
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Zitzmann M. Testosterone deficiency, insulin resistance and the metabolic syndrome. Nat Rev Endocrinol. 2009;5:673–81.
Hebert LE, Scherr PA, Bienias JL, et al. Alzheimer disease in the US population: prevalence estimates using the 2000 census. Arch Neurol. 2003;60:1119–22.
Raffaitin C, Feart C, Le Goff M, et al. Metabolic syndrome and cognitive decline in French elders: the Three-City Study. Neurology. 2011;76:518–25.
Yaffe K, Haan M, Blackwell T, et al. Metabolic syndrome and cognitive decline in elderly Latinos: findings from the Sacramento Area Latino Study of Aging study. J Am Geriatr Soc. 2007;55:758–62.
McEvoy LK, Laughlin GA, Barrett-Connor E, et al. Metabolic syndrome and 16-year cognitive decline in community-dwelling older adults. Ann Epidemiol. 2012;22:310–7.
Yaffe K, Blackwell T, Whitmer RA, et al. Glycosylated hemoglobin level and development of mild cognitive impairment or dementia in older women. J Nutr Health Aging. 2006;10:293–5.
Stolk RP, Breteler MM, Ott A, et al. Insulin and cognitive function in an elderly population. The Rotterdam Study. Diabetes Care. 1997;20:792–5.
Wolf PA, Beiser A, Elias MF, et al. Relation of obesity to cognitive function: importance of central obesity and synergistic influence of concomitant hypertension. The Framingham Heart Study. Curr Alzheimer Res. 2007;4:111–6.
Gunstad J, Lhotsky A, Wendell CR, et al. Longitudinal examination of obesity and cognitive function: results from the Baltimore longitudinal study of aging. Neuroepidemiology. 2010;34:222–9.
van den Berg E, Biessels GJ, de Craen AJ, et al. The metabolic syndrome is associated with decelerated cognitive decline in the oldest old. Neurology. 2007;69:979–85.
Xia W, Wang S, Sun Z, et al. Altered baseline brain activity in type 2 diabetes: a resting-state fMRI study. Psychoneuroendocrinology. 2013;38:2493–501.
Moran C, Phan TG, Chen J, et al. Brain atrophy in type 2 diabetes: regional distribution and influence on cognition. Diabetes Care. 2013;36:4036–42.
Manschot SM, Brands AM, van der Grond J, et al. Brain magnetic resonance imaging correlates of impaired cognition in patients with type 2 diabetes. Diabetes. 2006;55:1106–13.
Luchsinger JA, Reitz C, Patel B, et al. Relation of diabetes to mild cognitive impairment. Arch Neurol. 2007;64:570–5.
Arvanitakis Z, Wilson RS, Li Y, et al. Diabetes and function in different cognitive systems in older individuals without dementia. Diabetes Care. 2006;29:560–5.
van den Berg E, Reijmer YD, de Bresser J, et al. A 4 year follow-up study of cognitive functioning in patients with type 2 diabetes mellitus. Diabetologia. 2010;53:58–65.
Reijmer YD, van den Berg E, de Bresser J, et al. Accelerated cognitive decline in patients with type 2 diabetes: MRI correlates and risk factors. Diabetes Metab Res Rev. 2011;27:195–202.
Sullivan MD, Katon WJ, Lovato LC, et al. Association of depression with accelerated cognitive decline among patients with type 2 diabetes in the ACCORD-MIND Trial. JAMA Psychiatry. 2013;70:1041–7.
Ott A, Stolk RP, van Harskamp F, et al. Diabetes mellitus and the risk of dementia: the Rotterdam Study. Neurology. 1999;53:1937–42.
Arvanitakis Z, Wilson RS, Bienias JL, et al. Diabetes mellitus and risk of Alzheimer disease and decline in cognitive function. Arch Neurol. 2004;61:661–6.
Luchsinger JA, Tang MX, Shea S, Mayeux R. Hyperinsulinemia and risk of Alzheimer disease. Neurology. 2004;63:1187–92.
Hassing LB, Johansson B, Nilsson SE, et al. Diabetes mellitus is a risk factor for vascular dementia, but not for Alzheimer's disease: a population-based study of the oldest old. Int Psychogeriatr. 2002;14:239–48.
