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Journal of Diabetes Research
Volume 2017, Article ID 7420796, 7 pages
https://doi.org/10.1155/2017/7420796
Review Article

Antidiabetic Drugs in Alzheimer’s Disease: Mechanisms of Action and Future Perspectives

1Neurology Imaging Unit, Imperial College London, London, UK
2Division of Geriatrics, Department of Translational Medical Sciences, Federico II University of Naples, Naples, Italy
3Center for Translational Medicine and Department of Pharmacology, Lewis Katz School of Medicine, Temple University, Philadelphia, PA, USA
4Department of Medicine and Health Sciences, University of Molise, Campobasso, Italy
5Istituti Clinici Scientifici Maugeri SpA Società Benefit, Telese Terme Institute (BN), Italy

Correspondence should be addressed to Nicola Ferrara; ti.aninu@arrefcin

Received 10 March 2017; Accepted 7 May 2017; Published 1 June 2017

Academic Editor: Soledad Ballesteros

Copyright © 2017 Grazia Daniela Femminella et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Linked References

  1. H. X. Gao, E. E. Regier, and K. L. Close, “International Diabetes Federation World Diabetes Congress 2015,” Journal of Diabetes, vol. 8, no. 3, pp. 300–302, 2016. View at Publisher · View at Google Scholar · View at Scopus
  2. F. El Gaamouch, P. Jing, J. Xia, and D. Cai, “Alzheimer’s disease risk genes and lipid regulators,” Journal of Alzheimer's Disease, vol. 53, no. 1, pp. 15–29, 2016. View at Publisher · View at Google Scholar · View at Scopus
  3. P. Scheltens, K. Blennow, M. M. Breteler et al., “Alzheimer’s disease,” Lancet, vol. 388, no. 10043, pp. 505–517, 2016. View at Publisher · View at Google Scholar · View at Scopus
  4. K. Akter, E. A. Lanza, S. A. Martin, N. Myronyuk, M. Rua, and R. B. Raffa, “Diabetes mellitus and Alzheimer’s disease: shared pathology and treatment?” British Journal of Clinical Pharmacology, vol. 71, no. 3, pp. 365–376, 2011. View at Publisher · View at Google Scholar · View at Scopus
  5. G. J. Biessels, S. Staekenborg, E. Brunner, C. Brayne, and P. Scheltens, “Risk of dementia in diabetes mellitus: a systematic review,” The Lancet Neurology, vol. 5, no. 1, pp. 64–74, 2006. View at Publisher · View at Google Scholar · View at Scopus
  6. S. M. de la Monte, “Type 3 diabetes is sporadic Alzheimer’s disease: mini-review,” European Neuropsychopharmacology, vol. 24, no. 12, pp. 1954–1960, 2014. View at Publisher · View at Google Scholar · View at Scopus
  7. M. N. Haan, “Therapy insight: type 2 diabetes mellitus and the risk of late-onset Alzheimer’s disease,” Nature Clinical Practice. Neurology, vol. 2, no. 3, pp. 159–166, 2006. View at Publisher · View at Google Scholar · View at Scopus
  8. A. Ott, R. P. Stolk, F. van Harskamp, H. A. Pols, A. Hofman, and M. M. Breteler, “Diabetes mellitus and the risk of dementia: the Rotterdam study,” Neurology, vol. 53, no. 9, pp. 1937–1942, 1999. View at Publisher · View at Google Scholar
  9. K. Mittal and D. P. Katare, “Shared links between type 2 diabetes mellitus and Alzheimer’s disease: a review,” Diabetes & Metabolic Syndrome, vol. 10, no. 2 Suppl 1, pp. S144–S149, 2016. View at Google Scholar
  10. Y. Zhong, Y. Miao, W. P. Jia, H. Yan, B. Y. Wang, and J. Jin, “Hyperinsulinemia, insulin resistance and cognitive decline in older cohort,” Biomedical and Environmental Sciences : BES, vol. 25, no. 1, pp. 8–14, 2012. View at Publisher · View at Google Scholar · View at Scopus
  11. S. D. Edland, “Insulin-degrading enzyme, apolipoprotein E, and Alzheimer’s disease,” Journal of Molecular Neuroscience, vol. 23, no. 3, pp. 213–217, 2004. View at Publisher · View at Google Scholar
