Snyder, H. M. et al. Vascular contributions to cognitive impairment and dementia including Alzheimer’s disease. Alzheimers Dement. 11, 710–717 (2015).
Montine, T. J. et al. Recommendations of the Alzheimer’s disease-related dementias conference. Neurology 83, 851–860 (2014).
Stoeckel, L. E. et al. Complex mechanisms linking neurocognitive dysfunction to insulin resistance and other metabolic dysfunction. F1000Res. 5, 353 (2016).
Chatterjee, S. et al. Type 2 diabetes as a risk factor for dementia in women compared with men: a pooled analysis of 2.3 million people comprising more than 100,000 cases of dementia. Diabetes Care 39, 300–307 (2016).
Gao, C., Liu, Y., Li, L. & Holscher, C. New animal models of Alzheimer’s disease that display insulin desensitization in the brain. Rev. Neurosci. 24, 607–615 (2013).
Yaffe, K. et al. Diabetes, glucose control, and 9-year cognitive decline among older adults without dementia. Arch. Neurol. 69, 1170–1175 (2012).
Biessels, G. J., Staekenborg, S., Brunner, E., Brayne, C. & Scheltens, P. Risk of dementia in diabetes mellitus: a systematic review. Lancet Neurol. 5, 64–74 (2006).
Fontbonne, A., Berr, C., Ducimetiere, P. & Alperovitch, A. Changes in cognitive abilities over a 4-year period are unfavorably affected in elderly diabetic subjects: results of the Epidemiology of Vascular Aging Study. Diabetes Care 24, 366–370 (2001).
Logroscino, G., Kang, J. H. & Grodstein, F. Prospective study of type 2 diabetes and cognitive decline in women aged 70–81 years. BMJ 328, 548 (2004).
Luchsinger, J. A. et al. Relation of diabetes to mild cognitive impairment. Arch. Neurol. 64, 570–575 (2007).
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. 14, 77–83 (2002).
Ott, A. et al. Diabetes mellitus and the risk of dementia: the Rotterdam Study. Neurology 53, 1937–1942 (1999).
Ravona-Springer, R. et al. Changes in glycemic control are associated with changes in cognition in non-diabetic elderly. J. Alzheimers Dis. 30, 299–309 (2012).
Schrijvers, E. M. et al. Insulin metabolism and the risk of Alzheimer disease: the Rotterdam Study. Neurology 75, 1982–1987 (2010).
Wu, J. H. et al. Impact of diabetes on cognitive function among older Latinos: a population-based cohort study. J. Clin. Epidemiol. 56, 686–693 (2003).
Wu, J. H. et al. Impact of antidiabetic medications on physical and cognitive functioning of older Mexican Americans with diabetes mellitus: a population-based cohort study. Ann. Epidemiol. 13, 369–376 (2003).
Wu, J. H. et al. Diabetes as a predictor of change in functional status among older Mexican Americans: a population-based cohort study. Diabetes Care 26, 314–319 (2003).
Yaffe, K. et al. Diabetes, impaired fasting glucose, and development of cognitive impairment in older women. Neurology 63, 658–663 (2004).
Arvanitakis, Z., Wilson, R. S. & Bennett, D. A. Diabetes mellitus, dementia, and cognitive function in older persons. J. Nutr. Health Aging 10, 287–291 (2006).
Henquin, J. C. Regulation of insulin secretion: a matter of phase control and amplitude modulation. Diabetologia 52, 739–751 (2009).
Wortham, M. & Sander, M. Mechanisms of β-cell functional adaptation to changes in workload. Diabetes Obes. Metab. 18 (Suppl. 1), 78–86 (2016).
Torres-Aleman, I. Toward a comprehensive neurobiology of IGF-I. Dev. Neurobiol. 70, 384–396 (2010).
Dyer, A. H., Vahdatpour, C., Sanfeliu, A. & Tropea, D. The role of Insulin-Like Growth Factor 1 (IGF-1) in brain development, maturation and neuroplasticity. Neuroscience 325, 89–99 (2016).
De Meyts, P. The insulin receptor and its signal transduction network. Endotext https://www.ncbi.nlm.nih.gov/books/NBK378978/ (2000).
Sano, H. et al. Rab10, a target of the AS160 Rab GAP, is required for insulin-stimulated translocation of GLUT4 to the adipocyte plasma membrane. Cell Metab. 5, 293–303 (2007).
Rui, L. Energy metabolism in the liver. Compr. Physiol. 4, 177–197 (2014).
King, G. L., Park, K. & Li, Q. Selective insulin resistance and the development of cardiovascular diseases in diabetes: the 2015 Edwin Bierman Award lecture. Diabetes 65, 1462–1471 (2016).
Marks, J. L., Porte, D. Jr., Stahl, W. L. & Baskin, D. G. Localization of insulin receptor mRNA in rat brain by in situ hybridization. Endocrinology 127, 3234–3236 (1990).
Unger, J. W. & Betz, M. Insulin receptors and signal transduction proteins in the hypothalamo-hypophyseal system: a review on morphological findings and functional implications. Histol. Histopathol. 13, 1215–1224 (1998).
Werther, G. A. et al. Localization and characterization of insulin receptors in rat brain and pituitary gland using in vitro autoradiography and computerized densitometry. Endocrinology 121, 1562–1570 (1987).
Zhao, W. et al. Brain insulin receptors and spatial memory. Correlated changes in gene expression, tyrosine phosphorylation, and signaling molecules in the hippocampus of water maze trained rats. J. Biol. Chem. 274, 34893–34902 (1999).
Bromander, S. et al. Cerebrospinal fluid insulin during non-neurological surgery. J. Neural Transm. (Vienna) 117, 1167–1170 (2010).
Wallum, B. J. et al. Cerebrospinal fluid insulin levels increase during intravenous insulin infusions in man. J. Clin. Endocrinol. Metab. 64, 190–194 (1987).
Banks, W. A. The source of cerebral insulin. Eur. J. Pharmacol. 490, 5–12 (2004).
Baura, G. D. et al. Saturable transport of insulin from plasma into the central nervous system of dogs in vivo. A mechanism for regulated insulin delivery to the brain. J. Clin. Invest. 92, 1824–1830 (1993).
Banks, W. A., Jaspan, J. B., Huang, W. & Kastin, A. J. Transport of insulin across the blood-brain barrier: saturability at euglycemic doses of insulin. Peptides 18, 1423–1429 (1997).
Pardridge, W. M., Eisenberg, J. & Yang, J. Human blood-brain barrier insulin receptor. J. Neurochem. 44, 1771–1778 (1985).