Cheng G, Huang C, Deng H, Wang H. Diabetes as a risk factor for dementia and mild cognitive impairment: a meta-analysis of longitudinal studies. Intern Med J. 2012;42:484–91.
Whitmer RA, Gustafson DR, Barrett-Connor E, et al. Central obesity and increased risk of dementia more than three decades later. Neurology. 2008;71:1057–64.
Anstey KJ, Cherbuin N, Budge M, Young J. Body mass index in midlife and late-life as a risk factor for dementia: a meta-analysis of prospective studies. Obes Rev. 2011;12:e426–37.
MacKnight C, Rockwood K, Awalt E, McDowell I. Diabetes mellitus and the risk of dementia, Alzheimer's disease and vascular cognitive impairment in the Canadian Study of Health and Aging. Dement Geriatr Cogn Disord. 2002;14:77–83.
van Harten B, Oosterman JM. Potter van Loon BJ, et al. Brain lesions on MRI in elderly patients with type 2 diabetes mellitus. Eur Neurol. 2007;57:70–4.
Hsu JL, Chen YL, Leu JG, et al. Microstructural white matter abnormalities in type 2 diabetes mellitus: a diffusion tensor imaging study. Neuroimage. 2012;59:1098–105.
Tiehuis AM, van der Graaf Y, Visseren FL, et al. Diabetes increases atrophy and vascular lesions on brain MRI in patients with symptomatic arterial disease. Stroke. 2008;39:1600–3.
Li ZG, Zhang W, Sima AA. Alzheimer-like changes in rat models of spontaneous diabetes. Diabetes. 2007;56:1817–24.
Jung HJ, Kim YJ, Eggert S, et al. Age-dependent increases in tau phosphorylation in the brains of type 2 diabetic rats correlate with a reduced expression of p62. Exp Neurol. 2013;248C:441–50.
Kim B, Backus C, Oh S, et al. Increased tau phosphorylation and cleavage in mouse models of type 1 and type 2 diabetes. Endocrinology. 2009;150:5294–301.
Planel E, Tatebayashi Y, Miyasaka T, et al. Insulin dysfunction induces in vivo tau hyperphosphorylation through distinct mechanisms. J Neurosci. 2007;27:13635–48.
Biessels GJ, Kamal A, Urban IJ, et al. Water maze learning and hippocampal synaptic plasticity in streptozotocin-diabetic rats: effects of insulin treatment. Brain Res. 1998;800:125–35.
Jolivalt CG, Lee CA, Beiswenger KK, et al. Defective insulin signaling pathway and increased glycogen synthase kinase-3 activity in the brain of diabetic mice: parallels with Alzheimer's disease and correction by insulin. J Neurosci Res. 2008;86:3265–74.
Zhao L, Teter B, Morihara T, et al. Insulin-degrading enzyme as a downstream target of insulin receptor signaling cascade: implications for Alzheimer's disease intervention. J Neurosci. 2004;24:11120–6.
Chesneau V, Vekrellis K, Rosner MR, Selkoe DJ. Purified recombinant insulin-degrading enzyme degrades amyloid beta-protein but does not promote its oligomerization. Biochem J. 2000;351(Pt 2):509–16.
Farris W, Mansourian S, Chang Y, et al. Insulin-degrading enzyme regulates the levels of insulin, amyloid beta-protein, and the beta amyloid precursor protein intacellular domain in vivo. Proc Natl Acad Sci U S A. 2003;100:4162–7.
Ho L, Qin W, Pompl PN, et al. Diet-induced insulin resistance promotes amyloidosis in a transgenic mouse model of Alzheimer's disease. FASEB J. 2004;18:902–4.
Cao D, Lu H, Lewis TL, Li L. Intake of sucrose-sweetened water induces insulin resistance and exacerbates memory deficits and amyloidosis in a transgenic mouse model of Alzheimer disease. J Biol Chem. 2007;282:36275–82.
Schulingkamp RJ, Pagano TC, Hung D, Raffa RB. Insulin receptors and insulin action in the brain: review and clinical implications. Neurosci Biobehav Rev. 2000;24:855–72.
Frolich L, Blum-Degen D, Bernstein HG, et al. Brain insulin and insulin receptors in aging and sporadic Alzheimer's disease. J Neural Transm. 1998;105:423–38.