  12. M. Vandal, P. J. White, C. Tremblay et al., “Insulin reverses the high-fat diet-induced increase in brain Abeta and improves memory in an animal model of Alzheimer disease,” Diabetes, vol. 63, no. 12, pp. 4291–4301, 2014. View at Publisher · View at Google Scholar · View at Scopus
  13. L. Li and C. Holscher, “Common pathological processes in Alzheimer disease and type 2 diabetes: a review,” Brain Research Reviews, vol. 56, no. 2, pp. 384–402, 2007. View at Publisher · View at Google Scholar · View at Scopus
  14. C. Sims-Robinson, B. Kim, A. Rosko, and E. L. Feldman, “How does diabetes accelerate Alzheimer disease pathology?” Nature Reviews Neurology, vol. 6, no. 10, pp. 551–559, 2010. View at Publisher · View at Google Scholar · View at Scopus
  15. B. Clodfelder-Miller, P. De Sarno, A. A. Zmijewska, L. Song, and R. S. Jope, “Physiological and pathological changes in glucose regulate brain Akt and glycogen synthase kinase-3,” The Journal of Biological Chemistry, vol. 280, no. 48, pp. 39723–39731, 2005. View at Publisher · View at Google Scholar · View at Scopus
  16. L. M. Chua, M. L. Lim, P. R. Chong, Z. P. Hu, N. S. Cheung, and B. S. Wong, “Impaired neuronal insulin signaling precedes Abeta42 accumulation in female AbetaPPsw/PS1DeltaE9 mice,” Journal of Alzheimer's Disease, vol. 29, no. 4, pp. 783–791, 2012. View at Publisher · View at Google Scholar · View at Scopus
  17. N. Beeler, B. M. Riederer, G. Waeber, and A. Abderrahmani, “Role of the JNK-interacting protein 1/islet brain 1 in cell degeneration in Alzheimer disease and diabetes,” Brain Research Bulletin, vol. 80, no. 4-5, pp. 274–281, 2009. View at Publisher · View at Google Scholar · View at Scopus
  18. V. Wieser, A. R. Moschen, and H. Tilg, “Inflammation, cytokines and insulin resistance: a clinical perspective,” Archivum Immunologiae et Therapiae Experimentalis, vol. 61, no. 2, pp. 119–125, 2013. View at Publisher · View at Google Scholar · View at Scopus
  19. P. S. Patel, E. D. Buras, and A. Balasubramanyam, “The role of the immune system in obesity and insulin resistance,” Journal of Obesity, vol. 2013, p. 616193, 2013. View at Publisher · View at Google Scholar · View at Scopus
  20. H. Akiyama, S. Barger, S. Barnum et al., “Inflammation and Alzheimer’s disease,” Neurobiology of Aging, vol. 21, no. 3, pp. 383–421, 2000. View at Publisher · View at Google Scholar · View at Scopus
  21. Q. Sun, J. Li, and F. Gao, “New insights into insulin: the anti-inflammatory effect and its clinical relevance,” World Journal of Diabetes, vol. 5, no. 2, pp. 89–96, 2014. View at Google Scholar
  22. B. Kim and E. L. Feldman, “Insulin resistance as a key link for the increased risk of cognitive impairment in the metabolic syndrome,” Experimental & Molecular Medicine, vol. 47, no. article e149, 2015. View at Publisher · View at Google Scholar · View at Scopus
  23. C. A. Magalhaes, M. G. Carvalho, L. P. Sousa, P. Caramelli, and K. B. Gomes, “Leptin in Alzheimer’s disease,” Clinica Chimica Acta; International Journal of Clinical Chemistry, vol. 450, pp. 162–168, 2015. View at Publisher · View at Google Scholar · View at Scopus
  24. Z. S. Tan, A. S. Beiser, C. S. Fox 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, vol. 34, no. 8, pp. 1766–1770, 2011. View at Publisher · View at Google Scholar · View at Scopus
  25. L. D. Baker, D. J. Cross, S. Minoshima, D. Belongia, G. S. Watson, and S. Craft, “Insulin resistance and Alzheimer-like reductions in regional cerebral glucose metabolism for cognitively normal adults with prediabetes or early type 2 diabetes,” Archives of Neurology, vol. 68, no. 1, pp. 51–57, 2011. View at Publisher · View at Google Scholar · View at Scopus