Schwartz, M. W. et al. Evidence for entry of plasma insulin into cerebrospinal fluid through an intermediate compartment in dogs. Quantitative aspects and implications for transport. J. Clin. Invest. 88, 1272–1281 (1991).
Banks, W. A., Owen, J. B. & Erickson, M. A. Insulin in the brain: there and back again. Pharmacol. Ther. 136, 82–93 (2012).
Heni, M. et al. Evidence for altered transport of insulin across the blood-brain barrier in insulin-resistant humans. Acta Diabetol. 51, 679–681 (2014).
Sartorius, T. et al. The brain response to peripheral insulin declines with age: a contribution of the blood-brain barrier? PLOS ONE 10, e0126804 (2015).
Stanley, M., Macauley, S. L. & Holtzman, D. M. Changes in insulin and insulin signaling in Alzheimer’s disease: cause or consequence? J. Exp. Med. 213, 1375–1385 (2016).
Giddings, S. J., Chirgwin, J. & Permutt, M. A. Evaluation of rat insulin messenger RNA in pancreatic and extrapancreatic tissues. Diabetologia 28, 343–347 (1985).
Clarke, D. W. et al. Insulin is released from rat brain neuronal cells in culture. J. Neurochem. 47, 831–836 (1986).
Young, W. S. III. Periventricular hypothalamic cells in the rat brain contain insulin mRNA. Neuropeptides 8, 93–97 (1986).
Devaskar, S. U. et al. Insulin gene expression and insulin synthesis in mammalian neuronal cells. J. Biol. Chem. 269, 8445–8454 (1994).
Deltour, L. et al. Differential expression of the two nonallelic proinsulin genes in the developing mouse embryo. Proc. Natl Acad. Sci. USA 90, 527–531 (1993).
Schechter, R. et al. Developmental regulation of insulin in the mammalian central nervous system. Brain Res. 582, 27–37 (1992).
Adamo, M., Raizada, M. K. & LeRoith, D. Insulin and insulin-like growth factor receptors in the nervous system. Mol. Neurobiol. 3, 71–100 (1989).
Coker, G. T. III, Studelska, D., Harmon, S., Burke, W. & O’Malley, K. L. Analysis of tyrosine hydroxylase and insulin transcripts in human neuroendocrine tissues. Brain Res. Mol. Brain Res. 8, 93–98 (1990).
Devaskar, S. U., Singh, B. S., Carnaghi, L. R., Rajakumar, P. A. & Giddings, S. J. Insulin II gene expression in rat central nervous system. Regul. Pept. 48, 55–63 (1993).
Woods, S. C., Seeley, R. J., Baskin, D. G. & Schwartz, M. W. Insulin and the blood-brain barrier. Curr. Pharm. Des. 9, 795–800 (2003).
Dorn, A., Rinne, A., Hahn, H. J., Bernstein, H. G. & Ziegler, M. C-Peptide immunoreactive neurons in human brain. Acta Histochem. 70, 326–330 (1982).
Frolich, L. et al. Brain insulin and insulin receptors in aging and sporadic Alzheimer’s disease. J. Neural Transm. (Vienna) 105, 423–438 (1998).
Steen, E. 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. 7, 63–80 (2005).
Mehran, A. E. et al. Hyperinsulinemia drives diet-induced obesity independently of brain insulin production. Cell Metab. 16, 723–737 (2012).
Nelson, T. J., Sun, M. K., Hongpaisan, J. & Alkon, D. L. Insulin, PKC signaling pathways and synaptic remodeling during memory storage and neuronal repair. Eur. J. Pharmacol. 585, 76–87 (2008).
van der Heide, L. P., Ramakers, G. M. & Smidt, M. P. Insulin signaling in the central nervous system: learning to survive. Prog. Neurobiol. 79, 205–221 (2006).
Werther, G. A. et al. Localization and characterization of insulin-like growth factor-i receptors in rat brain and pituitary gland using in vitro autoradiography and computerized densitometry* A distinct distribution from insulin receptors. J. Neuroendocrinol. 1, 369–377 (1989).
Mielke, J. G., Taghibiglou, C. & Wang, Y. T. Endogenous insulin signaling protects cultured neurons from oxygen-glucose deprivation-induced cell death. Neuroscience 143, 165–173 (2006).
Abbott, M. A., Wells, D. G. & Fallon, J. R. The insulin receptor tyrosine kinase substrate p58/53 and the insulin receptor are components of CNS synapses. J. Neurosci. 19, 7300–7308 (1999).
Bockmann, J., Kreutz, M. R., Gundelfinger, E. D. & Bockers, T. M. ProSAP/Shank postsynaptic density proteins interact with insulin receptor tyrosine kinase substrate IRSp53. J. Neurochem. 83, 1013–1017 (2002).
Mielke, J. G. & Wang, Y. T. Insulin, synaptic function, and opportunities for neuroprotection. Prog. Mol. Biol. Transl Sci. 98, 133–186 (2011).
Gralle, M. The neuronal insulin receptor in its environment. J. Neurochem. 140, 359–367 (2017).
Fadel, J. R. & Reagan, L. P. Stop signs in hippocampal insulin signaling: the role of insulin resistance in structural, functional and behavioral deficits. Curr. Opin. Behav. Sci. 9, 47–54 (2016).
De Felice, F. G. Alzheimer’s disease and insulin resistance: translating basic science into clinical applications. J. Clin. Invest. 123, 531–539 (2013).
van der Heide, L. P., Kamal, A., Artola, A., Gispen, W. H. & Ramakers, G. M. Insulin modulates hippocampal activity-dependent synaptic plasticity in a N-methyl-D-aspartate receptor and phosphatidyl-inositol-3-kinase-dependent manner. J. Neurochem. 94, 1158–1166 (2005).
Chiu, S. L., Chen, C. M. & Cline, H. T. Insulin receptor signaling regulates synapse number, dendritic plasticity, and circuit function in vivo. Neuron 58, 708–719 (2008).
Lee, C. C., Huang, C. C. & Hsu, K. S. Insulin promotes dendritic spine and synapse formation by the PI3K/Akt/mTOR and Rac1 signaling pathways. Neuropharmacology 61, 867–879 (2011).
Peineau, S. et al. LTP inhibits LTD in the hippocampus via regulation of GSK3β. Neuron 53, 703–717 (2007).
Kim, S. J. & Han, Y. Insulin inhibits AMPA-induced neuronal damage via stimulation of protein kinase B (Akt). J. Neural Transm. (Vienna) 112, 179–191 (2005).
Heidenrich, K. A., Gilmore, P. R. & Garvey, W. T. Glucose transport in primary cultured neurons. J. Neurosci. Res. 22, 397–407 (1989).