Steen E, Terry BM, Rivera EJ, et al. Impaired insulin and insulin-like growth factor expression and signaling mechanisms in Alzheimer's disease–is this type 3 diabetes? J Alzheimers Dis. 2005;7:63–80.
Farris W, Mansourian S, Leissring MA, et al. Partial loss-of-function mutations in insulin-degrading enzyme that induce diabetes also impair degradation of amyloid beta-protein. Am J Pathol. 2004;164:1425–34.
Bennett RG, Hamel FG, Duckworth WC. An insulin-degrading enzyme inhibitor decreases amylin degradation, increases amylin-induced cytotoxicity, and increases amyloid formation in insulinoma cell cultures. Diabetes. 2003;52:2315–20.
Shiiki T, Ohtsuki S, Kurihara A, et al. Brain insulin impairs amyloid-beta (1-40) clearance from the brain. J Neurosci. 2004;24:9632–7.
Qiu WQ, Walsh DM, Ye Z, et al. Insulin-degrading enzyme regulates extracellular levels of amyloid beta-protein by degradation. J Biol Chem. 1998;273:32730–8.
Luchsinger JA, Palmas W, Teresi JA, et al. Improved diabetes control in the elderly delays global cognitive decline. J Nutr Health Aging. 2011;15:445–9.
Watson GS, Cholerton BA, Reger MA, et al. Preserved cognition in patients with early Alzheimer disease and amnestic mild cognitive impairment during treatment with rosiglitazone: a preliminary study. Am J Geriatr Psychiatry. 2005;13:950–8.
Chen Y, Zhou K, Wang R, et al. Antidiabetic drug metformin (GlucophageR) increases biogenesis of Alzheimer's amyloid peptides via up-regulating BACE1 transcription. Proc Natl Acad Sci U S A. 2009;106:3907–12.
Craft S, Baker LD, Montine TJ, et al. Intranasal insulin therapy for Alzheimer disease and amnestic mild cognitive impairment: a pilot clinical trial. Arch Neurol. 2012;69:29–38. This initial report from a clinical trial provides evidence that, even in the absence of diabetes, insulin-based therapy may provide cognitive benefits at early stages of AD.
Searcy JL, Phelps JT, Pancani T, et al. Long-term pioglitazone treatment improves learning and attenuates pathologic markers in a mouse model of Alzheimer's disease. J Alzheimers Dis. 2012;30:943–61.
Long-Smith CM, Manning S, McClean PL, et al. The diabetes drug liraglutide ameliorates aberrant insulin receptor localisation and signalling in parallel with decreasing both amyloid-beta plaque and glial pathology in a mouse model of Alzheimer's disease. Neuromolecular Med. 2013;15:102–14.
Eriksson A, Attvall S, Bonnier M, et al. Short-term effects of metformin in type 2 diabetes. Diabetes Obes Metab. 2007;9:330–6.
Wang M, Tong JH, Zhu G, et al. Metformin for treatment of antipsychotic-induced weight gain: a randomized, placebo-controlled study. Schizophr Res. 2012;138:54–7.
Kalariya NM, Shoeb M, Ansari NH, et al. Antidiabetic drug metformin suppresses endotoxin-induced uveitis in rats. Invest Ophthalmol Vis Sci. 2012;53:3431–40.
Barron AM, Rosario ER, Elteriefi R, Pike CJ. Sex-specific effects of high fat diet on indices of metabolic syndrome in 3xTg-AD mice: implications for Alzheimer's disease. PLoS One. 2013;8:e78554.
Murakami K, Yokoyama S, Murata N, et al. Insulin receptor mutation results in insulin resistance and hyperinsulinemia but does not exacerbate Alzheimer's-like phenotypes in mice. Biochem Biophys Res Commun. 2011;409:34–9.
Freude S, Hettich MM, Schumann C, et al. Neuron.al IGF-1 resistance reduces Abeta accumulation and protects against premature death in a model of Alzheimer's disease. FASEB J. 2009;23:3315–24.
Killick R, Scales G, Leroy K, et al. Deletion of Irs2 reduces amyloid deposition and rescues behavioural deficits in APP transgenic mice. Biochem Biophys Res Commun. 2009;386:257–62.
Lumeng CN, Saltiel AR. Inflammatory links between obesity and metabolic disease. J Clin Invest. 2011;121:2111–7.