  26. K. Jauch-Chara, A. Friedrich, M. Rezmer et al., “Intranasal insulin suppresses food intake via enhancement of brain energy levels in humans,” Diabetes, vol. 61, no. 9, pp. 2261–2268, 2012. View at Publisher · View at Google Scholar · View at Scopus
  27. A. M. Saunders, “Apolipoprotein E and Alzheimer disease: an update on genetic and functional analyses,” Journal of Neuropathology and Experimental Neurology, vol. 59, no. 9, pp. 751–758, 2000. View at Publisher · View at Google Scholar
  28. I. J. Martins, T. Berger, M. J. Sharman, G. Verdile, S. J. Fuller, and R. N. Martins, “Cholesterol metabolism and transport in the pathogenesis of Alzheimer’s disease,” Journal of Neurochemistry, vol. 111, no. 6, pp. 1275–1308, 2009. View at Publisher · View at Google Scholar · View at Scopus
  29. W. J. Brecht, F. M. Harris, S. Chang et al., “Neuron-specific apolipoprotein e4 proteolysis is associated with increased tau phosphorylation in brains of transgenic mice,” The Journal of Neuroscience, vol. 24, no. 10, pp. 2527–2534, 2004. View at Publisher · View at Google Scholar · View at Scopus
  30. N. Sasaki, S. Toki, H. Chowei et al., “Immunohistochemical distribution of the receptor for advanced glycation end products in neurons and astrocytes in Alzheimer’s disease,” Brain Research, vol. 888, no. 2, pp. 256–262, 2001. View at Publisher · View at Google Scholar · View at Scopus
  31. P. I. Moreira, M. S. Santos, A. M. Moreno, R. Seica, and C. R. Oliveira, “Increased vulnerability of brain mitochondria in diabetic (Goto-Kakizaki) rats with aging and amyloid-beta exposure,” Diabetes, vol. 52, no. 6, pp. 1449–1456, 2003. View at Publisher · View at Google Scholar · View at Scopus
  32. D. A. Butterfield, F. Di Domenico, and E. Barone, “Elevated risk of type 2 diabetes for development of Alzheimer disease: a key role for oxidative stress in brain,” Biochimica et Biophysica Acta, vol. 1842, no. 9, pp. 1693–1706, 2014. View at Google Scholar
  33. A. S. Shingo, T. Kanabayashi, S. Kito, and T. Murase, “Intracerebroventricular administration of an insulin analogue recovers STZ-induced cognitive decline in rats,” Behavioural Brain Research, vol. 241, pp. 105–111, 2013. View at Publisher · View at Google Scholar · View at Scopus
  34. S. Craft, S. Asthana, J. W. Newcomer et al., “Enhancement of memory in Alzheimer disease with insulin and somatostatin, but not glucose,” Archives of General Psychiatry, vol. 56, no. 12, pp. 1135–1140, 1999. View at Publisher · View at Google Scholar
  35. G. Verdile, S. J. Fuller, and R. N. Martins, “The role of type 2 diabetes in neurodegeneration,” Neurobiology of Disease, vol. 84, pp. 22–38, 2015. View at Publisher · View at Google Scholar · View at Scopus
  36. H. B. Schioth, S. Craft, S. J. Brooks, W. H. Frey 2nd, and C. Benedict, “Brain insulin signaling and Alzheimer’s disease: current evidence and future directions,” Molecular Neurobiology, vol. 46, no. 1, pp. 4–10, 2012. View at Publisher · View at Google Scholar · View at Scopus
  37. C. Benedict, M. Hallschmid, A. Hatke et al., “Intranasal insulin improves memory in humans,” Psychoneuroendocrinology, vol. 29, no. 10, pp. 1326–1334, 2004. View at Publisher · View at Google Scholar · View at Scopus
  38. C. Benedict, M. Hallschmid, K. Schmitz et al., “Intranasal insulin improves memory in humans: superiority of insulin aspart,” Neuropsychopharmacology, vol. 32, no. 1, pp. 239–243, 2007. View at Google Scholar
  39. M. Hallschmid, C. Benedict, B. Schultes, J. Born, and W. Kern, “Obese men respond to cognitive but not to catabolic brain insulin signaling,” International Journal of Obesity, vol. 32, no. 2, pp. 275–282, 2008. View at Google Scholar