Uemura, E. & Greenlee, H. W. Insulin regulates neuronal glucose uptake by promoting translocation of glucose transporter GLUT3. Exp. Neurol. 198, 48–53 (2006).
Jurcovicova, J. Glucose transport in brain – effect of inflammation. Endocr. Regul. 48, 35–48 (2014).
Talbot, K. et al. Demonstrated brain insulin resistance in Alzheimer’s disease patients is associated with IGF-1 resistance, IRS-1 dysregulation, and cognitive decline. J. Clin. Invest. 122, 1316–1338 (2012).
Duelli, R. & Kuschinsky, W. Brain glucose transporters: relationship to local energy demand. News Physiol. Sci. 16, 71–76 (2001).
Apelt, J., Mehlhorn, G. & Schliebs, R. Insulin-sensitive GLUT4 glucose transporters are colocalized with GLUT3-expressing cells and demonstrate a chemically distinct neuron-specific localization in rat brain. J. Neurosci. Res. 57, 693–705 (1999).
McEwen, B. S. & Reagan, L. P. Glucose transporter expression in the central nervous system: relationship to synaptic function. Eur. J. Pharmacol. 490, 13–24 (2004).
Grillo, C. A., Piroli, G. G., Hendry, R. M. & Reagan, L. P. Insulin-stimulated translocation of GLUT4 to the plasma membrane in rat hippocampus is PI3-kinase dependent. Brain Res. 1296, 35–45 (2009).
Pearson-Leary, J. & McNay, E. C. Novel roles for the insulin-regulated glucose transporter-4 in hippocampally dependent memory. J. Neurosci. 36, 11851–11864 (2016).
Komori, T. et al. Subcellular localization of glucose transporter 4 in the hypothalamic arcuate nucleus of ob/ob mice under basal conditions. Brain Res. 1049, 34–42 (2005).
Reno, C. M. et al. Brain GLUT4 knockout mice have impaired glucose tolerance, decreased insulin sensitivity, and impaired hypoglycemic counterregulation. Diabetes 66, 587–597 (2017).
Pelvig, D. P., Pakkenberg, H., Stark, A. K. & Pakkenberg, B. Neocortical glial cell numbers in human brains. Neurobiol. Aging 29, 1754–1762 (2008).
Blinkow, S. & Glezer, I. in The Human Brain in Figures and tables (ed. Blinkow, F. G.) 237–253 (Plenum Press, 1968).
Wender, R. et al. Astrocytic glycogen influences axon function and survival during glucose deprivation in central white matter. J. Neurosci. 20, 6804–6810 (2000).
Pellerin, L. et al. Evidence supporting the existence of an activity-dependent astrocyte-neuron lactate shuttle. Dev. Neurosci. 20, 291–299 (1998).
Benarroch, E. E. Brain glucose transporters: implications for neurologic disease. Neurology 82, 1374–1379 (2014).
Berhane, F. et al. Plasma lactate levels increase during hyperinsulinemic euglycemic clamp and oral glucose tolerance test. J. Diabetes Res. 2015, 102054 (2015).
Albrecht, J., Wroblewska, B. & Mossakowski, M. J. The binding of insulin to cerebral capillaries and astrocytes of the rat. Neurochem. Res. 7, 489–494 (1982).
Garwood, C. J. et al. Insulin and IGF1 signalling pathways in human astrocytes in vitro and in vivo; characterisation, subcellular localisation and modulation of the receptors. Mol. Brain 8, 51 (2015).
Spielman, L. J., Bahniwal, M., Little, J. P., Walker, D. G. & Klegeris, A. Insulin modulates in vitro secretion of cytokines and cytotoxins by human glial cells. Curr. Alzheimer Res. 12, 684–693 (2015).
Heni, M. et al. Insulin promotes glycogen storage and cell proliferation in primary human astrocytes. PLoS ONE 6, e21594 (2011).
Clarke, D. W., Boyd, F. T. Jr., Kappy, M. S. & Raizada, M. K. Insulin binds to specific receptors and stimulates 2-deoxy-D-glucose uptake in cultured glial cells from rat brain. J. Biol. Chem. 259, 11672–11675 (1984).
Ye, P., Li, L., Lund, P. K. & D’Ercole, A. J. Deficient expression of insulin receptor substrate-1 (IRS-1) fails to block insulin-like growth factor-I (IGF-I) stimulation of brain growth and myelination. Brain Res. Dev. Brain Res. 136, 111–121 (2002).
Cui, Q. L. et al. Response of human oligodendrocyte progenitors to growth factors and axon signals. J. Neuropathol. Exp. Neurol. 69, 930–944 (2010).
Mamik, M. K. et al. HIV-1 viral protein R activates NLRP3 inflammasome in microglia: implications for HIV-1 associated neuroinflammation. J. Neuroimmune Pharmacol. 12, 233–248 (2017).
Pardini, A. W. et al. Distribution of insulin receptor substrate-2 in brain areas involved in energy homeostasis. Brain Res. 1112, 169–178 (2006).
Debons, A. F., Krimsky, I. & From, A. A direct action of insulin on the hypothalamic satiety center. Am. J. Physiol. 219, 938–943 (1970).
Hatfield, J. S., Millard, W. J. & Smith, C. J. Short-term influence of intra-ventromedial hypothalamic administration of insulin on feeding in normal and diabetic rats. Pharmacol. Biochem. Behav. 2, 223–226 (1974).
Strubbe, J. H. & Mein, C. G. Increased feeding in response to bilateral injection of insulin antibodies in the VMH. Physiol. Behav. 19, 309–313 (1977).
Woods, S. C. & Porte, D. Jr. The role of insulin as a satiety factor in the central nervous system. Adv. Metab. Disord. 10, 457–468 (1983).
Schwartz, M. W., Figlewicz, D. P., Baskin, D. G., Woods, S. C. & Porte, D. Jr. Insulin in the brain: a hormonal regulator of energy balance. Endocr. Rev. 13, 387–414 (1992).
Ajaya, B. & Haranath, P. S. Effects of insulin administered into cerebrospinal fluid spaces on blood glucose in unanaesthetized and anaesthetized dogs. Indian J. Med. Res. 75, 607–615 (1982).
Air, E. L., Benoit, S. C., Blake Smith, K. A., Clegg, D. J. & Woods, S. C. Acute third ventricular administration of insulin decreases food intake in two paradigms. Pharmacol. Biochem. Behav. 72, 423–429 (2002).
Woods, S. C., Lotter, E. C., McKay, L. D. & Porte, D. Jr. Chronic intracerebroventricular infusion of insulin reduces food intake and body weight of baboons. Nature 282, 503–505 (1979).