Lee YH, Pratley RE. The evolving role of inflammation in obesity and the metabolic syndrome. Curr Diabetes Rep. 2005;5:70–5.
Deans KA, Sattar N. "Anti-inflammatory" drugs and their effects on type 2 diabetes. Diabetes Technol Ther. 2006;8:18–27.
Yaffe K, Kanaya A, Lindquist K, et al. The metabolic syndrome, inflammation, and risk of cognitive decline. JAMA. 2004;292:2237–42.
Wellen KE, Hotamisligil GS. Obesity-induced inflammatory changes in adipose tissue. J Clin Invest. 2003;112:1785–8.
Zhang X, Dong F, Ren J, et al. High dietary fat induces NADPH oxidase-associated oxidative stress and inflammation in rat cerebral cortex. Exp Neurol. 2005;191:318–25.
Thaler JP, Yi CX, Schur EA, et al. Obesity is associated with hypothalamic injury in rodents and humans. J Clin Invest. 2012;122:153–62. This initial report from a clinical trial provides evidence that, even in the absence of diabetes, insulin-based therapy may provide cognitive benefits at early stages of AD.
Viscogliosi G, Marigliano V. Alzheimer's disease: how far have we progressed? Lessons learned from diabetes mellitus, metabolic syndrome, and inflammation. J Am Geriatr Soc. 2013;61:845–6.
Griffin WS, Stanley LC, Ling C, et al. Brain interleukin 1 and S-100 immunoreactivity are elevated in Down syndrome and Alzheimer disease. Proc Natl Acad Sci U S A. 1989;86:7611–5.
Motta M, Imbesi R, Di Rosa M, et al. Altered plasma cytokine levels in Alzheimer's disease: correlation with the disease progression. Immunol Lett. 2007;114:46–51.
Matsuoka Y, Picciano M, Malester B, et al. Inflammatory responses to amyloidosis in a transgenic mouse model of Alzheimer's disease. Am J Pathol. 2001;158:1345–54.
Benzing WC, Wujek JR, Ward EK, et al. Evidence for glial-mediated inflammation in aged APP(SW) transgenic mice. Neurobiol Aging. 1999;20:581–9.
Tanzi RE. The genetics of Alzheimer disease. Cold Spring Harb Perspect Med. 2012;2:
Cote S, Carmichael PH, Verreault R, et al. Nonsteroidal anti-inflammatory drug use and the risk of cognitive impairment and Alzheimer's disease. Alzheimers Dement. 2012;8:219–26.
Rodrigue KM. Contribution of cerebrovascular health to the diagnosis of Alzheimer disease. JAMA Neurol. 2013;70:438–9.
Zlokovic BV. Neurovascular pathways to neurodegeneration in Alzheimer's disease and other disorders. Nat Rev Neurosci. 2011;12:723–38.
Tamaki C, Ohtsuki S, Terasaki T. Insulin facilitates the hepatic clearance of plasma amyloid beta-peptide (1 40) by intracellular translocation of low-density lipoprotein receptor-related protein 1 (LRP-1) to the plasma membrane in hepatocytes. Mol Pharmacol. 2007;72:850–5.
Deane R, Wu Z, Sagare A, et al. LRP/amyloid beta-peptide interaction mediates differential brain efflux of Abeta isoforms. Neuron. 2004;43:333–44.
Terrand J, Bruban V, Zhou L, et al. LRP1 controls intracellular cholesterol storage and fatty acid synthesis through modulation of Wnt signaling. J Biol Chem. 2009;284:381–8.
Liu W, Singh R, Choi CS, et al. Low density lipoprotein (LDL) receptor-related protein 6 (LRP6) regulates body fat and glucose homeostasis by modulating nutrient sensing pathways and mitochondrial energy expenditure. J Biol Chem. 2012;287:7213–23.
Xi YD, Li XY, Ding J, et al. Soy isoflavone alleviates Abeta1-42-induced impairment of learning and memory ability through the regulation of RAGE/LRP-1 in neuronal and vascular tissue. Curr Neurovasc Res. 2013;10:144–56.
Basta G, Schmidt AM, De Caterina R. Advanced glycation end products and vascular inflammation: implications for accelerated atherosclerosis in diabetes. Cardiovasc Res. 2004;63:582–92.
Schmidt AM, Yan SD, Yan SF, Stern DM. The biology of the receptor for advanced glycation end products and its ligands. Biochim Biophys Acta. 2000;1498:99–111.