  40. T. M. Schilling, D. S. Ferreira de Sa, R. Westerhausen et al., “Intranasal insulin increases regional cerebral blood flow in the insular cortex in men independently of cortisol manipulation,” Human Brain Mapping, vol. 35, no. 5, pp. 1944–1956, 2014. View at Publisher · View at Google Scholar · View at Scopus
  41. M. A. Reger, G. S. Watson, W. H. Frey 2nd et al., “Effects of intranasal insulin on cognition in memory-impaired older adults: modulation by APOE genotype,” Neurobiology of Aging, vol. 27, no. 3, pp. 451–458, 2006. View at Publisher · View at Google Scholar · View at Scopus
  42. M. A. Reger, G. S. Watson, P. S. Green et al., “Intranasal insulin improves cognition and modulates beta-amyloid in early AD,” Neurology, vol. 70, no. 6, pp. 440–448, 2008. View at Publisher · View at Google Scholar · View at Scopus
  43. M. A. Reger, G. S. Watson, P. S. Green et al., “Intranasal insulin administration dose-dependently modulates verbal memory and plasma amyloid-beta in memory-impaired older adults,” Journal of Alzheimer's Disease, vol. 13, no. 3, pp. 323–331, 2008. View at Publisher · View at Google Scholar
  44. S. Craft, L. D. Baker, T. J. Montine et al., “Intranasal insulin therapy for Alzheimer disease and amnestic mild cognitive impairment: a pilot clinical trial,” Archives of Neurology, vol. 69, no. 1, pp. 29–38, 2012. View at Publisher · View at Google Scholar · View at Scopus
  45. A. Claxton, L. D. Baker, A. Hanson et al., “Long-acting intranasal insulin detemir improves cognition for adults with mild cognitive impairment or early-stage Alzheimer’s disease dementia,” Journal of Alzheimer's Disease, vol. 44, no. 3, pp. 897–906, 2015. View at Publisher · View at Google Scholar · View at Scopus
  46. K. Labuzek, D. Suchy, B. Gabryel, A. Bielecka, S. Liber, and B. Okopien, “Quantification of metformin by the HPLC method in brain regions, cerebrospinal fluid and plasma of rats treated with lipopolysaccharide,” Pharmacological Reports, vol. 62, no. 5, pp. 956–965, 2010. View at Publisher · View at Google Scholar
  47. A. Gupta, B. Bisht, and C. S. Dey, “Peripheral insulin-sensitizer drug metformin ameliorates neuronal insulin resistance and Alzheimer’s-like changes,” Neuropharmacology, vol. 60, no. 6, pp. 910–920, 2011. View at Publisher · View at Google Scholar · View at Scopus
  48. E. Kickstein, S. Krauss, P. Thornhill et al., “Biguanide metformin acts on tau phosphorylation via mTOR/protein phosphatase 2A (PP2A) signaling,” Proceedings of the National Academy of Sciences of the United States of America, vol. 107, no. 50, pp. 21830–21835, 2010. View at Publisher · View at Google Scholar · View at Scopus
  49. J. Li, J. Deng, W. Sheng, and Z. Zuo, “Metformin attenuates Alzheimer’s disease-like neuropathology in obese, leptin-resistant mice,” Pharmacology, Biochemistry, and Behavior, vol. 101, no. 4, pp. 564–574, 2012. View at Publisher · View at Google Scholar · View at Scopus
  50. P. Imfeld, M. Bodmer, S. S. Jick, and C. R. Meier, “Metformin, other antidiabetic drugs, and risk of Alzheimer’s disease: a population-based case-control study,” Journal of the American Geriatrics Society, vol. 60, no. 5, pp. 916–921, 2012. View at Publisher · View at Google Scholar · View at Scopus
  51. E. M. Moore, A. G. Mander, D. Ames et al., “Increased risk of cognitive impairment in patients with diabetes is associated with metformin,” Diabetes Care, vol. 36, no. 10, pp. 2981–2987, 2013. View at Publisher · View at Google Scholar · View at Scopus
  52. J. A. Luchsinger, T. Perez, H. Chang et al., “Metformin in amnestic mild cognitive impairment: results of a pilot randomized placebo controlled clinical trial,” Journal of Alzheimer's Disease, vol. 51, no. 2, pp. 501–514, 2016. View at Publisher · View at Google Scholar · View at Scopus