Jessen, L., Clegg, D. J. & Bouman, S. D. Evaluation of the lack of anorectic effect of intracerebroventricular insulin in rats. Am. J. Physiol. Regul. Integr. Comp. Physiol. 298, R43–R50 (2010).
Pocai, A. et al. Hypothalamic K(ATP) channels control hepatic glucose production. Nature 434, 1026–1031 (2005).
Obici, S., Feng, Z., Karkanias, G., Baskin, D. G. & Rossetti, L. Decreasing hypothalamic insulin receptors causes hyperphagia and insulin resistance in rats. Nat. Neurosci. 5, 566–572 (2002).
Obici, S., Zhang, B. B., Karkanias, G. & Rossetti, L. Hypothalamic insulin signaling is required for inhibition of glucose production. Nat. Med. 8, 1376–1382 (2002).
Scherer, T. et al. Brain insulin controls adipose tissue lipolysis and lipogenesis. Cell Metab. 13, 183–194 (2011).
Iwen, K. A. et al. Intranasal insulin suppresses systemic but not subcutaneous lipolysis in healthy humans. J. Clin. Endocrinol. Metab. 99, E246–E251 (2014).
Shin, A. C. et al. Brain insulin lowers circulating BCAA levels by inducing hepatic BCAA catabolism. Cell Metab. 20, 898–909 (2014).
Ruiz, H. H. et al. Increased susceptibility to metabolic dysregulation in a mouse model of Alzheimer’s disease is associated with impaired hypothalamic insulin signaling and elevated BCAA levels. Alzheimers Dement. 12, 851–861 (2016).
Benedict, C., Kern, W., Schultes, B., Born, J. & Hallschmid, M. Differential sensitivity of men and women to anorexigenic and memory-improving effects of intranasal insulin. J. Clin. Endocrinol. Metab. 93, 1339–1344 (2008).
Hallschmid, M., Benedict, C., Schultes, B., Born, J. & Kern, W. Obese men respond to cognitive but not to catabolic brain insulin signaling. Int. J. Obes. (Lond.) 32, 275–282 (2008).
Benedict, C. et al. Intranasal insulin improves memory in humans. Psychoneuroendocrinology 29, 1326–1334 (2004).
Brunner, Y. F., Kofoet, A., Benedict, C. & Freiherr, J. Central insulin administration improves odor-cued reactivation of spatial memory in young men. J. Clin. Endocrinol. Metab. 100, 212–219 (2015).
Novak, V. et al. Enhancement of vasoreactivity and cognition by intranasal insulin in type 2 diabetes. Diabetes Care 37, 751–759 (2014).
Reger, M. A. et al. Effects of intranasal insulin on cognition in memory-impaired older adults: modulation by APOE genotype. Neurobiol. Aging 27, 451–458 (2006).
Craft, S. et al. Intranasal insulin therapy for Alzheimer disease and amnestic mild cognitive impairment: a pilot clinical trial. Arch. Neurol. 69, 29–38 (2012).
Claxton, A. et al. Long acting intranasal insulin detemir improves cognition for adults with mild cognitive impairment or early-stage alzheimer’s disease dementia. J. Alzheimers Dis. 45, 1269–1270 (2015).
Reger, M. A. et al. Intranasal insulin administration dose-dependently modulates verbal memory and plasma amyloid-β in memory-impaired older adults. J. Alzheimers Dis. 13, 323–331 (2008).
Krug, R., Benedict, C., Born, J. & Hallschmid, M. Comparable sensitivity of postmenopausal and young women to the effects of intranasal insulin on food intake and working memory. J. Clin. Endocrinol. Metab. 95, E468–E472 (2010).
Guthoff, M. et al. Insulin modulates food-related activity in the central nervous system. J. Clin. Endocrinol. Metab. 95, 748–755 (2010).
Zhang, H. et al. Intranasal insulin enhanced resting-state functional connectivity of hippocampal regions in type 2 diabetes. Diabetes 64, 1025–1034 (2015).
Schilling, T. M. et al. Intranasal insulin increases regional cerebral blood flow in the insular cortex in men independently of cortisol manipulation. Hum. Brain Mapp. 35, 1944–1956 (2014).
Kern, W., Born, J., Schreiber, H. & Fehm, H. L. Central nervous system effects of intranasally administered insulin during euglycemia in men. Diabetes 48, 557–563 (1999).
Hallschmid, M. et al. Transcortical direct current potential shift reflects immediate signaling of systemic insulin to the human brain. Diabetes 53, 2202–2208 (2004).
Stingl, K. T. et al. Insulin modulation of magnetoencephalographic resting state dynamics in lean and obese subjects. Front. Syst. Neurosci. 4, 157 (2010).
Tschritter, O. et al. The cerebrocortical response to hyperinsulinemia is reduced in overweight humans: a magnetoencephalographic study. Proc. Natl Acad. Sci. USA 103, 12103–12108 (2006).
Craft, S. et al. Insulin effects on glucose metabolism, memory, and plasma amyloid precursor protein in Alzheimer’s disease differ according to apolipoprotein-E genotype. Ann. NY Acad. Sci. 903, 222–228 (2000).
McNay, E. C. & Cotero, V. E. Mini-review: impact of recurrent hypoglycemia on cognitive and brain function. Physiol. Behav. 100, 234–238 (2010).
Stollery, B. & Christian, L. Glucose improves object-location binding in visual-spatial working memory. Psychopharmacol. (Berl.) 233, 529–547 (2016).
Crane, P. K., Walker, R. & Larson, E. B. Glucose levels and risk of dementia. N. Engl. J. Med. 369, 1863–1864 (2013).
McNay, E. C., Fries, T. M. & Gold, P. E. Decreases in rat extracellular hippocampal glucose concentration associated with cognitive demand during a spatial task. Proc. Natl Acad. Sci. USA 97, 2881–2885 (2000).
McNay, E. C. & Gold, P. E. Food for thought: fluctuations in brain extracellular glucose provide insight into the mechanisms of memory modulation. Behav. Cogn. Neurosci. Rev. 1, 264–280 (2002).
Rinkel, M. & Himwich, H. E. Insulin Treatment in Psychiatry (Philosophical Library, 1959).
Mezuk, B., Eaton, W. W., Albrecht, S. & Golden, S. H. Depression and type 2 diabetes over the lifespan: a meta-analysis. Diabetes Care 31, 2383–2390 (2008).
Hallschmid, M. et al. Euglycemic infusion of insulin detemir compared with human insulin appears to increase direct current brain potential response and reduces food intake while inducing similar systemic effects. Diabetes 59, 1101–1107 (2010).