Yan SD, Zhu H, Zhu A, et al. Receptor-dependent cell stress and amyloid accumulation in systemic amyloidosis. Nat Med. 2000;6:643–51.
Yan SD, Chen X, Fu J, et al. RAGE and amyloid-beta peptide neurotoxicity in Alzheimer's disease. Nature. 1996;382:685–91.
Lue LF, Walker DG, Brachova L, et al. Involvement of microglial receptor for advanced glycation endproducts (RAGE) in Alzheimer's disease: identification of a cellular activation mechanism. Exp Neurol. 2001;171:29–45.
Deane R, Du Yan S, Submamaryan RK, et al. RAGE mediates amyloid-beta peptide transport across the blood-brain barrier and accumulation in brain. Nat Med. 2003;9:907–13.
Stern DM, Yan SD, Yan SF, Schmidt AM. Receptor for advanced glycation endproducts (RAGE) and the complications of diabetes. Ageing Res Rev. 2002;1:1–15.
Schmidt AM, Stern DM. Receptor for age (RAGE) is a gene within the major histocompatibility class III region: implications for host response mechanisms in homeostasis and chronic disease. Front Biosci. 2001;6:D1151–60.
Saunders AM, Strittmatter WJ, Schmechel D, et al. Association of apolipoprotein E allele epsilon 4 with late-onset familial and sporadic Alzheimer's disease. Neurology. 1993;43:1467–72.
Mahley RW. Apolipoprotein E: cholesterol transport protein with expanding role in cell biology. Science. 1988;240:622–30.
Schmechel DE, Saunders AM, Strittmatter WJ, et al. Increased amyloid beta-peptide deposition in cerebral cortex as a consequence of apolipoprotein E genotype in late-onset Alzheimer disease. Proc Natl Acad Sci U S A. 1993;90:9649–53.
Irie F, Fitzpatrick AL, Lopez OL, et al. Enhanced risk for Alzheimer disease in persons with type 2 diabetes and APOE epsilon4: the Cardiovascular Health Study Cognition Study. Arch Neurol. 2008;65:89–93.
Peila R, Rodriguez BL, Launer LJ. Type 2 diabetes, APOE gene, and the risk for dementia and related pathologies: the Honolulu-Asia Aging Study. Diabetes. 2002;51:1256–62.
Hanson AJ, Bayer-Carter JL, Green PS, et al. Effect of apolipoprotein e genotype and diet on apolipoprotein e lipidation and amyloid peptides: randomized clinical trial. JAMA Neurol. 2013;70:972–80.
Cook DG, Leverenz JB, McMillan PJ, et al. Reduced hippocampal insulin-degrading enzyme in late-onset Alzheimer's disease is associated with the apolipoprotein E-epsilon4 allele. Am J Pathol. 2003;162:313–9.
Craft S, Peskind E, Schwartz MW, et al. Cerebrospinal fluid and plasma insulin levels in Alzheimer's disease: relationship to severity of dementia and apolipoprotein E genotype. Neurology. 1998;50:164–8.
Craft S, Asthana S, Schellenberg G, et al. Insulin effects on glucose metabolism, memory, and plasma amyloid precursor protein in Alzheimer's disease differ according to apolipoprotein-E genotype. Ann N Y Acad Sci. 2000;903:222–8.
Reger MA, Watson GS, Green PS, et al. Intranasal insulin administration dose-dependently modulates verbal memory and plasma amyloid-beta in memory-impaired older adults. J Alzheimers Dis. 2008;13:323–31.
Morley JE. Andropause, testosterone therapy, and quality of life in aging men. Cleve Clin J Med. 2000;67:880–2.
Pike CJ, Carroll JC, Rosario ER, Barron AM. Protective actions of sex steroid hormones in Alzheimer's disease. Front Neuroendocrinol. 2009;30:239–58.
Hogervorst E, Williams J, Budge M, et al. Serum total testosterone is lower in men with Alzheimer's disease. Neurol Endocrinol Lett. 2001;22:163–8.
Rasmuson S, Nasman B, Carlstrom K, Olsson T. Increased levels of adrenocortical and gonadal hormones in mild to moderate Alzheimer's disease. Dement Geriatr Cogn Disord. 2002;13:74–9.