  53. G. Landreth, “Therapeutic use of agonists of the nuclear receptor PPARgamma in Alzheimer’s disease,” Current Alzheimer Research, vol. 4, no. 2, pp. 159–164, 2007. View at Publisher · View at Google Scholar · View at Scopus
  54. Y. Kitamura, S. Shimohama, H. Koike et al., “Increased expression of cyclooxygenases and peroxisome proliferator-activated receptor-gamma in Alzheimer’s disease brains,” Biochemical and Biophysical Research Communications, vol. 254, no. 3, pp. 582–586, 1999. View at Publisher · View at Google Scholar · View at Scopus
  55. Q. Jiang, M. Heneka, and G. E. Landreth, “The role of peroxisome proliferator-activated receptor-gamma (PPARgamma) in Alzheimer’s disease: therapeutic implications,” CNS Drugs, vol. 22, no. 1, pp. 1–14, 2008. View at Publisher · View at Google Scholar
  56. T. Pancani, J. T. Phelps, J. L. Searcy et al., “Distinct modulation of voltage-gated and ligand-gated Ca2+ currents by PPAR-γ agonists in cultured hippocampal neurons,” Journal of Neurochemistry, vol. 109, no. 6, pp. 1800–1811, 2009. View at Publisher · View at Google Scholar · View at Scopus
  57. G. S. Watson, B. A. Cholerton, M. A. Reger et al., “Preserved cognition in patients with early Alzheimer disease and amnestic mild cognitive impairment during treatment with rosiglitazone: a preliminary study,” The American Journal of Geriatric Psychiatry, vol. 13, no. 11, pp. 950–958, 2005. View at Google Scholar
  58. M. E. Risner, A. M. Saunders, J. F. Altman et al., “Efficacy of rosiglitazone in a genetically defined population with mild-to-moderate Alzheimer’s disease,” The Pharmacogenomics Journal, vol. 6, no. 4, pp. 246–254, 2006. View at Publisher · View at Google Scholar · View at Scopus
  59. C. Harrington, S. Sawchak, C. Chiang 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,” Current Alzheimer Research, vol. 8, no. 5, pp. 592–606, 2011. View at Publisher · View at Google Scholar · View at Scopus
  60. T. Sato, H. Hanyu, K. Hirao, H. Kanetaka, H. Sakurai, and T. Iwamoto, “Efficacy of PPAR-γ agonist pioglitazone in mild Alzheimer disease,” Neurobiology of Aging, vol. 32, no. 9, pp. 1626–1633, 2011. View at Publisher · View at Google Scholar · View at Scopus
  61. D. S. Geldmacher, T. Fritsch, M. J. McClendon, and G. Landreth, “A randomized pilot clinical trial of the safety of pioglitazone in treatment of patients with Alzheimer disease,” Archives of Neurology, vol. 68, no. 1, pp. 45–50, 2011. View at Publisher · View at Google Scholar · View at Scopus
  62. H. Cheng, Y. Shang, L. Jiang, T. L. Shi, and L. Wang, “The peroxisome proliferators activated receptor-gamma agonists as therapeutics for the treatment of Alzheimer’s disease and mild-to-moderate Alzheimer’s disease: a meta-analysis,” The International Journal of Neuroscience, vol. 126, no. 4, pp. 299–307, 2016. View at Google Scholar
  63. G. D. Femminella and P. Edison, “Evaluation of neuroprotective effect of glucagon-like peptide 1 analogs using neuroimaging,” Alzheimer's & Dementia, vol. 10, no. 1 Suppl, pp. S55–S61, 2014. View at Google Scholar
  64. V. Calsolaro and P. Edison, “Novel GLP-1 (glucagon-like peptide-1) analogues and insulin in the treatment for Alzheimer’s disease and other neurodegenerative diseases,” CNS Drugs, vol. 29, no. 12, pp. 1023–1039, 2015. View at Publisher · View at Google Scholar · View at Scopus
  65. C. Holscher, “Central effects of GLP-1: new opportunities for treatments of neurodegenerative diseases,” The Journal of Endocrinology, vol. 221, no. 1, pp. T31–T41, 2014. View at Publisher · View at Google Scholar · View at Scopus
  66. P. L. McClean, V. Parthsarathy, E. Faivre, and C. Holscher, “The diabetes drug liraglutide prevents degenerative processes in a mouse model of Alzheimer’s disease,” The Journal of Neuroscience, vol. 31, no. 17, pp. 6587–6594, 2011. View at Publisher · View at Google Scholar · View at Scopus