Goldstein, B. J. Insulin resistance as the core defect in type 2 diabetes mellitus. Am. J. Cardiol. 90, 3G–10G (2002).
Mielke, J. G. et al. A biochemical and functional characterization of diet-induced brain insulin resistance. J. Neurochem. 93, 1568–1578 (2005).
Miles, W. R. & Root, H. F. Psychologic tests applied in diabetic patients. Arch. Internal Med. 30, 767–777 (1922).
Perlmuter, L. C. et al. Decreased cognitive function in aging non-insulin-dependent diabetic patients. Am. J. Med. 77, 1043–1048 (1984).
Reaven, G. M., Thompson, L. W., Nahum, D. & Haskins, E. Relationship between hyperglycemia and cognitive function in older NIDDM patients. Diabetes Care 13, 16–21 (1990).
Grodstein, F., Chen, J., Wilson, R. S., Manson, J. E. & Nurses’ Health, S. Type 2 diabetes and cognitive function in community-dwelling elderly women. Diabetes Care 24, 1060–1065 (2001).
Ruis, C. et al. Cognition in the early stage of type 2 diabetes. Diabetes Care 32, 1261–1265 (2009).
Manschot, S. M. et al. Brain magnetic resonance imaging correlates of impaired cognition in patients with type 2 diabetes. Diabetes 55, 1106–1113 (2006).
Ebady, S. A., Arami, M. A. & Shafigh, M. H. Investigation on the relationship between diabetes mellitus type 2 and cognitive impairment. Diabetes Res. Clin. Pract. 82, 305–309 (2008).
Ding, J. et al. Diabetic retinopathy and cognitive decline in older people with type 2 diabetes: the Edinburgh Type 2 Diabetes Study. Diabetes 59, 2883–2889 (2010).
Kivipelto, M. et al. Midlife vascular risk factors and late-life mild cognitive impairment: a population-based study. Neurology 56, 1683–1689 (2001).
Yaffe, K. et al. The metabolic syndrome, inflammation, and risk of cognitive decline. JAMA 292, 2237–2242 (2004).
DeCarli, C. et al. Cerebrovascular and brain morphologic correlates of mild cognitive impairment in the National Heart, Lung, and Blood Institute Twin Study. Arch. Neurol. 58, 643–647 (2001).
Strachan, M. W., Deary, I. J., Ewing, F. M. & Frier, B. M. Is type II diabetes associated with an increased risk of cognitive dysfunction? A critical review of published studies. Diabetes Care 20, 438–445 (1997).
Stewart, R. & Liolitsa, D. Type 2 diabetes mellitus, cognitive impairment and dementia. Diabet Med. 16, 93–112 (1999).
Yau, P. L. et al. Preliminary evidence for brain complications in obese adolescents with type 2 diabetes mellitus. Diabetologia 53, 2298–2306 (2010).
Yau, P. L., Castro, M. G., Tagani, A., Tsui, W. H. & Convit, A. Obesity and metabolic syndrome and functional and structural brain impairments in adolescence. Pediatrics 130, e856–e864 (2012).
Rees, D. A., Udiawar, M., Berlot, R., Jones, D. K. & O’Sullivan, M. J. White matter microstructure and cognitive function in young women with polycystic ovary syndrome. J. Clin. Endocrinol. Metab. 101, 314–323 (2016).
Weinstein, G. et al. Glucose indices are associated with cognitive and structural brain measures in young adults. Neurology 84, 2329–2337 (2015).
Brundel, M., Kappelle, L. J. & Biessels, G. J. Brain imaging in type 2 diabetes. Eur. Neuropsychopharmacol. 24, 1967–1981 (2014).
Del Bene, A. et al. Is type 2 diabetes related to leukoaraiosis? an updated review. Acta Neurol. Scand. 132, 147–155 (2015).
Baker, L. D. et al. Insulin resistance and Alzheimer-like reductions in regional cerebral glucose metabolism for cognitively normal adults with prediabetes or early type 2 diabetes. Arch. Neurol. 68, 51–57 (2011).
Willette, A. A. et al. Association of insulin resistance with cerebral glucose uptake in late middle-aged adults at risk for alzheimer disease. JAMA Neurol. 72, 1013–1020 (2015).
Roberts, R. O. et al. Diabetes and elevated hemoglobin A1c levels are associated with brain hypometabolism but not amyloid accumulation. J. Nucl. Med. 55, 759–764 (2014).
Starr, J. M. et al. Increased blood-brain barrier permeability in type II diabetes demonstrated by gadolinium magnetic resonance imaging. J. Neurol. Neurosurg. Psychiatry 74, 70–76 (2003).
Yoo, D. Y. et al. Chronic type 2 diabetes reduces the integrity of the blood-brain barrier by reducing tight junction proteins in the hippocampus. J. Vet. Med. Sci. 78, 957–962 (2016).
Prasad, S., Sajja, R. K., Naik, P. & Cucullo, L. Diabetes mellitus and blood-brain barrier dysfunction: an overview. J. Pharmacovigil. 2, 125 (2014).
Arnold, S. E. et al. High fat diet produces brain insulin resistance, synaptodendritic abnormalities and altered behavior in mice. Neurobiol. Dis. 67, 79–87 (2014).
Liu, Z. et al. High-fat diet induces hepatic insulin resistance and impairment of synaptic plasticity. PLoSONE 10, e0128274 (2015).
Martins, I. V., Rivers-Auty, J., Allan, S. M. & Lawrence, C. B. Mitochondrial abnormalities and synaptic loss underlie memory deficits seen in mouse models of obesity and Alzheimer’s disease. J. Alzheimers Dis. 55, 915–932 (2017).
Ramos-Rodriguez, J. J. et al. Differential central pathology and cognitive impairment in pre-diabetic and diabetic mice. Psychoneuroendocrinology 38, 2462–2475 (2013).
Anthony, K. et al. Attenuation of insulin-evoked responses in brain networks controlling appetite and reward in insulin resistance: the cerebral basis for impaired control of food intake in metabolic syndrome? Diabetes 55, 2986–2992 (2006).
Tschritter, O. et al. Variation in the FTO gene locus is associated with cerebrocortical insulin resistance in humans. Diabetologia 50, 2602–2603 (2007).
Bucht, G., Adolfsson, R., Lithner, F. & Winblad, B. Changes in blood glucose and insulin secretion in patients with senile dementia of Alzheimer type. ActaMed. Scand. 213, 387–392 (1983).
Bosco, D. et al. Dementia is associated with insulin resistance in patients with Parkinson’s disease. J. Neurol. Sci. 315, 39–43 (2012).