Rosario ER, Chang L, Stanczyk FZ, Pike CJ. Age-related testosterone depletion and the development of Alzheimer disease. JAMA. 2004;292:1431–2.
Rosario ER, Chang L, Head EH, et al. Brain levels of sex steroid hormones in men and women during normal aging and in Alzheimer's disease. Neurobiol Aging. 2011;32:604–13.
Moffat SD, Zonderman AB, Metter EJ, et al. Free testosterone and risk for Alzheimer disease in older men. Neurology. 2004;62:188–93.
Grossmann M, Thomas MC, Panagiotopoulos S, et al. Low testosterone levels are common and associated with insulin resistance in men with diabetes. J Clin Endocrinol Metab. 2008;93:1834–40.
Kapoor D, Aldred H, Clark S, et al. Clinical and biochemical assessment of hypogonadism in men with type 2 diabetes: correlations with bioavailable testosterone and visceral adiposity. Diabetes Care. 2007;30:911–7.
Hougaku H, Fleg JL, Najjar SS, et al. Relationship between androgenic hormones and arterial stiffness, based on longitudinal hormone measurements. Am J Physiol Endocrinol Metab. 2006;290:E234–42.
Goncharov NP, Katsya GV, Chagina NA, Gooren LJ. Three definitions of metabolic syndrome applied to a sample of young obese men and their relation with plasma testosterone. Aging Male. 2008;11:118–22.
Kapoor D, Clarke S, Stanworth R, et al. The effect of testosterone replacement therapy on adipocytokines and C-reactive protein in hypogonadal men with type 2 diabetes. Eur J Endocrinol. 2007;156:595–602.
Bhasin S, Parker RA, Sattler F, et al. Effects of testosterone supplementation on whole body and regional fat mass and distribution in human immunodeficiency virus-infected men with abdominal obesity. J Clin Endocrinol Metab. 2007;92:1049–57.
Kapoor D, Goodwin E, Channer KS, Jones TH. Testosterone replacement therapy improves insulin resistance, glycaemic control, visceral adiposity and hypercholesterolaemia in hypogonadal men with type 2 diabetes. Eur J Endocrinol. 2006;154:899–906.
Lage MJ, Barber BL, Markus RA. Association between androgen-deprivation therapy and incidence of diabetes among males with prostate cancer. Urology. 2007;70:1104–8.
Keating NL, O'Malley AJ, Smith MR. Diabetes and cardiovascular disease during androgen deprivation therapy for prostate cancer. J Clin Oncol. 2006;24:4448–56.
Braga-Basaria M, Dobs AS, Muller DC, et al. Metabolic syndrome in men with prostate cancer undergoing long-term androgen-deprivation therapy. J Clin Oncol. 2006;24:3979–83.
Haidar A, Yassin A, Saad F, Shabsigh R. Effects of androgen deprivation on glycaemic control and on cardiovascular biochemical risk factors in men with advanced prostate cancer with diabetes. Aging Male. 2007;10:189–96.
Hogervorst E, Lehmann DJ, Warden DR, et al. Apolipoprotein E epsilon4 and testosterone interact in the risk of Alzheimer's disease in men. Int J Geriatr Psychiatry. 2002;17:938–40.
Raber J, Bongers G, LeFevour A, et al. Androgens protect against apolipoprotein E4-induced cognitive deficits. J Neurosci. 2002;22:5204–9.
Pfankuch T, Rizk A, Olsen R, et al. Role of circulating androgen levels in effects of apoE4 on cognitive function. Brain Res. 2005;1053:88–96.
Rizk-Jackson A, Robertson J, Raber J. Tfm-AR modulates the effects of ApoE4 on cognition. J Neurochem. 2008;105:63–7.
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This work was supported by NIH grant AG34103 (CJP).
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Anusha Jayaraman declares that she has no conflict of interest. Christian J. Pike declares that he has no conflict of interest.
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This article is part of the Topical Collection on Pathogenesis of Type 2 Diabetes and Insulin Resistance
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Jayaraman, A., Pike, C.J. Alzheimer’s Disease and Type 2 Diabetes: Multiple Mechanisms Contribute to Interactions. Curr Diab Rep 14, 476 (2014). https://doi.org/10.1007/s11892-014-0476-2
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DOI: https://doi.org/10.1007/s11892-014-0476-2