  67. W. N. Han, C. Holscher, L. Yuan et al., “Liraglutide protects against amyloid-beta protein-induced impairment of spatial learning and memory in rats,” Neurobiology of Aging, vol. 34, no. 2, pp. 576–588, 2013. View at Publisher · View at Google Scholar · View at Scopus
  68. V. Parthsarathy and C. Holscher, “Chronic treatment with the GLP1 analogue liraglutide increases cell proliferation and differentiation into neurons in an AD mouse model,” PloS One, vol. 8, no. 3, article e58784, 2013. View at Google Scholar
  69. P. Kelly, P. L. McClean, M. Ackermann, M. A. Konerding, C. Holscher, and C. A. Mitchell, “Restoration of cerebral and systemic microvascular architecture in APP/PS1 transgenic mice following treatment with liraglutide,” Microcirculation, vol. 22, no. 2, pp. 133–145, 2015. View at Publisher · View at Google Scholar · View at Scopus
  70. L. Qi, L. Ke, X. Liu et al., “Subcutaneous administration of liraglutide ameliorates learning and memory impairment by modulating tau hyperphosphorylation via the glycogen synthase kinase-3beta pathway in an amyloid beta protein induced Alzheimer disease mouse model,” European Journal of Pharmacology, vol. 783, pp. 23–32, 2016. View at Publisher · View at Google Scholar · View at Scopus
  71. P. L. McClean and C. Holscher, “Liraglutide can reverse memory impairment, synaptic loss and reduce plaque load in aged APP/PS1 mice, a model of Alzheimer’s disease,” Neuropharmacology, vol. 76, Part A, pp. 57–67, 2014. View at Publisher · View at Google Scholar · View at Scopus
  72. M. Gejl, A. Gjedde, L. Egefjord et al., “In Alzheimer’s disease, 6-month treatment with GLP-1 analog prevents decline of brain glucose metabolism: randomized, placebo-controlled Double-Blind Clinical Trial,” Frontiers in Aging Neuroscience, vol. 8, p. 108, 2016. View at Publisher · View at Google Scholar · View at Scopus
  73. W. Xu, Y. Yang, G. Yuan, W. Zhu, D. Ma, and S. Hu, “Exendin-4, a glucagon-like peptide-1 receptor agonist, reduces Alzheimer disease-associated tau hyperphosphorylation in the hippocampus of rats with type 2 diabetes,” Journal of Investigative Medicine, vol. 63, no. 2, pp. 267–272, 2015. View at Publisher · View at Google Scholar · View at Scopus
  74. J. Kosaraju, C. C. Gali, R. B. Khatwal et al., “Saxagliptin: a dipeptidyl peptidase-4 inhibitor ameliorates streptozotocin induced Alzheimer’s disease,” Neuropharmacology, vol. 72, pp. 291–300, 2013. View at Publisher · View at Google Scholar · View at Scopus
  75. J. Kosaraju, V. Murthy, R. B. Khatwal et al., “Vildagliptin: an anti-diabetes agent ameliorates cognitive deficits and pathology observed in streptozotocin-induced Alzheimer’s disease,” The Journal of Pharmacy and Pharmacology, vol. 65, no. 12, pp. 1773–1784, 2013. View at Publisher · View at Google Scholar · View at Scopus
  76. W. Q. Qiu and H. Zhu, “Amylin and its analogs: a friend or foe for the treatment of Alzheimer’s disease?” Frontiers in Aging Neuroscience, vol. 6, p. 186, 2014. View at Publisher · View at Google Scholar · View at Scopus
  77. B. L. Adler, M. Yarchoan, H. M. Hwang et al., “Neuroprotective effects of the amylin analogue pramlintide on Alzheimer’s disease pathogenesis and cognition,” Neurobiology of Aging, vol. 35, no. 4, pp. 793–801, 2014. View at Publisher · View at Google Scholar · View at Scopus
  78. J. L. Cummings, T. Morstorf, and K. Zhong, “Alzheimer’s disease drug-development pipeline: few candidates, frequent failures,” Alzheimer's Research & Therapy, vol. 6, no. 4, p. 37, 2014. View at Publisher · View at Google Scholar · View at Scopus