Cereda, E., Barichella, M., Cassani, E., Caccialanza, R. & Pezzoli, G. Clinical features of Parkinson disease when onset of diabetes came first: a case-control study. Neurology 78, 1507–1511 (2012).
Cereda, E. et al. Diabetes and risk of Parkinson’s disease. Mov Disord. 28, 257 (2013).
Driver, J. A. et al. Prospective cohort study of type 2 diabetes and the risk of Parkinson’s disease. DiabetesCare 31, 2003–2005 (2008).
Hu, G., Jousilahti, P., Bidel, S., Antikainen, R. & Tuomilehto, J. Type 2 diabetes and the risk of Parkinson’s disease. Diabetes Care 30, 842–847 (2007).
Kotagal, V. et al. Diabetes is associated with postural instability and gait difficulty in Parkinson disease. Parkinsonism Relat. Disord. 19, 522–526 (2013).
Sandyk, R. The relationship between diabetes mellitus and Parkinson’s disease. Int. J. Neurosci. 69, 125–130 (1993).
Sun, Y. et al. Risk of Parkinson disease onset in patients with diabetes: a 9-year population-based cohort study with age and sex stratifications. Diabetes Care 35, 1047–1049 (2012).
Wahlqvist, M. L. et al. Metformin-inclusive sulfonylurea therapy reduces the risk of Parkinson’s disease occurring with Type 2 diabetes in a Taiwanese population cohort. Parkinsonism Relat. Disord. 18, 753–758 (2012).
Xu, Q. et al. Diabetes and risk of Parkinson’s disease. Diabetes Care 34, 910–915 (2011).
Golimstok, A. et al. Cardiovascular risk factors and frontotemporal dementia: a case-control study. Transl Neurodegener. 3, 13 (2014).
Ahtiluoto, S. et al. Diabetes, Alzheimer disease, and vascular dementia: a population-based neuropathologic study. Neurology 75, 1195–1202 (2010).
Hassing, L. B. 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. 14, 239–248 (2002).
Hayden, K. M. et al. Vascular risk factors for incident Alzheimer disease and vascular dementia: the Cache County study. Alzheimer Dis. Assoc. Disord. 20, 93–100 (2006).
Kimm, H. et al. Mid-life and late-life vascular risk factors and dementia in Korean men and women. Arch. Gerontol. Geriatr. 52, e117–e122 (2011).
Ohara, T. et al. Glucose tolerance status and risk of dementia in the community: the Hisayama study. Neurology 77, 1126–1134 (2011).
Peila, R., Rodriguez, B. L., Launer, L. J. & Honolulu-Asia Aging Study. Type 2 diabetes, APOE gene, and the risk for dementia and related pathologies: The Honolulu-Asia Aging Study. Diabetes 51, 1256–1262 (2002).
Posner, H. B. et al. The relationship of hypertension in the elderly to AD, vascular dementia, and cognitive function. Neurology 58, 1175–1181 (2002).
Xu, W. et al. Mid- and late-life diabetes in relation to the risk of dementia: a population-based twin study. Diabetes 58, 71–77 (2009).
Gudala, K., Bansal, D., Schifano, F. & Bhansali, A. Diabetes mellitus and risk of dementia: a meta-analysis of prospective observational studies. J. Diabetes Investig. 4, 640–650 (2013).
de la Monte, S. M. Therapeutic targets of brain insulin resistance in sporadic Alzheimer’s disease. Front. Biosci. (Elite Ed.) 4, 1582–1605 (2012).
Kimura, N. Diabetes mellitus induces Alzheimer’s disease pathology: histopathological evidence from animal models. Int. J. Mol. Sci. 17, 503 (2016).
Rotermund, C., Truckenmuller, F. M., Schell, H. & Kahle, P. J. Diet-induced obesity accelerates the onset of terminal phenotypes in alpha-synuclein transgenic mice. J. Neurochem. 131, 848–858 (2014).
van Harten, B., de Leeuw, F. E., Weinstein, H. C., Scheltens, P. & Biessels, G. J. Brain imaging in patients with diabetes: a systematic review. Diabetes Care 29, 2539–2548 (2006).
den Heijer, T. et al. Type 2 diabetes and atrophy of medial temporal lobe structures on brain MRI. Diabetologia 46, 1604–1610 (2003).
Gold, S. M. et al. Hippocampal damage and memory impairments as possible early brain complications of type 2 diabetes. Diabetologia 50, 711–719 (2007).
Benedict, C. et al. Impaired insulin sensitivity as indexed by the HOMA score is associated with deficits in verbal fluency and temporal lobe gray matter volume in the elderly. Diabetes Care 35, 488–494 (2012).
Tan, Z. S. et al. Association of metabolic dysregulation with volumetric brain magnetic resonance imaging and cognitive markers of subclinical brain aging in middle-aged adults: the Framingham Offspring Study. Diabetes Care 34, 1766–1770 (2011).
Rasgon, N. L. et al. Insulin resistance and hippocampal volume in women at risk for Alzheimer’s disease. Neurobiol. Aging 32, 1942–1948 (2011).
Willette, A. A. et al. Insulin resistance, brain atrophy, and cognitive performance in late middle-aged adults. Diabetes Care 36, 443–449 (2013).
Hsu, F. C. et al. Adiposity is inversely associated with hippocampal volume in African Americans and European Americans with diabetes. J. Diabetes Compl. 30, 1506–1512 (2016).
Zhang, Y. W. et al. Memory dysfunction in type 2 diabetes mellitus correlates with reduced hippocampal CA1 and subiculum volumes. Chin. Med. J. (Engl.) 128, 465–471 (2015).
Yau, P. L., Kluger, A., Borod, J. C. & Convit, A. Neural substrates of verbal memory impairments in adults with type 2 diabetes mellitus. J. Clin. Exp. Neuropsychol. 36, 74–87 (2014).
Hempel, R., Onopa, R. & Convit, A. Type 2 diabetes affects hippocampus volume differentially in men and women. Diabetes Metab. Res. Rev. 28, 76–83 (2012).
Moran, C. et al. Type 2 diabetes mellitus and biomarkers of neurodegeneration. Neurology 85, 1123–1130 (2015).
Willette, A. A., Modanlo, N., Kapogiannis, D. & Alzheimer’s Disease Neuroimaging Initiative. Insulin resistance predicts medial temporal hypermetabolism in mild cognitive impairment conversion to Alzheimer disease. Diabetes 64, 1933–1940 (2015).
Garcia-Casares, N. et al. Cognitive dysfunctions in middle-aged type 2 diabetic patients and neuroimaging correlations: a cross-sectional study. J. Alzheimers Dis. 42, 1337–1346 (2014).
Marano, C. M. et al. The relationship between fasting serum glucose and cerebral glucose metabolism in late-life depression and normal aging. Psychiatry Res. 222, 84–90 (2014).
Thambisetty, M. et al. Impaired glucose tolerance in midlife and longitudinal changes in brain function during aging. Neurobiol. Aging 34, 2271–2276 (2013).
Brundel, M. et al. Cerebral haemodynamics, cognition and brain volumes in patients with type 2 diabetes. J. Diabetes Compl. 26, 205–209 (2012).
Musen, G. et al. Resting-state brain functional connectivity is altered in type 2 diabetes. Diabetes 61, 2375–2379 (2012).
Cui, Y. et al. Cerebral perfusion alterations in type 2 diabetes and its relation to insulin resistance and cognitive dysfunction. Brain Imaging Behav. 11, 1248–1257 (2017).
Hoscheidt, S. M. et al. Insulin resistance is associated with lower arterial blood flow and reduced cortical perfusion in cognitively asymptomatic middle-aged adults. J. Cereb. Blood Flow Metab. (2016).
Xia, W. et al. Blood pressure is associated with cerebral blood flow alterations in patients with T2DM as revealed by perfusion functional MRI. Med. (Baltimore) 94, e2231 (2015).
Xia, W. et al. Disrupted resting-state attentional networks in T2DM patients. Sci. Rep. 5, 11148 (2015).
Xia, W. et al. Insulin resistance-associated interhemispheric functional connectivity alterations in T2DM: a resting-state fMRI study. Biomed. Res. Int. 2015, 719076 (2015).
Xia, W. et al. Altered baseline brain activity in type 2 diabetes: a resting-state fMRI study. Psychoneuroendocrinology 38, 2493–2501 (2013).
Willette, A. A. et al. Insulin resistance predicts brain amyloid deposition in late middle-aged adults. Alzheimers Dement. 11, 504–510 (2015).
Thambisetty, M. et al. Glucose intolerance, insulin resistance, and pathological features of Alzheimer disease in the Baltimore Longitudinal Study of Aging. JAMA Neurol. 70, 1167–1172 (2013).
Tomita, N. et al. Brain accumulation of amyloid-β protein visualized by positron emission tomography and BF-227 in Alzheimer’s disease patients with or without diabetes mellitus. Geriatr. Gerontol. Int. 13, 215–221 (2013).
Fukasawa, R. et al. Identification of diabetes-related dementia: longitudinal perfusion SPECT and amyloid PET studies. J. Neurol. Sci. 349, 45–51 (2015).
Starks, E. J. et al. Insulin resistance is associated with higher cerebrospinal fluid tau levels in asymptomatic APOε4 Carriers. J. Alzheimers Dis. 46, 525–533 (2015).
Heitner, J. & Dickson, D. Diabetics do not have increased Alzheimer-type pathology compared with age-matched control subjects. A retrospective postmortem immunocytochemical and histofluorescent study. Neurology 49, 1306–1311 (1997).
Beeri, M. S. et al. Insulin in combination with other diabetes medication is associated with less Alzheimer neuropathology. Neurology 71, 750–757 (2008).
Sonnen, J. A. et al. Different patterns of cerebral injury in dementia with or without diabetes. Arch. Neurol. 66, 315–322 (2009).
Arvanitakis, Z. et al. Diabetes is related to cerebral infarction but not to AD pathology in older persons. Neurology 67, 1960–1965 (2006).
Nelson, P. T. et al. Human cerebral neuropathology of Type 2 diabetes mellitus. Biochim. Biophys. Acta 1792, 454–469 (2009).
Abner, E. L. et al. Diabetes is associated with cerebrovascular but not Alzheimer’s disease neuropathology. Alzheimers Dement. 12, 882–889 (2016).
Malek-Ahmadi, M. et al. Increased Alzheimer’s disease neuropathology is associated with type 2 diabetes and ApoE ε4 carrier status. Curr. Alzheimer Res. 10, 654–659 (2013).
Crane, P. K. et al. Glucose levels during life and neuropathologic findings at autopsy among people never treated for diabetes. Neurobiol. Aging 48, 72–82 (2016).
Aronson, S. M. Intracranial vascular lesions in patients with diabetes mellitus. J. Neuropathol. Exp. Neurol. 32, 183–196 (1973).
Alafuzoff, I., Aho, L., Helisalmi, S., Mannermaa, A. & Soininen, H. β-Amyloid deposition in brains of subjects with diabetes. Neuropathol. Appl. Neurobiol. 35, 60–68 (2009).
Guerrero-Berroa, E., Schmeidler, J. & Beeri, M. S. Neuropathology of type 2 diabetes: a short review on insulin-related mechanisms. Eur. Neuropsychopharmacol 24, 1961–1966 (2014).
Vagelatos, N. T. & Eslick, G. D. Type 2 diabetes as a risk factor for Alzheimer’s disease: the confounders, interactions, and neuropathology associated with this relationship. Epidemiol. Rev. 35, 152–160 (2013).
Bateman, R. J. et al. Clinical and biomarker changes in dominantly inherited Alzheimer’s disease. N. Engl. J. Med. 367, 795–804 (2012).
Morris, J. K., Vidoni, E. D., Honea, R. A., Burns, J. M. & Alzheimer’s Disease Neuroimaging Initiative. Impaired glycemia increases disease progression in mild cognitive impairment. Neurobiol. Aging 35, 585–589 (2014).
Morris, J. K. et al. Impaired fasting glucose is associated with increased regional cerebral amyloid. Neurobiol. Aging 44, 138–142 (2016).
Chaudhary, R. et al. Apolipoprotein E gene polymorphism: effects on plasma lipids and risk of type 2 diabetes and coronary artery disease. Cardiovasc. Diabetol. 11, 36 (2012).
El-Lebedy, D., Raslan, H. M. & Mohammed, A. M. Apolipoprotein E gene polymorphism and risk of type 2 diabetes and cardiovascular disease. Cardiovasc. Diabetol 15, 12 (2016).
Mohlke, K. L. & Boehnke, M. Recent advances in understanding the genetic architecture of type 2 diabetes. Hum. Mol. Genet. 24, R85–R92 (2015).
Kaul, N. & Ali, S. Genes, genetics, and environment in type 2 diabetes: implication in personalized medicine. DNA Cell Biol. 35, 1–12 (2016).
Sun, X., Yu, W. & Hu, C. Genetics of type 2 diabetes: insights into the pathogenesis and its clinical application. Biomed. Res. Int. 2014, 926713 (2014).
Chouraki, V. & Seshadri, S. Genetics of Alzheimer’s disease. Adv. Genet. 87, 245–294 (2014).
Karch, C. M. & Goate, A. M. Alzheimer’s disease risk genes and mechanisms of disease pathogenesis. Biol. Psychiatry 77, 43–51 (2015).
Goodarzi, M. O. et al. SORCS1: a novel human type 2 diabetes susceptibility gene suggested by the mouse. Diabetes 56, 1922–1929 (2007).
Liang, X. et al. Genomic convergence to identify candidate genes for Alzheimer disease on chromosome 10. Hum. Mutat. 30, 463–471 (2009).
Lane, R. F. et al. Diabetes-associated SorCS1 regulates Alzheimer’s amyloid-beta metabolism: evidence for involvement of SorL1 and the retromer complex. J. Neurosci. 30, 13110–13115 (2010).
DeFronzo, R. A. Glucose intolerance and aging. Diabetes Care 4, 493–501 (1981).
Shimokata, H. et al. Age as independent determinant of glucose tolerance. Diabetes 40, 44–51 (1991).
Meigs, J. B. et al. The natural history of progression from normal glucose tolerance to type 2 diabetes in the Baltimore Longitudinal Study of Aging. Diabetes 52, 1475–1484 (2003).
Ferrannini, E. et al. Insulin action and age. European Group for the Study of Insulin Resistance (EGIR). Diabetes 45, 947–953 (1996).
Rivera, E. J. et al. Insulin and insulin-like growth factor expression and function deteriorate with progression of Alzheimer’s disease: link to brain reductions in acetylcholine. J. Alzheimers Dis. 8, 247–268 (2005).
Moloney, A. M. et al. Defects in IGF-1 receptor, insulin receptor and IRS-1/2 in Alzheimer’s disease indicate possible resistance to IGF-1 and insulin signalling. Neurobiol. Aging 31, 224–243 (2010).
Hoyer, S. Is sporadic Alzheimer disease the brain type of non-insulin dependent diabetes mellitus? A challenging hypothesis. J. Neural Transm. (Vienna) 105, 415–422 (1998).
Hoyer, S. & Nitsch, R. Cerebral excess release of neurotransmitter amino acids subsequent to reduced cerebral glucose metabolism in early-onset dementia of Alzheimer type. J. Neural Transm. 75, 227–232 (1989).
Tong, M., Dong, M. & de la Monte, S. M. Brain insulin-like growth factor and neurotrophin resistance in Parkinson’s disease and dementia with Lewy bodies: potential role of manganese neurotoxicity. J. Alzheimers Dis. 16, 585–599 (2009).
Pei, J. J. et al. Role of protein kinase B in Alzheimer’s neurofibrillary pathology. Acta Neuropathol. 105, 381–392 (2003).
Rickle, A. et al. Akt activity in Alzheimer’s disease and other neurodegenerative disorders. Neuroreport 15, 955–959 (2004).
Li, X., Alafuzoff, I., Soininen, H., Winblad, B. & Pei, J. J. Levels of mTOR and its downstream targets 4E-BP1, eEF2, and eEF2 kinase in relationships with tau in Alzheimer’s disease brain. FEBS J. 272, 4211–4220 (2005).
Griffin, R. J. et al. Activation of Akt/PKB, increased phosphorylation of Akt substrates and loss and altered distribution of Akt and PTEN are features of Alzheimer’s disease pathology. J. Neurochem. 93, 105–117 (2005).
Avila, J., Wandosell, F. & Hernandez, F. Role of glycogen synthase kinase-3 in Alzheimer’s disease pathogenesis and glycogen synthase kinase-3 inhibitors. Expert Rev. Neurother 10, 703–710 (2010).
Hooper, C., Killick, R. & Lovestone, S. The GSK3 hypothesis of Alzheimer’s disease. J. Neurochem. 104, 1433–1439 (2008).
Bomfim, T. R. et al. An anti-diabetes agent protects the mouse brain from defective insulin signaling caused by Alzheimer’s disease-associated Abeta oligomers. J. Clin. Invest. 122, 1339–1353 (2012).
Yarchoan, M. et al. Abnormal serine phosphorylation of insulin receptor substrate 1 is associated with tau pathology in Alzheimer’s disease and tauopathies. Acta Neuropathol. 128, 679–689 (2014).
Tramutola, A. et al. Alteration of mTOR signaling occurs early in the progression of Alzheimer disease (AD): analysis of brain from subjects with pre-clinical AD, amnestic mild cognitive impairment and late-stage AD. J. Neurochem. 133, 739–749 (2015).
Taga, M. et al. Metaflammasome components in the human brain: a role in dementia with alzheimer’s pathology? Brain Pathol. 27, 266–275 (2017).
Moroo, I. et al. Loss of insulin receptor immunoreactivity from the substantia nigra pars compacta neurons in Parkinson’s disease. Acta Neuropathol. 87, 343–348 (1994).
Takahashi, M. et al. Insulin receptor mRNA in the substantia nigra in Parkinson’s disease. Neurosci. Lett. 204, 201–204 (1996).
Timmons, S., Coakley, M. F., Moloney, A. M. & O’Neill C. Akt signal transduction dysfunction in Parkinson’s disease. Neurosci. Lett. 467, 30–35 (2009).
Craft, S. et al. Effects of regular and long-acting insulin on cognition and alzheimer’s disease biomarkers: a pilot clinical trial. J. Alzheimers Dis. 57, 1325–1334 (2017).
Yarchoan, M. & Arnold, S. E. Repurposing diabetes drugs for brain insulin resistance in Alzheimer disease. Diabetes 63, 2253–2261 (2014).
Luchsinger, J. A. et al. Metformin in amnestic mild cognitive impairment: results of a pilot randomized placebo controlled clinical trial. J. Alzheimers Dis. 51, 501–514 (2016).
Koenig, A. M. et al. Effects of the insulin sensitizer metformin in alzheimer disease: pilot data from a randomized placebo-controlled crossover study. Alzheimer Dis. Assoc. Disord. 31, 107–113 (2017).
Agarwal, S., Yadav, A. & Chaturvedi, R. K. Peroxisome proliferator-activated receptors (PPARs) as therapeutic target in neurodegenerative disorders. Biochem. Biophys. Res. Commun. 483, 1166–1177 (2017).
Harrington, C. et al. Rosiglitazone does not improve cognition or global function when used as adjunctive therapy to AChE inhibitors in mild-to-moderate Alzheimer’s disease: two phase 3 studies. Curr. Alzheimer Res. 8, 592–606 (2011).
Li, Y., Li, L. & Holscher, C. Incretin-based therapy for type 2 diabetes mellitus is promising for treating neurodegenerative diseases. Rev. Neurosci. 27, 689–711 (2016).